Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Investigations relevant to semipinacol rearrangements for the formation of 1-azaspirocycles Easton, Leah Pearl 2007

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-ubc_2007-0390.pdf [ 10.03MB ]
Metadata
JSON: 831-1.0059832.json
JSON-LD: 831-1.0059832-ld.json
RDF/XML (Pretty): 831-1.0059832-rdf.xml
RDF/JSON: 831-1.0059832-rdf.json
Turtle: 831-1.0059832-turtle.txt
N-Triples: 831-1.0059832-rdf-ntriples.txt
Original Record: 831-1.0059832-source.json
Full Text
831-1.0059832-fulltext.txt
Citation
831-1.0059832.ris

Full Text

INVESTIGATIONS RELEVANT TO SEMIPINACOL REARRANGEMENTS FOR THE FORMATION OF 1-AZASPIROCYCLES by L E A H P E A R L E A S T O N B.Sc, The University of British Columbia, 2000 A THESIS SUBMITTED I N P A R T I A L F U L F I L L M E N T OF T H E R E Q U I R E M E N T S FOR T H E D E G R E E OF M A S T E R OF SCIENCE i n T H E F A C U L T Y OF G R A D U A T E STUDIES (Chemistry) T H E UNIVERSITY OF BRITISH C O L U M B I A August 2007 © Leah Pearl Easton, 2007 ii Abstract Investigations related to semipinacol rearrangements for the formation of 1-azaspirocycles including substrate synthesis, reaction scope, and application to the Erythrina alkaloid skeleton are reported. Nickel(II) and chromium(II) salts are used to promote the addition of enol triflates derived from 6-valerolactam to aldehydes to produce substrates such as A. The use of N-Boc-protected triflate 1.21 results in higher yields than the corresponding N-Ts or N-Bz-protected analogues. Additions to aliphatic aldehydes are most efficient while electron-rich aldehydes prove less reactive. The optimized reaction conditions are also applicable to additions of 1.21 to cyclobutanone. The scope of the semipinacol rearrangement of siloxy-epoxides is extended to include substrates with larger rings. Using Lewis acid tin(IV) chloride the 6 to 7-membered and 7 to 8-membered ring expansions of the corresponding epoxides, 2.33 and 2.37, are possible. Two general strategies towards the Erythrina alkaloid skeleton which feature a sernipinacol rearrangement to form the spirocyclic ring junction are explored. However, both approaches are yet to provide a means to the total synthesis of the desired framework. During the course of investigations the semipinacol rearrangement of epoxide 3.59 involving a migration to a benzylic position is attained. Erythhna alkaloid skeleton 3.59 Table of Contents Abstract ii Table of Contents , iv List of Tables... ..ix List of Figures xi List of Schemes xii List of Abbreviations xvi Acknowledgements xx CHAPTER 1: Nickel(II) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates to Carbonyl Compounds 1 1.1 Introduction 2 1.1.1 Lithiation of Enamine Derivatives 2 1.1.2 Lactam-Derived Enol Triflates: Stability 5 1.1.3 Lactam-Derived Enol Triflates: Preparation 9 1.1.4 Reactions of Lactam-Derived Enol Triflates 11 1.2 Proposed Chrornium(II) and Nickel(II)-Mediated Couplings of Lactam-Derived Enol Triflates 26 1.3 Results: Additions of Lactam-Derived Enol Triflates to Aldehydes 31 1.3.1 Preparation of Lactam-Derived Enol Triflates 31 1.3.2 Ni/Cr-Mediated Addition of N-Boc Triflate 1.21 to Benzaldehyde 32 1.3.3 Ni/Cr-Mediated Additions of N-Ts Triflate 1.91 and N-Bz Triflate 1.17 34 1.3.4 Ni/Cr-Mediated Addition of N-Boc Triflate 1.21 to Various Aldehydes ....35 1.4 Results: Additions of Lactam-Derived Enol Triflates to Ketones 37 1.5 Summary & Concluding Remarks 41 1.6 Experimental 42 1.6.1 General Information 42 1.6.2 N-Substituted Lactams 43 1.6.3 Lactam-Derived Enol Triflates 46 1.6.4 Ni/Cr-Meditated Additions to Aldehydes 49 1.6.5 Bipyridyl Ligand Preparation 58 1.6.6 Ni/Cr-Meditated Additions to Cyclobutanone 61 1.7 Selected Spectra 63 1.8 References 76 CHAPTER 2: Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 81 2.1 Introduction 82 2.1.1 Bronsted Acid Promoted Semipinacol Rearrangements : 83 2.1.2 NBS Promoted Semipinacol Rearrangements 86 2.1.3 Lewis Acid Promoted Semipinacol Rearrangements :... 88 2.2 Proposed Further Investigations of Semipinacol Rearrangements 94 2.3 Results: Expansions of Larger Rings 96 2.3.1 Preparation of Epoxides 2.33 and 2.37 96 2.3.2 Semipinacol Rearrangement of Epoxide 2.33 97 2.3.3 Semipinacol Rearrangement of Epoxide 2.37 102 2.4 Summary & Concluding Remarks 104 2.5 Experimental 105 2.5.1 General Information 105 2.5.2 Syntheses of Epoxides 2.33 & 2.37 106 2.5.3 Semipinacol Rearrangement Investigations of Epoxide 2.33 113 2.5.4 Semipinacol Rearrangement of Epoxide 2.37 116 2.6 Selected Spectra 118 2.7 X-Ray Crystallographic Data \ 121 2.8 References 123 CHAPTER 3: Semipinacol Approaches to the Erythrina Alkaloid Skeleton 124 3.1 Introduction to the Erythrina Alkaloids 125 3.1.1 Occurrence and Isolation „. 125 3.1.2 Biological Activity 125 3.1.3 Structural Features 126 3.1.4 Biosynthesis 127 3.1.5 Previous Synthetic Approaches 129 3.2 Proposed Semipinacol Approach to the Erythrina Alkaloid Skeleton 137 3.3 Semipinacol Approach I to the Erythrina Alkaloid Skeleton 139 3.3.1 Retrosynthetic Analysis 139 3.3.2 Results & Discussion 139 3.3.3 Future Directions & Conclusions 143 3.4 Semipinacol Approach II to the Erythrina Alkaloid Skeleton 145 3.4.1 Retrosynthetic Analysis .....145 3.4.2 Synthesis of Epoxide 3.53 147 3.4.3 Attempted Semipinacol Rearrangement of Epoxide 3.53 149 3.4.4 Synthesis of Epoxide 3.59 152 3.4.5 Ring Expansion of Epoxide 3.59 154 3.4.6 Investigations from 1-Azaspirocycle 3.64 ...156 3.5 Summary & Concluding Remarks 167 3.6 Experimental 168 3.6.1 General Information 168 3.6.2 Semipinacol Approach 1 169 3.6.3 Semipinacol Approach II 177 viii 3.7 Selected Spectra 195 3.8 X-Ray Crystallographic Data 218 3.9 References 219 List of Tables Table 1.1 Effect of N-Substituent on 13C NMR 6 and Basicity at C-3 of Enamines 6 Table 1.2 Stability of Lactam-Derived Enol Triflates of Various Ring Sizes 8. . Table 1.3 Optimization of Conditions for the Synthesis of Triflate 1.14 11 Table 1.4 Ni/Cr-Meditated Addition of Triflate 1.21 to Benzaldehyde 33 Table 1.5 Ni/Cr-Mediated Additions of Triflates 1.91 & 1.17 to Aldehydes... 35 Table 1.6 Ni/Cr-Mediated Addition of N-Boc Triflate 1.21 to Various Aldehydes 36 Table 1.7 Attempted Ni/Cr-Mediated Additions to Cyclobutanone using Ligand 1.103 , 38 Table 2.1 Acid Promoted Semipinacol Rearrangements 84 Table 2.2 NBS Promoted Semipinacol Rearrangements 87 Table 2.3 Effect of Lewis Acid on Diastereoselectivity 90 Table 2.4 Effect of Protecting Group on Diastereoselectivity 91 Table 2.5 Attempted Ring Expansion of Siloxy-Epoxide 2.33 93 Table 2.6 Ring Expansion of Epoxide 2.33 99 Table 2.7 Crystallographic Data for 2.47a... 121 Table 2.8 Crystallographic Data for 2.48 122 Table 3.1 AUylation of 3.50 ; 142 Table 3.2 Attempted Semipinacol Rearrangement of 3.53 150 Table 3.3 Semipinacol Rearrangement of Epoxide 3.59 154 Table 3.4 Deprotonation of Amide 3.66 160 Table 3.5 Deprotonation of Sulfone 3.68 163 Table 3.6 Deprotonation & Subsequent D 2 O Addition to Sulfone 3.68 164 Table 3.7 Crystallographic Data for 3.69 218 List of Figures Figure 1.1 Stabilization in Lithiated Enamine Derivatives 3 Figure 1.2 Stabilization via Electron-Withdrawing Ring Substituents 7 Figure 1.3 Stability of Pyrrolidinone-Derived Enol Triflates 8 Figure 2.1 Alkaloids Contairung 1-Azaspirocycles.. 82 Figure 2.2 Possible Transition States for the Semipinacol Rearrangement 84 Figure 2.3 ORTEP Plot of 2.47a Showing Relative Stereochemistry ...100 Figure 2.4 Determination of Diastereomeric Ratio via JH NMR Spectroscopy 101 Figure 2.5 ORTEP Plot of 2.48 Showing Relative Stereochemistry 103 Figure 3.1 Examples of Erythrina flowers 125 Figure 3.2 Erythrina Alkaloids ....126 Figure 3.3 Proposed Semipinacol Rearrangement Precursor 3.53 147 figure 3.4 ]H NMR Spectrum Aromatic Region of Enamide 3.57 149 Figure 3.5 Proposed Semipinacol Rearrangement Precursor 3.59 152 Figure 3.6 Possible Transition State for Cyclization 158 Figure 3.7 Selective Reduction of 3.66 159 Figure 3.8 Structural Similarities of 3.69 & 3.71 161 Figure 3.9 ORTEP Plot of Byproduct 3.69 161 xii List of Schemes Scheme 1.1 Synthetic Approaches to 2-Alkenyl 2-Substituted N-Heterocycles 2 Scheme 1.2 Synthesis and Lithiation of Enamides 4 Scheme 1.3 Synthesis and Lithiation of Enamides 5 Scheme 1.4 Decomposition Pathway of Lactam-Derived Enol Triflates 5 Scheme 1.5 Syntheses Involving Sonogashira Coupling of Lactam-Derived Enol Triflates 14 Scheme 1.6 Applications Involving Stille Coupling of Lactam-Derived Enol Triflates ; 16 Scheme 1.7 First Carbonylation of a Lactam-Derived Enol Triflate 17 Scheme 1.8 Syntheses Involving Carbonylation of Lactam-Derived Enol Triflates... 18 Scheme 1.9 Suzuki Coupling of Lactam-Derived Enol Triflates 19 Scheme 1.10 Synthetic Applications Involving Suzuki Coupling of Lactam-Derived Triflates '. 20 Scheme 1.11 Organocuprate Additions to Lactam-Derived Enol Triflates 21 Scheme 1.12 Conversion to a Vinylboronate and Subsequent Suzuki Coupling 22 Scheme 1.13 Conversion to a Vinylstannane then a Vinyllithium 22 Scheme 1.14 Approach to Rosephilin via a Vinylstannane 23 Scheme 1.15 Semipinacol Precursor Synthesis via a Vinylstannane 23 Scheme 1.16 Synthesis of Fasicularin via Vinylstannane 1.95 25 Scheme 1.17 Mechanism for the Formation of Undesired Bicyclic Carbamate 26 Scheme 1.18 Proposed Nickel(II)/Chromium(II)) Approach to Semipinacol Precursors '. 27 Scheme 1.19 Simplified Mechanism of Nozaki-Hiyama-Kishi Ni/Cr-Mediated Reaction..., 28 Scheme 1.20 Cr/Ni-Mediated Coupling with Lactone-Derived Enol Triflate 29 Scheme 1.21 Examples of N H K Additions to Ketones without a Bipyridyl Ligand... 30 Scheme 1.22 Preparation of N-Ts-Protected Triflate 1.21 31 Scheme 1.23 Preparation of N-Ts and N-Bz-Protected Lactams and Triflates 32 Scheme 1.24 Synthesis of the Bipyr idyl Ligand 37 Scheme 2.1 Byproduct Formation via Undesired Elimination 85 Scheme 2.2 Bronsted A c i d Promoted Epoxide Semipinacol Rearrangement 86 Scheme 2.3 Proposed Transition State for NBS Promoted Semipinacol Reactions .... 88 Scheme 2.4 Epoxidation and Subsequent Ring Expansion of 2.19 89 Scheme 2.5 SnCL Promoted Prins-Pinacol Rearrangement 94 Scheme 2.6 Preparation of Epoxides 2.33 and 2.37...; 97 Scheme 2.7 Possible Mechanisms for the Formation of 2.34 and 2.36 98 Scheme 2.8 Stereoselectivity in the Semipinacol Rearrangement of Epoxide 2.33... 101 Scheme 2.9 Possible Mechanism for the Formation of Byproduct 2.35 102 Scheme 2.10 Stereoselectivity in the Semipinacol Rearrangement of 2.48 ....103 xiv Scheme 3.1 Biosynthesis of Erythrina Alkaloids 128 Scheme 3.2 V i n y l Tricarbonyl Iminium Approach 130 Scheme 3.3 Thionium Pummerer/Iminium Cyclization Approach 130 Scheme 3.4 Purnmerer / lMDAAminium Cascade Approach 131 Scheme 3.5 AlMe 3 -Mediated/Iminium Cascade Approach 132 Scheme 3.6 NBS-Promoted Irninium Approach i 132 Scheme 3.7 Iminium Salt-Allylsilane Diradical Approach 133 Scheme 3.8 Trichloroacetamide Radical Approach 134 Scheme 3.9 Xanthate Radical Cyclization Approach 134 Scheme 3.10 a-Thioacetamide Radical/Irninium Approach 135 Scheme 3.11 Acylnitrilium/[3+2] Approach 136 Scheme 3.12 [1+4] Cycloaddition Approach 136 Scheme 3.13 General Proposed Semipinacol Approach to the Erythrina Alkaloid Skeleton 137 Scheme 3.14 Retrosynthetic Analysis I 139 Scheme 3.15 Synthesis of Enamide 3.46 140 Scheme 3.16 Synthesis of Al ly l ic Alcohol 3.50 140 Scheme 3.17 Proposed Mechanism for the Formation of Byproduct 3.52 142 Scheme 3.18 Retrosynthetic Analysis II 145 Scheme 3.19 Proposed Semipinacol Rearrangement 146 X V Scheme 3.20 Synthesis of Epoxide 3.53 147 Scheme 3.21 Proposed Mechanism for Byproduct 3.58 Formation 151 Scheme 3.22 Attempted Preparation of Alternate Substrates 151 Scheme 3.23 Synthesis of Epoxide 3.59 152 Scheme 3.24 Undesired Rearrangement of Epoxide 3.59 153 Scheme 3.25 Proposed Mechanism for Semipinacol Rearrangement 155 Scheme 3.26 Proposed Approach to the Erythrina Skeleton via 1-Azaspirocycle 3.64 156 Scheme 3.27 Cyclizations Involving Sulfonyl Carbanion Additions to Ketones 157 Scheme 3.28 Synthesis of Sulfone 3.68 158 Scheme 3.29 Proposed Mechanism for the Formation of Byproducts 3.69 & 3.70.... 163 Scheme 3.30 Proposed Future Investigations 166 List of Abbreviations A - angstrom Ac - acetyl AMU - atomic mass unit anal. - analysis Bn - benzyl Boc - f-butoxycarbonyl br - broad Bu - butyl Bz - benzoyl °C - degrees Celsius calcd. - calculated cat. - catalytic Cbz - carbobenzoxy CSA - (lS)-(+)-10-camphorsulfonic acid d - doublet 6 - chemical shift in parts per million dba - dibenzylideneacetone DCC - 1,3-dicyclohexylcarbodiimide DCE - 1,2-dichloroethane DCM - dichloromethane DMAP - 4-dimethylarninopyridine DMF - N,N-dimethylforma'mide DMDO - dimethyldioxirane DMSO - dimethyl sulfoxide dppf - diphenylphosphinoferrocene Ed., Eds. - editor, editors Eq. - equation equiv. - equivalent(s) ESI - electrospray ionization Et - ethyl g - gram(s) GC - gas chromatography h - hour(s) II MPA - hexamethylphosphoramide hv - light Hz - hertz i - iso 1 M D A - intramolecular Diels-Alder IR - infrared / . - coupling constant KHMDS - potassium hexamethyldisilazide LA - Lewis acid l.DA - lithium diisopropylamide I .ilTMDS - lithium hexamethyldisilazide LR - low resolution M - molar M' - molecular ion m - multiplet jri-CPBA - raeta-chloroperbenzoic acid Me - methyl mg - milligram(s) MHz - megahertz min - minute (s) uL - microlitre(s) ml - millilitre(s) mmol - millimole(s) MOM - methoxymethyl nip - melting point MS - mass spectroscopy Ms - methanesulfonyl (mesyl) n - normal NBS - N-bromosuccinimide NI IK - Nozaki-Kishi-Hiyama NMP - N-methyl-2-pyrrolidone NMR - nuclear magnetic resonance p - page p - para Ph - phenyl Piv - pivolate I'MB - pflra-methoxybenzyl ppm - parts per million Pr - propyl psi - pound(s)-force per square inch Q - quaternary q - quartet R - rectus (configuration) ret. - reference rt - room temperature S - sinister (configuration) singlet secondary substitution nucleophilic bimolecular triplet tertiary ferf-butyldiphenylsilyl ferf-butyldimethylsilyl ferf-butylformamidinyl triethylsilyl trifluoromethanesulfonyl (triflate) tetrahydrofuran tetrahydropyran triisopropylsilyl thin layer chromatography , trimethylsilyl toluene meso-tetraphenylporphine pflrfl-toluenesulfonyl (tosyl) ultraviolet coordination complex sonication copyright X X Acknowledgements I would like to thank my supervisor, Prof. Greg Dake for providing guidance throughout my graduate studies and also the means and facilities required to make the following research possible. I would additionally like to thank all past and present members of the Dake research group. I would like to acknowledge the staff and technicians of the shops and services in the Department of Chemistry at the University of British Columbia. I would like to thank Dr. Brian Patrick for providing X-ray crystallographic data. I would especially like to thank my classmates Paul Hurley, Wayne Chou, Jay Reid, Emily Seo, Richard Ting, Heidi Huttunen, Jo Ling Foo, and Jim Nelson for their encouragement, support, and friendship. Nk-keScfl) and Chromiuni(Il)-Mediated Addit ions of Lactam-Derived Enol Triflates... CHAPTER 1: Nickel(II) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates to Carbonyl Compounds' A version of this chapter has been published: Easton, L . P.; Dake, G. R. Can. ]. Chem. 2004, 82,139-144. NiCfeSUfi) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 2 1.1 Introduction During the course of investigating semipinacol rearrangements (these will be discussed further in Chapter 2), our research group became interested in new methods for accessing the required N-heterocyclic precursors A, particularly with n = 2 (see Scheme 1.1). The two general approaches for the synthesis of 2-alkenyl 2-substituted N-heterocycles such as A, (i) lithiation of enamine derivatives B and their subsequent addition to electrophiles and (ii) reactions of enol triflates C derived from lactams D, will be summarized in the following sections. Selection of an appropriate route is dependent on a number of factors including ring size, nitrogen protecting group, and the desired 2-alkenyl substituent. Scheme 1.1 Synthetic Approaches to 2-Alkenyl 2-Substituted N-Heterocycles 1.1.1 Lithiation of Enamine Derivatives The lithiation of enamine derivatives is facilitated by nitrogen protecting capable of directing organolithium reagents and activating the a-carbon for D c groups such as terf-butylformarnidinyl (TBF) and r-butoxycarbonyl (Boc), which are Nic-k£{(fl) and Chromium(Il)-Mediated Additions of Lactam-Derived Enol Triflates... "3 deprotonation.1'2 These moieties also stabilize the carbanion-lithium bond of a lithiated intermediate through complexation, induction, and dipole alignment (see Figure 1.1). Donation of an electron lone pair from a nitrogen or oxygen atom, X, requires the orthogonal alignment of the carbon4ithium bond and the p-orbitals of the foramidine or amide. ( | L i Boc: X = O, R = Of-Bu X x , > > TBF: X = Nf-Bu, R = H 0 Figure 1.1 Stabilization in Lithiated Enamine Derivatives2 In 1985, Meyers and co-workers disclosed a method for the synthesis and lithiation of enamidines with TBF N-substiruents.1 Treatment of feri-butylformamidrne 1.1 with fert-butyllithium and diphenylselenide in 4:1 EtaO/THF at -78 °C generated a-selenide 1.2,. which underwent elimination in the presence of potassium carbonate to give enamidine 1.3 in 90% yield (see Scheme 1.2). Reaction of 1.3 with butyllithium gave rise to alkenyllithium species E , which was subsequently quenched with a number of different electrophiles. This reaction worked well for Mel, which lead to the formation of 1.4 in 95% yield, and for, primary halides. Although the addition of benzaldehyde to E produced ally lie alcohol 1.5 in 90% yield, carbonyl compounds with acidic a-protons failed to add. This approach was also effective for the a-lithiation and subsequent a-substitution of the analogous 5 and 7-membered AJ-heterocycles. Nifike'U'il) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 4 i 90% f-Bu 1.5 Scheme 1.2 Synthesis and Lithiation of Enamides (Meyers et al)1 In 1 9 9 3 , Beak and Lee reported the lithiation of N-f-butoxycarbonyl-protected piperidine 1.6 to intermediate F, which underwent elimination to give enarnide 1.7 (see Scheme 1 .3 ) . 2 Treatment of 1.7 with additional sec-butyllithium generated alkenyllithium G, which could react with a variety of electrophiles. The addition of berizaldehyde led to the formation of an alkoxide ion which subsequently cyclized onto the carbonyl carbon of the N-Boc substituent of intermediate H, with elimination of f-butoxide. The resulting bicyclic carbamate 1.8 was isolated in 9 2 % yield. Nk-kSi(fl) and Chromium(Il)-Media ted Addit ions of Lactam-Derived Enol Triflates. 5 N C0 2 NBu 1.6 s-BuLi -78 °C OCH-ex i |_ C0 2f-Bu o s'-BuLi N I C0 2 f-Bu 1.7 O A. Ph H N ! O ' l O Ph 92% G H Scheme 1.3 Synthesis and Lithiation of Enamides (Beak & Lee) 2 1.8 1.1.2 Lactam-Derived Enol Triflates: Stability Prior to discussing the reactions of lactam-derived enol triflates, their stability and preparation should be considered. Lactam-derived enol triflates C are susceptible to hydrolysis back to the corresponding lactam precursors D, as illustrated in Scheme 1.4. Several factors contribute to triflate stability: nitrogen protecting group, ring substitution, and ring size. 3,4 (< H - O H OTf N C n = 1, 2, 3 H I O - H f ^ T o H 4> I Scheme 1.4 Decomposition Pathway of Lactam-Derived Enol Triflates Carbonyl or sulfonyl nitrogen protecting groups are generally required for stable lactam-derived enol triflates. These electron-withdrawing groups decrease the basicity of the nitrogen lone electron pair thus circumventing triflate Nifik#i(il) and Chromium(Il)-Mediated Addit ions of Lactam-Derived Enol Triflates... 6 decomposition. The relative electron-withdrawing ability of carbonyl and sulfonyl groups can be inferred from the 13C NMR data for C-3 of enamines 1.9 to 1.12 (see Table 1.1). Higher chemical shift values (entries i to iii) reflect a lower electron density at this position resulting from a strong electron-withdrawing group P on the nitrogen.5'6 In contrast, N-methyl-substituted enamine (entry iv) allows donation of the nitrogen lone electron pair into the double bond resulting in a lower chemical shift for C-3 (97.3 ppm).7 In fact, this phenomenon renders enamine 1.12 extremely unstable. Table 1.1 Effect of N-Substituent on 1 3 C NMR 5 and Basicity at C-3 of Enamines 5 7 0 ' 1.9-1.12 Entry P Compound 1 3C NMR 6 for C-3 (ppm) 104.55<a 108.55<a 108.26<b 97.37<c ;-50 M H z , CDC1 3 ; b75 M H z , CDC1 3 ; c20 M H z , benzene-^-Electronegative substituents on the ring can also stabilize lactam-derived enol triflates. Lactam-derived enol triflate 1.13 lacks a carbonyl or sulfonyl protecting-group on the nitrogen (see Figure 1.2).8 However, the adjacent carbon i COPh 1.9 ii C02Bn 1.10 iii S02PhMe 1.11 iv Me 1.12 Kn.;;k£S([I) and Chr6mium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 7 has a trifluoromethyl group and an alkoxide group, both of which are electron-withdrawing and contribute to the overall stability of triflate 1.13. 1.13 Figure 1.2 Stabilization via Electron-Withdrawing Ring Substituents (Jiang et alY The relative stability of lactam-derived enol triflates with ring size is: 6-membered > 7-membered > 5-membered (see Table 1.2 for examples).3 Triflates of 6-membered rings (entries ii & iii) are relatively stable; they can be purified via chromatography and stored at room temperature for days or at 4 °C for months.910 Although triflates of 7-membered rings (entry iv) can be purified via chromatography, they are less stable and partially decompose during subsequent coupling reactions.1112 Triflates derived from 5-membered rings lacking further substitution (entry i) are extremely sensitive; they often decompose during chromatography or under conditions required for coupling reactions.913 Nicke-KII) and Chromium(Il)-Mediated Addit ions of Lactam-Derived Enol Triflates... Table 1.2 Stability of Lactam-Derived Enol Triflates of Various Ring Sizes 9 1 2 Entry n P Stability i 1 COPh sensitive to aqueous work-up, decomposition during coupling913 ii 2 COPh relatively stable9'10 iii 2 C02Bn relatively stable11 , iv 3 C02Bn partial decomposition during coupling1112 Speckamp and co-workers identified certain structural features which enable the isolation of a more robust pyrrolidinone-derived enol triflate.414 An ethoxy substituent adjacent to nitrogen was found to be stabilizing. Whereas triflates of 5-membered rings lacking an ethoxy group are highly prone to decomposition, triflate 1.14 exhibited superior thermal stability and could be purified via chromatography (see Figure 1.3). The strongly electron-withdrawing p-toluenesulfonyl substituent on the nitrogen was found to be crucial; attempts to form the analogous N-Boc-protected triflate 1.15 failed. EtO N OTf E t O ^ N OTf Ts .Boc 1.14: stable 1.15: unstable Figure 1.3 Stability of Pyrrolidinone-Derived Enol Triflates (Speckamp et al)414 NiCk#{(il) and Chromium(Il)-Mediated Addit ions of Lactam-Derived Enol Triflates... 9 In 1998, Nicolaou and co-workers reported the synthesis enol phosphates derived from lactams (Eq. 1.1).15 These can exhibit superior stability compared to the corresponding triflate analogues, especially for larger ring sizes. In cases where lactam-derived enol triflate stability is an issue, phosphates have been used as an alternative since they possess similar chemical reactivities.3 k > = 0 KHMDS, (PhQ)2P(Q)CI C ^ O P ( O P h ) 2 I THF, -78 °C I C 0 2 R C 0 2 R R = Ph, f-Bu n= 1-4, 9, 12 81-96% (1.1) 1.1.3 Lactam-Derived Enol Triflates: Preparation The first synthesis of an enol triflate from an N-substituted lactam was reported in 1994 by Okita and Isobe (Eq. 1.2).1316 N-benzoyl-2-piperidone 1.16 was treated with lithium hexamethyldisilazide and HMPA in THF at -78 °C. Upon warming the reaction to 0 °C, N-phenyltriflimide was added to afford enol triflate 1.17 in 60% yield. a LiHMDS, HMPA, PhNTf2 I Jl , N O : : ^ ^ N ^ O T f (1 .2) I THF,-78 °C to 0 °C I COPh COPh 1.16 60% 1.17 In 1995, Foti and Comins reported a general method for the synthesis of vinyl triflates from the enolates of 6 and 7-membered N-substituted lactams.10 Accordingly, lactam 1.18 was treated with LiHMDS in THF at -78 °C and the Nic;kei( l l ) and Chromium(II)-Media ted Additions of Lactam-Derived Enol Triflates... 10 resulting enolate was subsequently trapped with N-(5-chloro-2-pyridyl)triflimide (Comins' reagent) to yield enol triflate 1.19 in 90% yield (Eq. 1.3). Whereas N-phenyltriflimide required use of either toxic additive HMPA or stronger base KHMDS to form lactam-derived enol triflates, Comins' reagent was more reactive. C/^Xs. LiHMDS, X^NTf 2 C^}L N ^ O ^ N OTf 1.3 I THF, -78 °C I C0 2Ph C0 2Ph 1.18 90% 1.19 In 1995, Murai and co-workers also reported the synthesis of various enol triflates from 6 and 7-membered N-acyl lactams.9 Using LiHMDS, HMPA, and then N-phenyltriflimide in THF at -78 °C to rt, lactam 1.20 was converted to triflate 1.21 in 89% yield (Eq. 1.4). L J^ . LiHMDS, HMPA, PhNTf2 L JL N ^ O + N OTf (1-4) I THF, -78 °C to 25 °C I Boc Boc 1.20 89% 1.21 In 1996, Speckamp and co-workers optimized the synthesis of stabilized pyrrolidinone triflate 1.14 from lactam 1.22 (see Eq. 1.5 & Table 1.3).4'17 No reaction occurred with lithium hexamethyldisilazide, however switching to potassium hexamethyldisilazide led to the formation of triflate 1.14 in 60% yield (entries i & ii). The purity of Comins' reagent used to trap the potassium enolate was found to greatly affect the yield. Kugelrohr distillation of the commercially available reagent i prior to use increased the yield of triflate 1.20 from 60% to 97% (entries ii & iii). NiSkei(il) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates. 11 Table 1.3 Opt imizat ion of Condit ions for the Synthesis of Trif late 1.14 (Speckamp et al)*1 i \ Base, N ' NTf 2 1 X. E t O ^ N ^ O ^ E t O ^ N OTf (1.5) I THF, -78 ° C I Ts .- Ts 1.22 1.14 Entry Base Purity of Comins'Reagent Yield 1.14 (%) i LiHMDS Commercial 0 ii KHMDS Commercial 60 iii KHMDS Kugelrphr distilled 97 1.1.4 Reactions of Lactam-Derived Enol Triflates Lactam-derived enol triflates undergo many of the same reactions as enol triflates; transition metals such as palladium and copper can insert into the alkenylcarbon-triflate bond. However, stability issues arise with lactam-derived enol triflates, especially with the 5 and 7-membered derivatives, therefore mild reaction conditions are necessary. Since the discovery of lactam-derived enol triflates many methods have been reported for forming 2-alkenyl 2-substituted N-heterocycles including: (i) Sonogashira coupling, (ii) Stille coupling, (iii) Negishi coupling, (iv) carbonylation (v) Suzuki coupling, (vi) cuprate addition, and (vii) conversion to vinylboranes or vinylstannanes and subsequent reactions. NifiteJHfl) and Chrpmium(II)-Mediaied Addit ions of Lactam-Derived Enol Triflates... 12 1.1.4.1 Sonogashira Coupling Lactam-derived enol triflate 1.17 was used by Okita and Isobe in 1994 for Sonogashira cross-coupling with trimethylsilylacetylene (see Eq. 1.6).13-16 Using 5% of Pd2(dba)3-CHC13, 20% of P(o-tol)3, (z'-Pr)2NEt, and trimethylsilylacetylene, coupled product 1.23 was obtained in 69% yield. I JL Pd 2 (dba) 3 CHCI 3 , P(o-tol) 3, (/-Pr) 2NEt N OTf + SiMe 3 — COPh D M F ' 6 0 ° C COPh 1 . 1 7 69% 1 . 2 3 Fori and Comins reported the coupling of lactam-derived enol triflate 1.19 with trimethylsilylacetylene to give 1.24 in 97% yield using PdCl2(PPh3)2, Cul, and (z'-Pr)2NH in THF at room temperature (Eq. 1.7).10 These milder conditions were also effective for Sonogashira coupling with the less stable 7-membered enol triflate. OL.._ . ^ ^ PdCI 2 (PPh 3 ) 2 , Cul N OTf + SiMe 3 "-NT (1.7) ' _ „ . (;-Pr) 2NH, THF, rt I C 0 2 P h \ a . CO z Ph SiMe 3 1 . 1 9 97% 1 . 2 4 Jiang and co-workers reported the Sonogashira coupling of enol triflate 1.13 with propargyl alcohol to give coupled product 1.25 in 76% yield, using similar reaction conditions (Eq. 1.8).8-18 C F 3 C F 3 PdCI 2 (PPh 3 ) 2 , Cul V -NL + = . - — V - N _ ^ (1.8) Y \ H (/-Pr) 2NH, THF, 20 °C f ^ Ph OTf P H I 1 . 1 3 76% 1 . 2 5 I NiCketCJI) and Oiromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 13 Sonogashira coupling of lactam-derived enol triflates has been applied to the syntheses of several alkaloid natural products (see Scheme 1.5). In 1997, Cha and co-workers reported the syntheses of clavepictines A (1.28) and B (1.29) via triflate 1.26 and its coupled product, 1.27.19'20 In 2000, Halberg and co-workers utilized Sonogashira coupling of triflate 1.19 to give 1.30, which was elaborated to anabasine analogue 1.31.21 In 2003, Toyooka and Nemoto reported the first enantioselective synthesis of (+)-quinolizidine 2071 (1.34), which incorporated the coupling of triflate 1.32 to give 1.33.22 In 2005, Kim and Kim utilized a Sonogashira coupling of triflate 1.13, to give coupled product 1.35, towards the synthesis of (+)-trifluoromethyl monomorine (1.36).23 NicfceKfl) and Chromium(I.I)-Mediated Additions of Lactam-Derived Enol Triflates. 14 TIPSO, , ^ - > . ~ O P l v T IPSO, , ^ O H P d ( P P h 3 ) 4 , Cu l ' N ' "OTf +~ I E t 3 N , T H F , rt C b z 1.26 88% O A c a N OTf C 0 2 P h 1.19 N P d C I 2 ( P P h 3 ) 2 , Cul_ E t 3 N , T H F , rt 70% C 0 2 P h 1.30 OPiv 1.28: clavepictine A R 1 = Ac, R 2 = Et 1.29: clavepictine B R 1 = H, R 2 = Et 1.31: anabasine analogue T B D P S O . ..^ CjL_ Pd(P .OTHP P d ( P P h 3 ) 4 , Cu l T B D P S O . ,x ~ N ' "OTf * -I (/-Pr) 2NH, T H F , rt I C 0 2 M e C 0 2 M e 98% P d C I 2 ( P P h 3 ) 2 , Cu l 1.33 C F , O 1.13 (/-Pr) 2 NH, T H F , rt OTf P h 1.35 65% - N O T H P J 1.34: (+)-quindizidine 207I 1.36: (+)-trifluoromethyl monomorine H O Bu Scheme 1.5 Syntheses Involving Sonogashira Coupl ing of Lactam-Derived Enol Triflates 1 9" 2 3 1.1.4.2 Stille Coupling In 1995, Fori and Cornins reported the Stille coupling of lactam-derived enol triflate 1.19 with tributyl(vinyl)stannane using 2% Pd(PPh3)4 and LiCl in refluxing THF to give 1.37 in 78% yield (Eq. 1.9). 10 a N OTf + B u ^ n . ^ ^ I C 0 2 P h 1.19 P d ( P P h 3 ) 4 , LiCl THF, reflux 78% N I C 0 2 P h 1.37 (1.9) Nk;kgi(f f) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates.... 15 Speckamp and co-workers adopted milder conditions for effecting the Stille coupling of enol triflate 1.38 with alkenylstannane 1.39 (Eq. 1.10).41417 The reaction was able to proceed at room temperature using in situ generated Pd(0) and NMP to yield coupled product 1.40 in 67% yield. Using this method, the Stille coupling of enol triflates derived from both 5 and 6-membered lactams with various alkenylstannanes was possible. XX „ _ ^ B u 3 S n . .OEt Pd(MeCN) 2 CI 2 , Ph 3 As ^K. ^OEl E t O ' " N T " O T f + Y " — E K T ^ N ^ Y I NMP I 1 1 Ts 11 Ts 1.38 1.39 67% 1.40 Some synthetic applications of Stille coupling with lactam-derived enol triflates are outlined in Scheme 1.6. In 1999, Cha and co-workers investigated the Diels-Alder reaction with dienes such as 1.41, which was synthesized via a Stille coupling of triflate 1.26.2024 Using this methodology functionalized octahydroquinolines such as 1.42 were constructed. In 2005, Toyooka and co-workers used Stille coupling of triflate 1.43 to give 1.44, which was elaborated to 223V diastereomer 1.45.25 NifikgKII) and Chromium(I.l)-Mediated Addit ions of Lactam-Derived Enol Triflates. 16 TIPSO,, TIPSO, [ |1 B u 3 S n ' ^ ' Pd2(dba)3, ZnCI2 N OTf I NMP, rt Cbz 1.26 80% 1.41 79% 1.42 A Pd(PPh 3) 4, LiCI TBDPSO. A J> TBDPSO. ^ N OTf +~ ^ N v ^ 0 N N I THF, rt I * ^ \ / C0 2 Me C0 2 Me > ' 1.43 92% 1.44 1.45: 223V diastereomer Scheme 1.6 Applications Involving Stille Coupling of Lactam-Derived Enol Triflates20 2 4 2 5 1.1.4.3 Negishi Coupling In 1996, Speckamp and co-workers reported the Negishi coupling of lactam-derived enol triflates.4 Phenelzine chloride, generated in situ from PhLi and 2nCl2, was coupled to enol triflate 1.38 using Pd(PPh3)4 in THF to give coupled product 1.46 in 80% yield (Eq. 1.11). Arylation of the analogous 5-membered lactam-derived enol triflate was also successful. J L J L PhZnCI, Pd(PPh 3) 4 J L J L E t O ^ N ^ O T f =V E t O ^ N ^ P h (1 .11) . I THF, rt I Ts Ts 1.38 80% 1-46 In 1999, Jiang and co-workers applied similar reaction conditions in the arylation of lactam-derived triflate 1.13 to give enamine 1.47 in 88% yield (Eq. 1.12).8 PhZnCI, Pd(PPh 3) 4_ x , , THF, rt OTf 1.13 88% 1.47 i \ ! i i ; k e ! ( f l ) and Chromium(II)-VTediated Additions of Lactam-Derived Enol Triflates. 1.1.4.4 Carbonylation In 1995, Comins and Foti reported the methoxy carbonylation of lactam-derived enol triflate 1.19 (see Scheme 1.7).10 Using catalytic Pd(OAc)2 and EtjN under 50 psi carbon monoxide in methanol, a 71% yield of methyl ester 1.48 was obtained, which was elaborated to (S)-pipecolic acid (1.49). L JL Pd(OAc)2, Et 3N, MeOH L JL I * X. ^ N ^ O T f ^ N ^ C 0 2 M e „ ^ N ^ V o H I 50 psi CO, DMF, rt I 1 *~ A U U 2 H C 0 2 P h C 0 2 P h H H 1.19 71% 1.48 1.49: (S)-pipecolic acid Scheme 1.7 First Carbonylat ion of a Lactam-Derived E n o l Triflate (Comins & Foti) 1 0 Speckamp and co-workers applied carbonylation to pyrrolidinone-derived enol triflate 1.14 to obtain methyl ester 1.50 in 65% yield (Eq. 1.13).4'14-17 JL \~~rs-rf Pd2(dba)3, Ph 3As, Et 3N, MeOH 1 V^,-. ..Q E t O ^ N O T f — — E t O ^ r g C ° 2 M e (1-13) I CO, DMF, rt I Ts Ts 1.14 6 5 o / o 1.50 Some syntheses involving carbonylation of lactam-derived enol triflates are outlined in Scheme 1.8. In 1997, Speckamp and co-workers used a methoxycarbonylation of triflate 1.38 to give 1.51, a precursor to desoxoprpsophylline (1.52).26 In 2000, Speckamp and co-workers approached the roseophilin core 1.54, via carbonylation of triflate 1.53.27 Toyooka and co-workers reported the syntheses of lepadin B (1.57) 2 8 2 9 223A (1.59),30 and 205B (1.62),31 which involved the carbonylation of lactam-derived enol triflates (1.55, 1.32, & 1.60) and NiSkelill) and Chromium(l.l)-Mediated Additions of Lactam-Derived Enol Triflates. 18 subsequent cuprate additions to the generated unsaturated methyl esters (1.56, 1.58, & 1.61). XL XX Pd(AsPh 3) 4, Et 3N, MeOH EtO" " N " "OTf „ - . *~ EtO" ~ N ' "C0 2 Me I CO, DMF, rt I Ts Ts 61% 1.38 C 1 2H,«> N rr0H 1.51 OMe T S O T f Pd2(dba)3, AsPh 3 , LiCI 1.53 Et 3N, MeCN, CO, 50 °C MeO 80% C0 2 Me OMe M O M O ^ ^ ^ M O M O ^ / - ^ ,, J\K|JLnxf Pd(PPh 3) 4, PPh 3 , Et 3N, MeOH X JL Me N OTf Me N C0 2 Me I CO, DMF, rt I C0 2 Me C0 2 Me 1.55 74% 1.56 TBDPSO, ""OL , , Pd(PPh 3) 4, Et,N T B D P S O ^ . , , , N ° T f CO. MeOH ' ^ V C ° 2 M e C0 2 Me C0 2 Me 1.32 1.58 TBDPSO. 75% , „ Pd(PPh 3) 4, Et 3N TBDPSO. ^ , , ^ N OTf ' . ; * *• ^ N "C0 2 Me I CO, MeOH I Z C0 2 Me C0 2 Me 1.52: desoxoprosophylline 1.54: roseophilin core M e ^ N ^ ^ H 1.57: lepadin B 1.59: 223A 1.60 88% 1.61 Scheme 1.8 Syntheses Involving Carbonylation of Lactam-Derived Enol Triflates 2 6 ' 3 1 1.1.4.5 Suzuki Coupling In 2000, Occhiato and co-workers reported the Suzuki coupling of boronic acids and esters with lactam-derived enol triflates (see Scheme 1.9). 1 2 3 2 This method was effective in introducing aryl, alkenyl, allyl, and aikyl groups to 6 and 7-membered lactam derivatives. Initially, catalytic (Ph3P)4Pd and K3PO4 in dioxane Ni;';kgi(fl) and Chromium(Il)-Mediated Addit ions of Lactam-Derived Enol Triflates... 19 (conditions typically used in Suzuki couplings of enol triflates) failed. By switclving the catalyst to (Ph3P)2PdCl2, the base to Na2C03, and the solvent to THF/water, the coupling of lactam-derived enol triflate 1.21 with alkenylboronate 1.63 proceeded to give coupled product 1.64 in 82% yield. Alkylboronic acids are less reactive; triflate 1.21 and alkylboronic acid 1.65 required (dppf)PdCl2/ Ag20 as an accelerant,33 and K2CO3 in toluene at 80 °C to afford coupled product 1.66 in 88% yield. Scheme 1.9 Suzuki Coupl ing of LactamrDerived Enol Triflates (Occhiato et al)1232 Some examples of synthetic applications involving the Suzuki coupling of lactam-derived triflates are shown in Scheme 1.10. In 2002, Kozlowski and co-workers accessed 2,6-substituted-l,5-diaza-cis-decalin 1.69 via the coupling of bistriflate 1.67 with phenylboronic acid to give 1.68.34-35 Occhiato and co-workers mvestigated the Suzuki coupling of triflates such as 1.70 with boronates including 1.71.113637 The resulting alkoxytrienes, such as 1.72, were used as substrates for Nazarov reactions which formed bicyclic products analogous to 1.73. Ni;M'i(II) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. 20 Boc Boc I I H 1.67 B o c 97% 1:68 B o c .1-69 ( , ~ | ° \ PdCI 2(PPh 3) 2, NaC0 3 ( ~ v N OTf + , B . — N I O THF, 50 °C I Ts l E l Ts "OEt 1.70 1.71 54% 1.72 Scheme 1.10 Synthetic Applications Involving Suzuki Coupl ing of Lactam-Derived Trif lates 1 1 - 3 4 3 7 1.1.4.6 Cuprate Addition In 1995, Comins and Fori investigated the addition of organocuprates to lactam-derived enol triflate 1.19 (Eq. 1.14).10 Triflate 1.19 was treated with Bu2CuLi in THF at 0 °C then the reaction was quenched with butyl iodide to give coupled product 1.74 in 80% yield. Without the addition of the corresponding aikyl iodide, Significant amounts of the a-unsubstituted tetrahydropyridine were obtained. L JL. 0 Bu 2CuLi L JL. N OTf ' „ , *- N Bu (1.14 I n) Bui I v ' C 0 2 P h THF, 0 °C C 0 2 P h 1.19 80% 1.74 Some examples of organocuprate additions to lactam-derived triflates are shown in Scheme 1.11. In 1995, Murai and co-workers reported the addition of Various organocuprates to triflates of 6 and 7-membered lactam derivatives in good yields without quenching with the corresponding aikyl iodides.9 Triflate 1.75 was added to a solution of cuprate 1.76 in HMPA and THF at -78 °C, then warmed to 25 Sfic'k<li{il) and. Chromium(lI)-Mediaied Addit ions of Lactam-Derived Enol Triflates... 91 °C/ to yield enamide 1.77 in 8 5 % yield. In 1997, Speckamp and co-workers reacted Bu2CuLi with triflate 1.14. Following addition of butyl iodide, only a 40 % yield of 1.78 was obtained.14 In 1999, Jiang and co-workers added Me2CuLi to triflate 1.13 to furnish 1.79 in 85 % yield.8 85% 1.77 I ^ i) Bu 2 CuLi f~\ E t O A r A o T f i i ™ ^ E t O ^ N ^ B u I HMPA, THF, 0 °C I Ts Ts 40% i) Me 2 CuLi O ii) Mel THF, -5 °C OTf 1.13 8 5 % 1.79 Scheme 1.11 Organocuprate Additions to Lactam-Derived Enol Triflates8-914 1.1.4.7 Conversion to Vinylboranes & Vinylstannanes and Subsequent Reactions Conversion of lactam-derived triflates to the corresponding vinylboronates or Vinylstannanes results in an umpolung or reversal in reactivity. In 2004, Occhiato and co-workers reported the synthesis of lactam-derived vinylboronates such as 1.81 (see Scheme 1.12).38-39 Triflate 1.80 was treated with bis(pinacolato)diboron, PdCl2(PPh3)2, Ph3P, and K2C03 in dioxane at 90 °C to give 1.81 in 8 5 % yield. Subsequent reaction with 3-bromopyridine, Pd(OAc)2, Ph3P, and K3P04-H20 in dioxane at 100 °C gave coupled product 1.82 in 77% yield. Lactam-derived Nifikgl(fl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 22 vinylboronates can be used as Suzuki coupling partners with various vinyl, aryl, and acyl halides. ft T<> o-K- ft k A. P d C I 2 ( P P h 3 ) 2 , P h 3 P , K 2 C 0 3 ^ 1^ X „ Q . . - 7 v " ^ . . " ^ . ' v — j ^ , Pd(OAc)2, Ph 3P, K 3 P 0 4 - H 2 0 N OTf • — — N B \S - ' IN SJ i I ^ IN D V / - — , - _ n _ IN I I dioxane, 90 °C I I / v . dioxane, 100 C I Cbz Cbz O - V ^ Cbz ^ Cbz 1.80 85% 1.81 ' 77% 1.82 Scheme 1.12 Conversion to a Vinylboronate and Subsequent Suzuki Coupl ing (Occhiato et al) 3 8 3 9 In 1997, Speckamp and co-workers reported the synthesis of vinylstannane 1.83 in 62% yield from lactam-derived enol triflate 1.38 using Me6Sn2 and in situ generated Pd(0) (see Scheme 1.13).14 Treatment of 1.83 with 1.1 equiv. of Meli in EtaO between -40 and -10 °C resulted in transmetalation to form vinyllithium I, which underwent addition to acetone to give allylic alcohol 1.84 in 60% yield. JL Me 6 Sn 2 , Pd(AsPh 3) 4 JL EtO N OTf *~ EtO N SnMe 3 I THF, 40 to 50 °C ' Ts Ts 1.38 62% 1.83 E t O ^ O ^ L i I Ts i) MeLi . Et 2 0, -40 to -0 °C ii) acetone 60% I 1.84 Scheme 1.13 Conversion to a Vinylstannane then a Vinyl l i th ium (Speckamp et al)14 In 2005, Occhiato and co-workers generated vinylstannane 1.87 from triflate 1.86 using similar reaction conditions (see Scheme 1.14).40 Vinylstannane 1.87 was Stille coupled with acyl chloride 1.88 in 24% overall yield from the lactam 1.85. The resultant divinyl ketone 1.89 was elaborated to 1.90, a precursor of roseophilin. MiekelCil) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... ...cv N I Ts 1.85 O KHMDS, Ph 2NTf THF, -78 °C ...CV N I Ts 1.86 OTf Me 6 Sn 2 , Pd(MeCN)2CI2, Ph 3As THF, 40 °C, 4 h ...CV Cl 1.88 1 Pd(PPh 3) 4 PhCH 3 , reflux 24% (three steps) N I Ts 1.87 SnMe 3 1.89 1.90: roseophilin precursor Scheme 1.14 Approach to Rosephilin via a Vinylstannane (Occhiato et al)40 The Dake group adapted and improved the vinylstannane method originally reported by Speckamp and co-workers to access the 2-alkenyl 2-substituted N-heterocyclic precursors required for eventual semipinacol rearrangement investigations (see Scheme 1.15).41"43 Generation of vinylstannane 1.92 from enol triflate 1.91 via a Pd(0) catalyzed coupling with hexamethyldistannane required some optimization. Application of heat (55 °C), as previously reported, resulted in only a 35% yield of 1.92. Improved yields were obtained by reducing the reaction temperature to room temperature. The reaction was also found to be sensitive to time. Running the reaction for 7 hours gave vinylstannane 1.92 in 65%, while longer reaction periods resulted in lower yields due to product decomposition. a a Me 6 Sn 2 , Pd 2dba 3 , Ph 3As * N ' "OTf "N" "SnMe 3 7 c -} s THF,rt ,7h | s ii) 0=<> i) MeLi, MgBr2 -78 to 0 °C, 10 min 1.91 65% 1.92 Et 2 0, -100 °C 89% N Li I Ts CXe: N I Ts 1.93 Scheme 1.15 Semipinacol Precursor Synthesis via a Vinylstannane (Fenster et al)4143 Likewise, the transmetalation of vinylstannane 1.92 to vinyllithium J and subsequent addition of cyclobutane to yield allylic alcohol 1.93 required Nit;ke>(II) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 24 adjustments. Interestingly, at least 2 equiv. of MeLi were required for complete transmetalation to vinyllithium J. The addition of MgBr20Et2 following transmetalation was found to be critical. However, varying yields arising from inconsistent batches of this reagent from Aldrich have since led to the substitution of anhydrous MgBr2 from Strem. Cooling the reaction to -100 °C prior to addition of cyclobutane was found to increase product yield. The MgBr2 OEt.2 additive and low addition temperature minimized the generation of unwanted byproduct formed via proton quenching of vinyllithium J and led to the isolation of desired allylic alcohol 1.93 in 89% yield. This methodology was successfully employed in the synthesis of fasicularin (see Scheme 1.16).44-45 Following the optimized conditions, lactam-derived triflate 1.94 was converted to vinylstannane 1.95 in 71% yield. Subsequent transmetalation and addition of cyclopentanone gave an 89% yield of allylic alcohol 1.96, which was elaborated in a formal synthesis of fasicularin (1.97) featuring a semipinacol rearrangement as a key step. This strategy has also been explored by our research group for application towards the synthesis of other natural products including the Erythrina alkaloids (refer to Chapter 3), halichlorine,46 and cylindricine B.47 _Ni£k#i(fI) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... C-6H13 1.96 1.97: fasicularin Scheme 1.16 Synthesis of Fasicularin via Vinylstannane 1.954445 i) MeLi,- M g B r 2 -78 to 0 °C, 10 min ii) o=Q Et 2 0, -100 °C 89% Nieke'S(iI) and Chromium(II)-Mediated Additions.or' Lactam-Derived Enol Triflates... 26 1.2 Proposed Chromium(II) and Nickel(II)-Mediated Couplings of Lactam-Derived Enol Triflates There are some issues and limitations of the vinylstannane approach to construct the allylic alcohol substrates required for semipinacol investigations. Hexamethyldistannane is a very toxic and expensive reagent (especially since one trimetMytin group is wasted for every equivalent used); if possible its use should be avoided.48 Even though the process of converting a vinyl triflate via a vinylstannane to a vinyllithium prior to electrophilic addition achieves the required bond formation, it is indirect and time consuming (refer to Scheme 1.15). Furthermore, this method is limited in terms of N-substituent compatibility; only substrates with a p-toluenesulfonyl protecting group on the nitrogen have been synthesized. Access to analogues with acyl ester N-substituents is prohibited by the elimination of alkoxide via intermediate K which results in the formation of undesired bicyclic carbamate L as outlined in Scheme 1.17. Scheme 1.17 Mechanism for the Formation of Undesired Bicyclic Carbamate The goal of this project is to investigate an alternate means of accessing the required semipinacol rearrangement precursors. This method should be compatible with other protecting groups on the nitrogen and be more direct than the presently R 1 ~R2 K L NfiGkeUII) and Chromium(U)-Mediated Additions of Lactam-Derived Enol Triflates... 07 used vinylstannane route. Only examples of palladium and copper metals have been reported inserting into the C-O bond of lactam-derived enol triflates (refer to section 1.1.4). We wanted to find a metal that would enable the direct addition of a carbonyl compound in one step from a vinyl triflate M to give an allylic alcohol N (see Scheme 1.18). Although low valent nickel is known to insert into vinyl triflates,49 its insertion into lactam-derived enol triflates is unprecedented. Nickel is an attractive metal since vinylnickel species can be converted to vinylchromium species in situ which are known to add to carbonyl compounds in Nozaki-Hiyama-Kishi (NHK) reactions.50 5 3 Me 6 Sn 2 , Pd(0) L JL i) MeLi, MgBr2 N SnMe 3 • R R 2 C^ JL_, NiCI2 (cat.), CrCI2 C^ I O , 1 * ^OH ~ N ' "OTf • -_ l - - ."-- - - t +~ ~ N ' ~ M N 1 R 2 Scheme 1.18 Proposed Nicke l ( I I ) /Chromium ( I I ) ) Approach to Semipinacol Precursors The NHK reaction involves the addition of vinyl halides or pseudohalides to aldehydes mediated by nickel(II) and chromium(II) salts. A simplified mechanism is illustrated in Scheme 1.19.51 Two molecules of chromium(II) are required to reduce niekel(II) to nickel(O), which undergoes oxidative insertion into a vinyl halide or pseudohalide bond. Next, transmetalation with chromium(III) occurs to give a vinylchromium species O. Nucleophilic addition to an aldehyde yields ah Nifike'l(fl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 2 8 alkoxide-chromium(III) species P. The stability of the newly formed 0-Cr3+ bond provides the driving force of the reaction. Scheme 1.19 Simplified Mechanism of Nozaki-Hiyama-Kishi Ni /Cr-Mediated Reaction 5 1 The initial goal of the proposed nickel(II) and chromium(II)-mediated reactions of lactam-derived enol triflates is the addition to aldehydes. This would represent a novel reaction type. Although examples of NHK reactions with ketones are limited, the eventual goal would be to extend this methodology to additions with ketones to generate substrates for semipinacol investigations. This could potentially provide access to substrates with protecting groups other than p-toluenesulfonyl and provide an alternate synthetic route to the vinylstannane There are a few examples of NHK reactions which are especially relevant to the proposed project. In 1995, Nicolaou and co-workers reported the monumental synthesis of brevetoxin B (1.101; see Scheme 1.20).54'55 A key step of its construction involved a nickel(II) and chromium(II)-mediated coupling of lactone-derived enol triflate 1.98 and aldehyde 1.99. Product 1.100 was obtained in 66% yield using 6 equiv. of aldehyde 1.99, 0.02 equiv. of NiCl2, and 6.0 equiv. of CrCb. in DMF under X = I, Br, OTf ^ X method. NicJkeKlI) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates.-.. 29 sonication. Although lactam-derived triflates are electronically different from lactone-derived triflates, since nitrogen is less electronegative than oxygen, this example suggests the feasibility of the proposed addition of an aldehyde to a lactam-derived enol triflate meditated by nickel(II) and chxomium(II). Scheme 1.20 Cr/Ni-Mediated Coupling with Lactone-Derived Enol Triflate (Nicolaou et al)5*55 Chen and co-workers reported an asymmetric version of the NHK reaction which involved a chiral bipyridyl ligand.5658 Interestingly, addition of the ligand was also found to suppress the formation of homocoupled byproducts. This enabled the use of a 1:2 stoichiometric ratio of nickel to chromium, which provided a significant enhancement to the rate of reaction. Using these conditions, even ketones were reported to react (Eq. 1.15).56-57 The example of enol triflate 1.102 coupling with cyclohexanone in the presence of bipyridyl 1.103 to give 1.104 in 72% provides a basis for our proposed additions with ketones. Ni£k&i(JI) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 30 o / — \ / — \ B n / U + | ^ | 1.103 W , ( 1 1 5 ) \ l ^ J NiCI2/CrCI2(1:2) [ J THF, rt, 11 h \ ^ 1.102 72% 1-104 It is noteworthy that under typical NHK conditions enol triflate 1.102 did not react with acetophenone, even after heating to 60 °C (see Scheme 1.21).51 The best reported example of a vinylchromium addition to a ketone without a pyridyl ligand is the reaction of 2-iodo-prop-l-ene with cyclohexanone to give 1.105 in 22% yield.50 Bu O c a t N i C | 2 C r C | 2 Bu =< + APh * = ( y O H x0 T f Ph 60 "C, DMF V M e ^ 1.102 O cat. NiCI2, CrCI 2 Ph ! 50 °C, DMF 22 % Scheme 1.21 Examples of N H K Addit ions to Ketones without a Bipyridyl Ligand 5 0 - 5 1 NifitaJHlI) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 31 1.3 Results: Additions of Lactam-Derived Enol Triflates to Aldehydes 1.3.1 Preparation of Lactam-Derived Enol Triflates Previously reported lactam-derived enol triflate 1.21 was prepared in two steps from 5-valerolactam (see Scheme 1.22).9 Deprotonation of 6-valerolactam with n-butylk'thium followed by addition of di-ter£-butyldicarbonate gave N-Boc-protected lactam 1.20 in 99% yield. Lactam 1.20 was treated with lithium hexamethyldisilazide at -78 °C and the resulting enolate was trapped with N-(5-chloro-2-pyridyl)triflimide to yield triflate 1.21 in 84% yield according to the protocol reported by Foti and Comins.10 n-BuLi, Boc 2 0 iT^ L LiHMDS, X^NTf 2 C^ jL N O N ^ O *~ N OTf H THF, -78 °C I THF, -78 °C to 25 °C I Boc Boc 99% 1 2 0 84% 1 - 2 1 Scheme 1.22 Preparation of iV-Ts-Protected Triflate 1.21 Known N-Ts-protected and N-Bz-protected triflates 1.91 and 1.17 were prepared according to standard procedure (see Scheme 1.23). 6-Valerolactam was treated with n-BuLi then either p-toluenesulfonyl chloride or benzoyl chloride in THF at -78 °C to yield lactams 1.106 (74%) and 1.16 (70%). Subjection of each lactam to KHMDS followed by PhNTf2 in THF at -78 °C lead to the formation of triflates 1.91 and 1.17 in 64% and 79% yields, respectively. Triflates 1.21,1.91, and 1.17 were hJiCkeUII) and Chromium(H)-Mediated Addit ions of Lactam-Derived Enol Triflates... 32 Stable to purification via column chromatography and could be handled neat at rOdm temperature for hours or stored in solution at -20 °C for months. I X r>-BuLi,®-CI L -L KHMDS, PhNTf2 L J L N ^ - 0 » - N O *~ N OTf H THF, -78 °C ^ THF, -78 °C to 25 °C ^ 1.106: P = Ts (74%) 1.91: P = Ts (64%) 1.16: P = Bz(70%) 1.17: P = Bz (79%) Scheme 1.23 Preparation of N-Ts and 7V-Bz-Protected Lactams and Triflates 1.3.2 Ni/Cr-Mediated Addition of N-Boc Triflate 1.21 to Benzaldehyde Next, the Ni/Cr-meditated addition of N-Boc triflate 1.21 to benzaldehyde was investigated, initially employing reaction conditions similar to those reported by Nicolaou and co-workers (Eq. 1.16).5455 Triflate 1.21 was sonicated in degassed DMF-THF (1:1) at room temperature in the presence of 6 equiv. of benzaldehyde, 2 mOl% NiCl2, and 6 equiv. of CrCl2 (see Table 1.4; entry i). After 15 h, the starting material had been consumed according to TLC and allylic alcohol 1.107 was isolated in 60% yield. The structure of 1.107 was established by spectroscopic methods. Absorptions characteristic of alcohol (3404 cm1) and carbonyl (1682 cm1) functional groups were present in the IR spectrum. The signals in the XH NMR spectrum at 5 5.35 ppm (d, / = 9.2 Hz, IH) and 6 1.29 ppm (s, 9H) corresponded to the benzylic methine proton and the methyl protons of the terr-butyl group, respectively. Significantly, the reaction yielded allylic alcohol 1.107 rather than a bicyclic carbamate product (refer to Scheme 1.17). Niekeliil) and Chromium(ll)-Mediated Addit ions of Lactam-Derived Enol Triflates... Table 1.4 Ni/Cr-Meditated Addit ion of Triflate 1.21 to Benzaldehyde r^^i 2 m o l % N i C ' 2 - C r C ' 2 r^^i !L conditions L J N ^ O T f + O H C ' ^ " N T Y ^ (1-16) I rt, 15 h Boc 1.21 1.107 Entry equiv. PhCHO equiv. CrQb Solvent Agitation Yield 1.20 (%)a i 6 . 6 DMF-THF sonication 60 ii 6 6 THF-DMSO sonication 10 iii 6 6 THF sonication -iv 6 6 DMSO sonication 26 V 6 6 DMF sonication 66 vi 6 6 DMF stirring 50 vii 6 4 DMF sonication 27 viii 2 6 DMF sonication 63 •Isolated yield after chromatography. Next, the effects of different reaction parameters on the addition of triflate 1.21 to benzaldehyde were probed (see Table 1.4). Solvent choice was found to have a dramatic influence on the yield of the reaction. NHK reactions generally require polar organic solvents or co-solvents in which the CrCl2 salt is partially soluble.53 A 1:1 combination of THF-DMSO gave a paltry 10% yield of 1.107 (entry ii). Individually, use of THF resulted in no reaction, while use of DMSO resulted in only 26% yield (entries iii & iv). The best solvent surveyed was DMF; its use led to the isolation of allylic alcohol 1.107 in 66% yield (entry v). The reducing ability of Nu.*ki!(il) and Chromium(II)-Mediated Addit ions or! Lactam-Derived Enol Triflates... 34 chromium(II) has been demonstrated to increase in the presence of donor amine ligands, especially DMF, which may account for the observed solvent effect.59 Stirring, which contributed to a somewhat reduced yield of 50%, proved to be a less effective agitation method than sonication (entry vi). It is conceivable that ultrasound might facilitate dissolution of the CrCb. salt.54 Six equivalents of CrCb. were necessary; reduction to four equivalents resulted in only 27% yield of 1.107 (entry vii). However, use of just two equivalents of benzaldehyde did not diminish the yield (entry viii). Employing six equivalents of CrCF; and either two or six equivalents of aldehyde in DMF with sonication was adopted as the general protocol for the addition of lactam-derived enol triflates to aldehydes (entry v or viii). 1.3.3 Ni/Cr-Mediated Additions of N-Ts Triflate 1.91 and N-Bz Triflate 1.17 Compatibility of this methodology with protecting groups other than Boc was tested. Using the developed standard protocol, N-Ts triflate 1.91 was added to benzaldehyde and hexanal to yield allylic alcohols 1.108 (46%) and 1.109 (42%), respectively (see Table 1.5; entries i & ii). The addition of N-Bz-protected triflate 1.17 to benzaldehyde was also tested. Allylic alcohol 1.110 was obtained in 21% yield. The reactivity of N-Ts triflate 1.91 and N-Bz triflate 1.17 in Ni/Cr-meditated additions to aldehydes is significantly lower compared with N-Boc triflate 1.21. NifikeHfl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... Table 1.5 Ni /Cr-Mediated Additions of Triflates 1.91 & 1.17 to Aldehydes ' L JL H R 2 mol% NiCI2, CrCI 2 L JL.R N OTf + X N Y" (1.17) ® \ DMF.rt.15h,))) ® OH Entry P Triflate R Product Yield (%)a i Ts 1.91 Ph 1.108 46 ii Ts 1.91 n-OHii 1.109 42 iii Bz 1.17 Ph 1.110 21 "Isolated yield after chromatography. 1.3.4 Ni/Cr-Mediated Addition of N-Boc Triflate 1.21 to Various Aldehydes The addition of N-Boc-protected triflate 1.21 to aldehydes other than benzaldehyde was investigated (see Eq. 1.18 & Table 1.6). Reaction of triflate 1.21 with aromatic aldehydes such as p-anisaldehyde and 2-furfural resulted in the formation of products 1.111 and 1.112 in modest yields of 42% and 49%, respectively (entries i & ii). Additions to aliphatic aldehydes were most efficient; use of hexanal and. isobutyraldehyde gave rise to 1.113 and 1.114 in 84% and 76% yields, respectively (entries iii & iv). No reaction was observed with a,(3-unsaturated aldehydes such as acrolein or cinnamaldehyde (entries v & vi). These aldehydes are inherently less electrophilic due to resonance of the adjacent double bond which may account for the observed lack of reactivity. Additions to aldehydes bearing functionalities such as acetals (entry vii, 1.115, 62%), ethers (entry viii, 1.116, 71%), and alkynes (entry ix, 1.117, 51%) were also tolerated. This is not surprising, NiOk^I(fl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 36 considering NHK reactions have been demonstrated to be a useful tool in complex total synthesis since they are compatible with a variety of functionalities in both reaction partners.53 Table 1.6 Ni /Cr-Mediated Addit ion of N-Boc Triflate 1.21 to Various Aldehydes a 2 mol% NiCI2 l-k 6 equiv. CrCI2 J L . R N OTf + V *~ N T (1-18) I II rt, ~15h,))) I I Boc O Boc OH 1.21 Entry R equiv. RHCO Product Yield (%)a i 6 1.111 42 ii 6 1.112 49 iii 6 1.113 84 iv 6 1.114 76 V 6 - -vi 2- - -vii • ^ - ^ " O T H P 2 1.115 62 viii .Yv^OPMB 2 1.116 71 ix ^^j^Silvle3 6 1.117 51 isolated yield after chromatography. NkivisiJHfJ) and Qtcomium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 3 7 1.4 Results: Additions of Lactam-Derived Enol Triflates to Ketones In order to employ Chen's conditions for NHK reactions involving ketones (refer to Eq. 1.15), it was necessary to first prepare bipyridyl ligand 1.103 according to previously reported procedures.58 2-Acetylpyridine was treated with I2 in pyridine at 100 °C to yield 58% of pyridinium salt 1.118 (see Scheme 1.24).60 The chiral portion of the ligand was derived from (R)-(+)-pinene, which was photo-oxygenated to enone 1.119 in 60% yield.61 Finally, chiral enone 1.119 was Condensed with pyridinium salt 1.118 using NH4OH in AcOH at 120 °C to give chiral bipyridyl ligand 1.103 in 69% yield.62 (R)-(+)-pinene 60% 1.119 69% 1.103 Scheme 1.24 Synthesis of the Bipyridyl Ligand Initially, the conditions originally applied by Chen were tested with triflate 1.21 and cyclobutanone (Eq. 1.19).57 The expected addition product 1.120 was a desirable precursor for semipinacol substrates. Selection of cyclobutanone had a further advantage since this ketone is particularly activated towards nucleophilic addition reactions.63 The sp2-hybridized carbonyl carbon in cyclobutanone is restricted to a bond angle of approximately 90° rather than its ideal of 120°, which Mt£k§!(tt) and Chromium(II)-Mediated Addi t ions of Lactam-Derived Enol Triflates... 38 creates considerable internal strain. Additions to this site could alleviate this strain by creating a s/?3-hybridized carbon with ideal bond angles of only 109.5°. Using 2 equiv. of triflate 1.21, 1 equiv. of cyclobutanone, 4 equiv. of ligand 1.103, 2.7 equiv. of CrCl2, and 1.3 equiv. of NiCl2 in THF at rt only compound 1.7 was obtained (see Table 1.7; entry i). Employing cyclobutanone in twofold excess relative to triflate 1.21 did not improve reactivity (entry ii). The reaction was also attempted using DMF as solvent, which also produced byproduct 1.7 (entry iii). Table 1.7 Attempted Ni/Cr-Mediated Additions to Cyclobutanone using Ligand 1.103 a Y i O / O r N OTf + , 1 : — * ~ N / N — i I I—I CrCI2, NiCI2 • I I Boc . Boc 1 Boc 1 — 1 1.21-CrCI2, NiCI2 solvent, rt I Boc 1.7 \ 1.120 recovered \ not observed (1.19) equiv. Entry equiv. 2.21 equiv. CrCl2 equiv. NiCl2 cyclobutanone i 2 2.7 1.3 1 Solvent u iii 2.7 2.7 1.3 1.3 2 2 THF THF DMF The isolation of product 1.7 can attributed to activation of the alkenyl-triflate bond via an alkenylmetal species but no subsequent addition to the ketone. To probe this issue further, triflate 1.21 was reacted with hexanal (Eq. 1.20), since this was previously demonstrated to be a viable addition, occurring in 84% using the developed protocol (refer to Table 1.6; entry iii). However, employing 4 equiv. of NiflteKH) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 39 bipyridyl ligand 1.103,1.7 equiv. of CrCl2, and 1.3 equiv. of NiCl2 in THF only a 35% yield of allylic alcohol 1.113 was obtained. a . 4 equiv. ^—N N -1.103 ^ ^ 2.7 equiv. CrCI 2 , 1.3 equiv. N iCI 2 " N ^ O T f + ^ ^N^^Y"^ ^ (1.20) I II THF, rt I I Boc O Boc OH 1.21 35% 1.113 It is possible that the lack of reactivity exhibited in the presence of the bipyridyl ligand may have been due to sterics. The intermediate alkenylchromium(III) species would have had a bulky Boc substituent on the adjacent nitrogen atom. The octahedral Cr(III) metal center would also have been coordinated to the sterically demanding bipyridyl ligand. Prior to carbon-carbon bond formation the chromium(III) species must precoordinate the oxygen atom of the carbonyl. Perhaps there was limited space for the electrophile in tlie coordination sphere of the metal. Cyclobutanone has two alkyl substituents adjacent to the carbonyl carbon, whereas hexanal only has one alkyl substituent and a hydrogen atom. The different steric demands of the two electiophiles may be the cause of the observed reactivities. If this attribution is correct then a new approach to the Ni/Cr-mediated additions to ketones, which does not involve the use of bipyridyl ligand 1.103, should be investigated. Since cyclobutanone is an especially reactive ketone, the addition of triflate 1.21 was tested employing the protocol previously developed with aldehydes (Eq. Nic:teil(fj) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 40 1.21). Using 2 mol% of NiCl2 and 6 equiv. of CrC^ in DMF with sonication, desired allylic alcohol 1.120 was isolated in 36% yield. Diagnostic absorptions in the IR spectrum of 1.120 at 3340 cm"1 and 1682 cm"1 suggested the presence of alcohol and carbonyl functional groups. Signals in the ^H. NMR spectrum of allylic alcohol 1.120 at 6 5.69 ppm (br s, IH) and 6 5.37 ppm (t, / F= 3.7 Hz, IH) were attributed to the hydroxyl proton and the alkenyl proton, respectively. a 2 mol% NiCI2 X^\\ V i 6 equiv. C X * „ IX? N OTf + : — ^ N ' I 1 — 1 rt, 15 h,))) I Boc Boc 1.21 36% 1.120 OH (1.21) Nk;ke>([I) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 41 1.5 Summary & Concluding Remarks A novel Ni/Cr-mediated addition reaction of lactam-derived enol triflates bearing Boc, Bz, or Ts N-protecting groups with various aldehydes to yield functionalized allylic alcohols was discovered. The use of N-Boc-protected triflate 1.21 resulted in the highest product yields. Additions of 1.21 to aliphatic aldehydes were the most efficient, while electron-rich aldehydes proved less reactive. These findings were also reported in a Can. J. Chem. article in 2004 (special issue dedicated to Prof. E. Piers).64 Extension of the developed procedure to include the addition of 1.21 to cyclobutanone was moderately successful. Although this method provided limited quantities of 1.120 it was not applied in a general fashion to other ketones. A major drawback associated with the developed methodology is the use a large excess of chromium(II) chloride which prevents the application of this reaction on a large scale. Efforts to reduce the required six equivalents resulted in compromised product yield. Although versions of the NHK reaction catalytic in CrCla have been reported, these have yet to be exploited with lactam-derived enol triflates.53 Nii:ks?l(JI) and Chromiuni(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 42 1.6 Experimental 1.6.1 General Information All reactions were carried out under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran was distilled from sodium using benzophenone as an indicator. Dimethyl sulfoxide was distilled from calcium hydride under reduced pressure. N -^Dimethylformamide was dried over 4 A molecular sieves and degassed. Commercially available aldehydes were distilled over sodium sulfate under reduced pressure prior to use. n-Butyllithium in hexanes concentration was determined by titration with diphenylacetic acid. Nickel(II) chloride (98%) was purchased from Aldrich and chromium(II) chloride (99.9%) was purchased from Strem. Irradiation was performed using UV light with a quartz filter (> 190 nm). Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 U V 2 5 4 pre-coated TLC plates. Sonication was carried out using a Branson 3200 sonicator. Melting points were performed using a Mel-Temp II apparatus (lab devices USA) and are uncorrected. Infrared (IR) spectra were obtained using a Perkin-Elmer 1710 FT-IR spectrometer. Proton nuclear magnetic resonance QH NMR) spectra were recorded in deuterated chloroform using either a Bruker WH-400 spectrometer or a Bruker AV-300 spectrometer. Carbon nuclear magnetic NiikeKfl ) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 43 resonance (13C NMR) spectra were recorded in deuterated chloroform using a Bruker AV-300 spectrometer. Chemical shifts (6) are reported in parts per million (ppm) and are referenced to deuterated chloroform (6 7.24 ppm ]H NMR; 6 77.0 ppm 13C NMR). Low-resolution mass spectra (LRMS) were recorded using either a Kratos-AEI model MS 50 or an Aligent 6890 series GC with a 5973 MS. Microanalyses were performed on either a Carlo Erba Elemental Analyzer Model 1106 or a CHN-O Elemental Analyzer Model 1108. 1.6.2 N-Substituted Lactams l-benzoylpiperidin-2-one (1.16) a O ^ P n To a solution of 1.0 g of 6-valerolactam (10.1 mmol) in 30 mL of THF at -78 °C was added 7.77 mL of a 1.30 M solution of n-butyllithium in hexanes (10.1 mmol). After 30 min, 1.17 mL of benzoyl chloride (10.1 mmol) in 10 mL of THF were added. After 40 min, 15 mL of an aqueous solution saturated with ammonium chloride were added. The aqueous portion was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (3:7 ethyl acetate-hexanes) yielded 1.43 g of white crystals (70%). Nickel;!!) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 44 mp: 112-113 °C. IR (KBr): 2961, 1673, 1449, 1389, 1286 cm"1. ]H NMR (400 MHz, CDC13): 6 7.57-7.34 (m, 5H), 3.80 (t, / = 6.4 Hz, 2H), 2.56 (t, / = 6.4 Hz, 2H), 1.96 (t, / = 3.2 Hz, 4H). The obtained spectral data was in agreement with the previously reported literature values.10 tert-butyl 2-oxopiperidine-l-carboxylate (1.20) A 1.35 M solution of n-butyllithium in hexanes (15 mL, 20.2 mmol) was added dropwise to a solution of 2.0 g of 6-valerolactam (20.2 mmol) in 50 mL of THF at -78 °C. After 30 min, 4.4 g of di-terf-butyldicarbonate (20.2 mmol) in 15 mL of THF were added. After 2 h, the reaction was quenched with 30 mL of an aqueous solution saturated with ammonium chloride. The aqueous portion was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification via flash chromatography (3:7 ethyl acetate-hexanes) yielded 3.98 g of clear colourless oil (99%). IR (film): 2979, 2953, 1771, 1714, 1300, 1161, 1144 cm1. NMR (400 MHz, CDCL): 6 3.62 (t, / = 6.1 Hz, 2H), 2.47 (t, / = 6.7 Hz, 2H), 1.82-1.77 (m, 4H), 1.50 (s, o o NiekfiKII) and Chromium(Il)-Mediated Addit ions of Lactam-Derived'Enol Triflates... 45 911). The obtained spectral data was in agreement with the previously reported literature values.65 l-/Moluensulfonylpiperidin-2-one (1.106) To a solution of 6-valerolactam (20 g, 200 mmol) in 260 mL of THF at -78 °C was added a 1.55 M solution of n-butylli thrum in hexane (142 mL, 220 mmol). After 30 min, a solution of 42 g of p-toluenesulfonyl chloride (220 mmol) in THF at -78 °C was added. After 1 h, the reaction was quenched with 200 mL of an aqueous solution saturated with ammonium chloride. The aqueous portion was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. The crude solid was triturated in diethyl ether at 0 °C and filtered to yield 37.74 g of white powder (74%). mp: 112-113 °C. IR (KBr): 2953, 1686, 1596, 1350, 1283, 1263, 1173 cm1. NMR (300 MHz, CDC13): 5 7.90 (d, / = 8.2 Hz, 2H), 7.30 (d, / = 8.2 Hz, 2H), 3.90 (t, / = 5.9 Hz, 2H), 2.42 (s, 3H), 2.40 (t, / = 6.9 Hz, 2H), 1.94-1.84 (m, 2H), 1.82-1.72 (m, 2H). o=s=o Nififcei(II) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 46 The obtained spectral data was in agreement with the previously reported literature values.6 1.6.3 Lactam-Derived Enol Triflates l-benzoyl-l,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (1.17) To a solution of lactam 1.16 (203 mg, 1 mmol) in 4 mL of THF at - 78 °C was added 2.39 mg of potassium hexamethyldisilazide (1.2 mmol) in 3 mL of THF. After 1 h, N-phenyltriflimide (428 mg, 1.2 mmol) was added in 3 mL of THF. After 30 min, the reaction was quenched with a 10% sodium hydroxide aqueous solution (6 mL). The aqueous portion was extracted with diethyl ether (3x3 mL). The combined ethereal extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification via flash chromatography (3/7 ethyl acetate-hexanes containing 1% tiiethylamine) gave 266 mg of white solid (79%). mp: 94-95 °C. IR (KBr): 2940, 1687, 1660, 1421, 1208 cm1. JH NMR (300 MHz, CDCI3): 6 7.69-7.59 (m, 2H), 7.56-7.40 (m, 3H), 5.47 (t, / = 3.9 Hz, IH), 3.79-3.75 (m, 21 I), 2.35 (dt, / = 3.9, 6.7 Hz, 2H), 1.86-1.77 (m, 2H). The obtained spectral data was in agreement with the previously reported literature values.10 o- P h NiCk£i(fl) and Chromium(n)-Mediated Additions of Lactam-Derived Enol Triflates... 47 tot-butyl 6-(trifluoromethylsulfonyloxy)-3,4-dihydropyridine-l(2H)-carboxylate (1.21) To a solution of 1,1,1,3,3,3-hexamethyldisilazane (367 mg, 2.27 mmol) and 3 mt of THF at - 78 °C, was added drop wise 1.57 mL of 1.44 M n-butyllithium in hexanes (2.26 mmol). Upon stirring for 20 min, the mixture was transferred to a solution of lactam 1.20 (300 mg, 1.50 mmol) and 5 mL of THF at - 78 °C. After 2 h, 1.18 g of N-(5-cluoro-2-pyridy)triflimide (3.30 mmol) was added in 5 mL of THF. The cold bath was removed and the mixture was allowed to warm to 25 °C. After one hour, the reaction was quenched with a 10% sodium hydroxide aqueous solution (8 mL). The aqueous phase was extracted with three 5 mL portions of diethyl ether. The combined ethereal extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% hiethylarnine) gave 415 mg of a clear colourless oil (84%). IR (film): 2982, 2939, 1726, 1684, 1422, 1211, 1141 cm"1. ]H NMR (400 MHz, CDCI3): 6 5.26 (t, / = 4.0 Hz, 1H), 3.60-3.56 (m, 2H), 2.24 (td, / = 4.0, 6.7 Hz, 2H), 1.77-1.70 (m, 2H), 1.47 (s, H). The obtained spectral data was in agreement with the previously reported literature values.12 NickS'KII) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. 48 l-/>-toluensulfonyl-l,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (1.91) To lactam 1.106 (200 mg, 0.79 mmol) in 6 mL of THF at - 78 °C was added a solution of potassium hexamethyldisilazide (189 mg, 0.947 mmol) in 2 mL of THF. After stirring the reaction for 45 minutes at - 78 °C, N-phenyltriflimide (118 mg, 0.33 mmol) was added in 3 mL of THF. The cold bath was removed and the mixture was allowed to warm to 25 °C. After one hour, the reaction was quenched with an ammonium chloride aqueous saturated solution (5 mL). The aqueous phase was extracted with three 4 mL portions of dichloromethane. The combined extracts were then dried over sodium sulfate, filtered, and concentrated via rotary evaporation. Purification via flash chromatography (1/3 ethyl acetate-hexanes containing 1% triethylamine) gave 195 mg of white crystals (64%). mp: 47-48 °C. IR (KBr): 3436, 2952, 1674, 1425, 1362, 1213, 1173 cm"1. 'H NMR (400 MHz, CDC13): 6 7.75 (d, / = 8.2 Hz, 2H), 7.32 (d, / = 8.2 Hz, 2H), 5.43 (t, / = 4.0 Hz, IH), 3.60-3.64 (m, 2H), 2.42 (s, 3H), 2.09-2.14 (m, 2H), 1.53-1.45 (m, 2H). The obtained spectral data was in agreement with the previously reported literature o=s=o o values. 6 Nickel;!!) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 49 1.6.4 Ni/Cr-Meditated Additions to Aldehydes Representative Procedure: tert-butyl 6-[hydroxy(phenyl)methyl]-3,4-dihydropyridine-l(2H)-carboxylate (1.107) Chrornium(II) chloride (111 mg, 0.91 mmol) and 0.4 mg of nickel(II) chloride (0.003 mmol) were weighed out under an inert atmosphere. DMF (1 ml) was added and the thick green suspension was stirred for 10 minutes. Benzaldehyde (96 mg, 0.91 mmol) and a solution of triflate 2.21 (50 mg, 0.15 mmol) in 1 mL of DMF were added sequentially. The mixture was sonicated for 15 hours. Diethyl ether (5 mL) and water (2 mL), containing 1% of triethylamine, were added. The aqueous phase was extracted with three 3 mL portions of diethyl ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% .triethylamine) gave 27 mg of clear colourless oil (66%). IR (film): 3404, 2976, 2932, 1682, 1394, 1368, 1256, 1160 cm"1. ]H NMR (400 MHz, CDC13): 6 7.34-7.15 (m, 5H), 5.85 (br s, IH), 5.45 (t, / = 3.7 Hz, IH), 5.35 (d, / = 9.2 Hz, IH), 3.73 (dt, / = 4.3, 12.5 Hz, IH), 3.03 (t, / = 11.0 Hz, IH), 2.19-2.13 (m, 2H), 1,83-1.68 (m, 2H), 1.29 (s, 9H). 13C NMR (75 MHz, CDC13): 6 155.6, 143.7, 142.9, 129.1, Ni;:;tel(fl) and Chromium(Il)-Mediated Additions of Lactam-Derived Enol Triflates... 50 127.9, 127.2, 119.7, 82.6, 67.2, 46.9, 29.4, 24.5, 24.4. LRMS (EI) m/z (relative intensity): 289 (M+ + 1, 3), 233 (17), 215 (17), 189 (60), 187 (12), 172 (12), 171 (38), 170 (84), 156 (16), 143 (18), 130 (21), 115' (12), 105 (15), 82 (13), 77 (24), 59 (19), 57 (100), 55 (18). (l-/?-toluensulfonyl-l,4,5,6-tetrahydropyridin-2-yl)phenylmethanol (1.108) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 58 mg of triflate 1.91 (0.15 mmol). Purification via flash chromatography (1/3 ethyl acetate-hexanes containing 1% triethylamine) gave 21 mg of cloudy colourless oil (46%). IR (film): 3516, 2925, 1715, 1455, 1341, 1163 cm"1. aH NMR (400 MHz, CDCh): 6 7.61 (d, / = 8.6 Hz, 2H), 7.40-7.10 (m, 7H), 5.84 (d, / = 1.2 Hz, 1H), 5.46 (t, / = 3.7 Hz, 111), 3.48-3.42 (m, 1H), 3.41-3.35 (m, 1H), 2.40 (s, 3 H), 1.88 (dt, / = 1.2, 10.7 Hz, 2H), 1,39-1.29 (m, 2H). 13C NMR (75 MHz, CDC13): 6 145.2, 143.4, 142.8, 138.1, 131.1, 129.6, 128.9,128.8,128.1, 121.5, 75.9, 48.6, 23.5, 22.9, 21.4. LRMS (EI) m/z (relative intensity): 343 (M+ + 1, 8), 205 (11), 189 (19), 188 (100), 170 (22), 108 (23), 107 (25), 105 (18), 91 (36), 86 (37), 82 (27), 79 (38), 77 (35), 65 (13), 58 (15), 55 (29), 51 (12). Nifikeufl) and Qvxoiraum(u)-Mediated Addit ions ot Lactam-Derived Enol Triflates... 51 l-(l-p-toluensulfonyl-l,4,5,6-tetrahydropyridin-2-yl)hexan-l-ol (1.109) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 58 mg of triflate 1.91 (0.15 mmol) and 91 mg of hexanal (0.91 mmol). Purification via flash chromatography (1/4 ethyl acetate-hexanes containing 1% triethylamine) gave 21 mg of cloudy colourless oil (42%). IR (film): 3525, 2931, 2859, 1457, 1343, 1161 cm1. *H NMR (400 MHz, CDC13): 6 7.70 (d, /. = 8.2 Hz, 2H), 7.26 (d, / = 7.9 Hz, 2H), 5.60 (t, / = 3.7 Hz, IH), 4.47 (q, / = 6.1 Hz, IH), 3.48-3.43 (m, 2 H), 3.19 (d, / = 6.1 Hz, IH), 2.40 (s, 3H), 1.90-1.83 (m, 2H), 1.80-1.60 (m, 2H), 1.42-1.17 (m, 8H), 0.86 (t, / = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCI3): 6 145.2, 142.9, 138.2, 131.1, 128.8, 119.8, 74.9, 48.7, 36.9, 33.1, 27.1, 24.0, 23.3, 23.0, 21.2, 15.4. LRMS (EI) mlz (relative intensity): 337 (M+ + 1, 6), 182 (37), 126 (12), 112 (100), 111 (12), 91 (20), 82 (11), 55 (25). (6-benzoyl-l,4,5,6-tetrahydropyridin-2-yl)(phenyl)methanol (1.110) Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 82 2.1 Introduction The semipinacol rearrangement was developed by the Dake research group as a means of effecting ring expansions for the construction of 1-azaspirocycles. Since this methodology was first disclosed in 2001,1 our group has investigated its application towards the syntheses of natural products which contain a 1-azaspirocyclic moiety including fasicularin, halichlorine, cylindricine B, and the Erythrina alkaloids (see Figure 2.1).24 Our ongoing goal is to increase the scope of the reaction to allow a wider range of substrates, thus increasing the power of this methodology. The following sections provide a summary of the different types of semipinacol reactions previously developed by the group. These include (i) BrOTisted acid, (ii) N-bromosuccinimide (NBS), and (iii) Lewis acid promoted ring expansions.14"6 Other strategies for forming 1-azaspirocycles were recently reviewed by Dake in 2006.7 halichlorine Erythrina skeleton Figure 2.1 Alkaloids Containing 1-Azaspirocycles NiGkgKfi) and Chxomiuni(lI)-Mediated Additions of Lactam-Derived Enol Triflates... IR (film): 3384, 2976, 2933, 2837, 1695, 1683, 1512, 1395, 1368, 1248, 1160 cm"1, ' l i NMR (400 MHz, CDC13): 6 7.24-7.20 (m, H), 6.83-6.79 (m, 2H), 5.73 (br s, IH), 5.43 (t, / = 3.7 Hz, IH), 5.33 (d, / = 8.2 Hz, IH), 3.77 (s, 3H), 3.70 (dt, / = 4.0,12.2 Hz, IH), 3.05 (t, / = 11.6 Hz, IH), 2.17-2.12, (m, 2H), 1.80-1.69 (m, 2H), 1.32 (s, 9H). 13C NMR (75 MHz, CDC13): 6 159.8, 155.6, 143.3, 136.0, 128.4, 119.2, 114.6, 82.6, 76.9, 56.7, 47.0, 29.5, 24.5, 24.4. LRMS (EI) mlz (relative intensity): 319 (M+ + 1, 4), 246 (11), 245 (53), 219 (19), 202 (19), 201 (86), 200 (69), 187 (15), 186 (100), 171 (11), 170 (55), 160 (22), 158 (13), 146 (13), 137 (18), 135 (30), 128 (10), 121 (10), 115 (12), 91 (13), 77 (32), 65 (11), 63 (11), 59 (90), 57 (85), 56 (12), 55 (21), 51 (16). tert-butyl 6-[furan-2-yl(hydroxy)methyl]-3,4-dihydropyridine-l(2H)-carboxylate A protocol analogous to the one outlined for compound 1.107 was followed except substituting 104 mg of 2-furfural (0.91 mmol). Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% triethylamine) gave 21 mg of clear colourless oil (49%). IR (film): 3420, 2977, 2933, 1681, 1393, 1368, 1161 cm1. 'H NMR (400 MHz, CDCI3): 6 7.30 (s, IH), 6.28 (dd, / = 1.8, 3.4 Hz, 2H), 5.43 (t, / = 3.7 Hz, IH), 5.35 (s, IH), 3.72-3.64 (m, IH), 3.28-3.19 (m, IH), 2.15 (td, / = 3.7, 7.0 Hz, 2H), 1.81-1.71 (m, (1.112) Nic?kel(il) and Chromium(U)-Mediated Addit ions of Lactam-Derived Enol Triflates... 54 211), 1.40 (s, 9H). 13C NMR (75 MHz, CDCI3): 6 156.7, 155.8, 142.8, 141.2, 119.3, 111.5, 107.6, 82.8, 72.4, 46.7, 29.6, 24.5, 24.3. LRMS (EI) mlz (relative intensity): 279 (M+ + 1, 3), 223 (16), 179 (20), 161 (24), 160 (12), 144 (13), 132 (13), 111 (31), 107 (16), 86 (14), 84 (22), 82 (12), 59 (10), 57 (100), 55 (30). tot-butyl 6-(l-hydroxyhexyl)-3,4-dihyclropyricline-l(2H)-carboxylate (1.113) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 91 mg of hexanal (0.91 mmol). Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% triethylamine) gave 36 mg of clear colourless oil (84%). IR (film): 3424, 2956, 2932, 2860, 1742, 1683, 1393, 1368, 1256, 1163 cm1. NMR (400 MHz, CDCL): 6 5.38 (t, / = 3.7 Hz, 1H), 5.10 (br s, 1H), 4.05 (dd, / = 7.3,15.3 Hz, 1H), 3.75 (dt, / = 4.3,11.9 Hz, 1H), 3.14 (t, / = 8.9 Hz, 1H), 2.13-2.07 (m, 2H), 1.77-1,69 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 6H), 0.90-0.82 (m, 5H). 13C NMR (75 MHz, CDCI3): 6 156.1,143.4, 118.0, 82.6, 75.9, 47.0, 36.1, 33.2, 29.7, 27.3, 24.7, 24.3, 24.0,15.4. LRMS (GC) mlz (relative intensity): 283 (M+ + 1, 2), 209 (11), 152 (51), 139 (29), 138 NickeU ' f l) and Chromium(II)-Medialed Addit ions of Lactam-Derived Enol Triflates... 5 5 (10), 126 (29), 113 (100), 112 (17), 111 (10), 110 (11), 84 (37), 82 (15), 57 (55), 56 (13), 55 (20), 54 (13). tert-butyl 6-(l-hydroxy-2-methylpropyl)-3,4-cUhydropyridine-l(2H)-carbo (1.114) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 66 mg of hexanal (0.91 mmol). Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% triethylamine) gave 29 mg of white crystals (76%). mp: 58-60 °C. IR (KBr): 3378, 2956, 1670, 1656, 1396, 1367, 1166, 1032 cm1. NMR (400 MHz, CDC13): 6 5.38 (t, / = 3.7 Hz, IH), 5.14 (br s, IH), 3.83 (d, / = 8.9 Hz, IH), 3.58 (t, / = 9.2 Hz, IH), 3.04 (t, / = 9.8 Hz, IH), 2.13-2.07 (m, 2H), 1.80-1.66 (m, 21I), 1.45 (s, 9H), 0.98 (d, / = 6.7 Hz, 3H), 0.73 (d, / = 6.7 Hz, 3H). 13C NMR (75 MHz, i CDCI3): 6 156.2, 142.7, 119.2, 82.7, 82.6, 47.0, 33.0, 29.7, 24.7, 24.3, 21.2, 20.8. LRMS (GC) mlz (relative intensity): 255 (M+ + 1, 3), 156 (12), 139 (13), 138 (18), 113 (100), 112 (34), 84 (11), 82 (10), 57 (51), 55 (11). 56 tert-butyl 6-[l-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-3,4-dihydropyridine-l(2H)-carboxylat (1.115) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 157 mg of 5-(tetrahydro-2H-pyran-2-yloxy)pentanal (0.91 mmol). Purification via flash chromatography (1/9 ethyl acetate-hexanes containing 1% triemylamine) gave 33 mg of clear colourless oil (62%). IR (film): 3441, 2932, 1682, 1393, 1368, 1161 cm1. lH NMR (400 MHz, CDCL): 6 5.39 (t, / = 3.7 Hz, 1H), 5.14 (br s, 1H), 4.56-4.51 (m, 1H), 4.10 (q, / = 6.7 Hz, 1H), 3.87-3.79 (m, 1H), 3.75-3.65 (m, 2H), 3.50-3.43 (m, 1H), 3.41-3.32 (m, 1H), 3.18 (t, / = 10.4 Hz, 1H), 2.10 (td, / = 7.0, 3.7 Hz, 2H), 1.84-1.45 (m, 12H), 1.45 (s, 9H). 13C NMR (75 MHz, CDC13): 6 156.1, 143.2, 118.0, 100.2, 82.6, 75.7, 75.6, 69.0, 68.9, 63.8, 63.7, 47.0, 33.0, 32.2, 32.1, 29.7, 28.0, 26.9, 24.7, 24.3, 21.1, 21.0. LRMS (EI) m/z (relative intensity): 355 (M+ + 1, 2), 198 (14), 197 (18), 196 (38), 171 (40), 170 (45), 167 (11), 155 (11), 154 (37), 152 (20), 149 (22), 126 (24), 113 (67), 112 (11), 110 (24), 97 (23), 85 (62), 82 (10), 67 (14), 57 (100), 55 (21). Niekgl(If) arid Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. tert-butyl 6-[3-(4-methoxybenzyloxy)-l-hydroxypropyl]-3,4-dihydropyridine-l(2H)-carboxylate (1.116) A protocol analogous to the one outlined for compound 1.107 was followed except substituting 49 mg of 3-(p-methoxybenzyloxy)propanal (0.30 mmol). Purification via flash chromatography (1/9 ethyl acetate-hexanes containing 1% triethylamine) gave 40 mg of clear colourless oil (71%). IR (film): 3420, 2932, 2860, 1681, 1515, 1393, 1368, 1249, 1161 cm"1. ]H NMR (400 MHz, CDC13): 6 7.22 (d, / = 8.6 Hz, 2H), 6.84 (d, / = 8.6 Hz, 2H), 5.41 (t, / = 3.7 Hz, II I), 5.05 (br s, IH), 4.41 (dd, / = 11.3, 18.0 Hz, 2H), 4.37-3.31 (m, IH), 3,77 (s, 3H), 3.59 (s, IH), 3.56-3.44 (m, 2H), 3.19 (s, IH), 2.10-2.05 (m, 2H), 1.92-1.77 (m, 2H), 1.75-1,65 (m, 2H), 1.45 (s, 9H). 13C NMR (75 MHz, CDC13): 6 160.6, 155.9, 143.1, 132.0, 130.7, 117.6,115.2, 82.6, 74.1, 72.8, 68.9,56.7, 46.9, 36.2, 29.7, 24.6, 24.2. Anal, calcd. for C21H31NO5: C 66.82, H 8.28, N 3.71; found: C 66.53, H 8.47, N 4.11. tot-butyl 6-[l-hydroxy-5-(trimethylsilyl)pent-4-ynyl]-3,4-dihydropyridine-l(2H)-carboxylate (1.117) Nifikei(fl) and Chromium(ll)-Mediated Additions of Lactam-Derived Enol Triflates... 58 A protocol analogous to the one outlined for compound 1.107 was followed except substituting 46 mg of 5-(trimethylsilyl)pent-4-ynal (0.30 mmol). Purification via flash chromatography (1/9 ethyl acetate-hexanes containing 1% triethylamine) gave 26 mg of clear colourless oil (51%). IR (film): 3417, 2961, 2175, 1681, 1392, 1368, 1250, 1162 cm1. 'H NMR (400 MHz, CDC13): 6 5.40 (t, / = 3.7 Hz, IH), 5.19 (br s, IH), 4.19 (dd, / = 8.2,14.7 Hz, IH), 3.76 (dt, / = 4.0,11.9 Hz, IH), 3.15 (t, / = 10.7 Hz, IH), 2.24 (t, / = 7.6 Hz, 2H), 2.10 (m, 2H) 1.86-1.64 (m, 4H), 1.46 (s, 9H), 0.11 (s, 9H). »C NMR (75 MHz, CDC13): 6 156.1, 142.6, 118.5, 108.5, 86.0, 82.8, 74.7, 47.0, 35.0, 29.7, 24.6, 24.3, 18.3, 1.6. Anal, calcd. for CixH3iN03Si: C 64.05, H 9.26, N 4.15; found: C 64.45, H 9.40, N 4.45. 1.6.5 Bipyridyl Ligand Preparation l-(2-oxo-2-pyridin-2-ylethyl)pyridinium iodide (1.118) r 2-Acetylpyridine (2.00 g, 16.5 mmol), iodine (4.18 g, 16.5 mmol), and 20 mL of pyridine were heated to 100 °C for 15 h. The resulting crude dark green crystals were filtered and rinsed with diethyl ether. Recrystallization in ethanol with celite and charcoal yielded 3.14 g of shiny pale yellow crystals (58%). NitikeKII) and Chromium(II)-Media ted Addit ions ot Lactam-Derived Enol Triflates... 59 mp: 196-197 °C. IR (KBr): 3053, 2880, 1712, 1632, 1484 1334 cm1. NMR (400 MHz, CDC13): 6 9.00 (d, / = 5.6 Hz, 1H), 8.88 (ddd, / = 0.8,1.5, 4.7 Hz, 2H), 8.72 (t, / » 7.8 Hz, 1H), 8.26 (dd, / = 6.8, 7.5 Hz, 1H), 8.13 (dt, / = 1.6, 7.7 Hz, 1H), 8.07 (d, / = 7.8 Hz, 2H), 7.82 (ddd, / = 1.3, 4.7, 7.4 Hz, 1H), 6.50 (s, 2H). The obtained spectral data was in agreement with the previously reported literature values.60 (lS,5S)-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptan-3-one (1.119) An rb flask was charged with 3.0 g of (R)-(+)-pinene (22 mmol), 2.3 g of acetic anhydride (22 mmol), 0.87 g of pyridine (11 mmol), 54 mg of DMAP (0.44 mmol), 1.5 mg of TPP, and 20 mL of DCM. Oxygen was bubbled through the mixture while it was irradiated for 10 h with a quartz-mercury lamp. The solution was then diluted 'with 20 mL of DCM and washed with saturated NaHC03 aqueous solution (2 x 15 ml), 1 N HCI aqueous solution (2 x 10 mL), saturated C U S O 4 aqueous solution (10 mt), and saturated NaCl aqueous solution (15 mL). The organic portion was dried over NaS04, filtered, and concentrated via rotary evaporation. The crude oil was purified via a filter column followed by a Kugelrohr distillation at 1 torr from 70 °C to 110 °C which yielded 2.0 g of clear colourless oil (60%). 'H NMR (400 MHz, CDC13): 6 5.95 (d, / = 1.7 Hz, 1H), 4.99 (d, / = 1.7 Hz, 1H), 2.77-2.65 (m, 2H), 2.64-2.52 (m, 2H), 2.19 (ddd, / = 3.0, 6.3, 9.3 Hz, 1H), 1.35 (s, 3H), Niek&H'fl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 60 1,28 (d, / = 10.3 Hz, 1H), 0.79 (s, 3H). The obtained spectral data was in agreement with the previously reported literature values.61 (lS,9S)-10,10-dimethyl-5-pyridin-2-yl-6-azatricyclo[7.1.1.02'7]undeca-2,4,6-triene A solution of enone 1.119 (0.69 g, 4.6 mmol), pyridinium salt 1.118 (1.5 g, 4.6 mmol), NH4OAc (4.7 g, 6.1 mmol), and 8 mL of acetic acid was heated to 120 °C for 4 h. The reaction mixture was extracted with three 10 mL portions of diethyl ether. The combined extracts were dried over Na2S04, filtered, and concentrated in vacuo. Purification via flash chromatography (1/5 ethyl acetate-hexanes) gave 794 mg of white powder (69%). mp: 76-78 °C. IR (KBr): 2928, 1579, 1560, 1435 cm1. W NMR (400 MHz, CDC13): 6 8.64 (br d, / = 4.2 Hz, 1H), 8.34 (d, / = 8.3 Hz, 1H), 8.03 ( d, / = 7.8 Hz, 1H), 7.76 (dt / = 1.8, 7.7 Hz, 1H), 7.31 (d, / = 7.8 Hz, 1H), 7.24 (ddd, J = 1.2,4.8, 7.6 Hz, 1H), 3.18 (d, / = 2.8 Hz, 2H), 2.79 (t, / = 5.6 Hz, 1H), 2.69 (td, / = 5.8, 9.5 Hz, 1H), 2.39 (qd, / = 2.9, 8.8 Hz, 1H), 1.41 (s, 3H), 1.30 (d, / = 9.6 Hz, 1H), 0.68 (s, 3H). The obtained spectral data was in agreement with the previously reported literature values.62 (1.103) "NlCke-i(fl) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. 61 1.6.6 Ni/Cr-Meditated Additions to Cyclobutanone tt?rt-butyl 3,4-dihydropyridine-l(2H)-carboxylate (1.7) 0 A mixture of chromium(II) chloride (50 mg, 0.41 mmol), nickel(II) chloride (25 mg, 0.20 mmol), and bipyridyl ligand 1.103 (151 mg, 0.60 mmol) in 8 mL of THF was Stirred for lh. Cyclobutanone (llmg, 0.15 mmol) and triflate 1.21 (100 mg, 0.30 mmol) were added in 2 mL of THF. After stirring the reaction mixture for 24 h, 7 mL of water, containing 1% of triethylamine, were added. The aqueous phase was extracted with three 5 mL portions of diethyl ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (1/19 ethyl acetate-hexanes containing 1% triethylamine) gave 16 mg of clear colourless oil (59%). IR (film): 2980, 2935, 1812, 1703, 1653, 1373, 1118 cm"1. ]H NMR (400 MHz, CDC13): 6 6.77 (dd, / = 7.6 Hz, 38.9 Hz, IH), 4.83 (d, / = 23.4 Hz, IH), 3.59-3.49 (m, 2H), 2.06-1.98 (m, 2H), 1.80 (td, / = 5.9, 11.5 Hz, 2H), 1.52 (s, 3H), 1.48 (s, 3H). The Obtained spectral data was in agreement with the previously reported literature values.65 Nickel;!!) and Oiromium(H)-Mediated Addit ions of Lactam-Derived Enol Triflates... 62 tert-butyl 6-(l-hydroxycyclobutyl)-34-dihydropyridine-l(2H)-carboxylate (1.120) o A protocol analogous to the one outlined for compound 1.107 was followed except substituting 68 uL of 5-(trimethylsilyl)pent-4-ynal (0.91 mmol). Purification Via chromatotron (1/19 ethyl acetate-hexanes) gave 14 mg of clear colourless oil (36%). IR (film): 3440, 2979, 2943, 1682, 1392, 1161 cm1. lH NMR (400 MHz, CDC13): 6 5.69 (br s, IH), 5.37 (t, / = 3.7 Hz, IH), 3.49-3.45 (m, 2H), 2.25-2.17 (m, 4H), 1.97-1.89 (m, IH), 1.77-1.69 (m, 2H), 1.56-1.47 (m, IH), 1.44 (s, 9H). 13C NMR (75 MHz, CDC13): 6 155.8, 145.5, 115.4, 82.4, 77.3, 46.8, 36.1, 29.7, 24.7, 24.1, 15.3. LRMS (EI) mlz (relative intensity): 253 (M+ + 1, 0.4), 197 (46), 180 (15), 179 (10), 154 (12), 153 (83), 152 (51), 151 (25), 136 (19), 134 (13), 126 (10), 125 (100), 124 (32), 110 (19), 97 (48), 96 (16), 83 (18), 82 (22), 57 (99), 54 (15). .Cks!(H) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. 7 Selected Spectra NiGtaSifil) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. 1.107: Nietel(il) and Chromium(H)-Mediated Additions of Lactam-Derived Enol Triflates. 1.108: p - i — r ~ i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i — | — i i i i | i i i i | i i i i | r 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 MifikiHII) and Chromium(II)-Mediaied Additions of Lactam-Derived Enol Triflates. NifikeKII) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 1.111: 7.0 6.0 5.0 4 . 0 3.0 2.0 1 .0 0.0 . . . , . . . . . . . . 4()i«)/i 3600 3200 2300 3400 2000 1800 IfiOO 1400 1200 1000 800 600 56(1.0 NiftkeKII) and Chromium(H)-Mediated Addit ions of Lactam-Derived Enol Triflates. Niqkgl(II) and Chromium(H)-Mediated Additions of Lactam-Derived Enol Triflates... 1.113: •\—r~'~> ' i i ' ' 1 i 1 1 i — 1 i 1 | — i i i ' i 1 1 1 1 i 1 1 1 1 i 1 1 • 1 i 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 NiG'kel(fl) and Chromiurn(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. N i c i s e H I I ) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 1.116: 7.0 6.0 - 5.0 4.0 3.0 2.0 1.0 0.0 4(km,0 3600 3200 2300 2400 2000 ISOO . 1600 1400 1200 1000 800 600 506.0 NiCtaJKfl) and Chromium(I.l)-Mediated Addit ions of Lactam-Derived Enol Triflates... 1.117: [ ! | ! j ! ( | ! j ( | — | — r , , | , | | | | | | | | | | | | | | | | | | | 8,0 7.0 6.0 . 5.0 4.0 3.0 2.0 1.0 0.0 NiekclCfi) and Chromiu.m(II)-Mediated Addit ions of Lactam-Derived Enol Triflates. Nidkel(II) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 76 1.8 References (1) Meyers, A. I.; Edwards, P' D.; Bailey, T. R.; JagdmannJr., G. E.J. Org. Chem. 1985,50, 1019-1026. (2) Beak, P.; Lee, W. /. Org. Chem. 1993, 58,1109-1117. (3) Occhiato, E. G. Mini-Rev. Org. Chem. 2004,1,149-162. (4) Luker, T.; Hiemstra, H.; Speckamp, W. Tetrahedron Lett. 1996,37, 8257-8260. (5) Kim, S.; Yoon, J.-Y. Synthesis 2000,1622-1630. (6) Fenster, M. D. Doctoral Thesis, University of British Columbia; 2004. (7) Beeken, P.; Fowler, F. W. /. Org. Chem. 1980,45,1336-1338. (8) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J. /. Am. Chem. Soc. 1999, 122, 593-594. (9) Tsushima, K.; Hirade, T.; Hasegawa, H.; Murai, A. Chem. Lett. 1995, 801-802. (10) Foti, C; Comins, D. /. Org. Chem. 1995,60,2656-2657. (11) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Deagostino, A.; Venturello, P. /. Org. Chem. 2002, 67, 7144-7146. (12) Occhiato, E. G.; Trabocchi, A.; Guarna, A. /. Org. Chem. 2001, 66, 2459-2465. (13) Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737-3744. (14) Luker, T.; Hiemstra, H.; Speckamp, W. N. /. Org. Chem. 1997, 62, 8131-8140. (15) Nicolaou, K. C; Shi, G. Q.; Namoto, K.; Bernal, F. Chem. Commun. 1998,1757-1758. NifikeU'il) and Chromium(II)-Mediated Addit ions of Lactam-Derived Enol Triflates... 77 (16) Okita, T.; Isobe, M. Synlett 1994, 589-590. (17) Bernabe, P.; Rutjes, F. P. J. T.; Hiemstia, H . ; Speckamp, W. N . Tetrahedron Lett. 1996,37,3561-3564. (18) Jiang, J.; DeVita, R. J.; Goulet, M. T.; Wyvratt, M . J.; Lo, J. L. ; Ren, N . ; Yudkovitz, J. B.; Cu i , J.; Yang, Y. T.; Cheng, K. ; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2004,14, 1795-1798. (19) Ha , D . H . ; Lee, D.; Cha, J. K . /. Org. Chem. 1997, 62, 4550-4551. (20) Ha , D. H . ; Cha, J. K . /. Am. Chem. Soc. 1999, 121,10012-10020. (21) Lindstrom, S.; Ripa, L . ; Hallberg, A . Org. Lett. 2000, 2, 2291-2293. (22) Toyooka, N.; Nemoto, H . Tetrahedron Lett. 2003, 44, 569-570. (23) K i m , G.; K i m , N . Tetrahedron Lett. 2005, 46, 423-425. (24) Ha , D. H . ; Kang, C. H . ; Belmore, K . A . ; Cha, J. K . /. Org. Chem. 1998, 63, 3810-3811. (25) Toyooka, N . ; Nemoto, H . ; Kawasaki, M.; Garraffo, H . M.; Spande, T. F.; Daly, J. W. Tetrahedron 2005, 61,1187-1198. (26) Luker, T.; Hiemstra, H . ; Speckamp, W. N . /. Org. Chem. 1997, 62, 3592-3596. (27) Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra, H . Org. Lett. 2000, 2, 1157-1160. (28) Toyooka, N . ; Okumura, M.; Takahata, H . ; Nemoto, H . Tetraheron 1999, 55, 10673-10684. N i e k i K i l ) and Chromium(II)-Mediated Additions of Lactam-Derived Enol Triflates... 78 (29) Toyooka, N.; Okumura, M.; Takahata, H. /. Org. Chem. 1999, 64, 2182-2183. (30) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J. W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4,1715-1717. (31) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Tetrahedron 2004, 60, 6197-6216. (32) Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett. 2000,2,1241-1242. (33) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. /. Am. Chem. Soc. 1987, 209, 4756-4758. (34) Li, X.; Xu, Z.; DiMauro, E. F.; Kozlowski, M. C. Tetrahedron Lett. 2002, 4 3 , 3747-3750. (35) Xu, Z.; Kozlowski, M. C. /. Org. Chem. 2002, 67, 3072-3078. (36) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P. /. Org. Chem. 2003, 68, 9728-9741. (37) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.; Occhiato, E. G. /. Org. Chem. 2004, 69, 7705-7709. (38) Ferrali, A.; Guarna, A.; L., G. F.; Occhiato, E. G. Tetrahedron Lett. 2004,45, 5271-5274. (39) Occhiato, E. G.; Lo Galbo, F.; Guarna, A. /. Org. Chem. 2005, 70, 7324-7330. (40) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A. /. Org. Chem. 2005, 70, 4542-4545. NickeKil) and Chromium(Il)-Mediated Additions of Lactam-Derived Enol Triflates... 7S (41) Fenster, M. D.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109-2112. (42) Dake, G. R.; Fenster, M. D.; Hurley, P. B.; Patrick, B. O.J. Org. Chem. 2004, 69, 5668-5675. (43) Dake, G. R.; Fenster, M. D.; Fleury, M.; Patrick, B. O. /. Org. Chem. 2004, 69, 5676-5683. (44) Fenster, M. D.; Dake, G. R. Org. Lett. 2003, 5, 4313-4316. (45) Fenster, M. D.; Dake, G. R. Chem. Eur. f. 2005,11, 639-649. (46) Hurley, P. B.; Dake, G. R. Synlett 2003, 2131-3134. (47) Fleury, M. Master's Thesis, University of British Columbia, 2003. (48) Mitchell, T. N. In Encyclopedia of reagents for organic synthesis; Paquette, L. A., Ed.; John Wiley & Sons: London, 1995; Vol. 4, p 2664-2666. (49) Saccomano, N. A. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 1, p 173-209. (50) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983,24,5281-5284. (51) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. /. Am. Chem. Soc. 1986,108, 6048-6050. (52) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. /. Am. Chem. Soc. 1986, 108, 5644-5646. (53) Furstner, A. Chem. Rev. 1999, 99, 991-1045. Niek6*l(fl) and Chromium(H)-Mediated Addit ions of Lactam-Derived Enol Triflates... 80 (54) Nicolaou, K. C; Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X. Y. /. Am. Chem. Soc. 1995, 227,1171-1172. (55) Nicolaou, K. C; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. /. Am. Chem. Soc. 1995, 227, 1173-1174. (56) Chen, C. P.; Tagami, K.; Kishi, Y. /. Org. Chem. 1995, 60, 5386-5387. (57) Chen, C. P. Synlett 1998,1311-1312. (58) Hayoz, P.; von Zelewsky, A. Tetrahedron Lett. 1992, 33, 5165-5168. (59) Okazoe, T.; Takai, K.; Utirrioto, K. /. Am. Chem. Soc. 1987, 209, 951-953. (60) Polin, J.; Schmohel, E.; Balzani, V. Synthesis 1998, 321-324. (61) Mihelich, E. D.; Eickhoff, D. J. /. Org. Chem. 1983, 48, 4135-4137. (62) Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P. Organometallics 2001,20, 673-690. (63) Brown, H. C; Ichikawa, K. Tetrahedron 1957, 2, 221-230. (64) Easton, L. P.; Dake, G. R. Can. J. Chem. 2004, 82,139-144. (65) Dieter, R. K.; Sharma, R. R. /. Org. Chem. 1996, 61, 4180-4184. mdirtg die Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles CHAPTER 2: Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 8 2 2.1 Introduction The semipinacol rearrangement was developed by the Dake research group as a means of effecting ring expansions for the construction of 1-azaspirocycles. Since this methodology was first disclosed in 2001,1 our group has investigated its application towards the syntheses of natural products which contain a 1-azaspirocyclic moiety including fasicularin, halichlorine, cylindricine B, and the Erythrina alkaloids (see Figure 2.1).24 Our ongoing goal is to increase the scope of the reaction to allow a wider range of substrates, thus increasing the power of this methodology. The following sections provide a summary of the different types of semipinacol reactions previously developed by the group. These include (i) Bremsted acid, (ii) N-bromosuccinimide- (NBS), and (iii) Lewis acid promoted ring expansions.1'4"6 Other strategies for forming 1-azaspirocycles were recently reviewed by Dake in 2006.7 fasicularin cylindricine B O. halichlorine Erythrina skeleton Figure 2.1 Alkaloids Containing 1-Azaspirocycles Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles. 83 2.1.1 Bronsted Acid Promoted Semipinacol Rearrangements The construction of 1-azaspirocycles via the semipinacol reaction was initially realized using allylic alcohol 2.1a (Eq. 2.1).1 Protonation of the double bond by (1 S)-(+)-10-camphorsulfonic acid (CSA) led to the formation of azacarbenium ion A, which underwent a semipinacol rearrangement to produce 1-azaspirocycle 2.2 in 73% yield. (2 .1) 2.1a 73% A 2.2 Semipinacol rearrangement of substrates bearing a substituent R1 or,R2 on the heterocyclic ring gave rise to mixtures of diastereomers (see Eq! 2.2 & Table 2.1).4'5 Cooler reaction temperatures were found to produce the best diastereoselectiviti.es (entries i to iii). Treatment of allylic alcohol 2.1b with HCI at 0 °C resulted in the formation of 1-azaspirocycles 2.3b and 2.4b in a 14:1 ratio (entry iii). Reaction of allylic alcohol 2.1c under analogous conditions gave a moderate 3.7:1 ratio of product diastereomers (entry iv). Substrates 2.1d and 2.1e (bearing electronegative R 1 substituents) were found to be more reactive but gave rise to poorer product diastereoselectivities (entries v & vi). These substrates were sensitive to HCI so CSA combined with higher reaction temperatures was applied instead. Interestingly, the reaction of substrate 2.1e slightly favoured diastereomer 2.4e (entry vi). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 84 Table 2.1 Acid Promoted Semipinacol Rearrangements R 2 1 R 2 R2 i ° R1YS ° 1 Ts OH acid 1 Ts i s (2.2) DCM, T (°C), t (h) 1 x ~^ 2.1b: R 1 = H, R 2 = Ph 2.3b: R 1 = H, R 2 = Ph 2.4b: R 1 = H, R 2 = Ph 2.1c: R 1 = H, R 2 = Me 2 . 3 c : R 1 = H, R 2 = Me 2.4c: R 1 = H, R 2 = Me 2.1d: R 1 =OTBS, R 2 = H 2 . 3 d : R 1 = OTBS, R 2 = H 2.4d: R 1 = OTBS, R 2 = = H 2.1e: R 1 = OPNB, R 2 = H 2.3e: R 1 = OPNB, R 2 = H 2.4e: R 1 = OPNB, R 2 =  H Entry Substrate Acida T(°C) t(h) Product Yield (%) Ratio I 2.1b CSA 45 144 2.3b/2.4b 89 4.5:1.0b ii 2.1b HCI 25 11 2.3b/2.4b 93 11.0:1.0b iii 2.1b HCI 0 48 2.3b/2.4b 93 14.0:1.0b iv 2.1c HCI 0 67 2.3c/2.4c 68 3.7:1.0b V 2.1d CSA 45 •13 2.3d/2.4d 81 2.7:1.0b vi 2.1e CSA 45 13 2.3e/2.4e 51 1.0:1.8C 4.1-1.2 Equiv of acid. bRatio determined by G C . cRatio determined by *FL N M R . Major diastereomer 2.3 was suggested to arise from the preference for a chair-like transition state B with pseudoequatorial orientation of substituents (see Figure 2.2).4-5 Minor diastereomer 2.4 could result from either a chair-like transition State C with pseudoaxial substituents or a twist-boat-like transition state D with pseudoequatorial substituents. R 2 B C D Figure 2.2 Possible Transition States for the Semipinacol Rearrangement Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 85 Substrate 2.5, derived from a 7-membered lactam, failed to undergo semipinacol rearrangement when treated with acid (Eq. 2.3).5 Instead, protonation and subsequent elimination of the allylic alcohol occurred via intermediate E resulting in the formation of diene 2.6. / V. HCI, DCM, rt or CSA, DCM, 45 °C Ts I — 1 2.5 (2.3). N I Ts 2.6 Attempted ring expansion of cyclopentanol substrates such as 2.7 also proved unsuccessful (see Scheme 2.1).4-5 Subjection of 2.7 to CSA in DCM led to protonated intermediate F, which underwent elimination to form diene 2.8. Protonation of 2.8 to form azacarbenium ion G, followed by nucleophilic attack of water, resulted in the isolation of enone 2.9. TBSO, , O H CSA, DCM, rt 2.7 42% I TBSO. TBSO. TBSO. TBSO. 2.8 Scheme 2.1 Byproduct Formation via Undesired Elimination Addition of an allyl group to compounds 2.1a and 2.10 led to concomitant elimination of the allylic alcohol to form enamines 2.11 and 2.12, respectively (see Scheme 2.2).6 Epoxidation of each 2.11 and 2.12 occurred with "axial" attack of Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 86 tti-CPBA from the less hindered face of a chair-like conformer, in which the allyl group was pseudoaxial to avoid 1,3-allylic strain. Upon exposure of epoxides 2.13 and 2.14 to 1 M HCI in DCM, ring expansion occurred, generating the corresponding 1-azaspirocles, 2.15 and 2.16. The reaction was completely selective for the diastereomeric product corresponding to a syn aikyl group migration relative to the epoxide. L N X^ H B F 3 0 E t 2 I Ts N CH 2 CI 2 , -78 °C I V)n Ts 2.1a: n = 1 2.11: n = 1,84% 2.13: n = 1,60% 2.15: n = 1,90% 2.10: n = 2 2.12: n = 2, 89% 2.14: n = 2, 82% 2.16: n = 2 , 9 1 % Scheme 2.2 Bronsted A c i d Promoted Epoxide Semipinacol Rearrangement 6 2.1.2 NBS Promoted Semipinacol Rearrangements An alternative method for promoting semipinacol rearrangements to form 1-azaspirocycles was discovered. It was found that reaction of allylic alcohol 2.1a with 1.2 equivalents of NBS in a 1:1 mixture of z-propanol and propylene oxide (as an acid scavenger) at -78 °C resulted in ring expansion via bromonium ion H to give 1-azaspirocycle 2.17a as a single diastereomer in 85% yield (Eq. 2.4).4 In general the NBS promoted reaction was found to be milder, higher yielding, and more selective than the Bronsted acid version. However, it proved unsuccessful in effecting ring expansions of cyclopentanol substrates. Extending tlie Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 87 C j^LPH 1.2 equiv. NBS N I Ts 2.1a 1:1 /PrOH-propylene oxide -78 to 25 °C 85% (2.4) O 2.17a The effects of substrate substituents R1, R2, and R3 on the NBS promoted semipinacol rearrangement were examined (see Eq. 2.5 & Table 2.2).4 In every case, the major diastereomer obtained had the acyl substituent of the piperidine ring cis to the bromide (entries i to vi). Switching the R3 substituent from Ph to Me drastically reduced diastereoselectivity from exclusive formation of 2.17b to a 1.9:1.0 ratio of 2.17c to 2.18c (entries i & ii). Moderate selectivities were attained with electronegative R2 substituents OTBS or OBn (entries iii & iv). Ethoxy and allyl R1 substituents each led to formation of a single diastereomer (entries v & vi). Table 2.2 N B S Promoted Semipinacol Rearrangements R 3 R3 R 3 R2< R2< s / ^ i v B r R2>^V • Br R 1 JL^  JL^ /OH 1.2 equiv. NBS R1 N- / :S (p 1 L» + R 1 N ' l I ft Tsg ^ (2-5) IN 1 Ts 1—1 1:1 /PrOH-propylene oxide -78 to 25 °C 2.1 b-g 2.17b-g 2.18c-e Entry Substrate R1 R2 R3 Product Yield (%)a Ratiob i 2.1b H H Ph 2.17b 80 single isomer ii 2.1c H H Me 2.17c/2.18c 79 1.9:1.0 iii 2.1d H OTBS H 2.17d/2.18d 95 3.5:1.0 iv 2.1e H OBn H 2.17e/2.28e 90 5.0:1.0 V ' 2.1f OEt H H 2.17f 96 single isomer vi 2-lgc allyl H H . 2.17& 98 single isomer "Isolated yield. bRatio determined by *H N M R . °Enantiomer shown. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 88 The reaction preference of substrates with groups R1, R2, or R3 for diastereomer 2.17 can be rationalized according to Scheme 2 . 3 . 4 In the most stable chair-like conformation of 2.1, a substituent R1 or R3 resides in a pseudoaxial orientation to minimize allylic strain with either the p-toluenesulfonyl group on nitrogen or the vinyl proton of the enamine, respectively, while an R2 substituent prefers a pseudoequatorial orientation. The electrophilic bromine should approach the substrate with "axial" attack and in the case of pseudoaxial substituents, from the least hindered face. Migration occurs in a SN2-like fashion anti to the bromonium ion. 2.1 2.17 Scheme 2.3 Proposed Transition State for N B S Promoted Semipinacol Reactions 2.1.3 Lewis Acid Promoted Semipinacol Rearrangements Another variant of the semipinacol rearrangement was developed in an effort to extend the methodology to cyclopentanol substrates suitable for applications such as the synthesis of fasicularin. Previously, under Bransted acid promotion of allylic alcohols, elimination prevented the possibility of ring expansion (refer to Scheme 2 . 1 ) . It was anticipated that epoxidation of the double bond would circumvent Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles .. 89 elimination of the alcohol.1-5-6 In general, epoxidation required the prior protection of the alcohol. Epoxidation of 2.19 with dimethyldioxirane generated siloxy-epoxide 2.20 as a Single diastereomer in 98% yield (see Scheme 2.4).1-5-6 The stereoselectivity arose from the "axial" approach of the electrophilic oxygen to the low energy chair-like conformer of 2.19, with the OTBS substituent residing in a pseudoequatorial orientation. Treatment of 2.20 with Lewis acid TiCL in DCM at -78 °C led to the exclusive formation of 1-azaspirocycle 2.21 in 96% yield. The ring expansion occurred with migration of the aikyl group anti to the epoxide. 1-Azaspirocyele 2.21 was later successfully elaborated in a formal synthesis of fasicularin.2-3 T B S O , Scheme 2.4 Epoxidation and Subsequent Ring Expansion of 2.19 Semipinacol rearrangement of siloxy-epoxide 2.22 occurred selectively to give 1-azaspirocycle 2.23 (Eq. 2.6).1-5-6 The cis relationship of the alcohol and the carbonyl group is in accord with the proposed SN2-like transition state. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 90 (2.6) 2.22 95% 2.23 The corresponding siloxy-epoxide ring expansion of cyclobutane rings proved to be less selective (see Eq. 2.7 & Table 2.3).5'6 Treatment of substrates 2.24a and 2.24b with TiCl4 in DCM at -78 °C yielded mixtures of diastereomers 2.25 and 2.26 in ratios of 2.6:1.0 and 1.1:1.0, respectively (entries i & iii). After considerable optimization, it was found that use of a milder Lewis acid such as Yb(OTf)3 resulted in the best selectivities. Reaction of 2.24a and 2.24b with Yb(OTf)3 gave rise to diastereomers 2.25 and 2.26 in improved ratios of 7.4:1.0 and 4.4:1.0, respectively (entries ii & iii). Table 2.3 Effect of Lewis A c i d on Diastereoselectivity 2.24 2.25 2.26 Entry Substrate R Lewis Acida T(°C) Product Yield" Ratio0 I 2.24a H TiCl4 -78 2.25a/2.26a 96 2.6:1 Ii 2.24a H Yb(OTf)3 -45 to 0 2.25a/2.26a 99 7.4:1.0 Iii 2.24b OTBS TiCl4 -78 2.25b/2.26b 95 1.1:1.0 Iv 2.24b OTBS Yb(OTf)3 0 2.25b/2.26b 87 4.4:1.0 4.1-1.4 equiv. Isolated yield, de termined by H P L C . Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 91 The lack of diastereoselectivity demonstrated by the reaction is thought to arise from the considerable contribution of a syn migration pathway in addition to the expected anti migration pathway.5'6 The effect of different protecting groups was also investigated (see Eq. 2.8 & Table 2.4).5'6 A bulkier silyl ether gave rise to increased amounts of the diastereomer 2.26a, corresponding to syn migration. In fact, treatment of trhsopropylsilyl ether 2.29 with TiCLt produced 2.26a exclusively (entry iv). Table 2.4 Effect of Protecting Group on Diastereoselectivity OH OH; 2.25a 2.26a Entry Substrate P Yield (%)a Ratio 2.25a:2.26ab i 2.24a TMS 96 2.6:1.0 ii 2.27 TES 99 2.5:1.0 iii 2.28 TBS 89 1.3:1 iv 2.29 TIPS 88 0:1.0 ^Isolated yield. bDetermined by H P L C . Epoxidation of unprotected allylic alcohol 2.1a led to spontaneous ring expansion, following work-up and placement under vacuum for 10 h, to form diastereomers 2.25a:2.26a in a ratio of 13.2:1.0 (Eq. 2.9).5'6 Unfortunately, although tlie direct epoxidation of unprotected allylic alcohol 2.1a gave rise to the highest Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 92 proportion of diastereomer 2.25a, corresponding to anti migration, attempts to apply this approach to additional substrates were unsuccessful. OH ll OH ^ C ^ J L / 0 ' ' i) DMDO I Ts ii) work-up iii) 10 h vacuum ^s 2.1a 89% Semipinacol rearrangement of 7-membered heterocycle 2.30 occurred upon treatment with Yb(OTf)3 to yield a mixture diastereomers 2.31 and 2.32 in 65% yield (Eq. 2.10).5 Attempted ring expansion of the analogous 5-membered carbocycle failed. i Ts DCM, -78 °C to rt I Ts -OOTMS Yb(OTf)3 ^ „ . ^ ^ . ,„ „„ x - N ' ^A-, L l . N'T > + ^ N l > (2.10) 2.30 65% 2.31 1.5 : 1.0 2.32 Although various conditions were screened for the ring expansion of larger rings none gave rise to the desired 1-azaspirocycle (see Eq. 2.11 & Table 2.5).56 Reaction of epoxide 2.33 led only to the formation of byproducts 2.34, 3.35, and 2.36 in varying proportions. Interestingly, by employing different reaction conditions, each of the three byproducts could be formed selectively (entries ii to iv). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 93 Table 2.5 Attempted Ring Expansion of Siloxy-Epoxide 2.33 , O H ^ . O H OTMS Lewis acid solvent, -78 ° C to rt N H N ^ 6^ TO 1 J OH 2.33 2.34 2.35 2.36 Entry Lewis Acid3 Solvent Yield 2.34 Yield 2.35 Yield 2.36 i T i C L D C M 23% 15% 33% i i M g B r 2 D C M 73% Trace Trace i i i TMSOTf D C M - 77% Trace iv B F 3 O E t 2 M e O H 14% - - 85% V BF 3 -OEt 2 P h C H 3 - Trace 53% vi BF 3 -OEt 2 E t 2 0 - Trace 41% vi i B F 3 O E t 2 D C M - 9% 63% "1.1-1.4 equiv. Likewise, the attempted semipinacol rearrangement of epoxide 2.37 yielded analogous byproducts 2.38, 2.39, and 2.40 (Eq. 2.12).5 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-AzaspirocycIes 94 2.2 Proposed Further Investigations of Semipinacol Rearrangements Subsequent to the studies of semipinacol rearrangements outlined above, new insights prompted further investigations. Prof. A. Wang from the University of British Columbia performed model studies in order to predict the probable i semipinacol rearrangement transition states.5 Based on these approximations he surmised that the use of strongly polar solvents might favour ring expansion. We also were compelled by the report of Overman and co-workers on the general success of SnCL in promoting the Prins-pinacol rearrangement.8 An example where SnCL is used to activate acetal 2.41 for a Prins cyclization followed by a pinacol ring expansion to cyclooctanone 2.42 is illustrated in Scheme 2.5. Prins 2.42 Scheme 2.5 S n C L Promoted Prins-Pinacol Rearrangement (Overman et al)s We wondered if use of a strongly polar solvent or a Lewis acid such as SnCL might be successful in promoting the semipinacol rearrangements involving expansions of larger rings (Eq. 2.13). Previous conditions which were tested yielded nolle of the desired [5.6] or [5.7]-l-azaspirocycles (refer to section 2.1.3). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 95 OH (2.13) n = 1, 2 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 96 2.3 Results: Expansions of Larger Rings 2.3.1 Preparation of Epoxides 2.33 and 2.37 The epoxides 2.33 and 2.37 required for further semipinacol investigations were synthesized in parallel as outiined in Scheme 2.6.5 To a solution of hexamethyldistannane and methyllithium at -41 °C was added copper(I) cyanide. Triflate 1.91 (previously synthesized in section 1.3.1) was subjected to the resulting mixture to form vinylstannane 1.92 in 81% yield. Transmetalation of vinylstannane 1.92 with methyllithium and subsequent addition of magnesium bromide then the appropriate ketone (cyclohexanone or cycloheptanone) led to the formation of the corresponding allylic alcohol, 2.43 (78%) or 2.44 (81%). Exposure of each allylic alcohol to 2,6-lutidine and trimethylsilyl trifluoromethanesulfonate in THF produced silyl ethers 2.45 (73%) and 2.46 (26%), which were each treated with 7?i-chloroperoxybenzoic acid to yield epoxides 2.33 (84%) and 2.37 (88%), respectively. Extending the Scope of Semipinacoi Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles i) MeLi ii) MgBr 2 l i • ^ • E U C C N k Jk ^ ^ - O H I THF -41 C I E t 2 ° , -100 to 0 C Ts ' Ts , „. In 1 . 9 1 8 1 % 1 . 9 2 2 . 4 3 : n = 1 (78%) 2 . 4 4 : n = 2 (81 %) TMSOTf, - ^ N ^ JL OTMS m-CPBA, NaCH0 3 THF I f > H 2 0 , C H 2 C I 2 2 . 4 5 : n = 1 (73%) 2 . 3 3 : n = 1 (84%) 2 . 4 6 : n = 2 (26%) 2 . 3 7 : n = 2 (88%) Scheme 2.6 Preparation of Epoxides 2.33 and 2.375 2.3.2 Semipinacol Rearrangement of Epoxide 2.33 Initially, the semipinacol rearrangement of epoxide 2.33 was attempted. Previously, titanium tetrachloride was successful in promoting the analogous 4 to 5-membered and 5 to 6-membered ring expansions in dichloromethane at -78 °C.5 However, these conditions had proved ineffective for the corresponding semipinacol rearrangement of epoxide 2.33. Treatment of 2.33 with titanium tetrachloride in a relatively polar solvent such as acetonitrile failed to promote the desired ring expansion (Eq. 2.14). Instead, compounds 2.34 and 2.36 were isolated in 15% and 36% yields, respectively. These are identical byproducts to the ones that were obtained during prior ring expansion attempts of epoxide 2.33.5 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycies 98 2.33 2.34(15%) 2.36(36%) The formation of byproducts 2.34 and 2.36 was proposed to occur according to Scheme 2.7.5 A Lewis acid-coordinated epoxide intermediate I could react through two possible pathways. A 1,2-hydride migration to give carbocation J, followed by the elimination of TMSOH from K could generate enone 2.34. Alternatively, addition of water to carbocation L could result in the hydrolysis of the N-heterocyclevia structure M to give dihydroxy ketone 2.36. LA I Scheme 2.7 Possible Mechanisms for the Formation of 2.34 and 2.36s Semipinacol rearrangement of epoxide 2.33 was also attempted employing tin tetrachloride as the Lewis acid in various solvents (Eq. 2.15 & Table 2.6). Ring expansion was first achieved in dichloromethane at -78 °C (entry i). An inseparable mixture of diastereomeric 1-azaspirocycles 2.47a and 2.47b was isolated in 64% yield in a corresponding ratio of 10:1. Byproduct 2.35 was also obtained in 17% yield. Use Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 99 of acetonitrile or toluene as the solvent led to lower yields of the desired product (entries ii & iii). Interestingly, the selectivity of the semipinacol rearrangement seemed to be highest in non-polar solvents (entries i & iii). Table 2.6 R ing Expansion of Epoxide 2.33 Entry Solvent T (°C) Yield 2.47a/b (%)a Ratio 2.47a:2.47bb Yield 2.35 (%)a i C H 2 C 1 2 -78 64 10:1 17 n C H 3 C N -41 17 4:1 28 Iii P h C H 3 -78 40 15:1 23 "Isolated yield after column chromatography. bRatio determined by 1 H N M R . Initially, the structures of 1-azaspirocycles 2.47a and 2.47b were assigned based on diagnostic signals in the IR, 1H NMR, and 1 3 C NMR spectra. Absorptions at 3520 and 1702 cm1 in the IR spectrum were characteristic of alcoholand ketone functionalities, respectively. The broad singlet at 4.07 ppm and the signal at 3.97 ppm (dd, / = 2.9, 5.8 Hz, IH) in the : H NMR spectrum could be attributed to the hydroxyl proton and the methine proton adjacent to the alcohol, respectively. In the " C NMR spectrum, the peak at 214 ppm provided further evidence of a carbonyl functional group, while the peak at 71.9 ppm was indicative of the spirocyclic carbon. The lack of functionality besides the alcohol and ketone groups was in accord with the proposed 1-azaspirocyclic structures. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 100 The structure and relative stereochemistry of compounds 2.47a and 2 .47b were definitively determined by X-ray crystallography (see Figure 2.3). As initially proposed based on spectral data, a l-azaspiro[5.6]dodecanone structure was indeed obtained. The relative stereochemistry of the hydroxyl and the carbonyl substituents on the piperidine ring of the major diastereomer was cis. This was in accord with prior ring expansions which preferentially formed the analogous [5.4] and [5.5]-l-azaspirocycles.5 Figure 2.3 O R T E P Plot of 2.47a Showing Relative Stereochemistry (50% ellipsoids) The presence of the minor diastereomer was evident from the aromatic portion of the JH NMR spectrum (see Figure 2.4). At a chemical shift of 7.78 ppm there was a doublet which corresponded to the protons on C-18 and C-22 of the major diastereomer (2 .47a) , whereas the doublet at 7.65 ppm corresponded to the analogous protons of the minor diastereomer (2 .47b) . The diastereomeric ratio was determined by comparing the relative integration of these signals. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 101 ~ l 1 ' 1 1 I ' ' 1 1 1 1 ' 1 1 1 1 • 1 ' I 1 1 ' ' I 7.850 7.800 7.7SO 7.700 7.650 7.600 Figure 2.4 Determination of Diastereomeric Ratio via 1 H N M R Spectroscopy (300 M H z ) The observed stereoselectivity for the semipinacol rearrangement of epoxide 2.33 could be rationalized according to the transitions states depicted in Scheme 2.8. 6 Major diastereomer 2.47a was formed via a pathway in which migration of the alkyl group anti to the epoxide occurred in an S -^like fashion, while a syn migration pathway occurred to a lesser extent to form nrinor diastereomer 2.47b. 4 J TMS 2.47b Scheme 2.8 Stereoselectivity in the Semipinacol Rearrangement of Epoxide 2.33 The formation of 2.35, like 2.36 (refer to Scheme 2.7), occurred via hydrolysis of carbocation L (see Scheme 2.9).5 Elimination of TMSOH from intermediate M led to the observed byproduct, 2.40. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 102 Scheme 2.9 Possible Mechanism for the Formation of Byproduct 2.355 2.3.3 Semipinacol Rearrangement of Epoxide 2.37 The analogous semipinacol reaction of epoxide 2.37 was accomplished by treatment with tin tetrachloride in dichloromethane at -78 °C (Eq. 2.16). The desired 1-azaspirocycle 2.48 was isolated in 50% yield along with byproduct 2.39 (22%). (2.16) Tentative assignment of structure 2.48 was made based on key spectral features. The presence of alcohol and ketone functional groups was inferred from the absorptions in the IR spectrum at 3544 and 1698 cm1, respectively. In the ]H NMR spectrum, the signals at 4.05 ppm (dd, / = 4.1, 8.4 Hz, 1H) and 3.71 ppm (d, / = 4.7 Hz, 1H) were attributed to the methine proton adjacent to the alcohol and the hydroxyl proton, respectively. The peak in the 13C NMR spectrum at 215.9 ppm provided further evidence for a ketone functional group, while the peak at 72.3 ppm was indicative of the spirocyclic carbon. Extending the Scope of Semipinaco 1 Rearrangements of Siloxy-Epoxides to l-Azaspirocycles The absence of additional peaks in the ' H N M R spectrum supported the formation of 2.48 as a single diastereomer. X-ray crystallographic analysis confirmed the tentatively assigned [5.7]-spirocyclic structure (see Figure 2.5). The acyl group was determined to be on the same face of the piperidine ring as the alcohol. Figure 2.5 O R T E P Plot of 2.48 Showing Relative Stereochemistry (33% ell ipsoids) 1-Azaspirocycle 2.48 was formed via the exclusive migration of the aikyl group anti to the activated epoxide (see Scheme 2.10). Byproduct 2.39 was likely formed via an analogous mechanism to the one proposed for byproduct 2.35 (refer to Scheme 2.9). TMS 2.48 Scheme 2.10 Stereoselectivity in the Semipinacol Rearrangement of 2.48 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 104 2.4 Summary & Concluding Remarks Tin tetrachloride was successful in effecting the semipinacol rearrangements of epoxides 2.33 and 2.37 whereas previously investigated Lewis acids including titanium tetrachloride, boron trifluoride diethyl etherate, magnesium bromide, and trimethylsilyl trifluoromethanesulfonate failed. Clearly, tin tetrachloride should be considered as a prospective Lewis acid in future investigations of semipinacol rearrangements. The semipinacol rearrangement of 2.33 and 2.37 provided access to the corresponding [5.6] and [5.7]-l-azaspirocycles. This methodology is significant since the construction of larger rings, especially 8-membered rings, is a challenging endeavor in organic synthesis. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 105 2.5 Experimental 2.5.1 General Information All reactions were carried out under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran and diethyl ether were distilled from sodium using benzophenone as an indicator. Dichloromethane and acetonitrile were distilled over calcium hydride. Reagents trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine were distilled also over calcium hydride prior to use, while cyclohexanone and cycloheptanone were distilled over sodium sulfate. Methyllithium in diethyl ether concentration was determined by titration with diphenylacetic acid. Tin tetrachloride (99.995%) was purchased from Aldrich. Magnesium bromide (98%) and titanium tetrachloride (99.8+%) were purchased from Strem. Tin tetrachloride and titanium tetrachloride 1.0 M solutions in dichloromethane were prepared in a glove box prior to use. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Flash column chromatography was carried out using 230-400 mesh silica gel. Melting points were performed using a Mel-Temp II apparatus (lab devices USA) and are uncorrected. Infrared (IR) spectra were obtained using a Perkin-Elmer 1710 FT-IR spectrometer. Proton nuclear magnetic resonance (TH NMR) spectra were recorded in deuterated chloroform using a Bruker Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 106 AV-300 spectrometer. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterated chloroform using a Bruker AV-300 spectrometer. Chemical shifts (6) are reported in parts per million (ppm) and are referenced to deuterated chloroform (6 7.24 ppm 1TT NMR; 6 77.0 ppm 13C NMR). Low-resolution mass spectra (LRMS) were recorded using either a Kratos-AEI model MS 50. Microanalyses were performed on either a Carlo Erba Elemental Analyzer Model 1106 or a CHN-O Elemental Analyzer Model 1108. 2.5.2 Syntheses of Epoxides 2.33 & 2.37 l-p-toluenesulfonyl-6-(trimethylstannyl)-l,2,3,4-tetrahydropyridine (1.92) N " ^ S n M e 3 To a mixture of hexamethyldistannane (6.88 g, 21 mmol) in 200 mL of tetrahydrofuran at -41 °C was added 14.7 mL of a 1.40 M solution of methyllithium in diethyl ether (21 mmol). Upon warming the reaction mixture to 0 °C for 20 min, it was cooled again to -41 °C for the addition of copper cyanide (1.88 g, 21 mmol) in one portion. After 20 min, a solution of triflate 1.91 (2.70 g, 7.0 mmol) in 70 mL of tetrahydrofuran was added. The reaction mixture was stirred for 30 min then quenched with an ammonium chloride saturated aqueous solution (200 mL) and an additional 200 mL of water. The aqueous portion was extracted with diethyl ether (3 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 107 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (1/19 ethyl acetate-hexanes) yielded 2.31 g of white solid (83%). mp: 92-93 °C. IR (KBr): 2930, 2836, 1597, 1340, 1161 cm"1. ]H NMR (300 MHz, CDCL): 6 7.62 (d, / = 8.4 Hz, 2H), 7.27 (d, / = 8.4 Hz, 2H), 5.26 (t, / = 3.6 Hz, IH), 3.43 (m, 2H), 2.40 (s, 3H), 1.91 (dt, / = 3.6, 6.4 Hz, 2H), 1.29 (m, 2H), 0.24 (s, 9H). The obtained spectral data was in agreement with the previously reported literature Alkenylstannane 1.93 (1.20 g, 3.0 mmol) and 35 mL of diethyl ether were cooled to -78 °C. Subsequently, a 1.02 M solution of MeLi (6.47 mL, 6.6 mmol) in diethyl ether was added. The reaction mixture was warmed to 0 °C for 10 min. After cooling the mixture back to -78 °C, a solution of magnesium bromide (144 mg, 7.8 mmol) in 50 mL of diethyl ether was added. The reaction mixture was stirred for 30 min then cooled to -100 °C prior to the addition of 840 uL of cyclohexanone (8.1 mmol) in 50 mL of diethyl ether. After warming the reaction mixture gradually to room temperature, it was quenched with 50 mL of an ammonium chloride saturated values.5 l-d-p-toluenesulfonyl-l^ /S -^tetrahydropyridin-Z-ylJcyclohexanol (2.43) Extending the Scope of Semipinacol Rearrangements of Siloxy : Epoxides to 1-Azaspirocycles " 108 aqueous solution. The aqueous portion was extracted with diethyl ether (3 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced in Vacuo. Purification via flash column chromatography (3/17 ethyl acetate-hexanes) gave 0.79 g of a white solid (78%). mp: 109-110 °C. IR (KBr): 3512, 2942, 1593, 1330, 1159 cm"1. !H NMR (300 MHz, CDC13): 6 7.78 (d, / = 8.2 Hz, 2H), 7.25 (d, / = 8.2 Hz, 2H), 5.82 (t, / = 4.3 Hz, 1H), 4.65 (s, 1H), 3.44 (t, / = 6.3 Hz, 2H), 2.40 (s, 3H), 1.99-1.24 (14H). The obtained spectral data was in agreement with the previously reported literature values.5 l-(l-p-toluenesulfonyl-l,4,5,6-tetrahydropyridin-2-yl)cycloheptanol (2.44) Alkenylstannane 1.93 (600 mg, 1.5 mmol) and 15 mL of diethyl ether were cooled to -78 °C. Subsequently, a 0.95 M solution of MeLi (3.47 mL, 3.3 mmol) in hexane was added. The reaction mixture was warmed to 0 °C for 10 min. After cooling the mixture back to -78 °C, a solution of 718 mg of magnesium bromide (3.9 mmol) in 20 mL of diethyl ether was added. The reaction mixture was stirred for 30 min then cooled to -100 °C prior to the addition of 480 uL of cycloheptanone (4.05 mmol) in 20 mL of diethyl ether. After warming the reaction mixture gradually to room temperature, it was quenched with 20 mL of an ammonium chloride saturated Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 109 aqueous solution. The aqueous portion was extracted with diethyl ether (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced in Vacuo. Purification via flash column chromatography (3/17 ethyl acetate-hexanes) gave 423 mg of a white solid (81%). mp 88-89 °C. IR (KBr): 3500, 2926, 2858, 1330, 1158 cm1. *H NMR (300 MHz, CDCL): 6 7.80, (d, / = 8.3 Hz, 2H), 7.26 (d, / = 8.3 Hz, 2H), 5.82 (t, / = 4.4 Hz, IH), 4.65 (s, IH), 3.46-3.41 (m, 2H), 2.41 (s, 3H), 2.01-1.96 (m, IH), 1.76-1.25 (m, 12H). The obtained spectral data was in agreement with the previously reported literature values.5 l-p-toluenesulfonyl-6-(l-(trimethylsilyloxy)cyclohexyl)-l,2,3,4-tetrahydropyridine (2.45) To 20 mL of tetrahydrofuran was added 620 uL of 2,6-lutidine (5.36 mmol) then 620 uL of trimethylsilyl trifluoromethanesulfonate (3.43 mmol). The mixture was stirred for 10 min before it was transferred to a solution of allylic alcohol 2.43 (720 mg, 2.15 mmol) in 20 mL of tetrahydrofuran. After 30 min, the reaction was quenched with a sodium bicarbonate saturated aqueous solution (10 mL). The aqueous portion was extracted with diethyl ether (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Extending the Scope of Semipinacoi Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 1 1 0 Purification via flash column chromatography (1/33 ethyl acetate-hexanes containing 1% triethylamine) yielded 640 mg of clear colourless oil (73%). IR (film): 2930, 2860, 1450, 1343, 1164 cm"1.. 'H NMR (300 MHz, CDCL): 6 7.77 (d, / = 8.3 Hz, 2H), 7.23 (d, / = 7.9 Hz, 2H), 6.02 (t, / = 4.6 Hz, IH), 3.44 (t, / = 6.5 Hz, 111), 2.40 (s, 3H), 2.38-2.27 (m, 2H), 1.71-1.50 (m, 6H), 1.49-1.23 (m, 6H), 0.12 (s, 9H). The obtained spectral data was in agreement with the previously reported literature Values.5 l-/?-toluenesulfonyl-6-(l-(trimethylsilyloxy)cycloheptyl)-l,2,3,4-tetrahydropyridine (2.46) To 10 mL of tetrahydrofuran were added 330 uL of 2,6-lutidine (2.88 mmol) and 330 uL of trimethylsilyl trifluoromethanesulfonate (1.84 mmol), sequentially. The mixture was stirred for 10 min before it was transferred to a solution of allylic alcohol 2.44 (402 mg, 1.15 mmol) in 10 mL of tetrahydrofuran. After 1 h, the reaction was quenched with a sodium bicarbonate saturated aqueous solution (5 mL). The aqueous portion was extracted with diethyl ether (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Purification Via flash column chromatography (1/33 ethyl acetate-hexanes containing 1% triethylamine) yielded 124 mg of clear colourless oil (26%). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 111 IR (film): 3497, 2952, 2851, 1347, 1165 cm1. ]H NMR (300 MHz, CDC13): 6 7.76 (d,./ = 8.3 Hz, 2H), 7.24 (d, / = 8.1 Hz, 2H), 6.03 (t, / = 4.70 Hz, 1H), 3.43 (t, / = 6.6 Hz, 2! I), 2.40 (s, 1H), 2.38-2:28 (m, 1H), 1.85-1.35 (m, 15H), 0.10 (s, 9H). The obtained spectral data was in agreement with the previously reported literature values.5 (IS*, 6R*)-2-p-toluenesulfonyl-l-(l-(trimethylsilyloxy)cyclohexyl)-7-oxa-2-aza-bicyclo[4.1.0]heptane (2.33) A 0.5 M sodium bicarbonate (9.74 mL, 4.87 mmol) aqueous solution (in deionized water) then m-chloroperoxybenzoic acid (542 mg, 3.14 mmol) were sequentially added to a solution of silyl ether 2.45 (640 mg, 1.57 mmol) in 45 mL of dichloromethane. The mixture was stirred overnight before it was quenched with 20 mL of a sodium bicarbonate saturated aqueous solution. The aqueous portion was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification by flash column chromatography (1/9 ethyl acetate-hexanes containing 1% triethylamine) produced 560 mg of white foam (84% yield). mp: 113-114 °C. IR (KBr): 2937, 2860, 1450, 1348, 1163 cm1. 'H NMR (300 MHz, CDCI3): 6 7.86 (d, / = 8.3 Hz, 2H), 7.26 (d, / = 8.3 Hz, 2H), 3.43 (dt, /•= 3.8, 14.6 Hz, 1H), 3.20 (t, / = 2.7 Hz, 1H), 2.86-2.74 (m, 1H), 2.41 (s, 3H), 2.21 (br d, / = 14.0 Hz, Exieiidlrig the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 112 111), 1.87 (td, / = 3.7, 13.6 Hz, IH), 1.78-1.69 (m, 2H), 1.68-0.80 (m, 10H), 0.18 (s, 9H). The obtained spectral data was in agreement with the previously reported literature values.5 (IS*, 61c*)-2-p-toluenesulfonyl-l-(l-(trimethylsilyloxy)cycloheptyl)-7-oxa-2-aza-bicyclo[4.1.0]heptane (2.37) A 0.5 M sodium bicarbonate (1.24 mL, 0.62 mmol) aqueous solution (in deionized water) then m-chloroperoxybenzoic acid (69 mg, 0.40 mmol) were sequentially added to a solution of silyl ether 2.46 (84 mg, 0.20 mmol) in 25 mL of dichloromethane. The mixture was stirred overnight before it was quenched with 15 mL of a sodium bicarbonate saturated aqueous solution. The aqueous portion was extracted with dichloromethane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification by flash column chromatography (1/19 ethyl acetate-hexanes containing 1% triethylamine) yielded 75 mg of white solid (88% yield). mp: 105-107 °C. IR (KBr): 2926, 2860, 1349, 1162 cm1. NMR (300 MHz, CDCL): 6 7.68 (d, /.= 8.1 Hz, 2H), 7.24 (d, / = 8.2 Hz, 2H), 3.47 (td, / = 4.4, 14.5 Hz, IH), 3.22 (dd, / = 1.7, 4.3 Hz, IH), 2.88 (ddd, / = 4.1, 10.8, 14.7 Hz, IH), 2.38-2.31 (m, 111), 2.01-1.84 (m, 2H), 1.80-1.37 (m, 11H), 1.28-0.80 (m, 2H), 0.15 (s, 9H). The Ext#hdlng the Scope of Semipinacoi Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 113 obtained spectral data was in agreement with the previously reported literature values.5 2.5.3 Semipinacol Rearrangement Investigations of Epoxide 2.33 To a mixture of epoxide 2.33 (25 mg, 0.06 mmol) in 3 mL of acetonitrile at -41 6C was added 66 uL of a 1.0 M solution of tin tetrachloride (0.06 mmol) in dichloromethane. The reaction mixture was stirred at -41 °C for 30 min then gradually warmed to room temperature over 1 h. A sodium chloride saturated aqueous solution (5 mL) and dichloromethane (5 mL) were added. The aqueous portion was extracted with dichloromethane (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (1/3 ethyl acetate-hexanes) yielded clear colourless oils 2.34 (3 mg; 15%) and 2.36 (8 mg; 36%). 2-cyclohexylidene-l-p-toluenesulfonylpiperidin-3-one (2.34) IR (film): 3448, 2937, 2860, 1693, 1428, 1250 cm1. 'H NMR (300 MHz, CDC13): 5 7.59 (d, / = 8.1 Hz, 2H), 7.26 (d, / = 8.3 Hz, 2H), 3.76-3.64 (m, IH), 3.61-3.51 (m, IH), 2.87-2.74 (m, IH), 2.72-2.46 (m, 3H), 2.39 (s, 3H), 2.04 (td, / = 2.3, 16.7 Hz, IH), 1.92-Extending the Scope of Semipinacol Rearrangements of'Siloxy-Epoxides to 1-Azaspirocycles 114 1.80 (m, 1H), 1.79-1.67 (m, 2H), 1.64-1.45 (m, 5H), 1.23-1.12 (m, 1H). The obtained spectral data was in agreement with the previously reported literature values.5 N-(4-hydroxy-5-(l-hydroxycyclohexyl)-5-oxopentyl)-p-toluenesulfonamide (2.36) IR (film): 3418, 2926, 1714, 1598, 1161 cm1. ]H NMR (300 MHz, CDCL): 6 7.72 (d, J = 8^2 Hz, 2H), 7.29 (d, / = 8.0 Hz, 2H), 4.98-4.88 (m, 1H), 4.61 (ddd, / = 2.7, 6.6, 9.0 Hz, 1H), 3.27 (d, / = 6.7 Hz, 1H), 2.99 (dd, / = 6.3, 12.8 Hz, 2H), 2.73 (br s, 1H), 2.41 (s, 311), 2.09-1.85 (m, 2H), 1.81-1.48 (m, 10H), 1.47-1.35 (m, 1H), 1.33-1.16 (m, 1H). The obtained spectral data was in agreement with the previously reported literature values.5 To a mixture of epoxide 2.33 (21 mg, 0.05 mmol) in 2.5 mL of dichloromethane at -78 °C was added 60 uL of a 1.0 M solution of tin tetrachloride (0.06 mmol) in dichloromethane. The reaction mixture was stirred at -78 °C for 30 min then gradually warmed to room temperature over 1 h. A sodium chloride saturated aqueous solution (5 mL) and dichloromethane (5 mL) were added. The aqueous portion was extracted with dichloromethane (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 115 Purification via flash column chromatography (1/3 ethyl acetate-hexanes) produced byproduct 2.35 (3 mg of clear colourless oil; 17%) and an inseparable mixture of 1-azaspirocycles 2.47a & 2.47b (11 mg of white solid; 64%). AT-(5-cyclohexenyl-4-hydroxy-5-oxopentyl)-p-toluenesulfonamide (2.35) IR (film): 3520, 2932, 2864, 1702, 1322, 1154 cm1. W NMR (300 MHz, CDCh): 6 7.71 (d, / = 8.3 Hz, 2H), 7.29 (d, / = 8.3 Hz, 2H), 6.87-6.82 (m, 1H), 4.75^ .66 (m, 1H), 4.56 (t, / = 6.2 Hz, 1H), 3.62 (d, / = 6.3 Hz, 1H), 2.97 (ddd, /.= 2.2, 6.4, 12.8 Hz, 2H), 2.41 (s, 3H), 2.37-2.23 (m, 2H), 2.14-1.98 (m, 2H), 1.90-1.75 (m, 2H), 1.71-1.59 (m, 4H), 1.46-1.31 (m, 2H). The obtained spectral data was in agreement with the previously reported literature values.5 (5S*, 6R*)-5-hydroxy-l-/?-toluenesulfonyl-l-azaspiro[5.6]dodecan-8-one (2.47a) (5S*, 6S*)-5-hydroxy-l-p-toluenesulfonyl-l-azaspiro[5.6]dodecan-8-one (2.47b) mp: 138-140 °C. IR (KBr): 3520, 2932, 2864, 1702, 1322, 1154 cm1. 'H NMR (300 MHz, CDCI3): 6 7.78 (d, / = 8.2 Hz, 2H), 7.65 (d, / = 8.0 Hz, 2H), 7.33 (d, / = 8.4 Hz, 2H), 7.27 (d, / = 8.4 Hz, 2H), 4.07 (br s, 1H), 3.97 (dd, / = 2.9, 5.8 Hz, 1H), 3.30-3.18 OH OH E x i i d ing the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 116 (m, 2H), 3.00 (dt, / = 1,9, 12.6 Hz, IH), 2.65 (dd, / = 7.4, 12.2 Hz, IH), 2.48-2.32 (m, 111), 2.40 (s, 3H), 2.11-1.98 (m, IH), 1.97-1.74 (m, 4H), 1.67-1.18 (m, 6H). 13C NMR (75 MHz, CDC13): 6 214.5, 144.8, 139.0, 130.8, 129.2, 71.9, 68.8, 44.0, 43.8, 33.5, 31.9, 27.0, 26.8, 25.0, 22.9, 19.5. Anal, calcd. for QgEfesNCUS: C 61.51, H 7.17, N 3.99; found: C 61.33, H 7.00, N 3.69. 2.5.4 Semipinacol Rearrangement of Epoxide 2.37 To a mixture of epoxide 2.37 (22 mg, 0.05 mmol) in 2.5 mL of dichloromethane at -78 °C was added 60 uL of a 1.0 M solution of tin(IV) tetrachloride (0.06 mmol) in dichloromethane. The reaction mixture was stirred at -78 °C for 20 min then warmed to room temperature. Sodium chloride saturated aqueous solution (5 mL) and dichloromethane (5 mL) were added. The aqueous portion was extracted with dichloromethane (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (1/3 ethyl acetate-hexanes) led to the isolation of byproduct 2.39 (4 mg of clear colourless oil; 22%) and 1-azaspirocycle 2.48 (9 mg of white solid; 50%). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 117 (E)-N-(5-cycloheptenyl-4-hydroxy-5-oxopentyl)-p-toluenesulfonamide (2.39) IR (film): 3544, 2927, 1698, 1324, 1157 cm1. 1TT NMR (300 MHz, CDC13): 5 7.71 (d, J = 8.3 Hz, 2H), 7.29 (d, / = 8.0 Hz, 2H), 6.98 (t, / = 6.8 Hz, 1H), 4.79- 4.71 (m, 1H), 4.56 (t, / = 4.2 Hz, 1H), 3.64 (d, / = 6.4 Hz, 1H), 2.97 (ddd, / = 2.5, 6.4, 7.7 Hz, 2H), 2.56-2.33 (m, 1H), 2.41 (s, 3H), 1.86-1.70 (m, 2H), 1.67-1.13 (10H). The obtained spectral data was in agreement with the previously reported literature values.5 (5S*, 6R*)-5-hydroxy-l-/?-toluenesulfonyl-l-azaspiro[5.7]tridecan-9-one (2.48). IR (KBr): 3544, 2928, 1698, 1325, 1156 cm1. ]H NMR (300 MHz, CDCL): 6 7.76 (d, / = 8.3. Hz, 2H), 7.28 (d, / = 8.1 Hz, 2H), 4.05 (dd, / = 4.1, 8.4 Hz, 1H), 3.71 (d, / = 4.7 Hz, 1H), 3.59-3.48 (m, 1H), 3.25-3.15 (m, 1H), 3.04 (m, 1H), 2.53-2.37 (m, 1H), 2.41 (s, 311), 2.32-2.18 (m, 1H), 1.94-1.10 (m, 12H), 0.93-0.79 (m, 1H). 13C NMR (75 MHz, CDC13): 5 215.9, 143.5, 138.9, 129.6, 127.7, 72.3, 67.6, 44.1, 39.2, 29.5, 27.5, 27.0, 26.2, 25.0, 22.9, 21.7, 19.7. LRMS (EI) mlz (relative intensity): 365 (M+ + 1, 5), 273 (12), 219 (21), 216 (14), 210 (64), 203 (100), 182 (31), 155 (17), 105 (29). Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 118 2.6 Selected Spectra Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 1 Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 2.48: OH 400(1,0 J600 3200 2800 2400 2000 1800 1600 1400 1200 1000 8o0 660.O Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 121 2.7 X-Ray Crystallographic Data Table 2.7 Crystallographic Data for 2.47a (5S*, 6K*)-5-hydroxy-l-p-toluenesulfonyl-l-azaspiro[5.6]dodecan-8-one (2.47a)a Formula C, XH 25N0 4 S F W 351.45 Colour, habit colourless, irregular Crystal size, mm 0.25 x 0.25 x 0.12 Crystal system monoclinic Space group P 2i/n (#14) a, A 7.4684(7) b, A 14.715(2) c, A 15.893(2) P, deg 90.582(4) V , A 3 1746.5(4) Z 4 Dcaic, g/cm 3 1.337 F(000) 752.00 )j.(MoKa), a i r 1 2.07 transmission factors 0.866 - 0.975 2$nax, deg 55.8 total no. of reflns 38716 No. of unique reflns 4125 R (F 2, all data) 0.048 R w (F2, all data) 0.101 R (F, I >2o(I)) 0.036 R w (F, I >2o(I)) 0.097 goodness of fit indicator 1.13 aX-ray crystallographic data was acquired using a Bruker X8 diffractometer. For more information on data collection contact Dr. Brian Patrick, Manager of the X-Ray Crystallographic Services at the University of British Columbia. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to l-Azaspirocycles 12 (5S*, 6R*)-5-hydroxy-l-p-toluenesulfonyl-l-azaspiro[5.7]tridecan-9-one (2.48) A Formula C19H27NO4S FW Colour, habit Crystal size, m m Crystal system Space group a, A b, A c, A deg V, A 3 Z Dcaic, g/cm 3 F(000) p(MoKa), c m 1 transmission factors 26max, deg total no. of reflns no. of unique reflns R (F2, all data) Rw(F2, all data) R (F, I >2a(I)) Rw (F, I >2o(I)) goodness of fit indicator 365.48 colourless, needle 0.05 x 0.05 x 0.35 monoclinic P2i/c 7.0091(7) 37.026(4) 14.0446(17) 90.226(4) 3644.8(7) 8 1.332 1568 0.201 0.638 - 0.990 45.6 11281 4534 0.1610 0.3007 0.1092 0.2714 1.09 •'X-ray crystallographic data was acquired using a Bruker X 8 diffractometer. For more information on data collection contact Dr. Brian Patrick, Manager of the X-Ray Crystallographic Services at the University of British Columbia. Extending the Scope of Semipinacol Rearrangements of Siloxy-Epoxides to 1-Azaspirocycles 123 2.8 References (1) Fenster, M. D.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109-2112. (2) Fenster, M. D.; Dake, G. R. Org. Lett. 2003, 5, 4313-4316. (3) Fenster, M. D.; Dake, G. R. Chem. Eur. J. 2005, 11, 639-649. (4) Dake, G. R.; Fenster, M. D.; Hurley, P. B.; Patrick, B. O. /. Org. Chem. 2004, 69, 5668-5675. (5) Fenster, M. D. Doctoral Thesis, University of British Columbia, 2004. (6) Dake, G. R.; Fenster, M. D.; Fleury, M.; Patrick, B. O. /. Org. Chem. 2004, 69, 5676-5683. (7) Dake, G. R. Tetrahedron 2006, 62, 3467-3492. (8) Ando, S.; Minor, K. P.; Overman, L. E. /. Org. Chem. 1997, 62, 6379-6387. nacol Approaches to the Er if thrill g Alka lo id Skeleton 124 CHAPTER 3: Semipinacol Approaches to the Erythrina Alkaloid Skeleton Serrupinacol Approaches to the Erythrina Alka lo id Skeleton 125 3.1 Introduction to the Erythrina Alkaloids 3.1.1 Occurrence and Isolation1 The Erythrina genus includes 108 species of orange or red-flowered trees, shrubs, and herbaceous plants found in tropical and subtropical regions of the world (see Figure 3.1 for examples). Nearly 100 alkaloids have been isolated from the Seeds, root, stem, bark, leaves, and flowers of Erythrina species. In 1937, Folkers and Major isolated (3-erythroidine (refer to Figure 3.2), the first Erythrina alkaloid to be identified.2 Figure 3.1 Examples of Erythrina flowers: a) Erythrina crista-galli,3 b) Erythrina Blakei,* c) Erythrina flabelliformis5 3.1.2 Biological Activity6-7 An interesting pharmacological effect of many Erythrina alkaloids is muscle paralysis referred to as curare-like activity. Curare is the deadly arrow poison used by indigenous people of South America. Curare-like agents are administered during medical operations to relax the muscles. They prevent nerves from triggering muscle at the myoneural junction. The paralyzing ability of Erythrina alkaloids SeirUfjlriacol. Approaches to the Erythrirta Alka lo id Skeleton 126 prompted a great deal of interest in their isolation, structural elucidation, and synthesis. However, clinical trials of the most active Erythrina alkaloids showed depression of both blood pressure and respiration as side effects. 3.1.3 Structural Features The Erythrina alkaloids have a tetracyclic skeleton with a spirocyclic carbon fusing the A, B, and C rings together (see Figure 3.2). There are two general classes of Erythrina alkaloids: those with aromatic D-rings, such as erythratine (3.1) and erysotramidine (3.2), and those with unsaturated lactone D-rings, such as (3-erythroidine (3.3). The former type is the most prevalent. The basic aromatic erythrinan skeleton A consists of a tetrahydroisoquinoline subunit (C and D rings) fused to a hydroindole subunit (A and B rings). Erythrina alkaloids with aromatic D-rings can be further categorized into the subgroups dienoid, like erysotramidine (3.2), or alkenoid, like erythratine (3.1), according to the unsaturation of the A and B rin^ s. R0' RO. OH 3.1: erythratine A: aromatic erythrinan skeleton 3.2: erysotramidine 3.3: p-erythroidine Figure 3.2 Erythrina Alkaloids: Basic Aromatic Skeleton & Representative Examples Semipinacol Approaches to the Erythrina Alka lo id Skeleton 127 3.1.4 Biosynthesis In 1999, Zenk proposed the Erythrina alkaloid biosynthesis outlined in Scheme 3.1.8 The Erythrina alkaloids arise from (S)-norcoclaurine (3.7), a precursor cornmon to other isoquinoline alkaloids. Norcoclaurine synthase condenses dopamine (3.5) and 4-hydroxyphenylacetaldehyde (3.6), both of which are derived from L-tyrosine (3.4), to give (S)-norcoclaurine (3.7). Methylation leads to (S)-coclaurine (3.8), which is suggested to be the precursor of (S)-norreticuline (3.9). Coupling of the phenol rings at the para positions would give norisosalutaridine (3.10). Introduction of a methylenedioxy group could lead to noramurine (3.11). Carbon-carbon bond migration would yield spirocyclic intermediate B, which could ring-open to iminium ion C. Reduction would lead to amine 3.12 (the methylenedioxy group desymmetrizes this compound). Following a series of one electron oxidations, nucleophilic attack of the nitrogen onto the resulting cation of intermediate D would construct the spirocyclic erythrinan skeleton 3.13. From precursor 3.13, various Erythrina alkaloids could be biosynthesized through further enzymatic manipulations. Sernipihacol Approaches to the Erythrina Alkaloid Skeleton 128 Semi pTha col Approaches to the Erythrina Alkaloid Skeleton 129 3.1.5 Previous Synthetic Approaches Although the pharmological profile of the Erythrina alkaloids is interesting, it is the challenging tetracyclic framework that has attracted the attention of synthetic organic chemists. There have been many approaches for the synthesis of the erythrinan skeleton A (refer to Figure 3.2). This framework is often used to demonstrate the effectiveness of new methodologies in ring construction. Innovative cyclization strategies that have been thus far applied to the erythrinan skeleton fall into three categories: (i) cyclizations involving acyl iminium ions, (ii) radical cyclizations, and (iii) cycloadditions. 3.1.5.1 Cyclizations Involving Iminium Ions Methodologies applied to erythrinan skeleton which involve the generation of iminium ions often use the electrophilicity of this reactive intermediate to promote electrophilic aromatic substitution with the D-ring, thus forming the C-ring. For example, in 1989 Wasserman and co-workers utilized the "ti'ielectiophilic" nature of vinyl tricarbonyls to construct the B and C-rings of the erythrinan skeleton (see Scheme 3.2).910 Primary amine 3.14 underwent sequential hucleophilic addition to the central carbonyl and the enone of tricarbonyl 3.15, to form the B-ring. Treatment of intermediate 3.16 with phosphorus oxychloride SenlijSlhacol Approaches to the Erythrirta Alkaloid Skeleton 130 produced irriinium ion E, which subsequently underwent cyclization to form the C-ring of 3.17 in 41% yield. » 3.15 3.16 E - 1 3.17 Scheme 3.2 Vinyl Tricarbonyl Iminium Approach (Wasserman et al)910 Tamura and co-workers explored the Pummerer reaction of thionium ions, generated from a-sulfinylacetamides, with olefins.1 1 In 1982, this methodology was applied to the erythrinan skeleton (see Scheme 3.3).12-13 Treatment of sulfoxide 3.18 with p-toluenesulfonic acid resulted in a Pummerer cyclization of thionium ion F to give intermediate iminium ion G, which underwent electrophilic aromatic substitution to erythrinan 3.19 in 60% yield. Scheme 3.3 Thionium Pummerer/Iminium Cyclization Approach (Tamrua et al)12'13 Padwa and co-workers also employed a Pummerer reaction, which indirectly generated an acyl iminium ion, in their 1998 synthesis of the erythrinan skeleton (see Scheme 3.4).14 In a one-pot three reaction sequence sulfoxide 3.20 produced Seiii if inacol Approaches to the Eri/fhrina Alka lo id Skeleton 131 erymrinan 3.24 in 83% yield. A Purrvrnerer reaction of intermediate H resulted in the formation of furan 3.21, which underwent an intramolecular Diels-Alder eycloaddition to intermediate 3.22. Following rmg-operving to iminium ion I and a 1,2-thio shift to enamine 3.23, methoxide elimination generated acyl iminium ion J for subsequent electrophilic aromatic substitution to erythrinan 3.24. MeO I, C 0 2 M e (CF 3 CO )0 , B F 3 O E t 2 ^ S N 3.20 O Et NEt, 83% H 3 CO. H , C O MeO fl -o - H + ,C0 2 Me Et O 3.21 H 3 CO. H 3 C O MeO ,CQ 2Me SEt MeO' C 0 2 M e 3.22 C 0 2 M e II hcOzMe 3.23 1,2-thio shift C 0 2 M e H 3 C O H 3 CO' C 0 2 M e 3.24 Scheme 3.4 Pummerer/IMDA/Iminium Cascade Approach (Padwa et al)u In 2004, Tietze and co-workers also reported the use of a reaction cascade involving an acyl iminium intermediate as a means of accessing the erythrinan framework (see Scheme 3.5).15 Amine 3.14 reacted with ester 3.25 in the presence of AIMe3 to generate aluminum complex K. Intramolecular addition of the amide nitrogen with the enol acetate followed by loss of acetic acid was suggested to result M'nacol Approaches to the Erythrina Alka lo id Skeleton 132 in the formation of acyl iminium ion L. Subsequent electrophilic aromatic substitution gave 79% of erythrinan 3.26.. N H ' C0 2 Et AIMe 3 + I .,— J benzene, reflux OAc 79% 3crv a . - A I M e 2 3.25 H 3 CO H 3 C O H,CO. H-,CO L 3.26 Scheme 3.5 AlMe3-Mediated/Iminium Cascade Approach (Tietze et al)15 In 2003, Padwa and co-workers treated unsaturated bicyclic lactam 3.27 with N-bromosuccinimide to form acyl iminium ion M, which promoted an electrophilic aromatic substitution to construct erythrinan 3.28 (see Scheme 3.6).16 Many groups have used analogous Bronsted acid initiated cyclizations; however these strategies don't involve the incorporation of a bromide functional group.17" 19 H 3 C O NBS MeCN* 78% 3.27 M Scheme 3.6 NBS-Promoted Iminium Approach (Padwa et al)16 H3CO. H3CO. H 3 C O 3.28 Semipinacol Approaches to the Erythrina Alkaloid Skeleton. 133 3.1.5.2 Radical Cyclizations In 1987, Mariano and co-workers used the intramolecular photocyclization of imiruum salt-allylsilane systems in the synthesis of the erythrinan framework (see Scheme 3.7).20-21 Irradiation of iminium ion 3.29 led to single electron transfer according to intermediate N. Subsequent desilylation generated diradical O, which underwent cyclization to form the spirocyclic A-ring of compound 3.30. 3.30 Scheme 3.7 Iminium Salt-Allylsilane Diradical Approach (Mariano et al)20n The approaches to the erythrinan skeleton reported by Zard in 1998 and 2002 and by Ishibashi in 2001 all involved similar enamine cyclization precursors but utilized novel methods of radical generation.2224 In 1998, Zard and co-workers reacted trichloroacetamide 3.31 with 30 equivalents of nickel powder, 20 equivalents of AcOH, and 3 equivalents of NaOAc in refluxing 2-propanol to generate radical P (see Scheme 3.8). A 5-endo cyclization gave radical Q, which was oxidized via cation R to unsaturated lactam 3.32 in 55% yield. Seri i lpTiiacol Approaches to the Erythrina A l k a l o i d Skele ton 134 Scheme 3.8 Trichloroacetamide Radical Approach (Zard et al)22 In 2002, Zard and co-workers reacted xanthate 3.33 with lauroyl peroxide in refluxing 1,2-dichloroethane to create radical S, which underwent a 5-endo cyclization to radical T (see Scheme 3.9). Following oxidation to allyl cation U, p-toluenesulfonic acid catalyzed electrophilic aromatic substitution and deprotection of the ketal to give erythrinan 3.34 in 82% yield. Scheme 3.9 Xanthate Radical Cyclization Approach (Zard et al)23 Ishibashi and co-workers treated a-thioacetamide 3.35 with 6 equivalents of ivIn(OAc)3 in the presence of one equivalent of Cu(OTf)2 in refluxing trifluoroacetic SeniifHftacol Approaches to the Erytftriria Alka lo id Skeleton 135 acid (see Scheme 3.10). Radical V underwent a 5-endo cyclization to form radical W, which was subsequently oxidized to cation X. Electrophilic aromatic substitution produced erythrinan 3.36 in 54% yield. X 3.36 Scheme 3.10 a-Thioacetamide Radical/Iminium Approach (Ishibashi et al)2i 3.1.5.3 Cycloadditions In 1986, Livinghouse and co-workers treated a-keto imidoyl bromide 3.37 with silver salts to mediate electrophilic aromatic substitution via acylnitrilium ion Y (see Scheme 3.11).25 Conversion of the resulting imine (3.38) to azomethine ylide Z enabled the application of a [3+2] eycloaddition strategy to simultaneously construct the A and B-rings of the erythrinan 3.39 in 87% yield.26 Sernipihaeol Approaches to the Erythrina Alkaloid Skeleton 136 Z 3.39 Scheme 3.11 Acylnitrilium/[3+2] Approach (Livinghouse et al)15 In 1991, Rigby and co-workers demonstrated the utility of [1+4] cycloadditions involving vinyl isocyanates and isocyanides by applying this chemistry to the AB-ring fragment of the erythrinan skeleton (see Scheme 3.12).2728 Treatment of a,|3-unsaturated acid 3.40 with diphenylphosphoryl azide formed vinyl isocyanate 3.41, which underwent a [1+4] cycloaddition with cyclohexyl isocyanide to give 3.42 in 66% yield. Scheme 3.12 [1+4] Cycloaddition Approach (Rigby et al)27™ SerWpTnacol Approaches to the Erythrina A lka lo id Skeleton • • 137 3.2 Proposed Semipinacol Approach to the Erythrina Alkaloid Skeleton We wanted to develop an approach to the Erythrina alkaloid skeleton that would exploit the semipinacol rearrangement methodology established in our laboratory (refer to Chapter 2). It was envisioned that the A-ring of erythrinan A could be formed via a 5 to 6-membered ring expansion to produce a compound possessing the substructure A A from a precursor possessing the substructure BB (see Scheme 3.13). This key transformation would establish the required [5.5]-l-azaspirocyclic junction. The proposed route to the erythrinan core would fall under the classification of a cyclization strategy towards the Erythrina skeleton involving an iminium ion (refer to section 3.1.5). Unlike previous approaches of this type, the semipinacol method would not form the spirocyclic junction by electrophilic aromatic substitution. Scheme 3.13 General Proposed Semipinacol Approach to the Erythrina A lka lo id Skeleton The Bronsted acid promoted semipinacol rearrangements of epoxides 2.13 and 2.14 to the corresponding 1-azaspirocycles 2.15 and 2.16 were the basis for our retrosynthetic analysis (Eq. 3.1). •eirtipihacol Approaches to the Erythrina Alka lo id Skeleton 138 Ts 1 M H C I , ) n C H 2 C I 2 , rt (3.1) 2.15: n = 1, 90% 2.16: n = 2, 9 1 % Two different routes to the Erythrina alkaloid skeleton, each featuring a semipinacol rearrangement as the key step, were investigated. These will be presented in the following sections. 139 3.3 Semipinacol Approach I to the Erythrina Alkaloid Skeleton 3.3.1 Retrosynthetic Analysis Initially, we planned to approach the Erythrina skeleton (A) as outlined retrosynthetically in Scheme 3.14. Target A could arise from the elaboration of 1-azaspirocycle 3.43. The D and A rings of erythrinan A could be formed from epoxide 3.44 by ring closing metathesis and semipinacol rearrangement, respectively. Introduction of allyl and cyclopentyl substituents to vinylstannane 3.45 could provide access to the carbon framework of 3.44. Cuprate addition to known enamide 3.46, followed by functional group manipulation could produce the requisite vinylstannane. Scheme 3.14 Retrosynthetic Analysis I 3.3.2 Results & Discussion Known enamide 3.46 was synthesized as summarized in Scheme 3.15.29 S-Valerolactam was deprotonated with n-butyllithium in THF at -78 °C then quenched with p-toluenesulfonyl chloride to yield N-protected lactam 2.108 in 74% yield. Deprotonation of lactam 2.108 with potassium hexamethyldisilazide in THF Semtpfhacol Approaches to the Erythrina Alka lo id Skeleton • 140 at -78 °C and subsequent addition of diphenyl disulfide led to the formation of 3.47 in 52% yield.30 Oxidation of 3.47 with ra-chloroperbenzoic acid in DCM followed by elimination induced by heating in toluene produced enamide 3.46 in 78% yield. N H n-BuLi, p-TsCI^ f ^ PhSSPh, KHMDS I ^ i) m-CPBA [I jj, THF, -78 °C |f' T s THF, -78 °C P n S |f T s ii) toluene, A \f T s O O O O 5-valerolactam 74% 2.108 52% 3.47 78% 3.46 Scheme 3.15 Synthesis of Enamide 3.4629 Treatment of enamide 3.46 with trimethylsilyl chloride, copper(II) bromide dimethylsulfide complex, and allylmagnesium bromide produced cuprate addition product 3.48 in 55% yield (see Scheme 3.16).29 Signals in the product NMR spectrum at 5.67 (IH) and 5.09-4.98 (2H) ppm were indicative of the vinyl protons of the newly introduced allyl side-chain. (C^N TMSCI, C u B r S M e 2 ^ ff^l^^lj KHMDS, P h N T f 2 > f f ^ l ^ / X [f V _ r s THF, -78 °C |f " T s THF, -78 °C . J * T s O O OTf 3 4 6 55% 3.48 96% 3.49 • MeLi, Me 6 Sn 2 , CuCN II L N ^ MeLi, MgBr 2 " 4 1 ° c | T s E t 2 0 , - 1 0 0 t o 0 ° C SnMe 3 83% 3 .45 76% 3 5 0 Scheme 3.16 Synthesis of Al ly l ic Alcohol 3.50 Upon subjection to N-phenyl tiiflirnide and potassium hexamethyldisilazide, amide 3.48 was converted to enol triflate 3.49 in 96% yield.29 A doublet in the ]H NMR spectrum at 5.36 ppm was assigned as the vinyl proton of the enol triflate Semifinacpl Approaches to the Erythrina Alkaloid Skeleton 141 moiety. Further evidence for the triflate group was provided by the quartet in the 13C NMR spectrum at 114.2 ppm which was diagnostic of the trifluoromethyl carbon. The addition of hexamethyldistannane, metbyllithium, and copper cyanide to triflate 3.49 generated vinylstannane 3.45 in 83% yield.29 The methyl groups attached to tin exhibited diagnostic signals at 0.24 ppm in the }H NMR spectrum and at -5.7 ppm in the 13C NMR spectrum. Following exposure of vinylstannane 3.45 to methyllithium and magnesium bromide, subsequent addition of the resulting mixture to cyclopentanone.led to the formation of allylic alcohol 3.50 (76%).29 The broad singlet present in the 'H NMR spectrum of 3.50 at 4.52 ppm was attributed to the alcohol proton. Further evidence of an alcohol product was provided by the signal in the 13C NMR spectrum at 83.3 ppm, assigned to the carbon bound to oxygen, and the absorption in IR spectrum at 3522 cm-1. An SN2' reaction of allylic alcohol 3.50 was achieved by treatment with Lewis acid and allyltrimethylsilane in dichloromethane (see Eq. 3.2).31 Use of BF3-OEt2 as the Lewis acid led to only a 34% yield of desired product 3.51 (a mixture of diastereomers) along with byproduct 3.52 in 52% yield (see Table 3.1; entry i). The presence of two alkyl side-chains in enamine 3.51 was apparent from the integration of Six vinyl protons in the alkenyl region of the lH NMR spectrum. 142 Table 3.1 Allylation of 3.50 (3.2) 3.50 3.51 3.52 Entry LA a Equiv. * ^ S i M e 3 Yield 3.51 (%) Yield 3.52 (%) ~~i BF3OEt2 3X1 34 38 ~ ii BF3-OEt2 5.0 42 52 iii TiCl4 5.0 44 34 a3.0 equiv. The structure of byproduct 3.52 was established based on spectral data. An enone motif was inferred from the absorption in the IR spectrum at 1652 cm-1 (C=0 stretch) combined with the signal in the 1TT NMR spectrum at 6.69-6.65 (m, 1H) from the vinyl (3-proton. The IR spectrum also contained a signal at 3279 cm1, which was indicative of the N-H bond. Byproduct 3.52 was proposed to form according to the mechanism illustrated in Scheme 3.17. Elimination of the activated alcohol from the Lewis acid-coordinated intermediate CC could occur to give intermediate DD. Subsequent protonation of the enamine would result in the formation of iminium ion EE, which could undergo hydrolysis to produce the observed byproduct (3.52). Scheme 3.17 Proposed Mechanism for the Formation of Byproduct 3.52 Semipinacol Approaches to the Erythrina Alka lo id Skeleton • 143 In order to promote the desired SN2' reaction pathway the amount of ailyltrimethylsilane was increased from 3 to 5 equiv., which resulted in a 42% yield of 3.51 (Table 3.1; entry ii). Substitution of TiCl4 as the Lewis acid had little effect (entry iii); a comparable yield of 44% was obtained. While this allylation procedure previously worked well on the analogous allylic alcohol lacking a substituent at the 4-position (refer to Scheme 2.2), in this case only mediocre yields were obtained. Although the product was a mixture of diastereomers, the relative stereochemistry of the allylic ring substituents was of little consequence since they were to be ultimately transformed to sp2-hybridized aromatic carbons. A preliminary attempt to epoxidize 3.51 using m-chloroperbenzoic acid led to a complex mixture of products via TLC. Unfortunately, due to a limited quantity of this compound other epoxidation methods, such as DMDO, were not tested. 3.3.3 Future Directions & Conclusions Due to unsatisfactory yields and the large number of steps in this synthetic approach to erythrinan A, instead of preparing additional enamide 3.52, this route was abandoned. Even after achieving the desired ring expansion, much further manipulation would be required to form the B-ring and the aromatic D-ring. Furthermore, this synthesis required carrying diastereomeric mixtures through multiple steps, which could complicate product analysis. However, this strategy did Sernif iiiaco! Approaches to the'Erythrirta Alkaloid Skeleton . 144 have the attractive feature of incorporating the D-ring last, which could have proved useful if there was a need for accessing erythrinan analogues wi th various groups on the aromatic ring. 145 3.4 Semipinacol Approach II to the Erythrina Alkaloid Skeleton 3.4.1 Retrosynthetic Analysis A more efficient approach to the Erythrina skeleton based upon the semipinacol rearrangement was conceived, as outlined retrosynthetically in Scheme 3.18. The proposed ring expansion product, 1-azaspirocycle FF, would only require installation of the B-ring to complete the construction of the Erythrina skeleton A-Semipinacol precursor epoxide G G could be accessed via a Bischler-Napieralski reaction of amide H H , which could be made from a commercially derived amine II and cyclopentanecarbonyl chloride. In this strategy the D-ring would be introduced preformed thus eliminating the need for its construction. Scheme 3.18 Retrosynthetic Analys is II However, the feasibility of the proposed semipinacol rearrangement featuring an adjacent aromatic ring was difficult to determine a priori, A possible reaction pathway leading to ring expansion product FF is illustrated in Scheme 3.19. Senupmacol Approaches to the Erytiirimi Alkaloid Skeleton 146 Epoxide G G could coordinate a Lewis acid to form intermediate JJ. The alkoxy substituents on the aromatic ring could promote electron donation to the benzylic position as shown by resonance contributor K K . Additionally, electron donation from the nitrogen atom could occur according to resonance contributor LL. In order to favour semipinacol rearrangement to form 1-azaspirocycle FF, stabilization of intermediate JJ through resonance contributors K K and L L should be minimized. Scheme 3.19 Proposed Semipinacol Rearrangement This resonance effect was taken into consideration in the selection of the alkoxy substituents, R, and the N-protecting group, P of the proposed semipinacol rearrangement precursor, 3.53 (see Figure 3.3). In place of the alkoxy substituents a bridging methylene group was chosen. Since the methylene substituent would be cOplanar with the aromatic ring, it could prevent the proper alignment of the oxygen electrons for donation into the aromatic ring. The methylenedioxy substitution motif is also naturally present in certain Erythrina alkaloids. In order to reduce Seituflhacol Approaches to the Erythrirta Alka lo id Skeleton 147 electron donation from the nitrogen atom, trifluoroacetyl was chosen as the A/protecting group, P. f O ^ ^ s ^ -/ II 1 ^ J L J L 3.53 ( K C F 3 Figure 3.3 Proposed Semipinacol Rearrangement Precursor 3.53 3.4.2 Synthesis of Epoxide 3.53 Synthesis of the proposed semipinacol rearrangement precursor 3.53 started with the reduction of commercially available 3,4-methylenedioxy-(3-nitrostyrene using lithium aluminum hydride to produce 3,4-methylenedioxyphenethylamine (3.54) in 92% yield (see Scheme 3.20).32 Subsequent reaction of crude amine 3.54 with cyclopentanecarbonyl chloride and triethylamine in CH2CI2 resulted in the formation of amide 3.55 in 32% yield following recrystallization. o Scheme 3.20 Synthesis of Epoxide 3.53 Semipinacol Approaches to the Erythrirta Alka lo id Skeleton 148 Spectral signals diagnostic of an amide functional group provided structural confirmation for compound 3.55. The absorption in the IR spectrum at 1635 cm'1 was attributed to the C=0 stretch of the amide. Additionally, the peak in the 13C NMR spectrum at 176.3 ppm was indicative of the amide carbon, while the broad singlet in the lH NMR spectrum at 5.39 ppm was indicative of the proton attached to the amide nitrogen. Bischler-Napieralski reaction of amide 3.55 promoted by phosphorus oxychloride in refluxing CH2C12 gave imine 3.56. The NMR spectrum of compound 3.56 contained a signal at 3.28-3.15 ppm (m, IH) which corresponded to the methine proton a to the imine. Crude 3.56 was treated directly with trietliylamine and trifluoroacetic anhydride to generate N-protected enamide 3.57 in 93% yield over both steps following recrystallization. The !H NMR and 13C spectra of enamide 3.57 were indicative of a mixture of two different product isomers. The aromatic portion of the JH NMR spectrum contained four distinct signals (see Figure 3.4). The two singlets at 6.95 and 6.81 ppm were attributed to isomeric aromatic protons which were present in an approximately equal ratio according to peak area integrations. Semipinacol Approaches to t h e £ry&n'rt<T-Alkaloid.Skeleton 149 ' i * 1 1 1 i 1 1 1 i i 7.10 7.00 6.90 6.80 6.70 6.60 6.50 6.40 Figure 3.4 T H N M R Spectrum Aromatic Region of Enamide 3.57 Enamide 3.57 likely existed as a mixture of the two restricted rotation isomers depicted in Eq. 3.3. These atropisomers probably arose from the A 1,3-strain between the amide functional group and the proximal allylic cyclopentane carbon. (3.3) Epoxidation of enamide 3.57 using m-CPBA produced epoxide 3.53 in 7 7 % yield. As expected, with the removal of the double bond, epoxide 3.53 did not exist as a mixture of rotamers according to spectral data. The peak at 74.7 ppm in the 13C NMR spectrum was attributed to the carbon bonded to the oxygen of the epoxide distal to the amide functional group. 3.4.3 Attempted Semipinacol Rearrangement of Epoxide 3.53 Attempted semipinacol rearrangement of epoxide 3.53 proved unsuccessful. Treatment of epoxide 3.53 with CSA or BF3OEt2 resulted in complex mixtures of Seriiifihacol Approaches to the Erythrina Alka lo id Skeleton 150 products (see Table 3.2; entries i & iii). Subjection of epoxide 3.53 to magnesium bromide or ytterbium triflate led to the isolation of byproduct 3.58 (entries ii & iv). The 1TT NMR spectrum of 3.58 contained signals at 8.88 ppm (s, 1H) and 6.55-6.50 (m, 1H) which were attributed to the amide proton and the vinyl proton, respectively. Table 3.2 Attempted Semipinacol Rearrangement of 3.53 H 3.53 3.58 Entry LAa Product i CSA Complex mixture ii MgBr2 3.58 (50%) iii BF3OEt2 Complex mixture iv Yb(OTf)3 3.58(67%) 1.2 equiv. Byproduct 3.58 was proposed to form according to the mechanism illustrated in Scheme 3.21. Lewis acid-coordinated intermediate M M had azacarbenium ion NN as a resonance contributor. However, this carbocation intermediate was probably too highly stabilized for semipinacol rearrangement and was merely attacked by water upon work-up to form intermediate OO, which underwent elimination to give byproduct 3.58. SerivlpThacol Approaches to the Erythrina Alkaloid Skeleton 151 t H K^P C F 3 3.58 Scheme 3.21 Proposed Mechanism for Byproduct 3.58 Formation An effort was made to prepare substrates PP for the -5 to 6-membered ring expansion containing R groups on the aromatic ring which would be less electron-donating than the methylenedioxy substituent (see Scheme 3.22). However various amides HH, where R = acetyl, mesyl, or TMS, failed to undergo Bischler-Napieralski reaction. R O v RO' POCU H N ^ ^ 0 x R = Ac, Ms, TMS DCM, reflux PP \ I HH Scheme 3.22 Attempted Preparation of Alternate Substrates Similarly, attempts at incorporating alternate protecting groups with P = Ts, Tf, or Boc failed (Eq. 3.5). This may be in part due to the allylic strain of the N-substituent with the double bond in enamide QQ. TsCI, T f 2 0 , or Boc20 / N X - \ Et 3 N, DCM (3.5) P = Ts, Tf, Boc Sentlpihacol Approaches to the Erijthrim Alka lo id Skeleton 152 3.4.4 Synthesis of Epoxide 3.59 In order to test the general feasibility of the proposed semipinacol rearrangement involving a migration to a benzylic position, the analogous 4 to 5-membered ring expansion of epoxide 3.59 was investigated (see Figure 3.5). This cyclobutane-based substrate was more likely to favour ring expansion in order to alleviate angle strain. Figure 3.5 Proposed Semipinacol Rearrangement Precursor 3.59 Proposed semipinacol rearrangement precursor 3.59 was synthesized as outlined in Scheme 3.23. Dicyclohexylcarbodiimide (DCC) coupling of amine 3.54 with cyclobutanecarboxylic acid produced amide 3.60 in 95% yield following recrystallization. The 13C NMR spectrum of 3.60 contained a signal at 175.1 ppm which was indicative of the carbonyl carbon of the amide functional group. o Scheme 3.23 Synthesis of Epoxide 3.59 Seriupihacol Approaches to the Erythrina Alkaloid Skeleton 153 Subsequent Bischler-Napieralski reaction of amide 3.60 using phosphorous oxychloride in refluxing dichloromethane led to the formation of crude imine 3.61. The signal in the ]H NMR spectrum at 3.47-3.60 (m, IH) was attributed to the allylic methine proton. N-Protection of crude imine 3.61 with a trifluoroacetyl group produced enamide 3.62 in 93% yield over two steps. The ]H and 13C NMR spectra of 3.62 suggested a mixture of two atropisomers, analogous to those of enamide 3.57 (refer to Eq. 3.3). This was also reflected by the two IR absorptions at 1699 and 1682 cm4, which indicated the presence of the two amide isomers. Use of m-CPBA for the epoxidation of enamide 3.62 was problematic due to the presence of trace acid; rearrangement product 3.63 was observed. Structural evidence for 3.63 included peaks in the 13C NMR spectrum at 87.7 and 162.4 ppm, which corresponded to the carbon bonded to the trifluoracetate group and the imine carbon, respectively. The rearrangement of the initially formed epoxide 3.59 to 3.63 could result via the donation of a lone electron pair from nitrogen in protonated epoxide R R to generate iminium ion SS, which could undergo intramolecular nucleophilic attack by the hydroxyl group to give 3.63 (see Scheme 3.24) Scheme 3.24 Undesired Rearrangement of Epoxide 3.59 Sei'hif Inacol Approaches to the Erythrina A lka lo id Skeleton 154 Dimethyldioxirane was found to be a superior oxidant compared to ra-CPBA. According to TLC, the epoxidation of enamide 3.62 using DMDO resulted in complete conversion to epoxide 3.59. However, epoxide 3.59 was so unstable that it was found to partially decompose to 3.63 upon concentration in vacuo. 3.4.5 Ring Expansion of Epoxide 3.59 Due to the extreme sensitivity of epoxide 3.59, it was treated directly with various Lewis acids (Eq. 3.6). Exposure of epoxide 3.59 to magnesium bromide in dichloromethane at -78 °C led to the formation of a minor amount (6%) of the expected semipinacol product 3.64 (Table 3.3; entry i). The major product was 1-azaspirocycle 3.65, which was isolated in 29% yield. In addition 3.63, formed via the rearrangement of epoxide 3.59, was produced in 19% yield. Table 3.3 Semipinacol Rearrangement of Epoxide 3.59 Entry LA a % Yield 3.62 % Yield 3.63 % Yield 3.64 % Yield 3.65 (ii) Lewis acid DCM, -78 °C (i) DMDO NH (3.6) O 1 MgBr2 19 6 29 i i Yb(OTf) 14 12 57 ;i1.5 Equiv. Seriii plhacol Approaches to the Erythrina A lka lo id Skeleton 155 Alternatively, when crude epoxide 3.59 was subjected to ytterbium triflate in dichloromethane at -78 °C 1-azaspirocycle 3.64 was obtained as the major product in 57% yield along with 14% of recovered 3.62 and 12% of byproduct 3.63 (entry ii). 1-Azaspirocycles 3.64 and 3.65 were proposed to form according to the mechanism illustrated in Scheme 3.25. Lewis acid-coordinated epoxide intermediate T T could undergo a semipinacol rearrangement to form ring-expanded product 3.64, which could undergo cleavage of the trifluoroacetyl group to give 1-azaspirocycle 3.65. Scheme 3.25 Proposed Mechanism for Semipinacol Rearrangement The structures of 1-azaspirocycles 3.64 and 3.65 were established by spectroscopic methods. The IR spectrum of 3.64 contained absorptions at 1749 and 1682 cm1, which were attributed to the OO stretches of the ketone and the trifluoroacetamide, respectively. Further evidence for the proposed semipinacol rearrangement structure 3.64 was provided by key signals in the 13C NMR spectrum ' at 213.2 ppm (due to the newly introduced carbonyl) and at 69.6 ppm (due to the adjacent spirocyclic carbon). The IR spectrum of 1-azaspirocycle 3.65 contained absorptions at 3299 and 1735 cm-1, which were indicative of the presence of N-H and C=0 bonds. The Semipinacol Approaches to the Erythrina A lka lo id Skeleton 156 signals in the 13C NMR spectrum at 217.0 and 65.5 ppm were assigned as the carbonyl carbon and the 1-azaspirocyclic carbon, respectively. 3.4.6 Investigations from 1-Azaspirocycle 3.64 3.4.6.1 Proposed Approach • Investigations were made exploring the viability of utilizing 1-azaspirocycle 3.64 towards the completion of the Erythrina skeleton. This approach would entail a 5 to 6-membered ring expansion and the formation of the B-ring, which were envisioned to occur simultaneously via a one-pot tandem reaction as illustrated in Scheme 3.26. Substituent X was chosen to be a sulfone since this functionality is known to enable the generation of an adjacent carbanion and also act as a leaving group.33 A stabilized anion resembling UU could undergo intramolecular addition to the carbonyl group to produce an intermediate VV, which could undergo a semipinacol rearrangement to set the erythrinan framework. Scheme 3.26 Proposed Approach to the Erythrina Skeleton via 1-Azaspirocycle 3.64 Seniipirtacol Approaches to the Erylhrimi A lka lo id Skeleton 157 A few examples of cyclizations involving the addition of a sulfonyl-stabilized carbanion to a ketone to have been reported (see Scheme 3.27).3436 The employed reaction conditions, especially those capable of forming a 6-membered ring,36 seemed promising. However, the authors were unable to apply the protocol developed on the model system to a more complex substrate. F. 35) no reaction (ref. 36) Scheme 3.27 Cyclizations Involving Sulfonyl Carbanion Additions to Ketones3436 If conditions were developed to execute the nucleophilic carbonyl addition, a semipinacol rearrangement could spontaneously occur. During the cyclization the incoming carbanion should approach so that the sulfonyl group is pseudoequatorial as depicted in Figure 3.6. This orientation of the leaving group would be well aligned (i.e. anti-periplanar) for reaction with the expected migrating bond. The migratory aptitude of this bond should be increased by the fact that it would be both a to a nitrogen and benzylic. The driving force for migration would be the Serii i|H ha col Approaches to the Erythrina Alka lo id Skeleton 158 generation of the neutral product which should be the thermodynamic sink of the one-pot reaction. Figure 3.6 Possible Transition State for Cyclization 3.4.6.2 Sulfone Substrate Synthesis The synthesis of the required sulfone substrate was carried out as outlined in Scheme 3.28. Amide 3.64 was converted to amine 3.65 using potassium carbonate in refluxing wet methanol in quantitative yield. . Mass spectrum molecular weight agreement and the presence of an N-H stretch in the IR spectrum at 3299 cm1 supported the formation of the deprotected amine. Scheme 3.28 Synthesis of Sulfone 3.68 Condensation of amine 3.65 with 3-(phenylsulfonyl)proprionic acid was accomplished using 1,3-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in Seriiiplnacol Approaches to the Ert/thrina Alka lo id Skeleton • 159 \ dichloromethane to produce amide 3.66 in 96% yield. The introduced amide functionality displayed a strong absorption in the IR spectrum at 1622 cm1. The 13C spectrum contained peaks at 167.5 and 52.0 ppm, which corresponded to the amide carbon and the carbon attached to the sulfone, respectively. Although amide 3.66 was a potential substrate for cyclization, there were concerns over the additional acidic site adjacent to the amide. While deprotonation of the sulfone should be favoured, deprotonation of the amide could lead to (3-elimination of the sulfonyl group. To circumvent this issue sequential global reduction to remove the amide and oxidation to restore the ketone were necessary. Reduction was accomplished by treatment of amide 3.66 with aluminum trichloride and lithium aluminum hydride in THF and ether, conditions previously reported for the reduction of similar amides.37 Alcohol 3.67 was obtained in 79% yield. Although the stereochemistry of the alcohol was not important, presumably reduction occurred from the less hindered face of the cyclopentanone ring according to Figure 3.7. The diastereoselectivity of this reaction was supported by the lack of additional peaks in 13C spectrum. The peak at 80.2 ppm was attributed to the carbon attached to the alcohol. i Hydride delivered from this face 3.66 Figure 3.7 Selective Reduction of 3.66 Seriti jSihacol Approaches to the Erythrina Alka lo id Skeleton 160 Oxidation of alcohol 3.67 was accomplished using Moffat-Swern conditions to produce the desired sulfone 3.68 in 97% yield. Confirmation of a ketone functional group was provided by the absorption in the IR spectrum at 1739 car1 and the signal in the 13C spectrum at 219.7 ppm. 3.4.6.3 Rearrangement Investigations of Amide 3.66 Despite the concerns over the multiple acidic sites of amide 3.66, it was exposed to various bases in hopes of effecting the desired cyclization and rearrangement. Due to the limited solubility of this amide, dimethyl sulfoxide and tetrahydrofuran were selected as solvents. Exposure of amide 3.66 to the conditions outlined in Table 3.4 led to the formation of two new compounds, which were eventually elucidated to be byproducts 3.69 and 3.70. Table 3.4 Deprotonation of Amide 3 .66 3.66 3.69 3.70 Entry Base Equiv. Solvent T (°C) t (h) Yield 3.69 Yield 3.70 <%) (%) i KHMDS 2.0 THF -78 to 0 1 29 29 ii KHMDS 2.0 DMSO 25 1 0 75 iii KHMDS 1.2 DMSO 25 24 60 33 vi LiHMDS 1.2 DMSO 25 24 27 47 Semipinacol Approaches to the Erythrina Alkaloid Skeleton lb! Byproduct 3.69 and the intended rearrangement product 3.71 had such similar structural features that definitive structural assignment based on spectral data proved difficult (see Figure 3.8). Both compounds had the same molecular formula, therefore the same expected molecular weight, and similar functionality and connectivity. Absorptions at 1749 and 1626 cm'1 in the IR spectrum diagnostic of ketone and amide functional groups were indicative of either compound. Similarly, the methine peak at 46.0 ppm in the aikyl region of the 13C attached proton test NMR spectrum could have resulted from either compound. methine carbon Figure 3.8 Structural Similar i t ies of 3.69 & 3.71 In order to make the correct structural assignment, a solid state structure was obtained (see Figure 3.9). This proved that the obtained compound was in fact die undesired byproduct 3.69. Although this result was not useful for our purposes, this method may be useful in building similar 7-membered rings. Figure 3.9 O R T E P Plot of Byproduct 3.69 (50% ellipsoids) Seiliipinacol Approaches to the Erythrina Alka lo id Skeleton 162 Spectroscopic data for compound 3.70 support the assigned structure. The IR spectrum contained absorptions at 3313 and 1656 cm4, which were attributed to alcohol and amide functional groups, respectively. An APT 13C NMR experiment revealed two methine carbons at 45.1 and 43.9 ppm. The relative downfield shift of these aikyl carbon signals was in accord with their proposed connectivity, adjacent to the tertiary alcohol. A proposed mechanism for the formation of byproducts 3.69 and 3.70 is outlined in Scheme 3.29. Deprotonation of the carbon a to the amide of substrate 3.66 followed by -^elimination of the sulfonyl group and deprotonation a to the ketone could give intermediate WW. The generated enolate could then undergo a 1,4-Michael addition to the a,[3-unsaturated amide to give intermediate XX. Intermediate XX could be in equilibrium with intermediate YY via an aldol and a retro-aidol reaction. Although the pKa of an amide versus an alcohol would favour the right side of the equilibrium, angle strain inherent in the generated 4-membered ring would disfavour this side. Upon work-up, the addition of water to intermediates XX and YY would lead to the isolation of the obtained byproducts 3.69 and 3.70. Sert-ipinacoi. Approaches to the Erythrina Alka lo id Skeleton 163 3.4.6.4 Rearrangement Investigations of Sulfone 3.68 Sulfone 3.68 was exposed to a variety conditions in order to deprotonate adjacent to the sulfonyl group and effect cyclization onto the ketone (see Table 3.5). However, only recovered sulfone 3.68 or byproduct 3.72 were observed. Table 3.5 Deprotonation of Sulfone 3.68 Entry Base Equiv. Solvent T (°C) Result i LDA 1.2 THF -78 to 25 No reaction ii KHMDS 1.2 THF -78 to 25 No reaction iii KHMDS 4.0 THF 25 to 66 No reaction iv KO'Bu 1.2 THF 25 No reaction v KOBu 1.2 DMSO 25 No reaction vi KHMDS 1.4 DMF 25 3.68 (6%), 3.72 (29%) vii KHMDS 1.2 DMSO 25 to 50 3.68 (11%), 3.72 (50%) Serru pihacol Approaches to the Erythrina Alka lo id Skeleton 164 IR analysis of compound 3.72 revealed absorptions at 3360 and 1708 cm4, diagnostic of alcohol and ketone functional groups. The 1TT NMR spectrum contained a triplet peak at 6.72 ppm, which indicated an alkenyl proton adjacent to a methylene group. These data combined with the determination of 3.72 to be 14 AMU heavier than the starting sulfone 3.68 led to the proposed structural assignment. The fact that 3.72 was an obtained product pointed to deprotonation adjacent to the carbonyl rather than the sulfonyl. In order to determine if any deprotonation of the sulfone. was occurring deuterium experiments were performed as summarized in Table 3.6. Table 3.6 Deprotonation & Subsequent D 2 0 Addit ion to Sulfone 3.68 (3.9) Entry Base3 T(°C) Yield 3.73 (%) i KOBu 0to25 89 ii LiHMDS -78 93 a1.2 Equiv. When sulfone 3.68 was treated with base either under more thermodynamic conditions (entry i) or more kinetic conditions (entry ii) and then quenched with deuterium oxide the ]H NMR integrations of the resulting compound 3.73 indicated that a deuterium atom had been incorporated. Unfortunately, while the multiplet in Serriiplhacol Approaches to the Erythrina Alka lo id Skeleton . 165 the NMR spectrum at 3.72-3.03 ppm due to the methylene protons adjacent to the sulfonyl group remained, the multiplet containing the proton adjacent to the carbonyl at 2.46-2.27 ppm integrated to 3 protons rather than 4. 3.4.6.5 Future Directions & Conclusions Epoxide 3.59 successfully underwent a 4 to 5-membered ring expansion to 1-azaspirocycle 3.64 in 57% yield over 2 steps from enamide 3.62 (71% based on recovered 3.62). This result proved that semipinacol rearrangements involving migrations to benzylic positions to form 1-azaspirocycles are indeed possible. The reactivity of epoxide 3.59 was attributed to the propensity of cyclobutane to ring expand in order to relieve angle strain since attempts to effect the analogous 5 to 6-membered ring expansion of epoxide 3.53 under similar reaction conditions failed. In the later case the stability of the Lewis acid-coordinated intermediate due to electron donation from the adjacent aromatic ring was not sufficiently compensated for by relief of angle strain. So far attempts at executing the proposed tandem cyclization and rearrangement of derivatives of 1-azaspirocycle 3.64 have proved unsuccessful. This has been a result of difficulty in the selective generation of a sulfonyl carbanion in the presence of an intramolecular ketone functional group. Semifiihacol Approaches to the Erythrina Alka lo id Skeleton 166 An attractive modification to this approach would be the utilization of geminal bis-sulfone 3.74 instead (see Scheme 3.30). This substrate should prove easier to cyclize either through deprotonation or reductive cyclization. In fact, upon further investigations into this approach, precedence was found for the proposed cyclization and rearrangement combination. Cr° 3 . 6 5 (i) reductive cyclization ( y=0 — S 0 2 P h (ii) semipinacol \ / I rearrangement v — ' SO z Ph 3.74 •> N — i erythrinan 1 skeleton ^ Scheme 3.30 Proposed Future Investigations In 1992, Trost and co-workers reported the cyclizations of keto bis-sulfones using samarium diiodide to form hydroxyl sulfones which were subsequently treated with aluminum Lewis acids to effect semipinacol rearrangements as exemplified by Eq. 3.9.38 1) Sml 2 , THF, rt, 30 min O y ^ s 0 2 P h 2) EtAICI2, DCM, 0 °C, 10 min S 0 2 Ph (Eq. 3.9) This established methodology could potentially be applied to bis-sulfone 3.74 to allow the completion of the Erythrina skeleton. Although time and material restraints prevent further current investigations, this approach would be worth future reexamination. Semipinacol Approaches to the Erythrina Alkaloid Skeleton 167 3.5 Summary & Concluding Remarks The application of a semipinacol strategy towards the construction of the Erythrina alkaloid skeleton was attempted. In the first approach (I), the large number of synthetic steps and the generation of diastereomeric mixtures hampered further investigations. While the second approach (II) was more direct, it initially involved the obstacle of a 5 to 6-membered ring expansion to a benzylic position. However, the analogous 4 to 5-membered ring expansion was attained. This represents the first example of a semipinacol rearrangement to a 1-azaspirocle with an aromatic substituent adjacent to the spirocyclic center. Despite the success of this rearrangement, it has not yet led to the synthesis of an erythrinan derivative. If the proposed cyclization and ring expansion are achieved, this approach to the Erythrina skeleton would demonstrate the effectiveness of the semipinacol rearrangement as a powerful tool in organic synthesis. Serhtpfhacol Approaches to the Enjlkrina A lka lo id Skeleton 168 3.6 Exper imental 3.6.1 General Information All reactions were carried out under a nitrogen atmosphere in flame-dried glassware. Tetrahydrofuran and diethyl ether were distilled from sodium using benzophenone as an indicator. Dichloromethane was distilled over calcium hydride. Reagents trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chloride, trietiiylamine, allyltrimethylsilane, and trifluoroacetic anhydride were also distilled over calcium hydride prior to use. Methyllithium in hexane concentration was determined by titration with diphenylacetic acid. Tin(IV) tetrachloride and titanium(IV) tetrachloride 1.0 M solutions in dichloromethane were prepared in a glove box prior to use. Magnesium bromide was purchased from Strem. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates. Flash column chromatography was carried out using 230-400 mesh silica gel. Melting points were performed using a Mel-Temp II apparatus (lab devices USA) and are uncorrected. Infrared (IR) spectra were obtained using a Perkin-Elmer 1710 FT-IR spectrometer. Proton nuclear magnetic resonance (]H NMR) spectra were recorded in deuterated chloroform using a either a Bruker WH-400 spectrometer or a Bruker AV-300 spectrometer. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded in deuterated chloroform Serni pihacol Approaches to the Erytkrirta Alka lo id Skeleton 169 using a Bruker AV-300 spectrometer. Chemical shifts (5) are reported in parts per million (ppm) and are referenced to deuterated chloroform (6 7.24 ppm ]H NMR; 6 77.0 ppm 13C NMR). Low-resolution mass spectra (LRMS) were recorded using either a Kratos-AEI model MS 50 or an Aligent 6890 series GC with a 5973 MS. Microanalyses were performed on either a Carlo Erba Elemental Analyzer Model 1106 or a CHN-O Elemental Analyzer Model 1108. 3.6.2 Semipinacol Approach I 3-(phenylthio)-l-(p-toluenesulfonyl)piperidin-2-one (3.47) A solution of lactam 2.108 (20.3 g, 80 mmol) and 19.2 g of diphenyl sulfide (88 mmol) in 870 mL of THF was cooled to -60 °C using a chloroform/dry ice bath. To this solution was added a 320 mL of a freshly prepared 0.5 M solution of potassium hexamethyldisilazide (31.9 g, 160 mmol) in toluene at 0 °C. The mixture was warmed gradually to room temperature then subsequently quenched with 115 mL of an ammonium chloride saturated aqueous solution. Next, 250 mL of each diethyl ether and ethyl acetate were added. The aqueous portion was extracted with three 150 mL portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and reduced via rotary evaporation. Flash Sermpinacol Approaches to the Erythrina Alka lo id Skeleton 170 column chromatography (3:7 ethyl acetate-hexanes) followed by recrystallization (ethyl acetate and hexanes) of the crude product led to the isolation of 17.2 g of white crystals (59%). mp: 105-106 °C IR (KBr): 2962, 1694, 1353, 1169 cm1. lH NMR (400 MHz, CDC13): 6 7.90 (d, / = 8.3 Hz, 2H), 7.32-7.15 (m, 7H), 3.99-3.83 (m, 2H), 3.68 (t, / = 6.0 Hz, IH), 2.43 (s, 3H), 2.20-2.01 (m, 2H), 1.99-1.79 (m, 2H). l-(/?-toluenesulfonyl)-5,6-dihydropyridin-2(lH)-one (3.46) To a solution of 11.9 g 3.47 (32.8 mmol) in 330 mL dichloromethane was added 6.22 g of ra-chloroperbenzoic acid (36.1 mmol). After 2 h, 300 mL of a sodium bicarbonate saturated aqueous solution were added. The aqueous portion was extracted with two 100 mL portions of dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. The resulting crude foam was refluxed in toluene for 20 min. The toluene was removed via rotary evaporation. Recrystallization of the crude product in ethyl acetate and hexanes led to the isolation of 6.45 g of white crystals (78%). mp: 123-125 °C. IR (KBr): 3430, 2949, 1690, 1354, 1288, 1169 cm1. ]H NMR (400 MHz, CDCL): 5 7.91 (d, / = 8.4 Hz, 2H), 7.30 (d, / = 8.5 Hz, 2H), 6.77 (td, / = 4.2, 9.6 Hz, IH), 5.83 (td, / = 1.8, 9.8 Hz, IH), 4.04 (t, / = 6.5 Hz, 2H), 2.52 (ddt, / = 1.8, 4.2, o Sernipihacoi Approaches to'the Erythrina A lka lo id Skeleton 171 6.4 Hz, 2H), 2.40 (s, 3H). The obtained spectral data was in agreement with the previously reported literature values.29 To a solution of 2.06 g of copper bromide dimethylsulfide complex (10.0 mmol) in 100 mL of tetrahydrofuran at -78 °C was added 10 mL of a 1.0 M solution of allylmagnesium bromide (10.0 mmol) in ether. After stirring for 30 min, 1.90 mL of trimethylsilyl chloride (15.0 mmol) and 1.26 g of enone 3.46 (5.0 mmol) were added. Upon stirring for 2 h, the reaction was quenched with 60 mL of 2 N HCI. The aqueous portion was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with a sodium chloride saturated aqueous solution, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Purification via flash column chromatography (1:3 ethyl acetate-hexanes) yielded 0.81 g of white solid (55%). mp: 73-74 °C. IR (KBr): 2922, 1693, 1552, 1169 cm1. ]H NMR (300 MHz, CDCI3): 6 7.90 (d, / = 8.4 Hz, 2H), 7.30 (d, / = 8.0 Hz, 2H), 5.67 (tdd, / = 7.1, 10.5, 17.4 Hz, 1H), 5.09-4.98 (m, 2H), 4.18 (ddd, / = 3.9, 5.1,12.3 Hz, 1H), 3.63 (ddd, / = 4.3,11.1, 12.2 Hz, 1H), 2.50 (ddd, / = 2.0, 5.1, 17.4 Hz, 1H), 2.42 (s, 3H), 2.13-1.99 (m, 4H), 1.95-1,79 (m, 1H), 1.51 (dtd, / = 5.1,10.9, 13.7 Hz, 1H). 13C NMR (75 MHz, CDCI3): 6 171.3, 4-allyl-l-(p-toluenesulfonyl)piperidin-2-one (3.48) o Seitiipinacol Approaches to the Erythrina A lka lo id Skeleton 172 146.2,137.5,136.0,130.7, 130.1, 119.1, 47.3, 41.4, 40.9, 33.5, 30.2, 23.0. Anal, calcd. for CisHioNCbS: C 61.41, H 6.53, N 4.77; found: C 61.65, H 6.55, N 4.64. 4-allyl-l-(p-toluenesulfonyl)-l,4,5,6-tetrahydropyridin-2-yl trifluoromethanesulfonate (3.49) To a solution of amide 3.48 (1.47 g, 5.0 mmol) in 45 mL of tetrahydrofuran at -78 °C was added a solution of potassium hexamethyldisilazide (1.20 g, 6.0 mmol) in 25 mL of tetrahydrofuran at -78 °C. After 30 min, N-phenyltriflimide (2.14 g, 6.0 mmol) in 60 mL of tetrahydrofuran at -78 °C was added. After 10 min, the reaction was quenched with ammonium chloride saturated aqueous solution (30 mL). The aqueous portion was extracted with dichloromethane (3 x 20 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography yielded 2.02 g of clear pale yellow oil (96% yield). IR (film): 3078, 2931, 1670, 1425, 1212, 1174 cm1. 'H NMR (300 MHz, CDCL): 6 7.75 (d, / = 8.3 Hz, 2H), 7.34 (d, / = 8.1 Hz, 2H), 5.52 (tdd, / = 7.1,10.2, 17.2 Hz, 1H), 5.36 (d, / = 3.6 Hz, 1H), 5.01-4.88 (m, 2H), 3.76 (ddd, / = 3.0, 9.5,14.1 Hz, 1H), 2.44 (s, 3H), 2.33 (dtd, / = 3.7, 7.1, 14.1 Hz, 1H), 2.00-1.80 (m, 2H), 1.50 (dtd, / = 3.0, 6.7, 9.8 Hz, 1H), 1.15-1.01 (m, 1H). 13C NMR (75 MHz, CDCL): 6 145.1, 139.6, 135.3, 134.6, OTf SeriupTnacol Approaches to the Enjthrma Alka lo id Skeleton 173 130.1,128.0, 117.9, 114.2 (q, JC-F = 321 Hz), 113.3, 47.4, 39.2, 32.8, 25.9, 21.8. LRMS (EI) mlz (relative intensity): 425 (M+ + 1, 2), 385 (11), 384 (65), 155 (100). 4-allyl-l-(p-toluenesulfonyl)-6-(trimethylstannyl)-l,2,3,4-tetrahydropyricline (3.45) SnMe 3 To a solution of hexamethyldistannane (4.52 g, 13.8 mmol) in 140 mL of tetrahydrofuran at -41 °C was added a 1.43 M solution of methyllithium in hexanes (9.65 mL, 13.8 mmol). The mixture was warmed to 0 °C for 20 min then returned to -41 °C prior to the addition of 1.24 g of copper cyanide (13.8 mmol) in one portion. After 20 min, 1.96 g of triflate 3.49 (2.6 mmol) in 45 mL of tetrahydrofuran at -41 °C were added. The reaction rnixture stirred for 1 h at 0 °C then poured into a pH 8 solution of ammonium hydroxide saturated with ammonium chloride (100 mL). The aqueous portion was extracted with ether (3 x 200 mL) and the resulting ethereal extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Purification via flash column chromatography yielded 1.67 g of clear colourless oil (83%). IR (film): 3074, 2977, 2922, 1343, 1163 cm-1. ]H NMR (400 MHz, CDC13): 6 7.60 (d, / = 8.2 Hz, 2H), 7.27 (d, / = 8.0 Hz, 2H), 5.67-5.56 (m, 1H), 5.16 (d, / = 2.6 Hz, 1H), 4.96-4.87 (m, 2H), 3.55 (ddd, / = 3.3, 6.2 13.3 Hz, 1H), 3.26 (ddd, / = 3.0,10.1, 13.3 Hz, 111), 2.40 (s, 3H), 2.11-2.01 (m, 1H), 1.90 (tdd, / = 6.9, 13.8, 21.1 Hz, 2H), 1.46-1.37 (m, Semipinacol Approaches to .the Enjthri.ua A lka lo id Skeleton 174 111), 0.99-0.85 (m, 1H), 0.24 (s, 9H). 13C NMR (75 MHz, CDC13): 6 143.4, 140.8,' 136.2, 136.1,129.7,127.6,127.3,116.6, 44.1, 40.1, 40.1, 33.3, 26.0, 21.7, -5.7. l-(4-allyl-l-(/?-toluenesulfonyl)-l,4,5,6-tetrahydropyridin-2-yl)cyclopentanol (3.50) To a solution of vinylstannane 3.45 (600 mg, 1.36 mmol) in 15 mL of diethyl ether at -78 °C was added a 1.43 M solution of methyllithium in hexanes (2.10 mL, 3.00 mmol). The mixture was warmed to 0 °C then returned to -78 °C prior to the addition of magnesium bromide (653 mg, 3.54 mmol) in 30 mL of diethyl ether. After 30 min, the reaction mixture was cooled to -100 °C and a solution of cyclopentanone (326 uL, 3.68 mmol) in 20 mL of diethyl ether at -100 °C was added. After 2 h the reaction was complete and 20 mL of ammonium chloride saturated aqueous solution were added. The aqueous portion was extracted with diethyl ether (3 x 20 mL) and the resulting ethereal extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Purification via flash column chromatography led to the isolation of 372 mg of clear colourless oil in 76 % yield. IR (film): 3522, 2954, 2871, 1334, 1162 cm1. 5H NMR (400 MHz, CDC13): 6 7.78 (d, / = 8.3 Hz, 2H), 7.30 (d, / = 8.1 Hz, 2H), 5.72 (d, / = 3.2 Hz, IH), 5.49 (tdd, / = 7.0, 10.1, 17.0 Hz, IH), 4.94-4.73 (m, 2H), 4.52 (br s, IH), 3.55 (ddd, / = 4.3, 6.4, 14.2 Hz, SeritipIhacol Approaches to the Erythrina Alka lo id Skeleton • 175 IH), 3.35 (ddd, / = 3.7, 9.3, 14.2 Hz, IH), 2.42 (s, 3H), 2.30-2.11 (m, 2H), 2.02-1.61 (m, 611), 1.34-1.20 (m, IH), 0.80 (dddd, / = 4.3, 7.1, 9.3, 14.0 Hz, IH). 13C NMR (75 MHz, CDC13): 5 144.1, 143.4, 136.4, 135.7,129.8, 128.1, 125.7, 117.0, 83.3, 47.6, 40.1, 40.0, 39.6, 32.2, 25.4, 23.2, 22.9, 21.7. LRMS (EI) mlz (relative intensity): 361 (M+ + 1, 2), 321 (11), 320 (34), 302 (12), 206 (40), 164 (15), 155 (15), 148 (100), 146 (13), 138 (10), 137 (49), 95 (21), 92 (10), 91 (48), 81 (10), 67 (23), 65 (12), 55 (16). A solution of allyl alcohol 3.50 (40 mg, 0.11 mmol), allyltrimethylsilane (53 uL, 0.33 mmol), and 2 mL of dichloromethane was cooled to -78 °C and a 1.0 M solution of titanium tetrachloride in dichloromethane (330 uL, 0.33 mmol) was added. After 10 min, silica gel (300 mg) arid diethyl ether (3 mL) were added to the reaction mixture. The solvent was subsequently removed in vacuo. Purification via flash column chromatography led to the isolation of 19 mg of 3.51 (44%) as well as 13 mg of byproduct 3.52 (34%) as clear colourless oils. 3,4-diallyl-2-cyclopentylidene-l-(/?-toluenesulfonyl)piperidine (3.51) IR (film): 3072, 2948, 2866, 1337, 1157 cm-1. 'H NMR (300 MHz, CDC13): 6 7.78 (d, J = 8.4 Hz, 2H), 7.77 (d, / = 8.4 Hz, 2H), 7.26 (d, / = 7.98 Hz, 2H), 6.04 (dtd, / = 4.6, Seihipshaco! Approaches to the Erythrina Alka lo id Skeleton 176 9.5,16.8 Hz, 1H), 5.93-5.82 (m, 1H), 5.69 (tdd, / = 7.0,10.2,17.2 Hz, 1H), 3.73-3.65 (m, III), 3.47 (ddd, / = 3.0, 4.5,13.5 Hz, 1H), 3.06 (ddd, / = 3.1,12.5,13.4 Hz, 1H), 2.85 (dt, / = 3.9, 13.7 Hz, 1H), 2.55-1.14 (m, 16H), 2.40 (s, 3H). 13C NMR (75 MHz, CDC13): 6 145.6, 143.8, 143.5, 143.0, 143.0, 143.0, 138.5, 138.4, 138.2, 137.7, 137.5, 136.8, 136.8, 136.6, 136.0, 129.5, 129.5, 128.8, 128.4, 127.9, 127.6, 126.1, 121.3, 116.7, 116.5, 115.9, 115.5, 48.2, 46.2, 43.6, 42.4, 42.3, 40.8, 40.0, 38.4, 37.1, 37.0, 36.8, 34.2, 32.9, 32.7, 32.4, 32.4, 30.8, 30.7, 29.4, 26.7, 26.6, 26.0, 25.9, 23.9, 23.8, 21.7, 21.7. LRMS (EI) mlz (relative intensity): 385 (M+ + 1, 4), 344 (39), 321 (18), 320 (11), 318 (11), 302 (41), 281 (22), 280 (93), 238 (16), 231 (19), 230 (100), 190 (28), 189 (10), 188 (55), 162 (13), 155 (14), 149 (13), 148 (98), 147 (12), 146 (33), 120 (11), 95 (18), 94 (11), 93 (15), 92 (16), 91 (76), 81 (14), 79 (19), 77 (14), 67 (38), 65 (23), 55 (20), 55 (20), 53 (15). N-(3-(2-cyclopentenyl-2-oxoethyl)hex-5-enyl)-4-methylbenzenesulfonamide (3.52) IR (film): 3279, 2926, 1359, 1652, 1329, 1160 cm1, m NMR (300 MHz, CDCL): 6 7.72 (d, / = 8.3 Hz, 2H), 7.26 (d, / = 8.2 Hz, 2H), 6.69-6.65 (m, 1H), 5.65-5.53 (m, 1H), 4.99-4.88 (m, 2H), 2.96 (dt, / = 6.7,13.4 Hz, 1H), 2.79 (dt, / = 6.9,12.5 Hz, 1H), 2.62 (dd, / = 4.7,16.8 Hz, 1H), 2.55-2.40 (m, 5H), 2.39 (s, 3H), 2.11-1.82 (m, 5H), 1.50 (td, / = 7.0, 13.3 Hz, 1H), 1.32 (dt, ]w 6.6,13.3 Hz, 1H). 13C NMR (75 MHz, CDC13): 6 198.7, 145.7, Serhjpmacoi Approaches to the Erythrina Alka lo id Skeleton 177 14.4.0, 143.1, 137.0, 135.9, 129.5, 127.1, 117.1, 42.7, 41.0, 38.8, 34.1, 33.9, 30.6, 30.4, 22.6, 21.4. LRMS (EI) mlz (relative intensity): 361 (M+ + 1, 4), 207 (11), 206 (61), 184 (21), 163 (30), 155 (37), 110 (48), 96 (100), 95 (71), 92 (12), 91 (74), 81 (13), 67 (32), 65 (20). 3.6.3 Semipinacol Approach II 3,4-methylenedioxyphenethylamine (3.54) To a mixture of lithium aluminum hydride (2.65 g, 70 mmol) and 20 mL of tetrahydrofuran was added solution of 3,4-memylenedioxy-(3-nitrostyrene (3.86 g, 20 mmol) in 150 mL of tetrahydrofuran dropwise. After heating to 65 °C for 6 h, water sequentially. Upon stirring for 1 h, the mixture was dried over sodium sulfate, filtered, and concentrated via rotary evaporation to yield 3.0 g of crude brown oil (92%) which was used without purification. IR (film): 2898,1668, 1505, 1489, 1445, 1248 cm1. ! H NMR (300 MHz, CDC13): 6 6.84-6.62 (m, 3H), 5.93 (s, 2H), 2.93 (t, / = 6.8 Hz, 2H), 2.67 (t, / = 6.8 Hz, 2H). (2.65 mL), 3 N sodium hydroxide (2.65 mL), and then water (8 mL) were added AT-(2-(benzo[d][l,3]dioxol-5-yl)ethyl)cyclopentanecarboxamide (3.55) Semipinacol Approaches to the Erytkrirte Alka lo id Skeleton 178 To a solution of amine 3.54 (2.97 g, 9 mmol) in 150 mL of dichloromethane were added 2.5 mL of triethylamine (18 mmol) and 2.6 mL of cyclopentanecarbonyl chloride (21.6 mmol). After 10 min, the reaction mixture was washed with water (2 x 100 mL), dried over sodium sulfate, filtered, and reduced in vacuo. Recrystallization from ethyl acetate and hexanes led to the isolation of 1.5 g of white crystals (32%). mp: 138-139 °C. IR (film): 3293, 2953, 1635, 1247 cm1. 'H NMR (300 MHz, CDCL): o 6.73 (d, / = 7.8 Hz, IH), 6.66 (s, IH), 6.61 (d, / = 7.8 Hz, IH), 5.92 (s, 2H), 5.39 (br s, IH), 3.44 (q, / = 6.5 Hz, 2H), 2.71 (t, / = 6.9 Hz, 2H), 2.49-2.35 (m, IH), 1.86-1.63 (m, 6H), 1.60-1.47 (m, 2H). 13C NMR (75 MHz, CDCL-): 6 176.3, 147.9, 146.3, 132.9, 121.8, 109.2, 108.5, 101.1, 46.1, 40.9, 35.6, 30.6, 26.0. Anal, calcd. for C ,5H 1 9 N0 3 : C 68.94, H 7.33, N 5.36; found: C 69.30, H 7.47, N 5.49. 5-cyclopentyl-7,8-dihydro-[l,3]dioxolo[4,5-g]isoquinoline (3.56) A solution of 1.09 g of amide 3.55 (4.2 mmol), 80 mL of dichloromethane, and 3 mL of phosphorous oxychloride (32 mmol) was heated to reflux for 12 h. Upon cooling, the reaction mixture was poured into 50 mL of water. Sodium hydroxide (3 N) was added until the solution tested basic (pH -10). The aqueous portion was Semipinacol Approaches to the En/thrina Alka lo id Skeleton 179 extracted with dichloromethane (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 1.0 g of a crude yellow solid (quantitative yield), which was unstable and thus used immediately without purification. IR (film): 2954, 1735, 1595, 1506, 1484 cm1. 'H NMR (300 MHz, CDC13): 5 7.02 (S, IH), 6.64 (s, IH), 5.96 (s, 2H), 3.62-3.54 (m, 2H), 3.28-3.15 (m, IH), 2.58-2.50 (m, 211), 1.97-1.53 (m, 8H). l-(5-cyclopentylidene-7,8-dihydro-[l,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2,2-trifluoroethanone (3.57) To a solution of crude imine 3.56 (1.0 g, 4.2 mmol) in 40 mL of dichloromethane at 0 °C was added triethylamine (1.2 mL, 8.4 mmol), followed by trifluoroacetic anhydride (1.2 mL, 8.4 mmol). After stirring the reaction mixture for 20 min, it was poured into a saturated sodium bicarbonate aqueous solution (50 mL). The aqueous portion was extracted with dichloromethane (3 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate and hexanes led to the isolation of 1.3 g of white powder-like crystals (93 %). Semipinacol Approaches to the Erythrina A lka lo id Skeleton 180 mp: 122-124 °C IR (film): 3440, 2958, 1697, 1505, 1485, 1205 cm1. 'H NMR (300 MHz, CDC13): 0 6.95 (s, IH), 6.81 (s, IH), 6.57 (s, IH), 6.56 (s, IH), 5.94-5.90 (m, 4H), 4.64 (ddd, / = 2.7, 7.1, 12.5 Hz, IH), 4.21 (dd, / = 5.6, 13.6 Hz, IH), 3.63 (ddd, / = 5.3, 11.1, 13.4 Hz, IH), 3.34-3.22 (m, IH), 3.09 (ddd, / = 6.4, 12.3, 16.9 Hz, 2H), 2.86-2.21 (m, 10H), 1.97-1.80 (m, 2H), 1.78-1.58 (m, 6H). 13C NMR (75 MHz, CDC13): 6 155.1 (dd, JC-F = 36, 257 Hz), 146.9, 146.9, 146.0, 145.7, 143.9, 142.3, 128.8, 127.7, 127.2, 126.9, 125.9, 124.7, 116.7 (dd, JC-F = 38, 289 Hz), 108.7, 108.4, 107.6, 106.7, 101.2, 45.5, 45.0, 32.6, 32.1, 32.0, 31.8, 29.9, 27.4, 26.7, 25.7, 25.3. LRMS (EI) mlz (relative intensity): 340 (M+ + 2, 21), 339 (M+ + 1, 100), 338 (11), 311 (26), 270 (41), 243 (17), 242 (100). (3.53) To a mixture of 1.2 g of enamide 3.57 (3.5 mmol), 28 mL of a 0.5 M sodium bicarbonate aqueous solution, and 100 mL of dichloromethane was added 1.2 g of ;?i-chloroperbenzoic acid. After stirring the reaction mixture for 15 h, it was poured into 75 mL of a saturated sodium bicarbonate aqueous solution. The aqueous portion was extracted with dichloromethane (3 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Seriypiriacoi Approaches to the Erythrina A lka lo id Skeleton 181 Purification via flash column chromatography (1:17 ethyl acetate-hexanes) yielded 0.95 g of white solid (77%). mp: 127-130 °C. IR (film): 2955, 1681, 1487, 1254, 1162 cm1. ]H NMR (300 MHz, CDC13): 6 6.64 (s, 1H), 6.60 (s, 1H), 5.93 (dd, / = 1.2, 3.7 Hz, 2H), 4.84-4.69 (m, 111), 3.37-3.06 (m, 2H), 2.75 (d, / = 17.1 Hz, 1H), 1.93-1.75 (m, 4H), 1.73-1.48 (m, 4H). | lC NMR (75 MHz, CDC13): 6 1483, 146.3, 129.8, 125.8, 116.2 (q, JC-F = 286 Hz) 108.5, 104.9, 101.4, 74.7, 43.9, 30.1, 29.1, 27.6, 25.8, 25.5. LRMS (EI) mlz (relative intensity): 355 (M+ + 1, 9), 287 (14), 286 (70), 271 (13), 242 (16), 203 (13), 202 (100), 174 (15), 172 (10), 144 (13), 134 (12), 116 (24) 2,2,2-trifluoro-N-(2-(6-(l-hydroxycyclopentanecarbonyl)benzo[d][l,3]dioxol-5-yl)ethyl)acetamide (3.58) To a" solution of 37 mg of ytterbium(III) triflate (0.06 mmol) in 0.5 mL of dichloromethane at -78 °C was added a solution of 18 mg of epoxide 3.53 (0.05 mmol) in 1 mL of dichloromethane also at -78 °C. The reaction mixture was warmed to room temperature and stirred for 30 min prior to the addition of 3 mL of a saturated sodium bicarbonate solution. The aqueous portion was extracted with 3 x 4 mL of dichloromethane. The combined organic extracts were dried over sodium H Semipinacol Approaches to the Erythrina Alka lo id Skeleton 182 sulfate, filtered, and reduced in vacuo. Purification via flash column chromatography led to the isolation of 12 mg of white solid (67%). mp: 103-106 °C. IR (film): 3252, 3078, 2930, 1718, 1635, 1608/ 1488 cm1. 'H NMR (300 MHz, CDC13): b 8.88 (s, IH), 6.88 (s, IH), 6.76 (s, IH), 6.55-6.50 (m, IH), 6.02 (s, 2H), 3.56 (dd, / = 4.7, 11.4 Hz, 2H), 2.83-2.75 (m, 2H), 2.74-2.66 (m, 2H), 2.65-2.57 (m, 2H). 13C NMR (75 MHz, CDC13): 6 195.8, 157.8 (q, JC-F = 37 Hz), 151.3, 150.1, 146.2, 145.8, 132.8, 132.6, 114.1 (q, JC-F = 247 Hz), 110.4, 109.4, 102.0, 42.2, 34.6, 31.3, 30.7, 23.1. LRMS (EI) mlz (relative intensity): 355 (M+ + 1, 10), 242 (12), 230 (17), 229 (100), 201 (17). N-(3,4-methylenedioxyphenethyl)cyclobutanecarboxamide (3.60) To a solution of amine 3.54 (2.9 g) in 40 mL of dichloromethane was added 4.09 g of 1,3-dicyclohexyldicarbodiimide (19.8 mmol) and 242 mg of 4-(dimethylamino)pyridine (1.98 mmol). Upon cooling the mixture to 0 °C, cyclobutanecarboxylic acid was added in 20 mL of dichloromethane. After stirring the reaction mixture for 12 h at rt, the resulting precipitate was removed by filtering though a celite pad with dichloromethane. Recrystallization from ethyl acetate and hexanes yielded 2.11 g of white crystals (95%). Sernipihacol Approaches to the Erythrina Alkaloid Skeleton 1.83 mp: 114-115 °C. IR (film): 3290, 2932, 1636, 1246 cm1. 'H NMR (300 MHz, CDC13): 6 6.75 (d, / = 7.8 Hz, l.H), 6.67 (d, / = 1.8 Hz/1H), 5.94 (s, 2H), 5.34 (br s, 1H), 3.45 (dd, / = 12.8, 6.9 Hz, 2H), 2.93 (p, / = 8.7 Hz, 1H), 2.72 (t, / = 6.9 Hz, 2H), 2.31-2.04 (m, 4H), 2.02-1.79 (m, 2H). 13C NMR (75 MHz, CDC13): 6 175.1, 147.9, 146.2, 132.9, 121,7, 109.2, 108.4, 101.2, 40.8, 40.0, 35.6, 25.4, 18.3. Anal, calcd. for C 1 4 H , 7 N 0 3 : C 68.00, H 6.93, N 5.66; found: C 68.40, H 7.17, N 5.93. 5-cyclobutyl-7,8-dihydro-[l,3]dioxolo[4,5-g]isoquirtoline (3.61) A solution of 2.0 g of amide 3.60 (8.0 mmol), 150 mL of dichloromethane, and 3 mL of phosphorus oxychloride (32 mmol) was heated to reflux for 12 h. Upon cooling, the reaction mixture was poured into 100 mL of water. A 3 N sodium hydroxide aqueous solution was added until the mixture tested basic (pH -10). The aqueous portion was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 1.8 g of a crude orange solid (quantitative yield), which was subsequently used without purification. IR (film): 2938, 1634, 1598 1487, 1382 cm1. 'H NMR (300 MHz, CDCI3): 6 6.78 (s, 1H), 6.58 (s, 1H), 5.88 (s, 2H), 3.58 (t, / = 7.8 Hz, 2H), 3.47-3.60 (m, 1H), 2.52 (t, / = Semipihacoi. Approaches to the Erythrina Alka lo id Skeleton 184 7.3 Hz, 2H), 2.33-2.11 (m, 4H), 2.06-1.89 (m, IH), 1.88-1.65 (m, IH). 13C NMR (75 MHz, CDC13): 6 168.0 148.7, 146.4, 133.4, 122.6, 108.0, 105.7, 101.2, 47.1, 39.9, 35.0, 26.5,18.2. LRMS (ESI) mlz (relative intensity): 231 (M+ + 1,100). l-(5-cyclobutylidene-7,8-dihycbo-[l,3]cUoxolo[4,5-g]isoquinolin-6(5H)-yl)-2,2,2-trifluoroethanone (3.62) To a solution of crude imine 3.61 (1.6 g, 7.0 mmol) in 70 mL of dichloromethane at 0 °C was added Methylamine (2.0 mL, 14 mmol), followed by tiifluoroacetic anhydride (2.0 mL, 14 mmol). After stirring the reaction mixture for 20 min, it was poured into a saturated sodium bicarbonate aqueous solution (80 mL). The aqueous portion was extracted with dichloromethane (3 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (1:17 ethyl acetate-hexanes) yielded 2.12 g of white crystals (93%). mp: 99-101 °C. IR (film): 2915, 1699, 1682, 1505, 1485 1151 cm1. 'H NMR (300 MHz, CDCL): 6 6.77 (s, IH), 6.63 (s, IH), 6.59 (s, IH), 6.58 (s, IH), 5.94 (s, 2H), 5.94 (s, 211), 4.77 (dd, / = 5.8, 11.8 Hz, IH), 3.92 (br s, 2H), 3.30-2.88 (m, 8H), 2.82-2.57 (m, 411), 2.09 (dt / = 8.3, 15.4 Hz, 4H). 13C NMR (75 MHz, CDC13): 6 154.7 (dd, JC-F = 36, 291 Hz), 147.1, 146.8, 146.5, 146.0, 139.4, 139.1, 126.9, 126.2, 126.1, 126.0, 125.1, 124.2, Semipinacol Approaches to the Erythrina Alka lo id Skeleton 185 116.6 (del, JC-F = 34, 289 Hz), 109.0, 108.6, 105.9,105.5, 101.3, 101.2, 45.3,45.2,45.0, 32.3, 32.3, 31.6, 30.9, 30.2, 28.3, 18.0. LRMS (ESI) mlz (relative intensity): 326 (M+ + 1,100). To a solution of 2.1 g of enamide 3.62 (6.5 mmol) and 9.0 g of potassium carbonate (65 mmol) was added 320 mL of a 0.05 M solution of dimethyldioxirane (13 mmol) in acetone at -78 °C. The reaction mixture was warmed to rt and stirred for 12 h prior to the addition of saturated sodium chloride aqueous solution. Extraction was performed with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Dichloromethane (30 mL) was immediately added to the isolated crude epoxide 3.59 and the solution was cooled to -78 °C prior to its addition to a solution of ytterbium triflate (4.8 g, 7.8 mmol) in 20 mL of dichloromethane also at -78 °C. The reaction mixture was warmed to rt and stirred for 2 h prior to the addition of 30 mL of a saturated sodium chloride aqueous solution. Extraction was performed with three 20 mL portions of dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Purification via flash column chromatography led to the isolation of compounds 3.62 (clear colourless oil; 298 mg, 14%), 3.63 (clear colourless oil; 132 mg, 12%), and 3.65 (white solid; 773 mg, 57%). Sernipiftacol Approaches to the Erythrina Alka lo id Skeleton 186 (3.63) IR (film): 2951, 1781, 1505, 1488, 1367 cm1. ]H NMR (300 MHz, CDCfe): 5 6.86 (s, 1H), 6.68 (s, 1H), 5.97 (s, 2H), 3.77-3.70 (m, 2H), 3.07-2.96 (m, 2H), 2.65-2.51 (m, 411), 2.14-1.98 (m, 1H), 1.96-1.78 (m, 1H). 13C NMR (75 MHz, CDCb): 6 162.4, 147.3 (d, /G-F = 39 Hz) 149.1, 146.0, 134.7, 118.6, 114.3 (q, J C - F = 286 Hz), 108.5, 106.3, 101.5, 87.7, 47.5, 32.6, 26.3, 14.1. LRMS (EI) m/z (relative intensity): 241 (M+ + 1, 18), 244 (13), 229 (17), 228 (100), 69 (19). mp: 129-130 °C. IR (film): 2920, 1749, 1682, 1506, 1489 cm1. 5H NMR (300 MHz, CDC13): 6 6.65 (s, 1H), 6.48 (s, 1H), 5.94 (dd, / = 1.4, 9.4 Hz, 2H), 3.98-3.88 (m, 111), 3.60 (ddd, / = 3.4, 9.0, 12.3 Hz, 1H), 3.07-2.89 (m, 1H), 2.86 (dd, / = 7.6, 9.5 Hz, III), 2.76 (ddd, / = 3.1, 6.3,15.3 Hz, 1H), 2.68-2.43 (m, 2H), 2.40-2.24 (m, 2H), 2.13-1.95 (m, 1H). 13C NMR (75 MHz, CDC13): 6 213.2, 147.2, 147.1, 129.1, 128.8, 114.6 (q, JC-F = 270 Hz), 108.8, 105.7, 101.5, 69.6, 38.3, 36.1, 30.0, 18.7. LRMS (EI) m/z (relative (3.64) 1.87 intensity): 341 (M+ + 1, 41), 313 (24), 286 (10), 285 (70), 284 (39), 283 (27), 245 (16), 244 (100), 217 (10), 216 (71), 189 (14), 188 (55), 172 (13), 102 (10). (3.65) To a solution of 34 mg of amide 3.64 (0.10 mmol) in 220 uL of water and 3 mL of methanol was added 72 mg of potassium carbonate (0.52 mmol). The mixture was heated to reflux for 30 min then reduced via rotary evaporation. Water (10 mL) was added and the aqueous solution was extracted with three 15 mL portions of dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate, filtered, and reduced in vacuo. Purification via flash column chromatography (3:2 ethyl acetate-hexanes) led to the isolation of 25 mg of white solid (quantitative). mp: 143-144 °C. IR (film): 3299, 2932, 1735, 1504, 1487, 1240, 1039 cm1. 'H NMR (300 MHz, CDC13): 6 6.56 (s, IH), 6.34 (s, IH), 5.88 (dd, / = 1.4, 8.3 Hz, 2H), 3.15-2.95 (m, 2H), 2.68 (t, / = 5.8 Hz, IH), 2.64-2.58 (m, IH), 2.43-1.96 (m, 5H). 13C NMR (75 MHz, CDCb): 6 216.8, 146.4, 146.2, 130.1, 129.8, 109.2, 106.0, 100.9, 66.5, 40.3, 39.4, 37.0, 30.2, 18.7. LRMS (GC) mlz (relative intensity): 245 (M+ + 1, 1), 217 (26), 190 (12), 189 (100), 188 (12). Sentipiftacoi Approaches to the Erythrirta A lka lo id Skeleton 188 (3.66) S0 2 Ph To a suspension of 206 mg of 3-(phenylsulfonyl)propionic acid (0.96 mmol) in dichloromethane at 0 °C was added a solution of 147 mg of amine 3.65 (0.60 mmol), 198 mg of 1,3-dicyclohexylcarbodiimide (0.96 mmol), and 8 mg of 4-(dimethylamino)pyridine (0.07 mmol) in 10 mL of dichloromethane. The reaction mixture was warmed to room temperature and after 12 h filtered through celite. The filtrate was reduced via rotary evaporation. Purification via flash column chromatography (1:1 ethyl acetate-hexanes) led to the isolation of 255 mg of white foam (96%). mp: 86-89 °C. IR (film): 3317, 2914, 2848, 1735, 1622, 1575 cm"1. 'H NMR (300 MHz, CDCh): 6 7.89 (d, / = 7.8 Hz, 2H), 7.68-7.60 (m, 1H), 7.55 (t, / = 7.6 Hz, 2H), 6.61 (s, 1H), 6.39 (s, 1H), 5.89 (d, / = 9.0 Hz, 2H), 3.74-3.61 (m, 1H), 3.58-3.40 (m, 2H), 3.39-3.26 (m, 1H), 3.09-2.61 (m, 5H), 2.55-2.29 (m, 2H), 2.25-2.04 (m, 2H), 1.97-1.80 (m, 1H). 13C NMR (75 MHz, CDCb): 6 214.7, 167.5, 146.9,146.8,139.2, 134.1, 130.3, 129.5, 128.8, 128.0, 108.6, 105.8, 101.4, 68.6, 52.0, 43.6, 39.0, 36.6, 30.2, 27.2, 18.7. LRMS (EI) mlz (relative intensity): 441 (M+ + 1, 4), 413 (31), 271 (10), 245 (22), 244 (100), 243 (11), 242 (14), 228 (18), 216 (29), 214 (14), 190 (52), 189 (13), 188 (10), 125 (15), 77 (17), 55 (34). S e m i p i n a c o l Approaches to the Erythrina Alkaloid Ske le ton / 189 (3.67) O H k so 2 Ph To a solution of amide 3.66 (353 mg, 0.80 mmol) in 20 mL of tetrahydrofuran at 0 °C was added a solution of lithium aluminum hydride (360 mg, 9.6 mmol) and aluminum trichloride (427 mg, 3.2 mmol) in 25 mL of diethyl ether. After 30 min, the reaction mixture was carefully quenched with a 10% ammonium hydroxide aqueous solution and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and reduced in vacuo. Purification via flash column chromatography (ethyl acetate) led to the isolation of 272 mg of white foam (79%). mp: 51-53 °C. IR (film): 3529, 2957, 1505, 1485 cm"1. 'H NMR (300 MHz, C D C L ) : 5 7.86 (d, / = 7.1 Hz, 2H), 7.68-7.47 (m, 3H), 6.64 (s, IH), 6.50 (s, IH), 5.84 (d, / » 1.2 Hz, 2H), 3.37 (td, / = 9.8, 10.6 Hz, IH), 3.22 (ddd, / = 5.9, 9.8, 15.4 Hz, IH), 3.14-3.01 (m, IH), 2.89-2.70 (m, 2H), 2.40 (t, / = 6.5 Hz, 2H), 2.37-2.30 (m, IH), 2.23-1.95 (m, 211), 1.94-1.42 (m, 7H). 1 3 C NMR (75 MHz, CDCb): 6 146.4, 145.9, 139.3, 133.8, 129.8, 129.7, 129.4, 128.1, 108.9, 107.6, 100.9, 80.2, 71.1, 54.1, 46.0, 41.6, 36.1, 34.0, 24.0, 21.7, 20.0. LRMS (EI) mlz (relative intensity): 429 (M+ + 1, 23), 428 (11), 412 (17), 411 (67), 384 (22), 358 (22), 289 (20), 288 (100), 247 (13), 246 (79), 245 (11), 244 (66), 242 (48), 231 (13), 230 (76), 228 (21), 216 (20), 214 (22), 200 (12), 189 (14), 77 (13). Seiia phacoi Approaches to the Erythrina Alkaloid Skeleton 190 (3.68) Oxalyl chloride (122 uL, 1.4 mmol) was added to a solution of dimethyl sulfoxide (199 uL, 2.8 mmol) in 2 mL of dichloromethane at -78 °C. "Next, a solution Of alcohol 3.67 (150 mg, 0.35 mmol) in 2 mL of dichloromethane was added. After 30 min, 0.8 mL of triethylamine was added. After an additional 30 min, the reaction mixture was warmed to 0 °C and quenched with a saturated sodium bicarbonate aqueous solution. The aqueous portion was extracted with dichloromethane and the combined extracts were washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and reduced via rotary evaporation. Purification via flash column chromatography (2:4 ethyl acetate-hexanes) led to the isolation of 144 mg of white foam (97%). mp: 114-116 °C. IR (film): 3063, 2960, 2922, 1739, 1505, 1487 cm1. 'H NMR (300 MHz, CDCb): 5 7.88 (d, / = 7.4 Hz, 2H), 7.61 (t, / = 7.0 Hz, 1H), 7.53 (t, / = 7.3 Hz, 2H), 6.49 (s, 1H), 6.24 (s, 1H), 5.82 (d, 2H), 3.16 (tdd, / = 7.2, 14.5, 29.4 Hz, 2H), 3.02-2.89 (m, 1H), 2.80-2.65 (m, 2H), 2.64-2.50 (m, 2H), 2.47-2.27 (m, 4H), 2.16-1.78 (m, 5H). 1 3 C NMR (75 MHz, CDCb): 6 219.7, 146.4, 146.2, 139.5, 133.8, 131.0, 129.4, 128.4, 128.2, 108.9, 105.9, 101.0, 71.0, 53.6, 47.9, 43.1, 38.7, 34.8, 26.9, 21.3, 18.2. LRMS (EI) mlz (relative intensity): 427 (M+ + 1, 2), 411 (24), 410 (17), 409 (61), 400 (23), 399 (74), 398 Semipinacol Approaches to the Erythrina Alkaloid Skeleton 191 (61), 268 (11), 258 (30), 240 (13), 231 (63), 230 (100), 228 (17), 216 (55), 214 (16), 212 (13), 203 (32), 188 (20), 77 (13). To a solution of 22 mg of amide 3.66 (0.05 mmol) in 2 mL of dimethyl Sulfoxide was added 13 mg of potassium hexamethyldisilazide (0.06 mmol) in 1 mL of dimethyl sulfoxide. The reaction mixture was stirred for 24 h at room temperature, and then quenched with water (5 mL). The aqueous portion was extracted with ethyl acetate (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Purification via flash column chromatography led to the isolation of 9 mg (white solid; 60%) of byproduct 3.69 (1:1 ethyl acetate-hexanes) and 5 mg (white solid; 33%) of byproduct 3.70 (ethyl acetate). mp: 168-171 °C. IR (film): 3321, 2927, 1749, 1626 1489 c m i ] H NMR (300 MHz, CDCb): 6 6.56 (s, IH), 6.24 (s, IH), 5.90 (d, / = 5.8 Hz, 2H), 4.48-4.20 (m, IH), 3.61-3.34 (m, IH), 3.08-2.53 (m, 5H), 2.51-2.15 (m, 3H), 2.07-1.53 (m, 2H), 1.47-0.96 (m, I I I ) . 1 3 C NMR (75 MHz, CDCb): 5 214.7, 172.1, 146.9, 146.6, 130.3, 129.0, 108.3, 106.7, 101.3, 66.4, 49.3, 46.0, 40.1, 39.2, 35.8, 34.1, 29.4, 29.2, 25.8, 25.4, 25.1. LRMS (EI) mlz (3.69) Sernifinacol Approaches to the Erylhriria Alka lo id Skeleton 192 (relative intensity): 299 (M+ + 1, 3), 271 (50), 256 (15), 244 (17), 243 (100), 242 (72), 230 (17), 228 (35), 215 (65), 214 (38), 190 (13), 189 (38), 188 (33). (3.70) o mp: 142-144 °C. IR (film): 3314, 2937, 1656, 1486 cm1. NMR (300 MHz, CDCb): 6 6.69 (s, IH), 6.48 (s, IH), 5.83 (dd, / = 1.0, 4.4 Hz, 2H), 4.25 (dd, / = 5.3,12.8 Hz, IH), 3.20 (d, / = 4.6 Hz, IH), 3.02-2.59 (m, 5H), 2.58-2.44 (m, IH), 2.29-2.00 (m, 311), 1.67-1.40 (m, 2H). 13C NMR (75 MHz, CDCb): 5 173.9 (Q), 146.6 (Q), 146.0 (Q), 128.5 (Q), 128.4 (Q), 109.0 (CH), 108.1 (CH), 101.1 (CH2), 86.2 (Q), 75.0 (Q), 45.1 (CH), 43.9 (CH), 43.1 (CH2), 35.8 (CH2), 31.1 (CH2), 29.2 (CH2), 25.8 (CH2). LRMS (EI) mlz (relative intensity): 300 (M+ + 2, 18), 300 (M+ + 1, 94), 270 (12), 245 (16), 244 (100), 243 (25), 242 (14), 174 (14). To a solution of 21 mg of sulfone 3.68 (0.05 mmol) in 1 mL of dimethyl sulfoxide was added a solution of potassium hexamethyldisilazide in 2 mL of (3.72) OH SetHif fnacol Approaches to the,Erythrina Alka lo id Skeleton 193 dimethyl sulfoxide. The reaction mixture was heated to 50 °C for 4 h, then quenched with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and reduced in vacuo. Purification via flash column chromatography led to the recovery of 2 mg (white solid; 10%) of sulfone 3.68 (2:3 ethyl acetate-hexanes) in addition to the isolation of 11 mg (white solid; 50%) of byproduct 3.72 (3:2 ethyl acetate-hexanes). mp: 88-90°C. IR (film): 3360, 2923, 1708, 1487 cm"1. *H NMR (300 MHz, CDCb): 6 7.91 (d, / = 7.2 Hz, 2H), 7.65 (t, / = 7.4 Hz, 1H), 7.56 (t, / = 7.4 Hz, 2H), 6.72 (t, / = 3.1 Hz, 1H), 6.53 (s, 1H), 6.31 (s, 1H), 5.86 (dd, / = 1.3, 11.6 Hz, 2H), 3.25-3.08 (m, 3H), 2.84-2.61 (m, 5H), 2.57-2.45 (m, 1H), 2.38-2.28 (m, 1H), 1.91 (td, / = 7.0, 14.0 Hz, 2H). 13C NMR (75 MHz, CDCb): 6 205.1, 152.9, 146.8, 146.7, 139.4, 133.8, 130.3, 130.0, 129.4, 128.5, 128.1, 108.7, 104.2, 101.1, 67.5, 53.7, 48.3, 44.0, 38.0, 29.8 20.9. LRMS (EI) mlz (relative intensity): 442 (M+ + 1, 11), 441 (41), 425 (11), 423 (18), 414 (12), 413 (37), 412 (100), 397 (35), 272 (27), 258 (10), 256 (18), 244 (20), 242 (14), 230 (45), 229 (54), 226 (10), 216 (11), 214 (24), 212 (10), 200 (11), 183 (11), 77 (12). (3.73) To a solution of 5 mg of lithium hexamethyldisilazide (0.030 mmol) in 1 mL of tetrahydrofuran at -78 °C was added 11 mg of sulfone 3.68 (0.025 mmol) in 2 mL of SeitiipTnacol Approaches to the Erythrina Alka lo id Skeleton- 194 tetrahydrofuran at -78 °C. After stirring the reaction mixture at -78 °C for 45 min, it was quenched with 0.5 mL of deuterium oxide and allowed to warm to room temperature. A saturated aqueous solution of ammonium chloride was added (5 ml) and the aqueous phase was extracted with ethyl acetate (3x5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and reduced via rotary evaporation. Purification via flash column chromatography (2:3 ethyl acetate-hexanes) led to the isolation of 10 mg of white solid (93%). 'H NMR (300 MHz, CDCb): 6 7.89 (d, / = 7:2 Hz, 2H), 7.61 (t, / = 7.3 Hz, 1H), 7.53 (t, / = 7.4 Hz, 2H), 6.49 (s, 1H), 6.23 (s, 1H), 5.83 (dd, / = 10.3, 1.0 Hz, 2H), 3.72-3.03 (m, 2H), 3.01-2.90 (m, 1H), 2.79-2.65 (m, 2H), 2.64-2.51 (m, 2H), 2.46-2.27 (m, 3H), 2.17-1.80 (m, 5H). •mipihacol Approaches to tine Erythrina Alka lo id Skeleton 7 Selected Spectra Semipinacol Approaches to the Erythrina Alkaloid Skeleton 3.49: Semipinacol Approaches to the Erythrina A lka lo id Skeleton Seriiifinacol Approaches to the Erythrina Alka lo id Skeleton 3.58: H ~\" i i i — | — i — i i — i — | i i i i | i i" i — i — | i TI i i | i i i i | i i i i | i i i i | i m i | 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 SeretpTnacol Approaches to the Erythrina Alka lo id Skeleton 3.64: 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 4iii)li.6 3600 3200 2800 2400 2000 1S0O I600 1400 1200 1000 800 600.0 Semipinacol Approaches to the Erythrina Alka lo id Skeleton 3.8 X -Ray C r y s t a l l o g r a p h i c D a t a Table 3.7 Crystallographic Data for 3.69 (3.69)a Formula Q7H17NO4 FW 299.32 Colour, habit colourless, irregular Crystal size, mm 0.08 x 0.10 x 0.25 Crystal system monoclinic Space group P 2i/c (#14) a, A 12.2587(6) b, A 7.7866(4) c, A 14.4970(6) deg 102.943(2) V, A 3 1348.6(1) Z 4 Dcaic, g/cm3 1.474 F(000) 652.00 (a(MoKa), cm-' 1.06 transmission factors 0.866 - 0.992 28caAx, deg 56.0 total no. of reflns 28499 no. of unique reflns 3240 R (F2, all data) 0.064 Rw (F2, all data) 0.122 R (F, I >2o(I)) 0.046 Rw (F, I >2o(I)) 0.112 goodness of fit indicator 1.04 "X-ray crystallographic data was acquired using a Bruker X8 diffractometer. For more information on data collection contact Dr. Brian Patrick, Manager of the X-Ray Crystallographic Services at the University of British Columbia. Sernipfnacol Approaches to the Erythrina Alka lo id Skeleton 219 3.9 References (1) Chawla, A. S.; Kapoor, V. K. In The Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: 1995, p 86-153. (2) Folkers, K.; Major, R. T. /. Am. Chem. Soc. 1937, 59, 1580-1581. (3) http://www.cas. vanderbilt.eduA?ioimages/image/e/ercr6-flinflorl0876.htm; accessed 2006. (4) http://www.myamaca.edu/ohweb/Australia%20Photos/Melbourne%20 Photos.asp; accessed 2006. (5) http://wc.pima.edu/~bfiero/tucsonecology/plants/shrubs_scbe.htm; accessed 2006. (6) Deulofeu, V. In Curare and Curarelike Agents; Bovet-Nitti, F., Mariru-Bettolo, G. B., Eds.; Elsevier: Amsterdam, 1959, p 163-169. (7) Craig, L. E. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1955; Vol. 5, p 265-293. (8) Maier, U. H.; Rodl, W.; Deus-Neumann, B.; Zenk, M. H. Phytochemistry 1999, 52, 373-382. (9) Wasserman, H. PL; Amici, R. M. /. Org. Chem. 1989, 54, 5843-5844. (10) Wasserman, H. PL; Fukuyama, J.; Murugesan, N.; van Duzer, J.; Lombardo, L.; Rotello, V.; McCarthy, K. /. Am. Chem. Soc. 1989, 212, 371-372. Semipinacol Approaches to the Eri/lhrma Alkaloid Skeleton 220 (11) Tamura, Y.; Maeda, H.;. Akai, S.; Ishiyama, K.; Ishibashi, H. Tetrahedron Lett. 1981,22, 4301-4304. (12) Tamura, Y.; Maeda, H.; Akai, S.; Ishibashi, H. Tetrahedron Lett. 1982, 23, 2209-2212. (13) Ishibashi, H.; Sato, K.; Iked, M.; Maeda, H.; Akai, S.; Tamura, Y. /. Chem. Soc, Perkin Trans. 1 1985, 605-609. (14) Padwa, A.; Hermig, R.; Kappe, C. O.; Reger, T. S. /. Org. Chem. 1998, 63, 1144-1155. (15) El Bialy, S. A.; Braun, H.; Tietze, L. F. Angew. Chem. Int. Ed. Engl. 2004,43, 5391-5393. (16) Lee, H. I.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 5067-5070. (17) Ito, K.; Haruna, M.; Furukawa, H. /. Chem. Soc. Chem. Comm. 1975, 681-681. (18) Tsuda, Y.; Sakai, Y.; Kashiwaba, N.; Sano, T.; Toda, J.; Isobe, K. Heterocycles 1981,16,189-189. (19) Iida, PL; Aoyagi, S.; Kohno, K.; Sasaki, N.; Kibayashi, C. Heterocycles 1976, 4, 1771-1775. (20) Ahmed-Schofield, R.; Mariano, P. S. /. Org. Chem. 1987,52, 1478-1482. (21) Ahmed-Schofield, R.; Mariano, P. S. /. Org. Chem. 1985, 50, 5667-5677. Semipinacol Approaches to the Ert/lhrhm Alka lo id Skeleton 22 (22) Cassayre, J.; Quiclet-Sire, B.; Saunier, J. B.; Zard, S. Z. Tetrahedron Lett. 1998, 39,8995-8998. (23) Miranda, L. D.; Zard, S. Z. Org. Lett. 2002,4,1135-1138. (24) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.; Muraoka, C; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42,1729-1732. (25) Westling, M.; Smith, R.; Livinghouse, T. /. Org. Chem. 1986,51,1159-1165. (26) Smith, R.; Livinghouse, T. /. Org. Chem. 1983,48,1554-1555. (27) Rigby, J. H.; Qabar, M. /. Am. Chem. Soc. 1991, 213, 8975-8976. (28) Rigby, J. H.; Deur, C.; Heeg, M. J. Tetrahedron Lett. 1999, 40, 6887-6890. (29) Dake, G. R.; Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. /. Org. Chem. 2004, 69,5668-5675. (30) Torisawa, Y.; Nakagawa, M.; Hosaka, T.; Tanabe, K.; Lai, Z.; Ogata, K.; Nakata, T.; Oishi, T.; Hino, T. /. Org. Chem. 1992, 57, 5741-5747. (31) Fluery, M. Master's Thesis, University of British Columbia, 2003. (32) Batra, S.; Sabnis, Y. A.; Rosenthal, P. J.; Avery, M. A. Bioorg. Med. Chem 2003, 11, 2293-2299. (33) Thomas, P. J.; Stirling, C. J. M. /. Chem. Soc. Chem. Comm. 1976, 829-830. (34) Snowden, R. L.; Brauchli, R.; Sonnay, P. Helv. Chim. Acta. 1989, 72, 570-593. (35) Molander, G. A.; Jeffrey, S. C. Tetrahedron Lett. 2002, 43, 359-362. (36) Loughlin, W. A.; Haynes, R. K.; Sitpaseuth, S. Aust. J. Chem. 1995,48, 491-503. Seriapiriacol Approaches to the Ert/thrirta Alkaloid Skeleton 222 i (37) Tsuda, Y.; Nakai, A.; Ito, K.; Suzuki, F; Haruna, M. Heterocycles 1984, 22, 1817-1820. (38) Trost, B. M.; Neilsen, J. B.; Hoogsteen, K. /. Am. Chem. Soc. 1992, 114, 5432-5434. 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0059832/manifest

Comment

Related Items