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Applications of hypervalent iodine reagents in organic synthesis : the development of iodonium metathesis… Kasahara, Takahito 2015

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  APPLICATIONS OF HYPERVALENT IODINE REAGENTS IN ORGANIC SYNTHESIS:  THE DEVELOPMENT OF IODONIUM METATHESIS REACTION AND EFFORT TOWARDS HIMANDRINE    by    Takahito Kasahara     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)          October 2015  © Takahito Kasahara, 2015  ii  Abstract   This thesis discloses two different applications of hypervalent iodine(III) reagents in organic synthesis.  In the first part, a novel reactivity of diaryliodonium triflates towards aryl iodides will be discussed.  The new mode of reactivity allows various diaryliodonium triflates to be accessed, simply by heating a mixture of electron deficient diaryliodonium triflate with a moderately electron rich aryliodide.  In the second part of the thesis, the use of (diacetoxyiodo)benzene in oxidative amidation in the context of total synthesis will be made.    iii  Preface   The thesis is written by, and is based on experiments conducted by Kasahara, T.  Professor Ciufolini, M. A. provided the overall synthetic strategy and tactic, helpful suggestions, and thorough editing of the thesis.   The research reported in Chapter 1 has been published in:  Kasahara,T.; Jang, Y. J.; Racicot, L.; Panagopoulos, D.; Liang, S. H.; Ciufolini M. A. Angew. Chem. Int. Ed. 2014, 53, 9637.  Professor Ciufolini, M. A. wrote the manuscript, Kasahara, T. and Racicot, L. wrote the supporting information.  The data shown in Table 1.1 and 1.2 are based on experiments performed by Racicot, L.  The results shown in Scheme 1.15 are based on experiments peformed by Jang, Y. J.  Semi-empirical calculations (HyperChem) shown in Figure 1.6 was performed by Professor Ciufolini, M. A.   A portion of the research reported in Chapter 2 has been published in:  Kasahara, T.; Ciufolini, M. A. Can. J. Chem. 2013, 91, 82.  Professor Ciufolini, M. A. wrote the manuscript and Kasahara, T. wrote the supporting information.  All experiments were performed by Kasahara, T.   iv  Table of Contents  Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables ............................................................................................................................... vii List of Figures ............................................................................................................................. viii List of Schemes ............................................................................................................................. ix List of Abbreviations ................................................................................................................. xiii Acknowledgements .................................................................................................................. xviii Chapter 1  The Development of Iodonium Metathesis Reaction .................................................. 1 1.1  Hypervalent iodine compounds: general aspects .............................................................. 1 1.2  Diaryliodonium salts ......................................................................................................... 5 1.2.1  Preparation of diaryliodonium salts .......................................................................... 6 1.2.2  Synthetic applications of diaryliodonium salts ......................................................... 8 1.3  The development of iodonium metathesis reaction .......................................................... 9 1.3.1  Inception of project ................................................................................................... 9 1.3.2  Iodonium metathesis ............................................................................................... 14 1.4  Conclusion ...................................................................................................................... 23 1.5  Experimental ................................................................................................................... 24 v  Chapter 2  Synthetic Studies Towards Himandrine .................................................................... 31 2.1  Introduction ..................................................................................................................... 31 2.1.1  The oxidative amidation of phenols ........................................................................ 31 2.1.2  Desymmetrization of dienones obtained though oxidative amidation .................... 34 2.1.3  Isolation and biological properties of (−)-himandrine ............................................ 39 2.1.4  Biosynthesis of himandrine ..................................................................................... 41 2.2   Synthetic efforts towards himandrine ............................................................................ 42 2.2.1  Mander’s approach to the framework of himandrine .............................................. 43 2.2.2  Movassaghi's total synthesis of (–)-himandrine ...................................................... 46 2.3  Prior work from the Ciufolini group ............................................................................... 51 2.3.1  Retrosynthetic considerations ................................................................................. 51 2.3.2  Preliminary results .................................................................................................. 53 2.4  An approach to himandrine via the oxidative amidation of a phenol ............................. 55 2.4.1  Directing effect of a C3 pyrrolidine substituent ...................................................... 56 2.4.2  Formation of ring C: conjugate addition strategy ................................................... 62 2.4.3.  Formation of ring C: hydroacylation strategy ........................................................ 64 2.5  An advanced synthetic intermediate for himandrine ...................................................... 67 2.5.1  Tandem oxidative cyclization-IMDA-epimerization sequence with 2.166 ............ 69 2.5.2  Identification of a suitable forerunner of the MeO group of himandrine ............... 73 2.5.3   Methodology for the creation of ring D of himandrine .......................................... 77 vi  2.5.4  Early-stage installation of the C5 alkyne substituent .............................................. 80 2.5.5  Elaboration of 2.222 to a precursor of himandrine incorporating ring D ............... 87 2.6  Summary and outlook ..................................................................................................... 93 2.7  Experimental ................................................................................................................... 95 References .................................................................................................................................. 147 Appendix A ................................................................................................................................ 155 Appendix B ................................................................................................................................ 164 Appendix C ................................................................................................................................ 216     vii  List of Tables  Table 1.1  Screening of conditions for diaryliodonium metathesis reaction ................................ 14 Table 1.2  Survey of aryl iodide for the diaryliodonium metathesis reaction............................... 16 Table 1.3  Iodonium metathesis reaction using 1.40a and 1.40b ................................................. 18    viii  List of Figures  Figure 1.1  Examples of organoiodine compounds at the oxidation state of −1 ............................. 1 Figure 1.2  Examples of hypervalent iodine compounds ................................................................ 1 Figure 1.3  Nomenclature of hypervalent iodine compounds ......................................................... 2 Figure 1.4  3c-4e bond of a generic hypervalent iodine compound IL3 ......................................... 3 Figure 1.5  Neutral and ionic depiction of a generic diaryliodonium salt ...................................... 6 Figure 1.6  Calculated values of partial positive charge residing on the iodine atom .................. 22 Figure 2.1  Structure of the alkaloid, himandrine ......................................................................... 31 Figure 2.2  Structures of (−)-himandrine depicted in different perspective ................................. 40 Figure 2.3  Structures of (+)-himbacine and ent-himbacine derivatives ...................................... 41 Figure 2.4  Comparison of stereochemical outcome of dienone 2.99 and 2.105 from the IMDA reaction ....................................................................................................................... 61 Figure 2.5  1H NMR (CD3CN, 300 MHz) of (a) pure 2.243 (b) crude mixture obtained after treating 2.243 with SmI2 and (c) crude mixture after treatment with DMP ............... 92 Figure 2.6  HSQC and HMBC plot indicating the key correlation seen for compound 2.247 ..... 92    ix  List of Schemes  Scheme 1.1  Simplified mechanism for ligand exchange reaction ................................................. 4 Scheme 1.2  Mechanistic dichotomy in the reductive elimination of I–L from 1.4 ....................... 5 Scheme 1.3  An overview of synthetic approaches to prepare diaryliodonium salt 1.12 ............... 6 Scheme 1.4  One-pot synthesis of diaryliodonium salt from iodine (I) compound or I2 ................ 8 Scheme 1.5  Generic mechanism for the aryl transfer reaction to a nucleophile ............................ 8 Scheme 1.6  Asymmetric α-arylation reported by Aggarwal ......................................................... 9 Scheme 1.7  Simplified mechanism for the oxidation of aryl iodide by mCPBA ........................ 10 Scheme 1.8  Yamamoto’s cascade aldol reaction catalyzed by triflimide and iodobenzene ........ 10 Scheme 1.9  I-Arylation of aryl iodides: the iodonium metathesis reaction ................................. 11 Scheme 1.10  Preparation of 5-18F-uridine by a hypothetical iodonium metathesis reaction....... 11 Scheme 1.11  Koser’s report on redox transfer reaction ............................................................... 12 Scheme 1.12  Aryl exchange observed by DiMagno .................................................................... 13 Scheme 1.13  Metathesis reaction of bis(p-anisyl)iodonium triflate (1.33) with p-iodotoluene .. 17 Scheme 1.14  Origin of selective aryl transfer for Beringer-Ochiai mechanism .......................... 19 Scheme 1.15  Iodonium metathesis reaction of 1.45 .................................................................... 20 Scheme 1.16  Proposed mechanism of the iodonium metathesis reaction ................................... 21 Scheme 1.17  Mechanism of sulfonium metathesis reaction ........................................................ 23 Scheme 2.1  Overview of intermolecular oxidative dearomatization process .............................. 32 Scheme 2.2  Intramolecular oxidative dearomatization of a phenol ............................................. 32 Scheme 2.3  Typical oxidative amidation reactions in the intramolecular (eq 1-3) and bimolecular (eq 4) regime ........................................................................................ 33 x  Scheme 2.4  Stereochemical aspects of dienone modification: 2.11 / 2.12 and 2.13 / 2.14 have opposite configurations at the spiro-carbon ............................................................. 34 Scheme 2.5  Diastereoselective desymmetrization of 2.16 by conjugate addition ....................... 36 Scheme 2.6  Diastereoselective desymmetrization of dienone 2.21 ............................................. 37 Scheme 2.7  Chelation controlled desymmetrization of dienone 2.25 ......................................... 38 Scheme 2.8  Tandem oxidative amidation-intramolecular nitrile oxide cycloaddition process ... 39 Scheme 2.9  Proposed biosynthesis for (−)-himandrine ............................................................... 42 Scheme 2.10  Mander’s retrosynthetic analysis of compound 2.44 ............................................. 43 Scheme 2.11  Preparation of ester 2.51......................................................................................... 44 Scheme 2.12  Assembly of enone 2.60 in Mander’s synthesis ..................................................... 45 Scheme 2.13  Completion of Mander’s synthesis ......................................................................... 46 Scheme 2.14  Movassaghi’s retrosynthetic analysis of (−)-himandrine ....................................... 47 Scheme 2.15  Synthesis of tetraene 2.68....................................................................................... 48 Scheme 2.16  Synthesis of tricycle 2.67 ....................................................................................... 49 Scheme 2.17  The crucial union of fragments 2.66 and 2.67 ........................................................ 49 Scheme 2.18  End game of Movassaghi’s synthesis of (−)-himandrine ....................................... 50 Scheme 2.19  Retrosynthetic analysis of himandrine: identification of precursor 2.90 ............... 51 Scheme 2.20  Possible assembly of tricyclic enone 2.90 via a tandem IMOA-IMDA of 2.92 .... 52 Scheme 2.21  Conformational aspects of the IMDA reaction of dienone 2.91 ............................ 53 Scheme 2.22  Directing effect of the C5 substituent of the pyrrolidine ring ................................ 54 Scheme 2.23  Presumed mechanism for the formation of trans Diels-Alder adduct 2.100 ......... 55 Scheme 2.24  Objectives and challenges towards the synthesis of himandrine ........................... 56 Scheme 2.25  Opportunities for the construction of ring C of himandrine ................................... 56 xi  Scheme 2.26  Sythesis of compound 2.115 .................................................................................. 57 Scheme 2.27  Proposed mechanism of the Tozer reaction ........................................................... 58 Scheme 2.28  Tozer reaction using phenol 2.115 ......................................................................... 59 Scheme 2.29  Typical product distribution observed in the IMDA-epimerization of dienone 2.105 and its conversion into alcohol 2.130 .................................................................... 60 Scheme 2.30  Conjugate addition approach for the assembly of ring C of himandrine ............... 62 Scheme 2.31  Attempts to form the C ring with nitrile 2.134 ....................................................... 63 Scheme 2.32  Base mediated cyclization of keto-aldehyde 2.137 ................................................ 63 Scheme 2.33  Cyclization of keto-aldehyde 2.137 via enamine 2.139 ......................................... 64 Scheme 2.34  Hydroacylation strategy to construct the C ring..................................................... 65 Scheme 2.35  Presumed mechanism of Stetter reaction with thiazolium pre-catalyst 2.141 ....... 65 Scheme 2.36  Attempts to carry out Stetter reaction with compound 2.106 using pre-catalysts 2.150-2.152 ............................................................................................................ 66 Scheme 2.37  Stetter reaction with Glorius pre-catalyst 2.153 ..................................................... 67 Scheme 2.38  Retrosynthetic analysis of seco-himandrine 2.154 ................................................. 68 Scheme 2.39  Synthetic route en route to phenol 2.166................................................................ 68 Scheme 2.40  Tandem IMOA-IMDA-epimerization reaction with phenol 2.166 ........................ 70 Scheme 2.41  Possible mechanism for the formation of compound 2.169 ................................... 71 Scheme 2.42  Modified protocol for the tandem IMOA-IMDA-epimerization sequence ............ 72 Scheme 2.43  Retrosynthetic analysis of 2.1 ................................................................................ 73 Scheme 2.44  Attempted synthesis of dienone 2.182 ................................................................... 74 Scheme 2.45  The use of silyldiene 2.183 in IMOA-IMDA-epimerization reaction to access compound 2.186 .................................................................................................... 74 xii  Scheme 2.46  Proposed mechanism of Tamao-Fleming oxidation............................................... 75 Scheme 2.47  Preparation of silyldiene 2.183............................................................................... 76 Scheme 2.48  Stetter reaction with compound 2.197.................................................................... 78 Scheme 2.49  Failures to functionalize the C5 substituent from compound 2.199 ...................... 79 Scheme 2.50  Preparation of aldehyde 2.205 ................................................................................ 81 Scheme 2.51  Presumed mechanism of Ohira-Bestmann reaction ............................................... 81 Scheme 2.52  Unexpected outcome of Ohira-Bestmann reaction with aldehyde 2.205 ............... 82 Scheme 2.53  Synthesis of alkynyl phenol 2.222 ......................................................................... 83 Scheme 2.54  Attempted Mitsunobu reaction with compound 2.227 ........................................... 84 Scheme 2.55  Mitsunobu reactions with compound 2.227 ........................................................... 85 Scheme 2.56  A possible rationale for the generation of 2.230 .................................................... 86 Scheme 2.57  Derivatization experiments of compound 2.230 .................................................... 86 Scheme 2.58  IMOA of phenol 2.222 ........................................................................................... 87 Scheme 2.59  IMDA-epimerization reaction of dienone 2.236 .................................................... 88 Scheme 2.60  Synthesis of diketone 2.243 ................................................................................... 89 Scheme 2.61  Synthetic strategies to convert 2.243 into 2.247 .................................................... 90 Scheme 2.62  Synthesis of compound 2.247 ................................................................................ 91 Scheme 2.63  Synthetic summary en route to compound 2.247 ................................................... 94    xiii  List of Abbreviations  Δ heat ‡ transition state 1,3-DC 1,3-dipolar cycloaddition Ac acetyl ADDP 1,1’-(azodicarbonyl)dipiperidine AM1 Austin model 1 app apparent aq. aqueous Ar generic aryl group Bn benzyl BHT butylated hydroxytoluene br broad Bu butyl °C degree Celsius calcd calculated cat. catalyst Cbz carboxybenzyl c-Hex cyclohexyl d doublet DCE 1,2-dichloroethane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene xiv  DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone dec decomposition DIAD diisopropyl azodicarboxylate DIB (diacetoxyiodo)benzene DIBAL diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMP Dess-Martin periodinane DMPU N,N’-dimethylpropylene urea dr diastereomeric ratio ESI electrospray ionization Et ethyl equiv equivalent(s) eq equation fod 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedinato g gram(s) h hour(s) HDA hetero-Diels-Alder HFIP 1,1,1,3,3,3-hexafluoro-2-propanol HRMS high resolution mass spectroscopy Hz hertz imid imidazole IMDA intramolecular Diels-Alder reaction IMOA intramolecular oxidative amidation xv  INOC intramolecular nitrile oxide cycloaddition J coupling constant L generic ligand LDA lithium diisopropylamide μ micro m milli or multiplet M molarity mCPBA meta-chloroperbenzoic acid Me methyl min minute(s) mol mole(s) M.P. melting point MNDO modified neglect of diatomic overlap MNDO/d extension of MNDO to d orbitals MO molecular orbital Ms methanesulfonyl NCA no-carrier-added NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance pNs para-nitrophenylsulfonyl PET positron emission tomography Ph phenyl xvi  Phth phthaloyl PM3 parameterized model 3 PMP para-methoxyphenyl ppm parts per million PPTS pyridinium para-toluenesulfonate pre-cat pre-catalyst pyr pyridine q quartet quant. quantitative R generic substituent rt room temperature s singlet sat. saturated SET single electron transfer t triplet taut. tautomerization TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl Tf trifluoromethanesulfonate TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin layer chromatography xvii  tol toluene Ts para-toluenesulfonyl  xviii  Acknowledgements   First and foremost, I would like to express my sincere gratitude to my supervisor, Professor Marco A. Ciufolini, for letting me join his group and allowing to work on two challenging research projects.  Your passion and dedication for chemistry, as well as your teaching, patience and support has allowed me to develop the skills required to be a synthetic chemist.  In particular, I am thankful for the time spent in the lab demonstrating how to prepare reagents, using HyperChem, and explaining chemistry in general.  The weekly group meetings were of invaluable pedagogy that provided an excellent opportunity to practice cognitive skills under pressure as well as expanding my knowledge of chemistry.    To the numerous professors who have educated me at UBC, I am thankful for their effort providing great lectures and mentorship.  At UBC, I was fortunate to take a course lectured by Professor Glenn Sammis and Professor Gregory Dake, where I was able to deepen my understanding of organic chemistry.  In addition, I would like to thank Professor Glenn Sammis for proofreading my thesis and taking part of the thesis committee.  I would also like to thank my past mentors, Dr. Michael K. Georges and Professor Andrei K. Yudin who have provided me the chance to make a transition from synthetic polymer to synthetic organic chemistry.  I would like to thank the past and present group members of the Ciufolini group, who have made my time in the lab into a memorable, entertaining and educational experience.  Especially to the residents of A312 (Dr. Joshua Zaifman, Leanne Racicot, Patrick Xu, and Marco Paladino), who have shared their time to discuss both chemistry and non-chemistry topics.  It has been a pleasure to work closely with you in the “main lab”.  I was also fortunate to participate on the iodonium project along with Leanne, Alvin Jang, and Dimitrios Panagopoulos.  Despite the xix  initial difficulties early in the project, I am thankful for the collaborative effort we were able to make during the short time span.  The research performed at UBC would not have been possible without the countless assistance provided from the Departmental staff.  Particularly, I would like to acknowledge Derek Smith for obtaining high resolution mass spectra, Dr. Yun Ling and Marshall Lapawa for maintaining a great mass-spec facility, Dr. Paul Xia for his assistance with NMR, Dr. Brian Patrick for obtaining x-ray data, and Brian Ditchburn for fixing and making specialty glassware (especially columns).  I am also grateful to Milan Coschizza and David Tonkin of the electronic engineering services who have helped fix the group’s NMR.  A thank you to the staff in chemistry stores for providing many chemicals and equipments within a reach from the lab.  To my friends and co-workers outside the group, I would like to thank you all for your support and friendship.  In particular, I would like to thank the Yee family, Dr. Eugene Chong, Andrea Ng, Ryo Matsumoto, and Jo Fung for providing enjoyable moments and words of comfort.  To the former occupants of A303 / 304, Dr. Emmanuel Castillo-Contreras and Ben Loosley, thank you for generously providing the chemicals that our grouped lacked in, as well as using the glovebox and stills.  Specifically, I would like to acknowledge Dr. Emmanuel Catillo-Contreras for introducing me the Glorius pre-catalyst which was essential to the success of Stetter reaction for the himandrine project.  I would like to acknowledge UBC and Department of Chemistry for the financial support provided throughout my studies.  Lastly, I would like to thank my family for their love and support.  I am very thankful to my parents who have been supporting me throughout the years in school.  1  Chapter 1   The Development of Iodonium Metathesis Reaction  1.1  Hypervalent iodine compounds: general aspects  Organoiodine compounds usually incorporate a monovalent iodine atom, formally present at the oxidation state of −1.  Familiar examples are alkyl, vinyl, and aryl iodides; e.g., iodomethane, iodoethene, and iodobenzene (Figure 1.1).   Figure 1.1  Examples of organoiodine compounds at the oxidation state of −1  In contrast, some organic compounds exhibit an iodine atom bonded to multiple ligands and in a formal oxidation state of +3 or +5; e.g., iodobenzene dichloride and the Dess-Martin reagent (Figure 1.2).  Some inorganic compounds incorporate iodine at the oxidation state of +7; e.g., iodine heptafluoride and sodium periodate.  The iodine in such compounds is said to be hypervalent, because it possesses more than eight electrons in its valence shell.1   Figure 1.2  Examples of hypervalent iodine compounds  2   Two different conventions are used to described the oxidation state of an hypervalent iodine: the IUPAC2 and Martin-Arduengo3 method (Figure 1.3).  In the former convention, a “λ” symbol with a numerical value in superscript is used while the latter uses the N-X-L formulation, where N refers to the number of valence electrons assigned to the hypervalent atom X that is bonded to L number of ligands.  Accordingly, PhICl2 would be described as a 3-iodane (IUPAC) or a 10-I-3 species (Martin-Arduengo); the Dess-Martin periodinane as a 5-iodane or a 12-I-5 compound, and IF7 as a 7-iodane or a 14-I-7 substance.   Figure 1.3  Nomenclature of hypervalent iodine compounds   Bonding in hypervalent compounds may be understood as involving one or more three-center-four-electron (3c-4e) bonds, also described as hypervalent bonds.4  To illustrate, consider a generic trivalent iodine (III) compound, IL3 (Figure 1.4, left).  The iodine atom and the two linearly arranged apical ligands (Lap) contribute one p-orbital each to the total bonding.  Furthermore, the I atom provides 2 electrons (one for each bonding interaction with an apical 3  ligand), while the ligands contribute one electron each.  Mixing of the three p-orbitals generates three new MOs (Figure 1.4, right).  Two of the MOs, the bonding and non-bonding orbitals, are occupied by the four electrons donated from the iodine atom and apical ligands.  The result is the establishment of a bonding interaction between 3 atomic centers; i.e. a 3c-4e bond.mm   Figure 1.4  3c-4e bond of a generic hypervalent iodine compound IL3   Notice that electrons in the non-bonding orbital are localized on the apical ligands, since a node is present at the iodine atom.  This results in polarization of the hypervalent bond and generation of significant electrophilic character on the iodine atom.  This interpretation of hypervalent bonding is widely accepted,1,5,6 although recent computational studies suggest that other orbital contributions may be present in a hypervalent bond.7  Regardless, the polarized nature of the hypervalent bond accounts for the general reactivity of hypervalent iodine compounds.  One of the fundamental reactions of hypervalent iodine compounds is ligand exchange.  Thus, an incoming nucleophile (including a solvent molecule) may react with 1.1 and generate a new species 1.4 (Scheme 1.1).  Generally speaking, 1.1 and 1.4 will exist in dynamic equilibrium.  Two different pathways could be hypothesized for this process: either an associative or a dissociative mechanism.  In an associative mechanism, a nucleophile would first coordinate with 4  the hypervalent iodine to generate an anionic intermediate (1.2).  This would be followed by expulsion of a ligand.  The sequence is reversed in a dissociative mechanism, where a ligand first leaves to form a cationic intermediate (1.3), which then is captured by a nucleophile.  Although the details for the reaction has not been elucidated and probably to vary depending on the reaction conditions, the associative mechanism is generally favored over the dissociative mechanism.6,8   Scheme 1.1  Simplified mechanism for ligand exchange reaction   Ligand exchange between a hypervalent iodine agent and a nucleophile leads to intermediate 1.4, which may undergo reductive elimination of I–L (Scheme 1.2).  In this process, the iodine (III) is reduced to iodine (I) and in turn, the nucleophile is oxidized.  In one scenario, the nucleophile can couple to the cis–disposed ligand, resulting in formation of product 1.5 and liberation of I–L (Scheme 1.2, path a).  Reductive elimination can also occur so that the nucleophile is oxidized to a transient cationic intermediate 1.6, which then is trapped by another nucleophile (RH).  This furnishes products of the type 1.7 (Scheme 1.2, path b).  The precise fate 5  of 1.4 is dependent on the choice of iodine (III) reagent and the reaction conditions.  Both outcomes will be discussed in this thesis.   Scheme 1.2  Mechanistic dichotomy in the reductive elimination of I–L from 1.4  1.2  Diaryliodonium salts  Diaryliodonium salts are 3-iodanes in which the iodine atom is bound to two aryl groups and a heteroatomic ligand, X, such as a halide, carboxylate, or sulfonate (Figure 1.5).  These species were first described by Hartmann and Meyer in 1894,9 and a great variety of these compounds has been made since their discovery.  The term “salts” implies that the compounds are ionic; however, X-ray crystallography reveals that in the solid state the heteroatomic ligand X is covalently bonded to the hypervalent iodine, resulting in an electrostatically neutral molecule (1.8a) with the expected T-shaped geometry (VSEPR).10  On the other hand, solutions of these compounds display significant conductance,11 indicating that ionic dissociation does occur in solution (1.8b).  An 17O NMR experiment of (diacetoxyiodo)benzene derivatives provides support for this conclusion.12  Despite the inaccurate representation, the ionic depiction is often seen in the literature as it reminds the reader that these compounds are highly electrophilic at the iodine atom.  6   Figure 1.5  Neutral and ionic depiction of a generic diaryliodonium salt  1.2.1  Preparation of diaryliodonium salts  Numerous procedures for the synthesis of diaryliodonium salts have appeared since the seminal report by Hartmann and Meyer.  A common synthetic strategy is the addition of an aryl group to an electrophilic iodine (III) species.13  Thus, an aryl iodide 1.9 is oxidized to an iodosoarene 1.10 (Scheme 1.3, eq 1), which subsequently combines under acidic conditions with a second arene, or an organoboron, -silicon, or -tin derivative thereof.  This yields diaryliodonium salt 1.11, in which ligand A is the conjugate base of the acid employed in the   Scheme 1.3  An overview of synthetic approaches to prepare diaryliodonium salt 1.12 7  reaction.  Compound 1.11 may not have the desired solubility and/or reactivity, in which case a ligand exchange is performed, leading to compound 1.12 that possess better physiochemical properties.  Because a number of aryliodine (III) reagents (e.g., iodosobenzene, Ph–I=O; (diacetoxyiodo)benzene, Ph–I(OAc)2, and Koser reagent, Ph–I(OH)OTs) are now commercially available, one can often bypass the initial oxidation step and use these as starting materials (Scheme 1.3, eq 2).  However, the ligand exchange step is still required to incorporate ligand X in the product.  Diaryliodonium triflates (X = OTf), have emerged as valuable reagents,13,14 which find use in various applications (vide infra), particularly on account of their greater solubility in relatively nonpolar organic solvents.  One method to access these substances involves the treatment of the corresponding tosylate with triflic acid (TfOH).  The highly Bronsted acidic TfOH readily protonates the tosylate ligand, converting it into tosic acid.  The triflate ion then replaces the tosylate ligand in the iodonium complex.  It should be noted that Kitamura and collaborators have devised a synthesis of diaryliodonium triflates that avoids the final ligand exchange.15  Thus, the coupling of an iodine (III) reagent with a second arene is carried out in the presence of triflic acid to produce diaryliodonium triflates 1.12 directly (X = OTf; Scheme 1.3, eq 3).  More recently, the groups of Kitamura16 and Olofsson17 have independently shown that it is possible to prepare diaryliodonium triflates through a single-flask procedure starting from a iodine (I) compounds (Scheme 1.4).  In their approach, the union of an aryl iodide with an arene in the presence of an oxidant (potassium persulfate16 or mCPBA17) and TfOH leads to an unsymmetrical diaryliodonium triflate 1.14 (eq 1).  When the reaction is carried out with an arene and I2, a symmetrical product (1.15) is obtained (eq 2).  Olofsson has since described numerous one-pot protocols for the preparation of various diaryliodonium salts.18 8   Scheme 1.4  One-pot synthesis of diaryliodonium salt from iodine (I) compound or I2  1.2.2  Synthetic applications of diaryliodonium salts  A major synthetic application of diaryliodonium salts is their use as aryl transfer agents.  Indeed, they behave as carriers of an aryl cation synthon, which may be easily transferred to heteroatomic- and carbon-nucleophiles (Scheme 1.5).  The reaction is thought to proceed by an initial ligand exchange with the incoming nucleophile,1,14 followed by a ligand coupling to afford the arylated product 1.16.  Arenes, silyl enol ethers, stabilized enolates (malonates, etc.) and non-stabilized one, are readily arylated in this manner.14   Scheme 1.5  Generic mechanism for the aryl transfer reaction to a nucleophile  9  A noteworthy example of the latter reaction is the asymmetric arylation of a cyclohexanone derivative by Aggarwal (Scheme 1.6).19  The α-arylation was carried out with the enolate derived from ketone 1.17, which then reacted with diaryliodonium reagent 1.17.  The arylated product 1.19 was obtained with good ee after recrystallization and used towards the synthesis of (−)-epibatidine.   Scheme 1.6  Asymmetric α-arylation reported by Aggarwal   Heteroatomic nucleophiles such as phenoxides, sulfinic acids, and fluoride ions are also readily arylated.  The arylation of fluoride is of significant interest, as it enables production of [18F]-radiolabelled aryl fluorides, which are important PET imaging agents.20  Short reaction times and ability to perform the radiofluorination at a late-stage of a synthesis are advantageous in the latter respect, given the relatively short half-life of 18F (ca. 110 min).21  1.3  The development of iodonium metathesis reaction 1.3.1  Inception of project  The iodine atom of an organoiodine compound exhibits moderately nucleophilic character.  For instance, it is readily oxidized to the iodoso state upon reaction with peroxyacids:  a reaction that involves nucleophilic attack on an electrophilic oxygen (Scheme 1.7).  Although 10  some related reactions may proceed through a SET mechanism,22 it is evident that the iodine atom is donating electrons to the electrophilic oxygen, hence demonstrating nucleophilic behavior.   Scheme 1.7  Simplified mechanism for the oxidation of aryl iodide by mCPBA   More significantly, Yamamoto has employed aryl iodides as nucleophilic catalysts in Mukaiyama-type aldol reactions (Scheme 1.8, eq 1).23  The aldol product 1.20 does not form in the absence of the aryl iodide, and yields diminish if the Lewis basicity of the latter is reduced through the introduction of electron withdrawing substituents on the aryl nucleus.  Furthermore, mass spectra (ESI+) of CH2Cl2 solutions containing (TMS)3SiNTf2 and iodobenzene showed a signal corresponding to a [(TMS)3Si + IPh + CH2Cl2]+ complex, indicating that iodobenzene is able to coordinate with the silylium cation.     Scheme 1.8  Yamamoto’s cascade aldol reaction catalyzed by triflimide and iodobenzene 11  Based on these data, the authors suggest that iodobenzene behaves as a Lewis base towards the tris(trimethylsilyl)silylium ion to form complex 1.21, which is thought to be the active catalyst for the cascade aldol reaction (Scheme 1.8, eq 2).    A logical question thus arises: is it possible to arylate an aryl iodide with a diaryliodonium salt to accomplish an iodonium metathesis reaction (Scheme 1.9)?   Scheme 1.9  I-Arylation of aryl iodides: the iodonium metathesis reaction   Such a question is not of mere academic interest.  The above method would greatly simplify the preparation of diaryliodonium salts.  A significant application in radiochemistry would be the synthesis of 5-18F uridine, an especially important radiochemical.  Thus, a hypothetical metathesis reaction of readily available 5-iodouridine triacetate (1.22) could afford 1.23, which upon reaction with [18F]-fluoride will produce 1.24 (Scheme 1.10). 20  In addition to  the short synthesis, this approach utilizes no-carrier-added (NCA) [18F]-fluoride to incorporate   Scheme 1.10  Preparation of 5-18F-uridine by a hypothetical iodonium metathesis reaction 12  the fluorine atom into 1.24.  This is a desireable feature to a radiosynthetic chemist as the product is obtained with high radiochemical yield.  At the onset of our work, the literature contained no examples of the exact process depicted in Scheme 1.9.  However, two important facts had been recorded.  First, Koser had demonstrated in 1980 that contact between an aryl iodide, Ar–I, and Ph–I(OH)OTs results in formation of an equilibrium mixture of starting compounds, Ar–I(OH)OTs, and Ph–I (Scheme 1.11).24   Scheme 1.11  Koser’s report on redox transfer reaction  In light of a mechanistic hypothesis first advanced by Moriarity,25 the reaction may involve reversible dissociation of the Koser reagent (1.25) to iodonium species 1.26, which reacts with Ar–I to form intermediate 1.27.  This is followed by a ligand transfer process to generate 1.28, which then combines with triflate anion to give complex 1.29.  This intermediate is believed to undergo reductive elimination to release a molecule of Ph–I and tosylate anion.  The resulting 13  species 1.30 subsequently recombines with tosylate anion to furnish the new iodonium compound 1.31.  Second, DiMagno and co-workers determined that fluoride ion promotes aryl ligand exchange between two diaryliodonium salts (Scheme 1.12, eq 1).26  The authors reported that treatment of 1.32 with tetramethylammonium fluoride (TMAF), followed by addition of TMSOTf to sequester remaining fluoride ions, resulted in formation of 1.33 and 1.34.  These products were detected by mass spectral analysis of crude reactions mixtures, whereupon three peaks, corresponding to 1.32, 1.33 and 1.34, were observed.  Only one peak was seen for the starting material in the mass spectrum, which the authors concluded that the ligand exchange process occurred only in the presence of fluoride ions.  Similar to DiMagno’s findings, Olofsson has also observed the phenomenon of aryl exchange between two diaryliodonium compounds in the presence of basic nucleophiles.27   Scheme 1.12  Aryl exchange observed by DiMagno   Whereas the above observations provide some support for the feasibility of the desired transformation, an important report by Olofsson and collaborators cast serious doubts on it.  Thus, these researchers detected no evidence of aryl ligand exchange upon heating a DMF solution of 2,6-dimethyl-iodobenzene and bis(p-tolyl)iodonium triflate.27  14  1.3.2  Iodonium metathesis28  Initial attempts to induce an iodonium metathesis reaction centered on the thermal activation of a DCE solution of diphenyliodonium triflate (1.34) and excess p-iodotoluene.  No reaction occurred at temperatures below reflux.  However, heating to reflux did cause formation of products 1.35 and 1.36 (Table 1.1).29  The reaction seemed to require an induction period of about 3 h, during which no change was apparent (entry a).  Conversely, the presence of diarylodonium species 1.35 and 1.36 was observed by mass spectroscopy (ESI+) and 1H NMR after refluxing overnight (entry b), albeit the products were obtained in low yield (15 %).  When the reaction was conducted at a lower temperature, no reaction was observed (entry c).   Table 1.1  Screening of conditions for diaryliodonium metathesis reaction  15  Solution-phase reactions run on small scales occasionally dried out during prolonged refluxing in an ordinary round bottom flask fitted with a condenser.  The solid residue recovered from one such reaction contained a significantly higher proportion of metathesis products relative to a reaction that did not go to dryness; however, the results were often difficult to reproduce.  In aim to develop a reproduceable protocol by avoiding loss of solvent, the metathesis reaction was carried out in a sealed pressure tube (entry d).  This resulted in high conversion (98 %) of starting materials and moderate yields (50 %) of metathesis products obtained in reasonable reaction time (48 h).  Importantly, this provided results that was readily reproduceable.  Solvent-free, melt conditions were also investigated by melting a mixture of Ph2IOTf and p-iodotoluene in a sealed tube or in a microwave vial (Table 1.1, entry e).  In either case, metathesis did occur, albeit only a moderate conversion (69 %) is attained through prolonged (60 h) reaction time.  Decomposition of the aryl iodide was also observed under the melt condition.  It was therefore determine that the modus opernadi for the iodonium metathesis is to heat the reagents in DCE, utilizing a sealed pressure tube as the reaction vessel (entry d).  Only diaryliodonium triflates underwent metathesis; the corresponding tetrafluoroborates, as well as dithienyliodonium tosylates and hexafluorophosphates, did not.30  The choice of solvent was also crucial.  Among the various solvents that were tested (DCE, DMSO, DMF, MeCN, chlorobenzene, 1,2-dichlorobenzene, THF, acetone, CH2Cl2, CHCl3) only DCE proved effective.  Either no reaction or decomposition of the starting diphenyliodonium triflate was observed in other solvents.  These observations bear on the probable mechanism of the reaction, which will be discussed later.  The metathesis of iodonium salt 1.34 with various aryl iodides was then investigated (Table 1.2)29 under the conditions developed in Table 1.1 (entry d).  Both p-iodoanisole and 1-16  iodonaphathlene were viable substrates for the metathesis reaction with little to no starting iodonium left (entries a, b).  The low yield obtained for the reaction with 1-iodonaphthalene may result from the decomposition of a sterically encumbered bis-substituted product 1.38b (entry b).  It has been reported that an ortho-substituted aryl ligand in a diaryliodonium salt is transferred more readily than an unsubstituted one to external nucleophiles.31  This phenomenon is attributed to the release of steric congestion imposed by the ortho-substituted aryl ligand upon the hypervalent iodine complex.  A similar reasoning could be used to explain the propensity of di(1-naphthyl)iodonium triflate to undergo decomposition.  Furthermore, it is consistent with the fact that the bis-substituted product 1.38b is obtained as the minor component, where as in other cases, the bis-substituted product 1.36 was the major one (cf. Table 1.1, entries d, e).   Table 1.2  Survey of aryl iodide for the diaryliodonium metathesis reaction  17   Excessively electron-rich aryl iodides, such as iodoveratrole (Table 1.2, entry c) and p-iodo-dimethylaniline (entry d) were poor substrates for the reaction.  A mixture of these iodides with Ph2IOTf in DCE caused the rapid appearance of a green color, which slowly became darker and in some cases, turned to brown and then black.  Intractable mixtures of products were thus obtained.  It seems likely that this was due to the occurrence of SET processes that undermine the metathesis pathway.  No reaction occurred at all between Ph2IOTf and methyl p-iodobenzoate (entry e).  In this case, we presume that the electron-withdrawing carbonyl substituent reduces the nucleophilic character of the I atom to such an extent that metathesis is no longer possible.  This appears to be consistent with Yamamoto's observations where the yields for the desired product diminished when an electron-withdrawing group is introduced on the aryl iodide.22  Thus, only moderately electron-rich aryl iodides undergo metathesis with Ph2IOTf.  Turning now to the electronic characteristics of the diaryliodonium triflate, we determined that electron-donating substituents of the aryl groups of the latter retard the rate of the metathesis reaction.  An extreme case was bis(p-anisyl)iodonium triflate (1.33).  Reaction with p-iodotoluene at 120 °C proceeded to only 46 % conversion after 16 h to afford a 2.0 : 1.3 : 1.0 (1H NMR) mixture of 1.33, 1.39, and 1.36 (Scheme 1.13).  This observation also is relevant to the probable mechanism of the process (vide infra).   Scheme 1.13  Metathesis reaction of bis(p-anisyl)iodonium triflate (1.33) with p-iodotoluene  18   In contrast with the foregoing, fast rates, high conversions, and good yields of metathesis products were obtained with diaryliodonium triflates in which one aryl group bears electron-withdrawing substituents (Table 1.3).  Thus, the effect of using an "electron deficient" iodonium salt 1.40a (entries a-d) and and "donor-acceptor" iodonium salt 1.40b (entries e-h) were investigated.  Remarkably, metathesis reactions of these species occurred with very selective transfer of the more electron-rich aryl ligand.  In most cases, no products arising from the transfer of the electron deficient aryl group were detected by MS (ESI+) and 1H NMR.  Only in   Table 1.3  Iodonium metathesis reaction using 1.40a and 1.40b 19  one case did the aryl transfer occur on to the electron deficient group (entry h).  Curiously, a minute amount of iodonium species 1.33 was observed in two instances (entries e, h).  We presume that this material arises through the aryl exchange process described by DiMagno.26  The selective transfer of electron rich ligands was unexpected, as previous reports on aryl transfer reaction from diaryliodonium salts to nucleophiles was found to proceed with migration of the electron deficient ligand.  A rationale for this phenomenon was first suggested by Beringer32 and later elaborated by Ochiai,33 according to whom, the stabilization of the partial negative charge during the reductive elimination step in 1.43 favors the transfer of the aryl ligand that bears the electron withdrawing group (Scheme 1.14, path a).34  The accumulating charge on the aromatic ligand is less stabilized in the case of 1.44, in which the reductive elimination proceeds with the electron deficient aryl group at the axial position (path b).  As the opposite selectivity is observed for the metathesis reaction in question, a different mechanism must operate.   Scheme 1.14  Origin of selective aryl transfer for Beringer-Ochiai mechanism 20   To complicate matters, we confirmed the observation, originally made by our coworker A. Jang,28 that iodonium triflate 1.45 selectively transfers the p-(carbomethoxy)phenyl group to iodobenzene and p-iodotoluene (Scheme 1.15), as if the reaction were taking place through a Beringer-Ochiai mechanism.  Thus, the formation of iodonium species 1.47 could be detected in 1H NMR and MS, while compound 1.48 was never observed.  It seems unlikely that only 1.45 reacted through a Beringer-Ochiai type mechanism to transfer the electron deficient ligand, while 1.34, 1.40a, and 1.40b did not.  A better mechanistic understanding of the reaction was clearly necessary.   Scheme 1.15  Iodonium metathesis reaction of 1.45   On the basis of the mechanism proposed by Beringer and Ochiai, and the evidence accumulated during the present study, we propose the following general mechanism for the iodonium metathesis reaction (Scheme 1.16).  In a moderately polar solvent such as DCE ( = 10.4),35 the starting diarylidonium triflate 1.49 reversibly dissociates to form diaryliodonium ion 1.50.  An external aryl iodide then intercepts 1.50 to give complex 1.51.  The latter undergoes reductive elimination of an iodoarene 1.53 with concomitant ligand coupling (cf. 1.52), leading to a new iodonium species 1.54.  Recombination of the latter with triflate anion yields the ultimate product 1.55. 21    Scheme 1.16  Proposed mechanism of the iodonium metathesis reaction   The mechanism depicted in Scheme 1.16 accounts the fact that the metathesis reaction occurs only with triflate salts.  The exceptional nucleofugal properties of triflate ion36 enable dissociation more readily than chloride, tosylate, etc., while retarding decomposition of the diaryiodonium salt into an aryl chloride (tosylate, etc.) and an aryl iodide.  Solution-phase metathesis reactions of the type detailed above occur only in DCE.37  The solvent must be sufficiently high-boiling to favor the dissociation of 1.49 (Scheme 1.16), yet poorly Lewis basic, so as not to interact with 1.50 too strongly.  Given the weak nucleophilic character of an aryl iodide, it seems likely that donor solvents such as DMSO, DMF, MeCN, THF, etc., will outcompete aryl iodides in the reaction with 1.50, impeding the formation of 1.51 and promoting decomposition of the diaryliodonium salt.  The observation that the metathesis reactions are slow with electron-rich diaryliodonium triflates and fast with electron-deficient ones could be explained as follows.  Electron-donating substituents diminish the electrophilic reactivity of the iodine atom in iodonium ion 1.50, hampering the addition of weakly nucleophilic Ar3–I thereto 22  and retarding the overall reaction rate.  Electron-withdrawing substituents operate in the opposite direction.  A rationale for the aryl transfer selectivity requires a refinement of the above proposal.  Considering that one of the aryl groups in 1.51 is expelled as an aryl iodide through a formal reductive elimination, it seems plausible that the departing aryl iodide 1.53 will be the one with the greater extent of positive character on the I atom and be more electrophilic.  The charge on the I atom of various organoiodine compounds was estimated by semi-empirical methods.38  The final values for each molecule represent the geometric average of the charge calculated using four different methods (MNDO, MNDO/d, AM1, PM3).28  As shown in Figure 1.6, an excellent correlation is seen between the partial positive charge on the iodine atom of an aryl iodide and its ability to function as the departing Ar2–I (1.53) in the metathesis reaction (Scheme 1.16).  Furthermore, the latter tends to occur so that a more electron-rich aryl iodide displaces a more electron-deficient one.  In cases where incoming and departing aryl iodide exhibit a comparable positive charge, incomplete reactions are observed.   Figure 1.6  Calculated values of partial positive charge residing on the iodine atom  23   On the basis of the foregoing mechanistic hypothesis, one may anticipate that a species incorporating a heteroatom, X, that is more nucleophilic than the I atom of an aryl iodide should undergo X-arylation even more readily upon reaction with diaryiodonium triflates (Scheme 1.17).  This surmise was tested by studying the reaction of diphenyl sulfide and diphenyl ether with compound 1.34 under the conditions developed earlier for the iodonium metathesis process.  While Ph2O failed to react, Ph2S was rapidly and quantitatively converted into the known Ph3SOTf (1.60),39 arguably through the mechanism outlined in Scheme 1.17.  Further development of this chemistry was assigned to our coworker, L. Racicot, who demonstrated that aryl transfer is possible to selenium and tellurium as well.39   Scheme 1.17  Mechanism of sulfonium metathesis reaction  1.4  Conclusion  In this section, we have demonstrated that metathesis between a diaryliodonium triflate and an aryl iodide has is indeed possible.  The reaction occurs under thermal conditions without the need for any transition metal catalysts, and it is applicable to a variety of diaryliodonium 24  triflates.  Best results are realized when moderately electron rich aryl iodides interact with diaryliodonium triflates that incorporates an aryl ligand that can depart as an aryl iodide with a calculated partial I-positive charge greater than about 0.09 e.  As this project is still in its infancy, further investigations are currently in progress to expand the scope of reaction and clarify several aspects thereof.  Analogous reactions of diaryl sulfides occur even more efficiently, and have recently been extended to diaryl selenides and tellurides.39  1.5  Experimental General.  Unless otherwise indicated, all reactions were performed with oven-dried glassware under Ar atmosphere.  All commercially available chemicals were used as received.  Thin layer chromatography was performed on EMD Silica gel 60 F254 plates.  TLC plates were visualized by exposing to UV light (254 nm). Instrumentation.  1H (300 MHz) and 13C (75 MHz) spectra were recorded with Bruker AVANCE II+ at room temperature in acetone-d6.  Chemical shifts (δ scale) are reported in ppm and referenced to the residual solvent (δH 2.05 ppm and δC 29.84 ppm).  Coupling constants, J, are reported in Hz.  Multiplicities are described as s (singlet), d / dd / ddd (doublet / doublet of doublets / doublet of doublet of doublets), t (triplet), m (multiplet), and further qualified as app (apparent).      25  Metathesis of iodonium salt 1.33 and p-iodotoluene   A 15 mL heavy walled pressure tube equipped with a screw-cap seal was charged with the p-iodotoluene (109 mg, 0.5 mmol) and bis(p-methoxyphenyl)iodonium triflate (49 mg, 0.1 mmol) in 1,2-dichloroethane (0.5 mL, 0.2 M in iodonium triflate).  The tube was sealed with a screw cap and immersed in an oil bath maintained at 120 C.  Heating was continued for 16 h, then the mixture was cooled to rt and concentrated under reduced pressure.  1H NMR of the crude indicated the presence of 1.33, 1.39, and 1.36 in an approximate ratio of 2.0 : 1.3 : 1.0, respectively.  This corresponds to a 46 % conversion.  General procedure for solution phase iodonium metathesis reactions:  A 15 mL heavy walled pressure tube equipped with a screw-cap seal was charged with the aryl iodide (0.5 mmol) and iodonium triflate (0.1 mmol) in 1,2-dichloroethane (0.5 mL, 0.2 M in iodonium triflate).  The tube was sealed with a Teflon® screw cap and immersed in an oil bath maintained at 125 C.  Heating was continued for the specified time, then the mixture was cooled to rt and concentrated under reduced pressure.  The crude product was purified by silica gel flash chromatography (gradient 10% → 40% acetone/CH2Cl2).  The theoretical yield is based on the weighted average of the compounds present in the purified material, which the reaction was yield was calculated from.  26  Metathesis of iodonium salt 1.40a and iodobenzene (Table 1.3, entry a)  Iodobenzene (56 μL, 0.5 mmol) and p-nitrophenylphenyliodonium triflate (48 mg, 0.1 mmol) werer combined and stirred for 12 h to afford mixture of products (28 mg, 65%) after purification.  1H: p-nitrophenyl-phenyliodonium triflate (A): 8.61 (app d, J = 9.1 Hz, 2H), 8.38-8.33 (m, 4H), 7.82-7.72 (m, 1 H), 7.67-7.57 (m, 2H).  diphenyliodonium triflate (B): 8.34 (app dd, J = 8.3, 1.1 Hz, 4H), 7.75 (tt, J = 7.4, 1.0 Hz, 2H), 7.59 (app t, J = 7.9 Hz, 4H).  13C: 137.8, 136.9, 136.1, 133.8, 133.3, 133.2, 128.5, 127.2, 124.2, 119.9, 115.9, 115.3.  Metathesis of iodonium salt 1.40a and p-iodotoluene (Table 1.3, entry b)  p-Iodotoluene (109 mg, 0.5 mmol) and p-nitrophenylphenyliodonium triflate (48 mg, 0.1 mmol) were combined and stirred for 12 h to afford mixture of products (33 mg, 73%) after purification.  1H: phenyl-p-tolyliodonium triflate (B): 8.34-8.27 (m, 2H), 8.24-8.18 (m, 2H), 7.73 (tt, J = 7.5, 1.0 Hz, 1H), 7.58 (app t, J = 7.9 Hz, 2H), 7.43-7.37 (m, 2H), 2.40 (s, 3H).  bis-(p-tolyl)iodonium triflate (C): 8.18 (app d, J = 8.5 Hz, 4H), 7.39 (app d, J = 8.3 Hz, 4H), 2.40 (s, 6H).  13C: 144.6, 144.5, 136.5, 136.32, 136.29, 133.7, 133.6, 133.4, 133.0, 124.2, 112.0, 115.4, 111.7, 111.5, 21.6.  27  Metathesis of iodonium salt 1.40a and iodobenzene (Table 1.3, entry c)  p-Iodoanisole (117 mg) and p-nitrophenyl-phenyliodonium triflate (48 mg, 0.1 mmol) were combined and stirred for 12 h to afford mixture of products (36 mg, 76%) after purification.  1H: p-anisyl-phenyliodonium triflate (B): 8.31-8.23 (m, 4 H), 7.72 (tt, J = 7.4, 1.1 Hz, 1H), 7.76 (app t, J = 7.9 Hz, 2H), 7.12 (app d, J = 9.2 Hz, 2H), 3.88 (s, 3H).  bis-(p-anisyl)iodonium triflate (C): 8.22 (app d, J = 9.2 Hz, 4H), 7.09 (app d, J = 9.2 Hz, 4H), 3.87 (s, 6H).  13C: 164.0, 163.8, 138.7, 138.2, 136.0, 133.3, 132.9, 124.2, 112.0, 118.7, 118.6, 115.8, 104.3, 103.5, 56.3.  Metathesis of iodonium salt 1.40a and 1-iodonaphthalene (Table 1.3, entry d)  1-Iodonaphthalene (73 μL, 0.5 mmol) and p-nitrophenyl-phenyliodonium triflate (48 mg, 0.1 mmol) were combined and stirred for 12 h to afford mixture of products (29 mg, 59%) after purification.  1H: 1-naphthyl-phenyliodonium triflate (B): 8.88 (dd, J = 7.5 Hz, 1.0 Hz, 1H), 8.40-8.30 (m, 4H), 8.08 (app dd, J = 8.2, 1.1 Hz, 1H), 7.84 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.78-7.57 (m, 3H), 7.51 (app t, J = 7.8 Hz, 2H).  bis-(1-naphthyl)iodonium triflate (C): 8.94 (dd, J = 7.6, 1.0 Hz, 2H), 8.52 (app dd, J = 8.5, 0.6 Hz, 2H), 8.25 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 28  2H), 7.84 (ddd, J = 8.3, 7.0, 1.3 Hz, 2H), 7.75-7.58 (m, 4H).  13C: 139.3, 139.0, 137.2, 136.5, 136.0, 135.9, 135.3, 135.0, 133.5, 133.3, 133.0, 132.9, 132.4, 131.0, 130.9, 130.6, 130.5, 129.6, 129.5, 129.1, 129.0, 128.6, 128.5, 124.3, 120.0, 118.0, 115.04, 115.00.  Metathesis of iodonium salt 1.40b and iodobenzene (Table 1.3, entry e)  Iodobenzene (56 µL, 0.5 mmol) and p-anisyl-p-nitrophenyliodonium triflate (50 mg, 0.1 mmol) were combined and stirred for 12 h to afford a mixture of prdocuts (27 mg, 60 %) after purification.  1H: p-anisyl-phenyliodonium triflate (A): 8.29 (app dd, J = 8.4, 1.0 Hz, 2 H), 8.27 (app d, J = 9.2 Hz, 2 H), 7.72 (tt, J = 7.1, 1.2 Hz, 1 H), 7.58 (app t, J = 7.4 Hz, 2 H), 7.12 (app d, J = 9.3 Hz, 2 H), 3.88 (s, 3 H).  diphenyliodonium triflate (C): 8.34 (app dd, J = 8.5, 1.0 Hz, 4 H), 7.75 (tt, J = 7.3, 1.1 Hz, 2 H), 7.60 (app t, J = 7.8 Hz, 4 H).  13C: 164.0, 139.2, 138.7, 138.2, 137.2, 136.5, 136.0, 133.5, 133.3, 133.0, 132.9, 128.5, 127.1, 124.2, 120.0, 118.9, 118.7, 118.6, 115.9, 115.3, 104.3, 103.5, 56.3.  Metathesis of iodonium salt 1.40b and p-iodotoluene (Table 1.3, entry f)  29  p-Iodotoluene (109 mg, 0.5 mmol) and p-anisyl-p-nitrophenyliodonium triflate (50 mg, 0.1 mmol) were combined and stirred for 12 h to afford mixture of products (37 mg, 79 %) after purification.  1H: p-anisyl-p-tolyliodonium triflate (B): 8.24(app d, J = 9.2 Hz, 2 H), 8.16 (app d, J = 8.5 Hz, 2 H), 7.38 (app d, J = 8.7 Hz, 2 H), 7.11 (app d, J = 9.2 Hz, 2 H), 3.87 (s, 3 H).  bis-(p-tolyl)iodonium triflate (C): 8.18 (app d, J = 8.4 Hz, 4 H), 7.39 (app d, J = 8.6 Hz, 4 H), 3.87 (s, 6 H).  13C: 163.9, 144.5, 144.4, 138.5, 138.2, 136.3, 136.0, 133.64, 133.57, 124.2, 120.0, 118.64, 118.56, 112.2, 111.8, 103.8, 56.3, 21.3.  Metathesis of iodonium salt 1.40b and p-iodoanisole (Table 1.3, entry g)  p-Iodoanisole (117 mg, 0.5 mmol) and p-anisyl-p-nitrophenyliodonium triflate (50 mg, 0.1 mmol) were combined and stirred for 12h to afford mixture of products (33 mg, 89%) after purification.  When the experiment was repeated by Racicot, L., the reaction returned a mixture of products (44 mg, 89%) after purification.  1H: p-anisyl-p-nitrophenyliodonium triflate (A): 8.55 (app d, J = 9.2 Hz, 2 H), 8.33 (app dd, J = 9.2, 1.5 Hz, 4 H), 7.17-7.08 (m, 2 H), 3.88 (s, 3 H).  bis-(p-anisyl)iodonium triflate (B): 8.22 (app d, J = 9.2 Hz, 4 H), 7.09 (app d, J = 9.2 Hz, 4 H), 3.86 (s, 6 H).  13C: 164.2, 163.8, 150.9, 139.1, 138.61, 138.58, 137.83, 137.79, 137.2, 130.3, 128.4, 127.1, 124.2, 121.8, 119.9, 119.0, 118.9, 118.13, 118.07, 115.7, 104.0, 56.3, 55.5.   30  Metathesis of iodonium salt 1.40b and 1-iodonaphthalene (Table 1.3, entry h)  1-Iodonaphthalene (73 µL, 0.5 mmol) and p-anisyl-p-nitrophenyliodonium triflate (50 mg, 0.1 mmol) were combined and stirred for 12 h to afford mixture of products (29 mg, 64%) after purification.  1H: p-anisyl-p-nitrophenyliodonium triflate (A): 8.54 (app d, J = 9.1 Hz, 2 H), 8.39-8.33 (m, 4 H), 7.14 (app d, J = 9.2 Hz, 2 H), 3.88 (s, 3 H).  p-anisyl-1-naphthyliodonium triflate (B): 8.84 (dd, J = 7.5, 0.9 Hz, 1 H), 8.39 (app dd, J = 8.5, 0.7 Hz, 1 H), 8.32 (app d, J = 8.0 Hz, 1 H), 8.28 (app d, J = 9.2 Hz, 2 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.85 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.73 (ddd, J = 8.1, 7.0, 1.0 Hz, 1 H), 7.66 (app t, J = 7.9, 1 H), 7.02 (app d, J = 9.2 Hz, 2 H), 3.79 (s, 3 H).  bis-(1-naphthyl)iodonium triflate (C): 8.94 (dd, J = 7.6, 1.0 Hz, 2 H), 8.52 (app d, J = 8.3 Hz, 2 H), 8.31-8.26 (m, 2 H), 8.01 (d, J = 8.3 Hz, 2 H), 7.85 (ddd, J = 8.3, 7.0, 1.3 Hz, 2 H), 7.76-7.59 (m, 4 H).  bis-(p-anisyl)iodonium triflate (D): 8.22 (app d, J = 9.3 Hz, 4 H), 7.09 (app d, J = 9.2 Hz, 4 H), 3.86 (s, 6 H).  1-naphthyl-p-nitrophenyliodonium triflate (E): 8.94 (dd, J = 7.5, 1.0 Hz, 1 H), 8.58 (app d, J = 9.2 Hz, 2 H), 8.42-8.25 (m, 4 H), 8.12-8.07 (m, 1 H), 7.89-7.63 (m, 3 H).  13C: 164.2, 163.8, 150.9, 139.8, 139.1, 139.0, 138.8, 137.2, 136.0, 135.9, 135.8, 135.6, 135.04, 135.01, 132.4, 132.2, 131.2, 130.9, 130.6, 130.54, 130.50, 129.6, 129.5, 129.2, 129.05, 129.02, 128.7, 128.51, 128.47, 127.14, 127.12, 124.2, 121.8, 120.0, 118.9, 118.7, 118.0, 115.8, 104.3, 103.9, 103.4, 56.3, 56.2.  31  Chapter 2 Synthetic Studies Towards Himandrine  2.1  Introduction  This chapter will discuss an application of the oxidative amidation of phenols mediated by iodine (III) reagents, specifically, (diacetoxyiodo)benzene (DIB), in the context of a synthetic approach to himandrine, 2.1.  A brief overview on the chemistry of oxidative amidation and himandrine will be given, followed by a summary of synthetic work performed by other research groups.  Finally, our effort towards himandrine will be discussed.   Figure 2.1  Structure of the alkaloid, himandrine  2.1.1  The oxidative amidation of phenols  Phenols typically exhibit nucleophilic reactivity, due to their electron rich nature.  However, oxidative activation of a phenol with a hypervalent iodine (III) reagent such as DIB, can induce the expression of electrophilic character; i.e., bring about the umpolung40 of the phenol.  While the mechanistic details of the process may vary depending on reaction conditions,41 a simplified representation is outlined in Scheme 2.1.  First, ligand exchange occurs between the iodine (III) reagent and substituted phenol 2.2 to give intermediate 2.3, which then undergoes reductive α-elimination to generate a resonance stabilized phenoxonium species, 2.4.  32  This will then react with a nucleophile to give either an ortho- or para-substituted dienone product, 2.5 and 2.6, respectively.  The overall transformation is described as the oxidative dearomatization of phenols.   Scheme 2.1  Overview of intermolecular oxidative dearomatization process   If the nucleophile is tethered to the phenol (2.7 or 2.9), nucleophilic capture of the phenoxonium intermediate will from a new ring to give a spirocyclic dienone (Scheme 2.2).  Thus, the intramolecular variant of the reaction will afford compounds 2.8 or 2.10 from ortho- or para-substituted phenols, respectively.  Scheme 2.2  Intramolecular oxidative dearomatization of a phenol 33   Carbon-42 and oxygen-centered43 nucleophiles have been widely employed in phenolic oxidative dearomatization during the past decades.  By contrast, no examples of this chemistry with nitrogen-based nucleophiles were known prior to 1998, when our group disclosed the use of oxazolines for oxidative dearomatization.44  This is because nitrogen atoms, generally being more nucleophilic than phenols, severely interfere with oxidative activation of the aromatic nucleus, resulting in polymerization and/or decomposition of the substrate.  By moderating the nucleophilic character of the nitrogen atom, our group first demonstrated the feasibility of the foregoing transformation. 45  Other researchers soon followed suit. 46  The reaction in question is best carried out in such a manner that the nitrogen nucleophile always emerges in the form of an amide: either a carboxamide, a sulfonamide, or a phosphoramide.  Accordingly, the process was christened the oxidative amidation of phenols.  The technique has enabled efficient syntheses of diverse nitrogenous natural products.47  Various modes of oxidative amidation have been developed in order to assemble key structural motifs    Scheme 2.3  Typical oxidative amidation reactions in the intramolecular (eq 1-3) and bimolecular (eq 4) regime  34  present in our synthetic targets (Scheme 2.3).  Intramolecular oxidative amidation (IMOA) reactions commonly employ oxazolines (eq 1),48 sulfonamides49 or phosphoramides (eq 2),50 as well as N-acylsulfonamides (eq 3)51 as nitrogen nucleophiles.  Intermolecular variants rely on capture of the phenoxonium intermediate with acetonitrile, which is used as the reaction solvent, followed by in situ hydrolysis to give the product (eq 4).52  2.1.2  Desymmetrization of dienones obtained though oxidative amidation  The spirocyclic dienone moiety generated through an oxidative amidation process is symmetrical, and the newly formed spiro-carbon bearing a chiral center is thus chirotopic and non-stereogenic.53  Modification of one of the double bonds, e.g., by conjugate addition of a nucleophile, desymmetrizes dienone 2.10 and renders the spiro-carbon stereogenic.54  In principle, four products could form if this transformation occurred without any stereocontrol: addition from the - or - faces of the pro-(R) double bond produces stereoisomers 2.11 and 2.12, while 2.13 and 2.14 emerge from a facially indiscriminate addition to the pro-(S) double    Scheme 2.4  Stereochemical aspects of dienone modification: 2.11 / 2.12 and 2.13 / 2.14 have opposite configurations at the spiro-carbon 35  bond (Scheme 2.4).  If one could control at least the regioselectivity of the addition process, then a spiro-center of well-defined configuration would result.  In such a case, one would achieve the enantiocontrolled creation of a tetra-substituted, nitrogen-bearing, carbon center.  The enantioselective assembly of such centers, wherein a nitrogen atom is bound to a tertiary carbon, remains an interesting challenge for which few options are available.55  This stands in sharp contrast to the impressive array of techniques for the asymmetric construction of amines exhibiting the N-atom bound to a secondary carbon.56  A major driving force for the development of oxidative amidation chemistry in our laboratories was the anticipation that suitable methods would be found to enable the stereocontrolled desymmetrization of the product dienones.  In that regard, it appeared that facial selectivity could be controlled by means of intramolecular addition processes, while the more complex issues of regioselectivity seemed addressable on the basis of conformational factors.   The foregoing expectations were fully realized.  For instance, compound 2.16, which is the product obtained through the oxidative amidation of 2.15, was found to cyclize spontaneously to a single diastereomer of 2.17 (Scheme 2.5).57  The intramolecular nature of the reaction allows cyclization only from the -face of the dienone, while the well-documented conformational properties of the emerging N-acylmorpholine moiety58 direct the nucleophile towards the pro-(R) dienone double bond.  We note that cyclization through transition state 2.18, leading to the observed 2.17, minimizes an extremely unfavorable A1,3-interaction between the benzyl group (which strongly favors the axial orientation in such systems) and the amide carbonyl that is present in 2.19.  Thus, the chirality of the nitrogen-bearing carbon in 2.15 orchestrated a completely diastereoselective desymmetrization of the dienone.  A recently detailed synthesis of (+)-erysotramidine relies on this principle.59 36   Scheme 2.5  Diastereoselective desymmetrization of 2.16 by conjugate addition   A different mode of dienone desymmetrization was demonstrated in connection with the synthesis of (–)-cylindricine C.60  Thus, oxidative cyclization of D-homotyrosinol derivative 2.20, followed by protection of the alcohol, afforded 2.21 (Scheme 2.6).  Deprotonation of the methanesulfonamide generated an anion that can add to the dienone in a 1,4-sense.  To do so, the anion must adopt conformation syn-2.22 or anti-2.22.  One may readily appreciate that syn-2.22 suffers from an unfavorable steric interaction between the sulfonyl and the CH2OTBDPS groups.  Such an interaction is absent in anti-2.22.  Thus, cyclization occurs preferentially through the anti-2.22 conformer to give tricycle 2.23 as the major diastereomer (7 : 1).  Furthermore, the steric demand of the O-protecting group influences the level of selectivity observed in the reaction, progressively better selectivity being observed with increasing steric bulk.61  37   Scheme 2.6  Diastereoselective desymmetrization of dienone 2.21   A variation on the foregoing theme was detailed in connection with the synthesis of presumed lepadiformine.50  For this purpose, L-homotyrosinol derivative 2.24 was first converted to 2.25 via intramolecular oxidative amidation (Scheme 2.7).  The dianion obtained by deprotonation of dienone 2.25 cyclized in a more highly diastereoselective manner (dr = 14 : 1), probably on account of its existence as chelated complex 2.26, wherein the sulfonamide anion is oriented towards the pro-(R) double bond.  Without isolation, the resulting alcohol 2.27 was protected to give the tricyclic compound 2.28 as the major diastereomer.  38   Scheme 2.7  Chelation controlled desymmetrization of dienone 2.25   The logic developed above suggests that the desymmetrization of dienones obtained through oxidative amidation could also be achieved through pericyclic reactions.  To illustrate, preliminary studies towards tetrodotoxin explored a tandem bimolecular oxidative amidation/1,3-dipolar cycloaddition reaction of phenolic oxime 2.29 (Scheme 2.8).62  Exposure of the latter to excess DIB in MeCN caused rapid formation of dienone 2.30.  More slowly, the oxime was oxidized in situ to nitrile oxide 2.31, which underwent intramolecular 1,3-dipolar cycloaddition (1,3-DC) to furnish 2.32 as a diastereomerically pure product, albeit in low yield.  A rationale for the stereochemical outcome of this reaction is as follows.  Whereas the nitrile oxide can add to either of the olefins, greater steric compression will develop if the reaction proceeds through transition state 2.33, as the R group is forced inside the concavity of the emerging tricyclic system.  This unfavorable interaction is absent if cyclization occurred through conformer 2.34, 39  where the R group is oriented outwards.  Consequently, cyclization occurred exclusively through the latter pathway to generate 2.32 as the sole detectable product.   Scheme 2.8  Tandem oxidative amidation-intramolecular nitrile oxide cycloaddition process    With an eye towards a specific synthetic problem (see next section), a question arose at this juncture: can one achieve dienone desymmetrization through an intramolecular Diels-Alder reaction?  The strategic power of the latter transformation63 promised to bring a completely new range of interesting synthetic targets within the scope of oxidative amidation chemistry, a case in point being the structurally unique alkaloid, himandrine, 2.1.  2.1.3  Isolation and biological properties of (−)-himandrine  In 1965, Ritchie and Taylor reported the isolation of numerous alkaloids from the bark of Galbulimima belgraveana, a rainforest tree native to Papua New Guinea and northern 40  Australia.64  To date, 30 alkaloids have been identified from the tree and these compounds are collectively known as the galbulimima alkaloids (GB alkaloids).  One of the compounds, himandrine (2.1), has a fascinating molecular architecture, the absolute configuration of which was determined by X-ray structure analysis.65  As shown in Figure 2.2, the compound consists of a hexacyclic framework containing a trans-decalin system that is attached to a highly substituted spirocyclic pyrrolidine ring.   Figure 2.2  Structures of (−)-himandrine depicted in different perspective   Biological studies on some of the GB alkaloids have been reported.  For example, it was shown that (+)-himbacine (2.35) is an antagonist of the muscarinic receptor, and used as a candidate to develop structural analogues that is effective towards Alzheimer disease.66  The ent-derivatives (2.36) have showed promising results for the development of antiplatelet agents (Figure 2.3).67  In constrast, himandrine is seemingly devoid of any beneficial pharmacological activity,68 and it is no longer the subject of further biological investigations.  41   Figure 2.3  Structures of (+)-himbacine and ent-himbacine derivatives  2.1.4  Biosynthesis of himandrine  The GB alkaloids are believed to derive from linear polyketide 2.37, which has been hypothesized to be assembled from one pyruvate and nine acetate units.69  Baldwin postulated the biosynthetic pathway detailed in Scheme 2.9.70  Condensation of polyketide derivative 2.37 with NH3 leads to cyclic iminium ion 2.38, which then cyclizes to form the trans-decalin intermediate 2.39.  A vinylogous Mannich reaction then advances 2.39 to cyclopentanone 2.40, which undergoes double bond isomerization to form 2.41.  Aza-Michael reaction of the latter establishes the pyrrolidine ring and leads to seco-intermediate 2.42.  The enamine of 2.42 now adds in a 1,2-fashion to the ketone carbonyl and reduction of the intervening iminium species forms hexacyclic compound 2.43.  The final (−)-himandrine (2.1) emerges after appropriate modifications of the oxygen functionalities.  42   Scheme 2.9  Proposed biosynthesis for (−)-himandrine  2.2   Synthetic efforts towards himandrine  Pioneering synthetic studies towards the GB alkaloids, emanating from the laboratories of L. N. Mander,71 culminated with an important paper detailing the assembly of the complete carbon framework of himandrine.72  However, the first total synthesis of the natural product was achieved in 2009 by Movassaghi and his group.73  Key aspects of these noteworthy accomplishments are discussed in the following section.   43  2.2.1  Mander’s approach to the framework of himandrine  In 2004, Mander disclosed the synthesis of compound 2.44, which exhibits the hexacyclic framework present in himandrine.73  The retrosynthetic logic explored by these authors (Scheme 2.10) envisioned a late stage construction of pyrrolidine and piperidine rings via SN2 and reductive amination reactions, respectively.   Scheme 2.10  Mander’s retrosynthetic analysis of compound 2.44   44  The carbonyl substrate, ketone 2.45, for the latter step would be prepared by a Wacker oxidation, the requisite alkene 2.46 for which is available by olefination of the product of oxidative cleavage of enone 2.48.  Intermediate 2.48 could be made from pentacyclic compound 2.49, which is the product of a Diels-Alder reaction between diene 2.50 and dienophile 2.51.  Diene 2.50 was readily accessed by enol silylation of the corresponding ketone.  The route to dienophile 2.51 was more elaborate,74 and started with the Birch reductive alkylation of 2.52 followed by an acid mediated cyclization to afford alcohol 2.54 (Scheme 2.11).75  Decarboxylation and protection of the tertiary alcohol gave compound 2.55, which was converted to diazoketone 2.56 by a deformylative Regtiz diazo transfer reaction.  Compound 2.56 was then subjected to photochemical Wolff rearragement followed by α-selenation and thermal elimination to give unsaturated ester 2.51.   Scheme 2.11  Preparation of ester 2.51 45   The Diels-Alder reaction between 2.50 and 2.51, followed by desilylation with AcOH, afforded cis-decalone 2.57 (Scheme 2.12).  Ester cleavage under nucleophilic conditions (sodium propylthiolate, HMPA) took place with concomitant epimerization and afforded to the trans-fused isomer of acid 2.58.  Curtius rearrangement of 2.58 and trapping of the intermediate isocyanate with sodium methoxide furnished 2.59.  Birch reduction of this material caused the reduction of aryl moiety and the ketone to a secondary alcohol, which was protected prior to a final acidic hydrolysis leading to 2.60.   Scheme 2.12  Assembly of enone 2.60 in Mander’s synthesis   To set the stage for the oxidative cleavage of cyclohexenone, enone 2.60 was reduced with 9-BBN followed by dihydroxylation of the olefin to afforded triol 2.61 (Scheme 2.13).  Oxidative cleavage of this compound with lead tetraacetate afforded keto-aldehyde, which was homologated and then reduced under dissolving metal condition to give olefin 2.62.  Mesylation of the secondary alcohol followed by base promoted cyclization and deprotection of carbamate 46  lead to pyrrolidine 2.63.  The methyl ketone was formed upon a subsequent Wacker oxidation of the olefin that reacted immediately with the secondary amine to produce an enamine, which was hydrogenated and deprotected to give hexacyclic compound 2.44.  Overall, Mander’s route to 2.44 required 29 steps from compound 2.52 (Scheme 2.11, p. 44).   Scheme 2.13  Completion of Mander’s synthesis  2.2.2  Movassaghi's total synthesis of (–)-himandrine  In 2009, the Movassaghi group at MIT reported the first asymmetric synthesis of (−)-himandrine.74  Their approach relied on construction of the pyrrolidine segment by a late-stage, intramolecular SN2' reaction of allylic chloride 2.64 (Scheme 2.14), which would be obtained by halogenation of 2.65.  A noteworthy aspect of this strategy is that 2.65 is accessible via a biomimetic, formal [3+3] cycloaddition reaction of imine 2.66 with enone 2.67.  In turn, tricycle 2.67 may be rapidly prepared by a tandem intramolecular Diels-Alder reaction / Mukaiyama aldol condensation of linear tetraene 2.68. 47   Scheme 2.14  Movassaghi’s retrosynthetic analysis of (−)-himandrine   Tetraene 2.68 was prepared starting from commercial 7-octene-1,2-diol (2.69), which was converted into highly enantioenriched (>98.5 % ee) 2.70, detailed in Scheme 2.15.  Reductive cleavage of the hydroxylamine was followed by a sequence for the selective methylation of secondary alcohol to afford 2.71.  This material was subjected to Parikh-Doering oxidation and Fuchs homologation to produce dibromoolefin 2.72.  The more accessible vinylbromide was utilized in a Suzuki coupling while the remaining bromide was used in a Cu-promoted coupling with azetidinone to give triene 2.75.  The protected secondary alcohol was then converted to a silyl enol ether and a metathesis reaction with acrolein using Hoveyda-Grubbs 2nd generation catalyst (2.76) provided the key tetraene 2.68. 48   Scheme 2.15  Synthesis of tetraene 2.68   The azetidinone present in 2.68 was essential in order to obtain good yields in the crucial IMDA reaction, seemingly because it favored the s-cis geometry of the diene segment.  Thus, thermal activation of 2.68 afforded a 5 : 1 mixture of adducts 2.77 (desired, 63 % yield) and 2.78 (undesired, 13 % yield), which were separated by column chromatography (Scheme 2.16).  Treatment of the major diastereomer with TiCl4 induced an intramolecular Mukaiyama aldol reaction, and the resultant intermediate was dehydrated to 2.67 by the use of the Martin sulfurane (2.79). 49   Scheme 2.16  Synthesis of tricycle 2.67   With the key tricyclic intermediate 2.67 in hand, the stage was set to execute the formal [3+3] addition with imine 2.66 (Scheme 2.17).  Thus, an organometallic cuprate generated in situ from 2.66 underwent conjugate addition to enone 2.67 to form adduct 2.80.  Due to the excess base present in the reaction mixture, imine 2.80 tautomerized to the corresponding enamine species, which attacked the ketone to give tertiary alcohol 2.81.   Scheme 2.17  The crucial union of fragments 2.66 and 2.67  50   The total synthesis was completed as shown in Scheme 2.18.  Reduction of imine 2.81, Cbz protection of the newly formed amine, followed by a hydrolysis of azetidinone afforded pentacyclic ketone 2.82.  To install the carbomethoxy group, compound 2.82 was first transformed into vinylogous lactone 2.83 through the reaction with the Vilsmeier reagent.  Compound 2.83 was then oxidized consecutively with DDQ and NaClO2 to afford the α,β-unsaturated keto-carboxylic acid, which was treated with diazomethane to provide methyl ester 2.84.  After deprotection of the amine, addition of NCS caused an intramolecular cyclization to occur, affording the hexacyclic compound 2.85.  Finally, the synthesis of (−)-himandrine was completed after a reduction and a benzoylation step, with a total of 31 steps from the commercially available 7-octene-1,2-diol (2.69) and an overall yield of 3.1 %.   Scheme 2.18  End game of Movassaghi’s synthesis of (−)-himandrine    51  2.3  Prior work from the Ciufolini group 2.3.1  Retrosynthetic considerations  The nexus between desymmetrization of dienones obtained by oxidative amidation chemistry and himandrine becomes apparent from the following retrosynthetic considerations.  The piperidine unit of 2.86 (E ring) may be created at a late stage of the synthesis, e.g., by an intramolecular SN2 reaction of seco-intermediate 2.87 (Scheme 2.19), while the tertiary alcohol in 2.87 might arise upon intramolecular Barbier reaction of organometallic agent 2.88.  Creation of the cyclopentanone unit (C ring) by intramolecular conjugate addition of 2.89, would enable assembly of himandrine from precursor 2.90.   Scheme 2.19  Retrosynthetic analysis of himandrine: identification of precursor 2.90  52   In principle, compound 2.90 could be prepared via a facially- and regiochemically selective, endo-Diels-Alder reaction of 1-methoxybutadiene with dienone 2.91 (Scheme 2.20), which is recognized as a product of oxidative cyclization of phenolic sulfonamide 2.92.49  The initially formed cis-decalone Diels-Alder product would then be epimerized to the more favorable trans-isomer and selectively hydrogenated to furnish the AB rings of himandrine.  The correct facial selectivity in the Diels-Alder step can be secured by connecting the diene to the nitrogen atom through the sulfonyl bridge (cf. 2.91 → 2.90; Z = OMe or equivalent group).   Scheme 2.20  Possible assembly of tricyclic enone 2.90 via a tandem IMOA-IMDA of 2.92   The desired regioselectivity may be anticipated on the basis of conformational considerations.  Assuming that the reaction will favor an endo topology,76 then compound 2.91 can undergo IMDA reaction either through conformer 2.93 or via 2.94.  We describe the first conformation as syn, because the sulfonyl group is oriented towards the alkyl substituents of the pyrrolidine ring.  53   Scheme 2.21  Conformational aspects of the IMDA reaction of dienone 2.91  This significant steric compression that developeds between SO2 and substituents is absent in anti-conformer 2.95, which therefore should be energetically favored.  An IMDA reaction evolving from the more energetic 2.93 may be said to occur by a syn-endo topology, and it would lead to the undesired syn-endo product 2.94.  Conversely, one taking place from the less energetic 2.95 (anti-endo topology) would deliver the desired anti-endo adduct 2.96, which should therefore prevail over 2.94.  2.3.2  Preliminary results  An initial phase of the project aimed to ascertain the hypothesis of utilizing the pyrrolidine substituents to direct the IMDA reaction.  Thus, the individual directing ability of substituents R (C5 position) and R' (C3 position) of the pyrrolidine ring (see 2.95, Scheme 2.21) was determined first.  Subsequently, the synergistic directing effect of the two was evaluated.  The stereoinduction exerted by the substituent group at the C5 position of pyrrolidine ring was determined through a study of the IMDA reaction of 2.99 (Scheme 2.22).77  This material was prepared by sequential Tozer reaction78 of L-homotyrosinol derivative 2.97 with 54  acrolein, desilylation, and DIB-mediated oxidative amidation in neat trifluoroacetic acid.  Dilution of the reaction mixture containing crude 2.99 with toluene and heating to reflux triggered the formation of an 8 : 1 mixture of trans-decalones 2.100 (anti-endo product, major; structure confirmed by X-ray diffractometry) and 2.101 (syn-endo product, minor).   Scheme 2.22  Directing effect of the C5 substituent of the pyrrolidine ring   The direct formation of trans-fused products is attributable to a TFA-mediated epimerization process.  In the presence of acid, the initially formed cis-adduct 2.102 equilibrates to the corresponding enols, which upon tautomerisation of the latter to the energetically more favorable trans-isomer generates 2.100 (Scheme 2.23).  Thus, a mere CH2OH adjacent to the pyrrolidine N atom promotes an appreciable 8 : 1 diastereoselectivity in the anticipated sense, validating the above hypothesis (Scheme 2.21, p. 53).  55   Scheme 2.23  Presumed mechanism for the formation of trans Diels-Alder adduct 2.100   The next section will detail the directing ability of C3 pyrrolidine substituent, the combined effect of C3 and C5 substituents on the stereochemistry of the IMDA step, and the translation of these findings en route to an advanced synthetic intermediate for himandrine.  2.4  An approach to himandrine via the oxidative amidation of a phenol  The preliminary results detailed in the previous section constitute the basis for the research presented here, which aimed to address the following major issues:   a.  The ability of a substituent at C3 of the pyrrolidine ring (Scheme 2.24) to direct the crucial IMDA reaction in an anti-fashion;  b.  The extent of steroinduction promoted by the presence of substituents at both C3 and C5 of the pyrrolidine ring;  c.  Methodology for the formation of ring C of the himandrine framework;  d.  Methodology for the formation of ring D of the natural product;  e.  Proper choice of Z (forerunner of the MeO group in 2.91 (Scheme 2.24)).  56   Scheme 2.24  Objectives and challenges towards the synthesis of himandrine   2.4.1  Directing effect of a C3 pyrrolidine substituent79  The anti-directing ability of a pyrrolidine C3 substituent was evaluated by studying the IMDA reaction of (±)-2.105, which is the product of oxidative cyclization of (±)-2.104 (Scheme 2.25).  The choice of 2.104 was also motivated by the recognition that, at an appropriate post-IMDA stage, the oxygen functionality could be elaborated into aldehyde 2.106 or a homologated derivative 2.108, wherein EWG represent an electron-withdrawing group.  This would enable the construction of ring C either by hydroacylation chemistry or by conjugate addition, respectively.   Scheme 2.25  Opportunities for the construction of ring C of himandrine  57   The synthesis of compound 2.115 commenced with a Knovenagel condensation of ethyl cyanoacetate (2.110) with p-anisaldehyde (2.111) (Scheme 2.26).  The product underwent Michael addition of the enolate of ethyl acetate followed by Krapcho decarboxylation80 to afford nitrile 2.112.  Selective reduction of the nitrile with NaBH4 in the presence of CoCl2 resulted in the formation of a lactam,81 which was N-mesylated to give 2.113.  The aryl ether was demethylated and the N-mesyl lactam was reduced to give alcohol 2.114, which was sequentially protected to afford N-Boc sulfonamide 2.115.   Scheme 2.26  Sythesis of compound 2.115   As indicated earlier (Scheme 2.22, p. 54), the introduction of the N-Boc sulfonamide served as a prelude to a transformation developed by Tozer:78 the condensation of the anion of the methanesulfonimide with acrolein, leading to 1-sulfonamidodiene 2.121.  This process is believed to occur though the mechanism depicted in Scheme 2.27.  First, deprotonation of methylsulfonyl group of compound 2.116 by t-BuOK generates anion 2.117, which reacts with 58  acrolein to form intermediate 2.118.  This is followed by an intramolecular transfer of the Boc group to the alkoxide.  The resulting species 2.119 then undergoes elimination, presumably by an E1cb mechanism, leading to 2.120, which yields sulfonamide diene 2.121 upon protonation.   Scheme 2.27  Proposed mechanism of the Tozer reaction   In practice, N-Boc sulfonamide 2.115 was subjected to Tozer conditions followed by a selective deprotection of phenolic TBS to afford compound 2.104.  The oxidative cyclization leading to 2.105 was carried out by adding 2.104 to a CH2Cl2 solution of DIB and TFA (1.1 equiv relative to DIB) to give dienone 2.105 in moderate yield.  This procedure deviated from the previously developed one (Scheme 2.22, p. 54), wherein TFA was used as the solvent, to allow the acid-labile TBS group intact.  Furthermore, dienone 2.105 was isolated and purified whereas in the previous case, the dienone was directly subjected to the IMDA reaction.  The yield of 2.105 was largely unaffected by these modifications and the conduct of the IMDA step with pure dienone resulted in much cleaner products, greatly facilitating the purification of the cycloadducts.  59   Scheme 2.28  Tozer reaction using phenol 2.115   Moving forward, the crucial IMDA reaction was executed by heating a solution of dienone 2.105 in toluene (Scheme 2.29).  The 1H NMR spectra of crude reaction mixtures typically revealed three major products, which were ultimately assigned as 2.122, 2.123, and 2.124.  No evidence could be garnered for the presence of syn-exo cycloadduct 2.125.  The ratio of the three products varied for each experiment, but a typical IMDA step would return an approximately 1.2 : 1.0 : 1.1 mixture of 2.122, 2.123, and 2.124, respectively.  Thus, a substituent at the C3 position of pyrrolidine ring induces a modest 2 : 1 selectivity for the IMDA reaction in favor of the anti-diastereomers over the syn-diastereomers.  A rationale for the diminished anti-directing ability of a pyrrolidine C3 substituent (ca. 2 : 1) relative to a C5 one (8 : 1) may be ventured as follows.  A substituent at the C5 position of the pyrrolidine ring is closer to the sulfone group compared to one at the C3 position (Figure 2.4, p. 61).  Therefore, the steric interaction between the SO2 group and the C5 substituent will be more unfavorable than that with the C3 alkyl.82  On the other hand, the C3 substituent will exert a reduced degree of stereoinduction during the IMDA reaction, thereby lowering the anti : syn selectivity during the IMDA reaction.   60   Scheme 2.29  Typical product distribution observed in the IMDA-epimerization of dienone 2.105 and its conversion into alcohol 2.130   61   Figure 2.4  Comparison of stereochemical outcome of dienone 2.99 and 2.105 from the IMDA reaction   Scrutiny of the crude reactions mixtures obtained from the IMDA step also revealed the presence of epimerized cycloadduct (2.126).  The extent of formation of 2.126 varied from batch to batch of material, ranging from barely detectable to about 20-25 % of the product mixture.  The presence of increased quantities of 2.126 was always accompanied by a corresponding decrease in 2.122.  We surmise that trace amounts of residual TFA were responsible for the in situ epimerization of 2.122 to 2.126 via acid-promoted enol formation.  Notably, only 2.122 can isomerize to 2.126 under acidic conditions.  Without purification, the crude mixture obtained from the IMDA process was treated with DBU, resulting in epimerization of 2.122 and 2.123 to 2.126, and of 2.124 to 2.127 (Scheme 2.29, p. 60).  This operation was best carried out in toluene at 60 °C over 2 h, at which time approximately 30 % of the starting 2.122 remained.  The isomerisation of 2.122 was considerably faster than that of 2.123, which must also undergo epimerization at the less acidic α-position of the sulfonamide.  Longer reaction times and / or higher temperatures promoted the formation of two byproducts, assigned as vinylsulfonamides 2.128 and 2.129, which may arise 62  from 2.122, 2.123, or 2.126.  Therefore, it was preferable to halt the reaction at ca. 70 % conversion (2 h at 60 °C), rather than forcing it to completion.  It was later discovered that complete epimerization is achieved upon treatment of the crude mixture with TBAF.  In addition to the desilylation caused by TBAF, the basic nature of this reagent resulted in epimerization of the remaining 2.122 into 2.126, which occurred without significant increase in the amount of the isomeric vinylsulfonamides, 2.128 and 2.129.  It should be noted that the chromatographic mobility of 2.130 and 2.131 were too similar to permit complete separation.  Accordingly, subsequent experiments were carried out with 85 : 15 mixture of 2.130 and 2.131.  2.4.2  Formation of ring C: conjugate addition strategy  The newly established availability of 2.130 enabled an investigation of possible modes of ring C formation.  One option in that regard was to induce a conjugate addition of anion 2.132 (EWG = electron-withdrawing group; e.g., CN or CHO) to the enone (Scheme 2.30).  Geometric constraints would cause this anion to add to the enone from the -face, thereby securing the correct configuration of the B-C ring junction.  We note that the configuration of EWG in product 2.133 is immaterial, since the carbon bearing it would ultimately become a carbonyl group.    Scheme 2.30  Conjugate addition approach for the assembly of ring C of himandrine 63   The possible formation of ring C by Michael cyclization was first explored with nitrile 2.134, which was prepared by Appel reaction83 of alcohol 2.130 and SN2 displacement of the resultant iodide with cyanide ion (Scheme 2.31).  Disappointingly, treatment of 2.134 with bases (t-BuOK or DBU) produced only intractable mixtures containing none of the desired pentacycle 2.136.    Scheme 2.31  Attempts to form the C ring with nitrile 2.134   Suspecting that the anion of nitrile 2.135 was not forming efficiently, we turned our attention to an analogous cyclization of aldehyde 2.1137 (Scheme 2.32).  The latter, being significantly more -acidic than the nitrile,84 should undergo deprotonation much more readily.  Treatment of nitrile 2.134 with DIBAL reduced both the cyano and the ketone functionalities, and the aldehydo-alcohol thus obtained was reoxidized (Dess-Martin reagent)85 to    Scheme 2.32  Base mediated cyclization of keto-aldehyde 2.137 64  keto-aldehyde 2.137.  In accord with the above hypothesis, cyclization was realized in low yield when 2.137 was treated with suspension of K2CO3 in methanol.  Better yields were obtained upon exposure of 2.137 to pyrrolidine, which presumably combined with the aldehyde to form a transient enamine species 2.139 (Scheme 2.33).  Conjugate addition of the latter to the enone moiety then produced intermediate 2.140, which upon acidic workup afforded 2.138 in slightly improved yield.  These result proved that conjugate addition of an aldehyde to the enone is a viable strategy to construct the C-ring of himandrine.   Scheme 2.33  Cyclization of keto-aldehyde 2.137 via enamine 2.139  2.4.3.  Formation of ring C: hydroacylation strategy  Parallel work centered on a hydroacylation strategy for the construction of ring C.  This approach entails the conjugate addition of a formal acyl anion derived from aldehyde to the enone through a Stetter reaction (Scheme 2.34).86  This transformation is mediated by an N-heterocyclic carbene ("NHC", the actual catalyst), which is produced in situ by deprotonation of an appropriate aromatic nitrogen heterocycle (the pre-catalyst).  The latter is normally an N-quaternized nitrogen heterocycle; for instance, commercial thiazolium salt 2.141 (Scheme 2.35). 65   Scheme 2.34  Hydroacylation strategy to construct the C ring  Deprotonation of 2.141 with triethylamine reversibly forms ylide 2.142, which may be also represented with the NHC resonance structure 2.143.  This nucleophilic species reversibly adds to the aldehyde, and the resultant 2.145 then equilibrates with nucleophilic enamine-type intermediate 2.146.  Nucleophilic addition of the latter to the enone portion of 2.146, ultimately   Scheme 2.35  Presumed mechanism of Stetter reaction with thiazolium pre-catalyst 2.141 66  leads to 2.148, which fragments to regenerate 2.142 plus a molecule of product (2.149).  A major advantage of creating ring C by this method is that cyclopentanone 2.107 would emerge directly (Scheme 2.34).  Recall that a cyclopentanone moiety (2.88) is required for the assembly of the D-ring of the natural product (Scheme 2.19, p 51).  The precursor for the Stetter reaction, aldehyde 2.106, was obtained by DMP oxidation of alcohol 2.130.  As mentioned previously, the alcohol was contaminated with about 15 % of the syn- regioisomer emanating from the IMDA reaction.  Such a contamination thus propagated to aldehyde 2.106, which nonetheless remained perfectly serviceable for a study of the hydroacylation step.  This reaction was attempted using triazolium (2.150 or 2.151)87 or thiazolium (2.152)88 pre-catalysts in the presence of triethylamine in dry THF (Scheme 2.36).  While triazolium salts 2.150 and 2.151 promoted the formation of complex mixtures containing none of the desired product 2.107, marginal conversion (ca. 30 %) was seen with 2.152.  It is worthy of note that the use of 2.152, a silylated variant of 2.141, was chosen for its better solubility in THF.   Scheme 2.36  Attempts to carry out Stetter reaction with compound 2.106 using pre-catalysts 2.150-2.152 67   A dramatic improvement was seen when the bicyclic thiazolium pre-catalyst 2.153 developed by Glorius was used,89 whereupon diketone 2.107 was obtained in high yield (Scheme 2.37).  Contrary to the cases utilizing pre-catalysts 2.150-2.152, no side reactions were observed with the Glorius pre-catalyst, which proved to be the reagent of choice for this Stetter reaction.   Scheme 2.37  Stetter reaction with Glorius pre-catalyst 2.153  2.5  An advanced synthetic intermediate for himandrine  The favorable results detailed above encouraged us to prepare a more complex himandrine precursor that would enable the determination of the combined directing effect of substituents at both C3 and C5 of the pyrrolidine, as well as to explore methodology for the formation of ring D.  The retrosynthetic diagram in Scheme 2.38 reveals substrate 2.157 is appropriate to serve this purpose.  68   Scheme 2.38  Retrosynthetic analysis of seco-himandrine 2.154   Scheme 2.39  Synthetic route en route to phenol 2.166   69   Preparation of phenol derivative 2.157 began with an Yb(III)-catalyzed hetero-Diels-Alder (HDA) reaction between α keto-ester 2.158 and vinyl ether 2.159 (Scheme 2.39).90  The  HDA reaction occurred in a highly diastereoselective manner to afford the endo-adduct, which was subjected to hydrogenation to give tri-substituted tetrahydropyran 2.160.  Reduction of the ester followed by benzylation of the resultant alcohol furnished substance 2.161, which was hydrolyzed to the lactol and further reduced to diol 2.162.  Selective deprotection of the aryl ether was achieved at this stage by heating 2.162 in NMP with sodium sulfide, and the emerging phenol was converted into bis-TBS intermediate 2.163.  The unprotected secondary alcohol in 2.163 underwent Mitsunobu reaction91 with N-Boc-methanesulfonamide (2.164) to form sulfonamide 2.165, which was converted to dienic sulfonamide 2.166 through a Tozer reaction.78  An expedient modification of the latter step entailed the use of excess t-BuOK, resulting in simultaneous deprotection of the phenolic TBS ether, leading to compound 2.166 directly, and setting the stage for a tandem oxidative cyclization-IMDA sequence according to the previously developed protocol.  2.5.1  Tandem oxidative cyclization-IMDA-epimerization sequence with 2.166  Addition of compound 2.166 to a solution of DIB and TFA resulted in formation of dienone 2.167  (Scheme 2.40).  While a small amount of this product was purified and fully characterized, the practicalities of process work were best served by evaporating the reaction mixture to dryness and advancing crude 2.167, which was already of good quality, to the IMDA step.  A toluene solution of crude 2.167 was thus heated to reflux until complete conversion of the starting dienone into 2.168.  This substance was isolated simply by evaporation of the reaction mixture to dryness, but it was not purified.  The 1H NMR spectrum of crude 2.168 70  revealed the presence of a small amount of a byproduct, which was subsequently determined to be 2.169 by X-ray crystallography.  On the other hand, none of the regioisomeric syn-adduct 2.170 could be detected, indicating that the synergistic anti-directing effect of the pyrrolidine C3 and C5 substituents is greater than one might anticipate based on the directing abilities of each individual group.92   Scheme 2.40  Tandem IMOA-IMDA-epimerization reaction with phenol 2.166  71   Following the IMDA reaction, the epimerization was performed in a THF solution of crude 2.168 (contaminated with some 2.169) with DBU at room temperature (Scheme 2.40).  Contrary to the case of C3 substituted analogs 2.122 (Scheme 2.29, p. 60), compound 2.168 withstood prolonged exposure to DBU without incurring significant isomerization to the corresponding vinylsulfonamide.  Consequently, complete epimerization of 2.168 was achieved by stirring the reaction mixture overnight (12 h).  Chromatographic purification of the products thus obtained returned the desired trans-fused tetracycle 2.171 in a moderate 40 % yield from 2.166, plus readily separable, more polar, 2.169 (6 % yield), while the remainder constituted from a mixture of uncharacterizable products.  Comments regarding the genesis of 2.169 are in order at this juncture.  Dienone 2.167 was not thoroughly purified prior to the IMDA step, so it seems likely that it might have been contaminated with trace amount of TFA or AcOH (from DIB).  The formation of 2.169 could    Scheme 2.41  Possible mechanism for the formation of compound 2.169 72  then be rationalized as shown in Scheme 2.41.  Acid catalyzed enolization of Diels-Alder adducts (cis or trans) will form 2.172, which can generate 2.173 and / or 2.174 upon protonation.  The nucleofugal character of the protonated sulfonamide may then promote fragmentation of 2.174 to cation 2.175, which upon deprotonation generates aromatic product 2.169.  Based on this hypothesis, it was anticipated that the conduct of the IMDA step in the presence of base should suppress the formation of 2.169, thereby increasing the yield of the desired product.  Thus, azeotropic removal of acid (TFA and HOAc) was accomplished by adding toluene and concentrating under reduced pressure (rotary evaporator connected to high vacuum) to afforded crude dienone 2.167 (Scheme 2.40, p. 70).  The sample was determined to be free of acid by 1H NMR of the crude material, which lacked broad peaks that is indicative of the presence of acid species.  Furthermore, the subsequent IMDA reaction was carried in the presence of 2,6-lutidine as the base (Scheme 2.42).  Under these conditions, no detectable amount of 2.169 was observed by 1H NMR after the IMDA reaction.  Subsequent epimerization and chromatography afforded the desired tetracycle 2.171 with an improved yield of 61 % over the three-step sequence (reaction carried out with 5.4 g / 10.0 mmol of phenol 2.166).   Scheme 2.42  Modified protocol for the tandem IMOA-IMDA-epimerization sequence  73  2.5.2  Identification of a suitable forerunner of the MeO group of himandrine  Ketone 2.171 obtained as described above contains rings A, B, and F of the natural product, but it lacks the methoxy group on ring A of himandrine (Scheme 2.43).  This induced us to refocus briefly on possible methods for the introduction of that substituent.  A logical approach was to execute the tandem IMOA-IMDA-epimerization sequence with substrate 2.177, which differs from 2.166 only for the presence of a methoxy group at the terminal dienic position.   Scheme 2.43  Retrosynthetic analysis of 2.1   To test the feasibility of a methoxydienic sulfonamide as a substrate for the tandem IMOA-IMDA reaction, a model study was carried out to assemble 2.181 (Scheme 2.44) from 2.178 and (E)-3-methoxyacrolein (2.179).  The latter may be prepared by hydrolysis of bis-dimethyl acetal of malonaldehyde,93 but it is obtained as a ca. 1 : 1 mixture with 3,3-dimethoxypropanal (2.180).  This was inconsequential, as the product obtained from the Tozer reaction contained only the vinyl ether and none of the acetal moiety.  This may be rationalized as compound 2.180 converted into 2.179 under the basic condition employed in the Tozer step.  Compound 2.181 was obtained by Tozer reaction followed by deprotection of phenolic TBS ether.  Unfortunately, this methoxydiene proved to be quite sensitive to acid.  Substantial losses were incurred during chromatographic purification (silica or neutral alumina), which resulted in 74  diminished yields.  Furthermore, attempted oxidative cyclization of 2.181, either in CH2Cl2 with TFA (1.1 equiv) or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent,49 resulted in formation of an intractable mixture of products.   Scheme 2.44  Attempted synthesis of dienone 2.182   The failure of the above reaction was attributed to the acid-sensitive nature of the methoxydiene segment of 2.181.  Given that acid is required in the oxidative cyclization step, it was apparent that an acid-resistant analog for the oxygen functionality was necessary.  The choice of Z = SiMe2Ph was reasonable solution.  Indeed, a silyldiene such as 2.183 (Scheme 2.45), being a vinylsilane,94 was anticipated to survive the mildly acidic conditions of the oxidative cyclization step.  Furthermore, solid literature precedent indicates that vinylsilanes   Scheme 2.45  The use of silyldiene 2.183 in IMOA-IMDA-epimerization reaction to access compound 2.186 75   undergo Diels-Alder reactions normally.95,96  Moreover, adduct 2.184 could be converted into 2.185 by a Tamao-Fleming oxidation,97 which occurs with retention of configuration at the silicon bearing carbon, followed by methylation of the newly formed alcohol to furnish 2.186.  The stereochemical outcome of the Tamao-Fleming reaction, which would install the OH group with the correct configuration, follows its accepted mechanism (Scheme 2.46).  An initial treatment of compound 2.187 with Br2 induces ipso-electrophilic aromatic substitution via intermediate 2.188, leading to silylbromide 2.189 and bromobenzene.  Addition of a peroxy acid displaces the bromide from 2.189 to form 2.190, which then undergoes a 1,2-alkyl shift towards the proximal oxygen atom of the peroxy functionality.  The alkyl migration is a sigmatropic process which occurs suprafacially, resulting in a retention of configuration at the migrating carbon atom.  Therefore, alcohol 2.192 that is generated by basic hydrolysis of intermediate 2.191 has the same configuration as the starting material (2.187).   Scheme 2.46  Proposed mechanism of Tamao-Fleming oxidation   76   In preparation of silyldienic sulfonamide substrate, β-silylacrolein 2.196 was synthesized by a method described by Panek98 (Scheme 2.47), starting with Pt-catalyzed syn-hydrosilylation of propargyl alcohol (2.193).  This afforded trans-silyl allylic alcohol 2.195, which in turn was oxidized to furnish 2.196 in good yield.  The compound was subsequently used in Tozer reaction with 2.165 to afford silyldiene 2.183, which was purified by chromatography (silica) without any notable decomposition.  Gratifyingly, addition of 2.183 to a solution of DIB and TFA (1.1 equiv each) formed the dienone, which was subjected to IMDA reaction condition.  Preliminary results obtained from small scale reactions demonstrate signals (1H NMR and MS) which correspond to 2.184.  Although no further work was carried out with 2.183, the notion that a silyldiene is serviceable in the tandem IMOA-IMDA was validated.   Scheme 2.47  Preparation of silyldiene 2.183    77  2.5.3   Methodology for the creation of ring D of himandrine  The development of methodology for the creation of ring D of himandrine from intermediate 2.171 was deemed to constitute a more urgent matter than the advancement of 2.184 to a methoxy derivative via Tamao oxidation.  Therefore, our attention refocused on the conversion of 2.171 into a more elaborate intermediate incorporating ring D (Scheme 2.48).  Aldehyde 2.197, the precursor for the Stetter reaction, was obtained uneventfully from tetracycle 2.171 in two steps.  Initial attempts to induce Stetter cyclization of 2.197 under the previously established conditions (NEt3, THF, 55 °C) were unfruitful (Scheme 2.48).  Whereas no pentacyclic product 2.199 formed, variable amounts of 2.197 were converted into acid 2.198.  It is known than NHC catalysts can promote oxidation of aldehydes to carboxylic acids99 or esters,100 the oxidant being molecular oxygen.101  A more rigorous exclusion of O2 from reaction mixtures was clearly necessary.  Concerning the reason(s) why such a problem did not seem to affect the cyclization of simpler substrate 2.106 (Scheme 2.37, p. 67), it was reasoned that the additional steric hindrance posed by the C5 substituent present in 2.197 could retard the hydroacylation reaction.  A reactive intermediate of the type 2.146 (Scheme 2.35, p. 65) might thus become sufficiently long-lived as to undergo oxidation by molecular oxygen faster than addition to the enone.  If so, this issue could be addressed by conducting the reaction at a higher temperature in a high boiling point solvent.  The use of a stronger base to generate a greater proportion of active catalyst might also be beneficial.  78   Scheme 2.48  Stetter reaction with compound 2.197   Optimization of the reaction conditions led to the development of a protocol that reproducibly afforded pentacycle 2.199 in 55 % yield (Scheme 2.48, bottom).  This entailed thorough degassing of the reaction with Argon (under sonication prior to heating), carrying out the reaction in refluxing 1,4-dioxane (b.p. 101 °C) instead of THF (b.p. 66 °C), and using DBU (pKaH in MeCN ≈ 24.3) instead of NEt3 (pKaH in MeCN ≈ 18.5) as the base.102  Furthermore, the presence of 2,6-di-tert-butyl-4-methylphenol (BHT; 5 mol %) in the reaction mixture provided an added insurance against the unwanted oxidation of the aldehyde.  In the retrosynthetic analysis (Scheme 2.38, p. 68), recall that the formation of ring D requires an alkynyl group at the C5 position of the pyrrolidine ring.  Such a feature may be installed from aldehyde 2.201, which could be obtained by debenzylation-oxidation of 2.199.  79   Scheme 2.49  Failures to functionalize the C5 substituent from compound 2.199   Debenzylation of 2.199 was achieved in moderate yield by the action of BBr3 in CH2Cl2 at –95 °C (Scheme 2.49, top).  Such an unusually low temperature was mandated by the tendency of the product to decompose in the presence of BBr3 at bath temperatures higher than −85 °C.  This had an adverse effect on yields when the reaction was scaled up, presumably due to an insufficient rate of heat transfer.  For instance, a reaction executed with 0.98 g (2.3 mmol) of benzyl ether 2.199, returned 2.200 in only 39 % yield.  Further challenges were encountered during the oxidation of alcohol 2.200 under Parikh-Doering, Swern, or PCC conditions, whereupon crude aldehyde 2.201 was obtained in consistently poor crude yield.  It is unclear whether the loss of material was due to decomposition of aldehyde 2.201 during aqueous work up or to facile formation of the water-solube hydrate which would then be lost during aqueous extraction of the reaction mixture.  In the latter case, avoidance of an aqueous work should alleviate the problem.  Indeed, Dess-Martin 80  oxidation of 2.200 and non-aqueous processing of the reaction mixture by filtration through a plug of Celite® gave crude aldehyde 2.201 with good (quantitative crude yield) mass recovery (Scheme 2.49, top).  This crude material was then directly subjected to the action of various nucleophiles (allylsilane with TiCl4, Grignard, Ohira-Bestmann reagent).  However, such attempts resulted only in the formation of intractable material.  One possible reason for such failures was that the two enolizable ketones present in the molecule might have induced undesirable aldol-type reactions, which would convert 2.201 into a variety of byproducts.  A decision was thus made to protect the carbonyl groups prior to C5 functionalization (Scheme 2.49, bottom).  Hydrogenation of 2.199 affected both the olefin and the benzyl group and cleanly furnish 2.203, which was then subjected to ketalization.  Perhaps unsurprisingly, only the cyclohexanone moiety underwent protection while the more hindered cyclopentanone remained intact.  The mono-ketal thus obtained was oxidized with Dess-Martin periodinane to produce keto-aldehyde 2.204.  Disappointingly, treatment of compound 2.204 with Ohira-Bestmann reagent only returned an intractable mixture of products.  All these difficulties led to the conclusion that the C5 acetylenic unit had to be introduced at an earlier stage and necessitated a re-evaluation of the synthetic route.  2.5.4  Early-stage installation of the C5 alkyne substituent  Compound 2.205 was regarded as a plausible substrate for the creation of the alkyne functionality prior to the oxidative cyclization-IMDA-epimerization sequence.  Accordingly, hydrogenolytic debenzylation and oxidation of compound 2.165 delivered aldehyde 2.205 (Scheme 2.50), the conversion of which into an alkyne was attempted by an Ohira-Bestmann reaction.103 81   Scheme 2.50  Preparation of aldehyde 2.205   This transformation occurs when an aldehyde is treated with 2.206 in the presence of NaOMe (Scheme 2.51).  A reversible addition of methoxide ion to the carbonyl group of 2.206 is believed to induce the release of MeOAc and generate anion 2.208, which then undergoes a Wadsworth-Emmons-type reaction104 with the aldehyde.  The initially formed adduct 2.209 is thought to generate oxaphosphetane 2.210, which fragments into diazoalkene 2.211.  This intermediate is exceedingly unstable and rapidly loses N2 to form singlet alkylidenecarbene 2.212, which instantly rearranges to alkyne 2.213.   Scheme 2.51  Presumed mechanism of Ohira-Bestmann reaction 82   Treatment of aldehyde 2.205 under such conditions resulted only in formation of compound 2.214 (Scheme 2.52).  This product is likely to arise by nucleophilic attack of methoxide onto aldehyde 2.205 to form 2.215, followed by acyl migration through intermediate 2.216.  No further attempts were made to introduce the alkyne from 2.205.  Instead, an alternative route evolving from 2.163, wherein no opportunity exists for intramolecular acylation of anions such as 2.215, was explored.   Scheme 2.52  Unexpected outcome of Ohira-Bestmann reaction with aldehyde 2.205   Catalytic debenzylation of 2.163 returned a vicinal diol, which was protected as cyclic acetal 2.218 (3 : 2 mixture of diastereomers; 1H NMR) in preparation for a regioselective, reductive ring opening with DIBAL (Scheme 2.53).  The primary alcohol 2.219 thus obtained underwent sequential DMP oxidation and Ohira Bestmann reaction in high yield to give alkyne 2.220.  The PMB group was then oxidatively released (DDQ) to reveal the secondary alcohol, 83   Scheme 2.53  Synthesis of alkynyl phenol 2.222  which was subjected to Mitsunobu condition with 2.164.  Congruent with previous observations, the reaction occurred smoothly to afford 2.221, Tozer condensation of which produced compound 2.222.  A brief aside is in order at this point.  Parallel work explored the introduction of an alkynyl group from tetrahydropyran 2.160.  Conversion of 2.160 into 2.224 was achieved by DIBAL reduction followed by homologation of the resultant aldehyde 2.223 (Scheme 2.54).  Alkylation of the anion of compound 2.224 delivered 2.226, a substrate that already contains the seeds of the future ring E of the natural product.  A subsequent hydrolysis of the ethoxypyran, 84    Scheme 2.54  Attempted Mitsunobu reaction with compound 2.227  reduction, and selective protection of the primary alcohol also occurred smoothly to furnish secondary alcohol 2.227.  But to our complete dismay, this substrate resisted conversion into N-Boc sulfonamide 2.228.  No reaction was observed under the same Mitsunobu conditions developed earlier to advance 2.163 to 2.165 (PPh3, DIAD, 2.164, 55 °C, Scheme 2.39, p. 68).  In an effort to initiate the reaction, more forcing conditions were applied by operating the reaction at higher temperature (sealed tube, 85 °C) and by using the more reactive ADDP (2.232)105 in lieu of DIAD (Scheme 2.55, top).  To our surprise, the product thus obtained was not the desired 2.228, but rather what ultimately proved to be the N-mesylcarbamate 2.231, and this regardless of whether the sulfonamide reactant was provided in the form of tert-butyl (2.164) or ethylcarbamate (2.229).  Curiously, full consumption of the starting 2.227 was never achieved 85   Scheme 2.55  Mitsunobu reactions with compound 2.227  in these reactions, even under vigorous conditions.  This is in sharp contrast to the formation of 2.221 (Scheme 2.53, p. 83), for which full conversion was usually observed.  Notice that 2.230 formed with retention of configuration at the former alcohol-bearing carbon, indicating that its genesis probably does not involve Mitsunobu chemistry.  A control experiment involving Mitsunobu reaction of 2.227 with p-bromophenol gave the expected product 2.231 in reasonable yield (Scheme 2.55, bottom), indicating that the abnormal course of reactions involving 2.164 or 2.229 must be due to some unfavorable property of the sulfonamides, and not to an innate property of 2.227.  At this stage, a cogent explanation to why alkyne 2.227 resists Mitsunobu reaction with 2.164 or 2.229 could not be offered.  The formation of 2.230, however, could be envisaged as follows.  The higher temperatures employed in the Mitsunobu reaction resulted in the decomposition of N-mesyl carbamates 2.164 or 2.229 into a molecule of alcohol (t-BuOH or 86  EtOH) and one of methanesulfonylisocyanate (2.233).  The latter then reacted with alcohol 2.227 to furnish 2.230 (Scheme 2.56).  Note that 2.230 is also an N-mesyl carbamate, thus it can also undergo thermal decomposition to generate 2.233 and secondary alcohol 2.227.  This may explain why full consumption of 2.227 was not observed under the reaction condition.   Scheme 2.56  A possible rationale for the generation of 2.230   We conclude this section by describing a control experiment which ascertained that 2.230 had formed with retention of configuration (Scheme 2.57).  Compound 2.230 was N-methylated (MeI, K2CO3), and the resultant 2.234 was subjected to basic methanolysis (MeOH, K2CO3).  This resulted in formation of an alcohol that was spectroscopically (1H and 13C NMR) indistinguishable from the starting 2.227.   Scheme 2.57  Derivatization experiments of compound 2.230   87  2.5.5  Elaboration of 2.222 to a precursor of himandrine incorporating ring D  This section illustrates how phenol 2.222 (Scheme 2.53, p. 83) was progressed to an advanced intermediate for himandrine that incorporates rings C and D.  The oxidative cyclization of 2.222 occurred uneventfully to produce spirocycle 2.236 as the only detectable compound by 1H NMR (Scheme 2.58, path a).  It is worthy of note that the alkynyl group did not interfere with the sulfonamide during the nucleophilic capture of presumed cationic intermediate 2.235, even though it has been established that π-bonds of olefins and alkynes can intercept the cationic intermediate to afford products derived from 2.237 (Scheme 2.58, path b).106   Scheme 2.58  IMOA of phenol 2.222   In accord to the previously developed protocol (Scheme 2.42, p. 72), trace amounts of acid were removed from the crude mixture that contained dienone 2.236 and the subsequent IMDA step was performed in the presence of 2,6-lutidine (Scheme 2.59).  The resultant Diels-Alder adduct was then epimerized with DBU to yield compound 2.238, which was isolated in a 88  moderate 34 % yield after chromatography.  The tandem reaction also returned a significant amount of several uncharacterized byproducts (ca. 40 % of the mass of starting 2.222).  One of these was tentatively assigned as 2.239, based on the fact that its 1H NMR spectrum indicated the presence of an intact dienone but no terminal alkyne.  This material is most likely to form through an IMDA reaction between the diene and the alkyne via conformer 2.240.  The initially formed 1,4-diene 2.241 subsequently isomerized into the conjugated 1,3-diene 2.239 upon exposure to DBU.  No efforts were made to optimize this step at the present juncture, in that a more pressing issue was the identification of suitable conditions for ring D formation.   Scheme 2.59  IMDA-epimerization reaction of dienone 2.236   Moving forward, compound 2.238 was converted to aldehyde 2.242 in preparation for the Stetter reaction (Scheme 2.60).  Desilylation of 2.238 and oxidation of the corresponding alcohol delivered compound 2.242 (62 % yield) which then underwent intramolecular hydroacylation in 89  71 % yield under the influence of Glorious pre-catalyst 2.153.  The structure of crucial intermediate 2.243 was ascertained by X-ray crystallography, which also indicated that the cyclopentanone carbonyl (C15) and inner acetylenic carbon (C16) were distant a mere 3.89 Å.   Scheme 2.60  Synthesis of diketone 2.243   The proximity of these two atoms should greatly facilitate the formation of ring D of himandrine, for instance through reaction of 2.243 with a Ti(II) reagent with the generic formulation Ti(II)Ln; where L is a generic ligand (Scheme 2.61, top).  It was anticipated that the low-valent metal species will exchange ligands with 2.243 to form 2.244, then undergo a cycloisomerization process to generate Ti(IV) species 2.245.107  The titanacyclopropene can insert into the carbonyl leading to 2.246 and furnish 2.247 upon acidic workup.  Alternatively, suitable 1-electron reductants could react with 2.243 to produce ketyl 2.248 (SET to the carbonyl group), which would attack the alkyne, resulting with vinyl radical species 2.249 (Scheme 2.61, 90  bottom).108  A subsequent SET generates dianion 2.250, leading to the formation of hexacyclic ketone 2.247 upon protonation.   Scheme 2.61  Synthetic strategies to convert 2.243 into 2.247   Initial forays directed towards the creation of ring D centered on the reaction of 2.243 with Ti(II) species 2.251 (Scheme 2.62, top), which is readily generated in situ from Ti(Oi-Pr)4 and i-PrMgCl.  This complex is reported to be quite effective for the desired transformation;109 however, no reaction was observed when 2.243 was added into a solution of 2.251 at 78 °C.  Disappointingly, raising the temperature above 0 °C resulted in formation of a mixture of compounds, one of which appeared to be 2.252, the product of reduction of two carbonyl groups present in 2.243.  91   Scheme 2.62  Synthesis of compound 2.247   These setbacks induced us to turn to the reaction of 2.243 with the powerful one electron reducing agent, Sm(II)I2 (Scheme 2.62, bottom).110  Addition of THF solution SmI2 (6 equiv) to a THF solution of 2.243 induced the formation of five compounds (vide infra).  The 1H NMR spectrum of the crude mixture displayed a new pair of olefinic signals consistent with the formation of an exo-methylene group.  The presence of 4 types of olefinic proton resonances discounted the possibility that the ethynyl unit was reduced to a terminal vinyl group, for which the corresponding spectrum should exhibit 5 types of olefinic proton signals.  Additional spectral evidence indicated that the probable structures of the major species present in the crude corresponded to the two epimers of 2.253, resulting from a non-stereoselective reduction of the cyclohexanone carbonyl.  A small amount of non-cyclized compound 2.252 and desired product 2.247 were also be seen in the crude spectrum (Figure 2.5, b).  Accordingly, the crude mixture 92  was treated with DMP, resulting in formation of a single stereoisomer of compound 2.247 and 2.243 (Figure 2.5, c).   Figure 2.5  1H NMR (CD3CN, 300 MHz) of (a) pure 2.243 (b) crude mixture obtained after treating 2.243 with SmI2 and (c) crude mixture after treatment with DMP   The structure of 2.247111 was ascertained by 2D NMR data (HSQC and HMBC) which displayed key correlations between the terminal vinylic protons and the carbon atoms as shown   Figure 2.6  HSQC and HMBC plot indicating the key correlation seen for compound 2.247 93  in Figure 2.6.  The HSQC plot confirmed the presence of terminal olefin through the 1JH,C correlation between the two vinylic protons and the exo-olefinic carbon atom (C1).  On the other hand, the HMBC plot shows two 2JH,C correlations made by the vinylic protons: one to the tertiary carbon (C2) and another to the quaternary carbon (C3).  In combination with MS data, these data corroborate with the structure shown for 2.247.  2.6  Summary and outlook  Efforts towards himandrine have produced good solutions to a number of synthetic problems.  An approach based on a tandem oxidative cyclization of a dienic sulfonamide-intramolecular Diels-Alder reaction-epimerization sequence has been validated for complex substrates such as 2.166 (Scheme 2.42, p. 72), 2.183 (Scheme 2.47, p. 76), and 2.222 (Schemes 2.58 and 2.59, p. 87 and 88).  Stereochemical aspects of the IMDA step have been studied in detail and are likely to be valuable well beyond the conclusion of the himandrine campaign.  Methodology has been established for the creation of ring C by an unique intramolecular hydroacylation reaction, and of ring D by a SmI2-mediated reductive coupling.  Finally, a potential solution has been identified for the introduction of a MeO group via IMOA-IMDA reaction of a silyldiene 2.183 (Scheme 2.47, p. 76).  An advanced synthetic intermediate 2.247 that includes five of the six rings present in the natural product is now available, albeit in racemic form, prepared in 24 steps from enone 2.158 (Scheme 2.63).  Technology for the advancement of 2.247 to (±)-himandrine is already being researched in our group, as is the transposition of the findings detailed herein to an enantiocontrolled route. It is anticipated that a junior colleague of the Author will probably complete a total synthesis of 94  (–)-himandrine in the near future.  Such a synthesis promises to be competitive with the best alternative yet known.   Scheme 2.63  Synthetic summary en route to compound 2.247   95  2.7  Experimental General.  Unless otherwise indicated, all reactions were performed with flame-dried glassware under Ar atmosphere.  Tetrahydrofuran and 1,4-dioxane were distilled from Na/benzophenone, while acetonitrile, dichloromethane, and toluene were distilled over CaH2 prior to use.  All other commercially available chemicals were used as received.  Thin layer chromatography was performed on EMD Silica gel 60 F254 plates.  TLC plates were visualized by exposing to UV light (254 nm), or staining with KMnO4, p-anisaldehde, or molybdic acid stain. Instrumentation.  Unless otherwise indicated, 1H (300 MHz) and 13C (75 MHz) spectra were recorded with Bruker AVANCE 300 spectrometer at room temperature in CDCl3.  Chemical shifts (δ scale) are reported in ppm and referenced to the residual solvent (δH 7.26 ppm and δC 77.16 ppm for CDCl3, δH 2.05 ppm and δC 29.84 ppm for acetone-d6, δH 1.94 ppm and δC 1.32 ppm).  Coupling constants, J, are reported in Hz.  Multiplicities are described as s (singlet), d / dd / ddd (doublet / doublet of doublets / doublet of doublet of doublets), t (triplet), q (quartet), p (pentet), AB quartet (ABq), m (multiplet), and further qualified as app (apparent) and br (broad).  Infrared (IR) spectra (cm–1) were recorded on a Perkin–Elmer FT-IR equipped with attenuated total reflectance.  High-resolution mass spectra (ESI, positive or negative detection) were recorded on a Micromass LCT mass spectrometer by Mr. Derrick Smith of UBC Mass Spectrometry Centre.  Melting points were measured on a Mel-Temp apparatus and reported uncorrected.  X-ray crystal measurements were made on a Bruker APEX DUO diffractometer by Dr. Brian Pratick of UBC.   96  Synthesis of arylidene 2.254 Compound 2.254 was prepared following a literature procedure.112  To a round-bottom flask equipped with Dean-Stark apparatus, a solution of p-anisaldehyde (24.0 mL, 198 mmol), ethyl cyanoacetate (21.1 mL, 198 mmol), acetic acid (9.0 mL, 160 mmol), and ammonium acetate (3.05 g, 40 mmol) in toluene (40 mL) was refluxed for 2 h.  The reaction was cooled to rt and diluted with EtOAc (100 mL).  The crude mixture was sequentially rinsed with 1 M HCl (50 mL), H2O (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL).  The crude was dried over NaSO4 and concentrated under reduced pressure to give yellow-orange solid.  Purification was done by triturating three times with 25% Et2O/hexanes to give the title compound (40.5 g, 93%) as a faintly yellow solid.  M.P.: 81-84 °C [lit., 81-82 °C].113  1H: 8.17 (s, 1H), 8.04-7.97 (m, 2H), 7.03-6.96 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).  13C: 164.0, 163.4, 154.6, 133.9, 124.6, 116.5, 115.0, 99.6, 62.7, 55.9, 14.4.  Synthesis of cyano-ester 2.255 To a solution of i-Pr2NH (8.0 mL, 57 mmol) in THF (35 mL) at 0 °C,  n-BuLi (2.5 M in hexanes, 22.0 mL, 55.0 mmol) was added dropwise over a period of 3 min.  The mixture was stirred for 10 minutes at rt and then transferred to a cool bath at −78 °C.  Anhydrous EtOAc (5.3 mL, 54.1 mmol) was added dropwise over a period of 4 min and maintained the temperature for 30 min.  The enolate of EtOAc was then cannulated into a solution of 2.254 (10.86 g, 50.0 mmol) in THF (70 mL) at 0 °C.  The vessel containing the enolate was rinsed with THF (5 mL x 2) and cannulated as well.  The reaction was stirred at 0 °C for 2 h, then quenched with 1 M HCl at 0 °C.  The mixture was 97  diluted with EtOAc (150 mL), added more 1 M HCl until the aqueous layer became acidic, and then separated.  The aqueous layer was extracted three times with EtOAc (30 mL x 3), organic layers were combined, rinsed with brine, dried over Na2SO4 and concentrated to give crude diester as a dark orange oil (14.81 g, 93%) which was used without further purification.  To the crude diester (14.81 g, 46.4 mmol) in DMSO (153 mL) was added NaCl (1.46 g, 25.0 mmol) dissolved in H2O (17 mL).  The solution was purged with Argon for 15 min and then a water condenser was attached.  The mixture was then heated in an oil bath at 180 °C for 2.5 h and cooled to rt.  The crude mixture was then diluted with EtOAc (200 mL) and H2O (200 mL), and the biphasic mixture was separated.  The aqueous layer was extracted with EtOAc (20 mL x 5), organic fractions were combined, rinsed with brine (20 mL x 4), dried over Na2SO4, and concentrated under reduced pressure to give a dark brown oil.  Purification by column chromatography (gradient elution, 10% → 25% EtOAc/hexanes) afforded 2.255 (9.05 g, 73% over 2 steps) as a yellow oil that solidified upon standing.  M.P.: 53-55 °C.  IR: 2987, 2966, 2246, 1722, 1613, 1519.  1H: 7.21-7.14 (m, 2H), 6.91-6.84 (m, 2H), 4.09 (app q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.46 (p, J = 7.1 Hz, 1H), 2.77 (m, 2H), 2.71 (d, J = 6.6 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H).  13C: 171.2, 159.2, 132.6, 128.2, 118.2, 114.4, 60.9, 55.4, 39.4, 37.5, 24.7, 14.2.  HRMS: calcd for C14H17NO3Na [M + Na]+: 270.1106; found: 270.1112.  Synthesis of lactam 2.256 To cyano ester 2.255 (10.5 g, 42.3 mmol) dissolved in THF (90 mL) at rt was added CoCl2•6H2O (3.1 g, 12.7 mmol), H2O (54 mL) and i-PrOH (18 mL).  The solids were stirred until all contents had been dissolved resulting in a purple solution.  The reaction vessel was cooled to 0 °C and NaBH4 (3.2 98  g, 84.6 mol) was added in small portions over 10 min.  The reaction was capped with a septum with an Ar balloon and stirred for 30 min at 0 °C.  A second portion of NaBH4 (3.2 g, 84.6 mmol) was added at 0 °C and stirred the reaction for 30 min.  A final portion of NaBH4 (3.2 g, 84.6 mmol) was added at 0 °C.  The reaction mixture was then gradually warmed up to rt and stirred overnight (18 h).  The reaction was quenched by slowly adding 1 M HCl (50 mL) and then evaporated off most of the organic solvents.  The black solids were suspended in 1:1 CH2Cl2/H2O (200 mL) and concentrated HCl (100 mL) was added until all contents was dissolved.  The biphasic mixture was separated and extracted the aqueous layer with CH2Cl2 (15 mL x 3).  The organic fractions were combined, rinsed with 1 M HCl (50 mL, repeated if the aqueous phase is colored), saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give crude 2.256 as an off-white solid.  Triturating twice with 20% EtOAc/hexanes afforded the title compound (6.2 g, 71%) as a white fluffy solid.  M.P.: 148-150 °C.  IR: 3179, 3034, 2958, 1659, 1610, 1512.  1H: 7.17-7.10 (m, 2H), 6.91-6.85 (m, 2H), 6.55 (br s, 1H), 3.80 (s, 3H), 3.43-3.34 (m, 2H), 3.06 (tdd, J = 11.1, 5.3, 3.1 Hz, 1H), 2.67 (ddd, J = 17.6, 5.3, 1.8 Hz, 1H), 2.45 (dd, J = 17.6, 10.9 Hz, 1H), 2.11-2.01 (m, 1H), 1.96-1.82 (m, 1H).  13C: 172.4, 158.5, 135.8, 127.6, 114.2, 55.4, 41.5, 39.0, 37.7, 29.9.  HRMS: calcd for C12H16NO2 [M + H]+: 206.1181; found: 206.1181.  Synthesis of N-mesyl lactam 2.113 To a solution of hexamethyldisilazane (8.00 mL, 37.2 mmol) in THF (10 mL) at 0 °C, was added n-BuLi (2.5 M in hexanes, 14.0 mL, 35.0 mmol) and stirred for 30 min.  The solution was cannulated into a suspension of 2.256 (6.22 g, 30.3 mmol) in THF (60 mL) at 0 °C and allowed to stir for 30 min.  99  A solution of MsCl (2.45 mL, 31.5 mmol) in THF (20 mL) was added by cannula and stirred the reaction mixture for 30 min at 0 °C and then at rt for 1.5 h.  The reaction was quenched by adding NH4Cl (30 mL) at rt and diluted with EtOAc (100 mL).  The mixture was separated and the organic layer was rinsed with 1 M HCl (30 mL), brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give a yellow to beige solid.  Purification by column chromatography (5% EtOAc/CH2Cl2) afforded 2.113 (5.03 g, 59%) as a white solid.  M.P.: 130-132 °C.  IR: 3016, 2932, 2835, 1686, 1516.  1H: 7.15-7.08 (m, 2H), 6.93-6.86 (m, 2H), 4.06-3.96 (m, 2H), 3.80 (s, 3H), 3.65 (ddd, J = 12.2, 10.8, 4.3 Hz, 1H), 3.38 (s, 3H), 3.12 (tdd, J = 10.8, 5.2, 3.4 Hz, 1H), 2.87 (app ddd, J = 17.7, 5.4, 2.0 Hz, 1H), 2.64 (m, 1H), 2.29-2.19 (m, 1H), 2.07-1.92 (m, 1H).  13C: 171.3, 158.8, 134.2, 127.5, 114.5, 55.5, 45.2, 41.9, 41.5, 37.4, 30.7.  HRMS: calcd for C13H17NO4SNa [M + Na]+: 306.0776; found: 306.0784.  Synthesis of N-Boc sulfonamide 2.115 Neat BBr3 (4.20 mL, 44.4 mmol) was added dropwise to a solution of 2.113 (5.03 g, 17.8 mmol) in CH2Cl2 (60 mL) at −78 °C.  The bright orange suspension was kept at −78 °C for 30 min, then stirred at rt for 30 min.  The reaction was carefully diluted with CH2Cl2 (60 mL) and quenched with 1 M HCl (50 mL) at 0 °C.  The resulting biphasic mixture was stirred vigorously at rt until it became colorless.  The layers were separated and the aqueous layer was extracted once with CH2Cl2 (20 mL).  The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to afford crude phenol as an off white solid.  This crude material was dissolved in THF (60 mL) and cooled to 0 °C.  A solution of LiBH4 (1.73 g, 71.5 mmol) in THF (36 mL) was added by cannula and the flask was rinsed twice 100  with THF (5 mL) and also added to the reaction.  The resulting white suspension was warmed up to rt and stirred overnight (16 h).  The reaction was quenched by slowly adding sat. aq. NH4Cl (10 mL) followed by 1 M HCl (30 mL) at 0 °C.  The mixture was stirred vigorously at rt until all solids had been dissolved.  EtOAc (75 mL) was added to the mixture and separated.  The aqueous layer was extracted with EtOAc (20 mL x 3), organic fractions were combined, washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give crude alcohol 2.114 as an off-white solid.  The substance was dissolved in 1:1 MeOH/EtOAc (80 mL), removed solvent under vacuum, and the resulting residue was used in the subsequent step without further purification.  The crude alcohol 2.114 (4.32 g, 15.8 mmol) was dissolved in MeCN (16 mL) and treated with TBSCl (5.74 g, 36.9 mmol), imidazole (4.52 g, 66.4 mmol), and DMAP (193 mg, 1.58 mmol) at rt.  The resulting white suspension was stirred at rt for 2 h at which point, TLC analysis indicated disappearance of 2.114.  The reaction was diluted with EtOAc (30 mL) and partitioned with sat. aq. NH4Cl (20 mL).  The mixture was separated and the aqueous layer was extracted once with EtOAc (10 mL).  The organic fractions were combined, rinsed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain an amber oil.  The crude mixture was passed through a pad of silica (2 cm in height x 6 cm in diameter, 80% EtOAc/hexanes) to obtain crude bis-TBS sulfonamide (7.3 g, 14.5 mmol) as a pale oil.  The crude obtained from above was dissolved in CH2Cl2 (30 mL) and Boc2O (3.49 g, 16.0 mmol), NEt3 (2.4 mL, 17.2 mmol), and DMAP (177 mg, 1.45 mmol) was added at rt.  The solution was stirred at rt for 3 h at which point 1H NMR indicated disappearance of starting material.  The reaction mixture was diluted with CH2Cl2 (30 mL), partitioned with sat. aq. NH4Cl (20 mL) and separated.  The organic fraction was rinsed with brine (20 mL), dried over Na2SO4, 101  and concentrated under reduced pressure to give a bright yellow oil.  Purification by column chromatography (gradient elution, 10% → 15% EtOAc/hexanes) afforded compound 2.115 (7.96 g, 74% over 4 steps) as a pale oil.  IR: 2955, 2931, 2858, 1725, 1510, 1354, 1252, 1137.  1H: 7.01-6.97 (m, 2H), 6.80-6.72 (m, 2H), 3.61-3.30 (m, 4H), 3.21 (s, 3H), 2.74-2.61 (m, 1H), 1.99-1.79 (m, 3H), 1.73-1.62 (m, 1H), 1.49 (s, 9H), 0.97 (s, 9H), 0.86 (s, 9H), 0.18 (s, 6H), −0.04 (s, 3H), −0.05 (s, 3H).  13C: 154.2, 151.7, 136.4, 128.5, 120.1, 84.4, 60.8, 45.7, 42.4, 39.9, 39.3, 36.7, 28.1, 26.1, 25.8, 18.4, 18.3, −4.3, −5.3.  HRMS: calcd for C29H55NO6Si2SNa [M + Na]+: 624.3186; found: 624.3192.  Synthesis of phenol 2.104 A freshly prepared THF solution of t-BuOK (2.0 M, 23 mL, 46 mmol) was added dropwise to a solution of N-Boc sulfonamide 2.115 (7.94 g, 13.2 mmol) in THF (16 mL) at –78 °C.  The resulting pale yellow solution was stirred for 1 h at –78 °C and a solution of acrolein (1.2 mL, 16.1 mmol) in THF (11 mL) was added dropwise.  The light green mixture was stirred for 1 h at –78 °C, then gradually warmed up to rt and stirred overnight (12 h).  The resulting brown solution was quenched with sat. aq. NH4Cl (10 mL) and diluted with EtOAc (20 mL).  The biphasic mixture was filtered through a pad of Celite with EtOAc (60 mL).  The mixture was separated and the organic layer was rinsed again with sat. aq. NH4Cl (20 mL).  The combined aqueous phases were extracted with EtOAc (10 mL x 2).  The organic fractions were combined, rinsed with brine (10 mL), dried over Na2SO4, and concentrated to give a brown oil that contained white solids.  The residue was filtered through a pad of Celite with EtOAc (50 mL) and the filtrate was evaporated to give crude diene sulfonamide as a brown oil. 102   To the crude diene sulfonamide (6.83 g, 12.7 mmol) dissolved in DMF (35 mL) was added LiOAc•2H2O (259 mg, 2.54 mmol) and H2O (0.72 mL), and stirred at 75 °C for 6 h.  The reaction was cooled to rt, diluted with EtOAc (70 mL), and washed sat. aq. NH4Cl (20 mL x 2).  The combined aqueous layers were back-extracted with EtOAc (20 mL x 3).  The combined organic fractions were rinsed with brine (20 mL x 3), dried over Na2SO4, and concentrated to furnish a brown oil.  Purification by column chromatography (gradient elution, 20% → 40% EtOAc/hexanes) afforded phenol 2.104 (4.03 g, 72%) as a viscous pale yellow oil.  IR: 3287, 2930, 2857, 1515.  1H: 7.01-6.90 (m, 3H), 6.77-6.70 (m, 2H), 6.34 (dt, J = 16.9, 10.4 Hz, 1H), 6.15 (d, J = 14.9 Hz, 1H), 6.02 (br s, 1H), 5.61 (d, J = 16.9 Hz, 1H), 5.53 (d, J = 10.2 Hz, 1H), 4.51 (br t, J = 6.0 Hz, 1H), 3.52-3.33 (m, 2H), 2.83 (br q, J = 6.7 Hz, 2H), 2.70 (app tt, J = 4.9 Hz, 1H), 1.94-1.63 (m, 4H), 0.86 (s, 9H), –0.02 (s, 6H).  13C: 154.6, 141.8, 135.3, 132.7, 128.8, 128.3, 127.4, 115.7, 61.1, 41.5, 39.9, 38.9, 37.0, 26.2, 18.5, –5.10, –5.14.  HRMS: calcd for C21H36NO4SiS [M + H]+: 426.2134; found: 426.2133.  Synthesis of dienone 2.105 The following procedure was performed with non-flamedried glassware and unpurified solvents.  A solution of phenol 2.104 (3.01 g, 7.07 mmol) in CH2Cl2 (35 mL) was added dropwise (addition funnel) over 8 min into a cooled (0 °C) solution of DIB (2.56 g, 7.79 mmol) and TFA (600 μL, 7.79 mmol) in CH2Cl2 (39 mL).  The addition funnel originally containing the solution of 2.104 was rinsed twice with CH2Cl2 (2 mL), and the washes were added to the reaction mixture.  The ice bath was removed and the reaction was stirred for an additional 45 min at rt.  Anhydrous K2CO3 (20 mg) was added, and the light brown suspension was concentrated under reduced 103  pressure to give an orange slurry.  Purification by column chromatography (gradient elution, 25% → 30% EtOAc/hexanes) afforded dienone 2.105 (1.57 g, 52%) as a viscous orange oil.  IR: 2930, 2857, 1669, 1343.  1H: 7.00 (app dd, J = 14.9, 10.9 Hz, 1H), 6.82 (app dd, J = 9.9, 2.7 Hz, 1H), 6.67 (app dd, J = 10.6, 3.3 Hz, 1H), 6.39 (dt, J = 16.9, 10.3 Hz, 1H), 6.32-6.26 (m, 2H), 6.19 (d, J = 14.9 Hz, 1H), 5.66 (d, J =16.9 Hz, 1H), 5.58 (d, J = 10.1 Hz, 1H), 3.65-3.52 (m, 4H), 2.52-2.30 (m, 2H), 1.84-1.67 (m, 1H), 1.41-1.29 (m, 1H), 1.23-1.10 (m, 1H), 0.85 (s, 9H), –0.01 (s, 6H).  13C: 185.4, 151.3, 145.8, 142.8, 132.5, 130.2, 129.1, 127.9, 126.8, 66.6, 61.0, 47.9, 47.7, 31.7, 29.8, 26.0, 18.3, –5.27, –5.33.  HRMS: calcd for C21H33NO4SiSNa [M + Na]+: 446.1797; found: 446.1801.  Synthesis of tetracycle 2.126 A degassed (Ar bubbling, sonication, 15 min) solution of dienone 2.105 (1.57 g, 3.71 mmol) in toluene (9.0 mL) was heated to 120 °C for 5 h, whereupon disappearance of the starting material was observed by 1H NMR.  The solution was cooled to rt and diluted with more toluene (9.6 mL).  Neat DBU (165 μL, 1.10 mmol) was added; the solution was again degassed with Ar (5 min) and then heated to 60 °C for 2 h.  The mixture was cooled to rt, diluted with EtOAc (20 mL), and washed with sat. aq. NH4Cl (10 mL).  The organic phase was separated and washed with brine (5 mL), dried over Na2SO4, and concentrated to give crude 2.126 (1.53 g, contaminated with isomers as per the discussion) as a brown oil.  This crude material was used without further purification.  A 80% pure sample for characterization was prepared as follows:  Dienone 2.77 (125 mg, 0.295 mmol) in toluene (1.5 mL) was subjected to IMDA reaction conditions (5 h, 120 °C).  Upon completion of the IMDA reaction, the solvent was evaporated 104  under reduced pressure and the residue was subjected to column chromatography (gradient elution, 20% → 30% EtOAc/hexanes).  Fractions containing the 2.122 (anti-endo adduct) and some 2.123 (anti-exo), plus compound 2.126 (desired product, arising through in situ epimerization of 2.122) were combined and evaporated to afford an ~ 4.2 : 1.9 : 1 mixture of the three isomers, respectively.  This material (33 mg, 0.078 mmol) was dissolved in toluene (0.26 mL) to which DBU (6 μL, 0.04 mmol) was added.  The mixture was stirred at 40 °C for 3.5 h, then it was cooled to rt, diluted with EtOAc (5 mL), rinsed with sat. aq. NH4Cl, washed with brine, dried over Na2SO4, and concentrated.  Purification by column chromatography (20% EtOAc/hexanes) afforded compound 2.126 as a clear film, contaminated with about 20% of 2.122 which produced a characteristic signal at 6.11 ppm (d, J = 10.2 Hz, 1H).  IR: 2955, 2930, 2857, 1693, 1151.  1H: 6.48 (d, J = 10.4 Hz, 1H), 6.35-6.27 (m, 1H), 6.18 (d, J = 10.4 Hz, 1H), 5.89-5.81 (m, 1H), 3.92-3.78 (m, 2H), 3.71-3.40 (m, 4H), 2.69 (dd, J = 13.7, 7.1 Hz, 1H), 2.65-2.55 (m, 1H), 2.43-2.31 (m, 1H), 2.19-2.03 (m, 2H), 1.92-1.74 (m, 1H), 1.51-1.40 (m, 2H), 0.85 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).  13C: 198.1, 142.6, 135.3, 130.0, 115.9, 68.9, 60.8, 57.8, 48.5, 45.4, 40.2, 38.7, 32.0, 30.3, 25.97, 18.3, 24.3, –5.3.  HRMS: calcd for C21H33NO4SiSNa [M + Na]+: 446.1797; found: 446.1794.  Synthesis of alcohol 2.130 A cold (–25 °C) solution of the crude tetracycle 2.126 (1.53 g, produced from dienone 2.105 (1.57 g, 3.71 mmol) as detailed previously) in THF (7.2 mL) was treated with TBAF (1 M solution in THF, 11.0 mL, 11.0 mmol).  The resulting dark brown mixture was stirred at –25 °C for 4 h, then H2O (10 mL) was added dropwise and the mixture was warmed to rt and diluted with 105  EtOAc (20 mL).  The organic phase was separated and the aqueous layer was extracted with EtOAc (3 mL x 3).  The combined organic phases was rinsed with H2O (5 mL), then with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (gradient eluent, 90% EtOAc/hexanes → EtOAc) afforded alcohol 2.130 (615 mg, 53% over three steps from 2.105) as a white foam.  This material contained approximately 15% of 2.131, that emanates from compound 2.127.  IR: 3529, 2936, 2894, 1689, 1306, 1148.  1H: 6.47 (d, J = 10.4 Hz, 1H), 6.35-6.27 (m, 1H), 6.17 (d, J = 10.4 Hz, 1H), 5.88-5.80 (m, 1H), 3.96-3.89 (m, 1H), 3.88-3.69 (m, 2H), 3.66-3.38 (m, 3H), 2.68 (dd, J = 13.6, 7.1 Hz, 1H), 2.65-2.54 (m, 1H), 2.46-2.34 (m, 1H), 2.20-2.04 (m, 2H), 1.91-1.74 (m, 1H), 1.68 (br s, 1H), 1.60-1.35 (m, 2H).  13C: 198.1, 142.6, 135.3, 130.0, 115.7, 68.9, 60.7, 57.8, 48.5, 45.6, 40.2, 38.7, 31.6, 30.0, 24.2.  HRMS: calcd for C15H19NO4SNa [M + Na]+: 332.0932; found: 332.0935.  Synthesis of iodide 2.257 Solid I2 (506 mg, 1.99 mmol) was added to a chilled (0 °C) solution of alcohol 2.130 (265 mg, 867 μmol), PPh3 (459 mg, 1.75 mmol), and imidazole (148 mg, 2.17 mmol) in THF (2.8 mL).  After 5 min, the reaction flask was taken out of the ice bath and the solution was stirred at rt for 2 h.  The mixture was diluted with EtOAc (10 mL) and rinsed with 10% aq. Na2S2O3 solution (5 mL x 2).  The combined aqueous phases was extracted once with EtOAc (3 mL).  The combined organic phases was rinsed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification of the residue by column chromatography (gradient elution, 30% → 40% EtOAc/hexanes) afforded the title compound (318 mg, 87%) as a yellow solid.  This material contained approximately 15% of the isomer emanating from compound 2.131.  M.P.: 189-106  192 °C (dec).  IR: 2934, 2898, 1689, 1306, 1137.  1H: 6.45 (d, J = 10.4 Hz, 1H), 6.36-6.28 (m, 1H), 6.17 (d, J = 10.4 Hz, 1H), 5.89-5.82 (m, 1H), 3.98-3.81 (m, 2H), 3.58-3.38 (m, 2H), 3.35-3.26 (m, 1H), 3.09-2.98 (m, 1H), 2.66-2.55 (m, 2H), 2.45-2.34 (m, 1H), 2.20-2.02 (m, 2H), 1.84-1.61 (m, 3H).  13C: 197.7, 142.1, 135.3, 130.2, 115.6, 68.5, 57.7, 49.2, 48.1, 40.1, 38.6, 32.6, 29.0, 24.2, 4.0.  HRMS: calcd for C15H19NO3SI [M + H]+: 420.0130; found: 420.0130.  Synthesis of cyanide 2.134 Solid tetraethylammonium cyanide (132 mg, 0.794 mmol) was added in one portion to a chilled (0 °C) solution of iodide 2.257 (300 mg, 0.716 mmol) in MeCN (2.4 mL).  The reaction flask was taken out of the ice bath and stirred at rt for 30 min.  The suspension was diluted with EtOAc (5 mL) and rinsed with 10% Na2S2O3 aq. solution (2 mL x 2).  The aqueous fractions were combined and extracted with EtOAc (1 mL x 3).  The combined organic extracts were washed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification of the residue by column chromatography (gradient elution, 60% → 65% EtOAc/hexanes) afforded 2.134 (200 mg, 88%) as a white solid.  This material contained approximately 15% of the isomer emanating from compound 2.131.  M.P.: 183-187 °C (dec).  IR: 2936, 2248, 1690, 1307, 1148.  1H: 6.45 (d, J = 10.5 Hz, 1H), 6.37– 6.28 (m, 1H), 6.21 (d, J = 10.5 Hz, 1H), 5.89-5.81 (m, 1H), 3.98-3.83 (m, 2H), 3.61-3.51 (m, 1H), 3.50-3.39 (m, 1H), 2.68-2.31 (m, 5H), 2.20-1.98 (m, 2H), 1.93-1.80 (m, 1H), 1.76-1.62 (m, 1H), 1.61-1.46 (m, 1H).  13C: 197.6, 141.5, 135.4, 130.6, 118.5, 115.5, 68.6, 57.7, 48.3, 47.9, 40.2, 39.0, 29.3, 25.1, 24.2, 16.5.  HRMS: calcd for C16H18N2O3SNa [M + Na]+: 341.0936; found: 341.0949.   107  Synthesis of enone-aldehyde 2.137 Commercial DIBAL (1 M solution in hexanes, 0.25 mL, 0.25 mmol) was added dropwise to a cold (–78 °C) solution of 2.134 (26 mg, 0.082 mmol) in CH2Cl2 (0.3 mL).  The mixture was stirred at –78 °C for 5 h, and then it was quenched by careful addition of MeOH (0.1 mL).  The reaction was taken out of the cold bath, diluted with EtOAc (2 mL), and treated with sat. aq. Rochelle’s salt (2 mL).  The resulting biphasic mixture was vigorously stirred overnight at rt.  The organic phase was separated and the aqueous layer was extracted with EtOAc (1 mL x 3).  The combined organic phases were rinsed with brine, dried over Na2SO4, and concentrated under reduced pressure to give crude aldehyde-alcohol as a mixture of diastereomers.  The crude was directly dissolved in CH2Cl2 (0.35 mL) and Dess-Martin periodinane (52 mg, 0.12 mmol) was added in one portion at rt.  The white suspension was allowed to stir at rt for 2 h.  The reaction was diluted with EtOAc (2 mL) and rinsed with 1:1 (v/v) 10% aq. Na2S2O3 / sat. aq. NaHCO3 (1 mL x 2).  The combined aqueous layers were back-extracted with EtOAc (1 mL x 3).  The combined extracts were rinsed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification of the residue by column chromatography (gradient elution, 75% → 80% EtOAc/hexanes) gave 2.137 as a clear film (7 mg, 27%).  This material contained approximately 15% of the isomer emanating from compound 2.131.  IR: 2927, 1719, 1690, 1307, 1148.  1H: 9.76 (br s, 1H), 6.47 (d, J = 10.5 Hz, 1H), 6.36-6.28 (m, 1H), 6.20 (d, J = 10.5 Hz, 1H), 5.89-5.81 (m, 1H), 3.93-3.76 (m, 2H), 3.56-3.37 (m, 2H), 2.74 (dd, J = 13.6, 7.1 Hz, 1H), 2.68-2.48 (m, 3H), 2.35-2.25 (m 1H), 2.21-2.07 (m, 1H), 1.93-1.64 (m, 3H), 1.44-1.29 (m, 1H).  13C: 200.7, 197.8, 142.1, 135.3, 130.3, 115.6, 69.0, 57.8, 48.2, 48.0, 42.0, 108  40.2, 38.6, 29.7, 24.2, 21.1.  HRMS: calcd for C17H24NO5S [M + MeOH + H]+: 354.1375; found: 354.1387.  Synthesis of pentacycle 2.138 Pyrrolidine (49 μL, 0.59 mmol) was added to solution of aldehyde 2.137 (19 mg, 0.059 mmol) in THF (0.6 mL) at rt.  The mixture was heated to 30 °C and stirred for 14 h, then it was quenched with 1 M HCl (1 mL), stirred for 30 min at rt, and then diluted with EtOAc (3 mL).  The organic phase was separated and the aqueous layer was extracted with EtOAc (1 mL x 5).  The combined extracts were rinsed with brine (2 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification of the residue by column chromatography (70% EtOAc/hexanes) afforded pentacyclic keto-aldehyde 2.138 (8 mg, 42%, clear film) as a 1:1 mixture of α- and β-aldehyde diastereomers.  This material was free of isomeric products emanating from compound 2.131.  IR: 2936, 1716, 1151.  1H: 9.79 (s, 1H) and 9.70 (s, 1H), 6.31-6.22 (m, 2H), 5.88-5.78 (m, 2H), 4.15-4.04 (m, 1H), 3.86-3.76 (m, 1H), 3.58-3.08 (m, 9H), 2.75 (d, J = 5.4 Hz, 1H), 2.69 (d, J = 5.4 Hz, 1H), 2.60-2.28 (m, 7H), 2.27-2.17 (m, 3H), 2.14-2.00 (m, 3H), 1.98-1.78 (m, 4H), 1.66-1.55 (m, 2H).  13C: 209.6, 209.0, 200.7, 199.7, 134.5, 134.4, 115.7, 115.5, 79.7, 79.2, 60.54, 60.51, 56.0, 55.2, 52.1, 52.0, 51.7, 50.2, 44.52, 44.48, 43.5, 42.6, 41.7, 41.6, 41.3, 37.3, 32.9, 30.3, 28.7, 27.5, 24.4 (2 signals).  HRMS: calcd for C16H20NO4S [M + H]+: 322.1113; found: 322.1109.    109  Synthesis of diketone 2.107 To a suspension of aldehyde 2.106 (15 mg, 0.049 mmol) and 2.153 (3.6 mg, 9.7 μmol) in THF under Ar atmosphere, was added NEt3 (10 μL, 0.072 mmol) at rt.  The reaction was stirred overnight (14 h) in an oil bath at 55 °C and cooled to rt.  The crude mixture was diluted with EtOAc (5 mL) and partitioned with 1 M HCl (2 mL).  The aqueous phase was extracted with EtOAc (1 mL x 3) and the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (70% EtOAc/hexanes eluent) gave the title compound (15 mg, 90% based on impurity) that was contaminated with 10% of starting material.  IR: 2961, 2925, 1745, 1718, 1332, 1307, 1151.  1H: 6.32-6.24 (m, 1H), 5.87-5.79 (m, 1H), 4.14-4.04 (m, 1H), 3.62-3.45 (m, 2H), 3.31-3.19 (m, 2H), 3.01-2.81 (m, 2H), 2.71 (dd, J = 18.4, 6.3 Hz, 1H), 2.56-2.43 (m, 2H),  2.28 (dd, J = 18.5, 12.1, 1H), 2.27-2.17 (m, 1H), 2.16-2.02 (m, 2H), 1.89 (app dd, J = 13.3, 6.1 Hz, 1H).  13C: 212.6, 207.3, 134.6, 115.2, 75.7, 60.0, 52.9, 50.2, 47.3, 42.9, 42.6, 40.6, 37.2, 31.0, 24.4.  HRMS: calcd for C15H17NO4SNa [M + Na]+: 330.0776; found 330.0782.  Synthesis of enone 2.158 The title compound was prepared through a literature procedure with minor modification.114  To a flame dried 1 L 3-neck round bottom flask equipped with an overhead stirrer and addition funnel was added p-anisaldehyde (61 mL, 0.50 mol), pyruvic acid (39 mL, 0.56 mol), and MeOH (50 mL).  The flask was cooled to 0 °C and the addition funnel was charged with a solution of KOH (48 g, 0.87 mol) in MeOH (160 mL).  The KOH solution was added dropwise over 30 min 110  during which time precipitation had occurred halfway through the addition.  After the addition had completed, the reaction appears as a yellow slurry with an oily residue at the bottom of the vessel.  The ice bath was switched to a warm water bath (temperature maintained between 30 ~ 45 °C) and stirred for 1 h, after which the reaction mixture appears as a yellow homogenous, opaque, suspension.  The warm bath was then removed and the mixture was stirred overnight at rt.  The resulting yellow paste was filtered by suction and allowed to air dry (approximately 1 h) until it became brittle solids.  The resulting solid was suspended in a beaker containing MeOH (200 mL), agitated, and then filtered by suction.  The process was repeated two more times using MeOH (200 mL) followed by Et2O (200 mL) as solvents to rinse the crude.  The brittle yellow solids (~116 g) obtained was dried under vacuum and used without further purification.  A sample for 1H NMR was prepared by dissolving the crude in 1 M HCl followed by extraction with EtOAc.  Upon removal of solvent with rotary evaporator , 1H NMR of the residue revealed that the crude material was contaminated with p-anisaldehyde (~13%).  To a flame dried 1 L round bottom flask equipped with an addition funnel was added MeOH (600 mL) and cooled to 0 °C.  The addition funnel was charged with AcCl (100 mL, 1.41 mol) and added dropwise over a period of 10 min (CAUTION: exothermic process).  Upon completion, the addition funnel was replaced with a short stem powder funnel and the aforementioned solid was added in small portions over a period of 15 min.  Then the ice bath was removed and the flask was equipped with a water condenser.  After stirring the yellow suspension at rt for 30 min, the reaction was refluxed for 5 h and then cooled to rt.  The solvent was removed under reduced pressure to give a yellow/orange residue.  The crude material was dissolved in CH2Cl2 (200 mL), partitioned with H2O (250 mL), and the aqueous layer was extracted with CH2Cl2 (50 mL x 3).  The combined organic layer was rinsed with half sat. aq. 111  NaHCO3 solution (150 mL), brine (100 mL), and dried over Na2SO4.  Concentration under reduced pressure followed by recrystallization from hot MeOH gave enone 2.158 (61.6 g, 55%) as a yellow crystalline powder.  Spectral data and physical property was in agreement to those reported in the literature.  M.P.: 101-104 °C [lit., 107-108 °C].115  1H: 7.85 (d, J = 16.1 Hz, 1H), 7.64-7.58 (m, 2H), 7.26 (d, J = 16.0 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H).  13C: 182.4, 163.0, 162.8, 148.7, 131.3, 127.0, 118.2, 114.8, 55.6, 53.1.  Synthesis of dihydropyran 2.258 To a round bottom flask containing enone 2.158 (61.6 g, 280 mmol) and ethyl vinyl ether (81 mL, 0.85 mol) in CH2Cl2 (180 mL) was added Yb(fod)3 (1.49 g, 1.4 mmol) in one portion.  The yellow murky solution was stirred at rt for 45 h, at which point crude 1H NMR showed complete consumption of enone 2.158.  The solvent was removed under reduced pressure and the crude material was passed through a plug of silica (150 mL) using EtOAc (350 mL) as the eluent.  Removal of solvent under vacuum afforded the endo hetero-Diels-Alder adduct 2.258 as a yellow oil.  This material was used without further purification.  IR: 2977, 2953, 2933, 1730, 1512, 1250, 1029.  1H: 7.18-7.09 (m, 2H), 6.89-6.80 (m, 2H), 6.12 (dd, J = 3.0, 0.8 Hz, 2H), 5.14 (dd, J = 7.9, 2.1 Hz, 2H), 4.03 (dq, J = 9.5, 7.1 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.72-3.63 (m, 1H), 3.63 (dq, J = 9.5, 7.0 Hz, 1H), 2.34-2.22 (m, 1H), 1.93 (ddd, J = 13.6, 9.3, 8.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H).  13C: 163.3, 158.6, 142.2, 135.0, 128.6, 115.1, 114.1, 100.1, 64.8, 55.4, 52.3, 37.1, 36.3, 15.2.  HRMS: calcd for C16H20O5Na [M + Na]+: 315.1208; found 315.1213.  112  Synthesis of tetrahydropyran 2.160 To a solution of hetero Diels-Alder adduct 2.258 (~280 mmol) in EtOH (300 mL) under argon atmosphere was added palladium on carbon (10% weight loading, 2.98 g, 2.80 mmol).  A balloon filled with hydrogen gas was attached and the reaction was stirred for 61 h (the balloon was refilled with hydrogen gas twice at 15 h and 43 h).  The suspension was filtered through pad of Celite® (EtOAc eluent) and concentrated under reduced pressure to obtain ester 2.160 (74.0 g, 90%) as a yellow oil.  IR: 2977, 2954, 2929, 2838, 1755, 1738, 1514, 1249, 1064, 1032, 1014.  1H: 7.15-7.08 (m, 2H), 6.89-6.82 (m, 2H), 4.60 (dd, J = 9.4, 2.1 Hz, 1H), 4.20 (dd, J = 11.7, 2.3 Hz, 1H), 4.05 (dq, J = 9.5, 7.1 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.59 (dq, J = 9.5, 7.1 Hz, 1H), 2.86 (tt, J = 12.5, 3.8 Hz, 1H), 2.15-1.96 (m, 2H), 1.77-1.58 (m, 2H), 1.26 (t, J = 7.1 Hz).  13C: 171.0, 158.4, 135.9, 127.7, 114.1, 102.0, 74.4, 64.7, 55.3, 52.3, 39.4, 38.0, 36.1, 15.3.  HRMS: calcd for C16H22O5Na [M + Na]+: 317.1365; found 317.1364.  Synthesis of benzyl ether 2.161 To a suspension of LiAlH4 (16.5 g, 413 mmol) in THF (100 mL) cooled to 0 °C was added a solution of ester 2.160 (74.0 g, 251 mmol) in THF (150 mL) via cannula.  The flask was rinsed with THF (10 mL x 3) and also added to the reaction.  After the addition had completed, the ice bath was removed and the reaction was stirred overnight (11 h) at rt.  On the following day, the reaction was cooled to 0 °C and Et2O (150 mL) was added slowly.  The reaction was quenched by sequential addition of H2O (16 mL), 15% NaOH aq. solution (45 mL), H2O (45 mL), and a scoop of MgSO4.  The resulting grey suspension was stirred at rt for 10 min 113  and then filtered through Celite.  The grey solids were collected, suspended in EtOAc (250 mL) and filtered.  The process was repeated two more times and the filtrate was concentrated under reduced pressure to give a clear oil.  The crude material was used without further purification.  To a flame dried round bottom flask was added NaH (57% dispersion in mineral oil, 17.1 g, 406 mmol) and rinsed with hexanes (30 mL x 2) and then suspended in THF (100 mL) at 0 °C.  The solution of crude from above in THF (80 mL) was added via cannula and the flask was rinsed with THF (5 mL x 2) was also added.  The ice bath was removed to let the reaction stir at rt for 1 h and then cooled to 0 °C.  A solution of BnBr (33.0 mL, 275 mmol) in THF (30 mL) was added to the reaction (rinsing the flask with THF, 10 mL x 2) followed by addition of NaI (371 mg, 2.48 mmol).  The reaction was stirred at 0 °C for 10 min, then at rt for 2 h to give a baige/light tanned mixture.  At this point, the reaction was judged complete by TLC (1:1 EtOAc/hexanes) and quenched by slowly adding 1 M HCl (100 mL) at 0 °C.  The mixture was diluted with Et2O (200 mL) and separated.  The aqueous layer was extracted with Et2O (50 mL x 3), combined the organic extracts, rinsed with 10% aq. Na2S2O3 aq. solution (100 mL), brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain an orange residue.  Subjecting the crude to column chromatography (gradient elution, 5% → 15% EtOAc/hexanes) gave benzyl ether 2.161 (87.9 g, 88%) as a pale oil.  IR: 2975, 2930, 2860, 1611, 1513, 1246, 1129, 1101, 1068, 1033.  1H: 7.40-7.26 (m, 5H), 7.18-7.10 (m, 2H), 6.91-6.83 (m, 2H), 4.68-4.55 (m, 3H), 4.04 (dq, J = 9.5, 7.1 Hz, 1H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.67 (dd, J = 10.0, 5.9 Hz, 1H), 3.62 (dq, J = 9.5, 7.1 Hz, 1H), 3.55 (dd, J = 10.0, 5.0 Hz, 1H), 2.82 (tt, J = 12.6, 3.8 Hz, 1H), 2.08-1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.64 (td, J = 12.7, 9.6 Hz, 1H), 1.46-1.32 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H).  13C: 158.2, 138.4, 136.9, 128.5, 127.8, 127.71, 114  127.68, 114.0, 101.8, 74.8, 73.6, 73.3, 64.4, 55.3, 39.3, 38.6, 36.2, 15.4.  HRMS: calcd for C22H28O4Na [M + Na]+: 379.1885; found 379.1882.  Synthesis of diol 2.162 To a solution of benzyl ether 2.161 (43.1 g, 121 mmol) in MeCN (150 mL) and H2O (200 mL) was added a solution of pTsOH•H2O (69.0 g, 363 mmol) in H2O (100 mL).  The reaction mixture was stirred at rt for 36 h then cooled to 0 °C.  Sat. aq. NaHCO3 (100 mL) was slowly added and followed by the addition of sat. aq. Na2CO3 (150 mL) to make the aqueous phase basic.  The aqueous phase was extracted with EtOAc (25 mL x 3), then the combined organic extract was sequentially rinsed with sat. aq. Na2CO3 (50 mL), brine (50 mL), and dried over Na2SO4.  Upon concentration under reduced pressure, white solids were and used without further purification.  To the aforementioned crude material dissolved in EtOH (120 mL) and Et2O (200 mL) was added NaBH4 (6.87 g, 182 mmol) over 5 min at rt and stirred overnight (15 h).  The reaction was quenched with MeOH (50 mL) and stirred the mixture for 15 min at rt.  The mixture was cooled to 0 °C and 6 M HCl (35 mL) was slowly added to give a white suspension.  After stirring for 3 h at rt, the solvent was removed to obtain a white slurry.  The residue was suspended in H2O (200 mL) and extracted with EtOAc (100 mL x 3).  The combined organic extracts was rinsed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain a pail oil.  Purification by column chromatography (gradient elution, 60% EtOAc/hexanes → 100% EtOAc → 15% acetone/EtOAc) afforded diol 2.162 (33.1 g, 83%) as a pale oil.  IR: 3372, 2933, 2860, 1610, 1511, 1246, 1030.  1H: 7.37-7.23 (m, 5H), 7.15-7.07 (m, 2H), 6.87-6.80 (m, 2H), 4.46 (s, 2H), 3.78 (s, 3H), 3.59-3.42 (m, 3H), 3.33 (dd, J = 9.4, 3.2 Hz, 1H), 3.25 (dd, J = 115  9.4, 7.8 Hz, 1H), 3.08-2.95 (m, 1H), 2.12 (br s, 2H), 1.93-1.78 (m, 2H), 1.76 (ddd, J = 13.9, 10.1, 4.0 Hz, 1H), 1.56 (ddd, J = 13.8, 11.1, 2.7 Hz, 1H).  13C: 158.2, 138.0, 136.4, 128.8, 128.6, 127.89, 127.86, 114.1, 75.1, 73.4, 68.3, 61.1, 55.4, 40.2, 40.1, 37.7.  HRMS: calcd for C20H26O4Na [M + Na]+: 353.1729; found 353.1725.  Synthesis of phenol 2.259 To a solution of diol 2.162 (29.3 g, 88.7 mmol) in NMP (150 mL) was added pulverized anhydrous Na2S (28.0 g, 359 mmol) at rt.  The burgundy colored suspension was purged with argon under sonication for 20 min then attached a water condenser before immersing into an oil bath preheated to 170 °C.  The reaction was stirred overnight (13 h) at which point the starting material has been consumed based on TLC analysis (10% hexanes/EtOAc eluent).  The greyish yellow suspension was cooled to 0 °C then H2O (250 mL), 1 M HCl (150 mL, slow addition), 6 M HCl (85 mL) were added in sequentially.  The suspension was filtered through a pad of Celite (EtOAc eluent, 250 mL) and the layers were separated.  The aqueous was extracted with EtOAc (50 mL x 15) and the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure.  The resulting dark oil was subjected to Kugelrohr distillation to remove residual NMP and compounds containing sulfur to give a dark amorphous solid.  On a small scale (< 5g), the crude material could be purified by column chromatography (gradient elution, 70% EtOAc/hexanes → EtOAc → 2% MeOH/EtOAc).  On large scale (> 5g), the material was used in the subsequent step without further purification.  IR: 3331, 2934, 2861, 1614, 1514, 1236.  1H (300 MHz, acetone-d6): 8.11 (br s, 1H), 7.37-7.21 (m, 5H), 7.11-7.02 (m, 2H), 6.81-6.72 (m, 2H), 4.44 (s, 2H), 3.52-3.34 (m, 3H), 3.31 (br s, 1H), 3.30 (br s, 1H), 3.04 (tt, J = 10.2, 5.3 Hz, 116  1H), 1.9-1.58 (m, 4H).  13C (75 MHz, acetone-d6): 156.4, 139.8, 136.6, 129.6, 129.0, 128.3, 128.1, 115.9, 76.4, 73.5, 68.4, 60.7, 41.9, 41.6, 38.2.  HRMS: calcd for C19H24O4Na [M + Na]+: 339.1572; found 339.1575.  Synthesis of bis-TBS 2.163 To a solution of crude diol 2.259 in MeCN (180 mL) was added TBSCl (32.7 g, 213 mmol) and imidazole (14.5 g, 213 mmol).  The resulting suspension was stirred at rt for 2.5 h and quenched with sat. aq. NH4Cl (100 mL).  The suspension was diluted with H2O (50 mL) and EtOAc (100 mL), then the layers were separated.  The aqueous layer was extracted with EtOAc (50 mL x 3) and the combined organic extract was rinsed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure.  Purification of the resulting residue by column chromatography (gradient elution, 5% → 20% EtOAc/hexanes) gave bis-TBS 2.163 (28.6 g, 59%) and tris-TBS 2.260 (19.1 g, 33%), both as an amber oil.  IR: 3454, 2932, 2859, 1508, 1255, 1097.  1H: 7.37-7.24 (m, 5H), 7.05-6.97 (m, 2H), 6.79-6.71 (m, 2H), 4.46 (s, 2H), 3.57-3.47 (m, 1H), 3.46-3.37 (m, 2H), 3.33 (dd, J = 9.4, 3.2 Hz, 1H), 3.23 (dd, J = 9.4, 7.7 Hz, 1H), 2.96 (tt, J = 10.4, 5.3 Hz, 1H), 2.20 (br d, J = 3.7 Hz, 1H), 1.92-1.67 (m, 3H), 1.61-1.49 (m, 1H), 0.98 (s, 9H), 0.85 (s, 9H), 0.18 (s, 6H), −0.039 (s, 3H), −0.042 (s, 3H).  13C: 154.0, 138.1, 137.1, 128.8, 128.6, 127.88, 127.85, 120.1, 75.1, 73.4, 68.3, 61.4, 40.6, 40.4, 37.7, 26.1, 25.9, 18.4, 18.3, −4.3, −5.2.  HRMS: calcd for C31H52O4Si2Na [M + Na]+: 567.3302; found 567.3306. tris-TBS 2.260  IR: 2955, 2929, 2895, 2857, 1509, 1252, 1098.  1H: 7.39-7.23 (m, 5H), 7.08-6.99 (m, 2H), 6.82-6.74 (m, 2H), 4.44 (s, 2H), 3.68-3.57 (m, 1H), 3.52-3.24 (m, 2H), 3.31 (t, J = 5.0 Hz, 2H), 2.97 (tt, 117  J = 9.7, 4.5 Hz, 1H), 1.97-1.57 (m, 4H), 1.01 (s, 9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.20 (s, 6H), 0.00 (s, 3H), −0.01 (s, 3H), −0.03 (s, 3H), −0.04 (s, 3H).  13C: 153.8, 138.6, 137.5, 129.0, 128.4, 127.7, 127.6, 120.0, 75.4, 73.2, 69.6, 61.1, 41.8, 41.3, 37.3, 26.2, 26.1, 25.9, 18.42, 18.38, 18.36, −3.8, −4.3, −4.6, −5.2.  HRMS: calcd for C37H66O4Si3Na [M + Na]+: 681.4167; found 681.4154.  Synthesis of N-Boc methansulfonamide (2.164) The title compound was prepared through a literature procedure.116  To a suspension of methanesulfonamide (4.90 g, 50 mmol) in CH2Cl2 (50 mL) was added DMAP (617 mg, 5 mmol) followed by NEt3 (7.7 mL, 55 mmol) at rt.  To the mixture was added a solution of Boc2O (12.6 g, 55 mmol) was added via syringe at rt.  The reaction was stirred for 3 h at rt and the solvent was removed under reduced pressure.  The residue was dissolved in EtOAc (200 mL) and was successively rinsed with 1 M HCl (75 mL), H2O (75 mL), brine (75 mL), and then dried over Na2SO4.  Upon evaporation with rotary evaporator, a white solid was obtained, which was triturated with hexanes (15 mL x 2) to give pure 2.164 (9.06 g, 93%) as crystalline white solids.  M.P.: 115-117 °C [lit., 108-109 °C].116  1H: 7.85 (d, J = 16.1 Hz, 1H), 7.64-7.58 (m, 2H), 7.26 (d, J = 16.0 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H).  13C: 182.4, 163.0, 162.8, 148.7, 131.3, 127.0, 118.2, 114.8, 55.6, 53.1.  Synthesis of N-Boc sulfonamide 2.165 To a round bottom flask containg alcohol 2.163 (21.4 g, 39.2 mmol), sulfonamide 2.164 (10.1 g, 51.5 mmol), PPh3 (13.6 g, 51.5 mmol) in THF (80 mL) cooled to 0 °C was added DIAD (10.7 mL, 51.6 mmol) dropwise over 5 min.  A water condenser was attached to the flask and 118  after stirring for 10 min at rt, the reaction was stirred overnight (17 h) in an oil bath (65 °C).  The solvent was removed under reduced pressure and 1:1 Et2O/hexanes (40 mL) was added to precipitate out OPPh3 from the crude.  The mixture was cooled inside a freezer (−20 °C) for 0.5 h, filtered the solids, and the filtrate was concentrated under reduced pressure.  A second round of recrystallization was performed using 20% Et2O/hexanes and the remaining residue was purified by column chromatography (gradient elution, 5% → 11% EtOAc/hexanes) to obtain Mitsunobu product 2.165 (19.1 g, 67%) as a yellow oil.  IR: 2932, 2859, 1727, 1355, 1254, 1149.  1H: 7.37-7.23 (m, 5H), 7.03-6.96 (m, 2H), 6.80-6.72 (m, 2H), 4.58-4.36 (m, 3H), 3.82 (t, J = 9.8 Hz, 1H), 3.48 (dd, J = 9.9, 5.2 Hz, 1H), 3.47-3.28 (m, 2H), 3.11 (s, 3H), 2.72-2.59 (m, 1H), 2.18-1.86 (m, 3H), 1.70-1.56 (m, 1H), 1.46 (s, 9H), 0.98 (s, 9H), 0.85 (s, 9H), 0.18 (s, 6H), −0.06 (s, 6H).  13C: 154.1, 151.6, 138.0, 136.7, 128.6, 128.5, 127.9, 120.2, 84.3, 73.1, 69.9, 60.9, 56.7, 41.6, 39.3, 38.4,, 38.1, 28.1, 26.1, 25.8, 18.4, 18.3, −4.3, −5.25, −5.31.  HRMS: calcd for C37H63NO7Si2SNa [M + Na]+: 744.3762; found 744.3459.  Synthesis of phenol 2.166 To a solution of Mitsunobu adduct 2.165 (19.1 g, 26.5 mmol) in THF (44 mL) cooled to −78 °C was added a solution of t-BuOK (2.0 M solution in THF, 27 mL, 54 mmol).  The resulting yellow mixture was stirred for 1 h at −78 °C and then a solution of acrolein (2.4 mL, 34.5 mmol) in THF (7 mL) was added dropwise.  The flask containing acrolein was rinsed with THF (3 mL) and also added to the reaction mixture.  The turquoise colored reaction mixture was stirred 1 h at −78 °C and a second aliquot of of t-BuOK (2.0 M solution in THF, 48 mL, 96 mmol) was added.  The cool bath was gradually warmed up to −30 °C over 30 min, then the 119  reaction vessel was taken out from the cool bath.  The reaction was stirred for 30 min at rt, then stirred overnight (15 h) at 50 °C.  On the following day, the reaction was cooled to rt and quenched with NH4Cl (50 mL) and H2O (10 mL).  The biphasic mixture was stirred at rt for 10 min, separated and the aqueous layer was extracted with EtOAc (50 mL x 3).  The combined organic layers were rinsed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (gradient elution, 25% → 35% EtOAc/hexanes) gave phenol 2.166 (9.52 g, 66%) as an orange oil.  IR: 3285, 2931, 2859, 1514, 1094.  1H: 7.40-7.26 (m, 5H), 6.98-6.91 (m, 2H), 6.83 (dd, J = 14.9, 10.9 Hz, 1H), 6.76-6.68 (m, 2H), 6.26 (app dt, J = 17.0, 10.4 Hz, 1H), 6.04 (d, J = 14.9 Hz, 1H), 5.58 (app d, J = 16.9 Hz, 1H), 5.52 (app d, J = 10.0 Hz, 1H), 5.16 (s, 1H), 4.61 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H), 3.49-3.29 (m, 4H), 3.21-3.07 (m, 1H), 2.71-2.57 (m, 1H), 1.92 (t, J = 7.4 Hz, 2H), 1.87-1.74 (m, 1H), 1.70-1.54 (m, 1H), 0.86 (s, 9H), −0.03 (s, 6H).  13C: 154.3, 141.1, 137.8, 135.5, 132.7, 129.2, 128.8, 128.7, 128.1, 128.0, 127.0, 115.6, 73.4, 70.6, 60.8, 51.9, 40.5, 39.1, 37.9, 26.1, 18.4, −5.20, −5.22.  HRMS: calcd for C29H43NO5SiSNa [M + Na]+: 568.2529; found 568.2508.  Synthesis of dienone 2.167 The following reaction was performed with non-flame dried glassware and unpurified solvents.  To a suspension of DIB (42 mg, 0.13 mmol) in CH2Cl2 (0.43 mL) was added TFA (10 μL, 0.13 mmol) and stirred at rt for 5 min.  A solution of 2.166 (63 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) was added dropwise by pipette.  The reaction was stirred at rt for 15 min and then concentrated under reduced pressure.  Purification by column chromatography (15% EtOAc/hexanes) gave the title compound as a amber oil (27 mg, 43%).  IR: 2955, 2928, 2856, 1668, 1150, 1086.  1H: 7.43-120  7.27 (m, 5H), 7.05-6.90 (m, 2H), 6.85 (app dd, J = 14.9, 10.9 Hz, 1H), 6.27-6.09 (m, 4H), 5.55 (app d, J = 17.1 Hz, 1H), 5.47 (app d, J = 9.97 Hz, 1H), 4.54 (ABq, ΔδAB = 0.07, JAB = 11.6 Hz,  2H), 4.35-4.26 (m, 1H), 4.13 (dd, J = 10.3, 3.1 Hz, 1H), 3.61-3.45 (m, 3H), 2.47-2.31 (m, 2H), 2.02 (td, J = 14.5, 9.4 Hz, 1H), 1.41-1.27 (m, 1H), 1.19-1.04 (m, 1H), 0.86 (s, 9H), 0.003 (3H), 0.000 (s, 3H).  13C: 185.7, 152.0, 147.4, 140.7, 137.7, 132.5, 129.8, 129.6, 128.7, 128.2, 127.9, 127.8, 127.1, 73.6, 68.7, 67.1, 61.5, 61.0, 46.2, 33.3, 31.6, 26.0, 18.3, 5.2, 5.3.  HRMS: calcd for C29H41NO5SiSNa [M + Na]+: 566.2372; found 566.2379.  Synthesis of tetracycle 2.171 The following reaction was performed with non-flame dried glassware and unpurified solvents.  To a suspension of DIB (3.60 g, 11.0 mmol) in stock CH2Cl2 (37 mL) was added TFA (0.84 mL, 10.9 mmol) and stirred at rt for 5 min.  Meanwhile, an addition funnel was charged with a solution of phenol 2.166 (5.43 g, 9.95 mmol) in stock CH2Cl2 (50 mL) and added dropwise over 10 min.  The reaction was stirred at rt for 30 min during which time the reaction gradually turns brown.  The solvent and acetic acid was removed azeotropically with toluene (5 mL x 2) under reduced pressure to obtain a dark brown oil.  The crude was dissolved in anhydrous toluene (100 mL) and 2,6-lutidine (1.8 mL, 15.5 mmol) was added at rt.  A water condenser was attached the solution was purged with argon under sonication for 30 min.  The reaction was heated to reflux for 1.5 h then cooled to rt.  Evaporation of solvent under reduced pressure gave a brown oil, which contained a mixture of Diels-Alder adducts and uncharacterizable compounds. 121   The crude mixture obtrained from Diels-Alder reaction was dissolved in dry THF (17 mL) and DBU (0.75 mL) was added.  The mixture was stirred overnight (20 h) at rt and quenched with 0.1 M HCl (20 mL).  The phases were separated and the aqueous layer was extracted with EtOAc (30 mL x 3).  The organic extracts were combined, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (gradient elution, 20% → 30% EtOAc/hexanes) to give tetracyclic enone 2.171 (3.28 g, 61%) as a light brown oil.  IR: 2953, 2928, 2856, 1691, 1329, 1151, 1094.  1H: 7.38-7.25 (m, 5H), 6.56 (d, J = 10.4 Hz, 1H), 6.35-6.25 (m, 1H), 6.11 (d, J = 10.4 Hz, 1H), 5.89-5.80 (m, 1H), 4.59 (ABq, ΔδAB = 0.06, JAB = 11.9 Hz, 2H), 4.37-4.25 (m, 1H), 3.91-3.82 (m, 1H), 3.66-3.43 (m, 5H), 2.65 (dd, J = 13.6, 7.1 Hz, 1H), 2.65-2.54 (m, 1H), 2.38 (dt, J = 12.7, 6.8 Hz, 1H), 2.25-2.02 (m, 2H), 1.85 (td, J = 12.7, 9.8 Hz, 1H), 1.52-1.32 (m, 2H), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).  13C: 198.1, 143.5, 138.1, 135.3, 129.5, 128.5, 127.7 (2 signals), 115.6, 73.6, 73.0, 68.7, 61.8, 60.7, 57.9, 46.0, 39.9, 38.6, 32.8, 32.0, 25.9, 24.3, 18.2, −5.4.  HRMS: calcd for C29H42NO5SiS [M + H]+: 544.2553; found 544.2546.  Synthesis of macrocycle 2.169 The title compound is obtained as a byproduct when the tandem IMDA reaction was performed in the absence of 2,6-lutidine.  A solution of phenol 2.166 (358 mg, 0.656 mmol) in CH2Cl2 (3.3 mL) was added into a solution of DIB (237 mg, 0.721 mmol) in CH2Cl2 (2.4 mL) and TFA (55μL, 0.71 mmol).  After stirring the reaction for 30 min at rt, the solvent was removed under reduced pressure.  The crude was dissolve in toluene (6 mL) and refluxed for 3 h.  The solvent was removed and redissolved in THF (3.3 mL) and DBU (50 μmL, 122  0.34 mmol) was added.  The reaction was stirred overnight (12 h) at rt and quenched with NH4Cl (5 mL).  The mixture was passed through a pad of Celite® (EtOAc eluent, 30 mL) and the phases were separated.  The aqueous layer was extracted with EtOAc (2 mL x 3), the organic extracts were combined, rinse with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure.  The residue was purified by column chromatography (25% → 30% EtOAc/hexanes) to give enone 2.171 (144 mg, 40%) and tricyclic phenol 2.169 (34 mg, 6%) as a baige solid.  IR: 3400, 2953, 2929, 2858, 1141, 1100.  1H: 7.38-7.23 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.48 (ddd, J = 9.7, 5.1, 2.5 Hz, 1H), 6.18 (ddd, J = 8.7, 5.6, 2.3 Hz, 1H), 5.40-5.32 (br m, 1H), 5.05 (br s, 1H), 4.48 (ABq, ΔδAB = 0.05, JAB = 11.9 Hz, 2H), 3.91 (br d, J = 10.3 Hz, 1H), 3.79-3.65 (m, 1H), 3.57-3.48 (m, 2H), 3.47-3.36 (m, 3H), 3.34-3.24 (m, 1H), 3.22-3.10 (m, 1H), 2.07 (dd, J = 14.1, 2.4 hz, 1H), 2.00-1.90 (m, 2H), 1.77 (dt, J = 14.2, 11.5 Hz, 1H), 0.81 (s, 9H), −0.11 (s, 3H), −0.15 (s, 3H).  13C: 151.0, 137.9, 135.9, 133.8, 129.4, 128.6, 127.92, 127.89, 125.0, 123.4, 118.2, 115.6, 74.4, 73.6, 61.4, 60.3, 55.4, 41.8, 39.6, 35.1, 26.1, 26.0, 25.8, 18.3, −5.4, −5.5.  HRMS: calcd for C29H41NO5SiSNa [M + Na]+: 566.2372; found 566.2374.  Synthesis of silyldienic phenol 2.183 To a solution of Mitsunobu adduct 2.165 (567 mg, 0.79 mmol) in THF (1.6 mL) cooled to −78 °C was added a solution of t-BuOK (1.5 M solution in THF, 1.1 mL, 1.7 mmol).  The resulting yellow mixture was stirred for 1 h at −78 °C and then a solution of 3-(phenyldimethylsilyl)acrolein (211 mg, 1.11 mmol) in THF (1.0 mL) was added dropwise.  The reaction mixture was stirred for 30 min at −78 °C and then a second 123  aliquot of of t-BuOK (1.5 M solution in THF, 2.1 mL, 3.2 mmol) was added.  The reaction was stirred for another 30 min at −78 °C, then gradually warmed the cool bath to 0 °C over 1 h, at which point the cool bath was removed and stirred the reaction at rt for 30 min.  The reaction was then stirred in an oil bath at 70 °C for 3.5 h and cooled to rt.  The resulting reddish-brown slurry was quenched with NH4Cl (5 mL) and diluted with EtOAc (5 mL).  The mixture was separated and the aqueous phase was extracted with EtOAc (10 mL x 3) and the organic fractions were combined, rinsed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (gradient elution, 20% → 25% EtOAc/hexanes) gave the title compound as a yellow oil (439 mg, 82%).  IR: 3381, 2954, 2929, 2857, 1515, 1251, 1099.  1H: 7.57-7.50 (m, 2H), 7.44-7.38 (m, 3H), 7.35-7.25 (m, 5H), 6.95-6.88 (m, 2H), 6.80 (ddd, J = 14.8, 6.3, 3.4 Hz, 1H), 6.66-6.59 (m, 2H), 6.44 (d, J = 6.4 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 5.97 (d, J = 14.8 Hz, 1H), 5.00 (br s, 1H), 4.63 (d, J = 7.7 Hz, 1H), 4.45 (s, 2H), 3.48-3.28 (m, 4H), 3.16-3.04 (m, 1H), 2.70-2.56 (m, 1H), 1.92 (app t, J = 7.6 Hz, 2H), 1.87-1.73 (m, 1H), 1.69-1.55 (m, 1H), 0.87 (s, 9H), 0.42 (s, 3H), 0.41 (s, 3H), 0.02 (s, 6H).  13C: 154.2, 144.3, 142.5, 140.2, 137.8, 137.4, 135.5, 134.0, 129.6, 129.0, 128.8, 128.6, 128.2, 128.1, 128.0, 115.5, 73.3, 70.5, 60.8, 51.9, 40.6, 39.1, 38.0, 26.1, 18.4, 2.87, 2.90, 5.2.  HRMS: calcd for C37H53NO5SSi2Na [M + Na]+: 702.3081; found 702.3077.  Synthesis of enone-aldehyde 2.197 To a solution of tetracyclic enone 2.171 (3.99 g, 7.34 mmol) in THF (15 mL) cooled to 0 °C was added TBAF (1.0 M solution in THF, 12.5 mL, 12.5 mmol).  The dark brown reaction mixture was stirred for 1.5 h while allowing the cool bath to gradually warm up to 10 °C.  At this point, TLC 124  (20% EtOAc/hexanes eluent) showed absence of starting material.  The reaction was diluted with cold EtOAc (−20 °C, 30 mL) and H2O (8 mL) was added dropwise.  The reaction was stirred for 10 min at rt and the white solids were filtered through a cotton plug.  The solids were rinsed with cold EtOAc (−20 °C, 10 mL x 4) and the combined organic filtrate was rinsed with H2O (30 mL x 2) then with brine (30 mL) and dried over Na2SO4.  Removal of solvent under reduced pressure gave a dark orange oil that was used without further purification.  To the solution of crude alcohol in CH2Cl2 (25 mL) was added DMP (4.26 g, 9.54 mmol) at rt.  The reaction was stirred for 50 min at rt and then filtered through a pad of Celite® (CHCl3 eluent, 25 mL).  The filtrate was concentrated and purified by column chromatography (gradient elution, 60% → 70% EtOAc/hexanes).  The collected product was contaminated with byproducts emanating from DMP.  The product was dissolved in CHCl3 (50 mL) and rinsed with 1:1:2 mixture of 10% aq. Na2S2O3/sat. aq. NaHCO3/H2O (16 mL).  The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give aldehyde 2.197 (2.78 g, 89%) as an off white foam.  IR: 3036, 2859, 2733, 1722, 1691, 1327, 1307, 1150.  1H: 9.68 (br s, 1H), 7.34-7.25 (m, 5H), 6.53 (d, J = 10.4 Hz, 1H), 6.33-6.24 (m, 1H), 6.11 (d, J = 10.4 Hz, 1H), 5.88-5.78 (m, 1H), 4.56 (ABq, ΔδAB = 0.06, JAB = 11.9 Hz, 2H), 4.41-4.28 (m, 1H), 3.98-3.90 (m, 1H), 3.63-3.40 (m, 3H), 2.67-2.38 (m, 6H), 2.16-2.02 (m, 1H), 1.82 (td, J = 11.7, 9.3 Hz, 1H).  13C: 198.9, 197.8, 142.9, 138.0, 135.3, 129.8, 128.5, 127.81, 127.75, 115.5, 73.7, 72.5, 68.2, 61.8, 57.9, 43.2, 42.7, 40.0, 38.7, 32.4, 24.2.  HRMS: calcd for C23H25NO5SNa [M + Na]+: 450.1351; found 450.1367.    125  Synthesis of pentacycle 2.199 A suspension of aldehyde 2.197 (1.79 g, 4.19 mmol), Glorius pre-catalyst 2.153 (295 mg, 0.793 mmol), and BHT (46 mg, 0.21 mmol) in dioxane (85 mL) was prepared in a round bottom flask,.  This was purged with Argon under sonication for 30 min, then DBU (115 μL, 0.770 mmol) was added dropwise at rt.  The reaction immediately turns vermilion and the reaction was refluxed in an oil bath for 1.5 h, then cooled to rt.  The reaction was quenched by adding 1:1 mixture of 1 M HCl/brine (30 mL) and partitioned.  The aqueous layer was extracted with EtOAc (30 mL x 4) and the combined organic extracts was rinsed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give a bright yellow foam.  Purification by silica gel chromatography (gradient elution, 15% → 20% EtOAc/CHCl3) afforded pentacyclic diketone (0.98 g, 55%) as a yellow foam.  IR: 2926, 2892, 2863, 1746, 1720, 1325, 1307, 1150.  1H: 7.38-7.23 (m, 5H), 6.31-6.20 (m, 1H), 5.86-5.74 (m, 1H), 4.56 (ABq, ΔδAB = 0.04, JAB = 12.0 Hz, 2H), 4.58-4.49 (m, 1H), 3.84-3.76 (m, 1H), 3.59 (br d, J = 4.0 Hz, 2H), 3.55-3.41 (m, 2H), 2.75-2.58 (m, 3H), 2.56-2.28 (m, 5H), 2.17-2.02 (m, 1H), 2.01-1.87 (m, 1H).  13C: 212.2, 207.4, 137.7, 135.5, 128.6, 127.9, 127.6, 115.1, 74.8, 73.5, 72.2, 63.5, 58.3, 53.7, 44.2, 43.1, 42.5, 40.0, 36.0, 33.8, 24.4.  HRMS: calcd for C23H24NO5S [M − H]−: 426.1375; found 426.1367.  Synthesis of alcohol 2.200 To a solution of benzyl ether 2.199 (154 mg, 0.360 mmol) in CH2Cl2 (1.5 mL) cooled to −95 °C was added BBr3 (1.0 M solution in CH2Cl2, 0.8 mL, 0.8 mmol) dropwise via syringe.  The orange-brown mixture was stirred for 30 min at −95 °C before diluting with EtOAc (10 mL) and quenching with 1 M 126  HCl (5 mL).  The resulting dark green mixture was stirred at rt for 3 h and then the phases were separated.  The aqueous phase was extracted with EtOAc (10 mL x 3) and the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure.  The residue was purified by column chromatography (gradient elution, 70% EtOAc/hexanes → EtOAc) to give alcohol 2.200 (81 mg, 67%) as a slightly tanned foam.  On a smaller scale (0.18 mmol), the yield was 70%, while a large scale reaction (2.3 mmol) returned the product in 39% yield.  IR: 3486, 2927, 2888, 1744, 1719, 1321, 1306, 1150.  1H: 6.35-6.20 (m, 1H), 5.89-5.74 (m, 1H), 4.46 (tt, J = 8.5, 3.8 Hz, 1H), 3.88-3.76 (m, 2H), 3.63 (dd, J = 11.8, 3.9 Hz, 1H), 3.57-3.45 (m, 1H), 3.44 (dd, J = 7.7, 3.5 Hz, 1H), 2.88-2.62 (m, 3H), 2.55-2.32 (m, 6H), 2.19-2.03 (m, 1H), 2.00-1.86 (m, 1H).  13C: 212.2, 207.4, 135.8, 115.0, 74.9, 66.0, 64.6, 58.5, 54.1, 44.5, 43.5, 42.6, 39.9, 36.2, 33.5, 24.5.  HRMS: calcd for C16H19NO5SNa [M + Na]+: 360.0882; found 360.0876.  Synthesis of diol 2.261 To a solution of benzyl ether 2.163 (19.27 g, 35.4 mmol) in EtOAc (40 mL) under atmosphere of argon was added palladium on carbon (10% weight loading, 3.77 g, 3.54 mmol).  The reaction vessel was purged with hydrogen (balloon) and stirred at rt.  A small aliquot of the reaction was taken every 20 ~ 24 h to monitor the progress by 1H NMR.  If the starting material was observed, the reaction was stopped and filtered through a pad of Celite with EtOAc.  The solvent was removed under reduced pressure, dissolved the crude in EtOAc (40 mL), added 10% Pd/C (3.77 g, 3.54 mmol) and attached a hydrogen balloon to resume the reaction.  This process was repeated one more time until no more starting material was seen in the crude 1H NMR (total of 67 h).  When the reaction has completed, the mixture was filtered through Celite and concentrated under reduced 127  pressure to give diol 2.261 as a colorless oil.  This material was used without further purification.  IR: 3371, 2955, 2931, 2897, 2859, 1509, 1255, 1099.  1H: 7.06-6.97 (m, 2H), 6.81-6.72 (m, 2H), 3.52-3.28 (m, 5H), 2.93 (tt, J = 10.2, 4.8 Hz, 1H), 2.07 (br s, 2H), 1.93-1.67 (m, 3H), 1.57 (ddd, J = 13.8, 10.9, 2.9 Hz, 1H), 0.97 (s, 9H), 0.86 (s, 9H), 0.18 (s, 6H), −0.03 (s, 6H).  13C: 154.1, 136.9, 128.7, 120.2, 70.2, 67.3, 61.2, 40.4, 40.2, 37.7, 26.1, 25.8, 18.4, 18.3, −4.3, −5.2.  HRMS: calcd for [M + Na]+: C24H46O4Si2Na: 477.2832; found 477.2840.  Synthesis of PMB ether 2.219 To a solution of diol 2.261 (35.4 mmol) in CH2Cl2 (38 mL) was added a solution of p-anisaldehyde dimethyl acetal (~70% purity, 11.0 g, 42.3 mmol) in CH2Cl2 (5 mL) via syringe.  Solid PPTS (890 mg, 3.54 mmol) was added in one portion and the resulting mixture was stirred at rt for 5 h, then quenched with sat. aq. NaHCO3 (50 mL).  The biphasic mixture was stirred for 5 min, diluted with EtOAc (100 mL) and the two phases were separated.  The aqueous layer was extracted with EtOAc (20 mL x 3) and the combined organic layers was rinsed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure to give PMP acetal 2.218 as a mixture of diastereomers (3:2 ratio).  To the cooled (−78 °C) solution of the above crude in CH2Cl2 (90 mL) was added DIBAL (1.0 M solution in hexanes, 124 mL, 124 mmol) over a period of 20 min.  The cool bath was gradually warmed up to 5 °C over 3.5 h, at which point the reaction was judged complete by TLC analysis (20% EtOAc/hexanes).  The reaction was cooled to −30 °C and quenched by slowly adding MeOH (3 mL).  The cool bath was removed and the reaction was stirred for 5 min at rt, followed by addition of sat. aq. Rochelle salt (200 mL) and EtOAc (100 mL).  The cloudy 128  biphasic mixture was stirred for 1 h and then separated.  The aqueous layer was extracted with EtOAc (50 mL x 3) and the organic fractions were combined, and rinsed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure.  Occasionally, an emulsion formed during the extraction process, which was resolved by passing the mixture through a pad of Celite®.  Purification by column chromatography (gradient elution, 10% → 25% EtOAc/hexanes) afforded alcohol 2.219 as a clear oil (12.91 g, 63%).  IR: 3447, 2953, 2930, 2858, 1510, 1250.  1H: 7.28-7.21 (m, 2H), 7.00-6.92 (m, 2H), 6.92-6.85 (m, 2H), 6.79-6.72 (m, 2H), 4.37 (ABq, ΔδAB = 0.06, JAB = 11.0 Hz, 2H), 3.81 (s, 3H), 3.60 (dd, J = 11.5, 3.6 Hz, 1H), 3.49-3.30 (m, 3H), 3.28-3.19 (m, 1H), 2.94 (tt, J = 10.5, 4.6 Hz, 1H), 1.97 (ddd, J = 13.9, 9.1, 4.3 Hz, 1H), 1.92-1.78 (m, 1H), 1.76-1.57 (m, 4H), 0.98 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), −0.035 (s, 3H), −0.043 (s, 3H).  13C: 159.4, 154.0, 137.2, 130.8, 129.6, 128.8, 120.1, 114.1, 71.6, 64.5, 61.1, 55.4, 40.6, 39.2, 37.8, 26.1, 25.8, 18.4, 18.4, −4.3, −5.2.  HRMS: calcd for C32H54O5Si2Na [M + Na]+: 597.3408; found 597.3400.  Synthesis of aldehyde 2.262 To a solution of alcohol 2.219 (2.53 g, 4.40 mmol) in stock CH2Cl2 (15 mL) was added DMP (2.56 g, 5.73 mmol) in one portion.  The reaction was stirred at rt until disappearance of the starting material was observed (1 h) by TLC analysis (20% EtOAc/hexanes).  The reaction was quenched by adding 10% aq. solution of Na2S2O3 (30 mL) and EtOAc (30 mL).  The biphasic mixture was stirred for 10 min and then partitioned.  The aqueous layer was extracted with EtOAc (10 mL x 3) and the combined organic fractions was rinsed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give a yellow slurry.  Purification 129  by column chromatography (gradient elution, 5% → 10% EtOAc/hexanes) afforded aldehyde 2.262 (2.00 g, 79%) as a pale oil.  IR: 2954, 2930, 2858, 1510, 1249.  1H: 9.53 (d, J = 1.9 Hz, 1H), 7.27-7.21 (m, 2H), 6.96-6.91 (m, 2H), 6.90-6.85 (m, 2H), 6.78-6.72 (m, 2H), 4.35 (ABq, ΔδAB = 0.19, JAB = 11.0 Hz, 2H), 3.82 (s, 3H), 3.49-3.29 (m, 3H), 3.01 (tt, J = 10.5, 4.7 Hz, 1H), 1.94-1.65 (m, 4H), 0.99 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), −0.04 (s, 3H), −0.05 (s, 3H).  13C: 204.2, 159.7, 154.3, 135.9, 130.0, 129.6, 128.9, 120.3, 114.1, 81.8, 72.7, 61.0, 55.4, 40.1, 37.4, 37.2, 26.1, 25.8, 18.39, 18.35, −4.3, −5.26, −5.27.  HRMS: calcd for C32H52O5Si2Na [M + Na]+: 595.3251; found 595.3248.  Synthesis of alkyne 2.220 To a solution of Ohira-Bestmann reagent (1.24 g, 6.45 mmol) in THF (22 mL) cooled to −78 °C was added NaOMe (25% solution in MeOH, 1.45 mL, 6.34 mmol) dropwise over 15 min.  The resulting bright yellow solution was kept at −78 °C for 10 min.  Meanwhile, a THF (12 mL) solution of aldehyde 2.262 (2.00 g, 3.49 mmol) was prepared in a separate flask and transferred to the cold mixture by cannula.  The flask that contained 2.262 was rinsed with THF (2 mL x 2) and added to the reaction as well.  The temperature was maintained at −78 °C for 1 h, then allowed to gradually warm up to −20 °C over 1.5 h.  The reaction was quenched at −15 °C with sat. aq. NH4Cl (20 mL), diluted with EtOAc (30 mL) and stirred 10 min at rt.  The aqueous layer was separated and extracted with EtOAc (10 mL x 3) and the combined organic fractions was rinsed with brine (20 mL), and dried over Na2SO4.  The solvent was removed under reduced pressure followed by chromatographic purification (gradient elution, 1% → 3% EtOAc/hexanes) to afforded alkyne 2.220 (1.63 mg, 82%) as a pale oil.  IR: 3311, 2954, 2930, 130  2858, 1510, 1251, 1098.  1H: 7.29-7.23 (m, 2H), 6.92-6.84 (m, 4H), 6.73-6.67 (m, 2H), 4.64 (d, J = 11.0 Hz, 1H), 4.21 (d, J = 11.0 Hz, 2H), 3.82 (s, 3H), 3.72-3.64 (m, 1H), 3.46-3.30 (m, 2H), 2.95 (tt, J = 10.5, 4.9 Hz, 1H), 2.39 (d, J = 2.0 Hz, 1H), 2.13 (ddd, J = 14.2, 10.3, 4.3 Hz, 1H), 1.92-1.62 (m, 3H), 0.98 (s, 9H), 0.85 (s, 9H), 0.18 (s, 6H), −0.05 (s, 3H), −0.07 (s, 3H).  13C: 159.4, 154.0, 136.3, 130.1, 123.0, 128.8, 120.1, 113.9, 83.7, 73.3, 70.5, 66.0, 61.2, 55.4, 43.6, 39.7, 37.3, 26.1, 25.8, 18.4, 18.3, −4.3, −5.2, −5.3.  HRMS: calcd for C33H52O4Si2Na [M + Na]+: 591.3302; found 591.3295.  Synthesis of propargyllic alcohol 2.263 To a suspension of PMB ether 2.220 (2.12 g, 3.73 mmol) in stock CH2Cl2 (10 mL) and H2O (2 mL) was added DDQ (1.19 g, 5.24 mmol) at rt.  The biphasic mixture was vigorously stirred for 1 h, where TLC (10% EtOAc/hexanes) analysis indicated presence of starting material.  A second portion of DDQ (310 mg, 1.37 mmol) was added and left the reaction stirring for 45 min, at which point, the reaction was judged complete by TLC analysis.  The reaction was quenched with brine (15 mL), diluted with EtOAc (30 mL) and the phases were separated.  The organic layer was rinsed with brine (20 mL) again and the combined aqueous phase was extracted with EtOAc (10 mL x 3).  The combined organic fraction was dried over Na2SO4 and concentrated under reduced pressure to give a purple slurry.  The 1H NMR of the crude material indicated approximately 1:1 ratio between the p-anisaldehyde and product, which the former was purified as follows.  To a solution of crude material in THF (10 mL) and EtOH (10 mL) cooled to 0 °C was added NaBH4 (167 mg, 4.4 mmol) in one portion.  The ice bath was removed and the reaction was stirred at rt for 30 min.  At this point, TLC (20% EtOAc/hexanes) 131  showed presence of p-anisaldehyde, thus a second portion of NaBH4 (100 mg, 2.64 mmol) was added at rt and stirred for another 1 h.  The reaction was quenched with MeOH (10 mL) and stirred 10 min at rt.  The solvent was removed under reduced pressure and then suspended in EtOAc (50 mL) and brine (40 mL).  The contents were stirred until an emulsion formed which and diluted with H2O (100 mL).  The aqueous layer was separated and extracted with EtOAc (15 mL x 3).  The combined organic fractions was rinsed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a burgundy oil.  Purification by chromatography (15% EtOAc/hexanes eluent) afforded propargyl alcohol 2.263 (1.44 g, 86%) as a yellow oil.  IR: 3313, 2954, 2930, 2886, 2858, 1509, 1252.  1H: 7.09-6.99 (m, 2H), 6.82-6.72 (m, 2H), 4.13-4.04 (m, 1H), 3.51-3.33 (m, 2H), 3.01 (tt, J = 10.1, 5.0 Hz, 1H), 2.41 (d, J = 2.1 Hz, 1H), 2.05 (ddd, J = 14.0, 9.3, 4.7 Hz, 1H), 1.91 (ddd, J = 14.2, 10.6, 3.9 Hz, 1H), 1.89-1.65 (m, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.18 (s, 6H), −0.03 (s, 3H), −0.04 (s, 3H).  13C: 154.3, 136.3, 128.9, 120.3, 85.4, 72.8, 61.1, 60.3, 45.0, 39.8, 37.4, 26.1, 25.8, 18.4, 18.3, −4.3, −5.2.  HRMS: calcd for C25H44O3Si2Na [M + Na]+: 471.2727; found 471.2721.  Synthesis of N-Boc sulfonamide 2.221 To a round bottom flask containing alcohol 2.263 (66.0 mg, 0.147 mmol), sulfonamide 2.164 (46.0 mg, 0.236 mmol), and PPh3 (62.0 mg, 0.234 mmol) in THF (0.8 mL) was added DIAD (49.0 μL, 0.236 μmol) dropwise at 0 °C.  The ice bath was removed after 5 min and the reaction was warmed at rt (15 min) and then placed in an oil bath at 55 °C.  After stirring the reaction overnight (17 h), the solvent was removed under reduced pressure and purified by column chromatography (gradient elution 5% → 10% EtOAc/hexanes) to give 132  Mitsunobu product 2.221 (67 mg, 73%) as a faintly faintly yellow oil.  On a larger scale, the product was contaminated with a byproduct emanating from DIAD (no greater than 5% by 1H NMR), however, the presence of this impurity did not affect the outcome of subsequent transformation.  IR: 3312, 3279, 2955, 2930, 2858, 1732, 1509, 1359, 1253, 1149.  1H: 7.08-6.99 (m, 2H), 6.82-6.73 (m, 2H), 4.72 (ddd, J = 10.3, 5.2, 2.6 Hz, 1H), 3.50-3.29 (m, 2H), 3.19 (s, 3H), 2.91 (tt, J = 10.4, 4.5 Hz, 1H), 2.52 (ddd, J = 13.0, 10.4, 4.6 Hz, 1H), 2.40 (d, J = 2.5 Hz, 1H), 2.04 (ddd, J = 12.9, 11.0, 5.4 Hz, 1H), 1.94-1.81 (m, 1H), 1.76-1.63 (m, 1H), 1.50 (s, 9H), 0.97 (s, 9H), 0.86 (s, 9H), 0.18 (s, 6H), −0.04 (s, 3H), −0.05 (s, 3H).  13C: 154.3, 151.0, 135.4, 128.7, 120.2, 85.1, 80.7, 72.9, 60.7, 48.3, 42.2, 42.0, 39.8, 38.4, 28.0, 26.0, 25.8, 18.29, 18.35, −4.4, −5.3.  HRMS: calcd for C31H55NO6Si2SNa [M + Na]+: 648.3186; found 648.3187.  Synthesis of phenol 2.222 To a solution of Boc-sulfonamide 2.221 (1.76 g, 2.81 mmol) in THF (9.0 mL) cooled to −78 °C was added a solution of t-BuOK (2.86 M solution in THF, 2.0 mL, 5.72 mmol).  The reaction was kept at −78 °C for 1 h, during which time the mixture gradually turned yellow.  In a separate flask, a solution of acrolein (0.3 mL, 4.31 mmol) in THF (0.5 mL) was prepared and added to the reaction via syringe.  The flask that contained acrolein was rinsed with THF (0.2 mL) and it was also added to the reaction.  The reaction was stirred at −78 °C for 1 h, then a second aliquot of t-BuOK (2.86 M solution in THF, 3.5 mL, 10.0 mmol) was added.  After stirring at −78 °C for 10 min the cool bath was gradually warmed to −5 °C over 2.5 h.  The cool bath was then removed and stirred the reaction at rt overnight (15 h), the brown mixture was cooled to rt, quenched with sat. aq. NH4Cl (20 mL) and the biphasic mixture was stirred for 10 133  min.  The mixture was diluted with EtOAc (20 mL) and separated.  The aqueous layer was extracted with EtOAc (5 mL x 3), organic extracts were combined, sequentially rinsed with H2O (15 mL) then brine (20 mL), dried over Na2SO4 and concentrated under vacuum.  Purification by column chromatography (gradient elution, 20% → 30% EtOAc/hexanes) gave the title compound 2.222 (610 mg, 48%) as an oil.  IR: 3443, 3279, 2953, 2930, 2858, 1515, 1145.  1H: 7.06-6.98 (m, 2H), 6.91 (dd, J = 14.9, 10.9 Hz, 1H), 6.78-6.71 (m, 2H), 6.35 (dt, J = 17.0, 10.4 Hz, 1H), 6.25 (d, J = 14.9 Hz, 1H), 5.61 (d, J = 16.9 Hz, 1H), 5.55 (d, J = 10.1 Hz, 1H),  5.32 (br s, 1H), 4.67 (d, J = 8.7 Hz, 1H), 3.73-3.61 (m, 1H), 3.54-3.34 (m, 2H), 2.98 (tt, J = 10.0, 5.0 Hz, 1H), 2.39 (d, J = 2.3 Hz, 1H), 2.10-1.65 (m, 4H), 0.87 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H).  13C: 154.5, 141.9, 134.7, 132.5, 128.9, 128.7, 127.5, 115.7, 82.3, 73.7, 60.8, 44.4, 43.5, 39.9, 38.0, 26.1, 18.4, −5.2.  HRMS: calcd for C23H35NO4SiSNa [M + Na]+: 472.1954; found 472.1953.  Synthesis of alkyne 2.224 To a solution of ester 2.160 (990 mg, 3.36 mmol) in CH2Cl2 (7 mL) cooled to −78 °C was added DIBAL (1.0 M solution in hexanes, 4.4 mL, 4.4 mmol) dropwise.  The reaction was stirred for 3 h at −78 °C and then quenched by adding cold MeOH (−78 °C, 2.2 mL) by cannula.  The mixture was stirred for 10 min at −78 °C, then at rt for 10 min to give a white viscous suspension.  The mixture was slowly pipetted into a beaker containing sat. aq. NaHCO3 (50 mL) at 0 °C over a period of 5 min and vigorously stirred at rt for 30 min.  The biphasic mixture was separated and the aqueous layer was extracted with CHCl3 (10 mL x 4).  The organic fractions were combined, rinsed with brine (20 mL), dried over Na2SO4, and 134  concentrated under reduced pressure to give crude aldehyde 2.223.  This material was used in the following reaction without further purification.  To a solution of Ohira-Bestmann reagent (1.04 g, 5.41 mmol) in THF (11 mL) cooled to −78 °C was added NaOMe (25% solution in MeOH, 1.2 mL, 5.2 mmol).  The yellow solution was allowed to stir 5 min before adding a solution of crude aldehyde 2.223 in THF (3.0 mL) by syringe.  The flask that contained the crude aldehyde 2.223 was rinsed with THF (1 mL) and added as well.  The reaction was stirred at −78 °C for 30 min and then gradually warmed to 0 °C over a period of 3 h, at which point TLC indicated disappearance of the starting material.  The reaction was quenched with sat. aq. NH4Cl (20 mL) at 0 °C and stirred for 5 min.  The aqueous phase was separated and extracted with EtOAc (10 mL x 3), combined the organic fractions, rinsed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (20% EtOAc/hexanes eluent) provided alkyne 2.224 (723 mg, 82%) as a clear oil.  IR: 3284, 2976, 2955, 2925, 2839, 1514, 1249, 1060.  1H: 7.15-7.07 (m, 2H), 6.89-6.82 (m, 2H), 4.54 (dd, J = 9.5, 2.0 Hz, 1H), 4.30 (dt, J = 11.3, 2.2 Hz, 1H), 4.05 (dq, J = 9.5, 7.1 Hz, 1H), 3.79 (s, 3H), 3.58 (dq, J = 9.5, 7.1 Hz, 1H), 2.80 (tt, J = 12.6, 3.8 Hz, 1H), 2.47 (d, J = 2.2 Hz, 1H), 2.06-1.95 (m, 2H), 1.85-1.61 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).  13C: 158.4, 136.0, 127.8, 114.2, 101.9, 82.2, 72.9, 65.5, 64.7, 55.4, 39.8, 39.5, 38.2, 15.3.  HRMS: calcd for C16H20O3Na [M + Na]+: 283.1310; found 283.1310.      135  Synthesis of alkylated alkyne 2.226 To a round bottom flask containing alkyne 2.224 (1.42 g, 5.44 mmol) and Ph3CH (7 mg, 0.5 mol%) in THF (10 mL) cooled to −20 °C was added n-BuLi (1.52 M solution in hexanes, 5.30 mL, 8.06 mmol) dropwise.  The bright orange mixture was stirred for 1 h at the temperature between −15 °C and −5 °C, after which time the reaction had turn dark red in color.  The reaction was then cooled down to −78 °C and DMPU (2.4 mL, 20 mmol) was added, resulting in a bright pink solution.  After stirring for 5 min, a solution of alkyl iodide 2.225 (2.37 g, 8.58 mmol) in THF (8 mL) was added by syringe at −78 °C.  The flask that contained the alkyl iodide was rinsed with THF (1 mL) and added to the reaction as well.  Upon addition of alkyl iodide, the pink color disappeared immediately and turned into a pale solution.  The reaction was gradually warmed up to 5 °C over a period of 4 h, at which point the cool bath was removed, and allowed to stir overnight (23 h) at rt.  The reaction was quenched with sat. aq. NH4Cl (15 mL) at rt and diluted with EtOAc (20 mL).  The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (5 mL x 3).  The organic extracts were combined, rinsed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (gradient elution 5% → 15% EtOAc/hexanes) provided the alkylated alkyne 2.226 (1.46 g, 66%) as a clear oil.  IR: 2925, 2858, 1514, 1249, 1055.  1H: 7.36-7.21 (m, 5H), 7.15-7.07 (m, 2H), 6.89-6.82 (m, 2H), 4.53 (dd, J = 9.4, 1.9 Hz, 1H), 4.50 (s, 2H), 4.26 (dq, J = 11.2 2.0 Hz, 1H), 4.05 (dq, J = 9.5, 7.1 Hz, 1H), 3.79 (s, 3H), 3.57 (dq, J = 9.5, 7.1 Hz, 1H), 3.55 (t, J = 6.2 Hz, 2H), 2.77 (tt, J = 12.6, 3.8 Hz, 1H), 2.35 (td, J = 7.1, 1.9 Hz, 2H), 2.03-1.89 (m, 2H), 1.81 (p, J = 6.2 Hz, 2H), 1.76-1.57 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).  13C: 158.4, 138.6, 136.3, 128.5, 127.8, 127.7, 127.6, 114.1, 101.8, 84.8, 79.0, 73.0, 136  68.9, 66.0, 64.6, 55.4, 40.4, 39.5, 38.2, 28.8, 15.8, 15.3.  HRMS: calcd for C26H32O4Na [M + Na]+: 431.2198; found 431.2194.  Synthesis of diol 2.264 To a solution of tetrahydropyran 2.226 (886 mg, 2.17 mmol) in THF (35 mL) and H2O (15 mL) was added pTsOH·H2O (1.26 g, 6.62 mmol) at rt.  After attaching a water condenser, the reaction was stirred overnight (15 h) at 70 °C.  The reaction was cooled down to rt and quenched with sat. aq. NaHCO3 (25 mL).  The mixture was diluted with EtOAc (15 mL) and the two phases were separated.  The aqueous layer was extracted with EtOAc (10 mL x 3), combined the organic extracts, rinsed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give crude lactol as a mixture of diastereomers.  The crude lactol from above was dissolved in EtOH (5 mL), cooled to 0 °C and NaBH4 (410 mg, 10.8 mmol) was added in small portions.  Once the effervescence had diminished, the ice bath was removed and the reaction was stirred for 2 h at rt.  At this point, no starting material was observed by TLC and the reaction was quenched by slow addition of MeOH (5 mL) followed by 1 M HCl (20 mL) and 6 M HCl (5 mL).  After removal of EtOH under reduced pressure, the mixture was diluted with EtOAc (20 mL) and separated.  The aqueous layer was extracted with EtOAc (15 mL x 3) and the combined organic extracts was rinsed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (gradient elution, 50% → 80% EtOAc/hexanes) afforded diol 2.264 (610 mg, 74%) as a clear oil.  IR: 3370, 2934, 2861, 1610, 1510, 1245.  1H: 7.38-7.23 (m, 5H), 7.15-7.08 (m, 2H), 6.88-6.81 (m, 2H), 4.50 (s, 2H), 4.07-4.00 (m, 1H), 3.79 (s, 3H), 3.61-3.41 (m, 2H), 137  3.53 (t, J = 6.1 Hz, 2H), 3.00 (tt, J = 10.1, 5.1 Hz, 1H), 2.29 (td, J = 7.1, 2.0 Hz, 2H), 2.00 (d, J = 14.0, 9.4, 4.7 Hz, 1H), 1.92-1.71 (m, 3H), 1.77 (p, J = 6.3 Hz, 2H).  13C: 158.4, 138.6, 135.8, 128.8, 128.5, 127.8, 127.7, 114.2, 84.7, 81.9, 73.0, 68.8, 61.1, 60.4, 55.4, 45.4, 39.7, 37.7, 28.9, 15.8.  HRMS: calcd for C24H30O4Na [M + Na]+: 405.2042, found 405.2038.  Synthesis of alcohol 2.227 To a solution of diol 2.264 (599 mg, 1.57 mmol) in MeCN (5.2 mL) was added TBSCl (295 mg, 1.95 mmol) followed by imidazole (160 mg, 2.36 mmol).  The reaction was stirred at 60 °C for 2 h, at which point TLC indicated the presence of starting material.  Additional TBSCl (50 mg, 0.33 mmol) was added and stirred the reaction for 10 min at 60 °C.  The reaction was removed from the oil bath and quenched with sat. aq. NH4Cl (20 mL) and diluted with EtOAc (20 mL).  The two phases were separated and the aqueous phase was extracted with EtOAc (10 mL x 3).  The organic extracts were combined, rinsed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure.  The residue was purified by flash chromatography (gradient elution, 15% → 20% EtOAc/hexanes) to give mono-TBS product 2.227 (622 mg, 80%) as a colorless oil and bis-TBS product 2.265 (37 mg, 4%) as a faintly yellow oil.  IR: 3437, 2954, 2926, 2854, 1511, 1248, 1102, 1081.  1H: 7.38-7.25 (m, 5H), 7.13-7.06 (m, 2H), 6.87-6.80 (m, 2H), 4.50 (s, 2H), 4.08-4.00 (m, 1H), 3.79 (s, 3H), 3.52 (t, J = 6.2 Hz, 2H), 3.50-3.35 (m, 2H), 2.99 (tt, J = 10.1, 5.0 Hz, 1H), 2.29 (td, J = 7.1, 1.9 Hz, 2H), 1.99 (ddd, J = 13.9, 9.1, 4.7 Hz, 1H), 1.91-1.71 (m, 3H), 1.77 (t, J = 6.7 Hz, 2H), 1.60 (br s, 1H), 0.87 (s, 9H), −0.020 (s, 3H), −0.024 (s, 3H).  13C: 158.2, 138.6, 136.1, 128.9, 128.5, 127.8, 127.7, 138  114.0, 84.6, 82.0, 73.0, 68.8, 61.2, 60.6, 55.4, 45.6, 39.9, 37.5, 28.9, 26.1, 18.4, 15.7, −5.2.  HMRS: calcd for C30H44O4SiNa [M + Na]+: 519.2907; found 519.2910. bis-TBS 2.265  IR: 2952, 2928, 2856, 1512, 1248, 1099.  1H: 7.39-7.24 (m, 5H), 7.11-7.03 (m, 2H), 6.87-6.79 (m, 2H), 4.50 (s, 2H), 4.05-3.96 (m, 1H), 3.79 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.51-3.31 (m, 2H), 2.98 (tt, J = 10.1, 5.0 Hz, 1H), 2.28 (td, J = 7.1, 1.9 Hz, 2H), 1.99 (ddd, J = 13.9, 9.7, 4.4 Hz, 1H), 1.91-1.62 (m, 3H), 1.77 (t, J = 6.7 Hz, 2H), 0.91 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), −0.018 (s, 3H), −0.021 (s, 3H), −0.025 (s, 3H).  13C: 158.0, 138.6, 136.3, 129.0, 128.5, 127.74, 127.68, 113.8, 83.8, 82.9, 73.1, 69.1, 61.1, 60.8, 55.4, 46.6, 40.4, 37.2, 26.11, 26.09, 18.4, 18.3, 15.7, −4.0, −4.8, −5.2.  HMRS: calcd for C36H58O4Si2Na [M + Na]+: 633.3771; found 633.3764.  Synthesis of carbamate 2.230 To a THF (0.25 mL) solution of propargyl alcohol 2.227 (34 mg, 68 μmol) in a conical vial was added sulfonamide 2.164 (20 mg, 0.10 mmol), PPh3 (27 mg, 0.10 mmol), and ADDP (26 mg, 0.10 mmol) in order.  The vial was purged with Ar for 1 min and then a screw cap was placed.  The reaction was stirred overnight (16 h) in an oil bath at 85 °C.  The solvent was evaporated under vacuum then subjected to purification by column chromatography to afford the title compound (17 mg, 37%) as a clear oil.  IR: 2954, 2928, 2856, 1750, 1512, 1454, 1248, 1147.  1H: 7.39-7.24 (m, 5H), 7.07-6.99 (m, 2H), 6.88-6.79 (m, 2H), 5.15-5.05 (m, 1H), 4.50 (s, 2H), 3.78 (s, 3H), 3.52 (t, J = 6.1 Hz, 2H), 3.51-3.42 (m, 1H), 3.41-3.31 (m, 1H), 3.23 (s, 3H), 2.91 (tt, J = 9.9, 5.0 Hz, 1H), 2.31 (td, J = 7.2, 1.9 Hz, 2H), 2.14 (ddd, J = 14.2, 8.6, 139  4.9 Hz, 1H), 1.99 (ddd, J = 14.2, 10.0, 4.9 Hz, 1H), 1.92-1.65 (m, 4H), 0.87 (s, 9H), −0.02 (s, 3H), −0.03 (s, 3H).  13C: 158.4, 150.1, 138.5, 135.3, 128.8, 128.5, 127.7 (2 peaks), 114.2, 87.3, 77.0, 73.0, 68.8, 66.6, 60.8, 55.4, 42.5, 41.3, 39.6, 37.4, 28.6, 26.1, 18.4, 15.7, −5.2.  HMRS: calcd for C32H47NO7SiSNa [M + Na]+: 640.2740; found 640.2742.  Synthesis of compound 2.231 To a conical vial charged with alcohol 2.227 (13 mg, 26 μmol), bromophenol (7 mg, 0.04 mmol), and PMe3 (1.0 M in THF, 42 μL, 0.04 mmol) in THF (0.2 mL) was added ADDP (10 mg, 0.04 mmol) at rt.  The resulting yellow suspension was immersed into a preheated oil bath at 60 °C and stirred overnight (19 h).  Crude 1H NMR indicated low conversion, thus the crude was suspended in THF (0.2 mL) and added bromophenol (4 mg, 0.02 mmol), PMe3 (46 μL, 0.04 mmol) and ADDP (10 mg, 0.04 mmol).  The reaction was resumed by stirring overnight (20 h) in an oil bath at 90 °C to give a yellow solid upon cooling to rt.  The crude material was dissolved in minimal amount of CH2Cl2 and subjected to column chromatography (20% EtOAc/hexanes eluent) to give compound 2.231 (11 mg, 65%).  IR: 2952, 2928, 2855, 1511, 1486, 1248, 1234.  1H: 7.37-7.24 (m, 7H), 7.14-7.08 (m, 2H), 6.87-6.81 (m, 2H), 6.73-6.67 (m, 2H), 4.45 (s, 2H), 4.31 (app tt, J = 6.5, 1.7 Hz, 1H), 3.80 (s, 3H), 3.59-3.34 (m, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.07 (tt, J = 9.2, 5.7 Hz, 1H), 2.34 (app td, J = 7.3, 1.8 Hz, 2H), 2.14 (app ddd, J = 9.2, 6.3, 2.8 Hz, 2H), 1.97-1.71 (m, 2H), 1.78 (p, J = 6.4 Hz, 2H), 0.87 (s, 9H), −0.02 (s, 3H), −0.03 (s, 3H).  13C: 158.3, 156.7, 138.7, 135.8, 132.1, 128.7, 128.5, 127.71, 127.69, 117.7, 114.0, 113.3, 87.7, 78.1, 73.1, 68.8, 67.3, 60.8, 55.4, 42.7, 39.9, 37.7, 28.9, 26.1, 18.4, 15.8, −5.2.  HMRS: calcd for C36H47O4Si79BrNa [M + Na]+: 673.2325, found 673.2333. 140  Synthesis of N-methyl carbamate 2.234 To a solution of sulfonyl carbamate 2.230 (7 mg, 0.01mmol) in stock acetone (0.1 mL) was added MeI (10 μL, 0.16 mmol) followed by K2CO3 (22 mg, 0.16 mmol) at rt.  The white suspension was stirred overnight (16 h) at rt.  Upon filtration through Celite® (acetone eluent) and evaporation of solvent under reduced pressure, N-methyl sulfonyl carbamate 2.234 was obtained (7 mg, quant.).  This material was sufficiently pure and used for the subsequent step.  IR: 2953, 2929, 2856, 1734, 1513, 1359, 1249, 1143, 1106.  1H: 7.38-7.24 (m, 5H), 7.07-6.99 (m, 2H), 6.86-6.78 (m, 2H), 5.15-5.06 (m, 1H), 4.49 (s, 2H), 3.78 (s, 3H), 3.52 (t, J = 6.1 Hz, 2H), 3.51-3.42 (m, 1H), 3.40-3.29 (m, 1H), 3.25 (s, 3H), 3.15 (s, 3H), 2.96 (tt, J = 9.9, 4.6 Hz, 1H), 2.31 (td, J = 7.1, 1.9 Hz, 2H), 2.20 (ddd, J = 14.2, 8.8, 5.0 Hz, 1H), 2.02 (ddd, J = 14.1, 10.1, 4.7 Hz, 1H), 1.92-1.65 (m, 2H), 1.78 (app t, J = 6.4 Hz, 2H), 0.86 (s, 9H), −0.03 (s, 3H), −0.04 (s, 3H).  13C: 158.4, 152.3, 138.6, 135.3, 128.7, 128.5, 127.73, 127.69, 114.1, 87.1, 77.3, 73.1, 68.8, 66.9, 60.8, 55.4, 42.5, 41.6, 39.7, 37.4, 32.6, 28.7, 26.1, 18.4, 15.8, −5.3.  HMRS: calcd for C33H49NO7SiSNa [M + Na]+: 654.2897, found 654.2900.  Hydrolysis of carbamate 2.234 to alcohol 2.227  To a solution of N-methyl sulfonyl carbamate 2.234 (7 mg, 11 μmol) in MeOH (0.3 mL) was added K2CO3 (25 mg, 0.18 mmol) at rt.  The reaction was stirred for 1.5 h, at which point TLC 141  (15% EtOAc/hexanes) showed disappearance of the starting material.  The suspension was filtered through a plug of cotton (MeOH eluent) and concentrated under reduced pressure.  Crude 1H NMR and MS (ESI+) matched those of alcohol 2.227, confirming that the configuration of the secondary propargyl alcohol remained intact from the attempted Mitsunobu reaction of 2.227.  Synthesis of tetracycle 2.238 Non-flame dried glassware and unpurified solvents were used for the IMOA reaction.  To a round bottom flask equipped with an addition funnel, a solution of DIB (450 mg, 1.37 mmol) and TFA (105 μL, 1.36 mmol) in CH2Cl2 (4.6 mL) was prepared.  The vessel was sparged with Ar for 5 min and then the addition funnel was charged with phenol 2.222 (555 mg, 1.23 mmol) in CH2Cl2 (4.0 mL).  The solution was added dropwise by pipette over a period of 2 min and the reaction was stirred for another 30 min at rt.  The mixture was concentrated under reduced pressure to obtain an oil.  The residue was redissolved in toluene (5 mL) and concentrated to azeotropically remove residual acid present in the crude.  The process was repeated two more times.  The residue from above was dissolved in anhydrous toluene (10 mL) and BHT (5 mg, 0.02 mmol) was added.  A water condenser was attached to the flask and the mixture was purged with Ar for 10 min under sonication followed by the addition of 2,6-lutidine (14 μL, 0.12 mmol).  The reaction was stirred in an oil bath at 120 °C for 3 h, then cooled to rt.  The solvent was removed under reduced pressure to give a dark brown amorphous residue.  The crude was then dissolved in THF (4 mL) and DBU (0.3 mL, 2.0 mmol) was added at rt.  The resulting dark brown solution was stirred overnight (19 h) and quenched with sat. aq. NH4Cl (20 mL).  The 142  mixture was diluted with EtOAc (20 mL) and separated.  The aqueous layer was extracted with EtOAc (10 mL x 3) and the organic layers were combined, rinsed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by flash column chromatography (gradient elution, 30% → 50% EtOAc/hexanes) afforded the epimerized Diels-Alder adduct 2.238 (186 mg, 34%) as a yellow foam.  IR: 3277, 2954, 2928, 2856, 1692, 1151, 1096.  1H: 6.63 (d, J = 10.4 Hz, 1H), 6.37-6.28 (m, 1H), 6.22 (d, J = 10.4 Hz, 1H), 5.90-5.81 (m, 1H), 4.78 (ddd, J = 9.7, 7.8, 2.2 Hz, 1H), 3.88-3.80 (m, 1H), 3.66-3.51 (m, 2H), 3.47 (ddd, J = 13.8, 11.0, 4.4 Hz, 1H), 2.81-2.55 (m, 3H), 2.42 (d, J = 2.2 Hz, 1H), 2.24-1.94 (m, 3H), 1.53-1.42 (m, 2H), 0.85 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).  13C: 197.8, 142.4, 135.6, 130.2, 115.3, 83.4, 72.4, 69.2, 60.6, 58.0, 51.6, 45.5, 40.0, 38.6, 38.5, 31.7, 26.0, 24.3, 18.3, −5.3.  HRMS: calcd for C23H33NO4SiSNa [M + Na]+: 470.1797; found 470.1791.  Synthesis of dienone 2.239 Non-flame dried glassware and unpurified solvents were used for the IMOA reaction.  To a round bottom flask, a solution of DIB (106 mg, 0.323 mmol) and TFA (25 μL, 0.34 mmol) in CH2Cl2 (1.1 mL) was prepared.  The flask was sparged with Ar for 1 min and then a solution of phenol 2.222 (132 mg, 0.294 mmol) in CH2Cl2 (1.0 mL) was added dropwise by pipette.  After the addition, the reaction was stirred for another 25 min at rt, and then concentrated under reduced pressure.  Azeotropic removal of residual acid was accomplished by dissolving in the crude in toluene (1 mL x 2) and concentrating under reduced pressure.  To the residue from above dissolved in anhydrous toluene (3.0 mL) was added 2,6-lutidine (4 μL, 0.03 μmol) at rt.  The mixture was sparged with Ar for 20 min under sonication.  143  The reaction was heated in an oil bath at 120 °C for 5 h, then cooled to rt.  The crude mixture was diluted in CHCl3 (5 mL) and passed through Celite®, then concentrated under reduced pressure.  The crude was dissolved in dry THF (1.5 mL), to which DBU (44 μL, 0.030 μmol) was added and allowed to stir overnight (19 ) at rt.  The reaction was quenched with NH4Cl (3 mL) and diluted with EtOAc (5 mL).  The mixture was separated and the aqueous layer was extracted with EtOAc (2 mL x 3).  The organic fractions were combined, rinsed with brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography afforded enone 2.238 (23 mg, 17%) and dienone 2.239 (12 mg, 9%).  IR: 2954, 2929, 2856, 1668, 1314, 1156, 1094.  1H: 6.87 (dd, J = 10.5, 3.2, 1H), 6.70 (dd, J = 10.3, 2.8 Hz, 1H), 6.37-6.29 (m, 2H), 6.16 (br d, J = 10.2 Hz, 1H), 6.07-6.00 (m, 1H), 4.71 (dd, J = 10.2, 7.3 Hz, 1H), 3.57 (app t, J = 5.8 Hz, 2H), 2.73-2.60 (m, 2H), 2.57-2.35 (m, 5H), 1.64 (td, J = 14.2, 10.2 Hz, 1H), 1.42-1.30 (m, 1H), 0.87 (s, 9H), 0.01 (s, 6H).  13C: 185.4, 150.1, 146.6, 144.4, 134.4, 130.7, 130.30, 130.29, 114.5, 67.5, 65.4, 61.0, 48.7, 33.6, 31.1, 26.0, 22.3, 21.5, 18.3, 5.2, 5.3.  HRMS: calcd for C23H33NO4SiSNa [M + Na]+: 470.1797; found 470.1808.  Synthesis of enone-aldehyde 2.242 To a cooled solution of silyl ether 2.238 (186 mg, 0.42 mmol) in THF (2.0 mL) at 0 °C was added TBAF (1.0 M solution in THF, 0.75 mL, 0.75 mmol) dropwise.  The reaction was stirred for 1.5 h in the ice bath while maintaining the temperature between 0 °C ~ 5 °C.  The reaction was stopped by adding H2O (20 mL) and EtOAc (20 mL), and the biphasic mixture was separated.  The organic layer was rinsed with H2O (5 mL) and the combined aqueous layer was extracted with EtOAc (5 mL x 3).  The organic layers were combined, rinsed with brine (15 mL), dried 144  over Na2SO4, and concentrated under reduced pressure to give the corresponding crude alcohol as a yellow oil.  The crude from above was dissolved in CH2Cl2 (2 mL) and DMP (280 mg, 0.63 mmol) was added in one portion at rt.  The reaction immediately turned into a brownish-red mixture, which was stirred for 1 h at rt.  The reaction was then quenched by adding 10% aq. Na2S2O3 (15 mL), diluted with EtOAc (15 mL) and partitioned.  The organic layer was rinsed again with 10% aq. Na2S2O3 (15 mL) and the aqueous layers were combined and extracted with EtOAc (5 mL x 3).  The organic layers were combined, rinsed with 1:1 brine/sat. aq. NaHCO3 (20 mL), dried over Na2SO4, and concentrated under vacuum to obtain a dark brown oil.  Purification by column chromatography (60% EtOAc/hexanes) afforded enone-aldehyde 2.242 (85 mg, 62%) as a baige solid.  M.P.: 210-212 °C.  IR: 3278, 2927, 2852, 1721, 1691, 1328, 1309, 1150.  1H: 9.73 (s, 1H), 6.61 (d, J = 10.4 Hz, 1H), 6.36-6.28 (m, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.89-5.81 (m, 1H), 4.82 (ddd, J = 9.7, 7.8, 2.2 Hz, 1H), 3.97-3.89 (m, 1H), 3.45 (ddd, J = 13.7 11.0, 4.4 Hz, 1H), 2.93-2.81 (m, 1H), 2.67-2.48 (m, 5H), 2.43 (d, J = 2.2 Hz, 1H), 2.18-1.90 (m, 2H).  13C: 198.5, 197.4, 141.7, 135.6, 130.5, 115.2, 83.0, 72.7, 68.7, 57.9, 51.4, 42.9, 42.0, 40.0, 38.7, 38.1, 24.2.  HRMS: calcd for C17H16NO4S [M – H]–: 330.0800; found 330.0796.  Synthesis of pentacycle 2.243 A suspension of enone-aldehyde 2.242 (92 mg, 0.28 mmol), Glorius pre-catalyst 2.153 (21 mg, 56 μmol), BHT (4 mg, 0.02 mmol) in dioxane (6 mL) was prepared in a round bottom flask and purge with Ar for 10 min while being sonicated.  To the suspension was added DBU (8 μL, 0.06 mmol) to form a red solution and the flask was immersed in an oil bath at 120 °C.  The reaction was stirred 145  for 2 h, during which time the color gradually changed from red to brown.  The reaction was cooled to rt and sat. aq. NH4Cl (15 mL) and EtOAc (20 mL) was added.  The phases were separated and the aqueous layer was extracted with EtOAc (5 mL x 3).  The combined organic layer was rinsed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by chromatography (60% → 90% EtOAc/hexanes) gave the title compound as a off white solid (65 mg, 71%).  M.P.: 195 °C (dec).  IR: 3233, 2955, 2921, 2854, 1761, 1721, 1306, 1147, 1130.  1H: (300 MHz, CD3CN): 6.32-6.22 (m, 1H), 5.83-5.71 (m, 1H), 4.96 (dt, J = 9.0, 3.0 Hz, 1H), 3.82-3.75 (m, 1H), 3.26-3.02 (m, 3H), 2.85 (dd, J = 20.0, 10.3 Hz, 1H), 2.74 (d, J = 2.5 Hz, 1H), 2.70 (dd, J = 13.5, 7.9 Hz, 1H), 2.61 (dd, J = 19.9 Hz, 1.3 Hz, 1H), 2.60-2.51 (m 1H), 2.59 (app d, J = 17.8 Hz, 1H), 2.43-2.31 (m, 1H), 2.41 (dd, J = 17.6, 10.4 Hz, 1H), 2.09 (dt, J = 13.8, 3.4 Hz, 1H), 2.06-1.98 (m, 1H).  13C (75 MHz, CD3CN): 214.1, 208.0, 135.8, 115.9, 85.0, 77.5, 74.2, 60.0, 54.84, 54.83, 47.3, 43.3, 42.5, 41.6, 38.4, 37.6, 25.1.  HRMS: calcd for C17H16NO4S [M – H]–: 330.0800; found 330.0797.   Synthesis of hexacyclic ketone 2.247 To a solution of alkyne 2.243 (7 mg, 0.021 mmol) in THF (0.5 mL) and degassed H2O (0.05 mL) at rt, was added SmI2 (0.07 M in THF, 2.0 mL, 0.14 mmol) via syringe pump (0.1 mL/min, 20 min duration) with the needle immersed into the reaction mixture.  When the addition had completed, the reaction was stirred for 5 min at rt and quenched by adding sat. aq. NaHCO3 (3 mL).  After stirring for 5 min, the mixture was diluted with EtOAc (5 mL) and separated.  The aqueous layer was extracted with EtOAc (2 mL x 3) and the organic layers were combined, rinsed with brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure. 146   The crude residue was dissolved in CH2Cl2 (0.5 mL) and DMP (28 mg, 0.063 mmol) was added in one portion at rt.  The reaction was stirred at rt for 25 min and quenched by adding 20% aq. solution of Na2S2O3 (3 mL) and diluted with EtOAc (3 mL).  The mixture was separated and the aqueous layer was extracted with EtOAc (1 mL x 3).  The combined organic layers was rinsed with sat. aq. NaHCO3 (2 mL), brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure.  Purification by column chromatography (1% → 1.5% MeOH/CH2Cl2) afforded the title compound (4 mg, 34%) which was contaminated with an uncharacterizable impurity (~ 40% contamination based on 1H NMR).  1H (300 MHz, CD3CN):  6.23-6.15 (m, 1H), 5.83-5.73 (m, 1H), 5.12 (d, J = 1.4 Hz, 1H), 5.02 (br d, J = 1.3 Hz, 1H), 4.67 (dd, J = 3.5, 1.8 Hz, 1H), 4.01-3.92 (m, 1H), 3.53 (br s, 1H), 2.79-2.72 (m, 2H), 2.65 (td, J = 7.0, 1.8 Hz, 1H), 2.55-2.42 (m, 1H), 2.42-2.30 (m, 4H), 2.23-2.15 (m, 1H), 2.08-1.99 (m, 1H), 1.67 (d, J = 11.7 Hz, 1H), 1.49 (d, J = 11.7 Hz, 1H).  13C (75 MHz, CD3CN):  210.4, 152.5, 134.1, 117.7, 106.5, 81.2, 75.3, 66.8, 61.8, 54.7, 46.3, 43.7, 43.6, 42.8, 37.3, 35.6, 24.6.  HRMS: calcd for C17H19NO4SNa [M + Na]+: 356.0932; found 356.0932.  147  References     1 Zhadankin, V. V. Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic Applications of Polyvalent Iodine Compounds; John Wiley & Sons: West Sussex, 2014; pp 1-20. 2 Powell, W. H. Pure Appl. 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Chem. 1992, 57, 5279. 97  (a) Tamao, K.; Akita, M.; Kumada, M. J. Organomet. Chem. 1983, 254, 13.  (b) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun.  1984, 29.  (c) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229. 98  (a) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006, 71, 3639.  (b) Su, Q.; Dakin, L. A.; Panek, J. S. J. Org. Chem. 2007, 72, 2. 99  Chiang, P.-C.; Bode, J. W. Org. Lett. 2011, 13, 2422.  (b) For a review, see: Mӧhlmann, L.; Ludwig, S.; Blechert, S. Beilstein J. Org. Chem. 2013, 9, 602. 100 (a) Liu, Y.-K.; Li, R.; Yue, L.; Li, B.-J.; Chen, Y.-C.; Wu, Y.; Ding, L.-S. Org. Lett. 2006, 8, 1521.  (b) Maji, B.; Vedachalan, S.; Ge, X.; Cai, S.; Liu, X.-W. J. Org. Chem. 2011, 76, 3016.  (c) For a review, see: De Sarkar, S.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664. 101  Bortolini, O.; Chiappe, C.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.; Pomelli, C. S.; Ragno, D. Chem. Commun. 2014, 50, 2008. 102 Kaljurand, I.; Kütt, A.; Soovӓli, L.; Rodima, T.; Mӓemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019. 103  (a) Ohira, S. Synth. Commun. 1989, 19, 561.  (b) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521. 104  Wadsworth, W. S.; Emmons, W. J. Am. Chem. Soc. 1961, 83, 1733. 105  Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639. 106  Desjardins, S.; Andrez, J.-C.; Canesi, S. Org. Lett. 2011, 13, 3406. 107  Chatt, J.; Duncanson, L. A. J. Chem. Soc. 1953, 2939. 108  (a) Kagan, H. Tetrahedron 2003, 59, 10351.  (b) Harb, H. Y.; Procter, D. J. Synlett 2012, 6. 109  Morlender-Vais, N.; Solodovnikova, N.; Marek, I. Chem. Commun. 2000, 1849.  154   110  For reviews, see: (a) Molander, G. A. Org. React. 1994, 46, 211.  (b) Kagan, H. B. Tetrahedron 2003, 59, 10351. (c) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem. Int. Ed. 2009, 48, 7140. 111  Compound 2.247 was contaminated with an uncharacterized byproduct (~ 40% by 1H NMR) which could not be separated by column chromatography due to identical Rf values. 112  Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004, 60, 4481. 113  Lee, J.; Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999, 64, 3060. 114  Meng, Q.; Zhu, L.; Zhang, Z. J. Org. Chem. 2008, 73, 7209. 115  Stecher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74, 4392. 116  Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379. 155     Appendix A  1H and 13C NMR spectra from Chapter 1    156  Metathesis of iodonium salt 1.40a and iodobenzene (Table 1.3, entry a) 1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    157  Metathesis of iodonium salt 1.40a and p-iodotoluene (Table 1.3, entry b)   1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    158  Metathesis of iodonium salt 1.40a and p-iodoanisole (Table 1.3, entry c)   1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)     159  Metathesis of iodonium salt 1.40a and 1-iodonaphthalene (Table 1.3, entry d)   1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    160  Metathesis of iodonium salt 1.40b and iodobenzene (Table 1.3, entry e) 1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    161  Metathesis of iodonium salt 1.40b and p-iodotoluene (Table 1.3, entry f)   1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    162  Metathesis of iodonium salt 1.40b and p-iodoanisole (Table 1.3, entry g)   1H NMR (300 MHz, acetone-d6)   13C NMR (75 MHz, acetone-d6)    163  Metathesis of iodonium salt 1.40b and 1-iodonaphthalene (Table 1.3, entry h)   1H NMR (300 MHz, acetone-d6)    13C NMR (75 MHz, acetone-d6)  164     Appendix B  1H and 13C NMR from Chapter 2     165  1H NMR (300 MHz, CDCl3) for compound 2.255   13C NMR (75 MHz, CDCl3) for compound 2.255   166  1H NMR (300 MHz, CDCl3) for compound 2.256   13C NMR (75 MHz, CDCl3) for compound 2.256    167  1H NMR (300 MHz, CDCl3) for compound 2.113   13C NMR (75 MHz, CDCl3) for compound 2.113    168  1H NMR (300 MHz, CDCl3) for compound 2.115   13C NMR (75 MHz, CDCl3) for compound 2.115    169  1H NMR (300 MHz, CDCl3) for compound 2.104   13C NMR (75 MHz, CDCl3) for compound 2.104    170  1H NMR (300 MHz, CDCl3) for compound 2.105   13C NMR (75 MHz, CDCl3) for compound 2.105   171  1H NMR (300 MHz, CDCl3) for compound 2.126   13C NMR (75 MHz, CDCl3) for compound 2.126   172  1H NMR (300 MHz, CDCl3) for compound 2.130   13C NMR (75 MHz, CDCl3) for compound 2.130    173  1H NMR (300 MHz, CDCl3) for compound 2.257   13C NMR (75 MHz, CDCl3) for compound 2.257    174  1H NMR (300 MHz, CDCl3) for compound 2.134   13C NMR (75 MHz, CDCl3) for compound 2.134    175  1H NMR (300 MHz, CDCl3) for compound 2.137   13C NMR (75 MHz, CDCl3) for compound 2.137    176  1H NMR (300 MHz, CDCl3) for compound 2.138   13C NMR (75 MHz, CDCl3) for compound 2.138    177  1H NMR (300 MHz, CDCl3) for compound 2.107   13C NMR (75 MHz, CDCl3) for compound 2.107    178  1H NMR (300 MHz, CDCl3) for compound 2.258   13C NMR (75 MHz, CDCl3) for compound 2.258    179  1H NMR (300 MHz, CDCl3) for compound 2.160   13C NMR (75 MHz, CDCl3) for compound 2.160    180  1H NMR (300 MHz, CDCl3) for compound 2.161   13C NMR (75 MHz, CDCl3) for compound 2.161    181  1H NMR (300 MHz, CDCl3) for compound 2.162   13C NMR (75 MHz, CDCl3) for compound 2.162    182  1H NMR (300 MHz, acetone-d6) for compound 2.259   13C NMR (75 MHz, acetone-d6) for compound 2.259    183  1H NMR (300 MHz, CDCl3) for compound 2.163   13C NMR (75 MHz, CDCl3) for compound 2.163    184  1H NMR (300 MHz, CDCl3) for compound 2.260   13C NMR (75 MHz, CDCl3) for compound 2.260    185  1H NMR (300 MHz, CDCl3) for compound 2.165   13C NMR (75 MHz, CDCl3) for compound 2.165    186  1H NMR (300 MHz, CDCl3) for compound 2.166   13C NMR (75 MHz, CDCl3) for compound 2.166    187  1H NMR (300 MHz, CDCl3) for compound 2.167   13C NMR (75 MHz, CDCl3) for compound 2.167    188  1H NMR (300 MHz, CDCl3) for compound 2.169   13C NMR (75 MHz, CDCl3) for compound 2.169    189  1H NMR (300 MHz, CDCl3) for compound 2.171   13C NMR (75 MHz, CDCl3) for compound 2.171    190  1H NMR (300 MHz, CDCl3) for compound 2.183   13C NMR (75 MHz, CDCl3) for compound 2.183    191  1H NMR (300 MHz, CDCl3) for compound 2.197   13C NMR (75 MHz, CDCl3) for compound 2.197    192  1H NMR (300 MHz, CDCl3) for compound 2.199   13C NMR (75 MHz, CDCl3) for compound 2.199    193  1H NMR (300 MHz, CDCl3) for compound 2.200   13C NMR (75 MHz, CDCl3) for compound 2.200    194  1H NMR (300 MHz, CDCl3) for compound 2.261   13C NMR (75 MHz, CDCl3) for compound 2.261    195  1H NMR (300 MHz, CDCl3) for compound 2.219   13C NMR (75 MHz, CDCl3) for compound 2.219    196  1H NMR (300 MHz, CDCl3) for compound 2.262   13C NMR (75 MHz, CDCl3) for compound 2.262    197  1H NMR (300 MHz, CDCl3) for compound 2.220   13C NMR (75 MHz, CDCl3) for compound 2.220    198  1H NMR (300 MHz, CDCl3) for compound 2.263   13C NMR (75 MHz, CDCl3) for compound 2.263    199  1H NMR (300 MHz, CDCl3) for compound 2.221   13C NMR (75 MHz, CDCl3) for compound 2.221    200  1H NMR (300 MHz, CDCl3) for compound 2.222   13C NMR (75 MHz, CDCl3) for compound 2.222    201  1H NMR (300 MHz, CDCl3) for compound 2.224   13C NMR (75 MHz, CDCl3) for compound 2.224    202  1H NMR (300 MHz, CDCl3) for compound 2.226   13C NMR (75 MHz, CDCl3) for compound 2.226    203  1H NMR (300 MHz, CDCl3) for compound 2.264   13C NMR (75 MHz, CDCl3) for compound 2.264    204  1H NMR (300 MHz, CDCl3) for compound 2.227   13C NMR (75 MHz, CDCl3) for compound 2.227    205  1H NMR (300 MHz, CDCl3) for compound 2.265   13C NMR (75 MHz, CDCl3) for compound 2.265    206  1H NMR (300 MHz, CDCl3) for compound 2.230   13C NMR (75 MHz, CDCl3) for compound 2.230    207  1H NMR (300 MHz, CDCl3) for compound 2.231   13C NMR (75 MHz, CDCl3) for compound 2.231    208  1H NMR (300 MHz, CDCl3) for compound 2.234   13C NMR (75 MHz, CDCl3) for compound 2.234    209  1H NMR (300 MHz, CDCl3) for compound 2.238   13C NMR (75 MHz, CDCl3) for compound 2.238    210  1H NMR (300 MHz, CDCl3) for compound 2.239   13C NMR (75 MHz, CDCl3) for compound 2.239    211  1H NMR (300 MHz, CDCl3) for compound 2.242   13C NMR (75 MHz, CDCl3) for compound 2.242    212  1H NMR (300 MHz, CD3CN) for compound 2.243   13C NMR (75 MHz, CD3CN) for compound 2.243    213  Expansion (1.0 to 3.5 ppm region) of 1H NMR (300 MHz, CD3CN) for compound 2.243    214  1H NMR (300 MHz, CD3CN) for compound 2.247   13C NMR (75 MHz, CD3CN) for compound 2.247   215  Expansion (1.0 to 3.0 ppm region) of  1H NMR (300 MHz, CD3CN) for compound 2.247   216      Appendix C  X-ray Crystal Data      217  X-ray crystal data for compound 2.169  Empirical formula C14H17NO4S Formula weight 295.35 Crystal color, habit colourless, plate Crystal dimensions 0.02 x 0.17 x 0.22 mm Crystal system monoclinic Lattice type primitive Lattice parameters a = 5.9458(2) Å  b = 8.0579(4) Å  c = 13.6348(6) Å   = 90°   = 90.922(3)°   = 90°  V = 653.17(5) Å3 Space group P 21  (#4) Z value 2 Dcalc 1.502 g/cm3 F000 312.00 (Mo-K) 2.61 cm-1 Diffractometer Bruker X8 APEX II Radiation MoK ( = 0.71073 Å)  graphite monochromated Data images 1696 exposures @ 30.0 seconds Detector position 40.00 mm 2max 52.1° Total no. of reflections measured 9749 No. of unique reflections 2578 Residuals (refined on F2, all data): R1; wR2 0.047; 0.079 Residuals (refined on F): R1; wR2 0.035; 0.075 Goodness of it indicator 1.03 218  X-ray crystal data for compound 2.243       Empirical formula C17H17NO4S Formula weight 331.37 Crystal colour, habit colourless, needle Crystal dimensions 0.02 x 0.07 x 0.61 mm Crystal system monoclinic Lattice type primitive Lattice parameters a = 9.3522(11) Å  b = 5.9706(6) Å  c = 26.864(3) Å   = 90°   = 98.101(4)°   = 90°  V = 1485.0(3) Å3 Space group P 21/c (#14) Z value 4 Dcalc 1.482 g/cm3 F000 696.00 (Mo-K) 2.39 cm-1 Diffractometer Bruker APEX DUO  Radiation Mo-K ( = 0.71073 Å) Data images 1128 exposures @ 10.0 seconds Detector position 40.17 mm 2max 56.6° Total no. of reflections measured 15984 No. of unique reflections 3684 Residuals (refined on F2, all data): R1; wR2 0.064; 0.101 Residuals (calculated on F2): R1; wR2 0.042; 0.092 Goodness of fit indicator 1.00 

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