The Development of New Oxabicyclic-Based Strategies for the Stereo- and Enantioselective Synthesis of Azepines, Thiepines and Thiocines, Polysubstituted Decalins and Related Fused Polycycles
by
Eric Fillion
A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Chemistry University of Toronto
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The synthesis and investigation of the reactivity of dioxatetra- and pentacycles, as weil as hetero-oxabicycles were the overall objectives. The utility of these rigid templates in the development of new enantio- and stereoselective synthetic strategies toward seven- and eight- membered nitrogen and sulfur heterocycles, polysubstituted decalins and related fused polyc ycles was defined.
The fnst objective was to explore the scope of the tandem "pincer" Diels-Alder reaction. consisting of two consecutive [4+2] cycloadditions between two equivalents of furan denvatives and an acetylenic bis-dienophile for the rapid construction of bndged polyoxacyclic ring systems. We have addressed the issues of regio-, chemo- and stereocontrol in the tandem Diels- Alder reac tion.
Subsequent to the successful synthesis of dioxacyclic compounds, the second objective was to study the flexibility and limitations of the sequential ring opening process. A chemo-, regio- and stereocontrolled methodology for the simple and efficient synthesis of a large variety of cis-decalins and related fused polycyclic systems, based on the sequential ring opening of dioxacyclic ternplates is reported.
Our third objective, the base-promoted desymmetrization of rneso aza[3.2.l]oxabicyclic and thia[3.2.1] and [3.3.l]oxabicyclic compounds, has been exploited to give enantioenriched azepines. thiepines and thiocines. The regioselective openhg of unsyrnmevical hetero- oxabicyclic compounds as well as the mechanism of deprotonation have also ken iovestigated.
Finally, we have briefly studied the intramolecular anionic ring opening of oxabicyclo[2.2.1] systems as a route to tram-hised bicyclo[4.3.0]nonenes. The Development of New Oxabicyclic-Based Strategies for the Stereo- and Enantioselective Synthesis of Azepines, Thiepines and Thiocines, Polysubstituted Decalins and Related Fused Polycycles
Ph. D., 1998 Eric Fillion, Department of Chemistry, University of Toronto
Abstract
The development of new oxabicyclic-based enantio- and stereoselective synthetic strategies are described in this thesis. Their synthetic potential, vesatility and flexibility were demonstrated by the preparation of seven- and eight-membered nitrogen and sulfur heterocycles, polysubstituted decalins and related fused polycycles.
In Chapter 1, the tandem "pincer" Diels-Alder reaction, consisting of two consecutive [4+2] cycloadditions between two dienes and an acetylenic bis-dienophile was applied toward the rapid construction of bndged polyoxacyclic ring systems when furan derivatives are used as the diene components. The smdy has demonstrated the stereoselectivity (exu-exo adduct), the chemoselectivity ("pincer" vs "domino") as well as the regioselectivity of the reaction. The reaction has been successfully applied to a variety of 2-substituted funns and tethered bis- furans in combination with monoactivated and diactivated dienophiles.
Chapter 2 describes a chemo-, regio- and stereocontroiied methodology for the simple and efficient synthesis of a large variety of cis-decalins and related fused polycyclic systems with conîrol at up to six stereocenters, based on the sequential ring opening of dioxacyclic templates. We have established that the most useful feanire of the reactivity of the dioxacyclic iv compounds is that the first ring opening reaction is significantiy faster than the second allowing the sequential transformation of the oxabicyclic moieties. The fiexibility of the sequential ring opening process and its limitations have been dernonshated and a new enantioselective mode of opening was reported.
The base-promoted desymmetrization of meso aza[3.2.l]oxabicyclic and thia[3.2. Il and oxa[f.3. l ]bicyciic compounds has been expioited in Chapter 3 to give enantioenriched azepines, thiepines and thiocines. The regioselective opening of unsy mmetrical aza[3.2.l]oxabicycli~and thia[3.2.1] and [3.3.l]oxabicyclic compounds bearing a methyi substituent at the bndgehead as wel1 as the mechanism of deprotonation have also been inves tigated.
In Chapter 4, we have briefly studied the intramoiecular anionic ring opening of oxabicyclo[2.2.1] systems as a route to bicyclo[4.3.0]nonenes which are tram fused. The influence of the Iength of the dl-carbon tether on the cyciization has been investigated. Cyclization of the 2-carbon tether substrate via an unexpected s~2endo anack gave access to the spiro f5.2.01 skeleton. Stabiiïzed anions have dso been successfully cyclized. Acknowledgements
1 would Lke to thank Professor Mark Lautens for his guidance and advice throughout the course of this work. His support and encouragement in the pursuit of my goals contributed to my personal and professional e~chrnent.1 greatly appreciated the opportunities 1had to mvel aqd present my research during my studies.
This thesis would not be possible without the friendship, guidance and support of a number of colleges: Yi Ren, John Colucci, Tom Rovis, James Blackwell, Renee Aspiotis, Christophe Meyer, Greg Hughes, Graham Meek, Dennis Ostrovski, Shawn Johnstone. Their interest in research, advice and constructive comments conmbuted to the excellent spirit in the laboratory. 1speciaily thank the summer students Michael Sarnpat and Shahia Yekta.
Je ne peux m'empêcher de souligner de façon toute spéciale le soutien constant de Sophie. Son énergie, son sourire et sa tenacité ont rendu l'impossible plus que possible. le remercie également tout les membres de ma famille pour leur encouragement et soutien au cours de mes études.
The technical assistance of Nick Plavac, Dr. AIan Lough, Dr. AIex Young and Dr. Tim
Burrows was greatly appreciated. The "Fonds pour la formation de Chercheurs et l'aide a la Recherche" (FCAR), the Govemment of Ontario and the University of Toronto are thanked for frnancial support.
I finaiiy would like to extend my thanks and appreciation to the members of the examination cornmittee: Prof. G. S. Espie, Prof. T. T. Tidwell, Prof. M. Lautens, Prof. R. A. Batey, Prof. A. G. Faiiis, Prof. D. G. B. Boocock and Prof. J. B. Jones. À mes parents, Lierte et Luc
À Sophie vii
TABLE OF CONTENTS
Objectives ll ... Abs trac t u
Acknowledgements v Dedication vi
Table of contents vii List of abbreviations xii List of appendices xv
INTRODUCTION
9 1 Synthetic Strategies Based on [2.2.l ]oxabicycles 5 2 Synthetic Strategies Based on [3.2.l]oxabicycles 9 3 Medium-Sized Oxygen Heterocycle Synthesis Using Oxabicycles
§ 4 References and Notes
CaAfTER 1. STEREOSELECTIVE CONSTRUCTION OF BRIDGED POLYHETEROCYCLIC RING SYSTEMS USING THE TANDEM "PINCER" DIELS-ALDER REACTION
5 1.1 Introduction 5 1.1.1 Background $1.1.2 Historicd Lnforrnation 5 1.2 Results and Discussion 9 1.2.1 Preparation of the Dienes 9 1.2.2 Preparation of the Acetylenic Unsyrnmetncal Bis-Dienophiles 1.2.3 Synthesis of the Oxa and Azanorbomadiene Type Adducts 9 1.2.4 Study of the Tandem "Pincer" Diels-Aider Cycloaddition 9 1.2.5 Surnmary 8 1.3 Experimental Section L3.1 Generai Experimental 9 1.3.2 Solvents and Reagents 8 L3.3 B is-Furan Preparation L3.4 Preparation of the Acetylenic Dienophiles
§ 1.3.5 Preparation of the Azanorbomadiene Type Adduct 9 1.3.5 Tandem "Pincer" Diels-Alder Cycloaddition S 1.4 References and Notes
CHAPTER 2. EXPLORING THE REACTIVITY OF DIOXACYCLIC COMPOUNDS AS A ROUTE TO POLYSUBSTITUTED DECALINS
AND FUSED POLYCYCLES 78
5 11.1 Introduction 79 5 11.2 Results and Discussion 83 5 K2.1 Substrate Preparation 83 $ II.2.2 Unsubstituted Dioxatetracycle Nucleophilic Ring Opening 86 3 II.2.3 Substituted Dioxatetracycle Ring Openhg 89 8 II.2.4 Azaoxatetracycle and Unsymmetrical Dioxacycles Nucleophilic Ring Opening 92 9 II.2.5 Dioxapentacycle, Trioxapentacycle, and Azadioxapentacycle Ring Opening 95 8 II.2.6 Enan tioselec tive Desy mme trimiion. Thiadioxapentacycle and Azadioxapentacycle Base-Induced Ring Opening 10 1 9 IT.2.7 Surnmary 104 6 11.3 Experimental Section 105 5 11.3.1 Solvents arid Reagents L05 5 I1.3.2 Substnte Preparation f 05 5 II.3.3 Sequential Ring Opening Study 123 5 11.4 References and Notes 153
CHAPTER 3. BASE-INDUCED RING OPEMNG OF AZA- AND TU- OXA[3.2.1] AND [3.3.1]BICY CLES AS AN ENANTIOSELECTIVE AND STEREOSELECTIVE APPROACH TO AZEPINES, THIEPINES AND THIOCINES 156
5 111.1 Introduction 157 5 III. 1.1 Monocyclic Medium Ring Heterocycles Synthesis 157 $ III. 1.2 Enantioselective Desymmetrization of Oxabicyclo[2.2. 11 and f3.2.11 Substrates, and Tropinone 165 8 III. 1.3 Base-Induced Oxabicyclo[2.2.1] and [3.2.1] Substrates Ring Opening 169 8 111.2 Results and Discussion 17 1 5 III.2.1 Symmetrical Substrate Preparation 171 8 III.2.2 Unsymmeaical Substrate Preparation 175 § m.2.3 Enantioselective Based-Induced Ring Opening Smdy 176 5 III.2.4 Regioseiective Based-Induced Ring Opening Study 182 9 III.2.5 Mechanism of Deprotonation 184
§ m.2.6 Vinylsulfide Oxidation 190
$ m.2.7 Sumrnary 190 5 III.3 Experimental Section $ DI.3.1 Solvents and Reagents 3 lII.3.1 Substrate Preparation m.3.2 Deprotonation Study
§ 111.4 References and Notes
CHAPTER 4. ANIOMC INTRAMOLECULAR RING OPENING OF OXABICYCLO[2.2.1] COMPOUNDS
5 IV.1 Introduction 3 IV.2 Results and Discussion 5 W.2.f Preparation of the Furan Derivatives 5 N.2.2 Preparation of the [2.2.l]Oxabicycles 5 N.2.3 Cyclization Studies 5 rV.2.4 Summary 5 1.3 Experimental Section $ IV.3.1 Solvents and Reagents 5 IV.4 References and Notes
APPENDIX 1 SELECI23 SPECTRA OF REPRESENTATIVE COMPOUNDS 260
Seiected Spectra fmm Chapter 1 26 1 Selected Spectra from Chapter II 266 Selected Spectra form Chapter III 285
Selected Spectn fom Chapter TV 295 APPENDIX 2 X-RAY CRYSTAL DATA FOR COMPOUND 107,109,131, 169, and 181 302 Single Crystal X-Ray Detemination of 107 303
Single Crystai X-Ray Determination of 109 3LI
Single Crystal X-Ray Determination of 131 3 18 Single Crystai X-Ray Determination of 169 330
Single Crystd XRay Determination of 181 34 1 List of Abbreviations
[a?~ specific rotation measured at 589 nm Ac acetyl
acac acetylacetonate, or 1 &pentanedionate AIBN 2-2'-azobisisobutyronitrile Anal. analysis BINOL 1.1'-bi-Znaphthol Bn benzyi BOC teri-butoxycarbonyl calcd caicuiated CP* pentamethylcyclopentadieny 1 COD 1.5-cyclooctadiene CSA camphorsulphonic acid dba nans, nam-dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Dm dihydrop yran dr diastereoisorneric ratio DIBAL-H diisobuty ialuminum hy dride DIPHOS dipheny lphosphinoethane DMAD dimethyl acetylenedicarboxylate DMAP 4-(dimethy1amino)pyndine DMF dime thyifonnamide DMSO dimethylsulfoxide dppb diphenylphosphinobutane E generic ester group enantiomeric excess equiv. equivdent FT Fourier transform
GC gas chromatography HMPA hexarnethylphosphoric triamide HRMS high resolution mass spectrum i-B u isobutyl IpqBH düsopinocampheylborane IR infiared KHDMS potassium bis(trimethylsilyl)amide
LDA lithium düsopropyl amide LiHMDS lithium bis(trimethylsilyl)amide L-Seleceride lithium tri-sec-butyl borohydride LW lithium tetramethylpiperidide m-CPBA metashioroperoxybenzoic acid Me me thyi MOM methoxy methy l MOP 2-methoxy-2'-dipheny Iphosphino- 1,l'-binaphthy 1 mE' melting point Mi mesyl, rnethanesulfony 1 MTPA a-methoxy-a-trifluoromethylphenylaceticacid n-Bu n-buyt MM0 4-methylmorpholine N-uxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect P generic protecting group PCC pyridinium chiorochromate PDC pyridinium dichromate Ph phenyl PMI3 para-me thoxy benzyl PMI' para-methoxypheny 1 PPTS pyridiniurn p-toluenesulfonate FY= pyridine R generic group s-B u sec- bu tyl rt room temperature T temperature TBAF tetrabutyIarnmonium fiuoride TBDMS tert-buty idime thy lsilyl t-B u tert-butyl Tf trifluoromethanesulfony1 THF iecrahydro furan THP tetrahydropyran TLC thin layer chromatography TMEDA tetrarnethylethylene diamine TMS trime thylsily 1 TPP 5,10,15,20-tetraphenyl-2IH, 23H-porphine Ts p-toluenesulfony 1 X generic halogen atom List of TabIes
Table 1.1 Unsy metrical "Pincer"[4+2] Cycloadducts Table 1.2 "Pincer"[4+2] Cycloaddition
Table 2.1 Dioxatetracyclic Substrate Preparation Table 2.2 Dioxapentacyclic Substrate Preparation Tabie 2.3 Nucleophilic ring opening of 127, Temperature Effect Table 2.4 Nucleophiiic ring opening of 155
Table 3.1 Monocyclic Medium-Sized Heterocycle Nomenclam Table 3.2 Enantioselective Desymrneüization Table 3.3 LiCl Effect on the Deprotonation of 274 Table 3.4 Regioselective Base-Induced Ring Opening INTRODUCTION 2 The synthetic utility of stereochemically well-defined oxabicyclo[2.2.1] and l3.2.11 systems has been dernonstnted by their abiIity to be transformed and further ring-opened with high stereocontrol to n wide variety of cyclic and acyclic products containing multiple stereocenters. Other types of oxabicycles have also been exploited in synthesis. The publication of many articles and reviews in the last few years reflects the growing interest for the utilization of oxabicyclic templates in organic synthesis. l2
The use of oxabicyclic templates as synthetic precursors generally involves the cleavage of one or more bonds to access cyclic or acycIic units. Various regio- and stereoselective ring opening process of oxabicyck [2.2.1] systems have been developed.2 The fragmentation strategies cm be classified based on the choice of the bridge which is broken. As shown in Figure 1, the cieavage of either of the two carbon bridges leads to substituted tetrahydrofuran derivatives with high stereocontrol. CIeavage of the bridging ether has been applied to the synthesis of highly functionalized six-membered carbocycles.
Figure 1 Tetrahydrofuran derivatives Tetrahydrofuran derivatives
Six-membered carbocycles
Tetrahydrofuran derivatives Tetrahydropyran derivatives antkAldol synthons
The [3.2.1] oxabicyclic systems are particularly versatile and have been transformed into a large variety of synthetic intermediates and naturai products (Figure 1).2-3 Highly substituted tetrahydropyran derivatives could be accessed by cleavage of the two-carbon bridge. The cleavage of the three-carbon bridge was envisaged for the preparation of tetrahydrofuran derivatives and related anti-aldol synthons. Entry into seven-membered carbocycles have been accomplished via the cleavage of the bridging ether. The latter is also an alternative to the synthesis of anfi-aldol synthons. Each of these strategies have been described in the literature and used in the total synthesis of natural products or in the preparation of building blocks of synthetic interest. Some representative examples are discussed in the next sections.
8 1 Synthetic Strategies Based on [2.2.l]oxabicycles
Oxabicyclic [2.2.1] compounds have ken widely uiilized as precueors in many natural product syntheses. As mentioned above. two general types of structure could be derived from the ring cleavage of oxabicyclic [2.2.1] systems, namefy six-membered carbocycles and tetrahydrofuran derivatives. The most efficient and used method to access 7- oxabicyclo[2.2. llheptenes is the Diels-Alder reaction of furan with various dienophiles.2
Gasparini and Vogel reported the synthesis of C-glycosides and C-nucleosides of ribose starting from furan (Scheme 1)? The 7-oxabicyclo[2.2.1]hept-en-2-one 1 was prepared in an enantiomerically pure form from a Lewis acid catalyzed Diels-Aider by usinp a camphanate denvative as the chiral awulary. The latter was cleaved to give the ketone 1, which was protected as a ketal and epoxidized giving the intermediate 2. Regioselective opening of the epoxide 2 was reaiized by treatment with Li-, followed by protection of the resulting alcohol and deprotection of the ketone. The TBDMS en01 ether was prepared and ozonolized to give, after NaB& reduction, the desired tetrahydrofuran derivative 3. Condensation of the carboxylic acid 3 with 4.5-6-tnaminopynmidine afforded the C-nucleoside analog of cordycepine. Scheme 1
1) O3 2) NaBH4 /=N
I N&N~~
H oVo2' H2N
"O B n OBn 3 H"vNH cordycepin C
Evans and Barnes utilized the base-induced cleavage of the bndging ether of an oxabicycle [2.2.1] compound to accomplish the synthesis of ent-shikirnic acid (Scheme 2).5 The oxabicyclo[2.2.1] system 4 was accessed by the asymmetric Diels-Alder of furan cataiyzed by a chiral Lewis acid in excellent enantiorneric excess. After cleavage of the oxazolidinone moiety, the ester 5 was treated with a lithium amide base to induce the ether bridge disconnection and form the diene 6 after protection of the resulting dcohol. The enantiomer of the natural shikimic acid was obtained by selective dihydroxylation of the diene 6 and protecting groups removal. Scheme 2 O0 chiral u es O u
1) LiHMDS 2) TBDMSOTf
1) TBAF 0s04, NMO 2) TMSOK
en6stiikimic acid
5 2 Synthetic Strategies Based on [3.2.l]oxabicycles
As mentioned in the introduction, three general types of structure couId be denved from the ring cleavage of oxabicyclic [3.2.1] systems, namely seven-membered carbocycles. tetrahydrofuran and tetrahydropyran derivatives. It has aiso been demonstrated that the opening of oxabicyclic 13.2.1 1 systems is an alternative strategy to generate anti-aldol synthons. The 8-oxabicyclo[3.2.l]octene substrates are usuaily assembled by a [4 + 31 cycloaddition between furan derivatives and oxyaliyl cations.3
An approach to the synthesis of the tevahydropyran moiety of Pederin via cleavage of the two-carbon bridge of l3.2.11 oxabicycle has been reported by the group of Meinwald (Scheme 3).6 The dimethyl oxabicyclo[3.2.1] octenone template was prepared via a [4 + 31 cycloaddition between furan and the oxydyl cation of 1,3-dïbromo-3-methylbutan-2-one. After stereoselective reduction using L-Selectride reagent, the two carbon-bridge was cleaved 6 by ozonolysis. Treatment of the ozonide with Me2S afforded the tricyclic acetal-herniacetal7 as the major product. Chrorniurn oxide oxidation gave the tricyclic lactone 8 which was further cieaved under acidic conditions in methmol to yield the desired tetrahydropyran moiety 9.
Scheme 3
Pederin
Me02Cf,,.QH(OMe)2 MeOH, H+
4
OH O 9 8
Cleavage of the two-carbon bridge of oxabicycles [3.2.1] has also been used in the synthesis of acycles with control of multiple stereocenters. Rao and coworkers have reported the synthesis of the C-21 to C-27 segment of rifamycin (Scherne 4).7 Cycloaddition of furan and the oxyallyl action derived from 2,4-dibromopentan-3-one gave the dimethyl oxabicyclo[3.2. Iloctenone 10. Diastereoselective reduction of the oxabicyclic ketone was accomplished with DIBAL-H giving exclusively the endo-alcohol which was subsequently protected as its benzyl ether. Hydroboration of the bicyclic alkene followed by oxidation yielded the ketone 11. Baeyer-ViUiger oxidation of the latter afforded the key intemediate lactone 12 with high regioselectivity. Diastereoselective methylation of the lactone foilowed by LiAil& opening generated the C-2 1 to C-27 subunit of rifamycin. Scheme 4 Oh QBn
8'po.& 1) DIBAL-H G, - 1) BH3-THF 8 'P -
- 2) BnBr 2) H202, NaOH 3) PCC 10 = --@.'"H O
QE3n QBn
@ 'e, hHLiAIH4 LDA, Mel .d - 4 OH OH OBn C-21 to C-27 subunit of rifamycin O 12--Q O
Tetrahydmfuran uni& are frequently found in natural products, and could be obtained by the cleavage of the threecarbon bridge of oxabicyclo[3.3.1] systems. White and coworkers applied this strategy to the synthesis of nonactic a~id.~The synthesis started from the cycloadduct 10 which had been hydrogenated prior to the Baeyer-Villiger oxidation. The lactone 13 was obtained and fragmented by treatment with sodium methoxide providing the advance intermediate tetrahydrofuran 14. Further transformations were necessq to access the desired nonactic acid.
Scheme 5 B MeONa MeOH
nonactc acid The synthesis of functionalized seven-membered ring carbocycles by cleavage of the ether bond of oxabicyclic l3.2.11 ternplate was demonstrated in the synthesis of the pseudoguaianolide skeleton (Scheme 6).9 Once again. the dimethyl oxabicycle 10, after hydrogenation. was used as the starting material. The bicyclic ketone was first alkylated and the ether bridge was subsequentiy cleaved by treatrnent with Na1 or KI and BF3-0Et2 to form the bicyclic [5.3.0] lactone 15. Light-promoted [2+2] cycloaddition between the newly formed enone 15 and 2-trimethylsiloxybu ta- 1.3-diene gave the cyclobutanol intermediate 16. Palladium-induced rearrangement of the cyclobutanol moiety 16 produced the desired pseudoguaianolide skeleton.
Scheme 6
LDA
'** '** O PC~CI~(P~CN)~ - H H pseudoguaianolide skeleton 16
Lautens and Kumanovic have investigated the intraaolecular anionic ring opening of oxabicyclo[3.2. i ] systems as a route to bicyclo[S.3.0]decenes (Scheme 7). The generality of this methodology was dernonstrated by using a variety of tethered oxabicyclic molecules. The organolithium 17 was generated either from the iodide or tributyltin denvatives. The most important feature of this cyclization is the exclusive attack from the exo face leading to the tram ring junction bearing a tertiary alcohol. This methodology is presently being applied toward the synthesis of phorbol.
Scheme 7
phorbol
Lautens and Belter reported the synthesis of the C-2 1 to C-27 rifarnycin subunit via fragmentation of the ether bridge of oxa[3.2.l]bicycle (Scheme 8).11 Nucleophilic ring opening of the dcohol derïved from the oxabicyclic 10 gave the cycioheptene derivative 18. Subsequent protection of the hydroxy groups followed by ozonolysis and NaBb reduction afforded a linear carbon chah bearing five contiguous stereocenters corresponding to the C-2 1 to C-27 rifarnycin subunit. Differentiation of the two pnmary alcohol's was realized by treatment with DDQ.
Scheme 8 QPMB- - - '0, MeLi 1) TBDMSCI %QmB TMEDA 2) PMBBr Me
DDQ
OMe C-21 to C-27 subunit of rifamycin 5 3 Medium-Shed Oxygen Heterocycle Synthesis Using Oxabicycles
Medium-sized oxygen heterocycles have recently attracted the interest of the synthetic community. The synthetic challenge is associated with the difficulty in theû preparation as well as the discovery of a variety of rnonocyclic (Zairrencia derived) and polycyclic medium-sized ethers (brevotoxin, ciguatoxin) natural products.
Several strategies for the synthesis of seven- to nine-membered ether have recently been reported. l2 Of the variety of methodologies availabie, the utilization of oxabicycle templates has emerged as a powerful tool. The most significant strategies developed towards the synthesis of the family of medium-sized heterocycles are presented below.
Cha and coworkers reported an elegant strategy utilizing the [4 t 33 cycloadduct 19 to generate cis-2,8-disubstituted-oxocaneskeleton and appiied it to the synthesis of (+)-cis-lauthisan (Scheme 9).12= The tricyclic cycloadduct 19 was obtained from the reacûon of 3-chioro-2- pyrrolidinocyclohexanone with furan. Cycloadduct 19 was first converted to di01 20 by standard transformations. the key step being the cleavage of the two-carbon bridge by ozonolysis. The enzymatic desyrnmetrization of the meso di01 20 was accomplished by the use of Amano PS-30 lipase to give the mono acetate 21 in 85% ee. After protecting group manipulation, the intermediate alcohol22 was submitted to the Suiirez cleavage by the action of
PhI(0Ac)a and 12 to provide a mixture of lactone 23. Subsequent transformation of this intermediate gave the medium-sized cyclic ether lauthisan. Scheme 9
O AgBF4, CH2CI2 2) TBDMSOTf then NaOH TBDMSO 19 0
1) HF 4 lipase H 092) PDG 3) LiOH TBDMSO
1) TBDPSCI 2) LiOH
1
Martin and coworkers reported several strategies towards the construction of polycyclic medium-ring ethed3 Three examples are presented below. The key design features are the synthesis of complex bridged oxabicyclic systems and their subsequent stereoselective transformation and cleavage into a variey polycyclic medium-ring ethers.
The first exarnple is directed toward the preparation of highly oxygenated oxepane systems (Scheme 10). 13 The stereoselective synthesis of the oxabicyclo[4.2. llnonanone 25 was achieved by iodination of the cyclooctenone-epoxide 24 which was prepared in four steps from 1,5-cyclooctadiene. Its siiyl en01 ether was hydroborated and oxidized io give the mono- 12 protected di01 26 as a mixture of diastereomers. The mixture 26 was oxidized and stereoselectively reduced using NaBH4, followed by deprotection to give the cis-di01 27. Treatment with DBU led to the formation of the diene 28. Fragmentation of the oxabicycle 28
by action of periodinate, gave after reduction and protection. the oxepane 29. Reaction with singlet oxygen followed by reduction gave the oxepane 30, containing the functionality and
stereochemistry of the oxepane rings found in polycyclic nanird products such as ciguatoxin and the brevotoxins,
Scheme
TBDMSOTf Et3N 1 HO OH TBDMSQ TBDMSO 1) Swern oxidation BH3-Me2S
p4@-y 2) NaBH4 pb- ***JI H202, NaOH ps'. "'1 27 3) TBAF 26
Ac0 H yAc 1) Na104 ''t,..kO q..' 1) Oz,h v, TPP C b 2) NaBH4 2) H2, Lindlar catalyst
A similar transannular iodine-mediated epoxide opening of the diepoxide 31. prepared in four steps from 1,s-cyclodecadiene, provided the oxabicyclic [4.4.1] system 32 (Scheme 1 1). 13 Acetolysis of 32 provided the di01 33 which was cleaved with periodinate giving a seven- membered oxygen ether diaidehyde which was readily protected as its diacetai 34. Further manipulation provided the 6,7-fused system 35 as a single stereoisorner.
Scheme 11 12, Ti(OCPr)4 AcOAg - -*:OH AcOH 8'"O H 2) ethylene glycol, H' 1
PhS - 1) K2co3 2) PhSH, CSA
Lastly. iodine-induced cyciization of the readily available epoxy-acetate, followed by base-induced hydrolysis afTorded the oxabicyclic [8.2.1] system 36 (Scheme 12). I3 The latter rearranged to the oxabicyclic [7.3.1] compound 37 upon acetolysis. Cleavage of the seven- carbon bridge of the oxabicyclic template by ozonolysis gave a polysubstituted teuahydropyran derivative. Protecting group manipulation provided ihe intemediate 38 which was cyclized in the presence of thiophenol and acid to the desired 6,6,7-tram-fused polycyclic ether 39. This strategy has also been applied to the synthesis of 7,6,8-tram-fused polycyclic ethers. Scheme 12
1) MsCt 2) 0s04, NMO 3) Na104 4) ethylene glycol, CSA 5) K2CO3
PhSH CuO /-O '. p-TsOH PhS O SPh odoH
An extensive ring-expansion suategy was reported by Hirama and coworkers for the synthesis of oxepene 48, oxocane 50 and oxonene 45, which correspond to rings present in the polycyclic ether natural product ciguatoxin.l*i The key intermediate to die preparation of these medium-sized oxygen heterocycles derived frorn the ring opening of the oxabicyclic [2.2.1] system 40. The dimesyl bicycle 40 was prepared in three steps from furan and maleic anhydride. and further ozonolyzed and reduced to give the tetrahydrofuran denvative 41. The synthesis of the key intermediate 42 was achieved in thestraightfomard steps (Scheme 13).
Scheme 13
3) DBU PO OP 42, P = TBDMS The pivotai intermediate 42 was fit reacted with maleic anhydride followed by hydrolysis and methy Mon to provide the diester 43 (Scheme 14). Oxidative cleavage of the double bond followed by NaBH4 reduction gave the nine-rnembered cis-di0144 exclusively. A few other steps were necessary to access the desired oxonene 45 found in the naturd product ciguatoxin.
Scheme 14 Me02C, C02Me
1) maleic anhydride 1) 0s04, NMO C 2) H20 2) P~(OAC)~ OH PO OP 3) w2N2 = 3) NaBH4 POM OP PO OP 42, P = TBDMS 43 44
The route to oxepene and oxocane started from intermediate 42 which undergoes a photoelectrocyciic reaction resulting in the formation of the cyclobutene 46 (Scheme 15). The latter was readily ozonolyzed and stereoselectively reduced with NaBH. to provide rhe oxepane di01 47. This intermediate was transfonned into the di01 48 previously reported by Martin (see Scheme 10). Oxocane 50, which possesses a secondary rnethyl group, was synthesized from the di01 48. The latter was transformed into the bicyclic [S. 1.O] intermediate 49 in few sreps and submitted to a hydroxy group-directed hydrogeoation to give the regioselective opening of the cyclopropane ring and thus providing the desired eight-membered heterocycle 50. Scheme 15
PO OP 42, P = TBDMS 1) 12, PPh3, imidazole 2) DBU 3) 02,hv, TPP 4) H2, Lindlar catalyst
ff Ofb. -.iO H H2, Rh/AI2O3 I
OTlPS OTlPS OTlPS OTlPS PO OP 49 48
From the successful utilization of oxabicyclic ternplates in synthesis by our group and others. we were interested to investigate the synthesis and reactivity of two new families of oxacyclic compounds.
In the first Chapter of this thesis, the synthesis of exo,exo- l1,12-dioxatetracyclo [6.2.1.13*6.0**7]dodeca-4,9-dienesand their pentacyclic analogs is described. The objective of the second Chapter is to explore the reactivity and the synthetic utility of dioxacyclic compounds as a route to polysubstituted decalins and related fused-polycycles.
The preparation of azaoxa[3.2.1] bicyclic and thiaoxa [3.2.1] and [3.3. l ]bic yclic systems and their utilization in the enantioselective and stereoselective synthesis of medium-sized nitrogen and sulfur heterocycles is the topic of Chapter 3.
Finally, the intramolecular ring opening of oxabicyclic [2.2.1] systems as a route to L4.3 .O] bicyclic will be briefly discussed in Chapter 4. Part of the results presented in this thesis have already been published. '4
3 4 References and Notes
(1) For a recent review on aromatic heterocycles as intermediates in synthesis, see: Shipman, M. Contemp. Org. Synth. 1995,2, 1.
(2) (a) For recent reviews on the ring opening of oxabicyciic systerns, see: Chiu, P.; Lautens, LU.
Topics in Current Chernistry; Spnnger-Verlag: Berlin, 1997, Vol. 190, p 1. (b) Woo, S.; Keay, B. Synthesis 1996, 669. (c)Lautens, M. Synlen 1993, 177. (3) Hoffmann, H. M. R. Angew. Chem. [nt. Ed Engl. 1984,23, 1. (4) Gasparini, F.; Vogel, P.; Kelv. Chîm. Acta 1989, 72, 271. (5) Evans, D. A.; Barnes, D-M. Tetrahedron Letî. 1997,38,57. (6) Meinwdd, J. Pure and AppL Chem. 1977,49, 1375.
(7) Rao, A. V. R.; Yadav, J. S.; Vidyasagar, V. J. Chem. Soc.. Chem. Comm. 1985, 55. (8) Arco, M. J.; Trammell, M. H.; White, J. D. J. Org. Chern. 1976,41, 2075. (9) (a) Cummins, W. J.; Drew, M. G. B.; Mann. J.; Markson, A. J. Tetrahedron 1988, 34, 515 1. (b) de Aimeida Barbosa, L.-C.;Mann, J. J. Chern. Soc. Perkin Tram 1 1990,
177. (c) Montafia, A. M.; Nicholas, K. M. J. Org. Chem. 1990.55, 1569. (10) Lautens, M.; Kurnanovic, S. J. Am. Chem. Soc. 1994,117, 1954.
( 11) Lautens, M.; Belter, R, K. Tetrahedron Lett. 1992.33. 26 17.
( 12) For the recent developments in the synthesis of medium-sized oxygen heterocycles, see: (a) EUiott, M. C. Contemp. Org. Synth. 1994, 457. (b) Belen'kii, L. 1. In Cornprehensivr Heterocyclic Chernistry II; Newkome, G. R., Ed.; Pergamon: Oxford, 1996; Vol. 9. p 45. For recent reports, see: (c) Kim, H.; Ziani-Cherif, C.;Oh, J.; Cha, I. K. J. Org. Chem. 1995, 60, 792 and references cited therein. (d) Bratz, M.; Buiiock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, I17, 5958. (e) Nakata, T.; Nomura, S.; Matsukura, H. Tetrahedt-un Len. 1996,37, 213. (f) Alvarez, E.; Delgado, M.; Diaz, M. T.; Hanxing, L.; Pérez, R.; Martin, J. D. Tetrahedron Lett. 1996, 37, 2865. (g) Oishi, T.; 18 Shoji, M.; Maeda. K.; Kumahara, N.; Hirarna, M. Synlett 1996, 1 165. (h) Brunei, Y.; Rousseau, G. J. Org. Chem. 1996,61, 5793. (i) Rychnovsky, S. D.; Dahanukar, V. H. J. Org. Chem. 1996.61, 7648. (j) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.;
Hoveyda. A. H. J. Am. Chem. Soc. 1996,118,4291.
(13) Alvarez, E.; Diaz, M. T.; Pérez, R.; Ravelo, J. L.; Regueiro, A.; Vera, J. A.; Zurita, D.; Martin, J. D. J. Org. Chem. 1994.59, 2824 and references cited therein.. (14) (a) Lautens. M.; Fillion, E. J. Org. Chem. 1996.61, 7994. (b)Lautens, M.; Fillion, E. J. Org. Chem. 1997.62. 44 18. (c) Lautens, M.; Fillion, E.; Sampat, M. J. Org. Chern. 1997, 62, 7080. (d) Lautens, M.; Fillion, E. J. Org. Chem. in press. (e) Lautens, M.; Fillion, E.; Sampat, M. Tetrahedron Lett. in press. CHAPTER 1
STEREOSELECTIVE CONSTRUCTION OF BDGED POLYHETEROCYCLIC RING SYSTEMS USING THE TANDEM "PINCER" DIELS-ALDER REACTION 5 1.1 Introduction
4 1.1.1 Background
The Diels-Aider reaction is among the most powerful C-C bond forming processes and one of the most widely used and studied transformations in organic chernistry.1 Its widespread application arises from the versatility and the predictability of the stereo- as well as the regiochemical outcome of the reaction based on well-defined niles.2 The developrnent of a variety of elegant strategies using tandem Diels-Alder cycloadditions has allowed the construction of multiple carbon-carbon bonds generating an array of complex polycyciic structures in a single chernical step with controi of multiple stereocenters.3
The terrninology used to desctibe the combination of multiple reactions in a single operation is not rigorous and an al1 encompassing definition of tandem, domino, sequential, consecutive, cascade, successive or rnulti-stage reactions is very diff'lcult to formulate because of the continuum of chemicd reactivity. In two independant reviews on cycioadditions. Denmark and ~horarensen3"as well as Winkler3b have reponed different classifications of tandem cycloadditions. In both cases, some ambiguity and contradictions are noticeable between the authors depending mostly of the arbitrary choices of the defuiitions based on the intermediate, the reactant structure, the reaction conditions, etc ... For the purpose of this chapter, the term tandem will be used to describe any unintempted (single chernical operation) or interrupted multiple cycloaddition. In the larter case, the "intermediate" is an isolable entity containing the functionaiity (created in the fmt step) to paaicipate into a second cycloaddition reaction afier modification of the reaction conditions or reagents.
The tandem "pincer" Diels-Alder reaction consists of two consecutive Diels-Alder cycloadditions between two dienes and an acetylenic dienophile which acts as a bis-dienophile.
The sequence is called a tandem "dominot1Dieh-Alder when the second cycloaddition occurs at 2 1 the newly formed double bond of the ambident cyclohexadiene intermediate (Scheme 1.1).3%4c
Scheme 1.1 "Domino" Diels-Alder
"Pincer" Oiels-Aider
The tandem "pincer" and "domino" Diels-Aider have served as the comentone in Paquette's classic synthesis of dodecahedrane4 (Scheme 1.2) and Prinzbach's synthesis of pagodane5 respectively.
Scheme 1.2
1520% 1:l ratio - Dodecahedrane -__t
An example of tandem interrupied "pincer" Diels-Alder is illustrated in Scheme 1.3. Danishefsky and coworkers have used this strategy for the synthesis of naturai products such as vernolepin and vernomenin.6 Despite these successful examples. the synthetic potential of the tandem "domino" and "pincer" Diels-Alder reactions remaias underutilized in organic synthesis.' Scheme 1.3 OMe
The dioxacyclic compounds obtained from the "pincer" Diels-Alder reaction between two equivalents of a furan derivative and one equivalent of an acetylenic dienophile have been known for 65 years.8 However, they have essentidy remaineci a chemicai "curiosity" and no substantial progress has been made in optimizing their preparation. As far as their utilization in synthesis is concemed, it has been limited to very few examples and will be discussed in Chapter 2.9 In the cases reported to date, the diene counterparts were limited to f~ran,~~~~1,3- diphenylisobenzofuran '2 and few others symrnetrical furan derivatives. 3 The dienophiles generally used were dimethyl acetylenedicarboxylate (DMAD) 51 and acetylenedicarboxylic acid 52. The conditions used for their synthesis have generally led. in modesr yields, to mixtures of stereo- and regioisomers ("pincer" vs "domino" adducts) and to the formation of mono,bis and tris cycloadducts. Very reactive dienophiles as well as Lewis acidd4 or high pressure conditions 15 did not enhance the yield or the seIectivity of the reaction. Finally, dioxacycles have been isolated as side products in the Diels-Alder reaction between a furan derivative and an acetylenic dienophile16 especially when the reaction was carried out in the presence of highly reactive fluorinated acetylenes. '7 The main problem encountered in the synthesis of this family of compounds is the reversibility of the cycloaddition reactions. l4
During the course of Our studies, an example of tandem Diels-Alder appiied to the synthesis of dioxapentacycles was reported by Vogel and Marchionni (Equation 1. L ). l8 The authors reported that the cycloadduct is a potential precursor for the synthesis of long-chain polypropionate fragments. 5 kbar
5 1.1.2 Historical Information
In 193 1, while exploring the reaction of dienophiles with furan, Diels and Alder isolated a cycloadduct with a moIar ratio of 2: 1 arising from the reaction of an excess of furan with dimethyl acetylenedicarboxylate 51 a&elevated temperature? They suggested that the "pincer" adduct 53 was the product of this reaction despite the fact that the catalytic hydrogenation of the cycloadduct was complete after one equivalent of hydrogen had reacted suggesting a non-equivalence of the double bonds (Figure 1.1). in 1940, Diels and Olsen repeated the previous experiment but this tirne at room temperature and characterized the 2:l cycloadduct 53 by forming its dibromodilactone10a which suggested that the first compound initially reported to be 53 was in fact the adduct 54. It is aiso noteworthy that the mono adduct 55 and some tris cycloadducts were aiso isolated.
Figure 1.1 C02Me
At the time these adducts were prepared, it was difficult to make sI tereochernicai assignments and it was fuially Slee and LeGoff in 1970 who determined the configurations of the cycloadducts reported by Diels, Alder and Olsen using iH NMR spectroscopy (Scheme 1.4). lof This series of reactions illustrates the temperature dependence of furan-dimethyl 24 acetylenedicarboxylate bis-adduct formation. In fact, at low temperature. the double bond substituted with carbomethoxy groups acts as a dienophile ("pincer" mode),lg whereas at high temperature, equilibntion occurred to give reaction at the Iess substituted but less activated double bond ("domino" mode). These observations were explained by the thermal lability of the furm
Diels-Alder adducts. The exo addition observed for the addition of the second equivaient of diene, yielding predominantiy the exo-endo adduct, was explained by Slee and LeGoff in terms of the bulk of the methyl esters which favor exo attack.[Of Exclusive attack of the incoming diene on the exo face of the oxanorbornadiene intermediate 55 was a key feature of these reactions.
Scheme 1.4 Diels and Alder (1 931 )
DMAD, (neat) 100 OC,18 h H exo-endo exo -ex0 E = C02Me Diels and Olsen (1 940) O A DMAD, (neat) rt, 5 weeks E
exo-endo exo-exo
An important contibution relating to the thermal lability of the furan and pyrrole Diels-
Alder adducts was made by Visnick and Battiste in 1985 (Scheme 1.5).20 They showed that the reaction of the N,N1-dipyrrolylmethane56 with hexafluorobutyne 57 at room temperature gave exclusively the "kinetic" "pincer" cycloadduct 58 having a C2, symmetry. When heating the cycloadduct 58 in toluene, the " thermodynarnic" "domino" Diels-Alder adduct 59 having a Cs symmetry was obtained in quantitative yield. It is noteworthy that the conversion of 58 to 59 was rnonitored by NMR spectroscopy and that the azanorbomadiene intermediate was never observed. Scheme 1.5
Benzene, rt A / Toluene
In 1961, Stockmann published the reaction between excess furan and acetylenedicarboxylic acid at room temperature. lob A single cycloadduct was selectively obtained and its stereochemistry assigned as the 2x0-endo "pincer"adduct based on an iodometric titration technique. In this technique, the formation of a lactone proves unequivocaily the endo configuration of the carboxyiic acid group whereas the exo cycloadduct does not react (Scheme
Scheme 1.6 O
No reaction
Exo 26 Some contradictary results were obtained depending on the reagents and the conditions used to perform the titration. In some case, the results were in favor of the exo-endo adduct and in the other case in favor of the exo-exo product.21 The formation of the exo-exo adduct was contrary to al1 known experimentd results regarding the stenc course of the addition to the double bond in the bicyclo[2.2.l]heptene system reported to that date. Stockmann concluded that a Wagner-Meerwein rearrangement22 of the carbonium ion intermediate previously observed in similas systems may have occurred giving the "non-expected" exo-exo stereochernistry (Scheme
1 -6).
Deslongchamps and Kallos used chernical methods to definitely established that the
"pincer" cycloadduct possessing the exo-exo stereochernistry is the exclusive product when acetylenedicarboxylic acid 52 is used as the dienophile, instead of DMAD 51. at room temperature.lOd No explmation was put forward by Deslongchamps to rationalize this result (Equation i .2).
H02C-C02H (52) 0 > O rt. 3 weeks, Et20 &pC02H (1.2) (2 eq) 66% C02H
In 196 1, Cram and coworkers reported the fxst and only example of a "pincer" Diels- Alder using tether bis-furan to give an hexacyclic adduct but five years elapsed before they were able to assign the exo-exo stereochemistry of the observed product (Equation 1.3).23
DMAD Benzene, 105 OC,19 h 7-i% /602~e C02Me
Inspired by Slee and LeGoffs NMR study, in 1973, Mchnes and coworkers repeated the Diels, Alder, Olsen and Deslongchamps experiments and followed them by IH NMR.1' 27 They concluded that the molar ratio of diene and dienophile, the temperature and the reaction time
are the important factors in controlling the final ratio of each product in the reaction mixture. They also confmed the reversible nature of the Diels-Alder reactions since the ratio of the products changed with time (Scheme 1.7). Deslongchamps and Kailos observation of seiective
Formation of the exo-exo product when acetylenedicarboxylic acid 52 is used as the dienophile was ntionalized on the basis of a selective crystallization of the latter from the ethereal solution.
The exo-endo adduct is the major product after a few houn whereas the exo-exo adduct becomes predorninant in solution over time and starts to crystaliize, thus driving the equiiibrium towards
its further formation. 14
Scheme 1.7
1 C02Me COMe 53 (exo-exo) \ 53 (exo-endo)
H H 54 (exo-exo) 54 (exo-endo)
Since the mid-sixties, interest in the dioxacycles has been minimai. It is ody recentiy that these compounds have been "rediscovered" and used as templates for the construction of belt and cavity rnole~ules,~~as weil as cage molecules,25 and ladder polymers.2526
Pollmann and Müllen reported the synthesis of semitlexible ribbon-type structures (ladder 28 polymers) using the repetitive Diels-Alder reaction.25 Several strategies were reported in the paper, one of them is illustrated in Scheme 1.&. Starting from a bis-furan and its dioxatetracyciic denvative, the cornpetitive formation of the linear structures versus the cage compound was shown to be dependent on the temperature and pressure condtions. The authors demonstrated that perfonning the reaction under high temperature conditions favored the cage formation consequence of the retro Diels-Alder side reaction. However, the high pressure conditions favored the oligomerization process. Some Iarger size cages were isolated but are not shown in Scheme 1.8.
Scheme 1.8
1 bar L
Diels-Alder
retr/
intrarnolecular II Diels-Alder
The growing interest in molecular recognition led Warrener and coworkers to study the synthesis of ngid cavity molecules containing functionality on their imer face (Scheme 1.9).24 29 The ngid framework was constructed using a sequence of intempted "pincer","domino", and [2 + 21 cycloaddition strategy allowing control of the stereochemistry.
Scheme 1.9
An explanation of the stereoselectivity cycloaddition of furan with oxanorbornadienomaleimide based on experimentd results and semi-empWcal molecular orbital caiculations has been recentiy reported by Warrener and coworkers.27
Scheme 1.10
I NMe O 30 They proposed that the oxygen-oxygen repulsive interaction between the incoming furan and the oxanorbornadiene intermediate is the dominant but not the exclusive factor in detennining the stereochemical outcome of the cycloadditions (entry a and b, Scheme 1.10). However, some subtle steric contributions as welI as a repulsive x-bond-oxygen Ione pair interaction could modify the stereochemical outcomes and render the prediction of the cycloaddition specificities difficult without the aid of computationai studies (entry c and d, Scheme l.l0).*7
In some cases the "intermediate" aza and oxanorbornadiene type systems can be isolated in good yields by careiül control of the reaction conditions.28~29 Two examples of synthesis of "mixed" dioxatetracyclic compounds starting from an isolated oxanorbomadiene system and reaction with a second and different diene have been reported in Iiterature. Weisl" reported the preparation of a "mixed-pincer" Diels-Ader adduct in an excellent yield of 96%. No details on the stereochemistry of the final adduct was mentioned (Scheme 1.1 1). In 1970, Slee and
Le~offlof reported an example of "mixed-domino" cycloadduct in a Low yield, 13%.
Scherne 1.11
NC-CN * THF, rt, 3 days CN THF, reflux, 6 h
These studies fomed the foundation of our investigations which are described herein and which illustrate that a wide variety of furan dienes and acetylenic dienophiles can be used in the synthesis of complex dioxacyciic compounds in a chemo-, regio- and stereoselective manner.
We were interested in the applicability of the "pincer" Diels-Alder reaction of furan derivatives as the diene component directed towards the rapid construction of bridged polyoxacyclic ring systems. The latter are valuable and important intemediates arising from their ability to be ring-opened to highly functiondked cyclohexane derivatives.30~31 3 1 Our overd plan relies on the "pincer" Diels-Alder reaction between 2 equivaients of a substituted furan component and one equivalent of an acetylenic dienophile (Equation 1.4). Many permutations can be envisioned for the rapid construction of a large variety of bndged polycycles by varying the furans andor the dienophiles.
In this study, we have addressed the issue of regio-, chemo- and stereocontrol in the tandem Diels-Alder reaction directed towards the synthesis of a variety dioxacyclic compounds, and shown that the starting materials are readily available. The dioxacycles thus obtained cm be utilized as precursors to a wide variety of fused polycyclic compounds and will be discussed in the following chapted2
5 1.2 Results and Discussion
8 1.2.1 Preparation of the Dienes
The aikyl tethered bis-furan substrates ernployed in this study required no more than two steps for their preparation. The synthesis of the furan derivatives 60 and 61 was effected by trapping 2-lithiofuran with either 1.3-diiodopropane or l ,Cdiiodobutane in modest to excellent yields (Equation 1.5).
nBuLi, THF OO then ICH2(CH2)CH21 -
60, n=1,37% 61, n=2, quant. 32 According to Wedcert's procedure, 1,2-bis(2-fury1)ethane 63 was prepared from the commercially available furoin 62 using a deoxygenation prornoted by trimethylsilyl iodide followed by a Wofff-Kishner reduction (Equation LA)?
1) TMSCVNal, CH3CN, 59% C 2) W2NNH2-H20, KOH OH ethylene glycol, 72%
Alkylation of 2-lithiofuran with 1-bromo-3-chi oropropane provided 3-(2-fi1ry1)- 1 - chloropropane34 64 in good yield. Further transformation of 64 into the iodide 65 was performed under Finkelstein conditions.34 Furan 64 was deprotonated with n-BuLi and coupled with the alkyl iodide 65 affording the tethered bis-furan 66 in 48% yield (Scheme 1-12),
Scheme 1.12 n MuLi, THF ~Buti,THF, 48% - then 89% eci Nal Acetone Wh
The heteroatom substituted tethered bis-furans 67,68 and 69 were synthesized in one step kom hifiryl bromide, prepared fkom furfuryl alcohol and PBr3 in Et20.35 The latter was subsequently condensed with fumiryl aicohol and hirfùryl amine to give respectively the ether 67 in 85% yield and the secondary amine 68 in 36% yield (Scheme 1-13)? Upon treatment of two equivalents of furfuryl brornide with one equivalent of p-anisidine, the p- methoxyphenyl (PMP)protected bis-furan 69 could be obtained in 34% yield. Scheme 1.13
- KOH, Et20 34% Y?PMP
Conversion of the secondary amine 68 to its tertiary benzyl70 and p-methoxybenzyl
(PMB) 71 denvatives was accomplished under standard conditions (Scheme 1.14).
Scheme 1.14
Benzyl brornide Ph
NaH, KH, THF, DMF > p -Methoxybenzyl bromide 88%
The synthesis of tetrahydro-benzofuran 73 cornrnenced with the preparation of benzofuranone 72 as descnbed by Hammond (Equation 1.7).37 The latter was reductively deoxygenated with a 1: 1 mixture of LiAlH4 and AiCl3 to give 4,5,6,7-tetrahydro-4-benzofuran 3 1.2.2 Preparation of the Acetyienic Unsyrnmetricai Bis-Dienophiles
WhiIe the symmevical acetylenic bis-dienophiles 51 and 52 were commercially availabie, most of the unsyrnmetrical aikynes were prepared using standard routes. Methyl3- benzenesulfonyl-prop-2-ynoate 75 was synthesized in 2 steps using Schultz's protocoP9 starting from methyl propiolate 74 (Scheme 1.15). After a rapid purification, the unstable dienophile was immediately used in the cycloaddition reaction. On the other hand, methyl4- 0x0-pent-2-ynoate 76 was prepared via a modification of Jones and coworkers procedure?o
Methyi propiolate 74 was deprotonated with LDA and treated with acetaldehyde. The resulting propargylic alcohol was oxidized using Jones reagent to yield the keto-ester 76 in 30% ovedl yield (Scheme 1.15).
Scheme 1.15 1) LDA, THF 1) LDA, THF then PhSS02Ph then H3CCH0 - 2) mCPBA, Ct-f2C12 !OzMe 2) Jones Reagent rZMeS02Ph H Acetone - r2MeCOMe
Finaily, the synthesis of 4-benzenesuifonyl-but-3-yn-2-one 81 started with 3-butyn-2- 01 77 which was protected as its tetrahydropyran derivative 78-41 Deprotonation of the latter mixture of diastereomers using n-BuLi and ûapphg of the resultiag organolithium species with diphenyldisulfide gave a mixture of phenylthioaikynes which were deprotected to provide the free alcohol79 in 84% yield for the two operations. Oxidation of the alcoho142 gave the keto- 35 sulfide 80 which was further oxidized to the keto-sulfone 81 upon treatment with rn-CPBA.
The latter was not purified due to its instability (rapid poiymerization) and was used directly in the cycioaddition reaction (Scheme 1.16).
Scheme 1.16 DHP, PPTS - 1) nBuLi, THF CH2C12 then PhSSPh H 83"/0 2) p-TsOH, MeOH SP~ TI 70 84% 79
Swem Oxidation l 85%
8 1.2.3 Synthesis of the Oxa and Azanorbornadiene Type Adducts
Under appropriate conditions, it was shown that when treating furan or pyrrole denvatives and acetyienic dienophiles in a 1: 1 ratio, it is possible in some cases to isolate the correspondkg oxa and azanorbomadiene interme~iiate.~829Foilowing the Anderson and Dewey procedure, 2-methylfuran 82 and DMAD 51 were mixed together in a 1: 1 ratio at reflux in Et20 to produce the oxanorbornadiene intermediate 83 (Equation 1.s) .29b*c
O' O' ' reflux F 36 As for the azanorbornadiene systern. three steps were necessary to access the precursor 85. Pyrrole was tosylatedP3 de~rotonated~~with t-BuLi and then alkylated with Me1 to give 84. The latter was submitted to the Diels-Aider reaction under Prinzbach's conditions2ga in the presence of DMAD 51 generating the azanorbornadiene denvative 85 in 33% yield (Scheme 1.17).
Scheme 1.17 f-BuLi, THF O - * N THF N then Me1 H Wh Ts 81% Ts
xyfenes, reflux DMAD
=/O
Ts-N
5 1.2.4 Study of the Tandem "Pincer" Diels-Alder Cycloaddition
The furan derivatives and syrnmetncal and unsymmetrical acetylenic dienophiles were investigated in the "pincer" Diels-Alder cycloaddition. The feasibility of the regio- and stereocontrolled "pincer" Diels-Alder reaction was first explored using 2-methylfuran 82 as the diene counterpart. A solution of acetylenedicarboxylic acid 52 and two equivalents of 2- methylfuran 82 in Et20 was allowed to stand for 3 weeks at room temperature during which time the "pincer" cycloadduct 87 slowly crystailized out of the solution (Scheme 1.18). The only product isolated of the 16 possible isomen was identified as the C2 syrnmetrical exo-ex0 adduct 87 bearing the two bndgehead methyl groups in an "anti"relationship as readily confrrmed by
13~NMR spectroscopy. Stenc repulsion between the methyl group on the oxanorbornadiene 37 intermediate 86 and the methyl group on the incoming 2-methylfuran 82 in the transition state of the second cycloaddition must be responsible for the production of the "anti" product.
Scheme 1.18
C02H 3 weeks
A IH NMR study of the ethered solution showed that the oxanorbomadiene intermediate
86 is the predominant component in the reaction mixture. The cycloadduct 87 is found in low concentration in solution possibly due to its insolubility in ether and its rapid crystallization as soon as it is formed. The "anti"dimethyl exo-endo cycloadduct was also detected but no trace of the "syn"dimethyl cycloadducts was observed. The stereoselectivity (exo vs endo) as well as the chemoselectivity ("pincer" vs "domino") of 2-methylfuran 82 towards the ambident dienophile 86 are in agreement with Deslongchamps and Kallos observation on the reactivity of furan with acetylenedicarboxylic acid. [Od The stereoselectivity may be driven by crystd packing forces that cause selective crystaliization of the symmetrical exo-exo product whereas the chemoselectivity of 2-methylfuran 82 towards the tetrasubstituted olefin of the ambident dienophile 86 is due to kinetic control in the tandem Diels-Alder reaction.20 In a single step, two new rings, four C-C bonds and six stereocenters have been formed.
We originally believed that this result represented the first example of a regioselective "pincer" Diels-Aider reaction controlled solely by steric factors. However, a publication by Brunner and Loskot attracted our attention; in 1973, they reported the reaction between an equirnolar quantity of Zbromofuran 88 and DMAD 51.16a The oxanorbomadiene adduct 89 was isolated as the major product, but no yield was reported due to its instability and 89 was further reacted with CpCo(NO)2 to form stereoselectively the Co-olefin complex 90. The "pincer" Diels-Alder cycloadduct 91 was isolated as a side product in only 9% yield (Scheme 38 1-19). The relationship between the two bromides was determined to be anti and the stereochemistry of the adduct to be exo-endo using Stockman's iodotitntion technique and IH NMR. The latter was ais0 reacted with CpCo(NO)2 to form a bis-Co complex. The authors reported the unexpected isomerization of 91 to the exo-exo adduct 92 when hydrolyzing the esters with 2 N NaOH in MeOH.
Scheme 1.19 C02Me + 0 benzene &C02Me + 111 O Br cyclo hexane 8r C02Me C02Me reflux, 20 h (unstable)
2 N NaOH MeOH
In order to vem the hypothesis of the steric interaction between the methyl groups in the regioselective formation of 87, the experiment described above was repeated using the unsymmerrical diactivated dienophile 75 (Scheme 1.20). The highly activated dienophile 75 has been shown to react in a highly regioselective manner with an unsyrnmetncal diene where the methoxycarbonyl group was the directing gr0up.~9After a few minutes at room tempenture, the dienophile 75 and 2-methylfuran 82 yielded the oxanorbornadiene intermediate 93. However, even after standing for 3 weeks with an excess of 2-methylfuran 92, no trace of the dioxatetracyclic adducts 94 bearing the two methyl groups in a "syn" relationship was detected by 'H NMR analysis of the crude mixture. The only product present in the reaction mixture was the oxanorbornadiene intermediate 93 which iffusvates the signifcance of the steric interaction in 39 the inhibition of the formation of the "syn" dimethyl cycloadduct in the reaction between acetylenedicarboxylic acid 52 and 2-methylfuran 82.
The generaiization of this observation was achieved by the synthesis of unsymmetrïcai dioxatetracycles and "rnixed" azaoxatetracycle starting from the oxa and azanorbomadiene
intermediates 83 and 85 (Table 1.1). Under the conditions previously used, the hetero-
norbornadiene dienophiles were unreactive to undergo cycloaddition. This diffkdty was overcome by utilizing the lithium perchlorate mediated Diels-Alder reaction developed by Grieco" and successfully employed in the recent synthesis of a N-siloxyazanorbornadiene
derivative (Equation 1.9).46
OTBDMS 5 M LiCI04 - - 0 in Et20 65 days, rt e/o
In a typical experiment, the heteronorbomadiene dienophile and the diene were dissolved in a 5 M LiC104 solution in ether and stirred for 6 weeks at room temperature. The dienophile 83 reacted with 64 and 73 to give the dioxacyclic compounds 95 and 96 respectively in modest yield (entries 1 and 2, Table 1.1). In the case of the azaoxatetracycle 97, the latter was prepared by treatment of the dienophile 85 with 2-methylfuran 82 in 26-63% yield (entry 3, Table 1. i)P7 Table 1.1 Unsymmetrical "Pincer" [4+2] Cycloadducts
Entry Dienophile Diene Product a Yield
a [4+2]Cycloaddition, details in the Experimental Section. lsolated yield of analyücally pure product.
Anaiysis of the cmde reaction mixtures by 'H NMR indicated that the exo-exo adducts bearïng the bridgehead substituents in an "anti" relationship were the only products. The structural assignments of the cycloadducts were effected by examination of the IH NMR spectra and nOe results. The nOe correlations for the cycloadduct 96 are represented in Figure 1.2. In the case of 97, the stereochemistry has been confirmed by X-ray crystailography of the di01 derivative fomed by reduction with LiAiH(OMe)3 (see Appendk 2, p 3 18). In al1 the examples illustrated below, the remaïning products were predominantly the unreacted diene and dienophile.
Figure 1.2 In order to access the isomeric substrates with "syn" substituents, the preparation of dioxapentacyclic adducts linked at the bridgehead position was envisaged. This was accomplished by reacting the tethered bis-furan 60 with acetylenedicarboxylic acid 52 and DMAD 51 which provided the cycloadducts 98 and 99 in good yields (entries L and 2, Table
1.2). The syrnmetrical structure of the adducts was readily ascertained by IH and 13~NMR spectroscopy due to the simplification of the spectra. Reaction of acetylenedicarboxylic acid 52 with 60 under the previously described conditions was significantly faster than the one of 2- methylfuran 82 and provided the exo-exo dioxapentacyclic adduct 98 after one week at room temperature. None of the other 7 possible isomen was observed. A IH NMR anaiysis of the reaction mixture showed the absence of the oxanorbornadiene intermediate. This suggests that the intramolecular cycloaddition is much faster than the reaction with a second mole of furan and that the second step (intramolecular cycloaddition) is significantly faster than the first one (intermolecular Diels-Alder). Aiso, no trace of the exo-endo cycloadduct was detected in the reaction mixture. The formation of three new ring and six stereocenters was performed in a single step.
The scope of the reaction has been fully defined by using a variety of bis-furans and reacting them with acetylenedicarboxylic acid 52 or DMAD 51 to give the exo-exo cycloadducts in yields ranging frorn 63%-79% (entries 3 to 8, Table 1.2). Table 1.2 "Pincer"[4+2] Cycloaddition
------Entry Dienophile Bis-Diene Producta Yield
(i) syrnmefrical diactivated dienophile
(i i) unsyrnmetrical diactivated dienophile
a [4+2]Cycloaddition. details in the Experimental Section. lsolated yield of analytidly pure product. Furfuryl sulfide 1û5 is commercially available. The overall yield includes the oxidation of the sulfide 80 to the sulfone and the cycloaddition. * Obtained as a 4:1 mixture of regioisomers 109 and 110. ' Ethynyl p-tolylsulfone 11 2 is commercially available, 43 2 J-Substitution of the bis-diene moiety 66 did not interfere with the course of the cycloaddition and the cycloadduct 100 was obtained in good yield (entry 3, Table 1.2). Interestingly, the protecring group on the runine had no effect on the reactivity of the bis-diene (entries 5 to 7, Table 1.2) except in the case of 102 (entry 5, Table 1.2) where the reaction had to be perfomed neat in order to proceed.
The unsymmetrical diactivated dienophiles 75 and 81 gave the exo-exo cycloadducts 107 and 108 as single regioisomers (entries 9 and 1O, Table 1.2). Id The keto-suifone 81 gave a Lower yield of the cycloadduct probably due to its fast polyrnerization (entry 10, Table 1.2). The reactions were complete after a few minutes but it took several hours before the product began to crystaliize out of the solution. The structure of 107 was proven by X-ray crystailography (see Appendix 2, p 303) while the [H NMR spectrum showed that the chernical shift of the bridgehead proton moved upfield due to the presence of the nearby phenyl group. A similar observation was noted for 108. However, in the case of keto-ester 76, a 4: 1 mixture of regioisomers 109 and 110 was observed in favor of the product where the methyl ketone was the dominant directing group (entry 1 1, Table 1.2). The lower yield can be attributed to the fact that the major isomer did not crystallize out of the solution to drive the reaction to completion. Finaily, the structure of the major isomer 109 was determined by X-ray crystailography (see
Appendix 2. p 3 11).
The reaction widi the mono-activated dienophiles was also studied. The difference with the previously described conditions was that the reaction had to be performed in an ethereal solution of LiC104 (entries 12 and 13, Table 1.2). The reactions were highly regioselective and the structure of the cycloadducts 111 and 113 were determined by NOE experiments. In both cases, irradiation of the bridgehead signal gave nOe enhancements for the proximal olefm proton and the hydrogen situated at the ring junction (Figure 1.3). Irradiation of the methyl signal in 11 1 showed nOe enhancements for the olefin hydrogens proximal to the bridgehead substituent and methylene protons in the three carbon tether. It is notewonhy that the methoxycarbonyl 44 group is a stronger directing group than the phenylsulphonyl substituent (entry 9 vs 12, Table
1.2) even though the latter is reported to be a better activating group of the triple bond (entry 12
vs 13, Table 1.~).39*~~
Figure 1.3 n
We have also shown that the presence of a weakly electron-donating methyl group present on the monoactivated dienophile deactivates the alkyne and inhibits the formation of the cycloadduct even in the presence of LE104 (Equation 1-10). Reaction at high temperature resulted in complex mixture of products.
Fmaily, the synthesis of dioxapentacyclic systems was undertaken by changing the length of the tether separating the furans. When 61 and 63 were treated with DMAD 51 under the conditions previously used for the three carbon tether bis-furan 60, mixtures of two cycloadducts were obtained (Scheme 1.21). The major adducts (114 and 116) arose from the reaction of one equivalent of DMAD with the bis-furans without subsequent intramolecular cycloaddition. As for the minor products (115 and 117). they arose hom the reaction of two equivdents of DMAD 51 with the bis-furans and it should be noted that a mixture of stereoisomers was expected even if 45 their presence was not detected by IH NMR. In both cases, 19% of the unreacted starting materiai was recovered.
Scheme 1.21
DMAD * Et20, 3 weeks
Similar results were obtained by Grigg and coworkers in 1967 when reacting 2,2'-bifuryl
118 with DMAD 51 (Equation 1.11).50 The authors reported an equimolar mixture of isomeric cycloadducts 119 and 120 separable by fractionnai crystailization. However, the identification of each independent structure was not possible by NMR techniques.
DMAD benzene
6 1.2.5 Summary
In this chapter, a regio- and stereocontroiled approach for the simple and expedient synthesis of bridged polyheterocyclic ring systems was descnbed. The flexibility of the "pincer" Diels-Alder reaction in terrns of dienes and dienophiles has been demonstrated. 5 1.3 Experimental Section
5 1.3.1 General Experimental
The foilowing general expenmentai derails apply to ail subsequent experiments.
Analyticai thin-layer chromatography (TLC)was performed on precoated aluminum- backed silica gel (Merck 6ûF-254). Flash chromatography was performed as described by Stills 1 using 230-400 mesh sibca gel. Melting points were recorded with a Fisher-Johns melting point apparatus and are uncorrected. Bulb-to-buib distillations were perfomed on a Kugelrohr apparatus; boiling point refers to air bath temperatures which are uncorrected. Infrared spectra were recorded on a Nicolet 8210E FT-IR or Bomem Michelson Series FI-IR spectrophotometer. as a KBr pellet, solution in CC14 or CH2C12, or a neat film between NaCl plates 1H and 1% NMR spectra were recorded on a Varian Gemini-200 or VXR-40 spectrometer. Chernical shifts are reported in parts per rniliion (6) from tetramethylsilane with the solvent resonance as the intemal standard (1 H NMR, chlorofom: 6 7.24 ppm, 13~NMR, deurerochloroform: 8 77.0 pprn). Spectral features are tabulated in the foiiowing order: chernical shift (6,ppm); number of protons; multiplicity (s-singlet, d-doublet, t-triplet, q-qua.net, ququintet, m-complex multiplet, b- broad). High resolution mass spectra were obtained on a VG 70-2509 spectrometer. Elementai analyses were peifonned by Canadian Microanalyllcal Service Ltd., Delta, B.C. Optical rotations were measured on a Perkin-Elmer Mode1243 Polarirneter using the sodium D Line with spectro- grade chloroform in a 1 dm ceil. Capillary GC analyses were performed on a Hewlett Packard 5890 gas chromatograph using chiral columns P-TA and y-TA. HPLC analyses were performed on a Waters 600E equipped with a Waters 486 tunable absorbance detector using a chinl column Cbiralcel OD. Ozone was generaîed by an OREC (Ozone Research and Equipment Corporation), Model V5-0 ozonator, operating typically at 0.4 Umin of air flow and generating 1 -0.6% wt of 03in 02. Al1 glassware was flame dried under an atmosphere of dry nitrogen. Solvents and solutions were msferred with syringes and canuiae using standard inert atrnosphere techniques. 5 1.3.2 Solvents and Reagents
Unless stated otherwise, commercial reagents were used without purification. Tetrahydrofuran and diethyl ether were distilled immediately prior to use from sodium/benzophenone. Diisopropylamine, dichloromethane, dimethyl suifoxide, triethylamine and xylenes were distiüed imrnediately prior to use from calcium hydride.
5 1.3.3 Bis-Furan Preparation
General Procedure for the AIkyl Tethered Bis-Furan Preparation: 1,3- Bis(2-fury1)propane (60).
n-BuLi, THF 0.3
A solution of n-butyllithium (200 mL, 2.5 M solution in hexanes. 500 mmol) was added dropwise to a solution of furan (37 mL, 509 rnmol) in THF (300 mL) at O OC. The mixture was stirred 1 h at O OC and an additional 1 h at rt. The reaction was then cooled to O OC prior to the dropwise addition of L,3-diiodopropane (25 g, 84.5 rnmol). Afier the addition was complete, stimng was continued at rt for an additional 15 h. The reaction was quenched by the addition of water (10 mL) and the solvent was removed in vacuo. The residue was filtered over silica gel and the product eluted with hexanes (1000 id).The fduate was concentnted and a bulb-to-bulb distillation (0.20 mmHg, 50-60 OC) of the residual oil yielded 60 (5.5 g, 37%) as a colorless oil:
Rf = 0.33 on silica gel (100% hexanes); IR (neat) 3 1 14,2945, 1595, 151 1, 1462 cm-1; IH NMR (200 MHz, CDC13) S 7.33 (2H, s), 6.3 1-6-30 (2H. m), 6.04-6.03 (2H,m), 2.70 (4H. t, J = 7.5
Hz), 2.02 (2H,qu, J = 7.5 Hz); 13~NMR (50 MHz, CDC13) 6 155.5, 140.8, 1 10.0, 105.0,
27.3, 26.5. And. Calcd for Ci H1202:C, 74.98; H, 6.86. Found: C, 74.70; H, 6.56. MuLi, THF then ICH2(CH2)2CH21 - 6l The reaction was carried out as in the general procedure using n-butyllithium (134 mL, 2.5 M solution in hexanes, 335 mmol), furan (24.2 mL, 333 mmol), and 1.Cdiiodobutane (7.4 mL, 56 mrnol). Bulb-to-bulb distillation (0.20 mmHg. 60-70 OC) provided 61 (10.7 g, 100%) as a colorless oil: Rf= 0.25 on silica gel (100% hexanes); IR (neat) 3 150, 3140, 2930, 2860, 1596, 1507, 1462, 1438 cm-'; IH NMR (400 MHz, CDClj) 6 7.28 (2H.m), 6.26 (2H,dd, J=
3.2, 2.1 Hz), 5.96 (2H, dd, J = 3.1, 0.9 Hz), 2.64 (4H.t, J = 6.8 Hz), 1.68 (4H, qu, J = 7.3
Hz); 13~NMR (50 MHz, CDCl3) 6 155.9, 140.6, 110.0. 104.7, 27.6, 27.4; HRMS calcd for
C 12H 1402 [h4J+ l90.0994, found 190.0999.
64 A solution of n-butyllithium (21.5 mL, 2.5 M solution in hexanes, 54.8 rnmol) was added dropwise to a solution of furan (5.0 mL, 68.5 rnrnoi) in THF (100 mL) at O OC. The mixture was stirred for 1 h at O OCpnor to the dropwise addition of a solution of l-chloro-3- iodopropane (10.0 g, 48.9 mmol) in THF (20 mL) over 1 h. After the addition was complete. the mixture was stirred for 15 h at rt. The reaction was quenched by the slow addition of Hz0 and THF was removed in vacuo. The aqueous Iayer was extracted (3x) with Et20 and the combined organic layers were dried (MgS04), fdtered and concentrated. Bulb-to-bulb distillation (1.5 mmHg, 38-40 OC) of the residuai oil yielded 64 (6.0 g, 89%) as a colorless 02: Rf= 0.47 on silica gel (100% hexanes); 'H NMR (200 MHz, CDCl3) 6 7.33 (LH, dd, J = 3.2, 1.8 Hz), 6.3 1
(lH, dd, J = 3.2, 1.8 Hz), 6.08-6.05 (iH, m), 3.58 (2H, t, J = 6.5 Hz), 2.83 (SH,t, J = 7.1 Hz), 2.12 (2H. qu, J= 7.0 Hz); '3~NMR (50 MHz, CDClî) 6 154.3, 141.1, 110.1, 105.6, Nal Acetone 64 65 A solution of 64 (12.0 g, 83 mmol) and Nd (37.3 g, 249 mmol) in acetone (400 mL)
was heated at reflux for 24 h. Acetone was removed in vacuo and the residue was Fiitered
through a pad of silica gel and washed with Et2O. The filtrate was concentrated and a bulb-to- bulb distillation (1.5 rnmHg, 60-70 OC) of the residuai oil yielded 65 (19.7 g, 87%) as a colorless oil: Rf= 0.47 on silica gel (100% hexanes); JHNMR (200 MHz, CDC13) 6 7.32 (lH, dd, J=
1.8, 0.8 Hz), 6.29 (lH, dd, J = 3.1, 1.8 Hz), 6.06 (lH, dd, J = 3.1,0.8 Hz), 3.20 (2H, t, J=
7.0 Hz), 2.77 (2H, t, J = 7.0 Hz), 2.15 (2H, qu, J = 7.0 Hz); 3~ NMR (50 MHz, CDC13) 6 153.8, 141.1, 110.1, 105.7, 31.6, 28.6, 6.0.
MuLi, THF
64 66 86 A solution of n-butyllithium (7.26 mL, 2.5 M solution in hexanes, 18-15 mmol) was added dropwise to a solution of 3-(2-fury1)-1-chloropropane 64 (2.50 g, 17.29 mrnol) in THF (30 rnL) at O OC. Afier stimng for 2 h at O OC,a solution of 3-(2-fury1)- 1-iodopropane 65 (4.08 g, 17.28 mmol) in THF (20 mL) was added dropwise and the mixture was stirred for an additional 15 h at rt. The reaction was quenched by the addition of water (10 mL) and the solvent was removed Nt vacuo. The aqueous layer was extracted (3x) with Et20 The combined organic layers were dried (MgS04), filtered and concentrated. Purification of the residual oil by flash chromatography ( 100% hexanes) yielded 66 as a colorless oii (2.1 1 g, 48%): Rf = 0.09 on silica 50 gel (100% hexanes); IR (neat) 31 14,2952, 1433,732 cd; NMR (200 MHz, CDC13) 6 7.32
(LH,s), 6.32-6.29 (LH, m), 6.03 (IH, d, J = 2.3 Hz), 5.95-5.90 (2H,m), 3.58 (2H, t, j = 7.7
Hz), 2.81-2.61 (6H,m), 2.17-1.91 (4H,m); 13~NMR (50 MHz. CDCl3) 6 155.5, 154.0,
152.4, 140.7, 109.9, 105.9, 105.4, 104.9, 44.1, 3 1.0, 27.4, 27.3, 26.5, 25.2. And. Calcd for C14H1702CI: C,66.53; H, 6.78. Found: C, 66.7 1; H, 6.47.
General Procedure for the Heteroatom Substituted Tethered Bis-Furan Preparation: Di-or-furfuryl ether (67).35
A solution of phosphorus tribromide (5.0 g, 18.5 mrnol) in Et20 (5 mL) was added over 20 min to a solution of freshiy distiiied fumiryl alcohol(5.0 g. 5 1.0 rnmol) in Et20 (25 mL) at O
OC. The mixture was diowed to stand for 30 min at rt and then decanted into an erlenmeyer flask.
The solution wris cooled to O OC and treated cautiousiy with a 40% KOH solution (15 mL). The ether layer was decanted into a round-bottom fiask and treated with excess solid KOH (10 g).
Furfuryl alcohol (4.0 g, 40.8 mmol) was added to the furfuryl brornide solution and the solvent
was boiled off. The remaining residue was dissolved in water and extracted with Et20 (3x). The
combined organic layers were washed with brine (2x). dried (MgS04). filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 9: 1) gave 67 (6.2 g, 85%) as a colorless oi1: Rf= 0.50 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3 149, 3 121, 2910. 2861, 1504, 1068 cm-'; IH NMR (200 MHz, CDC13) 6 7.4 1-7-40 (2H, rn), 6.34-6.32 (4H,m), 4.47 (4H. s); 13~ NMR (50 MHz, CDCl3) 6 151.2, 142.5, 110.0, 109.3. 63.1. PBr3, Et20 then KOH
The reaction was canied out as in the general procedure using phosphoms tribromide (5.0 g, 18.5 mol). fumiryl alcolîol (5.0 g, 51.0 mmol) and fumiryl amine (4.0 g, 41.2 mmol).
Purification by ff ash chromatography (hexanes-EtOAc 1: 1) gave 68 (2.63 g, 36%) as a colorless oil: RI= 0.43 on silica gel (hexanes-EtOAc 1: 1); IR (neat) 3339,3276,3 114,2924, 2833, 1602 cm-';fH NMR (200 MHz, CDClî) 8 7.30 (2H,dd, J= 1.8, 0.9 Hz), 6.24 (2H, dd, J= 3.2, 1.8
Hz), 6.12 (2H,dd, 3.3, 0.7 Hz), 3.70 (4H, s), 1.72 ( lH, bs); 13C NMR (50 MHz, CDC13) 6
The reaction was camied out as in the general procedure using phosphorus tribromide (12.0 g, 44.1 mmol), furfuryl alcohol (12.0 g, 121.8 mmol) and p-anisidine (5.0 g, 40.6 mmol). Purification by flash chromatography (hexanes-EtOAc 9: 1) gave 69 (3.9 g, 34%) as a colorless oïl: Rf= 0.47 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3 117,3047,2993,2935, 2906,2833. 15 13, 1454, 1244, 1183, 1149, 1042, 1009 cd;LH NMR (400 MHz, CDC13) 6 7.34 (2H, dd,
J = 1.9, 0.9 Hz), 6.88-6.85 (2H, m), 6.81-6.78 (ZH,m), 6.28 (2H,dd, J = 3.2, 1.7 Hz), 6.13 (2H. bs), 4.37 (4H.s), 3.73 (3H, s); 13c NMR (100 MHz, CDC13) 6 152.5, 152.2, 143.0, 14 1.8, 1 16.3, 114.4, 110.2, 107.6, 55.5, 48.3; HRMS caicd for Cl7H 17N03[Ml+ 283.1208, found 282.12 10. A solution of n-butyliithium (1.06 rnL, 2.5 M solution in hexanes, 2.65 mmol) was
added dropwise to a solution of 68 (426 mg, 2.4 1 mrnol) in THF (5 rnL) at -78 OC. The mixture
was stirred 10 min at -78 OCand 10 min at O OC. The mixture was cooied to -78 OC for the dropwise addition of benzy! bromide (358 mL, 3.01 mol). The mixture was stirred 2 h at rt. The reaction was quenched by the addition of water (10 m.)and the solvent was removed in vucuo, The residue was dissolved in water and extracted (3x) with EtS. The combined organic layers were dned over MgS04, filtered and concentrated. Purification by flash chmmatognphy (hexanes-EtOAc 9: 1) yielded 70 (463 mg, 72%) as a colorless oil: Rf = 0.49 on silica gel
(hexanes-EtOAc 9: 1); IR (neat) 3 1 L2, 3053, 3030, 2928, 2830, 1598, 1497, 1455 cm-' ; IH NMR (400 MHz, CDCl3) 6 7.40-7.22 (7H.m), 6.3 3 (2H, dd, J = 2.9, 1.8 Hz), 6.23 (2H, d, J = 2.9 Hz), 3.66 (4H, s), 3.62 (2H, s); 13c MAR (100 MHz, CDC13) 6 152.4, 141.9, 138.9,
128.9, 128.2, 126.9, 110.0, 108.7, 57.1, 49.3. Anal. Calcd for C17H 17NO2: C,76.38; H, 6.41; N, 5.24. Found: C, 76.75; H, 6.51; N, 5.16.
NaH, KH, THF, DMF p-Methoxybenzyl bromide H PM8 68 7l
A solution of 68 (3.0 g, 16.9 mmol) in THF (20 mL) was added to a suspension of NaH (745 mg, 18.6 mmol, 80% in oil) and KH (194 mg, 1.7 mrnol, 35% in oil) (washed 3 times with pentane) in THF (30 mL) and DMF (5 mL). The mixnire was stirred for 3 h at rt. A solution of p-methoxybenzyl bromide (3.7 g, 18.6 mmol) in TEIF (10 mL) was added dropwise and the 53 mixture was stirted for an additional 15 h at rt. The reaction was quenched by the addition of water and the solvent was removed in vacuo. The residue was dissolved in water and extracted (3x1 with Et2O. nie combined organic Iayen were dned over MgS04, fütrated and concentrated.
Purification by flash chromatography (hexanes-EtOAc 9: 1) gave 71 (4.43 g, 88%) as a coforless oil: Rf = 0.44 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3062,3032,2999.295 1. 2928,2830, 16 1 1, 1509. 1454, 1245 cm-!; IH NMR (400 MHz, CDCl3) 6 7.39 (2H, dd, J = 1.8, 0.7 Hz), 7.30-7.26 (2H, m), 6.87-6.83 (2H, m), 6.32 (2H, dd, J = 3.0, 1.9 Hz), 6.2 1 (2H, m), 3.78 (3H, s), 3.63 (4H9 s), 3.54 (2H9 s); I3c NMR (100 MHz, CDClj) 6 158.6, 152.4, 14L.9, 130.8, 130.0, 113.6, 110.0, 108.7, 56.4, 55.2, 49.1; HRMS calcd for CigHi9N03 FI]+ 297. 1365, found 297.1358.
A solution of Lia(LOO mL, 1.0 M in Et20, 10mmol) was piaced in a 3-necked Bask equipped with a dropping funnel, a reflux condenser and a large vent. A solution of AlCl3 ( 13.3
D ' 100 mol) in Et20 (100 mL) was added dropwise. The formation of a white precipitate was observed. A solution of 4,5,6,7-tetrahydro-4-be~zofuranone3772 (13.6 g, 100 mmol) in Et20 (200 mL) was added at a rate such as to produce a gentle reflux. After the addition was complete, the reaction mixture was stirred for an additional 2 h at rt. The reaction was quenched by the addition of water (20 mL) followed by 6N H2SO4 (50 mL) and extracted with Et20 (3x). The combined organic layers were washed with water (lx) foilowed by brine (lx), dried over Na2S04, filtered and concentrated in vacuo. Vacuum distillation (-lOmmHg, 95 "Cj using a water pump produced 73 (5.93 g, 50%) as a co1orless oil: Rf = 0.8 1 on silica gel (hexanes-
EtOAc 10: 1); IR (neat) 31 14, 293 1, 2854, 163 1, 1560, 1511, 1448, 1300, 1223, 1103, 1033 cd;1H NMR (400MHz, CDCl3) 67.26 (1H. d, J= 1.8 Kz),6.22 (lH, d, J= 1.8 Hz), 2.61 (2H,t, J = 5.7 Hz), 2.49-2.42 (2H,m), 1.9 1-1.68 (4H,m); 13C NMR ( LOOMHz, CDC13) 6
151.2, 140.6, 117.1, 110.9, 23-6 (2C), 22.6 (2C).
8 1.3.4 Preparation of the Acetylenic Dienophiles
Methyl 4-0x0-pent-2-ynoate (76).40
C02Me 1) LDA, TH F C02Me then H3CCH0
2) Jones Reagent- H Acetone COMe 74 76
A solution of n-butyllithium (25.0 mL, 2.5 M solution in hexanes, 62.5 mmol) was
added dropwise to a solution of diisopropylamine (8.6 mL, 59.5 mol) in THF (300 mL) at O
OC. The mixture was stirred 15 min at -78 OC and 15 min at O OC. The reaction was cooled to -78 OC pnor to the dropwise addition of a solution of methyi propiolate 74 (5.0 g, 59.5 mmol) in
THF (25 mL). The mixture was stirred i. h at -78 OC and a solution of acetaidehyde (4.0 mL,
75-56mmol) in THF (25 mL) was added. The mixture was stirred for m additionnai 2 h at -78 OC. The reaction was quenched by the addition of satunted aqueous NH&I. THF was removed in vacuo and the residue was extracted with Eh0 (3x). The combined organic layes were dried (MgS04), fil tered and concentrated. The cmde alcohol was dissolved in acetone (150 mL) and carefully treated with a solution of Jones' reagent at O OC until the solution remained a dark brown color. The mixture was stirred for an additionai 15 min at O OC pnor to the addition of NaHCO3 (5.0 g) and MgS04. The
mixture was filtered over siiica gel and the solid washed several times with Et20. The fitrate was concentrated and the residue purifed by flash chromatography (hexanes-EtOAc 5: 1) to give 76 (2.22 g, 30%) as a colorless oil: Rf = 0.51 on silica gel (hexanes-EtOAc 4: 1); IR (neat) 3009, 2966,2847,2362,2341, 1729, 1694, 1265 cm-l; IH NMFt (200 MHz, CDQ)8 3.83 (3H. s),
2.41 (3H, s); "C NMR (50 MHz, CDC13) 6 182.1, 152.3, 80.8, 77.1, 53.1, 32.0. DHP, PPTS C CH2C12
PPTS (1.43 g, 5.69 mmol) was added to a solution of 3-butyn-2-01 77 (4.00 g, 57.07 mmol) and DHP (12.50 mL, 136.97 mmol) in CH2C12 (30 mL). After stirring for 5 h at a, the mixture was diluted with CH2C12 (100 mL),washed with a saturated NaHC03 solution (2x) and brine (lx), dried (MgS04), fdtered and concentrated. Bulb-to-bulb distillation (0.20 mmHg, 50- 60 OC) of the residual oil yielded a 1: 1 mixture of diastereomen 78 (8.80 g, 83%) as a colorless oïl: Rf = 0.39 and 0.28 on silica gel (hexanes-EtOAc 15: 1); IR (neat) 3290, 2945, 2 11 1, 1448,
1370, 1265, 1201, 1 124 cm-'; IH NMR (200 MHz, CDC13) 6 4.95-4.9 1 (1H, m), 4.77 (lH, t, J = 3.1 Hz), 4.54 (lH, dq, J = 6.7, 2.0 Hz), 4.45 (lH, m), 4.04-3.93 (IN, m). 3.89-3.76 (LH, m), 3.57-3.46 (SH,m), 2.43 (IH, d, J = 2.2 Hz), 2.37 (IH,d, J = 1.9 Hz), 1.83-1.54 (12H, m), 1.47 (3H, d, J = 6.6 Hz), 1.44 (3H,d, J = 6.6 Hz); 13~NMR (50 MHz, CDCl,) 6 96.9,
95.7, 84.5, 83.5, 72.4, 71.8, 62.3, 62.1, 62.0, 60.4, 30.4, 25.4, 22.0, 21.7, 19.4, 19.0; HRMS calcd for CgH1402 m+154.0994, found 154.0999.
1) nBuLi, THF > then PhSSPh H 2) p-TsOH, MeOH SP~ 78 79 A solution of n-butyiiithium (9.53 mL, 2.5 M solution in hexanes, 23.83 mmol) was added dropwise to a solution of 7841 (3.50 g, 22.70 rnmol) in TKF (75 mL) at -78 OC. After stirring for 1 h at -78 OC, a solution of phenyl disulfide (5.20 g, 23.82 mmol) in THF (25 mL) was added dropwise. Afier the addition was complete, the mixture was warmed to rt %idstirring was continued for an additional 2 h. The reaction was quenched by the addition of water and 56 diluted with Et2O. The organic layer was washed with a 5 M NaOH solution (4X) and brine
( 1x), dried (MgSO4), filiered and concentrated. The residual oïl was dissolved in MeOH (300 rnL) and treated with p-TsOH (432 mg, 2.27 mrnol) and stirred at a for 5 h. The reaction was quenched by adding 300 mL of a saturated solution of NaHCO3 and extracted with CH2C12 (3x). The combined organic layers were washed with brine (2x), dried over MgS04, filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 4: 1) yielded the alcohol79 (3.40 g, 84%) as a colorless oil: R/
= 0.34 on silica gel (hexnnes-EtOAc 4: 1); IR (neat) 3543,3339, 3058, 298 1, 2875,2184, 158 1.
1370, 1 124, 1075, 688 cm-i ; I H NMR (200 MHz, CDC13) 6 7.45-7.18 (5H,m), 4.75 ( 1H, q, J = 6.7 Hz), 2.66 (1 H, bs), 1.54 (3H, d, J = 6.6 Hz); '3C NMR (50 MHz, CDC13) 6 132.3.
129.1, 126.5, 126.1, 100.6, 70.9, 59.1, 24.1; HRMS calcd for CloHioOS Fi]+178.0452, found 178.O449.
oxalyl chlodde C DMSO, Et3N SPh CH2CI2 SPh 79 80 Oxalyl chioride (2.83 mL, 32.40 mmol) was added dropwise to a solution of DMSO
(3.07 mL, 43.20 rnmol) in CH2C12 (125 mL) at -78 OC. Mer the addition was complete, the reaction was stirred at -78 OC for 30 min. A solution of the alcobol79 (3.85 g, 2 1.60 mmol) in
CH2C12 (25 mL) was then added dropwise and, &ter the addition was complete the reaction was stirred at -78 OC for an additional 30 min. Et3N (15.00 mL, 108.62 mol) was added and the mixture stirred for an additional 15 min at -78 OC. The reaction was poured into CH2C12 and the organic layer was washed with a 1 M HCI solution (2x) and brine (lx), dried (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 80 (3.23 g, 85%) as a colorless oll: Rf= 0.47 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3065, 3002, 2924, 2137, 2095, 1667, 1580, 1479, 1441, 573 cm-1; IH NMR (200 MHz, CDCI3) 6 7.48- 57 7.25 (SH,m), 2.37 (3H, s); 13C NMR (50 MHz, CDCI3) 6 181.2, 129.2, 127.5, 126.6, 100.6,
84.6,3 1.2; HRMS calcd for C 1oHsOS Fi]+ 176.0296, found 176.030 t .
5 1.3.5 Preparation of the Azanorbornadiene Type Adduct
0 KH, TsCl N THF N H 0Ts
KH (35.9 g, 35% in oil, 3 13 mmol) was washed with pentane (3x) and then suspended
in THF (300 rd). A solution of pyrrole (20.0 g, 298 mol) in THF (50 mi,) was added dropwise at O OC and the mixture was stirred vigorously for 3 h at rt. The mil@ solution was cooled to O OC prior to the addition of a solution of p-TsCl(56.8 g, 298 mmol) in TH'(50 rd). After stirring for 15 h at a, the reaction was quenched with 2-propanol. The solvent was removed in vacuo and the residue was dissolved in water. The aqueous phase was extracted with Et20 (5X)and the combined organic layers were dried (MgS04), filtered and concentrated. The residue was recrystallized from absolute EtOH to yield N-tolyl-pyrrole (58.9 g, 89%) as a white solid: Rf= 0.37 on silica gel (hexanes-EtOAc 9:l); mp 101-102 OC (EtOH); IR (KBr) 3 150,
3128, 3052, 3030.2925, 1590, 1457, 1367, 1171 cm-1; IH NMR (200 MHz, CDC13) 6 7.74
(2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 7-16 (2H, t, J = 2.3 Hz), 6.29 (2H. t, J = 2.3
Hz), 2.39 (3H, s); 13~NMR (50 MHz, CDCl3) 6 144.8, 136.0, 129.8, 126.7, 120.6, 113.4,
2 1.5.
WuLi, THF 0N then Me1 Ts Ts
A solution of t-butyliithium (14.6 mL, 1.7 M solution in pentane, 24.9 mrnol) was added 58 dropwise to a solution of 1-p-tolyi-l~-pyrrole4~(5.00 g. 22.6 mol) in THF (120 mL) at -78
OC. The mixture was stirred LO min at -78 OC, 10 min at O OC and 20 min at rt. The mixture was cooled to O°C prior to the slow addition of iodomethane (7.0 mL, 112 rnmol). After the addition
was cornpiete, the mixture was siirred 1 h at rt and the reaction was quenched by the addition of a saturated aqueous NH4CI solution. The aqueous layer was extracted with ether (3x), the combined organic layers were dned (MgS04), filtered and concentrated. The residue was recrystallized from MeOH to yietd 84 (4.29 g, 8 1%) as a white solid: Rf = 0.43 on silica gel (hexanes-EtOAc 9: 1); mp 87-88 OC (MeOH); IR (Dr) 3 142, 3 107,2966,2924, 1595, 1490, 1455, 1358, 1174 cm-l; IH NMR (200 MHz, CDCf3) 6 7.67 (2H, d, J = 8.5 Hz), 7.3 1-7.26
(3H,m), 6.16 (1H. t, / = 3.3 Hz), 5.96-5.93 (1H. ml, 2-41 (3H, s), 2.29 (3H. s); 13~NMR (50 MHz, CDC13) 6 144.7, 136.2, 130.7, 129.8, 126.8, 121.9. 113.0, 111.1, 21.5, 13.5.
Anal. Calcd for C 2W3NO2S: C, 6 1-25; H, 5.57; NT5.95. Found: C, 6 1.25; H, 5.79; NT5.85.
Dimethyl l-methyl-7-p-toiyI-7-aza-bicycIo[2.2.1]hepta-2,5-diene-2,3- dicarboxylate (85).
xylenes, reflux - &C02Me DMAD Ts COzMe 84 86
A solution of 84 (4.3 g, 18.3 mol) and DMAD 51 (1 3.0 g, 9 1.1 mrnol) in xylenes (30 mL) was heated at reflux for 7 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes-EtOAc 2: 1) to yield 85 (2.3 g, 33%) as a white crystalline soiid: Rf= 0.28 on silica gel (hexanes-EtOAc 2:l); mp 112-1 15 OC (CH2Cl2); IR (KBr) 3 100, 3002. 2945, 2847, 1724, 1700, 1635, 1439, 1345, 1 16 1 cm-1; 1H NMR (200 MHz, CDCl3) 87.59 (2H,d, J=8.4Hz), 7.26 (2H,d,J= 8.2 Hz), 7.06 (IH,dd, J=5.2, 2.9
Hz), 6.78 (lH, d, J = 5.5 Hz), 5.46 (lH, d, J = 2.9 Hz), 3.72 (3H, s), 3.68 (3H, s), 2.40 (3H, s), 1.87 (3H9 s); I3C NMR (50 MHz, CDC13) 6 164.1, 161.6, 155.8, 148-5, 148.0, 143.7.
143.5, 135.4, 129.6, 128.3, 79.0, 69.0, 52.1(2C), 21.5, 13.6. And. Calcd for C18H19N06S: C, 57.28; H, 5.07; N, 3.71. Found: C, 57.18; H, 5.13; NT3.73. 8 1.3.5 Tandem "Pincer" Diels-Alder Cycloaddition
General Procedure for the Diels-Alder Reaction in EtzO. Method A. exo,exo-l,6-~imethyl-ll,12-dioxatetracyclo[6.2.1.1~~~.0~~~]dodeca-4,9-die~- 2,7-dicarboxylic acid (87).
82 S? 87 Acetylenedicarboxylic acid 52 (15 g. 132 mol) and 2-rnethylfuran 82 (28 mL, 3 10 mmol) were dissolved in Et20 (75 mL) and the solution was Left for 3 weeks at rt with daily stirrïng, during which time the product crystaiiized out. The crystals were isolated by filtration and washed with Et20 to yield the cycloadduct 87 (22.6 g, 62%) as a white solid. Mp 141-143 "C (EtzO); IR (Dr) 3459-2453. 1750, 1729 cm-';'H NMR (200 MHz, CD3OD) 6 6.66 (2H, dd, J = 5.5, 1.7 Hz), 6.38 (2H, d, J = 5.5 Hz), 5.07 (2H,d, J = 1.8 Hz), 1.64 (6H,s); 13~ NMR (50 MHz, CD30D) 6 173.9, 143.8, 140.1, 91.5, 81.9, 75.2, 15.1. Anal. Calcd for
C14H1406:C, 60.43; H, 5.07. Found: C, 60.19; H, 5.34.
Methyl 3-Benzenesulfonyl-l-methyl-7-oxa-bicyclo[202011 hepta-2,5-diene- 2-carboxylate (93).
Freshly prepared 7539 (5 13 mg, 2.29 mmol) and Zmethylfuran 82 ( 1.O mL, L 1.O8 mmol) in Et20 (5 mL) were stured at rt for 15 h. The soIvent was removed in vacuo and the residue was purified by flash chromatography (hexanes-EtOAc 3: 1) to give the cycloadduct 93 (432 mg, 62%) as a colorless oil: Rf= 0.26 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3066, 60 2988,2953, 1730, 163 1, 1443, 13 1 1, 1262, 1160, 1089 cm-l; NMR (400 MHz, CDCI3) 6 7.94-7.90 (2H, m), 7.68-7.64 (IH. m), 7.58-7.55 (2H, m), 7.06 (lH, dd, J = 5.2, 1.9 HZ),
6.93 (1H, d, J = 5-1 HZ),5.48 (IH, d7J = 1.9 HZ), 3.82 (3H, s), 1-74 (3H7s); '3~NMR (100 MHz, CDC13) 6 163.3, 158.5, 155-6, 145.0, 143.8, 138.4, L34.1, 129.3, 128-0, 95.0, 83.5,
52.6, 14.8; HRMS calcd for C 15H14O5S CM]+ 306.0562, found 306.0570.
General Procedure for the Diels-Alder reaction in 5 M LiCiO4/EtzO. Method B. Cycloadduct (95).
95 The cy~loadduct29b-~83 (900 mg, 4.01 mmol) and the furan derivative34 64 (580 mg, 4.01 mmoi) were dissolved in a solution of 5 M LiCI04 in Eh0 (5 mL) adallowed to stand at rt for 6 weeks in a sealed Bask with stirring. The mixture was diluted with EtOAc (LOO mL) and the organic layer was washed (3x) with water, brine (lx), dned (MgS04), filtered and concentrated. Purification by flash chromatognphy (hexanes-EtOAc 3: 1) yielded the cycloadduct
95 (503 mg, 34%) as a paie yelfow oil: Rf= 0.13 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3095, 3014, 2953. 2873, 1716, 1457, 1436, 1387, 1242, 1083 cm-[; 'H NMR (400 MHz. CDC13) 6 6.62 (2H, dd. J = 5.5, 1.4 Hz), 6.34 (lH, d, J = 5.5 Hz), 6.28 (lH, d, J = 5.5 Hz),
5.12 (lH, d, J = 1.8 Hz), 5.11 (lH, d, J = 1.8 Hz), 3.65-3.48 (2H, m), 3.60 (3H, s), 3.59
(3R s), 2.17-1.95 (3H, m), 1.89-1.78 (lH, m), 1.62 (3H,s); 13~NMR (100 MHz, CDCl3) 6
170.5, 170.4, 142.4, 140.8, 139.2, 139.0, 93.1, 90.0, 80.5(2C), 74.6, 74.3, 52.0, 51.9, 45.0,
28.0, 26.4, 14.9; HRMS cdcd for C18&1C106 [Ml+ 368.1027, found 368.1021- Cycloadduct (96).
The reaction was chedout as in the generd procedure B using the dienophile 83 (9 18 mg, 4.09 mmoi) and 4,5,6,7-tetrahydro-4-benzofUran73 (500 mg, 4.09 inmol) in a solution of 5 M LiC104 in Et20 (5 mL) for 6 weeks. Purification by flash chrornatography (hexanes-EtOAc
1: 1) yielded the cycloadduct 96 (702 mg, 50%) as a white solid: Rf= 0.44 on silica gel (hexanes-
EtoAc 1: 1); mp 107-1 10 OC (Et20); IR (neat) 3016,2945,2861, 1742, 1715, 1435, 1241 cm-1; IH NMR (400 MHz, CDC13) 6 6.56 (lH, dd, J = 5.5, 1.8 Hz), 6.26 (lH, d, J = 5.5 Hz), 6.25-
6.23 (IH, m), 5.12 (lH, d, J = 1.8 Hz), 4.93 (IH, d, J = 1.8 Hz). 3.57 (6H,s), 2.48-2.34 (2H. m), 1.97-1.57 (4H, m), 1-52 (3H, s), 1.32- 1.O3 (2H. m); 13cNMR ( LOO MHz, CDC13) 6
27.6, 26.7, 23.7, 22.5, 14.6. Anal. Cdcd for ClgH2206: C,65.88; H, 6.40. Found: C, 65.79;
Cycloadduct (97).
The reaction was carried out as in the generd procedure B using the dienophile 85 (2.70
0'0 7.16 mol) and 2-methylfuran 82 (3.23 mL, 35.80 mmol) in a solution of 5 M LiC104 in
Et20 (25 mL) for 6 weeks. Purifcation by flash chromatography (CH2C12-EtOAc 9:l) yielded the cycloadduct 97 (840 mg, 26%) as a white solid: Rf= 0.45 on siüca gel (CH2C12-EtOAc 9: 1); mp 44-46 OC (CH2CI2); IR (neat) 3094, 2988, 2952, 2847, 1743, 1716, 1599, 1436, 1348, 62 1160 cm-'; 'H NMR (400 MHz, CDCl3) 8 7.68 (2H,d, J = 8.4 Hz), 7.2 1 (2H, d, J = 8.4 Hz),
6.6 1 (IH, dd, J = 5.5, 1.8 HZ),6-35 (IH, dd* J = 5- 1, 2.2 HZ), 6-24 (IH, d, J = 5.5 HZ),5.95
(lHTd. J = 5.5 HZ),5.11 (lH, d, J = 2.2 HZ), 5.00 (lH, d, J = 1.8 Hz), 3.59 (3H, s), 3.56
(3H, s), 2.37 (3H, s), 1.64 (6H.s); 13C NMR (100 MHz, CDCl3) 6 170.0, 169.7, 143.1,
142.8, 142.5, 139.5, 138.2, 137.7, 129.3, 127.9, 90.3, 80.4, 76.5, 74.9, 72.6, 65.7, 52.1, 52.0, 2 1.5, 14.8, 13.6. Anal. Calcd for C23H25N07S: C, 60.12; H, 5.48; N, 3.05. Found: C, 60.10; H, 5.37; N, 3.25.
Cycloadduct (98).
60 98 The reaction was carried out as in the generai procedure A using acetylenedicarboxylic
acid 52 (325 mg, 2.85 rnmol) and 60 (500 mg, 2.84 mol) in Et20 (1.5 mL) for 1 week to yield the cycloadduct 98 (608 mg, 74%) as a white solid. Mp 156-160 OC (Et20); IR (KBr) 3416- 2488, 2988, 2938, 1721, 1384 cm-l; 'H NMR (200 MHz, CD30D) 6 6.58 (2H. dd, J = 5.5,
1.7 Hz), 6.47 (2H, d, J = 5.6 Hz), 5.00 (2H, d, J = 1.7 Hz), 2.37-2.22 (2H, m), 2.08-1.79 (3H. m), 1.71-1.60 (lH, m); 13C NMR (50 MHz, CD3OD) 8 173.8, 173.7, 142.9, 139.6,
91.3, 84.7, 74.4, 69.7, 26.5, 18.1. Anal. Calcd forCL5H1406:C, 62.07; H, 4.86. Found: C, 61.95; H, 4.79.
Cycloadduct (99).
DMAD - Et20 63 The reaction was carried out as in the general procedure A using DMAD (500 mg, 2.63
mmol) and 60 (444 mg, 3.12 mol) in Et20 (2.0 mL) for 3 weeks to yield the cycloadduct 99 (644 mg, 71%) as a white solid: Rf= 0.39 on silica gel (hexanes-EtOAc 1: 1); rnp 151-153 OC (CH2Cl2); IR (Dr) 3002, 2959, 2924,286 1. 1736, 1708, 1434, 1272 cm-[; 1H NMR (400 MHz, CDC13) 6 6.50 (2H, dd, J = 5.5, 1.8 Hz), 6.42 (2H,d, J = 5.5 Hz), 4.99 (2H, d, I = 1.5
Hz), 3.56 (3H, s), 3.55 (3H, s), 2.13-2.10 (4H. rn), 1.984.86 (lH,m), 1.65 (1H.dqu, J =
13.6, 3.5 Hz); I3C NMR (100 MHz, CDCI3) 6 170.8, 170.5, 142.0, 138.1, 89.9, 83.4. 73.3,
68.5, 5 1.9, 5 1.8, 25.6, 17.0. Anal. Cdcd for C i7H 806: C, 64-14; H, 5.70. Found: C, 63.72; H, 5.80.
Cycloadduct (100).
@ 100 The reaction was carried out as in the general procedure A using acetylenedicarboxylic acid (453 mg, 4.0 mmol) and 66 (1.00 g, 4.0 mmol) in Et20 (5 mL) for 6 weeks to yield the cycloadduct 100 (1.15 g, 79%) as a white solid. Mp 186-189 OC (acetone); IR (KBr) 3416- 2545,2959, 1727, 1695, 1683, 1408,699 cd;lH NMR (400 MHz, CD3OD) 6 6.65 (lH, dd, J =5.5, 1.9 Hz), 6.47-6.43 (2H,m),6.37(1H,d, J=SS Hz), 5.12 (lH,d,J= 1.8 Hz),3.67-
3.57 (2H, m), 2.39 (lH, td, J = 14.0, 4.9 Hz), 2.23-1.86 (8H, m), 1.68-1.64 (lH, m); '3~ NMR (100 MHz, CD30D) 6 174.1, 173.8. 142.7, 142.4, 142.1, 140.5, 93.8, 91.4. 90.6,
52.1, 76.2, 72.6, 45.9, 29.6, 27.5, 26.6 (2), 18.1. Anal. Calcd for ClgHrg06Cll: C, 58.94; H, 5.22. Found: C, 58.67; FI, 5.17. Cycloadduct (101).
DMAD
67 101 The reaction was carried out as in the general procedure A using DMAD (2.3 1 g, 16.25 rnmol) and 67 (2.63 ,o. 14.77 mol) in Et20 (20 mL) for 3 weeks. The filtrate was concentated and the residue purified by flash chromatography (hexanes-EtOAc 1:2) to yield the cycloadduct
101 in a combined yield of 76% (3.59 g) as a white crystalline solid: Rf= 0.33 on silica gel (hexanes-EtOAc 1:2); mp 178-18 1 OC (Et20); IR (KBr) 3012. 2966, 1736, 1727, 17 17, 1428. 1255, 1080 cm-'; lH NMR (400 MHz. CD30D) 6 6.67 (2H, dd, J = 5.7, 1.7 Hz). 6.43 (2H, d,
J = 5.5 Hz), 5.14 (2H,d, J = 1.5 Hz), 4.25 (2H, d, J = 13.2 Hz), 4.13 (SH,d, J = 13.2 Hz), 3.60 (3H, s), 3.58 (3H, s); 13C NMR (100 MHz, CD3OD) 6 171.6, 171.5, 141.4. 138.5, 89.0,
85.1, 72.4, 68.5, 65.7, 52.6, 52.5. Anal. Cdcd for C 16H1607: C. 60.00; H, 5-04. Found: C,
59.6 1; H, 4.94.
DMAD - neat
89 1M
The reaction was carried out as in the general procedure A using DMAD (1.7 g, 1 1.7 mol) and 69 (3.0 g, 10.6 mmol) without solvent for 6 weeks to yield the cycloadduct 102 (2.82g, 63%) as a white solid: Rf = 0.40 on silica gel (hexanes-EtOAc 19); mp 128-13 1 OC (Et20); IR (neat) 3077,2997,289 1,2836. 1716. 15 13, 1444, 1399, 1265, 1183, 1070 cm-1; NMR (400 MHz, CDC13) 6 7.02-6.98 (2& m), 6.82-6.78 (2H, m), 6.65 (2H, dd, J = 5.5, 1.9
HZ),6.49 (2H,d, J = 5.5 Hz), 5.13 (ZH,d, J = 1-8 Hz), 3-90 (2H. d*J = 13.6 HZ),3.74 (3H9 65 s), 3.61 (3H, s), 3.59 (3H7 s), 3-53 (2H7d, J = 13.5 Hz); 13~NMR (100 MHz, CDCb) 6 170.3, 170.3, 154.0, 145.2, 139.7, 139.2, 119.6, 114.2, 88.1, 83.8, 71.9, 67.6, 55.5, 52.1 (SC), 49.9; HRMS calcd for C23H23N07 FIJ+425.1475, found 425.1457.
Cycloadduct (103).
DMAD
la3 The reaction was carried out as in the general procedure A using DMAD (234 mg, 1.65 mmol) and 70 (400 mg, 1.50 mmol) in Et20 (5 mL) for 6 weeks to yield the cycloadduct 103
(443 mg, 72%) as a white solid: Rf = 0.40 on silica gel (hexanes-EtOAc 1 :1); mp 162- 165 OC
(Et20); IR (Dr) 3030,3000,2950,2850,2790, 1735, 1708, 1465, 1437 cm-];'H NMR (400 MHz, CDC13) 6 7.34-7.20 (5H,m), 6.57 (2H. dd, J = 5.5, 1.8 Hz), 6.4 1 (2H. d, J = 5.5 Hz),
5.11 (2H, d, J= 1.9 HZ),3.77 (2H, s), 3.58 (3H,s), 3.53 (3H, s), 3.29 (2H, d, J= 13.2 Hz),
2.96 (2H, d, J = 12.9 Hz); I~cNMR (100 MHz, CDCI,) 6 170.5, 170.4, 139.7, 139.1, 136.9,
129.3, 128.2, L27.1, 88.4, 83.7, 72-0, 67.8, 62.5, 52.0, 51.9, 50.8. Anal. Calcd for
C23H23N06: C, 67.47; H, 5.66; N, 3.42. Found: C. 67.08; H, 5.80; N. 3.67.
Cycloadduct (104).
The reaction was carrïed out as in the general procedure A using DMAD (2.3 g, 16.4 mmol) and 71 (4.4 g, 14.9 mmol) in Et20 (15 mL) for 6 weeks to yield the cycloadduct 104 66 (4.26 g, 65%) as a white solid: Rf = 0.14 on silica gel (hexanes-EtOAc 1: 1); mp 159- 163 OC (acetone); IR (CCb) 3066, 3000, 2952, 2936, 2836, 2786, 1723, 1558, 1458, 1436, 1248, 1103, 1085, 1042, 1007 cm-1;'H NMR (400 MHz, CDCI3) 6 7.26-7.22 (2H,m), 6.84-6.80
(2H,m), 6.57 (2H,dd, J = 5.5, 1.9 Hz), 6.41 (2H, d, J = 5.5 Hz), 5.10 (ZH,d, J = 1.5 Hz), 3.77 (3H, s), 3.71 (2H,bs), 3.59 (3H, s), 3.53 (3H, s), 3.28 (2H,d. J = 13.2 Hz), 2.92 (2H, d* J = 13-2 HZ); '3~NMR (100 MHz, CDC13) 6 170-5, 170-4, 158-7, 139.8. 139.0, 130.6, 128.9, 113.6, 88.5, 83.7, 72.0, 67.8, 61.9, 55.2, 52.0, 51.9, 50.7. Anal. Calcd for C24H25N07: C,65.59; H, 5.73; N, 3.19. Found: C, 65.50; H, 5.84; N. 3.15.
DMAD
The reaction was cmied out as in the general procedure A using DMAD (2.19 g, 15.4 mmol) and furfuryl sulfide 105 (3.00 g, 15.4 mmol) in Et20 (10 mL) for 3 weeks to yield the cycloadduct 106 (3.68 g, 7 1%) as a white solid: R.= 0.33 on silica gel (hexanes-EtOAc 12); rnp
NMR (200 MHz, CDCl3) G 6.57 (2H, dd, J = 5.5, 1.8 Hz), 6.41 (2H, d, J = 5.5 Hz), 5.09
(2H. d, J= 1.7 Hz), 3.58 (3H, s), 3.57 (3H,s), 3.52 (ZH,ci, J= 15.1 Hz), 2.87 (2H, d,J=
15.1 Hz); I~cNMR (50 MHz, CDCI3) 8 170.2, 170.0, 141-3, 138.9, 87.1, 83.3, 73.4, 67.2, Cycloadduct (107).
The reaction was carried out as in the general procedure A using freshly prepared 7539 (424 mg, 1.89 mmol) and 60 (366 mg, 2.08 mol) in Et20 (10 mL) for 15 h. Recrystallisation from CH2Cl2 yielded the cycloadduct 107 (525 mg, 69%) as a white solid: Rf= 0.38 on silica gel (hexanes-EtOAc 1: 1); rnp 18 1- 183 OC (CH2C12); IR (KR)3002,2952,293 1, 17 15, 1574,
1448, 132 1, 1279, 1 152 cm- I; NMR (400 MHz, CDC13) 6 7.86-7.83 (2H,m), 7.7 1-7.67
(1H. m), 7.63-7.59 (ZH, m), 6.54 (4H,bs). 4.73 (2H, bs), 3.70 (3H,s), 2.21-2.08 (4H,m), 1.92-1.80 (1H. m), 1.68-1.61 (lH, m); L3CNMR (LOO MHz, CDCl3) 6 169.6, 142.1, 140.5.
138.6, 134.0, 129.4, 128.6, 91.5, 91.3, 83.4, 71.2, 52.3, 25.7, 16.7. Anal. Calcd for C21H2006S:C, 62.99; H, 5.03. Found: C,62.73; H, 4.8 1.
Cycloadduct (108).
OreSPh /SO~P~ COMe 80
A solution of 80 (500 mg, 2.84 mol) in CH2C12 (35 mL) was treated with m-CPBA 50% (2.94 g, 8.52 rnmol) at O OC and stirred for 3 h at a. The mixture was diluted with CH2C12, washed with a saturated solution of NaHC03 (lx), a 5 M solution of NaOH (Zx), and b~e(lx), dried (MgS04), filtered uid concentrated. The cmde keto-suifone 81 was dissolved in Et20 (3 mL) and treated with 60 (500 mg, 2.84 mmol). The mixture was stored for 24 h at rt during which time the product crystallized out. The crystals were isolated by fùtration and washed with 68 Et20 to yield the cycloadduct 108 (327 mg, 30%) as a white soiid: Rf= 0.38 on silica gel
(hexanes-EtOAc 1: 1); mp 138- 142 OC (CH2C12); IR (Dr) 3065,2952, 1684. 1574, 1306 cm- 1 ; 'H NMR (400 MHz, CDC13) 6 7.88-7.85 (28m), 7.76-7.72 (1H. m), 7.68-7.64 (2H, m),
6-80 (2HTddT J = 5.5, 1.8 HZ), 6.64 (28, d, J = 5.5 HZ),4-65 (2H. d, J = 1.5 HZ)?2.32 (3H, s), 2.18-2.05 (4H, m), 1.86-1.74 (1H. m), 1.64-1.59 (lH, m); 13C NMR (100 MHz, CDC13) 6 206.6, 142.4, 140.L, 139.3, 134.3, 129.7, 128.0, 92.0, 88.9, 83.2, 80.5, 32.3, 25.8, 16.6.
Anal. Calcd for C2 1 H200sS: C, 65.6 1; H, 5.24. Found: C, 65.28; H, 5.23.
Cycloadducts (109) and (110).
MeOC- C02Me Et20 &&+a/LO~M~ /&oM~ COMe C02Me 60 109 110
The reaction was cmed out as in the general procedure A using 76 (250 mg, 2.0 mmol)
and 60 (352 mg, 2.0 mmol) in Et20 (5 rnL) for 2 weeks. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes : EtOAc 1: 1) to yield a mixture of cycloadduct 109 (284 mg) ald 110 (76 mg) in a 4: 1 ratio as white solids in a combined yield of
60%. Cycloadduct 109: Ri= 0.43 on silica gel (hexanes-EtOAc 1: 1 ); mp 146- 148 OC (CH2C12);
IR (KBr) 3023, 3002, 2959, 2931. 2868, 1738, 1680 cm-'; lH NMR (200 MHz. CDC13) 6 6.55-6.49 (4H, m), 5-04 (2H, bs), 3.60 (3H,s), 2.20-1.75 (5H, m), 1.82 (3H, s), 1.69-1.57 (lH, m); 13~NMR (50 MHz, CDCI3) 6 207.4, 171.1, 142.8, 138.4, 90.3, 83.2, 76.0, 71.2,
52.0. 3 1.9, 25.5, 16.9; And. Calcd for C17H1g05:C, 67.54; H, 6.00. Found: C,67.25; H, 5.94. Cycloadduct 110: Rf = 0.26 on s$ca gel (hexanes-EtOAc 1: 1); rnp 139- 141 OC (CH2CI2); IR (KBr)3002,2945,2924,2861, 1726, 1704 cm-1; IH NMR (400 MmCDCl3) 6 6.59 (2H, d, J = 5.5 HZ), 6-42 (2HTdd, J = 5-7, f -9 HZ), 5.04 (2HV dTJ = 1.8 HZ),3.59 (3H7 s), 2.17-
2.04 (4H,m), 2.01-1.89 (lH, m), 1.98 (3H, s), 1.70-1.63 (IH, m); 13~NMR (100 MHz, CDC13) 6 204.3, 171.5, 144.6, 135.9, 90.5, 83.5, 82.6, 67.0, 52.0, 29.7, 25.6, 17.2. Anal.
Calcd for Cl7H1805: C, 67.54; Hi6.00. Found: C, 67-14; H, 5.97. Cycloadduct (111).
80 111
The reaction was carrieci out as in the generd procedure B using methyl propiolate 74
(7 16 mg, 8.52 mol) and 60 (1 -0g. 5.68 rnmol) in a solution of 5 M LiC104 in Et20 (7 d)for 8 weeks. Purification by flash chromatography (hexanes-EtOAc 1: 1) yielded the cycloadduct 111 (846 mg, 57%) as a white solid: Rf = 0.27 on silica gel (hexanes-EtOAc 1: 1); mp 119- 12 1 OC (CHtCI2); IR (KBr) 3065, 3009, 2952, 29 17, 2847, 1715 cm-1; [H NMR (400 MHz, CDC13) 6 6.56 (2H,dd, 1 = 5.7, 1.7 HZ), 6.12 (2H, d, J = 5.5 Hz), 4.82 (ZH, d, J = 1.5 Hz),
3.55 (3H,s), 2.56 (1H, s), 2.35 (2H, dt, J = 14.0, 4.5 Hz), 2.1 1 (2H, dt, J = 14.2, .3.1 Hz). 1.99 (1H. qt, 1 = 13.4, .3.9 Hz), 1.75-1.68 (LH, in); 13C NMR (100 MHz, CDC13) 6 172.1,
140.5, 139.5, 87.4, 80.8, 63.8, 55.5, 51.9, 24.8, 17.3. And. Cdcd for C15Hi604: C,69.22; H, 6.20. Found: C, 68.86; H, 6.01.
Cycloadduct (1 13).
The reaction was carried out as in the generai procedure A using ethynyl p-tolylsuifone
112 (200 mg, I. 11 mmol) and 60 (235 mg, 1.33 rnmol) in a solution of 5M LiC104 in Et20 (3 rnL) for 4 weeks. Purification by flash chromatography (hexanes-EtOAc 1:I) yieIded the cycloadduct 113 (328 mg. 83%) as a white solid: Rf= 0.32 on silica gel (hexanes-EtOAc 1: 1); 70 cm-l;IH NMR (400 MHz, CDClj) 6 7.53 (2H, d, J = 8.0 Hz), 7.21 (W,d, J = 8.4 Hz), 6.86
(2H, d, J=5.5 Hz), 6.38 (2H,dd, J= 5.5, 1.8 Hz), 4.64 (2H. d, J= 1.8 Hz), 2.62 (2H, dt, j = 14.0, 4.5 Hz), 2.39 (3H, s), 2.26 (2H, dt, J = 14.2, 3.1 Hz), 2.00 (IH, tq, J = 13.5, 4.1 Hz), 1.84 (IH, s), 1.83-1.76 (IH, s); 13C NMR (100 MHz, CDC13) 6 145.0, 144.2, 137.8,
137.2, 129.2, 129.0, 89.8, 83.5, 81.1, 64.0, 26.3, 21.6, 17.1. Anal. Cdcd for C~OH~~O~S: C, 67.40; H, 5.66. Found: C, 67.27; H, 5.60.
Dimethyl l-(2-Furan-2-yl-ethyI)-7-oxa-bicyclo[2.2.1]hepta-2,5-diene-2,3- dicarboxyiate (114) and cycloadduct (115).
DMAD
115 The reaction was carried out as in the general procedure A using DMAD (105 mg, 0.74 mmol) and 1,2-bi~(2-furyl)ethane~~63 (100 mg, 0.62 rnmol) in Et20 (1 rnL) for 3 weeks. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes- EtOAc 3: 1) to give the cycloadduct 114 (70 mg, 38%) as a coiorless oil and the unreacted starting material 63 (19 mg, 19%). Further elution with hexanes-EtOAc (1:l) gave the cycloadduct 115 as a white solid (44 mg, 16%). Cycloadduct 114: Rf= 0.43 on silica gel
(hexanes-EtOAc 3: 1); IR (neat) 3037,3002,2952,2854, 1715, 1638, 1509, 1436, 127 1, 1229, 1009 cm-1;1H NMR (400 MHz, CDCl3) 6 7.29 (LH,d, J = 1.8 Hz), 7.16 (IH, dd, J = 5.2, 1.9 Hz), 6.93 (lH, d, J = 5.1 Hz), 6.26 (lH, dd, J = 3.3, 1.9 Hz), 5.99 (IH, m), 5.64 (lH, d, J =
1.8 Hz), 3.82 (3H, s), 3.76 (3H, s), 2.82-2.70 (2H, m), 2.55-2.48 (2H, m); 13C NMR (100 MHz, CDC13) 6 164.8, 162.7, 155.6, 154.6, 151.8, 144.6, 144.5, 141.0, 110.1, 105.2, 96.8,
83.4, 52.4, 52.3, 27.5, 23.4; HmS cdcd for Cl(jH1606 [Ml+ 304.0947, found 304.0943. 71 Cycloadduct 115: Rf= 0.46 on siiica gel (hexanes-EtOAc 1: 1); rnp 189-1 92 OC (EtzO); IR (Dr)
3093, 3016, 2959, 2854, 1739, 1710, 1650, 1440, 1429, 1279, 1261, 1112 cm-'; IH NMR (400 MHzTCDC13) 6 7.16 (2H9 ddTJ = 5-1, 1.8 HZ), 6.95 (2H, dTJ = 5-1 HZ), 5.62 (2H, d, J
= 2.2 Hz), 3.81 (6H, s), 3.76 (6H, s), 2.36-2.24 (4H, m); NMR (100 MHz, CDCls) 8 164.7, 162.7, 155.5, 151.9, 144.8, 144.6, 97.0, 83.5, 52.4, 52.3, 24.3; HRMS calcd for C22H220 10 Ml+ 446.12 13, found 446.1238.
Dimethyl 1-(4-Furan-2-yl-butyl)-7-oxa-bicyclo[2.2.1]hepta-2,5-diene- 2,3-dicarboxylate (116) and cycloadduct (117).
DMAD
117
The reaction was carried out as in the general procedure A using DMAD (41 1 mg, 2.89 mmol) and 1.4-bis(2-fury1)butane 61 (500 mg, 2.63 mmol) in Et20 (2 mL) for 3 weeks. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexanes-
EtOAc 3: 1) to yield the cycloadduct 116 (330 mg, 388) as a colorless oil and the unreacted starting material 61 (93 mg, 19%). Further elution with hexanes-EtOAc (1: 1) gave the cycloadduct 117 as a dear oil (270 mg, 22%). Cycloadduct 116: Rf = 0.40 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3009, 2952, 2861, 17 18, 1639, 1508, 1437, 1272, 123 1, 120 1, 1006 cm-1; lH NMR (400 MHz, CDCl3) 6 7.25 (lH, dd, J = 1.8, 0.7 Hz), 7.14 (1H. dd, J =
5.2, 1.9 HZ), 6.95 (lH, dTJ = 5.5 HZ), 6.23 (lHTdd, J = 2-9, 1.8 HZ),5-94 (rH, ddTJ = 3.3, 0.7 Hz), 5.60 (lH, d, J = 1.8 Hz), 3.79 (3H, s), 3.74 (3H, s), 2.60 (2HTmt, J = 7.5 Hz), 2.22-2.08 (ZH,m). 1.68 (2H, qu, J = 7.5 Hz), 1.55-1.37 (2H, m); 13c NMR (100 MHz, CDCl3) 6 165.1, 162.6, 156.1, 155.8, 151.3, 144.9, 144.5, 140.6, 110.0, 104.7, 97.6, 83.2, 72 52.3, 52.2, 28.5, 28.0, 27.6, 24.3; HRMS calcd for C18H2006 [Ml+ 332.1260, found
332.1263- Cycloadduct 117: Rf = 0.53 on silica gel (hexanes-EtOAc 1: 1); IR (neat) 3093, 3002, 2952, 2868, 1745, 1717, 1641, 1561, 1437, 1378, 1 122, 1084 cm-[; [HNMR (400 MHz, CDC13) 6 7.14 (2H, dd, J = 5.3, 2.0 Hz), 6.95 (2H. d, J = 5.1 Hz), 5.61 (2H, d, J = 1.8 Hz), 3.81 (6H,s), 3.75 (5H,s), 2.19-2.08 (4H, rn), 1.58-1.41 (4H,m); '3C NMR (100 MHz, CDC13) 6 165.1, 162.7, 156.2, 151.4, 144.9. 144.6, 97.6, 83.3, 52.3, 52.2, 28.6, 25.0;
HRMS cdcd for C24H26010 (?dl+ 474.1526, found 474.1526.
5 1.4 References and Notes
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Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 199 1; Vol. 5, p 45 1. (e) Intrarnolecular Diels-Alder reactions: Roush, W. R. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 513. (f) Retrograde Diels- Alder reactions: Sweger, R. W.; Cza- A. W.In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, p 55 1. (2) For a critical survey on the mechanistic aspect of Diels-Alder reactions, see: Sauer, I.;
Sustmann. R. Angew. Chem. Int. Ed. Engl. 1980,19, 779. (3) For recent reviews on tandem Diels-Alder cycloadditions: (a) Denmark, S. E.; Thorarensen,
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Tetrahedron Lett. 1994,35,2389. (d) Warrener, R. N.; Maicsirnovic, L.; Butler, D. N. J. Chem. Soc., Chern. Cornm. 1994, 183 1. (e) Warrener, R. N.; Wang, S.; Maksimovic, L.; Tepperman, P. M.; Butler D. N. Tetrahedron Lett. 1995,36, 6 141. (0 Warrener, R. N.; Maksimovic, L.; Pitt, 1. G.; Mahadevan, 1.; Russell, R. A.; Tiekink, E. R. T. Tetrahedron Lett. 1996,36, 3773. (25) Pollrnann, M.; Müllen, K. J. Am. Chem. Soc. 1994,116, 23 18. 76 (26) (a) Luo, J.; Hart, H. J. Org. Chem. 1988,53. 1343. (b) Blatter, K.; Godt, A.; Vogel, T.; Schlüter, A.-D. Makromol. Chem. Macrornol. Symp. 1991,44, 265. (c) Packe, R.;
Enkelmann, V.; Schlüter, A. -D. Makromol. Chern. 1992,193, 2829. (d) Schürmann, B. L.; Enkelmann, V.; Loffler, M.; Schlüter, A.-D. Angew. Chem. Int. Ed. Engl. 1993.32, 123. (27) (a) Warrener, R. N.; Elsey, G. M.; Maksimovic, L.; Johnston, M. R.; Kennard, C. H. L. Tetrahedron Lett. 1995,42, 7753. (b) McCarrick, M. A.; Wu, Y.-D.;Houk, K. N. J.
Am. Chem. Soc. 1992,114, 1499. (28) (a) Kitzing, R.; Fuchs, R.; Joyeux, M.; Prinzbach, H. Helv. Chim. Acta 1968,51, 888. (b)Bansal, R. C.; McCulloch, A.W.; McInnes, A. G. Can. J. Chern. 1969,47, 2391. (c) Bansal, R. C.; McCulioch, A.W.; Mchnes, A. G. Can. J. Chern. 1970,48, 1472. (d) For a recent review on the synthesis of azabicyclic systerns see: Chen. 2.; Trudell, M. L. Chem. Rev. 1996, 96, 1179. (29) (a) McCulloch, A. W.; Stanovnik, B.; Smith, D. G.; McInnes, A. G. Cm J. Chem. 1969,
47, 4319. (b) Anderson, W. K.; Dewey, R. H. J. Med. Chem. 1977,20,306. (c) Xing, Y. D.; Huang, N. 2. J. Org. Chem. 1982,47, 140. (d) For the asymmetric synthesis of oxanorbornadiene intemediates see: Sha, C. -K.;Shen, C.-Y.; Lee, R.-S.; Lee, S.-R.; Wang, S.-L. Tetrahedron Le#. 1995,36, 1283. (30) (a) For a recent review on aromatic heterocycles as intermediates in synthesis, see: Shiprnan, M. Contemp. Org. Synth. 1995,2, 1. (3 1) (a) For recent reviews on the ring opening of oxabicyclic systems, see: Chiu. P.; Lautens.
M. Topics in Cuvent Chemistry; Springer-Verlag: Berlin, 1997, Vol. 190, p 1. (b) Woo, S.; Keay, B. Synthesis 1996, 669. (c) Lautens, M. Synleft 1993, 177. (32) (a) Lautens, M.: Fillion, E. J. Org. Chem. 1996,6I, 7994. (b) Loutens, M.; Filiion. E. J. Org. Chem. 1997,62,4418 (33) Wenkert, E.; Guo, M-; Lavilla, R.; Porter, B.; Rarnachandrrui, K.; Sheu, LH. J. Org. Chern. 1990,55, 6203. (34) Rogers, C.; Keay, B. A. Can. J. Chem. 1992, 70, 2929. (35) Zanetti, J. E. J. Am. Chem. Soc. 1927.49, 1065.
(36) Zanetti, J. E.; Beckmann, C. O. J. Am. Chern. Soc. 1928,50, 203 1. (37) Zarnbias, R. A.; Caldwell, C. G.; Kopka, 1. E.; Hammond, M. L. J. Org. Chem. 1988, 53, 4 135.
(38) (a) Nystrom, R. P.; Berger, C. R. A. J. Am. Chem. Soc. 1958,80, 2896. (b) Scharf, H.- D.; Wolters, E. Chem. Ber. 1978.111, 639. (c) Buxton, S. R.; Holm, K. H.; Skattebgl, L. Tetrahedron Lett. 1987,28,2 167. (39) Shen, M.; Schultz, A. G. Tetrahedron Lett. 1981,22, 3347. (40) Jones, E. R. H.; Shen, T. Y.; Whiting, M. C. J. Chem. Soc. 1950, 236. (41) Larock, R. C.; Liu, C.-L.J. Org. Chem. 1983.48, 2151. (42) Mancuso, A. J.; Swern, D. Synthesis, 1981, 165. (43) Papadopoulos, E. P.; Haidar, N. F. Tetrahedron Len. 1968.9, 1721. (44) Hasan. 1.; Marinelli, E. R.; Chang Lin L.-C.;Fowler, F. W.; Levy, A. B. J. Org. Chem. 1981, 46, 157. (45) (a) Grieco, P. A.; Nunes, J. J.; Gad, M. D. J. Am. Chem. Soc. 1990, 112, 4595. (b) Forman, M. A.; Dailey, W. P. J. Am. Chem. Soc. 1991,113, 2761. (46) Heard, N. E.; Turner J. J. Org. Chem. 1995,60,4302. (47) For the synthesis of an azaoxabicyciic system from the seaction of furor2.3-clpymoles with two equivalents of DMAD, see: Sha, C.-K.;Lee, R.-S.; Wang, Y.Tetrahedron 1995,51, 193. (48)A sirnilar observation has been noted by Danishefsky in his work with P-phenylsulfinyl- a$-unsaturated carbonyl dienophiles. Danishefsky, S.; Harayama, T. J.; Singh, R. K. J.
Am. Chern. Soc. 1979,101, 7008.
(49) (a) Commercially available (b) Truce, W. E.; Onken, D. W. J. Org. Chem. 1975,4& 3200.
(50) Grigg, R.; Roffey, P.; Sargent, M. V. J. Chem. Soc. C 1967, 2327. (5 1) SU, W.C.; Kahn, M.; Mitron, A. J. Org. Chem. 1978,43, 2923. CHAPTER 2
EXPLORING THE REACTMTY OF DIOXACYCLIC COMPOUNDS AS A ROUTE TO POLYSUBSTITUTED DECALINS AND FUSED POLYCYCLES 9 11.1 Introduction
The flexibiiity of the "pincer" Diels-Alder reaction in temis of dienes and dienophiles was demonstrated in the previous chapter by synthesizing a variety of bridged polyheterocyclic ring systems compounds with stereocontrol. The second step was to explore the reactivity of
dioxacyclic compounds and establish their potential usefulness in synthesis. As discussed in Chapter 1, dioxacyclic compounds have been used as templates for the constmction of belt and cavity moleculesl as weli as cage molecules2 and ladder polymen.2-3 However, there are only scattered reports in the iiterature describing their reactivity and subsequent transformations or their utility in synthesis. To the best of our knowledge, there are only two examples utilizing dioxacycles substrates in a synthesis that have been reported in the hterahire.
The most recent application appeared in 1988 by Lin and Chou and dealt with the synthesis of 2,3-dibromoanthracene 122 as illustrated in Scheme 2.1.4 In this synthesis, the dioxapentacycle 121 was hydrogeneted and dehydrated in the presence of perchlofic acid leading to the desired product 122 in good overai1 yield.
Scheme 2.1
autoclave - - xylene 175 OC, 4 h
PdC, H2 CH2CI2, MeOH rt, 2 h 96 % I
HCIO~ EtOH. toluene Br Br 80 OC, 6 h H 80 In 1978, Tochtermann and coworkers reported the synthesis of hydroxy- and oxosubstituted (partidly hydrogenated) benz[a]anthracenes from a dioxacyciic intermediate? The dioxacyclic substrate 123 was treated with strong acid to induce the ring opening reaction and give the derivative 124. No information was given on the stereochemis@y of the starting dioxacycle 123 or its derivative 124,
Scheme 2.2
Benzene - I reflux, 45 h
woOMe
In both examples, the authors developed and used similar suategies to prepare complex arornatic compounds via acid-induced opening of oxabicycles. However, in these synthetic methods, the stereochemicai information set by the "pincer" Diels-Alder reaction (6 stereocenters) was partially or completely lost .
We and others have used oxabicyclic remplates and revealed their importance and value as intermediates, arising fiom their ability to be stereoselectivity ring-opened to highly functionalized cyclohexane de~-ivatives.~-~Various regio- and stereoseiective ring opening process have been developed in our group over the past few years.6.8-lo The most relevant to this study, namely, the nucleophiiic ring opening reaction.698 the reductive nickel-catalyzed hydroalumination- 8 1 fragmentation sequenceg and the palladium-catalyzed hydrostannatiodtin-lithium exchange fragmentation sequence,lO are shown in Scheme 2.3 and described below.
Scheme 2.3
In the nucleophilic ring opening reaction, the nucieophiie adds to the alkene via an SN^' like process: carbometailation of the double bond followed by cleavage of the bridging ether. This reaction has been demonstrated to work for intermolecular as weli as for intramolecular nucleophiles in the case of [3.2.1]0xabic~cles.~~~The intramolecular ring opening also proceeds for [2.2.l]oxabicycles and will be dixussed in detail in Chapter 4. In al1 cases, the attack of the nucleophile occurs exclusively on the exo face of the substrate, thus setting the stereochemistry of
the reaction. When an alkyl substituent is present at the bridgehead position, the nucleophilic addition is highly regioselective and uccurs at the position distai to the bridgehead substitutent.8" It is noteworthy that the reaction works only for organolithium reagents in Et20 as the solvent. In addition, at least 5 equiv. of organolithium are required for the iniennolecular reaction to proceed, strongly suggesting an aggregation of the nucleophile with the substrate prior to ring opening. MeLi is only effective in ring opening unsubstituted oxabicycles when refluxing TMEDA is used as the solvent. Bridgehead substituted substrates are inert toward MeLi in TMEDA, however, the use of CeCl3lMeLi induces the opening of unsymmetrical [3.2.l]oxabicycles bearing a free hydroxy group in good yield as recently observed in Our Iaboratories.12
The nickel-catalyzed hydroalurnination-fragmentation sequence is the second mode of opening (Scheme 2.3).9 Treatment of an oxabicyclic subsvate with DIBAL-H as the source of hydride in the presence of a catûlytic amount of Ni(C0D)î gives the reduced ring-opened product. In the case of unsymmetrical oxabicyclics. high regioselectivity for the hydroalurnination is observed when a phosphine such as dppb (1,4-bis(dipheny1phosphino)butane) or PPh3 is used. The hydrogen is added distal to the bridgehead substituent and the metal in close proximity to the substituent. Further fragmentation of this intemediate gives a cyclohexenol bearing a trisubstituted double bond.
In marked contrat, the palladium-catalyzed hydrostannation gives complementary regioselectivity; the trialkyltin group ends up distal to the bridgehead substituent and the hydrogen is proximal.10 A homogenous catalyst such as Pdz(dba)j in the presence of PPh3 or an heterogenous catalyst such as Pd(OH)2 on carbon (Pearlman's catalyst)l3 and BujSnH as the hydride source have been reported. Further fragmentation of this intermediate upon tin-lithium exchange yyields a cycloakenol bearing a tertiary alcohol, and a disubstituted double bond, which constitutes the third mode of opening (Scheme 2.3).
Our objective was to design a strategy to rapidly prepare cis-decalins and related fused polycyclic compounds based on the stereocontrolled sequential ring opening of dioxacyclic templates using the reactions described above (Equation 2.1).14 In this strategy, the stereochemical information contained in the "pincer" Diels-Aider cycloadduct is retained by taking advantage of the rigidity of the dioxacyclic ternplate to control the stereochemical course of the reactions. By combining the vesatility of the "pincer" Diels-Alder reaction with the methods of oxabicyclic ring opening, we envisaged an efficient construction of stereochemically nch and rnultifunctional polycyclic systems in a limited nurnber of steps. Oxygenated polycyclic systems are found in many naturai products w hich exhibit wide-ranging biological ac tivities. In this chapter, we will present the scope of the sequential ring opening of a variety of dioxacyciic compounds for the stereoseiective synthesis of highly functiondized cis-decalins and related fused polycyclic systems. Using the reactions described above, we have investigated the electrophilicity of the dioxacyclic dienes toward organolithium, and hydndic reagents via metal- cataiyzed hydrometallation reactions. The issue of regio-, chemo-, enantio- and stereocontrol in the sequentid ring opening reactions was addressed. A new base-induced ring opening reaction is also described.
5 11.2 Results and Discussion
5 11.2.1 Substrate Preparation
The preparation of the required substrates commenced with the dioxacyclic dicarboxylic acid and diester systems reported in Chapter 1. Due to the susceptiblity of the carboxylic acid and ester functional groups to react with the organometallic reagents used in the ring opening reactions, the dioxacyclic compounds were fmt reduced to the corresponding diols and further protected as disilyl or dirnethyl ethers (Tables 2.1 and 2.2). Table 2.1. Dioxatetracyclic Substrate Preparation
Entry Su bstrate Produ& yieldb, %
a Reduction and protection, details in the Experirnental Section. Isolated yield of analytically pure product.
Reduction of the dicarboxylic acid substrates 125 (prepared using Deslongchamps' procedureis), 87, and 98 was performed in refluxing THE The use of the milder reducing agent LW(OMe)3 was essential in these cases since Limgave ring-opened side products
(triols) arising from the reductive ring cleavage of the oxabicyclic alkene moiety (- 10% yield).16 For exarnple, reduction of 87 using Li- in refluxing ?'HF provided the di01 128 in 56% yield in addition to the triol 137 obtained in 10%yield (Equaùon 2.2).
LiAIH4 - (22) THF, reflux, 5 h C02H C02H OH 85 For the diester substrates, 96,97,99,101-104,106 and the monoester 107, the reaction was performed at rt with LiALH(OMe)3 or Li- without any side products. In the case of 95, the presence of a primary aikyl chtonde group necessitated the use of a non- nucleophilic reducing agent like DIBAL-H giving the di01 131 in 59% yield (entry 8, Table 2.1). The structure of 136 was detemùned by X-ray crystallography (see Appendix 2, p xx).
Table 2.2. Dioxapentacyclic Substrate Preparation
Entry Substrate Producta yieldb, %
a Reduction and protection, details in the Experimental Section. Isolated yield of analytically pure product. 5 11.2.2 Unsubstituted Dioxatetracycle Nucleophilic Ring Opening
We first explored the reactivity of the unsubstituted dioxatetracycle 127 toward the nucleophiiic ring opening reaction. Treating 127 with an excess of n-BuLi (12 equiv.) at -78 OC to room temperature gave, after the sequential double ring opening reactions, two regioisomeric cis- decalin diois 153 and 154 easily distinguishable by 'H NMR and 13C NMR in a 2.8:1 ratio (Equation 2.3).
OTBDMS HO ,OTBDMS *BuLi (2.3) -78 OC to x OC ,Bu IFBU IFBU OTBDMS €t20 HO ;OH TBDMSO~OH
In an attempt to improve the regioselectivity, a brief study of the effect of the temperature was conducted (Table 2.3). Starting from -78 OC and further warming the soiution to either -30 OC or O OC gave a mixture of regioisomeric decalins 153 and 154 with a preference for the mes0 decalin 153 (Table 2.3, entries 2 and 3). The results showed that the temperature had Little effect on the regioselectivity of the second ring opening reaction. On the other hand, the reactivity of the second ring opening was highly influenced by the temperature. At room temperature or O OC,the second ring opening was cornpiete after 8 h whereas at -30 OC, 48 h was necessary to obtain the bis-opened products. Lowenng the temperature to -78 OC totally inhibited the opening of the second oxabicyclic moiety; the mono-opened product 155 was isolated in 9 1% yield (Table 2.3, entry 4). During the optirnization process, the number of equivalents of n-BuLi was reduced to 5 equiv. giving 155 after 5 h at -78 OC (Figure 2.1). Table 23. Nucleophilic Ring Opening of 127, Temperature Effect
- -- - Entry Temperature. OC Time, h Ratioa Products yieldc, %
1 rt 8 2.8/1 1531154 09 2 O 8 2.911 1531154 SQ 3 -3J 48 3.311 1531154 77 4 -78 5 - 155 91
------Ratio measured b y 'H NM R. Ring opening, details in the Experimental Section. lsolated yield of analyticafly pure products. 5 Equivalents of nBuLi were used.
The selective formation of the meso decalin 153 was rationaiized in ternis of two distinct ring opening reactions. The opening of the first oxabicyclic moiety generated a lithium aikoxide intermediate 156 (M=Li) in which, the Lithium alkoxide and the butyl group adopt a pseudo-axial and a pseudo-equatorïal orientation respectively in a hdf-chair conformation (Figure 2.1). Because of the rigidity of the tricyclic system, the Iithium atom may forrn a six-rnembered chelate with the remaining bndging oxygen. The lithium could then act as a Lewis acid assisting the C-O bond cleavage of the second ether bridge syn to the fint allcoxide group in order to maintain the six-rnembered chelate. Attack at the anti position would give a seven-membered chelate which should not be as energetically favored. The tight chelation of the lithium alkoxide with the bridging ether rnay weaken one of the C-O bonds and influence the electrophilicity of the two sp2 carbons thus affecting the orientation of the SN^' attack of the incoming nuc~eophile.~~In addition, aggregation of the excess n-BuLi centered at the alkoxide position should also favor the delivery of the second nucleophile at the syn position of 156 (M=Li).
Figure 2.1 anti OTBDMS / \
n-Bu TBDMSO~OH OTBDMS 155 156
We speculated that changing the counterion would enhance or even reverse the 88 regioselectivity of the reactioa (Equation 2.4). Since the mono-opened "intermediate" 155 could be isolatrd (Table 3, entry 4), the desired metal alkoxide intermediate 156 couid simply be generated via deprotonation with a basic organometallic reagent.
OTBDMS 155
A lcss in the selectivity was observed when the alcohol 155 was deprotonated with
BuMgBr (1 equiv.) pnor to treatment with n-BuLi (5 equiv.) resuiting in an equimolar mixture of decalins 153 and 154 (Table 2.4, entry 1). Deprotonation of 155 with diethylzinc (Table 2.4, entry 2) gave similar results as the one-pot n-BuLi opening (Table 2.3, entry 3). Reacting 155 with (i-Bu)gAf to obtain the aiuminum akoxide intermediate gave a reversai in selectivity (Table 2.4, entry 3).
Table 2.4. Nudeophilic Ring Opening of 155
a Ratio measured by 'H NMR. Ring opening, details in the Experimental Section, C lsolated yield of analytically pure product,
In order to rationalize this observation, we postulated the formation of an aluminate cornplex in the presence of excess n-BuLi. The latter is not Lewis acidic but could stiil complex with the remaining bridging ether via the Li ion forming the intermediate 157 (Figure 2.2). Due to the steric buk of the aluminate complex and its negative charge, repulsive interactions between the incoming negatively charged nucleophile favored the delivery at the position of the oiefin distal to the aikoxy group (anti position) leading to the decah 154. This sequential double opening is complementary to the one-pot n-BuLi opening and either decalins can be obtained in good yields. Figure 2.2 +Li- - =AIR3 anti ! I
5 11.2.3 Substituted Dioxatetracycle Ring Opening
After the limited success in con~obgthe regioselectivity in the nucleophilic ring openhg of the unsubstituted dioxatetracycle 127, the regioselective ring opening reaction of a bridgehead substituted dioxatetracycles was studied. The regioselectivity of the sequential aucleophilic attacks should be controlled by the bridgehead substituents as demonstrated in the case of unsymmetrical [2.2.l]oxabicycles.8a The opening of the "anti" dimethyl dioxatetracycle 129 was first studied
(Scheme 2.4). When 129 was treated with excess n-BuLi (12 equiv.) at O OC for 7 h, the decatin 158 bearing six stereocenters was obtained in 90% yield (Scheme 2.4). The attack of the incoming nucleophile occurred exclusively at the position distal to the bridgehead substituents as observed previously for the simple oxabicyclic system~.~aThe substituted system behaved like the unsubstituted dioxatetracyclic system 127, and the reactivity of the second oxabicyclic moiety was highly dependent on the temperature. hdeed. the mono ring opening was easily achieved by simply perfomiing the reaction at lower temperature. For example, treatment of 129 at -78 OC for 4 h with 5 equiv. of n-BuLi provided the mono ring-opened product 159 in 90% yield. The subsequent reaction of 159 with t-BuLi (7 equiv.) yielded the unsymmevical decalin 160. Scheme 2.4
/ OTBOMS
/ OTBDMS TBDMSO, HO ?
t-BuLi n-Bu Et20, O OC, 3 h *Bu 91%
Surpnsingly, MeLi, which usually fails to open bridgehead substituted oxabicycio[2.2. I ] systems, did induce the fist opening on the dioxatetracycle 130 after 24 h at n (Scheme 2.5).l Ring opening under our reductive conditions was also examined. Since the cleavage of primary
TBDMS ethers with DIB AL-H at room temperature has been previously reported, l the more robust methyl ether blocking group was used in the hydroalumination study. Attempted ring opening on the free aicohol 161 indicated the reaction was very sluggish and did not yield the expected product. Protection of the alcohoi 161 as its methyl ether 162 foilowed by the nickel catalyzed reductive reaction yielded the decalin 163 in 78% yield (Scheme 2.5).9 DIBAL-H was added over 1 h using a syringe pump to a solution of 162 in the presence of a catalytic amont of Ni(COD)2 (19 mol%) and dppb (38 mol%) giving only one regioisomer by IH NMR. The chemoselectivity of the hydroalumination is noteworthy since only the dioxacyclic olefin was hydroalurninated in the presence of a trisubstituted olefin. The IH and 13C NMR spectra of 162 were not resolved at rt and variable temperature experiments were performed at 70-80OC to obtain weli resolved spectra. Scheme 2.5
KH, Mel, THF 18-cr0~n-6 wX.2 b
0+OMe MeO, DIBAL-H, Ni(COD)2 * dppb, toluene Me rn! Me
The hydrostannation-fragmentation sequence was applied to the dioxatetracycle 129. When 129 was reacted with 4 equiv. of BujSnH added over 3 h via a syringe pump using Pearlman's catalyst or Pd2(dba)flPh3, the di(tributylstanny1) intermediate was obtained with high regioselectivity as judged by 1H NMR (Equation 2.5).10*13 After removal of the excess Bu3SnH and the hexabutylditin formed during the course of the reaction, the di(tributylstanny1) intermediate, obtained in >90% yield, was dissolved in THF and treated with an excess of n-BuLi
(9 equiv.) or MeLi (30 equiv.) at O OC. The sequence of four reactions (bis-hydrostannation. bis- tin-lithium exchange and ring openllig) generated the decalin 164 bearing 4 contiguous quaternary stereocenters in 25% yield. The modest yield was attributable to the formation of several unidentified side products in the tin-lithium exchange step. The IH and 13C NMR spectra of 164 were not resolved at rt and variable temperature experiments were performed at 70-80 OC to obtain well resolved spectra. 1) Pd2(dba)3, PPh3, toluene TBDMSO, .OH or Pd(OH)2/C, THF (2.5) Bu3SnH OTBDMS 2) MuLi, THF HO "'OTBDMS 129 25% 1M
Finally. the triol 137 obtained as a side product in the reduction of 87 using Li- was protected as the acetonide 165 (Scheme 2.6). The oxabicyclic substrate 165 was opened in good yield and as a single regioisomer when treated with n-BuLi (6 equiv.) giving the decalin 166.
Scheme 2.6 0OH
5 11.2.4 Azaoxatetracycle and Unsymmetrical Dioxacycles Nucleophilic Ring Opening
The reactivity of an azabicycle versus an oxabicycle in a nucleophilic ring opening was investigated using the azaoxatetracyclic substrate 136. Reaction of 136 with an excess of n- BuLi (12 equiv.) at O OC produced the aminohydroxydecalin 167 in 92% yield (Scheme 2.7).
The addition was regioselective for both the aza and the oxa openings, occumng exclusively at the positions distal to the bridgehead substituents. This represents the first example of a nucleophilic azabicyclic [2.2.1] ring opening.19 Chemoselective ring opening of the oxabicyclic moiety over the azabicyclic portion was observed when 136 was reacted at lower temperature with exactly 4 equiv. of n-BuLi for a few minutes to give 168 in 82% yield. Substrate 136 was more reactive than the dioxatetracyclic substrate 129. and the reaction time as well as the 93 number of equivalents of nucleophile were crucial in order to control the progress of the
reaction. For exarnple, reacting 136 with only 5 equiv. of n-BuLi at -78 OC gave exclusively the bis-opened product 167 after 4 h. The chemoselectivity may be rationaiized by comparing the pK& of the allylic Ieaving groups; 4-methyl-benzenesulfonamide is a better leaving group than a secondary alcohol.20 The subsequent reaction of 168 with r-BuLi (7 equiv.) yielded the
aminohydroxy decalin 169 in excellent yieid. The structure of 169 was confmed by X-ray crystallography (see Appendix 2, p 330).
Scheme 2.7 /OTBDMS TsHN n8uLi (1 2 equiv.) Mu Et20, O OC, 1 h or MuLi (5 equiv.) YB" Et20, -78 OC, 4 h i OH Ph TBDMS~ 167
n-BuLi (4 equiv.) Et20,-78 OC, 30 min l Wh / OTBOMS / OTBDMS
t-BuLi (7 equiv.) & Et20, O OC, 30 min %Y0
The sequential intramolecular-uitemolecular nucleophilic ring opening of the dioxacycle
132 was also examined (Scheme 2.8). In order to carry out the haiogen-lithium exchange, the alkyl chloride 132 was transposed into the alkyl iodide 170 under Finkelstein's c0nditions.2~ Treatment of 170 with t-BuLi at -78 OC gave the allcyllithium intermediate which cyclized giving
171 in 75% yield.8b The attack of the internai nucleophile was assumed to occur exclusively on the exo face leading to a tram ring junction based on our earlier res~lts.~bThis is the first 94 example of an intramolecular ring opening of an oxabicyclic (2.24 system. A study of this
reaction was performed on [2.2.l]oxabicycles and will be Giscussed in Chapter 4. No trace of
the r-BuLi ring opening reaction was observed, although, a trace of the reduced product was detected. The 'H and 13~NMR spectra of 171 were not well resolved at room temperature due to the presence of conformational isomers. The remaining oxabicyclic moiety in 171 was opened with an excess of n-BuLi (7 equiv.) yielding the tricycle 172 in 75% yield.
Scheme 2.8
Nal, Acetone reflux, 2 days CI OTBDMS 91% OTBDMS
TBDMSO, 1
nBu g OH \ OTBDMS 172
A study of the reactivity of a disubstituted double bond versus a visubstituted olefin toward nucleophilic ring opening using 134 was also investigated. Treatment of 134 at O OC with an excess of n-BuLi (5 equiv.) gave exclusively the mono-opened product 173 (Equation 2.6). The second oxabicyclic moiety resisted opening using t-BuLi at room temperature. The reluctance of trisubstituted double bond toward carbolithiation was previously reported in the Iitenture and observed in our laboratories.2' No other synthetic transformation of the mono- opened product 173 was examined. TBDMSO.
O OC, 10 min 89%
5 11.2.5 Dioxapentacycle, Trioxapentacycle, and Azadioxapentacycle Ring Opening
We also investigated the reactivity of dioxapentacyclic comporinds in ring opening reactions. In ail the previous examples of sequentid ring opening of substituted dioxacycles, the substrates were "anri" disubstituted. A different reactivi~profile was observed for the "syn" disubstituted substrates. The reactivity of the dioxapentacycle 139 is summarized Scheme 2.9. Careful control of the reaction temperature led to the mono ring opening of 174 using n-BuLi (5 equiv.), in excellent yield after 15 h at -78 OC. However, 139 failed to undergo double opening to 175 regardless of the reaction temperature or the number of equivaients of n-BuLi leading instead to decomposition. In order to increase the reactivity of 174 toward the second opening, a more Lewis acidic metal counterion was added. Thus, 174 was treated with 2 equiv. of n-
BuMgCl followed by 5 equiv. of n-BuLi in the presence of THF to cleanly provide the bis- opened product 175 (Scheme 2.9). These conditions were also successfui for the ring opening of 174 with t-BuLi to yield the tricycle 176 (Scheme 2.9). In this case, a combination t- BuMgCVt-BuLi (25)was used since the transfer of the n-butyl group was observed when n- BuMgCl was used in the deprotonation step. Scheme 2.9 TBDMSO, HO :OH nBuMgCI, Et20 nBu then nBuLi then THF, 12 h, rt 78% 175
TBDMSO, OH
&& MuLi, Et20 _I -78 OC, 15 h gffBU 1;=,ç~s 97% -\ 'OTBDMS 139 174 TBDMSO,
Lautens and Gajda repoited the fmt asymmetric ring opening of oxabicyclic compounds ushg (-)- sparteine and organolithium reagents although the ee's were modest (Equation 2.7).*3 When the oxabicycle 177 was treated with n-BuLi/(-)-sparteineVthe cyclohexenol 178 was obtained in good yield and low ee.
nBuLi (5 equiv.) OTBDMS (2-7) OTBDMS - ikz-OTBDMS (-)-sparteine (5 equiv.) n-Bu OTBDMS pentane, -78 OC, 16 h IYC OH ln 76%, 28% ee 178
Applying this strategy to the enantioselective desymrnetrization of 139 using a Iarge excess of the complex n-BuLi/(-)-sparteine in Eh0 gave 174 in 56% ee (EquaPon 2.8). The enantiomeric excess was mesured using the chiral shift reagent Yb(hfc)3 and integrating the oxabicyclic olefi signais. A longer reaction tirne compared to the racemic ring opening reaction and a larger excess of organolithium were necessary for the reaction to go to completion. 97 Because of solubility problems, pentane could not be used to enhance the enantioselectivity as demonstrated in the previous study. The absolute stereochemistry was not determined and no yield was obtained due to the modest enantioselectivity.
TBDMSO OH
&& MuLi (20 equiv.) z' (2.8) (-)-sparteine (20 equiv.) L;-çs Et20, -55 OC, 1 week 56% ee 139 chiral-174
MeLi also led to the mono ring opening of 140 after 24 h at rt although in modesr yield
(Scheme 2.10). We briefly investigated the reductive ring opening of 179 (Scheme 2.10). As we had previously shown for 130, the dimethyl ether protected substrate was used and the free alcohol was protected as a methyl ether. Reductive ring opening of 180 via a nickel catalyzed addition-P-elimination reaction provided the tricycle 181 in 72% yield.9 The structure of 181 was confïed by X-ray crystallography (see Appendix 2, p 341). Scheme&& 2.10 lCOhAe OMe
KH, Mel, THF 18+~1~-6 Wh 1
DIBAL-H, Ni(COD)2 - dppb, toluene 98 Finaily, we investigated the reactivity of 174 toward the hydrostannation-fragmentation sequence. No reaction occurred when 174 was reacted with Bu3Sn.H in the presence of ~d~(dba)~A?Ph~.l*aHowever, using PearLmanrs catalyst, a highly regioselective reaction was observed (955 by IH NMR).'Ob*13 The hydrostannation of the oxabicyclic alkene was chemoselective toward the disubstituted double bond and protection of the free alcohol was unnecessary, in contrast to the hydroaiumination reaction. After a quick purification to remove excess Bu3SnH, further treatment of the crude organostannane product with a large excess of MeLi (18 equiv.) gave the tricyclic di01 182 in 36% yield (Equation 2.9). The tin-lithium exchange was sluggish and additional side products were detected.
TBDMSO, OH TBDMSO, OH
Bu3SnH, THF 2) MeLi, THF 36% 174
Based on the successful sequential ring opening of dioxapentacyclic compounds, we decided to study the reactivity of the azadioxapentacyclic and trioxapentacyclic analogs. The reactivity of the trÏoxapentacyclic compound 142 was firsc examined and shown to be significantly higher than the carbon analogue 139, giving a mixture of regioisomeric opened products 183 and 184 in a 1.6:l ratio after few minutes at -78 OC in the presence of n-BuLi (Equation 2.10). This observation is in contrast to the opening of simple oxabicyclic [2.2.1] systerns bearing an ether functionality at the bridgehead position which were shown to undergo regioselective nucleophilic opening.6b-c.24 The rasons for the Loss in the regioselectivity and the high reactivity of this system compared to the carbon malog are stiil unclear. The ngid polyether substrate 142 may act as a crown ether trapping the organolithiurn reagent and facilitûting as weil as accelerating the aggregation process and the deLivery of the nucleophile.
Trîoxapentacycle 142 was very reactive yet aiso selective; the mono opening was achieved at -78 OC and no trace of bis-opened products was detected.
TBDMSO OH TBDMSO, 1~8uLi~Et20 + - Io Io (21 0) -78 OC, 10 min 0' IFBU 8Q0h - 5 OH 6 'OTBDMS -OTBDMS 142 183 ratio = 1.6:1 184
In contrast to the reaction of 142,183 and 184 underwent regioselective ring opening reactions. Treatment of 183 with t-BuMgCVt-BuLi (25) gave 185 and 186 in a 6.6: 1 ratio (Equation 2.1 1).
TBDMSO,
TBDMSO, OH HO = OH TBDMSO, OH PB" + 0' @*BU (211) then t-BuLi, 7 h, rt \ 0' / HO 713% - t-Bu = 6 'OTBDMS 6 'OTBDMS 183 185 ratio = 6.6:1 1s
Alcohol 184 reacted in a similar fashion to give a mixture of regioisomenc products 187 and 188 (10.1: 1) in a combined yield of 84% (Equation 2.12).
TBDMSO, HO ,OTBDMS /+ OTSDMS t-BuMgCl* Et20- + t-6up(212) mBu then t-BuLi, 4 h. rt '. *BU t-BU IFBU 84% OH HO OH 6'OTBDMS 6'OTBDMS 184 187 ratio = 10.1 :1 188
Unexpectedly, reacting the azadioxapentacyclic analogues 146 and 148 (PMB=p- methoxybenzyl) with 5 equiv. of n-BuLi in Et20, gave afier few minutes at -78 OC, a complex mixture of products in both cases (Equation 2.13). Complex mixture (2.1 3) of products
16 R= Bn 148 R = PMB
However, treatment of the parent p-methoxyphenyl (PMI?) amine 144 under the same conditions cledy provided the mono-opened product 189 in good yield accompanied by three minor products which were not characterized (Equation 2.14). The bis-opened product was obtained by treating 189 with the t-BuMgCVt-BuLi (25)reagent combination, and whiie the IH NMR of the crude reaction was very clean, ail the efforts to purio and characterize the final tricycle were unsuccessful since the latter decomposed in less than 1 h at rt.
nBuLi, Et20 (214) 10 min, -78 OC 75%
144 189
We were disappointed to find that the presence of a phenyl sulfone in close proximity to the alkenes of the dioxacycles inhibited the nucleophilic ring opening reaction of the dioxapentacycles 152 and 113 (Equation 2.15). The interaction phenyl-alkene may be responsible for the modification of the electronic nature of the double bond influencing the cabometalation step and leading to siuggish reactions. Due to these unsuccessful transformations, the utilization of other allcylIithium nucleophiles or ring opening reactions were not envisaged. v
5 11.2.6 Enantioselective Desymmetrization. Thiadioxapentacycle and Azadioxapentacycie Base-Induced Ring Opening
In order to have access to the "syn" dimethyl dioxatetracycle that would be complementary to the "anti" dimethyl substrate 129, the desulfurization of 150 was envisaged. Unfortunately, al1 attempts to desulfurize were unsuccessful and gave the hilly hydrogenated product without removal of the sulf'ur atom 191 due to the high reactivity of the strained olefins or the hydrogenated-desulfurized product 190 when Raney nickel was used (Scheme 2.11).25
Scheme 2.11 NiCl-H20 RaneyB NaBH4, EtOH nidel or nickelocene LiAIH4, THF OTBDMS 190 150 lm
Nevertheless, a ring opening study of the thiadioxapentacycle 150 was undertaken since reduction was dso considered possible after the ring opening. The reaction of 150 with 5 equiv. of n-BuLi at -78 OC was cornpiete after 30 min and unexpectedly gave two products, 192 and 193, in an equimolar ratio (Equation 2.16). The alcohol193 was identified as the expected ring opened product. The second product arose from the deprotonation of the methylene hydrogens adjacent to the sulfur atom, followed by fragmentation to give the thioether 192. This constitutes, to Our knowledge, a novel mode of ring opening which we have explored in some detail (see dso Chapter 3).6a-26 Treating 150 with the "less" nucleophilic MeLi gave exclusively 192 in 82% yield after 18h at rt.
150 n-BuLi (5 equiv), 30 min, -78 OC MeLi (5 equiv), 18 h, rt
We took advantage of this unexpected result and snidied the base-induced ring opening of 150 in the presence of a chiral base.*' The enantioselective desyrnmetrization of 150 was achieved using 3 equiv. of a lithium amide-LiC1 complex (1: 1) 194 in THF generated from the hydrochloride sait of (-)-bis[(S)-l-phenylethylwne 195 (Equation 2-17)? The tetracycle (+)-192 was obtained in >95% ee. The enantiomeric excess was rnesured using the chirai shift reagent Yb(hfc)3 and integrating the tert-butyl groups of the TBDMS ethers. The control of the temperature and the reaction time were critical in order to obiain a good yield of 192, since longer reaction times gave a large amount of the meso bis-opened product 200. The absolute stereochemistry of (+)-192 has yer to be determined.
TBDMSO, OH
LiCI, THF, 5 h -78 OC to -30 OC 73%, >95% ee
Other chiral bases were tested to perform the desymetrizaùon reaction (Figure 2.3). The proline denvative 196, extensively used in the desymmetnzation of mesu epoxides29 gave a modest enantiomenc excess of the (-)-enantiomer of 192 as well as the cornplex (-)-sparteine/s- BuLi 197. Figure 2.3
THF, rt, 72%, 46% ee (-)ml92 1s
In the course of our studies, Vogel and coworkers reported the desymmetrization of the dioxapentacycle 198 through hydroboration of its olefinic moieties using the homochiral hydroborating agent monoisopinocampheyiborane ((+)-IpcBH2) followed by an oxidative work- up.30 The desyrnmevized product 199 was obtained in 59% yield and 78% ee (Equation 2.18).
THF, -25 OC, 22 h then NaBO3-4H20 59%. 78% ee
The second opening of the oxabicycle 192 was problematic. Treating 192 with an excess n-BuLi at rt gave the mes0 tricycle 200 as the major product. Only a trace of the desired
SN^' nucleophilic ring-opened product 201 was observed (Equation 2.19).
TBDMSO, TBDMSO, TBDMSO, OH HO = OH HO = OH nBuLi 4 Et20, rt
We also examined the base-induced ring opening of azadioxapentacycle. In order to be able to achieve the deprotonation at the methylene position next to the nitrogen atom, the PMB @-rnethoxybenzyl) protected amino substrate 148 was transposed into the BOC protected amine 202 using the ACE-CI (l-chloroethyl chloroformate) method in 7 1% yield (Equation 2.20).s1 1) CICOCti(CI)CH3 Benzene, reflux * MO) && 2) MeOH, reflux PMB lC~i~~~~then Et3N, (B0C)20 BO^ [&OTBDMS OTBDMS 71% OTBDMS 148 202
Treatment of the BOC protected analogue 202 with s-BuLi in Et20 at -78 OC, did not give the desired base-induced ring-opened product, but instead, led to the SN^' nucleophilic ring-opened product 203 as a mixture of diastereomen (Equation 2.21).32 No trace of the base-induced product was detected in the crude lH NMR. The reaction was fast and clean, showing again the importance of an electron wiihdrawing group on the nitrogen atorn in the nucleophilic ring opening reaction. It is important to note that several signals of the 13C spectra of 202 and 203 were doubled or broad, and that the IH NMR spectra were not resolved due to the slow intemonversion of rotational isomers attributable to the carbarnate moiety.
10 min, -78 OC 81%
11.2.7 Summary
We have described a chemo-, regio- and stereocontrolled methodology for the simple and efficient synthesis of a Large variety of polycyclic systems with control at up to six stereocenters. We have established that the most useful feature of the reactivity of the dioxacyclic compounds toward the nucleophilic ring opening reaction is that the fitring opening reaction is significantly faster than the second allowing the sequential transformation of the oxabicyclic moieties. The flexibility of the sequential ring opening process and its Limitations have been demonstrated and a new enantioselective mode of opening was reported. The enantioselective base-induced 105 desymmetrization was successfully applied to thiadioxapentacycle in >95% ee using a chiral lithium amide base.
5 11.3 Experimental Section
6 II.3.1 Soivents and Reagents
For general experimental details, see Section L3.1, p 46. Unless stated othenvise, commercial reagents were used without purification. Tetrahydrofuran, diethyl ether and toluene
were distilled immediately prier to use from sodiumlbenzophenone. Pentane was distilled
immediately pnor to use from calcium hydride. Ni(C0D)z was prepared according to Cushing's
procedure.33 and kept and handled in a glove box.
8 11.3.2 Substrate Preparation
General Procedure for the LiAIH(0Me)j Reduction of Diacid and Diester. exo,exo - 1l,l2-dioxatetracyclo[6.2.1.1~~6.0~~~]dodeca-4,9-dien-2,7- dihydroxymethyl (126).
125 126
Anhydrous MeOH (16.7 1 mL, 412.6 mmol) was carefuliy, and slowly added to a suspension of Lm(5.22 g, 137.5 mmol) in TW(250 rnL) at O OC. After the addition was complete, the mixture was stirred for 15 min at rt. The diacid 12515 (2.50 g, 10.0 moi) was added portionwise and the mixture was heated at reflux for 12 h. The reaction was cooled to rt, and transferred into a large Erlenmeyer flask (IL),further diluted with THF (250 mL), and 106 quenched by the portionwise addition of powdered potassium sodium t-te tetrahydrate (38.8
g, 137.52 mmol), followed by water (5 mL), and stirred for an additional 8 h at rt. The suspension was filtered and the solid residue was washed several times with boiling THE The
filtrate was concentrated in vacuo and purification by flash chromatography (EtOAc-MeOH 4: 1) yielded 126 (745 mg, 34%) as a white solid: Rf= 0.12 on siiica gel (EtOAc-MeOH 95:5); mp
203-206 OC (MeOH); IR (KBr) 3501,3402,3255,3002,293 1,2882, 1673, (195, 106 1 cm-[; NMR (400 MHz, CD30D) 6 6.74 (4H, s), 5.02 (4H,s), 3.16 (4H.s); 13C NMR (100 MHz, CD30D) 6 140.7, 85.3, 67.3, 62.2; HRMS calcd for Cl2H11O4 Ml+ 222.0892, found
General Procedure for the Protection of Di01 as DiTBDMS Ether.
LLO H imidazole, DMF OH 126
Imidazole ( 1-07 g, 15.8 mol) and TBDMSC1 (1.90 g, 12.6 mmol) were successively added to a solution of 126 (700 mg, 3.2 mol) in DMF (4 rnL) and the mixture was stirred for
24 h at rt. The reaction was diluted with water and the resulting solution was extracted (4x1 with hexanes-CH2Cl2 9: 1. The combined organic layers were dried (MgS04), filtered and concentrated. Purification by flash chromatopphy (hexanes-EtOAc 5: 1) yielded 127 ( 1-27 g, 89%) as a white soiid: Rf= 0.34 on silica gel (hexanes-EtOAc 4: 1); mp 149-152 OC (Et20); IR (KBr) 3086, 3002,2945, 2889,2854, 1469, 1251 cm-l; lH NMR (200 MHz, CDCls) 8 6.62
(4H,s), 5.04 (4H, s), 3.13 (4H. s), 0.90 (18& s), 0.0 1 (12H. s); 13~NMR (50 MHz,
CDC13) 6 139.9, 84.2, 67.7, 6 1.2, 25.7, 18.0, -5.6. Anal. Calcd for C24H4204Si2:C, 63.95; H, 9.39. Found: C, 63.93; H, 9.40. The reaction was carried out as in the generd procedure using MeOH (7.0 mL, 172.8
mmol), LiAW (2.19 g, 57.7 mmol) and 87 (1.00 g, 3.6 mmol) in THF (70 mL). The reaction
was quenched with powdered potassium sodium tartrate tetrahydrate (16.3 g, 57.75 mmol).
Purification by flash chrornatography (EtOAc-MeOH 4:l) yielded 128 (648 mg, 72%) as a
white solid: Rf = 0.21 on silica gel (EtOAc-MeOH 955); mp 190-192 OC (MeOH); IR (KBr) 3480,3346,3072,3008,2938,2889,1645, 1476, 1455 cm-l; NMR (200 MHz, CD30D) 6
6.72 (2H. dd, J = 5.5, 1.6 HZ),6.56 (2H.d, J = 5.6 Hz), 5.03 (2H,d, 3 = 1.8 Hz), 3.24 (2H, d, J = 11.3 Hz), 3.15 (2H, d, J = 11.4 HZ), 1.70 (6H,s); '3C NMR (50 MHz, CD30D) 6
144.6, 140.9, 92.0, 81.3, 67.1, 64.7, 16.7. Anal. Calcd for C14H1g04:C, 67.18; H, 7.25.
Found: C, 67.1 1 ; H, 7.36.
TBDMSCI L imidazole, DMF ' ( C~~~~~~
The reaction was carried out as in the generai procedure using imidazole (2.34 g, 34.35 mmol), TBDMSCl (4.14 g, 27.48 -01) and 128 (1 SO g, 6.87 mmol) in DMF (20 mL).
Purification by flash chromatography (hexanes-EtOAc 6: 1) yielded 129 (3.22 g, 98%) as a white solid: Rf = 0.42 on silica gel (hexanes-EtOAc 6: 1); rnp 103-105 OC (EtzO); IR (KBr) 3079,3065,3023,2952,2931,2854, 163 1, 1469, 125 1 cm-1;1H NMR (200 MHz. CDCl3) 6 IO8 6.61 (2H, dd, J = 5.5, 1.7 Hz), 6.44 (2H,d, J = 5.5 Hz), 5.02 (2H, d, J = 1.8 Hz), 3.20 (2H. d, I = 10.1 Hz), 3.09 (2H,d, J = 10.1 Hz), 1.70 (6H,s), 0.89 (18H, s), 0.02 (6H. s), 0.01
(6H, s); l 'C NMR (50 MHz, CDCI3) 6 143.8, 140.3, 90.6, 80.4, 67.7, 63.8, 25.8, 18.1, 16.6, -5.5, -5.7. Anal. Calcd for C26H4604Si2: C, 65.22; H, 9.68. Found: C,65.35; H, 9.58.
General Procedure for the Methylation of Alcohol and Diols. exo,exo- l,6-~imethyl-ll,12-dioxatetracycio[6.2.1.1~~6.0~~~]dodeca-4,9-dien-2,7-bis- methoxyrnethyl (130).
KH, 18-crown-6 THF, Mel
The di01 128 (1.00 g, 3.82 mrnol) was added portionwise to a suspension of KH ( 1.3 1
g, 35% in oil, 11.45 mol) (washed 3 tirnes with pentane) in THF (40 mL) at O OC and the
mixture was stirred for 2h at rt. Me1 (1.43 mL, 22.89 mol) was added foilowed by 18-crown-
6 (10 1 mg, 0.38 mrnol) and the mixture was stined for an additionai 6 h at a. The reaction was
quenched with five drops of i-PrOH, and the solution was diluted with water and extracted (3x) with Et20. The combined organic layers were dned (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 1:l) yielded 130 (1.06 g, 100%) as a white solid: Rf = 0.45 on silica gel (hexanes-EtOAc 1:1); mp 171-172 OC (Et20); IR (KBr) 3086,2981,2939, 2910,2882,2812, 1462, 1384, 1195 cm-'; NMR (400 MHz, CDC13) 6
6.60 (2H, dd, J = 5.5, 1.8 HZ), 6.47 (2H,d, J= 5.5 Hz), 5.02 (2H. d, J = 1.8 Hz), 3.19 (6I.I. s), 2.98 (2H, d, J = 9.5 Hz), 2.87 (2H,d, J = 9.1 Hz), 1.68 (6H,s); [SC NMR (100 MHz, CDC13) 6 143.7, 140.2, 90.3. 80.2, 77.7, 62.5, 59.2, 16.3. Anal. Cdcd for C16H2204: C, 69.04; H, 7.97. Found: C, 68.81; H, 8.29. DIBAL-H CH2C12 CI Cl 95 131 DIBAL-H (7.23 mL, 40.59 mmol) was added dropwise to a solution of 95 (2.49 g,
6.76 mmd) in CH2C12 (60 mL) at -78 OC. The mixture was stirred for 1 h at -78 OC and for an additional 15 h at rt. The reaction mixture was diluted with THF (300 mL) prior to the portionwise addition of powdered potassium sodium tartrate tetrahydrate (1 1.50 g, 40.59 mmol) over 1 h. After the addition was complete, the mixture was sked for an additional 2 h at rt. The suspension was filtered and the solid residue was washed several times with boiling THE The filtrate was concenuated in vacuo and purification by flash chromatography (EtOAc-MeOH 955) yielded 131 (1.25 g, 59%) as a white solid: Rf= 0.35 on sika gel (EtOAc-MeOH 955): mp 130-135 "C (Acetone); IR (KBr)3382,2948,2933,2887, 1445, 1380, 1320, 1214, 1075, 1044 cm-!; 1H NMR (400 MHz, CD3OD) S 6.71-6.69 (lH, m), 6.68 (1H, dd, J = 5.9. 1.9
Hz), 6.59 (lH, d, J = 5.5 Hz), 6.54 (lHTd, J = 5.5 Hz), 5.05 (IH, d, J = 1.5 Hz), 5.03 (LH, d, J = 1.9 Hz), 3.64 (IH, dt, J = 10.4, 6.5 Hz), 3.58 (lH, dt, J = 11.0. 6.8 Hz), 3.22 (LH, d, J= 11.4Hz),3.21 (lH, d, J= 11.4Hz),3.14(1H,d, J= 11.0Hz). 3.13 (lH,d, J= 11.0
HZ), 2.51 (1H, ddd, J = 14.5, 10.1, 4.8 HZ), 2.04 (lH, ddd, J = 14.6, 10.2, 4.9 Hz), 1.99- 1.82 (2H, m), 1.69 (3H. s); 13C NMR (LOO MHz, CD30D) 8 144.7. 142.7, L41.2, 140.7, 95.0, 91.9, 81.3, 81.2, 67.2, 67.0, 65.2, 64.8, 46.2, 29-9, 28.7, 16.8. Anal. Calcd for C 14H21ClO4: C,6 1-44; H, 6.77. Found: C, 61.32; H, 6.82-
DiTBDMS ether (132).
TBDMSCI irnidazofe, DMF Cl 110 The reaction was carried out as in the general procedure using imidazole (545 mg, 8.01 rnmol), TBDMSCl (966 mg, 6.41 rnrnol) and 131 (500 mg, 1.60 mrnol) in DMF (1.6 mL).
Purification by flash chromatography (hexanes-EtOAc 7: 1) yielded 132 (789 mg, 9 1%) as a
colorless oil: Rf= 0.43 on silica gel (hexanes-EtOAc 7:1); IR (neat) 2954, 2930, 2857, 1468,
1379, 1255, 1078 cd; NMR (400 MHz, CDCS) 6 6.60-6.57 (2H.m), 6.46 (LH, d, J =
5.5 Hz), 6.43 (lH, d, J = 5.5 Hz), 5.05 (lH, d, J = 1.8 Hz), 5.03 (lH, d, J = 1.8 Hz), 3.70- 3.61 (lH, m), 3.49 (1H. ddd. J = 10.6, 8.6, 5.5 Hz), 3.20 (IH, d, J = 10.2 Hz), 3.19 (1H, d,
J = 10.2 Hz), 3.09 (1H. d, J = 9.9 Hz), 3.08 (lH, d, J = 10.3 Hz), 2.60-2.51 (lH, m), 2.1 1- 1-96 (2H, m), 1.87-1.75 (lH, m), 1-70(3H. s), 0.90 (9H, s), 0.89 (9H, s), 0.03 (3H, s), 0.01 (3H, s), 0.00 (6H,s); I3c NMR (100 MHz, CDCI3) 8 143.9, 141.7, 140.6, 140. 1, 93.6,
-5.6, -5.7 (2). Anal. Calcd for C2gH4gC104Si2: C. 62.13; A, 9.12. Found: C, 62.29; H. 9.08.
Diol (133).
96 133
The reaction was canied out as in the general procedure using MeOH (1.13 mL, 27.8 mrnol), Li- (390 mg, 9.28 mol), and 96 (400 mg, 1.16 mol) in THF (25 id)at rt for
12 h. The reaction was quenched with potassium sodium tartnte tetnhydrate (2.60 g, 9.28 rnmol). Purification by flash chromatography (EtOAc-MeOH 955) yielded 133 (289 mg, 86%) as a white solid: Rf= 0.27 on siiica gel (EtOAc-MeOH 955); mp 223-226 OC (MeOH); IR
(KBr) 3388,2995,2924, 1379, 1046 cm-[;lH NMR (400 MHz, CD30D) 6 6.65 (LH, dd, J =
5.5, 1.9 Hz), 6.44 (LH, d, J = 5.9 Hz), 6.16 (lHTm), 4.92 (IH, d, J = 1.8 Hz), 4.80 (LH, d, J = 1.8 Hz), 3.14-3.06 (4H,m), 2.58-2.52 (lH, m), 2.34-2.28 (IH, m), 2.11-1.89 (2H,m), 1.79-1.57 (3H,m), 1.37-1.25 (lH, m), 1.58 (3H, s); I3c NMR (100 MHz. CD30D) 6 154.7, 144.1, 140.6, 133.2, 92.1, 91.8, 81.3, 79.9, 67.5, 65.0, 64.9, 64.2, 29.0, 28.9, 25.6, 23.1, 16.8; HRMS calcd for C 17B2204 CIM]+ 290.15 18, found 290.1525.
DiTBDMS ether (134).
The reaction was carried out as in the general procedure using imidazole (293 mg, 4.3 1 mrnol), TBDMSC1 (520 mg, 3.45 mrnol) and 133 (250 mg, 0.86 mmol) in DMF (2 d). Purification by flash chromatography (hexanes-EtOAc 6: 1) yielded 134 (329 mg, 74%) as a white solid: Rf = 0.23 on silica gel (hexanes-EtOAc 6: 1); mp 1 1 1- 1 13 OC (Et2O); IR (KBr) 3079, 3009, 2959, 293 1, 2882, 2854, 1471, 1461, 1258, 1105 cm-'; 'H NMR (200 MHz, CDC13) 6 6.62 (lH, dd, J = 5.5, 1.6 Hz), 6.42 (1H. d, J = 5.5 Hz), 6.15 (lH, m), 5.00 (1H. d, J = 1.7 Hz), 4.89 (lH, d, J = 1.8 Hz), 3.26-3.04 (4H,m), 2.66-2.58 (lH, m), 2.40-2.30 (1H.ml, 2.11-1.62 (4H, m), 1.69 (3H,s), 1.54-1.16 (2H, m), 0.91 (9H,s), 0.89 (9H, s), 0.03 (6H. s), 0.01 (3H. s), 0.00 (3H, s); 13C NMR (50 MHz, CDC13) 6 153.4, 143.3, 139.8,
131.7, 90.6, 90.3, 80.2, 78.8, 67.8, 65.3, 63.9. 63.4, 28.2, 27.7, 25.8 (2), 24.2, 22.1, 18.0
(2)- 16.5, -5.3, -5.6, -5.7, -5.8. Anal. Calcd for C2gH5004Si2: C,67.13; H, 9.7 1. Found: C, 67.37; H, 9.64.
97 135 The reaction was carried out as in the general procedure using MeOH (847 PL, 20.9 i rnmol), LiAIH4 (293 mg, 6.97 mmol) and 97 (400 mg, 0.87 moi) in THF (25 mL) at rt for 4 112 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (1.97 g, 6.97 rnmol). Purification by flash chromatognphy (EtOAc-MeOH 955) yieided 135 (280 mg, 80%) as a white solid: Rf= 0.47 on silica gel (EtOAc-MeOH 955); mp 240-242 OC (MeOH); IR (KBr) 3470, 3320, 3090, 3000, 2960, 29 10. 1603, 1348, 1 160, 1 110, 1055 cm-l; IH NMR (400 MHz, CD3OD) 6 7.63 (2H, d. J = 8.4 Hz), 7.30 (2H, d, J = 7.7 Hz), 6.72 (lH, dd, J=5.7, 1.7 Hz), 6.56 (lH, d, J = 5.5 Hz), 6.31 (1H,dd, J = 5.5, 2.2 Hz), 6.03 (IH, d, J = 5.5 Hz), 5.00 (IH, d, J = 1.8 Hz), 4.98 (lH, d, J = 2.2 Hz), 3.23 (lH, d, J = 11.4 Hz), 3.18 (rH, d, J
= 11.3 Hz), 3.09 (IH, d, J = 11.4 Hz), 3.02 (IH,d, J = 11.4 Hz), 2.40 (3H, s), 1.83 (3H, s),
1.76 (3H,s); l3C NMR (100 MHz, CD30D) 8 145.2, 144.4, 143.3, 141.5, 140.0, 139.7,
130.5, 129.1, 92.4, 81.4, 77.0, 67.1, 66.6, 66.5, 66.0, 63.5, 21.4, 16.8, 15.5. Anal. Calcd for C21H25N05S: C,62.51; H, 6.25; N, 3.47. Found: C, 62.27; H, 6.28; N, 3.68.
DiTBDMS ether (136).
de, DMF ' 1 &OTBDMS
The reaction was carried out as in the generai procedure using imidazole (1.25 g, 18.33 rnmol), TBDMSCI (2.2 1 g, 14.66 rnrnol) and 135 (1.48 g, 3.66 mmol) in DMF (3.7 mL). Purification by flash chromatography (hexanes-EtOAc 51) yieided 136 (2.08 g, 90%) as a white solid: Rf = 0.53 on silica gel (hexanes-EtOAc 5: 1); mp 165- 167 OC (EtzO); IR (CH2C12) 3056,2943,2858, 1599, 1468, 1338, 1263, 115 1, 1084 cm-'; IH NMR (400 MHz, CDCl3) 6 7.77 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.0 Hz), 6.58 (lH, dd, J = 5.5, 1.9 Hz), 6.44 (lH, d, J = 5.8 HZ), 6.43 (IH, dd, J = 5.5, 2.2 Hz), 6.20 (lH, d, J = 5.5 Hz), 5.08 (lH, d, J = 2.2
Hz), 4.88 (lH, d, J = 1.5 Hz), 3.19 (2H, t, J = 10.3 Hz), 3.02 (2H, d, J = 10.2 Hz), 2.37
(3H, s), 1-75 (3H, s), 1.67 (3H, s), 0.91 (9H,s), 0.84 (9H,s), 0.02 (3H, s), 0.00 (3H, s),
-0.03 (3H, s), -0.04 (3K s); I3C NMR (100 MHz, CDC13) 6 144.3, 144.0, 142.6, 140.5, 113 18.1, 18.0, 16.5, 14.7, -5.5, -5.6. -5.7, -5.8; HRMS calcd for C33Hj3NOsSSi2 M+ 631.3183, found 631.3189.
LiAIH4 + THF C02H OH OH
The reaction was carried out as in the generd procedure using LiA.iH4 (1.90 g, 44.9 mmol) and 87 (5.0 g, 18.0 moi) in THF (250 mL). The reaction was quenched with powdered potassium sodium tartrate tetlahydrate ( 12.7 g, 45.0 mmol). Purification by flash chromatography (EtOAc-MeOH 955 foIlowed by EtOAc-MeOH 4: 1) gave the di01 128 (2.52 g,
56%) and the triol 137 (460 mg, 10%) as a white solids. Triol 137: Rf = 0.33 on silica gel
(EtOAc-MeOH955); mp 126-128 OC(MeOH); IR (KBr) 3445,3346,3030,2995,2917,2854, 1447, 1047 cm-'; 1H NMR (400 MHz, CDJOD)6 6.31-6.30 (2H, m), 5.63 (LH,d, J= 6.6
Hz),4.35 (IK, s), 4.26 (LH,dd, J= 12.0, 4.6 Hz), 3.87 (lH,d, J= 11.0 Hz), 3.74 (1H, d, J
= 11.7 Hz), 3.65 (lH,d, J = 11.0 Hz), 3.25 (1H,d, J = 12.1 Hz), 2.54-2.47 (lH, m), 2.14-
2-06 (lH,m), 1.84 (3H.s), 1.67 (3H, s); 13~NMR (50 MHz, CDjOD) 6 143.7, 138.7, 135.1, 126.6, 93.0, 86.3, 73.9, 65.9, 63.2, 61.1, 56.6, 32.8, 21.1, 19.9. Anal. Calcd for
C 14H2004: C,66.65; H, 7.99. Found: C, 66.42; H, 8.03.
Diol (138).
THF 114 The reaction was carried out as in the general procedure using MeOH (10.05 mL, 248.16 rnmol), Li- (3.47 g, 82.72 mmol) and 99 (1.50 g, 5.17 mmol) in THF (100 mL).
The reaction was quenched with powdered potassium sodium tartrate tetrahydrate (23.40 g, 82.72 mmol). Purification by flash chromatography (EtOAc-MeOH 955) yielded 138 (990
mg, 73%) as a white solid: Rf = 0.17 on silica gel (MeOH-EtOAc 95:5); rnp 138-141 OC (MeOH); IR (KBr)3452,3402,3072, 3001,2966,2910,2861, 1638. 1447, 1 1 10, 1047 cm-1; ' H NMR (400 MHz* CD3OD) 6 6-67 (2H9 dd, J = 5.5, 1.8 HZ),6.55 (2H, d, J = 5.5 HZ), 4.94 (2H, d, J = 1-8 HZ),3.24 (2H9 s), 3.14 (2H.s), 2-42 (2H, td, J = 13-69 4.5 HZ),2.02-
1.96 (2H, m), 1.91 (IH, qt, J = 13.6, 4.2 Hz), 1.67-1.61 (IH. m); '3~NMR (100 MHz, CD30D) 6 143.5, 140.4, 91.9, 84.3, 66.7, 66.6, 65.4, 57.9, 27.7, 18.5. And. Calcd for
C15H1804: C, 68.69; H, 6.92. Found: C, 68.30; H, 6.83.
DiTBDMS ether (139).
TBDMSCl imidazole. DMF
The reaction was canied out as in the general procedure using imidazole (649 mg, 9.53 rnmol). TBDMSCl (1.15 g, 7.62 mol) and 138 (500 mg, 1.9 1 mmol) in DMF (5 mi,). Purification by flash chromatography (hexanes-EtOAc 5:l) yielded 139 (697 mg, 74%) as a white solid: R.= 0.27 on silica gel (hexanes-EtOAc 9:l); mp 120-132 "C (CKCIj); IR (KBr) 3065, 2959, 2924, 2868, 1469, 1257, 11 IO cm-'; IH NMR (200 MHz, CDC13) 8 6.59 (2H,
(2H, s), 2.34 (2H, td, J = 13.4, 5.0 Hz), 2.09-1.59 (4H, m), 0.91 (9H, s), 0.89 (9H,s), 0.02 (6H, s), 0.01 (6H. s); 13c NMR (50 MHz, CDCls) 6 142.7, 139.8, 90.4, 83.2, 67.5, 66.9,
64.3, 56.6, 26.7, 25.8, 25.7, 18.1, 18.0, 17.4, -5.6, -5.7. Anal. Calcd for C27H4604Si2: C, 66.07; H, 9.45. Found: C, 65.91; H, 9.18. Dimethylether (140).
The reaction was carried out as in the general procedure using KH (787 mg, 35% in oil, 6.87 rnmol), 138 (600 mg, 2.29 mmol), Me1 (855 PL, L3.73 mmol), and 18-crown-6 (61 mg,
9.23 mmol) in THF (20 mL). Purification by flash chromatography (hexanes-EtOAc 1:l) yielded 140 (642 mg, 97%) as a white solid: Rf = 0.42 on silica gel (hexanes-EtOAc 1 :1); rnp
137-139 OC (Et2O); R (Dr) 3079, 2954, 2924, 2889, 2812, 1455, 1370, 1103 cm-'; IH NMR (400 MHz, CDC13) 6 6.56 (2H9 dd, J = 5-79 1.6 HZ), 6.42 (2HTdT J = 5.5 HZ),4.97
(2H, d, J = L.8 Hz), 3-20 (3H,s), 3.16 (3H, s), 2.94 (2H, s), 2.87 (2H, s), 2.26 (2H. td, = 13.8, 4.7 Hz), 2.04-1.98 (2H, m), 1.91 (LH, qt, J = 13.6, 4.1 Hz), 1.63-1.56 (lH, m); 13c NMR (LOO MHz, CDC13) 6 142.7, 139.6, 90.1. 83.0, 77.4, 77.1, 62.7, 59.1, 59.1, 55.9,
26.6, 17.4;. Anal. Calcd for C 17H2204: C, 70.32; H, 7.64. Found: C, 70.5 1; H, 7.65.
Diol (141).
- THF
101 141 The reaction was carried out as in the generai procedure using MeOH (4.56 mL, 1 L2.5 mol), Lim( 1.42 g, 37.5 mmol) and 101 (1 -50 g, 4.69 mmol) in THF ( 150 m.)at n for 5 h. The reaction was quenched with potassium sodium tamate teuahydrate (10.58 g, 37.49 mmol). Purification by flash chromatography (EtOAc-MeOH 4: 1) yielded 141 (657 mg. 53%) as a white solid: Rf= 0.23 on silica gel (EtOAc-MeOH 4: 1); mp 204-207 OC (MeOH); IR (KBr) 3487, 3423, 3086, 3002, 2924. 2889, 1616, 1448, 1075, 1047 cm-'; 1H NMR (400 MHz, L 16 CD30D) 6 6.74 (ZH,dd, J = 5.9, 1.9 Hz), 6.58 (2H, d, J = 5.8 Hz), 5.06 (2H, d, J = 1.5
HZ), 4.46 (2H,d, J = 12.1 HZ),4-06 (2H9 d, J = 12.5 HZ), 3.28 (2HTs), 3.12 (2H s); '3~
NMR (LOO MHz, CD30D) 6 141.3. 140.1, 90.0, 84.7, 66.9, 66.3, 66.1, 64.2, 56.2. Anal. Cdcd for Ci4H1605: C, 63.63; H, 6.10. Found: C,63.82; H, 6.51.
DiTBDMS ether (142).
TBDMSCl && imidazole, DMF ['-O H OH 141 142 The reaction was carried out as in the general procedure using imidazole (773 mg, 1 1.36 mmol), TBDMSCI (1.37 g, 9.09 rnmol) and 141 (600 mg, 2.27 mmol) in DMF (2.3 mL). Purification by flash chromatography (hexanes-EtOAc 5: 1) yielded 142 (925 mg, 85%) as a white solid: Rf = 0.19 on silica gel (hexanes-EtOAc 51); rnp 134-136 OC (Et20); IR (KBr) 2960,2931, 2889, 2854, 1476, 1462, 1251, 1075 cm-'; IH NMR (400 MHz, CDC13)8 6.65
(2H,dd, J = 5.7, 1.7 Hz), 6.43 (2H, d, J = 5.5 Hz), 5.07 (ZH,d, J = 1.8 Hz), 4.40 (2H, d, J
= 12.1 Hz), 4.20 (2H,d, J = 12.1 Hz), 3.26 (2H, s), 3.09 (2H s), 0.91 (9H.s), 0.89 (9H,s), 0.03 (6H, s), 0.01 (6H,s); I3c NMR (100 MHz, CDCl3) 6 140.8, 139.0, 88.5, 83.7, 67.3,
66.4, 65.8, 63.1, 55.0, 25.9, 25.7, 18.2, 18.1. -5.5,-5.6. Anal. Calcd for C26Ha05Si2: C, 63.37; H, 9.00. Found: C, 63.76; H, 9.19.
&& LiAIH4THF - && PMP' /&~e PMP' H C02Me OH
The reaction was carried out as in the general procedure using Lm(892 mg, 23.5 1 ll7 rnrnol) and 102 (2.50 g, 5.88 mmol) in THF (100 mL) at rt for 5 h. The reaction was quenched by the portionwise addition of potassium sodium tartrate tetrahydrate (6.64 g, 23.5 1 mmol).
Purification by flash chromatography (EtOAc-MeOH 4: 1) yielded 143 (940 mg, 43%) as a white solid: Rf = 0.5 1 on silica gel (EtOAc-MeOH 4: 1); mp 255-257 OC (MeOH); IR (KBr) 3441, 15 11, 1450, 1236, 1039 cm-'; 1H NMR (400 MHz, CD3OD) 6 7.01 (2H, d, J = 9.1
Hz), 6.82 (2H, d, J = 9.1 Hz), 6.76 (2H,dd, J = 5.7, 1.6 Hz), 6.67 (2H, d, J = 5.5 Hz), 5.05
(2H. d, J = 1.4 Hz), 3.77-3.72 (6H. m),3.73 (3H, s), 3.17 (2H, bs); 13~NMR (100 MHz, CD3OD) 6 155.2, 147.4, 141.6, 140.9, 120.3, 115.2, 90.5, 84.5, 66.4, 66.2, 64.7, 56.3,
55.9, 52.2. Anal. Calcd for C2 1 H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 67.98; H,
6.35; N, 3.7 1.
DiTBDMS ether (144).
TBDMSCI imidazole, DMF
The reaction was carrïed out as in the general procedure using imidazole (69 1 mg, 10.15 mmol), TBDMSCI (1.22 g, 8.12 mmol) and 143 (750 mg, 2.03 rnmol) in DMF (2.0 mL). Purification by flash chromatography (hexanes-EtOAc 3: 1) yielded 144 (1.13 g. 93%) as a beige solid: Rf= 0.32 on siiica gel (hexanes-EtOAc 3: 1); mp 100-103 OC(Et20); IR (neat) 3068, 2942,2855, 1737, 1512, 1467, 1445, 1249, 1107, 1074 cm-'; IH NMR (400 MHz, CDCl3) 6
6.99 (2H, d, J=9.1 Hz), 6.79 (2H,d, J=9.2 Hz), 6.67 (2H, dd, J=5.7, 1.7 Hz), 6.53 (2H, d,J= 5.5 Hz), 5.10 (2H, d, J= 1.8 Hz), 3.86 (2H,d, J= 12.8 Hz), 3.76 (2H, d, J= 11.0 Hz), 3.75 (3H, s), 3.29 (2H,s), 3.14 (2H,s), 0.90 (9H,s), 0.87 (9H, s), 0.03 (6H, s), 0.02
(6H, s); 13~NMR (100 MHz, CDC13) 6 153.4, 146.1, 140.50, 140.49, 119.3, 114.0, 89.0. 83.5, 67.3, 66.4, 63.6, 55.4, 55.2, 50.8, 25.9, 25.7, 18.1, 18.0, -5.6 (2); HRMS calcd for C33H5 N05Si2 [Ml+ 597.3306, found 597.3328. -- THF
103 145 The reaction was carried out as in the general procedure using MeOH (0.83 mL, 20.5 mmol), LiAIH4 (260 mg, 6.84 mol) and 103 (350 mg, 0.86 mmol) in THF (50 mL) at rt for 5 h. The reaction was quenched by the portionwise addition of potassium sodium tartrate tetrahydrate (1.93 g, 6.84 mmol). Purification by flash chromatography (EtOAc-MeOH 4: 1) yielded 145 (195 mg, 6546) as a white solid: Rf= 0.27 on silica gel (EtOAc-MeOH 4: 1); mp 209-214 OC (MeOH); IR (KBr) 3466, 3388, 3072, 2995, 2924, 2889, 1497, 1448, 1202, 1089, 1054 cm-'; IH NMR (400 MHz, CD3OD) 6 7.38-7.21 (SH,m), 6.69 (2H, dd. J = 5.7,
1.7 Hz), 6.55 (2H, d, J = 5.9 Hz), 5.01 (2H, d, J = 1.8 Hz), 3.73 (2H, s), 3.21 (2H. d, J =
11.4 Hz), 3.20 (2H, s), 3.13 (2H, ci, J = 11.0 Hz), 3.12 (2H, s); 13~NMR (LOO MHz, CD3OD) 6 141.5, 140.7, 138.3, 130.7, 129.2, 128.2, 90.7, 84.4, 66.2, 66.1, 64.5, 63.5, 56.7,53.2; HRMS calcd for C21H23N04 MC353.1627. found 353.1626.
DiTBDMS ether (146).
TBDMSCI
- 7 imidazole, DMF
The reaction was carried out as in the general procedure using imidazole ( 147 mg, 2. L2 mmol), TBDMSCl (256 mg, 1.70 mrnol) and 145 (150 mg, 0.42 mmol) in DMF (0.4 mL). Purification by flash chromatography (hexanes-EtOAc 3: 1) yielded 146 (21 1 mg, 85%) as a thick colorless oil: Rf = 0.19 on silica gel (hexanes-EtOAc 5: 1); IR (neat) 3065, 3002, 2952, 2854, 1602, 1469, 1463, 125 1 cm-'; 1H NMR (400 MHz, CDClî) 6 7.34-7.17 (33, m), 6.59 1 L9 (2H, dd, J = 5.7, 1.7 Hz), 6.42 (2N,d, J = 5.5 Hz), 5.06 (2H, d, J = 1.5 Hz), 3.79 (2H, s), 3.23 (2H,d, J= 12.1 Hz), 3.19 (2H, s), 3.16 (2H,d, J= 12.1 Hz), 3.08 (2H, s), 0.88 (9H, s), 0.84 (9H,s), 0.00 (6H, s), -0.07 (6H,s); '3~NMR (100 MHz, CDCI3) 6 140.7, 140.0, 137.3, 129.4, 128.0, 126.8, 89.2, 83.3, 67.3, 66.5, 63.4, 62.7, 55.4, 51.8, 26.0, 25.7, 18.2,
18.0, -5.5, -5.6; HRMS calcd for C33H5 1 N04Si2 FI]+58 1.3357. found 58 1.3373.
104 147 The reaction was carried out as in the general procedure using LiAlH4 (9 16 mg, 24.1 mrnol) and 104 (2.65 g, 6.04 mol) in THF (100 mL) at rt for 5 h. The reaction was quenched with potassium sodium tartrate tetrahydnte (6.81 g, 24.14 rnrnol). Purification by flash chromatopphy (EtOAc-MeOH 4:l) yielded 147 (2.03 g, 88%) as a white solid: Rf= 0.27 on silica gel (EtOAc-MeOH 4: 1); mp 242-245 OC (MeOH); IR (Dr) 3410, 3075, 2983, 2929, 2839, 161 1, 15 l3,l312, 1247,1179, 1086, 1055, 1037 cd;IH NMR (400 MHz, CD30D) 6
7.29 (2H, d, J = 8.4 Hz), 6.85 (2H, d, J = 8.8 Hz), 6.68 (2H ,dd, J = 5.7, 1.7 Hz), 6.55 (2H, d, J = 5.5 Hz), 5.00 (2H, d, J = 1.9 Hz), 3.76 (3H, br s), 3.66 (2H. bs), 3.20 (2H,bs), 3.18 (2H, d, J = 13.9 Hz), 3.11 (2H, bs), 3.10 (2H,d, J = 12.4 Hz); 13C NMR (100 MHz. CD3OD) 6 160.2, 141.8, 140.7, 131.7, 130.6, 114.5, 90.7, 84.4, 66.3, 66.2, 64.5, 62.8,
56.9, 55.6, 53.1; HRMS calcd for C22H25N05 FI]+383.1733, found 383.1728. DiTBDMS ether (148).
TBDMSCl imidazole, DMF PMB /C~~~~~~ OTBDMS
The reaction was carried out as in the general procedure using imidazoie ( 1.33 g, 19-58 mmol), TBDMSCl (2.36 g, 15.66 mrnol) and 147 (1.50 g, 3.92 mrnol) in DMF (4.0 mL).
Purification by flash chromatography (hexanes-EtOAc 3:l) yielded 148 (2.28 g, 95%) as a white solid: RI= 0.23 on silica gel (hexanes-EtOAc 3: 1); mp 118-128 OC (Et20); IR (CH2Cl2) 3054,2954, 2930,2857, 161 1, 15 12, 1468. 1260, 1082 cm-'; IH NMR (400 MHz, CDC13) 6
7.23 (2H,d, J = 8.4 Hz), 6.81 (2H, d, J = 8.4 Hz), 6.59 (2H,dd, J = 5.5, 1.9 Hz), 6.42 (2H, d, J = 5.5 Hz), 5.05 (ZH,d, J = 1.4 Hz), 3.76 (3H.s), 3.73 (2H, s), 3.21 (2H, d, J = 12.1 Hz), 3.18 (2H, s), 3.12 (2H, d, J= 12.1 Hz), 3.07 (2H, s), 0.88 (9H,s), 0.84 (9H,s), 0.00
(6H.s), -0.07 (6H, s); 13~NMR (100 MHz, CDCI3) 6 158.5, 140.6, 140.0, 130.6, 129.2,
113.4, 89.2, 83.3, 67.2, 66.5, 63.4, 62.0, 55.3, 55.1, 51.6, 25.9, 25.7, 18.1, 18.0, -5.58, -5.64. And. Calcd for C34H53N05Si2: C, 66.73; H, 8.73; NT2.29. Found: C, 66.3 1; H, 8.76; N, 2.29.
The reaction was carried out as in the generai procedure using MeOH (10.05 rnL,
248.16 mmol), (3.47 g, 82.72 mmol) and 106 ( 150 g, 5.17 mmol) in THF ( 100 rnL) at rt for 12 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (23.40 g, 82.72 mmol). Purification by flash chromatography (EtOAc-MeOH 9: 1) yielded 149 (990 mg. 12 1 73%) as a white solid: Rf= 0.13 on siiica gel (EtOAc-MeOH 9: 1); mp 2 17-224 OC (MeOH); IR (KBr) 3560, 3472, 3369, 3020, 3005, 2940, 2905, 1478, 1098. 1050 cm-'; 'H NMR (400 MHz, CD30D) 8 6.68 (2H,dd, J= 5.5, 1.8 Hz). 6.45 (2H,d, J= 5.5 Hz), 4.93 (2H, d, J=
1.5 Hz), 3.77 (2H.d, J = 14.7 Hz), 3.15 (2H. s), 3.05 (2H s), 2.64 (2H, d, J = 14.7 Hz); 13~ NMR (50 MHz, CD30D) 6 142.8, 141.6, 89.2. 84.5, 67.0, 66.6, 65.4, 56.9, 29.2. Anal. Calcd for C14H1604S:C, 59.98; H, 5-75. Found: C,59.72; H, 5.79.
DiTBDMS ether (150).
TBDMSCI - imidazole. DMF
The reaction was carrïed out as in the general procedure using imidazole (790 mg, 11.6 1 mmol), TBDMSCI (1.40 g, 9.28 mmol) and 149 (650 mg, 2.32 mmol) in DMF (2.5 mL).
Purification by flash chrornatography (hexanes-EtOAc 5: 1) yielded 150 (1.07 g, 9 1%) as a white solid: Rf = 0.32 on silica gel (hexanes-EtOAc 5: 1); mp 141-144 OC (EyO); R (KBr) 3086, 3023,2952, 2931, 2882, 2854, 1473, 1254 cm-[;IH NMR (200 MHz, CDC13) 6 6.68
(2H,dd, J = 5.6, 1.7 Hz), 6.40 (2H, d, J = 5.6 Hz), 5.06 (2H, d, J = 1.6 Hz), 3.77 (2H, d, J
= 14.2 Hz), 3.22 (2H, s), 3.11 (2H s), 2.83 (2H, d, J= 14.3 Hz), 0.94 (9H, s), 0.89 (9H, s),
0904 (6H,$1, 0.01 (6H. s); I3C NMR (50 MHz, CDCb) 8 141.5, 141.1, 87.6, 83.3, 67.8, 66.8, 64.3, 55.6, 28.3, 25.8, 25.6, 18.0, 17.9, -5.6, -5.7. Anal. Cdcd for C26H&o4SSi2: C, 61.37; H, 8.72. Found: C, 61.05; H, 8.32. Alcohol (151).
107 151
The reaction was canied out as in the general procedure using LiAl& (47 mg, 1.25 mmol) and 107 (250 mg, 0.63 rnmol) in THF (5 rnL) at a for 2 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (353 mg, 1.25 mmol). Purification by flash chromatography (hexanes-EtOAc 1: 1) yielded 151 ( 197 mg, 85%) as a white solid: Rf = 0.35 on siiica gel (hexanes-EtOAc M); mp 183-184 "C (CH2C12);IR (KBr) 3536, 3009, 2959,
293 1, 14-48, 1293, 1 138 cm- l; lH NMR (400 MHz, CDCL3) 6 7.84-7.8 1 (2H, m), 7.76-7.7 L
(lH, m), 7.68-7.64 (2H, m), 6.63 (2H, d, J = 5.5 Hz), 6.57 (2H, dd, J = 5.5, 1.8 Hz), 4.65
(2H, d, J = 1.4 Hz), 3.83 (ZH,d, J = 6.6 Hz), 2.62 (IH, t, J = 6.8 Hz), 2.12-2.01 (4H,mj, 1.90-1.78 (lH, m), 1.67-1.59 (lH, m); I3C NMR (LOO MHz, CDC13) 6 141.3, 139.5, 137.7,
134.3, 129.7, 128.1, 91.2, 86.4, 82.7, 69.3, 61.7, 25.5. 16.9. Anal. Cdcd for C20H2005S: C, 64.50; H, 5.4 1. Found: C,64.24; H, 5.24.
TBDMS ether (152).
TBDMSCI
The reaction was camied out as in the general procedure using irnidazole (124 mg, 1-83 mmol), TBDMSCI (207 mg, 1.37 mrnol) and 151 (170 mg, 0.46 mmol) in DMF (1.0 mL). Purification by flash chromatography (hexanes-EtOAc 1:l) yielded 152 (156 mg, 70%) as a white solid: Rf = 0.66 on silica gel (hexaoes-EtOAc 1: 1); mp 155-158 OC (CH2Cl2); IR (KBr) 3073, 2959, 2933, 2856, 1571, 1470, 1451, 13 13, 1252, 115 1, 1059 cm-'; lH NMR (400 133 MHz, CDCl3) 6 7.84-7.81 (2H,m), 7.74-7.70 ( 1H, m), 7.67-7.63 (2H, m), 6.80 (2H,dd, J =
5.5, 1.8 Hz), 6.58 (2H,d, J = 5.5 Hz), 4.58 (2H,d, J = 1.5 Hz), 3.94 (2H, s), 2.42 (2H. dt,
J = 13.9, 4.7 Hz), 2.1 1-2.04 (2H, m), 1.87 (1H. qt, J = 13.7, 4.2 Hz), 1.66-1.60 (1H, m), 0.95 (9H.s), 0.10 (6H,s); 13C NMR (100 MHz, CDC13) 6 141.1, 140.8, 140.4, 134.0,
129.5, 128.1, 92.4, 86.3, 82.3, 68.0, 67.2, 27.1, 25.9, 18.2, 16.7, -5.5. Anal. Calcd for C26H3405SSi: C,64.16; H, 7.04. Found: C,63.90; H, 6.83.
8 11.3.3 Sequential Ring Opening Study
General Procedure for the Nucleophilic Alkyllithium Ring Opening. (1R*,ZR *,7S*,8S*)-4a,8a-Bis-[(tert-butyldimethylsiloxy)-methyl]-2,7-dibutyI- 1,2,4a,7,8,8a-hexahydro-naphthalene-l,8-di01 (153) and (IR*,2R *,4aS*,SR *, 6R*,8aS*)-4a,8a-Bis-[(tert-butyldimethyfsiIoxy)-methyl]-2,6-dibutyl-l,2,4a,5, 6,8a-hexahydro-naphthalene-1,s-di01 (154).
OTBDMS HO ,OTBDMS 4' 4' *BuLi
Et20 mBu PSU OTBDMS HO : OH TBDMSO~OH
A solution of n-BuLi (1.07 mL, 2.5 M solution in hexanes, 2.66 mol) was added dropwise to a solution of 127 (100 mg, 0.22 mrnol) in Et20 (10 mL) at -78 OC. After the addition was complete, the mixture was stirred for 8 h at O OC. The reaction was quenched with a saturared WC1solution. The aqueous layer was extracted (3x) with Etfl and the cornbined organic layers were dried (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 153 (92 mg) and 154 (24 mg) as white solids in a 2.9: 1 ratio, in a combined yield of 92%. Diol 153: Rf = 0.64 on silica gel (hexanes-EtOAc
9:1); mp 70-72 OC (Et20); IR (CHC13) 3684, 3620, 3030, 2973. 2896, 1483, 1047 cm-'; 1H NMR (400 MHz, CDCl3) 6 5.66 (2H. dd, J = 10.3, 2.6 Hz), 5.23 (ZH,dd. J = 9.9,2.6 Hz), 4.57 (2H,t, J= 5.2 Hz), 3.90 (2H, s), 3.28 (2H, s), 2.86 (2H,d, J = 4.8 Hz), 2.32-2.26 (2H, m), 1.83-1.74 (2H,m), 1.49-1.24 (lOHT m), 0.91-0.88 (6H. m), 0.90 (9H,s), 0.85
(9H, s), 0.07 (6H. s), -0.01 (6K s); I3C NMR (100 MHz, CDCl3) G 130.7, 128.6, 70.3,
70.1, 67.2, 45.5, 44.4, 38.9, 30.6, 29.8, 25.9, 25.8, 23.0, 18.2, 18.1, 14.3, -5.5, -5.7; HRMS calcd for C32H6204Si2 566.41 86, found 566.4 173. Di01 154: Rf = 0.27 on silica gel
(hexanes-EtOAc 9:1); mp 95-97 OC (Et20); IR (CHC13) 3684,3620,3023,2966,293 1,2896,
286 1, 1483, 1223, 1047 cm-1; IH NMR (400 MHz, CDC13) 6 5.65 (2H, dd, J = 10.3, 2.6
Hz), 5.57 (2H, d, J=2.6 Hz), 3.91 (2H, d, J=3.3 Hz), 3.65 (2H, bs), 3.61 (2H, d, J=9.5 Hz), 3.41 (2H, d, J = 9.6 Hz), 2.23 (ZH,m), 1.61-1.52 (2H, m), 1.42-1.24 (IOH, m), 0.88
(6H, t, J = 6.6 Hz), 0.87 (18H, s), 0.01 (6H. s), 0.00 (6H. s); 13~NMR (100 MHz, CDCls) 6
130.0, 129.0, 69.1, 65.7, 46.9, 36.6, 31.1, 29.4, 25.8, 22.9, 18.1, 14.1, -5.5, -5.6; HRMS calcd for C32H6204S i2 566.4 186, found 566.4207.
/ OTBDMS nBuLi - Et20 *Bu OTBDMS TBDMSO~OH
127 155 The reaction was carried out as in the general procedure using n-BuLi (767 pL, 25 M solution in hexanes, 1.92 rnmol) and 127 (173 mg, 0.38 mmol) in Et20 (7 mL) at -78 OC for 4 h. Purification by Bash chrornatography (hexanes-EtOAc 7:1) yielded 155 as a colorless oil (178 mg, 9 1%): Rf = 0.5 1 on silica gel (hexanes-EtOAc 7: 1); IR (neat) 3536, 3086, 3016, 2945, 2854, 1469, 1258, 1082 cm-1;IH NMR (400 MHz, CDCI3) G 6.54 (lH, dd. J = 5.9,
1.8 Hz), 6.45 (lH, dd, J = 5.9, 1.5 Hz), 5.84 (lH, dd, J = 9.5, 2.9 Hz), 5.59 (LH, dd, J =
9.9, 1.8 Hz), 5.02 (1H. t, J = 1.3 Hz), 4.47 (lH, t, J = 1.3 Hz), 4.1 1 (lH, dt, J = 11.0, 1.3 HZ), 3.49 (lHTd, J = 10.3 HZ), 3.29 (IH,dT J = 9.5 HZ). 3.22 (IH, d7 J = 10.3 HZ),3.14 (IH, d, J = 9.5 Hz), 2.76 (lH, d, J = 10.6 HZ), 2.20-2.14 (IH, m), 1.64-1.19 (6H, m), 0.89- 125 0.87 (3H,m), 0.88 (9H,s), 0.84 (9H,s), 0.01 (3H,s), 0.00 (3H, s), -0.04 (3H, s), -0.05 (3H,s); 13~NMR (100 MHz, CDCIj) 6 136.3. 135.8. 134.0, 133.2, 84.8, 83.9, 71.1, 66.2,
64.0, 54.0, 51.8, 38.4, 31.3, 29.6, 25.8, 25.7, 22.8, 18.2, 18.1, 14.1, -5.5 (2), -5.6, -5.7; HRMS calcd for C2gb204Si2 - Bu]+ 451.2700, found 45 1.270 1.
Procedure for the Opening of 155 Using (i-Bu)3Al/n -BuLi.
HO ,OTBDMS OTBDMS &d3 - PBU* + then nBuLi \ ~ n-Bu Mu PSU OTBDMS TBDMSO~OH HO : OH TBDMSO' 155 1% 153
A solution of 155 (50 mg, 0.10 mmol) in Et20 (5 mL) was treated with (i-Bu)3Al (27 j.L, O. 11 mrnol) at O OC, and the mixture was stirred for 30 min. The solution was cooled to -78
"C prior to the addition of n-BuLi (275 uL, 2.5 M solution in hexanes, 0.69 mmol). After the addition was complete, the mixture was stirred for 10 min at -78 OC, and 48 h at -30 OC. The reaction was quenched with a saturated NH&l solution. The aqueous layer was extracted (3x) with Et20 and the combined organic layers were dried (MgS04), fiitered and concentrated.
Purification by flash chrornatography (hexanes-EtOAc 9: 1) yielded 153 ( L6 mg) and 154 (32 mg) as white soiids in a k3.8 ratio, in a combined yield of 87%.
/ OTBDMS 126 The reaction was carried out as in the gened procedure using n-BuLi (500 p.L, 2.5 M
solution in hexanes, 1.25 mrnol) and 129 (50 mg, 0.10 mmol) in Eh0 (3 mL) at O OC for 7 h. Purification by flash chromatognphy (hexanes-EtOAc 9: 1) yielded 158 as a white solid (55 mg, 90%): Rf = 0.74 on silica gel (hexanes-EtOAc 6: 1); mp 138-140 OC (Et20); IR (KBr) 341 6, 3262,2959,293 1,2860, 1469, 1258, 1089 cm-l; NMR (400 MHz, CDCI3) 6 5.35 (2H, d,
J= 1.1 Hz), 3.98 (2H, ci, J= 3.3 Hz), 3.76 (SH, d, J= 10.2 Hz), 3.62 (2H, bs), 3.56 (2H, d* J = 10.3 Hz), 2.16-2.05 (2H, rn), 1.80 (6H,dd, J = 2.4, 1.3 Hz), 1.52-1.47 (2H, m), 1.39-
1.28 (lOH, m), 0.89 (6H, t, / = 6.9 HZ),0.86 (18H, s), 0.01 (12H,s); 13~NMR (50 MHz, CDC1j) 6 134.3, 127.6, 68.4, 65.7, 50.5, 36.5, 31.7, 29.5, 25.9, 23.1, 21.0, 18.0, 14.2,
-5.6, -5.8. And. Calcd for C3&60&2: C, 68.63; H, 11.18. Found: C, 68.60; H, 1 1-28.
TBDMSOa I
The reaction was cmried out as in the general procedure using n-BuLi (627 pL. 2.5 M solution in hexanes, 1.57 mmol) and 129 (150 mg, 0.3 1 mol) in Et20 (7 mL) at -78 OC for 4 h. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 159 as a white solid (15 L mg, 90%): Rf= 0.40 on silica gel (hexanes-EtOAc 9: 1); mp 56-59 OC (EtzO); R (neat) 3543, 3079, 3009,2966,2854. L659, 1469, 1377, 1251 cm-1; [HNMR (400 MHz, CDC13) 6 6.33-
6.31 (2H, m), 5.44 (tH, d, J = 1.8 Hz), 4.69 (lH, d, J = 1.5 Hz), 4.25 (lH, d, J = 9.6 Hz),
3.85 (lH, d, J = 10.6 &), 3.38 (lH, d, J = 10.3 Hz), 3.32 (lH, d, J = 10.6 Hz), 3.08 (lH, d, J = 10.2 Hz), 2.90 (lH, d, J = 9.5 HZ),2.16-2.12 (lH, m), 1.85 (3H, s), 1.83 (3H, t, J =
1.8 Hz), 1.53-1.24 (6K m), 0.92-0.88 (3H, m), 0.90 (9H, s), 0.82 (9H. s), 0.02 (3H,s), 137 0.01 (3H, s). -0.05 (3H, s), -0.06 (3H, s); 13C NMR (50 MHz, CDC13) 6 141.5, 135.7, 134.9, 131.6, 92.5, 79.9, 69.6, 64.8, 62.4, 57.3, 54.6, 37.9, 31.6, 29.8, 25.9, 25.7, 22.9,
19.5, 18.7, 18.2, 18.0, 14.1, -5.6, -5.7, -5.8 (2). Anal. Calcd for C30H5604Si2: C, 67.11; H, 10.51. Found: C, 67.01; H, 10.29.
naphthalene 1,S-di01 (160).
0OTBDMS TBDMSO, 6*Bu t-BuLiEt20 - nBu = OH TBDMSO~ TBDMSO~ 159 160 The reaction was carried out as in the general procedure using tert-BuLi (835 pL, 1-56
M solution in pentane, 1.30 mmol) and 159 (100 mg, 0.19 mmol) in Et20 (5 mL) at O OC for 3 h. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 160 as a white solid ( 10 1 mg, 9 1%): Rf= 0.41 on silica gel (hexanes-EtOAc 9: 1); mp 45-47 OC (CHCI3); IR (KBr) 3416, 2959, 2931, 2860, 1638, 1469, 1398, 1258, 1089 cm-!; IH NMR (400 MHz, CDC13) 6 5.53
(LH, s), 5.36 (IH, s), 4- 17 (lH, d, J = 3.7 HZ),3.98 (lHTdT J = 4.4 HZ),3.79 (2H, bs), 3.73 (lH, d, J = 10.3 HZ),3.70 (LH, d, J = 10.2 HZ), 3-56 (lH, d, J = 10-2 HZ),3.55 (1H, d, J = 10.2 HZ),2.09 (lH, m), 1.86-1.85 (fH, m), 1.83 (3H, s), 1.78 (3H, dd, J = 2.2, 1-1 Hz),
1.53-1.48 (IH, m), 1.37-1.23 (SH,m), 0.99 (9H, s), 0.88-0.82 (3H, m), 0.87 (9H, s), 0.86
(9H. s), 0-01 (6HTs), 0-01 (6H9 s); 13C NMR (50 MHzT CDCI3) G 134.7, 133.8, 128.6,
20.9, 17.9, 14.1, -5.7 (2). -5.9, -6.0. Anai. Calcd for C34H6604Si2: C, 68.63; H, 1 1.18. Found: C, 68.78; H, 10.79. The reaction was carried out as in the general procedure using MeLi (7.70 mL, 1.4 M solution in Et20, 10.79 mmol) and 130 (600 mg, 2.16 mmol) in Et20 (25 mL) at rt for 24 h. Purification by flash chromatography (hexanes-EtOAc 2:1) yielded 161 (253 mg, 40%) as a white solid: Rf= 0.55 on silica gel (hexanes-EtOAc 2: 1); mp 49-52 "C (&O); IR (neat) 3529,
3079, 2973, 2924. 2875, 2812, 1455, 1377, 1166, 1103, 1068 cm-1;1~ NMR (400 MHz. CDC13) 6 6.36 (1H, dd, J = 5.9, 1.9 Hz), 6.28 (lH, d, J = 5.8 Hz), 5.35 (1H. q, J = 1.6 Hz),
4.79 (lH, d, J = 1.8 Hz), 4.05 (1H, dd, J = 11.0, 1.5 HZ), 3.41 (IH, d, J = 9.9 Hz), 3.24
(3H, s), 3-18 ([H, d, J = 9-6 Hz), 3.L5 (3H. s), 3.02 (LH,d, J = 9.9 Hz), 3.88-3.85 (2H, m), 2.36-2.23 (lH, m), 1.89 (3H, dd, J = 2.2, 1.5 Hz), 1.80 (3H, s), 1.10 (3H, d, I = 7.3 Hz);
13~NMR (100 MHz, CDCS) 6 141.1, 137.2. 135.2, 131.2, 92.1, 80.2, 74.4 (3,71.4, 59.2.
58.9, 55.2, 54.3, 32.5, 20.1, 18.2, 17.5; HRMS calcd for C17H2604[Ml+ 294.183 1, found
KH, 18-crown-6 THF, Mei Me @i OH - 9i OMe Me M~O/ M~O/ 161 162 The reaction was canied out as in the generai procedure using ICH (79 mg, 358 in oil, 0.69 mmol), 161 (136 mg, 0.46 mmol), Me1 (115 PL, 1.85 rnmol), and 18crown-6 (12 mg. 129 0.05 rnmol) in THF (5 mL). Purification by flash chromatography (CH2C12-EtOAc 9: 1) gave
162 (132 mg, 92 %) as a clem oil: Rf= 0.24 on silica gel (CH2C12-EtOAc 9: 1); IR (neat) 2969,
2907, 2812, 2747, 1614, 1448, 1383, 1197, Il03 cm-l; IH NMR (400 MHz, DMSO-do, 80
OC) 6 6.31 (lHTd. J = 5.5 Hz), 6.18 (IH, d, J = 5.5 Hz), 5.33 (rH, d, 3 = 2.6 Hz), 4.48 (IH, bs), 3.74 (lH, d, J = 4.1 Hz), 3.35-3.30 (1H. m), 3.28 (3H, s), 3.21 (3H, s), 3.16-3.1 1 (iH. m), 3.12 (3H,s), 3.07-3.01 (2H. m), 2.53-2.49 (1H. m), 1.78 (3H. s), 1.55 (3H, s), 1.1 I
(3H, d, J = 7.3 HZ); '3~NMR (100 MHz, DMSO-da, 80 OC) 6 151.0, 140.5, 137.2, 137.0,
136.1, 130.9, 129.8, 126.5, 109.9, 105.1, 71.4, 66.8, 57.1, 56.9, 48.2, 20.2, 18.4, 12.6;
HRMS calcd for C 1 gH2gO4 - CH30H]+ 276.1725, found 276.1720.
General Procedure for the Nickel-Catalyzed DIBAL-H Ring Opening. (1R*,4aS*,5R*,6R*,8aS*)-5-Methoxy-4a,8a-bis-methoxymethyl-4,6,8- trirnethyl-1,2,4a,5,6,8a-hexahydro-naphthalen-l01 (163).
.0 OMe
Ni(C0D)z (12 mg, 0.04 mmol) was dissolved in dry toluene (3 mL) and transferred via canula into a flask containing 1.4-bis(dipheny1phosphino)butane (dppb) (37 mg, 0.09 mmol). The mixture was stirred at rt for 30 min and transferred into a flask containing the substrate 162 (70 mg, 0.23 rnmol) in toluene (3 mL). DIBAL-H (250 pL, 1.0 M in hexanes, 0.25 mrnol) was added over 1 h via syringe pump. After the addition was complete, the mixture was stirred for an additional 30 min at rt. The reaction was quenched with a saturated mC1solution. The aqueous Iayer was extracted (3x) with Et20 and the combined organic layers were dkd (MgS04). filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 163 (55 mg, 78%) as a white solid: Rf= 0.35 on silica gel (hexanes-EtOAc 3: 1); rnp 100-
102 OC (Et20); IR (Dr) 33 11, 2959, 29 17, 2861, 2805, 1462, 1377, 1202, I166, 1 124, 130 1089, 1047 cm-'; IH NMR (400 MHz, CDC13) 8 6.24 (IH,d, J = 10.2 Hz), 5.56 (IH, m),
5.29 (lH, d, J = 1.1 Hz), 3.68 (lH, dd, J = 10.3, 2.6 Hz), 3.55 (2H,dd, J = 9.2, 1.5 Hz), 3.42 (4H, bs), 3.27 (tH,d, J = 9.2 Hz), 3.23-3.21 (fH, m), 3.21 (6H, s), 2.26-2.17 (lH, m), 2.14-2.10 (2H. m), 1.84 (3H, m), 1.76 (3H. dd, J = 2.4, 1.3 Hz), 1.02 (3H, d, J = 7.3 Hz); 13C NMR (100 MHz, CDCI3) 8 134.8, 133.2, 127.3, 123.2, 83.1, 75.2, 75.1, 67.5,
61.0, 58.6 (2), 49.2 (2)- 31.6, 31.3, 20.2, 19.0, 17.2. And. Calcd for C18H3004:C, 69.64; H, 9.74. Found: C, 69.89; H, 9.70.
General Procedure for the Sequential Palladium-Catalyzed Hydrostannation/Tin-Lithium Exchange Ring Opening. (1S*,4aR*,5S*,8aR*)- 4a,8a-Bis-[(tert-butyldimethylsiloxy)-methyI]-1,5-dimethyl-l,2,4a,5,6,8a- hexahydro-naphthalene-1,s-di01 (164).
TBDMSO, OH 1) Pd(OH)2/C, THF Bu3SnH d 2) nBuLi, THF 129 164 Bu3SnH (250 0.93 mmol) was added dropwise over 3 h using a syringe pump to a suspension of Pd(OH)2 on carbon (5 mg, 0.04 mmol) and 129 (1 11 mg, 0.23 mmol) in TKF (5 mL) at rt. After the addition was complete, the mixture was stirred for an additionai 30 min.
Et20 (20 mL) was poured into the reaction mixture and the resulting solution was filtered through a pad of Celite. The fütrate was concentrated and the residue was purified by flash chrornatography ( 100% hexanes followed by hexanes-EtOAc L 5: I) to give the dihydrostannylated product as a colorless oil. The latter was dissolved in THF (5 mL) and treated with n-BuLi (835 pL, 2.5 M solution in hexanes, 2.09 mol) at O OC. The mixture was stirred for 1 h at O OC and quenched a saturated WC1solution. The aqueous layer was extracted (3x) with Et20 and the combined organic layers were dned (MgS04), filtered, and concentrated. Purification by flash chrornatography (hexanes-EtOAc 3: 1) gave 164 (28 mg,
25%) as a white powder: Rf = 0.26 on silica gel (hexanes-EtOAc 3:l); mp 224-225 OC NMR (400 MHz, toiuene-ds, 70 OC) 6 5.90-5.85 (2H, m), 5.7 1 (2H, ddd, J = 10.6, 5.2, 3.0
Hz), 4.16 (2H. d, J = 10.6 Hz), 3.97-3.95 (4H. m), 2.46 (2H, d, J = 1.1 Hz), 2.06-2.04 (2H,
m), 1.49 (6H. s), 0.90 (18H, s), 0.05 (6H. s), 0.04 (6H.s); 13cNMR (100 MHz, CDCIs) 5 127.9, 127.0, 75.5, 64.6, 49.0, 37.6, 26.8, 25.7, 18.0, -5.5, -5.6; HRMS calcd for
C2&004Si2 - Ow+465.3220, found 465.3 198.
Acetonide (165). 12, acetone Qÿ' O' H O' g OH QYI O?... "1
Iodine (35 mg, 0.14 rnmol) was added to a stimng solution of 137 (240 mg, 0.95 mrnol) in acetone (10 mL). After 4h at rt, the reaction was quenched by the addition of a 1M aqueous solution of sodium thiosulfate (30 rnL) and the solution was extracted (4x) with CH2C12. The combined organic layers were dried (MgSO4). filtered and concentrated.
Purification by flash chromatography on siiica gel (hexanes-EtOAc 1: 1) yielded 165 ( 197 mg,
7 1%) as a white solid: Rf = 0.45 on silica gel (hexanes-EtOAc 1: 1); mp 14 1- 144 OC (Et20); IR (KBr) 3459, 3079, 3009, 2988, 2931, 2861, 1455. 1377, 1209, 1082 cm-1; IH NMR (400 MHz, CDC13) 6 6.49 (1H. d, J = 5.8 Hz), 6.23 (1H. dd, J = 5.5, 1.5 Hz), 5.77 (lH, d, J =
7.0 Hz), 4.36 (IH, d, J = 11.7 Hz), 4.33 (lNTd, J = 1.8 HZ), 4.16 (IH, dd, J = 12.1, 4.8 HZ), 3.73 (1H, d, J = 11.0 HZ), 3.55 (IH, d, J = 11.7 HZ), 2.90 (lH, d, J = 10.7 Hz), 2.48- 2.40 (LH,m), 2.05-1.98 (lH, rn), 1.85 (3H, s), 1.82 (3H.s), 1.57 (lH, bs), 1.44 (3H, s),
1.43 (3H, s); 13C NMR (50 MHz, CDC13) 6 144.5, 135.2, 132.6, 127.1, 98.8, 91.7. 83.6,
74.6, 68.1. 61.1, 58.0, 48.2. 29.0, 20.2, 20.1, 18.9. Anal. Cdcd for C17H2404:C, 69.84; H, 8.27. Found: C, 70.03; H, 8.27. 165 166
The reaction was carried out as in the general procedure using n-BuLi (408 pL, 2.5 M solution in hexanes, 1.02 mmol) and 165 (50 mg, 0.17 mmol) in Et20 (4 mL) at O OC for 2 h. Purification by flash chromatography (hexanes-EtOAc 9:l) yielded 166 (5 L mg, 85%) as a white solid: Rf= 0.33 on silica gel (hexanes-EtOAc 2: 1); mp 72-74 OC (Et2O); IR (KBr)3445, 2995, 2959, 2861, 1645, 1462, 1384, 1082, 738 cm-';iH NMR (400 MHz, CDC13) 6 5.59
(lH, d, J = 4.4 Hz), 5.44 (1H.d, J = 5.8 Hz), 4.43 (lH, d, J = 12.1 Hz), 4.23 (lH, dd, J = 11.4, 4.8 Hz), 4.1 1-4.07 (2H, m), 3.97 (1H,d, J = 12.1 Hz), 3.70 (IH, d, J = 12.5 Hz), 2.59 (LH,bs), 2.22 (lH, bs), 2-19-2.15 (2H, m), 2.07 (3H, s), 1.96 (IH, dt, J = 16.1, 5.5 Hz), 1.86 (3H, s), 1.74-1.69 (LH, m), 1.45 (3H,s), 1.39 (3H, s), 1.35-1.13 (5H,m), 0.87 (3H,t, J=5.7Hz); I~cNMR (50 MHz, CDCI3)G 138.6, 135.4, 128.9, 125.8, 99.9, 71.4, 68.8, 64.9, 63.7, 52.0, 47.4, 41.4, 30.8, 28.9, 28.8, 26.3, 24.2, 23.1, 22.6, 22.0, 14.1. Anal. Calcd for C~lH3~04:C, 71.96; H, 9.78. Found: C,72.14; H, 9.65. / OTBDMS TsHN =
MuLi Et20 mBll OTBDMS
The reaction was carried out as in the general procedure using n-BuLi (1.52 mL, 2.5 M solution in hexanes, 3.80 mol) and 136 (200 mg, 0.32 rnmoi) in Et20 (7 mL) at O OC for 1 h. Purification by flash chrornatography (hexanes-EtOAc 7: 1) yielded 167 (218 mg, 92%) as a white crystailine soiid: RI= 0.46 on silica gel (hexanes-EtOAc 6: 1); mp 205-207 OC (Et2O); IR (KBr) 3402, 2966, 293 1, 2861, 1469, 1321, 1265, i 152, 1096 cm-1; IH NMR (400 MHz, CDCI3) 6 8.02 (IH, brd, J=8.1 Hz), 7.64(2HTd, J= 8.6 Hz), 7.13 (ZH,d, J = 8.0 Hz),
5.47 (lH, bs), 4.86 (IH, bs), 4.11-4.08 (2H, rn), 3.72 (lH, d, J = 10.2 Hz), 3.64 (lH, d, J =
m), 1.77 (3H, bs), 1.46 (3H, d, J = 0.8 Hz), 1.42-1.13 (12H. m), 0.93-0.80 (6H,m), 0.88
(9H, s), 0.84 (9H, s), 0.01 (3H, s), 0.00 (3H, s), -0.01 (3H, s), -0.02 (3H, s); 13~NMR (100 MHz, CDC13) 6 141.3, 141.0, 134.9, 133.8, 129.0, 128.5, 126.6 (2), 69.2, 65.9, 65.4,
20.7, 17.92, 17.89, 14.19, 14.13, -5.6, -5-7, -5.9, -6.0. Anal. Calcd for C4iH73NOsSSi2: C, 65.81; H, 9.83; N, 1.87. Found: C, 65.71; H, 9.76; N, 1.88. r
MuLi C Et20 OTBDMS 'OTBDMS 136 168 The reaction was cmied out as in the general procedure: n-BuLi (127 pL + 64 pL + 64 yL, 2.5 M solution in hexanes, 0.64 mmol) was added in three portions to a solution of 136
( 100 mg, 0.16 mrnol) in Et20 ( 10 mL) at -78 OC over 20 min. After the addition was complete, the mixture was stirred for an additional 10 min at -78 OC. Purification by flash chromatography (hexanes-EtOAc 5: 1) yielded 168 (89 mg, 82%) as a white soiid: Rf = 0.33 on silica gel (hexanes-EtOAc 51); mp 125-128 OC (Ego); IR (Dr) 3743,3445,3417,3290,2952,2931, 2854, 1469, 1386, 13 14, 1257, 1150, 1090 cm-1; 'H NMR (400 MHz, CDC13) 6 7.64 (2H. d,
J = 8.4 Hz), 7.19 (2H, d, J = 8.5 HZ), 6.33 (1H. dd, J = 5.7, 1.7 Hz), 6.28 (IH, d. J = 5.5
HZ),5.5 1 (lH, d, J = 7.3 HZ), 5.29 (lH, bs), 4.7 1 (IH, d, J = 1-8 HZ),4.47 (IH, d, J = 7.3 Hz), 3.91 (lH, d, J = 10.6 Hz), 3.33 (lH, d, J = 11.0 Hz), 3.31 (lH, d, J = 10.2 Hz), 3.04 (lH, d, J = 10.3 Hz), 2.36 (3H,s), 2-12-2.09 (lH, m), 1.83 (3H, s), 1.82 (3H,s), 1.23-0.82
(6H, ml, 0.94 (9H, s), 0.78 (9H, s), 0.73 (3H, t, J = 7.2 Hz), 0.05 (3H, s), 0.03 (3W. s), -0-08(3H9 s), -0.10 (3H, s); 13c NMR (100 MHz, CDC13) 6 142-5. 141-7, 141.6, 136.4-
25.6, 22.6, 21.4, 19.5, 19.0, 18.2, 18.0, 13.9, -5.6, -5.7, -5.8, -5.9; HRMS calcd for C37H63N05SSi2 [Ml+ 689.3966, found 689.3952. OTBDMS OTBDMS
The reaction was carried out as in the general procedure using terî-BuLi (1.79 mL, 1.7
M solution in pentane, 3.05 mmol) and 168 (300 mg, 0.44 mmol) at O OC for 30 min. Purification by flash chromatography (hexanes-EtOAc 7:l) yielded 169 (306 mg, 94%) as a white solid: R.= 0.43 on siiica gel (hexanes-EtOAc 7: 1); mp 185- 187 OC (Et20); IR (KBr) 3432, 3054,2955,2930,2859, 1469, 1254, 1149, 1095 cm-[; [HNMR (400 MHz, CDCl3) 8
(2H, m), 3.77 (lH, d, J = 10.2 Hz), 3.62 (lH, d, J = 10.3 Hz), 3.56 (IH, d, J = 10.3 Hz), 3.50 (1H, d, J = 9.9 Hz), 2.35 (3H. s), 2.09 (IH, bs), 1.82 (lH, bs), 1.76 (3H,dl J = 1.1
Hz), 1.67 (3H, d, J = 1.5 Hz), 1.35-1.10 (6H. m), 1.06-0.93 (2H, m), 0.99 (9H, s). 0.89
(9H,s), 0.86 (9H. s), 0.81 (3H,t, J = 7.2 Hz), 0.01 (6H,s), 0.00 (6H, s); 13~NMR (LOO MHz, CDCl3) 6 141.6, 140.9, 136.1, 133.6, 130.0, 128.8, 126.6, 124.1, 69.3, 66.1, 65.4,
17.9, 14.1, -5.6, -5.7, -5.86, -5.94. Anal. Calcd for C41H73NO~SSi2:C, 65.81; H, 9.83;
N, 1.87. Found: C, 66.15; H, 9.86; N, 1.97. Iodide (170).
Nal Acetone CI OTBDMS OTBDMS 132 170
A solution of 132 (563 mg, 1.04 mol), and Nai (78 1 mg, 5.2 1 mmol) in acetone (40 mL) was heated at reflux for 48 h. The solvent was removed in vacuo and the resulting solid was washed sevenl times with EhO. Mer concentration of the filtrate, the residue was purifkd by flash c hromatography (hexanes-EtOAc 7: 1) to give 170 (586 mg, 89%) as a pale yellow oil: Rf= 0.41 on silica gel (hexanes-EtOAc 7: 1); IR (neat) 3073, 3009, 2909, 2737, 1462, 1375,
1245, 1 170, 1084 cmdi; l H NMR (400 MHz, CDC13) 6 6.60-6.57 (2H, m), 6.44 ( 1H, d, J =
4.4 Hz), 6.43 (lH, d, J=5.4 Hz), 5.04 (1H. d, J= 1.5 Hz), 5.02 (1H, d, /= 1.8 Hz), 3.34- 3.29 (IH, m), 3.20 (lH, d, J = 10.2 Hz), 3.18 (1H. d, J = 9.8 Hz), 3.15-3.09 (1H. m), 3.09 (IH, d, J = 10.3 Hz), 3.07 (IH, d, J = 10.2 Hz), 2.44 (lH, ddd, J = 14.0, 11.2, 4.4 Hz), 2.18-2.08 (1H,rn), 2.02-1.95 (lH, m), 1.93-1.82 (IH, m), 1.70 (3H, s), 0.91 (9H, s), 0.89
(9H, s), 0.05 (3H, s), 0.02 (3H, s), 0.01 (3H, s), 0.00 (3H.s); 13~NMR (100 MHz, CDC13) 6 143.9, 141.7, 140.6, 140.0, 93.4, 90.5, 80.3 (2), 67.6, 67.5, 64.3, 63.9, 31.3, 29.4, 26.0,
25.8, 18.2, 18.1, 16.5, 7.6, -5.3. -5.5, -5.6, -5.7. Anal. Calcd for C2gH4gI04Si2: C, 53.15; H, 7.81. Found: C, 53.12; FI, 7.96.
Alcohol (171).
TBDMSO, . I
170 171 A solution of tert-BuLi (499 PL, 1.7 M solution in pentane, 0.85 mmol) was added dropwise to a solution of 170 (244 mg, 0.39 rnmol) in pentane-Et20 3:2 (5.0 mL) at -78 OC. After the addition was complete, the mixture was stirred at -78 OC for 2 h. Purification by flash 137 chromatography (CH2C12-EtOAc 955) gave 171 (147 mg. 75%) as a white solid: Rf= 0.57 on silica gel (CH2C12-EtOAc 955);mp 84-87 OC (Et20); IR (neat) 3438,2953,2930,2857, 1467,
1378, 1254, 1097, 1065 cm-[ ; H NMR (400 MHz, CDC13) 6 6.45 ( I H, d, J = 4.8 Hz), 6.27
(IH, d, J = 5.5 Hz), 5.93-5.91 (IH, m), 5.86 (IH, dd, J = 9.9, 1.5 Hz), 4.83 (lH, bs), 3.79 (1H. bs), 3.43-3.35 (4H,m), 2.52 (IH, bs), 1.96-1.65 (6H. s), 1.56 (3H, s), 0.87 (9H, s),
0.84 (9H,s), -0.01 (3H. s), -0.02 (3H, s), -0.03 (3H, s), -0.04 (3H, s); '3~NEVZR (100 MHz. CDC13) G 139.6, 136.4, 132.3, 129.8, 89.2, 82.2, 82.1, 68.2, 63.5, 56.6, 54.0, 43.8, 34.2, 26.2, 25.9, 25.8, 21.5, 18.2, 17.9, 17.0, -5.5, -5.6, -5.8, -5.9. Anal. Calcd for
C28HSO04Si2:C, 66.35; H, 9.94. Foound: C,66.61; H, 9.96.
TBDMSO'1 TBDMSO,
The reaction was canied out as in the general procedure using n-BuLi (363 a,7.5 M solution in hexanes, 0.9 1 mmol) was added dropwise to a solution of 171 (66 mg, 0.13 mmol) in Et20 (5 mL) at O "C for 2 h. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 172 (55 mg. 75%) as a colorless oii: Rf= 0.33 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3408, 2954, 2929, 2857. 1466, 1254, 1085 cm-'; 'H MIR (400 MHz, CDCls) 6 6.22
(lH,dd, J= 10.4, 2.7 Hz), 5.71 (LH,d, J= 10.3 Hz), 5.32 (LH,bs). 4.15 (lH, d, J=2.6 HZ), 4.06 (IH, d, J = 9.6 Hz), 3.68 (IH. d, J = 10.6 Hz), 3.63 (IH, d, J = 10.2 Hz), 3.47 (lH, d, J = 9.5 Hz), 2.38-2.34 (lH, m), 2.30-2.25 (1H, m), 2.17 (LH,ddd, J = 13.8, 9.4, 4.3 HZ), 2.05 (IH,ddd, J = 14.1, 10.8, 6.4 HZ), 1.89-1.70 (2H. m). 1.79 (3H.s), 1.66-1.22 ([OH,m), 0.91-0.84 (3H, m), 0.88 (9H.s), 0.86 (9H, s), 0.04 (3H, s), 0.03 (3H, s), -0.03 138 (6H,s); I~cNMR (100 MHz, CDC13) 6 139.9, 134.9, 127.2, 125.8, 84.4, 76.8, 68.0, 66.0,
52.5, 50.5, 44.6, 40.6. 33.6, 31.4, 30.4, 26.0, 25.9, 23.1, 22.4, 21.7, 18.3, 18.1, 14.1, -5.5, -5.8; HRMS calcd for C32H6oO4Si2 - OH]* 547.4003, found 547.3978.
TBDMSO,
*BuLi COTBDMS Et2. - OTBDMS 'OTBDMS 134 173 The reaction was carried out as in the general procedure using n-BuLi (422 pL, 1.6 M solution in hexanes, 0.68 mmol) and 134 (50 mg, 0.10 rnrnol) in Et20 (3 rnL) at O OC for 10 min. Purification by flash chrornatography (hexanes-EtOAc 9: 1) yielded 173 (50 mg, 89%) as a white solid: Rf = 0.46 on silica gel (hexanes-EtOAc 6: 1); mp 62-65OC (Et2O); DR (KBr) 3529, 2959,2931,2854, 1472, 1462, 1261, 1248, 1109, 1085 cm-[;IH NMR (400 MHz, CDCl3) 6
5.93 (lH, m), 5.44 (LH, s), 4.51 (lH, d, J = 1.8 Hz), 4.29 (IH, d, J = 9.i Hz), 4.02 (LH, d, J = 11.4 HZ), 3.35 (lH, d, J = 10.6 Hz), 3.34 (lH, d, J = 11.0 Hz), 3.17 (LH,d, J = 9.4 Hz), 3.07 (lH, d, J = 10.6 Hz), 2.65-2.52 (2H, m), 2.21-2.09 (ZH,m), 1.93-L.73 (4H,m), 1.78 (3H, s), 1.59-1.23 (IOH, m), 0.89 (9H,s), 0.81 (9H, s), 0.03 (3H, s), 0.02 (3H,s), -0.06
(3H. s), -0.07 (3H. s); l3C NMR (100 MHz, CDC13) 6 151.1, 135.6, 131.0, 126.8, 92.9,
78.1, 69.9, 63.7, 62.1, 57.9, 54.6, 37.7, 32.0, 29.9, 29.3, 26.7, 26.0, 25.7, 23.6, 23.0, 22.0, 19.4, 18.4, 17.9, 14.1, -5.3, -5.4, -5.7, -5.8. And, Calcd for C33H6004Si2:C, 68.69; H, 10.48. Found: C, 68.33; H, 10.14. Alcohol (174).
TBDMSO, OH +BuLi C Et20
139 174 The reaction was carried out as in the general procedure using n-BuLi (1.63 mL, 2.5 M solution in hexanes, 4.08 mmol) and 139 (400 mg, 0.82 mmol) in Et20 (10 mL) at -78 OC for 15 h. Purification by flash chromatography (hexanes-EtOAc 9: 1) yielded 174 as a clear oil(433 mg, 97%): Rf = 0.44 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 3543, 343 1, 3093, 3023,
2966,2910, 2861, 1673, 1461, 1145, 1082, 1005 cm-'; IH NMR (400 MHz, CDC13) G 6.55
(lH, dd, J = 5.7, 1.7 Hz), 6.08 (lH, d, J = 5.8 Hz), 5.35 (lH, s), 4.95 (IH, d, J = 1.8 Hz), 4.07 (IH, d, J = 10.9 Hz), 3.64 (lH, d, J = 10.3 Hz), 3.62 (lH, d, J = 10.3 Hz), 3.30 (IH, d, J = 10.6 Hz), 3.10 (IH, d, J = 10.3 Hz), 2.67 (IH, d, 3 = L 1.0 Hz), 2.24-2.12 (4H,m), 1.91 (lH, dt, J = 14.1, 4.7 Hz), 1.69-1.18 (8H,m), 0.91-0.86 (3H,m), 0.88 (9H, s), 0.81 (9H. s), 0.00 (3H, s), -0.01 (3H, s), -0.06 (3H, s), -0.07 (3H. s); 13c NMR (50 MHz, CDCl3) 6 139.1, 138.3, 137.4, 129.5, 88.5, 83.1, 71.9, 64.4, 63.6, 56.0, 53.0, 37.2, 31.9,
31.5, 29.6 (2), 28.7, 25.9, 25.7, 22.8, 18.2, 18.0, 14.1, -5.6, -5.9. Anal. Calcd for
C31H5604Si2: C,67.83; H, 10.28. Found: C,67.44; H, 9.88.
General Procedure for the NucIeophiIic Alkylmagnesium chloride/Alkyllithium Ring Opening. (IR*,2R *,8S *,gS*,gaS*,9bS*)-9a,gb- Bis-[(tert-butyldimethylsiloxy)-methyl]-2,8-dibuty1-2,4,5,6,8,9,9a,9b- octahydro-lH-phenalene-1,9-di01 (175).
TBDMSO, TBDMSO,qffm OH H& OH n-BuMgCl, Et20 - *B"V then nBuLi, THF - - \ \ 'OTBDMS 'OTBDMS 174 175 140 A solution of n-BuMgCl (137 PL, 2.0 M solution in Et20, 0.27 mmol) was added dropwise to a solution of the alcohol 174 (75 mg, 0.14 mol) in Et20 (3 mL) at O OC. The mixture was stirred 30 min at O OC and n-BuLi (273 pL, 2.5 M solution in hexanes, 0.68 mrnol) was added dropwise. The mixture was stirred for an additionai 30 min at O OC after which time the solution turned cloudy. THF (3 mL) was added and the mixture was stirred for 12 h at rt. The reaction was quenched by the addition of a saturated WC1solution. The aqueous layer was extracted (3x) with Et20 and the combined organic Iayers were dned (MgS04), fdtered and concentrated. Purification by fiash chromatography (hexanes-EtOAc 15: 1) yielded 175 (65 mg, 78%) as a clear oil: Rf= 0.8 1 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 357 1, 3508, 2966, 29 10, 2847, 1666, 1462, 125 1, 1089 cm-'; lH NMR (400 MHz, CDC13) 6 5.41 (2H, bs), 4.56 (2H, d, J = 5.5 Hz), 3.99 (2H, s), 3.66 (2H, s), 2.98 (2H, bs), 2.35-2.16 (6H.m). 1.87- 1.7 1 (4H, m), 1.51-1.23 (lOH, m), 0.90-0.87 (6H. m), 0.89 (9H, s), 0.85 (9H, s), 0.06 (6H, s), 0.01 (6H, s); 13C NMR (50 MHz, CDC13) 6 136.9, 127.2, 70.9, 70.5, 62.8, 48.9, 46.3, 38.6, 33.1, 30.7, 30.1, 29.4, 25.8 (2), 23.1, 18.0 (2), 14.3, -5.6, -5.7. Anal. Cafcd for C35Hfj604Si2: C, 69.25; H, 10.96. Found: C, 69.53; H, 10.60.
TBDMSO, TBDMSO, OH HO = OH gmBU- FBuMgCI,then t-BuLi Et20 - t-";;x*a *BU - - \ \ 'OTBDMS 174 IIP The reaction was cmied out as in the general procedure using tert-BuMgCl(182 pL, 2.0
M solution in Et20.0.37 mmol), 174 (100 mg, 0.18 mmol) in Eh0 (5 mL) at O OC. tert-BuLi (536 PL, 1.7 M solution in pentane, 0.91 mmol) for 8 h at rt. Purification by flash chromatography (hexanes-EtOAc 15: 1) yielded 176 (93 mg, 84%) as a clear oil: Rf = 0.76 on 141 silica gel (hexanes-EtOAc 91); IR (neat) 3580, 3520, 2960, 2940, 2865, 1468, 1390, 1363,
1260, 1087 cm- ; IH NMR (400 MHz, CDC13) 6 5.55 ( 1H, d, J = 1.9 Hz), 5.45 ( 1H, d, I =
9.9 Hz), 3.88 (lH, d, J= 10.6 Hz), 3.41 (lH, d, J = 10.6 Hz), 2.44-2.15 (5H,rn). 1.95-1.83 (3H, m), 1.62- 1.53 (3H, m), 1.43-1.22 (SH,m), 0.99 (9H, s), 0.91 (9H,s), 0.90-0.86 (3H, m), 0.85 (9H.s), 0.08 (3H, s), 0.05 (3H, s), 0.02 (3H. s), -0.01 (3H, s); 13~NMR (LOO MHz, CDC13) 6 139.6, 135.3, 128.6, 123.0, 75.0, 70.5, 66.5, 62.8, 48.8, 46.9, 45.5, 39.6, 34.0, 32.8, 32.3, 31.6, 29.3, 28.7, 28.5, 26.0, 25.8, 23.2, 18.1, 18.0, 14.5, -5.3, -5.4, -5.8 (2). Anal. Cdcd for C35H6604Si2: C, 69.25; H, 10.96. Found: C, 69.54; H, 10.99.
Alcohol (179).
L OMe 140 The reaction was carried out as in the generai procedure using MeLi (6.15 mL, 1.4 M solution in Et20, 8.62 mrnol) and 140 (500 mg, 1.72 mol) in Et20 (15 rnL) at rt for 24 h. Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 179 (219 mg, 41%) as a white solid: Rf = 0.46 on silica gel (hexanes-EtOAc 2: 1); mp 132-134 OC (Et2O); IR (KBr) 3529. 2995, 2924, 2889, 2868, 1459, 1445, 1370, 1197, 1119, 1099, 1065 cm-'; 1H NMR (400 MHz, CDC13) 6 6.51 (lH, dd, J = 5.9, 1.9 Hz), 6.09 (lH, d, J = 5.8 Hz), 5.33 (LH,d, J
= 1.1 Hz), 4.96 (lH, d, J = 1.8 Hz), 3-91 (lH, d, J = 11.0 Hz), 3.45 (lH, d, J = 9.5 Hz),
3.32 (lH, d, J = 9.5 Hz), 3.24 (3H, s), 3.16 (3H, s), 2.95 (lH, d, J = 9.6 Hz), 2.85 (lH, d, J = 9.1 Hz), 2.54 (lH, d, J = 11.4 Hz), 2.39-2.29 (2H, m), 2.25-2.22 (IH, m), 2.14 (LH, d quintet, J = 14.6, 2.0 Hz), 1.97 (lH, dt, J = 14.1, 4.7 Hz), 1.71-1.65 (LH, m), 1.58 (1H. quintet of triplet, J = 13.2, 3.8 Hz), 1.11 (3H,d, J = 7.0 Hz); 13~NMR (100 MHz, CDCl3) 6 139.7, 238.2, 137.1, 129.5, 88.5, 82.7, 74.1, 74.0, 73.8, 59.1 (2), 55.2, 51.1, 32.2, 31.7, 28.6, 22.7, 17.5. Anal. Calcd for C 18H2604: C, 70.56; H, 8.55. Found: C, 70.57; H, 8.55. Methyl ether (180).
MeO, ?H MeO, QMe KH, 18çrown-6 C THF, Mel
The reaction was ckedout as in the general procedure using KH (79 mg, 35% in oil, 0.69 mmol), 179 (136 mg, 0.46 mmol), Me1 (1 15 pL, 1.85 mmol), and 18-crown-6 (12 mg,
0.05 mol) in TW (5 mL). Purification by flash chromatography (hexanes-EtOAc 3: 1) gave
180 (132 mg, 92 %) as a white solid: Rf= 0.24 on silica gel (hexanes-EtOAc 2:1); mp 122-124
OC (Et20); IR (Dr) 3073, 3032, 2970, 2937, 2878, 281 1, 1460, 1370, 1201, 1149, 11 19, 1098, 1077 cm-[; IH NMR (400 MHz, CDC13) S 6.51 (lH, dd, J = 5.7, 1.7 Hz), 6.06 (1H. d,
J = 5.5 Hz), 5.40 (lH, bs), 4.69 (IH, d, J = 1.8 Hz), 3.50 (2H, m), 3.48 (3H, s), 3.26 (3H, s), 3.23 (LH,d, J = 9.2 Hz), 3.15 (3H, s), 2.96 (lH, d, J = 9.1 Hz), 2.81 (IH, d, J = 9.5
Hz), 2.40-2.23 (3H, m), 2.13-2.08 (IH, m), 1.91 (lH, dt, J = 14.0, 4.6 Hz), 1.74 (IH, dq, J = 13.0, 4.1 Hz), 1.61-1.55 (lH, m), 1.12 (3H, d, J = 7.4 Hz): I3c NMR (100 MHz, CDC13) 6 139.4, 138.2, t37.8, 128.9, 87.9, 85.9, 81.9, 74.8, 74.4, 62.1, 59.1, 59.0, 562, 51.2,
3 1.8, 3 1.4, 28.5, 22.1, 17.4. Anal. Calcd for C19H2804: C, 71.22; H, 8.81. Found: C, 7 1.10; H, 8.50.
MeO. MeO, OMe DIBAL-H, Ni(CODI2 dppb, toluene
180 The reaction was carried out as in the general procedure using Ni(COD)2 (5 mg, 0.02 mmol), dppb (15 mg, 0.04 mmol), 180 (50 mg, 0.16 mmol) and toluene (6 mL). DIBAL-H 143 (172 pL, 1.O M in hexanes, 0.17 mol)was added over 8 h via a syringe pump and the mixture was stirred for 12 h at rt. Purifcation by flash chromatography (hexanes-EtOAc 3 :1) gave 181 (36 mg, 72%) as a white solid: Rf = 0.34 on silica gel (hexanes-EtOAc 3: 1); mp 80-87 OC (EtzO); IR (KBr) 3526,2964,2938.2906, 2859,2840, 1455, 1436, 1198, 1147, 11 13, 1093, 1083, 1068, IO15 cm-'; lH NMR (400 MHz, CDCl3) 6 5.37 (IH, m), 5.20 (lH, d, J = 1.1
Hz), 4.42 (IH, t, / = 8.6 Hz), 3.93 (IH, bs), 3.87 (1H,d, J = 2.2 Hz), 3.66 (IH. d, J = 9.5 Hz), 3.54 (LH, d, J = 10.2 Hz), 3.53 (lH, d, J = 9.5 Hz). 3.40 (3H. s), 3.32 (LH, d, J = 10.2 Hz), 3.32 (3H. s), 3.25 (3H. s), 2.49-2.07 (7H. m), 1.80-1.74 (1H. rn). 1.51-1.38 (LH, m),
1.09 (3H,d. J = 6.9 Hz); l3C NMR (100 MHz, CDCL3) 8 138.2, 135.8, 125.6. 121.0. 80.2. 78.9, 73.3, 73.2, 61.8, 59.5, 58.6, 48.4, 46.6, 33.4, 32.4, 31.9 (2),28.8, 17.6; HRMS calcd for CI9H3004 + H]+ 323.2222, found 323,2213.
TBDMSO, OH TBDMSO, O H 1) Pc~(OH)~/C,THF - Bu3SnH 2) Meti, THF
174 1831
The reaction was carried out as in the general procedure using Pd(OH)z on carbon (13 mg, 0.09 mmol), 174 (200 mg, 0.37 mol) in THF (10 inL) at rt. Bu3SnH (147 PL, 0.55 mmol) was added over 6 h. The filtrate was concentrated and the residue was purified by flash chromatography (100% hexanes foliowed by hexanes-EtOAc 15: 1) to give the hydrostannylated product as a colorless oil. The latter was dissolved in THF (10 mL) and treated with MeLi (3.80 mL, 1.4 M solution in Et20, 6.72 mol) at O OC. The mixture was stirred for 1 h at O OC and quenched using a saturated aqueous NH&1 solution. The aqueous layer was extracted (3x) with Et20 and the combined organic layers were dried (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 5:l) gave 182 (72 mg, 36%) as a white 144 solid: Rf= 0.35 on silica gel (hexanes-EtOAc 3:l); mp 66-68 OC (Et20); IR (CH2C12) 3349, 3054,2942,2856, 1466, 1263, 1089 cm-'; 1H NMR (400 MHz, CDCIj) 6 5.92 (1H, dd, J =
10.7. 1.9 Hz), 5.71 (LH, ddd, J = 10.6, 5.8, 1.8 Hz), 5.27 (IH, d, J = 1.1 Hz), 4.27 (M.d, J = 3.2 Hz), 4.14 (lH, bs), 3.97 (lH, d, J = 9.5 Hz), 3.79 (lH, d, J = 11.0 Hz), 3.73 (IH, d, J = 10.9 HZ),3.57 (lH, d, J = 9.9 Hz), 2.27-1.78 (7H,m), 1.60-1.23 (9H, m), 0.91-0.86
(3H, m), 0.88 (9HTs), 0.85 (9H,s), 0.04 (3H, s), 0.02 (3H, s), 0.01 (3H, s), -0.01 (3H, s);
'3~NMR (100 MHz, CDCI3) 6 137.2, 130.8, 125.0, 124.8, 71.6, 68.7, 67.4, 63.3, 50.7, 48.3, 37.9, 35.05, 35.02, 32.3, 31.7, 29.3, 25.9, 25.8, 22.9, 22.5, 18.2, 18.0, 14.2, -5.36,
-5.38, -5.43, -6.1. And. Calcd for C3 1H5804Si2: C, 67.58; H, 10.61. Found: C, 67.24; H, 10.59.
Alcohol (183) and Alcohol TBDMSO,@PB" OH + TBDMSO,
Io Io - / *Bu - OH 5 'OTBDMS 5 'OTBDMS 183 184
The reaction was carried out as in the general procedure using n-BuLi (1.02 mL,2.5 M solution in hexanes, 2.54 mol), and 142 (250 mg, 0.51 mol) in Et20 (15 mL) at -78 "C for 10 min. Purification by flash chromatography (hexanes-EtOAc 7: 1) yielded 183 (140 mg) and 184 (96 mg) as white solids in a 1.6: 1 ratio, in a combined yield of 84%. Aicohol 183: Rf= 0.34 on silica gel (hexanes-EtOAc 51); mp 69-72 OC (Et2O); IR (CH2C12) 3530, 3053, 2955, 2930, 2857, 1467, 1262, 1087, 1072 cm-1; 1H NMR (400 MHz, CDC13) 6 6.61 (LH, dd, J =
5.9, 1.9 Hz), 6.09 (lH, d, J = 5.9 Hz), 5.54 (IH,bs), 5.06 (LH, d, J = 1.8 Hz), 4.22-4.18 (2H, m), 4.1 1-4.08 (2H, m), 4.00 (lH, d, J = 13.1 Hz), 3.75 (lH, d. J = 10.2 Hz), 3.62 (1H. d, I = 10.3 Hz), 3.29 (1H.d, J = 10.3 Hz), 3.19 (lH, d, J = 10.2 Hz), 2.73-2.68 (IH, m), 2.23-2.18 (lH, in), 1.66-1.18 (6H,m), 0.91-0.87 (3H, m), 0.89 (9H, s), 0.81 (9H, s), O.OL
(3H, s), 0.00 (3H,s), -0.04 (3H,s), -0.06 (3H, s); 13~NMR (100 MHz, CDC13) 6 138.3, 135.8, 134.1, 132.0, 87.0, 83.2, 72.3, 69.0, 67.0, 64.2, 63.3, 55.4, 51.0, 37.2,31.3, 29.6, 145 25.9, 25.7, 22.8, 18.2, 18.1, 14.2, -5.5, -5.56, -5.59, -5.7; HRMS calcd for C3oHs40sSiz [m+550.35 10, found 550.3523. Alcohol 184: Rf= 0.63 on siiica gel (hexanes-EtOAc 5: 1); mp 104-107 OC (Et20); IR (Dr) 3501,3030,2959,2931,2882,2861, 1469, 1258, 1075 cm- '; lH NMR (400 MHz, CDC13) 6 6.67 (lH, dd, J = 5.5, 1.8 Hz), 6.32 (lH, d, J = 5.5 Hz), 6.21 (lH, dd, J = 10.1, 2.7 HZ), 5.63 (lH, dd, J = 10.1, 1.7 Hz), 4.92 (lH, d, J = 1.8 Hz),
4.71 (1H,d, J = 1.8 Hz), 4.38 (IH, d, J = 12.4 Hz), 4.25 (fK,d, J = 11.3 Hz), 4.19 (lH, ci, J = 12.4 Hz), 4.03 (IH, d, J = 9.9 Hz), 3.91 (lH, dd, J = 10.1, 1.8 Hz), 3.72 (lH, d, J = 9.2 HZ), 3.51 (lH, d, J = 9.2 Hz), 3.23 (LH, d, J = 11.4 Hz), 2.98-2.95 (LH, in), 1.46-1.12 (6H. m), 0.90-0.86 (3H, m), 0.89 (9H, s), 0.84 (9H, s), 0.02 (3H, s), 0.00 (3H,s), -0.02 (6H, s); l3C NMR (100 MHz, CDCl3) 6 140.3. 136.3, 132.7, 132.4, 91.2. 84.9, 73.6. 71.2, 71.0, 65.8, 65.3, 52.2, 51.9, 42.1, 30.0, 27.5, 25.9, 25.8, 23.2, 18.2, 18.0, 14.1, -5.4, -5.5, -5.7, -5.9. Anal. Calcd for C30H540sSi2: C, 67.36; H, 10.18. Found: C,66.96; H, 10.11.
(5S*,6R*,6aS*,7S*,8S*,9bR*)-6a,9b-Bis-[(tert-butyldimethylsiloxy)- methyl]-8-butyl-5-tert-butyl-1,3,5,6,6a,7,8,9b-octahydro-benzo[de] isochromene-6,7-di01 (185) and (3aS*,4R*,6aR*,7S*,8S*,9bR*}-6a,9Mis- [(tert-butyidimethylsiloxy)-methy~-8-butyl-4-tert-buty1-1,4,6a,7,8,9b- hexahydro-benzo[de]isochromene-3a,7-di01 (186).
TBDMSO, TBDMSO, OH HO : OH TBDMSO, OH
* then t-BuLi
183 186 1s The reaction was carried out as in the generai procedure using ten-BuMgCl (0.32 mL, 2.0 M solution in Et20, 0.64 mmol), 183 (175 mg, 0.32 mmol), and tert-BuLi (0.94 mL, 1.7
M solution in pentane, 1.59 mmol) in Et20 (7 mL) for 7 h at rt. Purification by flash chromatography (hexanes-EtOAc 7:l) yielded 185 (120 mg) and 186 (16 mg) as white solids in a ratio of 6.6: 1, in a combined yield of 70%: Di01 185: Rf = 0.37 on silica gel (hexanes- 146 EtOAc 7: 1); mp 88-92 OC (&O); IR (neat) 3416, 2943, 2858, 1468, 1254, 1094 cm-];1H
NMR (400 MHz, CDC13) 6 5.66 ( 1 H, bs), 5.53 ( 1 H, d, J = 2.9 Hz), 4.73 ( 1 H, bs), 4.65 ( 1 H, d, J = 5.9 Hz), 4.32-4.28 (2H. m), 4.14 (2H, s), 4-11 (IH,s). 3.94 (lH,d, J = 13.9 HZ), 3.91 (1H,d, J = 14.0 Hz), 3.86 (lH,d, J = 10.9 Hz), 3.61 (lH,d, J = 10.6 Hz), 2.37 (1H, m), 2.00 (1H,m), 1.84 (lH,m), 1.57-1.50 (1H,m), 1.42-1-17(5H, m), 1.02 (9H,s), 0.91 (9H. s), 0.89-0.87 (3H. m), 0.84 (9H, s), 0.07 (3H, s), 0.06 (3H,s), 0.03 (3H,s), 0.01 (3H, s); 13C NMR (100 MHz, CDClj) 6 137.2, 135.2, 127.7, 125.4, 74.8, 70.6, 69.4, 69.2, 67.9,
-5.4, -5.6, -5.7, -5.8; HRMS caicd for C34Hw05Si2 M+608.4292, found 608.4305. Diol 186: R.= 0.30 on silica gel (hexanes-EtOAc 7: 1); mp 52-55 OC (Et2O); IR (CH2C12) 3495, 3368, 3053,2956, 2857, 1467. 1387, 1264, 1093 cm-l; [HNMR (400 MHz, CDQ)6 6.00 (LH,dd, J = 11.0, 2.9 Hz), 5.76 (LH,dd, J = 11.0, 1.9 Hz), 5.56 (LH.bs), 5.08 (lH,bs), 4.24 (1H,d, J = 12.4 Hz), 4.22 (lH,s), 4.15 (IH, dd, J = 11.3, 2.2 Hz), 4.05 (IH,d, J = 11.0 Hz), 4.00 (IH,d, J = 12.4 Hz), 3.87 (lH,d, J = 9-9Hz), 3.85 (1H,d, J = 11.7 Hz),
3.80 (lH,d, J = 11.0 HZ),3.46 (lHTd, J = 9.8 Hz), 2.21 (lH,m), 1.68 (lH,t, J = 2.2 Hz), 1.67-1.60 (1H, in), 1.50-1.19 (6H,m), 1.04 (9H, s), 0.91-0.85 (3H, m), 0.88 (9H,s), 0.84 (9H.s), 0.08 (3H,s), 0.05 (3H,s), 0.02 (3H. s), -0.01 (3H,s); 13C NMR (100 MHz, CDC13) 6 L32.8, 131.7, 130.4, 126.9, 77.2, 72.2, 70.8, 67.3, 66.8, 62.3, 51.5, 47.6, 46.3, 35-6,
35.1, 31.5, 30.6, 29.2, 25.8, 25.7, 22.9, 18.1, 17.8, 14.1, -5.4,-5.5 (2). -6.1;HRMS cdcd for C3&40~S i2 F3[If 608.4292, found 608.4269. methyl]-4-butyl-8-tert-butyl-1,4,6a,7,8,9b-hexahydro-benzo[de]isochromene- 3a,7-di01 (187) and (3aS*,4R*,6aS*,9R*,9aR*,gbR*)-6a,9b-Bis-[(tert- butyldirnet hyIsiloxy)-rnethyll-9-butyl-4-tert- botyl-4,6a,9,9b-tetrahydro-
TBDMSO, OTBDMS
=-. *su then t-BuLi PSU t-BU
184 187 188 The reaction was carried out as in the general procedure using ten-BuMgCl (0.27 mL. 2.0 M solution in Et20, 0.55 mmol), 184 (150 mg, 0.27 mmol), and fea-BuLi (0.80 mL, 1.7
M solution in pentane, 1.36 mmol) in Et20 (7 rnL) for 4 h at rt. Purification by flash chromatography (hexanes-EtOAc 7: 1) yielded 187 (125 mg) and 188 (14 mg) as white solids in a ratio of 10.1: 1, in a combined yield of 848. Diol 187: Rf = 0.46 on silica gel (hexanes-
EtOAc 5:l); mp 70-75 OC (Et20); IR (CH2C12) 3509, 3349, 3054, 2916, 2859. 1467, 1263. 1106, 1082 cm-l; IH NMR (400 MHz, CDCL3) 6 5.90 (LH, dd, J = 10.6, 2.5 Hz), 5.79 (1H, bs), 5.60 (IH, d, J = 10.6 HZ), 4.45 (IH,d, J = 3.0 Kz), 4.20 (1H, dd, 3 = 11.7, 2.5 Hz), 4.00 (2H, d, J = 11.0 Hz), 3.94 (SH, d, J = 11.4 Hz), 3.91 (lH, d, J = 9.9 Hz), 3.82 (fH, d,
3 = 11.0 HZ), 3.76 (LH,d, J = 12.1 HZ), 3.49 (lH, d, J = 9.9 Hz), 1.94 (lH, bs), 1.82-1.79 (lHTm), 1.02 (9H, s), 0.89-0.85 (3H, m), 0.88 (9H, s), 0.82 (9H.s), 0.06 (3H, s), 0.03 (3H. s), 0.01 (3H, s), -0.01 (3H, s); 13C NMR (LOO MHz, CDCI3) 6 133.6, 130.1, 128.8, 126.9, 74.1, 70.8, 70.4, 67.5, 67.4, 62.0, 49.7, 48.3, 44.1, 37.5, 32.8, 29.9, 28.4. 28.2, 25.9, 25.7, 23.0, 18.1, 17.8, 14.1, -5.3, -5.4. -5.5, -6.1; HRMS calcd for C34H6405Si2 [m+ 608.4292, found 608.4272. Diol 188: Rf = 0.37 on silica gel (hexanes-EtOAc 5: 1); rnp 117-
12 1 OC (Et2O); IR (CH2C12)3497, 338 1, 3053, 2957, 2858, 1466, 1422, 1264, i 109, 1074 cm-!; 1H NMR (400 MHz, CDCb) 6 6.06 (lH, ddd, J = 10.1, 8.6, 2.6 Hz), 5.81 (IH, dd, J=
9.9, 3.0 Hz), 5.65 (lH, bs), 5.58 (lH, dd. J = 10.1, 1.7 Hz), 4.43 (IH,d, J = 11.0 Hz), 4.39 (lH, bs),4.36 (fH, d, J= 11.8 Hz),4.19 (lH,d, J= 11.7 Hz),4.17 (lH,d, J= 11.8 Hz), J = 9.1 Hz), 2.71 (1H, t, J = 2.8 HZ), 2.26-2.22 (IH, m), 1.59-1.10 (7H,m), 0.99 (9H, s),
0.92 (9H,s), 0.90-0.86 (3H. m), 0.86 (9H,s), 0.1 1 (3H. s), 0.10 (3H, s), -0.02 (6H,s); 13~ NMR (100 MHz, CDC13) 6 138.0, 134.8, 128.8, 128.3, 82.8, 77.8, 72.4, 71.2, 70.6, 65.3, 51.0, 49.4, 46.9, 40.1, 33.0, 29.7, 26.8, 26.2, 26.1, 23.1, 18.4, 18.3, 14.1, -4.9, -5.1,
-5.3, -5.4; HRMS calcd for C3&405Si2 M+608.4292, found 608.4292.
Alcohol (189).
y / TBDMSO vMp 144 189
The reaction was carried out as in the general procedure using n-BuLi (2.34 mL, 2.5 M solution in hexanes, 5.86 mrnol), and 144 (700 mg, 1.17 mol) in Et20 (15 mL) at -78 OC for
10 min. Purification by flash chromatography (hexanes-EtOAc 5: 1) yielded 189 (574 mg, 75%) as a pale yellow foarn: Rf= 0.25 on silica gel (hexanes-EtOAc 5: 1); mp 44-47 OC (Et20); IR (neat) 3525,2941,2857,2764, 1512, 1462. 1247, 1087 cm-1; 'H NMR (400 MHz, CDCl3) 6 6.94 (2H, d, J = 8.8 Hz), 6.81 (2H, d, J = 9.2 Hz), 6.63 (IH, dd, J = 5.9, 1.9 Hz), 6.17
(iHTdT J = 5.4 HZ),5.61 (1H. bs), 5.04 (1H,d? J = 1-4 HZ),4.1 1 (lH, d, J = 10.6 HZ),3.91 (IH, dd, J = 14.4, 1.5 Hz), 3.85 (lH, d, J = 13.2 Hz). 3.75 (3H, s). 3.73 (lH, d, J = 11.0
HZ), 3.66 (lH, dTJ = 10.2 HZ),3.57 (1H, bd, J = 14.3 HZ),3.33 (lHTdT J = 10.3 HZ),3-28 (lH, d, J = 13.5 Hz), 3.18 (IH, d, J = 9.9 Hz), 2.66 (IH, d, J = 11.7 Hz), 2.25 (lH, m), 1.54- 1.47 (IH, rn), 1.39-1.24 (5H,m), 0.92-0.85 (3H, m), 0.89 (9H,s), 0.82 (9H,s), 0.02
(3H, s), 0.01 (3H, s), -0.04 (3H, s). -0.05 (3H, s); 13~NMR (100 MHz, CDCI3) G 153.7,
144.9, 138.0, 135.7, 135.3, 132.0, 118.4, 114.3, 87.2, 83.1, 71.9, 64.1, 63.0, 55.5, 55.4, 53.9, 52.0. 51.2. 37.2, 31.2, 29.5, 25.7, 25.6, 22.7, 18.1, 17.9, 14.0, -5.67, -5.73 (2). -5.9; HRMS cdcd for C37H6 1N05Si2M+ 655.4088, found 655.4 114. AIcohol (192) and Alcohol (193).
TBDMSO, OH TBDMSO, OH
The reaction was camied out as in the generd procedure using n-BuLi (1-89 mL, 2.5 M solution in hexanes, 4.72 rnrnol), and 150 (400 mg, 0.79 rnmol) in Et20 (20 mL) at -78 OC for 30 min. Purification by flash chromatography (hexanes-EtOAc 7:!) yielded 192 (219 mg) and
193 ( 133 mg) as white solids in a 54:46 ratio, in a combined yield of 85%. Alcohol 192: Rf = 0.38 on silica gel (hexanes-EtOAc 7: 1); rnp 119-121 OC (Et20); IR (CC4) 3550, 3030,2959, 2931, 2861, 1553, 1469, 1420, 1377, 1258, 1216, 1089, 1005 cm-'; IH NMR (400 MHz. CDCl3) 6 6.61 (IH, dd, J = 5.9, 1.8 Hz), 6.46 (lH, d, J = 9.2 Hz), 6.33 (lH, d, J = 5.8 Hz),
6.15 (lH, dd, J = 9.0, 6.1 Hz), 6.04 (lH, s), 5.04 (IH, d, J = 1.8 Hz), 4.34 (lH, dd, J = 1 1.0, 5-9 HZ), 3-80 (1H, d, J = 13-6 HZ), 3.3 1 (lHTdT J = 9.5 HZ), 3.27 (lHTd, J = 9.9 HZ), 3.25 (lH, d, J = 9.5 Hz), 3.13-3.07 (2H, m), 2.84 (LH, d, J = 11.0 Hz), 0.87 (9H, s), 0.85
(9H, s), 0.00 (6H,s), -0.03 (3H, s), -0.04 (3H,s); 13C NMR (100 MHz, CDCls) 6 138.6, 137.8, 134.7, 131.3, 129.1, 116.0, 83.6, 83.5, 66.6, 65.2, 63.9, 58.3, 50.9, 27.0, 25.8 (21,
18.1 (2), -5.5 (2), -5.6, -5.7; HRMS caicd for C26H3404SSi2 [Mle 508.2499, found 508.2516. Alcohol193: Rf= 0.32 on silica gel (hexanes-EtOAc 7: 1); mp 92-95 OC (EtzO); IR (neat) 3524,2941,2857, 1467, 1255, 1140, 1110. 1084 cm-'; IH NMR (400 MHz, CDCls) 6
6.65 (lH, dd, J = 5.7, 1.6 Hz), 6.LO (lH, d, J = 5.8 Hz), 5.50 (lH, br s), 5.03 (lH, d, J =
1.8 Hz), 4.13 (IH, br-s), 3.63-3.58 (3H, m), 3.42 (lH, d, J = 14.6 Hz), 3.27 (lH, d, J = 10.6 Hz), 3.15 (lH, d, J = 10.3 Hz), 3.00 (IH, dd, J = 14.7, 2.6 Hz), 2.95 (1H. dd, J = 13.6, 2.6 HZ), 2.21 (IH, br-s), 2.16-2.13 (1H. m), 1.62-1.25 (6H.m), 0.91-0.86 (3H, m),
0.90 (9H, s), 0.82 (9H,s), 0.00 (6H, s), -0.04 (38 s), -0.05 (3H,s); 13~NMR (100 MHz, CDCl3) 6 138.3, 137.2, 135.3, 131.0, 86.1, 83.2, 71.6, 64.1, 63.5, 55.5, 52.7, 36.8, 32.7,
31.2, 31.0, 29.4, 25.8, 25.6, 22.7, 18.1, 17.9, 14.0, -5.65, -5.71, -5.73, -5.87. And. Cdcd for C30H5~0~SSi2:C, 63.55; H, 9.60. Found: C, 63.62; H. 9.64.
Procedure for the Enantioselective Desymmetrization of 150.
150 (i-)-192
A solution of (-)-bis[(S)- i -phenylethyl]acnine hydrochioride 195 ( 155 mg, 0.59 mol) in THF (5 mL) was treated with n-BuLi (472 pL. 2.5 M in hexanes, 1.18 -01) at O OC. After
the addition was complete, the mixture was stirred for 20 min and cooled to -78 "C prior to the rapid addition of the thiadioxapentacycle 150 (100 mg, 0.20 mol) as a solid. The mixture turned magenta after few minutes. The solution was stirred for an additionai 5 h at -78 OC. The
dry ice-acetone bath was removed and the mixture was dowed to warm. Immediately after the magenta color disappeared, the reaction was quenched by the addition of a saturated aqueous N&Ci solution. Purification by tlash chromatography (hexanes-EtOAc 7: 1) (2 purification's
were necessary to remove the excess base) gave (+)-192 (73 mg, 73%): >95% ee, [~r]2*~= t158" (c 1-32, CHC13).
6a,9b-Bis-[(tert-butyldimethyIsiloxy)-methy1]-6,6a,7,9b-tetrahydro-2- thia-phenalene-6,7-di01 (200) and (6S*,6aS*,7R*,SR*,9bS*)-6a,9bLIBis-[(tert- butyldimethyLsiloxy)-methyl]-8-butyl-1,6,6a,7,8,9b-hexahydro-2-thia- phenaiene-6,7-diol (201).
TBDMSO, TBDMSO, TBDMSO, OH HO, OH HO - OH A3uLi - Et20 151 Di01 200: IR (neat) 3483, 3034,2942,2857, 1538, 1467, 1253, 1072 cm-1; IH NMR (400 MHz, CDCl3) 6 6.39-6.33 (4H, m),5.78 (2H. dd. J = 9.7, 4.6 Hz), 5.13 (2H. bs), 4.08
(2H, bs), 3.49 (2H, bs), 1.55 (ZH,s), 0.90 (9H, s), 0.82 (9H. s), 0.06 (6H,s), -0.06 (6H,s);
13~NMR (LOO MHz, CDCI3) 8 132.4, 130.0. 125.7, 118.6, 71.0, 69.0, 58.5, 46.6, 44.4,
25.8, 25.7, 18.1, 18.0, -5.6, -5.7; HRMS calcd for C26H4404SSi~[Ml+ 508-2499. found 508.2496. Di01 201: 1H NMR (400 MHz, CDCl3) 8 6.01 (IH, dd, J = 10.0, 2.4 Hz), 5.86
(lH, bs), 5.56 (IH, d, J = 0.7 Hz), 5.49 (1H,dd, J = 9.9, 2.2 Hz), 4.98 (lH, bs), 4.58 (LH, t, J = 3.5 Hz), 4.04 (LH, d, J = 9.9 HZ),3.92 (1H. d, J = 9.9 Hz), 3.83-3.81 (2H, m), 3.76
( LH, ddd, J = 12-39 3-79 1.3 HZ), 3-61 (lH, d, J = 10.6 HZ), 3-23 (IH, dTJ = 12-1 HZ), 2.22 (LH, m), 1.70 (lH, d, J = 4.0 Hz), 1.63-1.24 (6H. m), 0.94-0.81 (3H, m), 0.90 (9H,s), 0.86
(9H, s), 0.09 (3H, s), 0.06 (3H, s), 0.03 (3H. s), 0.02 (3H. s); I~cNMR (100 MHz. CDCI3) 6 132.9, 130.1, 129.9, 127.7, 124.3, 119.4, 74.3, 70.7, 66.0, 65.2, 47.0, 44.2, 37.5, 32.2,
30.6, 29.2, 25.9, 25.8, 22.9, 18.1, 17.9, 14.1, -5-5, -5.70, -5.74, -6.0.
Carbarnate (202).
1) CICOCH(CI)CH3 Benzene 2) MeOH then Et3N, (60C)20 OTBDMS OTBDMS 148 2U2
A solution of 148 (175 mg, 0.29 mmol) in benzene (3 mL) was treated with 1- chIoroethyI chloroformate (34 pL, 0.32 mmol), stirred at rt for 30 min and heated at reflux for
90 min. The solvent was removed in vacuo and replaced by MeOH (5 mL). The solution was heated at reflux for 1 h. The mixture was cooled to a prior to the addition of Et3N (120 PL,
0.85 mmol) and (B0C)zO (75 mg, 0.34 mmol), and was stirred for an additional 1 h at rt. MeOH was removed in vacuo, and the residue was dissolved in Hz0 and extracted (3x) with
Et20. The combined organic layers were dried (MgSO4), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 202 (120 mg, 7 1%) as a white solid: Rf= 0.43 on silica gel (hexanes-EtOAc 3: 1); mp 136- 140 OC (&O); IR (neat) 2953. 2930, 2857. 152 1690, 147 1, 1390, 1256, 1173, 1 134, IO8 1 cmi; IH NMR (400 MHz, CDCI3) 6 6.66-6.63
(2H, ml, 6.47 (2H, d, J = 5.9 Hz), 5.04 (2H, d, J = 1.4 Hz). 4.59 (iH, d, I = 14.2 HZ). 4.46
(1H, d, = 13.2 Hz), 3-72 (LH, d, J = 14.4 HZ), 3.64 (IH,d, J = 12.9 Hz), 3.24 (ZH,s),
3.10 (2H. s), 1-44 (9H, s), 0.89 (9H, s), 0.88 (9H.s), 0.02 (6H,s), 0.01 (6H, s); 13~NMR (100 MHz, CDC13) 6 155.9, 140.8 and 140.6, 140.1, 88.2 and 88.1, 83.6, 79.8, 67.4, 66.4, 63.4, 55.7, 44.9 and 43.8, 28.5, 26.0, 25.8, 18.2, 18.1, -5.4, -5.5. Anal. Calcd for
C3 1&3N06Si2: C, 62.90; H, 9.02; N, 2.37. Found: C, 63.05; H, 9.02; N, 2.35.
TBDMSO, OH
s-8uLi * Et20
OTBDMS
2U2 203 The reaction was cmied out as in the general procedure using sec-BuLi (10 1 pL, 1.3 M in cyclohexane-hexane 92:8, 1.3 1 rnmol), and 202 (60 mg, 0.10 mol) in Et20 (5 rnL) at -78 OC for 10 min. Purification by flash chomatography (hexanes-EtOAc 7: 1) yielded a rnixtw of diastereoisomers 203 (53 mg, 81%) as a white foam: Rf= 0.35 on silica gel (hexanes-EtOAc 7:l); mp 45-47 OC (Et2O); IR (neat) 3539, 2954, 2929, 2889, 2857, 1693, 1464. 1255, 1168, 1141, 1084 cm-';IH NMR (400 MHz, CDCl3) 6 6.61 (2H, bs), 6.13 (2H,d. J = 5.9 Hz),
5.78 (LH,bs), 5.69 (1H, bs), 5.17 (2H, bs), 4.51-4.32 (6H. m), 3.64 (4H, d, J = 10.6 Hz), 3.58 (4H, dd, J= 10.3, 5.9 Hz), 3.49-3.39 (ZH,m), 3.26 (2H, d, J = 10.3 Hz), 3.16 (2H, dd. J = 10.3, 3.7 Hz), 2.57 (IH, bs), 2.41 (lH,bs), 1.91 (1K,m), 1.83 (lH, m), 1.66 (2H, m), 1.43 (18H,bs), 0.97-0.84 (14H, m), 0.89 (18H, s), 0.82 (9H,s), 0.81 (9H, s), 0.01
(3H, s), 0.00 (9H, s), -0.04 (6H, s), -0.06 (6H,s); 13~NMR (100 MHz, CDCI3) 6 155.2, 138.5, 135.0, 134.5, 131.2, 87.2, 83.3, 80.1, 70.2, 70.0, 64.08, 64.04, 63.4, 63.3, 55.7, 55.6, 51.6, 49.2, 48.0, 46.7, 45.6, 42.7, 42.3, 34.9, 33.7, 28-3, 27.5, 25.8, 25.77, 25.74, 25.71, 18.13, 18.10, 18.04, 18.0. 17.0, 16.3, 11.7, 10.5, -5.58, -5.61, -5.66, -5.87, -5.89; 8 11.4 References and Notes
(1) (a) Warrener, R. N.; Russell, R. A.; Solornon, R.; Pitt, 1. G.; Butler, D. N. Tetrahedron ktt. 1987,28, 6503. (b)Warrener, R. N.; Butler, D. N.; Liao, W. Y.; Pitt, 1. G.; Russell, R. A. Tetrahedron Lett. 1991.32. 1889. (c)Warrener, R. N.; Maksimovic, L. Tetrahedron
Lett. 1994,35, 2389. (d) Warrener, R. N.; Maksimovic, L.; Butler, D. N. J. Chem. Soc., Chem. Cornm. 1994, 1831. (e) Warrener, R. N.; Wang, S.; Maksimovic, L.; Tepperman.
P. M.; Butler D. N. Tetrahedron Lett. 1995.36, 6 141. (f) Warrener, R. N.; Maksimovic, L.; Pitt, 1. G.; Mahadevan, 1.; Russell, R. A.; Tiekink, E. R. T. Tetrahedron Lett. 1996, 36, 3773.
(2) Pollmann, M.; Müllen, K. J. Am. Chern. Soc. 1994,116, 23 18. (3) (a) Luo, J.; Hart, H. J. Org. Chem. 1988, 53, 1343. (b) Blatter, K.; Godt, A.; Vogel, T.; Schlüter, A.-D. Makrornol. Chern. Macromol. Symp. 1991, 44, 265. (c) Packe. R.; Enkelmann, V.; Schlüter, A. -D. Makrornol. Chem. 1992,193, 2829, (d) Schurrnann, B. L.; Enkelmann, V.; Loffler. M.; Schlüter, A.-D. Angew. Chem. Int. Ed. Engl. 1993,32, 123. (4) Lin, C.-T.;Chou, T.-C.Synthesis 1988, 628. (5)Tochtermann, W.; Malchow, A.; Tirnrn, H. Chem. Ber. 1978,111, 1233. (6) For recent reviews on the ring opening of oxabicyclic systems, see: (a) Chiu, P.; Lautens, M.
Topics in Current Chemistry: Springer-Verlag: Berlin, 1997, Vol. 190, p 1. (b) Woo. S.; Keay, B. Synthesis 1996, 669. (c) Lautens, M. Synlett 1993, 177. (d) For the recent use of dioxacyclic cornpounds in synthesis: Mosimann, H.; Vogel, P.; Pinkerton, A. A.; Kirschbaum, K. J. Org. Chem. 1997,62, 3002. (7) For a recent review on aromatic heterocycles as intermediates in synthesis, see: Shipman, M. Contemp. Org. Synth. 1995,2, 1. (8) (a) For regioselective opening: Lautens, M.; Chu, P. Tetrahedron Lett. 1993.34, 773. (b) 154 For intrarnolecular opening: Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1994, 117, 1954.
(9) Lautens, M.; Ma, S.; Chiu, P. J. Am. Chem. Soc. 1997,119, 6478.
( 10) (a) Lautens, M.; Klute, W. Angew. Chem Inr. Ed. Engl. 1996.35, 442. (b) Lautens, M.;
Aspiotis, R.; Colucci, J. J. Am. Chem. Soc. 1996,118, 10930.
( 11) Lautens, M.; Belter, R. K. Tetrahedm Lett. 1992,33, 26 17. (12) Lautens, M.; DeFrutos, O. Unpubiished results.
( 13) Lautens, M.; Kumanovic, S.; Meyer, C. Angew. Chem. Int. Ed. Engi. 1996,35, 1329. (14) Lautens, M.; Fillion, E. J. Org. Chem. 1996, 61, 7994. (15) Kallos, J.; Deslongchamps, P. Cun. J. Chem. 1966,44, 1239. (16) Brown, K. C.; Weissman, P. M. J. Am. Chem. Soc. 1965,87, 5614.
( 17) Caivani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994,50, 12999. (18) Corey, E. J.; Jones, G. B. J. Org. Chem. 1992,57, 1028. (19) We have preliminary evidence that azabicyclo[3.2.1]systerns also react with organolithium reagent: Lautens, M.; Goldnng, W.; Johnstone, S. Unpublished results. (20) (a) Bordweil, F. G. Acc. Chem. Res. 1988,21, 456. (b) March, J. Advanced Orgnnic Chemistry; Wiley Interscience, Ed.; John Wiley & Sons: New York, fourth edition, 1992, p. 248. (21) Schroder, C.; Wolff, S.; Agosta, W. C. J. Am Chem. Soc. 1987,109, 5491. (22) (a) The reluctance of a trisubstituted doubie bond toward carboiithiation reacrion was previously reported in the literature: Krief, A.; Barbeaux, P. Tetrczhedron Letr. 1991,32,
417. (b) Lautens, M.; Kumanovic, S. Unpublished results. (23) (a) For the opening of meso oxabicycIo[3.2.1] with n-BuLi/(-)-sparteine: Lautens, M.; Gajda,
C.; Chiu, P. J. Chem. Soc., Chem. Cornm. 1993, 1193. @) Gajda, C. M. Sc. Thesis, Ring Opening Reactions of Oxabicyclic Compounds: Asyrnrnetric Induction and Solvent Effects, University of Toronto, 1993. (24) Chiu, P. Ph. D. Thesis, Ring Opening Reactions of Oxabicyclic Compounds: Unsyrnmetrical Substrates and Reduction, University of Toronto, 1994. 155 (25) (a) Chan, M.-C.; Cheng, K.-M.;Ho, K. M.; Ng, C. T.; Yam, T. M.; Wang, B. S. L.; Luh.
T.-Y. J. Org. Chem. 1988,53, 4466. (b) Schut, J.; Engberts, J. B. F. N.; Wynberg, H.
Synth. Cornm. 1972,2, 4 15.
(26) For reported deprotonatiodfragmentation of "unactivated" oxabicyclic compounds: (a)
Arjona, O.; Conde, S.; Plumet, I.; Viso, A. Tetrahedron Lett. 1995,36,6157. (b) Lautens, M.; Ma, S. Tetrahedron Lett. 1996,37, 1727. (27) For a review on the synthesis of chiral compounds by bond disconnection, see: Gais, H.-I.
In Methods of Orgarzic Chemistry (Houben-Weyl), 1996, Vol. E 2 la, Part C, p 589. (d) Ho, T. L. Symmetry. A basis for synthetic design; Wiley Interscience, Ed.; John Wiley & Sons: New York, 1995. (28) Majewski, M.; Lamy, R. J. Org. Chem. 1995,60, 5825. (29) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996,52, 14361. (30) Marchionni, C.; Vogel, P.; Roversi, P. Tetrahedron Lett. 1996,37,4149. (3 1) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Mairoof, T. J. Org. Chem. 1984,49. 208 1. (32) (a) For an excellent review on enantioselective deprotonation: Beak, P.; Basu, A.; Gallagher,
D. I.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,29, 552. (b) For examples of deprotonation-diminailon, see: (b) Beak, P.; Lee, W. K. J. Org. Chem. 1993.58, 1109. (c) Garrido, F.; Mann, A.; Wermuth, C.-G. Tetrahedron Letr. 1997.38, 63. (33) Schunn, R. A.; fttel, S. D.; Cushing, M. A. Inorg. Synth. 1990,28, 94. CHAPTER 3
BASE-INDUCED RING OPENING OF AZA- AND THIA- OXA[3.2.1] AND [3.3.1]BICY CLES AS AN ENANTIOSELECTIVE AND STEREOSELECTIVE APPROACH TO AZEPINES, THIEPINES AND THIOCINES 5 III.1 Introduction
111.1.1 Monocyclic Medium Ring Heterocycles Synthesis
Medium-sized heterocycles are an important class of compounds which occur in a range of natural and unnatural products.1-3 Monocyclic medium ring (ring sizes = 7 to 12) are particularly challenging synthetic targets owing to the difficulties associated with their construction since methods which work well for five- and six-membered rings are unsatisfactory when applied to seven-membered rings and larger. For this reason, mmy new synthetic methods and strategies aimed specifcally at seven- and eight-membered heterocyclesl-
3 and carbocycles4-5 were recentiy developed. Medium-sized seven- and eight-rnembered oxygen heterocycles and carbocycles have received a great deal of attention because of the discovery of an ever increasing array of natural products containing such rings. Despite the successful work in this area, the development of flexible and stereoselective methods of fonning the family of medium ring nitrogen and sulfur heterocycles has been neglected. The latter are recognized for their usefulness as both synthetic intermediates as well as potential therapeutic agents. An overview of the synthetic methods related to the preparation of monocyclic medium-sized nitrogen and sulfur heterocycles reported in the last few yean is presented below. The synthesis of medium-sized ring lactams and thiolactones will not be considered. The synthetic strategies are classified according to the chemical transformation in which these families of rings are formed: cyclization. ring expansion, ring fragmentation and ring contraction.
Monocyclic compounds containing one or more heteroatoms in a three- to ten- membered ring are named according to the Hantzsch-Widman system.6 For simplification, the nomenclature reported in Table 3.1 wiii be used through this chapter to name saturated and unsanirated seven- and eight-membered oxygen-, nitrogen- and sulfur heterocycles. Table 3.1. Monocyclic Medium-Sized Heterocycle Nomencfature 1 Ring Siza 1 Etement 1 1 1 Ox~gen Nitrogen Sulfur 1
Oxepine Azepine Thiepine Oxepane Azepane Thiepane Unsatu rated Oxocine Azocine Thiocine 8 Satu rated Oxocane Amcane Thiocane
The intramolecular C-C or C-X (X=N, S) bond formation aiiows the direct cyciization to seven- and eight-membered ring systems and have been accomplished by severai types of ring closure. Although this strategy is useful, thermodynamic factors have to be taken into acco~nt.~The cychation rate is determined by the energy of activation and, consequently, the process wiil be controlled by the ground stare energy of the acyclic precursor and the energy of the transition state whose conformation can reasonably be expected to resemble that of the cyclic product. Thus, the formation of the cyclic compound is disfavored by entropy as well as enthalpy (vide infrn). The entropic factor is disfavored by the carbon chain becoming too long, and thus the probability of a reaction taking place between the two chain termini decreases. The enthalpic factor is mainly created by steric interactions and reflects the strain energy of the ring to be forrned. Three different interactions contribute to the strain energy, namely, the tonional effects in single bonds (Pitzer strain), the deformation of bond angles from their optimal values
(Baeyer strain) and the transannular strain (non-bonded intenctions), w hic h occ urs w hen atorns across are forced into close proximity. This strain WU be reflected in the endialpy of activation for the cyclization. The negative entropy necessary for cyclizations which give medium ring compounds disfavors the reaction, and in fact favors the intermolecular reaction. In some cases, performing the cyclization reaction under high dilution conditions counteracts the intermolecular process in favor of the intramolecular one. However, the high-dilution techniques do not always overcome the formation of oiigomers and it is technically not practical. In some cases, however, the intramolecular bond formation may be facilitated by L 59 favorable entropic and conformational characteristics. A few representative examples of cyclization methodoiogy used for the synthesis of seven- and eight-membered heterocycles are discussed below.
Overman and Rodnguez-Campos have estabiished a route to medium-nitrogen heterocycles based on an iodide-promoted Mannich cyclization of alkynylamines.8 For example, cydizing the intermediate 204 gave a mixture of azepane 205 and azocine 206 (Equation 3.1). The azepane 205 was obtained as the major product with a good selectivity. The method worked weil for the preparation of seven-membered nitrogen heterocycles, but was unsuccessful for the synthesis of eight-membered ring as showed in the cyclization of 207
giving the eight-rnembered ring 208 in low yield. In this case, no trace of the nine-membered ring 209 was observed.
Grieco reported a simiiar strategy using aliylsilanes to tnp the iminium ions, forming seven- and eight-membered nitrogen heterocycles in good yields (Equation 3.2).9
NHBn f' f' CF3C02H, HCHO
Hoveyda and coworkers recently published the synthesis of seven- and eight-membered nitrogen heterocycles, prepared efficiently by the Ru-cataiyzed diene metathesis method developed by Gmbbs (Equation 3.3).3j-l0
The synthesis of medium-sized heterocycles via C-X bond formation (X=S, N) was dso achieved. An approach to the synthesis of azasugars and thiosugars was designed based on the double nucleophilic opening of the C2-symmetric bis-epoxide 210 denved frorn D- mannitol (Scheme 3.1). l l In the first opening, the selectivity is high for attack at the least hindered carbon, however, the second intramolecular epoxide opening involves a cornpetition between 6-exo-fet ring closure versus 7-endo-tet ring closure. The ratio of six- versus seven- membered ring heterocycles 211 or 212 is highly dependant on the protecting groups on the bis-epoxide 210 and the reaction conditions.
Scherne 3.1
Despite this successful synthesis of a thiepane, limited attention has been paid to methods involving carbon-sulfur bond formation New synthetically interesting cyclizations involving carbon-sulfur bond formation have been reported. The reaction of electrophilic carbenes and carbenoids with divalent sulfur cornpounds to give the correspondhg sulfonium ylides is also well known. This reaction has been applied to the synthesis of thiepanes. Treatment of the diazo thiol213 with rhodium(II)acetate yielded the thiepanone 214 in 34% yield (Scheme 3.2)! Similady, diazo suifide 215 gave the thiepanone 217 in good yield via 161 a subsequent [2,3]sigmatropic rearrangement of the resulting suifur ylide 216 (Scheme 3-2).13
Scheme 3.2
Cyclization methods involving the C-N bond formation were also reported in the literature and are presented in Scheme 3.3. The allene 218 was treated with PdCL2(PhCN)2 and carbon monoxide to afford the azepane 219 resulting from a Wacker-type reaction, aithough in low yield. l4 Lambert and coworken described the intramolecular aza-Wittig reaction of the azido-ketone 220 as a route to the cyciic imine 221.l5 Primary amines have also been shown to directly cyclize onto alkynes. For example, the primary amine 222 underwent an organolanthanide-catalyzed hydroamination/cyclization reaction to yield the azepane 223. No yield was reported for this transf~rmation.~~
Scheme 3.3
CO, MeOH, Et3N 23%
benzene 162 In addition to the synthetic methods mentioned above, several other strategies of fomiing medium-sized heterocycles via cyclization process were found in the literanire. As seen from the examples given above, with few exceptions. the yield of the cyclization step is modest and works oniy for simple models and no enantio- or stereocontrol was reported. Due
to the problems associated with the formation of medium-sized ring via direct cyclization, severai methods for the seven- and eight-membered ring synthesis were developed based on the
ring expansion of srnaller rings which are generally easier to access.
The ring expansion of substituted piperidines by rneans of a free-radical rearrangement has been used to prepare azepanes. The seleno-intermediate 224 was converted into the azepane 225 by Bu3SnH in the presence of AIBN (Equation 34-17 The free radical expansion reaction has been dso appiied to the formation of thiepanone 227 by treating 226 under the same conditions as previously described.I7
benzene, reflux
The reaction of opticdiy active seven-membered ring P-ketoestes 228 with hydrazoic acid and a Lewis acid generated the tetrazoloazocanes 229 via the Schmidt rearrmgement.I8 The products were readily reduced by Lieto the chiral azocane carbinols 230 (Scheme 3 -4).
Scheme 3.4 163 The ring expansion of pyrrolidine and piperidine as a route to the parent seven- and eight-membered ring was reported by Kurihara and coworkers-19 Pyrolysis of 2- pyrrolidinylethyl O-phenyl thiooocarbonate 23 1 and 2-piperidinylethyl O-phenyl thionocarbonate 235 gave respectively the azepane 233 in 55% yield and the azocane 236 in 32% yield with Liberation of COS,via the intermediate azetidinium 232, accompanied of the side products 234 and 237 (Scheme 3.5). The ring expansion reaction of the sulfur analog 238 resulted in the formation of the thiepane 239 in 53% yield, the side product 240 being isolated in 33% yield.
Scheme 3.5 OPh '(Q1 - + .((*- OPh 231,X=NBn,n=1 233 and 234 235, X = NBn, n = 2 236 and 237 238, X = S,n = 1 239 and 240
Many synthetic routes to medium ring-sized heterocycles take advantage of the stereoselectivity and the predictable geometry of sigrnatropic ring expansion reactions. The tandem cyclopropanatiodCope rearrangement has been widely used in the synthesis of seven- membered carbocycles4 and has recendy been applied to the synthesis of azepines. Reacting the azabutadiene 241 with the alkenyl chromiun complex 242 afforded the azepine 243 in good yield (Scheme 3.6).*~ An asymrnetric version of this reaction was also developed.
Scherne 3.6 OMe Y OMe /
fAR BuHN THF m! Ph OMe The sigmatropic ring expansion strategy has also ken appiied to the synthesis of sulhr medium-sized heterocycles. One of the very few examples of synthesis of eight-membered and larger sulfur heterocycles via a [2,3]-sigmatropic ring expansion reaction was reported by Vedejs and coworkers.20 Ring expansion of vinyltetrahydrothiophene 244 by successive S- allçylation and ylide generationl[2,3]-remangement using DBU afforded Cthiacyclooctene 245 in 40% yield for 2 steps (Scheme 3.7).
Scheme 3.7
To avoid the problems related to the cyclization of acyclic precursors, the ring fragmentation of bicyclic systems has been widely used in a very efficient manner for the synthesis of eight-membered ring carbocycles since the rings present in the bicyclic compound are srnaller and much easier to con~tmct.~However, this strategy has not yet been applied to the synthesis of seven- and eight-membered sulfur- and nitrogen heterocycles. Ring closure via the ring contraciion of larger rings was also exploited for carbocycles and medium-sized oxygen heterocycles but not for the nitrogen and sulfur anal0gs.3~
As illustrated by the existing literature, it is clearly stated that the developrnent of flexible, enantio- and stereoselective methods to access the family of medium ring nitrogen, and sulfur heterocycles has been overlooked. 5 111.13 Enantioselective Desymmetrization of Oxabicyclo[2.2.1] and [3.2.1] Substrates, and Tropinone
The synthetic utility of stereochemically well-defined oxabicyclo[2.2.1] and [3.2.1] systems has been demonstrated by their ability to be transformed and further ring-opened with high stereocontrol to a wide variety of cyclic and acyclic products containing multiple stereocenters.2
Despite the synthetic value of the oxabicycles, few developments regarding their asymmetric synthesis have been reported. Two approaches to access enantiomerically pure oxabicyclic [Xi.11 or [2.2. L] compounds were exploited. The first one is the diastereoselective cycloaddition of opticaliy pure furans andor dienophiIes/oxyallyl cations
(Scheme 3.8).*2-23 For exarnple, in the case of oxabicyclic [3.2.1] synthesis, our group has reported the diastereoselective intermolecular [4 + 31 cycloaddition of optically pure furans and oxyailyl cations (Scheme 3.8).23" Aitematively, the [4 + 31 cycloaddition of an oxyaiiyi cation moiety bearing a chiral auxiliary with furan derivatives was also s~ccessful.~~~Recently, Davies and coworkers have shown that rhodium(I1) carboxylate catalyzed decomposition of vinyldiazomethanes bearing a chiral auxilary in the presence of furan resulted in a general synthesis of enantiomericaiiy enriched oxabicyclo[3.2. Ilocta-2?6-dienedenvatives viu a tandem cyclopropanatiodCope rearrangement.23~ In addition to the strategy mentioned above, enantiomericaily e~chedoxabicyclo[2.2.1] systems were accessed by the asymmehic Diels- Alder of furan derivatives cataiyzed by chiral Lewis acid, as described by the groups of Corey, Narasaka and ~vans.24 Scheme 3.8
II,... O neat 78%
As the second approach. enantiomerically pure oxabicyclo[2.2. Ilhepenes have been obtained either by chernical or enzymatic resolution of racemic derivatives or by desymmetrization of meso sysrems through enantioenrïched reagents or enzymatic proce~ses.~laThe enantiotopic discrimination of two fùnctiond groups in a mesu compound is a well-established and convenient procedure for preparing enantiopure compounds, which avoids separation and disposal of the unwanted enantiomer.25 Most of the methods reported in literature are based on the esterification of mes0 anhydrides, diesters or diols. and are often performed with enzymes. However, highly successful "chernical" desyrnmeuizations were developed and wiU be presented below.
We became interested in the desymmetrization methodologies due to the successful base-induced desymmetrization of thiadioxapentacycle 150 reported in Chapter 2. Two representatives examples of desymmetrkation of oxabicycles [2.2.1] are illustrated in Scheme 3.9. Treatment of the meso anhydride 246 with Seebachk TADDOLate fed to the desymmetrized acid-ester 247 in an excellent enantiomeric ex ces^.^^ While the formation of 249 was realized enzymatically in 75% ee by ueating the diester 248 with PLE.~~ Scheme 3.9 '=!R
pig liver esterase phosphate buffer 86%, 75% ee
Similar desymmetrization strategies were applied to oxabicyclic [2.2.1] systems via enantioselective reduction and oxidation as show in Scheme 3.10.28929
Scheme 3.10 O horse liver alcohol (+)-BINOL, LiAIH4 dehydrogenase EtOH, THF 83%, 98Oh ee O 72%. 83% ee O
Lautens and Ma used Brown's asymmetric hydroboration-oxidation reaction to desymmetrize the oxabicyclic [2.2.1] compound 250 giving the alcohol 251 in good enantiomenc excess (Scheme 3.1 1).3* The desymmetrization of oxabicyclo[3.2.1] substrates using this strategy was also rep0rted.3~ The same pnnciple was appiied to desyrnmetrize the oxabicyclic 252, via a catdytic asymmetnc hydrosilylation reaction, giving after oxidation of the C-Si bond, the enantiomencdy e~chedalcohol253 was obtained in 90% ee.32
Scheme 3.11 1) (-)-lpc2BH, THF OTBDMS 2) H202, NaOH - OTBDMS 95%, 83% ee 251
250, R = TBDMS 1) HSiC13, (R)-MOP 252, R = Me [PdCl(n-C3Hs)l2 2) KF, KHC03, Hz02 80%, 90% ee The asymmetric transformation of oxabicyclic L3.2.11 ketones into chiral silyl en01 ether was achieved using chirai bases.33 Simpkins and coworkers have demonstrated that treatment of the rneso compound 254 with a chiral lithium amide base led to enantioselective enoli~ation.3~The chiral enol was trapped in situ with TMSCI to give the product 255 in good yield and enantiomeric excess (Equation 3.5).
-- - (3.5) TMSCI, THF OTMS 79%, 00%ee
In an identical fashion, the reaction of tropinone 256 with LDA yielded the intermediate lithium enolate 257 which was trapped with a number of electrophiles giving a variety of tropinone denvatives 258 (Scheme 3.~2).~59~~Treatrnent with TMSCI Ied to the formation of the silyl en01 ether 259. The asymmetric desyrnrnetrization of tropinone was performed using the chiral amide bases 260 and 194 in the presence of LEI. Majewski and coworkers have published several papers on the enantioselective synthesis of seven-membered carbocycles via the C-N bond disconnection of tropinones.36 When the chiral lithium enolate 257 was reacted with methyl or benzylchloroformate, the formation of cycloheptenone 262 in good enantiomeric excess, via C-N bond cleavage, was obser~ed.~~The strongly electophilic chloroformates are known to react with tertiary amines suggesting that the elimination involves the reaction of the bridging nitrogen with the chloroformates, foiming the intermediate 261. in tandem with an Elcb elimination. This constitutes a good example of asyrnmevic bond discomection which is much less frequently employed than asyrnmetric bond formation for the synthesis of chiral compounds.37 Scheme 3.12
LDA \ OLi
(0.5 equiv. LiCI) 92% ee
Li (1.O equiv. LiCI) 90% ee
We aiso have to restate the desymrnetrizaion of [3.2.1] and [2.2.1] oxabicycles reported by Lautens and Gajda. and discussed in Chapter 2, via a nucleophiiic ring opening reaction using organolithium/(-)-sparteine cornplex? This methodology was extended to the desymmetrization of dioxapentacycle 139 in modest ee.
8 111.1.3 Base-Induced Oxabicyclo[2.2.1] and [3.2.1] Substrates Ring Opening
The base-induced opening of oxabicyciic [2.2.1] compounds &as been widely exploited in the synthesis of natural products.39 In the reported synthetic strategies, the main feature of the substrates is the presence of an electron withdrawing group in the a-position to the br-idging ether. Removal of the acidic proton and generation of a carbanion a to the carbon-oxygen bond induces ether cleavage and subsequent synthesis of a variety of 6-membered rings in a 170 stereocontrol fashion. No example of this strategy was used in the [3.2.l]oxabicyclic series.
base -
E = COOR, CN, S02Ph, COR OH
The opening of "unactivated" oxabicycles, having no acidic protons a to the bridgehead position, is less cornrnon. Lautens and Ma reported the base-induced ring opening of oxabicyciic [2.2.1] and [3.2.1] substrates using a strong akyllithium base suc h as n-BuLi via deprotonation of the allylic positionhridge cleavage sequence (Scheme 3.13).30 The methyIenecyclohexeno1 and methyienecycloheptendiol opened-products were obtained in good yields.
Scherne 3.13
n-Buli OTIPS OTIPS t OTIPS OTIPS Et20 06% OH
In an independent report, %ana and coworkers described the base-opening of the oxabicyclic [2.2.1] alcohol263 when treated with LDA in a complex solvent mixture (Equation
3.7). The selective deprotonation at the allylic methyl group foiiowed by bridge cleavage gave
LDA, THF > toluene, hexanes mw/o Q m.2 Results and Discussion
In the course of the sequential nucleophilic ring opening of dioxacyclic compounds study (see Chapter 2). we have unexpectedly observed a new mode of ring opening via deprotonation/C-O bond disconnection at an unactivated position adjacent to sulfur. In an effort to increase the versatility of this new methodology, we envisioned to extend the deprotonatiodc-O bond elimination sequence to meso C3.2.11 and [3.3.1] aza- and thiaoxabicyclic systems as an enantioselective approach to azepines, thiepines, and thiocines (Scheme 3.14). This strategy would allow the transformation of readily available symmevicai precurson into asymmetnc synthons of high value in a Limited number of steps.
Scheme 3.14 O O Chiral Base
X = S, NBOC n=1,2
The next sections descnbe our results on the exploration of the enantioselective base- induced ring opening of hetero-oxabicyclic [3.2.1] and [3.3.1] systems for the Facile construction of sulfur and nitrogen medium-sized heterocycles. We have explored the regio- and enantiocontrol in the bond-breakhg reaction, and the efficiency and ease of access of the starting materials. The mechanism of deprotonation has dso been investigated.
5 III.2.1 Symmetrical Substrate Preparation
There are scattered reports in the Literature descnbing the preparation of 3-aza- and 3- thia-8-oxa[3.2.l]bicycles. lA1,42 Newth and Wiggins have reported the synthesis of 8-oxa-3- azabicyclo[3.2. Iloctane 266 (R=H) by reacting 2,5-bis-(hydroxymethy1)-tetrahydrofuran 172 ditosylate 265 with amnonia in methanol (Scheme 3.15).~2&b This strategy was expanded by Cope and coworkers who used a variety of primary amines to prepare the azaoxabicycles 266 in rnodest to good yields (Scheme 3.15).42~* Baldwin and coworkers synthesized the 3-thia-8- oxabicycle 267 by reacting the ditosylate precursor 265 with sodium sulfide in DMSO
(Scherne 3.15).41d No reaction conditions were reported in his communication.
Scheme 3.15 NH3, MeOH 16û°C, 36h Na2S-9H20 TsO, ,,..-0-,,,,OTs O w RNH2, THF DMSO
Earlier, Birch and Dean cyclized the carbon analog ditosylate 268 giving the bicyclic system 269 in good yield (Equation 3.8).43
Based on the cyclization strategies described above, we have developed a simple and versatile route to substituted 3-aza- and 3-thia-8-oxa[3.2.1]bicycies in 5 to 6 steps from the cycloadduct of furan and maleic anhydride. The stereochemical attributes of the bicyclic substrates are set during the cyclcaddition reaction which ensures a predictable and high level of stereocontrol. Further, the installation of functional groups at key stereocenters could be achieved by appropriate modifcation of diene and dienophile.
We fxst prepared a series of unsubstituted substrates. The sequence begins with the oxa[2.2.l]bicycles and leads to the final [3.2. Llbicycles without purification of the di01 and ditosylate. The known di01 270" arising from the reduction of the cycloadduct of furan and maleic anhydride with LiAlH4, was protected to the correspondhg dimethyl ether 271TMa 173 dibenzyl ether 272,wb di-ter?-butyl ether 273 and disilyl ether respectively. Three straightforward steps were required for the incorporation of the heteroatom moiety: ozonolysis and reduction$5 tosylation with p-TsCl in pyridine to give the ditosylate followed by a double displacement of p-ioluenesulfonate wi th Na2S or benzylamine (Scheme 3.16) .41d*4*ae-43 The reported yields are for the three step sequence and have been performed on a multigrarn scde (up to 20 g). The diTBDMS ether substrate 277 was transposed into the diMOM ether 278 via a deprotection-protection sequence under standard conditions (Scheme 3.16). The transformation of the benzyl protected substrate 279 into the BOC analogue 280 was readily achieved (Scheme 3-16)? The iH and 13~NMR spectra of 280 were not resolved at room temperature due to the slow interconversion of rotational isomers attributable to the carbarnate moiety , consequently variable temperature expenments were performed at 70-80 OC to obtain weii resolved spectra.
Scheme 3.16 O
d, e, f O 7 S
274 R=Me 45% O> 275 R = Bn 31% O a, b, C R O& 276 R = t-Bu 38% + - 277 R = TBDMS 13% RO hC278 R = MOM 58% 270 R = H 271 R=Me 272 R = Bn \ d. e. g Zi3 R = t-BU 177 R = TBDMS
(a) neat, rt. (b) LiAIH4, THF, rt. (c) NaH, KH, Mel, THF, Z???(3 steps) or BnBr, NaH, KH, THF, 67% or 2-Methyfpropene, Amberlyst@ 15 ion-exchange resin, hexanes-CHzC12, rt, 51% or TBDMSCI, imidazole, DMF, 79% (d) 03, EtOH, O @I NaBH4. (e) TsCI, pyridine, rt. (f) Na2S-9H20, DMF or EtOH/H20, reflux. (g) BnNH2, NaHC03, DMF, reflux. (h) TBAF, THF; MOMCI, (i-Pr)*NEt, CH2CI2. (i) PdIC, HC02NH4, (BOC)*O, EtOH, rt. 174 Dimethylsubstituted substrate 283 was prepared in an identicai fashion starting from the known di01 281.44~ The latter was obtained from the Diels-Alder of 2,s-dimethylfuran and maleic anhydride followed by LiAiH4 reduction and methylation to give the intemediate 282 which was submitted to the three usuai steps leading to the substrate 283 in excellent yield (Scheme 3-17).
Scheme 3.17
NaH, KH 1) 03,EtOH; Na6H4 HO Mel, THF Me0 2) TsCI, pyridine Me0 3) Na2S, DMF 2&2 63% (3 steps)
Thiadioxatricyclic substrate 285 was prepared from the di01 270. Dehydration47 of the di01 270 gave the tetrahydrofuran derivative 284 which was transformed under the standard conditions to the substrate 285 (Scheme 3.18).
Scheme 3.18
p-TsOH, benzene 1) 03,EtOH; NaBH4
HO Dean-Stark trap 2) TsCI, pyridine 3) Na2S, EtOH, H20 284 34% (3 steps)
The oxathia[3.3.l]bicyclic subsaates have been prepared via an identical route. Starting from the known oxa[3.2.l]bicyclic alcohols 28648a and 287,48b the hydroxy group was methylated and the same sequence of steps led to the formation of the thiaoxa[3.3.l]bicycles
290 and 291 (Scheme 3.19). Scheme 3.19
(a) NaH, Mel, THF, 82% and 85%. (b) 03,EtOH, O OC;NaBHq. (c) TsCI, pyridine, rt. (d) Na2S-9H20, DMF or EtOH/H20, reflux,
5 111.2.2 Unsymmetrical Substrate Preparation
A series of unsymmetricai [3.2.1] substrates bearing a methyl substituent at the bridgehead position was prepared via the same strategy. Reduction of the anhydride arising from the cycloaddition of 2-methylfuran 82 and mdeic anhydride followed methylation of the resulting di01 provided the intermediate 292 in 75% yield for the three step sequence-44d-e Ozonolysis and in siru reduction with NaBH4, ditosyiation followed by a double displacement of the bis p-toluenesulfonate with Na2S or benzylamine were used for the incorporation of the heteroatorn moiety (Scheme 3.20). Further oxidation of the thioether 293 to the sulfone 294 was can-ied out using m-CPBA. In order to perform a-lithiation in the aza senes, the benzyl group in 295 was replaced by the N-BOC group giving the substrate 296. As observed for the symmetrical substrate 280, the slow interconversion of rotational isomers of 296 attributable to the carbarnate moiety forced us to perform variable temperature NMR at 80 OC to obtain weii resolved IH and l3~spectra Scheme 3.20
X 293 X=S C X=SQ 295 X = NBn 296 X = NBOC
(a) neat, rt. (b) LiAIH4, THF, rt. (c) NaH, KH, Mel, THF, 75% (3 steps). (d) 03,EtOH, O OC;NaBH4. (e) TsCI, pyndine, R(f) Na2S-9HS1 DMF, reflux, 43% (3 steps). (g) H2NBn, NaHC03, DMF, reflux, 39% (3 steps). (h) m-CPBA, CH2CI2, rt, 8goh.(i) Pd/C, HC02NH4, (BOC)20, EtOH, 51%.
The unsymmetrical thiaoxabicyclic [3.3.1] substrate was prepared from the known alcohol297, which was protected as its benzyl etlier 298- Incorporation of the sulfur atom using three conventional steps gave the substrate 299 in good yield (Scheme 3.2 1).
Scheme 3.21 O Me O Me
HO* NaHIKH + BnO* 1) 03,EtOH; NaBH4 BnBr, THF 2) TsCI, pyridine 297 W/O m 3) Na& DMF 299 40% (3 steps)
8 111.2.3 Enantioselective Based-Induced Ring Opening Study
Our studies on the enantioselective deprotonation-eiimination began by treating 274 with 3 equiv. of a lithium amide-LiCI complex (1:l) 194 in TKF generated from the hydrochloride salt of (-)-bis[(S)- 1-pheny1ethyI]amine 195 (Table 3.2).49 The reaction was sluggish. gave a poor yield and low enantioselectivity (Table 3.2, entry 1). Replacement of THF with a non-coordinating solvent such as benzene dramaticaiiy increased not ody the rate but ako the enantioselectivity to give the thiepine 301 in 9 1% yield and 89% ee after 1 h at -5
OC (Table 3.2, entry 2).37-50 This constitutes the ktexample of an asymmetric deprotonation- 177 elhination at an unactivated position adjacent to sulfurlfurS1The deprotonationelimination failed at -78 OC in toluene but at -50 OC, the substrate 274 reacted with an increase of the ee fiom 89% to 95% (Table 3.2, entry 3). The use of a six-fold excess of base (or three-fold excess base plus the-fold excess LiCl) was required to obtain a good yieId of the desired opened produc t.50b
Table 3.2- Enantioseiective Desymmetrization
- -- - Entry Substrate Base/Conditionsa Product eeb Yieldc % Y0
- -- a Deprotonation conditions, details in the Experirnental Section. Measured b y preparing the Mosher ester or by capilfary GG using a Chiraldex y-TA column or by HPLC using a Chimlcel O0 column. Isolated yield of analyticaily pure product. Wh Yield based on recovered starting material.
A pronounced LiCl effect was observed on the enantioselectivity of the deprotonation of 274 in benzene at -5 OC;in the absence of LiCl, the product 301 was formed in 7 1% ee (Table
3.3). However, the ratio of base 300 vs LiCl was not a determinhg factor and, in the presence of LiCI, the selectivity increased to 90% ee. In each case, LX1 was generated in situ by addition of n-BuLi to the hydrochloride sait of the chiral amine 195 since the addition of "solid" LiCl to the solution was not successful due to its insolubiiity in benzene. In fact, enhancement of enantioselectivity due to lithium chloride in a chiral lithium amide deprotonation has ken previously reported by Simpkins and others, in the desymmetrization of oxabicyclic 178 L3.2.11 compounds and tr0~inones.52 For practical reasons, the remaining studies were conducted using the 1:1 lithium amide-LiC1 cornplex 194 generated directly from the hydrochloride sait 195, as reported by ~ajewski.~ga
Table 3.3. LiCl Effect on the Deprotonation of 274 LiCI, equiv. Chiral base 300, equiv. eea, % ~iel&,%
a Measured by capillary GC using a Chiraldex y-TA column. Isolateci yield of analytically pure product.
Since al1 attempts to crystallize several derivatives of 301 failed, the absolute stereochemistry of 301, as illustrated in Table 3.2, was assigned by the Mosher rnethod.53
The resultant alcohol's obtained from the chiral base (-)-194 and its antipode (+)-194 were separately derivatized with S-(+)-MTPA chloride to give the unassigned esters 306 and 307. Scheme 3.22 illustrates the Mosher mode1 for both diastereomers 306 and 307; the ester is viewed via an "extended Newman projection", in which the ester linkage is omitted. The choice of rotarners places the CF3 group in an eclipsed orientation with the a-proton of the ester. Cornparison of the 'H NMR spectra at 400 MHz of both diastereomers revealed a chernical shifi difference between the proton of the methylene O! to the sulfur atom. The proton eclipsing the methoxy group in 307 is at 2.75 ppm. However, the phenyl group eclipses the same proton in 306 and its chernical shift rnoved upfield, to 2.63 ppm. Frorn these results, we can propose the absolute stereochemistry of both chiral alcohols. Desymmetization of 274 using (-)-194 gave the alcohoi corresponding to the ester 306, and consequentiy, the use of (+)-194 gave the ester derivative 307. The same sense of induction was assumed for al1 the other thiepines and thiocines. Scheme 3.22
Comparing the opening of 275, 276, 277, and 278 with 274 showed the dramatic effect of the remote hydroxy protecting groups on the reactivity, as wel1 as on the enantioselectivity of the reaction (Table 3.2). Reaction of the benzyl protected substrate 275
with 194 gave. after 10 h at 8 OC. the thiepane 302 in 81% yield and 76% ee (Table 3.2, entry 4). However, the intrinsic low reactivity of 275 prevented us from lowering the temperature to improve the enantioselectivity. The sterically bulky t-butyl ethers in 276 inhibited the deprotonation reaction (Table 3.2, entry 5). Nevertheless, the use of 6 equiv. of 300 (no LiCl present), yielded the opened product 303 in good yield but with a rnodest enantiomeric excess
(Table 3.2, entry 6). The nonchelating nature of silyl ether, as well as its steric bulk, inhibited
the ring opening reaction (Table 3.2, entry 7). Finally, the MOM group was chosen as a protecting group because of its ability to chelate as weli as its ease of removal. Treatment of the MOM protected substrate 278 with the base 194 gave similar ee and yield when compare to 274 (Table 3.2, envies 2 and 8). However, a longer reaction time as well as a larger excess of base was necessary (6 equiv. of baseLiCl) for the reaction to go to cornpletion.
The enantioselective ring opening of the disubstituted substrate 283 was completely inhibited using the chiral lithium base 300. either in the presence or absence of LiCI in benzene (Equation 3.9). However, when 283 was treated with LDA in THF or benzene for 24 h, a 180 trace of the opened product 308 was observed by IH NMR. However, oniy 20% conversion was noted. the balance being the starting matenal. Any attempts to improve the efficiency of the process by using a large excess of base or by perfonning the reaction under reflux were unsuccessful. The 'H and 13~NMR spectra of seven-membered carbocycle 308 were well- resolved by mnning variable temperature experiments at 80 OCin DMSO-&.
LDA * THF
The opening of the thiadioxatricycle 285 with the chiral base 194 gave two products 309 and 310 in poor yields and enantioselectivity (Equation 3.10). The unexpected product 310, for which the ee was not deterrnined, came from the deprotonation of the ailytic proton of 309 followed by opening of the tetrahydrofuran moiety. In addition to the thiepines, 6 1% of unreacted starting rnaterial was recovered. Carrying out the deprotonation in the absence of LiCl did not improve the results.
- LiCl (3 eq), benzene
285 61% recovered s.m. 309,15%, 5% ee
The BOC protected nitrogen analogue 280 was studied using the s-BuLi/(-)-sparteine complex 197 as the source of chirality. Beak and coworkers have established that BOC- pyrrolidine are deprotonated enantioselectively with s-BuLi/(-)-sparteine complex 197 at the position a to the nitogen.s The lithiated species was further trapped with a variety of electrophiles to give substituted pyrroiidines in high enantiomenc excess, 88-94% (Scheme 3.D). No example of enantioselective BOC-piperidine deprotonation has been reported in the iiterature. Scheme 3.23 s-BuLi(-)-sparteine 0 TMSCl N Et20 N "Li-sparteine 71%. 94% ee - BOC BOC BOC
When 280 was treated with the preformed complex 197 in Et20 at -78 OC, the azepine 311 was obtained in 95% yield while displaying a modest enantiomeric excess of 46%
(Equation 3. Il). Lowe~gthe temperature to -105 OC improved the enantioselectivity to 60% (Equation 3.11). The absolute stereochemistry of 311 was not determined. Again, variable temperature experiments at 70-80 OC were performed to obtain well resolved IH and [3C spectra.
s-BuLi/(-)-sparteine complex 197 C Me0 Et20 N BOC -78OC, 1 h, 95%. 46% ee HO 28) -1 05 OC, 1 h, 97%. 60% ee 31 1
Given the lirnited success in the deprotonation of the azaoxa[3.2.l]substrates, the thia series was exclusively studied in the formation of eight-membered heterocycles. Reacting 290 with 194 for 40 h at rt afforded the thiocine 312 in 97% ee although in only 37% yield (Equation 3.12). The reaction was sluggish and several side products were observed. The isomer 291, submitted to the identical conditions, gave a better yield of the heterocycle 313, but the ee decreased to 43% which points out to conforrnational andor complexaûon effects influencing the enantioselectivity (Equation 3.12). Some remaining staning material was observed. It is worth rnentioning th& in the preparation of the racemic mixture for the GC analyses, 291 was readily opened when treated with LDA within 1 hour at rt. However, the opening of 290 with LDA took 48 h under the same conditions. LiCl (3 eq), benzene, rt 40-48h
5 111.2.4 Regioselective Based-Induced Ring Opening Study
In addition to the study of the enantioselective ring opening, the influence of the acidiQing group on the regioselective base-induced ring opening of unsymmetrical hetero- oxabicyclic [3.Z 11 and [3.3.1] systems was investigated (Scheme 3.24).
Scheme 3.24
X = S, S02, NBOC n= l,2
The regioselectivity of the base-induced ring opening of 293 was examined first. in our studies of the enantioselective ring opening of meso oxathiabicycles, we showed that benzene gave the best results and bat an excess of base (6 equiv.) was required for the reaction to go to completion. Treating 293 with excess LDA in benzene at -5 OC gave a 955 mixture of thiepines 314 and 315 as rneasured by lH NMR (Table 3.4, entry 1). The deprotonation occurred selectively at the "more accessible" methylene group, opposite to the bridgehead substituent giving a thiepine bearing a tertiary alcohol as the major product.S5 The use of a more sterically demanding amide base iike LTMP (lithium tetramethylpipendide) enhanced the regioselectivity of the reaction to 98:2 (Table 3.4, entry 2). Variable NMR experiments were perfomed on 314. Table 3.4. Regioselective Base-Induced Ring Opening.
Entry Substrate Base Conditions Products Ratio a Yield b, Oh
HO 1 mx=s LDA PhH, 5 OC, 1 h 314/315 95:5 93 2 mx=s LTMP PhH, 5 OC, 1 h 314/315 98:2 89 3 294X=S02 LDA THF, -78 OC, 1 h 316/317 59:41 86 4 294x=so2 LDA PhCH3, -78 OC, 1 h 316 1317 68 :32 71 5 294X=S02 LTMP WF,-78 OC, 1 h 316/317 54A6 75 6 294 X= S02 LTMP PhCH3, -78 OC, 1 h 316 / 317 60 :40 €39 7 2% X = NBOC s-hLi &O, -78 OC, 1 h 318/319 48152 68
a The ratios have been determined by 'H NMR. lsolated yield of analytically pure products. 1 nseparable mixture.
In contrast, the deprotonation of the analogous sulfone 294 using 2 equiv. of LDA in THF at -78 OC gave low selectivity in favor of 316 vs 317 (Table 3.4, entry 3). Reaction in toluene (Table 3.4. entry 4) or using the more sterically demanding LTMP (Table 3.4, entries 5 and 6) did not significantly improve the regioselectivity of the deprotonation. In addition, the nitrogen substrate 296 was readiiy ring-opened at -78 OC using 1.5 equiv. of s-BuLi in Et20, leading to an equimolar mixture of regioisomers (Table 3.4, entry 7).s4 Flash chromatography did not allowed an adequate separation of the isomers. The latter were separated for characterization by treating the mixture with benzoic anhydride; the secondary alcohol319 reacted selectively. Separation of the mixture and hydrolysis of the ester using a NaOH solution in MeOH afforded the alcoho1319 in a pure form.
We also investigated the regioselectivity of the 9-oxa-3- thia-bic yclo [3.3. l ] nonane system 299. Treatment of 299 with 6 equiv. of LDA at room temperature for 2 days afforded the thiocines 320 and 321 in a 94:6 ratio as detennined by lH NMR,although the yield was oniy 42% (Equation 3.13). LDA (6 eq.) benzene, rt, 48 h 42%
5 111.2.5 Mechanism of Deprotonation
Our resuits suggest that the thiaoxabicyclic systems behave similarly to the well-
documented desymmetrization of meso cyclohexene oxide using nonracemic lithium amides.%
In the opening of cyclohexene oxide, the base creates at the site of deprotonation either a highfy ordered intermediate (1: 1 base/substrate complex) or an aggregated intermediate which selects between enantiotopic protons in a kinetically controiied deprotonation. This selection is based
on the preferential reaction of the chiral base with one of the two rapidly equilibrating enantiomeric hdf-chair conformations of cyclohexene oxide (Scheme 3.25). As demonstrated
by deuterîum labeling, the deprotonation involves removal of a proton syn to the leaving group
followed by the transfer of the lithium atom to the forming alkoxy group.57
Scheme 3.25 R
in the thiaoxabicyclic sy stems, an aggregate containing the su bstrate, the base and LiCl is proposed to be present in the reaction mixture as supported by both the requirement for a
non-polar solvent and an excess of base. By cornparison with the cyclohexene oxide model, an enantiotopic pseudoaxial hydrogen would be removed assuming a chair conformation in the bicyclic substrates. The substrate andfor the product is believed to incorporate more than one equivalent of base as suggested experimentaily by the number of equivalents required for the L85 reaction to go to completion. The large excess of baselLiCl also supports the notion that cheiation of the remote ethers in association with the bridging oxygen seems to be essentiai; the Li ions may act as a Lewis acid in the activation of the substrate in the deprotonation-elimination sequence (Figure 3.1). This postulate is supported by the absence of reactivity for the disilyl ether 277 which would suppress chelation, and also by the low reactivity of the [3.3.1] systems 289 and 299 with either LDA or the chiral base 194. A tridentate mode1 322 has been proposed by Bloch and Gilbert in the stereoselective addition of organometalhcs to related oxabicyclic systems (Figure 3. L).*~
Figure 3.1 X
Two models have been put fonvard to rationalize Our results, more specifically the influence of the remote protecting groups on the enantioselectivity as well as the reactivity observed in the deprotonation of the thiaoxabicyclic systerns (Scheme 3.27). The two models A and B. which constitute 2 different types of aggregates, are in dynamic equilibrium and would both lead to deprotonation/elirnination sequence. The tridentate aggregate A, in which a lithium ion complexes the bndging ether and the two remote ethers would lead to high reacùviw and enantioselectivity. The second aggregate B, in which the lithium chelates in a bidentate fashion, would result in a less activated species, and lead to low enantioselectivity. The displacement of the equilibrium behveen the two structures would be greatly affected by steric and electronic factors.
Accordingly to the above proposed models A and B, the methyl and MOM protected substrates 274 and 278 would easily form the intermediate A and give good results. The need for a larger excess of Lithium base in the case of 278 could be explained by the chelating nature 186 of the MOM ethers trapping extra equivalents of baseLiCl beforekfter deprotonation. In the case of the benzyl protected substrates 275. the phenyl groups could sterically or electronicaiiy interact with the chiral base infiuencing the nature of the aggregates as weU as their formation. The t-butyl protected substrate 276 afforded, although in low reactivity. the thiepine 303 only in the absence of LiCl. This hainsic Iow reactivity of the substrate 303 could be explained by the formation of the bidentate intermediate B. In order to bring additional evidence to support these proposed models, the synthesis of meso rnonoether compounds unable to form the chelate
A was rnandatory. This was realized by the synthesis of the modeis 285 and 291 represented as aggregates C and D in Scheme 3.27. Indeed, the Iow reactivity and enantioselectivity of the base-induced opening of monoether models 285 (5% ee) and 291 (43% ee) supports Our proposais. At this stage, it is not possible to rationalize the sense of induction.
Scheme 3.26 ,Y
X = Cf, R2N
A B 277, R = TBDMS,no opening 274, R = Me, 1 h, 89% ee 278, R = MOM, 10 h, 86% ee 275, R = Bn, 10 h, 76% ee 276, R = &Bu, 24 h, LiC1, no opening 276, R = &Bu, 24 h, (no LiCI), 43% ee
The role played by LiCl in the deprotonation process and the enhancement of the 187 enantioselectivity is not clear at this stage. Its importance in changing the nature of the "reactive species" has been proposed previously by other research groups. It is established that LiCl forms dimer 323 and 324 with LDA and LiHMDS in THF.~~Dimer 325 has also been crystallized by Simpkins and coworkers.60 This species has ken show to be the only species present in THF by 7~iand 15N NMR studies in the absence of LiC1.S9 No data concerning the aggregation state of LDA or the chiral base 300 in noncoordinating solvents such as benzene or toluene has been reported. If present in benzene, the dirners 323 and 324 might be more "enantioselective deprotonating reagents" than LiCl-free dirner 325.3JJji However, the monomer 300 or dimer 325 seemed to be more suitable than the "enantioselective deprotonating species" 323 and 324 in the case of the t-butyl protected substrate 276 which reacted exclusiveIy in the absence of LiCI. The fact that our system was not affected by the ratio chiral baseLiCl is also exceptional. Ail other reported enantioselective desymrnetrizations using chiral amide bases have usually an optimum baseLiCl ratio of VOS, suggesting the formation of the reactive species 324.52
Figure 3.2
The nature of the amide base also seemed to be a detemiining element in the base- induced ring opening reaction. In al1 cases, LDA was more efficient in affecting the reaction. Even the t-butyl protected substrate 276 (5 houn) and the thiadioxatncyclic substrate 285 (12 hours) were smoothly opened in the presence of LDA. Most Ïmpressive was the reactivity of the [3.3.1] system 291 which was opened by LDA within 1 hour compared to 48 hous for the chiral base 194. It is noteworthy that the silylether protected substrate 277 did nor undergo ring opening in the presence of LDA. A different degree of aggregation baselsubstnte could explain the difference of reactivity between LDA and the chiral amide base. The mechanism of opening of the azaoxabicyclic system 280 is clearly different from the thiaoxabicyciic analogues. The BOC group directs the removai of an equatorid proton cc to the nitrogen from a chair-ke conformation, as established for the deprotonation of BOC piperidine.62*63a The equatorially Lithiated species 326 is formed followed by the subsequent and npid elimination of the antiperiplanar bridging ether, providing the seven-membered ring dkoxide 327 (Scheme 3.27). In this case, the remote ethers were not involved in the process.
Scheme 3.27
Me04j -*BuLi Me04yLi C-O bond Me0 Me0 \ \ cleavage N BOC Nyb Li0
Examples of deprotonation-elimination a to nitrogen have been reported in the piperidine and piperazine senes as ihstrated in Scherne 3.28.63 To the best of our knowledge, however, no asymmetnc version of this transformation has ken published.
Scheme 3.28
TMEOA BOC 634 BOC
The formation of the aggregates base/LiCl/thiaoxabicyclic substrate and consequently the course of the deprotonation is also strongly affected by steric factors especially when dkyl substituents are present at the bndgehead positions; the substrate is totaily inert to the base- induced ring opening reaction. We took advantage of the reluctance of the methylene proximal 189 to the substituted bridgehead to be deprotonated and develop a regioselective reaction. The unsymmetrical mono-substituted thiaoxabicycle 293 was opened with high regioselectivity with LDA and LTMP, the deprotonation occumng at the Ieast hindered rnethylene group. The strong influence of the methyl bridgehead substituent on the deprotonation of the proximal rnethylene group was aiso illustrated by the unsuccessful kinetic resolution of 293 (Equation 3.14). When 293 was treated with the chiral base 194 under the optimum conditions of enantioselective deprotonation, 293 was isoiated in only 8% enantiorneric excess after 50% conversion. We concluded that the substrate controlled the course of the reaction and overrides the chirality of the base (or reagent control).
LiCt (3 eq), toluene -50 "C, 24 h -50% conversion
The lack of selectivity in the deprotonation of the sulfone and N-Boc derivatives crin be ntionalized by considering the effect of the acidiwing group on the proton which is absuacted. King and Rathore examined the rate of exchange of the a-hydrogens in a series of six- membered cyclic 1,4-0xasulfones.6~ This study concluded that a-equatorial hydrogens exchange faster than a-axial ones (using NaOD ) because of the antipenp1ana.r orientation of the a-equatorial hydrogens with respect to the S-Cal bond (which is aligned with the intemal bisector of the O-S-Omoiecy) and more importantly, because of the antiperiplanar orientation of the a-equatoriai hydrogen with respect to the C-O bond (Figure 3.3). The presence of a methyl group, situated in a position P to the suifone, has neither a significant steric nor electronic effect on the exchange rate of He vs He1. An identical geometry is found in substrate 294 and its deprotonation foiiowed the same pattern of reactivity as King's mode1 and displayed low regioselectivity (Figure 3.3). O King's rnodel L2.J a R". '. R
5 111.2.6 VinyIsulfide Oxidation
From a synthetic perspective, although the sulfone 294 failed to undergo selective deprotonation, chemoseiective oxidation of the vinylsulfide 314 using dimethyl dioxirane65 did provide the vinylsulfone 316 (Scheme 3.29). The enantiomencally e~chedthiepine 301 was aiso oxidized to the vinyl sulphone 328 in high yield.
Scheme 3.29 Me, OH O -0 Me0 OH ,-78OC - CH2CI2, Acetone Me0
,-TB0C Me0 CH2CI2, Acetone Me0
5 111.2.7 Summary
In summary, the results reported herein constitute a simple sequence for the enantioselective and stereoselective preparation of functionalized azepines. thiepines and thiocines which are othenvise difficult to synthesize and provide the fust examples of an asyrnrnetric deprotonation-elirnination at an unactivated position adjacent to suifur. Further 191 studies conceming the mechanism of the reaction. the nature of the aggregate, and its application to the synthesis of biologicaUy relevant compounds still need to be investigated.
5 III3 Experimental Section
5 III.3.1 Solvents and Reagents
For generai experimental details, see Section L3.1, p 46. Unless stated otherwise, commercial reagents were used without purification. Diisopropylarnine, dichloromethane, hexanes, (-)-sparteine, and 2,2,6,6-tetramethylpiperidinewere distilled immediately prior to use from calcium hydride. s-BuLi was fiitered through a pad of celite using a Schlenk apparatus. For 274-278,284,290, and 291, the racemates were prepared using LDA in benzene, and for 280, using s-BuLi in Et2O.
(i III3.1 Substrate Preparation
HO Amberlyst@ 15 ion-exchange resin
2-Methylpropene was bubbied through a solution of 270 (3.0 g, 19.2 mol) and Amberlyst@ 15 ion-exchange resin (1.5 g) in hexanes-CHzClz 1:l (100 mL) at n for 5 hours. The suspension was fdtered and the filtrate was concentrated in vacuo. Purification by flash chromatography (hexanes-EtOAc 5: 1) gave 273 (2.64 g, 5 1%)as a white solid: R.= 0.36 on silica gel (hexanes-EtOAc 5: 1); mp 43-46 OC (Et2O); IR (CH2C12)2965,2873, 1473, 1390, 1363, 1197 cm-1; [H NMR (400 MHz, CDCb) 6 6.33 (W,s), 4.78 (2H. s), 3.50 (2H, dd, J
= 8.1, 5.2 Hz), 3.28-3.21 (2H. m), 1.82-1.75 (2H. m), 1.19 (18H, s); 13~NMR (100 MHz, 192 CDC13) 6 135.2, 80.7, 72.4, 60.8,40.3, 27.6; HRMS cdcd for C 16H2803 m+269.2 1 17, found 269.2 1 13.
General Procedure for the Preparation of 3-thia-8-oxa[3.2.1] and 3-thia- 9-oxa[3.3.1]bicycles in MeOH1H2O. Method A. exo, exo -6,7-B is - rnethoxymethyl-8-oxa-3-thia-bicyclo[3~2.1]octae(274).
1) 03,EtOH; NaBH4 Me0 2) p-TsCI, pyridine Me0
Ozone was bubbled through a solution of 271 (15.0 g, 8 1.4 mmol) in EtOH (300 mL) at O OC until TLC showed no remaining starting matenal (ca. 5 hours). NaBH4 (3.7 g, 97.7 mmol) was carefully added portionwise at O OCand the mixture was shed for 15 h at rt. The reaction mixture uras cooled to O OC pnor to the slow addition of a 50% acetic acid aqueous solution until no more gas evolved and a clear solution was formed. EtOH was removed in vacuo and the residue was dissolved with brine and extracted (6x) with EtOAc. The combined organic layers were dried (MgS04), filtered and concentrated.
The viscous oily residue was dissolved in pyridine (LOO mL) and treated at O OC with p-
TsCI (46.6 g, 81.4 mmol). The mixture was stirred for L5 h at rt, subsequentiy diluted with water (300 mL) and extracted (4x) with Et2O. The combined orgaoic layers were washed (2x) with HCl NI%, and brine (lx), drîed (MgSQ), frltered, and concentrated. A solution of Na2S nonahydrate (15.7 g, 65.5 mol) in EtOH (450 mL) was placed in a three-neck round bottom Bask equipped with 2 addition fumels and a condenser, and heated at reflux. Solutions of the ditosylate in EtOH (50 mL) and Na2S nonahydrate (15.0 g, 62.5 mmol) in water (40 rnL) were added simultaneously over 2 h. After the addition was comple te, the reaction was heated at reflux for an additional 3 h. EtOH was rernoved in vacuo and the residue was dissolved in brine and extracted (5x) with Et20. The combined organic layers were dried (MgS04), filtered and concentrated. Purification by flash chrornatography (hexanes-EtOAc 2: 1) gave the bicycle 274 (8.0 g, 45%) as a white crystalline solid: Rf= 0.43 193 on silica gel (hexanes-EtOAc 2: 1); mp 55-57 OC (Et20); IR (KBr)3OO 1, 2972, 2938, 29 18, 1465, 1386, 1238, 1199, 1180, 1122 cd;IH NMR (400 MHz, CDC13) 6 4.34 (ZH,bs),
3.48 (2H, dd, J= 8.8, 5.2 Hz), 3.33-3.28 (2H, m), 3.31 (6H,s),3.15 (2H. dd, J= 13.4, 2.4
Hz), 2.85-2.78 (2H, m), 2.03 (2H,dt, J = 13.5, 1.8 Hz); 13C NMR ( 10Q MHz, CDQ) 6
79.1, 71.4, 58.7, 44.9, 31.4. Anal. Calcd for CloH1803S: C. 55.02; H, 8.3 1. Found: C, 55.27; H, 8.14.
General Procedure for the Preparation of 3-thia- and 3-aza-8-oxa[3.2.1] and 3-thia-9-oxa[3.3.l]bicycies in DMF. Method B. exo, exo-6,7-Bis- (benzyloxy-methyl)-8-oxa-3-thia-bicyclo[3.2.1]octane (275).
1) 03,EtOH; NaBH4
- - 7 B"OP&j 2) p-TsCl, pyridine BnO 3) Na2S-9H20, DMF S 272 275
The ozonolysiçlreduction and the activation of the di01 was camed out as in the generai procedure A. Ozonolysis of the oxabicycle 272 (5.0 g, 14.9 rnmol) in EtOH (40 mL) for 2 h at O OC followed by NaBa reduction (675 mg, 17.8 mmol) gave a di01 which was activated using pyridine (75 mL) and p-TsC1 (8.5 g, 44.6 mmol). In a three-neck round bottom flask equipped with an addillon funnel and a condenser, Na2S nonahydrate (7.14 g, 29.7 mmol) and a solution of the ditosylate in DMF (50 mL) were added simultaneously to boiling DMF (LOO mL) over 4 h. After the addition was complete, rhe mixture was heated at reflux for an additional 2 h. The mixture was allowed to cool to rt and diluted with brine (300 d),and extracted (5x) with hexanes-CH2C12 9: 1. The combined organic layers were washed with water (2x), and brine (2x). dried (MgSOQ, atered, and concentrated. Purification by flash chromatography (hexanes-EtOAc 5: 1) gave the bicycle 275 (1.69 g, 3 1%) as a white solid: Rf = 0.36 on silica gel (hexanes-EtOAc 5:l); mp 46-48 OC (EtzO); IR (neat) 3061. 3029, 2927, 2859, 1603, 1495, 1453, 1365 cm-'; lH NMR (400 MHz, CDC13) 6 7.34-7.26 (10HT m).
4-46 (4H, s), 4.39 (2H, bt), 3.59 (2H, dd, J = 8.8, 5.1 Hz), 3.42-3.37 (2H, m), 3.16 (2H, dd, J = 13.4, 2.4 Hz),2.94-2.86 (2H. m), 2.08-2.04 (2H, m); 13C NMR (100 MHz, CDC13) 194 6 138.1, 129.4, 128.3, 127.5, 79.1, 73.1, 69.1, 45.0, 31.5; HRMS calcd for C22H2603S [MHJ+ 371.1681, found 371.1692.
1) Os, EtOH; NaBH4 - 2) p-TsCI, pyridine
The reaction was carried out as in the general procedure A. Ozonolysis of the oxabicycle 273 (2.20 g, 8.20 mmol) in EtOH (30 mL) for 2 h at O OC followed by NaBQ reduction (372 mg, 9.84 mmol) gave a di01 which was activated using pyndine (35 mL) and p-
TsCl (4.70 g, 24.63 mol). Cyclization of the crude ditosylate was achieved with NqS nonahydrate (3.55 g, 14.76 mmol) in EtOH (120 rnL) and water (20 mL). Purification by flash chromatography (hexanes-EtOAc 7: 1) gave the bicycle 276 (953 mg, 38%) as a white solid: Rf = 0.38 on silica gel (hexanes-EtOAc 7: 1); mp 105-107 OC (Et2O); IR (CH2C12)3050. 2960, 2874, 1471. 1392, 1364, 1264, 1196 cm-1: 1H NMR (400 MHz, CDC13) 6 4.31 (2H, bs),
3.54 (2H, dd, J= 8.2, 5.3 Hz), 3.25 (2H. t, J= 8.8 Hz), 3.16 (2H, dd, J= 13.6, 2.6 Hz). 7.78-2.7 1 (2H. m), 2.08-2.04 (2H. m), i -16 (18H. s); 13C NMR (100 MHz, CDC13) 6 79.4. 72.6, 60.3, 45.5, 31.5, 27.6; HRMS calcd for C16H3003S [MH]+ 303.1994, found 3O3.W 1.
exo,exo-6,7-Bis-[(terf-b~fyIdimethyisiIoxy)-methyI]-8-oxa-3-thia- bicyclo [3.2.1] octane (277).
1) 03,EtOH; NaBH4 mmso+j 2) p-TsCI, pyridine TBDMSO
The reaction was cded out as in the general procedure A. Ozonolysis of the 195 oxabicycle 177 (4.50 g, 11.70 mol) in EtOH (100 mL) for 2 h at O OC followed by NaBh reduction (53 1 mg, 14.04 mmol) gave a diol which was activated using pyridine (70 mL) and p-TsCl (6.69 g, 35.09 mmol). Cyclization of the crude ditosylate was achieved with Na2S nonahydrate (5.62 g, 23.39 mmol) in EtOH (250 mL) and water (40 mL). Purification by flash chromatognphy (hexanes-EtOAc 9: 1) gave the bicycle 277 (65 1 mg, 13%) as a colorless oil: Rf = 0.35 on silica gel (hexanes-EtOAc 9: 1); IR (neat) 2938, 2856, 1468, 1389, 136 1, 1253 cm- 1; H NMR (400 MHz, CDC13) 6 4.34 (2H, bs), 3.76 (2H.dd, J = 9.6, 5.9 Hz), 3.52
(2H, t, J = 9.6 Hz), 3.18 (2H, dd, J = 13.2, 2.6 Hz), 2.75-2.68 (2H, m), 2.01 (2H, dt, J= 13.2, 1.7 Hz), 0.86 (18H, s), 0.03 (12H, s); I3C NMR (100 MHz, CDCI3) 6 78.9, 61.5, 47.7, 3 1.7, 25.9, 18.2, -5.26, -5.3 1; HRMS calcd for C20H4202SSi2 [MH]+419.2455, found 4 19.247 1.
exo,exo-6,7-Bis-(methoxymethoxy-methyl)-8-oxa-3-thia-bicycIo[3.2.1] octane (278).
1 ) TSAF-H20, THF
TBAF hydrate (844 mg, 3.23 mol) was added to a solution of 277 (540 mg, 1.29 rnmol) in TKF (10 rnL) and the mixture was sUrred for 2 h at a. The reaction was quenched by the addition of water (10 mL). THF was removed in vacuo and the aqueous layer was extracted (3x) with EtOAc, and the combined organic layea were dried (MgS04), filtered, and concentrated. The resulting di01 was dissolved in CH2C12 (2 mL) and i-Pr2NEt (2 DL),and ueated with MOMCl(216 pL, 2.84 mmol). The snixîure was stirred for 15 h at rt, diluted with CH2C12, and quenched by the addition of a saturated NK&1 solution. The aqueous layer was extracted (3x) with CH2C12, and the combined organic layers were dried (MgS04), filtered. and concentrated. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 278 (210 mg, 58%) as a white solid: Rf = 0.33 on silica gel (hexanes-EtOAc 3: 1); mp 50-52 OC (Et20); IR (CH2C12) 3053, 2938,2885,2824, 1465, 1267, 1151, 1109 cm-1; [HNMR (400 MHz, 196 CDCI3) 6 4.6 1 (2H. d, J = 9.5 Hz),4.59 (2H. d, J = 9.5 Hz). 4.39 (2H,bs), 3.67 (2H. dd, J
= 9.2, 4.8 Hz), 3.47 (2H, t, J = 9.3 Hz), 3.35 (6H,s), 3.19 (2H, dd, J = 13.6, 2.6 Hz),
2.91-2.84 (2H, m), 2.08 (2H. dt, J = 13.6, 1.8 Hz); 13~NMR (100 MHz, CDC13) 6 96.5, 79.1, 66.5, 55.3, 44.9, 3 1.3; HRMS calcd for C 12H2205S FI]+278.1 188, found 278.1 183.
exo, exo-3-Benzyl-6,7-bis-methoxymethyl-8-a-3-azaicyc10 [3.2.1] octane (279).
1) 03,EtOH; NaBH4 - 2) pTsCI, pyridine 3) H2NBn, DMF, NaHC03
The reaction was carried out as in the general procedure B. Ozonolysis of the oxabicycle 271 (20.0 g, 108.6 mmol) in EtOH (400 mL) for 6 h at O OC followed by NaBH4 reduction (4.9 g, 130.3 rnmol) gave a di01 which was activated using pyridine (150 mL) and p- TsCl (62.1 g, 325.7 mmol). A solution of the crude ditosylate and BnNH2 (23.7 mL, 2 l%1 mmol) in DMF (100 rnL) was added dropwise over 4 h in a refluxing suspension of NaHC03
(18.2 g, 217.1 rnmol) in DMF (500 mL). After the addition was complete, the mixture was heated at reflux for an additional 2 h. Purification by flash chromatography (hexanes-EtOAc
3:l) gave the bicycle 279 (13.8 g, 44%) as a colorless oil: Rf = 0.37 on silica gel (hexanes- EtOAc 3:l); IR (neat) 3086,3065,3030,2937.2875, 1495, 1454. 1238, 1207 cm-'; IH NMR (400 MHz, CDCl3) 6 7.28-7.17 (SH,m), 4.09 (2H, bs), 3.45-3.42 (4H,m), 3.30 (6H. s),
3.29-3.24 (2H.m), 2.72-2.65 (2H,m), 2.56 (2H. d, J = 10.6 Hz), 2.33 (2H.dd, J = 1 1.4,
1.8 Hz); 13C NMR (100 MHz. CDCI3) G 138.4, 128.6, 128.1, 126.8, 78.6, 71.7, 62.3, 58.7,
57.8, 44.3. Anal. Calcd for C17H25N03:C. 70.07; H, 8.65; N, 4.8 1. Found: C, 70.07; H, 8.55; N, 4.68. carboxylic acid tert-butyl ester (280).
PdfC, HC02NH4 Me0 (BOC)20, EtOH Me0 N N 279 Bn 280 SOC Pd on charcoal (palladium content 10%) (1.0 g, 0.9 mmol), and ammonium formate
( 1.1 g, 17.3 rnmol) were added successively to a solution of the amine 279 ( 1.O g, 3.5 rnrnol)
and (BOC)20 (906 mg, 4.2 mmol) in EtOH (20 mL) and the mixture was stirred at rt for 24 h.
The reaction mixture was filtered through a Ceiite pad and washed with Et20, and hexanes-
EtOAc 1: 1. The filtrate was concentrated and the residue puïified by flash chromatography (hexanes-EtOAc 1: 1) to give 280 (904 mg, 87%) as a white soiid: Rf = 0.57 on silica gel
(hexanes-EtOAc 1:l); mp 67-70 OC (Et2O); IR (neat) 2974, 2930, 2872, 1698, 1457, 1418, 1394, 1366. 1237, 117 1 cm-'; IH NMR (400 MHz, DMSO-d6, 80 OC) 6 4.04 (2H, bs), 3.54 (2H. d, J = 12.8 Hz), 3.39 (2H, dd, J = 9.2, 5.2 Hz), 3.26-3.22 (2H, m), 3.24 (6H,s), 2.98
(2H, d, J = 12.5 Hz), 2.31 (2H, m), 1.41 (s, 9H); 1% NMR (100 MHz, DMSO-d6, 80 OC) 6 154.3, 78.5, 76.4, 70.3, 57.5, 48.4, 42.8, 27.7. Anal. Calcd for C15H27N05: C, 59.78; HT 9.03; N, 4.65. Found: C, 60.1 1; H, 8.94; N, 4.58.
3) Na2S-9H20, DMF
The reaction was carried out as in the general procedure B. Ozonolysis of the oxabicycle 282 (3.5 g, 16.49 mmol) in EtOH (250 mL) for 1 h at O OC followed by NaBH4 reduction (686 mg, 18.14 rnrnol) gave a di01 which was activated using pyridine (100 mL) and p-TsC1 (9.43 g, 49.47 rnrnol). Cyclization of the crude ditosylate was achieved with Na2S 198 nonahydrate (7.92 g, 32.98 mol) in DMF (250 mL). Purification by flash chromatography (hexanes-EtOAc 3: 1) gave the bicycle 290 (1.62 g, 26%) as a colorless oil: Rf= 0.40 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 2975,2925,2875,2832,2809,2755, 1460, 1374, 1259, 1229, 1194, 1113, 1061 cm-'; IH NMR (400 MHz, mC13) 8 3.47 (2H, dt, J= 9.9,2.6 Hz),
3.42 (2H, dt, J= 9.2, 3.3 Hz), 3.26 (6H,s), 2.78 (ZH,bs), 2.71 (SH,d, J= 13.1 Hz), 2.20
(2H. d, J = 13.2 Hz), 1.27 (6H, s); 1% NMR (100 MHz, CDC13) 6 80.9, 70.6, 58.3, 47.7,
36.8, 22.9. Anal. Calcd for C12H2203S: C, 58.50; H, 9.00. Found: C, 58.79; H, 8.90.
p-TsOH, benzene
A solution of 270 ( 12.0 g, 76.8 mmol) and p-TsOH (73 1 mg, 3.8 mmol) in benzene
(125 mL) was heated at reflux for 4 h and the water was removed using a Dean-Stark trap. The reaction was quenched at rt with a NaHC03 solution (50 mL). Benzene was removed in vacuo and the aqueous layer extracted (3x) with Et20. The cornbined orgaoic layers were dned (MgS04). filtered and concentnted. Purification by flash chromatography (hexanes-EtOAc
1: 1) yielded 284 (4.59 g, 43%) as a white solid: Rf= 0.40 on silica gel (hexanes-EtOAc 1: 1); 'H NMR (400 MHz, CDC13) 6 6.38 (2H. t, J = 0.9 HZ),4.73 (2H,t, J = 1.O Hz), 3.95-3.88 (2H, ml, 3.61-3.54 (2H, m), 2.49-2.44 (2H. m); 13C NMR (100 MHz, CDC13) 6 L36.7,
The reaction was carried out as in the generai procedure A. Ozonolysis of the 199 oxabicycle 284 (4.59 g, 33.2 mmol) in EtOH (100 mL) for 3 h at O OC followed by NaBQ reduc tion ( 1.5 1 g, 39.9 mol)gave a di01 which was activated using pyridine (35 mL) and p- TsCl (12.50 g, 65.6 mol). Cyclization of the crude ditosylate was achieved with Na2S nonahydrate (9.80g, 42.0 mmol) in EtOH (300 mL) and water (50 mL). Purification by flash chromatography (hexanes-EtOAc 1: 1) gave the tricycle 285 (1.94 g, 34%) as a white soiid: Rf = O.xx on silica gel (hexanes-EtOAc 1: 1); 1H NMR (400 MHz, CDC13) 6 4.254.23 (2H. rn), 4.18-4.10 (2H. m), 3.49-3.41 (2Ht m), 31 13 (2H, dd. J = L3.8, 2.4 Hz), 3.10-3.30 (2Ht m),
2.09 (2H, dm, J = 13.7 HZ),; 13~NMR (100 MHz. CDCI3) 6 79.5, 73.8.49.8, 30.7; HRMS calcd for CgHl202S [Ml+ 172.0558, found 172.0564.
General Procedure for the Methylation of Alcohol. endo-3-Methoxy-8- (288).
O NaH, THF rn OMe 288 A solution of the aicohol286 (5.2 g, 41.2 mmol) in THF (20 mL) was added dropwise to a suspension of NaH (2.50 g. 60% in oil, 62.5 mol) (washed 3 times with pentane) in THF (100 mL) at O OC. After the addition was complete, the mixture was shed for 2h at rt.
Me1 (7.7 rnL, 123.7 mmol) was added dropwise at O OC and the mixture was stirred for an additional 15 hours at rt. The reaction was quenched with MeOH and the solution was diluted with water. TW was removed in vacuo and the residue was extracted (3x) with ether. The combined organic Iayers were dned (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 288 (4.76 g, 82%) as a volatile colorless oil: Rf = 0.39 on silica gel (hexanes-EtOAc 2:I); IR (neat) 3079, 2926, 1458, 1370, 1278, 1237, 11 13 cm-1; IH NMR (400 MHz, CDC13) 6 6.22 (2H, d, J = 0.8 Hz), 4.65 (2H, d, J = 4.4
Hz), 3.50-3.46 (lH, m), 3.20 (3H,s), 2.13-2.07 (ZH,m), 1.69 (2H,dd, J = 15.0, 1.1 Hz); l3c NMR (100 MHz, CDC13) 6 133.3, 77.2, 73.7, 56.0, 31.5; HRMS calcd for CgH1202 [Ml+ 140.0837, found 140.0833. rn 289 The reaction was camied out as in the general procedure using the alcohol287 (5.0 g, 39.5 mmol), THF (120 mL), NaH (2.37 g, 60% in oil, 59.3 rnmol), and Me1 (7.4 mi,, 118.5 mrnol). Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 289 (4.70 g, 85%) as a volatile colorless 02: Rf= 0.43 on silica gel (hexanes-EtOAc 2: 1); IR (neat) 3076, 2934, 2820, 1452, 1256, 1230, 1150, 1106 cm-'; 'H NMR (400 MHz, CDC13) 6 6.06 (2H. s), 4.76
(2H, d, J= 2.5 Hz), 3.45-3.37 (IH, m), 3.22 (3H, s), 1.92-1.87 (2H, m), 1.55 (2H, ddd, J
= 13.3, 9.6, 3.8); 13~NMR (100 MHz, CDCl3) 6 130.2, 77.1, 71.8, 54.5, 31.5; HRMS calcd for CgH1202 FI]+140.0837, found 140.0833.
H O 1) 03,EtOH; NaBH4 Meo* 2) pTsCI, pyndine 288 3) Na2S-9H20, DMF 290
The reaction was carried out as in the general procedure B. Ozonolysis of the oxabicycle 288 (5.0 g, 35.67 mmol) in EtOH (150 mL) for 4 h at O OC followed by NaBH4 reduction (1.62 g, 42.80 mmol) gave a di01 which was activated using pyridine (100 mL) and p-TsCI (20.40 g, 107.01 mmol). Cyclization of the cmde ditosylate was achieved with Na2S nonahydrate (17.13 g, 71.34 mmol) in DMF (250 mL). Purification by flash chromatography (hexanes-EtOAc 3: 1) gave the bicycle 290 (1.62 g, 26%) as a white solid: Rf= 0.5 1 on silica gel (hexanes-EtOAc 3:l); mp 56-58 OC (CH2C12);IR (neat) 2980, 2927, 2866, 1469, 1438,
1362, 1285. 1187, 1141 cm-1; IH NMR (400 MHz, CDCl3) 8 4.29-4.26 (2H. m), 3.58-3.49
(IH, m), 3.36 (3H, s), 3.15-3.11 (2H,m), 2.39-2.32 (2H,m), 1.95 (2H, d, J= 13.0 Hz), 20 1 1.83 (2H, dt, J = 11.9, 5.3 Hz); 13c NMR (100 MHz, CDCIj) 8 71.9, 65.7, 55.7, 3 1.9, 3 1.3; HRMS calcd for CgHi402S [Ml+ 174.07 15, found 174.07 14.
Me0 O Me0 O 1) 03,EtOH; NaBH4 _. 2) p-TsCI, pyridine
The reaction was carried out as'in the generai procedure A. Ozonolysis of the oxabicycle 289 (4.0 g, 28.5 mmol) in EtOH (100 rd) for 2 h at O OC followed by NaB&
reduction (1.3 g, 34.2 -01) gave a di01 which was activated using pyridine (70 mL) and p- TsCl (13.6 g, 7 1.2 mmol). Cyclization of the cmde ditosylate was achieved with Na2S nonahydrate (7.8 g, 32.3 rnrnol) in EtOH (250 mL) and water (20 mL). Purification by flash chromatography (CH2C12-EtOAc 9: 1) gave the bicycle 291 (0.9 1 g, 32%) as a white solid: Rf = 0.21 on silica gel (hexanes-EtOAc 3: 1); mp 38-40 OC (EtzO); IR (neat) 2920, 28 16, 1465, 1448, 1367, 1245, 1195, 1 116 cm-l; IH NMR (400 MHz, CDC13) 6 5.22-5.13 (1 H, m), 4.28
(2H, t, J = 4.8 Hz), 3.38 (3H,s), 3.32 (lH, dd, J = 3.9, 1.7 Hz), 3.28 (IH, dd, J = 3.9, 1.7 Hz), 2.23 (2H, dt, J = 13.9, 1.3 Hz), 2.13 (2H, dd, J = 13.6, 6.8 Hz), 1.86 (IH, ddd. J = 10.7, 6.3, 1.7 Hz), 1.83 (lH,ddd, J = 10.7, 6.5, 1.7 Hz); 13c NMR (100 MHz, CDC13) 6 7 1.O, 67.2, 55.4, 36.1, 30.1; HRMS calcd for C8Hl402S FI]+174.07 15, found 174.0715.
exo,exo-5,6-Bis-methoxymethyl-l-methyl-7-oxa-bicyclo[2.2.1]hept-2- ene (292).
1) neat 2) LiAlH4, THF Me0Me.& O 3) NaH, KH, Mel, THF 82 2%? Maleic anhydride (23.9 g, 244 mol) was dissolved in 2-methylfuran 82 (20.0 g, 244 mmol) and the mixture was stirred at rt for 3 h after which time the solution solidified. The 202 crude cycloadduct was dissolved in THF (100 mL), and was added dropwise via a canula to a suspension of LiAi~(18.5 g, 488 mmol) in THF (600 mL) at O OC. The mixture was stirred
for 3 b at rt, and transferred into a large Erlenmeyer fiask (2 L), further diluted with TW(400 mL), and quenched by the portionwise addition of powdered potassium sodium tartrate tetrahydrate (138 g, 488 rnmol), followed by water (10 mL), and stirred for an additionnai 15 h at rt. The suspension was filtered and the solid residue was washed several times with boiling
THF and EtOAc. The filtrate was concentrated in vacuo yielding the crude di01 (35.46 g) as a white solid. The cmde di01 was dissolved in THF (100 mL) and added via a canula to a suspension of NaH (12.56 g, 60% in oil, 314 mmol) and KH (1.72 g, 35% in oil, 15 mrnol)
(washed 3 times with pentane) in THF (500 rnL) at O OC placed in a flask equipped with a reflux condenser. The mixture was stirrred for 30 min at rt pnor to the addition of Me1 (27.8 rnL, 449 rnmol) at a rate such as to produce a gentle reflux. After the addition was complete, the mixture was heated at reflux for 1 h and stirred at rt for 15 h. The reaction was carefully quenched with MeOH and the solution was diluted with water. THF was rernoved in vacuo and the residue was extracted (3x) with ether. The combined organic Iayers were dried (MgS04), filtered and concentrated. Bulb-to-bulb distillation (0.20-0.25 mmHg, 62-76 OC) gave 292 (36.22 g, 75% for 3 steps) as a colorless oil: Rf = 0.48 on sZca gel (hexanes-EtOAc 3: 1); IR (neat) 3074, 2979,2903, 2810, 1454, 1387, 1316, 1193, 1154 cm-1; 1H NMR (400 MHz, CDC13) 6 6.3 1
(lH, dd, J = 5.9, 1.9 Hz), 6.13 (lH,d. J= 5.9 Hz). 4.75 (IH, d, J = 1.9 Hz), 3.57 (lH, dd, J = 8.8, 4.8 Hz), 3.43-3.37 (2H, m), 3.35 (3H, s), 3.31 (3H, s), 3.29 (1H,dd, J = 10.3, 8.8
Hz), 2.01 (lH, ddd, J = 10.4, 8.4, 4.9 Hz), 1.88-1.83 (lH, m), 1.51 (3H, s); l3C NMR (LOO MHz, CDC13) 6 139.7, 135.7, 87.2, 80.0, 72.2, 70.8, 58.7, 58.5, 42.4, 41.6, 15.9; HRMS calcd for C 1 1 Hl803 m+198.1256, found 198.1258. 203 exo ,exo-6,7-Bis-methoxymethy1- 1-methyl-8-oxa-3- thia-bicyclo [3.2.1] octane (293).
3) Na2S-9H20, DMF
The reaction was carried out as in the generai procedure B. Ozonolysis of the oxabicycle 292 (10.0 g, 50.4 mmol) in EtOH (100 mL) for 3 h at O OC followed by NaBb reduction (2.3 g, 60.5 mol) gave a di01 which was activated using pyridine (75 mL) and p- TsCI (26.9 g, 140.8 mmol). Cyclization was achieved in DMF (400 mL) using Na2S nonahydrate ( 18.8 g, 78.4 mmol). Purification by ff ash chromatography (hexanes-EtOAc 3: 1) gave the bicycle 293 (5.07 g, 43%) as a colorless oil: Rf= 0.48 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 2976,291 1,2808. 1455, 1377, 1243, 1195 cm-'; 1H NMR (400 MHz, CDC13) 6 4.33 (1H, bs), 3.51 (lH, dd, J = 8.8, 4.7 Hz), 3.38-3.31 (3H, m), 3.28 (3H, s), 3.26 (3H, s), 2-98 (lH, dd, J = 13.2, 2.6 Hz), 2.87-2.81 (2H,m), 2.75 (lH, dt, J = 9.9, 4.5 Hz), 2.03- 1-98(2H, ml, 1-23 (3H, s); 13c NMR (100 MHz, CDC13) 6 8 1.3, 78.2, 71.6, 70.3, 58.7, 58.4, 46.5, 45.7, 38.1, 30.0, 22.6. Anal. Calcd for Ci IH2003S: C, 56.87; H, 8.68. Found:
exo,exo-6,7-Bis-methoxymethyl-l-methyl-8-oxa-3-thia-bicyclo[3.2.1] octane 3,3-dioxide (294).
m-CPBA 80% (3.72 g, 17.23 mmol) was added portionwise to a solution the sulfide
293 (1.00 g, 4.31 mmol) in CH2C12 (100 mL) at O OCand the mixture was shed for 15 h at rt. The reaction mixture was diluted with CH2C12 and washed (3x) with a 2M NaOH solution and brine (lx), dried (MgS04), filtered and concentrated. Purification by flash 204 chromatography (hexanes-EtOAc 1: 1) gave the sulfone 294 (1-0 1 g, 89%) as a thick colorless
oil: Rf = 0.30 on silica gel (hexanes-EtOAc 1 :1); IR (neat) 298 1, 2929, 289 1, 2834. 1457,
1303, 1 197, 1103 cm-'; IH NMR (400 MHz, CDC13) 6 4.60 (IH, t. J = 2.2 Hz), 3.45 ( 1H, dd, J = 9.1, 4.4 Hz), 3.37-3.28 (4H, m), 3.29 (3H, s), 3.25 (3H, s), 3.22-3.05 (SK,m), 1.40 (3H, s); 13C NMR (100 MHz, CDC13) 8 83.2, 76.5, 71.1, 69.2, 65.2, 58.6, 58.3, 57.2,
44.5,43.7, 22.2- And. Cdcd for Cl lH200sS: C, 49.98; H, 7.63. Found: C, 49.95; H, 7.68.
1) 03,EtOH; NaBH4 - 2) p-TsCI, pyridine 3) H2NBn, DMF, NaHC03 N 2!92 295 Bn
The reaction was carried out as in the general procedure using the oxabicycle 292 ( 10.0 g, 50.4 mmol) in EtOH (100 mL) for 3 h at O OC and NaBb (2.3 g, 60.5 mmol). The di01 was activated using pyridine (75 mL) and p-TsC1 (26.9 g, 140.8 mrnol) at rt for 15 h. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave the bicycle 295 (6.0 1 g, 39%) as a colorless oil: R.= 0.5 1 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 306 1, 3028, 2974,
2929,288 1,2807,2760, 1494, 1454, 1385, 1197, 1107 cm-'; l H NMR (400 MHz, CDC13) 6
7.29-7.17 (5H,m), 4.10 (lH, t, J = 2.2 Hz), 3-52 (lH, dd, J = 8.8, 4.4 Hz), 3.45 (LH,d, J
= 13.2 Hz), 3.39 (lH, d, J = 13.2 Hz), 3.35-3.27 (3H, m), 3.30 (3H, s), 3.28 (3H,s), 2.72- 2.62 (2H, m), 2.57-2.51 (2H, m), 2.24 (lH, dd, J = 11.3, 2.2 Hz), 2.01 (LH, d, J = 10.3
Hz), 1.16 (3H. s); l3C NMR (100 MHz, CDC13) 6 138.5, 128.7, 128.2, 126.9, 81.1, 77.6,
7 1.9, 70.5, 64.8, 62.1, 58.7, 58.4, 56.9, 46.0, 45.6, 19.3. Anal. Calcd for CigH27N03: C,
70.79; H, 8.91; N, 4.59. Found: C, 70.85; H, 8.98; N, 4.53. octane-3-carboxylic acid tert-butyl ester (296).
MeOd~Pd/C, HC02NH4 - Me0 (BOC)20, EtOH Me0 N N 295 Bn BOC
Pd on charcoal(10%) (3.0 g, mol%) and ammonium formate (3.3 g, 5 1.9 mrnol) were
added successiveIy to a solution of the amine 295 (3.0 g, 10.4 mmol) in EtOH (30 mL) and the
mixture was stirred at rt for 20 h. The reaction mixture was fdtered through a Celite pad washed with CH2C12 and boiling warer. The filtrate was extracted (3x) with CH2C12. The combined organic layers were dried (MgS04), fitered and concentrated. The crude deprotected amine
was dissolved in Et20 (10 mL) and cooled at O OC for the treatement with (BOC)20 (2.7 g,
12.4 mrnol). The mixture was stirred for 1 h at rt. Purification by flash chromatography
(hexanes-EtOAc 1: 1) gave the carbamate 296 ( 1.79 g, 57%) as a white solid: Rf = 0.54 on silica gel (hexanes-EtOAc 1: 1); IR (neat) 2976, 2907, 28 10, 1695, 141 1, 1366, 1255, 1 172, 1 125, 1019 cm-1; IH NMR (400 MHz, DMSO-d6. 70 OC) 6 4.00 (lH, bs), 3.57-3.49 (2H,
m), 3.42 (LH,dd, J = 9.2, 4.8 Hz), 3.30 (2H, d, J = 6.6 Hz), 3.24-3.19 (lH, m), 3.23 (3H,
s), 3.20 (3H,s), 2.93-2.89 (lH, rn), 2.67-2.63 (LH,m), 2.31-2.18 (2H, m), 1.40 (9H, s),
1.14 (3H, s); 13C NMR (100 MHz, DMSO-d6, 80 OC) 6 154.2, 79.6, 78.7, 75.4, 70.4, 68.9,
57.7, 57.4, 54.5 (bs), 47.3 (bs), 44.6, 43.9, 27.8, 18.3; ascdcd for C16H29NO5[M - CH30H]+ 283.1784, found 283.1786.
NaH, THF
297 298 A solution of the alcohol 297 (3.67 g, 26.2 mol) in THF (20 mL) was added dropwise to a suspension of NaH (1-36 g, 60% in oi1, 34.0 mol) (washed 3 times with 206 pentane) in THF (20 mL) at O OC. After the addition was complete, the mixture was shed for 30 min at rt. Benzyl bromide (3.73 mL, 3 1.4 mmol) was added dropwise at O OC and the
mixture was heated at relux for an additionai 2 h. The reaction was quenched with MeOH and the solution was diluted with water. THF was removed in vacuo and the residue was extracted (3x) with Et2O. The combined organic layers were dried (MgSQ), fütered and concentrated. Purification by flash chromatography (hexanes-EtOAc 3:l) yielded 298 (4.82 g, 80%) as a colorless oil: RI= 0.55 on silica gel (hexanes-EtOAc 3A); IR (neat) 3065,3029, 2912, 1496, 1453, 1375, 1259, 1201, 1169, 1132, 1066 cm-1; 1H NMR (400 MHz, CDC13) 6 7.34-7.22
(SH,m), 6.22 (lH, dd, J = 5.9, 1.8 Hz), 6.05 (lH, d, J = 5.8 Hz), 4.75 (lH, m), 4.42 (2H, s), 3.77-3.73 (IH, rn), 2.04 (lH, ddd, J = 14.6, 5.9, 4.4 Hz), 1.93-1.84 (2H, rn), 1.74 (LH, dt, J = 14.6, 1.1 Hz), 1.34 (3H, s); 13C NMR (LOO MHz, CDCls) 6 139.1, 136.9, 133.7, 128.2, 127.2, 127.1, 82.4, 78.7, 72.0, 70.2, 38.6, 31.3, 24.1; HRMS calcd for C15H1802 [Ml+ 230.1307, found 230.1304.
O Me 1) 03,EtOH; NaBH4 - 2) p-TsCI, pyndine 298 3) Na2S-9H20, DMF 299
The reaction was carried out as in the general procedure B. Ozonolysis of the oxabicycle 298 (4.51 g, 19.6 mrnol) in EtOH (75 mL) for 90 min at O "C foilowed by NaBh reduction (0.89 g, 23.5 mmol) gave a di01 which was activated usiog pyridioe (50 mL) and p- TsCi (9.30 g, 48.8 mmol). Cyciization of the crude ditosylate was achieved with Na2S nonahydrate (7.0 g, 29.1 mmol) in DMF (400 mL). Purification by flash chromatography
(hexanes-EtOAc 3: 1) gave the bicycle 299 ( 1.55 g, 40%) as a white solid: Rf= 0.44 on silica gel (hexanes-EtOAc 5 : 1); IR (neat) 3029,2926,2866, 1716, 1496, 1451, 1358, 1085 cd; NMR (400 MHz, CDCb)6 7.36-7.25 (5H,m), 4.56 (2H, s), 4.414.26 (lHTm), 3.72- 3.64 (lH, m), 3.02 (lH, dd, J = 13.6, 3.3 Hz), 2.74 (LH,d, J = 13.2 Hz), 2.39-2.31 (1H. 307 m). 2.14 (1H, t, J = 11.9 Hz), 2.01-1.93 (3H, m), 1.83 (LH, dt, J = 11.8, 5.4 Hz), 1.22 (3H. s); l3cNMR (100 MHz, CDC13) 6 138.6, 128.1, 127.3, 127.2, 70.7, 70.1, 69.4, 67.2, 37.9,
37.5, 3 1.2 (2C), 3 1.1; HRMS calcd for Ci 5H2002S Ch/fj+ 264- 1184, found 264.1 185.
J 111.3.2 Deprotonation Study
General Procedure for the Enantioselective Deprotonation Using the Chiral Lithium Amide Base (195): (-)-(3S,4R,5R)-4,5-Bis-methoxymethyl- 2,3,4,5-tetrahydro-thiepin-3-01 (301).
F~,+-N Ri Li -L Me0 LiCI, benzene S HO 274 30t A solution of (-)-bis[(S)-1-phenyIethyl]amine hydrochloride 195 (720 mg, 2.75 mmol) in benzene (30 mL) was cooled using an ice bath, and was treated with n-BuLi (2.20 mL, 2.5 M in hexanes, 5.50 mmol). After the addition was cornpiete, the mixture was stirred for 20 min, and the thioxabicycle 274 (200 mg, 0.92 mol) was rapidly added to the solution as a soiîd, and the mixture was stirred for an additional 1 h at -5 OC. The reaction was quenched by the addition of a saturated NH&l solution. The aqueous layer was extracted (3x) with Et20, and the combined organic layers were dried (MgS04), lltered and concentrated. Purification by flash chromatography (hexanes-EtOAc 3 :1) gave 301 ( 183 mg, 9 L %) as a coIorless oii: Rf
= 0.26 on silica gel (hexanes-EtOAc 3: 1); 89% ee, [a]2SD = -1 1.8O (c 1.00, CHC13); IR (neat) 3427,2978,2922,2892, 1446, 1275, 1195, 1106 cm-'; LH NMR (400 MHz, CDC13) 6 6.35
(lH, dd, J = 9.6, 1.9 Hz), 5.79 (lH, dd, J = 9.4, 6.1 Hz), 4.00 (lH, bs), 3.93 (LH, dt, J = 11.0, 3.8 Hz), 3.56-3.45 (4H,m), 3.35 (3H, s), 3.29 (3H, s), 2.83-2.58 (4H, m); 13C NMR (100 MHz, CDC13) 6 136.2, 125.6, 77.9, 74.7, 71.3, 59.1, 58.8, 40.3, 39.7, 33.8. Anal.
Calcd for C loHi803S: C, 55.02; H, 8.3 1. Found: C, 55.18; H, 8.37. The optical purity was detennioed by capillary GC using a chirai column (Chiraidex y-TA). Q = 37.7 (minor) and 208 40.8 min (major) at 155 OC.
R~-N ph Li BnO LiC1, benzene B,O~ S HO 275 3x2 The reaction was carried out as in the generd procedure using 275 (100 mg, 0.27 mmol), (-)-bis[(S)-1-phenylethyllamine hydrochloride 195 (2 12 mg, 0.8 1 mmol), n-BuLi (648 pL, 2.5 M in hexanes, 1.62 mmol) in benzene (18 mL) for 10 h at 8 OC. Purification by flash chromatography (hexanes-EtOAc 5: 1) gave 302 (8 1 mg, 8 1%) as a coiorless oil: Rf= 0.18 on silica gel (hexanes-EtOAc 5: 1); 76% ee, [a]22D= -1 5.6O (c 1.go. CHCI3); IR (neat) 3429,3062,3028,2886, 1607, 1495, 1453, 1362 cm-1; iH NMR (400 MHz, CDC13) 6 7.37-
7.25 (lOH, m), 6.33 (lH, dd, J = 9.4, 1.7 Hz), 5.79 (lH, dd, J = 9.5, 6.2 Hz), 4.54 (lH, d, J = 14.6 HZ), 4.5 1 (TH, dTJ = 14.6 HZ), 4.46 (lH, d, J = 13.6 HZ),4.43 (lH, d, J = 13.9
Hz), 4.1 1 (lH, d, J = 8.8 Hz), 3.99-3.92 (TH, m), 3.64 (lH, t, J = 9.5 Hz), 3.59-3.52 (3H, m). 2.88-2.83 (lH, m). 2.74-2.63 (3H, m); I3c NMR (IO0 MHz, CDCI3) 6 137.9, 137.3, 136.3, 128.5, 128.4, 127,.9, 127.7, 127.6 (2C), 125.5, 78.0, 73.6, 73.1, 72.1, 68.7, 40.4,
39.9, 33.7; HRMS calcd for C22H2603S [Ml+ 370.1603, found 370-1586. The optical purity was determined by HPLC using a chiral colurnn (Chiralce1 OD), hexanes-i-PrOH 96:4. flow rate: 0.75 mUmin, t~ = 43.5 min (major) and 55.9 min (mhor). 276 303 The reaction was canied out as in the generai pmcedure using 276 (100 mg, 0.331 moi), (-)-bis[(S)-l-phenyiethy1]amhe (free base) (447 mg, 1.99 mmol), n-BuLi (794 PL,
2.5 M in hexanes, 1.99 mmol) in benzene (5 mL) for 24 h at rt. Purification by flash chromatography (several chromatography 's were necessary in order to entirely remove the excess chird base) (hexanes-EtOAc 7: 1) gave 303 (76 mg, 76%) as a white solid: Rf= 0.22 on
silica gel (hexanes-EtOAc 7: 1); 43% ee, [a]22D= -0.46' (c 1.73, CHQ); mp 55-56 OC (Et20); IR (neat) 3409,2926, 1478, 1428, 1391. 1234, 1193 cmi; IH NMR (400 MHz, CDC13) 5
6.30 (1H, dd, J = 9.2, 1.5 Hz), 5.82 (1H, dd, J = 9.4, 6.1 Hz), 4.79 (IH, d, J = 8.8 Hz),
3.95-3.88 (IH, m), 3.56 (1H.dd, J = 9.2, 4.8 Hz), 3.50 (lH, d, J = 10.3 Hz), 3.46 (lH, dd, J = 9.2, 5.5 HZ), 3.42 (lH, dd, J = 9.0, 6.5 HZ), 2.77 (IH, dd, J = 13.9, 11.3 HZ), 2.72-
2.67 (lH, m), 2.64 (IH, dd, J = 14.0, 4.1 Hz), 2.59-2.55 (lH, m), 1.18 (9H,s), 1.16 (9H, s); 13C NMR (100 MHz, CDCl3) 6 137.1. 124.7, 78.5, 73.9, 73.0, 63.8, 60.3, 40.9, 40.4,
33.7, 27.5, 27.3; HRMS cdcd for CltjH3003S 303.1994, found 303.MO7. The enantiomenc excess of the resultant alcohol was determined by derivatbaiion with S-(+)-mA chloride and cornparison of the lH NMR spectmrn of the product with that of an authentic racemate denvatized in an identical fashion. 2 IO (-)-(3S,4R,5R)-4,5-Bis-(methoxymethoxy-methyI)-2,3,4,5-tetrahydro-
The reaction was carried out as in the generd procedure using 278 (50 mg, O. 18 mmol), (-)-bis [(S)- 1-pheny Iethylrnne hydrochloride 195 (282 mg, L -08 mmol), n-BuLi (863 pL, 2.5 M in hexanes, 2.16 mmol) in benzene (20 mL) for 10 h at 9 OC. Purification by flash chromatography (hexanes-EtOAc 3: 1 followed by hexanes-EtOAc 1: 1) gave 305 (43 mg,
86%) as a colorless oii: Rf= 0.16 on silica gel (hexanes-EtOAc 3: 1); 86% ee, [a122~= -6.0" (C 0.67, CHC13); IR (neat) 3440, 2914,2823, 1466, 1442, 1420, 1274, 1214, 1150, 1109 cm-[; 1H NMR (400 M&, CDC13) 6 6.37 (lH, dd, J = 9.5, 1.8 Hz), 5.82 (1H, dd, J = 9.4, 6.1
Hz), 4.65 (lH, d, J = 7.7 Hz), 4.63 (lH, d, J = 7.7 Hz), 4.57 (lH, d, J = 8.4 Hz), 4.56 (IH, d, J = 8.4 Hz), 4.02-3.96 (lH, m), 3.82 (lH,d, J = 8.4 Hz), 3.74-3.60 (4H, m), 3.36 (3H, s), 3.34 (3H, s), 2.88-2.82 (lH, m), 2.75 (lH, dd, J = 13.9, 11.0 Hz), 2.67 (lH, dd, J = 13.9, 4.0 Hz), 2.63-2.61 (lH, m); I3c NMR (100 MHz, CDCI3) 6 136.3, 125.8, 96.6, 96.5, 78.0, 69.7, 65.9, 55.6, 55.4, 40.4, 40.0, 33.6; HRMS calcd for C12H2205S [m+278.1 188, found 278.1 180. The optical purity was determined by capillary GC using a chiral column
(Chiraldex y-TA). Q = 1 19.4 (minor) and 123.9 min (major) at 155 OC.
Mosher's Ester Derivatives 306 and 307.
306
The thiepane was obtained using (-)-bis[(S)- 1-phenylethyl] amine hydrochlonde (9)- 21 1 195 and the thiaoxabicycle 274, and coupling the resulting alcohol with (S)-(+)-MTPA-Cl. Purification by flash chrornatography (hexanes-EtOAc 7: 1) gave the Mosher ester 306 as a colorless oil: Rf = 0.32 on siiïca gel (hexanes-EtOAc 3: 1); lH NMR (400 MHz, CDCI3) 6 7.51-7.48 (2H, m), 7.43-7.35 (3H, m), 6.33 (lH, dd, J = 9.5, 1.5 Hz), 5.95 (1H ,dd, J = 9.4, 6.1 Hz), 5.37 (IH, dt. J= lI.4,4.5 Hz), 3.52 (38 m), 3.47 (2H, d,/=7.3 Hz), 3.33
(2H,d, J = 6.6 Hz), 3.28 (3H, s), 3.22 (3H, s), 2.91-2.86 (1H,m), 2.76-2.71 (LH,m), 2.54-2.58 (2H, m); HRMS cdcd for C20H25F305S M+434.1375, found 434-1363.
The thiepane was obtained using (+)-bis[(R)- 1-phenylethyi]amine hydrochioride (+)- 195 and the thiaoxabicycle 274, and coupling the resulting alcohol with (5')-(+)-MTPA-CI.
Purification by flash chromatography (hexanes-EtOAc 7: 1) gave the Mosher ester 307 as a colorless oil: Rf= 0.32 on silica gel (hexanes-EtOAc 3:l); IH NMR (400 MHz, CDC13) 6
7.52-7.49 (2H, m), 7.42-7.35 (3H, m), 6.34 (1H, dd, J = 9.4, 1.7 Hz), 5.97 (lH, dd, J = 9.5, 6.2 Kz), 5.37 (IH, ddd, J = 9.5, 6.4, 4.3 Hz), 3.56-3.52 (lH, m), 3.54 (3H,rn), 3.47
(lH, dd, J = 9.3, 6.1 Hz), 3.34-3.22 (lH, m), 3.29 (3H, s), 3.16-3.14 (lH, m), 3.12 (3H, s), 2.93-2.87 (1H, m), 2.76-2.74 (2H, m), 2.61-2.57 (lH, m); HRMS calcd for C20H25F305S m+434.1375, found 434.137 1. 212 The reaction was carried out as in the general procedure using LDA. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave the aicohol308 as a colorless oil: Rf= 0.29 on silica gel (hexanes-EtOAc 3:1); IR (neat) 3437, 2979, 2919, 2889, 2812, 2752, 1452, 1374, 1197, 11 10, 1057 cm-l; [H NMR (400 MHz, DMSO-d6.80 OC) 6 6.09 (1H,bs), 4.52 (lHTbs), 3.69 (lH, dd, J = 9.5, 8.4 Hz), 3.57 (1H, dd, J = 9.5, 4.0 Hz), 3.45 (1H. dd, J = 9.5, 5.9 Hz), 3.24 (3H, s), 3.23-3.18 (lH, m), 3.19 (3H, s), 3.01-2.98 (LH,m), 2-42 (lH, J = 13.9 Hz), 2.15 (lH, d, J = 13.6 Hz), 1.92 (IH, dd, J = 9.6, 3.7 Hz), 1.81 (3H, d, J = 1.1 Hz), 1.40 (3H, d, J = 0.7 HZ); 13C NMR (100 MHz, DMSO-d6, 80 OC) 6 1 17.5, 74.1. 72.6, 70.1, 57.4, 57.3, 45.7, 41.7, 26.6, 20.7.
(+)-3-Hydroxy-4,5-bis-methoxymethyl-2,3,4,5-tetrahydro-azepine-l- carboxyIic acid tert-butyl ester (3 11).
s-BuLi/(-)-sparteine + Me0 Et20 N HO 28~ BOC 31 1
A solution of (-)-sparteine (229 pL, 1.00 mol) in Et20 (6 rnL) at -78 OC was treated with s-BuLi (732 pL, 1.18 M in cyclohexane-hexane 92:8,0.86 mol) and the mixture was stirred for 20 min at -78 OC. The resulting mixture was added to a cold solution of 280 (200 mg, 0.66 mol)in Et20 (4 mL) via a canula and the reaction mixture was shed for 1 h at -78 OC. The reaction was quenched by the addition of a saturatec! NH&l solution. The aqueous layer was extracted (3x) with Et20. The combined organic layers were dried over MgS04, fdtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 1: 1) gave 311
(190 mg, 95%) as a colorless oil: RI= 0.43 on silica gel (hexanes-EtOAc 1: 1); 46% ee, [c~]~~~
= +76.7" (c 0.52, CHC13); IR (neat) 3453, 2959, 2923, 1703, 1653, 1458, 1378, 1241, 1165 cm- ; 'H NMR (400 MHz, DMSO-d6,80 OC) 6 6.4 1 ( 1H, dd, J = 8.6, 1.7 Hz), 4.92 ( 1H, dd, J = 8.6, 5.7 Hz), 4.73 (IH, bs), 4.00 (IH, dd, J = 13.9, 5.5 Hz), 3.88-3.82 (lH, rn), 3.54- 3.48 (ZH,m), 3.44-3.35 (2H, rn), 3.24 (3H, s), 3.22 (3H, s), 2.90-2.84 (lH, m), 2.57-2.51 2 13 (lH, m), 2.12-2.07 (LH,m), 1.42 (9H.s); 13C NMR (LOO MHz, DMSO-da, 80 OC) 6 152.4, 129.6, 116.4, 79.6, 74.4, 70.4, 68-6, 57.6, 57.5, 50.6, 41.7, 38.0, 27.6; HRMS calcd for
C15H27N05[Ml+ 301.1889, found 301.1880. The enantiomeric excess of the resultant dcohol was determined by derivatization with S-(+)-MTPA chlonde and cornparison of the IH NMR spectmm of the product with that of an authentic racemate derivatized in identical fashion. The absolute stereochemistry has not been determined.
290 312 The reaction was carried out as in the general procedure using 290 (100 mg, 0.57 rnrnol), (-)-bis[(S)- 1-phenyIethyl]amine hydrochloride 195 (45 1 mg, 1-72 rnrnol), n-BuLi f 1.38 mL, 2.5 M in hexanes, 3 -45 mmol) in benzene (25 mL) for 40 h at rt. Purification by flash chromatography (hexanes-EtOAc 1: 1) gave 312 (37 mg, 37%) as a colorless oil: Rf= 0.3 1 on silica gel (hexanes-EtOAc 1: 1); 97% ee, [a]21D= -59.8O (c 1.22, CHC13); IR (neat) 3383,2930. 2824, 1604, 1452. L355 cm-[;1H NMR (400 MHz, CDC13) 6 5.93 (lH, d, J =
10.6 Hz), 5.68 (IH, dt, J = 10.9, 8.5 Hz), 4.32-4.27 (lH, m), 3.57-3.50 (2H, m), 3.32 (3H, s), 2.77 (IH, dd, J = 15.4, 5.2 Hz), 2.60 (1H. dddd, J = 14.1, 9.7, 8-5, 1.2 Hz), 2.44 (lH, ddd, J = 14.2, 8.5. 5.8 HZ), 2.17 (lH, ddd, 3 = 14.6, 5.8, 3.0 Hz), 2.00 (lH, dd, J = 14.7, 2.6 Hz), 1.97 (lH, dd, J = 14.4, 2.4 Hz); I3C NMR (100 MHz, CDCl3) G 125.2, 124.6,
78.3, 68.5, 56.6, 38.7, 36.2, 30.1. Anal. Calcd for CsH 1402s:C, 55. L4; H, 8.10. Found:
C, 54.94; H, 8.16. The optical purity was determined by capillary GC using a chiral column (Chiraldex y-TA). t~ = 52.5 (minor) and 54.3 min (major) at 125 OC. LICI, benzene
The reaction was carried out as in the general procedure using 291 (100 mg, 0.57
rnmol), (-)-bis[(S)-1 -phenyIethyI Jenehydrochloride 195 (45 1 mg, 1.72 rnmol), n-BuLi (1.38 mL, 2.5 M in hexanes, 3.45 mmol) in benzene (25 mL) for 48 h at a. Purification by
flash chromatography (hexanes-EtOAc 1: 1) gave 313 (60 mg, 60%) as a white solid: Rf= 0.45 on silica gel (hexanes-EtOAc 1: 1); 43% ee, [c(]~~~= + 12.2' (c L -04, CHCI3); mp 5 1-53 OC
(EtzO); IR (neat) 3398, 2929, 2825, 1604, 1448, 1370, 1190 cm-'; 'H NMR (400 MHz, CDCI3) 8 5.94 (IH, d. J = 11.0, 1.1 HZ), 5.64 (lH, dt, 3 = 11.0, 8.6 HZ), 4.16-4.08 (lH, m), 3.72-3.66 (2H, m), 3.51 (1H, dd, J= 15.0, 9.9 Hz), 3.39 (3H, s), 2.96 (LH, dd, J = 15.0, 5.5 Hz), 2.77 (lH, dddd, J = 14.0, 9.6, 8.2, 1.4 Hz), 2.62 (IH,ddd, J = 14.4, 8.7,
5.8 Hz), 2.28 (1H.dt, J = 15.0, 5.9 Hz), 2.15 (lH, dt. J = 15.0, 2.7 Hz); 13C NMR (100 MHz, CDCl3) 6 125.1, 122.3, 8 1.4. 73.3, 57.0, 37.0, 33.4, 30.4; HRMS calcd for CgH1402S M+174.07 15, found 174.07 18. The optical purity was detemiined by capïilary
GC using a chiral column (Chiraldex y-TA). t~ = 42.8 (minor) and 44.1 min (major) at 125 Procedure for the Regioselective Deprotonation Using LDA: (3R*,4S*,5S*)-4,5-Bis-methoxymethyl-3-methpI-2,3,4,5-tetrahydro-thiepin- 3-01 (314) and (3S*,4R *,5R*)-4,s-Bis-methoxymethyl-6-methyl-2,3,4,5- tetrahydro-thiepin-3-01 (315).
Me,, O LDA Me0 benzene Me0 - Me S HO 293 514 515 A solution of diisopropylamine (3.4 mL, 25.9 mmol) in benzene (30 m.)was cooied using an ice bath and treated with a solution of n-butyllithium (10.3 mL, 2.5 M solution in hexanes, 25.9 mmol). The mixture was stirred for 20 min at 5 OC pnor to the addition of a solution of 293 ( 1.O g, 4.3 rnmol) in benzene ( 10 mL) via a canula. The mixture was stirred at rt for 1 h. The reaction was quenched by the addition of a saturated NaCl solution. The aqueous layer was exuacted (3x) with Et20 The combined organic layers were dried over MgS04, filtered, and concentrated. Purifcation by flash chromatography (hexanes-EtOAc 3: 1) gave a 955 ratio of alcohois 314 (908 mg) as colorIess oil and 315 (23 mg) as a white solid in a combined yield of 93%. Alcohol314: Rf= 0.27 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3428,2976,2905,2820, 1455, 1387, 1192, 1109 cmi; [H NMR (400 bMz, CDCI3) 6 6.30
(IH, dTJ = 9.1 HZ), 5-75 (1H3 dd, J = 9-0, 6.0 HZ),4-58 (1H.bs), 3.63 (LH, t, J = 9.7 HZ), 3.49-3.41 (3H. m), 3.35 (3H, s), 3.30 (3H.s), 2.89 (IH, dd, J= 12.8, 6.7 Hz), 2.84(1HT bs), 2.47 (lH, d, J = 14.2 Hz), 2.15 (IH, bs), 1.46 (3H,s); 13cNMR (100 MHz, DMSO-Q, 80 "C)6 137.4, 123.6, 75.5, 73.5, 70.5, 57.8, 57.7, 46.1, 26.9 (2 rnissing signais). Anal. Calcd for CilH2003S: C, 56.87; H. 8.68. Found: C, 56.87; H, 8.78. Alcohol 315: Rf= 0.19 on silica gel (hexanes-EtOAc 3:l); mp 56-60 "C (Et20); IR (neat) 3420, 2975, 2920, 2896,
2876, 1447, L 197 cm-';IH NMR (400 MHz. CDC13) 6 6.12 ( lH, bs), 3.98-3.93 (2H,m),
3.65 (lH, dd, J = 9.6, 7.0 HZ),3.53-3.45 (3H,m), 3.35 (3H, s), 3.30 (3H,s), 2.99 (lH, t, J 216 = 6.6 Hz), 2.71-2.58 (3H, m), 1-80 (3H,d, J = 1.1 Hz); 13~NMR (400 MHz, CDC13) 6
144.5, 119.8, 72.9, 71.6, 59.1. 58.8, 42.6, 40.6, 34.9, 22.7 (1 missing signal); HRMS calcd for C 1 1 H20O3S @Ml+232.1 133, found 232.1 141.
(3R*,4S*,5S*)-4,5-Bis-methoxymethyl-3-methyl-l,l-dioxo-2,3,4,5- tetrahydro-thiepin-3-ol (316) and (3S*,4R*,5R*)-4,5-Bis-rnethoxyrnethyl-6-
A solution of diisopropylamine (106 CIL, 0.76 rnmol) in toluene (3 rnL) was cooled using an ice bath and treated with a solution of n-butyllithiurn (303 PL, 2.5 M solution in hexanes, 0.76 rnmol). The mixture was stirred for 20 min at 5 OC and cooled to -78 OCpnor to the addition of a solution of the sulfone 294 (100 mg. 0.38 mmol) in toluene (2 mL) via a canula. The mixture was stirred at -78 OC for 1 h. The reaction was quenched by the addition of a saturated NH&I solution. and the aqueous Iayer was extracted (3x) with Et2O. The combined organic layers were dried (MgSQ), fdtered, and concentrated. Purification by flash chromatography (hexanes-EtOAc 1:1) gave a 68:32 ratio (1H NMR) of alcohols 316 (50 mg) and 317 (2 1 mg) as colorless oils in a combined yield of 7 1%. Alcohol 316: R.= 0.42 on silica gel (EtOAc-hexanes 2:l); IR (neat) 3435, 2977, 2913, 2817, 1624, 1457, 1385, 1292, 1196, 11 11 cm-[;IH NMR (400 MHz. CDC13) 6 6.48 (IH. dt, J = 11.0, 1.9 Hz), 6.3 1 (lH, dd, J = 11.2, 6.4 Hz), 4.59 (IH, bs), 3.62-3.55 (4H,m), 3.51 (lH, dd, J = 9.5, 5.9 Hz), 3.38 (3H, s), 3.35 (3H, s), 3.32-3.26 (lH, m), 3.22 (lH, dd, J = 15.0, 1.9 Hz), 2.39 (lH, t, J = 6.8 Hz), 1.64 (3H, s); 13C NMR (100 MHz, CDC13) 6 143.1. 134.8, 73.6, 73.0, 70.8, 62.6, 59.0, 58.9,46.5, 37.1, 28.0; HRMS cdcd for Cl lH2005S - OH]+ 247.1004, found 247.100% Alcohol 317: Rf = 0.35 on silica gel (EtOAc-hexanes 2: 1); IR (neat) 3443, 2977, 2909.2815, 1617. 1448, 1292, 1198, 11 11 cm-I; 1H NMR (400 MHz, CDC13) 6 6.27 (lH, 217 d, J = 1.5 Hz), 4.38-4.33 (LH, m), 3.68 (lH,dd, J = 9.8. 6.5 Hz), 3.63-3.55 (2H, m), 3.52
(lH, dd, J = 9.9. 5.3 Hz), 3.43-3.31 (4H, m), 3.35 (3H, s). 3.33 (3H, s), 2.84-2.70 (lH, m), 1.96 (3H, d, J = 1.3 Hz); I3C NiWl (100 MHz, CDCI3) 8 155.4, 130.7, 72.0, 70.3,
70.2, 59.2. 58.8,57.2, 42.0, 40.8, 22.6; HRMS cdcd for Ci 1 H2005S [Ml+ 265.1 1 10, found
265.1104.
(3R*,4S*,SR*)-3-Hydroxy-4,S-bis-methoxymethy1-3-methyl-2,3,4,5~ tetrahydro-azepine-1-carboxylicacid tert-butyl ester (318) and (3S*,4R*,5R*)- 3-Hydroxy-4,5-bis-methoxymethyl-6-methyl-2,3,4,5-tetrahydro-azepine-1- carboxylic acid tert-butyl ester (319).
A solution of 296 (73 mg, 0.23 mmol) in Et20 (5 mL) at -78 OC was treated with s- BuLi (266 uL, 1.3 M in cyclohexane, 0.35 rnmol) and the mixture was stirred for 1 h at -78 OC. The reaction was quenched by the addition of a saturated NH&L solution. The aqueous layer
was extracted (3x) with EtîO. The combined organic layes were dried (MgS04). fdtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 1: 1) gave an unsaparable
mixture of alcohols 318 and 319 (49 mg, 68%) as a colorless oil. Alcoho1319: Rf= 0.23 on silica gel (hexanes-EtOAc 2: 1); mp 90-92 OC (EtzO); IR (neat) 3429,2907, 1706, 1680, 165 1,
1452, 1386, 1237, 1167 cmi; IH NMR (400 MHz, DMSO-d6,60 OC) 6 6.22 (lH, bs), 4.76
(lH, bs), 3.86-3.83 (2H, m), 3.65 (lH, bs), 3.48 (2H,m), 3.32 (IH, t, J = 8.4 Hz), 3.22 (3H, s), 3.21 (3H,s), 2.89 (IH, bs), 2.49-2.37 (lH, m), 2.02 (lH, bs), 1.67 (3H, s), 1.40 (9H,s); 13C NMR (100 MHz, DMSO-d6, 60 OC) 6 152.8, 126.0 (2C). 79.4, 73.4, 71.6, 68.1, 57.9, 57.7, 50.6,42.6,42.0, 27.8, 21.3; HRMS calcd for Cl6H29N05 [Ml+ 3 15.2046, found 3 15.2046. The minor isomer 318 could not be isolated and characterized.
HO Me B " + B LDA or,.-^^ Q,,C b benzene - S HO 299 320 321 The reaction was carried out as in the generai procedure using diisopropylarnine (3 18 PL, 2.27 mmol), n-butyllithium (909 PL. 2.5 M solution in hexanes, 2.27 mmol), and 299
(100 mg, 0.38 mmol) in benzene (4 mL) at rt for 48 h. Purification by flash chromatography
(hexanes-EtOAc 3: 1) yielded 320 (42 mg, 42%) as a colorless oil: Rf = 0.36 on silica gel
(hexanes-EtOAc 3: 1); IR (neat) 3384, 3028, 2925, 2865, 1605, 1496, 1453, 1363, 1205, 1093, 1063 cm-'; IH NMR (400 MHz, CDQ) 6 7.35-7.24 (533, m), 5.89 (lH, d, J = 11.0
Hz), 5.66 (lH, dt, J = 11.0, 8.4 Hz), 4.68 (1H,s), 4.58 (lH, d, J = 11.8 Hz), 4.50 (1H. J =
12.1 Hz), 3.86-3.80 (LH,m), 3.30 (1H, d, J = 15.4 Hz), 2.99 (1H,d, J = 15.3 Hz), 2.69- 2.56 (2H, ml, 2.23 (lH, dd, J = 14.6, 6.6 Hz), 1.99 (LH,dd, J = 14.6, 3.3 Hz), 1.47 (3H, s); 13C NMR (100 MHz, CDC13) 6 140.8 and 138.6, 128.5 and 127.6, 128.4, 127.5 and
126.9, 127.4, 124.5 and 122.2, 74.3, 70.7, 65.3, 42.7, 40.8, 29.8, 29.4; MRMS calcd for C 15H2002Sm+ 264.1 184, found 264.1 19 1. The minor isomer 321 could not be isolated and characterized. 219 General Procedure for the Chemoselective Oxidation of the Vinyi Sulfide. Oxidation of the Sulfide 314 to the Sulfone X > CH2CI2,Acetone Me0
A solution of dimethyl dioxirane (-10 mL) was prepared using Murray and Singh method65 using 144 g of oxone, 112 mL of water, 88 mL of acetone, and 76.8 g of NaHC03. The peroxide solution was slowly added to a solution of 314 (100 mg, 0.43 mmol) in CHzCI2
(10 mL) at -78 OC. The mixture was sbed for 1 h at -78 OC and 1 h at room temperature. The
solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc- hexanes 2: 1) to give 316 (1 14 mg, 100%) as a colorless oil.
x CH2CI2, Acetone Me0
HO = HO 301 "eovo2 The reaction was carried out as in the general procedure using a solution of dimethyl dioxirane (-10 rnL) was prepared using Murray and Singh method65 using 144 g of oxone,
112 mL of water, 88 mL of acetone, and 76.8 g of NaHC03 and 301 (90% ee) (100 mg, 0.46 mmol) in CH2C12 (10 mL). Purification by flash chromatography (hexanes-EtOAc L: 1) gave the sulfone 328 (105 mg, 92%) as a colorless oil: Rf= 0.34 on silica gel (hexanes-EtOAc 1: 1);
[~r]*~~= +6 1. l0 (c 1.83, CHCl3); (neat) 3480, 3058, 2988, 2924, 2903, 2826, 1621, 1461, 1369, 1297, 1199. 1121. 1029 cm% NMR (400 MHz, CDC13) 6 6.49-6.46 (IH, m), 6.31 (lH, dd, J = 11.0. 6.2 HZ),4.38 (IH, bs), 4.05 (1H. bs), 3.67 (1H. dd, J = 9.2, 5.3 HZ), 3-58(IH, t, J = 10.1 HZ),3.53 (IH, dd, J = 9-5,6.2 HZ),3.46 (lHTdd, J = 9.5, 220 5.8 Hz). 3.41-3.38 (2H,m), 3.36 (3H, s), 3.33 (3H,s), 3.24 (lH, qt, J = 6.1, 1.8 Hz), 2.76-2.71 (lH,m); 13C NMR (100 MHz. CDC13)6 144.2, 134.8, 74.1, 71.3, 69.9, 59.3, 58.9, 56.7,42.5,37.5; HRMS calcd for C loH1805S + WC25 1.0953, found 25 1.0946. 22 1 § 111.4 References and Notes
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Tetrahedron Lett. 1983,24,4745. (g) Van Royen, L. A.; Mijngheer, R.; De Clercq, P. I. Tetrahedron Lett. 1983.24, 3 145. (h) Campbell, M. M.; Kaye, A. D.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron Lett. 1984.25, 1629. (i) Ager, D. J.; East, M. B. J. Chem. Research (S) 1986, 462. 0) Gustafsson, J.; Stemer, O. J. Org. Chem. 1994.59, 3994. (k) Koreeda, M.;Jung, K.-Y.;Ichita, 5. J. Chern. Soc., Perkin Trans. 11989, 2129. (1) Takahashi, T.; Iyobe, A.; Ami, Y.; Koizumi, T. Synthesis, 1989, 189. (m)Moore, B. S.; Cho, H.; Casati, R.; Kennedy, E.; Mocek, U.; Beale, J. M.; Ross, H. G. J. Am. Chern.
Soc. 1993, IIS, 5254. (n) Yang. W.; Koreeda, M. J. Org. Chem. 1992,57, 3836. (40) Arjona, O; Conde, S.; Plumet, J.; Viso, A. Tetrahedron Lefi. 1995,36, 6 157. (41) (a) Kuszmann, J.; Sohiir, P. Carbohyd. Res. 1973,27, 157. (b)Sohk, P.; Kuszmann, J. Acta Chim. Acad. Sci. Hung. 1975, 86,285. (c) Koyanagi, T.; Hayami, LI.; Kaji, A. Chem. Lett. 1976, 971. (d) Baldwin, J. E.; Crossley, M. J.; Lehtonen. E.-M. M. J. Chem. Soc., Chem. Cornm. 1979, 918. (42) (a) Newth, F. H.; Wiggins, L. P. J. Chern. Soc. 1948, 155. (b) Wood, D. J. C.: Wiggins, L. F. Nature 1949, 164, 402. (c) Cope, A. C.; Baxter, W. N. J. Am. Chem. Soc. 1955, 77, 393. (d) Cope, A. C.; Anderson, B. C. J. Am. Chem. Soc. 1955, 77. 995. (e) Cope, A. C.; Schweizer, E. E. J. Am. Chem. Soc. 1959.81, 4577. (0 Kilonda, A.; Dequeker, E.; Compernolle, F.; Delbeke, P.; Toppet, S.; Bila, B.; Hoomaert, G. J. Tetrahedron 1995.51, 849. 225 (43) Birch, V. S.. F.; Dean, R. A. Liebigs Ann. Chem. 1954,586, 234. (44) (a) Lautens, M.; Ma, S.; Belter, R. K.; Chiu, P.; Leschziner. A. J. Org. Chem. 1992, 57,4065. (b) Lautens, M.; Smith, A. C.; Adb-El-Aziz, A. S.; Huboux, A. A. Tetrahedron
Lett. 1990,3I, 3253. (c) Lautens, M.; .Chiu, P.; Ma, S.; Rovis, T. J. Am. Chem, Soc. 1995,117, 532. (d) Chiu, P. Ph. D. Thesis, Ring-Opening Reaciions of Oxabicyclic Compounds: Unsymmetrical Substrates and Reduction, University of Toronto, 1994, p 76. (e) Ma, S. Ph. D. Thesis. Ring-Opening Reac tions of Oxabicyclic Compounds: Formation of Substituted Cyclohexadienes, Cyclohexanols and Cycloheptanols, University of Toronto, 1996, p 76. (45) Klein. L. L.; Shanklin, M. S. J. Org. Chem. 1988.53, 5202. (46) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987,28, 5 15. (47) Wendler, N. L.; Slates. H. L. J. Am. Chem. Soc. 1958.80, 3937. (48) (a) Mann, J. Tetrahedron 1986,42,46 1 1. (b) Lautens, M.; Ma. S.; Yee, A. Tetrahedron Lett. 1995, 36, 4185. (49) (a) Majewski, M.; Lazny, R. J. Org. Chem. 1995,60, 5825. (b) Both enantiomers of 195 are commercialiy available from Aldrich Co. (50) (a) Asami, M. Bull. Chem. Soc. Jpn. 1990,63, 1402. (b) Milne, D.; Murphy, P. J. J. Chem. Soc., Chem. Comm. 1993, 884. (5 1) (a) Kaiser, B.; Hoppe, D. Angew. Chem. Int. Ed. Engl. 1995,34, 323. (b) Aggmal, V. K. Angew. Chem. Int. Ed. Engl. 1994,33, 175. (c) Cox, P. J.; Persad, A.; Simpkins, N. S. Synlett 1992, 194. (52) (a) Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533. (b) Bunn, B. I.; Simpkins, N. S.; Spavold, 2.; Crimmin, M. J. J. Chem. Soc. Perkin Trans. 11993,
3 113. (c) Majewski, M.; Lazny, R. Nowak, P. Tetrnhedron Let?. 1995,36,5465. (53) Yamaguchi, S. In Asymmetric Synthesis; Momson, J. D., Ed.; Academic Press: New York, 1983; Vol. 1, p 128.
(54) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,29, 552. 226 (55) For an example of regioselectivity using the chiral base 300. see: (a) Sobukawa, M.; Nakajima, M.; Koga, K. Tetrahedron: Asymrnetry 1990.1, 295. (b) Koga, K.; Shindo, M. J. Synth. Org. Chem. Jpn. 1995,53. 1021.
(56) Hodgson, D. M.; Gibbs. A. R.; Lee, G. P. Tetrahedron 1996,52,14361. (57) (a) Rickbom, B.; Thummel, R. P. J. Org. Chem. 1969,34, 3583. (b) Thummel, R. P.;
Rickborn, £3. J. Am. Chem. Soc. 1970, 92, 2064. (c) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980,45, 755. (d) CrandaIl, J. K.; Apparu, M. Org. React. 1983,29,345. (58) Bloch, R.; Gilbert, L. Tetrahedron Len. 1987,28,423.
(59)Collum, D. B. Acc. Chem. Res. 1993.26, 227. (60) Edwards. A. I.; Hockey, S.; Mair, F. S.; Raithby, P. R.; Snaith, R. L Org. Chem. 1993,58, 6942- (61) Majewski, M.; Gleave, D. M. J. Org. Chem. 1992,57, 3599.
(62) (a) Meyers, A. 1.; Milot, G. J. Am. Chern. Soc. 1993, 115, 6652 and references cited therein. (b) Meyers, A. 1.; Edwards, P. D.; Rieker, W. F.: Bailey, T. R. J. Am. Chem. Soc. 1984, 106, 3270. (c) Shawe, T. T.; Meyers, A. 1. J. Org. Chem. 1991, 56, 2751.
(d) Beak, P.; Lee, W. K. J. Org. Chem. 1990,55, 2578. (63) (a) Be*, P.; Lee, W. K. J. Org. Chem. 1993.58, 1109. (b) Garrido, F.; Mann, A.;
Wennuth, CG. Tetrahedron ktt. 1997,38,63.
(64) King, J. F.; Rathore, R. J. Am. Chern. Soc. 1990,112, 2001. (65) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 9 1. CHAPTER 4
ANIONIC INTRAMOLECULAR RING OPENING OF OXABICYCLO[2.2.1] COMPOUNDS 5 IV.1 Introduction
The presence of cyclic components within naniral products has led ring constniction via cyclization reactions to be one of the most studied and utilized strategies in organic synthesis. Cyclization reactions rnay be grouped into four main types, those involving cationic, radical, anionic and metal complex intermediates which rnay be stable species or transient. 1
Anionic cyclization is a cornmon approach to ring construction. The most frequently used strategy involves the intramo~ecuiarattack of an ionic center on electrophile in simple SN2 and SN^' fashions.2 A vast array of nucleophiles and electrophiles have been utilized in the anionic cyclization reaction. We were particularly interested in the cyclization of reactive anionic centers ont0 unactivated olefinic bonds. mainly due to growing interest in this field and its unexploited poten tial in organic synthesis.
The anionic cyclization ont0 unactivated olefinic bonds remained, until very recently, unprecedented. In the 19601s, and 70fs, some authors reported the cyclization of organomagnesium> organ~aluminium~~organolithiurn.5 and organomercury6 ont0 unactivated olefins.7 In these primary studies, the main problems were associated with the generation of the initial aikenylrnetal.
In 1987, Bailey and coworkers reported the generation of alkenyllithiums and their cyclization products (Scheme 4.1).8 It was shown that the treatment of 6-iodo-1-hexene with r- BuLi in pentane/Et20, with or without TMEDA at -78 OC,quantitatively effected lithium-iodide exchange to give an organoiithium which can be trapped by various electrophiles. On warming to room temperature, however, the anion cyclized in a 5-exo-trig fashion thus affording an anion which can subsequently be trapped by electrophilic species. Bailey extended this preliminary work to tandem carbolithiation reactions for the construction of complex carbocyclic 229 compounds.g The group of Bailey unequivocally proved the anionic nature of the reaction rather than a radical cyclization process foiIowed by a second eiectron transfer.10
Scheme 4.1
Substituted tetrahydrofurans were prepared by Broka and coworkers by anionic
cyclization of a-aikoxy anions ont0 unactivated olefins (Scheme 4.2). l The dkenyllithium
was generated from the alkenyltin via tin-lithium exchange. The reactions were highiy diastrereoselective but limited to the utilization of terminai olefins; 1.2-disubstituted oie fins being inert to the carbolithiation reaction. They improved the efficiency of the reaction by performing the cyclization ont0 allylic ethers. For example, when 329 was treated with n- BuLi, the tetrahydrofuran denvative 330 was generated in high diastereoselectivity via an SN^' reaction with concomitant iost of Lithium methoxide and formation of a tenninal oiefin. Scheme 4.2
fiBuLi, THF
R = H, 54Y0,predorninantly cisisorner R = Me, no cyclized product observed
MuLi, THF -78 OC to O OC
Lautens and Kumanovic have investigated the intramolecular anionic ring opening of oxabicyclo L3.2.11 systems as a route to bicyclo[5.3.0]decenes (Scheme 4.3).12 The generality of this methodology was demonstrared by using a variety of tethered oxabicyclic compounds. The organolithium was generated either from the iodide or tributyltin derivatives 331. The most important feature of this cyclization is the exclusive attack from the exo face leading to irans-fused bicyclo[5.3 .O]decenes 332 bearing a tertiary aicohol.
Scheme 4.3
x* t-BuLi x+$ - ... Ill or MeLi I OR OR Y Li I = bR
We have reported in Chapter 2 (see Scheme 2.8, p. 94), the fmt example of an anionic intramolecular ring opening reaction of dioxatetracyclic system leading to complex polycyclic compounds. From the precedents stated above and the expertise deveIoped in our laboratones. we were interested to study the anionic intramolecular nucleophilic ring opening of L2.2.11 oxabicycles directed toward the stereoselective construction of a varieiy of syntheticdy useful cyclic precursors (Scherne 4.4).
8 IV.2 Results and Discussion
8 IV.2.1 Preparation of the Furan Derivatives
The 2-substituted furan substrates employed in this study required no more than three steps for their preparation. Cornmercially available furfuryl alcohol was protected as its tetrahydropyranyl (THP) ether 333 in good yield (Equation 4.1).13 The known alcohol 334 was prepared from a literature procedure 14 by condensation of Zfuryllithium and ethylene oxide and further protected as its THP derivative 335.15
DHP, PPTS 232 The three- and four-carbon chah substituted furans were prepared using a different
route. 3-Bromo-1-propanol was protected as its THP derivative 336 and reacted with 2- lithiofuran to give the aikylated furan 337 in 92% yield (Scheme 4.5).12.l6 Freshly prepared 4-bromo-1-butanol, obtained by the opening of THF by HBr, was protected providing 338 and further reacted with Zlithiofuran under the usual conditions to give 339.17
Scheme 4.5
5 IV.Z.2 Preparation of the [2.2.l]0xabicycIes
With the furan dienophiles in hand, the preparation of the [2.2.1] systems bearing alkyliodo tether and alkylheterotin tether at the bridgehead position was investigated using the Diels-Alder cycloaddition as the key step.
The furans 333,335, 337 and 339 were treated with maleic anhydride (neat) to give the anhydride cycloadducts which were readily reduced to the diols 340,341, 342, and 343, respectively, after reaction with LiAIH4 in THF (Scheme 4.6). In ail cases, the exo dioIs were observed as the major product and the minor endo diols (40%) were easily removed by colurnn chromatography. The diols were isolated as equimolar mixtures of inseparable diastereomers, due to the presence of the THP protecting group on the furan moieties and CO the non-selectivity of the cycloadditions. The diols 341.342, and 343 were dimethylated and the THP ether directly transformed into the alkyl iodide substrates 347,348, and 349 using
Schmidt and Brooks procedure. l8
Scheme 4.6
2 2) LiAIH4, THF
NaH or KH, THF then Me1 +GAThe preparation alkylheterotin tether [2.2.1] substrate 351 started with the one-carbon tether di01 340 (Scherne 4.7). Protection of the di01 as its dimethyl ether was achieved followed by removal of the THP protecting group under acidic conditions which afforded the alcohol 350 in 79% for the two steps. Wlation of 350 with Bu3SnCH21 furnished the desired substrate 351 in good yield.lg
Scheme 4.7
1) KH, THF O then Me1 2) PPTS, MeOH eoEeBu3SnCH21W,THF - $GY THPO 79% HO Bu3Sn,0 340 350 351
In order to study the cyciization of a stabilized anion. the akyl iodide substrate 348 was
234 treated with NaCN in HMPA~Oto provide the butyronitrile bridgehead substituted [2.2.1] oxabicycle 352 (Equation 4.2).
5 IV.2.3 CycIization S tudies
The feasibility of the anionic intrarnolecular ring opening of oxabicyclic [2.2.1] substrates was first explored on the stannyl ether 351. Treating the substrate 351 with 3 equiv. of +MeMeLi at -78 OC in THF cleanly aiiowed the tin-lithium exchange and upon wmning to room temperature, gave the cyclized product 353 (Equation 4.3). The attack of the nucleophiie is believed to occur exclusively from the exo face leading to the tram ring junction aithough this was not rigorously proven. In addition to the bicycle 353, the presence of the bicyclic diene 354 was also observed. Its formation arose from the deprotonation of the allylic hydrogen of the cyclic product 353, with concomitant elimination of lithium methoxide. The ratio of both products 353 and 354 varied with time, and a longer reaction time ied to a cornplex mixture of products. Using less MeLi was not an option since a minimum of 3 equiv. of MeLi was required for the exchange step to go to completion. Attempting to optimize the reaction conditions to favor the formation of the diene 354 failed and the use of a large excess of MeLi led mostly to decomposition. Finaily, the probiem was overcome by using Et20 as the solvent. By perforrning the exchange at low temperature with 3 equiv. of MeLi, and warming the reaction mixture to room temperature, 353 was obtained in 80% yield.
OMe MeCi Et20 HF::OH + OH Me (4.3) Bu3Sn,0 3ç( 80% 353 364 The synthesis of 14.3.01 and [4.4.0] carbocycles was studied by cyclization of the
alkyliodo tethers substrates 348 and 349 (Equation 4.4).8 Treating 348 with t-BuLi in
pentaneEt20 3:2 immediately led to the iodide-lithium exc hange and the cyclization occurred at -78 OC,showing the enhanced reactivity compared to the 13.2. il oxabicycles. The temperature
was warmed to room temperature for a few minutes in order to complete the cyclization. The carbobicycle 355 was isolated in 83% yield and less than 10% of reduced product was observed by anaiysis of the lH NMR spectrum of the crude mixture. The formation of the tram-decalin 357 was problernatic and gave predominantiy the reduced product 358 as
observed by IH NMR. As reported by Bailey, the use of pentaneEt20 9: 1 and higher dilution
slightiy improved the raUo of cyciized/reduced products to 23 as judged by IH NMR.lOb The diffrculties associated with the preparation of six-membered rings using this rnethodology has ken previously reported by the groups of Broka and ~ailey.8-11
In an attempt to prepare functionalized 14.3.01 bicycles, a different strategy of cyclization was envisaged (Scheme 4.8). After iodide-lithm exchange of the two-carbon te ther su bstrate 347, the intermediate aikyiiithiurn 359 was treated with c-butylisocyanide to access the intermediate 360 which would subsequently cyclize onto the oiefin to give the cyclic ketone 361 after hydrolysis of the imine. However, no trace of the desired bicycle 361 was observed and hstead, the spiro[5.2.0] bicycle 362 was obtained. Scheme 4.8
The reaction was optimized by treating the two-carbon tether 12.2.11 substrate 347 under the usual lithium-iodide exchange conditions to provide the spiro [5.2.0] bicycle 362 in 62% yield (Equation 4.5). Due to geometric constrains, the intramolecular anionic attack presumably occurred from the endo face of the bicyclic template and the bridging ether was cleaved via an s~2process.
Few examples of cyclopropane preparation using cyclization of a carbanion species onro an electrophile via an SN2 or S$' rnechanism have been reported in the literature.21 Bailey and Tao recently published the preparation of vinylcyclopropane by cyclization of 5-iithio-1- methoxy-Zpentene 363 (Scheme 4.9). The lithio species 364 was obtained by iodide-lithium exchange of the precursor 363 at -78 OC. The cyclization occurred only at room temperature in the presence of TMEDA to give vinylcyclopropane 365 in 88% yield. The reduced product was obtained in the absence of TMEDA. 237 Scheme 4.9 t-BuLi 1) TMEDA I~OM~L~WOM~ Et20, -78 OC 2) 20°C - b 363 364 88% S5
Recently, Funk and coworkers reported that alkoxy- and thioaikoxyacetylenes participate in cyclization reactions with a variety of stabilized litho carbanions to provide
func tionalized exoc yclic and endocyclic en01 (thioenol) ethers (Scheme 4.10) -22 The reac tion have also been shown to work for a variety of length of tether. A proposed rnechanism would involve trans-carbometaiiation of the phenylsulfonyl anion 366 leading to vinyl anion 367. From the latter, the therrnodynamicaily prefered anion 368 was fomed and could be trapped by
reaction with electrophiles. The formation of the stable anion 368 is believed to be the driving force of the cyclization.
Scheme 4.10
*BuLi + HMPA, THF
Marek and Nomant reported the diastereoselective synthesis of polysubstituted pyrrolidines via a zinc-enolate cyclization (Equation 4.6).23 The Lithium enolate was unable to cyclize and must be transmetallated using zinc saits to favor the 5-exo-trig-cyclization. nie resulting alkylzinc was trapped with a variety of electrophiles. LDA, EtzO, ZnBr2 -40°C to tt - N C02Me (4.6) "Me
We briefly investigated the cyclization of stabilized anion using the butyronitrile bridgehead substituted [2.2.1] oxabicycle 352. Treatrnent of 352 with LiHMDS or LDA gave the a-cyano lithium anion which cyclized to give 369 after 24 h at room temperature. The
formation of the exocyclic olefin system 370 which arose from the loss of methanol was also observed. This is a reiteration of an identical problem encountered in the course of the cyclization of oxabicyclic system 351 (see Equation 4.3). An excess of base was necessq for the reaction to go to completion and the utilization of Et20 of THF as the solvent did not prevent the side reaction.
Forming the potassium anion using an excess KHMDS did not really solve the problems, however, the starting material was consumed after 1 hour at room temperature
(Equation 4.7). This represents the first example, to the best of our knowledge. of a carbopotassiation reaction. The desired cyclized product 369 could be isolated in 34% yield. Only one diastereomer was identified by analysis of the cmde IH NMR. From the coupling constant of 4.0 Hz between the proton adjacent to the nitrile group and the allylic proton at the bridgehead, a syn relationship between the cyano group and the hydrogen was deduced. nOe studies were dso performed on cyclized coumpounds 369 and 370 but were not conclusive. At this stage, it is too early to know if this selectivity derived from a selective cycLization or arose from an epimerization in the presence of the excess base. In this chapter, we have briefly demonstrated the potential of the anionic intnmoiecular ring opening of f2.2.11 oxabicyclic compounds for the efficient and stereocontrolled preparation of hetero and ail carbon tram-fused 14.3.01 bicycle as well as spuo [5.2.0] bicycle.
The cyciization of stabilized anion has also ken reported but with some limitations due to the propensity of the products to undergo cornpetitive side reactions. The synthesis of oxabicycles Iike 371 and 372 has been undertaken and the application of the strategy to the synthesis of natural products containing [4.3.0]bicycles bearing a tram junction and spiro l5.2.01 bicycle like ~acifigor~iol*~and ~taquilosin25is envisaged (Figure 4.1 ). The diastereoselectivity of the cyclization process will be investigated in detail shortly.
Figure 4.1
371 I 372 Pacifigorgiol Ptaquilosin
5 IV.3 Experimental Section
IV.3.1 Solvents and Reagents
For general experimental details, see Section 1.3.1, p 46. Unless stated otherwise, commercial reagents were used without purifcation. Tetrahydrofuran, diethyl ether and toluene were distilled immediately pnor to use from sodium/benzophenone. Dichloromethane was distiiled immediately prior ro use fiom calcium hydride. 240 General Proceduce for the Furanyl-Tetrahydro-Pyran Preparation. 2- (Furan-2-y1rnethoxy)-tetrahydco-pyran (333).
DHP, PPTS 4 CH2CI2 333 A solution of freshly distiiled hirfùryl alcohol (5.00 g, 5 1.O mrnol) in CHzCI;! (50 mL)
was treated with DHP (10.3 mL, 122.3 mmol) and PPTS ( 1-28 g, 5.1 mmol) and stirred for 1
h at rt. The mixture was diluted with CH2CI2 and washed (2x) with a saturated NaHC03
aqueous solution, brine (LX), dned over MgS04, filtered and concentrated. Bulb-to-bulb distillation of the residual oil(70 OC, 0.35 mmHg) gave 333 (8.9 g, 95%)as a colorless oii: Rf = 0.45 on siiica gel (hexanes-EtOAc 9:l); IR (neat) 3 121, 2938, 2875, 1607, 1503, 1454, 1442, 1153, 1 119, 1077 cm-I; IH NMR (400 MHz, CDCIî) 6 7.38 (lH, dd, J = 1.8, 0.7 Hz),
6.32-6.29 (2H, m), 4.69 (IH, t. J = 3.5 Hz), 4.64 (1H,dl J = 12.9 Hz), 4.47 (1H. d, J = 12.8 Hz), 3.91-3.85 (lH, m), 3.55-3.50 (lH, m), 1.86-1.77 (lH, m). 1.73-1.66 (IH, m), 1.63-1.47 (4H,m); 13C NMR (100 MHz, CDCl3) 6 151.6, 142.7, 110.1, 109.2, 97.2, 61.9, 60.5, 30.3, 25.4, 19.2; HRMS calcd for C1oHl403[Ml+ 182.0943, found 182.0938.
DHP, PPTS C CH2CI2
The reaction was carried out as in the general procedure using 334 (6.2 g, 55.3 rnmol),
DHP (10.1 mL, 110.6 mmol) and PPTS (1.4 g, 5.6 rnmol) at 0 OC for 1 h at n. Bulb-to-bulb distillation of the residual oil(80 OC, 0.9 mmHg) gave 335 (5.4 g, 77%) as a colorless oii: Rf = 0.46 on silica gel (hexanes-EtOAc 15:l); IR (neat) 2945, 2873, 1455, 1121 cd;IH NMR (400 MHz, CDC13) 6 7.29 (LH,dd, J = 1.9, 0.8 Hz), 6.27 (lH, dd, J = 3.3, 1.9 Hz), 6.06
(1H, dd, J = 3.0, 0.8 Hz), 4.60 (IH,t, J = 3.7 Hz), 3.96 (lH, dt, J = 9.7, 7.1 Hz), 3.79 (1H. ddd, J = 11.3, 8.1, 3.2 Hz), 3.66 (LH,dt, J = 9.8, 7.1 Hz), 3.50-3.45 (IH, m), 2.93 (2H.t, J = 7.0 Hz), 1.83- 1-42 (6H,m); l3~NMR (100 MHz, CDCl3) 6 153.2, 141 .O, 110.2, 105.8, 24 1 98.7, 65.5, 62.1, 30.6, 28.8, 25.4, 19.4; HRMS caicd for Ci 1H1603m+ 196.1099, found 196.1 104.
1) DHP, PPTS, CH2C12 Br-O H C !J,/..-OTHP O 337
The protection was carried out as in the general procedure using 3-bromo-1-propanol
(15.0 g, 110 mmol), CH2C12 (50 rnL), DHP (23.7 mL, 260 mmol), and PPTS (2.7 g, Il rnmol) for 5 h at rt. Bulb-to-bulb distillation (0.50 rnmHg, 50-60 OC) of the residual oil yielded 2-(3-bromo-propoxy)-tetrahydro-pyran 336 (22.2 g, 91%) as a colorless oil: R.= 0.3 1 on silica gel (hexanes-EtOAc 9: 1); H NMR (200 MHz, CDC13) 6 4.55 (1H, m), 3.87-3.62 (2H, m), 3.49-3.33 (2H, m), 3.24 (2H, t, J = 6.8 Hz), 2.03 (2H. quintet, J = 6.3 Hz), 1.78- 1-46
(6H, m); 13~NMR (50 MHz, CDCIî) 6 98.6, 66.6, 62.0, 33.4, 30.4, 25.3, 19.3, 3.3.
A solution of n-butyiiithium (39.7 mL, 2.5 M solution in hexanes, 74.3 mol) was added dropwise to a stirring solution of furan (5.9 mL, 8 1. 1 mol) in TH.(250 mL) at O OC.
The mixture was stirred for 1 h at O OC and for an additional 1 h at rt. The reaction was then cooled to O OC for the dropwise addition of a solution of 2-(3-bromo-propoxy)-tetrahydro-pyrm
336 (15.0 g, 67.6 mol) in THF (20 mL) over 1 hour. After the addition was complete, stirring was continued at rt for an additional 15 h. The reaction was quenched by the addition of water (10 mL) and the solvent was removed in vacuo. The aqueous layer was exuacted (3x) with Et20. The combined organic layers were washed with brine, dried (M~SOJ),fütered and concentrated in vacuo. Bulb-to-bulb distillation (1.0 mmHg, 80 OC) of the residuai oil gave 337 (13.1 g, 92%) as a colorless oïl: Rf =OS on siiica gel (hexanes-EtOAc 9: 1); IR (neat) 3 114,2938,2875, 1595, 1448, 1384, 113 1 cm-l; 1H NMR (200 MHz, CDCl3) 6 7.28 (LH, d,
J = 1.8 Hz), 6.26 (IH, dd, J = 3.1, 1.9 Hz), 5.98 (1H, d, J = 3.0 Hz), 4.58 (lH, t, J = 2.9
Hz), 3.87-3.73 (ZH, m), 3.53-3.40 (2H, m), 2.72 (2H,t, J = 7.3 Hz), 2.05-1.49 (8H,m); 242 3C Nhim (50 MHz, CDC13) 6 156.3, 141.3, 110.5, 105.3, 99.3, 67.1, 62.7, 31.2. 28.7, 26.0,25.3, 20.1; HRMS calcd for C 12H1803 m+2 10.1255, found 2 10.1255.
1) DHP, PPTS, CH2CI2 / \ A LOTHP ''-0 ''-0 H 339
The protection was carried out as in the general procedure using freshly prepared 4- bromo- 1-butanol (10.3 g, 67.4 mmol), CHzC12 (100 mL), DHP (14.8 mL, 16 1.9 rnmol) and
PPTS (1.7 g, 6.7 mol) for 1 h at n. Bulb-to-bulb distillation (1.40 mmHg, 75-90 OC) of the residual oil gave 338 (14.8 g, 92%) as a colorless oil: Rf= 0.47 on silica gel (hexanes-EtOAc
9: 1); lH NMR (200 MHz, CDCI3) 6 4.56 (lH, bs), 3.89-3.69 (2H, m), 3.5 1-3-34 (2H. m),
2.03-1.50 (12H, m); I3C NMR (50 MHz, CDCl3) 8 98.7, 66.4, 62.2, 33.6, 30.7, 29.8, 28.4, 25.4, 19.6.
The alkylation was carrieci out as in the above procedure using a solution of n- butyllithiurn (22.4 mL, 2.5 M solution in hexmes, 55.6 mmol), furan (4.4 mL. 6 1.0 mrnol), 'T73.F (100 rnL) and 2-(4-bromo-butoxy)-tetrahydro-pyran 338 (12.0 g, 50.8 mmol). Bulb-to- bulb distillation (1.6 Mg,85-100 OC) of the residual oii gave 339 (10.6 g, 93%) as a colorless oil: Rf=0.54 on silica gel (hexanes-EtOAc 9: 1); R (neat) 3 114, 2945, 2868, 1595, 1508, 1455, 1440. 1353, 1202, 1139, 1120, 1078, 1038 cm-[; 1H NMR (400 MHz, CDCl3) 6
7.27 (lH, dd, J = 1.8, 0.7 Hz), 6.25 (1H,dd, J = 2.9, 1.8 Eh),5.96 (lH, dd, J = 3.3, 0.7
Hz), 4.55 (LH, dd, J= 4.1, 2.8 Hz), 3.87-3.81 (lH, m), 3.74 (1H,td, J= 9.6, 6.6 HZ), 3.50-3.45 (LH,m), 3.38 (lH, td, J=9.9, 6.3 Hz),2.64(2H, t, J= 7.4Hz), 1.84-1.46 (IOH, m); I3C NMR (100 MHz, CDC13) 6 156.0, 140.6, 110.0, 104.7, 98.7, 67.1, 62.3, 30.7, 29.2, 27.8, 25.5, 24.8, 19.6; HRMS calcd for C13H2003FI]+ 224-1412, found 224.1409. 243 GeneraI Procedure for the Diels-AIder/LiAIHq Reduction Sequence.
1) w (neat) 2) LiAIH4, THF
Maleic anhydride (2.8 g, 28.6 mmol) was added to a solution of 333 (5.2 g, 28.6 mol) in Et20 (10 mL). The mixture was stirred und the maleic anhydride was completely dissolved and Et20 was rernoved NI vacuo. The resulting solution was stirred for 12 h at rt during which time the material crystailized. The cude mixture was dissolved in THF (20 mL) and added via a canula to a suspension of LMH4 (2.2 g, 57.1 rnmol) in THF ( 120 mL) at O OC. The mixture was stirred for an additional 15 h at n. The reaction was quenched by the portionwise addition of potassium sodium tartrate tetrahydrate ( 16.1 g, 57.1 mmol) followed by water (5 mL). The mixture was stirred for an additionnai 5 h at a. The suspension was filtered and the residue was washed several times with boiling THF. The filtrate was concenvated and purification by flash chromatography (EtOAc-MeOH 955) gave a 1: 1 mixture of diastereomeric diols 340 (5.13 g, 71%) as a colorless oil: Rf= 0.39 on silica gel (EtOAc-MeOH 955); IR
(neat) 3388, 3079, 2945, 2868, 1448, 1244, 1204, 1183, L 124 cm-'; 1H NMR (400 MHz, CDC13) 6 6.40 (lH, dd, J = 3.7, 1.9 Hz), 6.38 (1H,dd, J = 3.7. 1.9 Hz). 6.30 (1H. d. J =
5.5 HZ), 6.22 (lH, d, J= 5.9 HZ),4.78 (lH, d, J = 1.4 HZ), 4.72 (lH, d, J = 1.8 HZ), 4.69-
4.66 (2H,m), 4.25 (1H, d, J = 7.7 Hz), 4.22 (lW, d, J = 8.0 Hz), 3.98 (lH, bs), 3.87 (IH, d, J = 11.0 Hz), 3.86-3.81 (LOH, m), 3.76 (lH, d, J = 11.0 Hz), 3.57-3.50 (2H, m), 3.65-
3.61 (3H. m), 2.07-1.95 (4H. m), 1.95-1.65 (4H. m), 1.65-1.49 (8H, m); 13~NMR (100 MHz, CDCI3) 8 137.2, 137.1, 136.0, 135.8, 99.5, 99.2, 89.4, 88.9, 81.1, 80.9, 65.6, 65.3,
62.6, 62.5, 62.4, 62.1, 59.9, 59.8, 44.4, 34.3, 44.0, 43.8, 30.2, 30.19, 25.2, 35.1, 19.3,
19.2; HZiMS calcd for Clfi2205 27 1.1545, found 27 1.1538. 2) LiAIH4, THF ,J ,J 341 THPO The reaction was carried out as in the general procedure using mdeic anhydride (2.5 g, 25.5 rnmol) and 335 (5.0 g, 25.5 mmol) for 24 at rt. The reduction was carried out as in the general procedure using Li- (1.9 g, 51.0 mmol), THF (120 mL), potassium sodium tmte tetrahydrate ( 14.4 g, 5 1.0 rnmol) and water (5 mL). Purification by flash chromatography (EtOAc-MeOH 955) gave a mixture of diastereomenc diols 341 (3.83 g, 53%) as a colorless oil: Rf= 0.59 on silica gel (EtOAc-MeOH 955): IR (neat) 3356. 29 15, 1450, 1264, 1127,
1041 cm-1; 1H NMR (400 MHz, CDC13) 6 6.37-6.35 (2H, m), 6.3 1 (IH, d, J = 3.3 Hz), 6.30
(lH, d, J = 3.3 Hz). 4.63 (IH, d, J = 1.4 Hz), 4.62 (lH, d, J = 1.4 Hz), 4.59-4.57 (2H, m), 3.98-3.79 (12H, m), 3.58-3.47 (4H, m), 2.68 (4H. bs), 2.32-2.21 (2H, m), 2.16-2.01 (4H, m), 2.00-1.94 (2H, m), 1.87-1.73 (2H, m), 1.73-1.67 (2H, m), 1.63-1.53 (8H, m); 13~ NMR (100 MHz, CDC13) 6 137.8 and 137.6, L35.5 and 135.3, 98.8, 88.76 and 88.70, 80.47 and 80.44, 77.2, 64.16 and 64.13, 62.5 and 62.1, 59.8, 44.2, 44.04 and 43.99, 30.3, 29.6, 25. L, 19.2; HRMS calcd for Cl 5H24O5 MC284.1624, found 284-1639.
1) (neat) 2) LiAIH4, THF
The reactioa was cmied out as in the generai procedure using maleic anhydride ( 1.40 g, 14.3 mol) and 337 (3.0 g, 14.3 mol) for 2 weeks at rt. The reduction was carried out as in 245 the generai procedure using LiAiH4 ( 1.1 g, 28.6 nimol), THF (120 mL), potassium sodium
tartrate tetrahydrate (8.1 g, 28.6 mmol), and water (5 mL). Purification by flash chromatography (EtOAc-MeOH 955) gave a mixture of diastereorneric diols 342 (1.89 g. 47%) as a colorless oil: Rf = 0.27 on silica gel (EtOAc-MeOH 955); IR (neat) 3364. 29 16, 1452, 1366, 1259, 1 140, 1044 cm-1; [H NMR (400 MHz, CDC13) 6 6.38 (2H,dd, J = 5.7,
1.7 HZ),6.23 (2H, d, J = 5.9 HZ), 4.61 (2H, d, J = 1.1 Hz), 4.59-4.56 (2H, rn), 3.95-3.66 (12H, m), 3.52-3.37 (4H, m), 3.06 (4H, bs), 2.10-2.05 (2H, m), 2.03-1.92 (îH, rn), 1.88-
1.68 (12H, m), 1.58-1.50 (8H, m); 13~NMR (100 MHz, CDC13) 6 137.9, 136.0. 98.99 and 98.78, 90.7, 80.9, 67.4 and 67.3, 63.1, 62.44 and 62.41, 60.3, 44.8, 44.1, 30.67 and 30.64, 26.4, 25.71 and 25.67, 25.4, 19.6; HRMS caicd for C16H2605 - THUC 213.1127, found 213.1 134.
2) LiAIH4,THF THPO 343
The reaction was carried out as in the general procedure using maleic anhydride (4.37 g, 44.6 1 mol) and 339 (5.0 g, 22.3 1 mmol) for 18 h at rt. The reduction was carried out as in the general procedure using Lu(3.4 g, 89.24 mmol), THF (220 mL), potassium sodium
tartrate tetrahydrate (25.2 g, 89.24 mmol), and water (5 mL). Purification by flash chromatography (EtOAc-MeOH 955) gave a mixture of diastereomeric diols 343 (3.66 g, 53%) as a colorless oil: Rf= 0.35 on silica gel (EtOAc-MeOH 955); IR (neat) 3359, 2936, 2970, 1455, 1127, 1032 cm-l; 'H NMR (400 MHz, CDC13) 6 6.37 (2H. dd, J = 5.9. 1.5 Hz),
6.23 (lH, d, J = 5.8 Hz), 6.22 (lH, d, J = 5.9 Hz), 4.60 (2H. bs), 4.56-4.54 (2H, m), 3.95- 3.72 (12H, m), 3.5 1-3-46 (2H, m), 3.42-3.36 (ZH,m), 2.22 (4H, bs), 2.07 (2H. dt, J = 8.4, 4.8 Hz), 1.95 (2H, dt, J = 8.4, 3.8 Hz), 1.90-1.76 (6H.m), 1.73-1.60 (6H,m), 1.57-1.48 246 (12H. m); 13~NMR (100 MHz, CDCl3) 8 138.1, 136.0, 99.0, 98.9, 90.9, 80.9, 67.3,67.28, 63.3, 62.5, 62.4, 60.4, 44.8, 44.1, 30.7, 30.1, 30.0, 29.6, 29.5, 25.4, 22.2, 22.1, 19.7,
19.6; HRMS calcd for C17H2805 [M - OH]+ 295.1909, found 295.1909.
methanol (350).
1) KH, THF - 7 then Mel THPO 340
A solution of 340 (4.0 g, 15.7 mmol) in THF (1O mL) was added dropw ise to a suspension of KH (4.2 g, 35% in oil, 36.2 mnol) (washed 3 times with pentane) in THF (50 mL) at O OC and the-mixture was stirred for 2h at rt. After the dropwise addition of Me1 (2.9 mL, 47.2 mrnol) at O OC, the mixture was stïrred for an additionai 5 h at rt. The reaction was quenched with few drops of i-PrOH and the solution was diluted with water. TKF was
removed in vacuo and the aqueous Iayer was extracted (3x) with Et20. The combined organic
layers were dned (MgS04), filtered and concentrated. The crude product was dissolved in MeOH (75 mL) and treated with PPTS (396 mg, 1-57 mmol). The mixture was stirred at rt for 20 h and quenched by the addition of a saturated solution of NaHCO3. The aqueous layer was extracted (3x) with CH2CL2. The combined organic layers were washed with water (lx) and
brine (lx), dned (MgS04), fitered and concentrated. Purification by flash chromatography (hexanes-EtOAc 1: 1) gave 350 (2.68 g, 79%) as a colorless oïl: Rf= 0.20 on silica gel
(hexanes-EtOAc 1: 1); IR (neat) 3473, 3079, 2981, 293 1, 2882, 2812, 1462, 1244, 1202,
1103. 1040 cm-1; 1H NMR (400 MHz, CDC13) 6 6.43 (1H, d, J = 5.9 Hz), 6.32 ( lHTdd. J = 5.7, 1.0 Hz), 4.72 (IH, d, J = 1.5 Hz), 3.88 (lH, dd, J = 12.1. 5.2 Hz), 3.81 (lH, dd, J = 11.9, 9.8 Hz), 3.53 (lHTdd, J= 9.4, 3.2 Hz), 3.40-3.33 (3H, m), 3.35 (3H, s), 3.31 (3H, s), 3.23 (1H. t, J = 8.8 Hz), 2.09-2.00 (2H, m); 13C NlVLR (100 MHz, CDCl3) 6 137.3, 135.4, 90.3, 80.1, 71.8, 70.7, 60.6, 58.9, 58.8, 42.2, 40.2. Anal. Calcd for CllH1804: C, 247 61.66; H. 8.47. Found: C, 6 1.65; H, 8-25.
General procedure for the Methylation of the Diol. exo ,ex0 -5,6-Bis- methoxymethyl-l-[2-(tetrahydro-pyran-2-yoxy)ethyl]-7-oxa-bicycIo [2.2.1] hept-2-ene (344).
then Mel
THPO THPO 344
A solution of 341 (3.4 g, 12.0 mrnol) in THF ( 10 mL) was added to a suspension of NaH (1.1 g, 60% in oil. 27.8 mmol) (washed 3 times with pentane) in THF (50 mL) at O OC and the mixture was stirred for 1 h at n. After the dropwise addition of Me1 (2.3 mL, 36.1
mol)at O OC,the mixture was stirred for 1 h at rt and heated at reflux for an additionai 1h. The reaction was quenched with few drops of MeOH and the solution was diluted with water. THF was removed Nt vacuo and the aqueous layer was extracted (3x) with Et20. The combined organic layers were dried (MgS04), filtered and concentrated. Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 344 (3.57 g, 95%) as a colorless oil: Rf = 0.47 on silica gel (hexanes-EtOAc 2:l); IR (neat) 3075. 2933, 2878, 2509, 1452, 1384. 1199, I 1 15, 1074, 103 1 cm-!; iH NMR (400 MHz, CDC13) 6 6.29-6.26 (2H. m), 6.25 (lH, d, J =
5.5 Hz), 6.24 ( IH. d, J = 5.8 Hz), 4.77 (2H. bs), 4.56 (2H, rn), 3.94-3.8 1 (4H. m), 3.60- 3.4 1 (8H, m), 3.36-3.27 (4H, m), 3 -34 (6H.s), 3.29 (6H, s), 2.27-2.19 (2H, m), 2.12-2.03 (2H. m), 1-98 (2H, ddd, J = 10.3, 8.5, 4.8 Hz), 1.92-1.86 (2H, m), 1.84-L.76 (2H. m),
1.73-1.66 (2H, m), 1.59-1.47 (8H. m); 13~NMR (100 MHz, CDC13) G 137.9, 137.8, 135.2,
135.0, 98.7, 88.7, 88.6, 79.8, 79.7, 71.9, 70.4, 64.3, 61.98, 61.95, 58.5, 58.33. 58.32. 41.8, 41.7, 41.5, 41.4, 30.5, 30.4, 29.74, 29.70. 25.2, 19.4; HRMS calcd for C17H2g05 [Mlt 3 12.1937, found 3 12.1946. then Mel
The reaction was carried out as in the general procedure using 342 (1.50 g, 5.32 mmol), KH (1.40 g, 35% in oil, 12.24 mrnol), THF (60 mL), and Me1 (1.00 mL, 15.96 mmol). Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 345 (1.30 g, 79%) as a colorless oil: Rf = 0.53 on silica gel (hexanes-EtOAc 1: 1); IR (neat) 3072, 2938, 2875.
28 12. 1455, 1258, 1202, 1 124, 1103, 1033 cm-'; IH NMR (400 MHz, CDCI3) 6 6.28 (2H, dd, J = 5.7, 1.6 Hz), 6.15 (SH,d, J = 5.5 Hz), 4.75 (2H,d, J = 1.5 Hz), 4.56 (2H,t, J = 3.5
Hz), 3.86-3.68 (4H,m), 3.57 (2H,dd, J = 8.8, 4.7 Hz), 3.49-3.22 (10H,m), 3.32 (6H,s),
3.27 (3H, s), 3.26 (3H,s), 2.00-1.46 (24H.m); [3~NMR (LOO MHz, CDC13) 6 137.8,
135.8, 98.6, 98.5, 90.6, 80.0, 72.1, 70.6, 67.6, 67.5, 62.2, 62.1, 58.9, 58.6, 42.4, 41.6, 41.5, 30.8, 30.7, 26.5, 25.9, 25.8, 25.5, 19.6, 19.5; HRMS cakd for Cl8H300~FI - CH30H]+ 294.183 1, found 294.1833.
KH, THF THPO then Mel THPO 343
The reaction was carried out as in the general procedure using 343 (3.30 g, 10.57 mmol), KH (2.94 g, 35% in oil, 25.62 mmol), THF (100 mL), and Me1 (2.08 mL, 33.41 mmol). Purification by flash chromatography (hexanes-EtOAc 2: 1) yielded 346 (2.0 1 g, 56%) as a colorless oil: Rf= 0.32 on silica gel (hexanes-EtOAc 2A); IR (neat) 3074, 2909, 2809, 1454, 1385, 1259, 1197, 11 17, 1078, 1030 cm-1; 1H NMR (400 MHz, CDCb) 6 6.30 (IH, d, 249 J = 5.8 Hz), 6.29 (1H, d, J = 5.9 Hz), 6.18 (lH, d, J = 5.8 Hz), 6.17 (lH,d, J = 5.8 Hz), 4.78 (2H,d, 5 = 1.8 Hz), 4.57-4.54 (2H, m), 3.87-3.82 (2H, rn), 3.78-3.7 1 (2H. m), 3.60 (2H, dd, J = 8.8, 4.8 Hz), 3.50-3.45 (2H. m), 3.44-3.27 (8H,m), 3.35 (6H,s), 3.29 (6H, s), 2.03-1.94 (2H, rn), 1.9 1-1-50 (26H, m); l3C NMR (100 MHz. CDC13) 6 137.9, 135.7, - 98.8, 98.7, 90.7, 80.0, 72.2, 70.7, 67.4, 62.3, 62.2, 58.8, 58.5, 42.3, 41.5, 30.7, 30.3, 30.2, 29.6, 29.5, 25.5, 22.3, 19.7, 19.6; HRMS calcd for C1gH3205[M - OH]+ 323.2222, found 323.2203.
General Procedure for the Conversion of the OTHP Group to the Iodide. exo,exo-1-(2-Iodo-ethyl)-5,6-bis-methoxymethyI-7-oxa-bicyclo[2.2~1]hept-2- ene (347)-
12, DlPHOS CH2CI2
THPO 344 347
A solution of iodine (6.1 g, 24.0 mrnol) in CHzCl2 (200 rnL) was added dropwise to a solution of 1.2-bis(dipheny1phosphino)ethane (DIPHOS) (5.4 g, 13.5 mol) in CH;?CIî (30 rnL) at O OC. After the addition was complete, a solution of 344 (3.0 g, 9.6 mmol) in CHZCI;? (30 rnL) was added and the reaction mixture was stirred for 15 h at rt. The reaction was poured into a vigorously stimng mixture of Et20 (500 mL) and pentane (500 rnL). The mixture was shed for 15 min and was filtered through a pad of silica gei, and the fütrate was evaporated in vacuo. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 347 (1.89 g, 58%) as a pale yellow solid: Rf= 0.5 1 on siüca gel (hexanes-EtOAc 3: 1); mp 32-34 OC (Et2O); IR (KBr) 3016, 2972, 2930, 2888, 1447, 1382, 1338, 1200, 1173, 11 17 cm-'; 'H NMR (400 MHz, CDCl3) 6 6.35 (lH, dd, J = 6.6, 0.8 Hz), 6.16 (1H, d, J = 5.5 Hz), 4.78 (lH, d, J = 1.8 Hz),
3.51 (lH, dd, J = 8.8, 5.2 Hz), 3.38 (IH, dd, J = 9.5, 5.8 Hz), 3.35-3.33 (IH,m), 3.34 (3H, s), 3.31 (3H, s), 3.26 (1H, dd, J = 10.1, 9.0 Hz), 3.21 (lH,ddd, J = 10.1, 7.0, 2.4), 2.55 (iH, ddd, J = 14.5, 10.3, 6.8 Hz), 2.45-2.38 (lH, m), 1.99 (lH, ddd, J = 10.1, 8.4, 250
5.0 Hz), 1.87 (LH,dt, J= 8.1,6.8 Hz); I3C NMR (LOO MHz, CDCL3) 6 136.3, 136.2, 91.0,
79.8, 71.7, 70.1, 58.7, 58.5, 41.7. 41.5, 35.2; HRMS calcd for C12K 19103 [M - CH3]+ 323.0144, found 323.0138.
The reaction was carried ouf as in the generai procedure using iodine (1.02 g, 4.03 mmol) in CH2C12 (100 mL), DIPHOS (803 mg, 2.02 mrnol) in CH2C12 (12 rnL) and 345 (500 mg, 1.6 1 mmol) in CH2C12 (12 mL) for 15 h. Purification by flash chromatography (hexanes- EtOAc 3: 1) gave 348 (375 mg, 66%) as a colorless oil: Rf= 0.45 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3072,2981,293 1,2882,2812, 1448, 1384, 1237, 1201. 1173 cd;IH NMR (400 MHz, CDCI3) G 6.29 (IH, ddd, J = 5.5, 1.6, 0.9 Hz), 6.11 (IH, d, J = 5.9 Hz), 4.75
(lH, d, J = 1.8 Hz), 3.53 (1H. dd, J = 8.8, 4.8 Hz), 3.38 (IH, dd, J = 9.5, 7.3 Hz), 3.35
(lH, dd, J = 9.2, 8.1 Hz), 3.33 (3H, s), 3.29 (3H,s), 3.27-3.15 (3H, m), 2.03-1.77 (6H, m); l3C NMR (100 MHz, CDCI3) G 137.5, 136.0, 90.1, 80.0, 72.0, 70.5, 58.9. 58.6, 42.3, 41.7, 30.7, 29.7, 7.6: HRMS calcd for C13H21103 [Ml+ 352.0535, found 352.0537.
12, DIPHOS THPO CH2CI2 346 349
The reaction was carried out as in the general procedure using iodine (3.4 g, 13.2 rnmol) in CH2C12 (60 mL), DIPHOS (2.6 mg, 6.6 mmol) in CH2C12 (60 mL) 346 (1.8 g, 5.3 25 1 mmol) in CH2Cl2 (30 rnL) for 15 h. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 349 (1.04 g, 54%) as a colorless oil: Rf = 0.38 on silica gel (hexanes-EtOAc 3: 1); IR
(neat) 3079, 2981, 2924, 2882, 2812, 1459, 1196, 1185, 1121, 1102 cm-1; IH NMR (400 MHz, CDC13) 8 6.29 (lHTdd. J = 5.7, 0.9 Hz), 6.14 (LH, d, J = 5.8 Hz), 4.76 (lH, d, J =
1.4 Hz), 3.54 (IH,dd, J = 8.8, 4.8 HZ),3.40-3.24 (3H, m), 3.33 (3H, s), 3.28 (3H, s), 3.16
(2H, t, J = 7.0 Hz), 2.00- 1.70 (6H,m), 1.57-1.49 (2H, m); 13C NMR ( 100 MHz, CDC13) 6
137.7, 135.8, 90.5, 80.0, 72.1, 70.6, 58.8, 58.6, 42.3, 41.6, 34.0, 28.6, 26-6, 6.7; KRMS calcd for C 1 a23103 m+366.0692, found 366.0704.
KH, Bu3SnCH21 THF
A solution of the alcohol 350 (700 mg, 3.27 mrnol) in THF (10 mL) was added dropwise to a suspension of KH (449 mg, 35% in oil, 3.92 rnrnol) (washed 3 times with pentane) in THF (30 mL) at O OCand the mixture was stirred for 2 h at rt. After the dropwise addition a solution of Bu3SnCH2I (1.41 g, 3.27 mol) in THF (10 mL) at O OC, the mixture was srirred for an additional 12 h at rt. The reaction was quenched with few drops of i-PrOH and the solution was diluted with water and extracted (3x) with Et20. The combined organic Iayers were dned (MgS04), filtered and concentrated. Purification by fi ash chromatography (hexanes-EtOAc 9:l) gave 351 (1.27 g, 75%) as a colorless oil: Rf= 0.20 on silica gel
(hexanes-EtOAc 9: 1); IR (neat) 3072, 2966, 2924, 2868, 1464, 1379, 1 194, 1102 cm-'; lH
NMR (400 MHz, CDC13) 6 6.30 ( lH, dd, J = 5.7, 1.7 Hz), 6.26 ( 1H, d, J = 5.5 Hz), 4.80 (IH,d, J = 1.5 Hz), 3.89 (1H.d, J = 10.7 Hz), 3.79 (lH, d, J = 9.5 Hz), 3.78 (LH, d, J = 10.6 Hz), 3.58 (IH, d, J = 8.4 Hz), 3.57 (1H. d, J = 10.6 Hz), 3.46-3.31 (3H,m), 3.34 (3H, s), 3.29 (3H, s), 2.02- 1.93 (2H, m), 1.59-1.39 (6H,m), 1.28 (6H, sextet, J = 7.3 Hz), 0.97- 252
0.80 (15H,m); '3~NMR (100 MHz, CDCl3) 6 137.2, 135.2, 89.6, 80.5, 73.3, 72.1, 70.5, 63.4, 58.8, 58.5, 42.0, 41.0, 29.1, 27.4, 13.7, 9.1. Anal. Calcd for C24H4604Sn: C,55.72; H, 8.96. Found: C, 55.98; H, 8.84.
exo,exo-4-(5,6-Bis-methoxymethyl-7-oxa-bicyclo[2.2.l]hept-2-en-l-yl)- butyronitrile (352).
Sodium cyanide (2 1 mg, 0.43 mmol) was added in HMPA (1.O mL). After rnost of it had dissolved, a solution of the iodo compound 348 (100 mg, 0.28 mol) in KMPA (0.5 mL) was added and the mixture was stirred for 2 h at rt. The reaction mixture was diluted with water ruid extracted with Et20 (3x). The combined organic layers were washed with water
(3x), dried over MgS04, filtered and concentrated. Flash chromatography purification (hexanes-EtOAc 3: 1) yielded the product 352 (62 mg, 87%) as a colorless oit: Rf= 0.16 on silica gel (hexanes-EtOAc 3: 1); IR (neat) 3079, 293 1, 2896, 2875, 28 12, 2242, 1455, 1384, 1195, 1103 cm-'; 'H NMR (400 MHz, CDCl3) 6 6.3 1 (lH, dd, J = 5.7, 0.9 Hz), 6.1 1 (LH, d,
J = 5.8 Hz), 4.75 (lH, d, J = 1.4 Hz), 3.53 (IH, dd, J = 8.8, 4.8 Hz), 3.36 (SH,d, J = 6.6 Hz), 3.33 (3H, s), 3.29 (3H, s), 3.26 (lH, dd, J= 10.1, 9.0 Hz), 2.48-2.33 (2H, m), 2.09- 1.95 (2H, m), 1.90-1.76 (4H, m); 13C NMR (100 MHz, CDC13) 6 137.1, 136.4, 119.7, 90.3,
80.1, 72.0, 70.4, 58.9, 58.6, 42.2, 41.8, 28.5, 21.8, 17.5. Anal. Calcd for C14H21N03: C, 66.9 1; H, 8.42; N, 5.57. Found: C, 66.97; H, 8.48; N, 5.5 1. isobenzofuran-3a-ol (353) and (3aS*,4S*,7aR*)-4-rnethoxymethyl-S- methylene-l,4,5,7a-tetrahydro-isobenzofuran-3a-ol (354).
A solution of oxabicyclic compound 351 (200 mg, 0.39 mmol) in Et20 (5 rnL) was cooled to -78 OC and stirred while MeLi (0.83 mL, 1.4 M sohtion in Et20, 1.16 rnrnoi) was acided dropwise. Afier 5 min, the reaction was warmed to O OC and stirred for an additionai 30 min. The reaction was quenched by the addition of a saturated WC1solution. The aqueous layer was extracted (3x) with Et20. The combined organic Iayers were drïed (M~SOJ),filtered and concentrated. Purification by flash chromatography on silica gel (hexanes-EtOAc 1:2) gave 353 (71 mg, 80%) as a colorless oil: Rf = 0.16 on silica gel (hexanes-EtOAc 1:2); IR (neat)
34 16,3023,293 1,2875,28 12, 1462, 1202, 11 10, 1040 cm-'; 1H NMR (400 MHz, CDC13) 6 5.76 (IH, dt, J = 9.9, 1.9 Hz), 5.69 (lH, dt, J = 10.2, 2.9 Hz), 4.48 (lH, d, J = 2.5 Hz), 3.98 (lH, dd, J = 7.7, 6.6 Hz), 3.82 (lH, d, J = 8.4 Hz), 3.70-3.63 (2H, m), 3.55-3.45 (4H, m), 3.37 (3H, s), 3.33 (3H, s), 2.76-2.70 (lH, m), 2.57-2.51 (lH, m), 2.48-2.42 (lH, dt, J = 8.4, 6.6 Hz); 13C NMR (100 MHz, CDC13) 6 13 1.2, 123.8, 76.2, 75.0, 71.9, 71.3, 67.9, 58.9, 58.8, 47.9, 44.0, 38.2. Anal. Caicd for C12H2004: C, 63.14; H, 8.83. Found: C, 63.15; H, 8.85. Diene 354: IH NMR (400 MHz, CDCI3) 6 6.30 (LH, dd, J = 9.5, 3.3 HZ),
5.70 (IH, d, J = 9.5 Hz), 5.22 (lH, dd, J = 1.9, 0.8 Hz), 5.12 (lH, d, J = 0.8 Hz), 4.05 (lH, dd, J = 8.1, 7.0 Hz), 3.96 (lH, d, J = 9.5 Hz), 3.75 (LH,dd, J = 9.6, 1.5 Hz), 3.73- 3.65 (3H,m), 3.35 (3H, s), 2.86-2.78 (lH, m), 2.77-2.74 (lH, m), 2.15 (lH, d, J = 1.8
Hz); 13C NMR (100 MHz, CDC13) 6 141.5, 133.4, 123.4, 116.3, 78.3, 76.0, 71.3, 67.7, 59.0, 48.2, 46.2. 254 General Procedure for the Alkyliodide Cyclization.
A solution of oxabicyclic compound 348 (100 mg, 0.28 rnmol) in pentane-Et20 3:2 (5 mL) was cooled to -78 OC and treated with a solution of t-BuLi (367 yL, 1.7 M solution in pentane, 0.62 mrnol). The reaction was shed 5 min at -78 OC then the reaction was aiiowed to warm at O OC for 15 min. The reaction was quenched by the addition of a saturated mC1 solution and the aqueous layer was extracted (3x) with Et20. The combined organic layers were dried (MgS04), filtered and concentrated. Purification of the residue by flash chrornarography on silica gel (hexanes-EtOAc 3: 1) gave the cyclized product 355 (53 mg, 83%) as a colorless oil: Rf= 0.35 on silica gel (hexanes-EtOAc 3A); LR (neat) 3445, 3016,
2966, 2927, 2895, 287 1, 2835, 28 11, 1461, 1449, 1 110, 1037 cm-'; IH NMR (400 MHz, CDC13) 6 5.77 (LH,dt, J = 10.3, 1.8 HZ), 5.60 (lH, dt, J = 10.2, 3.1 Hz), 4.23 (lH, d, J =
2.9 Hz), 3.67 (lH, dd, J = 9.6, 4.8 Hz), 3.56-3.51 (ZH,m), 3.46 (lH, dd, J = 9.5, 2.9 Hz), 3.35 (3H,s), 3.33 (3H, s), 2.70-2.64 (lH, m), 2.34 (IH, ddd, J = 10.6, 8.4, 4.4 Hz), 2.14-
2.09 (1H,m), 1.91-1.81 (1H. rn), 1.75-1.55 (4H. m), 1.46-1.38 (lH, m); [3~NMR (100 MHz, CDC13) 6 129.5, 128.7, 75.7, 72.0, 71.8, 58.8, 58.6, 48.2, 46.1, 38.3, 35.3, 25.5, 2 1.4. Anal. Calcd for C13H2203: C, 68.90; H, 9.80. Found: C,68.53; H, 9.63. 255 The reaction was carried out as in the general procedure using 347 (100 mg, 0.30 mmol), t-BuLi (383 PL, 1.7 M solution in pentane, 0.65 mmol), in pentane-Et20 3:2 (5 mL) for 15 min at -78 OC and 2 h at rt. Purification by flash chromatography (hexanes-EtOAc 3: 1) gave 362 (37 mg, 62%) as a colorless oil: Rf = 0.22 on silica gel (hexanes-EtOAc 3:l); IR (neat) 34 10,3073,2907, 1644, 146 1. 1 193, 1 107, 1054 cm-';1H NMR (400 MHz, CDCl3) 6
5.72, (lH, dd, J = 9.9,4.7 Hz), 5.10 (lH, d, J = 9.5 Hz), 4.07-4.02 (lH, m), 3.90 (lH, d, J = 10.6 Hz), 3.70 (lH, dd, J = 9.7, 6.4 Hz), 3.56 (lH, dd, J = 9.2, 9.2 Hz), 3.50 (lH, dd, J = 10.3, 2.9 Hz), 3.37 (lH, dd, J = 10.3, 3.7 HZ), 3.34 (3H, s), 3.32 (3H. s), 2.46-2.40 (lH, m), 1.34-1.31 (lH, m), 0.82 (lH, ddd, J = 10.0, 5.4, 4.5 Hz), 0.66-0.51 (3H. m); 13C NMR (100 MHz, CDC13) 6 136.7, 127.1, 72.2, 72.0, 63.8, 59.1, 58.9, 41.2. 40.8. 21.8. 16.1, 12.3; HRMS cdcd for C i2H2003 [M - H]+ 2 1 1.1334, found 2 11.1324.
(1R*,3aS*,4S*,5R*,7aR*)-3a-Hydroxy-4,5-bis-methoxymethyl-2,3,3a, 4,5,7a-hexahyro-1H-indene-1-carbonitrile(369) and (lR*,3aS*,4S*,SR*)-3a- Hydroxy-4-methoxymethyl-5-methylene-2,3,3a,4,5,7a-hexahyro-1H-indene-l- carbonitrile (370).
A solution of 352 (80 mg, 0.32 mol) in Et20 (10 mL) at -78 OC was treated with a
KHMDS solution (3.2 mL, 0.5 M in toluene, 1.59 mmol). The mixture was stirred for 2 h at -78 OC and 30 min at rt. The reaction was quenched by the addition of a sanirated solution of NH4Cl and exvacted (3x) with Et2O. The combined organic layers were dried over MgSQ, filtered and concentrated. Purification by flash chrornatography (hexanes-EtOAc 1: 1) gave 369 (27 mg, 33%) as a colorless oil: Rf= 0.34 on silica gel (hexanesethyl acetate 2: 1); IR (neat) 3403, 3021. 2910,2237, 1457, 11 10 cd;1H NMR (400 MHz, CDC13) 6 5.89 (IH, bd, J =
10.1 Hz), 5.79 (lH, dt, J = 10.3, 3.1Hz), 4.56 (lH, d, J = 2.9 Hz), 3.62 (lH, dd, J = 9.5. 256 5.1 Hz), 3.54 (lH, d, J = 9.5 Hz), 3.53 (1H,d, I = 9.9 Hz), 3.52-3.44 (IH, m), 3.36 (3H, s), 3.34 (3H,s), 3.07 (LH, dt, J = 9.0, 4.0 HZ),2.73-2.68 (1H. rn), 2.40-2.21 (4H, m), 1.98-1.93 (lH, m), 1.47-1.38 (IH, rn); 13C NMR (100 MHz, CDC13) 6 132.3. 124.5, 122.6,
76.0, 71.5, 71.2, 58.8, 58.7, 49.8, 45.1, 38.1, 35.2, 28.1, 27.7; HRMS calcd for C 14H21N03[Ml+ 25 1.1521, found 25 1.1530. Diene 370: Rf = 0.34 on silica gel (hexanes-
EtOAc 2: 1); 1i-I NMR (400 MHz, CDCI3) 6 6.32 (1H.dd. J = 9.9, 3.0 Hz), 5.80 (1H, d, J =
9.6 Hz), 5.25 (1H. dd. J = 1.9, 0.8 Hz), 5.19 (IH, d, J = 1.1 Hz), 3.87 (LH,dd, 5 = 9.9, 3.7 Hz), 3.76 (1H. dd, J = 9.9, 4.4 Hz), 3.37 (3H. s), 2.89 (LH.ddd, J = 12.6. 10.0. 7.6 Hz), 2.71 (IH, s), 2.68 (lH, bd, J = 12.8 Hz), 2.57 (lHTm), 2.48-2.38 (1H.in), 2.16-2.05 (lH, m), 1.98 (IH,ddd, J= 12.6, 9.4, 2.6 Hz), 1.86-1.78 (lH, m); I3cNMR (100 MHz, CDC13) 6 141.3, 133.3, 124.0, 122.7, 116.0, 79.6, 71.4, 59.2, 53.0, 47.5, 34.8, 28.5, 27.4. 257 5 W.4 References and Notes
(1) (a) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC Press: London, 1994. (b) Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron 1990.46, 1385. (2) For a review on intramolecular SN' cyclizations, see: Paquette, L. A.; Stirling, C. I. M. Tetrahedron 1992,48,7383. (3) (a) Hill, A. E.; Richey, H. G. Jr.; Rees, T. C. J. Org. Chem. 1963,28, 2161. (b)Richey. H. G. Jr.; Rees, T. C. Tetrahedron Lett. 1966, 7,4297. (c) Kossa, W. C.; Rees, T. C.;
Richey, H. G. Jr. Tetrahedron Lett. 1971, 12, 3455. (d) Veale, H. S.; Richey, H. G. Jr. Tetrahedron Lett. 1975,16, 615. (e) Hill, E. A. J. Organomet. Chem. 1975. 91. 123.
(4) (a) Hata, G.; Miyake. A. J. Org. Chem. 1963,28, 3237. (b)Chum, P. W.; Wilson, S. E. Tetrahedron Lett. 1976,16, 1 257. (5) Drozd, II. N.; Ustynyuk, Y. A.; Tseleva, H. A.; Dimitrier, L. B. J. Gen. Chem. USSR 1969,39, 195 1. (6) (a) Saint Denis, I.; Oliver, I. P.; Smart, 1. B. J. Organomet. Chem. 1972, 44, C32. (b) Saint Denis, J.; Dolzine, T.; Oliver, f. P. J. Am. Chem. Soc. 1972, 94, 8260. (c) Dolzine, D. W.; Hortland, A. K.; Oliver, J. P. J. Organomet. Chem. 1974, 65, C 1. (d)
Albright, M. 3.; Saint Denis, J.; Oliver, J. P. J. Organomet. Chem. 1977, 125, 1. (7) Dolzine, T. W.;Oliver, J. P. J. Organomet. Chem. 1974. 78, 165.
(8) Bailey, W. F.; Nurmi, T. T.; Pauicia, J. J.; Wang, W. J. Am. Chem. Soc. 1987, 109,
2442.
(9) (a) Bailey, W. F.; Rossi, K. J. Am. Chem. Soc. 1989, 111, 765. (b) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990,55, 5404. (c) Bailey, W. F.: Khanoikar, A. D. J. Org. Chem. 1990,55, 6058. (d) Bailey, W. F.; Khanolkar. A. D. Tetrahedron Lett.
1990, 31, 5993. (e) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 5720. (f) Bailey, W. F.; Jiang, X.-L.; McLeod, C. E. J. Org. Chem. 1995.60, 7791. 258 (10) (a) Bailey, W. F.; Patricia, J. J.; Nurmi, T. T.; Wang, W. Tetrahedron Lett. 1986,27,
186 1. (b) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V.J. Am. Chem. Soc. 1992,
(1 1) (a) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989,111, 298 1. (b) Broka, C. A,; Lee, W.J.; Shen, T. J. Org. Chem. 1988.53, 1336. (12) Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1995,117, 1954.
(13) (a) Hoyer, S.; Laszlo, P.; Orlovic, M.; Polla, E. Synthesis 1985, 655. (b) Milbert, A. N.; Wiley, R. A. J. Med. Chern. 1978,21,245. (14) (a) Gschwend, H.; Rodriguez, H. R. Org. React. 1979.26, 1. (b) Jones, T. K.; Highet, R. J.; Don, A. W.;Blum,M. S.J. Org. Chem. 1986,51, 2712.
(15) Cowie, I. S.; Landor, P. D.; Landor, S. R. J. Chem. Soc. Perkin Trans, 1 1973, 720.
(16) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994,116, 1054. (17) (a) Vedejs, E.; Arnost, M. J.; Hagen, J. P. J. Org. Chem. 1979,44, 3230. (b)Snider, B. B.; Lu, Q. J. Org. Chem. 1996, 61, 2839. (c) Okawara, T.; Ikeda, N.; Yamazaki, T.; Furukawa, M. Chem. Pham. Bull. 1988,36, 3628. (18) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987,28, 767.
(19) (a) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927. (b) Still, W. C.; McDonaid III, J. H.; Collum, D. B.; Mitra, A. Tetrahedron Lett. 1979, 593. (c) Seyferth, D.; Andrews, S. B. J. Organomet. Chem. 1971,30, 151. (d) Still, W. C. J. Am. Chem.
Soc. 1978,100, 148 1. (20) Shaw, J. E.; Hsia, D. Y.; Parries, G. S.; Sawyer, T. K. J. Org. Chem. 1978,43, 1017. (21) (a) Bailey, W. F.; Tao, Y. Tetrahedron Lett. 1997,38, 6157. (b) Fischer, P. M.;
Howden, M. E. H. J. Chem. Soc. Perkin Trans. 1 1987, 475. (22) Funk, R. L,; Bolton, G. L.; Brummond, K. M.; Ellestad, K. E.; Stallman, J. B. J. Am.
Chem. Soc. 1993,115, 7023. (23) (a) Lorthiois, E.; Marek, L; Norrnant, I.-F. Tetrahedron Lett. 1997,38, 89. (b)Karoyan, P.; Chassaing, G. Tetrahedron Leît. 1997,38, 85. (24) Martin, M.; Clardy, J. Pure & Appl. Chem. 1982,54, 19 15. 259 (25) Padwa, A.; Sandanayaka, V. P.; Curtis, E. A. 1. Am. Chem. Soc. 1994,116, 2667. APPENDIX 1
SELECTED SPECTRA OF REPRESENTATIVE COMPOUNDS SELECTED SPECTRA FROM CHAPTER 1
SELECTED SPECTRA FROM CHAPTER 2
/ OTBDMS rV".i""~"-.i. --~I--~I----~.--.~IIII~~..-,--..~..~.~~.~-~~-..~....~.-~-~-. 14D 1- le@ II0 1.0 rn m. II OI U U -a LI 18 Ic.
/= OTBDMS
TBDMSO, HO = OH t-~uwm~u
- \ 'OTBDMS 176
SELECTED SPECTRA FROM CEtAPTER 3
SELECTED SPECTRA FROM CHAPTER 4
X-RAY CRYSTAL DATA FOR COMPOUND 107, 109, 131, 169, and 181 SINGLE CRYSTAL X-RAY DETERMINATION OF 107
Table 1. Crpstal data and structure mfinamant for 1.
Identification code
Exupirical fomula
Formula weight
Temperature
Wavelength
Cryetal syetem Monoclinic space group
Unit ce11 dimensions
- Volume
Density (calculated) 1.498 ng/rn3
Absorption coefficient 0.221 mm1
F(000) 840
Csystal size 0.35 x 0.15 x 0-40 mm
8 range for data collection 3.06 to 30.00~
Index ranges -21 Sh 421, -18 4k 50, O 5 Q S12
Reflections collected 5495
Independent reflections 5183 (Rint = 0.0343) 2 Refinement method Full-matrix least-squares on F
Data / restraints / parameters 5183 / O / 334 2 Goodness-of-fit on F 0-872
Final R indices [I>2a(I)] R1 = 0.0500, wR2 = 0.1075
R indices (al1 data) R1 = 0.0965, wR2 = 0.1203
Extinction coefficient O.OOOS(6)
Largest diff. peak and hole 0.327 and -0.499 4 Table 2. Atomic coordinates [ x 10 ] and equivalent isotropic 3 displacement parameters [A~x 10 1 for 1. O(eq) is defined an one thirà of the trace of the orthoiponrlired uij eemsor. Table 3. aond lemgths [Al and angles [O] for 1. Symmetry transformations used to generate equivalent atoms: -2 3 Table 4. Anisotropic displacement parameters [A x 10 ] for 1. The anisotropic displacement factor exponent takes the form: 2 * 2 * * -2n [ (ha ) Ull + .. . + 2hka b UIZ ] Tabla 5. Hydrogen coordinates < x 10~) and iaotropic 2 3 displacement parameters (A :. 10 ) for 1. SINGLE CRYSTAL X-RAY DETERMINATION OF 109
/C02Me COMe
Table 1. Crpstal data aad sttucturm refinemant for 1-
Identif kation code
Enpirical formula
Formula weight Temperature
Wavelength 0-71073 A
Crystal eystem Monoclinic Space group
Unit ce11 dimensions
- Volume z
Density (calculated)
Absorption coefficient
P(000)
Cryetal size
8 range for data collection
Index ranges
Reflections collected
Independent reflectians 4256 (Rint = 0.0194) 2 Refinement method Full-matrix least-squares on F
Data / restraints / parameters Goodness-of -f it on F 2
Final R indices [I>2a(1) 1
R indices (al1 data)
Extinction coefficient
Largest di£ f . peak and hole 0.231 and -0.171 eÀ-' 4 Table 2. Atotic coordinates [ x 10 ] and quivalent isotropie 3 displacement parameters [À~r 10 1 for 1. U(aq) is defimed as one thirâ of the trace of the orthogonalized Uij tensor. 3 15 Table 3. Bond lenqths [Àl and angles [O] for 1.
Symcnetry transformations used to generate equivalent atoms: 3 Table 4. Lnisotmpic displacement paramatris [À~x 10 1 for 1.
The anisotxopic displacement- factor exponent takes the form: 2 * 2 * X -2r [ (ha ) Ull + ... + 2hka b U12 ] Table 5. Hydrogen coordinatas ( t 104) and isotmpic 2 3 displacement par~eters(A x 10 ) for 1. SINGLE CRYSTAL X-RAY DETERMINATION OF 131
May 22, 1996
Empirical Formula H H N05S '21 2 23 Color; Habit colorlesa, plate
Crystal Size (cm)
Crystal System
Space Group
Unit Ce11 Dimensions
Volume z
Formula Weight
Density(ca1c.)
Absorption Coefficient
F(000) Data Collection
Diffractometer Used Siemens P4
Radiation Mo& (X = 0.71073 À)
Temperature (K)
Manochromator Highly oriented graphite crystal
28 Range
Scan Type
Scan Speed Variable; 4.00 to 45.00~/rnin. in w
Scan Range (w)
Background Measurement Stationary crystal and stationary - counter at beginning and end of scan, each for 25.0% of total scan the
Standard Ref lections 3 every 97 ref lections
Index Ranges
Reflections Collected
Independent Reflections
Observed Reflections
Absorption Correction System Used Siemens SHELXTL PLUS (PC Version)
Solution Direct Methods
Refinement Method Full-Matrix Least-Squares
Quantity Minimized
Absolute Structure
Extinction Correction x = -00025 ( 6 ) , where 2 F* = F [ 1 + 0.002~F /sin(2B) ] -1/4
Hydrogen Atoms Riding model, fixed isotropie U 2 2 Weighting- Scheme w-l = cr (F) CO.0002F Number of Parameters Refined
Final R Indices (obs. data)
R Indices (al1 data)
Goodness-of-Fit
Largest and Mean A/a
Data-to-Parameter Ratio
Largest Difference Peak
Largest Difference Hole Table 1. Atomic coordinates and equivalent isotropic displacement coefficients U(es) 0.022 (1) 0.020(1) 0.041(1) O.O22(l) 0.036(1) 0-029(1) 0.017(1) 0.019(1) 0.013(1) 0.016 (1) O.OSl(1) 0.025(1) 0.020(1) 0.016(1) 0.020(1) 0.027 (1) 0.023(1) 0.025(1) O-037(2) 0.022(1) 0.017 (1) 0.022 (1) 0.029(1) 0.036(2) 0.030(1) 0.030(1) 0.027(1) 0.047(2) 0.02s (O) O-019(1) 0,039(1) 0.026(1) 0,044(1) 0.036(1) O-019(1) 0.018(1) 0.015(1) 0.017(1) 0.021(1) 0.022(1) 0.018(1) 0.016(1) 0.019(1) 0.024(1) 0.023(1) 0,026(1) 0.031(1) 0.022(1) 0.021(1) 0.020(1) 0.031(1) 0,039 (2) 0.036 (2) 0.@30(1) * Equivalent isotropic U defined as one third of the trace of the orthogonalized rJ tensor ij Table 2. Bond lengths (À) Table 3. Bond angles (O) -2 Table 4- Anisotropic displacement coefficients (A )
%3 O. 001 (1) -0.001 (1) -0,003(2) 0,000(1) 0,003(1) -0.002(1) 0,001(1) -O*OOi(Z) 0*000(1) 0,001(2) -0.009(2) -0. Oll(2) 0,000(2) 0*000(2) -0,000 (2) -0-007(2) -0,008(2) -0, O04 (2; 0,007(2) -0,007(2) -0,001(2) 0,003(2) 0.004(2) 0-007(2) -0,006(2) -0,006(2) 0.003(2) -0 020 (3) -0.007 (O) -0.001(1) 0.014(2) O-OOl(1) -0.005 (2) -0.013 (2) 0.000(1) -0.001(2) -0.000(2) -0.004(2) -0.009(2) -0.007 (2) -0.001(2) 01001(2) -0.002(2) -0,007 (2) -0,oos (2) -0.004(2) O.OOS(2) O.OOl(2) -0.001(2) -0,002(2) 0,010(2) 0,009(2) -0.013 (3) -0-Oll(2) O.OOl(2) The anisotropie displacement exponent takes the form:
SINGLE CRYSTAL X-RAY DETERMINATION OF 169
/ OTBDMS
Table 1. Crpstal data and structure refinement for 1.
Identification code
Empirical formula
Formula weight
Temperature
Wavelengt h crystal system Monoclinic
Space group
Unit ce11 dimensions alpha = 90° beta = 11~.49(3)~ gamma = 90°
Volume, z
Density (calculated)
Absorption coefficient f (000)
Crystal size 0.21 x 0.22 x 0.23 mm
8 range for data collection 1.74 to 24.40~
Limiting indices -42 5h 443, -16 Sk 516, -31 51 S30
Reflections collected 28308
Independent reflections 9859 (Rint = 0.0639) 2 Refinement method Full-matrix least-squares on F
Data / restraints / parameters 9859 / O / 468 2 Goodness-of-fit on F 0.964
Final R indices [I>2u(I)] R1 = 0.0533, wRî = 0-1450
R indices (al1 data) R1 = 0.105Zr wR2 = 0-1599
Extinction coefficient 0.00013(9)
Largest diff. peak and hole 0.423 and -0.651 d3 4 Table 2. Atomic coordinates [ JC 10 and equivalent isotropie -2 3 displacement parameters [A x 10 J for 1. U(eq) is defined as one thirà of the trace of the orthogonalized U tensor, ij
335 Table 3. Bond lemgth. [A) and angles [O1 for 1.
Symmetry transformations used to generate equivalent atoms: -2 3 Table 4. Anisotropic displacument parameters [A x 10 ) for 1. The anisotropic displacement factor exponent takes the form: 2 * 2 * * -2n ( (ha ) UI1 + ... + 2hka b U12 1
Ull U2 2 U33 U23 U13 U12
Tabla 5. Hpdrogan coordinates < x 104> and isotropie 2 3 displacement par~leters(A x 10 ) for 1. SINGLE CRYSTAL X-RAY DETERMINATION OF 181
MeO, HO = OMe
Table 1. Crpstal data and structure refinement for 1.
Identification code
Empirical formula
Fornula weight
Temperature
Wavelength
Crystal syetem
Space group
Unit ce11 dimensions alpha = 90.00(1)~ beta = 79.73(lI0 O - gamma = 67.34(1)
Volume, 2
Density (calculated)
Absorption coefficient
F(000)
Crystal size 0.21 x 0.22 x 0.18 mm
8 range for data collection 2 -55 ta.30.02~
Limiting indices -10 Sh 4 10, -11 5 k 5 11, -22 5; 1 s22
Reflections collected 7732
Independent reflections 3958 (Rint = 0.0321) 2 Refinement method Full-matrix least-squares on F
Data / restraints / parameters 3958 / O / 217
Goodness-of-fit on F 2 0.859
Final R indices [ I>2u( 1 ) 1 RI = 0,0474, wR2 = 0.1088
R indices (al1 data) R1 = 0.1047, wR2 = 0.1234
Extinction coefficient O. 018 (4)
Largest diff. peak and hole 'o.ist ana -0.177 sr3 4 Table 2. Atopiic coordinates [ x 10 ] and equivalent isotropic 2 3 displacement parameters [A r 10 1 for 1. U(q) is definsd as one third of the trace of the orthogonalized Ciij tensor. 345
Table 3. Bond lsngths [A] and angles [O] for 1.
Symmetry transformations used to generate equivalent atoms: -2 3 Table 4. Anisotropic displacement parameters [A x 10 ] for 1. The anisotropic displacement factor exponent takes the form: 2 * 2 * X -2~[ (ha ) Ull + ... + 2hka b U12 1 Table 5. Hpdrogen coordinates ( x 104) and isotropie -2 3 displacement parameters (A x 10 ) for 1. lMAGE EVALUATION TEST TARGET (QA-3)
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