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Chiral hypervalent iodine mediated enantioselective oxidative dearomatization of naphthols Jain, Nikita 2017

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Chiral Hypervalent Iodine Mediated Enantioselective Oxidative Dearomatization of Naphthols  by  Nikita Jain  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  in  The Faculty of Graduate and Postdoctoral studies (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  August 2017 © Nikita Jain, 2017    ii  Abstract This dissertation investigates and describes the hypervalent iodine mediated dearomatization of naphthols, thereby yielding diversity of spiro-heterocyclic compounds in both racemic and chiral form. The first part of this thesis discloses the synthesis of racemic spiropyrrolidines and spirolactams via oxidative amidation of corresponding naphtholic sulfonamides, employing DIB as the oxidant. Enantioselective variant of the same have been demonstrated by using in situ generated chiral hypervalent iodine to provide chiral spiropyrrolidines. A noteworthy side reaction discovered in the course of these studies is the asymmetric oxidative addition of meta-chlorobenzoic acid to the naphtholic sulfonamides. The resulting acyloxylated adducts were formed with a greater degree of asymmetric induction compared to spiropyrrolidines in the same reaction mixture. Based on the results obtained from optimization study and substrate scope, plausible mechanistic insights of both cyclization and acyloxylation reactions have been provided. The second part of this thesis unravels the spiroetherification of naphtholic alcohols, thereby yielding spiroethers both in racemic and chiral form. Chiral hypervalent iodine reagents generated in situ provided a range of spiroethers with excellent ee’s and high yields. These chiral oxidants have been evaluated for kinetic resolution of naphtholic primary alcohols bearing stereogenic center at β-position in the side chain.    iii  Lay summary Hypervalent iodine reagents are used as environmentally friendly, mild and selective oxidants for various synthetic conversions. This thesis describes their utility to provide easy access to useful building blocks which forms the core of natural products with important biological significance.   iv  Preface This thesis is written by N. Jain. Prof. M. A. Ciufolini provided the overall project design, helpful suggestions during the course of research and thoroughly edited this thesis. All the experiments and data analyses in Chapters 3, 4 and 5 were carried out by N. Jain, except for the Coupled Preferential Crystallization of compound 4.2a mentioned in Section 4.3.9, which were performed by Prof. J. Hein (Department of Chemistry, UBC) and Dr. C. Rougeot. Prof. J. Hein thoroughly edited Section 4.3.9 of this thesis. Dr. S. Xu performed the analysis of COSY and NOESY data of compounds mentioned in section 5.2.6.  Sections 4.1 and 4.2 of Chapter 4 have been published in: Jain, N.; Ciufolini, M. A. Synlett 2015, 26, 631. Prof. M. A. Ciufolini wrote the manuscript, N. Jain wrote the supporting information. All the experiments were performed by N. Jain. A portion of research work reported in Chapter 5 has been published in: Jain, N.; Xu, S.; Ciufolini, M. A. Chem. Eur. J. 2017, 23, 4542. Prof. M. A. Ciufolini wrote the manuscript, N. Jain performed the experiments and wrote the supporting information. Dr. S. Xu analysed and drew the NOE correlations of compounds 5.18a-c, 5.19a-b, 5.21a, 5.22a and proofread the supporting information.    v  Table of Contents Abstract .......................................................................................................................................... ii Lay summary ................................................................................................................................ iii Preface ........................................................................................................................................... iv Table of Contents………………………………………………………………………………...v List of Tables ............................................................................................................................. xvii List of Figures ........................................................................................................................... xviii List of Schemes ............................................................................................................................ xx List of Abbreviations ............................................................................................................... xxiv Acknowledgements ................................................................................................................ xxviii Dedication ................................................................................................................................. xxxi Chapter 1: Introduction ............................................................................................................... 1 1.1 Hypervalency ........................................................................................................................ 1 1.2 History of hypervalent organoiodine compounds ................................................................. 2 1.3 Nomenclature of hypervalent iodine compounds .................................................................. 3 1.4 Structure and bonding in hypervalent iodine ........................................................................ 3 1.5 General reactivity pattern of hypervalent iodine ................................................................... 5 1.5.1 Ligand exchange and reductive elimination ................................................................... 6 1.6 Introduction to chiral hypervalent iodine complexes ............................................................ 8 1.7 Applications of chiral hypervalent iodine ........................................................................... 10 1.7.1 Oxidation of sulfides to sulfoxides ............................................................................... 10 1.7.2 α-arylation of ketones ................................................................................................... 12 1.7.3 α-functionalization of ketones ...................................................................................... 13 1.7.4 Functionalization of alkenes ......................................................................................... 14 1.7.5 Rearrangement .............................................................................................................. 21 1.7.6 Dearomatization reactions ............................................................................................ 23 Chapter 2: Background .............................................................................................................. 33 2.1 Genesis of the research project ............................................................................................ 33 Chapter 3. Preparation of the substrates employed in the present study.............................. 44 3.1 Initial objectives and preparation of the substrates ............................................................. 44 3.2 Synthesis of substrates: naphtholic alcohols ....................................................................... 44  vi  3.3 Synthesis of substrates: naphtholic sulfonamides ............................................................... 51 3.4 Synthesis of substrates: naphtholic N-acyl-sulfonamides ................................................... 53 Chapter 4: Oxidative amidation in naphthalene series ........................................................... 56 4.1 Oxidative cyclization of naphtholic sulfonamides in the racemic series ............................ 56 4.2 Oxidative cyclization of naphtholic N-acylsulfonamides in the racemic series .................. 58 4.3 Enantioselective oxidative cyclization of naphtholic sulfonamides ................................... 62 4.3.1 Screening of conditions ................................................................................................ 64 4.3.2 Effect of additives ......................................................................................................... 70 4.3.3 Precatalyst screening .................................................................................................... 71 4.3.4 Mechanistic aspects ...................................................................................................... 73 4.3.5 Asymmetric oxidative cyclization of naphtholic sulfonamides: a new catalyst design 76 4.3.6 Oxidative cyclization of para-substituted 1-naphtholic sulfonamides ......................... 81 4.3.7 Enantioselective oxidative amidation of 2-napththolic sulfonamides .......................... 85 4.3.8 Attempted enantioselective cyclization of acyl sulfonamides ...................................... 87 4.3.9 Enantioenriched 4.2a by flow resolution of the racemate ............................................ 87 4.3.10 Aspects of the enantioselective acyloxylation reaction .............................................. 91 4.3.11 Mechanistic aspects for acyloxylation reaction .......................................................... 96 Chapter 5: Oxidative cyclization of naphtholic alcohols with iodine(III) reagents ............ 102 5.1 Oxidative cyclization of naphtholic alcohols in the racemic series .................................. 102 5.2 Asymmetric oxidative cyclization of naphtholic alcohols: catalyst screening ................. 107 5.2.1 Screening of alternative reaction conditions .............................................................. 111 5.2.2 Substrate Scope........................................................................................................... 112 5.2.3 Recycling of the catalyst ............................................................................................. 115 5.2.4 Determination of absolute configuration of spiroethers ............................................. 116 5.2.5 Attempts to accelerate the reaction rate ...................................................................... 120 5.2.6 Kinetic resolution of primary naphtholic alcohols ..................................................... 121 5.2.7 Enantioselective oxidative cyclization of phenolic alcohol ....................................... 135 References .................................................................................................................................. 138 Appendices ................................................................................................................................. 146 A. Experimental protocols........................................................................................................ 146 B. Preparation of substrates employed in the present study experimental section ............ 148  vii  B.1 Preparation and characterization of intermediates towards naphtholic alcohol 3.10 ....... 148 B.1.1 Preparation of 1-(allyloxy)naphthalene (3.8) ............................................................. 148 B.1.2 Preparation of 2-allylnaphthalen-1-ol (3.9) ............................................................... 148 B.1.3 Preparation of 2-(3-Hydroxypropyl)naphthalen-1-ol (3.10) ...................................... 149 B.2 Preparation of 4-Chloro-2-(3-hydroxypropyl)-naphthalen-1-ol (3.11) ............................ 150 B.3 Preparation of 4-Bromo-2-(3-hydroxypropyl)naphthalene-1-ol (3.12) ............................ 150 B.4 General procedure for Suzuki coupling of 3.12 with aryl boronic acids .......................... 151 B.4.1 Characterization of 2-(3-Hydroxypropyl)-4-(3-methoxyphenyl)naphthalen-1-ol (3.13, Ar = C6H4-OMe-m) ............................................................................................................. 151 B.4.2 Characterization of 1-(4-(4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)phenyl)ethanone (3.13, Ar = C6H4-C(O)Me) .................................................................. 152 B.4.3 Characterization of 4-(4-Fluorophenyl)-2-(3-hydroxypropyl)naphthalen-1-ol (3.13, Ar = C6H4-F-p) ......................................................................................................................... 152 B.4.4 Characterization of 2-(3-Hydroxypropyl)-4-(4-(methylsulfonyl)phenyl)naphthalen-1-ol (3.13, Ar = C6H4-SO2Me-p) ............................................................................................ 153 B.4.5 Characterization of 2-(3-Hydroxypropyl)-4-(4-(trifluoromethyl)phenyl)naphthalen-1-ol (3.13, Ar = C6H4-CF3-p) .................................................................................................. 153 B.4.6 Characterization of 4-(3,5-Bis(trifluoromethyl)phenyl)-2-(3-hydroxypropyl)naphthalen-1-ol (3.13, Ar = 3,5bis(CF3)2C6H3) ......................................... 154 B.5 Preparation and characterization of intermediates towards naphtholic alcohol 3.18 ....... 154 B.5.1 General procedure for O-acylation of α-naphthols .................................................... 154 B.5.2 Preparation of Naphthalen-1-yl 4-methylbenzoate (3.14, R = p-tolyl) ...................... 155 B.5.3 General procedure for Fries rearrangement of 3.14 ................................................... 156 B.5.4 Preparation of compounds 3.16 ................................................................................. 157 B.5.5 Preparation of compounds 3.17 ................................................................................. 158 B.5.6 General procedure for the hydroboration oxidation of 3.17 for the synthesis of 4-acyl naphtholic alcohols 3.18 ...................................................................................................... 159 B.6 Preparation and characterization of intermediates towards naphtholic alcohol 3.26, R = Me ................................................................................................................................................. 162 B.6.1 Preparation of 4-Methoxynaphthalen-1-yl trifluoromethanesulfonate (3.19) ........... 162 B.6.2 Preparation of 1-Methoxy-4-methylnaphthalene (3.20) ............................................ 163 B.6.3 Preparation of 4-Methylnaphthalen-1-ol (3.23, R = Me) ........................................... 164 B.6.4 Characterization of 1-(Allyloxy)-4-methylnaphthalene (3.24, R = Me).................... 164  viii  B.6.5 Characterization of (2-Allyl-4-methylnaphthalen-1-ol (3.25, R = Me) ..................... 165 B.6.6 Characterization of 2-(3-Hydroxypropyl)-4-methylnaphthalen-1-ol (3.26, R = Me) 165 B.7 Preparation and characterization of intermediates towards naphtholic alcohols 3.26 ...... 165 B.7.1 General procedure for Suzuki coupling of triflate 3.19 with aryl boronic acids ....... 165 B.7.2 General procedure for the demethylation of compounds 3.21 ................................... 167 B.7.3 Characterization of 1-(Allyloxy)-4-phenylnaphthalene (3.24, R = Ph) ..................... 167 B.7.4 Characterization of 1-(Allyloxy)-4-p-tolylnaphthalene (3.24, Ar = 4-Tol) ............... 168 B.7.5 Characterization of 4-(4-(Allyloxy)naphthalen-1-yl)benzonitrile (3.24, Ar = 4-NC-C6H4) .................................................................................................................................... 168 B.7.6 Characterization of 2-Allyl-4-phenylnaphthalen-1-ol (3.25, R = Ph) ....................... 168 B.7.7 Characterization of 2-allyl-4-p-tolylnaphthalen-1-ol (3.25, Ar = 4-Tol) ................... 169 B.7.8 Characterization of 4-(3-Allyl-4-hydroxynaphthalen-1-yl)benzonitrile (3.25, Ar = 4-NC-C6H4) ............................................................................................................................. 169 B.7.9 Characterization of 2-(3-Hydroxypropyl)-4-phenylnaphthalen-1-ol (3.26, R = Ph) . 170 B.7.10 Characterization of 2-(3-Hydroxypropyl)-4-p-tolylnaphthalen-1-ol (3.26, R = 4-Tol) ............................................................................................................................................. 170 B.7.11 Characterization of 4-(4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)benzonitrile (3.26, R = 4-NC-C6H4) ........................................................................................................ 170 B.8 Preparation and characterization of intermediates towards 5-substituted naphtholic alcohols 3.32-3.33 ................................................................................................................... 171 B.8.1 Preparation of 5-hydroxynaphthalen-1-yl trifluoromethanesulfonate (3.28) ............. 171 B.8.2 Preparation of 5-phenylnaphthalen-1-ol (3.29) .......................................................... 172 B.8.3 Characterization of 1-(allyloxy)-5-phenylnaphthalene (3.30) ................................... 172 B.8.4 Characterization of 2-allyl-5-phenylnaphthalen-1-ol (3.31) ...................................... 172 B.8.5 Characterization of 2-(3-hydroxypropyl)-5-phenylnaphthalen-1-ol (3.32) ............... 172 B.8.6 Characterization of 4-chloro-2-(3-hydroxypropyl)-5-phenylnaphthalen-1-ol (3.33) 173 B.9 Preparation and characterization of intermediates towards naphtholic alcohols with gem-dimethyl substitution in side chain 3.43-3.46 ......................................................................... 173 B.9.1 Preparation of 4-Bromo-2-(bromomethyl)-1-methoxynaphthalene (3.35) ................ 173 B.9.2 Preparation of Methyl 3-(4-bromo-1-methoxynaphthalen-2-yl)-2,2-dimethylpropanoate (3.40)................................................................................................... 174 B.9.3 Preparation of 6-Bromo-3,3-dimethyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.42) ............................................................................................................................................. 175  ix  B.9.4 General procedure for reduction of lactone for the synthesis of naphtholic alcohols 3.43-3.44 .............................................................................................................................. 175 B.9.5 Preparation of 4-Chloro-2-(3-hydroxy-2,2-dimethylpropyl)naphthalen-1-ol (3.45) . 176 B.9.6 Characterization of 2-(3-Hydroxy-2,2-dimethylpropyl)-4-phenylnaphthalen-1-ol (3.46, Ar = Ph) ............................................................................................................................... 177 B.9.7 Characterization of 2-(3-Hydroxy-2,2-dimethylpropyl)-4-(4-(trifluoromethyl)phenyl)naphthalen-1-ol (3.46, Ar = C6H4-CF3-p) .................................... 177 B.10 Preparation and characterization of intermediates towards naphtholic alcohols 3.49-3.50 ................................................................................................................................................. 178 B.10.1 Preparation of 3,4-dihydro-2H-benzo[h]chromen-2-one (3.48) .............................. 178 B.10.2 Preparation of 2-(3-hydroxy-3-methylbutyl)naphthalen-1-ol (3.49) ....................... 178 B.10.3 Characterization of 4-chloro-2-(3-hydroxy-3-methylbutyl)naphthalen-1-ol (3.50) 179 B.11 Preparation and characterization of intermediates towards naphtholic alcohols 3.54-3.56 with stereogenic center at 2’ position ...................................................................................... 179 B.11.1 Preparation of compounds 3.52 ............................................................................... 179 B.11.2 Preparation of compounds 3.53 ............................................................................... 181 B.11.3 Preparation of 2-(3-hydroxy-2-methylpropyl)naphthalen-1-ol (3.54, R = Me) ....... 183 B.11.4 Preparation of compounds 3.54 ............................................................................... 184 B.11.5 Preparation of compounds 3.55 ............................................................................... 186 B.11.6 Preparation of compounds 3.56 ............................................................................... 188 B.12 Preparation and characterization of intermediates towards 3.59-3.60 ............................ 190 B.12.1 Preparation of 4-phenyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.58) ............... 190 B.12.2 Characterization of (±)-2-(3-hydroxy-1-phenylpropyl)naphthalen-1-ol (3.59) ....... 191 B.12.3 Characterization of (±)-4-chloro-2-(3-hydroxy-1-phenylpropyl)naphthalen-1-ol (3.60).................................................................................................................................... 191 B.13 Preparation and characterization of intermediates towards 3.63-3.64 ............................ 192 B.13.1 Preparation of 3,4-dihydro-2H-benzo[h]chromen-2-ol (3.61) ................................. 192 B.13.2 General procedure for reaction of Grignard reagent with 3.61 ................................ 192 B.13.3 Characterization of (±)-4-chloro-2-(3-hydroxybutyl)naphthalen-1-ol (3.63) .......... 193 B.13.4 Characterization of (±)-4-chloro-2-(3-hydroxy-3-phenylpropyl)naphthalen-1-ol (3.64).................................................................................................................................... 194 B.14 Preparation and characterization of various intermediates towards amine 3.72 ............ 194 B.14.1 General procedure for protection of 3.68 as TBS ether ........................................... 194  x  B.14.2 General procedure for hydroboration-oxidation of terminal alkenes 3.69 .............. 195 B.14.3 General procedure for azidation of primary alcohols .............................................. 197 B.14.4 General procedure for synthesis of amines from azides .......................................... 198 B.15 General procedure for coupling reaction between amine and sulfonyl chloride ............ 199 B.15.1 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)propyl)methanesulfonamide (3.73; R = Me, R’ = H) ..................................................... 200 B.15.2 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.73; R = 4-Tol, R’ = H) ....................................................... 200 B.15.3 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.73; R = C6H4-NO2-p, R’ = H) ................................................ 201 B.15.4 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-methoxybenzenesulfonamide (3.73; R = C6H4-OMe-p, R’ = H) ........................................ 201 B.15.5 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.73; R = Bn, R’ = H) ........................................................... 201 B.15.6 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)propyl)-2,2,2-trifluoroethanesulfonamide (3.73; R = CH2CF3, R’ = H) .......................................... 202 B.15.7 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)-4-phenylnaphthalen-2-yl)propyl)methanesulfonamide (3.73; R = Me, R’ = Ph) .................................................... 202 B.15.8 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)-4-methoxynaphthalen-2-yl)propyl)-methanesulfonamide (3.73; R = Me, R’ = OMe) ............................................... 203 B.16 General procedure for deprotection of TBS ether using TBAF ..................................... 203 B.16.1 Characterization of N-(3-(1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = H) ........................................................................................................ 203 B.16.2 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.74; R = 4-Tol, R’ = H) ....................................................... 204 B.16.3 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.74; R = C6H4-NO2-p, R’ = H) ................................................ 204 B.16.4 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-methoxybenzenesulfonamide (3.74; R = C6H4-OMe-p, R’ = H) ........................................ 205 B.16.5 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.74; R = Bn, R’ = H) ........................................................... 205 B.16.6 Characterization of 2,2,2-trifluoro-N-(3-(1-hydroxynaphthalen-2-yl)propyl)ethanesulfonamide (3.74; R = CH2CF3, R’ = H) ................................................. 206  xi  B.16.7 Characterization of N-(3-(1-hydroxy-4-phenylnaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = Ph) .................................................... 206 B.16.8 Characterization of N-(3-(1-hydroxy-4-methoxynaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = OMe) ................................................ 206 B.17 General procedure for para-bromination of naphtholic sulfonamides ........................... 207 B.17.1 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.76, R = Me) ................................................................... 207 B.17.2 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.76, R = 4-Tol) ..................................................................... 207 B.17.3 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.76, R = C6H4-NO2-p) ............................................................. 208 B.17.4 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.76, R = Me) ........................................................................ 208 B.17.5 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-2,2,2-trifluoroethanesulfonamide (3.76, R = Me) ......................................................................... 209 B.18 Preparation of N-(3-(4-chloro-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.77, R = Me) ......................................................................................................................... 209 B.19 General procedure for Suzuki coupling of 3.76 and aryl boronic acid ........................... 209 B.19.1 Characterization of N-(3-(4-(4-fluorophenyl)-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = C6H4-F-p) ....................................................... 210 B.19.2 Characterization of N-(3-(1-hydroxy-4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = C6H4-CF3-p) ................................................... 210 B.19.3 Characterization of N-(3-(4-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = 3,5-(bis)(CF3)2C6H3) ...................................... 211 B.20 Preparation and characterization of various intermediates towards 2-naphtholic sulfonamides 3.87.................................................................................................................... 211 B.20.1 General procedure for O-allylation of 2-naphthols .................................................. 211 B.20.2 General procedure for Claisen rearrangement of 3.80 ............................................. 212 B.20.3 General procedure for protection of 2-naphthols 3.81 as TBS ether ....................... 212 B.20.4 General procedure for hydroboration-oxidation of terminal alkenes ...................... 213 B.20.5 General procedure for azidation of 2-naphtholic primary alcohol ........................... 214 B.20.6 General procedure for synthesis of amine from azide ............................................. 215 B.20.7 General procedure for coupling of amine with methanesulfonyl chloride .............. 216 B.20.8 General procedure for deprotection of TBS ether using TBAF ............................... 216  xii  B.21 Preparation and characterization of various intermediates towards naphtholic acyl sulfonamides 3.93-3.95 ........................................................................................................... 218 B.21.1 Preparation of 3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propanoic acid (3.89).................................................................................................................................... 218 B.21.2 General procedure for coupling of carboxylic acid 3.89 and sulfonamide .............. 218 B.21.3 General procedure for deprotection of TBS ether of naphtholic acyl sulfonamides using TBAF ......................................................................................................................... 220 B.22 1H and 13C spectra from chapter 3 .................................................................................. 222 B.23 IR spectrum of compound crude 3.95 ............................................................................ 375 C. Oxidative amidation in naphthalene Series section .......................................................... 376 C.1 Synthesis and characterization of spiropyrrolidines ......................................................... 376 C.1.1 Representative protocol for ortho-oxidative cyclization of sulfonamides ................. 376 C.2 Characterization of N-(3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl)methanesulfonamide (4.3) ....................................................................................... 383 C.3 Synthesis and characterization of spirolactams ................................................................ 383 C.3.1 Representative protocol for the ortho-oxidative cyclization of N-acyl sulfonamides 383 C.3.2 Preparation of 1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.10) ................. 385 C.4 Synthesis and characterization of acyloxylated adducts ................................................... 385 C.4.1 Representative protocol for acyloxylation of naphtholic sulfonamides .................... 385 C.5 Preparation and characterization of intermediates towards acyloxylated adduct 4.68 ..... 389 C.5.1 Preparation of 2-propylnaphthalen-1-ol (4.66) .......................................................... 389 C.5.2 Preparation of 4-bromo-2-propylnaphthalen-1-ol (4.67) ........................................... 390 C.5.3 Characterization of (±)-4-bromo-1-oxo-2-propyl-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.68) .......................................................................................................... 390 C.6 Preparation of chiral iodoarene precatalysts ..................................................................... 390 C.6.1 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(2,4,6-trimethoxybenzamide) (4.23) ....................................................................... 390 C.6.2 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(3,5-dimethoxybenzamide) (4.21) ........................................................................... 391 C.6.3 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(4-methylbenzene-sulfonamide) (4.22) ................................................................... 392 C.6.4 General procedure for Mitsunobu reaction of amino alcohol with 2-iodo resorcinol 393 C.6.5 General procedure for Boc deprotection of 4.47 and 4.48 ......................................... 394  xiii  C.6.6 General procedure for the coupling of amine and 2,4,6-trimethylbenzoic acid ........ 395 C.7 Synthesis of (1S)-(+)-10-Camphorsulfonyl based derivatives of spiropyrrolidine and acyloxylated adducts ............................................................................................................... 396 C.7.1 Preparation of 4-bromo-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.61) ........... 396 C.7.2 Preparation of 4.63 ..................................................................................................... 397 C.7.3 Preparation of 4.64 ..................................................................................................... 397 C.8 General procedure for the synthesis of chiral spiropyrrolidines and acyloxylated adducts ................................................................................................................................................. 398 C.9 Data and chromatograms of chiral compounds ................................................................ 399 C.10 1H and 13C spectra from chapter 4 .................................................................................. 446 D. Asymmetric oxidative cycloetherification experimental section ..................................... 489 D.1 Representative protocols for cycloetherification of naphtholic alcohols at ortho-position ................................................................................................................................................. 489 D.2 Representative protocols for cycloetherification of naphtholic alcohols at ortho-position using PIFA............................................................................................................................... 489 D.3 Characterization of various spiroethers ............................................................................ 490 D.3.1 Characterization of (±)-4,5-Dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2l) ............................................................................................................................................. 490 D.3.2 Characterization of (±)-4'-Chloro-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2a) ............................................................................................................................. 490 D.3.3 Characterization of (±)-4'-Bromo-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2b)............................................................................................................................. 490 D.3.4 Characterization of (±)-4'-Methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2c) ............................................................................................................................. 491 D.3.5 Characterization of (±)-4'-Phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2d)............................................................................................................................. 491 D.3.6 Characterization of (±)-4'-p-Tolyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2e) ............................................................................................................................. 491 D.3.7 Characterization of (±)-4'-(3-Methoxyphenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2f) ..................................................................................................... 492 D.3.8 Characterization of (±)-4'-(3,5-Bis(trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2g) .......................................................................... 492 D.3.9 Characterization of (±)-4'-(4-Fluorophenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2h) .................................................................................................... 493  xiv  D.3.10 Characterization of (±)-4-(1'-Oxo-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalene]-4'-yl)benzo-nitrile (5.2i) ...................................................................................................... 493 D.3.11 Characterization of (±)-4'-(4-(Methylsulfonyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2j) ........................................................................... 493 D.3.12 Characterization of (±)-4'-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2k) .......................................................................... 494 D.3.13 Characterization of (±)-4'-(4-Acetylphenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2r) ..................................................................................................... 494 D.3.14 Characterization of (±)-4'-Benzoyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2o) ......................................................................................................................... 495 D.3.15 Characterization of (±)-4'-(4-Methylbenzoyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2p) .................................................................................................... 495 D.3.16 Characterization of (±)-4'-Acetyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2q) ........................................................................................................................ 495 D.3.17 Characterization of (±)-4,4-Dimethyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2m) ................................................................................................... 496 D.3.18 Characterization of (±)-4'-Chloro-4,4-dimethyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2n) .................................................................................................... 496 D.3.19 Characterization of (±)-4'-Bromo-4,4-dimethyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2u) .................................................................................................... 496 D.3.20 Characterization of (±)-4,4-Dimethyl-4'-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2v) .................................................................................................... 497 D.3.21 Characterization of (±)-4,4-Dimethyl-4'-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2w) ............................................................. 497 D.3.22 Characterization of (±)-5'-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2s) ......................................................................................................................... 498 D.3.23 Characterization of (±)-4'-chloro-5'-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2t) ..................................................................................................... 498 D.3.24 Characterization of (±)-4'-chloro-5,5-dimethyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2x) .................................................................................................... 498 D.4 Preparation of cycloadduct (±)-5.5 ................................................................................... 499 D.5 Characterization of 2-(3-Hydroxypropyl)naphthalene-1,4-dione (5.9) ............................ 499 D.6 Characterization of 4,5-Dihydro-1a'H,3H-spiro[furan-2,2'-naphtho[1,2-b]oxiren]-3'(7b'H)-one (5.10) ................................................................................................................................ 500 D.7 Synthesis of p-bromobenzoate esters of spiroether 5.2a and 5.2k ................................... 500  xv  D.7.1 Preparation of (±)-4'-Chloro-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-ol (5.13).................................................................................................................................... 500 D.7.2 Preparation of (±)-4'-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naph-thalen]-1'-ol (5.15) ............................................................................................... 501 D.7.3 General procedure for synthesis of p-bromobenzoate ester 5.14 and 5.16 ................ 502 D.8 General procedure for the synthesis of spiroethers (±)-5.18, (±)-5.19, (±)-5.21 and (±)-5.22 ................................................................................................................................................. 503 D.8.1 Characterization of (±)-4'-chloro-5-methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 55:45 mixture of 5.18b/5.19b) ...................................................... 503 D.8.2 Characterization of (±)-4'-chloro-5-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 55:45 mixture of 5.18a/5.19a) ....................................................... 505 D.8.3 Characterization of (±)-4'-chloro-3-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.18c) ................................................................................................... 505 D.8.4 Characterization of (±)-4'-chloro-4-isopropyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21a/5.22a) ........................................................... 505 D.8.5 Characterization of (±)-4-isopropyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21b/5.22b) .............................................................................. 506 D.8.6 Characterization of (±)-4'-bromo-4-isopropyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 4:1 mixture of 5.21c/5.22c) ........................................................... 506 D.8.7 Characterization of (±)-4-methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 7:3 mixture of 5.21d/5.22d) .................................................................................. 507 D.8.8 Characterization of (±)-4'-chloro-4-methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 7:3 mixture of 5.21e/5.22e) ........................................................... 507 D.8.9 Characterization of (±)-4'-bromo-4-methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 7:3 mixture of 5.21f/5.22f) ............................................................ 508 D.8.10 Characterization of (±)-4-cyclohexyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21g/5.22g) ........................................................... 508 D.8.11 Characterization of (±)-4'-chloro-4-cyclohexyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21h/5.22h) .......................................................... 509 D.8.12 Characterization of (±)-4'-bromo-4-cyclohexyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 4:1 mixture of 5.21i/5.22i) ............................................................ 509 D.8.13 Characterization of (±)-4'-chloro-4-(2,2,2-trifluoroethyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21j/5.22j) .................................. 510 D.8.14 Characterization of (±)-4-benzyl-4'-chloro-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 7:3 mixture of 5.21k/5.22k) .......................................................... 510  xvi  D.8.15 Characterization of (±)-4-benzyl-4'-bromo-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 3:1 mixture of 5.21l/5.22l) ............................................................ 511 D.8.16 Characterization of (±)-4'-chloro-4-phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (ca. 7:3 mixture of 5.21m/5.22m) ........................................................ 511 D.9 Preparation of (±)-2-((1-(4-bromobenzoyloxy)-4-chloronaphthalen-2-yl)methyl)-3-methylbutyl 4-bromobenzoate (5.27) ...................................................................................... 512 D.10 Preparation of chiral iodoarene precatalyst 5.26 ............................................................ 512 D.10.1 Preparation of tert-butyl (2R,2'R)-1,1'-(2-iodo-1,3-phenylene)bis(oxy)bis(propane-2,1-diyl)dicarbamate (5.24) ................................................................................................. 512 D.10.2 Preparation of (2R,2'R)-1,1'-(2-iodo-1,3-phenylene)bis(oxy)dipropan-2-amine (5.25) ............................................................................................................................................. 513 D.10.3 Preparation of N,N'-(2R,2'R)-1,1'-(2-iodo-1,3-phenylene)bis(oxy)bis(propane-2,1-diyl)bis(2,4,6-trimethylbenzamide) (5.26) .......................................................................... 513 D.11. General procedure for enantioselective oxidative spiroetherification of naphtholic alcohols .................................................................................................................................... 514 D.12 Data and SFC chromatograms of chiral compounds ...................................................... 515 D.13 1H and 13C spectra from chapter 5 .................................................................................. 589 D.14 COSY and NOESY spectra of spiroethers ..................................................................... 643 E. X-ray Crystal Data ............................................................................................................... 662     xvii  List of Tables Table 4.1 Optimization of solvent for oxidative cyclization of 4.1a ............................................ 56 Table 4.2 Substrate scope-Oxidative cyclization of 1-naphtholic sulfonamides .......................... 57 Table 4.3 Synthesis of spirocyclic γ-lactams ................................................................................ 59 Table 4.4 Synthesis of spirocyclic γ-lactams using modified conditions ..................................... 60 Table 4.5 Optimization of reaction conditions ............................................................................. 65 Table 4.6 Effect of addition of additives ...................................................................................... 70 Table 4.7 Precatalyst screening - I ................................................................................................ 71 Table 4.8 Precatalyst screening - II ............................................................................................... 72 Table 4.9 Optimization of conditions for the acylation of amines 4.51-4.52 ............................... 78 Table 4.10 Precatalyst screening with iodides 4.51 and 4.52 ....................................................... 80 Table 4.11 Oxidative cyclization and acyloxylation of 4-substituted naphtholic methane sulfonamides ................................................................................................................................. 84 Table 4.12 Oxidative cyclization of 2-naphtholic sulfonamides .................................................. 85 Table 4.13 Oxidative cyclization and acyloxylation of 4-bromo substrates with added MCBA . 93 Table 4.14 Acyloxylation of 1-naphtholic sulfonamides .............................................................. 94 Table 5.1 Oxidative cyclization of 5.1a in various solvents ....................................................... 103 Table 5.2 Relative efficiency of precatalyst 4.52 and 4.20 in the cyclization of 5.1l ................. 108 Table 5.3 Catalyst screening ....................................................................................................... 110 Table 5.4 Performance of newly designed iodoarenes in the spiroetherification reaction ......... 110 Table 5.5 Alternative reaction conditions ................................................................................... 111 Table 5.6 Substrate scope: 4-substituted naphtholic alcohols .................................................... 113 Table 5.7 Oxidative cyclization of 5-substituted naphtholic alcohols ........................................ 115 Table 5.8 Cyclization of alcohol 5.1a with recycled precatalyst 4.52 ........................................ 116 Table 5.9 Effect of gem-dimethyl substituents on the rate of cycloetherification ...................... 120 Table 5.10 Catalyst screening ..................................................................................................... 125 Table 5.11 Further optimization study ........................................................................................ 128 Table 5.12 Evaluation of iodide 4.51 in the cycloetherification of (±)-5.17a-b ......................... 132 Table 5.13 Oxidative cyclization of substrates with a 2’-stereogenic center ............................. 134 Table 5.14 Formation of enantioenriched dimer 5.5 ................................................................... 135    xviii  List of Figures Figure 1.1 Structures of DIB, IBX and DMP ................................................................................. 2 Figure 1.2 Examples of hypervalent iodine compounds ................................................................. 3 Figure 1.3 Pseudotrigonal bipyramidal structure of ArIL2 and 3c-4e- orbital diagram .................. 4 Figure 1.4 Square pyramidal structure of ArIL4 ............................................................................. 5 Figure 1.5 Examples of λ3-iodanes ................................................................................................. 5 Figure 1.6 Some commonly used organo-λ5-iodanes ..................................................................... 6 Figure 1.7 Chiral hypervalent iodine reagents of ArIL2 type ......................................................... 8 Figure 1.8 Catalytic cycle for generation of hypervalent iodine .................................................. 10 Figure 1.9 Some chiral diaryliodonium salts ................................................................................ 13 Figure 1.10 Structures of 4-hydroxymellein and monocerin ........................................................ 17 Figure 1.11 Structure of hypervalent iodine 1.88 ......................................................................... 18 Figure 1.12 Structures of iodoarene 1.152 and 1.153 ................................................................... 28 Figure 3.1 Structure of lactone 3.48 and carboxylic acid 3.96 ..................................................... 54 Figure 3.2 bis-tetrabutylammonium salt of 3.97 ........................................................................... 55 Figure 4.1 Structure of lactone 4.11 and carboxylic acid 4.12 ..................................................... 59 Figure 4.2 X-ray structure of spirolactam 4.9a ............................................................................. 61 Figure 4.3 Splitting of mesyl peak of (±)-4.2a in presence of Eu(hfc)3 ....................................... 67 Figure 4.4 Splitting of mesyl peak of (+)-4.2a (30% ee) in presence of Eu(hfc)3 ........................ 68 Figure 4.5 SFC chromatogram of (±)-4.2a (229 nm) ................................................................... 69 Figure 4.6 SFC chromatogram of (-)-4.2a (229 nm, 44% ee) ...................................................... 69 Figure 4.7 Ishihara’s X-ray structure of hypervalent form of 4.20 ............................................... 76 Figure 4.8 Working hypothesis for a new catalyst design ............................................................ 77 Figure 4.9 X-ray structure of iodide 4.52 ..................................................................................... 79 Figure 4.10 X-ray structure of (+)-(R)-4.2a .................................................................................. 80 Figure 4.11 X-ray structure of (-)-(S)-4.2a ................................................................................... 81 Figure 4.12 Side products formed during oxidative amidation of 4.1a ........................................ 82 Figure 4.13 X-ray structure of (+)-(R)-4.5b.................................................................................. 86 Figure 4.14 Crystal packing of a racemic solid: conglomerate (right) vs. racemic (left) ............. 88 Figure 4.15 Schematic of a two-vial CPC experiment for resolution of (±)-4.2a to result both enantiomers, (R) and (S), in high optical purity ............................................................................ 90 Figure 5.1 Trasition state model for heterodimerization of dienone (±)-5.4 .............................. 106 Figure 5.2 X-ray structure of 5.2h, R = 4-(4-F-C6H4) ................................................................ 116 Figure 5.3 X-ray structure of 5.2e, R = 4-Tol ............................................................................. 117 Figure 5.4 X-ray structure of (-)-(R, R)-5.14 .............................................................................. 118 Figure 5.5 X-ray structure of (-)-(R, R)-5.16 .............................................................................. 119 Figure 5.6 1-Naphtholic alcohol bearing a single substituent at the 1’, 2’, or 3’ position .......... 122 Figure 5.7 Spiroethers derived from substrates bearing a C-2’ substituent ................................ 124 Figure 5.8 X-ray structure of (-)-(S)-5.27 ................................................................................... 130  xix  Figure 5.9 X-ray structure of (S,S)-(-)-5.5 .................................................................................. 136    xx  List of Schemes Scheme 1.1 Pathways for the ligand exchange reactions of λ3-iodanes with nucleophiles Nu- ..... 7 Scheme 1.2 Types of reductive elimination of λ3-iodanes ............................................................. 8 Scheme 1.3 Oxidation of sulphides to sulfoxides using chiral 1.24 ............................................... 9 Scheme 1.4 Iodocarboxylation of cyclohexene using 1.29 ............................................................. 9 Scheme 1.5 Oxidation of sulfides to sulfoxides using in situ generated 1.33 .............................. 11 Scheme 1.6 Asymmetric oxidation of sulfides to sulfoxides using 1.36 ...................................... 11 Scheme 1.7 Catalytic asymmetric oxidation of sulfides to sulfoxides ......................................... 12 Scheme 1.8 General mechanism for aryl transfer to carbonyl enolates ........................................ 12 Scheme 1.9 Phenylation of cyclic β-ketoesters ............................................................................. 13 Scheme 1.10 General mechanism for α-tosyloxylation of ketone using Koser reagent 1.10 ....... 14 Scheme 1.11 Asymmetric tosyloxylation of ketones .................................................................... 14 Scheme 1.12 General mechanism of difunctionalization of alkenes using hypervalent iodine .... 15 Scheme 1.13 Tosyloxylation of styrene promoted by 1.67, 1.68 and 1.69 ................................... 15 Scheme 1.14 Syn- and anti-acetyloxylation of alkenes promoted by hypervalent iodine 1.72 .... 16 Scheme 1.15 Acetyloxylation of alkenes 1.76 .............................................................................. 16 Scheme 1.16 Oxylactonization of ortho-alkenyl benzoate ........................................................... 17 Scheme 1.17 Oxidation of ortho-alkenylbenzamide 1.84 ............................................................ 18 Scheme 1.18 Intermolecular diamination of alkenes mediated by hypervalent iodine 1.79 ........ 18 Scheme 1.19 Stereoselective oxyamination of alkenes ................................................................ 19 Scheme 1.20 Vicinal diamination of alkenes 1.92 ........................................................................ 19 Scheme 1.21 Reaction of silyl enol ethers with tethered nitrogen and oxygen ............................ 20 Scheme 1.22 Aminofluorination of alkenes mediated by chiral difluoroiodonium complex 1.101....................................................................................................................................................... 20 Scheme 1.23 Vicinal difluorination of alkene 1.105 .................................................................... 21 Scheme 1.24 Formation of rearranged products mediated by hypervalent iodine ....................... 21 Scheme 1.25 Oxidative rearrangement of alkene 1.111 and 1.114 .............................................. 22 Scheme 1.26 Mechanism of rearrangement mediated by hypervalent iodine yielding ketoacetals....................................................................................................................................................... 22 Scheme 1.27 Oxidative rearrangement of 1.119 to generate difluorinated product 1.121 ........... 23 Scheme 1.28 Rearrangement of 1.122 to 1.123 mediated by hypervalent iodine 1.90 ................ 23 Scheme 1.29 Total synthesis of (+)-biscarvacrol employing spiroketalization of 1.124 .............. 24 Scheme 1.30 Formal synthesis of (+)-maritidine employing oxidative dearomatization with concomitant C-C bond formation ................................................................................................. 24 Scheme 1.31 Total synthesis of (+)-Erysotramidine employing oxidative cyclization of phenolic oxazolines ..................................................................................................................................... 25 Scheme 1.32 Total synthesis of (±)-grandifloracin mediated by SIBX ........................................ 25 Scheme 1.33 Total synthesis of (±)-penicillone A employing IMDA reaction of ortho-quinols . 26  xxi  Scheme 1.34 Total synthesis of wasabidienone B1 and B0 employing dearomatization of phenol....................................................................................................................................................... 26 Scheme 1.35 Formal total synthesis of (±)-tetrodotoxin employing bimolecular oxidative dearomatization approach ............................................................................................................. 26 Scheme 1.36 Enantioselective dearomatization of naphthols to form ortho-substituted γ-lactones....................................................................................................................................................... 28 Scheme 1.37 Enantioselective oxidative dearomatization of phenols and subsequent Diels-Alder reaction with dienophiles .............................................................................................................. 29 Scheme 1.38 Enantioselective hydroxylative dearomatization of naphthols ................................ 30 Scheme 1.39 Hydroxylative dearomatization of 2,6-dimethylphenol .......................................... 30 Scheme 1.40 Enantioselective hydroxylative dearomatization of naphthols ................................ 31 Scheme 1.41 Hydroxylative phenol dearomatization/[4+2] dimerization cascade ...................... 31 Scheme 1.42 Asymmetric synthesis of para-quinols mediated by 1.177 ..................................... 32 Scheme 2.1 Presumed mechanism of para-oxidative amidation of phenols ................................ 33 Scheme 2.2 ortho-oxidative amidation of phenols ....................................................................... 34 Scheme 2.3 Oxidative amidation of phenolic sulfonamides and related substrates ..................... 35 Scheme 2.4 Possible enantioselective oxidative amidation of α-naphthols .................................. 35 Scheme 2.5 Oxidative dearomatization of amides 2.21 ................................................................ 36 Scheme 2.6 Resonance interactions showing the nucleophilicity of oxygen and nitrogen .......... 36 Scheme 2.7 Oxidative cyclization of phenolic oxazoline 2.31 ..................................................... 37 Scheme 2.8 Possible formation of spirolactams 2.37 via oxazoline technology .......................... 37 Scheme 2.9 Similar nucleophilic reactivity of alcohols and sulfonamides – I ............................. 38 Scheme 2.10 Similar nucleophilic reactivity of alcohols and sulfonamides – II .......................... 38 Scheme 2.11 Oxidative cyclization of phenolic primary amine 2.46 ........................................... 39 Scheme 2.12 Oxidative dearomatization of phenolic alcohols and sulfonamides ........................ 39 Scheme 2.13 Hypothetical oxidative cyclization of acyl sulfonamide 2.52 and release of the sulfonyl group ............................................................................................................................... 40 Scheme 2.14 Hypothetical oxidative cyclization of sulfonamide 2.55 and oxidative conversion to 2.54................................................................................................................................................ 40 Scheme 2.15 Possible enantioselective oxidative cycloetherification of naphtholic alcohols ..... 41 Scheme 2.16 Spiroetherification mediated by bleach ................................................................... 41 Scheme 2.17 Oxidative spiroetherification mediated by phenyltrimethylammonium tribromide 42 Scheme 2.18 Spiroetherification of 2.68 mediated by PIFA ........................................................ 42 Scheme 2.19 Synthesis of hemiacetals 2.72 mediated by PIFA ................................................... 43 Scheme 2.20 Enantioselective spiroetherification mediated by hypervalent form of 2.76 .......... 43 Scheme 3.1 Possible oxidative amidation and spiroetherification ................................................ 44 Scheme 3.2 Synthesis of 4-halide/aryl substituted naphtholic alcohols ....................................... 45 Scheme 3.3 Synthesis of 4-carbonyl substituted naphtholic alcohols .......................................... 46 Scheme 3.4 Synthesis of 4-alkyl/aryl substituted naphtholic alcohols ......................................... 46 Scheme 3.5 Synthesis of 5-substituted naphtholic alcohols ......................................................... 47  xxii  Scheme 3.6 Synthesis of naphtholic alcohols with gem-dimethyl group in side chain ................ 48 Scheme 3.7 Synthesis of 4-halo/aryl naphtholic alcohols with gem-dimethyl group at 2’ position....................................................................................................................................................... 48 Scheme 3.8 Synthesis of naphtholic alcohol 3.50 ......................................................................... 49 Scheme 3.9 Synthesis of substrates with stereogenic centre at 2’ position in side chain ............. 49 Scheme 3.10 Synthesis of substrates with stereogenic centre at benzylic position ...................... 50 Scheme 3.11 Synthesis of naphtholic secondary alcohol substrates 3.63-3.64 ............................ 50 Scheme 3.12 Possible synthesis of pyran 3.65 under Mitsunobu conditions ............................... 51 Scheme 3.13 Synthesis of naphtholic sulfonamide 3.74............................................................... 52 Scheme 3.14 Synthesis of 4-halo/aryl substituted naphtholic sulfonamides ................................ 52 Scheme 3.15 Synthesis of 2-naphtholic sulfonamides 3.87 .......................................................... 53 Scheme 3.16 Synthesis of N-acyl sulfonamide substrates ............................................................ 54 Scheme 4.1 Formation of naphthaquinone 4.3 ............................................................................. 58 Scheme 4.2 Oxidative cyclization of 2-naphtholic sulfonamides ................................................. 58 Scheme 4.3 N-Deblocking of nitrosulfonamide 4.9c .................................................................... 61 Scheme 4.4 Synthesis of Ishihara’s C2 symmetric chiral aryl iodides .......................................... 62 Scheme 4.5 Synthesis of chiral aryl iodide 4.20 ........................................................................... 63 Scheme 4.6 Synthesis of chiral aryl iodides 4.21-4.23 ................................................................. 63 Scheme 4.7 Synthesis of chiral iodide 4.25 .................................................................................. 64 Scheme 4.8 Oxidative amidation of 4.1a employing stoichiometric amount of iodide 4.20 ....... 73 Scheme 4.9 Initial steps of the oxidative cyclization of sulfonamides ......................................... 74 Scheme 4.10 Presumed mechanism of cyclization of complex 4.33 in polar, protic media ........ 75 Scheme 4.11 Presumed mechanism of formation of enantioenriched products ........................... 76 Scheme 4.12 Synthesis of amine 4.49-4.50 .................................................................................. 77 Scheme 4.13 Enantioselective oxidative amidation of acyl sulfonamide 4.8a ............................. 87 Scheme 4.14 Possible synthesis of cephalotaxine ........................................................................ 88 Scheme 4.15 Oxidative cyclization and acyloxylation of 4-unsubstituted naphtholic sulfonamides....................................................................................................................................................... 91 Scheme 4.16 Determination of ee of 4.2e ..................................................................................... 95 Scheme 4.17 Determination of ee of 4.54g via derivatization ...................................................... 95 Scheme 4.18 Synthesis of 2-propyl naphtholic substrate 4.67 ..................................................... 95 Scheme 4.19 Acyloxylation of control substrate 4.67 .................................................................. 96 Scheme 4.20 Possible mechanism for the formation of the acyloxylated product ....................... 97 Scheme 4.21 Possible equilibrium between 4.72 and 4.73 ........................................................... 98 Scheme 4.22 Possible mechanism for the formation of acyloxylated adduct ............................... 99 Scheme 5.1 Oxidative cyclization of 1-naphtholic alcohols with Ph-I / MCPBA in CH2Cl2 .... 104 Scheme 5.2 Oxidative cyclization of 1-naphtholic alcohols with PIFA in CH2Cl2 .................... 105 Scheme 5.3 Oxidative cyclization of substrate 5.1x ................................................................... 105 Scheme 5.4 Formation of cycloadduct (±)-5.5 ........................................................................... 106 Scheme 5.5 Side reactions when unsubstituted naphthol substrate 5.1l was used ..................... 107  xxiii  Scheme 5.6 Oxidative cyclization of 5.1a in the presence of iodide 4.20 .................................. 109 Scheme 5.7 Enantiocontrol during nucleophilic fragmentation of complex 5.11 ...................... 114 Scheme 5.8 Loss of enantiocontrol upon dissociation of complex 5.11 ..................................... 114 Scheme 5.9 Conversion of 5.13 back to 5.1a ............................................................................. 117 Scheme 5.10 Derivatization of spiroether 5.13 ........................................................................... 118 Scheme 5.11 Derivatization of spiroether 5.2k .......................................................................... 118 Scheme 5.12 Cycloetherification of 5.1x mediated by 4.52 ....................................................... 121 Scheme 5.13 Diastereoselectivity in the cyclization of 1’-substituted alcohols 5.17 ................. 122 Scheme 5.14 Cyclization of 3’-Ph alcohol (±)-5.17 ................................................................... 123 Scheme 5.15 Cyclization of 2’-substituted alcohols (±)-5.20 ..................................................... 123 Scheme 5.16 Synthesis of chiral iodoarene 5.26 ........................................................................ 127 Scheme 5.17 Evaluation of iodide 5.26 for cycloetherification of test substrate (±)-5.20a ....... 127 Scheme 5.18 Cycloetherification of (+)-5.20a mediated by 4.51 ............................................... 129 Scheme 5.19 Derivatization of (+)-5.20a as ester (-)-5.27 ......................................................... 130 Scheme 5.20 Cycloetherification of enantioenriched (+)-5.20a ................................................. 131 Scheme 5.21 Cycloetherification of (±)-5.17c mediated by 4.51 ............................................... 132    xxiv  List of Abbreviations Ac acetyl anh. anhydrous aq. aqueous Ar generic aryl group Bn benzyl Boc t-butyloxycarbonyl br broad brsm based on recovered starting material Bu butyl ca. circa calcd calculated Ch. chapter conv. conversion COSY correlation spectroscopy Cy cyclohexyl dec. decomposition DIAD diisopropyl azodicarboxylate diast diastereomer DIB diacetoxyiodobenzene DIBAL diisobutylaluminum hydride DIPA diisopropylamine DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMDO dimethyldioxirane  xxv  DMF N,N-dimethylformamide DMP Dess-Martin periodinane d.r. diastereomeric ratio e elementary charge EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess Et ethyl eq. equation equiv equivalent(s) g gram(s) h hour(s) hfc heptafluoropropylhydroxymethylene-(+)-camphorate HFIP 1,1,1,3,3,3-hexafluoro-2-propanol HOBt hydroxybenzotriazole HOMO highest occupied molecular orbital HPLC high-performance liquid chromatography HRMS high resolution mass spectrometry i iso (as an alkyl group) IBX 2-iodoxybenzoic acid IR infrared spectroscopy LAH lithium aluminum hydride LDA lithium diisopropylamide LUMO lowest unoccupied molecular orbital m milli or multiplet M molarity  xxvi  MCBA meta-chlorobenzoic acid MCPBA meta-chloroperoxybenzoic acid Me methyl MHz mega hertz min minute(s) mol mole(s) m.p. melting point Ms methanesulfonyl MTBE methyl-tert-butyl ether NBS N-bromosuccinmide n-BuLi n-butyllithium NCS N-chlorosuccinmide NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Nu generic nucleophile Ph phenyl PIFA phenyliodine bis(trifluoroacetate) ppm part per million Pr propyl pyr pyridine RSM recovered starting material RT room temperature satd. saturated SFC supercritical fluid chromatography  xxvii  t tertiary (as an alkyl group) tR retention time TBAF tetra-n-butylammonium fluoride TBS t-butyldimethylsilyl Tf triflate TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography 4-Tol para-methylphenyl Ts para-toluenesulfonyl UV ultraviolet µ micro °C degree Celsius  heat µ micro     xxviii  Acknowledgements First of all, I would like to express my heartfelt gratitude for my mentor and supervisor, Prof. Marco A. Ciufolini for providing me the opportunity to work under his guidance. I appreciate your dedication to science and commitment to students regarding helping them with their problems or answering their queries. You helped me realize where I lacked strength and your constant push for working on my weakness has helped me grow into my potential. Thank you for being an exemplary and visionary mentor. I appreciate and treasure all chemistry and life lessons that you have taught me.  I would like to thank Prof. J. Hein and Dr. C. Rougeot for their effort in separating the enantiomers of 4.2a via CPC technique. Prof. Hein, thank you for always being approachable and all the valuable discussions that we had while I was confronting problems with the crystallization of some of my compounds.  I express my sincere gratitude to Prof. Sammis for his valuable suggestions while proofreading my thesis even given extremely short deadline. Thank you for providing the facilities of SFC. It helped me with all the projects of my thesis. I would like to express my appreciation for members of my comprehensive exam committee, Prof. G. Sammis, Prof. L. Schafer and Prof. K. Ryan. I appreciated the suggestions that were given in the meeting and it helped me to pave the way towards completion of this degree. In addition, I would like to thank Prof. M. Tanner for agreeing to be a second reader of my thesis. At UBC, I was fortunate to take the courses by Prof. Sammis, Prof. Tanner, Prof. Perrin and Prof. Andersen which enabled deeper understanding of organic chemistry.  xxix  I was fortunate to work with Dr. Sanjia Xu and Chirag Apte on spiroetherification and sulfonamide project respectively involving discussions of new ideas or solution to the problems encountered in the project. I would like to thank Dr. Josh Zaifman and Dr. Takahito Kasahara for their valuable suggestions and constant support, especially when my thesis writing was in progress. I learnt a lot from you guys. I would also like to thank Dr. Matthew Smith, Dr. Léanne Racicot, Jason Hwang, Marco Paladino, Dimitrios Panagopoulos, Mara Tomassetti, Xueqing Wang, Dr. Manuel, Pamela and undergraduates for their friendship, insightful discussions and kind advice. My acknowledgements would remain incomplete if I do not mention the support of our fantastic technical staff. I would like to acknowledge Dr. Brian Patrick for obtaining X-ray data, David, Benny and Milan of electronic engineering services who have helped fix the SFC and the group’s NMR, Yun, Marshall and Derek, in the mass spectrometry lab, Paul and Maria, in the NMR facility, Emily and Yurou in the SIF, Brian Ditchburn in the glass shop, John Ellis and Pat Olsthoorn for the chemical acquisition and reception. I would like to thank Prof. R. A. Britton (Department of Chemistry, SFU) for allowing me to use the HPLC facility in his laboratory. I really appreciate the help that Dr. Milan Bergeron-Brlek’s provided while I was using HPLC facility at SFU. I am thankful to my friends Nishant, Taniya, Mampi, Arpita, Aagam, Namrata, Walid, Arvind, Wei and Swetha for their moral support and fun times together. You guys made it a lot easier for me! I really had good time while working as a TA for CHEM 233. It was an immense pleasure to work with very thoughtful Dana and Jonathan. There are some good memories which will never be forgotten.  xxx  I would like to thank UBC and Department of Chemistry for the financial support provided throughout my studies. My heartfelt gratitude is dedicated to my parents for believing in me, their unconditional love, encouragement and moral support throughout my stay in school. Last but not least, I am extremely grateful to my husband for always being there for me no matter what. Thank you for also being my best friend and my better half. Thank you for always pushing me to move out of my comfort zone in order to overcome my fear or weakness. Thank you for believing in me.    xxxi  Dedication        “Every accomplishment starts with the decision to try.”         -Steve Jobs          1  Chapter 1: Introduction 1.1 Hypervalency The Lewis octet rule states that atoms of main group elements tend to combine in such a way that the number of electrons formally assignable to the valence shell of each atom is closest to a noble gas configuration; i.e., it is equal to eight.[1] However, third-row and heavier elements in groups 15-18 form bonded states in which more than eight electrons are present within their valence shell.[2] According to a definition introduced by J. I. Musher in 1969,[2],[3] compounds of this sort are described as incorporating hypervalent or polyvalent atoms, because they establish more bonds than anticipated on the basis of the octet rule.  Iodine being the least electronegative and most polarizable of all the common halogens, forms a range of hypervalent compounds, in which it exists in the trivalent, pentavalent, and heptavalent state (oxidation states of +3, +5 and +7, respectively), instead of the anticipated monovalent one. Soon after the discovery of iodine by Bernard Courtois in 1813,[4] Joseph-Luis Gay-Lussac described iodine trichloride (oxidation state of iodine = +3) and potassium iodate (oxidation state of iodine = +5).[5]  Of special relevance to the present discussion are hypervalent organoiodine compounds; namely, those in which the iodine atom is bound to at least one carbon ligand.[6] Familiar examples are the common laboratory reagents, diacetoxyiodobenzene (DIB, 1.1), iodoxybenzoic acid (IBX, 1.2), and the Dess-Martin reagent (DMP, 1.3; Figure 1.1).  2   Figure 1.1 Structures of DIB, IBX and DMP 1.2 History of hypervalent organoiodine compounds The German chemist, Conrad Willgerodt was the first to prepare a hypervalent organoiodine compound. He obtained (dichloroiodo)benzene (PhICl2) in 1886 by passing excess chlorine gas through a cooled solution of iodobenzene in chloroform.[7] This was followed by discovery of several other hypervalent iodine compounds like iodosobenzene (1892) and DIB (1892), which will be discussed in further detail in section 1.5.  Several new polyvalent iodine compounds have been developed since the early 1980’s, many of which have found very useful synthetic applications.[8] Efforts in the area continue unabated to this day. Indeed, remarkable advances in the chemistry of hypervalent iodine compounds have been recorded since the beginning of 21st century, on account of their valuable oxidizing properties, environmentally benign nature, and easy commercial availability.[9] The generation of hypervalent iodine species in situ, by reaction of a substoichiometric amount of an organoiodine compound with oxidants such as MCPBA, peracetic acid, or oxone®, and their subsequent use in various transformations, has further expanded the application of hypervalent iodine for synthesis of a wide variety of products.[9c], [9f]    3  1.3 Nomenclature of hypervalent iodine compounds The Martin-Arduengo N-X-L designation[10] (N = number of electrons formally assignable to the valence shell of atom X, L = number of ligands) can be used to classify hypervalent species. Furthermore, hypervalent iodine compounds are currently described as iodanes. According to the Martin-Arduengo convention, (dichloroiodo)benzene 1.4 is then a 10-I-3 iodane; the Dess-Martin periodinane 1.3, a 12-I-5 iodane, and IF7 1.5, a 14-I-7 iodane (Figure 1.2).   Figure 1.2 Examples of hypervalent iodine compounds A more commonly employed nomenclature is the IUPAC lambda notation.[11] An electrostatically neutral compound incorporating an element in a non-standard valence state is designated as being a λn species, where n is the number of primary bonds at the iodine atom. For example, PhICl2 is referred to as a λ3-iodane and the Dess-Martin reagent as a λ5- iodane. In a λ3-iodane, the I atom itself has seven valence electrons and three more electrons are contributed from three ligands, creating a decet structure. Similarly, λ5- iodanes have a dodecet structure.  1.4 Structure and bonding in hypervalent iodine On the basis of molecular orbital considerations, G. C. Pimentel and R. E. Rundle proposed in 1951 that hypervalency is best understood in terms of 3-center, 4-electron (3c-4e) bonding.[12] To illustrate, a λ3-iodane like ArIL2 1.6 (L = ligand) has pseudotrigonal bipyramidal geometry. The aryl group forms an ordinary two-electron covalent σ bond with the iodine, and together  4  with two lone pairs, it resides in the equatorial plane of the molecule. Ligands L occupy apical position, and the L-I-L bond is linear, resulting in a T shape (Figure 1.3). The iodine contributes 2 electrons from one of its doubly occupied 5p orbitals; the ligands, one electron each. This result in formation of three molecular orbitals occupied by 4 electrons shared between three centers. The lowest-energy orbital is bonding; the high-energy one is antibonding, and the one of intermediate energy is nonbonding. The four electrons occupy the bonding and the nonbonding orbital; the latter corresponding to the HOMO.  Figure 1.3 Pseudotrigonal bipyramidal structure of ArIL2 and 3c-4e- orbital diagram The non-bonding orbital (HOMO) has a node at the central iodine atom and the electron density is concentrated towards the ligands. This result in the development of partial positive charge at the iodine centre, which therefore is electrophilic, while the negative charge is concentrated on the apical heteroatomic ligands. Hence, a hypervalent iodine compound of the type ArIL2 is best stabilized when the more electronegative atoms at the apical position.[13]  Hypervalent iodine species like ArIL4 1.7 (L = heteroatom) have a roughly octahedral geometry (Figure 1.4). The five groups bound to the iodine atom are arranged in a square pyramidal structure, in which the aryl substituent occupies the apical position and it established a normal covalent bond to the I atom. The ligands occupy basal positions. There are thus two orthogonal 3c-4e- bonds in the basal plane.  The remaining lone pair is trans to the Ar residue.[13]  5   Figure 1.4 Square pyramidal structure of ArIL4 1.5 General reactivity pattern of hypervalent iodine The strongly electrophilic character of hypervalent iodine centers, along with the excellent leaving group ability of an aryliodo group, enables a variety of unique reactions. Their chemical properties somewhat resembles to that of heavy metals like Hg(II), Ti (II), Pb (IV). However, hypervalent iodine species are considerably less toxic, enabling the replacement of heavy metals with more environmentally benign reagents.  Examples of some common λ3-iodanes appear in Figure 1.5. These are generally used for oxidative dearomatization of electron rich aromatics, oxidation of sulfides, functionalization of alkenes, arylation reactions, and α-functionalization of ketones. These applications are discussed in detail in section 1.7.  Figure 1.5 Examples of λ3-iodanes Organo-λ5-iodanes, especially IBX and DMP (Figure 1.6), have found application as efficient reagents for the oxidation of alcohols to carbonyl compounds. Recently, Wirth and coworkers  6  have developed a fluorinated analog of IBX, which they called FIBX 1.11. Due to its increased solubility in organic solvents, it is being used widely for oxidative synthetic transformations.  Figure 1.6 Some commonly used organo-λ5-iodanes There is no report of an organo-λ7-iodane in the literature so far, but inorganic iodine (VII) agents are known, e.g, IF7 and periodic acids such as H5IO6 and HIO4. The inorganic periodic acids and metal periodates are used for the oxidative cleavage of glycols, oxidation of sulfides, and other applications. The focus of this thesis is on synthetic transformations mediated by organo-λ3-iodanes. Hence, iodine at the oxidation states of +5 and +7 is not discussed further. 1.5.1 Ligand exchange and reductive elimination Reactions mediated by iodine(III) reagents generally involve nucleophilic ligand exchange followed by reductive elimination of an iodine(I) species. The latter step may take place with ligand coupling. In this respect, the chemistry of hypervalent iodine compounds reflects that of transitions metals. Two mechanistic pathways, associative and dissociative, have been proposed for ligand exchange in λ3-iodanes.[14],[16] The dissociative pathway starts with departure of a ligand from 1.6 to form dicoordinated λ2-iodane 1.12, which is trapped by a suitable nucleophile, Nu–, to provide 1.14 (Scheme 1.1). The associative pathway starts with the addition of the nucleophile to the  7  iodane 1.6, leading to the formation of square planar λ4-iodane 1.13. This is followed by dissociation of one of the original ligands from 1.13 to form 1.14.   Scheme 1.1 Pathways for the ligand exchange reactions of λ3-iodanes with nucleophiles Nu- Ligand exchange is customarily followed by an energetically favourable reductive elimination of Ar-I. This is due to excellent leaving ability of an Ar-I group (about a million times better than that of triflate ion, –OTf).[15] The reductive elimination of Ar-I can occur with or without concomitant ligand coupling. An especially significant mode of ligand coupling leads to the arylation of the incoming nucleophile, an outcome that requires an equatorial and apical placement of Ar1 and Nu (1.15  1.16; Scheme 1.2).[16] Reductive elimination without ligand coupling involves fragmentation of the hypervalent iodine complex by either an - or a -elimination mechanism. The -elimination pathway (1.17  1.18; Scheme 1.2) results in the liberation of an electrophilic, possibly cationic, form of one of the ligands. Of special interest is the release of Nu as Nu+: an event that achieves reactivity umpolung[17] of Nu- to Nu+ and that can result in the formation of products of nucleophilic capture, fragmentation, or rearrangement.[18] The -elimination mechanism typically results in formation of  bonds (1.19  1.20; Scheme 1.2).  8   Scheme 1.2 Types of reductive elimination of λ3-iodanes 1.6 Introduction to chiral hypervalent iodine complexes The widespread use of hypervalent iodine in organic synthesis has enabled the replacement of use of transition metal complexes with more environmentally benign reagents. In this context, increasing demand for the enantiopure compounds has led to remarkable advances in the field of chiral hypervalent iodine reagents, especially λ3-iodanes of the type ArIL2.[19]   Figure 1.7 Chiral hypervalent iodine reagents of ArIL2 type Hypervalent iodine reagents bearing chiral ligands (cf. 1.21) are used in stoichiometric amounts for oxidation of sulfides 1.25 to sulfoxides 1.27 (Scheme 1.3). Hypervalent iodine derived from (+)-menthol 1.24 reacted with sulfides generating mixture of diastereomers 1.27  9  which upon separation by crystallization followed by basic hydrolysis, afforded 1.28 with excellent optical purity.[20] Other types of hypervalent iodine (cf. 1.22) used for same transformation (1.25  1.28) is discussed in detail in Section 1.7.  Scheme 1.3 Oxidation of sulphides to sulfoxides using chiral 1.24 Hypervalent iodine reagent 1.30 (cf. 1.22) was used by Zhdankin and co-workers for iodocarboxylation reaction of cyclohexene 1.29 (Scheme 1.4). This process yielded racemic ester 1.30 as a mixture of 1:1 diastereomers in moderate to good yields.[21]   Scheme 1.4 Iodocarboxylation of cyclohexene using 1.30 More interesting are species like 1.23, wherein the chiral moiety is present as a substituent of aryl group. A noteworthy feature of these compounds is that they can be used in catalytic  10  amount, wherein a substoichiometric or catalytic quantity of the chiral aryl iodide 1.32 is converted to the hypervalent state in situ with oxidants such as MCPBA, peracetic acid, DMDO, Oxone®, and the like. The resulting 1.23 oxidizes the substrate into the product, in the process becoming reduced back to aryl iodide 1.32. The generated 1.32 is reoxidized to 1.23, and the cycle goes on (Figure 1.8).[22]   Figure 1.8 Catalytic cycle for generation of hypervalent iodine The use of chiral hypervalent iodine complexes for asymmetric transformations has emerged as an active area of research, and several comprehensive reviews of the field have appeared in recent times.[9d-f],[23] Important enantioselective reactions promoted by these reagents are highlighted below. 1.7 Applications of chiral hypervalent iodine Chiral hypervalent iodine reagents are known to perform a number of enantioselective transformations like oxidation of sulfides to sulfoxides, arylation of enolates, α-functionalization of ketones, functionalization of alkenes, and oxidative dearomatization reactions. These are discussed in detail below. 1.7.1 Oxidation of sulfides to sulfoxides The first chiral hypervalent iodine complex, diphenyliodonium tartrate, was described by Pribram[24] in 1907. In 1986, Imamoto et al. reported the enantioselective oxidation of sulfides  11  1.25 to sulfoxides 1.28 with a related reagent presumed to possess a seven membered cyclic structure 1.34. This material was prepared by reaction of iodosobenzene 1.9 with tartaric anhydrides 1.33 (Scheme 1.5).[25] Scalemic sulfoxides (5-53% ee) 1.28 were obtained in moderate to excellent yield.   Scheme 1.5 Oxidation of sulfides to sulfoxides using in situ generated 1.34 Subsequently, Koser et al. obtained hypervalent iodine complex 1.34 by treating diacetoxyiodobenzene (DIB) with dibenzoyl-L-tartaric acid.[26] An exhaustive NMR study revealed the compound to exist in polymeric form 1.37 (Scheme 1.6). The enantioselective oxidation of sulfides 1.35 to sulfoxides 1.36 with the new reagent 1.37 proceeded in yields and selectivities similar to those observed by Imamoto, suggesting that the reagent employed by the latter was also polymeric in nature.  Scheme 1.6 Asymmetric oxidation of sulfides to sulfoxides using 1.37 In 1999, Kita et al. described an asymmetric oxidation of sulfides 1.38 to sulfoxides 1.40 with iodoxybenzene (0.5 equiv) in the presence of 10 mol% of (S,S)-2-methoxydibenzoyl tartaric  12  acid 1.39 and 0.5 equiv of cetyltrimethylammonium bromide (CTAB) as a phase transfer agent (Scheme 1.7). Sulfoxides of up to 72% ee were thus obtained.[27]  Scheme 1.7 Catalytic asymmetric oxidation of sulfides to sulfoxides 1.7.2 α-arylation of ketones Diaryliodonium species of type 1.42 are known to arylate carbonyl enolates 1.41, presumably by the mechanism outlined in Scheme 1.8.[28] To illustrate, compounds containing active methylene group or corresponding carbanions 1.41 undergoes ligand exchange with 1.42 followed by ligand coupling to yield 1.44.   Scheme 1.8 General mechanism for aryl transfer to carbonyl enolates Asymmetric variants of this useful transformation have been pioneered by Ochiai and coworkers, who in 1999 described the phenylation of compound 1.45 with chiral, BINAP-based diaryliodonium salts 1.46-1.47.[29] Product 1.48 was obtained in moderate yield and ee (Scheme 1.9).   13   Scheme 1.9 Phenylation of cyclic β-ketoesters Curiously, very little additional work has been published in this area. For instance, chiral diaryliodonium salts like 1.49-1.52[30],[31] do not appear to have been tested in this reaction (Figure 1.9).  Figure 1.9 Some chiral diaryliodonium salts 1.7.3 α-functionalization of ketones The α-oxygenation of carbonyl compounds provides valuable intermediates for the synthesis of complex molecules. This transformation can be achieved by reaction of the enol derivative 1.55 of a carbonyl compound 1.54 with iodine(III) species such as hydroxy(tosyloxy) iodobenzene (Koser reagent, 1.10)[32] and related oxidants,[33] which can be generated in situ by MCPBA oxidation of iodobenzene 1.53 (Scheme 1.10).[22],[34b] Mechanistically, the reaction of 1.55 with in situ generated 1.10 is believed to produce 1.56 which is subsequently attacked by tosylate in SN2 fashion to produce α-tosylated ketone 1.57.[34b],[35]   14   Scheme 1.10 General mechanism for α-tosyloxylation of ketone using Koser reagent 1.10  On the basis of the foregoing, Wirth developed the first enantioselective variant of α-tosyloxylation of ketones through in situ MCPBA oxidation of chiral iodide 1.60 (Scheme 1.11).[34] Products 1.59 were obtained in good yield but poor ee. Enantioselectivities remained modest when oxazoline 1.61[35] or amide 1.62[36] were employed in lieu of 1.60.  Scheme 1.11 Asymmetric tosyloxylation of ketones 1.7.4 Functionalization of alkenes Many iodine (III) complexes undergo electrophilic addition to alkenes according to the general mechanism outlined in Scheme 1.12.[19],[38] Hypervalent iodine (III) 1.6 adds to the olefinic bond 1.63 to provide the presumed intermediate 1.64. Subsequent SN2 displacement of 1.64 by desired nucleophile affords 1.65 which undergoes another nucleophilic displacement to  15  afford product 1.66. Unlike α-arylation and oxidation of ketones, this transformation has been studied extensively, in that it provides access to a diversity of useful compounds such as diols, diamines, lactones and various rearranged products.  Scheme 1.12 General mechanism of difunctionalization of alkenes using hypervalent iodine Pioneering efforts by Wirth et al. on the enantioselective tosyloxylation of styrene 1.67 relied upon chiral Koser-type reagents 1.68-1.70 (Scheme 1.13). The extent of enantioinduction improved from 21% to 65% ee by changing functionality in hypervalent iodine from H (1.68)[37] to OMe (1.69)[38] to Et (1.70).[39]  Scheme 1.13 Tosyloxylation of styrene promoted by 1.68, 1.69 and 1.70 Fujita et al. reported an interesting variant of the above transformation that involves the reaction of alkenes 1.72 with chiral hypervalent iodine agent 1.73, acetic acid and trimethylsilyl acetate. This results in a Prévost-Woodward reaction: depending on whether the presumed 1,3- 16  dioxolan-2-yl cation intermediate 1.74 is generated in the presence of H2O or in an anhydrous medium, either the syn- or the anti- diacetoxylation product is obtained (Scheme 1.14).[40]   Scheme 1.14 Syn- and anti-acetyloxylation of alkenes promoted by hypervalent iodine 1.73 A very recent report on the diacetyloxylation of alkenes by Muñiz et al., describes the reaction of alkenes 1.77 with lactic acid derived C2 symmetric iodoarene 1.78 (10 mol%) and peracetic acid (2 equiv) to provide 1.79 in moderate to high enantioselectivity (63-94%) and yield (52-94%) (Scheme 1.15).[41]    Scheme 1.15 Acetyloxylation of alkenes 1.77  17  An intramolecular variant of the above reactions is the Fujita oxylactonization of ortho-alkenyl benzoate 1.80 mediated by iodine(III) species 1.81 (Scheme 1.16).[42] The result is the formation of 4-oxyisochroman-1-ones 1.82 with two cis substituents.  Scheme 1.16 Oxylactonization of ortho-alkenyl benzoate The same group subsequently disclosed a catalytic version of the process that relies on the treatment of the alkene with 10 mol% of chiral iodoarene version of 1.81, MCPBA (1.5 equiv) and trifluoroacetic acid, leading to trifluoroacetoxy lactones in high yield (up to 80%) and excellent enantioselectivity (up to 96%).[43] This methodology forms the centerpiece of the synthesis of 4-hydroxymellein 1.83 and monocerin 1.84 (Figure 1.10).[44]   Figure 1.10 Structures of 4-hydroxymellein and monocerin Recently, Fujita et al. reported similar reaction including oxidation of ortho-alkenylbenzamide 1.85 using chiral hypervalent iodine 1.73 to provide isochroman-1-imine products 1.86 with moderate yields (24-79%) and high enantioselectivity (71-90%; Scheme 1.17).[45]   18   Scheme 1.17 Oxidation of ortho-alkenylbenzamide 1.85 iz and coworkers demonstrated that hypervalent iodine reagent 1.81 can be used to effect the enantioselective diamination of alkenes 1.87 with mesylimide, providing compounds 1.88 in high yield and enantioselectivity (Scheme 1.18).[46]   Scheme 1.18 Intermolecular diamination of alkenes mediated by hypervalent iodine 1.81 The BINAP-based reagent 1.89 was not as efficient in this reaction, and it yielded product 1.88 only with 32% ee (Figure 1.11).[47]   Figure 1.11 Structure of hypervalent iodine 1.89 Wirth and coworkers achieved an asymmetric oxyamination of alkenes in the form of the cyclization of N-sulfonyl urea 1.90 with reagent 1.91 (Scheme 1.19).[48]    19   Scheme 1.19 Stereoselective oxyamination of alkenes More recently, these researchers devised an analogous vicinal diamination technique that affords good yields (45-72%) and selectivites (80-86% ee; Scheme 1.20).[49]  Scheme 1.20 Vicinal diamination of alkenes 1.93 The same authors elaborated a novel strategy for asymmetric α-heterofunctionalization of ketones. The process involves the condensation of an amine or an alcohol with the chlorosilyl enol ether derivative 1.98 of a ketone 1.97, followed by reaction of the resulting 1.99 (Nu = O-R or NH-R) with reagent 1.91 (Scheme 1.21).[50] Products 1.100 are thus obtained in high yields and enantioselectivities.   20   Scheme 1.21 Reaction of silyl enol ethers with tethered nitrogen and oxygen Nevado et al. developed an intramolecular aminofluorination of alkenes 1.101 promoted by chiral difluoroiodane 1.102 (Scheme 1.22).[51] The reaction proceeds regioselectively to furnish exclusively products of 6-endo cyclization, 1.103. Moreover, this methodology provided an access to 3-fluorinated azepanes 1.105. Additon of catalytic amount of [2-PicAuNTf2] was necessary to facilitate the activation of double bond; otherwise no conversion of 1.104 was observed even after prolonged reaction times (Scheme 1.22).  Scheme 1.22 Aminofluorination of alkenes mediated by chiral difluoroiodonium complex 1.102  21  Jacobsen and coworkers have devised an enantioselective alkene difluorination mediated by chiral iodide 1.107 (Scheme 1.23).[52] The reaction employs a nucleophilic fluoride source (pyr.9HF) with a sub-stoichiometric amount of 1.107 and MCPBA as the oxidant. Vicinal difluoride 1.108 was formed with moderate yield and excellent enantioselectivity.  Scheme 1.23 Vicinal difluorination of alkene 1.106 1.7.5 Rearrangement The ability of hypervalent iodine to behave as an electrophile and then a good leaving group enables the generation of carbocationic intermediates 1.111 (Scheme 1.24). Either 1.110 or 1.111 can then give rise to rearranged products.   Scheme 1.24 Formation of rearranged products mediated by hypervalent iodine Noteworthy examples of rearrangement have been described by Wirth et al. For instance, the action of PIFA upon 1.112 produces 1.113 or 1.114 (Scheme 1.25),[53] while reaction of DIB with 1.115 leads to lactones 1.116 (Scheme 1.26).[54]  22   Scheme 1.25 Oxidative rearrangement of alkene 1.112 and 1.115 Hypervalent iodine reagent 1.91 in conjunction with TMSOTf was found to convert enones 1.117 into enantioenriched ketoacetals 1.118[55] arguably by the mechanism delineated in Scheme 1.26.  Scheme 1.26 Mechanism of rearrangement mediated by hypervalent iodine yielding ketoacetals  Jacobsen and coworkers devised a variant of the above reaction that converts enones 1.120 into difluorides 1.122 (Scheme 1.27).[56]   23   Scheme 1.27 Oxidative rearrangement of 1.120 to generate difluorinated product 1.122 In a like vein, the reaction of aryl ketones 1.123 with 1.91 in the presence of triflic acid and triethyl orthoformate leads to enantioenriched esters 1.124 (Scheme 1.28).[57]   Scheme 1.28 Rearrangement of 1.123 to 1.124 mediated by hypervalent iodine 1.91 1.7.6 Dearomatization reactions Hypervalent iodine reagents efficiently promote a range of oxidative dearomatization reactions that have found use in the total synthesis of various natural products.[58] Many such reactions are intramolecular. For instance, Quideau employed a DIB-mediated oxidative cyclization of compound 1.125 to ketal 1.126 as a key step of the synthesis of (+)-biscarvacrol, 1.127 (Scheme 1.29).[59]   24   Scheme 1.29 Total synthesis of (+)-biscarvacrol employing spiroketalization of 1.125 While the above reaction created a new C-O bond, an oxidative C-C bond formation was key to a synthesis of (+)-maritidine, 1.131, by Kita and coworkers. Thus, exposure of phenol 1.128 to 10 mol% of 4-fluoro-iodobenzene and urea*H2O2 as the oxidant produced dienone 1.129, which was then elaborated to the target 1.131 (Scheme 1.30).[60]  Scheme 1.30 Formal synthesis of (+)-maritidine employing oxidative dearomatization with concomitant C-C bond formation The oxidative dearomatization of a phenol with concomitant C-N bond formation has been employed extensively by Ciufolini and collaborators in the total synthesis of several natural products.[61] A recent development in this area is the synthesis of (+)-Erysotramidine through an oxidative cyclization of phenolic oxazoline 1.132 with PIFA (Scheme 1.31).[62]   25   Scheme 1.31 Total synthesis of (+)-Erysotramidine employing oxidative cyclization of phenolic oxazolines Noteworthy among bimolecular oxidative dearomatization processes are the conversion of phenolic substrates into ortho- and para-quinols,[63] or para-amidodienones,[64] all of which are useful educts in natural products synthesis. For instance, the Quideau synthesis of (±)-grandifloracin, 1.137, starts with the formation of ortho-quinol 1.136 by reaction of 1.135 with SIBX (Scheme 1.33).[63e],[63f] SIBX is a nonexplosive formulation of IBX composed of a mixture of benzoic acid (22%), isophthalic acid (29%) and IBX itself (49%).[65] Compound 1.136 undergoes spontaneous Diels Alder dimerization in situ to generate the natural product.   Scheme 1.32 Total synthesis of (±)-grandifloracin mediated by SIBX A synthesis of (±)-penicillone A 1.140 by Liao co-workers relies instead on an intramolecular Diels-Alder reaction of an ortho-quinol ether. Thus, the action of DIB upon phenol 1.138 in the presence of crotyl alcohol produced species 1.139, which spontaneously cyclized in situ to the desired 1.140 (Scheme 1.33).[66]  26   Scheme 1.33 Total synthesis of (±)-penicillone A employing IMDA reaction of ortho-quinols Quideau and co-workers synthesized wasabidienone B1, 1.142, via a hydroxylative dearomatization of phenol 1.141 with SIBX (Scheme 1.35). Wasabidienone B0, 1.143, emerged upon heating 1.142 in refluxing benzene.[63a]   Scheme 1.34 Total synthesis of wasabidienone B1 and B0 employing dearomatization of phenol Our group recently described a formal total synthesis of (±)-tetrodotoxin, 1.146, from para-amidodienone 1.145 (Scheme 1.35),[67] which is easily prepared by oxidation of phenol 1.144 with DIB in MeCN.[68]  Scheme 1.35 Formal total synthesis of (±)-tetrodotoxin employing bimolecular oxidative dearomatization approach  27  Asymmetric variants of the above reactions began to appear in the literature in the late 2000's. In 2008, Kita et al. disclosed the enantioselective ortho-spirocyclization of 1-naphtholic acids 1.147 to lactones 1.148 with chiral iodane 1.149 (Scheme 1.36).[69] The same reaction could be carried out using only 15 mol% of aryl iodide 1.150 and 1.3 equiv of MCPBA as the oxidant to provide product 1.148 in moderate yield and enantioselectivity. In 2010, Ishihara et al. described a more efficient catalyst in the form of C2 symmetric iodide 1.152. The spirocyclization of substrates 1.147 could thus be achieved in higher yields and ee's in the presence of only 10 mol% of 1.152 (Scheme 1.36).[70] Recently, Kita and coworkers evaluated new spirobiindane iodides 1.151 for asymmetric ortho-lactonization of 1.147 and they found that enantioselectivity of 1.148 was improved by presence of ortho substituents in 1.150. Indeed, 1.151 having ethyl substitution at ortho position (ethyl) proved to be superior than its unsubstituted analog in terms of yield and ee of 1.148.[71]   28   Scheme 1.36 Enantioselective dearomatization of naphthols to form ortho-substituted γ-lactones Other chiral iodides such as 1.153[72] and 1.154[73] were also evaluated for ortho-spirocyclization of 1.147. Low to moderate yields (32-65%) and ee’s (18-67%) of the product were obtained which meant that these chiral aryl iodides were no better than 1.151 or even 1.149 (Figure 1.12).    Figure 1.12 Structures of iodoarene 1.153 and 1.154  29  However, in 2013 Ishihara discovered that iodide 1.156 performs even more efficiently than the structurally related 1.152.[74] This catalyst appears to be especially competent for the enantioselective ortho-lactonization of phenols 1.155 to reactive cyclohexadienones 1.157. The products 1.157 can be intercepted in situ with appropriate dienophiles 1.158-1.162, leading to tricyclic products 1.163 (Scheme 1.37).   Scheme 1.37 Enantioselective oxidative dearomatization of phenols and subsequent Diels-Alder reaction with dienophiles The enantioselective oxidative dearomatization in the bimolecular mode was disclosed in 2009 by Quideau and co-workers. They demonstrated the asymmetric hydroxylative dearomatization of 2-methyl-1-naphthol 1.164 with a reagent generated in situ by MCPBA oxidation of aryl iodide 1.165 (Scheme 1.38).[75] Ortho-quinols 1.166 was formed with moderate yields and ee. Addition of 2.5 equivalents of MCPBA resulted in the further oxidation of 1.166 to generate 1.167 with low ee (Scheme 1.38).  30   Scheme 1.38 Enantioselective hydroxylative dearomatization of naphthols Iodoxy compounds (λ5-iodanes) have also been employed in this type of transformation. Birman et al. described an early example in 2009, in the guise of the hydroxylative dearomatization of phenols with chiral iodane 1.169 (Scheme 1.39).[76] No external dienophile was used to intercept the primary products 1.170, which therefore dimerized to 1.171.  Scheme 1.39 Hydroxylative dearomatization of 2,6-dimethylphenol More recently, Quideau recorded moderate yields (33-55%) and variable ee’s (3-73%) in hydroxylative dearomatizations promoted by λ5-iodane 1.172 (Scheme 1.40).[77]   31   Scheme 1.40 Enantioselective hydroxylative dearomatization of naphthols Whereas products 1.166 derived from 1-naphthols were stable, ortho-quinols 1.175 obtained from 2-alkyl phenols 1.173 again underwent Diels-Alder dimerization to compounds 1.176 (Scheme 1.41). This propensity was nicely harnessed in a noteworthy synthesis of bis(sesquiterpene) (–)-bacchopetiolone.[78] Thus, hydroxylative dearomatization of phenol 1.173 mediated by λ5-iodane 1.174 triggered a highly stereoselective dimerization to tricyclic adduct 1.176, which was elaborated to the target compound as outlined in Scheme 1.41.  Scheme 1.41 Hydroxylative phenol dearomatization/[4+2] dimerization cascade The enantioselective para-oxidative dearomatization of phenolic substrates constitutes a more difficult goal, for which a good solution is still lacking. An important first step in this direction is apparent in the work of Harned et al., who devised a weakly enantioselective  32  oxidation of phenols 1.177 to para-quinols 1.179 with the hypervalent form of iodide 1.178 (Scheme 1.42).[79]  Scheme 1.42 Asymmetric synthesis of para-quinols mediated by 1.178 It is apparent from the foregoing that as of early 2017 no examples of enantioselective dearomatization of phenols with concomitant C–N bond formation were known. Likewise, no instances of enantioselective oxidative cyclization of phenolic substrates other than carboxylic acids had been described. The research summarized in the present dissertation aimed to devise techniques that would enable the conduct of such transformations.    33  Chapter 2: Background 2.1 Genesis of the research project The C-N bond is very important in the field of synthetic organic and medicinal chemistry, because nitrogen atoms are present in a variety of important intermediates and pharmaceutical drugs. The formation of C-N bond usually involves nucleophilic substitution or reductive amination reactions. Our group has developed a new technique for C-N bond formation that is described as the "oxidative amidation" of phenols.[80] As implied by this terminology, the reaction involves the oxidative dearomatization of phenols. Thus, the reaction of 2.2 or 2.6 with (diacetoxyiodo)benzene 2.1 (or related λ3-iodanes) results in formation of dienones 2.5 or 2.7 (Scheme 2.1, 2.2). The “N” group in 2.2-2.7 represents a suitable nitrogen nucleophile, while the dotted line signifies that “N” may be tethered to the phenol (intramolecular reaction) or be independent (bimolecular reaction). In all these cases, the nitrogen atom emerges as a part of amide functionality, hence the terminology "oxidative amidation." Depending on whether “N” connects to the phenolic para– (Scheme 2.1) or ortho-position (Scheme 2.2), the reaction is further qualified as a para– or an ortho-oxidative amidation.[81],[82]  Scheme 2.1 Presumed mechanism of para-oxidative amidation of phenols  34   Scheme 2.2 ortho-oxidative amidation of phenols Mechanistically, the process is believed to start with ligand exchange at the hypervalent iodine atom, leading to complex 2.3. A subsequent reductive fragmentation of the latter produces an electrophilic derivative of the starting phenol, perhaps cation 2.4, which is intercepted by "N" to furnish dienones 2.5 (Scheme 2.1).[83] The technique therefore achieves reversal of polarity (umpolung)[17] of the normally nucleophilic phenol, causing it to express electrophilic character. Dienones 2.5 have been used as key intermediates in a number of synthetic efforts.[62],[67],[84] Three modes – or generations – of oxidative amidation had been devised at the onset of the present research. The cyclization of oxazolines 2.8 to lactams 2.9 (Scheme 2.3, eq. 1) was the first reaction of this type ever recorded,[85] and it constitutes what we describe as the "first generation" process. Such a transformation was employed as the key step of the total synthesis of (-)-FR901483[84a-b] and Erythrina alkaloids.[62] The "second generation" reaction entailed the oxidative cyclization of sulfonamides (2.10 and 2.14) and phosphoramides 2.12, and it was devised to effect the equivalent of the cyclization of a primary amine (Scheme 2.3, eq. 2, 3 and 4).[86],[87] The method was applied to the total synthesis of cylindricine[84c] and it is currently being explored in connection with an ongoing synthesis of himandrine.[84d] In response to certain limitations of oxazoline and sulfonamide technology, a bimolecular, "third generation" oxidative amidation was developed, which relies on the reaction of phenols 2.16 with acetonitrile (Scheme 2.3, eq. 5).[88],[68] This methodology is key to a formal synthesis of (±)-tetrodotoxin.[67]  35   Scheme 2.3 Oxidative amidation of phenolic sulfonamides and related substrates The recent discovery of ansalactam A[89] (2.18, Scheme 2.4) ignited our interest in pursuing an enantioselective variant of oxidative amidation that would produce the spirocyclic core of the natural product by cyclization of α-naphthol substrates 2.19 (cf. 2.19  2.20). No such process was known at the onset of the research described in this dissertation.  Scheme 2.4 Possible enantioselective oxidative amidation of α-naphthols  36  Some comments are in order at this juncture. First, the conversion of amide 2.19 into spirolactam 2.20 was known not to be feasible. Already in 1987, Kita et al. had observed that the oxidative cyclization of phenolic amides 2.21 with PIFA or DIB yielded lactones 2.25 instead of lactams 2.26 (Scheme 2.5).[90]  Scheme 2.5 Oxidative dearomatization of amides 2.21 The effort that led to the development of the first-generation oxidative amidation started with the surmise that the undesired mode of cyclization of 2.21 was due to mesomeric redistribution of electron density from the amide nitrogen to the oxygen (2.22  2.23), causing the oxygen atom to capture electrophilic species 2.23. The resulting iminolactone 2.24 would then undergo hydrolysis to lactone 2.25.   Scheme 2.6 Resonance interactions showing the nucleophilicity of oxygen and nitrogen  37  The same resonance interactions that promote nucleophilicity at oxygen in amides (2.27  2.28) were expected to give rise to nucleophilic reactivity at nitrogen in imino analogues of amides; e.g., in oxazolines (2.29  2.30, Scheme 2.6). Indeed, oxidative activation of phenolic oxazolines 2.31 provided the desired spirolactams 2.34 (Scheme 2.7).   Scheme 2.7 Oxidative cyclization of phenolic oxazoline 2.31 In light of the above, spirolactams 2.36 could possibly be prepared by enantioselective cyclization of oxazolines 2.35, followed by release of the N-substituent (Scheme 2.8).  Scheme 2.8 Possible formation of spirolactams 2.37 via oxazoline technology A more direct approach was envisioned based on the fact that, in many respects, the nucleophilic reactivity of sulfonamides parallels that of alcohols.[81],[91] For instance the sulfonamide unit in 2.38, an intermediate in the synthesis of FR-901483,[84a-b] undergoes N-acetylation at a rate comparable to that of the primary alcohol moiety (Scheme 2.9).   38   Scheme 2.9 Similar nucleophilic reactivity of alcohols and sulfonamides – I Moreover, both furyl alcohols 2.40 and furyl sulfonamides 2.41 undergo efficient Achmatowicz reaction to provide dihydro-β-pyranones 2.42 and dihydro-β-pyridones 2.43, respectively,[92] whereas furyl amides or carbamates 2.44 are poor substrates for this transformation (Scheme 2.10).  Scheme 2.10 Similar nucleophilic reactivity of alcohols and sulfonamides – II The foregoing logic served as the guiding principle for the development of second-generation oxidative amidation technology. Various synthetic projects in our group required a method to achieve the oxidative cyclization of phenolic primary amines 2.46 (Scheme 2.11). Such a reaction proved to be extremely problematic,[93] even though analogous transformations of secondary amines are reasonably efficient.[94]   39   Scheme 2.11 Oxidative cyclization of phenolic primary amine 2.46 The fact that phenolic alcohols 2.48 cyclize smoothly to 2.50 upon exposure to DIB induced us to explore the same reaction of sulfonamides, a process that indeed proved to be clean and high-yielding (Scheme 2.12).[87]  Scheme 2.12 Oxidative dearomatization of phenolic alcohols and sulfonamides Accordingly, it was hypothesized that a phenolic/naphtholic N-sulfonyl carboxamide such as 2.52 (Scheme 2.13) might be a good substrate for oxidative cyclization, because its chemical behavior could be similar to that of the corresponding carboxylic acid, which would be an excellent substrate for oxidative cyclization (see above). Furthermore, a Fukuyama-type nitrosulfonyl group[95] in product 2.53 could be excised under mild nucleophilic conditions, enabling the facile release of the free lactam 2.54 and achieving the equivalent of an oxidative cyclization of a primary carboxamide. Again, no examples of oxidative cyclization of phenolic N-acylsulfonamides were known at the beginning of the present investigation, let alone in an enantioselective manner.  40   Scheme 2.13 Hypothetical oxidative cyclization of acyl sulfonamide 2.52 and release of the sulfonyl group Yet another option for the assembly of spirolactams 2.54 was an asymmetric cyclization of naphtholic sulfonamides 2.55 to products 2.56, followed by oxidative conversion of the latter into the desired 2.54 (Scheme 2.14). The oxidative cyclization of naphtholic sulfonamides such as 2.55, either in the racemic or the asymmetric series, was also undocumented.   Scheme 2.14 Hypothetical oxidative cyclization of sulfonamide 2.55 and oxidative conversion to 2.54  Two key objectives of this study thus were to ascertain the feasibility of the reactions depicted in Schemes 2.13 and 2.14 above, and to devise an enantioselective variant thereof. This also provided an incentive to explore the oxidative spiroetherification of naphtholic alcohols 2.57 (Scheme 2.15). Such a transformation was poorly documented at the beginning of this effort, and certainly was unknown in the enantioselective regime. Furthermore, it had never been carried out with hypervalent iodine oxidants.  41   Scheme 2.15 Possible enantioselective oxidative cycloetherification of naphtholic alcohols To illustrate, Ishihara et al. achieved the spiroetherification of α-naphthols 2.59 in high yield using bleach as the oxidant (Scheme 2.16),[96] whereas Sarkar et al. investigated the use of   Scheme 2.16 Spiroetherification mediated by bleach phenyltrimethylammonium tribromide 2.62 as a reagent for the analogous reaction of α-naphthols 2.61, β-naphthols 2.64, and phenols 2.66. Racemic spiro-oxacycles 2.63, 2.65 and 2.67 were thus obtained in moderate to high yields (Scheme 2.17).[97]   42   Scheme 2.17 Oxidative spiroetherification mediated by phenyltrimethylammonium tribromide  This stands in contrast to the oxidative cyclization of phenolic alcohols, which is well documented in the literature and that can be readily accomplished with hypervalent iodine reagents. For instance, the spiroetherification of phenolic alcohols 2.68 (Scheme 2.18) may be performed either with PIFA[90a] or with DIB.[98]  Scheme 2.18 Spiroetherification of 2.68 mediated by PIFA Related transformations include the oxidative cyclization of phenolic aldehydes 2.70 to hemiacetals 2.72 (Scheme 2.19),[99] a reaction that served as a key step in the total synthesis of the antibiotic, aranorosin.  43   Scheme 2.19 Synthesis of hemiacetals 2.72 mediated by PIFA So far, there has been only one report of enantioselective spiroetherification using chiral hypervalent iodine reagents. Thus, Harned and coworkers prepared spiroether 2.75 in low yield and ee by reaction of phenolic alcohol 2.74 with a catalytic amount of chiral iodide 2.76 in the presence of MCPBA (Scheme 2.20).[79]   Scheme 2.20 Enantioselective spiroetherification mediated by hypervalent form of 2.76    44  Chapter 3. Preparation of the substrates employed in the present study 3.1 Initial objectives and preparation of the substrates As indicated in chapter 2 (Scheme 2.13-2.15), an initial phase of this research focused on ascertaining whether the oxidative cyclization of alcohols 3.1, N-acylsulfonamides 3.2, and sulfonamides 3.3 were at all feasible (Scheme 3.1). This required the preparation a number of appropriate substrates.  Scheme 3.1 Possible oxidative amidation and spiroetherification 3.2 Synthesis of substrates: naphtholic alcohols  A number of compounds of general structure 3.13 were prepared from inexpensive 1-naphthol, 3.7, which upon O-allylation and Claisen rearrangement afforded 3.9 (Scheme 3.2). Hydroboration-oxidation of 3.9 returned naphtholic alcohol 3.10. The latter underwent a highly selective halogenation at the phenolic para-position upon exposure to an appropriate N-halo succinimide. Compound 3.12, was further elaborated to various 4-aryl derivatives 3.13 via Suzuki coupling.[100]  45   Scheme 3.2 Synthesis of 4-halide/aryl substituted naphtholic alcohols The synthesis of naphtholic alcohols bearing a 4-carbonyl substituent proceeded via Fries rearrangement of esters 3.14 in the presence of AlCl3 (Scheme 3.3).[101] The emerging phenols 3.15 were advanced to compounds 3.18 substantially by the method outlined earlier in Scheme 3.2, except that dicyclohexylborane was employed in lieu of BH3 in the hydroboration/oxidation sequence. This is due to the reduction of ketone in 3.17 by using BH3 along with hydroboration- oxidation of terminal alkene. Hydroboration-oxidation of 3.17 with 9-BBN resulted in formation of complex mixtures of products, but in situ generated dicyclohexylborane reacted only with the terminal alkene, leading to the desired 3.18 in moderate yield after a subsequent oxidation with sodium perborate.[102]   46   Scheme 3.3 Synthesis of 4-carbonyl substituted naphtholic alcohols Inexpensive 4-methoxy-1-naphthol was the starting material of choice for the preparation of alcohols 3.26. Conversion to triflate 3.19 followed by Kumada[103] or Suzuki[100] coupling provided 3.20 and 3.21 respectively (Scheme 3.4). These substances were advanced to 3.26 as seen earlier in Scheme 3.2.  Scheme 3.4 Synthesis of 4-alkyl/aryl substituted naphtholic alcohols  47  The 5-substituted naphtholic alcohols 3.33 were best made from very economical 1,5-dihydroxynaphthalene 3.27, which upon reaction with N-phenyl triflimide, provided mono-triflate 3.28 (Scheme 3.5).[104] Suzuki coupling afforded 3.29, which, once again, was elaborated to 3.32 – 3.33 as described above.  Scheme 3.5 Synthesis of 5-substituted naphtholic alcohols In the course of our efforts, it became desirable to explore how the so-called gem-dialkyl effect[105] influenced the rate of cyclization of naphtholic alcohols. Accordingly, substrates exhibiting a gem-dimethyl group at the 2’ position of the side chain were synthesized as delineated in Scheme (Scheme 3.6). In accord with a literature procedure,[106] commercial 1-hydroxy-2-naphthoic acid was advanced to compounds 3.34 and 3.35, either of which reacted with the lithium enolate of methyl isobutyrate 3.38 to provide 3.39 and 3.40 respectively. The action of BBr3 upon these resulted in demethylation of the phenol and lactonization. A final LAH reduction produced 3.43 and 3.44. The latter underwent Suzuki coupling with appropriate   48   Scheme 3.6 Synthesis of naphtholic alcohols with gem-dimethyl group in side chain boronic acids to furnish 4-aryl substituted alcohols 3.46 (Scheme 3.7). Substrate 3.45 was prepared by chlorination of 3.43 with NCS in acetonitrile. It is worthy of note that 3.43 failed to undergo chlorination at RT, but when the reaction mixture was refluxed for 2h, the desired 3.45 was obtained in 86% yield.  Scheme 3.7 Synthesis of 4-halo/aryl naphtholic alcohols with gem-dimethyl group at 2’ position  49  Related substrates displaying a gem-dimethyl group at the OH-bearing side-chain carbon atom were assembled starting with reaction of 1-naphthol 3.7 with acrylic acid 3.47 in the presence of the strongly acidic resin, Amberlyst® 15(H) (Scheme 3.8). The resulting lactone 3.48 reacted with MeMgBr to provide 3.49, which was converted into 3.50 as described above.   Scheme 3.8 Synthesis of naphtholic alcohol 3.50 Substrates incorporating a single substituent on the side chain also became of interest. The preparation of these compounds retraced the sequences outlined earlier in Schemes 3.6-3.7. Thus, 2'-monosubstituted compounds were obtained as shown in Scheme 3.9.   Scheme 3.9 Synthesis of substrates with stereogenic centre at 2’ position in side chain  50  Substrates carrying a single substituent at the benzylic position were accessed starting with Amberlyst® 15(H)-catalyzed reaction of conjugated carboxylic acids 3.57 with 1-naphthol 3.7 (Scheme 3.10).  Scheme 3.10 Synthesis of substrates with stereogenic centre at benzylic position Finally, secondary alcohol substrates emerged upon DIBAL reduction of lactone 3.48 to afford lactal 3.61 followed by Grignard reaction (Scheme 3.11).   Scheme 3.11 Synthesis of naphtholic secondary alcohol substrates 3.63-3.64  51  3.3 Synthesis of substrates: naphtholic sulfonamides The synthesis of sulfonamides 3.3 retraced that of the corresponding alcohols, but with one modification. The introduction of the nitrogenous functionality proved to be best achieved via a Mitsunobu reaction, which, however, would have failed if carried out with an unprotected naphthol. Indeed, a substrate such as 3.10 would probably cyclize to undesired pyran 3.65 under Mitsunobu conditions (Scheme 3.12). This mandated protection of the phenolic OH group immediately after the aromatic Claisen rearrangement shown in Schemes 3.2-3.5 above.   Scheme 3.12 Possible synthesis of pyran 3.65 under Mitsunobu conditions Protection of naphthols 3.68 as the TBS ethers 3.69 set the stage for hydroboration-oxidation to alcohols 3.70 and Mitsunobu reaction of the latter with DPPA to yield azides 3.71. Staudinger reaction, sulfonylation of the resulting amines 3.72, and release of the TBS group with TBAF generated desired sulfonamides 3.74 (Scheme 3.13).  52   Scheme 3.13 Synthesis of naphtholic sulfonamide 3.74  Compounds 3.74 were elaborated to more complex sulfonamides 3.76-3.78 by halogenation followed by Suzuki coupling of 3.76 with appropriate boronic acids (Scheme 3.14), just as shown earlier for alcohols 3.11-3.13.  Scheme 3.14 Synthesis of 4-halo/aryl substituted naphtholic sulfonamides  53  In the case of sulfonamides, we deemed it desirable also to explore the oxidative cyclization of 2-naphtholic substrates. These compounds were prepared from appropriate 2-naphthols 3.79 by the same method outlined above for 1-naphtholic sulfonamides (Scheme 3.15).   Scheme 3.15 Synthesis of 2-naphtholic sulfonamides 3.87 3.4 Synthesis of substrates: naphtholic N-acyl-sulfonamides Alcohol 3.88 obtained as described earlier in Scheme 3.13 was oxidized to carboxylic acid 3.89 using TEMPO and DIB. Subsequent EDCl mediated coupling of 3.89 with appropriate sulfonamides afforded products 3.90-3.92 in moderate (46%) to excellent (91%) yield (Scheme 3.16).   54   Scheme 3.16 Synthesis of N-acyl sulfonamide substrates Deprotection of the naphthol using TBAF provided 3.93-3.95. This step was problematic in the case of compound 3.92, because of the tendency of the product to cyclize to lactone 3.48 or form carboxylic acid 3.96 (Figure 3.1) as a consequence of the pronounced nucleofugal character of 4-nitrobenzenesulfonamide. For instance, desilylation with 1.1 equivalents of TBAF yielded mostly 3.48 and 3.96 and a very small amount of desired 3.95..  Figure 3.1 Structure of lactone 3.48 and carboxylic acid 3.96 Moreover, 3.95 decomposed to a mixture of 3.48 and 3.96 upon standing. Desilylation with HF•pyridine produced a very complex reaction mixture. Successful deprotection was finally achieved in the presence of 2.2 equivalents of TBAF, whereupon the expected product was obtained in the form of bis-tetrabutylammonium salt 3.97 (Figure 3.2).  55   Figure 3.2 bis-tetrabutylammonium salt of 3.97 Attempts to restore the neutral form of the compound by treatment with a mildly acidic solution (0.5 M HCl or satd. aq. NH4Cl) resulted in rapid degradation and precipitation of 4-nitrobenzenesulfonamide. The material was therefore employed as such in subsequent steps.   Crude 3.93-3.94 were amenable to purification by column chromatography. Such an operation was carried out rapidly, in order to minimize the formation of 3.48 or 3.96. Moreover, the purified products had limited shelf life. They could be stored at -20 °C under argon for some days, but decomposition into 3.48 and 3.96 was already apparent (1H NMR) after around 10 days. In contrast, the bis-tetrabutylammonium salt 3.97 was too sensitive. It did not withstand chromatography either on silica or neutral alumina, and attempted recrystallization induced extensive degradation. Hence, it was directly subjected to oxidative cyclization in crude form.    56  Chapter 4: Oxidative amidation in naphthalene series 4.1 Oxidative cyclization of naphtholic sulfonamides in the racemic series Non-nucleophilic protic solvents like trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), and especially trifluoroacetic acid (TFA) are ideal for the oxidative cyclization of phenolic sulfonamides.[87] Therefore, the same reaction of test substrate 4.1a was initially attempted in the same solvents. Spiropyrrolidine 4.2a was obtained in low yield when the reaction was carried out TFE or HFIP (Table 4.1, entry 1 and 2), but operation in TFA resulted in a satisfactory 65% yield (entry 3). Acetic acid was an especially poor solvent (entry 4).  Halogenated solvents like neat CH2Cl2 and CHCl3 were also unsatisfactory, even though addition of some TFA[87] was beneficial (entries 5-8). In accord with previous observations,[87] TFA was the best solvent for this reaction.  Entry Solvent Yield (%)b 1 CF3CH2OH 20 2 (CF3)2CHOH 28 3 CF3COOH 65 4 CH3COOH 4 5 CH2Cl2 14 6 CHCl3 12 7 CH2Cl2 + TFA (1.1 equiv) 30 8 CHCl3 + TFA (1.1 equiv) 18 aDIB (1.1 equiv), Solvent (0.3 M), 10-15 mins. bIsolated yields after column chromatography. Table 4.1 Optimization of solvent for oxidative cyclization of 4.1a   57  Based on the optimized conditions obtained as a result of solvent screening, the oxidative cyclization of other naphtholic sulfonamides was carried out in TFA, wherein conversion into spiropyrrolidines was achieved in moderate (45%) to excellent (96%) yield (Table 4.2). These reactions were best carried out by adding a TFA solution of sulfonamide to a TFA solution of DIB. A variety of substituents [Br, Cl, Ph, 4-F-C6H4, 4-CF3-C6H4, Ph, 3,5-(CF3)2C6H3] were tolerated at the naphtholic 4-position, with the exception of a methoxy group (entry 17). In the latter case, none of the spirocyclic sulfonamide was obtained. Instead, the starting 4.1q was oxidized to naphthoquinone 4.3 in 74% yield (Scheme 4.1).  Entry R1 R Product Yieldb 1 H 4-Me-C6H4 4.2b 74 2 Br 4-Me-C6H4 4.2c 73 3 H 4-O2N-C6H4 4.2d 75 4 Br 4-O2N-C6H4 4.2e 70 5 H 4-MeO-C6H4 4.2f 80 6 H PhCH2 4.2g 96 7 Br PhCH2 4.2h 87 8 H CF3CH2 4.2i 45 9 Br CF3CH2 4.2j 93 10 H Me 4.2a 65 11 Br Me 4.2k 83 12 Cl Me 4.2l 85 13 Ph Me 4.2m 55 14 4-F-C6H4 Me 4.2n 85 15 4-CF3-C6H4 Me 4.2o 85 16 3,5-(CF3)2C6H3 Me 4.2p 60 17 OMe Me - -- aDIB (1.1 equiv), TFA (0.3 M), 10-15 mins. bIsolated yields after column chromatography. Table 4.2 Substrate scope-Oxidative cyclization of 1-naphtholic sulfonamides  58   Scheme 4.1 Formation of naphthaquinone 4.3 The oxidative cyclization of 2-naphtholic sulfonamides afforded the expected spiropyrrolidines 4.5a-4.5b in lower yield compared to 1-naphtholic analogs (Scheme 4.2).  Scheme 4.2 Oxidative cyclization of 2-naphtholic sulfonamides 4.2 Oxidative cyclization of naphtholic N-acylsulfonamides in the racemic series As indicated earlier (Ch. 2, Scheme 2.13), the undocumented oxidative cyclization of N-acylsulfonamides 2.52 constitutes a direct avenue to spirolactams of the type found in ansalactam A. Furthermore, the successful execution of this transformation would circumvent the problems affecting the cyclization of carboxamides and thus establish a new mode ("fourth generation") of oxidative amidation. It was therefore pleasing to observe that reaction of 4.13 with DIB under the conditions developed earlier for the cyclization of sulfonamides indeed produced some of the desired spirolactams 4.9 (Table 4.3). However, it also became clear that the conditions for the reaction of sulfonamides were not immediately transposable to the N-acylsulfonamide series. This is due to returns of only small amounts of the desired products, accompanied by significant quantities of lactone 4.6 and acid 4.7 (Figure 4.1).  59   Figure 4.1 Structure of lactone 4.11 and carboxylic acid 4.12 It was determined that formation of byproducts 4.6 and 4.7 occurred simply upon dissolution of the substrates in TFA. It was thus essential to minimize contact time of 4.8 with TFA, which, in the absence of DIB, was promoting the acid-catalyzed conversion of the substrates into unwanted materials. Addition of TFA to a mixture of N-acyl sulfonamide and DIB, in the hope that oxidative cyclization would take place immediately upon dissolution of the reactants, led only to intractable mixtures. A better option was to minimize exposure of the substrates to TFA by operating as quickly as possible: rapid (seconds) dissolution of the acylsulfonamides in TFA and prompt addition the resulting solution to one of DIB resulted in formation of the desired spirolactams 4.9 in moderate yield (Table 4.3).   Entry Product Yieldb 1 4.9a (R = Me) 36 2 4.9b (R = MeO(CH2)2) 40 3c 4.9c (R = 4-O2NC6H4) 20 aDIB (1.1 equiv), TFA (0.3 M), RT, 10-15 mins. bIsolated yields after column chromatography. cYield obtained from bis-tetrabutylammonium salt 3.97. Table 4.3 Synthesis of spirocyclic γ-lactams An even better remedy was to dissolve the substrates in a solvent that was less acidic than TFA, so as to minimize decomposition, and then add the resulting solution to one of DIB. The  60  use of HFIP was revisited in that connection. While HFIP solutions of the acylsulfonamides were fairly stable, addition of such solutions to one of DIB also in HFIP produced no spirolactams. We thus concluded that an acidic medium was necessary for the success of the reaction. Accordingly, an HFIP solution of N-acylsulfonamide 4.8 was added to a TFA solution of DIB, whereupon spirolactams 4.9 were obtained in improved – if still moderate – yield. Additional experiments revealed that best results were obtained when the ratio of HFIP to TFA was 8:1 v/v. The yields of spirolactams thus obtained are reported in Table 4.4.   Entry Product Yieldb 1 4.9a (R = Me) 42 2 4.9b (R = MeO(CH2)2) 47 3c 4.9c (R = 4-O2NC6H4) 29 aDIB (1.1 equiv), HFIP:TFA (8:1 v/v, 0.05M), RT, 10-15 mins. bIsolated yields after column chromatography. cYield obtained from bis-tetrabutylammonium salt 3.97. Table 4.4 Synthesis of spirocyclic γ-lactams using modified conditions Single crystals of product 4.9a were obtained upon recrystallization via slow evaporation of its solution in toluene, which enabled a structural confirmation by X-ray diffractometry (Figure 4.2).   61   Figure 4.2 X-ray structure of spirolactam 4.9a As anticipated, the nitrosulfonyl group in compound 4.9c was easily released upon reaction with thiophenoxide ion, generated in situ by deprotonation of thiophenol with K2CO3 (Scheme 4.3). The resulting N-unsubstituted spirocyclic γ-lactam 4.10 was formed in 78% yield. Compound 4.10 possess structural similarity with the core of ansalactam A 2.18 (Scheme 4.3).   Scheme 4.3 N-Deblocking of nitrosulfonamide 4.9c    62  4.3 Enantioselective oxidative cyclization of naphtholic sulfonamides Having confirmed that the oxidative cyclization of naphtholic sulfonamides with hypervalent iodine reagents is indeed feasible, our attention refocused on the development of an enantioselective variant of the reaction. To the best of our knowledge, no such process had been recorded before in the literature. Initial experiments aiming to achieve the transformation of interest centered on the use of various Ishihara type, C2-symmetric, chiral aryl iodides in the presence of MCPBA.[70] The reason for using C2-symmetric chiral iodoarenes is that these had already been shown to be effective catalysts for the oxidative cyclization of carboxylic acids (Scheme 1.37) and are readily prepared. The synthesis of C2-symmetric chiral aryl iodides began with iodination of resorcinol,[107] 4.11, followed by Mitsunobu reaction of 2-iodo resorcinol 4.11[70] with (-)-(S)-methyl lactate, 4.13 (Scheme 4.4). Diester 4.14 was hydrolyzed under basic conditions to provide diacid 4.15, which was elaborated to 4.16 via the acid chloride.   Scheme 4.4 Synthesis of Ishihara’s C2 symmetric chiral aryl iodides Similarly, chiral iodoarenes 4.20[74] were made starting with Mitsunobu reaction of 2-iodoresorcinol with N-Boc-(R)-1-amino-2-propanol, 4.17 (Scheme 4.5). Amine 4.19 produced  63  upon release of the Boc units from 4.18 was then advanced to iodoarenes 4.20 (Scheme 4.5) and 4.21-4.22 (Scheme 4.6) by reaction with appropriate acid chlorides.  Scheme 4.5 Synthesis of chiral aryl iodide 4.20 The N,N-diacylation of 4.19 with 2,4,6-trimethoxybenzoyl chloride proceeded poorly (<5% yield). The problem was attributable to the inefficient conversion of 2,4,6-trimethoxybenzoic acid to the chloride upon reaction with SOCl2 or oxalyl chloride. Either method led to the formation of an uncharacterized complex mixture. Fortunately, EDCl mediated coupling of 4.19 with 2,4,6-trimethoxybenzoic acid provided 4.23 in 95% yield.  Scheme 4.6 Synthesis of chiral aryl iodides 4.21-4.23  64  Chiral iodide 4.31 was synthesized via Mitsunobu reaction of lactate (S)-4.19 with 2-iodophenol 4.30 as outlined in Scheme 4.7.[70]  Scheme 4.7 Synthesis of chiral iodide 4.25 4.3.1 Screening of conditions At the onset of this project, only iodoarenes 4.14-4.16 and 4.25 were known. Hence, these were used to explore the enantioselective cyclization of test substrate 4.1a. Treatment of the latter with MCPBA in the presence of 20-40 mol% of a chiral iodoarene, in TFA or in mixtures of TFA and HFIP (the best solvents for oxidative cyclization, Table 4.1-4.4), afforded a product that was racemic. Thus, the solvents that performed the best in the racemic series were entirely unsuitable for the enantioselective reaction. It will be recalled that the enantioselective cyclization of carboxylic acids had been carried out in CH2Cl2 (Scheme 1.37).[69-71] The same reaction of 4.1a was thus attempted in CH2Cl2, in the presence of 20 mol% of chiral iodide and MCPBA as the oxidant. Reactions run at 0 oC with the C1-symmetric iodide 4.25 afforded product 4.2a in poor yields and ee (Table 4.5, entry 1). The C2 symmetric iodides 4.14 and 4.16 provided better ee but comparable yields (entries 2 and 3). In all cases, however, reaction rates were considerably slower in CH2Cl2 than in protic solvents. Upon lowering the temperature from 0 to -10 °C to -20 oC, ee’s improved slightly, but at the cost of rate and yield (entries 4-5).  65   Entry Precatalyst Reaction conditions Yielda (%) eeb (%) 1 4.25 MCPBA (1.3 equiv.), 0 °C, CH2Cl2, 2.3 h 23 <5 2 4.14 MCPBA (1.3 equiv.), 0 °C, CH2Cl2, 2.5 h 12 19 3 4.16 MCPBA (1.3 equiv.), 0 °C, CH2Cl2, 1.5 h 20 11 4 4.16 MCPBA (1.3 equiv.), -10 °C, CH2Cl2, 7.5 h 12 16 5 4.16 MCPBA (1.3 equiv.), -20 °C, CH2Cl2, 13.5 h 13 20 6 4.14c MCPBA (1.3 equiv.), -20 °C, CH2Cl2, 26 h 15 37 7 4.14c MCPBA (1.3 equiv.), -20 °C, CHCl3, 24 h 10 31 8 4.14c MCPBA (1.3 equiv.), -20 °C, (CH2Cl)2, 36 h 14 26 9 4.14c MCPBA (1.3 equiv.), -20 °C, CH2Cl2: hexane (2:1), 18 h 12 30 10 4.14c MCPBA (1.3 equiv.), MeOH (2.0 equiv.), -20 °C, CH2Cl2, 12 h 15 31 11 4.16 MCPBA (1.3 equiv.), 0 °C, acetone -d - 12 4.16 Oxone® (3.0 equiv.), RT, CH2Cl2, 46 h -e - 13 4.14 Oxone® (3.0 equiv.), RT, MeOH:HFIP:H2O (10:10:1), 5.5 h -d - 14 4.14 Oxone® (3.0 equiv.), RT, CH3CN -d - 15 4.14 Oxone® (3.0 equiv.), RT, MeOH -d - 16 4.14 Oxone® (3.0 equiv.), RT, HFIP, 11 h 35 0 aIsolated yields after column chromatography. bEnantiomeric excess of the product were determined using Eu(hfc)3 (Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate) as a shift reagent. c40 mol% of the precatalyst was used. dThe starting compound was consumed generating a complex reaction mixture. eThe starting material remained unreacted.   Table 4.5 Optimization of reaction conditions Increasing the catalyst load to 40 mol% had a favorable influence on rate and ee but no effect on yield (entry 6). Solvents other than CH2Cl2, e.g., chloroform (entry 7) or 1,2-dichloroethane (entry 8) were less satisfactory. Attempts to modulate the polarity of the reaction  66  medium by admixture of CH2Cl2 with nonpolar hexanes (entry 9) or polar methanol (entry 10) failed to improve yields or ee’s. In the latter respect, Ishihara et al. had shown that addition of some MeOH to the reaction mixture improved the yield and the ee of products of oxidative ortho-lactonization.[74] Polar solvents such as acetone (entry 11) were especially poor, promoting the formation of complex product mixtures containing none of the desired 4.2a. The choice of this solvent was motivated by the expectation that its reaction with MCPBA would produce dimethyldioxirane (DMDO): it seemed interesting to explore alternative oxidants for the desired transformation. In that connection, Oxone® was also examined as the terminal oxidant. No reaction occurred when CH2Cl2 was used as the solvent (entry 12), presumably because of the insolubility of the oxidant in that medium. Attempts to solubilize Oxone® in CH2Cl2 by the use of one full equivalent of a phase-transfer agent such as tetrabutylammonium tetrafluoroborate (Bu4N+BF4-) were unproductive, resulting only in the formation of complex reaction mixtures. The same outcome was obtained in polar solvents like H2O, MeOH and MeCN (entries 13-15). The use of Oxone® in HFIP produced 4.2a in 35% yield, but the product was racemic (entry 16).  From the above results we concluded that CH2Cl2 is the best reaction solvent, just as in the case of the oxidative cyclization of phenolic acids. Polar solvents, and especially polar, protic ones such as HFIP or TFA, are entirely unsuitable, in that either no desired 4.2a is formed in these media, or the product is obtained as the racemate. This observation has significant mechanistic implications, as outlined in Section 4.3.4 below. At this point, a comment is in order about the technique that was employed to evaluate the extent of asymmetric induction in the above reactions. It was determined that a rapid way to do so entailed a 1H NMR shift study that relied upon europium tris[3-(heptafluoropropyl-hydroxymethylene)-(+)-camphorate (Eu(hfc)3) as a chiral shift reagent. Thus, progressive  67  addition of small portions (tip of a spatulaful) of Eu(hfc)3 to a CDCl3 solution of (±)-4.2a resulted in greater splitting of the resonances of the methyl group of methanesulfonamide in the two enantiomers (Figure 4.3). As seen in Figure 4.4, nearly baseline resolution of the methyl signals of (+)-4.2a was achieved. Integration of these resonances provided the enantiomeric ratio, and consequently the ee, of an enantioenriched product.   Figure 4.3 Splitting of mesyl peak of (±)-4.2a in presence of Eu(hfc)3  68   Figure 4.4 Splitting of mesyl peak of (+)-4.2a (30% ee) in presence of Eu(hfc)3 More accurate measurements of asymmetric induction were carried out using chiral Supercritical Fluid Chromatography (SFC), but only for those reactions that produced significant ee’s. The sample was prepared by dissolving ~3 mg of the compound in ~1.3 mL of methanol followed by its filtration so that the insoluble solid particles, if any, can be removed. The prepared sample was then run through chiral columns under high pressure (~120 bar) by using iPrOH with 0.1% of diethylamine as polar solvent and liquid CO2 as the non-polar form. The retention time (tR) of eluting enantiomers were recorded and compared to the enantiomeric peaks of racemic compound. Difference between the area of the peaks of enantiomers provided the ee of the product. Figure 4.5-4.6 shows that excellent separation of the enantiomers of the product could be achieved by using SFC.  69   Figure 4.5 SFC chromatogram of (±)-4.2a (229 nm)  Figure 4.6 SFC chromatogram of (-)-4.2a (229 nm, 44% ee)  70  4.3.2 Effect of additives The next phase of the research examined the use of additives in order to accelerate reaction rates and improve yields and ee’s (Table 4.6). Reportedly, additives such as AcOH[71] and MeOH[74] enhance the yield and ee of ortho-lactonization reactions of naphtholic acids. However, we had already determined that AcOH (Table 4.1, entry 4) or MeOH (Table 4.5, entry 10) were best avoided in our case. Conduct of the reaction in CH2Cl2 containing TFA (the best solvent for the generation of 4.2a in racemic form) resulted in a low yield of racemic product (entry 1).   Entry Additive (1.1 equiv) Precatalyst  Yieldb (%) eec (%) 1 TFA 4.14 29 0 4.16 19 0 2 BF3.OEt2 4.14 27 0 4.16 21 0 3 TBDMSOTf 4.14 20 0 4.16 25 0 4 Yb(OTf)3 4.14 24 0 5 TMSOTf 4.14 17 0 6 Sc(OTf)3 4.14 25 0 7 TfOH 4.14 15 0 aprecatalyst (20 mol%), MCPBA (1.3 equiv), additive (1.1 equiv), 0 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cEnantiomeric excess of the product were determined using Eu(hfc)3 (Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate) as a shift reagent.   Table 4.6 Effect of addition of additives  71  Use of BF3.OEt2 promoted formation of polymeric products from which only ~20% of racemic 4.2a was isolated (entry 2). No enhancement in yield and no enantioinduction was observed when triflic acid or other triflates like TBDMSOTf, Yb(OTf)3, TMSOTf , Sc(OTf)3 were used as additives (entries 3-7). These results indicate that Bronsted or Lewis acids promotes the formation of racemic 4.2a. Mechanistic ramifications of these results are discussed in Section 4.3.4 4.3.3 Precatalyst screening At this juncture, a screen of alternative chiral iodides was launched. Table 4.7 summarizes the results obtained with C1-symmetric iodoarene 4.25, and with various structural analogues of Ishihara iodide 4.16. All experiments were run in CH2Cl2 at -20 °C with 40 mol%   Entry Precatalyst Time (h) Yieldb (%) eec (%) 1 4.25 18  15 17 2 4.14 15.5  26 37 3 4.15 10.5  15 12 4 4.16 12  15 20 5 4.26 - -d - aPrecatalyst (40 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cEnantiomeric excess of the product were determined using Eu(hfc)3 (Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate) as a shift reagent. dThe starting compound was consumed generating a complex reaction mixture.   Table 4.7 Precatalyst screening - I  72  of precatalyst and MCPBA as the oxidant. The C1 symmetric iodide 4.25 was ineffective (entry 1). The C2 diester 4.14 fared better (entry 2), while the corresponding diacid 4.15 proved inferior (entry 3). Ishihara iodide 4.16 was less efficacious than diester 4.14. Chiral iodide 4.26, wherein electron-withdrawing CF3 groups were present on the aryl moiety in lieu of methyl, promoted the formation of complex mixtures of products containing no desired 4.2a (entry 5).  Entry Precatalyst Time (h) Yieldb (%) eec (%) 1 4.20d 14.5  20 46f 2 4.18 13  11 <5 3 4.21 12  15 6 4 4.23d 13.5 15 15 5 4.22d 12  15 18 aPrecatalyst (40 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cEnantiomeric excess of the product were determined using Eu(hfc)3 (Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate) as a shift reagent. d20 mol% of the precatalyst was used. fEnantiomeric excess of the product were determined using chiral SFC.   Table 4.8 Precatalyst screening - II During optimization of the oxidative amidation of 4.2a, Ishihara and coworkers described a “second generation” catalyst, iodide 4.20 (figure below Table 4.8) that was particularly effective for the oxidative cyclization of carboxylic acids.[74] This induced us to test 4.20 and its  73  structural congeners for the analogous reaction of 4.1a. Among all iodides tested, 4.20 indeed afforded by far the best degree of asymmetric induction in the cyclization of 4.1 (46%, Table 4.8, entry 1). The yield of 4.2a, however, was only 20%. The use of a stoichiometric amount of iodide 4.20 in the oxidative cyclization of 4.1a resulted only in a marginal increase in asymmetric induction (ee 46%  51%) which can be attributed to the instrumental errors, but chemical yields remained unaffected (Scheme 4.8). Thus, the use of sub-stoichiometric amount of chiral iodide was preferable.  Scheme 4.8 Oxidative amidation of 4.1a employing stoichiometric amount of iodide 4.20 4.3.4 Mechanistic aspects The above results lead to the following conclusions. First, polar, non-nucleophilic, protic, Bronsted acidic solvents, such as HFIP (pKa = 9.3)[108] and – especially – TFA (pKa = 0.3),[108] are optimal for the conduct of the oxidative cyclization of sulfonamides in the racemic series, but they are entirely inadequate for the asymmetric reaction, in that they promote the formation of racemic products. Second, the reaction of interest is best carried out in moderately polar CH2Cl2, just as in the case of the analogous cyclization of carboxylic acids. However, the use of this solvent results in slow reaction rates and yields of only about 20%, both in the racemic or the  74  asymmetric series. Third, the asymmetric reaction affords the best ee’s in the presence of 20-40 mol % of chiral catalyst, instead of the customary 10 mol %. Fourth, Bronsted or Lewis acidic additives also induce the formation of racemic products.   These observations lead to the following mechanistic picture. The phenolic OH must first ligate the hypervalent iodine species, whether DIB, PIFA, or the oxidized form of a chiral iodide, via a ligand exchange event. This step is more likely to occur by a dissociative mechanism than an associative one. Indeed, the observation that the reaction is faster in protic, Bronsted acidic solvents may reflect the fact that one of the original ligands, L, on the iodine atom departs either upon establishing a strong H-bond with the solvent (S-H in Scheme 4.9) or upon full protonation (structures 4.28 and 4.29). The resulting iodonium ion 4.30 then combines with the substrate, 4.31, to produce complex 4.33.   Scheme 4.9 Initial steps of the oxidative cyclization of sulfonamides By the same logic, it seems plausible that in polar, protic solvents, complex 4.34 or 4.35 will rapidly equilibrate with iodonium ion 4.36, which then fragments quickly to produce cation 4.37. The latter then cyclizes to give racemic 4.38 (Scheme 4.10).  75   Scheme 4.10 Presumed mechanism of cyclization of complex 4.33 in polar, protic media  Clearly, an enantioselective variant of the above process is possible only within the asymmetric environment of the chiral catalyst. The chiral iodoarene must then remain associated with the substrate for the reaction to occur with asymmetric induction: any factor that promotes dissociation of 4.36 to cation 4.37 will result in formation of racemic product. This may be the reason why polar solvents – especially protic ones – as well as Bronsted and Lewis acids have an adverse effect on asymmetric induction: electrostatic effects (polar solvents), H-bonding or protonation (protic solvents, Bronsted acids) interactions, as well as coordination of ligand L with a Lewis acid, would all favor equilibration of 4.34 or 4.35 with 4.36, and consequent rapid fragmentation of the latter to 4.37. Less polar, aprotic solvents such as CH2Cl2 retard the rate of fragmentation of complex 4.39. The chirality of 4.42 can now direct the nucleophilic sulfonamide to one diastereotopic face of the naphthalene segment, resulting in formation of an enantioenriched product (Scheme 4.11). On the other hand, the naphthalene ring in complex 4.39 is surely less electrophilic than than cation 4.37 (Scheme 4.10 above), accounting for a significantly slower overall reaction rate.  76   Scheme 4.11 Presumed mechanism of formation of enantioenriched products 4.3.5 Asymmetric oxidative cyclization of naphtholic sulfonamides: a new catalyst design  In 2013, Ishihara and collaborators obtained an X-ray crystal structure of the hypervalent form of iodide 4.20.[74] It thus transpired that – at least in the solid state – such a species exists as a helical structure held together by hydrogen bonds between the amide N–H's and the oxygen ligands on the iodine(III) atom (Figure 4.7). The authors further posited that such a helical arrangement is crucial for catalysts performance.  Figure 4.7 Ishihara’s X-ray structure of hypervalent form of 4.20 On such a basis, we hypothesized that relocating the stereocenters closer to the NH group might enforce the hydrogen-bonded conformation of the I(III) variant of the catalyst through a Thorpe-Ingold-like effect,[105] especially if one were to increase the steric demand of the R  77  group. The stereocenters would thus become closer to the iodine atom, enhancing the chiral nature of the environment around it and possibly providing a more efficient catalyst (Figure 4.8).  Figure 4.8 Working hypothesis for a new catalyst design As evident from results of precatalyst screening (Table 4.8), a mesitoyl amide was important for optimal catalyst performance. In addition, the presence of secondary amide was mandatory for H-bonding to occur. It was thus concluded that the new catalyst architecture should be embodied in the form of iodides 4.51 and 4.52. The synthesis of the new iodoarenes started with Mitsunobu reaction of 2-iodoresorcinol with Boc-protected valinol (4.45) or tert-leucinol (4.46), followed by deprotection of the resulting 4.47-4.48 (Scheme 4.12).   Scheme 4.12 Synthesis of amine 4.49-4.50 The subsequent acylation of free amines 4.49-4.50 proved to be less than straightforward. To illustrate, reaction of 4.49 with MesCOCl generated 4.51 in poor yield, possibly because of  78  the bulky nature of amine (Table 4.9, entry 1). The same reaction of the even bulkier 4.50 afforded no desired product whatsoever (1H NMR). An EDCI mediated coupling of the amines with 2,4,6-trimethylbenzoic acid in CH2Cl2 fared better, but yields were low (entry 2). A significant improvement in the yield of 4.51 (18%  52%) and 4.52 (13%  47%) was achieved by operating at reflux (entry 3). However, yields dropped drastically (4.51: 52%  5%; 4.52: 47%  6%) when the reaction was scaled up from 0.1 to 1.0 mmol (entry 4). This problem was circumvented by changing the solvent from CH2Cl2 to DMF[109] and employing HOBt[109],[110] as a catalyst. Compounds 4.51 and 4.52 were thus isolated in much higher yields even when the reaction was performed on 3.5 mmol scale (entry 5).  Entry Conditions Yielda (%) 4.51 4.52 1 MesCOCl (3.0 equiv), Pyridine (excess), CH2Cl2 C to RT 14 -b 2c MesCO2H (2.5 equiv), EDCI (2.5 equiv), DMAP (2.5 equiv), CH2Cl2, RT 18 13 3c MesCO2H (2.5 equiv), EDCI (2.5 equiv), DMAP (2.5 equiv), CH2Cl2,  52 47 4d MesCO2H (2.5 equiv), EDCI (2.5 equiv), DMAP (2.5 equiv), CH2Cl2,  5 6 5e MesCO2H (2.5 equiv), EDCI (2.5 equiv), HOBt (2.5 equiv), DMF, RT 53 57 aIsolated yields after column chromatography. bComplex reaction mixture was obtained with no desired compound seen in crude NMR. cReactions were done on 0.1 mmol scale. dReactions were done on 1.0 mmol scale. eReactions were done on 3.5 mmol scale. Table 4.9 Optimization of conditions for the acylation of amines 4.51-4.52 The structure of iodide 4.52 was confirmed via X-ray analysis of crystals grown via slow evaporation of an ethanolic solution (Figure 4.9).  79   Figure 4.9 X-ray structure of iodide 4.52 Compounds 4.51 and 4.52 were then evaluated for the enantioselective oxidative dearomatization of 4.1a. Catalyst 4.51 proved no better than Ishihara’s iodide 4.20 (Table 4.10, entry 1); however, the bulkier 4.52 provided significantly higher ee (66%), although yields remained around 20% (entry 2). Lowering the catalyst load from 40 mol% to 20 mol% had no effect on selectivity and yield (entry 3). However, a catalyst load lower than 20 mol% resulted in longer reaction times and formation of several side products (TLC), thereby diminishing the yield of desired 4.2a.  Entry Precatalyst Time (h) Yieldb (%) eec (%) 1 4.51 12  17 35 2 4.52 13.5  21 66 3 4.52d 15.5  20 67 aPrecatalyst (40 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cEnantiomeric excess of the product were determined using chiral SFC. d20 mol% of the precatalyst was used.  80   Table 4.10 Precatalyst screening with iodides 4.51 and 4.52 It is worthy of note that Ishihara iodide 4.20 and the new catalysts afforded an opposite sense of asymmetric induction: spiropyrrolidine 4.2a obtained by the use of 4.20 was levorotatory; that prepared in the presence of 4.51-4.52 exhibited positive rotation. Either racemic or enantioenriched 4.2a was nicely crystalline. This induced us to determine the absolute configuration of either enantiomer by X-ray diffractometry. A single recrystallization of material of 67% ee (Table 4.10, entry 3) from toluene-hexane afforded product of 96% ee. A single crystal of this compound was grown via the vapor diffusion technique, again using toluene/hexane as solvent pair. An X-ray diffractometric study revealed that the compound was of (R)-configuration (Figure 4.10).  Figure 4.10 X-ray structure of (+)-(R)-4.2a  81  In a like manner, a single crystallization of material obtained using Ishihara’s iodide 4.20 increased the ee from 46% to 88%. A single crystal grown as detailed above enabled a structural study by X-ray analysis, which confirmed that the compound was (-)-(S)-4.2a (Figure 4.11).  Figure 4.11 X-ray structure of (-)-(S)-4.2a 4.3.6 Oxidative cyclization of para-substituted 1-naphtholic sulfonamides Our apparent inability to achieve yields of 4.2a above 20% induced us to determine the nature of at least some of the side products formed in the course of the reaction, with the hope that pertinent information may assist us to devise a way to contain their formation. The major side product was identified as compound 4.53 (27% yield), which had obviously arisen through a bimolecular oxidative addition of MCBA to 4.1a. The fact that 4.45 was enantioenriched to an ee of 80% was noteworthy, in that virtually all known asymmetric dearomatization reactions promoted by chiral hypervalent iodine reagents are intramolecular. An exception is the Quideau-Birman ortho-hydroxylative dearomatization of phenols.[75-77] Yet, there seems to be no literature precedent for asymmetric bimolecular oxidative acyloxylation of phenolic or naphtholic substrates. Once again, an opposite sense of asymmetric induction was observed for catalyst 4.52 (generation of (+)-4.53) relative to Ishihara iodide 4.20 (formation of (-)-4.53). However, the absolute configuration of 4.53 remains to be determined. Further aspects of this novel oxidative  82  acyloxylation reaction, along with details of how the enantiomeric excess of 4.53 was determined, are discussed in Section 4.3.10.  Figure 4.12 Side products formed during oxidative amidation of 4.1a The second more significant by product was para-naphthoquinone 4.3 (Figure 4.12, 20-35%). The undesired formation of this material could arguably be contained / suppressed by the use of appropriately para-substituted substrates. Interestingly, most reported examples of oxidative cyclization of naphtholic acids employed substrates carrying a 4-substituent; often, a chlorine atom.[69-72],[74] In retrospect, this may be attributable to an effort to suppress naphthoquinone formation, even though the reason was not expressly mentioned. Regardless, the next phase of this research focused on the oxidative cyclization of 4-substituted naphtholic sulfonamides. Table 4.11 shows the results of a comparative study of the performance of catalyst 4.20 and 4.52 in oxidative cyclization of sulfonamides 4.1. In all cases, the acyloxylated adduct 4.54 was formed along with cyclized product 4.2. Entries 1 and 2 serve as a reminder that precatalyst 4.52 provided superior ee (67%) compared to Ishihara’s iodide 4.20 (46%). Doubling the loading of 4.52 had no effect on the ee of both cyclic product and MCBA adduct (entry 3). Hence, all other experiments were carried out using 20 mol% of chiral iodide.    83  As expected, the 4-substituent suppressed formation of quinone 4.3. Yields of cyclized products were generally higher relative to 4.2, but the ee’s were lower. The behavior of the 4-bromo substrate is representative: the yield of cyclized product nearly doubled, but the ee dropped from 67% to 17% (entries 4 and 5). However, the acyloxylated product 4.54, R = Br was still obtained in significantly enantioenriched form. Asymmetric induction was consistently better for acyloxylated adducts 4.54 than for the cyclic products 4.2. Yet, just as in the case of the cyclic products, 4-substitution was not beneficial to asymmetric induction. A 4-Br substituent caused a greater extent of ee erosion relative to a 4-Cl group (entries 4-7). Overall, precatalyst 4.52 provided a generally better extent of asymmetric induction relative to Ishihara iodide 4.20, except in the case of 4-chloro naphtholic sulfonamides 4.1, R = Cl (entries 6 and 7). Aryl substitution at the para position afforded spirosulfonamides with inferior ee’s (entries 8-15).  While corresponding acyloxylated products were still present in reaction mixtures arising from these substrates, their isolation proved to be quite problematic. Therefore, no yield and ee data are reported for these materials (entries 8-15) because of our inability to produce pure samples.     84   Entry Precatalyst R Time (h) Selectivity Yieldb (%) eec (%) 4.2 4.54 4.2 4.54 4.2 4.54 1 4.20 H 14.5 (-)-(S) (-)e 20 27 46 64 2 4.52 H 15.5 (+)-(R) (+)e 20 25 67 80 3 4.52d H 13.5 (+)-(R) (+)e 21 28 66 80 4 4.20 Br 12 (-)e (-)e 45 28 17 50 5 4.52 Br 13 (+)e (+)e 35 21 17 62 6 4.20 Cl 19 (-)e (-)e 16 17 37 59 7 4.52 Cl 26 (+)e (+)e 20 19 30 72 8 4.20 Ph 15.5 (-)e - 30 - 18 - 9 4.52 Ph 21 (+)e - 31 - 24 - 10 4.20 4-F-C6H4 15 (-)e - 25 - 24 - 11 4.52 4-F-C6H4 26 (+)e - 27 - 29 - 12 4.20 4-CF3-C6H4 15.5 (-)e - 22 - 20 - 13 4.52 4-CF3-C6H4 25.5 (+)e - 23 - 28 - 14 4.20 4-(3,5-di-CF3-C6H3) 14.5 (-)e - 15 - 14 - 15 4.52 4-(3,5-di-CF3-C6H3) 26 (+)e - 18 - 39 - aPrecatalyst (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cDetermined by chiral SFC. d40 mol% of precatalyst was used. eAbsolute configuration was not determined.   Table 4.11 Oxidative cyclization and acyloxylation of 4-substituted naphtholic methane sulfonamides     85  4.3.7 Enantioselective oxidative amidation of 2-napththolic sulfonamides The above results encouraged us briefly to examine the enantioselective cyclization of 2-naphtholic sulfonamide. Only two substrates of structure 4.4, wherein R = H or OMe, were examined (Table 4.12), because it was immediately apparent that the reaction was less efficient in the 2-naphtholic series. For instance, the oxidative cyclization of 4.4a, in the presence of catalyst 4.52 and under the same conditions developed for reaction of 1-naptholic substrates afforded a complex mixture containing only 15% of desired 4.5a. This material was formed in only 16% ee (entry 1). Iodide 4.20 provided better results in this case (22% yield of 4.5a, 36% ee; entry 2). A single recrystallization from EtOAc / hexanes increased the ee of the product to 47% (entry 2).   Entry Precatalyst Product Time (h) Yieldb (%) eec (%) 1 4.52 4.5a (R = H) 14 15 16 2 4.20 4.5a (R = H) 14.5 22 36(47)e  3 4.14d 4.5a (R = H) 12 26 24 4 4.20d 4.5b (R = OMe) 12 22 30 5 4.14d 4.5b (R = OMe) 36 21 47(96)e,f aPrecatalyst (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bIsolated yields after column chromatography. cDetermined by chiral SFC. d40 mol% precatalyst was used. eee after single crystallization. fee was determined by chiral HPLC.  Table 4.12 Oxidative cyclization of 2-naphtholic sulfonamides  86   Surprisingly, iodide 4.14 performed rather well in this case, except that reaction rates were especially slow at 20 mol% catalyst load. A faster rate was achieved through the use of 40 mol% of catalyst, but with no significant effect on yield and ee (entry 3). Because 4.14 performed better than 4.52 in terms of both ee and yield, the cyclization of 4.4b was carried out only with catalysts 4.14 and 4.20. Yields remained around 20%, but iodide 4.14 afforded the highest product ee (47%; entry 5). Formation of MCBA adduct could not be confirmed via 1H NMR of crude due to its complex nature. Moreover, mass spectrometry of crude sample and attempts to purify the reaction mixture did not give any indication of MCBA adduct formation. The enantiomeric excess of 4.5b increased from 47% to 96% upon a single recrystallization from methanol (slow evaporation of a solution), enabling a determination of the absolute configuration by X-ray diffractometry. The compound, which was dextrorotatory, was found to be of (R)-configuration (Figure 4.13).   Figure 4.13 X-ray structure of (+)-(R)-4.5b    87  4.3.8 Attempted enantioselective cyclization of acyl sulfonamides Conditions optimized for enantioselective oxidative amidation of naphtholic sulfonamides were applied to naphtholic acyl sulfonamide 4.8a (Scheme 4.13). The resulting spirolactam 4.9a could serve as the core of Ansalactam A. Unfortunately, complex product mixtures were obtained when 4.8a was subjected to enantioselective cyclization using iodide 4.20. Comparison of the 1H NMR spectra of such crude mixtures with that of authentic (±)-4.9a suggested that none of it had formed. Therefore, no attempts were made to purify the crude mixture, to optimize the reaction, or to examine the cyclization of other related substrates.  Scheme 4.13 Enantioselective oxidative amidation of acyl sulfonamide 4.8a 4.3.9 Enantioenriched 4.2a by flow resolution of the racemate It will be recalled from Section 4.3 that the preparation of spiropyrrolidine 4.2a is especially problematic because of concomitant formation of naphthoquinone 4.3 and MCBA adduct 4.53. Yet, 4.2a itself and congeners bearing substituents on the benzene ring, but not at the ketone 4-position 4.56, appear to be valuable building blocks in alkaloid synthesis (Scheme 4.14). For instance, cephalotaxine 4.55 (Cephalotaxus alkaloid) may be prepared from spiropyrrolidine 4.56 which can be produced via oxidative dearomatization of corresponding naphtholic sulfonamide 4.57 (Scheme 4.14). Moreover, chiral spiropyrrolidine would provide chiral cephalotaxine.  88   Scheme 4.14 Possible synthesis of cephalotaxine This provided an incentive to explore the preparation of enantiopure 4.2a, on scale, by methods other than solely asymmetric synthesis. An interesting solution emerged thanks to a collaborative effort with our colleague, Prof. Jason Hein. Prof. Hein and Dr. Rougeot from Hein group found that racemic 4.2a, crystallizes as a conglomerate. In a conglomerate, homochiral interactions, i.e., the energy of association of between molecules of identical chirality (R-R or S-S), is stronger than that of heterochiral (R-S) interactions.[111] Thus, for a conglomerate forming compound, the racemic mixture is composed of a mechanical mixture of two discrete homochiral crystals, each crystal comprising only one of the two enantiomers. This contrasts with the case of a true racemic crystal, which constitutes a heterochiral crystal phase, containing both enantiomers in the repeating unit cell of the crystal (Figure 4.14).  Figure 4.14 Crystal packing of a racemic solid: conglomerate (right) vs. racemic (left)  89  The physical properties of a conglomerate are such that the solubility of homochiral crystals is lower than that of heterochiral ones.[112] This enables efficient enantiomeric enrichment by recrystallization: the enantiomer present in excess tends to crystallize, leaving racemic material in the mother liquor. This is indeed what was observed with scalemic mixture of 4.2a (46% ee). The experiment for resolution of (±)-4.2a via Coupled Preferential Crystallization (CPC) was performed by Prof. Hein using the following procedure. A satd. solution of (±)-4.2a was prepared by suspending 80 mg of (±)-4.2a in toluene (~ 1.5 mL) and stirred overnight at 20 °C. The clear filtrate (satd. solution) obtained after filtering the suspended solution (~1.3 mL) was added to vial A of the EasyMax (T= 20 °C) (Figure 4.15). Vial A was then charged with 20 mg of (±)-4.2a (solid) and Vial B was charged with super satd. solution of (-)-4.2a (~30 mg, 0.5 mL, 46% ee). Both vials were stirred at 250 RPM for 30 minutes, keeping the internal temperature constant at 20 °C. Vials A and B were then connected to two separate Ismatec REGLO-CPF  Digital pumps using Teflon® PFA tubing (1/16 OD) fitted on the uptake with a fritted PTFE-filter (0.5 μm porosity). The filtered solution phase was circulated between the two flasks at 1.0 mL/min. After 30 minutes of stirring, temperature of the vial B was slowly decreased to 18 °C. During the crystallization process, the racemic liquid phase was circulated on the average of 1.0 mL/min for 24 hours. Solid phases from vial A and vial B were filtered to produce (-)-(S)-4.2a and (+)-(R)-4.2a in high optical purity (>98% ee by HPLC). This experiment was done only once and needs to be repeated on large scale in order to reproduce the resolution of 4.2a via CPC technique.   90   Figure 4.15 Schematic of a two-vial CPC experiment for resolution of (±)-4.2a to result both enantiomers, (R) and (S), in high optical purity     91  4.3.10 Aspects of the enantioselective acyloxylation reaction The novelty of the bimolecular acyloxylation reaction leading to enantioenriched products 4.54 kindled our interest in exploring this reaction further. Recall that the transformation was discovered during a study of the oxidative cyclization of methanesulfonamide 4.1a (Section 4.3.6). This led to the hypothesis that replacement of the methanesulfonyl group with a bulkier one might disfavor spiropyrrolidine formation and encourage that of the acycloxylated product. Accordingly, sulfonamides 4.1i, 4.1b and 4.1g were subjected to the action of MCPBA in the presence of Ishihara catalyst 4.20 (Scheme 4.15). This resulted largely in formation of naphthoquinone 4.59 (NMR). Insignificant amount of 4.58 were apparent from the 1H NMR spectra of crude reaction mixture, and no signals attributable to MCBA adduct 4.60 were detectable.    Scheme 4.15 Oxidative cyclization and acyloxylation of 4-unsubstituted naphtholic sulfonamides No attempts were made to isolate either 4.58 or 4.59. Instead, the same reaction was studied with a series of 4-bromo naphtholic sulfonamides, which had already been proven to resist naphthoquinone formation. Preliminary investigations revealed that the formation of acyloxylated products could be favored by running the reaction in the presence of added MCBA.   92  This resulted in higher yields, but ee’s were largely unaffected. However, ee’s were generally lower in the 4-bromo series relative to the unsubstituted case (80% ee; entries 2 and 3, Table 4.11). In any event, all but one (entry 1) of the experiments summarized in Table 4.13 were run in the presence of 2 equivalents of MCBA.  As evident from the Table, each sulfonamide afforded a mixture of enantioenriched spiropyrrolidine 4.2 and acyloxylated product 4.54. Substrates incorporating a bulky sulfonamide such a benzyl, tolyl, or nitrophenyl one, reacted to form a greater proportion of 4.54 at the expenses of spiropyrrolidine 4.2. The ee’s of spirocyclic compounds remained low in most cases (entries 2, 3 and 8-11). Unexpectedly, the trifluoroethyl sulfonamide reacted with a significant degree of asymmetric induction both as far as the cyclic product (44% ee) and the MCPBA adduct (74% ee) are concerned (entry 6). That product 4.54 was formed in higher ee relative to 4.2 is not unique to the trifluoroethyl sulfonamide: all substrates yet tested behaved in the same manner. Mechanistic implications of this observation are discussed in Section 4.3.11.   The same reaction provided only trace of cyclic product when iodide 4.52 was used. Hence, the ee of the same is not reported (entry 7). Overall, the performance of iodide 4.20 was better than 4.52 in terms of chemoselectivity in favor of 4.54. As far as asymmetric induction goes, no clear trends are apparent: some substrates afforded higher ee’s with 4.20 (entries 6-7), others with 4.52 (10-11), other still produced comparable results with either catalyst.    93   Entry Precatalyst R Time (h) Selectivity Yieldb eec (%) 4.60 4.61 4.60 4.61 4.60 4.61 1 4.52d Me 13 (+) (+) 35 21 17e 62e 2 4.20 Me 11 (-) (-) 22 33 22 62 3 4.52 Me 12 (+) (+) 31 28 24 58 4 4.20 Bn  11 (-) (-) 28 41 -f 54 5 4.52 Bn  12.5 (+) (+) 24 29 -f 60 6 4.20 CH2CF3  10.5 (-) (-) 16 37 44 74 7 4.52 CH2CF3  11 - (+) -g 28 - 60 8 4.20 4-Tol  11 (+) (-) 25 31 23 62 9 4.52 4-Tol  12.5 (-) (+) 22 30 26 65 10 4.20 4-NO2-C6H4 10.5 (-) (-) 18 37 37h 55h 11 4.52 4-NO2-C6H4 18 (+) (+) 13 24 11h 68h aPrecatalyst (20 mol%), MCPBA (1.3 equiv), MCBA (2.0 equiv) -20 °C, CH2Cl2 (0.02M). bYields after column chromatography. cDetermined by chiral HPLC. dNo extra MCBA was added. eDetermined by chiral SFC. fThe ee could not be determined because the enantiomers were inseparable by chiral HPLC. gTrace amount of product was obtained. hee were determined by synthesizing corresponding diastereomer using (1S)-(+)-camphorsulfonyl chloride.     Table 4.13 Oxidative cyclization and acyloxylation of 4-bromo substrates with added MCBA Enantiomeric excesses were mostly determined by comparison / integration of the chiral HPLC traces of racemic and enantioenriched products. In all but three cases, separation of enantiomeric products was achieved. The synthesis of racemic spiropyrrolidines 4.2 has already been discussed (Table 4.2). Racemic MCBA adducts were prepared in a similar manner. Thus, reaction of sulfonamides 4.1 with a stoichiometric amount of iodobenzene (in place of 20 mol% of chiral iodide), MCBA and MCPBA afforded racemic products 4.54 in low to moderate yields  94  (Table 4.14). Once again, methanesulfonamides generated the desired products in lower yield (entries 1, 2 and 3) relative to more sterically demanding sulfonamides (entries 4-7).  Entry R1 R Product Yieldb 1 H Me 4.54a 22 2 Br Me 4.54b 24 3 Cl Me 4.54c 17 4 Br Bn 4.54d 43 5 Br CF3CH2 4.54e 42 6 Br C6H4-Me-p 4.54f 36 7 Br C6H4-NO2-p 4.54g 39 aPhI (1.1 equiv), MCPBA (1.3 equiv), MCBA (2.0 equiv), CH2Cl2 (0.02 M), RT. bIsolated yields after column chromatography. Table 4.14 Acyloxylation of 1-naphtholic sulfonamides The enantiomers of cyclic compounds 4.2h, R = Bn or 4.2e, R = 4-NO2-C6H4, and acyloxylated adduct 4.54g, R = 4-NO2-C6H4 (Table 4.13) were inseparable by chiral HPLC. The enantiomeric ratio of these products was then determined as follows. The 4-nitrosulfonamido group in spirocycle 4.2e was removed by reaction with sodium thiophenoxide.[95] Subsequent reaction of free amine 4.61 with (1S)-(+)-camphorsulfonyl chloride 4.62 generated 4.63 as a mixture of diastereomers (Scheme 4.16). The diastereomeric ratio of camphorsulfonamides 4.63 was determined by integration of the 1H NMR spectrum of the crude reaction mixture, enabling a calculation of the ee of 4.63 and consequently of 4.2e.  95   Scheme 4.16 Determination of ee of 4.2e Similarly, acyloxylated product 4.54g was derivatized to a mixture of diastereoemers of (1S)-(+)-camphorsulfonylimides 4.64, and the ee of 4.64, and consequently of 4.54g, was calculated by integration of 1H NMR spectra (Scheme 4.17).  Scheme 4.17 Determination of ee of 4.54g via derivatization We conclude this section by pointing out that the sulfonamido group is not required for the acyloxylation reaction, as apparent from results obtained with control substrate 4.67, prepared by hydrogenation of 4.65 followed by para-bromination (Scheme 4.18).    Scheme 4.18 Synthesis of 2-propyl naphtholic substrate 4.67  96  When 4.67 was subjected to the reaction condition developed earlier (Table 4.13) for acyloxylation, the MCBA adduct 4.68 was obtained in 47% yield (Scheme 4.19). The specific optical rotation of the product was low {[α]25D = +8.2° (c 1.86, CHCl3)}. It remains unclear whether this corresponds to a low ee, since the enantiomeric enrichment of 4.68 could not be determined because of technical difficulties. For instance, the compound seemingly decomposed during chiral HPLC analysis, as suggested by the appearance of several peaks in the chromatogram. Moreover, the chiral shift reagent Eu(hfc)3 failed to produce desired splitting pattern of 4.68 for ee determination via 1H NMR.  Scheme 4.19 Acyloxylation of control substrate 4.67 4.3.11 Mechanistic aspects for acyloxylation reaction A naïve mechanism for the acyloxylation reaction may be envisioned as outlined in Scheme 4.20. Oxidation of chiral iodoarene 4.69 to the iodoso state (4.70) by MCPBA necessarily generates MCBA. Combination of substrate 4.1 with 4.70 produces 4.71, wherein R’ may be H, or 3-chlorobenzoyl, or even a second phenoxy ligand derived from the substrate.  Nucleophilic fragmentation of 4.71 by an intramolecular pathway orchestrated by the  97  sulfonamide (pathway a) produces spiropyrrolidine 4.2. Alternatively, a bimolecular reaction of complex 4.71 with MCBA leads to adduct 4.54 (pathway b).  Scheme 4.20 Possible mechanism for the formation of the acyloxylated product Plausible as it might be, such a mechanistic picture suffers from two major shortcomings. First, in many cases, the reaction produces a greater proportion of MCBA adduct relative to spiropyrrolidine, implying that the rate of the bimolecular pathway b is faster than that of the intramolecular one, a. Second, the ee of acyloxylated products is generally higher than that of spiropyrrolidines, implying that the bimolecular reaction occurs with a greater degree of diastereofacial selectivity relative to the intramolecular one. Either phenomenon seems improbable. That both operate simultaneously is even less likely. An alternative interpretation is as follows. The iodoso form of the chiral catalyst could combine with one molecule of substrate and one of MCBA to afford 4.72 (Scheme 4.21). It is well established that 3 iodanes undergo fast pseudorotation.[113],[114] Complex 4.72 could thus exist in rapid equilibrium with stereoisomer 4.73.    98   Scheme 4.21 Possible equilibrium between 4.72 and 4.73 While 4.72 appears to be liable only to nucleophilic fragmentation leading to a spiropyrrolidine, complex 4.73 can fragment by two competing intramolecular pathways: one leading to a spiropyrrolidine (a), the other, to the acyloxylated product (b; Scheme 4.22). Although it seems that aryl group bearing chiral motif 4.72 is more stable in equatorial position for the ground state, major product 4.54 is formed via reductive elimination of less stable isomer 4.73. This is presumably due to trans to cis (4.72  4.73) isomerisation, wherein the eliminating ligands are cis to each other and the transition state leading to MCBA 4.54 adduct from 4.73 is more stable compared to 4.72. Overall, the process appeared to be controlled by transition state and not ground state.  99   Scheme 4.22 Possible mechanism for the formation of acyloxylated adduct The above hypothesis is consistent with additional aspects of the asymmetric cyclization of naphtholic carboxylic acids, sulfonamides (this chapter), and alcohols (chapter 5).  Details will be discussed at the end of Chapter 5.  4.4 Summary and conclusion We have demonstrated the DIB-mediated oxidative cyclization of 1-naphtholic sulfonamides in the racemic series: a reaction that could be useful for the assembly of the core structure of the natural product, ansalactam A. An enantioselective version of the methodology that relies on the use of chiral iodoarene catalysts in the presence of MCPBA as the stoichiometric oxidant has been devised. The reaction can be been extended to 2-naphtholic sulfonamides, which, however, seem to react less efficiently.   New chiral iodides were designed and evaluated in an effort to maximize yields and ee’s of the products. Yet, the simultaneous attainment of high yields and high enantioselectivities  100  remains elusive, because solvents that afford high yields (TFA, etc.) promote the formation of racemic products, while solvents that promote asymmetric induction afford low yields.   The enantioselective reaction is highly sensitive to presence of Bronsted or Lewis acids, which completely suppress asymmetric induction. This is likely to be due to premature dissociation of the reactive complex formed upon combination of the substrate with the hypervalent form of the catalyst. This releases a cationic form of the substrate, which then cyclizes in an achiral environment, leading to racemic spiropyrrolidines.   A noteworthy side reaction discovered in the course of these studies is the asymmetric oxidative addition of meta-chlorobenzoic acid to the substrates. The resulting acyloxylated products were formed along with aza-spirocyclic compounds. The acyloxylation reaction often occurred with a greater degree of asymmetric induction compared to spirocyclization.  Furthermore, it was found to be more tolerant of substitutions in the naphthalene ring relative to the cyclization process. Addition of extra MCBA (2.0 equiv) led to slight improvement in the yield of acyloxylated adduct without affecting the enantioselectivity. The problem of poor to moderate ee’s for at least one aza-spirocyclic compound (4.2a) was circumvented upon the discovery that the racemic material crystallizes as a conglomerate. This enabled the development of a resolution method based on continuous preferential crystallization (CPC) in collaboration with Prof. J. Hein, of this Department. It is noted that CPC provides access to both enantiomers of a compound in excellent optical purity and nearly complete mass recovery. Thus, a sample of 4.2a, of 96% ee was secured after a single recrystallization of material prepared by enantioselective cyclization. This small sample (some mg) served as a seed crystal for the CPC resolution of a much larger quantity (several grams) of  101  racemic substance, which is readily prepared as described at the beginning of this chapter. Optimization of CPC technology is still in progress in the laboratory of Prof. Hein.    102  Chapter 5: Oxidative cyclization of naphtholic alcohols with iodine(III) reagents 5.1 Oxidative cyclization of naphtholic alcohols in the racemic series Similarities between the reactivity of sulfonamides and alcohols (Scheme 2.9-2.10) induced us to study the enantioselective oxidative cyclization of 1-naphtholic alcohols. As explained in Chapter 2 (Scheme 2.16-2.17), the reaction was known only in the racemic series at the beginning of this research. Moreover, it had never been accomplished with hypervalent iodine oxidants (Scheme 2.15). Therefore, our initial objective was to ascertain whether it could be carried out with such reagents. Alcohol 5.1a was selected as a test substrate to prevent quinone formation. Its oxidative cyclization was attempted with DIB or Ph-I / MCPBA in TFE, neat CH2Cl2, and CH2Cl2 containing TFA. Based on the experience accumulated during work with sulfonamides, we predicted that TFE was likely to be a better solvent for the racemic series, but that the asymmetric reaction would have to be carried out in CH2Cl2 to minimize dissociation of the reactive complex formed upon combination of the substrate with the hypervalent iodine species. Indeed, racemic 5.2a was obtained in moderate yield in all cases, but higher yields were observed when TFE was used as the solvent (Table 5.1). Notice that the conditions of entry 3 are identical to those employed for the asymmetric oxidative cyclization of sulfonamides, except for the nature of the aryl iodide. Notice also that the yield of spiroether 5.2a (40%) was double that of the corresponding spiro-methanesulfonamide (ca. 20%; Ch. 4, Table 4.1).  103   Entry Conditions Yielda 1 DIB (1.1 equiv), TFE (0.02 M), RT 51 2 DIB (1.1 equiv), TFA (2.0 equiv), CH2Cl2 (0.02 M), RT 30 3 PhI (1.0 equiv), MCPBA (1.3 equiv), CH2Cl2 (0.02 M), RT 40 aIsolated yields after column chromatography. Table 5.1 Oxidative cyclization of 5.1a in various solvents A number of racemic spiroethers were thus prepared by cyclization of 1-naphtholic alcohols in CH2Cl2, under conditions analogous to those that would be later employed for the asymmetric reaction. Pertinent results are summarized in Scheme 5.2. The yields of desired products were often around 40-50%, but poorer results were observed with a number of substrates. The reaction of 5.1q (R = C(O)Me), was quite inefficient, affording a complex mixture of products containing less than 5% of 5.2q as seen in crude 1H NMR. No desired spiroether 5.2q was isolated when this complex mixture was subjected to purification via column chromatography of the complex mixture. Oxidative cyclization with stoichiometric DIB in CH2Cl2 was equally poor (< 10% yield according to 1H NMR of crude), probably because of the low solubility of the reagent in CH2Cl2.  104   aPhI (1.0 equiv), MCPBA (1.3 equiv), CH2Cl2 (0.02 M), RT. bIsolated yields after column chromatography. cApproximate yield according to 1H NMR of crude reaction mixture. Scheme 5.1 Oxidative cyclization of 1-naphtholic alcohols with Ph-I / MCPBA in CH2Cl2 Much better results were obtained with stoichiometric PIFA in CH2Cl2, which gave the desired ( )-5.2q in 38% yield. This is shown in Scheme 5.2, which also tabulates further examples of the PIFA-mediated reaction.  105   a PIFA (1.1 equiv), CH2Cl2 (0.02 M), RT. bIsolated yields after column chromatography. Scheme 5.2 Oxidative cyclization of 1-naphtholic alcohols with PIFA in CH2Cl2 The oxidative cyclization of tertiary alcohol substrate 5.1x in the presence of PIFA was also efficient (67% yield, Scheme 5.3).  Scheme 5.3 Oxidative cyclization of substrate 5.1x As discussed earlier (Scheme 1.40 and 1.42), dienones arising upon ortho-oxidative dearomatization of phenolic substrates are quite prone to undergo Diels-Alder dimerization. Indeed, an attempt to obtain compound 5.4 by reaction of 5.3 with PIFA gave only dimer 5.5 (25% yield, Scheme 5.4), the structure of which was subsequently ascertained by X-ray diffractometry (Figure 5.9).   106   Scheme 5.4 Formation of cycloadduct (±)-5.5 It is noted that product (±)-5.5 was obtained in a highly diastereoselective manner through Diels-Alder dimerization of two dienones of identical configuration. This reflects the tendency of a spiroether of, e.g., (R) configuration to react with another (R)-molecule (homodimerization), instead of an (S)-one (heterodimerization). Considering that the product results through an endo-[4+2]-cycloaddition proceeding with topology 5.7 (Figure 5.1), the homodimerization pathway appears to be favored on steric grounds. In fact, transition state model 5.7 suffers from a nonbonding interaction between the oxygen atoms of the tetrahydrofuran ring. In contrast, a more severe nonbonding interaction subsists between an O atom and a more sterically demanding CH2 group in endo-[4+2]-heterodimerization transition state model 5.6.  Figure 5.1 Trasition state model for heterodimerization of dienone (±)-5.4   107  These results demonstrated that the oxidative cycloetherification of naphtholic alcohols may indeed be carried out by the use of iodine(III) reagents, albeit in generally moderate yields. This laid the foundation for the development of an asymmetric variant of the process. 5.2 Asymmetric oxidative cyclization of naphtholic alcohols: catalyst screening Preliminary experiments directed toward ascertaining the feasibility of an asymmetric variant of the reaction centered on the use of Ishihara iodide 4.20 under the conditions developed earlier for sulfonamides.[70] Accordingly, test substrate 5.1l was treated with 20 mol% of chiral iodoarene 4.20 and 1.3 equivalents of MCPBA in CH2Cl2 solution at -20 °C (Scheme 5.5). The desired spiroether 5.2l did form, but it was accompanied by several side products, the major one, not unexpectedly, being naphthoquinone 5.9, the yield of which approached 30%. Subsequent experiments were therefore carried out with the 4-chloro analog of 5.1l (vide infra).  Scheme 5.5 Side reactions when unsubstituted naphthol substrate 5.1l was used A second byproduct was epoxide 5.10, which was isolated as a single diastereomer by column chromatography. However, the quantities of 5.10 produced during the reaction were so small (ca. 5% yield) that the possible presence of a diastereomer in crude product mixtures could  108  neither be ascertained nor excluded (1H NMR). Furthermore, NOE correlations were not helpful in determining the product’s relative configuration, which remains undefined. A comparison of the relative effectiveness of iodides 4.20 and 4.52 in the oxidative cyclization of 5.1l under various conditions revealed that 4.52 retained efficacy, as far as ee’s are concerned, even at RT and 5 mol% catalyst loading (Table 5.2, entry 6). However, yields dropped significantly under the latter conditions, and much 5.1l was lost to formation of naphthaquinone 5.9 and epoxide 5.10.   Entry Precatalyst (mol%) C) Time (h) 4.52 (4.20) eeb 4.52 (4.20) (%) Yieldc 4.52 (4.20) (%) 1 20 -20 21 (12) 93 (93) 67 (61) 2 20 RT 3.5 (2.5) 93 (86) 45 (43) 3 10 -20 20.5 (16) 96 (90) 50 (46) 4 10 0 9.0 (5.5) 93 (89) 46 (42) 5 10 RT 6.5 (4.5) 92 (86) 41 (30) 6 5 RT 8.5 (7.0) 89 (82) 35 (23) aPrecatalyst, MCPBA (1.3 equiv), T °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields.  Table 5.2 Relative efficiency of precatalyst 4.52 and 4.20 in the cyclization of 5.1l In contrast to the case of 5.1l, the oxidative cyclization of alcohol 5.1a in the presence of iodide 4.20 proceeded quite well and afforded 5.2a in 65% yield and 90% ee (Scheme 5.6).  109   Scheme 5.6 Oxidative cyclization of 5.1a in the presence of iodide 4.20 Other Ishihara-type iodides produced results that nicely reflect trends observed earlier with naphtholic sulfonamides, except that chemical yields and ee’s were generally higher in the alcohol series (Table 5.3). As before, none of the alternative catalysts was better than 4.20 (entry 1). Diester 4.14 and diacid 4.15 afforded spiroether 5.2a in low yield and optical purity (entries 2 and 3). N-Mesitylamide 4.16 performed reasonably well (entry 4), but amides 4.21 and 4.23 were less efficient (entries 5 and 6), and tosylamide 4.22 was significantly poorer (entry 7).  Entry Catalyst Time (h) ee (%)b Yield (%)c 1 4.20 15 90 65 2 4.14  42 13 27 3 4.15 18 29 51 4 4.16 32 65 62 5 4.23 33 74 60 6 4.21 36 64 52 7 4.22  37 27 46 aPrecatalyst (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields.  110   Table 5.3 Catalyst screening As far as asymmetric induction is concerned, the new iodides 4.51 and 4.52, proved to be as efficient as 4.20 (Table 5.4). However, it was pleasing to discover that catalyst 4.52 afforded distinctively better yields than 4.20 (entry 2). This provided an incentive to launch a screen of reaction conditions aiming to improve efficiency even further.  Entry Precatalyst  Time (h) eeb (%) Yieldc (%) 1 4.51 12.5 90 66 2 4.52 25 93 79 aPrecatalyst (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02M). bDetermined by chiral SFC. cIsolated yields.  Table 5.4 Performance of newly designed iodoarenes in the spiroetherification reaction  111  5.2.1 Screening of alternative reaction conditions A rapid screen of alternative conditions served only to confirm that the protocol devised earlier for sulfonamides were optimal in the case of alcohols as well. Thus, varying solvent, catalyst loading, temperature and concentration led to generally less satisfactory results (Table 5.5). Both ee and yield of 5.2a remained unchanged when catalyst loading was increased from 20 to 30 mol% (Table 5.5, entry 1), but a reduction in the amount of 4.52 translated into longer reaction times and a significant drop in yields and asymmetric induction (entries 5, 7 and 8).   Entry Precatalyst (x mol%) Conditions eeb (%) Yieldc (%) 1 4.52 (30) MCPBA, CH2Cl2, -20 °C, 12.5 h 92 78 2 4.52 (20) MCPBA, CHCl3, -20 °C, 26 h 93 61 3 4.52 (20) MCPBA, CH3NO2, -20 °C, 29 h 58 46 4 4.52 (20) MCPBA, CH2Cl2, MeOH (10.0 equiv.), -20 °C, 42 h 77 45 5 4.52 (15) MCPBA, CH2Cl2, -20 °C, 38 h 92 58 6 4.52 (15) MCPBA, CH2Cl2 (0.04 M), -20 °C, 33 h 90 51 7 4.52 (10) MCPBA, CH2Cl2, -20 °C, 4.4 d 86 46 8 4.52 (5) MCPBA, CH2Cl2, -20 °C, 8.5 d 82 47 9 4.52 (20) MCPBA, CH2Cl2, 0 °C, 8.5 h 85 63 10 4.52 (20) MCPBA, CH2Cl2, 25 °C, 5.5 h 86 75 11 4.20 (20) MCPBA, CH2Cl2, 25 °C, 4 h 85 64 aPrecatalyst (x mol%), MCPBA (1.3 equiv), -20 °C, Solvent (0.02 M). bDetermined by chiral SFC. cIsolated yields.  Table 5.5 Alternative reaction conditions  112  Less polar solvent like CHCl3 had an adverse effect on yield, but not on ee (entry 2), whereas polar solvent like nitromethane or polar additives such as MeOH negatively affected both (entries 3 and 4). Lower yields were obtained when the concentration of substrate was doubled from 0.02 M to 0.04 M (entry 6). Catalysts 4.52 performed surprisingly well even at RT, better so than 4.20 in terms of yield of 5.2a (entries 10 and 11). However, best results were obtained by operating at -20 °C. At even lower temperatures (-50 °C), the reaction became exceedingly slow and generated a multitude of new side products. No efforts were made to purify the resulting crude reaction mixtures. 5.2.2 Substrate Scope The scope of the reaction with respect to the substrate was probed by examining the spiroetherification of various 4-substituted naphtholic alcohols under the previously optimized conditions. Pertinent results are summarized in Table 5.6. Substituents less electronegative than chlorine at the phenolic para-position of 5.1 afforded products of lower ee (entries 1, 2 and 3). In contrast, electron-withdrawing carbonyl groups at C-4 promoted high enantioselectivity (entries 4-7). Iodide 4.52 performed better than 4.20 with carbonyl-substituted alcohol 5.1p (entries 4 and 5). However, the reaction of the 4-acetyl substrate 5.1q was extremely slow and it generated a complex mixture of products, from which the desired 5.2q was isolated in poor yield (entry 6). The efficiency of the cyclization of substrates bearing a C-4 phenyl group was sensitive to the nature of substituents present on the same. Thus, the expected spiroethers emerged in good yield and high to excellent ee when the phenyl group bore electron-withdrawing substituents (entries 8, 13-17), but lower ee’s were obtained when phenyl group carried electron donating ones (entries 10, 11 and 12). Alcohol 5.1g cyclized equally efficiently in the presence of either 4.52 or 4.20 (entries 8 and 9).  113   Entry Product  Time (h) eeb (%) Yieldc (%) 1 5.2a (R = Cl)  25 93d 79 2 5.2b (R = Br) 27 84 73 3 5.2c (R = Me) 20 76 29 4 5.2p (R = C(O)(4-Tol)) 55 92 41e 5f 5.2p (R = C(O)(4-Tol)) 18  83 36g 6 5.2q (R = C(O)Me) 134 92 15 7 5.2o (R = C(O)Ph) 46 92 42h 8 5.2g (R = 3,5-(CF3)2C6H3) 35 93 47 9f 5.2g (R = 3,5-(CF3)2C6H3) 15 91 46 10 5.2d (R = 4-Ph) 18 80 63i 11 5.2e (R = 4-Tol) 38 75 (98)j 52 12 5.2f (R = 3-MeO-C6H4) 41 69 73 13 5.2r (R = 4-MeC(O)-C6H4) 21 88 75 14 5.2h (R = 4-F-C6H4) 14 83 (90)j 64 15 5.2i (R = 4-NC-C6H4) 38 92 71 16 5.2j (R = 4-MeSO2-C6H4) 13 90 78 17 5.2k (R = 4-CF3-C6H4) 39 90d (98)j 55 aPrecatalyst 4.52 (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields. dAbsolute configuration was found to be R. e50% yield based on RSM (Recovered Starting Material). fReaction was performed using 20 mol% of 4.20 as precatalyst. g41% yield based on RSM. h47% yield based on RSM. i69% yield based on RSM. jee of material remaining in the mother liquor after single recrystallization.    Table 5.6 Substrate scope: 4-substituted naphtholic alcohols  The foregoing observations are in accord with the principle that the substrate must remain firmly anchored to the chiral catalyst for the reaction to proceed with a high degree of  114  asymmetric induction (Ch. 4, Section 4.3.4). To illustrate, nucleophilic fragmentation of complex 5.11 by the mechanism shown in Scheme 5.7 is likely to produce 5.2 with a good degree of asymmetric induction.  Scheme 5.7 Enantiocontrol during nucleophilic fragmentation of complex 5.11 But if 5.11 were to fragment prematurely and liberate cation 5.12, the latter would cyclize to form a racemic spiroether (Scheme 5.8). Clearly, electron-withdrawing substituents R will disfavor fragmentation of 5.11 to 5.12, because they destabilize cationic species. This would promote good enantioselectivity. The opposite is true if electron-donating R groups were present.  Scheme 5.8 Loss of enantiocontrol upon dissociation of complex 5.11 Yields and ee’s for the asymmetric cycloetherification of two 5-substituted naphtholic alcohols of structure 5.1s-t mediated by catalyst 4.52, were very similar to those observed for the  115  5-unsubstituted case, suggesting that substitution at the 5-position has only a minor influence on the outcome of the reaction (Table 5.7).  Entry Product Time (h) eeb (%) Yieldc (%) 1 5.2s (R = H, R’ = Ph)  20 92 43 2 5.2t (R = Cl, R’ = Ph) 17 88 63 aPrecatalyst 4.52 (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields.  Table 5.7 Oxidative cyclization of 5-substituted naphtholic alcohols 5.2.3 Recycling of the catalyst Iodide 4.52 was easily retrieved from reaction mixtures by column chromatography (>90% recovery) and it could be recycled several times with no effect on product yield or ee. Results of the experiment carried out with 4.52 recycled three times appear in Table 5.8.  Cycle Time (h) ee (%)b Yield (%)c Recovered 4.52 (%)c 1d 25 93 79 96 2 29 93 74 90 3 27 92 77 95 4 27 92 78 93  116  aPrecatalyst 4.52 (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields after column chromatography. dFresh precatalyst.  Table 5.8 Cyclization of alcohol 5.1a with recycled precatalyst 4.52 5.2.4 Determination of absolute configuration of spiroethers Several enantioenriched spiroethers obtained during this study were oils; e.g., 5.2a, precluding a determination of absolute configuration by X-ray diffractometry. Among those that were solid, spiroethers 5.2h, R = 4-F-C6H4 and 5.2e, R = 4-Tol, crystallized in a centrosymmetric space group and their absolute configuration could not be determined. Moreover, the absence of heavy atoms caused these crystals to diffract poorly. Thus an X-ray analysis of crystals of 5.2h, R = 4-F-C6H4, and 5.2e, R = 4-Tol, grown in toluene/hexane by the vapor diffusion technique could only ascertain the constitution (Figures 5.2 and 5.3).  Figure 5.2 X-ray structure of 5.2h, R = 4-(4-F-C6H4)   117   Figure 5.3 X-ray structure of 5.2e, R = 4-Tol A derivatization scheme was thus devised to obtain crystalline derivatives suitable for X-ray analysis. Reduction of the ketone (LAH) 5.2a of 93% ee provided a 6.9:1 mixture of diastereomeric alcohols (Scheme 5.9). These were prone to eliminative aromatization back to 5.1a. Some naphthol was already apparent in the 1H NMR spectra of material that had been standing at RT for a few hours, and conversion back to 5.1a was complete in two days.  Accordingly, subsequent operations had to be performed rapidly.   Scheme 5.9 Conversion of 5.13 back to 5.1a The diastereomeric alcohols were readily separated by column chromatography and the major isomer 5.13 was immediately converted into the p-bromobenzoate ester 5.14, which seemed to be considerably more stable than the alcohol (Scheme 5.10). A single recrystallization by slow evaporation of a solution in CH2Cl2 and hexanes at RT afforded material of greater than 99% ee. X-ray diffractometry revealed the absolute configuration of spirocenter to be (R) (Figure 5.4).  118   Scheme 5.10 Derivatization of spiroether 5.13  Figure 5.4 X-ray structure of (-)-(R, R)-5.14 Similarly, p-bromobenzoate ester of 5.2k was synthesized as outlined in Scheme 5.11. It should be noted that 5.15 did not undergo any conversion back into corresponding starting material like 5.13.   Scheme 5.11 Derivatization of spiroether 5.2k  119  A single recrystallization by slow evaporation of a solution in CH2Cl2 and methanol at RT afforded material of 98% ee. X-ray analysis revealed the absolute configuration of spirocenter to be (R) as well (Figure 5.5).  Figure 5.5 X-ray structure of (-)-(R, R)-5.16    120  5.2.5 Attempts to accelerate the reaction rate The above cycloetherification reactions occurred at a rather slow rate, in some cases requiring upward of 12 hours to complete. This drawback induced us to explore the oxidative cyclization of alcohols incorporating gem-dimethyl substitution on the aliphatic chain, in the hope that the gem-dialkyl effect[105] would promote a rate acceleration.  Entry Product  Time (h) eeb (%) Yieldc (%) 1 5.2m (R = H)  70 98 61 2 5.2n (R = Cl) 60 76 66 3d 5.2u (R = Br) 36 74 77 4d 5.2v (R = Ph) 36 90 50 5d 5.2w (R = 4-CF3-C6H4) 36  87 64 aPrecatalyst 4.52 (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields after column chromatography. d1.8 equivalents of MCPBA was used.  Table 5.9 Effect of gem-dimethyl substituents on the rate of cycloetherification Contrary to the above expectation, the rate of cyclization of substrates with gem-dimethyl substitution in the side chain was much slower than that of unsubstituted congeners (Table 5.9). Interestingly, para-unsubstituted naphthol 5.1m afforded essentially enantiomerically pure product 5.2m (entry 1). Substitution at 4- position resulted in lowering of ee of spiroethers regardless of the nature of substituents (entries 2-5). Abnormally slow reaction rates were also observed with 5.1x (Scheme 5.12).  121   Scheme 5.12 Cycloetherification of 5.1x mediated by 4.52 5.2.6 Kinetic resolution of primary naphtholic alcohols The above results suggest that unfavorable steric interactions with the gem-dimethyl arrangement within the substrate-catalyst complex must override the Thorpe-Ingold effect. This raised an interesting question: could one harness such interactions and use a chiral catalyst to influence the stereochemical outcome of the oxidative cyclization of substrates bearing a single substituent on the side chain? Such compounds would be chiral, raising the possibility that a chiral catalyst might promote faster cyclization of one of the two enantiomers. This would allow the kinetic resolution of the substrates. Such a process would be especially interesting in the case of compounds 5.17 (Figure 5.6) displaying the R group at the 2’ carbon. The materials in question are primary alcohols incorporating a stereogenic center at β position. The kinetic resolution of primary alcohols of this type is challenging.[115] Furthermore, would a chiral catalyst modulate the innate degree of diastereoselectivity attending the cyclization of 5.17?  122   Figure 5.6 1-Naphtholic alcohol bearing a single substituent at the 1’, 2’, or 3’ position The foregoing issues were addressed by examining the behavior of alcohols 5.17 in the non-enantioselective reaction and in its asymmetric variant. Thus, oxidation of compounds 5.17 with PIFA in CH2Cl2 consistently furnished the expected racemic spiroethers in about 40% yield. Compounds bearing a C-1’ group cyclized with poor diastereoselectivity (d.r. = 55:45), regardless of the steric demand of the substituent (Scheme 5.13). Chiral SFC readily separated the four stereoisomers of the product (two enantiomers of each diastereomer), enabling a precise   Scheme 5.13 Diastereoselectivity in the cyclization of 1’-substituted alcohols 5.17 determination of diastereomeric ratios, and later, of ee’s. However, the diastereomers were inseparable by preparative column chromatography. Fortunately their 1H NMR signals were well resolved, enabling the assignment of relative configurations based on the NOESY-2D spectra of the purified product mixture. In either case, the major diastereomer was the one which the C-1’  123  group was cis to the olefinic segment within the newly formed tetrahydrofuran ring. This conclusion is based upon the diagnostic NOE enhancements indicated in Scheme 5.13.  The product 5.18c of oxidative cyclization of alcohol (±)-5.17c emerged as single diastereomer. Its NOESY-2D spectrum displayed the strong dipolar coupling shown in Scheme 5.14, indicating that the phenyl group was again cis to the olefinic substituent.  Scheme 5.14 Cyclization of 3’-Ph alcohol (±)-5.17 In contrast to the previous cases, substituent R was trans to the olefinic segment in the major product formed during the cyclization of 2’-substituted alcohols 5.20 (Scheme 5.15). Diastereoselectivity was consistently around 3-4:1, regardless of the nature of the 2’-group. Chemical yields were often better in this series, except when para-phenolic substituent R’ was H. As seen earlier, this was because of competing naphthoquinone formation. No attempts were made to isolate the quinone or determine its yield, since this material was of no interest to us. A tabulation of 13 racemic products of structure 5.21-5.22 thus obtained is provided in Figure 5.7.  Scheme 5.15 Cyclization of 2’-substituted alcohols (±)-5.20    124                     aIsolated yields after column chromatography. bDetermined by chiral SFC. cDetermined from 1H NMR of crude reaction mixture. Figure 5.7 Spiroethers derived from substrates bearing a C-2’ substituent   125  5.2.6.1 Enantioselective cyclization: catalyst screening  The enantioselective variant of spiroetherification reaction and the possible kinetic resolution of the substrate were initially explored using test alcohol 5.20a (Table 5.10). Compound (±)-5.20 was subjected to oxidative cyclization in the presence of various chiral catalysts. All reactions were run to ~50% conversion to evaluate the enantiomeric enrichment of both products and starting material. To that end, only 0.6 equivalents of MCPBA were used in each experiment.    Entry Pre catalyst  Time  (h) %  Conversionb  d.r.c (5.21a: 5.22a) Yieldd (%) ee (%)c ee (%) 5.20ac  Abs. conf. of 5.20ae Sf Product Rec. 5.20a 5.21a 5.22a 1 4.20 6 54 77:23 50 30 89 97 54 (R) 4.5 2 4.52 20 52 80:20 49 30 90 97 57 (S) 5.6 3 4.51 13.3 56  83:17 52 35 94 98 79 (S) 10.0 aPrecatalyst (20 mol%), MCPBA (0.6 equiv), -20 °C, CH2Cl2 (0.02 M). bConversion determined by 1H NMR using 3,5-dimethoxybenzaldehyde as the internal standard, c=(1-yield of starting material)*100%. cDetermined by chiral SFC. dIsolated yields. eAbsolute configuration of recovered starting material was determined via X-ray analysis of its derivative (See section 5.2.6.3). fSelectivity factor, S=ln[(1-c)(1-eeSM)]/ln[(1-c)(1+eeSM)]; eeSM=ee of recovered starting material, c=conversion.  Table 5.10 Catalyst screening   126  In all cases, the chiral catalyst had no effect on the diastereoselectivity of the reaction, which remained identical to that observed in the racemic series. The diastereomeric products were inseparable by column chromatography, and the relative configurations were assigned based on NOESY-2D study of the mixture after purification, as described earlier. Regarding the enantioselectivity of spiroethers obtained, all iodides (4.20, 4.51 and 4.52) provided spiroethers 5.21a and 5.22a with similar ee’s, except that, 4.51 and 4.52 promoted an opposite sense of asymmetric induction relative to 4.20 (Table 5.10, entries 1-3). This is consistent with previous observations (Table 5.3 and 5.4). With regard to kinetic resolution, 4.20 and 4.52 afforded unreacted alcohol of a moderate 54-57% ee (Table 5.10, entries 1 and 2). Much better results were obtained with catalyst 4.51, which returned recovered 5.20 of 79% ee and selectivity factor of 10 (entry 3). Reactions run with iodide 4.51 also proceeded at a faster rate relative to 4.52 (13.5 h vs. 20 h). The observation that a decrease in the steric demand of the alkyl group in the new chiral iodides (t-Bu  i-Pr) resulted in better catalytic performance induced us to evaluate their methyl analog, 5.26 (Scheme 5.16). Retracing established pathways, the compound was prepared by Mitsunobu reaction of Boc-protected (R)-2-amino-1-propanol 5.23 with 2-iodoresorcinol, followed by N-deprotection and EDCl mediated coupling of amine 5.25 with mesitoic acid.   127   Scheme 5.16 Synthesis of chiral iodoarene 5.26 Unfortunately, iodide 5.26 provided inferior degrees of asymmetric induction compared to other catalysts, in terms of both ee’s of cyclic products and of recovered starting material (S = 5.3; Scheme 5.17). Overall, 4.51 was the best catalyst for this type of transformation.  Scheme 5.17 Evaluation of iodide 5.26 for cycloetherification of test substrate (±)-5.20a   128  5.2.6.2 Alternative reaction conditions In accord with previous observations, any change in solvent, temperature and concentration translated into less satisfactory outcomes (Table 5.11). Reactions run in CHCl3 returned spiroethers of excellent ee, but the enantiomeric enrichment of recovered 5.20 was lower than in CH2Cl2 (entries 1 and 2). Polar solvents were deleterious (e.g., entry 5). An abnormally slow reaction ensued in a mixture of CH2Cl2 and MTBE, with an estimated 5% conversion attained after 6 h (entry 6).   Entry Solvent  Time  (h) %  Conv.b  d.r.c (5.21: 5.22) Yieldd (%) ee of productc ee (%)c 5.20a Se Product Rec. 5.20a 5.21  5.22 1 CHCl3 16.5 51 82:18 50 35 94 98 62 7.3 2 CH2Cl2 13.3 56 83:17 52 35 94 98 79 10.0 3 Toluene 14.3 53 88:12 34 38 90 71 45 3.5 4 MeNO2:CH2Cl2 (3:1 v/v) 18.5 50 82:18 44 30 80 79 48 4.5 5 CF3CH2OH 13.5 59 75:25 48 32 <5 <5 <5 - 6 MTBE:CH2Cl2 (4:3 v/v) 6 <5 - - - - - - - 7f CH2Cl2 7.3 58 84:16 53 36 89 92 80 8.9 8g CH2Cl2 9.7 60 80:20 52 35 90 97 78 7.2 a4.51 (20 mol%), MCPBA (0.6 equiv), -20 °C, Solvent (0.02 M). bConversion determined by 1H NMR using 3,5-dimethoxybenzaldehyde as the internal standard, c=(1-yield of starting material)*100%. cDetermined by chiral SFC. dIsolated yields. eSelectivity factor, S=ln[(1-c)(1-eeSM)]/ln[(1-c)(1+eeSM)]; eeSM=ee of recovered starting material, c=conversion. fReaction was performed at 0 °C. gConcentration of reaction mixture was 0.05 M with respect to starting material.  Table 5.11 Further optimization study  129  Higher temperature (-25 °C  0 °C) and concentrations (0.02 M  0.05 M) resulted in slightly lower ee of the spiroethers without affecting the ee of recovered 5.20 (entries 7 and 8). Overall, the best conditions for effective cycloetherification and kinetic resolution were the same as those developed earlier for other enantioselective reactions (entry 2). 5.2.6.3 Determination of the absolute configuration of 5.21a, 5.22a and recovered 5.20a The oily mixture of products 5.21a and 5.22a was inseparable by column chromatography. Their absolute configuration, as well as that of recovered 5.20a, was thus determined by a method similar to that described earlier for spiroethers 5.2a and 5.2k (Section 5.2.4). Recovered (+)-5.20a of 79% ee was subjected to a second round of oxidative cyclization mediated by iodide 4.51 (Scheme 5.18). The reaction was stopped at 43% conversion, whereupon residual (+)-5.20a was found to be 96% ee.  Scheme 5.18 Cycloetherification of (+)-5.20a mediated by 4.51 This highly enantioenriched material was converted into the crystalline bis-p-bromobenzoate ester (-)-5.27 (Scheme 5.19), which was found to be of (S)-configuration by X- 130  ray analysis (Figure 5.8). This means that (S)-(+)-5.20a is the slow reacting alcohol enantiomer when (±)-5.20a is subjected to spiroetherification using iodide 4.51, and (R)-(-)-5.20a is the fast reacting one (Table 5.10). Consequently, the absolute configuration of the carbon atom bearing the i-Pr group in major diastereomer 5.21a (94% ee, Table 5.10) must be (R).   Scheme 5.19 Derivatization of (+)-5.20a as ester (-)-5.27  Figure 5.8 X-ray structure of (-)-(S)-5.27 Because in 5.21a the i-Pr group and the olefinic residue are trans within the tetrahydrofuran ring (NOESY-2D spectroscopy, Figure 5.7), the spirocenter must be of (R)-configuration. Therefore, the major diastereomer is (R,R)-(+)-5.21a. Another portion of (S)-(+)-5.20a of 96% ee was subjected to cyclization in the presence of iodide 4.51, thereby yielding 5.22a as major diastereomer (Scheme 5.20). This product was identical to the major enantiomer of the minor diastereomer produced in the previous experiments. So, the absolute configuration of the carbon atom bearing the i-Pr group in 5.22a is  131  (S), and from the NOE correlations, the absolute configuration of the spirocenter must be (R). So, the overall absolute configuration of 5.22a is (R,S). This is consistent with the sense of enantioinduction that was obtained with simpler naphtholic alcoholic substrates.   Scheme 5.20 Cycloetherification of enantioenriched (+)-5.20a 5.2.6.4 Substrate scope The cyclization of 3’-substituted (±)-5.17c provided (+)-5.18c as a single diastereomer, but in poor yield and low ee. Recovered starting material was of only 9% ee (Scheme 5.21). Clearly, neither enantioinduction nor kinetic resolution operated properly in the cyclization of this type of alcohol, which nonetheless occurred with complete diastereoselectivity.  132   Scheme 5.21 Cycloetherification of (±)-5.17c mediated by 4.51 In contrast to the above, the cyclization of 1’-substituted alcohols (±)-5.17a-b was highly enantioselective, but poorly diastereoselective (Table 5.12). Also, recovered starting material was of low ee, indicating that the kinetic resolution of these substrates is problematic, at least with catalysts of the type 4.51.  Entry R  Time (h) % Conv.b  d.r.c (5.18 : 5.19) Yieldd (%) ee of productc ee (%)c 5.17 Product Recovered 5.17 5.18 5.19 1 Me 14.5 49  59:41 33 36 90 90 8 2 Ph 9.3 60  65:35 27 36 97 75 <5 a4.51 (20 mol%), MCPBA (0.6 equiv), -20 °C, CH2Cl2 (0.02 M). bConversion determined by 1H NMR using 3,5-dimethoxybenzaldehyde as the internal standard, c=(1-yield of starting material)*100%. cDetermined by chiral SFC. dIsolated yields after column chromatography.   Table 5.12 Evaluation of iodide 4.51 in the cycloetherification of (±)-5.17a-b  133  The observation that only naphtholic alcohols with a stereogenic center at the 2’ position undergo efficient kinetic resolution provided an incentive to examine the cyclization of substrates 5.20 incorporating diverse R and R’ groups. Pertinent results are summarized in Table 5.13. Spiroethers obtained from 4-H and 4-Cl naphtholic alcohols were of generally excellent ee (Table 5.13, entries 1-10), except for the minor diastereomer 5.22 with R = CH2CF3 (entry 7) or Ph (entry 10) and R’ = Cl. The 4-bromo substrates yielded spiroethers of slightly lower ee (entries 11-14). Most substrates cyclized with moderate diastereoselectivity; however, a high diastereomeric ratio (~10:1) was observed when R = CH2CF3, R’ = Cl (entry 7). With respect to kinetic resolution, the highest enantiomeric enrichments of recovered (+)-5.20 were attained in the 4-Cl series (ee > 70%), especially when R = CH2CF3 (S = 19). The recovered (+)-5.20 was obtained with lower ee (just under 50% in all cases) when R = Me.    134   Entry Product  % Conv.b  d.r.c (5.21 : 5.22) % Yield of  productd  % ee of productc Recovered 5.20 % Yieldd  (% ee)c  Se 5.21 5.22 1 R = Me, R’ = H 55 86:14f 50 -g -g 40 (48) 3.6 2 R = i-Pr, R’ = H 60  82:18 48 96 -g 35 (62) 4.3 3 R = CH2CF3,  R’ = H  48  83:17h 40i -g -g 44 (57) 7.4 4 R = Cy, R’ = H 57  81:19 45 94 -g 33 (41) 2.7 5 R = Me, R’ = Cl 44  79:21f 42 -g -g 40 (47) 6.2 6 R = i-Pr, R’ = Cl 56  83:17 52 94 98 35 (79) 10.0 7 R = CH2CF3,  R’ = Cl 47 91:9 45 94 79 37 (71) 19.0 8 R = Bn, R’ = Cl 50  87:13 47 94 91 40 (72) 13.0 9 R = Cy, R’ = Cl 58  80:20 53 92 95 38 (76) 7.6 10 R = Ph, R’ = Cl 42  86:14 37 93 59 40 (51) 9.5 11 R = Me, R’ = Br 59  81:19f 45 -g -g 35 (49) 3.2 12 R = i-Pr, R’ = Br 57  86:14 51 73 87 35 (67) 5.9 13 R = Bn, R’ = Br 52  88:12 45 86 82 42 (71) 10.0 14 R = Cy, R’ = Br 60  83:17 53 72 86 28 (65) 4.7 a4.51 (20 mol%), MCPBA (0.6 equiv), -20 °C, CH2Cl2 (0.02 M). bConversion determined by 1H NMR using 3,5-dimethoxybenzaldehyde as the internal standard, c=(1-yield of starting material)*100%. cDetermined by chiral SFC. dIsolated yields after column chromatography. eSelectivity factor, S=ln[(1-c)(1-eeSM)]/ln[(1-c)(1+eeSM)]; eeSM=ee of recovered starting material, c=conversion. fDetermined by 1H NMR after column chromatography. gThe ee could not be determined because the enantiomers were inseparable by chiral SFC. hDetermined by 1H NMR of crude reaction mixture. iCombined yield of individual diastereomers isolated (36% major + 4% minor).   Table 5.13 Oxidative cyclization of substrates with a 2’-stereogenic center    135  5.2.7 Enantioselective oxidative cyclization of phenolic alcohol  The relative efficacy of catalysts 4.20 and 4.52 was evaluated also in the cycloetherification of phenolic alcohol 5.3. Recall that the primary product of the reaction, 5.4 undergoes a highly diastereoselective [4+2]-homodimerization in situ to give cycloadduct 5.5 (Scheme 5.4).  Iodide 4.20 proved to be much better than 4.52 in the present case, providing (-)-5.5 in 57% yield and 94% ee (Table 5.14). A single recrystallization of the product by slow evaporation of a solution in ethanol at RT afforded material of >99% ee. X-ray analysis of crystals revealed that the spirocenters (-)-5.5 are of (S) configuration (Figure 5.9).  Entry Precatalyst  Product Time (h) eeb (%) Yieldc (%) 1 4.20  (-)-5.5 15 94 (>99)d 57 2 4.52 (+)-5.5 18 90 13 aPrecatalyst (20 mol%), MCPBA (1.3 equiv), -20 °C, CH2Cl2 (0.02 M). bDetermined by chiral SFC. cIsolated yields after column chromatography. dee after single recrystallization.  Table 5.14 Formation of enantioenriched dimer 5.5    136   Figure 5.9 X-ray structure of (S,S)-(-)-5.5 5.3 Summary and Conclusion The enantioselective oxidative cyclization of naphtholic alcohols mediated by hypervalent iodine reagents is generally more efficient that the analogous reaction of sulfonamides, in terms of both asymmetric induction and chemical yields. The transformation is best carried out under the same conditions employed for cyclization of sulfonamides (20 mol% of chiral catalyst, stoichiometric amount of MCPBA, CH2Cl2, -20 oC). Electron-withdrawing groups at the naphthol 4-position promoted high levels of asymmetric induction. The opposite was true for electron donating substituents. This is attributable to a greater ease of fragmentation of the complex resulting through the union of the substrate with the hypervalent form of the catalyst. Such an event releases a cationic form of the substrate that cyclizes in an achiral environment, leading to a racemic product.  Enantioselective cycloetherification reactions are generally slow. Attempts to harness the Thorpe-Ingold gem-dimethyl effect to increase their rate were unfruitful, resulting instead in further deceleration. This observation suggested that a kinetic resolution of racemic substrates mediated by chiral aryl iodides may be possible. This was found to be the case for naphtholic  137  alcohols bearing a single substituent at the side chain 2’ position. The best catalyst for such a process was iodide 4.51, which afforded good to excellent levels of asymmetric induction, but that had no influence on the innate diastereoselectivity of the transformation. 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[114] Racicot, L., Dissertation, University of British Columbia, 2016. [115] a) Terakado, D.; Koutaka, H.; Oriyama, T. Tetrahedron: Asymmetry 2005, 16, 1157. b) Sakai, T.; Kishimoto, T.; Tanaka, Y.; Ema, T.; Utaka, M. Tetrahedron Lett. 1998, 39, 7881. c) Ghanemi, A.; Aboul-enein, H. Y. Chirality 2005, 17, 1. d) Strübing, D.; Krumlinde, P.; Piera, J.; Bäckvall, J-. E. Adv. Synth. Catal. 2007, 349, 1577.     146  Appendices A. Experimental protocols Unless otherwise stated, 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded from CDCl3 solutions, at RT. Chemical shifts are reported in parts per million (ppm) on the δ scale and coupling constants, J, are in hertz (Hz). Multiplicities are reported as “s” (singlet), “d” (doublet), “t” (triplet), “q” (quartet), “p” (pentet), “dd” (doublet of doublets), “ddd” (doublet of doublet of doublets), “m” (multiplet), “td” (triplet of doublets) and further qualified as “br” (broad), “app” (apparent). Infrared (IR) spectra (cm–1) were recorded from films (Perkin Elmer® Universal ATR Sampling Accessories). Low and high-resolution mass spectra (m/z) were obtained in the electron impact (EI) or electrospray (ESI) mode, as specified, in methanol solution. Melting points (uncorrected) were measured on a Mel–Temp apparatus. Optical rotations were measured at the sodium D line (589 nm) with a Perkin Elmer® 241 polarimeter.  All reagents and solvents were commercial products and used without further purification except THF (freshly distilled from Na/benzophenone under argon), CH2Cl2 (freshly distilled from CaH2 under argon) and diisopropylamine (distilled from CaH2 under Ar then stored over KOH). Commercial n-BuLi was titrated against N-benzylbenzamide in THF at -40 °C until persistence of a light blue color. Commercial MCPBA of a stated purity of 77% was used as oxidant. The reactions were monitored by thin layer chromatography (TLC) using silica gel 60 F254 pre-coated plates. Spots were visualized with a UV lamp, KMnO4 stain or vanillin stain. Flash chromatography was performed on Silicycle® 230 – 400 mesh silica gel. All reactions were performed under dry argon in flame or oven dried flasks equipped with Teflon™ stirring bars. All flasks were fitted with rubber septa for the introduction of substrates, reagents and solvents  147  via syringe. Solvents, pure liquid reagents or reagents in solution, and solids were added in one portion, unless otherwise stated. Enantiomeric excesses were determined using a Thar SFC method station (Model 840) equipped with chiral columns OD-H (0.46 cm × 25 cm 5 μm), AD-H (0.46 cm × 25 cm 5 μm), AS-H (0.46 cm × 25 cm 5 μm), OJ-H (0.46 cm × 25 cm 5 μm) and Lux 3u Cellulose 2 (50 × 4.60 mm). The standard operating pressure was 120 bar and the temperature of the chiral column was 33-34 °C. Enantiomeric excesses of some of the compounds were determined using a high performance liquid chromatography (HPLC), which was performed on an Agilent 1100 HPLC, equipped with a variable wavelength UV-Vis detector and Chiralcel OD-H chiral column (0.46 cm x 25 cm 5 μm), Chiralcel AD-H chiral column (0.46 cm x 25 cm 5 μm), Chiralcel OJ-RH (0.46 cm × 15 cm 5 μm).    148  B. Preparation of substrates employed in the present study experimental section B.1 Preparation and characterization of intermediates towards naphtholic alcohol 3.10 B.1.1 Preparation of 1-(allyloxy)naphthalene (3.8) [known compound][1] Allyl bromide (6.5 mL, 76.3 mmol, 1.1 equiv) was added dropwise over 10 minutes to a solution of 1-naphthol (10.0 g, 69.4 mmol, 1.0 equiv) in acetone (70.0 mL) containing suspended K2CO3 (10.6 g, 76.3 mmol, 1.1 equiv). The mixture was stirred at RT for 15 min, then it was heated to reflux for 7 h, after which time TLC showed that the reaction was complete. The mixture was cooled to RT and the solvent was evaporated. The residue was quenched with H2O (80 mL) and extracted with Et2O (3×15 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated. The residue was dried under high vacuum to provide 12.5 g of 3.8 (98% crude yield) as light brown oil and used for the next step without purification. IR: 1271. 1H: 8.40-8.37 (m, 1H), 7.88-7.82 (m, 1H), 7.57-7.38 (m, 4H), 6.85 (d, 1H, J = 6.0), 6.29-6.16 (m, 1H), 5.58 (dd, 1H, J = 18.0, 3.0), 5.39 (dd, 1H, J = 12.0, 3.0), 4.76 (d, 2H, J = 3.0). 13C: 154.4, 134.7, 133.5, 127.6, 126.5, 125.9 (2C), 125.3, 122.2, 120.5, 117.5, 105.2, 69.0. B.1.2 Preparation of 2-allylnaphthalen-1-ol (3.9)  [known compound][1] A solution of crude 3.8 (12.0 g, 65.1 mmol, 1.0 equiv) in N,N-diethylaniline (120.0 mL) was refluxed overnight. The reaction mixture was cooled to RT and was diluted with EtOAc (90 mL) and washed with 3M HCl (4×30 mL). The                                                  [1] Reich, S. H.; Melnick, M.; Pino, M. J; Fuhry, M. A. M.; Trippe, A. J.; Appelt, K; Davies II, J. F.; Wu, B.-W; Musik, L. J. Med. Chem. 1996, 39, 2781.  149  organic phase was washed with brine (30 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:9 EtOAc/hexanes) to provide 9.5 g (79% yield) of 3.9 as yellow oil. IR: 3659-3055 (broad). 1H: 8.22-8.19 (m, 1H), 7.83-7.80 (m, 1H), 7.51-7.48 (m, 2H), 7.44 (d, 1H, J = 6.0), 7.25 (d, 1H, J = 9.0), 6.17-6.04 (m, 1H), 5,60 (br s, 1H), 5.31-5.25 (m, 2H), 3.61 (d, 2H, J = 9.0). 13C: 149.7, 136.3, 133.9, 128.6, 127.6, 125.9, 125.4, 125.0, 121.5, 120.5, 118.1, 117.0, 35.8.  B.1.3 Preparation of 2-(3-Hydroxypropyl)naphthalen-1-ol (3.10) [known compound][2] Commercial BH3•SMe2 (~10 M solution, 1.1 mL, 10.8 mmol, 2.0 equiv) was added to a cold (0 °C) solution of 3.9, (1.0 g, 5.4 mmol, 1.0 equiv) in THF (10 mL) and the mixture was stirred at 0 °C for 3 h. Aqueous 30% H2O2 (2 mL) was added followed by addition of NaHCO3 (2 mL) to the cold solution and the mixture was stirred at RT overnight. The reaction was quenched with aq. satd. NH4Cl (10 mL) and extracted with EtOAc (3×15 mL). The combined extracts were washed with brine (10mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 3:7 EtOAc/hexanes) to provide 854 mg (78% yield) of 3.10, light yellow solid, m.p.: 81-83 °C (lit.[3] 84-86 °C). IR: 3699-3097 (broad). 1H: 8.29-8.26 (m, 1H), 7.79-7.76 (m, 1H), 7.50-7.44 (m, 2H), 7.40 (d, 1H, J = 9.0), 7.22 (d, 1H, J = 9.0), 3.67 (t, 2H, J = 6.0), 2.97 (app t, 2H, J = 7.5), 1.96 (p, 2H, J = 6.0). 13C: 150.2, 133.6, 128.6, 127.3, 125.6, 125.3, 125.1, 122.1, 120.1, 119.7, 60.3, 31.4, 25.1. HRMS: calcd for C13H14O2Na [M+Na]+: 225.0891; found: 225.0886.                                                    [2] De Benneville, P. L.; Connor, R. J. Am. Chem. Soc. 1940, 62, 3067. [3] Huffman, J. W.; Wu, M. J.; Lu, J. J. Org. Chem. 1998, 63, 4510.  150  B.2 Preparation of 4-Chloro-2-(3-hydroxypropyl)-naphthalen-1-ol (3.11) Solid NCS (218 mg, 1.7 mmol, 1.1 equiv) was added in several portions over a period of 30 min to a solution of 3.10 (300 mg, 1.5 mmol, 1.0 equiv) in MeCN (1.5 mL) at RT. The mixture was stirred for 3h at RT, after which time TLC showed that the reaction was complete. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:3 EtOAc/hexanes) to provide 251 mg (72% yield) of 3.11 as light yellow solid, m.p.: 97-99 °C. IR: 3675-3045 (broad). 1H: 8.31 (d, 1H, J = 6.0), 8.16 (d, 1H, J = 9.0), 7.98 (br s, 1H), 7.59-7.50 (m, 2H), 7.31 (s, 1H), 3.68 (t, 2H, J = 6.0), 2.94 (app t, 2H, J = 6.0), 2.01-1.93 (m, 3H). 13C: 149.7, 130.4, 128.3, 126.6, 126.5, 125.8, 124.0, 122.8, 122.7, 120.1, 60.1, 31.1, 24.9. HRMS: calcd for C13H12O2Cl [M-H]-: 235.0526; found: 235.0526. B.3 Preparation of 4-Bromo-2-(3-hydroxypropyl)naphthalene-1-ol (3.12) [Known compound][4]  Solid NBS (288 mg, 1.7 mmol, 1.1 equiv) was added in several portions over a period of 30 min to a solution of 3.10 (300 mg, 1.5 mmol, 1.0 equiv) in MeCN (1.5 mL) at RT. The mixture was stirred for 3h at RT, after which time TLC showed that the reaction was complete. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:3 EtOAc/hexanes) to provide 266 mg (69% yield) of 3.12 as tan solid, m.p. 99-101 °C (lit. m.p.[4] not reported). IR: 3692-3009 (broad). 1H: 8.30 (d, 1H, J = 6.0), 8.12 (d, 1H, J = 9.0), 7.59-7.49 (m, 3H), 3.67 (t, 2H, J = 6.0), 2.93 (app t, 2H, J =                                                  [4] Sarkar, D.; Ghosh, M. K.; Rout, N. Org. Biomol. Chem. 2016, 14, 7883.  151  6.0), 1.96 (p, 2H, J = 6.0). 13C: 150.3, 132.0, 131.6, 126.9, 126.7, 126.6, 125.8, 122.7, 120.8, 112.8, 60.1, 31.2, 24.8. HRMS: calcd for C13H12O279Br [M-H]-: 279.0021; found: 279.0014. B.4 General procedure for Suzuki coupling of 3.12 with aryl boronic acids A solution of 3.12 (300 mg, 1.1 mmol, 1.0 equiv), Pd(PPh3)4 (64 mg, 55 µmol, 0.05 equiv), appropriate boronic acid (1.3 mmol, 1.2 equiv), and Cs2CO3 (424 mg, 1.3 mmol, 1.2 equiv) in 1,4-dioxane (6.0 mL) and water (1.2 mL) was stirred at 80 °C for 6 h, after which time TLC showed that the reaction was complete. The cooled mixture was diluted with Et2O (6.0 mL) and filtered through a Celite® pad, which was washed with more Et2O (3×10 mL). The combined filtrate was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography to provide corresponding products. B.4.1 Characterization of 2-(3-Hydroxypropyl)-4-(3-methoxyphenyl)naphthalen-1-ol (3.13, Ar = C6H4-OMe-m) The procedure described above, but employing 3-methoxyphenylboronic acid, afforded 312 mg (95% yield) of 3.13, Ar = C6H4-OMe-m from 300 mg of 3.12 (eluent: 1:9 to 1:3 EtOAc/hexanes), colorless oil. IR: 3636-3122 (broad). 1H: 8.38 (d, 1H, J = 9.0), 8.01 (br s, 1H), 7.91 (d, 1H, J = 9.0), 7.52-7.38 (m, 3H), 7.21 (s, 1H), 7.11-7.06 (m, 2H), 6.98 (d, 1H, J = 9.0), 3.88 (s, 3H), 3.71 (t, 2H, J = 4.5), 3.00 (app t, 2H, J = 6.0), 2.40 (br s, 1H), 1.98 (p, 2H, J = 6.0). 13C: 159.5, 149.9, 142.4, 132.5, 131.5, 129.6, 129.2, 125.7, 125.6, 125.5, 125.1, 122.8, 122.4, 119.4, 115.8, 112.4, 60.4, 55.4, 31.5, 25.2. HRMS: calcd for C20H21O3 [M+H]+: 309.1491; found: 309.1499.  152  B.4.2 Characterization of 1-(4-(4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)phenyl)ethanone (3.13, Ar = C6H4-C(O)Me) The procedure described above, but employing 4-acetylphenylboronic acid, afforded 216 mg (73% yield) of 3.13, Ar = C6H4-C(O)Me from 260 mg of 3.12 (eluent: 1:4 to 3:7 EtOAc/hexanes), light yellow solid, m.p. 147-149 °C. IR: 3643-2995 (broad), 1669. 1H: 8.39 (d, 1H, J = 8.3), 8.10 (br s, 1H), 8.07 (d, 2H, J = 8.2), 7.81 (d, 1H, J = 8.3), 7.60 (d, 2H, J = 8.2), 7.51 (app t, 1H, J = 7.3), 7.42 (app t, 1H, J = 7.2), 7.19 (s, 1H), 3.73 (t, 2H, J = 5.0), 3.01 (t, 2H, J = 6.4), 2.69 (s, 3H), 2.24 (br s, 1H), 2.00 (p, 2H, J = 6.0). 13C: 198.2, 150.8, 146.3, 135.6, 131.4, 131.3, 130.6, 130.1, 128.5, 126.2, 125.7, 125.4, 125.2, 122.8, 119.5, 60.4, 31.5, 26.9, 25.2. HRMS: calcd for C21H20O3Na [M+Na]+: 343.1310; found: 343.1313. B.4.3 Characterization of 4-(4-Fluorophenyl)-2-(3-hydroxypropyl)naphthalen-1-ol (3.13, Ar = C6H4-F-p) The procedure described above, but employing 4-fluorophenylboronic acid, provided 190 mg (60% yield) of 3.13, Ar = C6H4-F-p from 300 mg of 3.12 (eluent: 3:17 to 3:7 EtOAc/hexanes), yellow solid, m.p. 127-129 °C. IR: 3597-3045 (broad). 1H: 8.37 (d, 1H, J = 9.0), 7.92 (br s, 1H), 7.78 (d, 1H, J = 6.0), 7.52-7.39 (m, 4H), 7.19-7.13 (m, 3H), 3.72 (t, 2H, J = 6.0), 3.00 (app t, 2H, J = 6.0), 2.06-1.95 (m, 3H). 13C: 162.0 (d, J = 246.1), 150.0, 136.8 (d, J = 3.0), 131.7 (d, J = 8.3), 131.6, 131.5, 129.8, 125.8, 125.5, 125.3, 125.1, 122.5, 119.2, 115.1 (d, J = 21.1), 60.3, 31.4, 25.1. EI: calcd for C19H17O2F: 296.1213; found: 296.1208.  153  B.4.4 Characterization of 2-(3-Hydroxypropyl)-4-(4-(methylsulfonyl)phenyl)naphthalen-1-ol (3.13, Ar = C6H4-SO2Me-p) The procedure described above, but employing 4-(methylsulfonyl)-phenylboronic acid, returned 216 mg (85% yield) of 3.13, Ar = C6H4-SO2Me-p from 200 mg of 3.12 (eluent: 1:4 to 9:11 EtOAc/hexanes), light yellow solid, m.p.: 94-96 °C. IR: 3694-3134 (broad). 1H: 8.40 (d, 1H, J = 9.0), 8.27 (br s, 1H), 8.04 (d, 2H, J = 9.0), 7.75 (d, 1H, J = 6.0), 7.68 (d, 2H, J = 9.0), 7.53-7.40 (m, 2H), 7.17 (s, 1H), 3.72 (t, 2H, J = 4.5), 3.16 (s, 3H), 3.00 (t, 2H, J = 6.0), 2.51 (br s, 1H), 1.98 (p, 2H, J = 6.0). 13C: 151.0, 147.0, 138.6, 131.1, 131.0, 130.2, 127.3, 126.3, 125.6, 125.4, 124.7, 122.8, 119.5, 60.2, 44.7, 31.4, 25.2. HRMS: calcd for C20H20O4SNa [M+Na]+: 379.0980; found: 379.0977. B.4.5 Characterization of 2-(3-Hydroxypropyl)-4-(4-(trifluoromethyl)phenyl)naphthalen-1-ol (3.13, Ar = C6H4-CF3-p) The procedure described above, but employing 4-(trifluoromethyl)-phenylboronic acid, gave 241 mg (98% yield) of 3.13, Ar = C6H4-CF3-p from 200 mg of 3.12 (eluent: 1:9 to 1:4 EtOAc/hexanes), white solid, m.p. 145-147 °C. IR: 3548-3017 (broad). 1H: 8.39 (d, 1H, J = 9.0), 8.04 (br s, 1H), 7.79-7.72 (m, 3H), 7.61 (d, 2H, J = 9.0), 7.54-7.40 (m, 2H), 7.17 (s, 1H), 3.73 (t, 2H, J = 6.0), 3.01 (app t, 2H, J = 6.0), 2.08 (br s, 1H), 2.00 (p, 2H, J = 6.0). 13C: 150.6, 144.7, 131.2, 131.0, 130.5, 129.9, 129.0 (q, J = 32.5), 126.1, 125.5, 125.3, 125.2 (q, J = 3.8), 125.0, 124.4 (q, J = 271.8), 122.7, 119.3, 60.3, 31.4, 25.1. HRMS: calcd for C20H16F3O2 [M-H]-: 345.1102; found: 345.1094.    154  B.4.6 Characterization of 4-(3,5-Bis(trifluoromethyl)phenyl)-2-(3-hydroxypropyl)naphthalen-1-ol (3.13, Ar = 3,5bis(CF3)2C6H3) The procedure described above, but employing 3,5-bis(trifluoromethyl)-phenylboronic acid, produced 257 mg (87% yield) of 3.13, Ar = 3,5bis(CF3)2C6H3 from 200 mg of 3.12 (eluent: 1:9 to 1:4 EtOAc/hexanes), yellow solid, m.p. 124-126 °C. IR: 3689-3097 (broad). 1H: 8.41 (d, 1H, J = 6.0), 8.22 (br s, 1H), 7.95-7.92 (m, 3H), 7.66 (d, 1H, J = 6.0), 7.56-7.44 (m, 2H), 7.18 (s, 1H), 3.74 (t, 2H, J = 6.0), 3.02 (app t, 2H, J = 7.5), 2.19 (br s, 1H), 2.01 (p, 2H, J = 6.0). 13C: 151.2, 143.1, 131.6 (q, J = 33.2), 131.0, 130.4, 130.3 (app d, J = 3.0), 129.2, 126.6, 125.6, 125.5, 124.3, 123.5 (q, J = 272.6), 122.9, 120.8-120.5 (m), 119.4, 60.3, 31.3, 25.1. HRMS: calcd for C21H16O2F6: 414.1055; found: 414.1051. B.5 Preparation and characterization of intermediates towards naphtholic alcohol 3.18 B.5.1 General procedure for O-acylation of α-naphthols Neat acid chloride (4.5 mmol, 1.3 equiv) was added dropwise to the solution of 1-naphthol (500 mg, 3.47 mmol, 1.0 equiv), DMAP (208 mg, 1.74 mmol, 0.5 equiv) and Et3N (0.5 mL, 3.8 mmol, 1.1 equiv) in CH2Cl2 (10.0 mL) at 0 °C. The mixture was warmed to RT and then stirred overnight, after which time TLC showed that the reaction was complete. The reaction was quenched with 1M HCl (10 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed successively with H2O (10 mL), satd. NaHCO3 solution (2×5 mL), brine (10 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide corresponding products.  155  B.5.1.1 Characterization of Naphthalen-1-yl acetate (3.14, R = Me) [Known compound][5] 4.8 g (93% yield) from 4.0 g of 1-naphthol, light brown solid, m.p.: 40-42 °C (lit.[5] m.p. not reported), eluent: 1:19 to 1:9 EtOAc/hexanes. IR: 1756. 1H: 7.91-7.88 (m, 2H), 7.76 (d, 1H, J = 8.3), 7.56-7.50 (m, 2H), 7.47 (d, 1H, J = 8.), 7.27 (d, 1H, J = 7.4), 2.48 (s, 3H). 13C: 169.6, 146.7, 134.8, 128.2, 126.9, 126.6, 126.2, 125.5, 121.3, 118.2, 21.2. B.5.1.2 Characterization of Naphthalen-1-yl benzoate (3.14, R = Ph)  0.80 g (96% yield) from 0.50 g of 1-naphthol, colorless oil, eluent: 1:19 to 1:9 EtOAc/hexanes. IR: 1733. 1H: 8.43 (d, 2H, J = 7.8), 8.05-8.02 (m, 1H), 7.98-7.95 (m, 1H), 7.85 (d, 1H, J = 8.2), 7.76-7.71 (m, 1H), 7.64-7.53 (m, 5H), 7.46 (d, 1H, J = 7.4). 13C: 165.3, 146.9, 134.8, 133.9, 130.4, 129.5, 128.8, 128.2, 127.1, 126.6 (2C), 126.2, 125.6, 121.3, 118.3. B.5.2 Preparation of Naphthalen-1-yl 4-methylbenzoate (3.14, R = p-tolyl)  To a solution of 1-naphthol (2.5 g, 17.3 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added EDCI (4.0 g, 20.8 mmol, 1.2 equiv), DMAP (1.06 g, 8.7 mmol, 0.5 equiv) and p-toluic acid (2.8 g, 20.8 mmol, 1.2 equiv) at 0 °C with good stirring. The reaction mixture was warmed to RT and stirred for overnight, after which time TLC showed that the reaction was complete. The reaction was quenched with 1M HCl (15 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed successively with H2O (20 mL), satd. NaHCO3 solution (3×10 mL), brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 3:17:0.1 to 5:15:0.1 EtOAc/hexanes/Et3N) to                                                  [5] Barbero, M.; Cadamuro, S.; Dughera, S.; Venturello, P. Synthesis 2008, 3625.  156  provide 4.16 g (92% yield) of 3.14, R = p-tolyl, as white solid, m.p. 111-113 °C. IR: 1733. 1H: 8.27 (d, 2H, J = 9.0), 7.99-7.91 (m, 2H), 7.81 (d, 1H, J = 6.0), 7.57-7.49 (m, 3H), 7.42-7.38 (m, 3H), 2.51 (s, 3H). 13C: 165.3, 147.0, 144.7, 134.7, 130.4, 129.5, 128.1, 127.1, 126.7, 126.5, 126.0, 125.5, 121.4, 118.3, 21.8. B.5.3 General procedure for Fries rearrangement of 3.14 A mixture of 3.14 (12.2 mmol, 1.0 equiv) and anhydrous AlCl3 (1.8 g, 13.5 mmol, 1.1 equiv) in chlorobenzene (42 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to 0 °C, quenched with 1M HCl (30 mL) and extracted with EtOAc (4×15 mL). The combined extracts were washed with H2O (25 mL), brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 3.15. B.5.3.1 Characterization of 1-(4-Hydroxynaphthalen-1-yl)ethanone (3.15, R = Me) [Known compound][6] 0.91 g (18% yield) from 5.0 g of 3.14, R = Me, off white solid, dec. 197 °C (lit[6] m.p. not reported), eluent: 3:17 to 2:3 EtOAc/hexanes. IR: 3374-2553 (broad), 1638. 1H: 9.04 (d, 1H, J = 8.7), 8.28 (d, 1H, J = 8.2), 7.97 (d, 1H, J = 8.0), 7.68-7.53 (m, 2H), 6.84 (d, 1H, J = 8.0), 6.13 (br s, 1H). 13C: 200.3, 155.9, 132.6, 131.8, 129.1, 127.9, 126.6, 126.0, 124.7, 122.0, 107.0, 29.5. B.5.3.2 Characterization of (4-Hydroxynaphthalen-1-yl)(phenyl)methanone (3.15, R = Ph) [Known compound][7] 0.37 g (35% yield) from 1.1 g of 3.14, R = Ph, yellow solid, m.p.: 162-164 °C (lit.[7] m.p. 166-167 °C), eluent: 3:17 to 3:7 EtOAc/hexanes. IR: 3625-2925 (broad), 1630. 1H: 8.40-8.37 (m, 1H), 8.31-8.28 (m, 1H), 7.85 (d, 2H, J =                                                  [6] Allen, A.; Marquand, P. L.; Burton, R.; Villeneuve, K.; Tam, W. J. Org. Chem. 2007, 72, 7849. [7] Huffman, J. W.; Wu, M. J.; Lu, J. J. Org. Chem. 1998, 63, 4510.  157  7.3), 7.62-7.44 (m, 6H), 6.79 (d, 1H, J = 7.9). 13C: 198.3, 155.5, 139.4, 133.2, 132.9, 131.7, 130.6, 128.5, 128.3, 128.2, 126.0, 125.9, 124.8, 122.3, 107.0. B.5.3.3 Characterization of (4-Hydroxynaphthalen-1-yl)(p-tolyl)methanone (3.15, R = p-tolyl) 1.33 g (41% yield) from 3.21 g of 3.14, R = p-tolyl, yellow solid, dec. 184 °C, eluent: 1:4 to 7:13 EtOAc/hexanes. IR: 3618-2746 (broad), 1678. 1H (acetone-d6): 9.8 (br s, 1H), 8.38-8.31 (m, 2H), 7.70 (d, 2H, J = 6.0), 7.59-7.51 (m, 3H), 7.34 (d, 2H, J = 9.0), 6.98 (d, 1H, J = 6.0), 2.43 (s, 3H). 13C (acetone-d6): 196.8, 157.2, 143.9, 138.0, 134.0, 132.2, 131.0, 129.8, 128.5, 128.3, 126.6, 126.1, 126.0, 123.3, 107.3, 21.5.  B.5.4 Preparation of compounds 3.16 These substances were prepared by the same procedure described above for the synthesis of compound 3.8 and used in the subsequent step without purification. B.5.4.1 Characterization of (4-(Allyloxy)naphthalen-1-yl)(phenyl)methanone (3.16, R = Me)  688 mg (93% crude yield) from 606 mg of 3.15, R = Me, yellow solid, m.p.: 56-58 °C.  IR: 1663, 1230. 1H: 9.05 (d, 1H, J = 9.0), 8.38 (d, 1H, J = 9.0), 7.96 (d, 1H, J = 6.0), 7.64 (t, 1H, J = 7.5), 7.53 (t, 1H, J = 7.5), 6.73 (d, 1H, J = 9.0), 6.23-6.10 (m, 1H), 5.54 (d, 1H, J = 15.0), 5.38 (d, 1H, J = 12.0), 4.75 (d, 2H, J = 3.0), 2.70 (s, 3H). 13C: 200.0, 158.1, 132.5, 132.1, 131.9, 128.8, 127.3, 126.3, 125.9, 125.8, 122.2, 118.0, 103.1, 69.1, 29.3. B.5.4.2 Characterization of (4-(Allyloxy)naphthalen-1-yl)(phenyl)methanone (3.16, R = Ph) 288 mg (94% crude yield) from 265 mg of 3.15, R = Ph, colorless oil. IR: 1646, 1241. 1H: 8.43-8.36 (m, 2H), 7.85 (d, 2H, J = 6.0), 7.62-7.44 (m, 6H), 6.81 (d, 1H, J = 9.0), 6.27-6.14 (m, 1H), 5.57 (dd, 1H, J = 15.0, 3.0), 5.40 (dd, 1H, J = 9.0, 3.0),  158  4.81 (d, 2H, J = 3.0). 13C: 197.4, 157.2, 139.4, 132.7, 132.6, 132.5, 131.3, 130.3, 128.3, 128.2, 128.1, 125.9 (2C), 125.7, 122.4, 118.0, 103.1, 69.1. B.5.4.3 Characterization of (4-(Allyloxy)naphthalen-1-yl)(p-tolyl)methanone (3.16, R = p-tolyl) 659 mg (92% crude yield) from 624 mg of 3.15, R = p-tolyl, light yellow oil. IR: 1646, 1245. 1H: 8.43-8.40 (m, 1H), 8.32-8.29 (m, 1H), 7.76 (d, 2H, J = 6.0), 7.58-7.53 (m, 3H), 7.27 (d, 2H, J = 9.0), 6.81 (d, 1H, J = 9.0), 6.27-6.14 (m, 1H), 5.56 (d, 1H, J = 18.0), 5.40 (d, 1H, J = 9.0), 4.80 (d, 2H, J = 6.0), 2.44 (s, 3H). 13C: 197.1, 156.9, 143.4, 136.7, 132.7 (2C), 130.6, 130.5, 129.0, 128.7, 127.9, 125.9, 125.8 (2C), 122.3, 117.9, 103.1, 69.1, 21.7. B.5.5 Preparation of compounds 3.17 These substances were prepared by the same procedure detailed above for the synthesis of compound 3.9. B.5.5.1 Characterization of (3-Allyl-4-hydroxynaphthalen-1-yl)(phenyl)methanone (3.17, R = Me) 392 mg (59% yield) from 668 mg of 3.16, R = Me, yellow solid, m.p. 182-184 °C; eluent: 1:4 to 2:3 EtOAc/hexanes. IR: 3534-2837 (broad), 1639. 1H (acetone d6): 9.03 (d, 1H, J = 9.0), 8.35 (d, 1H, J = 6.0), 8.08 (s, 1H), 7.60-7.50 (m, 2H), 6.15-6.02 (m, 1H), 5.15-5.06 (m, 2H), 3.68 (d, 2H, J = 6.0), 2.66 (s, 3H). 13C (acetone d6): 198.9, 153.8, 136.4, 134.5, 131.3, 127.5, 126.7, 126.3, 125.5, 125.4, 121.8, 118.1, 115.3, 33.7, 28.5.  159  B.5.5.2 Characterization of (3-Allyl-4-hydroxynaphthalen-1-yl)(phenyl)methanone (3.17, R = Ph)  366 mg (66% yield) from 556 mg of 3.16, R = Ph, brown oil; eluent: 1:4 to 3:7 EtOAc/hexanes. IR: 3629-3122 (broad), 1641. 1H: 8.32-8.29 (m, 2H), 7.87 (d, 2H, J = 9.0), 7.63-7.44 (m, 7H), 6.12-5.99 (m, 1H), 5.29-5.23 (m, 2H), 3.57 (d, 2H, J = 6.0). 13C: 197.6, 153.1, 139.3, 135.6, 133.2, 132.7, 132.0, 130.4, 128.3 (2C), 127.4, 125.9, 125.7, 125.1, 121.9, 117.5, 116.4, 35.4. B.5.5.3 Characterization of (3-Allyl-4-hydroxynaphthalen-1-yl)(p-tolyl)methanone (3.17, R = 4-Tol)  431 mg (65% yield) from 659 mg of 3.16, R = 4-Tol, yellow solid, m.p.: 113-115 °C; eluent: 1:4 to 3:7 EtOAc/hexanes; IR: 3639-3136 (broad), 1635. 1H: 8.27-8.20 (m, 2H), 7.76 (d, 2H, J = 6.0), 7.54-7.47 (m, 2H), 7.41 (s, 1H), 7.27 (d, 2H, J = 9.0), 6.13-6.00 (m, 2H), 5.31-5.25 (m, 2H), 3.56 (d, 2H, J = 6.0), 2.45 (s, 3H). 13C: 197.2, 152.8, 143.6, 136.5, 135.6, 132.5, 131.9, 130.6, 129.1, 128.9, 127.3, 125.8 (2C), 125.0, 121.7, 117.6, 116.1, 35.6, 21.7. B.5.6 General procedure for the hydroboration oxidation of 3.17 for the synthesis of 4-acyl naphtholic alcohols 3.18 Neat cyclohexene (279 mg, 344 L, 3.4 mmol, 2.0 equiv) was added dropwise over 10 min to a cold (0 °C) solution of BH3•SMe2 (commercial 10 M solution, 170 L, 1.7 mmol, 1.0 equiv) in 1.5 mL THF and maintained under Ar atmosphere. The mixture was stirred for 1h at 0 °C, then a solution of 3.17 (1.7 mmol, 1 equiv) in THF (4.5 mL) was added dropwise. The mixture was warmed to RT and stirred for 2h. Solid NaBO3.4H2O (1.1 g, 6.8 mmol,  160  4.0 equiv) was then added to the mixture at RT and then H2O (3.0 mL) was added dropwise. The mixture was stirred for 2h at RT. The reaction mixture was extracted with EtOAc (4×10 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel to provide 4-acyl naphtholic alcohols. B.5.6.1 Characterization of 1-(4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)ethanone (3.18, R = Me)  246 mg (60% yield) from 382 mg of 3.17, R = Me yellow solid, m.p. 143-145 °C, eluent: 1:4 to 7:13 EtOAc/hexanes. IR: 3615-3020 (broad), 1632. 1H (acetone-d6): 9.02 (d, 1H, J = 9.0), 8.35 (d, 1H, J = 9.0), 8.12 (s, 1H), 7.52 (app p, 2H, J = 8.0), 3.64 (t, 2H, J = 6.0), 3.00 (app t, 2H, J = 6.0), 2.67 (s, 3H), 1.97 (p, 2H, J = 6.0). 13C (acetone-d6): 199.8, 155.9, 136.1, 132.2, 128.3, 127.3, 127.0, 126.6, 126.1, 123.1, 120.3, 60.4, 32.7, 29.4, 26.3. HRMS: calcd for C15H16O3Na [M+Na]+: 267.0997; found: 267.0992. B.5.6.2 Characterization of (4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)(phenyl)methanone (3.18, R = Ph) 243 mg (65% yield) from 354 mg of 3.17, R = Ph, yellow oil, eluent: 1:3 to 2:3 EtOAc/hexanes. IR: 3658-3113 (broad), 1637. 1H: 8.61 (br s, 1H), 8.40-8.36 (m, 1H), 8.31-8.26 (m, 1H), 7.86-7.83 (m, 2H), 7.62-7.43 (m, 6H), 3.66 (t, 2H, J = 4.5), 2.92 (app t, 2H, J = 6.0), 2.43 (br s, 1H), 1.90 (p, 2H, J = 6.0). 13C: 197.7, 154.2, 139.5, 133.9, 132.5, 131.9, 130.3, 128.3, 127.9, 127.3, 125.7, 125.6, 125.5, 122.7, 118.1, 60.1, 31.2, 25.0. HRMS: calcd for C20H18O3Na [M+Na]+: 329.1154; found: 329.1161.  161     162  B.5.6.3 Characterization of (4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)(p-tolyl)methanone (3.18, R = 4-Tol) 263 mg (62% yield) from 400 g of 3.17, R = 4-Tol, yellow solid, m.p. 107-109 °C, eluent: 1:3 to 2:3 EtOAc/hexanes. IR: 3650-3087 (broad), 1633. 1H: 8.73 (br s, 1H), 8.38-8.35 (m, 1H), 8.24-8.21 (m, 1H), 7.75 (d, 2H, J = 6.0), 7.50-7.47 (m, 2H), 7.41 (s, 1H), 7.26 (d, 2H, J = 6.0), 3.60 (t, 2H, J = 4.5), 3.01 (br s, 1H), 2.88 (t, 2H, J = 6.0), 2.44 (s, 3H), 1.85 (p, 2H, J = 6.0). 13C: 197.8, 154.0, 143.6, 136.7, 133.5, 131.8, 130.6, 129.1, 128.2, 127.1, 125.6 (2C), 125.5, 122.7, 118.3, 60.0, 31.2, 25.1, 21.7. HRMS: calcd for C21H20O3Na [M+Na]+: 343.1310; found: 343.1306. B.6 Preparation and characterization of intermediates towards naphtholic alcohol 3.26, R = Me B.6.1 Preparation of 4-Methoxynaphthalen-1-yl trifluoromethanesulfonate (3.19) This compound has been mentioned in the literature,[8] but seemingly neither experimental procedures for its preparation nor physical data have been reported.  Trifluoromethanesulfonic anhydride (~1.0 M in CH2Cl2, 6.9 mL, 6.9 mmol, 1.2 equiv) was carefully added dropwise to a cold (0 °C) solution of N,N-diisopropyl-ethylamine (1.2 mL, 6.9 mmol, 1.2 equiv), 1-naphthol (1.0 g, 5.7 mmol, 1.0 equiv) and DMAP (0.84 g, 6.9 mmol, 1.2 equiv) in CH2Cl2 (13.0 mL). The mixture was warmed to RT and then stirred at RT for 3h, after which time TLC showed that the reaction was complete. The mixture was cooled to 0 °C, quenched with H2O (10.0 mL), and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was                                                  [8] Peterson, G. A.; Kunng, F.-A.; McCallum, J. S.; Wulffe, W. D. Tetrahedron Lett. 1987, 28, 1381.  163  purified by flash column chromatography (eluent: 1:19 EtOAc/hexanes) to provide 1.7 g (95% yield) of 3.19 as white solid; m.p. 49-50 °C (lit. m.p. not reported). IR: 1209, 1088. 1H: 8.32 (d, 1H, J = 8.3), 8.02 (d, 1H, J = 8.3), 7.70-7.56 (m, 2H), 7.38 (d, 1H, J = 8.5), 6.75 (d, 1H, J = 8.6), 4.03 (s, 3H). 13C: 155.4, 139.3, 128.4, 127.3, 126.7, 126.5, 122.7, 120.7, 118.9 (q, J = 641.0, 320.6), 118.1, 102.4, 56.0. 19F: -73.67.  B.6.2 Preparation of 1-Methoxy-4-methylnaphthalene (3.20)  This compound is known,[9] but it was prepared by the following alternative method. Commercial MeMgBr (~3.0 M in Et2O, 1.6 mL, 4.9 mmol, 3.0 equiv) was added to a cold (0 °C) solution of triflate 3.19 (0.5 g, 1.6 mmol, 1.0 equiv) and NiCl2(dppe) (42 mg, 0.08 mmol, 0.05 equiv) in Et2O (5.0 mL) and the mixture was warmed to RT and then stirred at 50 °C for 4h, after which time TLC showed that the reaction was complete. The mixture was cooled to RT and diluted with Et2O (7.0 mL). The solution was then filtered through celite and the celite pad was washed with Et2O (3×15 mL). The filtrate was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 2:23 EtOAc/hexanes) to provide 218 mg (78% yield) of 3.20 as a colorless oil. IR: 1245, 1223, 1214, 1026. 1H: 8.32 (d, 1H, J = 9.0), 7.95 (d, 1H, J = 9.0), 7.58-7.48 (m, 2H), 7.23 (d, 1H, J = 9.0), 6.74 (d, 1H, J = 9.0), 4.00 (s, 3H), 2.63 (s, 3H). 13C: 154.1, 133.3, 126.2, 126.1 (2C), 125.7, 124.9, 124.0, 122.4, 103.4, 55.5, 18.8.                                                    [9] Xing, L.; Wang, X.; Cheng, C.; Zhu, R.; Liu, B.; Hu, Y. Tetrahedron 2007, 63, 9382.  164  B.6.3 Preparation of 4-Methylnaphthalen-1-ol (3.23, R = Me) [Known compound][10] Commercial BBr3 (~1.0 M solution in CH2Cl2, 1.2 mL, 1.2 mmol, 1.1 equiv) was added to a cold (0 °C) solution of 3.20 (180 mg, 1.1 mmol, 1.0 equiv) in CH2Cl2 (6.0 mL) and the mixture was warmed to RT and stirred for 5 h after which time TLC showed that the reaction was complete. The mixture was cooled to 0 °C and quenched with H2O (8.0 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 1:19 EtOAc/hexanes) to provide 157 mg (95% yield) of 3.23, R = Me as tan solid, m.p. 80-82 °C (lit.[10] m.p. 83-84 °C), eluent: 1:19 to 1:9 EtOAc/hexanes. IR: 3659-3113 (broad). 1H: 8.25 (dd, 1H, J = 7.5, 1.7), 7.97 (dd, 1H, J = 7.5, 1.4), 7.61-7.50 (m, 2H), 7.15 (d, 1H, J = 7.5), 6.75 (d, 1H, J = 7.6), 2.64 (s, 3H). 13C: 150.0, 133.6, 126.7, 126.3, 126.2, 125.0, 124.7, 124.3, 122.2, 108.3, 20.0.  B.6.4 Characterization of 1-(Allyloxy)-4-methylnaphthalene (3.24, R = Me)  The procedure described above for 3.8 gave 194 mg (93% crude yield) of 3.24, R = Me from 167 mg of 3.23, R = Me as light yellow oil. IR: 1274. 1H: 8.36 (d, 1H, J = 6.0), 7.94 (d, 1H, J = 9.0), 7.58-7.46 (m, 2H), 7.20 (d, 1H, J = 9.0), 6.73 (d, 1H, J = 6.0), 6.25-6.12 (m, 1H), 5.53 (dd, 1H, J = 18.0, 3.0), 5.34 (dd, 1H, J = 12.0, 3.0), 4.71 (d, 2H, J = 6.0), 2.62 (s, 3H). 13C: 152.9, 133.5, 133.4, 126.3, 126.2, 126.0, 125.9, 124.9, 124.0, 122.5, 117.3, 104.8, 69.0, 18.9.                                                    [10] Ballantine, M.; Menard, M. L.; Tam, W. J. Org. Chem. 2009, 74, 7570.  165  B.6.5 Characterization of (2-Allyl-4-methylnaphthalen-1-ol (3.25, R = Me)  The procedure described above for 3.9 delivered 181 mg (95% yield) of 3.25, R = Me from 190 mg of 3.24, R = Me as light brown oil, eluent: 1:9 to 1:4 EtOAc/hexanes. IR: 3653-3129 (broad). 1H: 8.25-8.21 (m, 1H), 7.97-7.91 (m, 1H), 7.55-7.49 (m, 2H), 7.08 (s, 1H), 6.17-6.04 (m, 1H), 5.31-5.24 (m, 2H), 3.57 (d, 2H, J = 6.0), 2.63 (s, 3H). 13C: 148.0, 136.3, 132.5, 128.9, 126.4, 125.6, 125.1, 125.0, 124.1, 121.9, 117.3, 116.9, 35.8, 18.7. B.6.6 Characterization of 2-(3-Hydroxypropyl)-4-methylnaphthalen-1-ol (3.26, R = Me) Hydroboration-oxidation of 3.25, R = Me (564 mg, 2.8 mmol) by the procedure described above for compound 3.10 afforded 143 mg (23% yield) of 3.26, R = Me as colorless oil, eluent: 1:9 to 1:5 EtOAc/hexanes. IR: 3660-3034 (broad). 1H: 8.32-8.29 (m, 1H), 7.92-7.89 (m, 1H), 7.68 (br s, 1H), 7.51-7.48 (m, 2H), 7.05 (s, 1H), 3.65 (t, 2H, J = 6.0), 2.93 (app t, 2H, J = 8.0), 2.61 (s, 3H), 2.30 (br s, 1H), 1.94 (p, 2H, J = 6.0). 13C: 148.5, 132.4, 129.1, 126.1, 125.6, 125.4, 124.8, 123.9, 122.6, 119.4, 60.3, 31.5, 25.0, 18.7. HRMS: calcd for C14H15O2 [M-H]-: 215.1072; found: 215.1073. B.7 Preparation and characterization of intermediates towards naphtholic alcohols 3.26 B.7.1 General procedure for Suzuki coupling of triflate 3.19 with aryl boronic acids A literature procedure[11] for the preparation of these compounds was modified as follows. A solution of 3.19 (500 mg, 1.6 mmol, 1.0 equiv), Pd(PPh3)4 (94 mg, 82 µmol, 0.05 equiv), an appropriate boronic acid (1.9 mmol, 1.2 equiv), and Cs2CO3 (620 mg, 1.9 mmol, 1.2 equiv) in 1,4-dioxane (6.0 mL) and H2O (1.5 mL) was stirred at 80 °C for 6 h, after which time                                                  [11] Zhao, Y. L.; Li, Y.; Gao, L. X.; Han, F. S. Chem. Eur. J. 2010, 16, 4991.  166  TLC showed that the reaction was complete. The cooled mixture was diluted with Et2O (6.0 mL) and filtered through a Celite® pad, which then was washed with more Et2O (3×10 mL). The combined filtrates were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography to afford corresponding products. Compound 3.21, Ar = Ph is known.[12] B.7.1.1 Characterization of 1-Methoxy-4-(p-tolyl)naphthalene (3.21, Ar = 4-Tol) [Known compound][11] 389 mg (96% yield) from 500 mg of 3.19 and 267 mg of p-tolylboronic acid, white solid, m.p. 112-114 °C (lit.[11] m.p. 114-116 °C), eluent: 1:19 to 1:9 EtOAc/hexanes. IR: 1236, 1082. 1H: 8.38 (d, 1H, J = 8.5), 7.92 (d, 1H, J = 8.3), 7.55-7.45 (m, 2H), 7.43-7.29 (m, 5H), 6.90 (d, 1H, J = 7.9), 4.07 (s, 3H), 2.49 (s, 3H). 13C: 154.9, 138.1, 136.6, 132.8, 132.7, 130.3, 129.1, 126.9, 126.6, 126.0, 125.8, 125.2, 122.3, 103.6, 55.7, 21.4.  B.7.1.2 Characterization of 4-(4-Methoxynaphthalen-1-yl)benzonitrile (3.21, Ar = 4-cyanophenyl) The above procedure, but using 4-cyanophenylboronic acid, gave 340 mg (80% yield) of 3.21, Ar = 4-cyanophenyl, from 500 mg of 3.19, white solid, m.p. 138-140 °C, eluent: 3:17 EtOAc/hexanes. IR: 2227, 1238. 1H: 8.39 (d, 1H, J = 9.0), 7.78-7.76 (m, 3H), 7.60 (d, 2H, J = 9.0), 7.56-7.46 (m, 2H), 7.33 (d, 1H, J = 6.0), 6.90 (d, 1H, J = 6.0), 4.07 (s, 3H). 13C: 155.8, 145.9, 132.1, 131.8, 130.9, 130.6, 127.3, 127.1, 125.7, 125.5, 124.9, 122.5, 119.1, 110.6, 103.4, 55.7.                                                   [12] Basarić, N.; Došlić, N.; Ivković, J.; Wang, Y-. H.; Veljković, J.; Mlinaric-Majerski, K.; Wan, P. J. Org. Chem. 2013, 78, 1811.  167  B.7.2 General procedure for the demethylation of compounds 3.21 These substances were prepared by the same procedure described above for the synthesis of compound 3.23, R = Me and used in the subsequent step without purification. Compound 3.23, R = Ph is known.[12] B.7.2.1 Characterization of 4-p-Tolylnaphthalen-1-ol (3.23, R = 4-Tol) 371 mg (97% crude yield) from 400 mg of 3.21, R = p-tolyl as tan solid, m.p. 115-117 °C. IR: 3481-3119 (broad). 1H: 8.28 (d, 1H, J = 9.0), 7.93 (d, 1H, J = 9.0), 7.56-7.44 (m, 2H), 7.39 (d, 2H, J = 6.0), 7.32-7.26 (m, 3H), 6.88 (d, 1H, J = 9.0), 5.25 (s, 1H), 2.47 (s, 3H). 13C: 150.7, 137.8, 136.6, 133.3, 132.8, 130.1, 129.5, 129.0, 126.8 (2C), 126.5, 126.1, 125.2, 124.4, 121.8, 108.2, 21.2. B.7.2.2 Characterization of 4-(4-Hydroxynaphthalen-1-yl)benzonitrile (3.23, Ar = 4-NC-C6H4) 305 mg (95% crude yield) of product from 340 mg of 3.21, R = 4-NC-C6H4 as white solid, m.p.: 205-206 °C. IR: 3636-2988 (broad), 2228. 1H (acetone-d6): 8.40-8.37 (m, 1H), 7.93 (d, 2H, J = 9.0), 7.83-7.80 (m, 1H), 7.71 (d, 2H, J = 9.0), 7.58-7.51 (m, 2H), 7.34 (d, 1H, J = 6.0), 7.06 (d, 1H, J = 9.0). 13C (acetone-d6): 153.6, 146.0, 132.2, 132.1, 131.0, 129.6, 127.8, 126.9, 125.1, 124.9, 124.7, 122.6, 118.6, 110.4, 107.7. B.7.3 Characterization of 1-(Allyloxy)-4-phenylnaphthalene (3.24, R = Ph) The procedure described above for 3.8 provided 1.17 g (99% crude yield) of 3.24, R = Ph from 0.9 g of 3.23, R = Ph as light brown oil. IR: 1234, 1074. 1H: 8.42 (d, 1H, J = 8.8), 7.88 (d, 1H, J = 8.3), 7.53-7.39 (m, 7H), 7.33 (d, 1H, J = 7.9), 6.89 (d, 1H, J = 7.9), 6.29-6.16 (m, 1H), 5.57 (dd, 1H, J = 17.3, 1.4), 5.38 (dd, 1H, J = 10.5, 1.2), 4.79 (dt,  168  2H, J = 5.1, 1.4). 13C: 153.8, 140.8, 133.3, 132.8, 132.5, 130.3, 128.2, 126.9, 126.8, 126.5, 125.8, 125.7, 125.1, 122.3, 117.5, 104.7, 69.0. HRMS: calcd for C19H15O [M-H]-: 259.1123; found: 259.1121.  B.7.4 Characterization of 1-(Allyloxy)-4-p-tolylnaphthalene (3.24, Ar = 4-Tol) The procedure described above for 3.8 provided 420 mg (98% crude yield) of product as light yellow oil from 365 mg of 3.23, R = 4-Tol. IR: 1235. 1H: 8.41 (d, 1H, J = 9.0), 7.89 (d, 1H, J = 9.0), 7.52-7.23 (m, 7H), 6.88 (d, 1H, J = 6.0), 6.28-6.16 (m, 1H), 5.57 (d, 1H, J = 15.0), 5.38 (d, 1H, J = 9.0), 4.78 (d, 2H, J = 3.0), 2.46 (s, 3H). 13C: 153.7, 137.9, 136.5, 133.4, 132.8, 132.6, 130.1, 129.4, 128.9, 126.8, 126.7, 126.4, 125.8, 125.1, 122.3, 117.4, 104.7, 69.0, 21.2. B.7.5 Characterization of 4-(4-(Allyloxy)naphthalen-1-yl)benzonitrile (3.24, Ar = 4-NC-C6H4)  The procedure described above for 3.8 provided 341 mg (96% crude yield) of 3.24, R = 4-NC-C6H4 from 305 mg of 3.23, R = 4-NC-C6H4 as white solid, m.p. 96-98 °C. IR: 2226. 1H: 8.45 (d, 1H, J = 6.0), 7.79-7.75 (m, 3H), 7.59 (d, 2H, J = 6.0), 7.55-7.47 (m, 2H), 7.31 (d, 1H, J = 9.0), 6.90 (d, 1H, J = 9.0), 6.28-6.16 (m, 1H), 5.58 (dd, 1H, J = 15.0, 3.0), 5.40 (dd, 1H, J = 9.0, 3.0), 4.79 (d, 2H, J = 6.0). 13C: 154.7, 145.8, 133.0, 132.1, 131.9, 130.9, 130.7, 127.3, 127.1, 125.9, 125.5, 124.9, 122.7, 119.1, 117.7, 110.6, 104.6, 69.1. B.7.6 Characterization of 2-Allyl-4-phenylnaphthalen-1-ol (3.25, R = Ph) The procedure described above for 3.9 provided 1.16 g (99% crude yield) of 3.25, R = Ph from 1.17 g of 3.24, R = Ph as brown oil. IR: 3651-3105 (broad). 1H: 8.27  169  (d, 1H, J = 8.3), 7.87 (d, 1H, J = 8.4), 7.53-7.40 (m, 7H), 7.20 (s, 1H), 6.19-6.06 (m, 1H), 5.35-5.26 (m, 2H), 3.63 (app d, 2H, J = 6.2). 13C: 149.2, 140.7, 136.1, 132.9, 131.7, 130.2, 129.5, 128.2, 126.9, 125.9, 125.8, 125.2, 125.0, 121.6, 117.3, 117.2, 35.9. HRMS: calcd for C19H15O [M-H]-: 259.1123; found: 259.1122.  B.7.7 Characterization of 2-allyl-4-p-tolylnaphthalen-1-ol (3.25, Ar = 4-Tol) The procedure described above for 3.9 furnished 353 mg (85% yield) of product from 414 mg of 3.24, R = p-tolyl as light yellow oil, eluent: 1:4 EtOAc/hexanes. IR: 3668-3312 (broad). 1H: 8.27 (d, 1H, J = 9.0), 7.90 (d, 1H, J = 9.0), 7.53-7.38 (m, 4H), 7.31 (d, 2H, J = 9.0), 7.19 (s, 1H), 6.19-6.06 (m, 1H), 5.59 (br s, 1H), 5.36-5.26 (m, 2H), 3.62 (d, 2H, J = 6.0), 2.47 (s, 3H). 13C: 149.1, 137.7, 136.6, 136.1, 132.9, 131.8, 130.1, 129.4, 129.0, 126.8, 125.9, 125.8, 125.2, 125.0, 121.6, 117.3, 117.2, 35.9, 21.2. B.7.8 Characterization of 4-(3-Allyl-4-hydroxynaphthalen-1-yl)benzonitrile (3.25, Ar = 4-NC-C6H4)  The procedure described above for 3.9 furnished 249 mg (75% yield) of product from 332 mg of 3.24, R = 4-NC-C6H4 as light yellow oil, eluent: 1:4 to 7:13 EtOAc/hexanes. IR: 3657-3147 (broad), 2228. 1H: 8.32 (d, 1H, J = 9.0), 7.78-7.75 (m, 3H), 7.60 (d, 2H, J = 6.0), 7.56-7.43 (m, 2H), 7.19 (s, 1H), 6.19-6.06 (m, 1H), 5.84 (br s, 1H), 5.35-5.28 (m, 2H), 3.64 (d, 2H, J = 6.0). 13C: 150.2, 145.7, 135.8, 132.1, 131.1, 131.0, 130.8, 129.8, 126.6, 125.6, 125.1, 125.0, 122.1, 119.1, 117.5 (2C), 110.6, 35.7.    170  B.7.9 Characterization of 2-(3-Hydroxypropyl)-4-phenylnaphthalen-1-ol (3.26, R = Ph) The hydroboration-oxidation procedure described above for compound 3.10 afforded 291 mg (74% yield) of product from 370 mg of 3.25, R = Ph as white solid, m.p.: 127-129 °C (dec.), eluent: 1:4 to 2:3 EtOAc/hexanes. IR: 3681-3108 (broad). 1H: 8.37 (d, 1H, J = 6.0), 7.91 (br s, 1H), 7.87 (d, 1H, J = 9.0), 7.52-7.39 (m, 7H), 7.19 (s, 1H), 3.72 (t, 2H, J = 6.0), 3.00 (app t, 2H, J = 8.0), 2.11 (br s, 1H), 1.99 (p, 2H, J = 6.0). 13C: 149.8, 140.9, 132.6, 131.5, 130.3, 129.7, 128.2, 126.8, 125.7, 125.6, 125.5, 125.0, 122.4, 119.3, 60.4, 31.4, 25.1. HRMS: calcd for C19H17O2 [M-H]-: 277.1229; found: 277.1221. B.7.10 Characterization of 2-(3-Hydroxypropyl)-4-p-tolylnaphthalen-1-ol (3.26, R = 4-Tol) The hydroboration-oxidation procedure described above for compound 3.10 afforded 278 mg (76% yield) of product from 343 mg of 3.25, R = 4-Tol as yellow solid, m.p.: 106-108 °C, eluent: 3:17 to 3:7 EtOAc/hexanes. IR: 3632-3143 (broad). 1H: 8.36 (d, 1H, J = 9.0), 7.87 (d, 1H, J = 9.0), 7.83 (br s, 1H), 7.49 (app t, 1H, J = 7.5), 7.42-7.37 (m, 3H), 7.29 (d, 2H, J = 9.0), 7.16 (s, 1H), 3.72 (t, 2H, J = 6.0), 3.00 (app t, 2H, J = 7.5), 2.46 (s, 3H), 1.99 (p, 2H, J = 6.0). 13C: 149.7, 138.0, 136.4, 132.6, 131.6, 130.1, 129.6, 128.9, 125.7, 125.6, 125.5, 125.0, 122.4, 119.2, 60.4, 31.4, 25.1, 21.2. HRMS: calcd for C20H19O2 [M-H]-: 291.1385; found: 291.1387. B.7.11 Characterization of 4-(4-Hydroxy-3-(3-hydroxypropyl)naphthalen-1-yl)benzonitrile (3.26, R = 4-NC-C6H4) The hydroboration-oxidation procedure described above for compound 3.10 afforded 190 mg (38% yield) of product from 472 mg of 3.25, R = 4-cyanophenyl (eluent: 1:3 to 7:13 EtOAc/hexanes), yellow solid, m.p. 149-151 °C. IR: 3674-3002 (broad), 2229. 1H: 8.39 (d, 1H, J = 6.0), 8.10 (br s, 1H), 7.78-7.73 (m, 3H),  171  7.61 (d, 2H, J = 9.0), 7.54-7.41 (m, 2H), 7.16 (s, 1H), 3.73 (t, 2H, J = 4.5), 3.01 (t, 2H, J = 6.0), 2.04-1.96 (m, 3H). 13C: 151.0, 146.0, 132.1, 130.9, 130.4, 130.1, 126.3, 125.6, 125.4, 124.7, 122.9, 119.3, 119.1, 110.4, 60.2, 31.3, 25.1. EI: calcd for C20H17O2N: 303.1259; found: 303.1262. B.8 Preparation and characterization of intermediates towards 5-substituted naphtholic alcohols 3.32-3.33 B.8.1 Preparation of 5-hydroxynaphthalen-1-yl trifluoromethanesulfonate (3.28) A literature procedure[13] for the preparation of these compounds was modified as follows. A solution of 1,5-dihydroxynaphthalene (4.0 g, 25.0 mmol, 1.0 equiv), N-phenyltrifluoromethanesulfonimide (8.9 g, 25.0 mol, 1.0 equiv), DMAP (367 mg, 3.0 mmol, 0.12 equiv) and 2,6-lutidine (2.9 mL, 25.0 mmol, 1.0 equiv) in CH2Cl2/DMF (19:5 v/v; 95 mL) was refluxed overnight, after which time TLC showed that the reaction was complete. The cooled mixture was evaporated under reduced pressure and then the residue was dissolved in EtOAc (60 mL). The organic layer was sequentially washed with aq. 5% HCl (30 mL), H2O (30 mL) and brine (15 mL). The combined filtrates were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography to provide 1.97 g (27% yield) of 3.28 as brown solid, m.p.: 62-64 °C (lit. m.p not reported), eluent: 1:3 to 1:1 EtOAc/hexane. IR: 3627-3434 (broad). 1H (DMSO-d6): 10.7 (s, 1H), 8.27 (d, 1H, J = 9.0), 7.63 (d, 1H, J = 9.0), 7.58-7.52 (m, 2H), 7.39 (d, 1H, J = 9.0), 7.05 (d, 1H, J = 6.0). 13C: 153.8, 145.0, 129.2, 126.9, 126.2, 124.2, 123.3, 118.6, 110.0, 109.7.                                                    [13] Giubellino, A.; Shi, Z-. D.; Miller J., Lisa M.; Worthy, K. M.; Bindu, L. K.; Athauda, G.; Peruzzi, B.; Fisher, R. J.; Appella, E.; Burke, T. R. J. Med. Chem. 2008, 51, 7459.  172  B.8.2 Preparation of 5-phenylnaphthalen-1-ol (3.29) [Known compound][12] See general procedure for Suzuki coupling of triflates with arylboronic acids, 0.77 g (87% yield) from 1.17 g of 3.28, light brown solid, m.p.: 81-83 °C (lit. m.p not reported), eluent: 1:9 to 1:3 EtOAc/hexane. IR: 3636-3119 (broad). 1H: 8.33 (d, 1H, J = 9.0), 7.63-7.50 (m, 8H), 7.30 (app t, 1H, J = 7.5), 6.86 (d, 1H, J = 9.0), 5.64 (br s, 1H). 13C: 151.6, 141.1, 140.2, 133.1, 130.2, 128.3, 127.7, 127.3, 125.9, 124.9 (2C), 121.2, 119.1, 108.7. B.8.3 Characterization of 1-(allyloxy)-5-phenylnaphthalene (3.30)  The procedure described above for 3.8 provided 0.77 g (90% crude yield) of product from 0.73 g of 3.29 as yellow oil. IR: 1234. 1H: 8.40 (d, 1H, J = 9.0), 7.57-7.45 (m, 8H), 7.33 (app t, 1H, J = 7.5), 6.86 (d, 1H, J = 6.0), 6.28-6.16 (m, 1H), 5.57 (d, 1H, J = 18.0), 5.38 (d, 1H, J = 9.0), 4.77 (d, 2H, J = 6.0). 13C: 154.6, 141.3, 140.0, 133.5, 132.9, 130.2, 128.3, 127.7, 127.3, 125.9, 124.8, 121.8, 118.7, 117.6, 114.9, 105.1, 69.2. B.8.4 Characterization of 2-allyl-5-phenylnaphthalen-1-ol (3.31) The procedure described above for 3.9 provided 0.64 g (85% yield) of product from 0.75 g of 3.30 as yellow oil, eluent: 1:19 EtOAc/hexane. IR: 3655-3212 (broad). 1H: 8.25 (d, 1H, J = 9.0), 7.56-7.40 (m, 8H), 7.18 (d, 1H, J = 9.0), 6.17-6.04 (m, 1H), 5.60 (s, 1H), 5.33-5.26 (m, 2H), 3.60 (d, 2H, J = 6.0). 13C: 150.0, 141.1, 140.1, 136.2, 132.1, 130.2, 128.5, 128.3, 127.3, 127.1, 125.4, 125.0, 121.1, 118.8, 117.7, 117.3, 35.9. B.8.5 Characterization of 2-(3-hydroxypropyl)-5-phenylnaphthalen-1-ol (3.32) The hydroboration-oxidation procedure described above for compound 3.10 afforded 0.40 g (62% yield) of product from 0.60 g of 3.31 as light yellow oil,  173  eluent: 1:9 to 1:3 EtOAc/hexanes. IR: 3632-3119 (broad). 1H: 8.37 (d, 1H, J = 9.0), 8.00 (br s, 1H), 7.57-7.40 (m, 8H), 7.18 (d, 1H, J = 9.0), 3.68 (t, 2H, J = 6.0), 2.98 (app t, 2H, J = 7.5), 2.51 (br s, 1H), 1.96 (p, 2H, J = 6.0). 13C: 150.3, 141.3, 139.9, 131.9, 130.2, 128.7, 128.3, 127.2, 126.8, 125.8, 124.8, 121.8, 120.0, 118.5, 60.4, 31.5, 25.2. HRMS: calcd for C19H19O2 [M+H]+: 279.1385; found: 279.1389. B.8.6 Characterization of 4-chloro-2-(3-hydroxypropyl)-5-phenylnaphthalen-1-ol (3.33) The procedure described above for 3.11 provided 0.064 g (14% yield) of product from 0.40 g of 3.32 as yellow oil, eluent: 1:9 to 3:7 EtOAc/hexane. IR: 3653-3108 (broad). 1H: 8.43 (d, 1H, J = 9.0), 7.50 (d, 1H, J = 9.0), 7.37-7.33 (m, 6H), 7.27 (s, 1H), 3.69 (t, 2H, J = 6.0), 2.93 (app t, 2H, J = 6.0), 1.96 (p, 2H, J = 6.0). 13C: 150.0, 143.7, 139.1, 131.5, 130.9, 129.8, 128.2, 127.9, 127.3, 126.7, 124.7, 122.9, 122.2, 120.4, 60.3, 31.2, 24.9. HRMS: calcd for C19H16O2Cl [M-H]-: 311.0839; found: 311.0835. B.9 Preparation and characterization of intermediates towards naphtholic alcohols with gem-dimethyl substitution in side chain 3.43-3.46 B.9.1 Preparation of 4-Bromo-2-(bromomethyl)-1-methoxynaphthalene (3.35)  Solid NBS (4.1 g, 22.9 mmol, 1.1 equiv) was added in several portions at RT over a period of 25 min to a solution of 2-bromomethyl-1-methoxynaphthalene, 3.34,[14] (5.2 g, 20.8 mmol, 1.0 equiv) in MeCN (78 mL). The mixture was stirred at RT for 3h, after which time TLC showed that the reaction was complete. The solution was diluted with H2O (20 mL) and extracted with Et2O (3×15 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified                                                  [14] Kongkathip, N.; Kongkathip, B.; Siripong, P.; Sangma, C.; Luangkamin, S.; Niyomdecha, M.; Pattanapa, S.; Piyaviriyagul, S.; Kongsaeree, P. Bioorg. Med. Chem. 2003, 11, 3179.  174  by flash column chromatography (eluent: 1:9 EtOAc/hexanes) to provide 6.7 g (98% yield) of 3.35 as off white solid, m.p.: 97-99 °C. IR: 1204, 990. 1H: 8.22-8.19 (m, 1H), 8.14-8.11 (m, 1H), 7.79 (s, 1H), 7.66-7.57 (m, 2H), 4.71 (s, 2H), 4.07 (s, 3H). 13C: 154.2, 133.3, 131.5, 129.2, 128.3, 127.8, 127.4, 127.3, 123.1, 118.2, 62.8, 27.3. B.9.2 Preparation of Methyl 3-(4-bromo-1-methoxynaphthalen-2-yl)-2,2-dimethylpropanoate (3.40) n-BuLi (~1.5 M solution in hexanes, 9.4 mL, 14.0 mmol, 1.0 equiv) was added dropwise over 5 minutes to the flame dried round bottom flask containing solution of diisopropylamine (2.1 mL, 15.0 mmol, 1.07 equiv) in THF (63 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes. Neat ester 3.38 (1.6 mL, 14.0 mmol, 1.0 equiv) was then added dropwise over 15 minutes at -78 °C and stirred for another 1 hour. Solution of 3.35 (5.5 g, 16.8 mmol, 1.2 equiv) in THF (28 mL) was then added dropwise over 20 minutes at -78 °C. The reaction mixture was then warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The reaction mixture was cooled to 0 °C and then quenched with H2O (25 mL) and extracted with Et2O (3×15 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 3:97 EtOAc/hexanes) to provide 4.53 g (94% yield) of 3.40 as colorless oil. IR: 1729. 1H: 8.19-8.16 (m, 1H), 8.10-8.07 (m, 1H), 7.60-7.55 (m, 2H), 7.53 (s, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.04 (s, 2H), 1.22 (s, 6H). 13C: 178.1, 154.6, 133.0, 132.5, 129.3, 127.7, 127.6, 127.2, 126.8, 122.9, 117.2, 62.1, 52.0, 44.1, 39.9, 25.2.    175  B.9.3 Preparation of 6-Bromo-3,3-dimethyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.42) Commercial BBr3 (~1.0 M solution in CH2Cl2, 20.1 mL, 20.1 mmol, 1.1 equiv) was added dropwise over 5 minutes to the solution of 3.40 (5.6 g, 18.3 mmol, 1.0 equiv) in CH2Cl2 (46 mL) at 0 °C. The reaction mixture was then warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The reaction mixture was cooled to 0 °C and then quenched with H2O (25 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was dried under high vacuum and used for further steps without purification. 4.72 g (98% crude yield); white solid, m.p.: 84-86 °C; IR: 1770. 1H: 8.26 (d, 1H, J = 7.9), 8.19 (d, 1H, J = 8.0), 7.66-7.60 (m, 2H), 7.57 (s, 1H), 2.98 (s, 2H), 1.35 (s, 6H). 13C: 173.1, 146.0, 131.8, 129.5, 127.9, 127.4, 127.2, 124.5, 121.7, 117.4, 38.5, 37.2, 24.9. B.9.4 General procedure for reduction of lactone for the synthesis of naphtholic alcohols 3.43-3.44 A solution of crude 3.41 or 3.42 (6.87 mmol, 1.0 equiv) in dry THF (17 mL) was added over 15 minutes to a cold (0 °C) solution of lithium aluminium hydride (0.65 g, 17.2 mmol, 2.5 equiv) in dry THF (9 mL). The mixture was then warmed to RT and stirred for 2 h, after which time TLC showed that the reaction was complete. The mixture was cooled to 0 °C, diluted with Et2O (20 mL) and sequentially treated with H2O (0.7 mL; added slowly and dropwise, CAUTION: vigorous reaction, evolution of flammable H2), 15% aq. NaOH (0.7 mL) and more H2O (2.1 mL). The mixture was warmed to RT and stirred for another 15 minutes, then it was filtered through a Celite® pad, which was washed with more Et2O (4×10 mL). The combined  176  filtrates were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography to provide corresponding products. B.9.4.1 Characterization of 2-(3-Hydroxy-2,2-dimethylpropyl)naphthalen-1-ol (3.43) [Known compound][14] 560 mg (80% yield) from 690 mg of crude 3.41[14], white solid, m.p.: 118-120 °C (lit. m.p.,[14]  123-124 °C), eluent: 1:3 EtOAc/hexane. IR: 3642-3000 (broad). 1H: 8.53-8.50 (m, 1H), 8.33-8.30 (m, 1H), 7.77-7.76 (m, 1H), 7.48-7.45 (m, 2H), 7.35 (d, 1H, J = 8.3), 7.17 (d, 1H, J = 8.3), 3.26 (d, 2H, J = 4.1), 2.78 (s, 2H), 2.42-2.36 (m, 1H), 1.05 (s, 6H). 13C: 151.1, 133.8, 130.9, 127.3, 125.8, 125.6, 125.0, 122.6, 119.1, 117.6, 69.4, 38.5, 36.8, 25.3. B.9.4.2 Characterization of 4-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)naphthalen-1-ol (3.44) 3.91 g (70% yield) from 5.51 g of crude 3.42, off-white solid, m.p.: 98-100 °C, eluent: 1:9 to 3:17 EtOAc/hexane. IR: 3641-3022 (broad). 1H: 8.33 (d, 1H, J = 7.9), 8.11 (d, 1H, J = 7.9), 7.59-7.48 (m, 2H), 7.46 (s, 1H), 3.28 (s, 2H), 2.74 (s, 2H), 1.06 (s, 6H). 13C: 151.2, 133.9, 131.8, 127.2, 126.9, 126.7, 125.8, 123.2, 118.7, 111.9, 69.4, 38.3, 36.8, 25.3. HRMS: calcd for C15H17O279BrNa [M+Na]+: 331.0310; found: 331.0311. B.9.5 Preparation of 4-Chloro-2-(3-hydroxy-2,2-dimethylpropyl)naphthalen-1-ol (3.45) Solid NCS (191 mg, 1.4 mmol, 1.1 equiv) was added in several portions over a period of 30 mins to a solution of 3.43 (300 mg, 1.3 mmol, 1.0 equiv) in MeCN (1.5 mL) at RT. The mixture was refluxed for 5h, after which time TLC showed that the reaction was complete. The solution was cooled to RT and then diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were washed with brine (10 mL),  177  dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:3 EtOAc/hexanes) to provide 296 mg (86% yield) of 3.45, yellow solid, m.p. 98-100 °C. IR: 3636-3041 (broad). 1H: 8.62 (br s, 1H), 8.34 (d, 1H, J = 9.0), 8.16 (d, 1H, J = 9.0), 7.59-7.50 (m, 2H), 7.26 (s, 1H), 3.27 (s, 2H), 2.74 (s, 2H), 2.34 (br s, 1H), 1.06 (s, 6H). 13C: 150.4, 130.5, 130.2, 126.7, 126.6, 125.6, 123.9, 123.1, 121.7, 117.9, 69.2, 38.3, 36.6, 25.1. HRMS: calcd for C15H16O2Cl [M-H]-: 263.0839; found: 263.0834. B.9.6 Characterization of 2-(3-Hydroxy-2,2-dimethylpropyl)-4-phenylnaphthalen-1-ol (3.46, Ar = Ph) The procedure described in title B.4, but employing phenylboronic acid, afforded 450 mg (91% yield) of 3.46, Ar = Ph from 500 mg of 3.44 (eluent: 1:9 to 3:17 EtOAc/hexanes), off white solid, m.p.: 110-112 °C.  IR: 3680-3001 (broad). 1H: 8.42 (d, 1H, J = 8.3), 7.87 (d, 1H, J = 8.3), 7.52-7.40 (m, 7H), 7.15 (s, 1H), 3.32 (s, 2H), 2.83 (s, 2H), 1.07 (s, 6H). 13C: 150.7, 141.1, 132.0, 131.7, 131.6, 130.4, 128.3, 126.9, 125.9, 125.7, 125.6, 125.0, 122.9, 117.2, 69.4, 38.6, 36.8, 25.4. HRMS: calcd for C21H21O2 [M-H]-: 305.1542; found: 305.1541. B.9.7 Characterization of 2-(3-Hydroxy-2,2-dimethylpropyl)-4-(4-(trifluoromethyl)phenyl)naphthalen-1-ol (3.46, Ar = C6H4-CF3-p) The procedure described in title B.4, but employing 4-(trifluoromethyl)-phenylboronic acid, delivered 310 mg (51% yield) of 3.46, Ar = C6H4-CF3-p from 500 mg of 3.44 (eluent: 1:9 to 3:17 EtOAc/hexanes), light yellow solid, m.p.: 165-167 °C. IR: 3671-3031 (broad). 1H: 8.42 (d, 1H, J = 8.2), 7.79-7.72 (m, 3H), 7.60 (d, 2H, J = 8.0), 7.53-7.41 (m, 2H), 7.12 (s, 1H), 3.33 (s, 2H), 2.82 (s, 2H), 1.07 (s, 6H). 13C: 151.5, 144.9, 132.2, 131.4, 130.7, 130.0, 129.0 (q, J = 32.4), 126.3, 125.8, 125.3 (q, J = 3.7), 125.2,  178  125.0, 124.5 (q, J = 272.1), 123.2, 117.2, 69.4, 38.5, 36.8, 25.3. HRMS: calcd for C22H20O2F3 [M-H]-: 373.1415; found: 373.1414. B.10 Preparation and characterization of intermediates towards naphtholic alcohols 3.49-3.50 B.10.1 Preparation of 3,4-dihydro-2H-benzo[h]chromen-2-one (3.48) A literature procedure[15] for the preparation of these compounds was as follows. Amberlyst® 15(H) (400 mg) was added to a solution of 1-naphthol (4 g, 27.8 mmol, 1.0 equiv) and acrylic acid (3.8 mL, 55.6 mmol, 2.0 equiv) in toluene (56 mL). The mixture was heated to reflux for 12 hours, after which time TLC showed that the reaction was complete. The reaction mixture was then filtered and evaporated. The residue was purified by flash column chromatography (eluent: 1:19 to 3:17 EtOAc/hexane) to provide 1.73 g (31% yield) of 3-W as yellow oil. IR: 1760. 1H: 8.24 (d, 1H, J = 6.0), 7.83 (d, 1H, J = 6.0), 7.60 (d, 1H, J = 6.0), 7.57-7.49 (m, 2H), 7.27 (d, 1H, J = 9.0), 3.14 (app t, 2H, J = 7.5), 2.89 (app t, 2H, J = 7.5). 13C: 168.6, 147.0, 133.5, 127.7, 126.7, 126.6, 125.4, 124.1, 123.8, 121.0, 117.3, 29.3, 24.0.  B.10.2 Preparation of 2-(3-hydroxy-3-methylbutyl)naphthalen-1-ol (3.49) This compound is known and was prepared by the literature procedure.[4] Commercial MeMgBr (~3.0 M in Et2O, 9.5 mL, 28.5 mmol, 5.0 equiv) was added dropwise to a cold (0 °C) solution of 3.48 (1.13 g, 5.7 mmol, 1.0 equiv) in dry THF (10.0 mL). The mixture was warmed to RT and then stirred for 1h, after which time TLC showed that the reaction was complete. The mixture was cooled to 0 °C and quenched with aq. satd. NH4Cl (15.0 mL) and extracted with Et2O (3×10 mL). The combined extracts were washed with brine                                                  [15] Rudolph, A.; Bos, P. H.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. 2011, 50, 5834.  179  (10 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 1:9 to 3:17 EtOAc/hexane) on silica gel to provide 1.20 g (91% yield) of 3.49 as white solid, m.p.: 91-93 °C (lit. m.p not reported). IR: 3634-3085 (broad). 1H: 8.29-8.26 (m, 1H), 7.79-7.76 (m, 1H), 7.49-7.41 (m, 2H), 7.38 (d, 1H, J = 6.0), 7.23 (d, 1H, J = 6.0), 5.05 (br s, 1H), 2.90 (t, 2H, J = 7.5), 1.89 (t, 2H, J = 6.0), 1.32 (s, 6H). 13C: 149.2, 133.6, 128.6, 127.5, 125.6, 125.5, 125.1, 122.4, 122.1, 119.8, 72.3, 43.1, 29.8, 24.9. HRMS: calcd for C15H18O2Na [M+Na]+: 253.1204; found: 253.1201.  B.10.3 Characterization of 4-chloro-2-(3-hydroxy-3-methylbutyl)naphthalen-1-ol (3.50) The procedure described above for 3.11 produced 0.35 g (76% yield) of product from 0.40 g of 3.49 as pale yellow oil, eluent: 1:9 to 3:17 EtOAc/hexane. IR: 3624-3099 (broad). 1H: 8.29 (d, 1H, J = 9.0), 8.15 (d, 1H, J = 9.0), 7.57-7.48 (m, 2H), 7.32 (s, 1H), 2.86 (t, 2H, J = 7.5), 1.88 (t, 2H, J = 6.0), 1.32 (s, 6H). 13C: 148.7, 130.4, 128.4, 126.7, 126.6, 125.8, 124.1, 122.9, 122.7, 122.3, 72.4, 42.8, 29.9, 24.7. HRMS: calcd for C15H16O2Cl [M-H]-: 263.0839; found: 263.0841. B.11 Preparation and characterization of intermediates towards naphtholic alcohols 3.54-3.56 with stereogenic center at 2’ position B.11.1 Preparation of compounds 3.52  These substances were prepared by the same procedure detailed above for the synthesis of compound 3.40.    180  B.11.1.1 Characterization of ethyl 2-((1-methoxynaphthalen-2-yl)methyl)-3-methylbutanoate (3.52; R = i-Pr, R’ = Et) 1.71 g (95% yield) from 0.9 mL of ethyl isovalerate (eluent: 1:19 to 1:9 EtOAc/hexane), colorless oil. IR: 1726. 1H: 8.09 (d, 1H, J = 8.2), 7.81 (d, 1H, J = 7.6), 7.55-7.42 (m, 3H), 7.30 (d, 1H, J = 8.5), 4.08-3.91 (m, 5H), 3.15 (dd, 1H, J = 15.0, 4.8), 3.00 (dd, 1H, J = 15.0, 10.2), 2.69-2.62 (m, 1H),2.07-1.96 (m, 1H), 1.11-1.03 (m, 9H). 13C: 175.1, 153.9, 134.0, 128.5, 128.4, 128.0 (2C), 125.8, 125.5, 123.8, 122.0, 61.9, 59.9, 53.3, 30.9, 30.2, 20.4, 20.2, 14.1. B.11.1.2 Characterization of ethyl 2-cyclohexyl-3-(1-methoxynaphthalen-2-yl)propanoate (3.52; R = Cy, R’ = Et) 1.81 g (96% yield) from 1.0 mL of ethyl cyclohexaneacetate (eluent: 1:19 EtOAc/hexane), colorless oil. IR: 1726. 1H: 8.09 (d, 1H, J = 8.2), 7.82 (d, 1H, J = 7.7), 7.56-7.42 (m, 3H), 7.30 (d, 1H, J = 8.5), 4.08-3.94 (m, 5H), 3.19 (dd, 1H, J = 13.5, 4.5), 2.98 (dd, 1H, J = 13.4, 10.6), 2.73-2.62 (m, 1H), 1.99-1.95 (m, 1H), 1.79-1.68 (m, 5H), 1.33-1.10 (m, 5H), 1.03 (t, 3H, J = 7.1). 13C: 175.4, 154.0, 134.1, 128.6 (2C), 128.1 (2C), 125.9, 125.6, 123.9, 122.1, 62.0, 60.0, 52.8, 40.7, 30.9 (2C), 30.2, 26.5 (2C), 26.4, 14.2. B.11.1.3 Characterization of methyl 3-(1-methoxynaphthalen-2-yl)-2-phenylpropanoate (3.52; R = Ph, R’ = Me) 0.924 g (83% yield) from 0.5 mL of methyl phenylacetate (eluent: 1:49 to 1:19 EtOAc/hexane), colorless oil. IR: 1732. 1H: 8.10 (d, 1H, J = 8.2), 7.82 (d, 1H, J = 7.6), 7.54-7.44 (m, 3H), 7.40-7.29 (m, 5H), 7.21 (d, 1H, J = 8.4), 4.12 (app  181  t, 1H, J = 7.7), 3.94 (s, 3H), 3.64-3.56 (m, 4H), 3.28 (dd, 1H, J = 13.7, 6.9). 13C: 174.2, 154.2, 139.1, 134.2, 128.8, 128.6, 128.1 (2C), 127.5 (2C), 125.9, 125.7, 123.9, 122.2, 62.0, 52.2, 52.1, 34.6. B.11.1.4 Characterization of ethyl 4,4,4-trifluoro-2-((1-methoxynaphthalen-2-yl)methyl)butanoate (3.52; R = CH2CF3, R’ = Et) 1.73 g (93% yield) from 0.8 mL of ethyl 4,4,4-trifluorobutyrate, colorless oil, eluent: 1:19 EtOAc/hexane. IR: 1730. 1H: 8.10 (d, 1H, J = 8.0), 7.85 (d, 1H, J = 7.4), 7.60 (d, 1H, J = 8.4), 7.57-7.47 (m, 2H), 7.27 (d, 1H, J = 8.4), 4.16-4.05 (m, 2H), 3.95 (s, 3H), 3.21-3.10 (m, 3H), 2.79-2.61 (m, 1H), 2.33-2.16 (m, 1H), 1.13 (t, 3H, J = 7.1). 13C: 173.8, 154.5, 134.5, 128.2, 128.1 (2C), 126.4 (q, J = 277.1), 126.3, 126.1, 125.9, 124.5, 122.3, 62.2, 61.2, 40.6 (q, J = 2.2), 35.4 (q, J = 29.0), 33.0, 14.1. B.11.1.5 Characterization of ethyl 2-benzyl-3-(1-methoxynaphthalen-2-yl)propanoate (3.52; R = Bn, R’ = Et) 2.13 g (97% yield) from 1.1 mL of ethyl 3-phenylpropionate, colorless oil, eluent: 1:19 to 1:9 EtOAc/hexane. IR: 1727. 1H: 8.08 (d, 1H, J = 6.0), 7.83 (d, 1H, J = 9.0), 7.56 (d, 1H, J = 6.0), 7.53-7.43 (m, 2H), 7.32-7.18 (m, 6H), 3.96 (q, 2H, J = 15.0, 9.0), 3.84 (s, 3H), 3.19-3.03 (m, 4H), 2.87-2.80 (m, 1H), 0.98 (t, 3H, J = 7.5). 13C: 175.3, 154.2, 139.4, 134.2, 129.1, 128.5 (2C), 128.1 (2C), 127.7, 126.5, 126.0, 125.7, 124.0, 122.2, 61.9, 60.4, 48.5, 38.7, 32.7, 14.1. B.11.2 Preparation of compounds 3.53 These substances were prepared by the same procedure described above for the synthesis of compound 3.42 and used in the subsequent step without purification.    182  B.11.2.1 Characterization of 3-isopropyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.53, R = i-Pr) 1.45 g (95% crude yield) from 1.91 g of 3.52 (R = i-Pr, R’ = Et), light yellow oil. IR: 1763. 1H: 8.24 (d, 1H, J = 8.3), 7.83 (d, 1H, J = 8.0), 7.59 (d, 1H, J = 8.3), 7.57-7.48 (m, 2H), 7.27 (d, 1H, J = 8.2), 3.14-2.99 (m, 2H), 2.65 (app q, 1H, J = 14.0, 8.0), 2.35-2.24 (m, 1H), 1.10 (d, 3H, J = 6.9), 1.06 (d, 3H, J = 6.8). 13C: 170.2, 146.3, 133.4, 127.6, 126.5, 126.3, 125.6, 123.8, 123.4, 121.0, 117.2, 45.4, 27.1, 25.6, 20.7, 18.8. B.11.2.2 Characterization of 3-cyclohexyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.53, R = Cy) 2.08 g (97% crude yield) from 2.61 g of 3.52 (R = Cy, R’ = Et), light yellow oil. IR: 1731. 1H: 8.24 (d, 1H, J = 9.0), 7.83 (d, 1H, J = 8.0), 7.59 (d, 1H, J = 8.3), 7.57-7.48 (m, 2H), 7.26 (d, 1H, J = 8.3), 3.16-3.01 (m, 2H), 2.67 (app q, 1H, J = 6.4), 1.89-1.66 (m, 6H), 1.31-1.07 (m, 5H). 13C: 170.3, 146.4, 133.5, 127.7, 126.6, 126.4, 125.7, 123.9, 123.5, 121.2, 117.3, 45.0, 36.8, 31.4, 29.3, 26.4, 26.3, 26.2. B.11.2.3 Characterization of 3-phenyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.53, R = Ph) 0.62 g (79% crude yield) from 0.91 g of 3.52 (R = Ph, R’ = Me), off white solid. IR: 1762. 1H: 8.31 (d, 1H, J = 8.3), 7.86 (d, 1H, J = 8.0), 7.63 (d, 1H, J = 8.0), 7.61-7.52 (m, 2H), 7.43-7.26 (m, 6H), 4.07 (dd, 1H, J = 10.8, 6.8), 3.47 (dd, 1H, J = 15.9, 11.2), 3.32 (dd, 1H, J = 16.1, 6.5). 13C: 169.2, 146.6, 136.7, 133.6, 128.9, 128.2, 127.9, 127.7, 126.7, 126.6, 125.3, 124.2, 123.6, 121.1, 117.3, 45.6, 31.9.  183  B.11.2.4 Characterization of 3-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[h]chromen-2-one (3.53, R = CH2CF3) 1.74 g (99% crude yield) from 2.13 g of 3.52 (R = CH2CF3, R’ = Et), light yellow oil. IR: 1766. 1H: 8.22 (d, 1H, J = 7.4), 7.85 (d, 1H, J = 7.7), 7.64 (d, 1H, J = 8.3), 7.60-7.52 (m, 2H), 7.28 (d, 1H, J = 9.2), 3.39-3.06 (m, 4H), 2.51-2.32 (m, 1H). 13C: 168.8, 146.4, 133.8, 127.8, 127.0, 126.9, 126.5 (q, J = 276.8), 125.3, 124.6, 123.6, 121.0, 116.5, 34.6 (q, J = 2.7), 34.1 (q, J = 29.6), 29.7. B.11.2.5 Characterization of 3-benzyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.53, R = Bn) 1.59 g (95% crude yield) from 2.03 g of 3.52 (R = Bn, R’ = Et), light yellow oil. IR: 1765. 1H: 8.26 (d, 1H, J = 6.0), 7.83 (d, 1H, J = 6.0), 7.59-7.50 (m, 3H), 7.38-7.28 (m, 3H), 7.25-7.16 (m, 3H), 3.48 (dd, 1H, J = 12.0, 4.5), 3.17-2.77 (m, 4H). 13C: 170.6, 146.6, 138.2, 133.6, 129.3, 128.8, 127.7, 127.0, 126.7, 126.6, 125.6, 124.1, 123.6, 121.1, 117.0, 41.0, 35.8, 28.6. B.11.3 Preparation of 2-(3-hydroxy-2-methylpropyl)naphthalen-1-ol (3.54, R = Me)  [Known compound][14] Hydroboration-oxidation of 2-(2-methylallyl)naphthalen-1-ol[14] (7.2 g, 36.3 mmol) by the procedure described above for compound 3.10 afforded 7.0 g (89% yield) of 3.54, R = Me, white solid, m.p.: 85-87 °C (lit. m.p.,[14] 89-90 °C), eluent: 1:9 to 3:7 EtOAc/hexane. IR: 3645-3096 (broad). 1H: 8.31-8.28 (m, 1H), 8.08 (br s, 1H), 7.79-7.76 (m, 1H), 7.50-7.42 (m, 2H), 7.37 (d, 1H, J = 6.0), 7.20 (d, 1H, J = 9.0), 3.63-3.59 (m, 1H), 3.41-3.34 (m, 1H), 2.95-2.81 (m, 2H), 2.23-2.05 (m, 2H), 1.08 (d, 3H, J = 9.0). 13C: 150.5, 133.8, 129.8, 127.4, 125.7, 125.5, 125.1, 122.4, 119.6, 118.5, 65.6, 36.0, 32.7, 17.2.  184  B.11.4 Preparation of compounds 3.54 These substances were prepared by the same procedure described above for the synthesis of compound 3.43-3.44. B.11.4.1 Characterization of (±)-2-(2-(hydroxymethyl)-3-methylbutyl)naphthalen-1-ol (3.54, R = i-Pr) 1.13 g (67% yield) from 1.65 g of crude 3.53, R = i-Pr, off white solid, m.p.: 81-83 °C, eluent: 1:9 to 1:4 EtOAc/hexane. IR: 3650-3021 (broad). 1H: 8.28 (d, 1H, J = 7.7), 8.21 (s, 1H), 7.76 (d, 1H, J = 6.9), 7.49-7.41 (m, 2H), 7.36 (d, 1H, J = 8.3), 7.21 (d, 1H, J = 8.3), 3.74-3.61 (m, 2H),  2.99 (dd, 1H, J = 14.1, 8.5), 2.82 (dd, 1H, J = 14.2, 4.4), 1.99 (br s, 1H), 1.90-1.79 (m, 1H), 1.65-1.52 (m, 1H), 1.12 (d, 3H, J = 6.6), 1.02 (d, 3H, J = 6.7). 13C: 150.4, 133.5, 129.1, 127.2, 125.5 (2C), 125.0, 122.3, 119.9, 119.6, 62.8, 48.0, 29.7, 29.1, 21.1, 20.6. HRMS: calcd for C16H19O2 [M-H]-: 243.1385; found: 243.1385. B.11.4.2 Characterization of (±)-2-(2-cyclohexyl-3-hydroxypropyl)naphthalen-1-ol (3.54, R = Cy) 1.49 g (71% yield) from 2.08 g of 3.53, R = Cy, off white solid, m.p.: 106-108 °C, eluent: 3:17 to 1:4 EtOAc/hexane. IR: 3648-3004 (broad). 1H: 8.41 (s, 1H), 8.31 (d, 1H, J = 8.7), 7.79 (d, 1H, J = 8.6), 7.50-7.43 (m, 2H), 7.39 (d, 1H, J = 8.3), 7.21 (d, 1H, J = 8.3), 3.68-3.57 (m, 2H),  2.98 (dd, 1H, J = 15.0, 8.4), 2.82 (dd, 1H, J = 14.2, 4.5), 2.45 (br s, 1H), 1.97-1.71 (m, 5H), 1.61-1.44 (m, 2H), 1.39-0.99 (m, 5H). 13C: 150.4, 133.6, 129.2, 127.4, 125.6 (2C), 125.1, 122.3, 120.4, 119.8, 62.6, 47.1, 39.7, 31.5, 30.8, 29.2, 26.7 (3C). HRMS: calcd for C19H24O2Na [M+Na]+: 307.1674; found: 307.1669.  185  B.11.4.3 Characterization of (±)-2-(3-hydroxy-2-phenylpropyl)naphthalen-1-ol (3.54, R = Ph) 0.59 g (95% yield) from 0.61 g of 3.53, R = Ph, colourless oil, eluent: 1:4 EtOAc/hexane. IR: 3669-3098 (broad). 1H: 8.33-8.30 (m, 1H), 7.84 (br s, 1H), 7.80-7.77 (m, 1H), 7.52-7.45 (m, 2H), 7.40-7.29 (m, 6H), 7.07 (d, 1H, J = 8.4), 3.81 (app br s, 2H), 3.45 (dd, 1H, J = 13.4, 8.7), 3.18-3.03 (m, 2H), 2.32 (br s, 1H). 13C: 150.4, 142.7, 133.8, 129.3, 128.9, 127.9, 127.5, 127.1, 125.8, 125.6, 125.3, 122.3, 120.1, 118.9, 64.8, 47.8, 31.9. HRMS: calcd for C19H17O2 [M-H]-: 277.1229; found: 277.1234. B.11.4.4 Characterization of (±)-2-(4,4,4-trifluoro-2-(hydroxymethyl)butyl)naphthalen-1-ol (3.54, R = CH2CF3) 1.38 g (78% yield) from 1.75 g of 3.53, R = CH2CF3, light yellow oil, eluent: 1:9 to 3:17 EtOAc/hexane. IR: 3710-3104 (broad). 1H: 8.27-8.24 (m, 1H), 7.80-7.77 (m, 1H), 7.52-7.45 (m, 2H), 7.41 (d, 1H, J = 8.4), 7.20 (d, 1H, J = 8.4), 3.65-3.55 (m, 2H), 3.05-2.91 (m, 2H), 2.39-2.25 (m, 3H). 13C: 150.7, 133.9, 129.1, 127.6, 127.1 (q, J = 277.1), 126.1, 125.5 (2C), 122.2, 120.4, 117.4, 62.2, 35.6 (q, J = 28.1), 35.5 (q, J = 2.0), 30.9. HRMS: calcd for C15H14O2F3 [M-H]-: 283.0946; found: 283.0942. B.11.4.5 Characterization of (±)-2-(2-benzyl-3-hydroxypropyl)naphthalen-1-ol (3.54, R = Bn) 1.46 g (81% yield) from 1.79 g of 3.53, R = Bn, yellow oil, eluent: 1:5 to 1:4 EtOAc/hexane. IR: 3680-3103 (broad). 1H: 8.31-8.28 (m, 1H), 8.14 (br s, 1H), 7.79-7.76 (m, 1H), 7.50-7.43 (m, 2H), 7.39-7.32 (m, 3H), 7.28-7.22 (m, 3H),  186  7.14 (d, 1H, J = 8.3), 3.55-3.44 (m, 2H), 3.03-2.71 (m, 4H), 2.28-2.15 (m, 1H). 13C: 150.6, 140.2, 133.8, 129.4, 129.2, 128.7, 127.4, 126.4, 125.8, 125.6, 125.2, 122.4, 119.9, 118.8, 62.8, 43.1, 38.4, 31.1. HRMS: calcd for C20H19O2 [M-H]-: 291.1385; found: 291.1393. B.11.5 Preparation of compounds 3.55 These substances were prepared by the same procedure detailed above for the synthesis of compound 3.11. B.11.5.1 Characterization of (±)-4-chloro-2-(3-hydroxy-2-methylpropyl)naphthalen-1-ol (3.55, R = Me) 1.10 g (87% yield) from 1.10 g of 3.54, R = Me, off white solid, m.p.: 74-76 °C; eluent: 1:9 to 1:4 EtOAc/hexane. IR: 3643-3017 (broad). 1H: 8.32 (d, 1H, J = 7.7), 8.20 (br s, 1H), 8.15 (d, 1H, J = 7.9), 7.59-7.50 (m, 2H), 7.30 (s, 1H), 3.63 (dd, 1H, J = 10.3, 3.5), 3.39 (dd, 1H, J = 9.9, 6.8), 2.92-2.78 (m, 2H),  2.18-2.00 (m, 2H), 1.09 (d, 3H, J = 6.9). 13C: 149.8, 130.5, 129.3, 126.8, 126.7, 125.8, 124.1, 122.9, 122.4, 119.1, 65.4, 35.8, 32.5, 17.2. HRMS: calcd for C14H14ClO2 [M-H]-: 249.0682; found: 249.0682. B.11.5.2 Characterization of (±)-4-chloro-2-(2-(hydroxymethyl)-3-methylbutyl)naphthalen-1-ol (3.55, R = i-Pr) 0.45 g (99% yield) from 0.40 g of 3.54, R = i-Pr, off white solid, m.p.: 95-97 °C; eluent: 3:17 EtOAc/hexane. IR: 3654-3035 (broad). 1H: 8.32 (d, 1H, J = 9.0), 8.15 (d, 1H, J = 9.0), 7.58-7.49 (m, 2H), 7.30 (s, 1H), 3.73 (dd, 1H, J = 9.0, 4.5), 3.65 (dd, 1H, J = 9.0, 3.0), 2.98 (dd, 1H, J = 15.0, 9.0), 2.78 (dd, 1H, J = 15.0, 3.0), 1.90-1.78 (m, 1H), 1.64-1.54 (m, 1H), 1.11 (d, 3H, J = 6.0), 1.02 (d, 3H, J = 6.0). 13C: 149.9,  187  130.5, 128.9, 126.8, 126.7, 125.8, 124.1, 123.0, 122.4, 120.6, 62.9, 48.0, 29.9, 29.1, 21.2, 20.7. HRMS: calcd for C16H18ClO2 [M-H]-: 277.0995; found: 277.0994. B.11.5.3 Characterization of (±)-4-chloro-2-(2-cyclohexyl-3-hydroxypropyl)naphthalen-1-ol (3.55, R = Cy) 0.46 g (90% yield) from 0.46 g of 3.54, R = Cy, off white solid, m.p.: 105-107 °C; eluent: 1:9 EtOAc/hexane. IR: 3662-3004 (broad). 1H: 8.46 (br s, 1H), 8.31 (d, 1H, J = 7.8), 8.15 (d, 1H, J = 7.9), 7.58-7.49 (m, 2H), 7.29 (s, 1H), 3.73-3.68 (m, 1H), 3.60-3.57 (m, 1H), 2.95 (dd, 1H, J = 14.1, 8.7), 2.76 (dd, 1H, J = 14.2, 4.1), 2.22 (br s, 1H), 1.94-1.69 (m, 5H), 1.59-1.46 (m, 2H), 1.34-0.99 (m, 5H). 13C: 149.8, 130.4, 128.8, 126.8, 126.7, 125.8, 124.1, 122.9, 122.4, 120.8, 62.5, 47.0, 39.8, 31.5, 30.8, 29.1, 26.7 (2C), 26.6. HRMS: calcd for C19H22ClO2 [M-H]-: 317.1308; found: 317.1315. B.11.5.4 Characterization of (±)-4-chloro-2-(3-hydroxy-2-phenylpropyl)naphthalen-1-ol (3.55, R = Ph) 0.18 g (67% yield) from 0.24 g of 3.54, R = Ph, colourless oil; eluent: 3:17 EtOAc/hexane. IR: 3650-3098 (broad). 1H: 8.34 (d, 1H, J = 7.7), 8.18 (d, 1H, J = 8.0), 8.03 (br s, 1H), 7.62-7.52 (m, 2H), 7.41-7.28 (m, 5H), 7.18 (s, 1H), 3.80 (app d, 2H, J = 4.4), 3.42 (dd, 1H, J = 13.8, 9.3), 3.16-3.08 (m, 1H), 3.00 (dd, 1H, J = 13.8, 4.7), 2.35 (br s, 1H). 13C: 149.7, 142.4, 130.6, 128.9 (2C), 127.8, 127.3, 126.9, 126.7, 126.0, 124.2, 122.9, 122.8, 119.4, 64.8, 47.6, 31.7. HRMS: calcd for C19H17ClO2Na [M+Na]+: 335.0815; found: 335.0818.  188  B.11.5.5 Characterization of (±)-4-chloro-2-(4,4,4-trifluoro-2-(hydroxymethyl)butyl)naphthalen-1-ol (3.55, R = CH2CF3) 0.37 g (96% yield) from 0.43 g of 3.54, R = CH2CF3, light yellow solid, m.p.: 69-71 °C; eluent: 1:9 to 1:4 EtOAc/hexane; IR: 3687-3032 (broad). 1H: 8.30 (d, 1H, J = 8.3), 8.17 (d, 1H, J = 8.3), 7.62-7.52 (m, 2H), 7.30 (s, 1H), 3.65-3.64 (m, 2H), 3.03-2.87 (m, 2H), 2.41-2.29 (m, 3H). 13C: 150.2, 130.8, 128.6, 127.2, 127.0 (q, J = 277.0), 126.7, 126.2, 124.3, 123.1, 122.9, 117.7, 62.2, 35.7 (q, J = 28.2), 35.3 (q, J = 2.0), 30.8. HRMS: calcd for C15H13ClO2F3 [M-H]-: 317.0556; found: 317.0561. B.11.5.6 Characterization of (±)-2-(2-benzyl-3-hydroxypropyl)-4-chloronaphthalen-1-ol (3.55, R = Bn) 0.39 g (86% yield) from 0.40 g of 3.54, R = Bn, off white solid, m.p.: 106-108 °C; eluent: 1:4 EtOAc/hexane; IR: 3666-3099 (broad). 1H: 8.32 (d, 1H, J = 7.7), 8.16 (d, 1H, J = 7.8), 7.60-7.50 (m, 2H), 7.37-7.20 (m, 6H), 3.56-3.45 (m, 2H), 2.99-2.71 (m, 4H), 2.27-2.14 (m, 1H). 13C: 149.9, 139.9, 130.6, 129.1, 128.9, 128.8, 126.8, 126.7, 126.6, 125.9, 124.1, 123.0, 122.5, 119.3, 62.9, 43.0, 38.5, 30.9. HRMS: calcd for C20H18ClO2 [M-H]-: 325.0995; found: 325.0988. B.11.6 Preparation of compounds 3.56 These substances were prepared by the same procedure detailed above for the synthesis of compound 3.12.   189  B.11.6.1 Characterization of 4-bromo-2-(3-hydroxy-2-methylpropyl)naphthalen-1-ol (3.56, R = Me) 0.54 g (79% yield) from 0.50 g of 3.54, R = Me, light brown solid, m.p.: 75-77 °C; eluent: 3:17 EtOAc/hexane; IR: 3638-3022 (broad). 1H: 8.31 (d, 1H, J = 7.7), 8.11 (d, 1H, J = 7.9), 7.58-7.50 (m, 3H), 3.48 (dd, 1H, J = 10.3, 3.8), 3.39 (dd, 1H, J = 10.3, 6.7), 2.92-2.78 (m, 2H), 2.15-2.06 (m, 1H), 1.09 (d, 3H, J = 6.9). 13C: 150.7, 133.0, 131.8, 127.1, 126.9, 126.7, 125.9, 123.0, 119.6, 112.4, 65.5, 35.8, 32.4, 17.2. HRMS: calcd for C14H1479BrO2 [M-H]-: 293.0177; found: 293.0182. B.11.6.2 Characterization of 4-bromo-2-(2-(hydroxymethyl)-3-methylbutyl)naphthalen-1-ol (3.56, R = i-Pr) 0.29 g (76% yield) from 0.29 g of 3.54, R = i-Pr, off white solid, m.p.: 96-98 °C, colour changes to black; eluent: 1:9 to 1:4 EtOAc/hexane; IR: 3655-3018 (broad). 1H: 8.31 (d, 1H, J = 7.7), 8.10 (d, 1H, J = 7.8), 7.58-7.48 (m, 3H), 3.73 (dd, 1H, J = 10.4, 5.5), 3.64 (dd, 1H, J = 10.3, 3.7), 2.97 (dd, 1H, J = 14.3, 8.6), 2.77 (dd, 1H, J = 14.3, 4.5), 1.90-1.79 (m, 1H), 1.64-1.54 (m, 1H), 1.11 (d, 3H, J = 6.7), 1.02 (d, 3H, J = 6.8). 13C: 150.6, 132.5, 131.7, 127.0 (2C), 126.7, 125.8, 123.0, 121.3, 112.5, 62.8, 48.0, 29.9, 29.1, 21.2, 20.7. HRMS: calcd for C16H1879BrO2 [M-H]-: 321.0490; found: 321.0499. B.11.6.3 Characterization of 4-bromo-2-(2-cyclohexyl-3-hydroxypropyl)naphthalen-1-ol (3.56, R = Cy) 0.34 g (83% yield) from 0.32 g of 3.54, R = Cy, off white solid, m.p.: 87-90 °C, colour changes to brown; eluent: 1:9 EtOAc/hexane; IR: 3648-3008 (broad). 1H: 8.31 (d, 1H, J = 7.7), 8.10 (d, 1H, J = 7.8), 7.57-7.49 (m, 3H), 3.75 (dd, 1H, J =  190  10.4, 5.1), 3.61 (dd, 1H, J = 10.4, 3.5), 2.96 (dd, 1H, J = 14.2, 8.8), 2.77 (dd, 1H, J = 14.1, 4.3), 1.96-1.70 (m, 5H), 1.61-1.45 (m, 2H), 1.39-0.99 (m, 5H). 13C: 150.6, 132.5, 131.7, 127.0 (2C), 126.7, 125.8, 123.0, 121.4, 112.5, 62.5, 47.0, 39.9, 31.6, 30.8, 29.0, 26.7 (2C), 26.6. HRMS: calcd for C19H2279BrO2 [M-H]-: 361.0803; found: 361.0805. B.11.6.4 Characterization of 2-(2-benzyl-3-hydroxypropyl)-4-bromonaphthalen-1-ol (3.56, R = Bn) 0.11 g (29% yield) from 0.30 g of 3.54, R = Bn, light brown solid, m.p.: 111-113 °C, colour changes to black; eluent: 1:9 to 1:4 EtOAc/hexane; IR: 3662-3099 (broad). 1H: 8.31 (d, 1H, J = 8.3), 8.10 (d, 1H, J = 7.8), 7.58-7.49 (m, 2H), 7.39-7.32 (m, 3H), 7.28-7.22 (m, 3H), 3.58-3.48 (m, 2H), 2.99-2.73 (m, 4H), 2.28-2.15 (m, 1H). 13C: 150.7, 139.9, 132.6, 131.8, 129.2, 128.8, 127.1, 126.9, 126.7, 126.6, 125.9, 123.0, 119.9, 112.6, 62.9, 43.0, 38.5, 30.9. HRMS: calcd for C20H1879BrO2 [M-H]-: 369.0490; found: 369.0498. B.12 Preparation and characterization of intermediates towards 3.59-3.60  B.12.1 Preparation of 4-phenyl-3,4-dihydro-2H-benzo[h]chromen-2-one (3.58) [Known compound][16] The procedure described above for 3.48 afforded 1.68 g (44% yield) of 3.58 from 2.0 g of 1-naphthol and 4.1 g of trans-cinnamic acid, light yellow solid, m.p.: 107-109 °C (lit.[16] m.p.: 111-113 °C); eluent: 1:9 to 1:3 EtOAc/hexane; IR: 1764. 1H: 8.34 (d, 1H, J = 9.0), 7.85 (d, 1H, J = 6.0), 7.62-7.54 (m, 3H), 7.38-7.30 (m, 3H), 7.20-7.18 (m, 2H), 7.12 (d, 1H, J = 9.0), 4.49 (t, 1H, J = 7.5), 3.23 (dd, 1H, J                                                  [16] Zadsirjan, V.; Heravi, M. M.; Tajbakhsh, M.; Oskooie, H. A.; Shiri, M.; Hosseinnejad, T. Res. Chem. Intermed. 2016, 42, 6407.  191  = 15.0, 6.0), 3.13 (dd, 1H, J = 15.0, 6.0). 13C: 167.6, 146.9, 140.8, 133.8, 129.3, 127.8, 127.7 (2C), 127.0, 126.9, 125.5, 124.4, 123.9, 121.5, 120.0, 41.2, 37.4.   B.12.2 Characterization of (±)-2-(3-hydroxy-1-phenylpropyl)naphthalen-1-ol (3.59) [Known compound][17] The procedure described above for 3.43-3.44 afforded 0.80 g (65% yield) of 3.59 from 1.20 g of 3.58, white solid, m.p.: 86-88 °C, eluent: 3:17 to 1:3 EtOAc/hexane. IR: 3638-3106 (broad). 1H: 8.29 (d, 1H, J = 7.8), 7.73 (d, 1H, J = 8.0), 7.51-7.43 (m, 3H), 7.34-7.31 (m, 5H), 6.99 (d, 1H, J = 8.6), 4.84 (dd, 1H, J = 11.4, 4.7), 3.95-3.87 (m, 1H), 3.54-3.47 (m, 1H), 2.59-2.47 (m, 1H), 2.26-2.15 (m, 1H), 2.08 (br s, 1H). 13C: 149.6, 144.0, 133.4, 128.6, 128.4, 127.5, 126.6, 126.4, 126.0, 125.7, 125.4, 123.8, 122.4, 120.8, 60.6, 38.4, 36.7. HRMS: calcd for C19H18O2Na [M+Na]+: 301.1204; found: 301.1211. B.12.3 Characterization of (±)-4-chloro-2-(3-hydroxy-1-phenylpropyl)naphthalen-1-ol (3.60) The procedure described for 3.11 afforded 0.298 g (76% yield) of (±)-3.60 from 0.35 g of (±)-3.59 as yellow solid, m.p.: 139-141 °C, colour changes to brown; eluent: 3:17 to 3:7 EtOAc/hexane; IR: 3631-3103 (broad). 1H: 8.36-8.33 (m, 1H), 8.14-8.10 (m, 1H), 7.69 (br s, 1H), 7.60-7.52 (m, 2H), 7.38-7.24 (m, 5H), 7.04 (s, 1H), 4.82 (dd, 1H, J = 11.6, 4.5), 3.99-3.92 (m, 1H), 3.50 (td, 1H, J = 10.9, 3.1), 2.59-2.47 (m, 1H), 2.24-2.14 (m, 1H), 2.01 (br s, 1H). 13C: 149.0, 143.2, 130.4, 128.8, 128.4, 127.1, 126.9, 126.3, 126.2, 124.4, 124.2, 123.7, 123.1, 60.5, 38.3, 35.5. HRMS: calcd for C19H16ClO2 [M-H]-: 311.0839; found: 311.0833.                                                  [17] Hong, L.; Wang, L.; Sun, W.; Wong, K.; Wang, R. J. Org. Chem. 2009, 74, 6881.   192  B.13 Preparation and characterization of intermediates towards 3.63-3.64 B.13.1 Preparation of 3,4-dihydro-2H-benzo[h]chromen-2-ol (3.61) This compound is known and was prepared by the literature procedure.[15] DIBALH (~1.0 M solution in hexane, 9.8 mL, 9.8 mmol, 1.12 equiv) was added by syringe pump over 30 minutes to a solution of 3.48 (1.73 g, 8.7 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at -78 °C. The mixture was stirred for 2 h at -78 °C and then poured into satd. aqueous solution of Rochelle’s salt (45mL). The mixture was then stirred for 2 h at RT and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 1:9 to 1:4 Et2O/pentane) on silica gel to provide 1.41 g (82% yield) of 3.61 as white solid, m.p.: 62-64 °C (lit. m.p. not reported). IR: 3645-3117 (broad). 1H: 8.18-8.15 (m, 1H), 7.78-7.75 (m, 1H), 7.49-7.43 (m, 2H), 7.39 (d, 1H, J = 8.4), 7.18 (d, 1H, J = 8.3), 5.83 (s, 1H), 3.16-3.04 (m, 2H), 2.85 (app dt, 1H, J = 16.5, 5.4), 2.22-2.06 (m, 2H). 13C: 146.8, 133.4, 127.6, 127.5, 125.8, 125.5, 125.3, 121.4, 120.4, 115.8, 92.5, 27.2, 20.8. B.13.2 General procedure for reaction of Grignard reagent with 3.61  Commercial Grignard (~3.0 M in Et2O, 1.3 mL, 4.0 mmol, 4.0 equiv) was added dropwise to a cold (0 °C) solution of 3.61 (0.2 g, 1.0 mmol, 1.0 equiv) in dry Et2O (2.0 mL). The mixture was warmed to RT and then stirred for 1h, after which time TLC showed that the reaction was complete. The mixture was cooled to 0 °C and quenched with aq. satd. NH4Cl (5.0 mL) and extracted with Et2O (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel to provide 3.62.  193  B.13.2.1 Characterization of (±)-2-(3-hydroxybutyl)naphthalen-1-ol (3.62, R = Me)  0.40 g (92% yield) from 0.4 g of 3.61 and 2.7 mL of MeMgBr, light yellow oil, eluent: 1:9 to 1:4 EtOAc/hexane. IR: 3650-3094 (broad). 1H: 8.29-8.26 (m, 1H), 8.06 (br s, 1H), 7.78-7.75 (m, 1H), 7.49-7.41 (m, 2H), 7.38 (d, 1H, J = 8.9), 7.21 (d, 1H, J = 8.3), 3.82-3.71 (m, 1H), 3.18-3.08 (m, 1H), 2.77 (dt, 1H, J = 14.3, 4.4), 1.86-1.80 (m, 2H), 1.24 (d, 3H, J = 6.1). 13C: 150.3, 133.7, 128.7, 127.4, 125.7, 125.5, 125.2, 122.3, 120.3, 120.1, 66.7, 38.8, 26.0, 24.2. HRMS: calcd for C14H15O2 [M-H]-: 215.1072; found: 215.1069. B.13.2.2 Characterization of (±)-2-(3-hydroxy-3-phenylpropyl)naphthalen-1-ol (3.62, R = Ph) 0.53 g (95% yield) from 0.4 g of 3.61 and 2.7 mL of PhMgBr, light yellow solid, m.p.: 94-96 °C, eluent: 1:9 to 1:3 EtOAc/hexane. IR: 3655-3103 (broad). 1H: 8.32-8.29 (m, 1H), 7.92 (br s, 1H), 7.81-7.78 (m, 1H), 7.51-7.46 (m, 2H), 7.42 (d, 1H, J = 8.4), 7.36-7.23 (m, 6H), 4.62 (dd, 1H, J = 11.0, 3.0), 3.30-3.20 (m, 1H), 2.87(dt, 1H, J = 14.3, 4.5), 2.41 (br s, 1H), 2.27-2.15 (m, 1H), 2.07-1.95 (m, 1H). 13C: 150.2, 143.8, 133.8, 128.8, 128.7, 128.2, 127.5, 125.9, 125.8, 125.4, 125.3, 122.3, 120.2, 120.1, 72.9, 39.1, 26.2. HRMS: calcd for C19H18O2Na [M+Na]+: 301.1204; found: 301.1204. B.13.3 Characterization of (±)-4-chloro-2-(3-hydroxybutyl)naphthalen-1-ol (3.63) The procedure described for 3.11 afforded 0.37 g (76% yield) of product from 0.42 g of 3.62, R = Me as white solid, m.p.: 64-66 °C, colour changes to brown; eluent: 1:9 EtOAc/hexane; IR: 3648-3011 (broad). 1H: 8.32-8.29 (m, 1H), 8.16-8.13 (m, 1H), 7.59-7.49 (m, 2H), 7.31 (s, 1H), 3.81-3.70 (m, 1H), 3.16-3.06 (m, 1H), 2.72 (dt, 1H, J = 14.4, 4.3), 1.86-1.80 (m, 2H), 1.75 (d, 3H, J = 6.1). 13C: 149.7, 130.5, 128.5,  194  126.8, 126.7, 125.9, 124.1, 122.9, 122.7, 120.8, 66.7, 38.5, 25.9, 24.2. HRMS: calcd for C14H14ClO2 [M-H]-: 249.0682; found: 249.0675. B.13.4 Characterization of (±)-4-chloro-2-(3-hydroxy-3-phenylpropyl)naphthalen-1-ol (3.64) The procedure described for 3.11 afforded 0.33 g (89% yield) of product from 0.33 g of 3.62, R = Ph as light yellow solid, m.p.: 108-110 °C, eluent: 1:9 to 1:4 EtOAc/hexane. IR: 3634-2994 (broad). 1H: 8.33 (d, 1H, J = 8.0), 8.19 (d, 1H, J = 8.0), 8.11 (br s, 1H), 7.61-7.52 (m, 2H), 7.34-7.30 (m, 6H), 4.62 (dd, 1H, J = 9.8, 2.5), 3.27-3.17 (m, 1H), 2.83 (dt, 1H, J = 14.4, 3.9), 2.44 (br s, 1H), 2.23-2.14 (m, 1H), 2.04-1.96 (m, 1H). 13C: 149.7, 143.5, 130.6, 128.9, 128.5, 128.4, 126.9, 126.6, 126.0, 125.9, 124.2, 122.9, 120.5, 72.9, 38.9, 26.1. HRMS: calcd for C19H16ClO2 [M-H]-: 311.0839; found: 311.0837. B.14 Preparation and characterization of various intermediates towards amine 3.72 B.14.1 General procedure for protection of 3.68 as TBS ether  A solution of 3.68 (35 mmol, 1.0 equiv), imidazole (46 mmol, 1.3 equiv) and TBSCl (42 mmol, 1.2 equiv) in CH2Cl2 (55 mL) was stirred at RT overnight, after which time TLC showed that the reaction was complete. The mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 3.69. Compound 3.69 with R = H is known.[18]                                                  [18] Schuenemann, K.; Furkert, D. P.; Connelly, S.; Fraser, J. D.; Sperry, J.; Brimble, M. A. Eur. J. Org. Chem. 2014, 122-128.  195  B.14.1.1 Characterization of 1-(tert-Butyldimethylsilyloxy)-2-allyl-4-phenylnaphthalene (3.69, R’ = Ph) 1.37 g (95% yield) from 1.65 g of 3.68, R' = Ph, colorless oil, eluent: 1:19 EtOAc/hexane. IR: 1252, 1099. 1H: 8.15 (d, 1H, J = 8.2), 7.84 (d, 1H, J = 7.9), 7.49-7.34 (m, 7H), 7.25 (s, 1H), 6.05-5.91 (m, 1H), 5.17-5.07 (m, 2H), 3.59 (dt, 2H, J = 6.6, 1.2), 1.16 (s, 9H), 0.23 (s, 6H). 13C: 147.6, 140.9, 137.0, 133.8, 131.6, 130.2, 129.3, 128.3, 128.2, 126.9, 125.8, 125.4, 124.6, 124.3, 123.3, 116.2, 34.5, 26.1, 18.7, -3.1. HRMS: calcd for C25H30OSiNa [M+Na]+: 397.1968; found: 397.1964. B.14.1.2 Characterization of 1-(tert-Butyldimethylsilyloxy)-2-allyl-4-methoxynaphthalene (3.69, R’ = OMe) 1.42 g (93% yield) from 1.55 g of 3.68, R' = OMe, colorless oil, eluent: 1:19 EtOAc/hexane. IR: 1258, 1096. 1H: 8.18 (dd, 1H, J = 7.8, 1.1), 8.02 (dd, 1H, J = 7.1, 1.9), 7.48-7.40 (m, 2H), 6.62 (s, 1H), 6.03-5.90 (m, 1H), 5.19-5.11 (m, 2H), 3.96 (s, 3H), 3.55 (app d, 2H, J = 6.5), 1.13 (s, 9H), 0.16 (s, 6H). 13C: 149.9, 141.5, 137.2, 128.8, 125.4, 125.3, 124.7, 124.0, 122.9, 121.7, 116.1, 105.8, 55.6, 34.8, 26.1, 18.7, -3.3.  B.14.2 General procedure for hydroboration-oxidation of terminal alkenes 3.69 These substances were prepared by the same procedure detailed above for the synthesis of compound 3.10.    196  B.14.2.1 Characterization of 1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl-propan-1-ol (3.70, R’ = H) This compound has been described only in a patent.[19] 4.03 g (76% yield) from 5.00 g of 3.69, R' = H, white solid, m.p.: 78-80 °C; eluent: 3:7 EtOAc/hexane; IR: 3636-3133 (broad). 1H: 8.08-8.05 (m, 1H), 7.79-7.76 (m, 1H), 7.48 (d, 1H, J = 8.3), 7.44-7.38 (m, 2H), 7.30 (d, 1H, J = 8.4), 3.58 (t, 2H, J = 6.3), 2.89 (t, 2H, J = 7.2), 1.90 (p, 2H, J = 6.9), 1.13 (s, 9H), 0.19 (s, 6H). 13C: 148.2, 133.7, 128.2, 128.1, 127.6, 126.7, 125.2, 124.8, 123.0, 121.9, 62.0, 33.1, 26.5, 26.1, 18.7, -3.2. B.14.2.2 Characterization of 1-(tert-Butyldimethylsilyloxy)-(4-phenylnaphthalen-2-yl)-propan-1-ol (3.70, R’ = Ph) 1.47 g (76% yield) from 1.85 g of 3.69, R' = Ph, white solid, m.p.: 57-59 °C; eluent: 1:3 EtOAc/hexane. IR: 3546-3168 (broad), 1252, 965. 1H: 8.16 (d, 1H, J = 7.8), 7.86 (d, 1H, J = 8.2), 7.52-7.35 (m, 7H), 7.27 (s, 1H), 3.63 (t, 2H, J = 6.4), 2.93 (app t, 2H, J = 7.2), 1.94 (p, 2H, J = 6.9), 1.17 (s, 9H), 0.24 (s, 6H). 13C: 147.7, 140.8, 134.2, 131.5, 130.2, 129.4, 128.2 (2C, shoulder), 126.9, 126.2, 125.9, 125.3, 124.7, 123.3, 62.1, 33.2, 26.5, 26.2, 18.7, -3.1. HRMS: calcd for C25H32O2SiNa [M+Na]+: 415.2069; found: 415.2077. B.14.2.3 Characterization of 1-(tert-Butyldimethylsilyloxy)-(4-methoxynaphthalen-2-yl)-propan-1-ol (3.70, R’ = OMe) 1.41 g (87% yield) from 1.63 g of 3.69, R' = OMe, colorless oil, eluent: 3:7 EtOAc/hexane; IR: 3693-3126 (broad). 1H: 8.19-8.16 (m, 1H), 8.02-7.99 (m,                                                  [19] Batt, D. G. Eur. Pat. Appl. 1986, EP 201071 A2 19861112.  197  1H), 7.49-7.39 (m, 2H), 6.61 (s, 1H), 3.97 (s, 3H), 3.56 (t, 2H, J = 6.2), 2.88 (t, 2H, J = 7.2), 1.90 (p, 2H, J = 6.8), 1.12 (s, 9H), 0.16 (s, 6H). 13C: 150.3, 141.5, 128.6, 125.9, 125.5, 125.2, 124.6, 122.8, 121.7, 105.8, 61.9, 55.6, 33.1, 26.8, 26.1, 18.6, -3.3. B.14.3 General procedure for azidation of primary alcohols Neat DPPA (10.4 mL, 48.3 mmol, 2.1 equiv) was added dropwise to a cold (0 °C) solution of 3.70 (23 mmol, 1.0 equiv) and PPh3 (48.3 mmol, 2.1 equiv) in THF (65 mL). Neat diisopropyl azodicarboxylate (9.5 mL, 48.3 mmol, 2.1 equiv) was then added dropwise to the cold solution over 10 min and with good stirring. The mixture was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The solution was evaporated and the residue was purified by flash column chromatography to provide 3.71. B.14.3.1 Characterization of 1-(tert-Butyldimethylsilyloxy)-2-(3-azido-1-propyl)-naphthalene (3.71, R’ = H)  2.1 g (78% yield) from 2.5 g of 3.70, R' = H, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 2092. 1H: 8.08-8.05 (m, 1H), 7.79-7.76 (m, 1H), 7.49-7.41 (m, 3H), 7.28 (d, 2H, J = 7.1), 3.27 (t, 2H, J = 6.9), 2.87 (t, 2H, J = 7.8), 1.93 (p, 2H, J = 7.2), 1.13 (s, 9H), 0.19 (s, 6H). 13C: 148.4, 133.7, 128.1(2C), 127.6, 125.9, 125.3, 124.9, 123.0, 121.7, 51.0, 29.4, 27.7, 26.1, 18.7, -3.2.  B.14.3.2 Characterization of 1-(tert-Butyldimethylsilyloxy)-2-(3-azido-1-propyl)-4-phenylnaphthalene (3.71, R’ = Ph)  0.81 g (65% yield) from 1.17 g of 3.70, R' = Ph, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 2094. 1H: 8.15 (d, 1H, J = 8.1), 7.86 (d, 1H, J = 8.4), 7.50-7.36 (m, 7H), 7.24 (s, 1H), 3.31 (t, 2H, J = 6.9), 2.91 (app t, 2H, J = 7.3), 1.97  198  (p, 2H, J = 7.2), 1.17 (s, 9H), 0.24 (s, 6H). 13C: 147.9, 140.7, 134.1, 131.6, 130.2, 129.2, 128.3, 128.2, 127.0, 125.9, 125.4 (2C), 124.8, 123.3, 51.1, 29.5, 27.7, 26.1, 18.7, -3.1.  B.14.3.3 Characterization of 1-(tert-Butyldimethylsilyloxy)-2-(3-azido-1-propyl)-4-methoxynaphthalene (3.71, R’ = OMe)  0.85 g (81% yield) from 1.05 g of 3.70, R' = OMe, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 2094. 1H: 8.19-8.16 (m, 1H), 8.02-7.99 (m, 1H), 7.49-7.40 (m, 2H), 6.59 (s, 1H), 3.98 (s, 3H), 3.28 (t, 2H, J = 6.9), 2.85 (app t, 2H, J = 7.3), 1.93 (p, 2H, J = 7.2), 1.12 (s, 9H), 0.16 (s, 6H). 13C: 150.1, 141.8, 128.7, 125.5, 125.3, 125.1, 124.7, 122.8, 121.7, 105.8, 55.6, 51.0, 29.4, 28.1, 26.1, 18.6, -3.3. HRMS: calcd for C20H29N3O2SiNa [M+Na]+: 394.1927; found: 394.1919. B.14.4 General procedure for synthesis of amines from azides Commercial 1M Me3P in THF (4.6 mL, 4.6 mmol, 2.0 equiv) was added slowly at RT to solution of 3.71 (23 mmol, 1.0 equiv) in THF (50 mL). H2O (25 ml) was added to the reaction mixture and the solution was stirred at RT for 7 h, after which time TLC showed that the reaction was complete. The mixture was quenched with aq. satd. NH4Cl (20 mL) and extracted with EtOAc (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated and the residue was dried under high vacuum and used for the next step without purification. B.14.4.1 Characterization of 3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)propan-1-amine (3.72, R’ = H)  2.7 g (96% crude yield) from 3.0 g of 3.71, R' = H, brown oil; IR: 3109-2752 (broad). 1H: 8.06-8.05 (m, 1H), 7.76-7.72 (m, 1H), 7.44-7.37 (m, 3H), 7.29 (d,  199  1H, J = 8.5), 3.71 (br s, 2H), 2.86-2.76 (m, 4H), 1.93 (p, 2H, J = 7.4), 1.11 (s, 9H), 0.16 (s, 6H). 13C: 148.2, 133.7, 128.1, 128.0, 127.6, 125.7, 125.3, 124.8, 123.0, 121.9, 40.3, 30.6, 27.4, 26.1, 18.7, -3.2. HRMS: calcd for C19H30NOSi [M+H]+: 316.2097; found: 316.2094. B.14.4.2 Characterization of 3-(1-(tert-butyldimethylsilyloxy)-4-phenylnaphthalen-2-yl)propan-1-amine (3.72, R’ = Ph)  898 mg (97% crude yield) from 986 mg of 3.71, R' = Ph, yellow solid; IR: 3403-2647 (broad). 1H: 8.11 (d, 1H, J = 7.7), 7.82 (d, 1H, J = 8.1), 7.48-7.33 (m, 7H), 7.21 (s, 1H), 5.42 (br s, 2H), 2.87-2.83 (m, 4H), 2.00 (p, 2H, J = 7.6), 1.12 (s, 9H), 0.19 (s, 6H). 13C: 147.8, 140.4, 134.3, 131.7, 130.2, 128.8, 128.2 (2C), 126.9, 125.9, 125.5, 124.7, 124.6, 123.3, 39.7, 28.0, 27.1, 26.1, 18.6, -3.1. HRMS: calcd for C25H34NOSi [M+H]+: 392.2410; found: 392.2411. B.14.4.3 Characterization of 3-(1-(tert-butyldimethylsilyloxy)-4-methoxynaphthalen-2-yl)propan-1-amine (3.72, R’ = OMe)  738 mg (93% crude yield) from 853 mg of 3.71, R' = OMe, colorless oil; IR: 2752-3172 (broad). 1H: 8.35 (br s, 2H), 8.15 (dd, 1H, J = 7.2, 1.9), 7.96 (dd, 1H, J = 7.3, 1.7), 7.48-7.39 (m, 2H), 6.65 (s, 1H), 3.93 (s, 3H), 2.86-2.78 (m, 4H), 2.11 (p, 2H, J = 7.2), 1.07 (s, 9H), 0.11 (s, 6H). 13C: 150.3, 141.8, 128.6, 125.6, 125.4, 124.8, 123.9, 122.8, 121.8, 105.4, 55.8, 39.1, 28.1, 27.4, 26.1, 18.6, -3.3. HRMS: calcd for C20H32NO2Si [M+H]+: 346.2202; found: 346.2199. B.15 General procedure for coupling reaction between amine and sulfonyl chloride An appropriate sulfonyl chloride (25.2 mmol, 1.2 equiv) was added to a cold (0 °C) solution of 3.72 (21 mmol, 1.0 equiv) and Et3N (3.8 mL, 27.3 mmol, 1.3 equiv) in CH2Cl2 (45  200  mL). The resulting mixture was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The mixture was quenched with aq. satd. NH4Cl (15 mL) and extracted with CH2Cl2 (3×15 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 3.73. B.15.1 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)propyl)methanesulfonamide (3.73; R = Me, R’ = H)  1.18 g (86% yield) from 1.10 g of 3.72, R’ = H, yellow solid, m.p.: 92-94 °C; eluent: 1:3 EtOAc/hexane; IR: 3150-3440 (broad). 1H: 8.07-8.04 (m, 1H), 7.79-7.76 (m, 1H), 7.50-7.42 (m, 3H), 7.28-7.25 (m, 1H), 4.44 (t, 1H, J = 5.9), 3.03 (q, 2H, J = 13.4, 6.8), 2.88 (t, 2H, J = 7.3), 2.83 (s, 3H), 1.93 (p, 2H, J = 7.0), 1.13 (s, 9H), 0.19 (s, 6H). 13C: 148.3, 133.7, 128.1, 127.8, 127.6, 125.7, 125.5, 125.0, 122.9, 122.2, 42.4, 40.1, 30.4, 27.0, 26.1, 18.7, -3.2. HRMS: calcd for C20H31NO3SSiNa [M+Na]+: 416.1692; found: 416.1686. B.15.2 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.73; R = 4-Tol, R’ = H)  397 mg (89% yield) from 300 mg of 3.72, R’ = H, colorless oil, eluent: 1:3 EtOAc/hexane; IR: 3441-3126 (broad). 1H: 8.06-8.02 (m, 1H), 7.77-7.74 (m, 1H), 7.60 (d, 2H, J = 8.3), 7.49-7.40 (m, 3H), 7.17-7.11 (m, 3H), 4.58 (t, 1H, J = 6.1), 2.82-2.75 (m, 4H), 2.34 (s, 3H), 1.82 (p, 2H, J = 7.0), 1.12 (s, 9H), 0.16 (s, 6H). 13C: 148.1, 143.1, 136.6, 133.7, 129.5, 128.0, 127.8, 127.6, 126.9, 125.7, 125.4, 125.0, 123.0, 122.1, 42.2, 29.8, 26.8, 26.1, 21.4, 18.7, -3.2. HRMS: calcd for C26H35NO3SSiNa [M+Na]+: 492.2005; found: 492.2002.  201  B.15.3 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.73; R = C6H4-NO2-p, R’ = H) 433 mg (91% yield) from 300 mg of 3.72, R’ = H, colorless oil, eluent: 1:2 EtOAc/hexane; IR: 3420-3168 (broad), 1530, 1347. 1H: 8.02-7.99 (m, 3H), 7.76-7.72 (m, 3H), 7.53-7.40 (m, 2H), 7.43 (d, 1H, J = 8.4), 7.13 (d, 1H, J = 8.4), 4.94 (t, 1H, J = 6.2), 2.84 (t, 2H, J = 6.9), 2.74 (q, 2H, J = 12.9, 6.5), 1.88 (p, 2H, J = 6.7), 1.13 (s, 9H), 0.17 (s, 6H). 13C: 149.6, 147.8, 145.3, 133.7, 127.9, 127.8, 127.7, 127.5, 125.8, 125.3, 125.2, 124.1, 122.8, 122.6, 42.0, 29.3, 26.2, 26.1, 18.7, -3.3. HRMS: calcd for C25H32N2O5SSiNa [M+Na]+: 523.1699; found: 523.1700. B.15.4 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-4-methoxybenzenesulfonamide (3.73; R = C6H4-OMe-p, R’ = H) 585 mg (90% yield) from 300 mg of 3.72, R’ = H, colorless oil, eluent: 1:3 EtOAc/hexane; IR: 3462-3168 (broad), 1259, 1093. 1H: 8.05 (dd, 1H, J = 8.6, 1.8), 7.76 (dd, 1H, J = 6.9, 2.1), 7.63 (d, 2H, J = 8.9), 7.49-7.40 (m, 3H), 7.16 (d, 1H, J = 8.4), 6.76 (d, 2H, J = 8.9), 4.59 (t, 1H, J = 6.2), 3.79 (s, 3H), 2.83-2.71 (m, 4H), 1.83 (p, 2H, J = 7.0), 1.12 (s, 9H), 0.16 (s, 6H) . 13C: 162.6, 148.1, 133.7, 131.2, 129.0, 128.0, 127.8, 127.6, 125.7, 125.4, 125.0, 123.0, 122.1, 114.0, 55.5, 42.1, 29.7, 26.8, 26.1, 18.7, -3.2. HRMS: calcd for C26H35NO4SSiNa [M+Na]+: 508.1954; found: 508.1956. B.15.5 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.73; R = Bn, R’ = H) 424 mg (95% yield) from 300 mg of 3.72, R’ = H, colorless oil, eluent: 1:3 EtOAc/hexane; IR: 3126-3441 (broad). 1H: 8.06-8.03 (m, 1H), 7.80-7.77 (m, 1H),  202  7.53-7.38 (m, 3H), 7.34-7.19 (m, 6H), 4.27-4.23 (m, 1H), 4.16 (s, 2H), 2.86 (q, 2H, J = 13.4, 6.7), 2.80 (t, 2H, J = 7.4), 1.81 (p, 2H, J = 7.1), 1.09 (s, 9H), 0.15 (s, 6H). 13C: 148.2, 133.7, 130.5, 129.3, 128.7, 128.6, 128.1, 127.9, 127.6, 125.7, 125.4, 125.0, 123.0, 122.1, 58.7, 42.8, 30.8, 27.0, 26.1, 18.7, -3.2. HRMS: calcd for C26H35NO3SSiNa [M+Na]+: 492.2005; found: 492.1994. B.15.6 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)propyl)-2,2,2-trifluoroethanesulfonamide (3.73; R = CH2CF3, R’ = H) 373 mg (85% yield) from 300 mg of 3.72, R’ = H, yellow oil; eluent: 1:3 EtOAc/hexane; IR: 3462-3189 (broad), 1253, 1162. 1H: 8.07-8.03 (m, 1H), 7.79-7.76 (m, 1H), 7.50-7.40 (m, 3H), 7.24 (d, 1H, J = 8.3), 4.81 (br s, 1H), 3.66 (q, 2H, J = 9), 3.04 (q, 2H, J = 6.6), 2.89 (t, 2H, J = 7.2), 1.93 (p, 2H, J = 7.0), 1.12 (s, 9H), 0.18 (s, 6H). 13C: 148.3, 133.8, 128.0, 127.7, 127.6, 125.6, 125.3, 125.1, 123.0, 122.3, 121.5 (q, J = 276.3), 54.0 (q, J = 31.0), 42.5, 30.5, 26.8, 26.1, 18.7, -3.3. HRMS: calcd for C21H31F3NO3SSi [M+H]+: 462.1746; found: 462.1750. B.15.7 Characterization of N-(3-(1-(tert-Butyldimethylsilyloxy)-4-phenylnaphthalen-2-yl)propyl)methanesulfonamide (3.73; R = Me, R’ = Ph) 963 mg (82% yield) from 980 mg of 3.72, R’ = Ph, colorless oil, eluent: 1:3 EtOAc/hexane; IR: 3462-3126 (broad), 1244, 1102. 1H: 8.14 (d, 1H, J = 8.3), 7.85 (d, 1H, J = 8.4), 7.50-7.36 (m, 7H), 7.22 (s, 1H), 4.44 (t, 1H, J = 5.7), 3.08 (q, 2H, J = 13.2, 6.7), 2.91 (t, 2H, J = 7.3), 1.96 (p, 2H, J = 7.1), 1.17 (s, 9H), 0.23 (s, 6H). 13C: 147.8, 140.6, 134.5, 131.7, 130.2, 128.9, 128.3, 128.2, 127.1, 125.9, 125.6, 125.2, 124.9, 123.2, 42.5, 40.1, 30.4, 27.1, 26.1, 18.7, -3.1.  203  B.15.8 Characterization of N-(3-(1-(tert-butyldimethylsilyloxy)-4-methoxynaphthalen-2-yl)propyl)-methanesulfonamide (3.73; R = Me, R’ = OMe) 883 mg (90% yield) from 800 mg of 3.72, R’ = OMe, yellow oil, eluent: 1:3 EtOAc/hexane; IR: 3462-3126 (broad). 1H: 8.18 (dd, 1H, J = 7.1, 1.9), 7.99 (dd, 1H, J = 7.1, 1.7), 7.50-7.40 (m, 2H), 6.57 (s, 1H), 4.50 (t, 1H, J = 6.0), 3.98 (s, 3H), 3.00 (q, 2H, J = 13.1, 6.6), 2.87 (t, 2H, J = 7.1), 2.80 (s, 3H), 1.94 (p, 2H, J = 6.9), 1.12 (s, 9H), 0.15 (s, 6H). 13C: 150.5, 141.6, 128.6, 125.7, 125.4, 124.9 (2C), 122.7, 121.9, 105.3, 55.6, 42.2, 39.9, 30.3, 27.2, 26.1, 18.6, -3.3. HRMS: calcd for C21H33NO4SSiNa [M+Na]+: 446.1797; found: 446.1806. B.16 General procedure for deprotection of TBS ether using TBAF A 1M solution of TBAF in THF (19.8 mL, 19.8 mmol, 1.1 equiv) was slowly added to a cold (0 °C) solution of 3.73 (18 mmol, 1.0 equiv) in THF (55 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, after which time TLC showed that the reaction was complete. The mixture was quenched with aq. satd. NH4Cl (20 mL) and extracted with EtOAc (3×15 ml). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 3.74. B.16.1 Characterization of N-(3-(1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = H) 0.78 g (85% yield) from 1.29 g of 3.73 (R = Me, R' = H), light yellow solid, m.p.: 78-80 °C, eluent: 2:3 EtOAc/hexane; IR: 3672-3399 (broad), 3399-3672 (broad). 1H: 8.08 (d, 1H, J = 8.1), 7.79 (d, 1H, J = 8.1), 7.51-7.41 (m, 3H), 7.22 (d, 1H, J = 8.4), 6.04 (br s, 1H), 5.01 (br s, 1H), 3.14 (t, 2H, J = 5.8), 2.96 (s, 3H), 2.90 (t, 2H, J = 7.1), 1.97  204  (p, 2H, J = 6.8). 13C: 148.4, 133.4, 128.1, 127.8, 125.7, 125.6, 124.7, 120.9, 120.7, 120.6, 42.2, 40.0, 30.3, 26.2. HRMS: calcd for C14H17NO3S [M+Na]+: 302.0827; found: 302.0826. B.16.2 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.74; R = 4-Tol, R’ = H) 230 mg (87% yield) from 350 mg of 3.73 (R = 4-Tol, R' = H), yellow oil, eluent: 2:3 EtOAc/hexane; IR: 3689-3399 (broad), 3399-3126 (broad). 1H: 8.05 (d, 1H, J = 7.7), 7.78-7.72 (m, 3H), 7.51-7.41 (m, 2H), 7.38 (d, 1H, J = 8.4), 7.15 (d, 1H, J = 8.4), 5.79 (br s, 1H), 4.93 (br s, 1H), 2.94 (app q, 2H, J = 11.5, 5.8), 2.84 (t, 2H, J = 7.3), 2.39 (s, 3H), 1.87 (p, 2H, J = 6.8). 13C: 148.4, 143.6, 136.4, 133.4, 129.7, 128.0, 127.8, 127.1, 125.6, 125.5, 124.6, 120.7(2C), 120.5, 42.2, 29.7, 26.2, 21.5. HRMS: calcd for C20H22NO3S [M+H]+: 356.1320; found: 356.1324. B.16.3 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.74; R = C6H4-NO2-p, R’ = H) 236 mg (94% yield) from 325 mg of 3.73 (R = C6H4-NO2-p, R' = H), green solid, m.p.: 133-135 °C; eluent: 2:3 EtOAc/hexane; IR: 3464, 3232, 1540, 1347. 1H: 8.25 (d, 2H, J = 8.6), 7.98-7.93 (m, 3H), 7.80 (d, 1H, J = 8.6), 7.55-7.45 (m, 2H), 7.41 (d, 1H, J = 8.6), 7.16 (d, 1H, J = 8.5), 5.03 (br s, 1H), 3.00 (app t, 2H, J = 6.2), 2.87 (t, 2H, J = 7.1), 1.91 (p, 2H, J = 6.8). 13C: 149.9, 147.9, 145.6, 133.4, 128.2, 128.0, 127.9, 125.8, 124.4 (2C), 124.3, 121.2, 120.7, 120.0, 42.2, 29.6, 26.0. HRMS: calcd for C19H17N2O5S [M-H]- 385.0858; found: 385.0847.  205  B.16.4 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-4-methoxybenzenesulfonamide (3.74; R = C6H4-OMe-p, R’ = H) 241 mg (92% yield) from 343 mg of 3.73 (R = C6H4-OMe-p, R' = H), yellow solid, m.p.: 145-147 °C; eluent: 2:3 EtOAc/hexane; IR: 3672-3420 (broad), 3420-3189 (broad), 1261, 1094. 1H: 8.08 (d, 1H, J = 8.3), 7.83-7.56 (m, 3H), 7.51-7.40 (m, 2H), 7.38 (d, 1H, J = 8.4), 7.16 (d, 1H, J = 8.4), 6.92 (d, 2H, J = 9.0), 5.86 (br s, 1H), 4.95 (br s, 1H), 3.83 (s, 3H), 2.95-2.91 (m, 2H), 2.85 (t, 2H, J = 7.3), 1.88 (p, 2H, J = 6.8). 13C: 162.9, 148.4, 133.4, 130.8, 129.3, 128.1, 127.8, 125.6, 125.5, 124.6, 120.7 (2C), 120.5, 114.3, 55.6, 42.1, 29.7, 26.2. HRMS: calcd for C20H21NO4SNa [M+Na]+: 394.1089; found: 394.1097. B.16.5 Characterization of N-(3-(1-Hydroxynaphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.74; R = Bn, R’ = H) 186 mg (91% yield) from 270 mg of 3.73 (R = Bn, R' = H), yellow solid, m.p.: 122-124 °C; eluting solvent: 2:3 hexane/EtOAc; IR: 3668-3420 (broad), 3420-3189 (broad). 1H: 8.03 (d, 1H, J = 8.0), 7.79 (d, 1H, J = 8.2), 7.53-7.45 (m, 2H), 7.41 (d, 1H, J = 8.4), 7.35-7.31 (m, 5H), 7.18 (d, 1H, J = 8.4), 4.57 (br s, 1H), 4.25 (s, 2H), 2.98 (q, 2H, J = 12.1, 6.1), 2.82 (t, 2H, J = 7.1), 1.86 (p, 2H, J = 6.8). 13C: 148.3, 133.4, 130.6, 129.2, 128.9, 128.8, 128.1, 127.9, 125.6, 125.5, 124.6, 120.9, 120.7, 120.5, 58.7, 42.6, 30.7, 26.1. HRMS: calcd for C20H21NO3SNa [M+Na]+: 378.1140; found: 378.1144.    206  B.16.6 Characterization of 2,2,2-trifluoro-N-(3-(1-hydroxynaphthalen-2-yl)propyl)ethanesulfonamide (3.74; R = CH2CF3, R’ = H) 163 mg (78% yield) from 278 mg of 3.73 (R = CH2CF3, R' = H), light yellow solid, m.p.: 100-102 °C; eluent: 2:3 EtOAc/hexane; IR: 3567, 3249, 1245, 1167. 1H: 7.98 (d, 1H, J = 8.1), 7.82 (d, 1H, J = 7.6), 7.55-7.44 (m, 3H), 7.24 (d, 1H, J = 8.4), 5.47 (br s, 1H), 5.13 (br s, 1H), 3.79 (q, 2H, J = 9.0), 3.19 (q, 2H, J = 6.3), 2.93 (t, 2H, J = 7.1), 1.99 (p, 2H, J = 6.8). 13C: 148.2, 133.6, 128.2 (2C), 125.9 (2C), 124.5, 121.7 (q, J = 277.8), 121.4, 120.9, 120.1, 54.4 (q, J = 31.7), 42.6, 30.6, 26.2. HRMS: calcd for C15H16F3NO3SNa [M+Na]+: 370.0701; found: 370.0705. B.16.7 Characterization of N-(3-(1-hydroxy-4-phenylnaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = Ph)  0.81 g (71% yield) from 1.50 g of 3.73 (R = Me, R' = Ph), white solid, dec. 165 °C, eluent: 2:3 EtOAc/hexane; IR: 3477, 3283. 1H (acetone-d6): 8.34 (d, 1H, J = 8.3), 8.19 (br s, 1H), 7.81 (d, 1H, J = 8.6), 7.53-7.38 (m, 7H), 7.28 (s, 1H), 6.01 (br s, 1H), 3.25-3.19 (m, 2H), 2.99 (app t, 2H, J = 7.7), 2.90 (s, 3H), 2.09-1.98 (m, 2H). 13C: 149.0, 140.9, 132.2, 131.3, 130.1, 129.7, 128.2, 126.8, 125.7, 125.4 (2C), 124.8, 122.0, 121.3, 42.8, 38.8, 30.6, 27.0. HRMS: calcd for C20H21NO3SNa [M+Na]+: 378.1140; found: 378.1141. B.16.8 Characterization of N-(3-(1-hydroxy-4-methoxynaphthalen-2-yl)propyl)methanesulfonamide (3.74; R = Me, R’ = OMe) 522 mg (83% yield) from 862 mg of 3.73 (R = Me, R' = OMe), yellow solid, m.p.: 112-114 °C; eluent: 2:3 EtOAc/hexane; IR: 3626-3378 (broad), 3378- 207  3126 (broad). 1H: 8.21 (d, 1H, J = 8.2), 8.00 (d, 1H, J = 8.2), 7.55-7.44 (m, 2H), 6.56 (s, 1H), 5.29 (s, 1H), 4.86 (br s, 1H), 3.96 (s, 3H), 3.13 (q, 2H, J = 12.6, 6.3), 2.98-2.89 (m, 5H), 1.99 (p, 2H, J = 6.7). 13C: 150.1, 141.7, 126.3, 125.9, 125.1, 125.0, 122.2, 120.9, 120.5, 105.7, 55.8, 42.0, 40.0, 30.3, 26.5. HRMS: calcd for C15H19NO4SNa [M+Na]+: 332.0932; found: 332.0926. B.17 General procedure for para-bromination of naphtholic sulfonamides These substances were prepared by the same procedure detailed above for the synthesis of compound 3.12. B.17.1 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.76, R = Me) 0.22 g (57% yield) from 0.3 g of  3.74 (R = Me, R' = H), white solid, m.p.: 101-103 °C; eluent: 2:3 EtOAc/hexane; IR: 3463, 3287, 1075. 1H: 8.15-8.11 (m, 2H), 7.59-7.50 (m, 3H), 6.14 (br s, 1H), 4.85 (t, 1H, J = 1.1), 3.17 (q, 2H, J = 12.5, 6.2), 2.99 (s, 3H), 2.88 (t, 2H, J = 7.3), 1.97 (p, 2H, J = 6.8). 13C: 148.5, 131.5, 131.4, 127.1 (2C), 126.3, 126.2, 121.7, 121.5, 113.7, 42.1, 40.1, 30.3, 25.9. HRMS: calcd for C14H16NO3S79BrNa [M+Na]+: 379.9932; found: 379.9924. B.17.2 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-4-methylbenzenesulfonamide (3.76, R = 4-Tol) 0.14 g (39% yield) from 0.3 g of 3.74 (R = 4-Tol, R' = H), yellow solid, dec. 110 °C, eluent: 1:5 EtOAc/hexane; IR: 3657-3129 (broad). 1H: 8.13 (t, 2H, J = 7.3), 7.75 (t, 2H, J = 8.1), 7.59-7.50 (m, 2H), 7.45 (s, 1H), 7.29-7.26 (m, 2H), 6.14 (s,  208  1H), 5.03 (br s, 1H), 2.95 (q, 2H, J = 12.2, 6.0), 2.83 (t, 2H, J = 7.4), 2.40 (s, 3H), 1.87 (p, 2H, J = 6.7). 13C: 148.5, 143.8, 136.0, 131.4 (2C), 129.8, 127.2, 127.0 (2C), 126.2, 121.7, 121.6, 113.5, 42.1, 29.6, 25.9, 21.5. HRMS: calcd for C20H19NO3S79Br [M-H]-: 432.0269; found: 432.0258. B.17.3 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-4-nitrobenzenesulfonamide (3.76, R = C6H4-NO2-p) 0.11 g (88% yield) from 0.98 g of 3.74 (R = C6H4-NO2-p, R' = H), yellow solid, dec. 98 °C, eluent: 1:3 EtOAc/hexane; IR: 3604-3393 (broad), 3287-3161 (broad). 1H (acetone-d6): 8.40 (d, 2H, J = 8.6), 8.27 (d, 1H, J = 8.1), 8.10 (d, 2H, J = 8.6), 8.06 (d, 1H, J = 8.3), 7.61-7.52 (m, 3H), 3.10 (t, 2H, J = 7.0), 2.87 (t, 2H, J = 7.5), 1.88 (p, 2H, J = 7.4). 13C (acetone-d6): 150.0, 149.5, 146.6, 131.9, 131.2, 128.3, 126.9, 126.8, 126.4, 125.9, 124.4, 122.9, 122.3, 111.8, 42.7, 29.9, 26.6. HRMS: calcd for C19H16N2O5S79Br [M-H]-: 462.9963; found: 462.9950. B.17.4 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-1-phenylmethanesulfonamide (3.76, R = Me) 0.13 g (86% yield) from 0.12 g of 3.74 (R = Bn, R' = H), yellow solid, dec. 129 °C, eluent: 1:4 EtOAc/hexane; IR: 3653-3157 (broad). 1H: 8.13 (app t, 2H, J = 7.5), 7.60-7.50 (m, 2H), 7.48 (s, 1H), 7.39-7.29 (m, 5H), 6.04 (s, 1H), 4.71 (t, 1H, J = 6.0), 4.26 (s, 2H), 2.97 (q, 2H, J = 12.4, 6.2), 2.78 (t, 2H, J = 7.2), 1.83 (p, 2H, J = 6.8). 13C: 148.4, 131.4, 130.6, 129.0, 128.9, 127.1, 127.0, 126.2 (2C), 121.7, 121.6, 113.6, 58.7, 42.6, 30.6, 25.8. HRMS: calcd for C20H19NO3S79Br [M-H]-: 432.0269; found: 432.0269.  209  B.17.5 Characterization of N-(3-(4-bromo-1-hydroxynaphthalen-2-yl)propyl)-2,2,2-trifluoroethanesulfonamide (3.76, R = Me) 0.05 g (86% yield) from 0.05 g of 3.74 (R = CH2CF3, R' = H), yellow solid, m.p.: 122-124 °C, eluent: 1:5 EtOAc/hexane; IR: 3629-3143 (broad). 1H (acetone-d6): 8.45 (br s, 1H), 8.32 (d, 1H, J = 8.2), 8.10 (d, 1H, J = 8.0), 7.69 (s, 1H), 7.64-7.54 (m, 2H), 6.80 (br s, 1H), 4.23 (q, 2H, J = 9.7), 3.36-3.26 (m, 2H), 2.99-2.94 (m, 2H), 2.03-1.96 (m, 2H). 13C (acetone-d6): 149.6, 132.0, 131.3, 126.9 (2C), 126.4, 125.8, 123.1, 122.6 (q, J = 276.3), 122.3, 111.8, 53.0 (q, J = 31.0), 42.8, 30.5, 26.7. HRMS: calcd for C15H14NO3F3S79Br [M-H]-: 423.9830; found: 423.9824. B.18 Preparation of N-(3-(4-chloro-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.77, R = Me) The procedure described above for 3.11 produced 365 mg (65% yield) of 3.77, R = Me from 500 mg of 3.74 (R = CH2CF3, R' = H) as off yellow solid, m.p.: 114-117 °C (color changes to brown), eluent: 1:3 to 2:3 EtOAc/hexanes; IR: 3615-3393 (broad), 3382-3136 (broad). 1H (acetone d6): 8.32 (d, 1H, J = 6.0), 8.12 (d, 1H, J = 6.0), 7.63-7.54 (m, 2H), 7.49 (s, 1H), 6.03 (br s, 1H), 3.77 (s, 1H), 3.20 (q, 2H, J = 12.0, 6.0), 2.97-2.86 (m, 2H), 1.96 (p, 2H, J = 6.0). 13C: 148.7, 129.9, 128.3, 126.5 (2C), 125.7, 123.6, 122.4, 122.2, 121.6, 42.5, 38.7, 30.3, 26.6. HRMS: calcd for C14H16NO3SClNa [M+Na]+: 336.0437; found: 336.0439. B.19 General procedure for Suzuki coupling of 3.76 and aryl boronic acid A solution of 3.76, R = Me (500 mg, 1.4 mmol, 1.0 equiv), Pd(PPh3)4 (81 mg, 50 µmol, 0.05 equiv), boronic acid (1.7 mmol, 1.2 equiv), and Cs2CO3 (547 mg, 1.7 mmol, 1.2 equiv) in 1,4-dioxane (4.0 mL) and water (1.0 mL) was stirred at 80 °C for 6 h, after which time TLC  210  showed that the reaction was complete. The cooled mixture was diluted with EtOAc (10.0 mL) and filtered through a Celite® pad, which was washed with more EtOAc (3×10 mL). The combined filtrate was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography to provide 3.78. B.19.1 Characterization of N-(3-(4-(4-fluorophenyl)-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = C6H4-F-p) 420 mg (80% yield) from 500 mg of 3.76, R = Me, off white solid, dec. 160 °C (color changes to brown), eluent: 1:4 to 2:3 EtOAc/hexanes; IR: 3636-3129 (broad). 1H: 8.34 (d, 1H, J = 9.0), 7.76 (d, 1H, J = 9.0), 7.51-7.39 (m, 4H), 7.27-7.22 (m, 3H), 6.03 (br s, 1H), 3.19 (t, 2H, J = 6.0), 2.99-2.94 (m, 2H), 2.91 (s, 3H), 1.98 (p, 2H, J = 9.0). 13C: 162.8 (d, J = 243.9), 150.0, 138.0 (d, J = 3.8), 132.7 (d, J = 8.3), 132.1, 131.8, 130.7, 126.6, 126.4, 126.0, 125.8, 122.9, 122.2, 117.7, 115.8 (d, J = 21.9), 43.6, 39.7, 31.4, 27.8. HRMS: calcd for C20H19NO3FS [M-H]-: 372.1070; found: 372.1078. B.19.2 Characterization of N-(3-(1-hydroxy-4-(4-(trifluoromethyl)phenyl)naphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = C6H4-CF3-p) 298 mg (50% yield) from 500 mg of 3.76, R = Me, off white solid, m.p.: 129-132 °C, eluent: 1:4 to 3:7 EtOAc/hexanes; IR: 3599-3388 (broad), 3360-3184 (broad). 1H: 8.20 (d, 1H, J = 6.0), 7.79 (d, 1H, J = 9.0), 7.73 (d, 2H, J = 6.0), 7.59-7.41 (m, 4H), 7.18 (s, 1H), 6.17 (s, 1H), 4.92 (t, 1H, J = 6.0), 3.21 (q, 2H, J = 12.0, 6.0), 3.00 (s, 3H), 2.95 (t, 2H, J = 7.5), 2.01 (p, 2H, J = 6.0). 13C: 148.8, 144.5, 132.0, 131.2, 130.6, 129.5, 129.3 (q, J = 32.5), 126.4, 125.9, 125.7, 125.4 (q, J = 3.8), 125.1, 124.5 (q, J = 271.8), 121.4, 120.3, 42.4, 40.3, 30.5, 26.4. HRMS: calcd for C21H19NO3F3S [M-H]-: 422.1038; found: 422.1044.  211  B.19.3 Characterization of N-(3-(4-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxynaphthalen-2-yl)propyl)methanesulfonamide (3.78, Ar = 3,5-(bis)(CF3)2C6H3) 625 mg (91% yield) from 500 mg of 3.76, R = Me, off white solid, m.p.: 153-155 °C, eluent: 1:3 to 1:2 EtOAc/hexanes. IR: 3550-3377 (broad), 3307-3148 (broad). 1H: 8.24 (d, 1H, J = 9.0), 7.92 (app s, 3H), 7.67 (d, 1H, J = 9.0), 7.57-7.45 (m, 2H), 7.20 (s, 1H), 6.35 (s, 1H), 4.96 (t, 1H, J = 6.0), 3.23 (q, 2H, J = 6.0), 3.03 (s, 3H), 2.97 (t, 1H, J = 7.5), 2.03 (p, 2H, J = 6.0). 13C: 149.5, 142.9, 131.8 (q, J = 33.2), 131.0, 130.4 (app d, J = 3.0), 130.1, 129.9, 126.9, 126.1, 125.2, 124.9, 123.6 (q, J = 273.3), 121.8, 121.1-120.9 (m), 120.3, 42.4, 40.2, 30.6, 26.3. HRMS: calcd for C22H18NO3F6S [M-H]-: 490.0912; found: 490.0918. B.20 Preparation and characterization of various intermediates towards 2-naphtholic sulfonamides 3.87 B.20.1 General procedure for O-allylation of 2-naphthols These substances were prepared by the same procedure described above for the synthesis of compound 3.8 and used in the subsequent step without purification. Compound 3.80, R = H is known.[15] B.20.1.1 Characterization of 2-(Allyloxy)-7-methoxynaphthalene (3.80, R = OMe) 3.65 g (99% crude yield) from 3.00 g of 3.79, R = OMe, yellow oil; IR: 1210, 1031. 1H: 7.67 (app dd, 2H, J = 8.7, 2.2), 7.13-6.99 (m, 4H), 6.20-6.08 (m, 1H), 5.48 (dd, 1H, J = 17.3, 1.5), 5.34 (dd, 1H, J = 10.5, 1.3), 4.67-4.65 (m, 2H), 3.92 (s, 3H). 13C: 158.2, 157.1, 135.8, 133.2, 129.2, 129.1, 124.3, 117.8, 116.3, 116.1, 106.5, 105.2, 68.8, 55.3.  212  B.20.2 General procedure for Claisen rearrangement of 3.80 These substances were prepared by the same procedure described above for the synthesis of compound 3.9 and used in the subsequent step without purification. Compound 3.81, R = H is known.[15] B.20.2.1 Characterization of 1-allyl-7-methoxynaphthalen-2-ol (3.81, R = OMe) 3.61 g (99% crude yield) from 3.65 g of 3.80, R = OMe, light brown oil; IR: 3626-3126 (broad). 1H: 7.68 (d, 1H, J = 8.9), 7.60 (d, 1H, J = 8.7), 7.19 (d, 1H, J = 2.3), 7.02 (dd, 1H, J = 8.9, 2.4), 6.96 (d, 1H, J = 8.7), 6.14-6.01 (m, 1H), 5.14-5.07 (m, 2H), 3.93 (s, 3H), 3.81-3.78 (m, 2H). 13C: 158.3, 151.7, 135.7, 134.6, 130.1, 128.0, 124.8, 115.9, 115.8, 115.4, 115.3, 102.3, 55.2, 29.5. HRMS: calcd for C14H13O2 [M-H]-: 213.0916; found: 213.0914. B.20.3 General procedure for protection of 2-naphthols 3.81 as TBS ether These substances were prepared by the same method detailed above in title B.14.1. B.20.3.1 Characterization of 1-Allyl-2-(tert-butyldimethylsilyloxy)naphthalene (3.82, R = H) 4.04 g (89% yield) from 4.54 g of 3.81, R = H, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 1244, 987. 1H: 7.93 (d, 1H, J = 8.4), 7.79 (d, 1H, J = 8.0), 7.65 (d, 1H, J = 8.9), 7.47 (ddd, 1H, J = 8.4, 6.8, 1.4), 7.35 (ddd, 1H, J = 8.0, 6.9, 1.1), 7.12 (d, 1H, J = 8.9), 6.10-5.97 (m, 1H), 5.05-4.94 (m, 2H), 3.86 (app dt, 2H, J = 5.7, 1.7), 1.08 (s, 9H), 0.29 (s, 6H). 13C: 150.7, 136.7, 133.6, 129.5, 128.3, 127.6, 126.0, 123.8, 123.3, 122.6, 120.4, 115.1, 29.6, 25.9, 18.3, -3.9.   213  B.20.3.2 Characterization of 1-Allyl-2-(tert-butyldimethylsilyloxy)-7-methoxynaphthalene (3.82, R = OMe) 5.67 g (88% yield) from 4.16 g of 3.81, R = OMe, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 1237, 889. 1H: 7.67 (d, 1H, J = 8.9), 7.56 (d, 1H, J = 8.8), 7.20 (d, 1H, J = 2.4), 7.01 (dd, 1H, J = 8.9, 2.5), 6.96 (d, 1H, J = 8.8), 6.06-5.93 (m, 1H), 5.06-4.98 (m, 2H), 3.91 (s, 3H), 3.81 (app dt, 2H, J = 5.8, 1.7), 1.06 (s, 9H), 0.27 (s, 6H). 13C: 157.9, 151.3, 136.5, 134.9, 129.8, 127.3, 124.9, 121.5, 117.9, 115.6, 115.1, 102.8, 55.2, 30.0, 25.9, 18.3, -3.9. HRMS: calcd for C20H29O2Si [M+H]+: 329.1937; found: 329.1934. B.20.4 General procedure for hydroboration-oxidation of terminal alkenes These substances were prepared by the same procedure detailed above for the synthesis of compound 3.10. B.20.4.1 Characterization of 3-(2-(tert-Butyldimethylsilyloxy)naphthalen-1-yl)propan-1-ol (3.83, R = H) 3.91 g (82% yield) from 4.77 g of 3.82, R = H, colorless oil, eluent: 3:7 EtOAc/hexane; IR: 3668-3084 (broad), 1244. 1H: 7.98 (d, 1H, J = 8.5), 7.79 (d, 1H, J = 8.0), 7.63 (d, 1H, J = 8.9), 7.49 (t, 1H, J = 7.8), 7.36 (t, 1H, J = 7.0), 7.10 (d, 1H, J = 8.9), 3.60 (q, 2H, J = 11.5, 5.7), 3.20 (t, 2H, J = 7.2), 1.98-1.92 (m, 3H), 1.07 (s, 9H), 0.29 (s, 6H). 13C: 150.5, 133.3, 129.8, 128.5, 127.3, 126.2, 124.5, 123.4 (2C), 120.5, 62.1, 32.4, 25.9, 21.4, 18.4, -3.9. HRMS: calcd for C19H28O2SiNa [M+Na]+: 339.1756; found: 339.1750.    214  B.20.4.2 Characterization of 3-(2-(tert-butyldimethylsilyloxy)-7-methoxynaphthalen-1-yl)propan-1-ol (3.83, R = OMe) 3.61 g (76% yield) from 4.50 g of 3.82, R = OMe, colorless oil, eluent: 1:3 EtOAc/hexane; IR: 3626-3126 (broad), 1230. 1H: 7.68 (d, 1H, J = 8.9), 7.55 (d, 1H, J = 8.8), 7.27 (s, 1H), 7.03 (dd, 1H, J = 8.9, 2.5), 6.95 (d, 1H, J = 8.8), 3.94 (s, 3H), 3.60 (t, 2H, J = 6.1), 3.16 (t, 2H, J = 7.2), 1.95 (p, 2H, J = 6.7), 1.06 (s, 9H), 0.28 (s, 6H). 13C: 158.1, 151.2, 134.5, 130.0, 127.1, 125.1, 123.4, 117.9, 115.6, 102.5, 62.0, 55.3, 31.8, 25.9, 21.5, 18.4, -3.9. HRMS: calcd for C20H31O3Si [M+H]+: 347.2042; found: 347.2044. B.20.5 General procedure for azidation of 2-naphtholic primary alcohol These substances were prepared by the same method detailed above in title B.14.3. B.20.5.1 Characterization of 1-(3-azidopropyl)-2-(tert-butyldimethylsilyloxy)naphthalene (3.84, R = H) 1.79 g (89% yield) from 1.87 g of 3.83, R = H, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 2095. 1H: 7.94 (d, 1H, J = 8.6), 7.79 (d, 1H, J = 8.1), 7.64 (d, 1H, J = 8.9), 7.50 (app td, 1H, J = 6.9, 1.3), 7.35 (app td, 1H, J = 7.0, 1.0), 7.10 (d, 1H, J = 8.9), 3.38 (t, 2H, J = 6.9), 3.18-3.13 (m, 2H), 1.94 (p, 2H, J = 7.3), 1.08 (s, 9H), 0.29 (s, 6H). 13C: 150.7, 133.2, 129.5, 128.5, 127.5, 126.3, 124.1, 123.3, 123.0, 120.3, 51.5, 29.1, 25.8, 22.7, 18.3, -3.9. B.20.5.2 Characterization of 1-(3-azidopropyl)-2-(tert-butyldimethylsilyloxy)-7-methoxynaphthalene (3.84, R = OMe) 2.82 g (86% yield) from 3.05 g of 3.83, R = OMe, colorless oil, eluent: 1:19 EtOAc/hexane; IR: 2096. 1H: 7.68 (d, 1H, J = 8.9), 7.55 (d, 1H, J =  215  8.8), 7.23 (d, 1H, J = 2.3), 7.02 (dd, 1H, J = 8.9, 2.4), 6.94 (d, 1H, J = 8.8), 3.95 (s, 3H), 3.38 (t, 2H, J = 6.7), 3.10 (t, 2H, J = 7.8), 1.94 (p, 2H, J = 7.2), 1.06 (s, 9H), 0.28 (s, 6H). 13C: 158.2, 151.3, 134.6, 130.1, 127.2, 124.8, 123.0, 117.7, 115.6, 102.0, 55.3, 51.4, 28.6, 25.8, 22.8, 18.3, -3.9. HRMS: calcd for C20H29N3O2SiNa [M+Na]+: 394.1927; found: 394.1931. B.20.6 General procedure for synthesis of amine from azide These substances were prepared by the same method detailed above in title B.14.4. B.20.6.1 Characterization of 3-(2-(tert-Butyldimethylsilyloxy)naphthalen-1-yl)propan-1-amine (3.85, R = H) 1.09 g (91% crude yield) from 1.30 g of 3.84, R = H, light brown oil; IR: 3378, 3294. 1H: 7.95 (d, 1H, J = 8.5), 7.78 (d, 1H, J = 8.1), 7.61 (d, 1H, J = 8.8), 7.47 (td, 1H, J = 7.8, 1.3), 7.32-7.27 (m, 1H), 7.08 (d, 1H, J = 8.9), 3.10 (t, 2H, J = 7.6), 2.80 (t, 2H, J = 7.0), 1.80 (p, 2H, J = 7.4), 1.07 (s, 9H), 0.28 (s, 6H). 13C: 150.4, 133.3, 129.5, 128.5, 127.1, 126.0, 125.2, 123.3, 123.2, 120.4, 42.4, 34.1, 25.9, 22.9, 18.3, -3.9.  B.20.6.2 Characterization of 3-(2-(tert-Butyldimethylsilyloxy)-7-methoxynaphthalen-1-yl)propan-1-amine (3.85, R = OMe) 1.24 g (89% crude yield) from 1.50 g of 3.84, R = OMe, light brown oil; IR: 3368, 3302. 1H: 7.65 (d, 1H, J = 8.9), 7.52 (d, 1H, J = 8.8), 7.15 (d, 1H, J = 2.3), 6.99 (dd, 1H, J = 8.9, 2.3), 6.91 (d, 1H, J = 8.8), 5.47 (br s, 2H), 3.89 (s, 3H), 3.07 (t, 2H, J = 7.4), 2.90 (t, 2H, J = 7.7), 1.99 (p, 2H, J = 7.5), 1.02 (s, 9H), 0.26 (s, 6H). 13C: 158.2, 151.2, 134.4, 130.0, 127.3, 124.9, 122.6, 117.7, 115.6, 102.3, 55.4, 40.6, 29.6, 25.9, 22.6, 18.3, -3.8.   216  B.20.7 General procedure for coupling of amine with methanesulfonyl chloride These substances were prepared by the same method detailed above in title B.15. B.20.7.1 Characterization of N-(3-(2-(tert-Butyldimethylsilyloxy)naphthalen-1-yl)propyl)methanesulfon-amide (3.86, R = H) 1.48 g (91% yield) from 1.30 g of 3.85, R = H, colorless oil; eluent: 1:3 EtOAc/hexane; IR: 3420-3168 (weak, broad). 1H: 7.91 (d, 1H, J = 8.5), 7.80 (d, 1H, J = 8.1), 7.64 (d, 1H, J = 8.9), 7.50 (app td, 1H, J = 7.6, 1.3), 7.37 (app td, 1H, J = 7.0, 0.9), 7.10 (d, 1H, J = 8.9), 4.62 (t, 1H, J = 5.8), 3.18 (t, 2H, J = 7.2), 3.10 (q, 2H, J = 13.2, 6.6), 2.84 (s, 3H), 1.98 (p, 2H, J = 7.1), 1.07 (s, 9H), 0.29 (s, 6H) . 13C: 150.6, 133.0, 129.7, 128.7, 127.7, 126.4, 123.6 (2C), 123.1, 120.5, 42.7, 40.2, 29.7, 25.9, 22.2, 18.4, -3.9. HRMS: calcd for C20H31NO3SSiNa [M+Na]+: 416.1692; found: 416.1692. B.20.7.2 Characterization of N-(3-(2-(tert-butyldimethylsilyloxy)-7-methoxynaphthalen-1-yl)propyl)methanesulfonamide (3.86, R = OMe) 2.41 g (83% yield) from 2.37 g of 3.85, R = OMe, colorless oil; eluent: 1:3 EtOAc/hexane; IR: 3100-3400 (weak, broad). 1H: 7.69 (d, 1H, J = 8.9), 7.56 (d, 1H, J = 8.8), 7.18 (d, 1H, J = 2.3), 7.04 (dd, 1H, J = 8.9, 2.4), 6.95 (d, 1H, J = 8.8), 4.65 (br s, 1H), 3.95 (s, 3H), 3.16-3.07 (m, 4H), 2.83 (s, 3H), 1.98 (p, 2H, J = 6.9), 1.06 (s, 9H), 0.29 (s, 6H). 13C: 158.2, 151.2, 134.3, 130.2, 127.5, 125.1, 122.5, 118.0, 115.7, 102.3, 55.4, 42.7, 40.1, 29.2, 25.9, 22.3, 18.4, -3.9.  B.20.8 General procedure for deprotection of TBS ether using TBAF These substances were prepared by the same method detailed above in title B.16.    217  B.20.8.1 Characterization of N-(3-(2-Hydroxynaphthalen-1-yl)propyl)methanesulfonamide (3.87, R = H) 451 mg (78% yield) from 815 mg of 3.86, R = H, white solid, m.p.: 89-91 °C; eluent: 2:3 EtOAc/hexane; IR: 3680-3100 (broad), 3256. 1H: 7.89 (d, 1H, J = 8.5), 7.79 (d, 1H, J = 8.0), 7.65 (d, 1H, J = 8.8), 7.50 (t, 1H, J = 8.0), 7.35 (t, 1H, J = 7.8), 7.10 (d, 1H, J = 8.8), 6.26 (br s, 1H), 5.43 (t, 1H, J = 6.2), 3.22 (t, 2H, J = 6.7), 3.10 (q, 2H, J = 6.4), 2.96 (s, 3H), 2.03 (p, 2H, J = 6.5). 13C: 150.7, 133.1, 129.5, 128.8, 128.2, 126.6, 123.3, 122.7, 118.1, 117.5, 41.9, 40.2, 29.1, 20.9. HRMS: calcd for C14H17NO3SNa [M+Na]+: 302.0827; found: 302.0820. B.20.8.2 Characterization of N-(3-(2-Hydroxy-7-methoxynaphthalen-1-yl)propyl)methanesulfonamide (3.87, R = OMe) 404 mg (80% yield) from 691 mg of 3.86, R = OMe, white solid, m.p.: 141-143 °C; eluent: 2:3 EtOAc/hexane; IR: 3252, 3315. 1H: 7.69 (d, 1H, J = 8.9), 7.57 (d, 1H, J = 8.7), 7.17 (d, 1H, J = 2.3), 7.03 (dd, 1H, J = 8.9, 2.4), 6.91 (d, 1H, J = 8.7), 5.64 (br s, 1H), 5.15 (br s, 1H), 3.95 (s, 3H), 3.19-3.08 (m, 4H), 2.94 (s, 3H), 2.03 (p, 2H, J = 6.5). 13C: 158.5, 151.1, 134.4, 130.3, 128.0, 124.9, 117.2, 115.3, 114.9, 102.0, 55.3, 42.0, 40.3, 28.7, 21.0. HRMS: calcd for C15H19NO4S [M+Na]+: 332.0932; found: 332.0937.    218  B.21 Preparation and characterization of various intermediates towards naphtholic acyl sulfonamides 3.93-3.95  B.21.1 Preparation of 3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)propanoic acid (3.89) To a solution of 3.70, R’ = H (0.32 g, 1.0 mmol, 1.0 equiv) and DIB (0.71 g, 2.2 mmol, 2.2 equiv) in CH3CN (2.5 mL) at RT was added TEMPO (31 mg, 0.2 mmol, 0.2 equiv) followed by H2O (2.5 mL). The resulting mixture was stirred overnight at RT, after which time TLC showed that the reaction was complete. The mixture was acidified by the addition of 1M HCl and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 194 mg (59% yield) of 3.89 as yellow solid, m.p.: 121-123 °C; eluent: 1:5 EtOAc/hexane; IR: 3350-2750 (broad), 1708. 1H: 8.10-8.07 (m, 1H), 7.80-7.77 (m, 1H), 7.49-7.43 (m, 3H), 7.31 (d, 1H, J = 8.4), 3.14 (t, 2H, J = 7.7), 2.71 (t, 2H, J = 8.2), 1.14 (s, 9H), 0.22 (s, 6H). 13C: 179.3, 148.5, 133.9, 128.1, 127.9, 127.6, 125.4, 125.2, 124.9, 123.0, 121.8, 34.4, 26.1, 26.0, 18.7, -3.1. HRMS: calcd for C19H26O3SiNa [M+Na]+: 353.1549; found: 353.1549.  B.21.2 General procedure for coupling of carboxylic acid 3.89 and sulfonamide  To a solution of 3.89 (500 mg, 1.5 mmol, 1.0 equiv) in CH2Cl2 (8 mL) was added EDCI (2.0 mmol, 1.3 equiv), DMAP (4.1 mmol, 2.7 equiv) and appropriate sulfonamide (1.8 mmol, 1.2 equiv) at 0 °C with good stirring. The reaction mixture was warmed to RT and stirred for overnight, after which time TLC showed that the reaction was complete. The reaction was quenched with 1M HCl and extracted with CH2Cl2 (3×15 mL). The combined extracts were  219  washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel to provide corresponding products. B.21.2.1 Characterization of 3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)-N-(methylsulfonyl)propanamide (3.90) 561 mg (91% yield) from 500 mg of 3.89, yellow solid, m.p.: 99-101 °C; eluent: 1:3 EtOAc/hexane; IR: 3300-3150 (weak, broad), 1715. 1H: 8.07-8.04 (m, 1H), 7.94 (br s, 1H), 7.79-7.76 (m, 1H), 7.50-7.43 (m, 3H), 7.25 (d, 1H, J = 7.2), 3.14 (t, 2H, J = 7.4), 3.06 (s, 3H), 2.67 (t, 2H, J = 7.4), 1.12 (s, 9H), 0.20 (s, 6H). 13C: 170.9, 148.4, 134.0, 128.0, 127.8, 127.7, 125.8, 125.3, 124.5, 122.8, 122.4, 41.2, 37.1, 26.0, 25.8, 18.7, -3.2. HRMS: calcd for C20H29NO4SSi [M+Na]+: 430.1484; found: 430.1492.  B.21.2.2 Characterization of 3-(1-(tert-butyldimethylsilyloxy)naphthalen-2-yl)-N-(2-methoxyethylsulfonyl)propanamide (3.91) 207 mg (46% yield) from 330 mg of 3.89, colorless oil, eluent: 3:4 EtOAc/hexane; IR: 3378-3083 (broad), 1716. 1H: 8.07-8.04 (m, 1H), 7.78-7.75 (m, 1H), 7.49-7.42 (m, 3H), 7.26 (d, 1H, J = 8.4), 3.59-3.52 (m, 4H), 3.15-3.10 (m, 5H), 2.66 (t, 1H, J = 7.6), 1.12 (s, 9H), 0.20 (s, 6H). 13C: 170.9, 148.4, 134.0, 128.0, 127.8, 127.7, 125.7, 125.2, 124.7, 122.9, 122.3, 65.8, 58.8, 52.3, 37.1, 26.1, 25.4, 18.7, -3.2.  B.21.2.3 Characterization of 3-(1-(tert-Butyldimethylsilyloxy)naphthalen-2-yl)-N-(4-nitrophenylsulfonyl)propanamide (3.92) 184 mg (55% yield) from 215 mg of 3.89, yellow oil, eluent: 1:4 EtOAc/hexane; IR: 3250-3100 (weak, broad), 1732, 1539, 1349. 1H:  220  8.05-8.02 (m, 1H), 7.95 (d, 2H, J = 9.0), 7.80 (d, 2H, J = 9.0), 7.76-7.73 (m, 1H), 7.53-7.46 (m, 2H), 7.32 (d, 1H, J = 8.4), 7.07 (d, 1H, J = 8.4), 3.03 (t, 2H, J = 7.0), 2.68 (t, 2H, J = 7.1), 1.11 (s, 9H), 0.17 (s, 6H). 13C: 169.7, 150.4, 148.0, 143.6, 134.0, 129.4, 127.9, 127.8, 127.4, 126.1, 125.5, 124.1, 123.6, 122.8, 122.6, 37.0, 26.0, 25.3, 18.7, -3.3. HRMS: calcd for C25H30N2O6SSiNa [M+Na]+: 537.1498; found: 537.1498. B.21.3 General procedure for deprotection of TBS ether of naphtholic acyl sulfonamides using TBAF   These substances were prepared by the same method detailed above in title B.16. B.21.3.1 Characterization of 3-(1-Hydroxynaphthalen-2-yl)-N-(methylsulfonyl)propanamide (3.93) 135 mg (74% yield) from 254 mg of 3.90, colorless oil; eluent: 3:7 EtOAc/hexane; IR: 3550-2950 (broad), 1694. 1H: 8.25-8.22 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.42 (m, 2H), 7.39 (d, 1H, J = 8.4), 7.15 (d, 1H, J = 8.4), 3.19 (s, 3H), 3.09-3.05 (m, 2H), 2.81-2.77 (m, 2H). 13C: 174.3, 149.4, 133.7, 128.0, 127.4, 126.0, 125.7, 125.4, 122.1, 120.6, 119.7, 41.5, 37.4, 23.9. HRMS: calcd for C14H15NO4SNa [M+Na]+: 316.0618; found: 316.0616. B.21.3.2 Characterization of 3-(1-hydroxynaphthalen-2-yl)-N-(2-methoxyethylsulfonyl)-propanamide (3.94) 97 mg (76% yield) from 170 mg of 3.91, colorless oil; eluent: 2:3 EtOAc/hexane; IR: 3693-3420 (broad), 3693-3420 (broad), 1696. 1H: 8.26-8.23 (m, 1H), 7.75-7.72 (m, 1H), 7.48-7.41 (m, 2H), 7.37 (d, 1H, J = 8.4), 7.14 (d, 1H, J = 8.4), 3.62-3.53 (m, 4H), 3.07-3.03 (m, 2H), 2.97 (s, 3H), 2.80-2.76 (m,  221  2H). 13C: 174.4, 149.4, 133.7, 128.0, 127.3, 126.0, 125.8, 125.4, 122.2, 120.6, 119.8, 65.7, 58.6, 52.4, 37.5, 23.8. HRMS: calcd for C16H18NO5SNa [M+Na]+: 336.0906; found: 336.0911. B.21.3.3 Preparation of Crude 3-(1-hydroxynaphthalen-2-yl)-N-(4-nitrophenylsulfonyl)propanamide (3.95), bis-tetrabutylammonium salt  The procedure detailed in title B.16 above was modified by employing 2.2 equivalents of TBAF (use of 1.1. equiv of TBAF resulted in formation of lactone 3.48; see (Figure 3.1, pp. 54). The crude product thus obtained was the bis-tetrabutylammonium salt of 3.95. The integrated 1H NMR spectra of the material clearly suggested the presence of two Bu4N+ ions for each molecule of "3.95" (Figure 3.2, pp. 55). No resonances for phenolic and the sulfonamide protons were apparent.  Furthermore, the IR spectrum of the substance showed no OH or NH absorptions. Attempts to obtain actual 3.95, either by chromatography or by partitioning of the crude between dilute aqueous acid and organic solvents, returned only lactone 3.48 (Figure 3.1, pp. 54). Therefore, the crude bis-Bu4N+ salt was used directly in the subsequent oxidative cyclization step. 233 mg (83% crude yield) from 165 mg of 3.92, yellow oil; 1H: 8.26-8.22 (m, 1H), 8.09 (app s, 4H), 7.71-7.67 (m, 1H), 7.40-7.34 (m, 2H), 7.26 (d, 1H, J = 8.5), 7.15 (d, 1H, J = 8.3), 2.93-2.89 (m, 2H), 2.73-2.69 (m, 2H). 13C: 180.3, 150.5, 148.7, 133.4, 129.2, 128.5, 127.8, 127.2, 126.3, 125.3, 124.5, 123.1, 122.7 (2C), 119.0, 40.2, 25.9. HRMS: calcd for C19H15N2O6S [M-H]-: 399.0651; found: 399.0652.     222  B.22 1H and 13C spectra from chapter 3  1H NMR spectrum of crude 3.8 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.8 (75 MHz, CDCl3)    223   1H NMR spectrum of 3.9 (300 MHz, CDCl3)  13C NMR spectrum of 3.9 (75 MHz, CDCl3)    224   1H NMR spectrum of 3.10 (300 MHz, CDCl3)  13C NMR spectrum of 3.10 (75 MHz, CDCl3)    225   1H NMR spectrum of 3.11 (300 MHz, CDCl3)  13C NMR spectrum of 3.11 (75 MHz, CDCl3)    226   1H NMR spectrum of 3.12 (300 MHz, CDCl3)  13C NMR spectrum of 3.12 (75 MHz, CDCl3)    227   1H NMR spectrum of 3.13, Ar = C6H4-OMe-m (300 MHz, CDCl3)  13C NMR spectrum of 3.13, Ar = C6H4-OMe-m (75 MHz, CDCl3)    228   1H NMR spectrum of 3.13, Ar = C6H4-C(O)Me (300 MHz, CDCl3)  13C NMR spectrum of 3.13, Ar = C6H4-C(O)Me (75 MHz, CDCl3)    229   1H NMR spectrum of 3.13, Ar = C6H4-F-p (300 MHz, CDCl3)  13C NMR spectrum of 3.13, Ar = C6H4-F-p (75 MHz, CDCl3)    230   1H NMR spectrum of 3.13, Ar = C6H4-SO2Me-p (300 MHz, CDCl3)  13C NMR spectrum of 3.13, Ar = C6H4-SO2Me-p (75 MHz, CDCl3)    231   1H NMR spectrum of 3.13, Ar = C6H4-CF3-p (300 MHz, CDCl3)  13C NMR spectrum of 3.13, Ar = C6H4-CF3-p (75 MHz, CDCl3)    232   1H NMR spectrum of 3.13, Ar = 3,5bis(CF3)2C6H3 (300 MHz, CDCl3)  13C NMR spectrum of Ar = 3,5bis(CF3)2C6H3 (75 MHz, CDCl3)    233   1H NMR spectrum of 3.14, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.14, R = Me (75 MHz, CDCl3)    234   1H NMR spectrum of 3.14, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.14, R = Me (75 MHz, CDCl3)    235   1H NMR spectrum of 3.14, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.14, R = 4-Tol (75 MHz, CDCl3)    236   1H NMR spectrum of 3.15, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.15, R = Me (75 MHz, CDCl3)    237   1H NMR spectrum of 3.15, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.15, R = Ph (75 MHz, CDCl3)    238   1H NMR spectrum of 3.15, R = 4-Tol (300 MHz, acetone-d6)  13C NMR spectrum of 3.15, R = 4-Tol (75 MHz, acetone-d6)    239   1H NMR spectrum of 3.16, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.16, R = Me (75 MHz, CDCl3)    240   1H NMR spectrum of 3.16, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.16, R = Ph (75 MHz, CDCl3)    241   1H NMR spectrum of 3.16, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.16, R = 4-Tol (75 MHz, CDCl3)    242   1H NMR spectrum of 3.17, R = Me (300 MHz, acetone-d6)  13C NMR spectrum of 3.17, R = Me (75 MHz, acetone-d6)    243   1H NMR spectrum of 3.17, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.17, R = Ph (75 MHz, CDCl3)    244   1H NMR spectrum of 3.17, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.17, R = 4-Tol (75 MHz, CDCl3)    245   1H NMR spectrum of 3.18, R = Me (300 MHz, acetone-d6)  13C NMR spectrum of 3.18, R = Me (75 MHz, acetone-d6)    246   1H NMR spectrum of 3.18, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.18, R = Ph (75 MHz, CDCl3)    247   1H NMR spectrum of 3.18, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.18, R = 4-Tol (75 MHz, CDCl3)    248   1H NMR spectrum of 3.19 (300 MHz, CDCl3)  13C NMR spectrum of 3.19 (75 MHz, CDCl3)    249   1H NMR spectrum of 3.20 (300 MHz, CDCl3)  13C NMR spectrum of 3.20 (75 MHz, CDCl3)    250   1H NMR spectrum of 3.23, R = Me (300 MHz, CDCl3)   13C NMR spectrum of 3.23, R = Me (75 MHz, CDCl3)    251   1H NMR spectrum of crude 3.24, R = Me (300 MHz, CDCl3)  13C NMR spectrum of crude 3.24, R = Me (75 MHz, CDCl3)    252   1H NMR spectrum of 3.25, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.25, R = Me (75 MHz, CDCl3)    253   1H NMR spectrum of 3.26, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.26, R = Me (75 MHz, CDCl3)    254   1H NMR spectrum of 3.21, Ar = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.21, Ar = 4-Tol (75 MHz, CDCl3)    255   1H NMR spectrum of 3.21, Ar = 4-cyanophenyl (300 MHz, CDCl3)  13C NMR spectrum of 3.21, Ar = 4-cyanophenyl (75 MHz, CDCl3)    256   1H NMR spectrum of 3.23, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.23, R = 4-Tol (75 MHz, CDCl3)    257   1H NMR spectrum of 3.23, R = 4-NC-C6H4 (300 MHz, acetone-d6)  13C NMR spectrum of 3.23, R = 4-NC-C6H4 (75 MHz, acetone-d6)    258   1H NMR spectrum of crude 3.24, R = Ph (300 MHz, CDCl3) 13C NMR spectrum of crude 3.24, R = Ph (75 MHz, CDCl3)    259   1H NMR spectrum of crude 3.24, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of crude 3.24, R = 4-Tol (75 MHz, CDCl3)    260   1H NMR spectrum of crude 3.24, R = 4-NC-C6H4 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.24, R = 4-NC-C6H4 (75 MHz, CDCl3)    261   1H NMR spectrum of 3.25, R = Ph (300 MHz, CDCl3) 13C NMR spectrum of 3.25, R = Ph (75 MHz, CDCl3)    262   1H NMR spectrum of 3.25, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.25, R = 4-Tol (75 MHz, CDCl3)    263   1H NMR spectrum of 3.25, R = 4-NC-C6H4 (300 MHz, CDCl3)  13C NMR spectrum of 3.25, R = 4-NC-C6H4 (75 MHz, CDCl3)    264   1H NMR spectrum of 3.26, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.26, R = Ph (75 MHz, CDCl3)    265   1H NMR spectrum of 3.26, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.26, R = 4-Tol (75 MHz, CDCl3)    266   1H NMR spectrum of 3.26, R = 4-NC-C6H4 (300 MHz, CDCl3)  13C NMR spectrum of 3.26, R = 4-NC-C6H4 (75 MHz, CDCl3)    267   1H NMR spectrum of 3.28 (300 MHz, DMSO-d6)  13C NMR spectrum of compound 3.28 (75 MHz, DMSO-d6)    268   1H NMR spectrum of 3.29 (300 MHz, CDCl3)  13C NMR spectrum of compound 3.29 (75 MHz, CDCl3)    269   1H NMR spectrum of crude 3.30 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.30 (75 MHz, CDCl3)    270   1H NMR spectrum of 3.31 (300 MHz, CDCl3)  13C NMR spectrum of 3.31 (75 MHz, CDCl3)    271   1H NMR spectrum of 3.32 (300 MHz, CDCl3)  13C NMR spectrum of 3.32 (75 MHz, CDCl3)    272   1H NMR spectrum of 3.33 (300 MHz, CDCl3)  13C NMR spectrum of 3.33 (75 MHz, CDCl3)    273   1H NMR spectrum of 3.35 (300 MHz, CDCl3)  13C NMR spectrum of 3.35 (75 MHz, CDCl3)    274   1H NMR spectrum of 3.40 (300 MHz, CDCl3)  13C NMR spectrum of 3.40 (75 MHz, CDCl3)    275   1H NMR spectrum of crude 3.42 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.42 (75 MHz, CDCl3)    276   1H NMR spectrum of 3.43 (300 MHz, CDCl3) \ 13C NMR spectrum of 3.43 (75 MHz, CDCl3)    277   1H NMR spectrum of 3.44 (300 MHz, CDCl3)  13C NMR spectrum of 3.44 (75 MHz, CDCl3)    278   1H NMR spectrum of 3.45 (300 MHz, CDCl3)  13C NMR spectrum of 3.45 (75 MHz, CDCl3)    279   1H NMR spectrum of 3.46, Ar = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.46, Ar = Ph (75 MHz, CDCl3)     280     1H NMR spectrum of 3.46, Ar = C6H4-CF3-p (300 MHz, CDCl3)  13C NMR spectrum of 3.46, Ar = C6H4-CF3-p (75 MHz, CDCl3)    281   1H NMR spectrum of 3.48 (300 MHz, CDCl3)  13C NMR spectrum of 3.48 (75 MHz, CDCl3)    282   1H NMR spectrum of 3.49 (300 MHz, CDCl3)  13C NMR spectrum of 3.49 (75 MHz, CDCl3)    283   1H NMR spectrum of 3.50 (300 MHz, CDCl3)  13C NMR spectrum of 3.50 (75 MHz, CDCl3)    284   1H NMR spectrum of 3.52, R = i-Pr, R’= Et (300 MHz, CDCl3) 13C NMR spectrum of 3.52, R = i-Pr, R’= Et (75 MHz, CDCl3)    285   1H NMR spectrum of 3.52, R = Cy, R’= Et (300 MHz, CDCl3)  13C NMR spectrum of 3.52, R = Cy, R’= Et (75 MHz, CDCl3)    286   1H NMR spectrum of 3.52, R = Ph, R’= Me (300 MHz, CDCl3)  13C NMR spectrum of 3.52, R = Ph, R’= Me (75 MHz, CDCl3)    287   1H NMR spectrum of 3.52, R = CH2CF3, R’= Et (300 MHz, CDCl3)  13C NMR spectrum of 3.52, R = CH2CF3, R’= Et (75 MHz, CDCl3)    288   1H NMR spectrum of 3.52, R = Bn, R’= Et (300 MHz, CDCl3)  13C NMR spectrum of 3.52, R = Bn, R’= Et (75 MHz, CDCl3)    289   1H NMR spectrum of 3.53, R = i-Pr (300 MHz, CDCl3)  13C NMR spectrum of 3.53, R = i-Pr (75 MHz, CDCl3)    290   1H NMR spectrum of crude 3.53, R = Cy (300 MHz, CDCl3)  13C NMR spectrum of crude 3.53, R = Cy (75 MHz, CDCl3)    291   1H NMR spectrum of crude 3.53, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of crude 3.53, R = Ph (75 MHz, CDCl3)    292   1H NMR spectrum of crude 3.53, R = CH2CF3 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.53, R = CH2CF3 (75 MHz, CDCl3)    293   1H NMR spectrum of crude 3.53, R = Bn (300 MHz, CDCl3)  13C NMR spectrum of crude 3.53 (75 MHz, CDCl3)    294   1H NMR spectrum of 3.54, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = Me (75 MHz, CDCl3)    295   1H NMR spectrum of 3.54, R = i-Pr (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = i-Pr (75 MHz, CDCl3)    296   1H NMR spectrum of 3.54, R = Cy (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = Cy (75 MHz, CDCl3)    297   1H NMR spectrum of 3.54, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = Ph (75 MHz, CDCl3)    298   1H NMR spectrum of 3.54, R = CH2CF3 (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = CH2CF3 (75 MHz, CDCl3)    299   1H NMR spectrum of 3.54, R = Bn (300 MHz, CDCl3)  13C NMR spectrum of 3.54, R = Bn (75 MHz, CDCl3)    300   1H NMR spectrum of 3.55, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = Me (75 MHz, CDCl3)    301   1H NMR spectrum of 3.55, R = i-Pr (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = i-Pr (75 MHz, CDCl3)    302   1H NMR spectrum of 3.55, R = Cy (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = Cy (75 MHz, CDCl3)    303   1H NMR spectrum of 3.55, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = Ph (75 MHz, CDCl3)    304   1H NMR spectrum of 3.55, R = CH2CF3 (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = CH2CF3 (75 MHz, CDCl3)    305   1H NMR spectrum of 3.55, R = Bn (300 MHz, CDCl3)  13C NMR spectrum of 3.55, R = Bn (75 MHz, CDCl3)    306   1H NMR spectrum of 3.56, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.56, R = Me (75 MHz, CDCl3)    307   1H NMR spectrum of 3.56, R = i-Pr (300 MHz, CDCl3)  13C NMR spectrum of 3.56, R = i-Pr (75 MHz, CDCl3)    308   1H NMR spectrum of 3.56, R = Cy (300 MHz, CDCl3)  13C NMR spectrum of 3.56, R = Cy (75 MHz, CDCl3)    309   1H NMR spectrum of 3.56, R = Bn (300 MHz, CDCl3)  13C NMR spectrum of 3.56, R = Bn (75 MHz, CDCl3)    310   1H NMR spectrum of 3.58 (300 MHz, CDCl3)  13C NMR spectrum of 3.58 (75 MHz, CDCl3)    311   1H NMR spectrum of 3.59 (300 MHz, CDCl3)  13C NMR spectrum of 3.59 (75 MHz, CDCl3)    312   1H NMR spectrum of 3.60 (300 MHz, CDCl3)  13C NMR spectrum of 3.60 (75 MHz, CDCl3)    313   1H NMR spectrum of 3.61 (300 MHz, CDCl3)  13C NMR spectrum of 3.61 (75 MHz, CDCl3)    314   1H NMR spectrum of 3.62, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.62, R = Me (75 MHz, CDCl3)    315   1H NMR spectrum of 3.62, R = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.62, R = Ph (75 MHz, CDCl3)    316   1H NMR spectrum of 3.63 (300 MHz, CDCl3)  13C NMR spectrum of 3.63 (75 MHz, CDCl3)    317   1H NMR spectrum of 3.64 (300 MHz, CDCl3)  13C NMR spectrum of compound 3.64 (75 MHz, CDCl3)    318   1H NMR spectrum of 3.69, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.69, R’ = H (75 MHz, CDCl3)    319   1H NMR spectrum of 3.69, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.69, R’ = OMe (75 MHz, CDCl3)    320   1H NMR spectrum of 3.70, R’ = H (300 MHz, CDCl3) 13C NMR spectrum of 3.70, R’ = H (75 MHz, CDCl3)    321   1H NMR spectrum of 3.70, R’ = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.70, R’ = Ph (75 MHz, CDCl3)    322   1H NMR spectrum of 3.70, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.70, R’ = OMe (75 MHz, CDCl3)    323   1H NMR spectrum of 3.71, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.71, R’ = H (75 MHz, CDCl3)    324   1H NMR spectrum of 3.71, R’ = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.71, R’ = Ph (75 MHz, CDCl3)    325   1H NMR spectrum of 3.71, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.71, R’ = OMe (75 MHz, CDCl3)    326   1H NMR spectrum of crude 3.72, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of crude 3.72, R’ = H (75 MHz, CDCl3)    327   1H NMR spectrum of crude 3.72, R’ = Ph (300 MHz, CDCl3) 13C NMR spectrum of crude 3.72, R’ = Ph (75 MHz, CDCl3)    328   1H NMR spectrum of crude 3.72, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of crude 3.72, R’ = OMe (75 MHz, CDCl3)    329   1H NMR spectrum of 3.73, R = Me, R’ = H (300 MHz, CDCl3) 13C NMR spectrum of 3.73, R = Me, R’ = H (75 MHz, CDCl3)    330   1H NMR spectrum of 3.73, R = 4-Tol, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = 4-Tol, R’ = H (75 MHz, CDCl3)    331   1H NMR spectrum of 3.73, R = C6H4-NO2-p, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = C6H4-NO2-p, R’ = H (75 MHz, CDCl3)    332   1H NMR spectrum of 3.73, R = C6H4-OMe-p, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of R = C6H4-OMe-p, R’ = H (75 MHz, CDCl3)    333   1H NMR spectrum of 3.73, R = Bn, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = Bn, R’ = H (75 MHz, CDCl3)    334   1H NMR spectrum of 3.73, R = CH2CF3, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = CH2CF3, R’ = H (75 MHz, CDCl3)    335   1H NMR spectrum of 3.73, R = Me, R’ = Ph (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = Me, R’ = Ph (75 MHz, CDCl3)    336   1H NMR spectrum of 3.73, R = Me, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.73, R = Me, R’ = OMe (75 MHz, CDCl3)    337   1H NMR spectrum of 3.74, R = Me, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.74, R = Me, R’ = H (75 MHz, CDCl3)    338   1H NMR spectrum of 3.74, R = 4-Tol, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of 3.74, R = 4-Tol, R’ = H (75 MHz, CDCl3)    339   1H NMR spectrum of 3.74, R = C6H4-NO2-p, R’ = H (300 MHz, CDCl3) 13C NMR spectrum of 3.74, R = C6H4-NO2-p, R’ = H (75 MHz, CDCl3)    340   1H NMR spectrum of R = C6H4-OMe-p, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of R = C6H4-OMe-p, R’ = H (75 MHz, CDCl3)    341   1H NMR spectrum of R = Bn, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of R = Bn, R’ = H (75 MHz, CDCl3)    342   1H NMR spectrum of R = CH2CF3, R’ = H (300 MHz, CDCl3)  13C NMR spectrum of R = CH2CF3, R’ = H (75 MHz, CDCl3)    343   1H NMR spectrum of R = Me, R’ = Ph (300 MHz, acetone-d6)  13C NMR spectrum of R = Me, R’ = Ph (75 MHz, acetone-d6)    344   1H NMR spectrum of R = Me, R’ = OMe (300 MHz, CDCl3)  13C NMR spectrum of R = Me, R’ = OMe (75 MHz, CDCl3)    345   1H NMR spectrum of 3.76, R = Me (300 MHz, CDCl3)  13C NMR spectrum of 3.76, R = Me (75 MHz, CDCl3)    346   1H NMR spectrum of 3.76, R = 4-Tol (300 MHz, CDCl3)  13C NMR spectrum of 3.76, R = 4-Tol (75 MHz, CDCl3)    347   1H NMR spectrum of 3.76, R = C6H4-NO2-p (300 MHz, acetone-d6)  13C NMR spectrum of 3.76, R = C6H4-NO2-p (75 MHz, acetone-d6)    348   1H NMR spectrum of 3.76, R = Bn (300 MHz, CDCl3)  13C NMR spectrum of 3.76, R = Bn (75 MHz, CDCl3)    349   1H NMR spectrum of 3.76, R = CH2CF3 (300 MHz, acetone-d6)  13C NMR spectrum of 3.76, R = CH2CF3 (75 MHz, acetone-d6)    350   1H NMR spectrum of 3.77, R = Me (300 MHz, acetone-d6)  13C NMR spectrum of 3.77, R = Me (75 MHz, acetone-d6)    351   1H NMR spectrum of 3.78, Ar = C6H4-F-p (300 MHz, acetone-d6)  13C NMR spectrum of 3.78, Ar = C6H4-F-p (75 MHz, acetone-d6)    352   1H NMR spectrum of 3.78, Ar = C6H4-CF3-p (300 MHz, CDCl3)  13C NMR spectrum of 3.78, Ar = C6H4-CF3-p (75 MHz, CDCl3)    353   1H NMR spectrum of 3.78, Ar = 3,5-bis(CF3)2C6H3 (300 MHz, CDCl3)  13C NMR spectrum of 3.78, Ar = 3,5-bis(CF3)2C6H3 (75 MHz, CDCl3)    354   1H NMR spectrum of crude 3.80, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of crude 3.80, R = OMe (75 MHz, CDCl3)    355   1H NMR spectrum of crude 3.81, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of crude 3.81, R = OMe (75 MHz, CDCl3)    356   1H NMR spectrum of 3.82, R = H (300 MHz, CDCl3)  13C NMR spectrum of 3.82, R = H (75 MHz, CDCl3)    357   1H NMR spectrum of 3.82, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.82, R = OMe (75 MHz, CDCl3)    358   1H NMR spectrum of 3.83, R = H (300 MHz, CDCl3)  13C NMR spectrum of 3.83, R = H (75 MHz, CDCl3)    359   1H NMR spectrum of 3.83, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.83, R = OMe (75 MHz, CDCl3)    360   1H NMR spectrum of 3.84, R = H (300 MHz, CDCl3)  13C NMR spectrum of 3.84, R = H (75 MHz, CDCl3)    361   1H NMR spectrum of 3.84, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.84, R = OMe (75 MHz, CDCl3)    362   1H NMR spectrum of crude 3.85, R = H (300 MHz, CDCl3)  13C NMR spectrum of crude 3.85, R = H (75 MHz, CDCl3)    363   1H NMR spectrum of crude 3.85, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of crude 3.85, R = OMe (75 MHz, CDCl3)    364   1H NMR spectrum of 3.86, R = H (300 MHz, CDCl3)  13C NMR spectrum of 3.86, R = OMe (75 MHz, CDCl3)    365   1H NMR spectrum of 3.86, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.86, R = OMe (75 MHz, CDCl3)    366   1H NMR spectrum of 3.87, R = H (300 MHz, CDCl3)  13C NMR spectrum of 3.87, R = H (75 MHz, CDCl3)    367   1H NMR spectrum of 3.87, R = OMe (300 MHz, CDCl3)  13C NMR spectrum of 3.87, R = OMe (75 MHz, CDCl3)    368   1H NMR spectrum of 3.89 (300 MHz, CDCl3)  13C NMR spectrum of 3.89 (75 MHz, CDCl3)    369   1H NMR spectrum of 3.90 (300 MHz, CDCl3)  13C NMR spectrum of 3.90 (75 MHz, CDCl3)    370   1H NMR spectrum 3.91 (300 MHz, CDCl3)  13C NMR spectrum of 3.91 (75 MHz, CDCl3)    371   1H NMR spectrum of 3.92 (300 MHz, CDCl3)  13C NMR spectrum of 3.92 (75 MHz, CDCl3)    372   1H NMR spectrum of 3.93 (300 MHz, CDCl3)  13C NMR spectrum of 3.93 (75 MHz, CDCl3)    373   1H NMR spectrum of 3.94 (300 MHz, CDCl3)  13C NMR spectrum of 3.94 (75 MHz, CDCl3)    374   1H NMR spectrum of crude 3.95 (300 MHz, CDCl3)  13C NMR spectrum of crude 3.95 (75 MHz, CDCl3)    375  B.23 IR spectrum of compound crude 3.95     376  C. Oxidative amidation in naphthalene Series section C.1 Synthesis and characterization of spiropyrrolidines C.1.1 Representative protocol for ortho-oxidative cyclization of sulfonamides A solution of sulfonamide 4.1 (0.4 mmol, 1.0 equiv) in TFA (0.7 mL) was slowly added at room temperature over a period of 2 minutes to a solution containing DIB (0.44 mmol, 1.1 equiv) in TFA (0.5 mL) so that the final concentration is 0.3 M. Upon completion of the reaction (TLC, 7-17 min), the mixture was evaporated to dryness. Chromatography of the residue afforded the azaspirocyclic compound. C.1.1.1 Characterization of (±)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.2a)  13 mg (65% yield) from 20 mg of 4.1a, white solid, m.p.: 112-114 °C; eluent: 2:3 EtOAc/hexane; IR: 1682. 1H: 8.01 (d, 1H, J = 7.7), 7.58 (td, 1H, J = 7.5, 1.3), 7.36 (td, 1H, J = 7.6, 1.0), 7.23 (d, 1H, J = 7.6), 6.53 (d, 1H, J = 9.8), 6.35 (d, 1H, J = 9.8), 3.80-3.66 (m, 2H), 3.01 (m, 3H), 2.31-2.02 (m, 4H). 13C: 199.4, 137.8, 137.7, 135.1, 128.5, 128.0, 127.6, 127.4, 123.7, 72.1, 49.3, 39.6, 39.5, 22.8. HRMS: calcd for C14H15NO3SNa [M+Na]+: 300.0670; found: 300.0672. C.1.1.2 Characterization of (±)-1'-Tosyl-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2b) 15 mg (74% yield) from 20 mg of 4.1b, yellow solid, m.p.: 115-117 °C; eluent: 1:3 EtOAc/hexane; IR: 1686. 1H: 8.03 (d, 1H, J = 7.2), 7.72 (d, 2H, J = 8.3), 7.58 (td, 1H, J = 7.5, 1.4), 7.36 (td, 1H, J = 7.6, 1.1), 7.29-7.24 (m, 3H), 6.59 (d, 1H, J = 9.9), 6.27 (d, 1H, J = 9.8), 3.64-3.60 (m, 2H),  2.42 (s, 3H), 2.26-2.03 (m, 2H), 2.02-1.95 (m, 2H). 13C: 198.4, 143.2, 137.4, 137.1, 136.6, 134.8, 129.3, 128.7, 128.0, 127.7, 127.6, 127.5,  377  124.5, 70.9, 48.9, 39.5, 23.0, 21.6. HRMS: calcd for C20H19NO3SNa [M+Na]+: 376.0983; found: 376.0983. C.1.1.3 Characterization of (±)-4-bromo-1'-tosyl-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2c) 11 mg (73% yield) from 15 mg of 4.1c, yellow solid, m.p. 63-65 °C, eluent: 1:4 EtOAc/hexane; IR: 1693. 1H: 8.10 (dd, 1H, J = 7.7, 1.1), 7.77-7.67 (m, 4H), 7.47 (td, 1H, J = 7.5, 1.3), 7.31 (d, 2H, J = 8.1), 6.52 (s, 1H), 3.77-3.70 (m, 1H), 3.60-3.52 (m, 1H), 2.44 (s, 3H), 2.29-2.16 (m, 2H), 2.09-1.99 (m, 2H). 13C: 196.7, 143.4, 137.2, 137.1, 135.4, 135.0, 129.5, 129.3, 128.8, 128.4, 127.8, 127.6, 119.2, 71.9, 48.8, 39.5, 23.3, 21.6. HRMS: calcd for C20H18NO3S79BrNa [M+Na]+: 454.0088; found: 454.0070. C.1.1.4 Characterization of (±)-1'-(4-Nitrophenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2d) 15 mg (75% yield) from 20 mg of 4.1d, green solid, dec. 134 °C; eluent: 2:3 EtOAc/hexane; IR: 1685. 1H: 8.34 (d, 2H, J = 8.9), 7.99 (m, 3H), 7.62 (td, 1H, J = 7.5, 1.3), 7.39 (td, 1H, J = 7.6, 1.1), 7.28 (d, 1H, J = 6.7), 6.62 (d, 1H, J = 9.8), 6.28 (d, 1H, J = 9.8), 3.77-3.61 (m, 2H), 2.24-1.99 (m, 4H). 13C: 198.0, 149.9, 145.4, 137.3, 136.1, 135.2, 129.0, 128.5, 128.4, 127.8, 127.5, 124.8, 123.9, 71.8, 49.4, 39.6, 22.9. HRMS: calcd for C19H16N2O5S [M+Na]+: 407.0678; found: 407.0685.    378  C.1.1.5 Characterization of (±)-4-bromo-1'-(4-nitrophenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2e) 10.5 mg (70% yield) from 15 mg of 4.1e, yellow solid, dec. 110 °C, eluent: 2:3 EtOAc/hexane; IR: 1691. 1H: 8.37 (d, 2H, J = 8.8), 8.07 (d, 1H, J = 7.7), 7.99 (d, 2H, J = 8.8), 7.79-7.71 (m, 2H), 7.50 (t, 1H, J = 7.4), 6.53 (s, 1H), 3.77-3.63 (m, 2H), 2.33-2.18 (m, 2H), 2.15-2.01 (m, 2H). 13C: 196.3, 150.0, 145.5, 136.6, 135.4, 135.3, 129.6, 128.8, 128.6 (2C), 127.8, 124.1, 119.6, 72.6, 49.3, 39.5, 23.3. HRMS: calcd for C19H15N2O5S79Br [M]+: 461.9885; found: 461.9887. C.1.1.6 Characterization of (±)-1'-(4-Methoxyphenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2f) 16 mg (80% yield) from 20 mg of 4.1f, colorless oil, eluent: 2:3 EtOAc/hexane; IR: 1690, 1149. 1H: 8.03 (d, 1H, J = 7.7), 7.78 (d, 2H, J = 8.9), 7.58 (td, 1H, J = 7.5, 1.3), 7.36 (td, 1H, J = 7.6, 0.9), 7.25 (d, 1H, J = 7.5), 6.94 (d, 2H, J = 8.9), 6.59 (d, 1H, J = 9.9), 6.30 (d, 1H, J = 9.8), 3.86 (s, 3H), 3.62-3.58 (m, 2H), 2.24-1.95 (m, 4H). 13C: 198.6, 162.8, 137.4, 136.7, 134.8, 131.7, 129.9, 128.7, 128.0, 127.6, 127.4, 124.5, 113.8, 70.9, 55.5, 48.8, 39.5, 23.0. HRMS: calcd for C20H20NO4S [M+H]+: 370.1113; found: 370.1115.   C.1.1.7 Characterization of (±)-1'-(Benzylsulfonyl)-4-bromo-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2g) 19 mg (96% yield) from 20 mg of 4.1g, colorless oil, eluent: 2:3 EtOAc/hexane; IR: 1685. 1H: 8.06 (d, 1H, J = 7.7), 7.59-7.54 (m, 3H), 7.38-7.36 (m, 4H), 7.20 (d, 1H, J = 7.6), 6.45 (d, 1H, J = 9.8), 6.03 (d, 1H, J = 9.8), 4.44 (d, 1H, J = 13.6), 4.28 (d, 1H, J = 13.5), 3.40 (t, 2H, J = 6.8), 2.23-1.85 (m, 4H). 13C: 199.3, 137.5 (2C),  379  134.9, 131.1, 129.6, 128.6 (2C, shoulder), 128.5, 128.0, 127.6, 127.5, 124.0, 72.1, 59.8, 50.0, 39.8, 23.1. HRMS: calcd for C20H19NO3SNa [M+Na]+: 376.0983; found: 376.0986. C.1.1.8 Characterization of (±)-1'-(benzylsulfonyl)-4-bromo-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2h) 13 mg (87% yield) from 15 mg of 4.1h, yellow solid, dec. 113 °C, eluent: 1:4 EtOAc/hexane; IR: 1693. 1H: 8.09 (d, 1H, J = 7.6), 7.72-7.62 (m, 2H), 7.56-7.37 (m, 6H), 6.17 (s, 1H), 4.42 (d, 1H, J = 13.7), 4.29 (d, 1H, J = 13.7), 3.53-3.36 (m, 2H), 2.23-2.00 (m, 4H). 13C: 197.4, 138.2, 135.6, 135.1, 131.0, 129.3, 129.2, 128.7, 128.6, 128.3, 127.8, 118.1, 73.4, 59.8, 49.8, 39.4, 23.2. HRMS: calcd for C20H18NO3S79BrNa [M+Na]+: 454.0088; found: 454.0074. C.1.1.9 Characterization of (±)-1'-(2,2,2-Trifluoroethylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2i)  9 mg (45% yield) from 20 mg of 4.1i, light yellow solid, m.p.: 121-123 °C; eluent: 2:3 EtOAc/hexane; IR: 1685. 1H: 8.02 (dd, 1H, J = 7.4, 0.7), 7.61 (td, 1H, J = 7.6, 1.4), 7.39 (td, 1H, J = 7.7, 1.1), 7.24 (d, 1H, J = 7.6), 6.56 (d, 1H, J = 9.8), 6.34 (d, 1H, J = 9.8), 4.11-3.75 (m, 4H), 2.31-2.03 (m, 4H). 13C: 199.1, 137.5, 136.6, 135.4, 128.4, 128.3, 127.7, 127.6, 124.5, 121.9(q), 72.8, 55.1(q), 49.8, 40.2, 23.0. HRMS: calcd for C15H14F3NO3SNa [M+Na]+: 368.0544; found: 368.0540.  C.1.1.10 Characterization of (±)-4-bromo-1'-(2,2,2-trifluoroethylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2j) 13.8 mg (93% yield) from 15 mg of 4.1j, yellow solid, m.p. 51-53 °C, eluent: 1:4 EtOAc/hexane; IR: 1690. 1H: 8.05 (d, 1H, J = 7.6), 7.75-7.69  380  (m, 2H), 7.48 (app t, 1H, J = 6.8), 6.77 (s, 1H), 4.12-3.71 (m, 4H), 2.31-2.13 (m, 4H). 13C: 197.3, 137.4, 135.6, 129.5, 128.5, 128.4, 127.8, 121.8 (q), 118.6, 74.1, 55.2 (q), 49.7, 40.2, 23.3. HRMS: calcd for C15H13NO3F3S79BrNa [M+Na]+: 445.9649; found: 445.9655. C.1.1.11 Characterization of (±)-4-Bromo-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2k) 21 mg (83% yield) from 25 mg of 4.1k, yellow oil; eluent: 3:7 EtOAc/hexane; IR: 1690. 1H: 8.05 (d, 1H, J = 7.6), 7.74-7.66 (m, 2H), 7.45 (t, 1H, J = 7.1), 6.78 (s, 1H), 3.79-3.65 (m, 2H), 3.02 (s, 3H), 2.28-2.07 (m, 4H). 13C: 197.6, 138.5, 135.8, 135.3, 129.2, 128.5, 128.4, 127.6, 117.9, 73.4, 49.2, 39.7(2C), 23.1. HRMS: calcd for C14H14NO3S79BrNa [M+Na]+: 377.9775; found: 377.9783. C.1.1.12 Characterization of (±)-4-chloro-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2l) 17 mg (85% yield) from 20 mg of 4.1l, colorless oil, eluent: 1:3 to 2:3 EtOAc/hexanes; IR: 1692. 1H: 8.07 (d, 1H, J = 6.0), 7.76-7.67 (m, 2H), 7.47 (app t, 1H, J = 7.5), 6.52 (s, 1H), 3.78-3.65 (m, 2H), 3.01 (s, 3H), 2.29-1.99 (m, 4H). 13C: 197.7, 135.4, 135.3, 134.4, 129.3, 128.6, 127.9, 127.5, 125.8, 72.6, 49.3, 40.1, 39.8, 23.3. HRMS: calcd for C14H14NO3SClNa [M+Na]+: 334.0281; found: 334.0276. C.1.1.13 Characterization of (±)-1'-(Methylsulfonyl)-4-phenyl-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2m) 11 mg (55% yield) from 20 g of 4.1m, white solid, m.p.: 145-147 °C (color changes to brown); eluent: 3:7 EtOAc/hexane; IR: 1688. 1H: 8.10 (dd, 1H, J = 7.7, 1.2), 7.52 (td, 1H, J = 7.7, 1.5), 7.44-7.36 (m, 6H), 7.16 (d, 1H, J = 7.8),  381  6.27 (s, 1H), 3.78-3.71 (m, 2H), 3.04 (s, 3H), 2.39-2.06 (m, 4H). 13C: 199.3, 138.4, 138.1, 136.5, 135.3, 134.8, 129.1, 128.7, 128.4, 127.9, 127.8 (2C), 126.8, 72.1, 49.3, 39.9, 39.6, 23.0. HRMS: calcd for C20H19NO3SNa [M+Na]+: 376.0983; found: 376.0990. C.1.1.14 Characterization of (±)-4-(4-fluorophenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2n) 16.9 mg (85% yield) from 20 mg of 4.1n, off white solid, turns brown at 125 °C and then melts at 148-149 °C, eluent: 1:4 EtOAc/hexanes; IR: 1687. 1H: 8.10 (d, 1H, J = 6.0), 7.55-7.50 (m, 1H), 7.41-7.32 (m, 3H), 7.15-7.09 (m, 3H), 6.26 (s, 1H), 3.80-3.67 (m, 2H), 3.03 (s, 3H), 2.34-2.05 (m, 4H). 13C: 199.4, 162.6 (d, J = 246.9), 138.1, 137.0, 135.0, 134.5 (d, J = 3.8), 134.4, 131.0 (d, J = 8.3), 128.7, 128.2, 128.1, 126.7, 115.6 (d, J = 21.1), 72.3, 49.4, 40.0, 39.7, 23.1. HRMS: calcd for C20H19NO3FS [M+H]+: 372.1070; found: 372.1078. C.1.1.15 Characterization of (±)-1'-(methylsulfonyl)-4-(4-(trifluoromethyl)phenyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2o) 17 mg (85% yield) from 20 mg of 4.1o, off white solid, m.p.: 160-161 °C (color changes to brown), eluent: 1:4 EtOAc/hexanes; IR: 1690. 1H: 8.12 (d, 1H, J = 9.0), 7.70 (d, 2H, J = 6.0), 7.56-7.49 (m, 3H), 7.43-7.38 (m, 1H), 7.07 (d, 1H, J = 6.0), 6.31 (s, 1H), 3.81-3.67 (m, 2H), 3.04 (s, 3H), 2.36-2.06 (m, 4H). 13C: 199.1, 142.3, 137.6, 137.5, 135.1, 134.3, 130.3 (q, J = 33.2), 129.7, 128.7, 128.5, 128.2, 126.6, 125.6 (q, J = 3.8), 120.6 (q, J = 272.6), 72.3, 49.4, 39.9, 39.7, 23.2. HRMS: calcd for C21H18NO3F3SNa [M+Na]+: 444.0857; found: 444.0859.  382  C.1.1.16 Characterization of (±)-4-(3,5-bis(trifluoromethyl)phenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2p) 12 mg (60% yield) from 20 mg of 4.1p, off white solid, m.p.: 76-78 °C, eluent: 1:4 EtOAc/hexanes; IR: 1715. 1H: 8.14 (d, 1H, J = 6.0), 7.93 (s, 1H), 7.83 (s, 2H), 7.61-7.42 (m, 2H), 6.96 (d, 1H, J = 6.0), 6.38 (s, 1H), 3.83-3.68 (m, 2H), 3.05 (s, 3H), 2.41-2.09 (m, 4H). 13C: 198.7, 140.7, 138.9, 136.9, 135.3, 133.0, 132.2 (q, J = 34.0), 129.5 (app d, J = 3.0), 128.9, 128.7, 128.5, 126.1, 123.3 (q, J = 273.3), 122.2-122.0 (m), 72.5, 49.4, 39.8 (2C), 23.2. HRMS: calcd for C22H17NO3F6SNa [M+Na]+: 512.0731; found: 512.0745. C.1.1.17 Characterization of (±)-1'-(Methylsulfonyl)-2H-spiro[naphthalene-1,2'-pyrrolidin]-2-one (4.5a) 16 mg (67% yield) from 25 g of 4.4a, white solid, m.p.: 116-118 °C; eluent: 2:3 EtOAc/hexane; IR: 1672. 1H: 7.62 (d, 1H, J = 7.8), 7.47-7.42 (m, 2H), 7.32-7.31 (m, 2H), 6.17 (d, 1H, J = 9.9), 3.99-3.92 (m, 1H), 3.80-2.72 (m, 1H), 3.10 (s, 3H), 2.43-2.34 (m, 1H), 2.22-2.13 (m, 2H), 2.07-1.98 (m, 1H). 13C: 200.5, 146.5, 146.0, 130.6, 129.8, 128.5, 127.7, 125.8, 123.7, 75.8, 49.9, 44.2, 40.0, 22.8. HRMS: calcd for C14H15NO3SNa [M+Na]+: 300.0670; found: 300.0665. C.1.1.18 Characterization of (±)-7-Methoxy-1'-(methylsulfonyl)-2H-spiro[naphthalene-1,2'-pyrrolidin]-2-one (4.5b) 12 mg (58% yield) from 20 mg of 4.4b, white solid, m.p.: 144-146 °C; eluent: 2:3 EtOAc/hexane; IR: 1669. 1H: 7.40 (d, 1H, J = 9.8), 7.25 (d, 1H, J = 7.6), 7.16 (d, 1H, J = 2.5), 6.81 (dd, 1H, J = 8.4, 2.5), 6.04 (d, 1H, J = 9.8), 3.98-3.91 (m, 1H), 3.86 (s, 3H), 3.78-3.71 (m, 1H), 3.11 (s, 3H), 2.42-2.34 (m, 1H), 2.21-2.12 (m, 2H), 2.06-1.98 (m, 1H).  383  13C: 200.4, 161.8, 149.0, 145.9, 131.5, 121.8, 121.0, 112.5, 112.3, 76.0, 55.5, 49.9, 44.3, 39.9, 22.7. HRMS: calcd for C15H17NO4SNa [M+Na]+: 330.0776; found: 330.0782. C.2 Characterization of N-(3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl)methanesulfonamide (4.3) 4.2-7.0 mg (20-35% yield) from 20 mg of 4.1q, yellow solid, m.p. 120-122 °C, eluent: 2:3 EtOAc/hexane; IR: 3378-3126 (broad), 1659. 1H: 8.11-8.06 (m, 2H), 7.78-7.72 (m, 2H), 6.85 (s, 1H), 4.57 (br s, 1H), 3.23 (q, 2H, J = 12.0, 6.0), 2.99 (s, 3H), 2.67 (app t, 2H, J = 7.5), 1.90 (p, 2H, J = 6.0). 13C: 185.3, 184.8, 150.3, 135.6, 133.9, 133.8, 132.1, 126.7, 126.2, 42.5, 40.6, 29.2, 26.6. HRMS: calcd for C14H15NO4SNa [M+Na]+: 316.0619; found: 316.0625. C.3 Synthesis and characterization of spirolactams  C.3.1 Representative protocol for the ortho-oxidative cyclization of N-acyl sulfonamides  A solution of sulfonamide 4.8 (0.1 mmol, 1.0 equiv) in HFIP (2.0 mL) was added to a solution containing DIB (0.11 mmol, 1.1 equiv) in TFA (0.23 mL) at RT so that the final concentration was 0.05 M. Upon completion of the reaction (TLC, 5-12 min), the reaction mixture was evaporated to dryness. Chromatography of the residue afforded the azaspirocyclic compound. C.3.1.1 Characterization of (±)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.9a) 8 mg (42% yield) from 19 mg of 4.8a, white solid, m.p.: 169-171 °C; eluent: 3:7 EtOAc/hexane; IR: 1737, 1686. 1H: 8.05 (d, 1H, J = 7.7), 7.64 (t, 1H, J = 7.5), 7.42 (t, 1H, J = 7.6), 7.30-7.27 (m, 1H), 6.61 (d, 1H, J = 9.8),  6.43 (d, 1H, J = 9.8), 3.38 (s,  384  3H), 2.84-2.58 (m, 2H), 2.33 (ddd, 1H, J = 13.4, 9.4, 3.9), 2.20-2.09 (m, 1H). 13C: 197.1, 174.7, 137.5, 135.8, 135.3, 128.6, 128.1, 127.9, 127.4, 124.7, 71.4, 41.6, 29.8, 28.9. HRMS: calcd for C14H13NO4SNa [M+Na]+: 314.0463; found: 314.0468. C.3.1.2 Characterization of (±)-1'-(2-methoxyethylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.9b) 9 mg (47% yield) from 20 mg of 4.8b, colorless oil, eluent: 2:3 EtOAc/hexane; IR: 1737, 1687. 1H: 8.05 (d, 1H, J = 7.6), 7.63 (t, 1H, J = 7.4), 7.41 (t, 1H, J = 7.6), 7.29-7.26 (m, 1H), 6.61 (d, 1H, J = 9.8), 6.43 (d, 1H, J = 9.8), 4.09-4.01 (m, 1H), 3.88 (td, 2H, J = 5.9, 1.2), 3.71-3.62 (m, 1H), 3.36 (s, 3H), 2.85-2.73 (m, 1H), 2.67-2.57 (m, 1H), 2.32 (ddd, 1H, J = 13.4, 9.3, 4.2), 2.19-2.08 (m, 1H). 13C: 196.9, 174.7, 137.4, 135.7, 135.0, 128.6, 128.0, 127.9, 127.5, 124.9, 70.9, 65.1, 58.9, 54.3, 30.1, 29.1. HRMS: calcd for C16H17NO5SNa [M+Na]+: 358.0725; found: 358.0729. C.3.1.3 Characterization of (±)-1'-(4-nitrophenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.9c) 6 mg (29% yield) from 20 mg of 4.8c, 29% yield, yellow solid, dec. 104 °C; eluent: 1:4 EtOAc/hexane; IR: 1747, 1679. 1H: 8.39 (d, 2H, J = 9.1), 8.25 (d, 2H, J = 9.1), 8.12 (d, 1H, J = 7.7), 7.69 (td, 1H, J = 7.6, 1.4), 7.48 (td, 1H, J = 7.7, 1.0), 7.35 (d, 1H, J = 7.6), 6.73 (d, 1H, J = 9.8), 6.48 (d, 1H, J = 9.8), 2.73-2.50 (m, 2H), 2.32 (ddd, 1H, J = 13.5, 8.9, 4.8), 2.20-2.10 (m, 1H). 13C: 196.3, 173.2, 150.9, 143.1, 137.2, 135.9, 134.3, 131.2, 128.9, 128.2, 128.0, 127.7, 125.8, 123.6, 71.1, 30.5, 29.0. HRMS: calcd for C19H14N2O6SNa [M+Na]+: 421.0470; found: 421.0463.  385  C.3.2 Preparation of 1H-spiro[naphthalene-2,2'-pyrrolidine]-1,5'-dione (4.10) A solution of sulfonamide 4.9c (20 mg, 0.05 mmol, 1.0 equiv) in CH3CN (1.0 mL) was added at RT to a solution of PhSH (15 µL, 150 µmol, 3.0 equiv) in CH3CN (0.4 mL) containing suspended K2CO3 (28 mg, 0.2 mmol, 4.0 equiv). Next, DMSO (0.1 mL) was added to the reaction mixture and stirring was continued at room temperature for 2 h, after which time TLC showed that the reaction was complete. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel (eluent: 3:4 EtOAc/hexane) to provide 8 mg (78% yield) of 4.10 as a white solid, m.p.: 131-133 °C. IR: 3430-3100 (broad), 1698. 1H: 8.03 (d, 1H, J = 7.6), 7.62 (td, 1H, J = 7.6, 1.3), 7.41 (td, 1H, J = 7.7, 0.7), 7.30-7.29 (m, 1H), 6.62 (d, 1H, J = 9.8), 6.18 (d, 1H, J = 9.8), 5.57 (br s, 1H), 2.71-2.59 (m, 1H), 2.46-2.31 (m, 2H), 2.17-2.05 (m, 1H). 13C: 199.4, 178.8, 137.1, 135.3 (2C), 128.7, 127.9, 127.7 (2C), 127.0, 65.0, 32.2, 28.2. HRMS: calcd for C13H11NO2 [M+Na]+: 236.0687; found: 236.0687. C.4 Synthesis and characterization of acyloxylated adducts C.4.1 Representative protocol for acyloxylation of naphtholic sulfonamides A solution of MCPBA (0.09 mmol, 1.5 equiv) in CH2Cl2 (2.5 mL) was added at RT to solution of a substrate 4.1 (0.06 mmol, 1.0 equiv), MCBA (0.12 mmol, 2.0 equiv) and iodobenzene (0.06 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL). The mixture was stirred at RT, whereupon TLC indicated complete reaction. The mixture was quenched with aq. sat. NaHCO3 (3.0 mL) and aq. sat. Na2S2O3 (1.5 mL) solutions and extracted with CH2Cl2 (3×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to afford product (±)-4.54.  386  C.4.1.1 Characterization of (±)-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54a) 17 mg (22% yield) from 50 mg of 4.1a, yellow oil, eluent: 2:3 Et2O/pentane; IR: 3390-3156 (broad), 1721, 1690. 1H: 8.09 (d, 1H, J = 7.8), 8.00 (s, 1H), 7.91 (d, 1H, J = 7.7), 7.64 (t, 1H, J = 7.5), 7.56 (d, 1H, J = 8.1), 7.45-7.37 (m, 2H), 7.32 (d, 1H, J = 7.7), 6.78 (d, 1H, J = 10.0), 6.13 (d, 1H, J = 9.9), 4.33 (t, 1H, J = 5.9), 3.15 (app q, 2H, J = 6.7), 2.93 (s, 3H), 2.20-2.10 (m, 1H), 2.06-1.96 (m, 1H), 1.91-1.75 (m, 1H), 1.68-1.57 (m, 1H). 13C: 195.7, 164.0, 136.8, 135.0, 134.6, 133.5, 132.6, 130.9, 129.9, 129.8, 129.4, 128.8, 128.2, 128.1, 127.7, 127.3, 80.6, 43.1, 40.4, 35.0, 23.5. HRMS: calcd for C21H19NO5SCl [M-H]-: 432.0672; found: 432.0670. C.4.1.2 Characterization of (±)-4-bromo-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54b) 7.0 mg (24% yield) from 20 mg of 4.1k, white solid, m.p.: 56-58 °C, eluent: 2:3 EtOAc/hexane; IR: 3421-3161 (broad), 1725, 1695. 1H: 8.12 (d, 1H, J = 7.7), 8.00 (s, 1H), 7.91 (d, 1H, J = 8.0), 7.84-7.73 (m, 2H), 7.59-7.50 (m, 2H), 7.41 (t, 1H, J = 7.9), 6.59 (s, 1H), 4.24 (t, 1H, J = 5.7), 3.18 (app q, 2H, J = 6.6), 2.95 (s, 3H), 2.23-2.13 (m, 1H), 2.09-2.00 (m, 1H), 1.87-1.75 (m, 1H), 1.71-1.59 (m, 1H). 13C: 193.8, 163.9, 135.2, 135.1, 134.7, 134.0, 133.7, 130.5, 129.9 (3C), 129.5, 129.0, 128.1, 127.5, 121.7, 81.5, 42.9, 40.5, 34.8, 23.5. HRMS: calcd for C21H18NO5SCl79Br [M-H]-: 509.9778; found: 509.9784.    387  C.4.1.3 Characterization of (±)-4-chloro-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54c) 12.7 mg (17% yield) from 50 mg of 4.1l, colorless oil, eluent: 1:3 EtOAc/hexanes; IR: 3426-3159 (broad), 1723, 1696. 1H: 8.15 (d, 1H, J = 9.0), 7.99 (s, 1H), 7.90 (d, 1H, J = 6.0), 7.85 (d, 1H, J = 6.0), 7.76 (app t, 1H, J = 7.5), 7.58-7.52 (m, 2H), 7.40 (app t, 1H, J = 9.0), 6.33 (s, 1H), 4.34 (br s, 1H), 3.17 (app q, 2H, J = 7.0), 2.94 (s, 3H), 2.18-2.00 (m, 2H), 1.89-1.75 (m, 1H), 1.70-1.60 (m, 1H). 13C: 194.0, 164.1, 135.3, 134.8, 134.6, 133.8, 131.4, 130.7, 130.1, 130.0 (2C), 129.8, 129.6, 128.3, 127.8, 126.4, 80.9, 43.1, 40.6, 35.2, 23.6. HRMS: calcd for C21H18NO5SCl2 [M-H]-: 466.0283; found: 466.0280. C.4.1.4 Characterization of (±)-4-bromo-1-oxo-2-(3-(phenylmethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54d) 9.3 mg (43% yield) from 16 mg of 4.1h, light yellow solid, m.p.: 86-88 °C, eluent: 1:5 EtOAc/hexane; IR: 3400-3207 (broad). 1H: 8.11 (d, 1H, J = 7.6), 7.98 (s, 1H), 7.89 (d, 1H, J = 7.7), 7.90-7.72 (m, 2H), 7.58-7.49 (m, 2H), 7.42-7.34 (m, 6H), 6.54 (s, 1H), 4.24 (s, 2H), 4.11 (t, 1H, J = 6.0), 2.97 (app q, 2H, J = 6.5), 2.12-2.01 (m, 1H), 1.99-1.89 (m, 1H), 1.74-1.57 (m, 1H), 1.55-1.43 (m, 1H). 13C: 193.8, 163.9, 135.2, 135.1, 134.6, 134.1, 133.7, 130.5, 129.9 (2C), 129.8, 129.5, 129.2, 128.9, 128.1, 127.5, 121.7, 81.5, 59.0, 43.4, 34.8, 23.7. HRMS: calcd for C27H22NO5SCl79Br [M-H]-: 586.0091; found: 586.0071.    388  C.4.1.5 Characterization of (±)-4-bromo-1-oxo-2-(3-(2,2,2-trifluoroethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54e) 11.5 mg (42% yield) from 20 mg of 4.1j, light yellow solid, m.p.: 48-50 °C, eluent: 3:17 EtOAc/hexane; IR: 3446-3182 (broad). 1H: 8.12 (d, 1H, J = 7.7), 7.99 (s, 1H), 7.90 (d, 1H, J = 7.8), 7.84-7.73 (m, 2H), 7.59-7.50 (m, 2H), 7.40 (t, J = 8.0, 1H), 6.58 (s, 1H), 4.66 (t, 1H, J = 6.1), 3.79 (q, 2H, J = 9.0), 3.22 (app q, 2H, J = 6.8), 2.22-2.12 (m, 1H), 2.08-1.98 (m, 1H), 1.89-1.77 (m, 1H), 1.73-1.60 (m, 1H). 13C: 193.8, 163.9, 135.3, 135.0, 134.7, 133.9, 133.7, 130.4, 129.9 (3C), 129.4, 129.0, 128.1, 127.6, 121.8, 121.5 (q, J = 277.5), 81.4, 54.4 (q, J = 31.5), 43.3, 34.6, 23.6. HRMS: calcd for C22H17BrNO5F3SCl79Br [M-H]-: 577.9651; found: 577.9659. C.4.1.6 Characterization of (±)-4-bromo-2-(3-(4-methylphenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54f)  9.7 mg (36% yield) from 20 mg of 4.1c, light yellow solid, m.p.: 73-75 °C; eluent: 1:4 EtOAc/hexane; IR: 3411-3178 (broad), 1723, 1695. 1H: 8.08 (d, 1H, J = 7.6), 7.97 (t, 1H, J = 1.6), 7.88 (d, 1H, J = 7.8), 7.81-7.70 (m, 4H), 7.57 (d, 1H, J = 7.5), 7.51 (t, 1H, J = 7.4), 7.39 (t, 1H, J = 7.9), 7.29 (d, 2H, J = 8.2), 6.52 (s, 1H), 4.41 (t, 1H, J = 5.9), 2.97 (app q, 2H, J = 6.6), 2.42 (s, 3H), 2.13-2.03 (m, 1H), 2.01-1.91 (m, 1H), 1.74-1.62 (m, 1H), 1.59-1.47 (m, 1H). 13C: 193.8, 163.9, 143.6, 136.7, 135.2, 135.0, 134.6, 134.0, 133.7, 130.5, 129.9 (2C), 129.8, 129.4, 128.9, 128.1, 127.5, 127.0, 121.6, 81.6, 42.9, 34.9, 23.0, 21.6. HRMS: calcd for C27H23NO5SCl79BrNa [M+Na]+: 610.0067; found: 610.0095.    389  C.4.1.7 Characterization of (±)-4-bromo-2-(3-(4-nitrophenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54g) 10.4 mg (39% yield) from 20 mg of 4.1e, yellow solid, m.p.: 72-74 °C; eluent: 1:3 EtOAc/hexane; IR: 3421-3199 (broad), 1725, 1700. 1H: 8.33 (d, 2H, J = 8.9), 8.06 (d, 1H, J = 7.3), 8.00 (d, 2H, J = 8.9), 7.95 (t, 1H, J = 1.8), 7.87 (d, 1H, J = 7.8), 7.81-7.71 (m, 2H), 7.57 (d, 1H, J = 8.0), 7.51 (td, 1H, J = 7.4, 1.4), 7.39 (t, 1H, J = 7.9), 6.52 (s, 1H), 4.74 (t, 1H, J = 6.1), 3.07 (app q, 2H, J = 6.8), 2.14-2.04 (m, 1H), 2.00-1.90 (m, 1H), 1.78-1.64 (m, 1H), 1.60-1.45 (m, 1H). 13C: 193.7, 163.8, 150.1, 145.8, 135.3, 134.9, 134.7, 133.8, 133.7, 130.4, 129.9, 129.3, 128.9, 128.2, 128.1, 127.5, 124.5, 121.8, 81.3, 43.1, 34.8, 23.1. HRMS: calcd for C26H20N2O7SCl79BrNa [M+Na]+: 640.9761; found: 640.9745. C.5 Preparation and characterization of intermediates towards acyloxylated adduct 4.68 C.5.1 Preparation of 2-propylnaphthalen-1-ol (4.66) A solution of commercial 10 wt % palladium on carbon (0.74 g, 0.05 equiv) and substrate 4.65 (2.72 g, 14.7 mmol) in EtOH (35.0 mL) was stirred under inert atmosphere at RT. Hydrogen gas was bubbled into the solution overnight. Upon the completion of the reaction, the mixture was filtered through 2-inch Celite using EtOH. The filterate was evaporated and was purified by flash column chromatography (eluent: 1:49 to 1:19 EtOAc/hexanes) on silica gel to provide 2.06 g (75% yield) of 4.66 as brown oil. IR: 3641-3152 (broad). 1H: 8.14 (d, 1H, J = 9.0), 7.80 (d, 1H, J = 9.0), 7.51-7.44 (m, 2H), 7.42 (d, 1H, J = 9.0), 7.26 (d, 1H, J = 6.0), 5.17 (s, 1H), 2.75 (t, 2H, J = 7.5), 1.80-1.68 (m, 2H), 1.03 (t, 3H, J = 7.5). 13C: 148.3, 133.4, 128.3, 127.7, 126.9, 125.5, 125.3, 124.6, 121.1, 120.3, 32.0, 23.3, 14.1.  390  C.5.2 Preparation of 4-bromo-2-propylnaphthalen-1-ol (4.67) The procedure described above for 3.12 afforded 1.36 g (64% yield) of 4.67 from 1.5 g of 4.66 as light yellow solid, m.p.: 73-75 °C (color changes to black), eluent: 1:19 EtOAc/hexanes. IR: 3525-3120 (broad). 1H: 8.17 (d, 2H, J = 6.0), 7.60-7.51 (m, 3H), 5.20 (br s, 1H), 2.69 (t, 2H, J = 7.5), 1.78-1.66 (m, 2H), 1.03 (t, 3H, J = 7.5). 13C: 148.2, 131.6, 131.4, 127.1, 127.0, 126.1, 125.8, 122.3, 121.7, 113.3, 31.8, 23.2, 14.1. HRMS: calcd for C13H12OBr [M-H]-: 263.0072; found: 263.0071. C.5.3 Characterization of (±)-4-bromo-1-oxo-2-propyl-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.68) The procedure described above for 4.54 afforded 33 mg (42% yield) of 4.68 from 50 mg of 4.67 as light yellow oil, eluent: 1:19 EtOAc/hexanes. IR: 3606-3314 (broad), 1724, 1697. 1H: 8.13 (d, 1H, J = 9.0), 8.02 (s, 1H), 7.92 (d, 1H, J = 9.0), 7.82-7.70 (m, 2H), 7.57 (d, 1H, J = 9.0), 7.50 (t, 1H, J = 7.5), 7.39 (t, 1H, J = 7.5), 6.61 (s, 1H), 2.11-1.91 (m, 2H), 1.67-1.49 (m, 1H), 1.41-1.26 (m, 1H), 0.95 (t, 3H, J = 7.5). 13C: 194.5, 164.2, 135.4, 135.1, 134.9, 134.7, 133.7, 131.0, 130.1, 129.9, 129.8, 128.9, 128.3, 127.6, 121.2, 82.6, 40.5, 16.4, 14.4. HRMS: calcd for C20H16O3Cl79BrNa [M+Na]+: 440.9869; found: 440.9871. C.6 Preparation of chiral iodoarene precatalysts C.6.1 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(2,4,6-trimethoxybenzamide) (4.23) A solution of (2S,2'S)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))bis(propan-1-amine)  391  4.19[20] (50 mg, 0.14 mmol, 1.0 equiv), DMAP (43 mg, 0.35 mmol, 2.5 equiv), 2,4,6-trimethoxybenzoic acid (74 mg, 0.35 mmol, 2.4 equiv), and EDCI (67 mg, 0.35 mmol, 2.4 equiv) in CH2Cl2 (5.0 mL) was stirred overnight at RT, whereupon TLC showed that the reaction was complete. The reaction was quenched with 1M HCl (10.0 mL) and extracted with CH2Cl2 (5×10 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 1:49 MeOH/CH2Cl2) to provide 100 mg (95% yield) of 4.23 as white solid, dec. 182 °C; [α]23D = +67.4° (c 2.0, CHCl3). IR: 3468-3286 (broad), 1652. 1H: 7.21 (t, 1H, J = 8.3), 6.56 (d, 2H, J = 8.3), 6.41 (t, 2H, J = 5.9), 6.05 (s, 4H), 4.66-4.61 (m, 2H), 3.88 (ddd, 2H, J = 13.8, 7.2, 3.4), 3.79 (s, 6H), 3.63 (s, 12H), 3.56-3.47 (m, 2H), 1.39 (d, 6H, J = 6.1). 13C: 166.0 (2C), 162.1 (2C), 158.5 (4C), 158.0 (2C), 129.9 (1C), 108.5 (2C), 106.8 (2C), 90.4 (4C), 81.7 (1C), 75.4 (2C), 55.7 (4C), 55.4 (2C), 44.4 (2C), 17.4 (2C). HRMS: calcd for C32H39IN2O10Na [M+Na]+: 761.1547; found: 761.1569. C.6.2 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(3,5-dimethoxybenzamide) (4.21) 3,5-Dimethoxybenzoyl chloride (114 mg, 0.57 mmol, 1.5 equiv) was added to a cold (0 °C) solution of (2S,2'S)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))bis(propan-1-amine) 4.19[20] (65 mg, 0.19 mmol, 1.0 equiv) and pyridine (0.15 mL, 1.9 mmol, 10.0 equiv) in CH2Cl2 (2.5 mL). The reaction was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The reaction was quenched with 1M HCl and extracted with CH2Cl2 (3×10 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash                                                  [20] Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2013, 52, 9215.  392  column chromatography (eluent: 1:49 MeOH/CH2Cl2) to provide 81 mg (64% yield) of 4.21 as white solid, m.p. 133-135 °C, [α]23D = +78.5° (c 0.84, CHCl3). IR: 3495-3175 (broad), 1645. 1H: 7.22 (t, 1H, J = 8.3), 6.93 (d, 4H, J = 2.3), 6.78 (t, 2H, J = 5.3), 6.57 (t, 2H, J = 2.3), 6.54 (d, 2H, J = 8.3), 4.70-4.61 (m, 2H), 3.90 (ddd, 2H, J = 13.9, 6.3, 3.3), 3.80 (s, 12H), 3.67-3.56 (m, 2H), 1.41 (d, 6H, J = 6.2). 13C: 167.3 (2C), 160.9 (4C), 157.7 (2C), 136.4 (2C), 130.2 (1C), 107.3 (2C), 104.8 (4C), 103.9 (2C), 81.9 (1C), 75.1 (2C), 55.6 (4C), 44.6 (2C), 17.4 (2C). HRMS: calcd for C30H35IN2O8Na [M+Na]+: 701.1336; found: 701.1335.  C.6.3 Preparation of N,N'-(2S,2'S)-2,2'-(2-Iodo-1,3-phenylene)bis-(oxy)bis(propane-2,1-diyl)bis(4-methylbenzene-sulfonamide) (4.22)  Tosyl chloride (97 mg, 0.51 mmol, 3.0 equiv) was added to a cold (0 °C) solution of (2S,2'S)-2,2'-((2-iodo-1,3-phenylene)bis(oxy))bis(propan-1-amine) 4.19[20] (60 mg, 0.17 mmol, 1.0 equiv) and pyridine (0.14 mL, 1.7 mmol, 10 equiv) in CH2Cl2 (2.5 mL). The reaction was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The reaction was quenched with 1M HCl (10.0 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (eluent: 2:1 hexanes/EtOAc) to provide 106 mg (94% yield) of 4.22 as white solid, m.p. 42-44 °C; [α]23D = +132.0° (c 0.55, CHCl3). IR: 3396-3208 (broad), 1157, 1085. 1H: 7.73 (d, 4H, J = 8.2), 7.25 (d, 4H, J = 8.3), 7.11 (t, 1H, J = 8.2), 6.34 (d, 2H, J = 8.3), 5.11 (t, 2H, J = 6.0), 4.46-4.40 (m, 2H), 3.33-3.25 (m, 2H), 3.17-3.08 (m, 2H), 2.40 (s, 6H), 1.31 (d, 6H, J = 6.1). 13C: 157.2 (2C), 143.5 (2C), 136.9 (2C), 129.8 (1C), 129.7 (4C), 127.0 (4C), 107.2 (2C), 82.0 (1C), 74.6 (2C), 48.1 (2C), 21.5 (2C), 17.3 (2C). HRMS: calcd for C26H31N2O6S2INa [M+Na]+: 681.0566; found: 681.0567.  393  C.6.4 General procedure for Mitsunobu reaction of amino alcohol with 2-iodo resorcinol Neat diisopropyl azodicarboxylate (0.18 mL, 0.93 mmol, 2.4 equiv) was added dropwise to a cold (0 °C) solution of 2-iodoresorcinol (87 mg, 0.37 mmol, 1.0 equiv), N-BOC-valinol 4.45 or N-BOC-tert-leucinol 4.46 (202 mg, 0.93 mmol, 2.4 equiv) and PPh3 (244 mg, 0.93 mmol, 2.4 equiv) in THF (2.0 mL). The mixture was then warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The solution was evaporated and the residue was purified by flash column chromatography to provide the desired product. C.6.4.1 Characterization of tert-Butyl (2S,2'S)-1,1'-(2-iodo-1,3-phenylene)bis(oxy)bis(3-methylbutane-2,1-diyl)dicarbamate (4.47) 115 mg (48% yield) from 93 mg of 2-iodoresorcinol, colorless oil; [α]23D = –102.7° (c 5.1, CHCl3);eluent: 1:3 EtOAc/ hexanes. IR: 3468-3286 (broad), 1699. 1H: 7.22 (t, 1H, J = 8.3), 6.46 (d, 2H, J = 8.3), 5.00 (d, 2H, J = 9.6), 4.15 (dd, 2H, J = 9.2, 2.4), 3.99 (dd, 2H, J = 9.2, 3.5), 3.70-3.64 (m, 2H), 2.21-2.10 (m, 2H), 1.44 (s, 18H), 1.03 (d, 6H, J = 6.8), 0.99 (d, 6H, J = 6.7). 13C: 158.5 (2C), 155.8 (2C), 130.0 (1C), 105.2 (2C), 79.3 (2C), 78.8 (1C), 69.5 (2C), 55.4 (2C), 29.8 (2C), 28.4 (6C), 19.7 (2C), 19.2 (2C). HRMS: calcd for C26H43N2O6INa [M+Na]+: 629.2064; found: 629.2058. C.6.4.2 Characterization of tert-Butyl (2S,2'S)-1,1'-(2-iodo-1,3-phenylene)bis(oxy)bis(3,3-dimethylbutane-2,1-diyl)dicarbamate (4.48) 91 mg (39% yield) from 87 mg of 2-iodoresorcinol, colorless oil; [α]23D = –70.5° (c 3.75, CHCl3); eluent: 1:3 EtOAc/ hexanes. IR: 3474-3240 (broad), 1699. 1H: 7.23 (t, 1H, J = 8.2), 6.46 (d, 2H, J = 8.3), 5.18 (d, 2H, J = 10.1), 4.19 (dd, 2H, J = 9.5, 3.0), 4.02 (dd, 2H, J = 9.6, 4.1), 3.80-3.76 (m, 2H), 1.45 (s, 18H), 1.06 (s, 18H). 13C: 158.7 (2C), 155.9 (2C), 129.9 (1C), 105.2 (2C), 79.2 (2C), 78.7 (1C), 68.8  394  (2C), 57.2 (2C), 34.6 (2C), 28.4 (6C), 27.4 (6C). HRMS: calcd for C28H47N2O6INa [M+Na]+: 657.2377; found: 657.2374.  C.6.5 General procedure for Boc deprotection of 4.47 and 4.48 Trifluoroacetic acid (61 µL, 0.8 mmol, 5 equiv) was slowly added to a solution of 4.47or 4.48 (0.16 mmol) in CH2Cl2 (0.3 mL) and the mixture was stirred overnight at RT, whereupon TLC showed that the reaction was complete. The mixture was cooled to 0 °C, quenched with 2M NaOH (1.0 mL) and extracted with CH2Cl2 (5×5 ml). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated to provide the N-deblocked product. The residue was dried under high vacuum and used in the subsequent step without purification. C.6.5.1 Characterization of (2S,2'S)-1,1'-(2-Iodo-1,3-phenylene)bis(oxy)bis(3-methylbutan-2-amine) (4.49) 51 mg (81% yield) from 95 mg of 4.47, yellow oil; [α]23D = +37.4° (c 2.05, CHCl3). IR: 3520-3208 (broad). 1H: 7.21 (t, 1H, J = 8.1), 6.47 (d, 2H, J = 8.2), 4.07 (dd, 2H, J = 8.8, 3.4), 3.84 (app t, 2H, J = 8.2), 3.03-2.97 (m, 2H), 1.91-1.79 (m, 2H), 1.61 (br s, 4H), 1.02 (d, 6H, J = 4.0), 0.99 (d, 6H, J = 4.1). 13C: 158.8 (2C), 129.8 (1C), 105.3 (2C), 79.1 (1C), 72.9 (2C), 56.1 (2C), 30.9 (2C), 19.5 (2C), 18.4 (2C). HRMS: calcd for C16H28IN2O2 [M+H]+: 407.1195; found: 407.1197.   C.6.5.2 Characterization of (2S,2'S)-1,1'-(2-Iodo-1,3-phenylene)bis(oxy)bis(3,3-dimethylbutan-2-amine) (4.50) 48 mg (87% yield) from 80 mg of 4.48, yellow oil; [α]23D = +40.5° (c 2.30, CHCl3). IR: 3468-3234 (broad). 1H: 7.21 (t, 1H, J = 8.2), 6.47 (d, 2H, J = 8.3), 4.20 (dd, 2H, J = 8.8, 3.0), 3.77 (t, 2H, J = 8.9), 3.01 (dd, 2H, J = 9.0, 2.9),  395  1.62 (br s, 4H), 1.01 (s, 18H). 13C: 158.7 (2C), 129.8 (1C), 105.5 (2C), 79.2 (1C), 71.4 (2C), 59.1 (2C), 33.1 (2C), 26.7 (6C). HRMS: calcd for C18H32N2O2I [M+H]+: 435.1509; found: 435.1500.  C.6.6 General procedure for the coupling of amine and 2,4,6-trimethylbenzoic acid A solution of 4.49 or 4.50 (1.1 mmol, 1.0 equiv) in DMF (3.0 mL) was added dropwise at RT over 10 min to a solution of EDCI (435 mg, 2.8 mmol, 2.5 equiv), HOBt (430 mg, 2.8 mmol, 2.5 equiv) and 2,4,6-trimethylbenzoic acid (460 mg, 2.8 mmol, 2.5 equiv) in dry DMF (1.2 mL) that had previously been stirred for 15 min. The mixture was stirred overnight at RT, whereupon TLC showed that the reaction was complete. The mixture was diluted with CH2Cl2 (20.0 mL) and the organic layer was sequentially washed with 0.1 M HCl (2×15 mL), H2O (10.0 mL), satd. aq. NaHCO3 (15 mL), and brine (10.0 mL), then dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to provide 4.51 and 4.52. C.6.6.1 Characterization of N,N'-(2S,2'S)-1,1'-(2-Iodo-1,3-phenylene)bis(oxy)bis(3-methylbutane-2,1-diyl)bis(2,4,6-trimethylbenzamide) (4.51) 406 mg (53% yield) from 447 mg of 4.49; white solid, m.p. 79-81 °C, [α]23D = –169.6° (c 0.80, CHCl3) eluent: 7:3 hexanes/EtOAc; IR: 3338-3156 (broad), 1636. 1H: 7.27 (t, 1H, J = 8.2), 6.83 (s, 4H), 6.52 (d, 2H, J = 8.3), 6.10 (d, 2H, J = 8.9), 4.29-4.16 (m, 6H), 2.33-2.25 (m, 20 H), 1.12 (d, 6H, J = 6.8), 1.07 (d, 6H, J = 6.7). 13C: 170.5 (2C), 158.3 (2C), 138.5 (2C), 134.8 (2C), 134.2 (4C), 130.2 (1C), 128.2 (4C), 105.3 (2C), 78.6 (1C), 69.0 (2C), 54.5 (2C), 29.2 (2C), 21.1 (2C), 19.8 (4C), 19.2 (4C). HRMS: calcd for C36H48N2O4I [M+H]+: 699.2659; found: 699.2657.   396  C.6.6.2 Characterization of N,N'-(2S,2'S)-1,1'-(2-Iodo-1,3-phenylene)bis(oxy)bis-(3,3-dimethylbutane-2,1-diyl)bis(2,4,6-trimethylbenzamide) (4.52) 143 mg (57% yield) from 150 mg of 4.50; white solid, m.p. 109-111 °C, [α]23D = –134.0° (c 2.10, CHCl3) eluent: 3:1 hexanes/EtOAc; IR: 3442-3156 (broad), 1638. 1H: 7.27 (t, 1H, J = 6.5), 6.82 (s, 4H), 6.52 (d, 2H, J = 8.3), 6.30 (d, 2H, J = 9.9), 4.40-4.34 (m, 4H), 4.12 (dd, 2H, J = 9.8, 4.3), 2.27 (s, 6H), 2.24 (s, 12H), 1.15 (s, 18H). 13C: 170.4 (2C), 158.5 (2C), 138.4 (2C), 135.0 (2C), 134.2 (4C), 130.2 (1C), 128.3 (4C), 105.2 (2C), 78.2 (1C), 68.5 (2C), 55.7 (2C), 34.1 (2C), 27.8 (6C), 21.1 (2C), 19.4 (4C). HRMS: calcd for C38H52N2O4I [M+H]+: 727.2972; found: 727.2972. C.7 Synthesis of (1S)-(+)-10-Camphorsulfonyl based derivatives of spiropyrrolidine and acyloxylated adducts C.7.1 Preparation of 4-bromo-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.61) A solution of sulfonamide 4.2e (9.0 mg, 0.02 mmol, 1.0 equiv) in CH3CN (0.8 mL) was added at RT to a solution of PhSH (6 µL, 0.06 mmol, 3.0 equiv.) in CH3CN (0.2 mL) containing suspended K2CO3 (11 mg, 0.08 mmol, 4.0 equiv). Next, DMSO (0.1 mL) was added to the reaction mixture and stirring was continued at RT for 3 h, after which time TLC showed that the reaction was complete. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel (eluting solvent: 2:3 EtOAc/hexane) to provide 4.1 mg (75% yield) of 4.61 as a brown oil. IR: 3467-3210 (broad), 1684. 1H: 7.98 (d, 1H, J = 9.0), 7.69-7.67 (m, 2H), 7.46-7.41 (m, 1H), 6.73 (s, 1H), 3.43-3.36 (m, 1H), 3.18-3.10 (m, 1H), 2.18-2.07 (m, 2H),  397  1.98-1.87 (m, 3H). 13C: 201.0, 140.0, 136.1, 134.9, 129.0 (2C), 127.9, 127.3, 117.6, 72.4, 48.1, 38.4, 25.4. HRMS: calcd for C13H1379BrNO [M+H]+: 278.0181; found: 278.0186. C.7.2 Preparation of 4.63 (1S)-(+)-10-Camphorsulfonyl chloride (15 mg, 0.06 mmol, 3.0 equiv) was added to a cold (0 °C) solution of 4.61 (6 mg, 0.02 mmol, 1.0 equiv) and Et3N (14 µL, 0.1 mmol, 5.0 equiv) in CH2Cl2 (0.4 mL). The resulting mixture was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The mixture was quenched with aq. satd. NH4Cl (2 mL) and extracted with CH2Cl2 (3×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was dried under high vacuum and analyzed for calculation for diastereomeric excess. The diastereomeric excess was obtained by integrating the peak for Ha. C.7.3 Preparation of 4.64  (1S)-(+)-10-Camphorsulfonyl chloride (0.05 mmol, 3.0 equiv) was added to a solution of 4.54g (0.015 mmol, 1.0 equiv) and Et3N (10 µL, 0.08 mmol, 5.0 equiv) in CH2Cl2 (0.4 mL) at 0 °C. The resulting mixture was warmed to RT and stirred overnight, after which time TLC showed that the reaction was complete. The mixture was quenched with aq. satd. NH4Cl (2 mL) and extracted with CH2Cl2 (3×5 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was dried under high vacuum and analyzed for the calculation of diastereomeric excess. The diastereomeric excess was obtained by integrating the peak for Ha.  398  C.8 General procedure for the synthesis of chiral spiropyrrolidines and acyloxylated adducts A solution of MCPBA (105 mg, 0.47 mmol, 1.3 equiv) in CH2Cl2 (8.0 mL) was added at –20 °C to solution of a substrate 4.1 (0.36 mmol, 1.0 equiv) and a chiral iodide precatalyst (0.072 mmol, 0.2 equiv) in CH2Cl2 (12.0 mL). The mixture was stirred overnight at –20 °C, whereupon TLC indicated complete reaction. The mixture was quenched with aq. sat. NaHCO3 (10.0 mL) and aq. sat. Na2S2O3 (5.0 mL) solutions and extracted with CH2Cl2 (4×15 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to afford products 4.2 and 4.54.    399  C.9 Data and chromatograms of chiral compounds C.9.1 (–)-(S)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2a) 20.1 mg (20% yield) from 100 mg of 4.1a as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = –24.2° (c 0.58, CHCl3). SFC analysis indicates a 46% ee. Column (OD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 44.50 min (major), tR (2) = 53.15 (minor).   chromatogram of (±)-4.2a (240 nm) chromatogram of (-)-4.2a, (240 nm, 46% ee)      400  One recrystallization (toluene/hexane; vapor diffusion technique, RT) afforded material of 88% ee, the optical purity of which was determined by chiral HPLC: Column (OD-H) 5:95 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 33.78 min (major), tR (2) = 40.88 (minor). chromatogram of (±)-4.2a (220 nm) chromatogram of (-)-4.2a, (220 nm, 88% ee)      401  (-)-2-(3-(methylsulfonamido)-propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54a)  41.7 mg (27% yield) from 100 mg of 4.1a as yellow oil, eluent: 2:3 Et2O/pentane; [α]25D = -13.4° (c 0.17, CHCl3). SFC analysis indicates a 64% ee. Column (OD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 43.11 min (major), tR (2) = 47.60 (minor).  chromatogram of (±)-4.54a (240 nm) chromatogram of (-)-4.54a, (240 nm, 64% ee)      402  C.9.2 (+)-(R)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2a) 19.9 mg (20% yield) from 100 mg of 4.1a as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = +36.5° (c 0.59, CHCl3). SFC analysis indicates a 67% ee. Column (OD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 44.53 min (minor), tR (2) = 52.79 (major).  chromatogram of (±)-4.2a (240 nm) chromatogram of (+)-4.2a, (240 nm, 67% ee)      403  Material of 96% ee was obtained after a single recrystallization from toluene/hexane (vapor diffusion technique) at RT. chromatogram of (±)-4.2a (240 nm) chromatogram of (+)-4.2a, (229 nm, 96% ee)      404  (+)-2-(3-(methylsulfonamido)-propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54a)  38.4 mg (25% yield) from 100 mg of 4.1a as yellow oil, eluent: 2:3 Et2O/pentane; [α]23D = +16.8° (c 0.06, CHCl3). SFC analysis indicates a 80% ee. Column (OD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 44.10 min (minor), tR (2) = 48.87 (major).  chromatogram of (±)-4.54a (240 nm) chromatogram of (+)-4.54a, (240 nm, 80% ee)      405  C.9.3 (–)-4-Bromo-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2k) 44.5 mg (45% yield) from 100 mg of 4.1k as yellow oil, eluent: 3:7 EtOAc/hexane; [α]23D = –7.1° (c 1.00, CHCl3). SFC analysis indicates a 17% ee: Column (OD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 51.92 min (major), tR (2) = 58.88 (minor).   chromatogram of (±)-4.2k (229 nm) chromatogram of (-)-4.2k, (229 nm, 17% ee)      406  (-)-4-bromo-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54b) 39.8 mg (28% yield) from 100 mg of 4.1k as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = -7.2° (c 0.89, CHCl3). SFC analysis indicates a 50% ee. Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 37.01 min (major), tR (2) = 51.75 (minor).  chromatogram of (±)-4.54b (229 nm) chromatogram of (-)-4.54b, (229 nm, 50% ee)      407  C.9.4 (+)-4-Bromo-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2k) 34.7 mg (35% yield) from 100 mg of 4.1k as yellow oil, eluent: 3:7 EtOAc/hexane; [α]23D = +7.4° (c 0.55, CHCl3). SFC analysis indicates a 17% ee: Column (OD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 51.89 min (minor), tR (2) = 58.80 (major).   chromatogram of (±)-4.2k (229 nm) chromatogram of (+)-4.2k, (229 nm, 17% ee)      408  (+)-4-bromo-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54b) 29.8 mg (21% yield) from 100 mg of 4.1k as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = +9.01° (c 0.36, CHCl3). SFC analysis indicates a 62% ee. SFC: Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 37.58 min (minor), tR (2) = 52.23 (major).  chromatogram of (±)-4.54b (229 nm) chromatogram of (+)-4.54b, (229 nm, 62% ee)      409  C.9.5 (-)-4-chloro-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2l) 16 mg (16% yield) from 100 mg of 4.1l as light yellow oil, eluent: 1:4 EtOAc/hexane; [α]25D = -7.4° (c 0.22, CHCl3). HPLC analysis indicates a 37% ee. Column (OJ-RH) 60:40 (0.1% AcOH in H2O: MeCN), flow rate = 0.7 mL/min; tR (1) = 10.38 min (major), tR (2) = 11.05 (minor).  chromatogram of (±)-4.2l (230 nm) chromatogram of (-)-4.2l, (230 nm, 37% ee)      410  (-)-4-chloro-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54c) 25.1 mg (17% yield) from 100 mg of 4.1l as colorless oil, eluent: 1:3 EtOAc/hexane; [α]25D = -7.22° (c 0.28, CHCl3). HPLC analysis indicates a 59% ee. Column (OJ-RH) 50:50 (0.1% AcOH in H2O: MeCN), flow rate = 0.7 mL/min; tR (1) = 10.63 min (minor), tR (2) = 10.99 (major). chromatogram of (±)-4.54c (230 nm) chromatogram of (-)-4.54c, (230 nm, 59% ee)      411  C.9.6 (+)-4-chloro-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2l) 20.2 mg (20% yield) from 100 mg of 4.1l as light yellow oil, eluent: 1:4 EtOAc/hexane; [α]25D = +15.7° (c 0.27, CHCl3). HPLC analysis indicates a 30% ee. Column (OJ-RH) 60:40 (0.1% AcOH in H2O: MeCN),, flow rate = 0.7 mL/min; tR (1) = 10.36 min (minor), tR (2) = 11.03 (major).  chromatogram of (±)-4.2l (230 nm) chromatogram of (+)-4.2l, (230 nm, 93% ee)      412  (+)-4-chloro-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54c)  28.5 mg (19% yield) from 100 mg of 4.1l as colorless oil, eluent: 1:3 EtOAc/hexane; [α]25D = +10.4° (c 0.36, CHCl3). HPLC analysis indicates a 72% ee. Column (OJ-RH) 50:50 (0.1% AcOH in H2O: MeCN), flow rate = 0.7 mL/min; tR (1) = 10.66 min (major), tR (2) = 11.04 (minor). chromatogram of (±)-4.54c (230 nm) chromatogram of (+)-4.54c, (230 nm, 72% ee)      413  C.9.7 (–)-1'-(methylsulfonyl)-4-phenyl-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2m) 29.6 mg (30% yield) from 100 mg of 4.1m as white solid, eluent: 3:7 EtOAc/hexane; [α]24D = –14.8° (c 0.27, CHCl3). SFC analysis indicates a 18% ee. SFC: Column (OD-H) 5: 95: 0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 52.61 min (major), tR (2) = 56.38 (minor).   chromatogram of (±)-4.2m (229 nm) chromatogram of (-)-4.2m, (229 nm, 18% ee)      414  C.9.8 (+)-1'-(methylsulfonyl)-4-phenyl-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2m) 30.6 mg (31% yield) from 100 mg of 4.1m as white solid, eluent: 3:7 EtOAc/hexane; [α]25D = +25.1° (c 0.14, CHCl3). SFC analysis indicates a 24% ee. SFC: Column (OD-H) 5: 95: 0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 50.14 min (minor), tR (2) = 53.11 (major).   chromatogram of (±)-4.2m (229 nm) chromatogram of (+)-4.2m, (229 nm, 24% ee)      415  C.9.9 (-)-4-(4-fluorophenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2n) 24.7 mg (25% yield) from 100 mg of 4.1n as off white solid, eluent: 1:4 EtOAc/hexane; [α]25D = -6.6° (c 0.25, CHCl3). SFC analysis indicates a 24% ee. Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 24.15 min (minor), tR (2) = 27.69 (major).   chromatogram of (±)-4.2n (240 nm) chromatogram of (-)-4.2n, (240 nm, 24% ee)      416  C.9.10 (+)-4-(4-fluorophenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2n) 26.5 mg (27% yield) from 100 mg of 4.1n as off white solid, eluent: 1:4 EtOAc/hexane; [α]25D = +10.9° (c 0.39, CHCl3). SFC analysis indicates a 29% ee. Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), tR (1) = 24.33 min (major), tR (2) = 28.09 (minor).   chromatogram of (±)-4.2n (240 nm) chromatogram of (+)-4.2n, (240 nm, 29% ee)      417  C.9.11 (-)-1'-(methylsulfonyl)-4-(4-(trifluoromethyl)phenyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2o) 22 mg (22% yield) from 100 mg of 4.1o as off white solid, eluent: 1:4 EtOAc/hexane; [α]26D = -9.5° (c 0.20, CHCl3). SFC analysis indicates a 20% ee. Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), tR (1) = 16.32 min (minor), tR (2) = 20.38 (major).   chromatogram of (±)-4.2o (240 nm) chromatogram of (-)-4.2o, (240 nm, 20% ee)      418  C.9.12 (+)-1'-(methylsulfonyl)-4-(4-(trifluoromethyl)phenyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2o) 23 mg (23% yield) from 100 mg of 4.1o as off white solid, eluent: 1:4 EtOAc/hexane; [α]25D = +15.5° (c 0.33, CHCl3). SFC analysis indicates a 28% ee. Column (AD-H) 10:90:0.1 (iPrOH: liq CO2: diethylamine), tR (1) = 16.18 min (major), tR (2) = 20.51 (minor).   chromatogram of (±)-4.2o (240 nm) chromatogram of (+)-4.2o, (240 nm, 28% ee)      419  C.9.13 (-)-4-(3,5-bis(trifluoromethyl)phenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2p) 15.1 mg (15% yield) from 100 mg of 4.1p as off white solid, eluent: 1:4 EtOAc/hexane; [α]24D = -5.4° (c 0.10, CHCl3). SFC analysis indicates a 14% ee. Column (AD-H) 1:99:0.1 (iPrOH: liq CO2: diethylamine), tR (1) = 22.20 min (major), tR (2) = 27.42 (minor).   chromatogram of (±)-4.2p (240 nm) chromatogram of (-)-4.2p, (240 nm, 14% ee)      420  C.9.14 (+)-4-(3,5-bis(trifluoromethyl)phenyl)-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2p) 17.7 mg (18% yield) from 100 mg of 4.1p as off white solid, eluent: 1:4 EtOAc/hexane; [α]24D = +11.2° (c 0.32, CHCl3). SFC analysis indicates a 39% ee. Column (AD-H) 1:99:0.1 (iPrOH: liq CO2: diethylamine), tR (1) = 22.60 min (minor), tR (2) = 27.74 (minor).   chromatogram of (±)-4.2p (240 nm) chromatogram of (+)-4.2p, (240 nm, 39% ee)   \   421  C.9.15 (-)-4-Bromo-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2k) 22.3 mg (22% yield) from 100 mg of 4.1k as yellow oil, eluent: 3:7 EtOAc/hexane; [α]23D = -4.3° (c 0.21, CHCl3); HPLC analysis indicates a 22% ee: Column (OD-H) 5:95 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 28.73 min (major), tR (2) = 32.57 (minor).    chromatogram of (±)-4.2k (220 nm) chromatogram of (+)-4.2k, (220 nm, 22% ee)      422  (-)-4-bromo-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54b) 47.4 mg (33% yield) from 100 mg of 4.1k as white solid, eluent: 2:3 EtOAc/hexane; [α]24D = -9.8° (c 0.24, CHCl3). HPLC analysis indicates a 62% ee. Column (AD-H) 10:90 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 12.56 min (major), tR (2) = 20.93 (minor).  chromatogram of (±)-4.54b (220 nm) chromatogram of (-)-4.54b, (220 nm, 62% ee)      423  C.9.16 (+)-4-Bromo-1'-(methylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2k) 30.5 mg (31% yield) from 100 mg of 4.1k as yellow oil, eluent: 3:7 EtOAc/hexane; [α]23D = +6.6° (c 0.59, CHCl3); HPLC analysis indicates a 23% ee: Column (OJ-RH) 60:40 (0.1% AcOH in H2O: MeCN), flow rate = 0.7 mL/min; tR (1) = 11.64 min (minor), tR (2) = 12.27 (major).  chromatogram of (±)-4.2k (230 nm) chromatogram of (+)-4.2k, (230 nm, 23% ee)      424  (+)-4-bromo-2-(3-(methylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54b) 39.6 mg (28% yield) from 100 mg of 4.1k as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = +9.6° (c 0.38, CHCl3). HPLC analysis indicates a 58% ee. Column (OJ-RH) 40:60 (0.1% AcOH in H2O: MeCN), flow rate = 0.7 mL/min; tR (1) = 5.68 min (major), tR (2) = 5.94 (minor). chromatogram of (±)-4.54b (250 nm) chromatogram of (+)-4.54b, (250 nm, 58% ee)      425  C.9.17 (-)-4-Bromo-1'-(benzylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2h) 28.1 mg (28% yield) from 100 mg of 4.1h as yellow solid, eluent: 1:4 EtOAc/hexane; [α]25D = –5.7° (c 0.18, CHCl3). The ee could not be determined because enantiomers failed to separate regardless of chiral column used. (-)-4-bromo-1-oxo-2-(3-(phenylmethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54d) 56.1 mg (41% yield) from 100 mg of 4.1h as light yellow solid, eluent: 1:5 EtOAc/hexane; [α]25D = -23.0° (c 0.37, CHCl3). HPLC analysis indicates a 54% ee. HPLC: Column (AD-H) 20:80 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 14.13 min (major), tR (2) = 29.97 (minor).      426  chromatogram of (±)-4.54d (220 nm) chromatogram of (-)-4.54d, (220 nm, 54% ee)      427  C.9.18 (+)-4-Bromo-1'-(benzylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2h) 24.1 mg (24% yield) from 100 mg of 4.1h as yellow solid, eluent: 1:4 EtOAc/hexane; [α]23D = +7.5° (c 0.24, CHCl3). The ee could not be determined because enantiomers of the compound failed to separate regardless of chiral column used. (+)-4-bromo-1-oxo-2-(3-(phenylmethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54d) 38.9 mg (29% yield) from 100 mg of 4.1h as light yellow solid, eluent: 1:5 EtOAc/hexane; [α]23D = +29.1° (c 0.12, CHCl3). HPLC analysis indicates a 60% ee. HPLC: Column (AD-H) 20:80 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 14.08 min (minor), tR (2) = 29.20 (major).      428  chromatogram of (±)-4.54d (220 nm) chromatogram of (+)-4.54d, (220 nm, 60% ee)      429  C.9.19 (-)-4-bromo-1'-(2,2,2-trifluoroethylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2j) 15.6 mg (16% yield) from 100 mg of 4.1j as yellow solid, eluent: 1:4 EtOAc/hexane; [α]23D = –13.1° (c 0.13, CHCl3); HPLC analysis indicates a 44% ee: Column (AD-H) 2.5:97.5 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 29.44 min (major), tR (2) = 39.44 (minor).    chromatogram of (±)-4.2j (220 nm) chromatogram of (-)-4.2j, (220 nm, 44% ee)      430  (-)-4-bromo-1-oxo-2-(3-(2,2,2-trifluoroethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54e) 49.8 mg (37% yield) from 100 mg of 4.1j as light yellow solid, eluent: 3:17 EtOAc/hexane; [α]23D = -12.7° (c 0.44, CHCl3). HPLC analysis indicates a 74% ee. HPLC: Column (AD-H) 10:90 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 25.78 min (major), tR (2) = 40.42 (minor).  chromatogram of (±)-4.54e (220 nm) chromatogram of (-)-4.54e, (220 nm, 74% ee)      431  C.9.20 (+)-4-bromo-1-oxo-2-(3-(2,2,2-trifluoroethylsulfonamido)propyl)-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54e) 37.9 mg (28% yield) from 100 mg of 4.1j as light yellow solid, eluent: 3:17 EtOAc/hexane; [α]25D = +9.8° (c 0.15, CHCl3). HPLC analysis indicates a 60% ee. HPLC: Column (AD-H) 10:90 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 26.01 min (minor), tR (2) = 40.34 (major).   chromatogram of (±)-4.54e (220 nm) chromatogram of (+)-4.54e, (220 nm, 60% ee)      432  C.9.21 (+)-4-Bromo-1'-(4-tolylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2c) 25.2 mg (25% yield) from 100 mg of 4.1c as yellow solid, eluent: 1:4 EtOAc/hexane; [α]26D = +7.21° (c 0.21, CHCl3); SFC analysis indicates a 23% ee: Column (OD-H) 5:95 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 21.94 min (minor), tR (2) = 24.91 (major).    chromatogram of (±)-4.2c (220 nm) chromatogram of (+)-4.2c, (220 nm, 23% ee)      433  (-)-4-bromo-2-(3-(4-methylphenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54f) 41.4 mg (31% yield) from 20 mg of 4.1c as light yellow solid, eluent: 1:4 EtOAc/hexane; [α]26D = -16.9° (c 0.32, CHCl3). HPLC analysis indicates a 62% ee. HPLC: Column (AD-H) 20:80 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 23.27 min (major), tR (2) = 31.28 (minor).  chromatogram of (±)-4.54f (220 nm) chromatogram of (-)-4.54f, (220 nm, 62% ee)      434  C.9.22 (-)-4-Bromo-1'-(4-tolylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2c) 21.8 mg (22% yield) from 100 mg of 4.1c as yellow solid, eluent: 1:4 EtOAc/hexane;, [α]23D = –7.5° (c 0.17, CHCl3); SFC analysis indicates a 26% ee: Column (OD-H) 5:95 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 21.84 min (major), tR (2) = 24.89 (minor).  chromatogram of (±)-4.2c (220 nm) chromatogram of (-)-4.2c, (220 nm, 26% ee)      435  (+)-4-bromo-2-(3-(4-methylphenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54f) 40.2 mg (30% yield) from 100 mg of 4.1c as light yellow solid, eluent: 1:4 EtOAc/hexane; [α]25D = +15.0 (c 0.2, CHCl3). HPLC analysis indicates a 65% ee. HPLC: Column (AD-H) 20:80 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 23.32 min (minor), tR (2) = 30.99 (major).  chromatogram of (±)-4.54f (220 nm) chromatogram of (+)-4.54f, (220 nm, 65% ee)      436  C.9.23 (-)-4-Bromo-1'-(4-nitrophenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2e) 17.4 mg (18% yield) from 100 mg of 4.1e as yellow solid, eluent: 2:3 EtOAc/hexane; [α]24D = –9.2° (c 0.16, CHCl3). The ee of this compound was determined by forming (1S)-(+)-10-Camphorsulfonyl derivative of 4.61. Diastereomeric excess obtained in this case was 37%.    1H NMR spectrum of crude (±)-4.63 (300 MHz, CDCl3)    437   1H NMR spectrum of chiral crude (±)-4.63 (37% de; 300 MHz, CDCl3) (-)-4-bromo-2-(3-(4-nitrophenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54g) 49.2 mg (37% yield) from 100 mg of 4.1e as yellow solid, eluent: 1:3 EtOAc/hexane; [α]23D = -22.3° (c 0.43, CHCl3). The ee of this compound was determined by forming (1S)-(+)-10-Camphorsulfonyl derivative of (-)-4.54g. Diastereomeric excess obtained in this case was 55%.     438   1H NMR spectrum of crude (±)-4.64 (300 MHz, CDCl3)  1H NMR spectrum of chiral crude 4.64 (55% de; 300 MHz, CDCl3)    439  C.9.24 (+)-4-Bromo-1'-(4-nitrophenylsulfonyl)-1H-spiro[naphthalene-2,2'-pyrrolidin]-1-one (4.2e) 13 mg (13% yield) from 100 mg of 4.1e as yellow solid, eluent: 2:3 EtOAc/hexane; [α]23D = +3.8° (c 0.13, CHCl3). The ee of this compound was determined by forming (1S)-(+)-10-Camphorsulfonyl derivative of 4.61. Diastereomeric excess obtained in this case was 11%.    1H NMR spectrum of crude (±)-4.63 (300 MHz, CDCl3)     440   1H NMR spectrum of chiral crude (±)-4.63 (11% de; 300 MHz, CDCl3) (+)-4-bromo-2-(3-(4-nitrophenylsulfonamido)propyl)-1-oxo-1,2-dihydronaphthalen-2-yl 3-chlorobenzoate (4.54g) 31.4 mg (24% yield) from 100 mg of 4.1e as yellow solid, eluent: 1:3 EtOAc/hexane; [α]23D = +25.6° (c 0.50, CHCl3). The ee of this compound was determined by forming (1S)-(+)-10-Camphorsulfonyl derivative of (+)-4.54g. Diastereomeric excess obtained in this case was 66%.      441   1H NMR spectrum of crude (±)-4.64 (300 MHz, CDCl3)  1H NMR spectrum of chiral crude 4.64 (68% de; 300 MHz, CDCl3)    442  C.9.25 (-)-1'-(methylsulfonyl)-2H-spiro[naphthalene-1,2'-pyrrolidin]-2-one (4.5a) 4.4 mg (22% yield) from 20 mg of 4.4a as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = -31.0° (c 0.65, CHCl3). SFC analysis indicates a 37% ee: Column (AD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 44.26 min (major), tR (2) = 58.02 (minor).   chromatogram of (±)-4.5a (229 nm) chromatogram of (-)-4.5a, (229 nm, 37% ee)      443  One recrystallization (EtOAc / hexane; slow evaporation, room temp.) afforded material of 46% ee, the optical purity of which was determined by SFC: Column (AD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 43.17 min (major), tR (2) = 56.58 (minor). chromatogram of (±)-4.5a (229 nm) chromatogram of (-)-4.5a, (229 nm, 46% ee)      444  C.9.26 (+)-(R)-7-methoxy-1'-(methylsulfonyl)-2H-spiro[naphthalene-1,2'-pyrrolidin]-2-one (4.5b) 4.2 mg (21% yield) from 20 mg of 4.4b as white solid, eluent: 2:3 EtOAc/hexane; [α]23D = +72.2° (c 0.67, CHCl3). SFC analysis indicates a 46% ee: Column (OD-H) 5:95:0.1 (iPrOH: liq CO2: diethylamine), flow rate = 1.0 mL/min; tR (1) = 55.89 min (major), tR (2) = 63.02 (minor).   chromatogram of (±)-4.5b (240 nm) chromatogram of (+)-4.5b, (240 nm, 46% ee)      445  One recrystallization (Methanol; slow evaporation, RT) afforded material of 96% ee, the optical purity of which was determined by chiral HPLC: Column (OD-H) 5:95 (iPrOH: hexane), flow rate = 1.0 mL/min; tR (1) = 67.85 min (major), tR (2) = 79.42 min (minor). chromatogram of (±)-4.5b (220 nm) chromatogram of (+)-4.5b, (220 nm, 96% ee)      446  C.10 1H and 13C spectra from chapter 4  1H NMR spectrum of 4.2a (300 MHz, CDCl3)  13C NMR spectrum of 4.2a (75 MHz, CDCl3)    447   1H NMR spectrum of 4.2b (300 MHz, CDCl3) 13C NMR spectrum of 4.2b (75 MHz, CDCl3)    448   1H NMR spectrum of 4.2c (300 MHz, CDCl3)  13C NMR spectrum of 4.2c (75 MHz, CDCl3)    449   1H NMR spectrum of 4.2d (300 MHz, CDCl3)  13C NMR spectrum of 4.2d (75 MHz, CDCl3)    450   1H NMR spectrum of 4.2e (300 MHz, CDCl3)  13C NMR spectrum of 4.2e (75 MHz, CDCl3)    451   1H NMR spectrum of 4.2f (300 MHz, CDCl3)  13C NMR spectrum of 4.2f (75 MHz, CDCl3)    452   1H NMR spectrum of 4.2g (300 MHz, CDCl3)  13C NMR spectrum of 4.2g (75 MHz, CDCl3)    453   1H NMR spectrum of 4.2h (300 MHz, CDCl3)  13C NMR spectrum of 4.2h (75 MHz, CDCl3)    454   1H NMR spectrum of 4.2i (300 MHz, CDCl3)  13C NMR spectrum of 4.2i (75 MHz, CDCl3)    455   1H NMR spectrum of 4.2j (300 MHz, CDCl3)  13C NMR spectrum of 4.2j (75 MHz, CDCl3)    456   1H NMR spectrum of 4.2k (300 MHz, CDCl3)  13C NMR spectrum of 4.2k (75 MHz, CDCl3)    457   1H NMR spectrum of 4.2l (300 MHz, CDCl3)  13C NMR spectrum of 4.2l (75 MHz, CDCl3)    458    1H NMR spectrum of 4.2m (300 MHz, CDCl3)   13C NMR spectrum of 4.2m (75 MHz, CDCl3)    459   1H NMR spectrum of 4.2n (300 MHz, CDCl3)  13C NMR spectrum of 4.2n (75 MHz, CDCl3)    460   1H NMR spectrum of 4.2o (300 MHz, CDCl3)  13C NMR spectrum of 4.2o (75 MHz, CDCl3)    461   1H NMR spectrum of 4.2p (300 MHz, CDCl3)  13C NMR spectrum of 4.2p (75 MHz, CDCl3)    462   1H NMR spectrum of 4.5a (300 MHz, CDCl3)  13C NMR spectrum of 4.5a (75 MHz, CDCl3)    463   1H NMR spectrum of 4.5b (300 MHz, CDCl3)  13C NMR spectrum of 4.5b (75 MHz, CDCl3)    464   1H NMR spectrum of 4.9a (300 MHz, CDCl3)  13C NMR spectrum of 4.9a (75 MHz, CDCl3)    465   1H NMR spectrum of 4.9b (300 MHz, CDCl3)  13C NMR spectrum of 4.9b (75 MHz, CDCl3)    466   1H NMR spectrum of 4.9c (300 MHz, CDCl3)  13C NMR spectrum of 4.9c (75 MHz, CDCl3)    467   1H NMR spectrum of 4.10 (300 MHz, CDCl3)  13C NMR spectrum of 4.10 (75 MHz, CDCl3)    468   1H NMR spectrum of 4.54a (300 MHz, CDCl3)  13C NMR spectrum of 4.54a (75 MHz, CDCl3)    469   1H NMR spectrum of 4.54b (300 MHz, CDCl3)  13C NMR spectrum of 4.54b (75 MHz, CDCl3)    470   1H NMR spectrum of 4.54c (300 MHz, CDCl3)  13C NMR spectrum of 4.54c (75 MHz, CDCl3)    471   1H NMR spectrum of 4.54d (300 MHz, CDCl3)  13C NMR spectrum of 4.54d (75 MHz, CDCl3)    472   1H NMR spectrum of 4.54e (300 MHz, CDCl3)  13C NMR spectrum of 4.54e (75 MHz, CDCl3)    473   1H NMR spectrum of 4.54f (300 MHz, CDCl3)  13C NMR spectrum of 4.54f (75 MHz, CDCl3)    474   1H NMR spectrum of 4.54g (300 MHz, CDCl3)  13C NMR spectrum of 4.54g (75 MHz, CDCl3)    475   1H NMR spectrum of 4.66 (300 MHz, CDCl3)  13C NMR spectrum of 4.66 (75 MHz, CDCl3)    476   1H NMR spectrum of 4.67 (300 MHz, CDCl3)  13C NMR spectrum of 4.67 (75 MHz, CDCl3)    477   1H NMR spectrum of 4.68 (300 MHz, CDCl3)  13C NMR spectrum of 4.68 (75 MHz, CDCl3)    478   1H NMR spectrum of 4.21 (300 MHz, CDCl3)  13C NMR spectrum of 4.21 (75 MHz, CDCl3)    479   1H NMR spectrum of 4.22 (300 MHz, CDCl3)  13C NMR spectrum of 4.22 (75 MHz, CDCl3)    480   1H NMR spectrum of 4.23 (300 MHz, CDCl3)  13C NMR spectrum of 4.23 (75 MHz, CDCl3)    481   1H NMR spectrum of 4.47 (300 MHz, CDCl3)  13C NMR spectrum of 4.47 (75 MHz, CDCl3)    482   1H NMR spectrum of 4.48 (300 MHz, CDCl3)  13C NMR spectrum of 4.48 (75 MHz, CDCl3)    483   1H NMR spectrum of 4.49 (300 MHz, CDCl3)  13C NMR spectrum of 4.49 (75 MHz, CDCl3)    484   1H NMR spectrum of 4.50 (300 MHz, CDCl3)  13C NMR spectrum of 4.50 (75 MHz, CDCl3)    485   1H NMR spectrum of 4.51 (300 MHz, CDCl3)  13C NMR spectrum of 4.51 (75 MHz, CDCl3)    486   1H NMR spectrum of 4.52 (300 MHz, CDCl3)  13C NMR spectrum of 4.52 (75 MHz, CDCl3)    487   1H NMR spectrum of 4.61 (300 MHz, CDCl3)  13C NMR spectrum of 4.61 (75 MHz, CDCl3)    488   1H NMR spectrum of 4.3 (300 MHz, CDCl3)  13C NMR spectrum of 4.3 (75 MHz, CDCl3)     489  D. Asymmetric oxidative cycloetherification experimental section D.1 Representative protocols for cycloetherification of naphtholic alcohols at ortho-position  A solution of MCPBA (123 mg, 550 mol, 1.3 equiv) in CH2Cl2 (10.0 mL) was added to solution of alcohol 5.1 (0.42 mmol, 1.0 equiv) and iodobenzene (0.42 mmol, 1.0 equiv) in CH2Cl2 (10.0 mL) at RT. The mixture was stirred for 4 to 6 hours at RT, whereupon TLC indicated complete reaction. The mixture was quenched with aq. sat. NaHCO3 (10.0 mL) and aq. sat. Na2S2O3 (5.0 mL) and extracted with CH2Cl2 (4×15 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography with an appropriate eluent to afford spiroethers. Spiroethers 5.2b - 5.2p were prepared by this method. D.2 Representative protocols for cycloetherification of naphtholic alcohols at ortho-position using PIFA  A solution of 5.1 (100 mg, 0.36 mmol, 1.0 equiv) in CH2Cl2 (12.0 mL) was slowly added at RT over a period of 2 minutes to a solution containing PIFA (170 mg, 0.4 mmol, 1.1 equiv) in CH2Cl2 (8.0 mL) so that the final concentration is 0.02 M. The reaction was stirred for 1 to 2 hours, after which time TLC showed that the reaction was complete. The mixture was evaporated to dryness. The residue was purified by flash column chromatography to afford spiroethers. Spiroethers 5.2q - 5.2w were prepared by this method.    490  D.3 Characterization of various spiroethers D.3.1 Characterization of (±)-4,5-Dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2l) 35 mg (35% yield) from 100 mg of 5.1l, colorless oil, eluent: 1:19 EtOAc/hexanes; IR: 1686. 1H: 7.97 (d, 1H, J = 9.0), 7.55 (td, 1H, J = 7.5, 3.0), 7.33 (t, 1H, J = 7.5), 7.19 (d, 1H, J = 9.0), 6.51 (d, 1H, J = 12.0), 6.17 (d, 1H, J = 12.0), 4.36-4.29 (m,1H), 4.19-4.12 (m, 1H), 2.32-2.17 (m, 2H), 2.11-1.97 (m, 2H). 13C: 201.7, 137.4, 136.5, 134.6, 128.9, 128.0, 127.2 (2C), 125.7, 84.1, 70.6, 36.5, 25.2. HRMS: calcd for C13H12O2Na [M+Na]+: 223.0735; found: 223.0736. D.3.2 Characterization of (±)-4'-Chloro-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2a) 40 mg (40% yield) from 100 mg of 5.1a, colorless oil, eluent: 1:19 EtOAc/hexanes; IR: 1690. 1H: 8.03 (d, 1H, J = 9.0), 7.74-7.66 (m, 2H), 7.49-7.43 (m, 1H), 6.37 (s, 1H), 4.33-4.26 (m, 1H), 4.20-4.13 (m, 1H), 2.33-2.21 (m, 2H), 2.14-1.98 (m, 2H). 13C: 199.5, 135.0, 134.8, 133.3, 129.3, 129.1, 128.8, 127.5, 125.5, 84.6, 70.6, 36.6, 25.4. HRMS: calcd for C13H10O2Cl [M+H]+: 233.0369; found: 233.0364. D.3.3 Characterization of (±)-4'-Bromo-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2b) 32 mg (32% yield) from 100 mg of 5.1b, colorless oil, eluent: 1:19 EtOAc/hexanes; IR: 1692. 1H: 7.99 (d, 1H, J = 9.0), 7.70-7.63 (m, 2H), 7.46-7.40 (m, 1H), 6.63 (s, 1H), 4.32-4.25 (m, 1H), 4.19-4.12 (m, 1H), 2.31-2.18 (m, 2H),  491  2.15-1.93 (m, 2H). 13C: 199.5, 137.7, 135.6, 134.8, 129.2, 128.9, 128.1, 127.3, 119.7, 85.4, 70.6, 36.4, 25.3. HRMS: calcd for C13H11O279BrNa [M+Na]+: 300.9840; found: 300.9844. D.3.4 Characterization of (±)-4'-Methyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2c) 26 mg (26% yield) 100 mg of 5.1c, colorless oil, eluent: 1:19 EtOAc/hexanes; IR: 1688. 1H: 7.99 (d, 1H, J = 6.0), 7.61 (app t, 1H, J = 8.0), 7.39-7.32 (m, 2H), 5.99 (s, 1H), 4.32-4.25 (m, 1H), 4.18-4.11 (m, 1H), 2.27-2.18 (m, 2H), 2.14 (s, 3H), 2.10-1.98 (m, 1H), 1.94-1.82 (m, 1H). 13C: 201.9, 138.4, 134.5, 133.1, 130.5, 128.9, 127.8, 127.3, 124.2, 83.9, 70.3, 36.3, 25.4, 19.2. HRMS: calcd for C14H15O2 [M+H]+: 215.1072; found: 215.1077. D.3.5 Characterization of (±)-4'-Phenyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2d) 41.5 mg (42% yield) of (±)-7g from 100 mg of 6g, white solid, m.p. 91-93 °C, eluent: 3:47 EtOAc/hexanes; IR: 1689. 1H: 8.05 (dd, 1H, J = 9.0, 3.0), 7.51-7.34 (m, 7H), 7.10 (d, 1H, J = 6.0), 6.12 (s, 1H), 4.37-4.30 (m, 1H), 4.20-4.13 (m, 1H), 2.38-2.22 (m, 2H), 2.17-1.97 (m, 2H). 13C: 201.6, 138.6, 137.8, 137.5, 135.1, 134.3, 129.2, 128.9, 128.5, 128.1, 127.9, 127.5, 126.7, 84.4, 70.5, 36.6, 25.4. EI: calcd for C19H16O2: 276.1150; found: 276.1152. D.3.6 Characterization of (±)-4'-p-Tolyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2e) 41.8 mg (42% yield) from 100 mg of 5.1e, white solid, m.p. 135-137 °C, eluent: 1:19 EtOAc/hexanes; IR: 1688. 1H: 8.04 (d, 1H, J = 9.0), 7.48 (app t, 1H, J =  492  7.5), 7.35 (app t, 1H, J = 6.0), 7.24 (br s, 4H), 7.13 (d, 1H, J = 9.0), 6.09 (s, 1H), 4.36-4.29 (m, 1H), 4.20-4.13 (m, 1H), 2.42 (s, 3H), 2.37-2.16 (m, 2H), 2.13-1.96 (m, 2H). 13C: 201.7, 137.9, 137.6, 137.4, 135.7, 134.8, 134.3, 129.2, 129.1, 128.8, 128.0, 127.5, 126.7, 84.4, 70.5, 36.6, 25.4, 21.3. HRMS: calcd for C20H19O2 [M+H]+: 291.1385; found: 291.1393. D.3.7 Characterization of (±)-4'-(3-Methoxyphenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2f) 41.6 mg (42% yield) from 100 mg of 5.1f, colorless oil, eluent: 2:23 EtOAc/hexanes; IR: 1702. 1H: 8.04 (d, 1H, J = 9.0), 7.51-7.46 (m, 1H), 7.38-7.32 (m, 2H), 7.13 (d, 1H, J = 6.0), 6.95-6.89 (m, 3H), 6.12 (s, 1H), 4.36-4.29 (m, 1H), 4.20-4.13 (m, 1H), 3.84 (s, 3H), 2.37-2.21 (m, 2H), 2.11-1.96 (m, 2H). 13C: 201.5, 159.6, 140.0, 137.7, 137.4, 134.9, 134.3, 129.5, 129.2, 128.1, 127.5, 126.7, 121.3, 114.5, 113.4, 84.3, 70.5, 55.3, 36.6, 25.4. HRMS: calcd for C20H19O3 [M+H]+: 307.1334; found: 307.1336. D.3.8 Characterization of (±)-4'-(3,5-Bis(trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2g) 33.9 mg (34% yield) from 100 mg of 5.1g, colorless oil, eluent: 1:19 EtOAc/hexanes. IR: 1695. 1H: 8.09 (d, 1H, J = 6.0), 7.93 (s, 1H), 7.83 (s, 2H), 7.55 (app t, 1H, J = 7.5), 7.44 (app t, 1H, J = 7.5), 6.92 (d, 1H, J = 9.0), 6.20 (s, 1H), 4.39-4.32 (m, 1H), 4.22-4.15 (m, 1H), 2.42-2.24 (m, 2H), 2.15-2.00 (m, 2H). 13C: 200.6, 140.7, 137.3, 136.3, 135.3, 134.7, 132.1 (q, J = 33.2), 129.2 (br s), 129.1, 128.9, 128.1, 125.8, 123.2 (q, J = 273.3), 122.0-121.8 (m), 84.2, 70.7, 36.6, 25.3. HRMS: calcd for C21H14O2F6: 412.0898; found: 412.0901.  493  D.3.9 Characterization of (±)-4'-(4-Fluorophenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2h) 44.8 mg (45% yield) from 100 mg of 5.1h, white solid, m.p.: 96-98 °C, eluent: 1:19 EtOAc/hexanes; IR: 1690. 1H: 8.04 (d, 1H, J = 6.0), 7.53-7.47 (m, 1H), 7.39-7.30 (m, 3H), 7.15-7.04 (m, 3H), 6.10 (s, 1H), 4.36-4.29 (m, 1H), 4.20-4.13 (m, 1H), 2.38-2.19 (m, 2H), 2.11-2.04 (m, 2H). 13C: 201.4, 162.5 (d, J = 246.9), 137.6, 136.6. 135.4, 134.5 (d, J = 3.8), 134.4, 130.6 (d, J = 8.3), 129.2, 128.2, 127.6, 126.5, 115.4 (d, J = 21.9), 84.4, 70.5, 36.6, 25.3. HRMS: calcd for C19H15O2F: 294.1056; found: 294.1055. D.3.10 Characterization of (±)-4-(1'-Oxo-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalene]-4'-yl)benzo-nitrile (5.2i) 57.6 mg (58% yield) from 100 mg of 5.1i, light yellow oil, eluent: 2:23 EtOAc/hexanes; IR: 2229, 1691. 1H: 8.06 (d, 1H, J = 6.0), 7.74 (d, 2H, J = 6.0), 7.54-7.47 (m, 3H), 7.43-7.38 (m, 1H), 6.98 (d, 1H, J = 9.0), 6.15 (s, 1H), 4.37-4.30 (m, 1H), 4.21-4.14 (m, 1H), 2.39-2.21 (m, 2H), 2.12-1.97 (m, 2H). 13C: 200.9, 143.4, 136.6, 136.4, 136.3, 134.5, 132.4, 129.9, 129.7, 129.6, 129.2, 128.7, 127.9, 126.1, 118.6, 111.9, 84.3, 70.7, 36.6, 25.3. HRMS: calcd for C20H15O2N: 301.1103; found: 301.1101.  D.3.11 Characterization of (±)-4'-(4-(Methylsulfonyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2j) 53.6 mg (54% yield) from 100 mg of 5.1j, white solid, m.p. 74-76 °C, eluent: 1:4 to 2:3 EtOAc/hexanes; IR: 1691. 1H: 8.07-8.01 (m, 3H), 7.58 (d, 2H, J = 9.0), 7.54-7.38 (m, 2H), 6.99 (d, 1H, J = 9.0), 6.16 (s, 1H), 4.37-4.30 (m,  494  1H), 4.21-4.14 (m, 1H), 3.13 (s, 3H), 2.40-2.22 (m, 2H), 2.19-2.04 (m, 2H). 13C: 200.9, 144.4, 140.1, 136.6 (2C), 136.2, 134.5, 129.9, 129.2, 128.7, 127.9, 127.7, 126.2, 84.3, 70.7, 44.5, 36.6, 25.3. HRMS: calcd for C20H19O4S [M+H]+: 355.1004; found: 355.0996. D.3.12 Characterization of (±)-4'-(4-(Trifluoromethyl)phenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2k) 31.5 mg (32% yield) from 100 mg of 5.1k, white solid, m.p. 155-157 °C, eluent: 1:19 EtOAc/hexanes. IR: 1691. 1H: 8.06 (d, 1H, J = 6.0), 7.71 (d, 2H, J = 9.0), 7.53-7.37 (m, 4H), 7.02 (d, 1H, J = 9.0), 6.14 (s, 1H), 4.35-4.31 (m, 1H), 4.21-4.14 (m, 1H), 2.37-2.22 (m, 2H), 2.13-2.02 (m, 2H). 13C: 201.1, 142.3, 137.0, 136.5, 136.0, 134.4, 130.2 (q, J = 34.0), 129.3, 129.2, 128.5, 127.7, 126.3, 125.5 (q, J = 3.8), 124.1 (q, J = 271.8), 84.3, 70.6, 36.6, 25.3. EI: calcd for C20H16O2F3: 345.1100; found: 345.1101. D.3.13 Characterization of (±)-4'-(4-Acetylphenyl)-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2r) 62.7 mg (63% yield) from 100 mg of 5.1r, off white solid, m.p. 134-136 °C, eluent: 1:9 EtOAc/hexanes; IR: 1683. 1H: 8.06-8.01 (m, 3H), 7.52-7.45 (m, 3H), 7.38 (app t, 1H, J = 7.3), 7.04 (d, 1H, J = 7.7), 6.15 (s, 1H), 4.37-4.30 (m, 1H), 4.21-4.14 (m, 1H), 2.66 (s, 3H), 2.40-2.21 (m, 2H), 2.19-1.98 (m, 2H). 13C: 201.3, 197.8, 143.5, 137.2, 136.9, 136.7, 135.9, 134.5, 129.3, 128.7, 128.5, 127.8, 126.5, 84.5, 70.7, 36.7, 26.8, 25.4. HRMS: calcd for C21H18O3Na [M+Na]+: 341.1154; found: 341.1154.   495  D.3.14 Characterization of (±)-4'-Benzoyl-4,5-dihydro-1'H,3H-spiro[furan-2,2'-naphthalen]-1'-one (5.2o) 38.7 mg (39% yield) from 100 mg of 5.1o, yellow oil, eluent: 1:19 to 1:9 EtOAc/hexanes; IR: 1694, 1665. 1H: 8.07 (d, 1H, J = 6.0), 7.97-7.94 (m, 2H), 7.65-7.39 (m, 6H), 6.43 (s, 1H), 4.40-4.33 (m,