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Further investigations on the use of camphor in terpenoid synthesis Clase, Juha Andrew 1990

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c - 2 FURTHER INVESTIGATIONS ON THE USE OF CAMPHOR IN TERPENOID SYNTHESIS By JUHA ANDREW CLASE B.Sc, Memorial University of Newfoundland, 1985 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September 1990 © J. Andrew Clase, 1990 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada Date t&r *0 f ^ O DE-6 (2/88) THIS THESIS IS DEDICATED TO THE M E M O R Y OF FELIX C H A U i i ABSTRACT The cyclopentyl compounds 113,114, and 115 and their enantiomers ent-113, ent-114 and ent-115 represent valuable chiral building blocks for the synthesis of steroids and triterpenoids. These compounds are readily available in chiral form from the Grob type cleavage of (+)-9,10-dibromocamphor (120) or (-)-9,10-dibromocamphor (ent-120) respectively. The hydroxyacid 114 was transformed into the bicyclic ester 153 in a series of seven steps, the key step of which was the mtramolecular Friedel-Crafts acylation of the methylene diacid 161. The ester 153 is considered to be a valuable steroidal CD synthon, incorporating functionality for introduction of both the A and B rings and a C(20) sidechain. It was demonstrated that it was possible to alkylate the ketal 169 stereospecifically and convert the product to the enone 168 in which the steroidal C(20) centre has been established with the natural R configuration. In a second approach to steroidal precursors, the hydroxydiene 299 was prepared in six steps from the bromoester 115. The enantiomer of 299, (ent-299) represents a potentially useful intermediate in the intramolecular Diels-Alder route to A-aromatic steroids such as estrone (3), and would be readily available from ent-115. The bromoester ent-115 and (+)-5,6-dehydrocamphor (223) were combined in a synthesis of the tetracyclic hydroxyenone 252, the key step of which was the anionic oxy-Cope rearrangement of the 5,6-dehydrocamphor derivative 241. The structure 252 is considered to represent the basic tetracyclic skeleton of euphane and apo-euphane triterpenoids, and posesses suitable functionality for incorporation of methyl groups at C(10) and C(8) (apo-euphane) or C(14) (euphane), as well as oxygen substituents at those centres at which it is commonly found in the triterpenoids. Finally, a mechanistic investigation of the rearrangement of 2-methylenebornane (314) to 4-methylisobornyl acetate (315) is described. The methyl region of the  lH NMR spectrum of 4-methylcamphor (308), derived from 314, was unambiguously assigned by a series of NMR i i i experiments and used to trace the fate of deuterium when 2-(dideuteriomethylene)bornane (323) and 8-deuterio-2-methylenebornane (324) were subjected to the rearrangement conditions. Table of Contents Dedication ii Abstract iii Table of Contents • v List of Figures vii List of Tables vii Contents of Appendices viii List of Abbreviations ix Acknowlegement xiii Chapter 1: The Enantiospecific Synthesis of a Steroidal CD Synthon . 1 1.1 Introduction 2 1.1.1 General Introduction 2 1.1.2 Synthetic Approaches to the Tetracyclic Skeleton 5 1.1.3 Previous Approaches to Steroidal CD Synthons 7 1.2 Discussion 26 1.3 Conclusion 49 1.4 Experimental 52 1.4.1 General Experimental 52 1.4.2 Experimental 54 Chapter 2: An Enantiospecific Approach to the Euphane and Apo-Euphane Triterpenoid Skeleton 95 2.1 Introduction 96 2.1.1 General Introduction to the Triterpenoids 96 2.1.2 Previous Laboratory Syntheses of the Triterpenoids 98 2.2 Discussion 105 2.3 Conclusion 122 v 2.4 Experimental 125 Chapter 3: The Synthesis of a Chirai D Ring Synthon for the Intramolecular Diels-Alder Route to Steroids 149 3.1 Introduction 150 3.2 Discussion 157 3.3 Conclusion 161 3.4 Experimental 163 Chapter 4: 2-Methylenebornane to 4-Methylisobornyl Acetate: A Mechanistic Investigation 169 4.1 Introduction 170 4.2 Discussion 174 4.2.1 The Assignment of the  lll NMR Spectrum of 4-Methylcamphor (308) 174 4.2.2 An Investigation of the Rearrangement of 2-Methylenebornane (314) 177 4.3 Conclusion 185 4.4 Experimental 186 References 195 Appendix 1: Selected Spectra from Chapter 1 206 Appendix 2: Selected Spectra from Chapter 2 208 Appendix 3: Selected Spectra from Chapter 3 211 Appendix 4: Selected Spectra from Chapter 4 212 vi List of Figures Figure 1: The Steroidal Numbering Convention 3 Figure 2: Presumed Transition State Configuration for the Ene Reaction of the Aldehyde 130 31 Figure 3: Most Stable Configuration of the Hydrindanols 140 and 141 35 Figure 4: Preferred Mode of Attack of Electrophiles on the Enolate of Ester 170 46 Figure 5: Configuration of the Keto Alcohol 250 118 Figure 6: Transition State Conformation of the o-Qumodimethane Intramolecular Diels-Alder Reaction 153 List of Tables Table 1: lH NMR Signals of the methyl groups of 4-methylcamphor (308) and 9-deuterio-4-(deuteriomethyl)camphor (322) recorded U1.CDCI3 and benzene-d6 Table 2: lU NMR Signals of the methyl groups of 4-methylcamphor (308), 4-(trideuteriomethyl)camphor (334) and 8-deuterio-4-methylcamphor (343) recorded in CDCI3. 174 180 vii Contents of Appendices Appendix 1: Selected Spectra from Chapter 1 la- X-Ray Crystal Structure of the Alcohol 175 206 lb. lH NMR Spectrum of the MTPA Ester 178 207 lc. 1 9 F NMR Spectrum of the MTPA Ester 178 207 Appendix 2: Selected Spectra from Chapter 2 2a. JH NMR Spectrum of the Tetracyclic Diol 251 208 2b. IH NMR Spectrum of the Acetate 252 208 2c. 1 3 C NMR Spectrum and APT Experiment of the Tetracyclic Diol 251 209 2d. X-Ray Crystal Structure of the Acetate 252 210 Appendix 3: Selected Spectra from Chapter 3 3a. IR Spectrum of the hydroxydiene 299 211 3b. *H NMR Spectrum of the hydroxydiene 299 211 Appendix 4: Selected Spectra from Chapter 4 4a. IH NMR Spectrum of 4-Methylcamphor (308) in CDCI3 212 4b. IH NMR Spectrum of 4-Methylcamphor (308) in C6D6 212 4c. IH NMR Spectrum of 9-deuterio-4-(deuteriomethyl)camphor (322) in CDCI3 213 4d. IH NMR Spectrum of 9-deuterio-4-(deuteriomethyl)camphor (322) in C6D6 213 4e. n.O.e. Difference Experiments of 4-Methylcamphor (308) 214 4f. IH NMR Spectrum of 4-(trideuteriomethyl)camphor (334) 215 4g. IH NMR Spectrum of 8-Deuterio-4-methylcamphor (343) 215 viii List of Abbreviations Ac acetyl AC2O acetic anhydride AcO acetate AcOD deuteriated acetic acid AcOH acetic acid AIBN azobis(isobutyronitrile) Anal. micToanalytically determined mass % APT Attached Proton Test ( 1 3 C NMR) aq aqueous solution Bn benzyl bp boiling point n Bu primary butyl l Bu tertiary butyl BU3S11D tributyltin deuteride c concentration (g/100 mL, specific rotation) Calc. calculated mass % Calc. Mass calculated exact mass cat catalytic amount COD cyclooctadiene cone. concentrated d doublet (NMR); days d^B AB doublet, i.e. one branch of an AB quartet (NMR) DIB AL diisobutyl aluminum hydride DIPHOS-4 l,4-bis-(diphenylphosphino)butane DMAP 44imemylannnopyridine ix DMF DMSO E + EE ent-Et Et20 Et3N EtOAc EtOH G C h H 6,2-H He Ht HMPA IR J U L m M+ Me 3,2-Me Meas. Mass MeOH min dimethyl formamide dimethyl sulphoxide electrophile ethoxyethyl enantiomer (of) ethyl diethyl ether methylamine ethyl acetate ethanol gas liquid chromatography hours proton(s) (NMR) 6,2-hydride shift cis proton (NMR) trans proton (NMR) hexamethyl phosphoramide infrared (spectrum) coupling constant (Hz) (NMR) literature reference multiplet (NMR) molecular ion (MS) methyl 3,2-exo-methyl shift exact mass determined by high resolution MS methanol minutes mm millimetres of mercury (distillation pressure) mp melting point Ms methanesulphonate (mesylate) MS mass spectrum MTPA a-riKu^oxy-a-trMuoTorriethylphenylacetyl n- normal (primary) NBD norbornadiene NMR nuclear magnetic resonance (spectrum) n.O.e. nuclear Overhauser effect Nu - nucleophile OTf trifluoromethanesulphonate (triflate) PCC pyridinium chlorochrornate PCy3 tricyclohexylphosphine PPC pyridinium dichromate PE low boiling (30-60) petroleum ether ppm parts per million (NMR) py pyridine q quartet (NMR) qAB AB quartet (NMR) rbf round bottomed flask it room temperature s singlet (NMR) SiC>2 silica gel t triplet (NMR) t- tertiary TBAF tetra-n-butylammonium fluoride TBDMS t-butyl dimethyl silyl xi THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TPAP tetra-n-propylammonium perruthenate Tr triphenylmethyl (trityl) TsOH p-toluenesulphonic acid W-M Wagner-Meerwein rearrangement [a] T specific rotation at 589 nm at T°C 8 chemical shift (ppm) (NMR) D absorption frequency (car1) (IR) x i i Acknowledgement I would like to thank the excellent technical support staff in the Chemistry Department's MS and NMR laboratories, without whom much of this work would have been more difficult. I would also like to thank Dr S. Rettig for performing X-Ray crystallographic analysis and Mr. P. Borda for performing the microanalyses. To all the members of Dr. Money's group over the past five years goes a note of thanks for valuable advice and discussions, not least to Dr. Tom Money himself whose support, encouragement, and advice throughout this project was gratefully received. I would like to thank my friends Jim Peers and Lisa Rosenberg for their help in proofreading this thesis. Finally I would like to acknowledge the financial support of the UBC Chemistry Department, Dr. Tom Money, and the Natural Sciences and Engineering Research Council. x i i i 1 Chapter 1 The Enantiospecific Synthesis of a Steroidal CD Svnthon 2 U Introduction U.1 General Introduction The steroids are a class of naturally occurring tetracyclic alcohols, which are found throughout the plant and animal kingdoms1. One of the most common steroids is cholesterol (1), which is found naturally in most members of the animal kingdom, where it plays an important physiological role2. BiosyntheticaUy, cholesterol is the precursor of a number of other biologically important steroids and steroid derivatives, such as the sex hormones testosterone (2) and estrone (3), the bile acids, such as cholic acid (4), and the calcium-regulating seco-steroid hormone la,25-dihydroxycholecalciferol (dihydroxy Vitamin D3) (5c)2. Obviously these are only five of I 5(a) R1=R2=H (b) R1=OH, R2=H (C) R 1 =R 2= OH 3 the many steroids that are known, however they do serve to illustrate the variety of structural features that are found in this class of compounds. The basic steroidal skeleton consists of seventeen carbon atoms, arranged in four rings and numbered as shown for cholesterol in Figure l 3 ; by convention, the rings are denoted A, B, C, 21/,. ^ 2 2 ^ ^ - 2 4 ^ ^ 2 6 18 » 11 13 „ 9>^ ^ 1 4 ^ { 20 23 25 7 } 19 / ' ^ j ^ V * / 1 1 5 2 „ 10 8 1 3 A j B .  , B . Figure 1: The Steroidal Numbering Convention and D as shown. In addition, most steroids possess methyl substituents at C(10) and C(13), numbered 19 and 18 respectively, and many have sidechains at C(17), numbered from 20 on up. It should be noted that a number of the carbon centres are asymmetric, specifically C(8), C(10), C(13) and C(14), as well as C(17) and C(20) in the case of those steroids with sidechains. In addition, a number of other centres are often chiral, for example C(3), which often has an alcohol substituent, and C(5), in the case of saturated compounds (or ones in which the double bond occupies another position). While the occurrence of asymmetry is not limited to these centres, they are the most common and most important Of particular importance is the presence of four contiguous chiral centres in the case of those steroids with sidechains. While discussing the stereochemistry of the steroids, it should also be noted that the common convention is to denote as a those substituents which are oriented "down" when the structure is represented as shown, and p those substituents which are oriented "up". As an illustration, the 3-hydroxy substituent of cholesterol is said to be (3. 4 The laboratory synthesis of the steroids has long been a subject of interest, and many successful syntheses have been reported. The interest stems from the fact that they present challenging targets and that they and their derivatives are often biologically active. This activity can take a wide variety of forms, depending on the steroid or derivative in question. The role of cholesterol ( 1 ) in lipid metabolism, for example, has been widely publicised, although little medicinal benefit could be gleaned from a synthesis of this compound. Other steroids, however, have considerable medicinal importance, such as estrone (3), a female sex hormone23, derivatives of which are used as oral contraceptives; and dihydroxy Vitamin D3 (5c), a lack of which has been linked to the disease osteoporosis2^4. In addition to these uses, steroids are widely used in other areas such as the agricultural industry, to improve meat and crop production, and in pest control5b. Thus, it is desirable to have a repertoire of syntheses of different steroids, not only so that they themselves can be produced, but also so that a variety of potentially more active derivatives are available. It is unlikely that any one synthesis could take into account all the different modifications that one might wish to incorporate into syntheses of such derivatives. Hence, contributions to this field are valuable, as they represent different approaches to the synthesis, and thus different potential modifications. The challenges associated with the laboratory synthesis of the steroids are two-fold. One must not only achieve the formation of the tetracyclic system, but also control the stereochemistry of up to eight chirai centres, including the four contiguous ones mentioned above. Ideally, one would like to be able to control not only the relative stereochemistry, but also the absolute stereochemistry of these centres, in order to avoid the problems associated with a racemic synthesis and the separation of enantiomers. When considering synthetic approaches to the steroids it is useful to look at them in two parts, i.e. the way in which the tetracyclic system and its associated stereochemistry is constructed 5 and, secondly, the way in which the sidechain and the stereochemistry at C(17) and/or C(20) is introduced. Obviously, the number of possible routes is large, and it is beyond the scope of this thesis to discuss more than a few of them. Thus only a brief description of general approaches and following this, a description of the various ways in which the steroidal sidechains have been introduced will be provided. 1.1.2 Synthetic Approaches to the Tetracyclic Skeleton It is obvious from examination of the steroidal skeleton that it is tailor-made for a variety of synthetic strategies involving multiple annulations. Indeed, most synthetic strategies, with one major exception, are of this type. The lone exception involves routes in which a readily available existing steroid is degraded to provide the basic skeleton, which can then be modified as desired. This approach will not be discussed further. In retrosynthetic terms, one can envision a number of disconnections of the tetracyclic system which lead to useful synthetic possibilities. The three most, common disconnections are shown schematically in equations 1,2 and 3. A fourth alternative is a disconnection of both B and C rings, as shown in equation 4. This latter alternative will be discussed in more detail in another chapter (vide infra, Chapter 3), and not considered further at this time. R R IU 6 Disconnection of the C ring (Equation 1 ) unveils a bicyclic decalin type AB fragment and a seco-CD fragment which can take on a variety of forms. In fact, many early approaches to the steroidal system stemmed from this type of disconnection1. Similarly, disconnection of both A and D rings (Equation 2 ) reveals a second decalin fragment, this time comprising the BC portion of the skeleton. This approach has also been used in a number of successful syntheses of steroids1. The third disconnection, of the B ring (Equation 3), provides a hydrindane, rather than a decalin, system as the bicyclic fragment. In some respects, this is the most attractive of the disconnections, as the CD portion of the steroidal skeleton is the one with the highest concentration of chirai centres. Once these have been established, it is a relatively straightforward matter to introduce the AB portion of the molecule. In addition, synthesis of an appropriate CD fragment leads not only into the steroids themselves, but also conveniently into seco-steroids such as the Vitamins D (eg. 5a-c) and their biological derivatives. This latter approach is the one which we 7 chose to undertake and, prior to a discussion of our efforts in this area, a brief review of some of the contributions made by other workers in this field will be presented. In addition to the basic tetracyclic skeleton, most steroids possess a sidechain attached to C(17), which is usually fJ-oriented. While in some cases this is as simple as an acetyl group, in the majority of cases it is more complicated, often taking the form of a substituted 2-heptyl unit. In these cases the carbon attached to C(17), i.e. C(20), is chiral and usually possesses (R)-stereochemistry. The synthetic problem of the steroid sidechain is two-fold, as one must control the stereochemistry of both C(17) and C(20), as well as the structure of the sidechain itself, which in some cases contains further chiral elements1'2. Since the sidechain is attached to the steroidal D ring, its synthesis and incorporation is not neccessarily divorced from the overall synthesis of the D or CD unit. In many cases the incorporation of the sidechain plays an integral part in the synthesis and/or control of overall stereochemistry of the remainder of the system. In other cases the sidechain is introduced following the synthesis of the C D subunit, which often allows for greater stereochemical control of the C( 17) and/or C(20) centres5. 1.1.3 Previous Approaches to Steroidal C D Svnthons Over the past two decades, a number of workers have taken the "CD synthon" approach to the synthesis of the steroids. The chief considerations in such approaches have been the control of * the relative stereochemistry of the four chiral centres, C(13), C(14), C(17), and C(20) , and the incorporation of suitable functionality in the C ring, at C(8) and/or C(9), to allow attachment of the In this chapter all centres will be numbered according to the steroidal convention (Fig. 1) unless otherwise specified. 8 AB portion of the steroid Because the total synthesis of these systems was, in some respects, a natural expansion of earlier efforts to utilise degraded steroids (the "partial synthetic" approach), many of the original CD synthon targets were themselves steroidal degradation products which had already been converted by other (or the same) workers to steroidal systems. One of the most versatile, and thus synthetically sought-after, of these compounds was the "Inhoffen-Lythgoe Diol" 6, originally obtained from the ozonolytic degradation of a Vitamin D2 (ergocalciferol) (7) derivative6. The pioneering work in this area of synthesis was by Lythgoe and co-workers, who reported the first total synthesis of the diol 6 in 19777. Their route is shown in abbreviated form in Scheme 1. The key features of the approach were a Claisen rearrangement8 of the allyl vinyl ether 10, to establish the stereochemistry at C(13), C(17) and C(20), and a second Claisen rearrangement of the amidic enol ether 12, which established the stereochemistry at C(14). The allyl vinyl ether 10 was obtained in chirai form from the condensation of the known chirai allylic alcohol 8 9 with the chirai cyclic orthoester 9, obtained in five steps from naturally-occurring (R)-methyl hydrogen JJ-methyl-glutarate (15)7a. The diol 6 was subsequently converted to a bicyclic diol 16, representing the CD portion and sidechain of la,25-dihydroxycholecalciferol (Sc)71*. Because of its potential for a high degree of stereoselectivity8, the Claisen rearrangement has proved to be a popular tool throughout organic synthesis. Like Lythgoe, a number of other workers in the steroidal area, including Tsuji10*11, and Kametani12, have chosen to use it to I. 9 Scheme 1 control the relative or absolute stereochemistry of one or more of the chirai centres in their approaches to steroidal CD synthons. In 1981, Tsuji and co-workers reported a racemic synthesis of de-AB-cholestan-9-one (17)10, in which sequential Claisen rearrangements were used to establish the correct relative stereochemistry of C(14) and C(13) (Scheme 2). The relative stereochemistry of C(17) and C(20) was subsequently controlled by a stereoselective hydroboration. In their approach, treatment of the racemic alcohol 19, obtained in three steps from 2-methylcyclopent-2-enone (18), with triethyl orthoacetate provided the enol ether 20, which rearranged in situ to the ester 21. The C(14) stereochemistry was thus defined by the configuration of the tertiary alcohol of 19. A second 10 Claisen rearrangement, of a vinyl ether derived from 21, provided the aldehyde 22, with the desired relative stereochemistry at C(13) and C(14). After closure of the C ring, stereoselective hydroboration of the alkene 23 occurred from the a-face and provided the alcohol 24, establishing the C(17) and C ( 2 0 ) stereochemistry as shown. Finally, nucleophilic S j s i 2 displacement of the tosylate 25 with an appropriate side-chain moiety, and subseqent functional group manipulation, provided the target compound 17. f O A c O . # / ^ . T AcO-i / - - - 1 Scheme 2 In 1985, Tsuji reported an approach to the racemic Vitamin D3 synthetic precursor, de-AB-cholesta-8(14),22-dien-9-one (26)11. Again, Claisen rearrangements were employed to establish the relative stereochemistry of two of the chiral centres, in this case C(17) and C(20) (Scheme 3). The racemic acyclic allylic alcohol 27 was treated with the orthoester 28 and provided, following 11 rearrangement, the diastereomeric esters 29, which were subsequently converted to the lactones 30. Alkylation of the corresponding enolate with methyl iodide provided the diastereomeric lactones 31a,b with the desired isomer predominating (31a:31b = 4.3:1). The major diastereomer was converted in seven steps to the cyclopentanone 32, in which the control of the relative stereochemistry of C(13) and C(17) is apparent A Claisen rearrangement of a vinyl ether derived from 32 provided the aldehyde 33, thus establishing the correct relative stereochemistry at C(20). The aldehyde 33 was then readily converted to the target compound 26 in three steps. Scheme 3 12 Subsequently, Kametani reported a synthesis of the same compound (26)12, this time in chiral form, which also involved the use of Claisen rearrangements to control the absolute TBDMSO 39b 40a 40b Scheme 4 stereochemistry at both C(17) and C(20) (Scheme 4). The absolute stereochemistry was derived from that of the chiral glyceraldehyde derivative 34, which was converted in four steps to the enol ether 35. A Claisen rearrangement provided the diester 36, establishing the future C(17) con-figuration. A Dieckmann condensation followed by demethoxycarbonylation then provided the substituted cyclopentanone 37. The aldehyde 38 was obtained after introduction of the C ring by a Stork-Robinson annulation sequence13 using the steric crowding of the fJ-face to control the C(13) stereochemistry, and subsequent functional group manipulation. It was hoped that 38 would undergo a stereoselective addition of isobutyl magnesium chloride; however the stereoselectivity was not good, and the undesired isomer 39a was formed in preference to the desired isomer 39b, in a 1.3:1 ratio. Conversion of the diastereomeric mixture of alcohols 39a,b 13 to the corresponding vinyl ethers, followed by a Claisen rearrangement, provided the separable aldehydes 40a and 40b. Decarbonylation of the minor diastereomer then provided the target compound 26. One of the most active groups in this area is that of the Hoffmann-LaRoche Company, who have reported numerous syntheses of loc,25-dihydroxy-Vitamin D3 (5c)14, its metabolites15, and analogues16. Much of this work stems from the discovery of a convenient, efficient, and enantiospecific route to the bicyclic keto enone 4117 (Scheme 5). The key feature of the synthesis was the use of the chirai amino acid (S)-(-)-proline (44) to asymmetrically catalyse the cyclysation of the intermediate triketone 45 in 95% optical purity. The resemblance of this system to the steroidal CD unit is obvious, and it is hardly surprising that 41 has proved to be a useful starting material in approaches to CD synthons. The general approach of the Hoffmann-LaRoche group can be illustrated by a synthesis of the Inhoffen-Lythgoe diol (6) 1 5 d» 1 8 (Scheme 6). The keto acid 47, derived from the enone 4119, was hydrogenated to provide the keto acid 48, with the correct absolute stereochemistry at C(14). The keto acid 48 was then converted in an eight-step sequence to the keto alcohol 49, Wittig 46 41 Scheme 5 14 olefination of which provided the alkene 50. An intermolecular ene reaction (cf. ref. 5), followed by a stereoselective hydrogenation then provided the target diol 6. 6 50 Scheme 6 F Scheme 7 15 Recently, a modified version of this approach was used in a synthesis of lo^ 25-dihydroxy-24(/?)-fluorocalciferol (51)16 (Scheme 7). In this case the keto alcohol 49, after protection as a tetrahydropyranyl ether, was converted to the ester 52 by a Wittig-Horner reaction followed by a selective catalytic hydrogenation of the C(17)-C(20) double bond from the a-face, to provide 52 with the correct absolute stereochemistry at C(17). Stereospecific alkylation of the enolate of 52 with the iodide 53 provided the alkylated ester 54, with over 95% of the product having the desired C(20) configuration. Subsequent reduction of the ester to a methyl group provided 55, which was readily converted to the target compound 51. In 1979, both Trost and Grieco published syntheses of chirai CD synthons, employing the high degree of stereoselectivity inherent in the [2.2.1] bicycloheptane system of the chirai hydroxy ketal 5620. Grieco made use of this to synthesise, in optically pure form, (+)-de-AB-cholest-ll-en-9-one (57)21, whereas Trost's approach was to the Inhoffen-Lythgoe diol (6)22. 57 61 60 Scheme 8 In Grieco's synthesis (Scheme 8)21, the methylated ketone 58 was obtained in three steps from 56, the last of which was a stereoselective alkylation with methyl iodide which occurred exclusively from the less-hindered endo-face of the [2.2.1] system. Baeyer-Villiger oxidation of 16 58 and an allylic rearrangement provided the lactone 59. Following incorporation of the sidechain to provide 60, the C(16) p-hydroxyl group was converted to a vinyl ether which underwent a Claisen rearrangement to provide the aldehyde 61, in which C(14) was chiral and possessed the correct absolute stereochemistry. Simple functional group manipulation and an aldol condensation then provided the desired compound 57. THPO t 6 Scheme 9 Trost's synthesis of the Inhoffen-Lythgoe diol (6), followed a very similar plan (Scheme 9) 2 2 . The ketone 62, derived from 56 in six steps, was transformed into the aldehyde 63 in a six-step sequence similar to that used by Grieco to convert 58 to 61, except that the C(20) sidechain was not elaborated. After conversion to the methyl ketone 64, the THP protecting group was replaced with a tosyl group; intramolecular alkylation then provided the bicyclic compound 65, which was readily transformed to the diol 6. Nu Nu Nu i5 [5] 18 17 Another attractive starting material for the syntheses of steroidal CD synthons has been 2-methylcyclopent-2-enone (18). Obviously it represents a D ring subunit, incorporating the C(13) methyl group as well as suitable functionality for addition of the C(17) sidechain and a sidechain at C(13) representing the C ring portion of the synthon. Indeed, one can envision a scheme whereby both these sidechains are introduced in a single operation (Equation 5) in which the nucleophile (Nu) represents the C(17) sidechain and the electrophile (E), the C ring subunit. It would be expected that if Nu were of a reasonable size, addition of the electrophile would take place from the opposite face, resulting in the desired relative stereochemistry of the C(13) and C(17) centres. In addition, an element of chirality in the nucleophile could result in a preferential attack on one of the two diastereomeric faces of the enone, leading to some degree of chiral induction. This latter aspect has not been exploited in the syntheses of steroidal CD synthons to date, although Tsuji has made use of it in syntheses of the C(20)-epi-compound 6623. 66 A variation of the approach discussed above was used by Ziegler in a synthesis of racemic de-AB-8-carbomethoxycholestan-9-one (67) (Scheme 10)2 4. Addition of the anion of the allylic dithiane 68 to 18 occurred in a 1,2 fashion and was followed by an anionic oxy-Cope rearrangement to provide the enolate 69. Formally, this can be considered a 1,4 addition of the allylic position of the anion to 18. Treatment of the enolate in situ with allyl bromide then provided the ketone 70 with the desired relative configurations at C(13), C(17) and C(20). A sequence of seven steps, involving functional group manipulation and elaboration of the C(20) sidechain, provided the keto acid 71, which was then converted to the bicyclic enone 72. 1 8 Introduction of a carboxylic acid group at C(8), stereoselective hydrogenation to provide the trans-hydrindanone and esterification then completed the synthesis of 67. Scheme 11 An asymmetric synthesis of Ziegler*s intermediate keto acid 71 was reported by Kametani in 1984 (Scheme l l ) 2 5 . The chirai starting material was the bicyclic methylene diketone 73, 1 9 derived from one enantiomer of the Hoffmann-LaRoche keto enone, ent-4119. Conjugate addition of isoamyl magnesium bromide to the enone 73 provided the homoprenyl compound 74, in which the sidechain occupied the thermodynamically more stable equatorial position, thus establishing the future C(20) stereochemistry. The dione 74 was converted in two steps to the aldehydo acid 75, which was then transformed to the chiral Ziegler intermediate 71 in a further eleven steps. S02Ph Scheme 12 Kametani later used a very similar approach in the synthesis of the bicyclic sulphone 76, a potential precursor to Vitamin D3 (5a) (Scheme 12) 2 6 . The homoprenylated ketone 74 was converted in four steps to the keto sulphone 77, the C ring of which was cleaved as before to provide the aldehydo acid 78. This was then converted in nine steps to the desired bicyclic sulphone 76. The conjugate addition / enolate trapping approach using 2-methylcyclopent-2-enone (18) has also been investigated by Haynes in an approach to the potential Vitamin D3 precursor 79 (Scheme 13) 2 7 . Addition of the anion of the phosphine oxide 80 to 18, followed by trapping of the intermediate enolate with the pVsulphonyl enone 81, provided the enone 82 as a 97:3 mixture of E and Z double bond isomers. As expected, addition of the enolate to the enone occurred from 2 0 the side opposite the newly-introduced sidechain, establishing the correct relative stereochemistry at C(13) and C(17). The bicyclic fra/w-hydrindanone 83 was prepared in three steps from 82, along with a small amount of the cis isomer 84 (< 5%). After reduction of the ketone, the sidechain was elaborated by condensation of the phosphine oxide moiety with methacrolein, providing the p-hydroxy phosphine oxide 85 as a mixture of diastereomers, epimeric at C(24). The target compound, 79, was obtained after elimination of (hphenylphosphinic aciti, separation of the C(9) epimers, and hydrogenation of the 9-B-hydroxyl diastereomer. O <^ POPh2 80 81 R O 18 82 t Three Steps OH HO T H R T H R POPh2 85 83 R . 84 O. Scheme 13 2 1 Desmaele and co-workers reported a synthesis of the bicyclic ester 86, the key feature of which was the establishment of the relative C(17) and C(20) stereochemistry by the thermodynamic equilibration and hydrolysis of the enamine 88, which was formed by a 2+2 cycloaddition of the acetylenic amine 87 to 2-methylcyclopent-2-enone (18) (Scheme 14) 2 8. Treatment of 88 with 5% aqueous formic acid provided only the desired acid 89 via thermodynamic equilibration of an intermediate iminium ion. Chemical resolution of the enantiomeric acids 89 obtained in this hydrolysis enabled the synthesis of 86 to be carried out on enantiomerically pure material. The C(21) carboxylic acid group of the resolved acid 89 was converted in a six-step sequence to a methyl group, providing the substituted cyclopentanone 90. The C ring of the target was then introduced by a Stork-Robinson annulation sequence13 analogous to that used by Kametani12 (cf. page 12) and provided the bicyclic enone 72 which had previously been synthesised by Ziegler24. A sequence of six steps then provided 86, which had been previously converted to la-hydroxy Vitamin D3 (5b) by Lythgoe29. C0 2Me 72 90 Scheme 14 Takano and co-workers subsequently reported a synthesis of Desmaele's intermediate cyclopentanone 90 (Scheme 15) 3 0 which, although enantiospecific, involved considerably more 2 2 steps and is probably less efficient overall, even considering that Desmaele had to resort to a resolution step. The main feature of the synthesis was the use of the chirai lactone 92, the bulky trityloxymethyl group of which was used to affect the stereochemical outcome of an equilibration step. The lactone 92, obtained in chirai form from the readily available (5)-(+)-glutamic acid 93 3 1 , underwent an aldol condensation with the ketone 94 to provide the unsaturated lactones 95 as a 3:1 ratio of E and Z isomers. After hydrogenation, the lithium enolates of the saturated lactones 96 were kinetically protonated from the face opposite the trityloxymethyl group, to provide 97a,b with the desired C(17) stereochemistry. The desired C(20) isomer, 97a, was separated, and then converted in a further ten steps to the cyclopentanone 90. Scheme 15 A unique, biomimetic approach was used by Johnson in his synthesis of the Inhoffen-Lythgoe diol (6) (Scheme 16)32. A chiraUy-directed polyene cyclisation was used to construct the bicyclic skeleton, with concomitant control of the C(13) and C(14) absolute stereochemistry. Treatment of the chirai acetal 98 with TiCL; provided the separable bicyclic allenes 99a and 99b in a 1:9 ratio. After removal of the chirai auxilliary of 99b, and protection of the resultant 23 hydroxyl group, partial hydrogenation of the allene 100 provided the Z alkene 101 exclusively. The desired absolute stereochemistry at C(20) and C(17) was then introduced by an intermolecular ene reaction and selective hydrogenation. Finally, hydrolysis of the acetate protecting group provided 6. It was found that the material produced in this synthesis had an optical purity of 92%; recrystallisation provided material of 100% optical purity. 102 103a 103b Scheme 17 24 Recently, Takano32 reported a modified vesion of Johnson's approach (Scheme 17), in which the chirai epoxide 102 cyclised to the allenic diols 103a,b on treatment with SnCL;. The stereoselectivity was less than in Johnson's case, being 5:1 in favour of the desired isomer 103a. This compound was subsequendy converted to the Inhoffen-Lythgoe diol (6) in a similar manner to that used by Johnson for 99b. 104 105 106 Scheme 18 The use of the intramolecular Diels-Alder reaction34 in the synthesis of steroidal CD synthons has met with limited success. A number of workers35 have attempted syntheses in which an intramolecular Diels-Alder reaction of compounds represented by 104 was used to construct the basic bicyclic skeleton (Scheme 18); however the selectivity between the trans-fused and cu-fused products (105 and 106) was found to be poor in most cases. In 1988, Grieco and co-workers reported a synthesis of the bicyclic ester 107 (Scheme 19)36 which employed an intermolecular Diels-Alder reaction344 to establish the absolute stereochemistry of C(13), C(17) and C(20). The sodium salt of the chirai diene carboxylic acid 108, derived in seven steps from (/?)-(-)-methyl 3-hydroxy-2-methylpropionate, was treated with methacrolein to afford a separable 4.5:1 mixture of the Diels-Alder adducts 109 and 110. The desired compound, 109, was then converted in nine steps to the cyclopentanol 111, the P-oriented alcohol group of which was used to direct a Claisen rearrangement to introduce the desired C(14) stereochemistry of 112. The aldehyde 112 was subsequently converted in a further six steps to the ester 109, which had previously been converted to the Inhoffen-Lythgoe diol (6)22. Scheme 19 26 L2 Discussion Previous work in our laboratory established an efficient and enantiospecific synthesis of the cyclopentanoid compounds 113,114 and 11537. The similarity of these compounds to the yC02H --C02H --C02Me "~X> "35 "T> 113 114 115 steroidal D ring is obvious and, indeed, the hydroxy acid 114 was used in a successful synthesis of (-)-estrone ent-338. In that synthesis, the exo-methylene substituent was used as a disguised form of the eventual 17-keto group and the carboxymethyl and hydroxymethyl sidechains were elaborated to the steroidal C ring, with the former representing C(8) and C(9), and the latter C(12) (Equation 6). 114 , ent-3 We also envisioned an approach to a steroidal CD synthon such as 116 in which the exo-methylene substituent would represent the future C(8) and the carboxymethyl sidechain would eventually become C(20) and C(21) (Equation 7). In this case, the absolute stereochemistry of both C(13) and C(17) is already present in the hydroxy acid 114. It was hoped that alkylation of the carboxymethyl group would occur stereoselectively, to append the remainder of the steroidal 27 114 116 sidechain with control over the absolute stereochemistry at C(20). In order that our synthesis could be made as generally applicable as possible, we chose to examine an approach in which the C ring would be constructed prior to the introduction of the remainder of the steroidal sidechain. i) Br 2 / C1S03H, 1 h, 72% ii) B r 2 / CISO3H, 5 -7 days iii) Zn / AcOH, Et 2 0, 0°C, 52% iv) KOH / DMSO, H 2 0 , rt - 90°C, 88%. Scheme 20 The key hydroxy acid 114 was obtained in four steps from commercially available (+)-e/ido-3-bromocamphor (117) (Scheme 20), following essentially the same route as had been previously described3 7 '3 9. Thus, treatment of 117 with bromine in chlorosulphonic acid for an hour at room temperature provided (+)-3,9-dibromocamphor (118) in 72% yield. It was found that better yields and purer products were obtained in the following two steps if the crude 118 was recrystallised from methanol/dichloromethane before carrying on, rather than using the crude material as was previously described39. Treatment of 118 with bromine in chlorosulphonic acid for between five and eight days at room temperature provided (+)-3,9,10-tribromocamphor (119), 28 which was not purified before being selectively debrominated with zinc in ethereal acetic acid. The (+)-9,10-dibromocamphor (120) thus produced (52% yield over the two steps) was recrystallised from methanol to provide the pure compound, the physical and spectroscopic characteristics of which were identical with authentic material. Finally, treatment of the pure 120 with aqueous KOH in DMSO at 90°C afforded the desired (-)-hydroxy acid 114 in 88% yield. It should be stressed that the brommation/debromination sequence could be conveniently performed on a scale which provided up to 60 g of 120 in one sequence. The cleavage of (+)-9,10-dibromocamphor (120) was routinely performed on a 20 g scale. 132 130 i) K 2 C 0 3 , CH 3I / DMF, 96% ii) TBDMSQ, imidazole, DMF, 87% iii) DIBAL / THF, 0°C, 96% iv)KH,CH 3I/THF,0°C,83% v) TBAF / THF, 96% vi) (COCl^, DMSO, Et 3 N / CH 2C1 2, -60°C, 98% vii) (MeO) 2P(0)CH 2C0 2Me (127), NaH/Toluene, 85°C, 88% viii) Mg/MeOH,85% ix) DIBAL / THF,-78°C, 85% x) Me 2 AlQ / CH 2C1^ 0°C, 78%. Scheme 21 29 Because our projected route involved formation of the C ring of the target by an intramolecular ene reaction40 of the aldehyde 130 (Scheme 21), itself obtained by a selective reduction of the methyl ester 129, it was necessary at this stage to protect the carboxylic acid in a manner which would not interfere with future steps. This was accomplished by a four-step sequence as shown in Scheme 21. The crude acid 114 was converted to the corresponding methyl ester 121 in 96% yield, by treatment with anhydrous K2CO3 in DMF, followed by the addition of iodomethane. This procedure was used in preference to the previously reported treatment with ethereal diazomethane41, as it proved to be equally effective and was potentially less hazardous on a large scale. The methyl ester 121 was readily purified on a small scale by column chromatography, or on a large scale by vacuum distillation. After protection of the hydroxyl group as a silyl ether, L1AIH4 reduction of the ester 122 afforded the alcohol 123, which in turn was protected as its methyl ether 124. After cleavage of the silyl ether protecting group the desired hydroxy methyl ether 125 was obtained in 66% yield from the hydroxy ester 121. The required ester sidechain was then constructed as shown in Scheme 21. Oxidation of the alcohol 125 using Swern's conditions42 provided the aldehyde 126 in 98% yield and excellent purity. While socially offensive, this method was found to be superior to oxidation with either P C C 4 3 or P D C 4 4 , both of which gave considerably lower yields of 126, probably due to the difficulties associated with the work-up and isolation of the products from the Cr(ILT) by-products. Wittig-Horner reaction of the aldehyde 126 with the sodium salt of trimethyl phosphonoacetate (127) provided the ct,(3-unsaturated ester 128. It was expected that the stereochemistry of the newly-formed double bond would be trans, by analogy with known reactions of this type4 5. Verification of this assignment was obtained from the !H-NMR spectrum, in which the observed coupling constant of the a and P vinyl protons was 16 Hz, as expected for a trans (^substituted alkene 4 6. Reduction of the unsaturated ester 128 to the saturated ester 129 was readily accomplished with dissolving Mg in methanol, the mechanism of which is not clear. The original reports of this reducing system were in relation to the reduction of a,P-unsaturated nitriles47, 30 although it was subsequently extended to the case of esters48. Interestingly, it was found that treatment of enones with this system failed to result in any reduction49. Subsequently we discovered (vide infra) that the use of this system to reduce an unsaturated t-butyl ester analogous to 128 was also not straightforward. Finally, the saturated ester 129 was selectively reduced with DIBAL in dichloromethane at -78°C to provide the aldehyde 130 in 64% yield from 126. It was found that these conditions were necessary to avoid over-reduction to the alcohol 131, which readily occurred at higher temperatures. The identity of the product 130 was unambiguously assigned by IR and lH NMR spectroscopy. The IR spectrum showed no O-H absorption at 3400 cm"1, and did exhibit the characteristic aldehyde absorptions at 2820 and 2700 (C-H) and 1720 cm-1 (C=O)S0. In addition, the presence of a triplet (IH, J = 3 Hz) at 9.76 ppm in the lH NMR spectrum was further evidence for the presence of the aldehyde group. The stage was now set for the key intramolecular ene reaction40 to form the C ring of the target compound. Treatment of the aldehyde 130 in dichloromethane with one equivalent of dimethyl aluminum chloride 4 0 ' 5 1 at 0°C resulted in the complete disappearance of the starting material within 5 minutes (as determined by TLC and GC) and the formation of a single, more polar, new compound in 78% yield, which was assigned the structure 132 based on spectroscopic evidence. That the product was an alcohol was readily established by IR spectroscopy, which showed a broad band at 3420 cm*1, and no carbonyl absorption. The *H NMR spectrum indicated that the characteristic pair of triplets at 4.80 - 5.00 ppm associated with the exo-methylene functional group had disappeared, and a single vinyl proton was observed (5.39 ppm) as expected 3 1 for 132. In addition, a quintet at 4.09 ppm (IH, J = 3.5 Hz) was assigned to the C(9) proton, adjacent to the secondary alcohol. The splitting pattern and coupling constant of this signal suggested that the newly-formed alcohol was axially oriented; the equatorial C(9) proton would be 1 3 2 Figure 2: Presumed Transition State Configuration for the Ene Reaction of the Aldehyde 130 expected to couple equally with all four adjacent protons with a coupling constant of between 3 and 5 Hz 4 6 . The axial orientation of the alcohol was expected from examination of a molecular model of the starting material 130 and consideration of the presumed transition state (Figure 2) 4 0 . It was found later that the use of one full equivalent of the Lewis acid was unnecessary, and the reaction proceeded well with even 0.1 equivalent, albeit not as rapidly (complete reaction still occurred within 20 minutes). [Rh(NBD)(DIPH0S-4)]+BF4 [lr(CQD)(pyHPCy3)]+PF6 NBD = norbornadiene COD = cyclooctadiene DJPHOS-4 = l,4-bis(diphenylphosphino)butane py = pyridine PCy 3 = tricyclohexylphosphine 1 3 3 134 3 2 Prompted by reports in which an allylic or homoallylic alcohol was used to direct the hydrogenation of the neighbouring double bond 5 2" 4, we hoped to be able to use the a-oriented alcohol group to introduce the stereochemistry at C(14). This methodology requires the use of homogeneous catalysis by an organometallic complex such as Brown's catalyst 13352 or Crabtree's catalyst 13453a. Both these catalysts were used by Corey and co-workers in a synthesis of retigeranic acid 135 (Equation 8) 5 4 , in which the allylic alcohol 136 was hydrogenated stereoselectively using either catalyst to provide the fra/is-hydrindanol 137. Because hydrogenation using Crabtree's catalyst 134 can be carried out at atmospheric pressure53-54, we chose to use it rather than Brown's catalyst 133 for our study. The catalyst, prepared as described by Stork and Kahne 5 3 b, had physical characteristics in agreement with those described, and the lK NMR spectrum was consistent with the expected structure and reported data5 3 a. "A "A " A H02C 136 137 135 132 138 139 i) 134, H 2 / CH 2C1 2 , 1 atm. The hydrogenation of 132 was then carried out as described by Stork and Kahne 5 3 b (Equation 9). A solution of the catalyst 134 and the alkenol 132 in degassed dichloromethane was saturated with hydrogen gas, resulting in the described colour change from orange to yellow. 33 The solution was stirred under a hydrogen atmosphere and the reaction monitored by TLC and GC. It was soon apparent that the starting material was being consumed very slowly and that two new compounds, one less polar and one more polar than the starting material, were being formed in roughly equal amounts. After the reaction had been stirred for 18 hours, GC indicated that 60% of the starting material remained and that the two new compounds were present to the extent of 15% and 25%. It was decided to stop the reaction at this stage and attempt to identify the products. These proved to be readily separable, both from each other and from starting material, by column chromatography and were assigned the structures 138 and 139, based on their IR and *H NMR spectra. The IR spectrum of the less polar of the two products exhibited no absorptions due to either a hydroxyl or a carbonyl group, but did show a weak absorption at 3020 cm-1 and medium absorptions at 1640, 830 and 820 cm-1, suggesting the presence of one or more double bonds. The *H NMR spectrum exhibited three signals in the region expected for vinyl protons, at 5.37 (IH, broad s), 5.74 (IH, multiplet) and 6.18 ppm (IH, dd, J = 10, 3 Hz), suggesting the presence of two double bonds, one disubstituted and one trisubstituted. The most likely structure consistent with these observations is the diene 138, formed by dehydration of the starting material 132. The IR spectrum of the second product again exhibited no hydroxyl absorption but did possess a strong peak at 1715 cm'1, suggesting the presence of a ketone in a cyclohexane ring. The lH NMR spectrum exhibited no signals attributable to vinyl protons. The most likely explanation of these observations is that the double bond had migrated into the C ring, providing an intermediate enol, which then isomerised to the ketone 139. The assignment of the stereochemistry at C(14) is based on the position of the angular methyl group signal in the *H NMR spectrum, at 0.92 ppm. It has been observed by a number of workers in this area27-35 that in cw-fused systems of this type the angular methyl signal is generally observed between 0.70 and 0.85 ppm, whereas for the trans-fused compounds this signal is generally seen between 0.90 and 1.00 ppm, suggesting that 139 is trans-fused. 34 It was somewhat surprising to observe no reduction product whatsoever, to either the desired a-directed trans stereochemistry 140 or even the undesired cis compound 141. A possible explanation for this result is that the homogeneous catalyst must complex with the alcohol group of the substrate to be effective52*, and that the hydroxyl group of 132 is simply too sterically congested for this complexation to occur. One can see that in the presumed conformation of 132 (Figure 2) the hydroxyl group is directed into the centre of the concave face of the molecule, and could indeed be sterically hindered. Following the failure of the hy<hmyl-directed hydrogenation, it was decided to attempt a heterogeneous reduction in the hope that it would prove to be more successful. Hydrogenation of the alkenol 132 at 1 atmosphere using 10% Pd on charcoal as the catalyst (Equation 10) proceeded slowly to produce two new compounds, different from those observed when Crabtree's catalyst was used, in a ratio of 2:3 as determined by GC. After stirring the mixture under hydrogen for 24 hours, GC indicated 60% conversion of the starting material, and it was decided to stop the reaction at this point and attempt to determine the nature of the two products. These proved to be readily separable, both from each other and from the remaining starting material, by column chromatography. Both products were alcohols, as evidenced by JR spectroscopy, suggesting that reduction had indeed occurred and that they were the alcohols 140 and 141, epimeric at C(14). The [10] 132 140 141 i) H2,10% Pd/C/EtOAc, 1 atm. 35 assignment of the structure of the major compound (30% yield) to the cw-hydrindanol 141 and that of the minor compound (19% yield) to the trans diastereomer 140 was made on the basis of their respective J H NMR spectra and examination of the most favourable conformations of the two compounds (Figure 3). Two striking differences between the *H NMR spectra of the two compounds were noted: the position of the angular methyl group was at 0.73 ppm for the major compound and at 0.92 ppm for the minor compound, and the C(9) proton signal was observed at 3.54 ppm (tt, J = 11.5 and 4 Hz) for the major compound and at 4.10 ppm (quintet, J = 3.5 Hz) for the minor comound. Using the argument presented above (page 33) to assign the trans-fused structure to the ketone 139, the positions of the methyl groups suggest that the major compound 141 is eis-fused, and the minor, 140, is trans-fused. This assignment is supported by the signals of the C(9) proton. That of the minor compound is a quintet, and is therefore consistent with this proton being in an equatorial position. The C(9) proton of the minor compound is seen as a triplet of triplets, indicating that it is coupling differently with two pairs of protons, which is consistent with it being in an axial position, as indeed it is in the most stable conformation of 141 (Figure 3). This result was by no means surprising. In the presumed configuration of the homoallylic alcohol 132 (Figure 2) the p-race is somewhat more exposed than the a-face, and hydrogenation would be expected to occur preferentially from this more exposed side to provide the cis-hydrindanol 141. Indeed, it may be considered surprising that the stereoselectivity was as low as the observed 3:2. OH OMe Figure 3: Most Stable Conformations of the Hydrindanols 140 and 141 36 Since it appeared that it would not be possible to control the C(14) stereochemistry at this stage, it was decided to oxidise die alcohol 132 to the enone 142, (Equation 11) hoping to be able i) PDC / C H 2 a 2 ii) C1O3, H 2 S 0 4 / Acetone iii) (COdfe, DMSO, Et 3 N / CH 2C1 2 , -60°C iv) TPAP, NMO / CH 2C1 2. to introduce the C(14) stereochemistry at a later stage. Unfortunately, the oxidation proved to be capricious at best. Attempts to oxidise the alcohol 132 with a variety of reagents, including P D C 4 4 , Jones' reagent (C1O3, H 2 S 0 4 ) 5 5 , Swern's reagent (DMSO, (COCl) 2, E t 3 N ) 4 2 and TPAP 5 6 , provided at best a mixture of the desired enone 142 and a second compound, identified as the enedione 143. The latter assignment was based primarily on TR and MS data. The JR spectrum exhibited strong peaks at 1720 and 1680 cm - 1 (compared to the enone 142, which exhibited a single strong peak at 1665 cm - 1), suggesting the presence of both ketone and enone functionality. The low resolution mass spectrum showed a molecular ion at m/z = 222, consistent with the formula C13H18O3. Further evidence was the fact that the pure compound was bright yellow in colour, which has been previously noted for the 2-ene-l,4-dione chromophore57. Needless to say, this result was both disappointing and somewhat puzzling, as we found no precedent for i t Whether the enedione 143 was formed by over-oxidation of the enone 142, or by a more complex mechanism involving initial delivery of oxygen to C(15) of the alkenol 132, is not clear. Certainly, in the case of the oxidation with TPAP, no enone 142 was isolated or even observed by GC while monitoring the reaction. This would tend to suggest that 142 is not an intermediate in the formation of 143. 1 3 2 1 4 2 1 4 3 37 OMe 144 Interestingly, an attempt to oxidise the alcohol 132 with aqueous NaOCl 5 8 provided neither the desired enone 142, nor the enedione 143, but produced instead the tricyclic chloro ether 144. This assignment was made on the basis of MS and *H NMR information. The low resolution mass spectrum clearly showed the presence of a single chlorine atom, as indicated by the characteristic isotope pattern of 3:1 peaks separated by two mass units. The molecular ion (246/244) suggested a molecular formula of C ^ r ^ i C l O ^ . The *H NMR spectrum showed no vinyl protons, but did exhibit peaks at 4.06 (IH, t, J = 7 Hz) and 4.45 (IH, t, J = 5 Hz), assigned to the methine protons a to the ether oxygen. Since aqueous hypochlorite solutions can be considered a source of C l + , it is likely that the ether 144 was formed by initial attack of C l + on the double bond, followed by cyclization of the alcohol onto the intermediate chloronium ion. At this point the assignment of the structure 132 to the product of the ene reaction came into some doubt, due to its failure to react as expected in so many instances. In order to verify our assignment and perhaps glean some insight into its perplexing reactivity, we attempted to prepare the p-bromobenzoate ester 145, in the hope that it would be crystalline and thus suitable for structural ^termination by X-ray diffraction. Unfortunately the alcohol 132 entirely failed to react with p-bromobenzoyl chloride in pyridine, even with the addition of 1 equivalent of DMAP 5 9 , and only starting material was recovered. It was possible to prepare the corresponding acetate 146, 145 146 38 however this proved to be an oil. Al l spectra obtained for this compound (IR, low resolution MS, *H NMR, and 1 3 C NMR) were consistent with the assigned structure, and the investigation was not pursued further. 147 [12] 148 It was clear that a re-evaluation of the strategy was necessary at this point. Prompted by a report in the literature60 in which the carboxylic acid 147 underwent an intramolecular Friedel-Crafts type acylation of the double bond to provide the enone 148 (Equation 12), we undertook a similar approach to the formation of our C ring. 129 149 i) KOH / MeOH, H 20,0°C, 100% ii) (GF 3CO) 20 / GH 2C1 2; NaHC0 3 / H 2 0 , 40% 150 + 53% 142 iii) p-TsOH / MeOH, 60% Scheme 22 OMe OMe 142 The desired carboxylic acid 149 (Scheme 22) was readily obtained by hydrolysis of the methyl ester 129. Treatment of 149 with trifluoroacetic anhydride in dichloromethane60 resulted in complete disappearance of the starting material within 30 minutes, and the appearance of two new compounds in roughly equal amounts as determined by TLC. The more polar of these compounds was tentatively identified as the enone 142, previously obtained by the oxidation of 39 the alcohol 132, on the basis of its TLC and GC characteristics; this assignment was confirmed spectroscopicaliy after purification. During silica gel chromatography of the product mixture it became apparent that the less polar component was being converted to the more polar one, suggesting that the former was the dienol trifluoroacetate 150. This was confirmed by IR and 1 H ' NMR spectroscopy. The IR spectrum showed a strong absorption at 1800 cm*1, consistent with the presence of the trifluoroacetate group50, and two medium absorptions in the C=C region, at 1660 and 1620 cm - 1 The *H NMR spectrum exhibited vinyl proton signals at 5.55 (IH, broad s) and 6.14 ppm (IH, d, J = 3 Hz), assigned to the y and a dienol protons respectively. Further evidence for this structure was obtained when 150 was treated with p-toluenesulphonic acid in methanol, resulting in conversion to the enone 142. --C02Mo 0 _^C02Me o -^C02Me HCX> - - ^ b 121 151 , 1 5 2 •C02Me 153 Scheme 23 Having established that an intramolecular acylation of this type was possible, we decided to amend our route as shown in Scheme 23. Since we eventually intended to introduce the sidechain at C(20) by a stereoselective alkylation, it was hoped that we could achieve the construction of the C ring with the carboxyl functionality of the ester 121 intact. In order to accomplish this, and yet be able to use the hydrolysis of an ester to unveil the carboxylic acid desired for the cyclization, we elected to prepare the t-butyl methyl diester 151, anticipating that it would be possible to hydrolyse the t-butyl ester selectively. 40 The preparation of the diester 151 was accomplished as shown in Scheme 24. The sequence was essentially that used in the earlier synthesis of the ester 129, with the exception that the four-step sequence involved in preparation of the methyl ether could be avoided, and t-butyl 157 151 i) (COCl)2, DMSO, Et 3 N / CH 2C1 2, -60°C, 95% ii) NaH, 155 / THF, 100% iii) Mg / MeOH, 66% 151 + 33% 157. Scheme 24 dimethyl phosphonoacetate (155) was used in the Wittig-Horner reaction, to provide the unsaturated ester 156 in 95% yield from the hydroxy ester 121. It was found that the reduction of the unsaturated t-butyl ester 156 with dissolving Mg in methanol48 was not as straightforward as that of the unsaturated methyl ester 128. Initially the yields of the saturated t-butyl ester 151 were found to be inexplicably low, on the order of 60%. It was subsequently discovered that acidification and extraction of the basic aqueous fraction of the work-up mixture afforded the unsaturated acid 157 in quantities which accounted for the "missing" product. The isolated acid was found to be uncontaminated with the saturated analogue 152, within the limits of spectroscopic determination (low resolution MS of the acid, and GC of the corresponding methyl ester). This result indicated that two competing processes were recurring: reduction of the unsaturated ester and cleavage of the t-butyl group. In addition, the latter process occurred only in the case of the unsaturated t-butyl ester! It seems likely that the reduction, like most dissolving 41 metal reductions61, proceeds by a radical mechanism, and it is not inconceivable that some radical-assisted cleavage of the t-butyl group was responsible for the second product (157). It is also possible that the M g 2 + produced in the reduction is catalysing the cleavage. Why either of these processes should occur only in the case of the unsaturated compound (156) is not obvious. R^-oA^ ^ R - ^ O ^ - * ~ R - ^ O + 1 1 3 1 The selective cleavage of t-butyl esters in the presence of methyl esters has been well-documented62. In general this cleavage is acid-catalysed; the protonated t-butyl ester (Equation 13) readily eliminates 2-methylpropene, whereas the non-aqueous acid-catalysed cleavage of methyl esters is notoriously slow6 3. A variety of reagents and conditions have been reported to effect this transformation, including trifluoroacetic acid 6 4, refluxing p-toluenesulphonic acid in benzene65, and iodotrimethylsilane66. Treatment of the t-butyl ester 151 with neat trifluoroacetic acid at room temperature (Scheme 25) 6 4 a for one hour afforded a single compound, different from the starting material, the TLC characteristics of which suggested that it was not the desired carboxylic acid 152. This was confirmed by the IR spectrum, which exhibited no sign of the expected broad peak at 2800 - 3400 cm - 1 associated with the acid OH stretch, but did show a very strong absorption at 1735 cm - 1 , suggesting the presence of one or more esters. The *H NMR spectrum indicated that the methyl ester was still present, as evidenced by a singlet of intensity 3H at 3.70 ppm, but also displayed two other methyl singlets, at 0.84 and 1.37 ppm Based on this evidence, the lactone 158 was proposed as the structure of the isolated product, in which cleavage of the t-butyl group to form 152 had indeed occurred, but was followed by lactonization onto the tertiary carbocation formed 42 by protonation of the double bond in the strongly acidic medium. This structure was supported by high resolution MS, which found a measured mass of 240.1353, in good agreement with the mass calculated for C13H20O4 of 240.1361. Attempts to prevent lactonization by carrying out the reaction in dichloromethane solution641* failed to result in cleavage of the t-butyl ester. 159 i) C F 3 C 0 2 H , 78% ii) TMSC1, Nal / CH 3 CN, 89% iii) p-TsOH / C 6 H 6 , 80°C, 90%. Scheme 25 A number of workers have used iodotrimethylsilane, prepared in situ from Nal and chlorotrimethylsilane in acetonitrile, to effect the selective cleavage of t-butyl esters67. Treatment of the ester 151 with this system, following the procedure of Sakurai 6 7 a, did indeed result in a carboxylic acid, as determined by IR spectroscopy. That the methyl ester was still intact was verified by l H NMR spectroscopy; a singlet of intensity 3H was observed at 3.70 ppm. Unfortunately, the *H NMR spectrum also indicated that the product was the endocyclic isomer 159 of the desired product 152; the characteristic pair of triplets between 4.80 and 5.00 ppm associated with the exo-methylene group was absent, and a single vinyl proton at 5.33 ppm and a broad singlet of intensity 3H at 1.59 ppm, assigned to the allylic methyl group, were observed. Previously in our laboratory we had found that the observed isomerization was particularly facile in the presence of HI 6 8 . Since it was not inconceivable that small amounts of HI could be formed in this reaction, thus catalysing the isomerization, the procedure was repeated in the presence of i 4 3 triethylarnine, but failed to result in any observable cleavage of the t-butyl group. After a final attempt at the selective cleavage using refluxing p-toluenesulphonic acid in benzene65 also provided the endocyclic isomer 159, this approach was abandoned. Our attention then turned to the diester 160, hydrolysis of which would provide the diacid 161 (Scheme 26). It was anticipated that only the desired cyclization, to provide the enone acid 162, would occur, the alternative cyclization, to 163, would be in violation of Bredt's Rule 6 9. MeO 163 Scheme 26 The synthesis of the methyl diester 16070 was accomplished in 80% yield from 154, as outlined in Scheme 27, differing from that of the diester 151 only in that trimethyl phosphonoacetate (127) was used in the Wittig-Horner reaction. No problems were encountered in the dissolving metal reduction in this case. Hydrolysis of the diester 160 provided the crystalline diacid 161, which was readily purified by recrystallization from ethyl acetate/hexane. Treatment of the diacid 161 with trifluoroacetic anhydride in dichloromethane60 followed by aqueous NaHCOj in methanol provided, after acidification, the desired acid enone 162 in 56% yield. Esterification with K2CO3 and iodomethane in DMF then provided the enone methyl ester 44 153 in 66% yield. It was subsequendy found that treatment of the crude product of the trifluoroacetic anhydride cyclization with methanolic p-toluenesulphonic acid, rather than aqueous base, resulted in conversion to the ester 153 direcdy, in 82% yield. Presumably the crude product of the cyclization is a mixture of the mixed anhydrides 165 and 166, which undergo methyl esterification concomitant with solvolysis of the dienol trifluoroacetate. C02Mo _^C02Me _ ^COaMe 0 H C^L-(. i Me0 2C^^sJ^( » Me02C 10 T \ __j _ " ^ 2 C ^ s 4 ^ \ 154 164 --C02Me --CC^H ' _-C02H £?6 j$5 -=-"*~35 153 162 161 i) NaH, 127 / THF, 86% ii) Mg / MeOH, 98% iii) KOH / H20, MeOH, 77% iv) (CF3CO)20 / CH2Cl2;NaHC03 / H20, MeOH, 56% (162); or p-TsOH / MeOH, 82% (153) v) K 2C0 3, CH3I / DMF, 66%. Scheme 27 C02COCF3 —COzCOCFj C F 3 C 0 2 ^ ^ > 165 166 We felt that the enone ester 153 could be considered a useful CD synthon en route to a variety of steroidal systems incorporating sidechains at C(20). One would simply need to stereospecifically introduce the requisite sidechain at C(20), reduce the methyl ester to a methyl 45 group, and solve the problem of controlling the C(14) stereochemistry in order to arrive at a system representing the intact CD portion of the target steroid (Scheme 28). To illustrate the potential of our system we chose to carry out the initial two steps of this sequence with a representative C(20) sidechain moiety, introduced by a stereospeciflc alkylation of the lithium enolate of the ester 169, in which the enone was prevented from interfering by protection as the ethylene ketal. C02M© 153 167 R = C02Me 116 168 R = CH 3 Scheme 28 Wicha and Ba l 7 1 showed that it was possible to alkylate stereoselectively the C(20) position of the steroidal ester 170 (Scheme 29), providing the alkylated product 171 in high yield and excellent stereochemical purity. Subsequent transformation of the methyl ester to a methyl group was straightforward and provided the cholesterol derivative 172, with the natural R configuration at C(20). The generality of this procedure was established by carrying out the alkylation with a number of different alkyl halides on both the same7! and related systems15b«c. Following this work, the method was extended to the monocyclic "D" case with similar stereochemical results72. When we embarked on this project no one had reported a case in which an isolated VCD* system such as 169 had been alkylated in this way; however, one such report has since been published16. 46 The attractive feature of this method of sidechain introduction is that it is applicable to a wide variety of sidechains, and one can produce a variety of analogous compounds with little change in the synthetic strategy. In addition, because the alkylation can be done at a relatively late stage in the synthesis, problems associated with functional group incompatibility are minimised. THPO 170 171 172 Scheme 29 It has been suggested73 that one can account for this observed stereoselectivity by a consideration of the most stable enolate geometry, shown in Figure 4. In this geometry, the Figure 4: Preferred Mode of Attack of Electrophiles on the Enolate of Ester 170 enolate double bond takes an orientation in which it is coplanar with, and eclipsing, the (3 C-H bond. If one then considers the size of the two groups flanking this plane (C(16) and C(13), in the case of steroids), and assigns them a size priority, it can be argued that the mcoming alkylating agent will approach from the side of the smaller group. Clearly, in the steroidal or analogous case, 4 7 the smaller group is the methylene carbon at C(16), and approach from this face indeed provides the observed products. C02Me MeO,C, ^ . 0-(fl)-MTPA 173 168 i) HO(CH2)2OH, PPTS / QHfi, 80°C, 75% ii) LDA / THF, -78°C, 40 min; 173, -78°C - rt, 95% iii) UAIH4 / THF, 0°C, 87% iv) (fl)-(+)-MTPACl, C 5 H 5 N / CH 2C1 2, 3 days, 80% v ) M s C l , D M A P , E t 3 N / C H 2 C l 2 vi) LiEt 3 B H / THF, 0°C, 84% vii) 1 N HC1 / Acetone, A, 91%. Scheme 30 We chose to use 5-iodo-2-methyl-2-pentene (homoprenyl iodide) (173) as our representative alkylating agent70, as it represents a cholesterol-type sidechain with suitable functionality for elaboration to either the saturated cholesterol sidechain or the 25-hydroxy sidechain associated with Vitamin D3 metabolites. After protection of the enone 153 as the ethylene ketal 169 (75% yield) (Scheme 30), the lithium anion of 169 was generated by treatment 48 with LDA in THF at -78°C. Neat homoprenyl iodide (173) was then added and the solution allowed to warm to room temperature overnight, providing the alkylated ester 174 in 95% yield. Both GC and the J H NMR spectrum indicated that the product was diastereomerically pure. The C(20) centre was assigned the R configuration, based on the analogy discussed above, although this remained to be proved. Reduction of the ester 174 with LiAfffy afforded an 87% yield of the alcohol 175 as an amorphous white solid, the melting point of which was 83-4°C. Recrystallization from diethyl ether/petroleum ether provided fine white needles, the melting point of which was found to be 72-3°C! This surprising result was explained when the results of an X-ray diffraction experiment became available74; it was found that the crystalline material was the hemihydrate of the alcohol 175 (see Appendix la for an ORTEP plot of the crystal structure). Presumably the water was picked up during the recrystallization, accounting for the change in the melting point. This result also explained the 'failure' of the recrystallised material to provide an acceptable elemental analysis; the observed analysis was correct for the formula C2oH3203"1/2H20. The X-ray diffraction experiment also confirmed that the C(20) centre had the expected R configuration. In order to establish the diastereomeric purity of the alcohol 175, it was converted to the corresponding (/?)-methoxytrifluoromethylphenylacetate (MTPA) ester 17875. Again, *H NMR indicated that this was a single compound, although the 282 MHz 1 9 F NMR spectrum did exhibit a very small peak at 4.896 ppm, adjacent to the major signal at 4.936 ppm (see Appendix lb), suggesting that a trace amount of the C(20)-S-diastereomer was present Finally, it remained to convert the alcohol 175 to the C(21) methyl compound 177, which was accomplished in 84% yield by the mesylation/reduction sequence shown in Scheme 30. Hydrolysis of the ketal then regenerated the enone 168 and concluded the synthesis of the potential steroidal precursor including an appropriate sidechain. 49 1.3 Conclusion The enantiospecific synthesis of the enone methyl ester 153 (Scheme 31), representing a potentially useful intermediate for the synthesis of a variety of steroids and seco-steroids, was accomplished in nine steps and 16% overall yield from commercially available (+)-endo-3-brornocamphor (117)70. The efficiency of the synthesis is detracted from by the initial three steps, which occur in an overall yield of only 40%, however this is more than compensated for by the ease with which these complex transformations occur, and by the fact that they can be routinely carried out on quantities in excess of 0.3 moles. Scheme 31 It was also established70 that it was possible to alkylate the ester 153 stereoselectively to introduce the natural R stereochemistry at C(20). The excellent diastereomeric purity of the alkylation product was established by 1 9 F NMR spectroscopy of the (/?)-MTPA ester 178, derived from 174, and the absolute stereochemistry of the C(20) centre was determined by X-ray diffraction74. Finally, the alkylation product was converted to the C(21) methyl compound 168, to form a representative steroidal C(17) sidechain. 50 The ester 153 could also represent an intermediate in the synthesis of the potentially interesting C(20)-ep/-steroids5b'12'23'76, which have received some synthetic attention. Alkylation of 169 with iodomethane would be expected to provide the ester 179, in which the ester group could potentially be elaborated to a steroidal sidechain (Scheme 32). Scheme 3 3 The one feature lacking in our synthesis is that the C(14) stereochemistry has not been established and, in order to do so, a stereoselective reduction of the enone double bond would be required. This problem has been addressed by a number of workers in this area, and can be regarded as having been solved77. The general strategy (Scheme 33) involves the introduction of a carboxyl substituent at C(8), followed by catalytic hydrogenation of the enone. It has been found that the C(8) substituent is essential for a high degree of a-selectivity; without it the ris-fused product predominates. The reason for the effect of the substituent is not clear, although it has been suggested2 7 1 5'7 7 that its presence results in a significant conformational change of the C ring, rendering the oc-face of the double bond more accessible to hydrogenation and increasing the steric effect that the C(13) methyl group and the C(17) sidechain have on the [J-face. Regardless of the 5 1 rationale, it should be possible to control the C(14) stereochemistry of our system using this methodology. 52 1.4 Experimental 1.4.1 General Experimental Al l reagents used were of commercial grade and were not purified unless otherwise specified. Dry solvents and reagents were obtained as follows: diethyl ether QBX2O) was distilled from lithium aluminum hydride (LiAULj); tetrahydrofuran (THF) was distilled from Na/benzophenone; benzene (CgHg), toluene, and dichloromethane (CH2CI2) were distilled from calcium hydride; methanol (MeOH) was distilled from Mg turnings in the presence of I2; triethylarnine (E13N) and pyridine were distilled from KOH; and dimethylsulphoxide (DMSO) and hexamethyl phosphoramide (HMPA) were stored over 4A molecular sieves. Low boiling petroleum ether (PE, the fraction boiling in the range 30-60°C), was distilled prior to use in chromatography. Al l reactions involving air- or moisture-sensitive reagents were performed in flame- or oven-dried glassware under an atmosphere of Ar. Where not specified, reactions were performed at room temperature (rt). Unless otherwise specified, all aqueous solutions of salts used in work-up were saturated. Thin layer chromatography (TLC) was performed on Merck 5735 Precoated Silica Gel 60, PF254 on plastic sheets, visualizing the plates with either I2 (g) or an ammonium molybdate/H2S04 spray. Gas liquid chromatography (GC) was performed on a Hewlett-Packard HP5830A instrument, using a 0.2 mm x 11 m column of OV-101, with He as the carrier gas. Column chromatography was performed on Merck Silica Gel 60, of either 70-230 or 230-400 mesh, column dimensions are given as diameter x height Radial chromatography was performed under an atmosphere of Ar on a Harrison Research Chromatotron® 7924T, using plates of Merck Silica Gel 60, PF254, containing gypsum, of 1,2, or 4 mm thickness and 4.0 -11.25 cm radius. 53 Infrared (IR) spectra were recorded on a Perkin Elmer 710B scanning spectrophotometer, either as neat films between NaCl plates or as solutions in NaCl cells of 0.1 mm path length. Proton nuclear magnetic resonance ( JH NMR) spectra were recorded at 300 MHz on a Varian XL-300 spectrometer, and at 400 MHz on a Bruker WH-400 spectrometer, with signal positions referenced to tetra-methylsilane (TMS). 1 3 C NMR spectra were recorded at 75 MHz on a Varian XL-300 spectrometer, with signal positions referenced to TMS. 1 9 F NMR spectra were recorded at 282 MHz on a Varian XL-300 spectrometer, with signal positions referenced to trifluoroacetic acid. Low resolution mass spectra (MS) were recorded on a Kratos MS-80 spectrometer and high resolution mass spectra were recorded on a Kratos MS-50 spectrometer. Specific rotations ([a]) were recorded on a PerkhvElmer 141 polarimeter, in a 1 dm cell at ambient temperature, using the sodium D line (589 nm); all compounds for which specific rotations were recorded were analytically pure and exhibited single spots on TLC and single peaks on GC. Melting points (mp) were measured on a Reichert heating stage, and are uncorrected. Boiling points (bp) were determined either as the temperature at the still head for those samples which were distilled in bulk, or as the temperature of the oil bath, when small-scale distillation was performed. Elemental analyses were performed by Mr. P. Borda, Microanalytical Laboratory, Department of Chemistry, UBC; all compounds submitted for elemental analysis exhibited a single spot by TLC and a single peak by GC, with the exception of those consisting of diastereomeric mixtures. X-ray structural determinations were performed by Dr. S. Rettig, UBC. 54 1.4.2 Experimental Bromination of (+)-3-endo-bromocamphor (117) to (+)-3,9-dibromocamphor (118): Br Br 117 118 (+)-£rtd0-3-bromocamphor (117, 100 g, 0.43 mol) was placed in a 500 mL flask equipped with a stir bar, and cooled in an ice bath. A solution of bromine (35 mL, 110 g, 0.68 mol) in chlorosulphonic acid (80 mL) was added cautiously, and after 5 min the ice bath was removed. The reaction was then stirred at rt for 1.5 h before being quenched by carefully pouring the solution into a slurry of NaHSO^ (25 g) and ice (250 g). The mixture was allowed to stand with occasional stirring, until all the orange colour of bromine had faded. The aqueous solution was decanted from the off-white solid and the latter was triturated with water (5 x 250 mL), collected by suction filtration, and washed further with NaHC03 (aq) (2 x 50 mL) and water (50 mL). The wet solid was dissolved in CH2CI2 (500 mL), the water separated, and the solution dried over MgSC»4. Methanol (75 mL) was added and the solvents removed by rotary evaporation until the first crystals appeared. The solution was then cooled and allowed to crystallise, affording (+)-3,9-dibromocamphor (118) as a white crystalline solid; yield: 80.0 g, 60%. The mother liquor was concentrated and a second crop of pale yellow crystals (21 g) was obtained; total yield: 101 g, 72%; mp: 157-159°C (lit.78 157-159°C); [a]23 91° (c = 0.43, CHC13), (lit78 [a]l9 100°, c = 1,CHC13). CmHuB^O Calc. Mass: 311.9371, 309.9391, 307.9411 Meas. Mass: 311.9381,309.9387,307.9433 IR (CHC13): x> = 2980,2895 (C-H); 1755 cnr1 (C=0). MS (70 eV): m/z (%) = 312, 310, 308 (M+, 4.6,9.5, 5.4); 231, 229 (25.9, 27.1); 203, 201 (29.6, 32.1); 81(100). 55 iH-NMR (CDCI3): 8 =1.02 (3H, s, C(10)H3); 1.10 (3H, s, C(8)H3); 1.48 - 1.57 (IH, ddd, J = 16, 7, 5 Hz, C(6) endo H); 1.73 (IH, ddd, J = 16, 12, 4 Hz, C(5) endo H); 1.84 -1.94 (IH, m, C(5) exo H); 2.19 (IH, ddd, J = 16, 10, 4 Hz, C(6) exo H); 2.70 (IH, t, J = 4 Hz, C(4)H); 3.29, 3.65 (2H, 0^3, J = 11 Hz, C(9)H2Br); 4.57 (IH, dd, J = 4, 1 Hz, C(3)H). Conversion of (+)-3,9-dibromocamphor (118) to (+)-9,10-Dibromocamphor (120): B r l l 8 B r H 9 120 (+)-3,9-Dibromocamphor (118, 105 g, 0.34 mol) was placed in a 500 mL flask equipped with a stir bar, and cooled in an ice bath. A solution of bromine (26 mL, 81 g, 0.51 mol) in chlorosulphonic acid (100 mL) was added cautiously and a vent equipped with a silica gel drying tube was placed on the flask. After stirring at 0°C for 15 min the ice bath was removed and stirring was continued; adding bromine (10 mL) and chlorosulphonic acid (10 mL) after 3 days and again after 6 days. After 8 days, the reaction was quenched by cautiously pouring into a slurry of NaHS03 (50 g) and ice (500 g). The mixture was extracted with CHC13 (2 x 250 mL), and the combined organic solvents were washed with water (100 mL) and NaHC03 (3 x 100 mL, until the washings were basic), and dried over MgSC»4. Evaporation of the solvents yielded crude (+)-3,9,10-tribromocamphor (119,124 g, 70% pure by gc) as an orange viscous oil, which was used without further purification. A 2 L Erlenmeyer flask was charged with a solution of the crude 3,9,10-tribromocamphor (119) in 1:1 Et20:AcOH (500 mL), cooled in an ice bath and equipped with an overhead mechanical stirrer. Zn (50 g, 0.76 mol) was added in portions over 90 min, maintaining the temperature below 20°C. Following the addition the mixture was stirred for a further 3 h, after which Celite (5 g) was added and the mixture filtered. The solution was washed with 50% brine (200 mL), water (2 x 100 mL), NaHC03 (6 x 100 mL, until the washings were basic) and brine 56 (100 mL), and dried over MgSO^.The solvent was evaporated to provide an orange solid which was triturated with methanol to give yellow crystals. Recrystallization from methanol provided (+)-9,10-dibromocamphor (120) as a white crystalline solid; yield: 55 g, 52% over two steps; mp: 97-8°C (lit.39: 98-100°C); [a] 2 2 67° (c = 1.1, CHC13) (Ht 3 9 [a] 2 0 68°, c = 2, MeOH). C 1 0 H 1 4 B r 2 O Calc. Mass: 311.9371, 309.9391, 307.9411 Meas. Mass: 311.9377, 309.9396, 307.9449 IR (CHC13): v = 2975,2900 (C-H); 1740 cm"1 (C=0). MS (70 eV): m/z (%) = 312, 310, 308 (M+, 0.5, 0.9, 0.4); 231, 229 (33.1, 33.4); 203, 201 (1.5, 1.3); 107 (100). lH NMR (CDC13): 8 = 1.10 (3H, s, C(8)H3); 1.43 - 1.58 (2H, m, C(5) and C(6) endo H); 1.98 (IH, d A B , J = 18 Hz, C(3) endo H); 2.05 (IH, ddd A B , J A B = 18 Hz, J = 5,4 Hz, C(3) exo H); 2.25 - 2.35 (IH, m, C(6) exo H); 2.41 (IH, dt, J = 19,4 Hz, C(5) exo H); 2.60 (IH, t, J = 5 Hz, C(4)H); 3.48 and 3.59 (IH each), 3.70 (2H) (3dAB, J = 12 Hz, C(9)H2Br and C(10)H2Br). Grob fragmentation of (+)-9,10-dibromocamphor (120) to (-)-hydroxyacid 114: (+)-9,10-Dibromocamphor (120, 20.0 g, 64.5 mmol) was added in one portion to a solution of KOH (18 g, 0.32 mol) in water (60 mL) and DMSO (530 mL). The mixture was stirred at rt for 1.5 h and then heated to 90°C and stirred overnight. The mixture was cooled, poured into a slurry of ice (100 g) and N e d (20 g), and extracted with Et 2 0 (2 x 75 mL). The aqueous solution was acidified to pH 1 by careful addition of 6 N HCl and immediately extracted with EtOAc (200 mL, 3 x 100 mL). The extracts were washed with water (2 x 100 mL) and brine (2 x 100 mL), and dried over MgSO^. Evaporation of the solvents afforded the hydroxyacid 114 as a white solid; yield: 10.5 g, 88%. A small amount was recrystallised from EtOAc/60-80 PE to 5 7 afford white needles; mp: 118-9<>C (lit.37 H8-9°C); [a] 2 2 -22° (c = 0.50, MeOH) (lit.37.21.40, c= 0.35, MeOH). CloH 1 6 0 3 Calc. Mass: 184.1099 Meas. Mass: 184.1103 IR (CHC13): v = 3400 - 2600 (COOH, OH); 2975,2895 (C-H); 1705 (C=0); 1650 (0=0^); 900 cm-1 (=C-H). MS (70 eV): m/z (%) = 184 (M+, 0.3); 166 (4.9); 154 (7.7); 153 (7.1); 94 (100). iH NMR (CDCI3): 5 = 0.88 (3H, s, CH 3 ) ; 1.33 - 1.44 (IH, m); 1.95 - 2.03 (IH, m); 2.23 (IH, dd, J = 15,9 Hz); 2.28 - 2.40 (IH, m); 2.43 - 2.55 (4H, m, partially simplifies with D 2 0); 3.43, 3.54 (2H, 0 ^ , J = 11.5 Hz, -CH 20-); 4.83, 5.03 (IH each, 2 t, J = 2.5 Hz, 2 Hz, =CH2). Esterification of acid 114 to methyl ester 121: _~C02H _-C02Me H0^> — mT> 114 121 The hydroxy acid 114 (2.33 g, 12.6 mmol) was dissolved in dry DMF (35 mL) and anhydrous K 2 C 0 3 (3.50 g, 25.3 mmol) was added. The suspension was stirred under Ar for 1.5 h, after which CH 3I (1.6 mL, 3.6 g, 25 mmol) was added by syringe, and stirring continued in the dark for 3 h. The mixture was poured into brine (50 mL), extracted with Et 2 0 (3 x 30 mL), and the combined extracts were washed with brine (30 mL) and water (30 mL), and dried over MgS04. The solvents were evaporated to provide a yellow oil which was purified by column chromatography (15 x 3.5 cm, 230-400 mesh silica gel), eluting with 4:1 PE:Et 20 to provide the methyl ester 121 as a pale yellow oil; yield: 2.42 g, 96%; bp 102°C/0.05 mm; [a] 2 4 -25.1° (c = 1.66, CHC13). C n H 1 8 0 3 Calc: C 66.64 H 9.15 % Anal.: C 66.45 H9.15% 5 8 IR (Neat): u = 3450 (O-H); 3090 (vinyl C-H); 2950,2880 (C-H); 1730 (C=0); 1655 (C=CR^); 885 cm*1 (vinyl C-H). MS (70 eV): m/z (%) = 198 (M+, 0.2); 180 (0.7); 168 (25.1); 167 (20.0); 135 (12.2); 107 (100); 94(99.1). !H-NMR (CDC13): 8 - 0.87 (3H, s, CH 3 ) ; 1.31 - 1.43 (IH, m); 1.79 (IH, broad s, -OH); 1.90 -1.99 (IH, m); 2.21 (IH, dd, J = 17,11 Hz); 2.28 - 2.40 (IH, m); 2.42 - 2.55 (3H, m); 3.41, 3.54 (2H, broad (JAB. J = 12 HZ, -CH 2 0); 3.70 (3H, s, -C0 2 CH 3 ) ; 4.83 and 5.02 (IH each, 2 t, J = 2 Hz, 2 Hz, =CH2). Protection of alcohol 121 as silyl ether 122: 121 122 The alcohol 121 (7.27 g, 36.7 mmol) was dissolved in dry DMF (50 mL), and TBDMSC1 (6.63 g, 44 mmol) and imidazole (6.26 g, 92 mmol) were added. The mixture was stirred under Ar for 18 h, poured into water (100 mL), and extracted with E t 2 0 (3 x 50 mL). The combined extracts were washed with water (25 mL) and brine (25 mL), and dried over MgSO^ The solvents were evaporated to provide a colourless mobile liquid which was purified by vacuum distillation to afford the silyl ether 122 as a colourless mobile oil; yield: 9.98 g, 87%; bp: 120-2°C(0.1 mm); [a] 2 3 -20° (c = 1.37, CHC13). C 1 7 H 3 2 0 3 S i Calc: C 65.33 H 10.32 % Anal.: C 65.20 H 10.35 % IR (Neat): v = 3080 (vinyl C-H); 2950,2925,2890,2850 (C-H); 1740 (C=0); 1655 (C=CH2); 895 cm-1 (vinyl C-H). MS (70 eV): m/z (%) = 297 (M+^u, 2.2); 281 (2.2); 255 (100). lH NMR (CDC13): 8 = 0.03 and 0.04 (3H each, 2 s, Si(CH 3) 2); 0.89 (9H, s, tBuSi); 0.90 (3H, s, CH 3 ) ; 1.23 -1.34 (IH, m); 1.86 - 1.95 (IH, m); 2.10 (IH, dd, J = 16, 11 Hz) and 2.65 (IH, dd, J = 16,4 Hz, -CH 2CO-); 2.24 - 2.45 (3H, m); 3.42 and 3.46 (2H, q^g, -CH 20-); 3.67 (3H, s, C0 2Me); 4.75 and 4.89 (IH each, 2 broad s, =CH2). 59 Reduction of ester 122 to alcohol 123: -C02Me T B D M S O ^ p V ^ TBDMSO^J-"\ 0" 122 123 The ester 122 (11.5 g, 36.8 mmol) was dissolved in dry THF (150 mL) and cooled under Ar to 0°C. DIBAL (1 M in hexanes, 81 mL, 81 mmol) was added by syringe and the mixture was stirred for 90 min, after which Na2SO4*10 H2O (1 g) was added. After stirring overnight the mixture was filtered and the solution was dried over MgSCXj and evaporated to provide the alcohol 123 as a colourless mobile liquid, which was used without further purification; yield: 10.1 g, 96%; [a]25 -21.3° (c = 1.72, EtOH). C16H3202Si Calc: C 67.54 H 11.34 % Anal.: C 67.67 H 11.20% IR (Neat): \) = 3325 (O-H); 3075 (vinyl C-H); 2940,2915,2860,2830 (C-H); 1650 (C=CH2); 900 cm-1 (vinyl C-H). MS (70 eV): m/z (%) = 227 (M+-C4H9, 10.1); 225 (4.7); 209 (2.7); 181 (6.2); 135 (52.8); 75 (100.0). iH NMR (CDCI3): 8 = 0.03 and 0.04 (3H each, 2 s, Si(CH3)2); 0.89 (3H, s, CH3); 0.90 (9H, s, tBuSi); 1.19 -1.33 (IH, m); 1.37 - 1.47 (IH, m); 1.75 - 1.90 (2H, m); 1.97 - 2.06 (IH, m); 2.21 - 2.31 (IH, m); 1.34 - 1.43 (IH, m), 3.42 and 3.47 (2H, Oj^, J = 10 Hz, CH2OSi); 3.61 - 3.78 (2H, m, QfcOH); 4.76 and 4.89 (IH each, 2 broad s, =CH2). Protection of alcohol 123 as methyl ether 124: T B D M S O ^ | ^ \ 123 124 A suspension of KH (3.19 g, 79.2 mmol) in CHjI (5.90 mL, 13.5 g, 95.0 mmol) and dry THF (250 mL) was cooled under Ar to 0°C and a solution of the alcohol 123 (18.0 g, 63.3 mmol) 60 in dry THF (80 mL) was added dropwise over 30 min. The mixture was stirred for a further 30 min after which water (SO mL) was added, cautiously at first The layers were separated and the aqueous phase was extracted with Et20 (25 mL). The combined organics were washed with water (50 mL), 10% Na 2S 203 (50 mL) and brine (2 x 40 mL). After drying over MgS0 4 the solvents were evaporated to provide a dark orange oil. This was redissolved in E t 2 0 (125 mL), washed with 10% N a 2 S 2 0 3 (2 x 40 mL) and brine (40 mL), and dried over MgSC>4. Evaporation of the solvents provided a pale yellow, mobile oil which was purified by vacuum distillation to afford the methyl ether 124 as a colourless mobile liquid; yield: 15.6 g, 83%; bp 120°C/0.1 mm; [a] 2 2 -22.9° (c = 3.40, CHC13). C 1 7 H 3 4 0 2 S i Calc: C 68.39 H 11.48 % Anal.: C 68.41 H 11.42% Calc. Mass: 241.1624 (M+-tBu) Meas. Mass: 241.1624 IR (Neat): x> = 3055 (vinyl C-H); 2940,2910,2890,2840 (C-H); 1650 (C=CH2); 895 cm-* (vinyl C-H). MS (70 eV): m/z (%) = 241 (M+-*Bu, 24.9); 209 (11.8); 135 (60.4); 89 (100). IH NMR (CDCI3): 8 = 0.02 and 0.03 (3H each, 2 s, (CH 3) 2Si); 0.87 (3H, s, CH 3); 0.89 (9H, s, *BuSi); 1.19 -1.41 (2H, m); 1.80 - 1.98 (3H, m); 3.34 (3H, s, -OCH 3); 3.37 -3.45 (4H, m, -CH 2OMe and -CH 2OSi); 4.78 and 4.87 (IH each, 2 broad s, =CH2). Deprotection of silyl ether 124 to alcohol 125: TBDMSO 124 125 The silyl ether 124 (8.02 g, 26.9 mmol) was dissolved in dry THF (150 mL) under Ar, and tetrabutylammonium fluoride (40 mL, 1 M/THF, 40 mmol) was added by syringe. The mixture was stirred overnight, after which E t 2 0 (100 mL) and water (25 mL) were added. The 61 layers were separated and the aqueous phase was extracted with Et20 (2 x 25 mL) and the combined organics were washed with brine (25 mL) and dried over MgSC«4. Evaporation of the solvents afforded a dark yellow oil which was purified by column chromatography (230-400 mesh silica gel, 25 x 5 cm), eluting with 3:2 PE:Et20, to provide the alcohol 125 as a pale yellow liquid; yield: 4.77 g, 96%; bp 80-82°C/0.05 mm; [a] 2 3 -17° (c = 0.86, CHC13). C11H20O2 Calc: C 71.70 H 10.94 % Anal.: C 71.69 H 11.03% IR (Neat): v = 3425 (-OH); 3075 (=C-H); 2935,2860 (C-H); 1650 (C=CH2); 1H0 (C-O); 880 cm-1 (=C-H). MS (70 eV): m/z (%) = 184 (M+ 0.6); 183 (1.2); 168 (2.0); 142 (76.4); 122 (52.2); 121 (59.2); 107 (53.6); 100 (98.7); 95 (96.9); 79 (100.0). J H NMR (CDCI3): 6 = 0.84 (3H, s); 1.24 - 1.46 (2H, m); 1.72 - 1.82 (2H, m); 1.83 - 1.93 (IH, m); 1.99 - 2.09 (IH, m); 2.21 - 2.33 (IH, m); 2.39 - 2.48 (IH, m); 2.83 (IH, broad s, OH); (3.34 (3H, s, -OCH 3); 3.37 - 3.55 (4H, m, 2 x -CH 20-); 4.89 and 5.00 (IH each, 2 t, J = 2 Hz, =CH2). Oxidation of alcohol 125 to aldehyde 126: A flame-dried, 100 mL, 3-necked flask was fitted with a pressure equalizing addition funnel and a low temperature thermometer, flushed with Ar, and charged with dry CH2CI2 (50 mL) and (C0C1)2 (1.47 mL, 2.13 g, 16.8 mmol). The solution was cooled to -70°C and DMSO (1.39 mL, 1.53 g, 19.6 mmol) in dry CH2CI2 (10 mL) was added dropwise over 20 min, maintaining the temperature below -60°C. After a further 15 min the alcohol 125 (2.58 g, 14 mmol) in dry CH2CI2 (10 mL) was added dropwise over 25 min, again maintaining the temperature below -60°C. During the addition a white solid formed and the solution turned yellow. After stirring for 60 min, Et 3 N (5.85 mL, 4.25 g, 42 mmol) was added, initially dissolving the 62 precipitate and then framing another one. The mixture was allowed to warm to rt over 3 h, after which water (20 mL) was added. The layers were separated and the aqueous phase was extracted with CH2CI2 (2 x 10 mL). The combined CH 2Cl2 layers were washed with 1 N HC1 (25 mL), 5% NaHC03 (25 mL) and brine (25 mL), and dried over MgSC«4. Evaporation of the solvents provided an orange oil which was purified by column chromatography (230-400 mesh SiC«2,15 x 4.5 cm) eluting with 3:1 PE:Et 20 to afford the aldehyde 126 as a pale yellow oil; yield: 2.49 g, 98%. C i iH 1 8 02 Calc. Mass: 182.1307 Meas. Mass: 182.1307 IR (neat): u = 3050 (=C-H); 2960,2920,2840 (C-H); 2790,2690 (H-CO); 1715 (C=0); 1640 (OCH2); 900 cm-1 (=C-H). MS (70 eV): m/z = 167 (M+-CH3,0.4); 153 (21.0); 152 (1.0); 151 (1.2); 150 (4.3); 123 (37.1); 122 (89.3); 121 (100.0). iH NMR (CDCI3): 8 = 1.06 (3H, s, CH 3); 1.43 - 1.54 (IH, m); 1.55 - 1.61 (2H, m); 1.95 - 2.03 (IH, m); 2.32 - 2.46 (2H, m); 2.52 (IH, dAudq, J = 17, 8, 2 Hz); 3.29 (3H, s, -OCH 3); 3.31 - 3.37 (2H, m, -CH20-); 4.72 and 5.07 (IH each, 21, J = 2 Hz, =CH2); 9.28 (IH, s, -CHO). Conversion of aldehyde 126 to unsaturated methyl ester 128: A solution of rrimethyl phosphonoacetate (127, 8.00 mL, 9.00 g, 49.4 mmol) in dry toluene (100 mL) was added dropwise over 30 min to a vigorously stirred suspension of NaH (2.37 g, 98.7 mmol) in dry toluene (100 mL) under Ar. After a further 30 min, the aldehyde 126 (6.00 g, 32.9 mmol) in dry toluene (100 mL) was added dropwise over 30 min and the temperature was increased to 85°C. The mixture was stirred for 2.5 h, cooled, and poured onto ice (100 g) and NaCl (20 g). The layers were separated, the aqueous extracted with Et^O (2 x 50 mL) 63 and the combined organics washed with water (3 x 50 mL) and brine (50 mL) and dried over MgSC<4. Evaporation yielded the unsaturated methyl ester 128 as a yellow oil which was used without further purification; yield: 6.90 g, 88%. C 1 4 H 2 2 ° 3 Calc. Mass: 238.1569 Meas. Mass: 238.1575 IR (neat): v = 3050 (=C-H); 2940,2925,2850 (C-H); 1725 (C=0); 1650 (C=C); 890 cnr* (=C-H). MS (70 eV): m/z (%) = 238 (M+,1.3); 223 (3.2); 207 (6.4); 206 (21.8); 45 (100). *H NMR (CDC13): 8 = 1.02 (3H, s, CH 3); 1.35 - 1.49 (2H, m); 1.57 - 1.68 (IH, m); 1.90 - 2.00 (2H, m); 2.33 - 2.45 (IH, m); 2.47 - 2.58 (IH, m); 3.31 (3H, s, CH3O-); 3.34 - 3.41 (2H, m, -CH2O-); 3.75 (3H, s, -CO2CH3); 4.68 and 4.89 (IH each, 21, J= 2 Hz, 2 Hz, =CH2); 5.85 (IH, d, J = 16 Hz, -CH=CHC0 2Me); 6.89 (IH, d, J = 16 Hz, -CH=CHC02Me). Reduction of a,fJ-unsaturated ester 128 to ester 129: 128 129 Mg (1.68 g, 70 mmol) was added in one portion to a solution of the unsaturated ester (128, 3.00 g, 12.6 mmol) in dry MeOH (50 mL). The mixture was stirred vigorously and an exothermic reaction took place, causing the MeOH to reflux for 30 min. Once this had ceased the mixture was stirred for a further 60 min and a second portion of Mg (1.50 g, 62.5 mmol) was added and stirring was continued for a further 1.5 h, before the mixture was poured into water (50 mL) and Et 2 0 (50 mL). While stirring vigorously, 6 N HC1 was added dropwise until all the solid had dissolved. The layers were separated, the aqueous phase was extracted with Et 2 0 (2 x 50 mL) and the combined organics were washed with water (25 mL) and NaHCC>3 (25 mL), and dried over MgS04- Evaporation of the solvents produced a pale yellow mobile liquid which was 6 4 purified by column chromatography (70-230 mesh Si0 2 ,15 x 3 cm) eluting with 9:1 PE:Et 20, to afford the saturated ester 129 as a colourless liquid; yield: 2.56 g, 85%. C14H24O3 Calc: C 69.96 H 10.07 % Anal.: C 70.06 H 10.13% Calc. Mass: 240.1725 Meas. Mass: 240.1718 IR (neat): \> = 3050 (=C-H); 2940,2925,2850 (C-H); 1740 (C=0); 1645 ( 0 = 0 ^ ; 890 cnr* (=C-H). MS (70 eV): m/z (%) = 240 (M+, 0.1); 209 (4.5); 208 (16.8); 95 (100). IH NMR (CDCI3): 5 = 0.88 (3H, s, CH 3 ) ; 1.22 - 1.41 (2H, m); 1.66 - 1.74 (2H, m); 1.75 -1.82 (2H, m); 1.83 - 1.89 (IH, m); 3.34 (3H, s, -OCH 3); 3.36 - 3.48 (2H, m, -CH 20-); 3.66 (3H, s, -CO2CH3); 4.73 and 4.91 (IH each, 21, J = 2 Hz, =CH2). Reduction of ester 129 to aldehyde 130: 129 130 A solution of the ester 129 (1.86 g, 7.74 mmol) in dry CH 2 C1 2 (75 mL) was cooled under Ar to -78°C and DfJBAL (9.5 mL, 1 M/hexanes, 9.5 mmol) was added by syringe. The solution was stirred for 1.5 h, when Na2SO4ol0 H 2 0 (s) was added, and stirring continued for a further 30 min at -78°C, before warming to rt The mixture was filtered, the solution dried over MgSC>4, and evaporated to provide the aldehyde 130 as a colourless oil, which was used without further purification; yield: 1.54 g, 85%. IR (neat): X) = 3050 (=C-H); 2940,2920,2855 (C-H); 2820,2700 (-CHO); 1720 (C=0); 1645 (C=CH2); 880cm-l (=C-H). MS (70 eV): m/z (%) = 210 (M+, 0.5); 178 (10.4); 95 (100). 65 *H NMR (CDCI3): 8 = 0.89 (3H, s, CH 3); 1.19 - 1.42 (3H, m); 1.64 - 1.91 (4H, m); 2.16 - 2.28 (IH, m); 2.40 (2H, td, J = 9 Hz, 3 Hz, -CH 2CHO); 2.40 - 2.49 (IH, m); 3.33 (3H, s, -OCH3); 3.35 - 3.48 (2H, m, -CH2O-); 4.70 and 4.91 (IH each, 21, J = 2 Hz, 2 Hz, =CH2); 9.76 (IH, t, J = 3 Hz, -CHO). Cyclisadon of aldehyde 130 to bicyclic homoallylic alcohol 132: 130 132 A solution of the aldehyde 130 (4.02 g, 19.1 mmol) in dry CH 2C1 2 (120 mL) was cooled under Ar to 0°C and M e ^ l C l (1.9 mL, 1 M/hexane, 1.9 mmol) was added by syringe. After 20 min, ice water (40 mL) and 1 N HCl (5 mL) were added. The layers were separated and the aqueous phase extracted with CH 2C1 2 (2 x 20 mL) and the combined organics were washed with water (40 mL), 5% NaHC03 (40 mL) and brine (40 mL). After drying over MgS04 the solvent was evaporated to yield a viscous, yellow oil. This was purified by column chromatography (70-230 mesh Si0 2,4 x 10 cm), eluting with 3:1 PE:Et20, to provide the homoallylic alcohol 132 as a viscous, pale yellow oil; yield: 3.12 g, 78%. C 1 3 H 2 2 ° 2 Calc- M a s s : 210.1620 Meas. Mass: 210.1617 IR (neat): t) = 3420 (OH); 3030 (=C-H); 2950,2920,2880, 2850,2815 (C-H); 1650 cur 1 (C=C). MS (70 eV): m/z (%) = 210 (M+, 2.0); 192 (47.8); 160 (59.5); 91 (100). *H NMR (CDCI3): 8 = 0.87 (3H, s, CH 3); 1.53 (1H, broad s, exchanges with D 2 0 , OH); 1.56 -1.66 (3H, m); 1.70 - 1.84 (3H, m); 1.87 - 1.98 (2H, m); 2.30 - 2.42 (3H, m); 3.35 (3H, s, -OCH 3); 3.39 - 3.48 (2H, m, -CH 20-); 4.09 (IH, quintet, J = 3.5 Hz, CflOH); 5.39 (IH, broad s, =CH). 66 Preparation of Crabtree's Catalyst (134): All solvents were degassed by freezing to -78°C, pumping at 0.1 mm for five minutes, and thawing, four times. Potassium hexafluorophosphate (KPF6,286 mg, 1.55 mmol) and [Ir(COD)Cl]2 (500 mg, 0.744 mmol) were placed in a 25 mL rbf and the atmosphere was flushed with Ar. Degassed pyridine (1.10 mL, 1.08 g, 13.6 mmol), acetone (7.2 mL), EtOH (3.6 mL) and water (0.72 mL) were added by cannula and the suspension was stirred vigorously for 30 min. The solvents were removed under vacuum and the remaining solid was triturated with degassed water (3x5 mL) and dried under vacuum to provide [Ir(C0D)py2]PF6 as a beige solid; yield: 709 mg, 79%. The [Ir(COD)py2]PF6 was dissolved in degassed CH2CI2 (15 mL) and added by cannula to tricyclohexylphosphine 0?Cy3,0.42 g, 1.5 mmol) under Ar and stirred at rt. The dark yellow solution turned red as the PCV3 dissolved. After 10 min the solvent was evaporated and the orange solid was recrystallised from degassed CH2CI2 and Et^ O to afford Crabtree's catalyst, [Ir(COD)py(PCy3)]PF6 (134) as small orange crystals; yield: 875 mg, 93%. IH NMR (Degassed CDCI3): = 0.95 -1.15 (m); 1.20 - 1.35 (m); 1.40 -1.60 (m); 1.60 - 2.10 (m); 2.24 - 2.45 (m); 3.99 and 4.08 (2H each, 2 broad s, COD vinyl H's); 7.67 (2H, t, J = 8 Hz, py C(3) and C(5) H's); 7.91 (IH, t, J = 8 Hz, py C(4) H); 8.29 (2H, d, J = 8 Hz, py C(2) and C(6) H's). Lit.53a lH NMR (CDCI3,35°C): = 0.8 - 2.5 (Cy); 4.00 (COD vinyl); 7.6 - 7.8 and 8.6 - 8.9 (py). 67 Homogeneous hydrogenation of homoallylic alcohol 132: H 132 138 139 A 25 mL rbf containing a stir bar was flame dried and cooled under Ar. Crabtree's catalyst (134, [Ir(COD)py(PCy3)]PF6, 31.5 mg, 0.039 mmol) was added, followed by dry, degassed CH2CI2 (1 mL), affording a bright orange solution, and the flask was flushed with Ar. The alcohol 132 (252 mg, 1.20 mmol) was degassed by freezing, pumping and thawing (3 x), and dissolved in dry, degassed CH2CI2 (0.60 mL). This solution was added to that of the catalyst by syringe, and the Ar atmosphere replaced by H2. Vigorous stirring caused the colour of the solution to fade to pale yellow within 5 min. Stirring was continued overnight before the mixture was diluted with CH2Cl2 (5 mL) and PE (5 mL), resulting in the precipitation of a pale yellow solid. The solvent was removed by pipette and the solid rinsed with 1:1 PE:CH2C12 (3x1 mL). The combined solvents were evaporated to provide a mixture of an orange solid and a yellow oil. The mixture was purified by column chromatography (230-400 mesh SiC>2, 1 x 10 cm), eluting with 9:1 PE:Et20 and increasing polarity to 1:1, to afford, in order of elution, the diene 138 (13.5 mg, 6%), starting material 132 (80 mg, 32 %), and the ketone 139 (22 mg, 9%). Diene 138: IR (neat): D = 3020 (=C-H); 2950,2910,2850,2825 (C-H); 1640 (C=C); 830, 820 cm-l (=C-H). *H NMR (CDCI3): 5 = 0.83 (3H, s, CH3); 1.36 (IH, td, J = 12.5 Hz, 6 Hz,); 1.58 - 1.71 (1 H, m); 1.75 - 1.90 (3H, m): 2.05 - 2.29 (3H, m); 2.32 - 2.43 (IH, m); 3.36 (3H, s, -OCH3); 3.39 - 3.48 (2H, m, -CH20-); 5.39 (broad s), 5.70 - 5.78 (m), 6.18 (dd, J = 10 Hz, 3 Hz), (IH each, 3 x =C-H). Ketone 139: IR (neat): x> = 2940,2860 (C-H); 1715 cm-l (c=0). 68 *H NMR ( CDC I 3 ) : 8 = 0.92 ( 3 H , s, CH 3); 1.12 - 1.21 ( 1H , m); 1.24 - 1.34 (IH, m); 1.39 - 1.48 (IH, m); 1.66 - 1.99 ( 7H , m); 2.18 - 2.34 ( 3H , m); 2.38 (IH, dj^d, J = 16, 5.5 Hz); 3.34 ( 3H , s, - O C H 3 ) ; 3.37 - 3.48 ( 2 H , m, -CH 2OMe). To a solution of the alkene 132 (75 mg, 0.36 mmol) in EtOAc (10 mL) was added 10% Pd on charcoal (19 mg, 0.02 mmol) and the suspension was stirred vigorously under an atmosphere of H 2 for 24 h, after which GC indicated the presence of starting material and two other major compounds. The solution was diluted with E t 2 0 (20 mL), Celite was added and the solvent filtered and evaporated to yield a pale yellow oil. Column chromatography (230-400 mesh Si0 2 ,1 x 5 cm), eluting with 2:1 Et 2 0:PE, afforded impure starting material 132; yield: 20 mg, 26%, followed by the /ra/w-diastereomer 140 as a colourless viscous oil; yield: 14 mg, 19%. IR (neat): u = 3450 (O-H); 2950,2910,2875 cnr * (C-H). lH NMR (CDCI3): 6 = 0.92 (3H, s, angular CH 3); 1.10 -1.95 (11 H, m); 2.19 - 2.31 (3H, m); 2.37 (IH, dAfid, J = 16, 6 Hz); 3.33 (3H, s, -OCH 3); 3.36 - 3.48 (2H, m, -CH 2OMe); 4.10 (IH, quintet, J = 3.5 Hz, -CH(OH)-). Further elution provided the cw-diastereomer 141 as a colourless viscous oil; yield: 22.7 mg, 30%. IR (neat): a) = 3400 (O-H); 2960,2915,2880 cm-l(C-H). *H NMR (CDCI3): 8 = 0.73 (3H, s, angular CH 3); 1.15 -1.43 (5H, m); 1.61 - 1.74 (5H, m); 1.77 (IH, broad s, exchanges with D 2 0 , -OH); 1.89 (IH, dAfid, J = 12, 6 Hz); 1.92 -2.09 (3H, m); 3.33 (3H, s, -OCH3); 3.36 - 3.44 (2H, -CH 2OMe); 3.54 (IH, tt, J = 11.5, 4 Hz, -CH(OH)-). Heterogeneous catalytic hydrogenation of bicyclic homoallylic alcohol 132: 132 140 141 69 PDC oxidation of bicyclic homoallylic alcohol 132: 132 142 143 A solution of the alcohol 132 (435 mg, 2.07 mmol) in dry CH2Cl2 (50 mL) was stirred under Ax, and PDC (1.58 g, 4.2 mmol) was added. The solution was stirred overnight and then filtered through a pad of Si02, Celite and MgS04 (5 g each), rinsing well with CH2CI2 (30 mL). The solvent was evaporated to afford a dark yellow oil which was purified by column chromatography (230-400 mesh Si02,2x8 cm), eluting with 4:1 PE:Et20 and increasing polarity quickly to 1:1 PE:Et20. This initially provided the enone 142 as a colourless oil; yield: 96 mg, 22%. C 1 3 H 2 0 ° 2 IR (neat): D = 3020 (=C-H); 2910,2855,2815 (C-H); 1665 cm-l (C=0). MS (70 eV): m/z (%) = 208 (M+, 37.4); 193 (36.8); 176 (21.8); 121 (100.0). IH NMR (CDCI3): 8 = 1.03 (3H, s, CH3); 1.45 - 1.58 (2H, m); 1.64 -1.84 (3H, m); 1.97 - 2.06 (2H, m); 2.37 (IH, d^ddd, J = 18, 5, 2, 1 Hz); 2.41 - 2.57 (2H, m); 2.67 (IH, d^dt, J = 20, 10.5, 2 Hz); 3.35 (3H, s, OCH3); 3.38 - 3.49 (2H, m, -CH20); 5.77 (IH, broad s, =C-H). Futher elution provided the enedione 143 as a yellow viscous oil; yield: 117 mg, 25%. Cl3H18°3 IR (neat): 0) = 3030 (=C-H); 2920,2855,2815 (C-H); 1720,1680 cm-l [C(0)CH=CRC(0)]. MS (70 eV): m/z (%) = 222 (M+ 26.8); 207 (3.4); 190 (49.1); 175 (9.1); 163 (90.1); 80 (100.0). 7 0 lH NMR (CDCI3): 8 = 1.19 (3H, s, CH3); 1.60 - 1.70 (IH, m); 1.87 - 1.99 (2H, m); 2.02 - 2.12 (IH, m); 2.24 (IH, dd, J = 19, 12 Hz); 2.23 - 2.28 (IH, m); 2.52 (IH, dARddd, J = 19, 5.5, 2, 1 Hz); 2.58 - 2.69 (2H, m); 3.36 (3H, s, OCH3); 3.40 - 3.51 (2H, m, -CH20); 6.27 (IH, s, =C-H). Jones oxidation of bicyclic homoallylic alcohol 132: A solution of the alcohol 132 (497 mg, 2.36 mol) in acetone (10 mL) was stirred at rt and Jones' reagent was added dropwise until a permanent orange colour was obtained (2.5 mL). The mixture was diluted with water (10 mL) and saturated NaHSC*3 (aq, 10 mL), and the resulting blue-green solution was saturated with NaCl and extracted with Et 20 (3 x 20 mL). The combined extracts were washed with water (10 mL) and saturated NaHCO^ (aq, 10 mL), and dried over MgSC«4. Evaporation of the solvent provided a bright yellow oil which was purified by column chromatography (230-400 mesh SiO ,^ 2x7 cm), eluting with 3:1 PE:Et20 and increasing polarity to 1:1 PE:Et20, to afford the enone 142 as a pale yellow oil; yield: 59 mg, 12%. The spectral details of this compound were identical with those obtained for 142 produced by the PDC oxidation. Further elution afforded the enedione 143 as a yellow viscous oil; yield: 121 mg, 23%. The spectral details of this compound were identical with those of 143 produced in the PDC oxidation. Swern oxidation of bicyclic homoallylic alcohol 132: A solution of oxalyl chloride (0.45 mL, 660 mg, 5.20 mmol) in dry CH2C12 (25 mL) was cooled under Ar to -78°C and DMSO (0.43 mL, 473 mg, 6.06 mmol) in dry CH2C12 (10 mL) was added dropwise over 5 min, keeping the temperature below -60°C. After stirring an additional 15 min, a solution of the alcohol (132,911 mg, 4.33 mmol) in dry CH2C12 (15 mL) was added over 7 1 10 min, again keeping the temperature below -60°C. The solution was stirred an additional 1.5 h before Et3N (1.8 mL, 1.3 g, 13 mmol) was added, and the temperature allowed to rise to rt overnight Water (15 mL) was then added, the layers were separated and the CH 2Cl2 was washed with brine (3 x 20 mL). The combined washings were extracted with CH2CI2 (20 mL) and the organics were combined and dried over MgS0 4 . Evaporation of the solvents provided a dark orange oil which was purified by column chromatography (230-400 mesh SiC<2, 3 x 12 cm), eluting with 9:1 PE:Et20 and increasing polarity to 1:1 PE:Et20, to afford the enone 142 as a colourless viscous oil; yield: 205 mg, 23%. The specrtal details of this compound were identical with those of 142 obtained from the PDC oxidation. Further elution afforded the enedione 143 as a yellow viscous oil; yield: 265 mg, 28%. The spectral details of this compound were identical with those of 143 obtained from the PDC oxidation. TPAP oxidation of bicyclic homoallylic alcohol 132: A solution of the alcohol 132 (591 mg, 2.81 mmol) and N-methylmorpholine-N-oxide (NMO, 494 mg, 4.22 mmol) in dry CH2CI2 (30 mL) was stirred under Ar and powdered 4A molecular sieves (500 mg) were added. The suspension was stirred for 5 min and tetrapropylammonium perruthenate (TPAP, 5 mg, 0.014 mmol) was added, and the mixture stirred overnight TLC indicated that considerable starting material was still present, so additional NMO (330 mg, 2.8 mmol) and TPAP (49 mg, 0.14 mmol) were added and stirring was continued for 2 d. The mixture was diluted with CH2CI2 (50 mL), filtered, and the solvent was washed with 10% NaHS0 3 (10 mL), brine (10 mL) and CuS0 4 (10 mL), and dried over MgS0 4 . Evaporation of the solvent provided a dark orange oil which was purified by column chromatography (230-400 mesh S i 0 2 ,2x7 cm), eluting with 1:1 PE:Et20, to provide recovered starting material 132; 136 mg, 7 2 23%. Further elution provided a yellow oil, the spectral characteristics of which were identical to those of the enedione 143 obtained from the PDC oxidation; yield: 46 mg, 7%. Conversion of homoallylic alcohol 132 to tricyclic chloro ether 144: 132 144 A solution of the alcohol 132 (497 mg, 2.36 mmol) in AcOH (3 mL) was cooled in an ice bath while stirring rapidly. A solution of NaOCl (aq, 5% by weight, 4 mL, 2.6 mmol) was added dropwise and the mixture was stirred for 30 min, after which a starch-KI test was negative. NaOCl was added to produce a positive test (4 mL) and the mixture was stirred a further S min, after which excess NaOCl was quenched with NaHS03 (2 mL). The solution was diluted with water (10 mL) and extracted with Et20 (3 x 10 mL). The combined extracts were washed with water (3 x 15 mL), NaHCC^ (3x5 mL) and brine (5 mL), and dried over MgSO^ Evaporation of the solvent provided a viscous, pale yellow oil which was purified by column chromatography (230-400 mesh Si0 2 ,2x8 cm), eluting with 2:1 PE:Et20 to afford the tricyclic chloro ether 144 as a colourless mobile oil; yield: 122 mg, 21%. C 1 3 H 2 1 C10 2 IR (neat): v = 2955,2940,2855,2810 (C-H); 1445; 1110 cm-l (C-O). MS (70 eV): m/z (%) = 246,244 (M+, 1.8,5.1); 245, 243 (1.9,2.6); 209 (78.2); 199 (47.9); 141 (100.0). lH NMR (CDC13): 8 = 1.19 (3H, s, CH 3); 1.39 - 1.47 (IH, m); 1.48 - 1.60 (3H, m); 1.77 - 1.93 (3H, m); 2.21 - 2.28 (IH, m); 2.34 - 2.44 (2H, m); 2.63 (IH, ddd, J = 13, 5, 2 Hz); 3.34 (3H, s, OCH3); 3.38 - 3.42 (2H, m, -CH 20); 4.06 and 4.45 (IH each, 2 t, J = 7 Hz, J = 5 Hz, protons a to cyclic ether oxygen). 7 3 A c e t y l a t i o n o f a l c o h o l 132 t o a c e t a t e 146: HO' OMe AcO OMe 132 146 A s o l u t i o n o f t h e a l c o h o l 132 ( 1 0 0 m g , 0 . 4 8 m m o l ) a n d D M A P ( 1 5 m g , 0 . 1 2 m m o l ) i n d r y p y r i d i n e ( 5 m L ) w a s s t i r r e d u n d e r A r , a n d a c e t i c a n h y d r i d e ( 0 . 0 7 0 m L , 7 4 m g , 0 . 7 2 m m o l ) w a s a d d e d b y s y r i n g e . T h e s o l u t i o n w a s s t i r r e d o v e r n i g h t , a f t e r w h i c h e x c e s s r e a g e n t w a s q u e n c h e d b y a d d i n g M e O H ( 0 . 5 m L ) a n d s t i r r i n g a f u r t h e r 3 0 m i n . T h e s o l u t i o n w a s t h e n d i l u t e d w i t h E t 2 0 ( 3 0 m L ) a n d w a s h e d w i t h 1 N H C l ( 3 x 1 0 m L ) , w a t e r ( 1 0 m L ) a n d 5 % N a H C 0 3 ( 1 0 m L ) , a n d d r i e d o v e r M g S O ^ . E v a p o r a t i o n o f t h e s o l v e n t p r o d u c e d a p a l e y e l l o w o i l w h i c h w a s p u r i f i e d b y c o l u m n c h r o m a t o g r a p h y ( 2 3 0 - 4 0 0 m e s h S i 0 2 , 1 x 5 c m ) , e l u t i n g w i t h 1 9 : 1 P E : E t 2 0 a n d i n c r e a s i n g p o l a r i t y t o 4 : 1 P E : E t 2 0 , t o p r o v i d e t h e a c e t a t e 146 a s a c o l o u r l e s s m o b i l e o i l ; y i e l d : 5 8 m g , 4 0 % . I R ( n e a t ) : \) = 3 0 1 0 ( = C - H ) ; 2 9 0 0 , 2 8 4 0 , 2 8 0 0 ( C - H ) ; 1 7 2 5 ( C = 0 ) ; 1 2 5 0 , 1 2 3 0 c m - l ( C - O ) . M S ( 7 0 e V ) : m / z ( % ) = 2 5 2 ( M + , 0 . 5 ) ; 1 9 2 ( 7 1 . 1 ) ; 1 7 7 ( 7 . 1 ) ; 1 6 0 ( 2 9 . 6 ) ; 1 3 3 ( 1 0 0 . 0 ) . * H N M R ( C D C 1 3 ) : 6 = 0 . 8 7 ( 3 H , s , C H 3 ) ; 1 . 5 0 - 1 . 6 5 ( 3 H , m ) ; 1 . 7 2 - 1 . 8 6 ( 3 H , m ) ; 1 . 9 0 - 1 . 9 6 ( 2 H , m ) ; 2 . 0 2 ( 3 H , s , C H 3 C O - ) ; 2 . 2 4 - 2 . 3 6 ( 2 H , m ) ; 2 . 5 1 ( I H , d t , J = 5 . 5 , 2 H z ) ; 3 . 3 5 ( 3 H , s , O C H 3 ) ; 3 . 3 9 - 3 . 4 7 ( 2 H , m , - C H 2 0 - ) ; 5 . 0 6 ( I H , q u i n t e t , J = 3 H z , - C H O A c ) ; 5 . 2 8 ( I H , s , = C - H ) . 13c N M R ( C D C 1 3 ) : 5 = 1 6 . 5 0 8 ( a n g u l a r C H 3 ) ; 2 1 . 4 6 5 ( R R ' C H ( C H 2 ) 2 O M e ) ; 2 6 . 1 5 6 , 2 9 . 8 6 5 , 3 0 . 6 2 8 , 3 4 . 2 2 9 , 3 5 . 8 4 1 ( 5 x " a l i p h a t i c " C H 2 ) ; 4 5 . 8 6 5 ( R R ' R " £ C H 3 ) ; 4 8 . 7 6 1 ( £ H 3 C O - ) ; 5 8 . 5 6 8 ( R R ' C H O A c ) ; 6 9 . 9 0 6 ( - O C H 3 ) ; 7 2 . 2 8 4 ( - C H 2 0 - ) ; 1 2 1 . 8 0 4 ( = C H R ) ; 1 4 5 . 1 7 8 ( R R ' C = ) ; 1 7 0 . 5 3 8 ( C H ^ O - ) . Hydrolysis of ester 129 to acid 149: 129 149 A solution of the ester 129 (1.86 g, 7.80 mmol) in MeOH (40 mL) was stirred at 0°C and KOH (1.31 g, 23.4 mmol) in water (20 mL) was added. The mixture was stirred for 45 min. at 0°C and then at rt for 2 h. The solution was poured into brine (50 mL) and extracted with Et20 (2 x 25 mL). The aqueous solution was acidified to pH 2 with 6 N HC1 and immediately extracted with Et20 (3 x 50 mL). The extracts were washed with water (2 x 25 mL) and dried over MgSO^ Evaporation of the Et20 afforded a pale yellow mobile oil which was purified by column chromatography (70-230 mesh Si02,3 x 15 cm), eluting with 1:1 PE:Et20 to provide the acid 149 as a colourless mobile oil; yield: 1.77 g, 100%. C13H2203 Calc. Mass: 226.1568 Meas. Mass: 226.1574 IR (neat): v = 2400 - 3300 (broad, -COOH); 2940,2885 (C-H); 1710 (C=0); 1650 (C=CH2); 880 cm-l (=C-H). MS (70 eV): m/z (%) = 226 (M+, 0.1); 208 (0.4); 195 (1.1); 194 (7.1); 176 (2.7); 95 (100.0). *H NMR (CDC13): 8 = 0.89 (3H, s, CH3); 1.18 - 1.43 (2H, m); 1.66 - 1.89 (5H, m); 2.14 - 2.25 (IH, m); 2.26 - 2.35 (2H, m, -CH2COO-); 3.33 (3H, s, -OCH3); 3.34 - 3.49 (2H, -CH20-); 4.73 and 4.92 (IH each, 2 broad s, =CH2). Cyclisation of acid 149 to bicyclic enone 142: 149 150 142 A solution of the acid 149 (1.00 g, 4.42 mmol) in dry CH2CI2 (75 mL) was stirred under Ar and trifluoroacetic anhydride (1.85 mL, 2.75 g, 13.1 mmol) was added by syringe. Stirring was continued for 45 ruin before water (20 mL) was added. The layers were separated and the CH2CI2 was washed with NaHCO^ (20 mL) and brine (20 mL), and dried over MgSO .^ Evaporation of the solvent provided a yellow oil which was purified by column chromatography (70-230 mesh SiO ,^ 3 x 9.5 cm), eluting with 4:1 PE:Et20, to afford the dienol trifluoroacetate 150 as a colourless mobile oil; yield: 510 mg, 40%. IR (neat): D = 3055 (=C-H); 2940,2875 (C-H); 1800 (CF3C=0); 1660,1620 cm"1 (C=C). *H NMR (CDCI3): 8 = 0.90 (3H, s, CH3); 1.46 - 1.58 (IH, m); 1.60 - 1.70 (IH, m); 1.72 - 1.94 (3H, m); 2.04 - 2.12 (IH, m); 2.14 - 2.27 (IH, m); 2.40 - 2.49 (IH, m); 2.54 - 2.61 (IH, m); 3.35 (3H, s, -OCH3); 3.39 - 3.50 (2H, m, -CH20-); 5.55 (IH, broad s, =Cy-H); 6.14 (IH, d, J = 3 Hz, =Ca-H). Further elution afforded the enone 142 as a pale yellow mobile oil; yield: 488 mg, 53%; [a]20 770 (C = 0.316, CHCI3). C 1 3 H 2 0 ° 2 Calc. Mass: 208.1463 Meas. Mass: 208.1463 IR (neat): x> = 2945,2870 (C-H); 1665 cnr* (C=C-C=0). MS (70 eV): m/z (%) = 208 (M+, 26.7); 193 (25.9); 180 (7.3); 176 (12.6); 121 (100). IH NMR (CDC13): 8 = 1.02 (3H, s, CH3); 1.45 - 1.59 (2H, m); 1.64 - 1.84 (3H, m); 1.97 - 2.07 (2H, m); 2.37 (IH, d^dd, J = 18 Hz, 5.5 Hz, 2 Hz); 2.41 - 2.57 (2H, m); 2.68 (IH, dAfidt, J = 18 Hz, 10.5 Hz, 2.5 Hz); 3.35 (3H, s, -OCH3); 3.39 - 3.49 (2H, m, -CH20-); 5.77 (IH, broad s, =C-H). 76 Treatment of a solution of the dienol trifluoroacetate 150 in MeOH (10 mL) with p-TsOH (35 mg, 0.2 mmol) for 1 h at rt provided a further 231 mg of 142 after chromatography; total yield: 719 mg, 78%. Oxidation of alcohol 121 to aldehyde 154: A solution of oxalyl chloride (2.64 mL, 3.85 g, 30.3 mmol) in dry CH2CI2 was cooled under Ar to -78°C. A solution of DMSO (2.15 mL, 2.37 g, 30.3 mmol) in dry CH 2 C1 2 (20 mL) was added dropwise over 20 min, keeping the temperature below -60°C. After stirring an additional 15 min, a solution of the alcohol 121 (5.00 g, 25.2 mmol) in dry CH2CI2 (40 mL) was added over 20 min, again keeping the temperature below -60°C. Following the addition, the solution was stirred for 1.5 h, after which triethylamine (10.5 mL, 7.65 g, 75.6 mmol) was added and the temperature was allowed to increase to rt overnight. Water (50 mL) was added, the layers were separated, and the aqueous phase was extracted with CH2CI2 (25 mL). The combined organics were washed with 1 N HC1 (2 x 25 mL), NaHC03 (25 mL), and brine (25 mL), and dried over MgS04- Evaporation of the solvent afforded a pale orange oil which was purified by column chromatography (70-230 mesh Si02,4.5 x 15 cm), eluting with 5:1 PE:Et20 to provide the aldehyde ester as a pale yellow mobile liquid; yield: 4.68 g, 95%; bp: 75°C (0.1 mm); [a] 2 4 -47.4° (c = 2.07, CHCI3). C n H 1 6 0 3 Calc: C 67.32 H 8.22 % IR (neat): \> = 3090 (=C-H); 2960,2895,2850 (C-H); 2820,2725 (-CO-H); 1740 (C=0,ester); 1710 (C=0, aldehyde); 1650 (C=C); 895 cm-1 (=0*2)-121 154 Anal.: C 67.21 H 8.36 % 77 MS (70 eV): m/z (%) = 182 (M+ 10.5); 168 (12.6); 167 (24.5); 166 (11.8); 165 (17.4); 123 (19.9); 107 (100.0). ! H NMR (CDC13): 8 = 1.05 (3H, s, CH 3); 1.51 (IH, qd, J = 12, 8.5 Hz); 1.98 - 2.06 (IH, m); 2.34 (2H, dd, J = 7,1.5 Hz, -CH 2 C0 2 Me); 2.38 - 2.47 (IH, m); 2.52 (IH, d A B dq, J = 17, 8.5, 2 Hz); 2.77 (IH, dq, J = 12,7 Hz); 3.67 (3H, s, -OCH3); 4.78 and 5.12 (IH each, 21, J = 2 Hz, 2 Hz, =CH2); 9.30 (IH, s, -CHO). t-Butyl dimethylphosphonoacetate (155): O 0 0 P(OMe) 3 + B rvA 0tB u ^ M e O ^ f ^ O ^ OMe 1 5 5 Trimethylphosphite (5.0 mL, 5.26 g, 42.4 mmol) was placed in a 25 mL rbf and cooled in a cold water bath. t-Butyl bromoacetate (6.85 mL, 8.27 g, 42.4 mmol) was added by syringe, a condenser was placed on the flask, and the mixture was heated to 80°C for 1 h. The resulting pale yellow liquid was purified by vacuum distillation to provide the phosphonoacetate 155 as a colourless mobile liquid; yield: 6.65 g, 70%; bp: 92-94°C (0.1 mm). IR (neat): v = 2995,2885 (C-H); 1730 (C=0). *H NMR (CDCI3): 8 = 1.48 (9H, s, *Bu-); 2.92 (2H, d, J = 22 Hz, P(0)CH 2-); 3.81 (6H, d, J = l l H z , - O C H 3 ) . Conversion of aldehyde 154 to a,B-unsaturated t-butyl ester 156: 156 A suspension of NaH (653 mg, 27.2 mmol) in dry THF (50 mL) was stirred under Ar, and a solution of lbutyl dimethyl phosphonoacetate (155, 6.10 g, 27.2 mmol) in dry THF (30 mL) was added dropwise over 20 min, causing evolution of H 2 and the solution to become turbid. 78 After stirring an additional 1 h, a solution of the aldehyde 154 (4.45 g, 22.7 mmol) in dry THF (50 mL) was added dropwise over 30 min, while stirring vigorously. Stirring was continued for a further 1 h, after which water (50 mL) and Et20 (50 mL) were added, the layers separated and the organics were washed with brine (25 mL). The combined aqueous phases were extracted with Et 2 0 (2 x 25 mL) and the combined organics were dried over MgS0 4 . Evaporation of the solvents afforded a thick orange oil which was purified by column chromatography (70-230 mesh SiO^, 4.5 x 15 cm) to provide the unsaturated t-butyl ester 156, as a pale yellow mobile oil; yield: 6.68 g, 100%; [a] 1 8 -33.9° (c - 1.01, CHC13). C17H26O4 Calc: C 69.36 H 8.90 % Anal.: C 69.60 H 9.00 % IR (neat): x> = 3095 (=C-H); 2980,2925,2895 (C-H); 1740 (C=0, methyl ester); 1710 (C=0, t-butyl ester); 1645 (C=C); 895 cm"1 (=CH2)-MS (70 eV): m/z (%) = 238 (M+-(CH3)2C=CH2,31.9); 220 (100.0). *H NMR (CDC13): 8 = 1.02 (3H, s, CH 3); 1.41 - 1.53 (IH, m); 1.50 (9H, s, *BuO-); 1.96 - 2.05 (IH, m); 2.15 (IH, dd, J = 16, 11 Hz); 2.28 - 2.37 (2H, m); 2.38 - 2.57 (2H, m); 3.65 (3H, s -OCH 3); 4.72 and 4.91 (IH each, 21, J = 2 Hz, 2 Hz, =CH2); 5.75 (IH, d, J = 16 Hz, -C(0)CH=CH-); 6.75 (IH, d, J = 16 Hz, -C(0)CH=Qi-). Conversion of a,fJ-unsaturated t-butyl ester 156 to t-butyl ester 151 and unsaturated acid 157: O y-C0 2Me Q _~C02Me Q --C0 2Me 156 151 157 A solution M the unsaturated ester 156 (3.18 g, 10.8 mmol) in dry MeOH (50 mL) was cooled to 0°C and Mg (790 mg, 32.4 mmol) was added in one portion. The mixture was stirred vigorously for 5 h, when no Mg remained. GC indicated that starting material was still present, so additional Mg (110 mg, 4.5 mmol) was added and stirring was continued overnight at rt. The mixture was diluted with Et20 (40 mL) and water (10 mL), and just enough 6 N HC1 was added to 79 dissolve the jellylike solid. The layers were separated and the aqueous phase was extracted with 1:1 PE:Et20 (2 x 30mL). The combined organic solvents were washed with water (25 mL), NaHC03 (25 mL) and brine (25 mL), and dried over MgSO^. Evaporation of the solvents afforded a pale yellow mobile liquid which was purified by column chromatography (70-230 mesh SiC>2,3x15 cm), eluting with 9:1 PE:Et20 to provide the saturated diester 151 as a colourless oil; yield: 2.13 g, 66%; [a] 19-24.0° (c = 1.72, CHC13). C17H28O4 Calc: C 68.89 H 9.52% Anal.: C 69.19 H 9.36 % IR (neat): v = 3080 (=C-H); 2970,2885 (C-H); 1730 (C=0); 1650 (C=C); 885 cm-l (=CH2). MS (70 eV): m/z (%) = 296 (M+, 0.2); 278 (1.1); 265 (0.4); 240 (11.6); 223 (21.0); 222 (41.4); 167 (100.0). lH NMR (CDCI3): 8 = 0.88 (3H, s, CH 3); 1.26 - 1.39 (IH, m); 1.44 (9H, s, tBuO-); 1.64 - 1.80 (2H, m); 1.88 - 1.96 (IH, m); 2.09 - 2.24 (4H, m); 2.25 - 2.34 (IH, m); 2.37 - 2.48 (2H, m); 3.70 (3H, s, -OCH3); 4.74 and 4.92 (IH each, 21, J = 2 Hz, 2 Hz, =CH2). The combined aqueous layers from the work-up were acidified to pH 1 with 6 N HCl and extracted with EtOAc (3 x 30 mL). The extracts were washed with water (2 x 25 mL), dried over MgSC»4, and evaporated to provide the unsaturated acid 157 as a viscous, pale yellow oil; yield: 851 mg, 33%. C 1 3 H 1 8 0 4 Calc. Mass: 238.1205 Meas. Mass: 238.1203 IR (neat): v = 3500 - 2500 (broad, -COOH); 2985,2935 (C-H); 1740 (C=0, ester); 1700 (C=0, acid); 1645 (C=C); 890 cm-l (=0^. MS (70 eV): m/z (%) * 238 (M + , U ) ; 220 (29.9); 206 (6.9); 192 (15,1); 188 (12.5); 178 (16.5); 119 (100.0). lH NMR (CDCI3): 8 = 1.05 (3H, s, CH 3); 1.44 - 1.57 (IH, m); 1.98 - 2.06 (IH, m); 2.14 - 2.23 (IH, m); 2.29 - 2.41 (2H, m); 2.42 - 2.49 (IH, m); 2.51 - 2.60 (IH, m); 3.66 (3H, s, -OCH3); 4.72 and 4.94 (IH each, 21, J = 2 Hz, 2 Hz, =CH2); 5.86 (IH, d, J = 15 Hz, -C(0)CH=CH-); 6.97 (IH, d, J = 15 Hz, -C(0)CH=CH-). 8 0 Cyclisation of ester 1 5 1 to lactone 158 : -C02Me y-COjMe 151 158 A solution of the ester 1 5 1 (860 mg, 2.90 mmol) in trifluoroacetic acid (5 mL) was stirred for 1 h. The solution was diluted with Et 2 0 (20 mL) and washed with water (3 x 10 mL). The combined washings were extracted with Et 2 0 (2 x 10 mL) and the combined Et 2 0 was dried over MgSO^. Evaporation of the solvent produced a purple oil which was purified by column chromatography (70-230 mesh Si0 2 ,2 x 10 cm), eluting with 2:3 PE:Et 20 to afford the bicyclic lactone 1 5 8 as a pale yellow oil; yield: 542 mg, 78%. C 1 3 H 2 0 O 4 Calc. Mass: 240.1361 Meas. Mass: 240.1353 IR (neat): v = 2980,2955,2895 (C-H); 1735 cnr 1 (C=0). MS (70 eV): m/z (%) = 222 (M+-H20,16.3); 213 (20.9); 212 (94.0); 209 (49.7); 208 (18.4); 194 (65.0); 43 (100.0). *H NMR (CDC13): d = 0.84 (3H, s, R3CCH3); 1.37 (3H, s, R 2C(CH 3)0-); 1.39 - 1.46 (IH, m); 1.68 (IH, d A B dd, J = 15, 8.5, 3 Hz); 1.76 (IH, d^dd , J = 15, 11, 8 Hz); 1.81 -1.93 (IH, m); 2.04 - 2.13 (2H, m); 2.27 (IH, d ^ d , J = 15,9 Hz) and 2.37 (IH, d A B d , J = 15, 5 Hz, -CH 2 C0 2Me); 2.53 (IH, d^dd , J = 20, 8, 3 Hz); 2.56 - 2.68 (2H, m); 3.70 (3H, s, -OCH3). Cleavage of ester 151 to carboxylic acid 159: 81 151 159 Dry Nal (300 mg, 2.00 mmol) was stirred in dry CH 3 CN (10 mL) under Ar, and TMSC1 (0.26 mL, 220 mg, 2.00 mmol) was added by syringe, resulting in the appearance of a white precipitate and a yellow colour. A solution of the ester 151 (500 mg, 1.69 mmol) in dry CH3CN (5 mL) was then added by cannula and the mixture was stirred for 15 min. The mixture was diluted with Et20 (30 mL) and water (10 mL), and the layers were separated. The aqueous phase was extracted with Et20 (2 x 10 mL) and the combined organics were washed with 10% Na2S203 (2 x 10 mL) and brine (10 mL), and dried over MgSC>4. Evaporation of the solvents produced an orange oil which was purified by column chromatography (70-230 mesh SiC»2,2x8 cm), eluting with 1:1 PE:Et20, to afford the carboxylic acid 159 as a colourless oil; yield: 360 mg, 89%. C13H20O4 Calc. Mass: 240.1361 Meas. Mass: 240.1367 IR (neat): 0) = 3600 - 2500 (broad, -COOH); 2975,2880 (C-H); 1740 (C=0, ester); 1710 cnr* (C=0, acid). MS (70 eV): m/z (%) = 240 (M+, 1.7); 222 (25.7); 191 (14.8); 190 (15.2); 167 (75.7); 107 (100.0). IH NMR (CDC13): 8 = 0.84 (3H, s, CH 3); 1.59 (3H, broad s, allylic CH 3); 1.63 - 1.79 (2H, m); 1.88 - 1.97 (IH, m); 2.12 - 2.22 (IH, m); 1.25 - 1.34 (IH, m); 1.35 - 1.49 (4H, m); 3.70 (3H, s, -OCH 3); 5.33 (IH, broad s, =C-H). 82 Treatment of t-butyl ester 151 with NaI/TMSCl/Et3N: C02Me • No Reaction 151 A solution of the ester 151 (118 mg, 0.40 mmol), Nal (72 mg, 0.48 mmol) and Et 3 N (0.17 mL, 120 mg, 1.2 mmol) in dry CH 3 CN (2 mL) was stirred under Ar. TMSC1 (0.06 mL, 52 mg, 0.48 mmol) was added by syringe, resulting in the immediate formation of a white precipitate. The mixture was stirred for 90 min, after which tic indicated that no reaction had taken place. The mixture was diluted with Et20 (10 mL) and water (2 mL) and the layers were separated. The Et20 was washed with brine (2x2 mL) and dried over MgSC«4. Evaporation of the solvent afforded a colourless mobile liquid which was identical with the starting material 151 by GC and IR; recovered yield: 104 mg, 88%. Treatment of t-butyl ester 151 with p-TsOH / CgHg: 151 159 A solution of the ester 151 (71.8 mg, 0.24 mmol) and TsOH (5 mg, 0.03 mmol) in dry CgH6 was heated to reflux under Ar for 3.5 h. The solvent was evaporated to provide a pale yellow oil which was purified by column chromatography (70-230 mesh S i 0 2 , 1 x 5 cm), eluting with 1:1 PE:Et20 to afford the carboxylic acid 159 as a pale yellow oil; yield: 50 mg, 90 %. The spectra of this compound were identical to those obtained previously. 83 Esterification of acid 157 to diester 164: C02Me C0 2Me HO MeO' 164 A solution of the unsaturated acid 157 (830 mg, 3.48 mmol) in dry DMF (10 mL) was stirred under Ar and K2CO3 (962 mg, 6.96 mmol) was added. The suspension was stirred vigorously for 2 h, when CH3I (0.43 mL, 990 mg, 7.0 mmol) was added, and stirring was continued for a further 1.5 h. The mixture was diluted with Et20 (20 mL) and water (5 mL) and the layers were separated. The aqueous phase was extracted with Et20 (10 mL) and the combined extracts were washed with brine (10 mL) and 10 % Na2S2C«3 (10 ml), and dried over MgS04. The solvents were evaporated to provide a yellow mobile liquid which was purified by column chromatography (70-230 mesh S i 0 2 , 3 x 6 cm), eluting with 9:1 PE:Et20 to afford the diester as a colourless, mobile oil; yield: 657 mg, 75%; bp: 140°C (0.1 mm); [a] 2 1 -38.1° (c = 0.962, CHC13). C14H20O4 Calc: C 66.65 H7.99% IR (neat): u = 3090 (=C-H); 2960,2925,2855 (C-H); 1735 (C=0, saturated); 1720 (C=0, unsaturated); 1650 (C=C); 890 cm-1 (=CH2). MS (70 eV): m/z (%) = 252 (M+, 10.6); 232 (1.7); 221 (23.6); 220 (72.6); 205 (8.4); 192 (26.8); 119(100.0). iH NMR (CDCI3): 8 = 1.02 (3H, s, CH 3); 1.43 - 1.53 (IH, m);1.97 - 2.05 (IH, m); 2.11 - 2.20 (IH, m); 2.28 - 2.39 (2H, m); 2.40 - 2.48 (IH, m); 2.50 - 2.58 (IH, m); 3.65 and 3.75 (3H each, 2 s, 2 -OCH 3); 4.70 and 4.93 (1 H each, 21, J = 2.5 Hz, 2.5 Hz, =CH2); 5.85 (IH, d, J = 16 Hz, -C(0)CH=CH-); 6.88 (IH, d, J = 16 Hz, -C(0)CH=CH-). Anal.: C 66.76 H 7.90 % 84 Conversion of aldehyde 154 to ester 164: 154 164 A suspension of NaH (1.35 g, 56.0 mmol) in dry THF (100 mL) was stirred under Ar, and a solution of trimethyl phosphonoacetate (127,10.2 g, 56.0 mmol) in dry THF (50 mL) was added dropwise over 15 min, forming a thick white suspension. This was stirred an additional 1 h before a solution of the aldehyde 154 (9.16 g, 46.7 mmol) in dry THF (100 mL) was added dropwise over 30 min. The mixture was stirred overnight, after which water (100 mL) and Et20 (100 mL) were added. The layers were separated and the organic phase was washed with brine (2 x 50 mL). The combined aqueous phases were extracted with Et20 (2 x 40 mL) and the combined organic solvents were dried over MgSC«4. Evaporation of the solvents produced a yellow oil which was purified by column chromatography (70-230 mesh SiC«2,6.5 x 12 cm), eluting with 5:1 PE:Et20, to afford the diester 164 as a pale yellow, mobile liquid; yield: 10.2 g, 86%. The spectral characteristics of this compound were identical to those described above. Reduction of a,B-unsaturated ester 164 to ester 160: _^C0 2Me _-C0 2Me 164 160 A solution of the unsaturated ester 164 (10.2 g, 40.4 mmol) in dry MeOH (300 mL) was cooled to 0°C and Mg (2.95 g, 120 mmol) was added in one portion. The suspension was stirred at 0°C for 2 h and at rt for a further 2 h before water (100 mL) was added. Just enough 6 N HC1 was added to dissolve the solids and the mixture was diluted further with water (300 mL), 8 5 extracted with 1:1 PE:Et20 (4 x 200 mL) and the combined extracts were washed with NaH(X>3 (50 mL) and brine (50 mL), and dried over MgSO^. The solvents were evaporated to provide the saturated diester as a pale yellow oil, which was used without further purification; yield: 10.1 g, 98%; bp: 140°C (0.1 mm); [a] 2 1 -29.8° (c = 0.752, CHC13). C14H22O4 Calc: C 66.12 H 8.72 % IR (neat): v = 3090 (=C-H); 2955,2880,2850 (C-H); 1740 (C=0); 1650 (C=C); 885 cm"1 (=CH2). MS (70 eV): m/z (%) = 254 (M+, 3.2); 224 (11.4); 223 (51.3); 222 (56.3); 220 (10.8); 207 (15.5); 180 (65.2); 107 (100.0). *H NMR (CDCI3): 8 = 0.89 (3H, s, CH 3 ) ; 1.27 - 1.37 (IH, m); 1.70 - 1.85 (2H, m); 1.86 - 1.94 (IH, m); 2.10 - 2.18 (2H, m); 2.22 - 2.34 (3H, m); 2.36 - 2.47 (2H, m); 3.66 and 3.68 (3H each, 2 s, 2 x -OCH 3); 4.73 and 4.93 (IH each, 21, J = 2 Hz, 2 Hz, =CH2). Hydrolysis of diester 160 to dicarboxylic acid 161: A solution of KOH (11.4 g, 0.20 mol) in water (200 mL) was added to a stirred solution of the diester 160 (10.1 g, 39.7 mmol) in MeOH (200 mL). After stirring for 2 h the solution was acidified to pH 2 with 6 N HCl and immediately extracted with EtOAc (4 x 100 mL). The combined extracts were washed with brine (2 x 50 mL) and dried over MgS04. Evaporation of the solvent provided an off-white solid which was recrystallised from hexane/EtOAc to afford the diacid 161 as white crystals; yield: 7.08 g, 77%; mp: 90-91°C; [a] 2 3 -58.7° (c = 1.54, CHC13). Anal.: C 66.11 H8.65% 1 6 0 1 6 1 C12H18O4 Calc: C 63.70 H 8.02 % Anal.: C 63.66 H7.89% 86 Calc. Mass: 226.1205 Meas. Mass: 226.1205 IR (CHC13): v = 3450 - 2300 (broad, -COOH); 2960,2945 (C-H); 1710 (C=0); 1655 (C=C); 885 cm-l (=CH2). MS (70 eV): m/z (%) - 208 (M+-H20,23.0); 190 (6.7); 180 (5.7); 166 (50.7); 153 (100.0). *H NMR (CDC13): 8 = 0.89 (3H, s, CH 3); 1.30 - 1.42 (IH, m); 1.85 and 1.91 (2H, qABt, J = 14, 7.5 Hz, -CH2CH2C02H); 2.00 - 2.10 (2H, m); 2.13 - 2.20 (IH, m); 2.24 - 2.38 (3H, m); 2.43 - 2.55 (2H, m); 4.72 and 4.93 (IH each, 21, J = 2.5 Hz, 2 Hz, =CH2); 11.20 -12.50 (2H, broad hump, 2 x -COOH). Cyclisation of acid 161 to bicyclic enone 162: 1 6 1 1 6 2 A solution of the diacid 161 (285 mg, 1.26 mmol) in dry CH 2 C1 2 (25 mL) was stirred under Ar, and trifluoroacetic anhydride (0.54 mL, 790 mg, 3.8 mmol) was added by syringe. The solution was stirred for 1 h before the CH 2 C1 2 was removed and replaced with MeOH (20 mL). Saturated NaHC0 3 (5 mL) was added and the solution was stirred for 1 h, after which it was diluted with water (30 mL), and acidified to pH 2 with 6 N HC1. The mixture was extracted with EtOAc (3 x 20 mL) and the combined extracts were washed with water (20 mL) and brine (20 mL), and dried over MgS04. Evaporation of the solvent provided a viscous yellow oil which was purified by column chromatography (60-100 mesh Florisil, 1 x 15 cm), eluting with 1:2 PE:Et 20, to provide the bicyclic enone, acid 162 as a pale yellow oil; yield: 148 mg, 56%. Cl2Hi60 3 Calc. Mass: 208.1099 Meas. Mass: 208.1100 IR (neat): v = 3700 - 2300 (broad, -COOH); 2980,2900 (C-H); 1720 (C=0, acid); 1660 cnr* (G=0, enone). 87 MS (70 eV): m/z (%) = 208 (M+ 21.1); 190 (11.1); 180 (11.3); 166, (15.0); 149 (20.9); 148 (24.7); 121 (100.0). IH NMR (CDC13): 8 = 1.06 (3H, s, CH 3 ) ; 1.50 - 1.67 (IH, m); 1.83 (IH, d^dd , J = 15, 14, 5 Hz); 2.02 (IH, d^dd , J = 15, 6, 2 Hz); 2.07 - 2.20 (2H, m); 2.29 - 2.36 (lH,m); 2.37 -2.44 (IH, m); 2.47 - 2.61 (3H, m); 2.71 (IH, d ^ d l , J = 20,11,2 Hz); 5.81 (IH, broad s, =C-H). Esterification of acid 162 to methyl ester 153: C0 2 H 162 The bicyclic enone acid 162 (203 mg, 0.97 mmol) was dissolved in dry DMF (5 mL) and K2CO3 (210 mg, 1.5 mmol) was added. The suspension was stirred vigorously for 1.5 h, after which CH3I (0.093 mL, 210 mg, 1.5 mmol) was added by syringe, and stirring was continued overnight in the dark. The mixture was diluted with Et/jO (30 mL) and washed with water (3x5 mL). The washings were extracted with Et20 (5 mL) and the combined Et20 was washed with 10% Na2S203 (5 mL) and dried over MgS04. Evaporation of the solvent provided an orange oil which was purified by radial chromatography (1 mm plate), eluting with 1:1 PE:Et20, to afford the ester 153 as a pale yellow oil; yield: 144 mg, 66%; bp: 110°C (0.1 mm); [a] 2 4 85.7° (c = 0.62, CHCI3). C 1 3 H 1 8 0 3 Calc: C 70.24 H 8.16 % Anal.: C 69.98 H 8.00 % Calc. Mass: 222.1256 Meas. Mass: 222.1260 IR (neat): v = 2950 (C-H); 1740 (C=0, ester); 1660 cm-l (c=0, enone). MS (70 eV): m/z (%) = 222 ( M + , 33.6); 207 (15.4); 194 (22.4); 191 (21.8); 180 (43.2); 121 (100.0). 88 lH NMR (CDCI3): 6 = 1.05 (3H, s, CH3); 1.54 - 1.66 (IH, m); 1.80 (1H, d A B d d , J = 15,14, 5 Hz); 1.97 (IH, dj&dd, J = 15, 6,2 Hz); 2.05 - 2.14 (2H, m); 2.30 (IH, d ^ d , J = 15, 9 Hz); 2.39 (IH, dAfidd, J = 18, 5, 2 Hz); 2.44 - 2.57 (3H, m); 2.68 (IH, dAB<it, J = 20, 11, 2 Hz); 3.71 (3H, s, -OCH3); 5.80 (IH, s, =C-H). Cyclisation of acid 161 to bicyclic enone ester 153: Trifluoroacetic anhydride (8.60 mL, 12.8 g, 60.8 mmol) was added by syringe to a solution of the diacid 161 (5.50 g, 24.3 mmol) in dry CH2CI2 (350 mL) and the solution was stirred under Ar for 1.25 h. The solvent was removed and replaced with dry MeOH (100 mL), and /7-TsOH (460 mg, 2.4 mmol) was added. The solution was stirred overnight before the MeOH was evaporated and the orange-brown residue was partitioned between water (100 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic solvents were washed with brine (50 mL) and dried over MgSO^ Evaporation of the solvents provided a viscous, orange oil which was purified by column chromatography (70-230 mesh Si02,4.5 x 16 cm), eluting with 2:3 PE:Et20 to afford the bicyclic enone methyl ester 153 as a pale yellow mobile oil; yield: 4.42 g, 82%. The spectral characteristics of this compound were identical to those described above. Further elution provided the bicyclic enone acid 162 as a viscous, pale yellow oil; yield: 300 mg, 6%. The spectral characteristics of this compound were identical to those obtained earlier. 161 153 89 Protection of enone 153 as ketal 169: -C02Me 153 ^ 169 A solution of ethylene glycol (1.70 mL, 1.86 g, 30 mmol) and PPTS 7 9 (120 mg, 0.46 mmol) in dry CgHg (50 mL) was refluxed in a Dean-Stark apparatus for 30 min. After cooling briefly, a solution of the enone 153 (684 mg, 3.08 mmol) in dry CgHg (10 mL) was added and the mixture was heated again to reflux, overnight The solution was cooled, poured into brine (100 mL), and the layers were separated. The aqueous phase was extracted with Et20 (2 x 25 mL) and the combined organic solvents were dried over MgS0 4 . After evaporation of the solvents, the resultant orange oil was purified by column chromatography (70-230 mesh SiC»2, 2 x 7 cm), eluting with 3:1 PE:Et20 to afford the ketal as a pale yellow, mobile liquid; yield: 615 mg, 75%; [a] 2 5 16.6° (c = 1.16, CHCI3). e1 5H2204 Calc: C 67.65 H 8.33 % Anal.: C 67.47 H8.30% Calc. Mass: 266.1518 Meas. Mass: 266.1522 IR (neat): v = 3050 (=C-H); 2960,2900,2860 (C-H); 1740 cm-l (c=0). MS (70 eV): m/z (%) = 266 (M+, 2.1); 235 (1.2); 99 (100.0). lH NMR (CDCI3): 8 = 0.92 (3H, s, CH 3); 1.51 - 1.59 (IH, m); 1.65 - 1.74 (2H, m); 1.79 - 1.88 (IH, m); 1.99 - 2.07 (IH, m); 2.32 - 2.52 (6H, m); 3.67 (3H, s, -OCH 3); 3.93 - 4.00 (4H, m, -0(CH 2) 20-); 5.33 (IH, s, =C-H). 90 Alkylation of ketal ester 169 to 174: A solution of dusopropylamine (0.30 mL, 210 mg, 2.1 mmol) in dry THF (10 mL) was cooled under Ar to 0°C and n BuLi (1.6 M/hexane, 1.2 mL, 2.0 mmol) was added by syringe. After stirring at 0°C for 30 min, the solution was cooled to -78°C and a solution of the ester 169 (433 mg, 1.63 mmol) in dry THF (5 mL) was added by cannula. After a further 40 min, 5-iodo-2-methyl-2-pentene (526 mg, 2.50 mmol) was added by syringe and the solution was stirred at -78°C for 1.5 h and the temperature was then allowed to increase to rt overnight. NH4C1 (5 mL) and water (5 mL) were added, and the mixture was diluted with Et20 (30 mL). The layers were separated and the organic phase was washed with water (10 mL), 10 % Na2S2C«3 (10 mL) and brine (10 mL), and dried over MgS0 4 . Evaporation of the solvents afforded an orange, mobile liquid which was purified by radial chromatography (2 mm plate), eluting with 4:1 PE:Et20, to afford the alkylated ester 174 as a pale yellow, mobile liquid; yield: 541 mg, 95%; [a] 2 5 26.0° (c = 0.534, CHC13). C21H32O4 Calc: C 72.38 H 9.26% 348.5 Anal.: C 72.51 H 9.19 % Calc. Mass: 348.2300 Meas. Mass: 348.2306 IR (neat): v = 3050 (=C-H); 2945,2900 (C-H); 1735 cm*l (C=0). MS (70 eV): m/z (%) = 348 (M+, 12.5); 317 (2.1); 267 (2.8); 266 (7.1); 99 (100.0). *H NMR (CDCI3): 5 = 0.99 (3H, s, angular CH 3 ) ; 1.47 - 1.67 (5H, m); 1.58 and 1.69 (3H each, 2 s, 2 allylic CH 3 's); 1.73 - 1.79 (IH, m); 1.89 and 1.93 (2H, qAB» J = 8 Hz); 1.96 - 2.01 (IH, m); 2.17 - 2.24 (IH, m); 2.31 - 2.42 (3H, m); 2.52 (IH, td, J = 11.5, 4.5 Hz); 3.68 (3H, s, -OCH3); 3.91 - 3.98 (4H, m, -CXCH^O-) ; 5.08 (IH, t, J = 7 Hz, -CH 2CH=C(CH 3) 2); 5.31 (IH, s, ring =C-H). 9 1 Reduction of ester 174 to alcohol 175: A suspension of LiAttfy (68 mg, 1.8 mmol) in dry THF (10 mL) was cooled under Ar to 0°C. A solution of the ester 174 (514 mg, 1.47 mmol) in dry THF (5 mL) was added by cannula and the mixture was stirred at 0°C for 1 h and then at rt for 2 h, before Na2SO4<>10 H2O (100 mg) was added and the mixture was diluted with Et20 (10 mL). After stirring vigorously overnight, MgSC>4 was added and the mixture was filtered. Evaporation of the solvents provided a viscous, colourless oil which was purified by radial chromatography (2 mm plate), eluting with 1:1 PE:Et20, to afford the alcohol 175 as a viscous, colourless oil which solidified on standing; yield: 412 mg, 87%; mp: 83-4°C; [a] 2 5 19.8° (c = 0.656, CHC13). Recrystallization of a small amount of the alcohol 175 from Et20/PE afforded white needles (mp 72-3°C) which were submitted for X-ray structural determination. The X-ray structure indicated that the crystal contained 1/2 equivalent of water of crystallization. C20H32O3 Calc: C 72.91 H 10.10 % (M + 1/2 H 2 0) Anal.: C 72.62 H 10.16% Calc. Mass: 320.2351 Meas. Mass: 320.2343 IR (neat): 0) = 3425 (O-H); 3060,3040 (=C-H); 2975,2950,2900 (C-H); 1190 cnr 1 (C-O). MS (70 eV): m/z (%) = 320 (M+, 2D.5); 302 (4.9); 292 (5.1); 291 (5.4); 290 (15.9); 289 (15.8); 99 (100.0). l H NMR (CDCI3): 8 = 0.97 (3H, s, angular CH 3); 1.09 -1.21 (IH, m); 1.35 - 1.42 (IH, m); 1.48 - 1.58 (2H, m); 1.61 and 1.69 (3H each, 2 s, 2 x allylic CH 3); 1.63 - 1.69 (IH, m); 1.71 (IH, broad s, -OH); 1.80 - 2.08 (6H, m); 2.31 - 2.40 (3H, m); 3.62 (IH, d ^ d , J = 12, 6 Hz) and 3.76 (IH, d ^ d , J = 12 Hz, 3.5 Hz, -CHCH 2OH); 3.92 - 3.99 (4H, m, -0(CH2)20-); 5.13 (IH, t, J = 8 Hz, -CH2CH=C(CH3)2); 534 (IH, s, ring =C-H). 92 Esterification of alcohol 175 to (+)-(/?)-MTPA ester 178: A solution of the alcohol 175 (301 mg, 0.94 mmol) in dry CH2CI2 (10 mL) was stirred under Ar, and pyridine (0.25 mL, 250 mg, 3.1 mmol) and a solution of MTPAC1 (475 mg, 2.0 mmol) in dry CH2CI2 (2 mL) were added by syringe. The solution was stirred for 3 d, when TLC indicated that none of the alcohol remained. After adding E12O (20 mL), the solution was washed with water ( 2 x 5 mL), 1 N HCl (5 mL), NaHC03 (5 mL) and brine (5 mL), and dried over MgS04. Evaporation of the solvents provided a viscous, yellow oil which was purified by radial chromatography (2 mm plate), eluting with 4:1 PE:Et20 to afford the ester 178 as a viscous, colourless oil; yield: 402 mg, 80%; [a] 2 5 29.1° (c = 0.412, CHC13). C3oH39F305 Calc: C 67.15 H 7.33% Anal.: C 67.36 H 7.51 % Calc. Mass: 536.2749 Meas. Mass: 536.2751 IR (neat): M = 3050 (=C-H); 2960,2900 (C-H); 1755 (C=0); 1460 (C=C, aromatic); 800,760, 715 cm - 1 (aromatic C-H bend). MS (70 eV): m/z (%) = 536 (M+ 0.2); 450 (0.3); 302 (1.3); 189 (9.0); 99 (100.0). IH NMR (CDCI3): 8 = 0.98 (3H, s, angular CH 3); 1.20 - 1.30 (IH, m); 1.36 - 1.45 (IH, m); 1.46 - 1.64 (2H, m); 1.56 and 1.67 (3H each, 2 s, 2 allylic CH 3 's); 1.74 (IH, dt, J = 13, 3 Hz); 1.81 (IH, d ^ d , J = 14, 4 Hz); 1.C4 - 2.05 (5H, m); 2.29 - 2.41 (3H, m); 3.54 (3H, s, -OCH3); 4.15 (IH, dAfid, J = 12, 6 Hz) and 4.56 (IH, d ^ d , J = 12,4 Hz, -CHCH 2 0-); 4.99 (IH, t, J = 8 Hz, -CH2CH=C(CH3)2); 5.31 (IH, s, ring =C-H); 7.37 -7.42 (3H, m) and 7.51 - 7.55 (2H, m, 1 9 F NMR (CDCI3): 8 = 4.936 (-2.82 F, s, C F 3 of major diastereomer), 4.896 (-0.18 F, s, CF 3 of minor diastereomer). 93 Conversion of alcohol 175 to 177: HO MsO A solution of the alcohol 175 (88 mg, 0.27 mmol) and DMAP (cat) in dry CH 2C1 2 ( 2 " L ) was stirred under Ar, and Et3N (0.27 mL, 190 mg, 1.9 mmol) and methanesulphonyl chloride (0.075 mL, 110 mg, 0.97 mmol) were added by syringe. The solution was stirred for 1.5 h after which it was diluted with Et 2 0 (15 mL) and water (5 mL). The layers were separated and the Et 2 0 was washed with water (5 mL) and dried over MgS04. Evaporation of the solvents provided the mesylate 176 as a pale yellow, viscous oil which was used without further purification, yield: 120 mg. A solution of the crude mesylate 176 (120 mg, 0.27 mmol maximum) in dry THF (5 mL) was cooled to 0°C under Ar, and LiEt3BH (1 M/THF, 1.1 mL, 1.1 mmol) was added by syringe. The solution was stirred for 3 h, allowing the temperature to increase to rt. E t 2 0 (20 mL) was added and the solution was washed with 1 N HC1 (2x5 mL) and brine (5 mL), and dried over MgSC»4. Evaporation of the solvents provided a pale yellow oil which was purified by radial chromatography (1 mm plate), eluting with 19:1 PE:Et 2O f to afford the reduced compound 177 as a colourless mobile liquid; yield: 69.2 mg, 84% over two steps; [a] 2 4 21° (c = 0.17, CHC13). C2()H3202 Calc: C 78.90 H 10.59 % Anal.: C 79.12 H 10.50% Calc. Mass: 304.2402 Meas. Mass: 304.2398 JR (neat): D = 3045 (=C-H); 2960,2945,2900 (C-H); 1120,1090 cm"1 (C-O). MS (70 eV): m/z (%) = 304 (M+, 1.5); 99 (100.0). 94 *H NMR (CDCI3): 8 = 0.95 (3H, d, J = 6 Hz, ai3CHRR,); 0.97 (3H, s, angular CH3); 1.05 -1.15 (IH, m); 1.39 - 1.47 (IH, m); 1.57 - 1.67 (3H, m); 1.60 and 1.69 (3H each, 2 s, 2 allylic CH3's); 1.81 - 2.09 (5H, m); 2.32 - 2.44 (4H, m); 3.91 - 3.99 (4H, m, -0(CH2)20-); 5.10 (IH, broad t, J = 7.5 Hz, -CH2CH=C(CH3)2); 5.30 (IH, broad s, ring =C-H). Hydrolysis of ketal 177 to enone 168: A solution of the ketal 177 (44.6 mg, 0.146 mmol) in acetone (4 mL) and 1 N HC1 (2 mL) was heated to reflux for 1 h. After diluting with water (5 mL), the solution was extracted with Et20 (3 x 10 mL), and the combined extracts were washed with NaHC03 (5 mL) and dried over MgSC<4. Evaporation of the solvents provided a yellow oil which was purified by radial chromatography (1 mm plate), eluting with 9:1 PE:Et20, to afford the enone 168 as a pale yellow oil; yield: 38.4 mg, 91%; [a]25 73° (c = 0.28, CHC13). C 18 H 28° C c^- M a s s : 260.2140 Meas. Mass: 260.2141 IR (neat): \> = 3035 (=C-H); 2960,2885 (C-H); 1670 cnr* (C=0). MS (70 eV): m/z (%) = 260 (M+, 71.6); 245 (29.6); 218 (31.0); 203 (5.6); 189 (10.7); 177 (30.7); 176 (27.2); 175 (61.4); 41 (100.0). IH NMR (CDC13): 8 = 0.99 (3H, d, J = 3 Hz, CH3CHRR'); 1.10 (3H, s, angular CH3); 1.12 -1.20 (IH, m); 1.39 - 1.60 (4H, m); 1.62 and 1.70 (3H each, 2 s, 2 allylic CH3's); 1.81 -1.97 (2H, m); 1.99 - 2.11 (2H, m); 2.25 (IH, ddd, J = 8, 3, 1 Hz); 2.29 - 2.37 (IH, m); 2.38 - 2.46 (IH, m); 2.48 - 2.58 (IH, m); 2.62 (IH, dAedt, J = 10, 5.5, 1 Hz); 5.10 (IH, tq, J = 3.5,1 Hz, -CH2CH=CMe2); 5.74 (IH, broad s, -C(0)CH=). Chapter 2 An Enantiospecific Approach to the Euphane and Apo-Euphane Triterpenoid Skeleton 96 2.1 Introduction 2.1,1 Ggneral Introduction to the Triterpenoids The triterpenoids are a family of naturally occurring compounds derived biosynthetically from the electrophilic cyclization of squalene-2,3-oxide (182) or of squalene (183)80. While most known triterpenoids have been isolated from plant sources, one important group, the lanostanes, are found in animals. Considering the size of this family of compounds (upwards of 500 triterpenoids were known as of 1972) it is hardly surprising to find a high degree of structural diversity. This is in part related to the fact that squalene-2,3-oxide (182) can take on a variety of conformations during cyclization, but also due to the propensity of intermediates in the biosynthetic route to undergo rearrangement and chemical modification after cyclization. The structural diversity can be best illustrated by presenting some representative examples of the triterpenoids. Tetrahymanol (184) and lanosterol (185) are two of the few triterpenoids isolated from animal sources, while euphol (186), limonin (187) and azadirone (188) have been isolated from plants. The latter two compounds have a carbon skeleton and are more correctly named tetranortri-terpenoids. While the structures of these compounds differ markedly, there are a number of elements common to most triterpenoids. A polycyclic carbon skeleton is universal, and in some cases [such 182 183 9 7 as limonin (187)] one or more of heterocyclic rings may also be present. The presence of a geminal dimethyl group at C(4)* is very common, as are angular methyl substituents at C(10), C(13) and either C(8) or C(14). The C(10) methyl group is invariably B-oriented, whereas those at C(13) and C(8)/C(14) are usually a- and B-oriented respectively, except in the case of the lanostanes and related compounds when the reverse is true. In addition to these carbon substituents, the triterpenoids usually possess some degree of oxygen functionality which is commonly found at C(l), C(3), C(7) and C(16), as well as on one or more of the methyl substituents. Double bonds are often found at C(l)-C(2), C(7)-C(8), C(8)-C(9) and C(14)-C(15) (the latter in the case of the apo-euphane triterpenoids). The presence of this high degree of oxidation often leads to structures (eg. limonin (187)) in which cleavage of one or more of the four carbocyclic rings has occurred during the biosynthetic process. * The numbering of the tetracyclic triterpenoids is analogous to that of the steroids, with the additions that the methyl groups at C(8)/C(14) and C(4) are denoted 32, 30 (4a), and 31 (4B) respectively. 98 The function of the triterpenoids and partially degraded triterpenoids in the natural system is almost as diverse as the structures of the compounds themselves. The limonoids, or bitter principles, are thought to act as antifeedants, imparting a bitter and often unpleasant taste to plants in which they occur80. The bitter taste associated with citrus fruit, for example, is largely due to the presence of limonoids. Lanosterol (185) is the biosynthetic precursor of the steroids in animals, whereas cycloartenol (189) plays the same role in plants2. This biological utility is not neccessarily limited to the organism in which a given triterpenoid is found. For example, Cephalosporin P l (190) has been found to be a useful antibiotic803. OAC 2.1.2 Previous Laboratory Syntheses of the Triterpenoids Considering that the structures of many of the common triterpenoids have been well-known for some decades80 and that their diverse structures present a considerable synthetic challenge, it is somewhat surprising to note that very few synthetic approaches to the triterpenoids have been reported. This fact is doubly surprising when one realises that the general structure of many triterpenoids is very similar to that of the steroids, in which there has been considerable synthetic interest. The most synthetically interesting of these compounds have structures which may be regarded as lanostane, euphane, and apo-euphane derivatives. The relationship of lanosterol (185) to the steroids has already been noted; euphol (186), and the related apo-euphol (191) and 9 9 tirucallol (192) are considered to be the biosynthetic precursors of the limonoids80. Thus, synthetic approaches to these triterpenoids can potentially lead to synthetic routes to steroid derivatives or the limonoids. The following discussion of previous triterpenoid syntheses will be limited to those in which the targets have possessed lanostane, euphane or apo-euphane structures. Scheme 34 The earliest reported synthesis of a triterpenoid was that of lanostenol (24,25-dihydrolanosterol, 193) (Scheme 34), by Woodward, Barton, and co-workers, in 1954 8 1. The similarity of 193 J cholesterol (1) is obvious, and it is hardly surprising that the synthesis was 100 based on the introduction of the requisite three methyl groups, at C(4) and C(14), to this latter compound. The geminal dimethyl group at C(4) was readily introduced by exhaustive methylation of cholest-4-en-3-orie (194) to provide 4,4-dimethyl-cholest-5-en-3-one (195). This was then converted in seven steps to the enone 196, to which the C(14) methyl group was introduced by alkylation of the corresponding potassium dienolate with iodomethane, providing 197. Removal of the ketone and isomerization of the A 7 double bond to the A 8 position provided the benzoate of the target compound, hydrolysis of which provided lanostenol (193). This work also represented a formal synthesis of lanosterol (185), as a degradation product of 193 had been successfully converted to 185 8 1 b. A number of workers have applied the biogenetic-type2-80 polyene cyclization approach to the synthesis of the triterpenoids. This work was pioneered by the group of van Tamelen, who studied the Lewis acid catalysed cyclization of a variety of epoxy polyenes and demonstrated that in vitro synthesis of triterpenoid skeletons in this manner was indeed possible82. Because the focus of this work was not so much on the synthesis as on the investigation of the technique, and because no specific syntheses of the three previously mentioned types of triterpenoid were realised, van Tamelen's work will not be discussed further. The first reported synthesis of the limonoid (tetranor-^ po-euphane) skeleton was by Corey and co-workers, and involved a polyene cyclization to construct the A, B and C rings (Scheme 35) 8 3 . The enol phosphate 199, derived in one pot from farnesyl bromide (198), methyl acetoacetate, and diethyl chlorophosphate, was treated with mercuric trifluoroacetate and sodium chloride, and provided the racemic bicyclic keto ester 200 (in ~30% yield). One can see that the requisite geminal dimethyl group at C(4) and the angular methyl groups at C(8) and C(10) were present in 200, and it remained to incorporate the D ring, C(17) sidechain, and cc-oriented C(13) methyl group. The first two of these were accomplished by a five-step conversion to the diketone 101 201, followed by an aldol condensation to afford the tetracyclic enone 202. Reduction of the ketone and epimerization of the resultant B-alcohol to the a configuration was followed by a cyclopropanation of the C(13)-C(17) olefin, directed by the a-hydroxyl group, to provide 203. Reduction of the corresponding cyclopropyl ketone with lithium in ammonia provided the target compound 204. The route was subsequently amended to incorporate oxygen functionality at C(7) 8 3. While 203 is not a known limonoid, it does represent the basic skeleton, complete with appropriate functionality for conversion to a number of known compounds, such as azadirone (188). Scheme 35 1 0 2 Scheme 3 6 103 Recently, Johnson and co-workers reported a synthesis of euphol (186) and tirucallol (192), again employing a polyene cyclization to establish key features of the tetracyclic skeleton (Scheme 36)84. The cyclization substrate 207 was prepared in nine steps from 2,3-dimethyl-l,3-butadiene (205) and the bromo diketal 206. Treatment of 207 with formic acid in pentane, followed by hydrolysis of the resultant enol formates, provided a 30% yield of a 56:44 mixture of tetracyclic ketones, the major of which proved to be the desired compound 208. After protection of the ketone as the acetate of the corresponding alcohol, the A ring was elaborated by an ozonolysis/aldol sequence, to provide the enone 209. The dione 210 was then obtained by introduction of the geminal dimethyl group, concomitant with reduction to the saturated ketone, and oxidation of the C(20) alcohol. This compound 211 was then converted to 186 and 192 by a six-step sequence. Addition of the Grignard reagent 211 to the C(20) ketone, dehydration of the resultant tertiary alcohols to a mixture of alkenes, reduction of the C(3) ketone and hydrogenation of the alkenes afforded the seperable acetals 212 and 213, epimeric at C(20), in a 2:1 ratio. The former was then converted to tirucallol (192) and the latter into euphol (186), by hydrolysis, and Wittig olefination with isopropylidene triphenylphosphorane. In 1985, Kolaczkowski and Reusch reported the synthesis of the 5-ep/-butyrospermol derivative 214 (Scheme 37) 8 5. This work stemmed from the previous discovery of Reusch and co-workers of a convenient synthesis of the bicyclic diketone 21586, the similarity of which to the CD portion of the euphanes and lanostanes is obvious. A Diels-Alder reaction of the diene 216, derived from 215 in two steps87, with the substituted benzoquinone 217 afforded the tetracyclic triketone 218. Photoisomerization of the corresponding enol acetate 219 provided the C(10) epimer 220, in which the methyl group was in the correct euphane-type configuration, relative to those at C(13) and C(14). Unfortunately, hydrolysis of the enol acetate moiety of 220 resulted in 221, containing the cis A-B ring junction, rather than the desired trans-fused compound, and all attempts to epimerise this centre were unsuccessful. The trione 221 was then converted to the 104 o Scheme 37 target 214 in a further eleven steps, involving manipulation of the A ring functionality and introduction of the C(4) geminal dimethyl group. While the reported synthesis was performed on racemic material, the authors note that since the dione 215 is derived from the Wieland-Miescher ketone 222, which in turn can be prepared in chirai form88, it would be possible to perform the synthesis in an enantiospecific manner. It is unfortunate that a potentially elegant synthetic route to euphane triterpenoids was thwarted by the inability to epimerise the C(5) centre, however the authors state that solutions to this problem are being investigated 105 2.2 Discussion Our interest in the synthesis of the euphane, apo-euphane and lanostane triterpenoids stemmed from two separate discoveries in our laboratory. The first of these, the Grob-type fragmentation89 of 9,10-dibromocamphor (120) to provide 113, 114 and 115 3 7 , and the similarity of the products to the steroidal D ring, has already been discussed (vide infra, Chapter 1). It requires little imagination to extend this similarity to the D ring of the triterpenoids; in the case of the euphanes and lanostanes only the C(14) methyl group is missing, while the apo-euphanes require no additional substituent The significant difference between the D rings of the lanostanes and euphanes/apo-euphanes is that they belong to opposite enantiomeric sets. We considered that both the cleavage products 113,114 or 115, and their enantiomers ent-113, ent-114 or ent-115 could represent valuable intermediates in triterpenoid synthesis, since either enantiomer of 9,10-dibromocamphor (120) is synthetically available39. Br 114 Scheme 38 The second discovery which led to this work was that the tertiary alcohol 224 (Scheme 39), derived from (+)-5,6-dehydrocamphor (223) and vinyl magnesium bromide, underwent a facile anionic oxy-Cope rearrangement90 to the bicyclic ketone 225, on treatment with base91. 106 226 Scheme 39 Scheme 40 107 This could be subsequently elaborated to the bicyclic keto enone 226, reminiscent of the AB portion of the triterpenoids. The structure 226 possesses the requisite geminal dimethyl group at C(4) as well as existing or potential oxygen functionality at C(l), G(3), and C(7). In addition (Scheme 40), one can see that simple modifications of the alkenyl Grignard reagent can result in carbon sidechains at C(8) and C(9), the stereochemistry of the latter centre being cbtermined by the cis or trans nature of the Grignard reagent The cis stereochemistry of the ring junction is a direct consequence of the concerted nature of the rearrangement901'. The only important feature that the structure 226 lacks is the angular methyl group at C(10). We envisioned that the coupling of a suitable D-ring Grignard reagent or equivalent, derived from 9,10-dibromocamphor (120), with 5,6-dehydrocamphor (223) and subsequent elaboration could lead very quickly into the basic triterpenoid skeleton (Scheme 41). The specific series of triterpenoid (euphane or lanostane) would be defined by the enantiomer of camphor (228/ent-228) that the D ring subunit was derived from. For this preliminary study we chose to work with the system derived from (-)-camphor (ent-228), which would lead into the euphane and apo-euphane triterpenoids. The reasons for this choice were that when we embarked on this project no one had reported the total synthesis of these types of triterpenoids and also that the same skeleton is possessed by the limonoids, some of the potentially more interesting triterpenoid derivatives. The key subunit containing the D ring and the necessary functionality for addition to (+)-5,6^dehydrocamphor was envisioned to be the acetylenic alcohol 235, the synthesis of which is outlined in Scheme 42. Because we were working with the (-)-camphor series it was necessary to prepare the desired (-)-ende>-3-bromocamphor (ent-117), as this enantiomer is not readily available commercially. Since (-)-camphor (ent-228) is considerably more expensive than (-)-borneol (229) it proved to be more economical to use this latter compound as the chiral starting material, oxidation of which provided the desired (-)-camphor (ent-228) in quantitative yield. 108 Scheme 41 Treatment of (-)-camphor (ent-228) with bromine in glacial acetic acid at 85°C 5 8 b resulted in monobrornination to provide (-)-e«do-3-bromocamphor (ent-117) in 70% yield. This compound was identical in every respect except the sign of optical rotation to commercial (+)-endo-3-bromocamphor (117). A bromination / debrornination sequence identical to that already described for the (+)-camphor series (see Chapter 1) then provided (-)-9,10-dibromocamphor (ent-120), again identical in all respects except the sign of rotation with authentic (+) material. Treatment of ent-120 with sodium methoxide in methanol37 resulted in cleavage to the monocyclic bromo ester ent-115 in 84% yield. At this stage we desired to neutralise the potential reactivity of the ester group, and chose to convert it to the corresponding methyl ether 231 in order to accomplish this. Thus, reduction of the ester ent-115 with LiAlrL; to the alcohol 230, followed 1 0 9 by treatment with potassium hydride and iodomethane afforded the desired ether 231 in 88% yield over the two steps. 229 ent-228 B r . I ent-120 vi I ent-117 T *OMe vui *OH vii Br I ^ C0 2 Me 230 *OMe 232 233 ent-115 *OMe : i OMe TMS 2 3 4 a a-OH 234b J3-OH 'OMe H 235a,b i) Cr0 3 , H 2 S 0 4 / H 2 0 , Acetone, 100% ii) Br 2 / AcOH, 85°C, 70% iii) Br 2 / C1S03H, 1 h, 74% iv) Br 2 / C l S C ^ l , 6 days v) Zn / AcOH, Et20,0°C, 45% vi) NaOMe / MeOH, 84% vii) LiAlHt / E^O, 0°C, 100% viii) KH, CH 3I / THF, 0°C, 88% ix) NaCN / HMPA, 95°C, 3 h, 85% x) DIBAL / Et20,0°C; K^la tatrtate, HCl / H 20,73% xi) n BuLi, TMSCGH/THF,0°C,98% xii) KOH/MeOH, CH 2C1 2,99%. Scheme 42 1 110 Having protected the ester we were then ready to begin appending the necessary three-carbon fragment corresponding to C(8), C(9) and C(l 1) of the future triterpenoid skeleton. This was accomplished in two steps, the first of which was displacement of bromine with sodium cyanide in HMPA, to afford the nitrile 232 in 85% yield. The identity of the product was verified by IR, iH NMR and mass spectroscopy. The IR spectrum displayed a characteristic nitrile stretch at 2220 cm' 1, and it was confirmed by the iH NMR spectrum that displacement of bromine had occurred; the characteristic AB quartet at 3.44 and 3.48 ppm, corresponding to the - C ^ B r protons, had shifted upfield to 2.47 and 2.48 ppm, as expected for the less deshielding nitrile substituent The low resolution MS provided further conformation of the product; the molecular ion at m/z = 193 was as expected for C12H19NO. [ 1 4 ] 237 It was interesting to note that the displacement reaction was found to be considerably less efficient when carried out in DMSO, even in the presence of catalytic amounts of KI, providing the nitrile 232 in yields of only ~60%, as well as a significant amount of very nonpolar material. This latter proved to be an inseparable mixture of compounds which could not be positively identified. It is likely that they were the products of ring expansion and aromatization, as shown in Equation 14; a compound of this type 236 was isolated from an attempt to convert the bromo ether (231) into the corresponding iodide 237 4 9 , and identified on the basis of its IR, i H NMR and low resolution mass spectra. The IR spectrum showed aromatic C=C stretches at 1600 (weak), 1500 and 1455 (medium) cnr 1 as well as a strong C-0 stretch at 1110 cm*1. The iH NMR spectrum I l l was the most informative, showing peaks at 2.28 (3H, s), 2.30 (3H, s), 2.87 (2H, t, J = 8 Hz), 3.36 (3H, s), 3.53 (2H, t, J = 8 Hz) and 6.92 - 7.06 ppm (3H, m). The peaks at 2.28 and 2.30 ppm were assigned to the two aromatic methyl substituents, while that at 3.36 was assigned to the methyl ether. The two triplets were obviously the methylene groups of the methoxyethyl sidechain, that at 2.87 being next to the aromatic ring and that at 3.53 being next to the ether oxygen. Finally, the high-field multiplet was assigned to the three aromatic protons. The low resolution MS showed a molecular ion at m/z = 164, corresponding to Ci jHjgO. It seems likely mat the improvement in yield that was observed on changing the solvent to HMPA was a reflection of the ability of the solvent to facilitate a Sjs[2 process. The formation of the nitrile 232 was certainly faster in HMPA than in DMSO. The nitrile 232 was then converted to the corresponding aldehyde 233 by reduction with DIBAL and hydrolysis of the intermediate iminoalane92. The identity of the product was confirmed by IR and *H NMR spectroscopy; the IR spectrum showed a characteristic aldehyde C-H stretch50 at 2750 cnr1 and a carbonyl absorption at 1720 cm-1, while the presence of a peak at 9.71 ppm (IH, dd, J = 3.5 and 2 Hz) in the *H NMR spectrum was further confirmation of the presence of a -CH2CHO unit. The final two carbon atoms of the D ring subunit were then introduced by condensation of 233 with the lithium anion of (irimethylsilyl)acetylene, affording the diastereomeric alcohols 234a,b as a 2:1 mixture. These diastereomers were not separated and it was not possible to assign the C(ll) (steroidal numbering) stereochemistry of either the major or minor compound at this point Based on evidence obtained later in the synthesis (vide infra), die major compound was assigned the C(,il)-(#) stereochemistry, 234a. The diastereomeric ratio was determined both by GC and *H NMR of the mixture. Finally, treatment of the alcohols 234a,b with methanolic KOH 9 3 afforded the key acetylenic alcohols 235a,b in 73% yield from the nitrile 232. Confirmation of the structures was provided by the IR spectrum which exhibited a broad O-H peak at 3400 cm-1 and a peak at 3290 1 1 2 cm - 1 , assigned to the terminal acetylenic C-H stretch. Interestingly, no absorption attributable to the triple bond was observed, although in the precursor 234 a peak at 2155 cm - 1 was seen; presumably this is a reflection of the relative strength of the acetylenic dipoles of 234 and 235. The *H NMR spectrum of 235 confirmed that the diastereomeric ratio was unchanged, and was consistent with the assigned structure, as were the low and high resolution mass spectra and elemental analysis. Scheme 43 The next phase of the project was the combination of the D ring subunit 235 with (+)-5,6-dehydrocamphor (223) in such a manner as to allow formation of the trans alkenyl diol 240 required for the anionic oxy-Cope rearrangement90. Two strategies for accomplishing this transformation were potentially available, differing in the stage at which the alkyne would be reduced to the desired trans alkene (Scheme 43). A number of methods are known for the conversion of a terminal alkynol such : ; 235 to the corresponding vinyl Grignard reagent or 113 equivalent 238 (Path A ) 9 4 , however these proved to be less than satisfactory in our hands and we chose to use the alternative approach (Path B and Scheme 44) involving reduction of the acetylenic unit after condensation with 223 9 5. iii) TBDMSOTf, 2,6-lutidine / CH 2C1 2,70% iv) K H / THF, 75%. Scheme 44 The lithium dianion of the alkynols 235 9 6 was condensed with (+)-5,6-dehydrocamphor (223) to provide the alkynyl diols 239 in 88% yield. The structural assignment was based on the IR spectrum, in which the characteristic terminal acetylenic C-H stretch was absent, and the *H NMR spectrum, which showed the presence of peaks attributable to both the 5,6-dehydrocamphor and the D ring subunits. Finally, the MS confirmed that condensation had occurred; the observed molecular ion at m/z = 372 in the low resolution MS was as expected for C24H36O3, and the measured exact mass of 372.2668 compared favourably with the calculated 372.2664. No kinetic resolution was observed in this condensation, as might have been expected: the ratio of diastereomers was determined by both GC and *H NMR to be 2:1. 1 1 4 The alkynyl diols 239 were then reduced with LIAIH4 in THF at 40°C 9 5 to afford the corresponding trans alkenyl diols 240 in 80% yield It was found that this reduction was particularly temperature-sensitive; at even moderately lower temperatures it was very slow, while at higher temperatures an anionic oxy-Cope rearrangement occurred to give inseparable mixtures of the desired diols 240 and the keto alcohols 243. Attempts to force complete conversion to 243 during this reaction were unsuccessful, and it was considered preferable to use those conditions which provided only 240. It was also found that attempts to reduce the monoprotected diol 244 in a similar fashion (Equation IS), resulted in considerable allene 245 formation97, a problem that was not encountered when reducing the unprotected compound 240. The reduction of the acetylenic linkage in the conversion of 239 to 240 was confirmed by *H NMR and MS. The low resolution MS exhibited a molecular ion at m/z = 374 as expected for 240. The *H NMR spectrum showed two new vinyl protons, confinmng that the site of reduction was the triple bond. Unfortunately the signals overlapped and were confused by the presence of the two diastereomers so the trans nature of the newly-formed double bond could not be confirmed at this stage. Fortunately, the *H NMR spectrum of the corresponding silyl ethers 241 was more well-defined. These compounds were obtained in 70% yield by treatment of the diols 240 with TBDMS triflate98, again as a 2:1 diastereomeric mixture. The vinyl region of the *H NMR spectrum included signals at 5.47 (0.33 H, d^g, J = 16 Hz) and 5.67 ppm (0.33 H, d^d, J = 16 and 7.5 Hz), and 5.54 (0.67 H, d ^ , J = 16 Hz) and 5.57 ppm (0.67 H, dj&d, J = 16 and 6 Hz), 1 1 5 corresponding to the two new vinyl protons of the minor and major diastereomers respectively. The observed 16 Hz coupling constant between these protons is indicative of a rra/ts-disubstituted double bond46. The confirmation of this stereochemistry was an important point, as it has a direct bearing on the eventual C(9) stereochemistry produced in the anionic oxy-Cope rearrangement A cis double bond would result in the D ring sidechain at C(9) being a-oriented, rather than the desired B-orientation (cf. Scheme 40). Treatment of the alcohols 241 with K H in THF resulted in the desired anionic oxy-Cope rearrangement, to provide the tricyclic ketones 242 in 75% yield. The structure of the products was confirmed by IR and *H NMR spectroscopy. The IR spectrum displayed no alcohol peak at j 3400 cm - 1 and a strong new absorption at 1720 cm*1, indicative of a cyclohexanone carbonyl. The characteristic *H NMR signals in the vinyl region corresponding to the dehydro bicyclo[2.2.1]-system and the trans double bond had disappeared and were replaced by broad singlets at 5.38 (0.33 H) and 5.66 ppm (0.67 H), corresponding to the single vinyl proton in the A ring of the minor and major diastereomers respectively. The cis ring junction and the C(9) stereochemistry follow from the transition state of the anionic oxy-Cope rearrangement (Scheme 40). Having constructed the tricyclic system 242, it remained to expand the A ring and connect C(8) and C(14) to form the C ring. It was hoped that this could be accomplished by an ozonolysis/aldol sequence (Scheme 45). Ozonolysis of the ketodienes 242 afforded, after reductive workup, a compound which was identified as the triketo aldehyde 246 on the basis of the TR spectrum of the crude material. The crude 246 was immediately treated with p-TsOH in refluxing benzene to bring about the aldol condensations. Unfortunately it was clear that neither of the two products obtained were tetracyclic, and only a single aldol condensation, to form the A 116 R = - (CH 2 ) 2 OMe i) 0 3 / CH 2C1 2, MeOH, -78°C; Zn / AcOH ii) p-TsOH / QHg, A, 51% (248) + 21% (249) iii) HC1/Acetone, H 20,65% iv) KOH / MeOH, E^O, 55% v) TBAF / THF, 62% vi)Ac 2 0, DMAP/pyridine, 77%. Scheme 4 5 1 1 7 ring, had occurred. The IR spectra of both compounds showed carbonyl stretches at -1740 and -1680 cm*1, suggesting the presence of both a ketone in a five-membered ring and an enone. In addition, the major compound (51% yield) exhibited a peak at 1710 cm' 1, indicating the presence of a cyclohexanone moiety, suggesting that it was the tricyclic diketo enones 248. The lR NMR spectrum supported this assignment; peaks were observed at 5.93 (0.67 H, dd, J = 10.5 and 3 Hz) and 7.59 ppm (0.67 H, d, J = 10.5 Hz), and 5.98 (0.33 H, dd, J = 10.5 and 3 Hz) and 7.10 ppm (0.33 H, d, J = 10.5 Hz), corresponding to the enone P and a vinyl protons of the major and minor diastereomers respectively. In addition, the characteristic peaks between 4.80 and 5.00 ppm associated with the exo-methylene group of the D ring were no longer observed, indicating that ozonolysis of this group had occurred and that this was the location of the cyclopentanone. The assignment of the structure 249 to the minor product (21% yield) was again based on the IR and  lH NMR spectra. The IR spectrum, as described above, exhibited only two carbonyl peaks; the absorption associated with the B ring ketone was absent. This observation was somewhat perplexing until it was noticed that the  lH NMR spectrum contained singlets at 3.07 (2H), 3.09 (IH), 3.14 (2H) and 3.15 ppm (IH), a fact which, along with the "absent" ketone, led us to suspect the presence of a dimethyl ketal; the peaks at 3.07 and 3.14 ppm corresponded to this group of the major diastereomer 249a (P-OTBDMS) whereas those at 3.09 and 3.15 could be assigned to 249b (oc-OTBDMS). Further evidence for this structure came from the MS; the observed molecular ion at m/z = 550 was as expected for 249 and the measured and calculated exact masses for C2iH540gSi (550.3684 and 550.3689 respectively) confirmed the assigned structure. Final evidence was obtained by chemical means; acid hydrolysis of the ketals 249 provided the diketo enones 248. It seems likely that residual methanol from the ozonolysis was carried through to the aldol condensation, the conditions of which were also suitable for the formation of 249. 118 The formation of the fourth ring was then achieved by a base-catalysed aldol condensation of the diketo enones 248, to provide the alcohols 250 in 55% yield. Unfortunately, dehydration of the intermediate aldols 250 to provide the (bis)enones 247 did not occur under these conditions, and subsequent attempts to bring about this transformation by treatment of 250 with p-TsOH in refluxing benzene furnished only the starting material. The yield of the condensation was somewhat lower than was hoped, which may be significant when combined with the fact that the diastereomeric ratio of the products was found to be 9:1, compared to the 2:1 ratio in the starting material. These observations suggest that the major diastereomer of the starting material 248a was undergoing condensation much faster than the minor diastereomer 248b, resulting in enhancement of the diastereomeric purity of the product 250, albeit at the expense of the yield. The fate of the remainder of the starting material was never determined, although it was certainly not present in unchanged form in the crude product mixture. OMe H v P = TBDMS Figure 5: Configuration of the keto alcohol 250 The structure of the aldol product was thought to be 250 on the basis of its IR and iH NMR spectra. The IR spectrum showed a weak hydroxyl stretch at 3525 cm*1, and two carbonyl stretches at 1695 and 1675 cm - 1 , corresponding to the p-hydroxy ketone and the enone respectively. It is known that hydrogen bonding to a ketone causes the carbonyl absorption to shift to lower frequency50, as observed for the B ring ketone of 250, which would normally be expected to occur around 1710 cm' 1. The fact that hydrogen bonding could occur between the C(7) ketone and the C(14) hydroxyl group suggested that the latter was oc-oriented; a P-oriented 119 alcohol at this centre would not be geometrically capable of hydrogen bonding to the C(7) ketone (Figure 5). The lH NMR spectrum provided a clear indication that the original 2:1 mixture of diastereomers had been enhanced to 9:1, as shown by the relative integrations of a number of characteristic peaks, including those of the A ring enone [6.07 (0.1 H) and 7.23 ppm (0.1 H), and 6.17 (0.9 H) and 6.91 ppm (0.9 H)] and the proton at C( l l ) [4.16 (0.9 H, td, J = 12 and 6 Hz) and 4.30 ppm (0.1 H, ddd, J = 12, 6 and 4 Hz)]. A broad singlet at 3.59 ppm (IH) was thought to be the C(14) hydroxyl proton, the strength of the hydrogen bonding of which to the C(7) ketone was illustrated by its failure to exchange with D2O. Further evidence for the structure 250 came from the low and high resolution mass spectra. While the highest observed peak in the low resolution MS was at m/z = 486, corresponding to the dehydrated product, a peak at m/z = 447 could only be explained by loss of the t-butyl group of 250. The measured exact mass of this ion (447.2569) corresponded very well with that calculated for 250 - l Bu (C25H3 90 5Si = 447.2567). The multiplicity of the *H NMR peaks of the C(l 1) proton provided a useful diagnostic tool for the final establishment of the complete stereochemistry of both the major and minor diastereomers. Because of the rigid nature of the newly-formed C ring, the splitting pattern of these signals could be directly related to the spatial relationship between the proton at C( l l ) and those on the neighbouring carbon atoms. The triplet of doublets observed for the major diastereomer suggested that the C(l 1) proton was axial, coupling equally with the axial protons at C(9) and C(12) (cf. Figure 5) and with a smaller coupling constant with the lone equatorial proton at C(12). An axial C( l l ) proton would be B-oriented, thus establishing that the silyloxy group was a-oriented, as in 250a. The equivalent signal of the minor diastereomer was consistent with this proton being equatorial, and thus a-oriented, as in 250b. Hydrolysis of the silyl ether provided the diol 251, obtained as a single diastereomer, in 62% yield. The fate of the minor diastereomer was not determined, although in all probability it 120 was simply "lost in the wash"; the quantities of material being used at this stage were reasonably small, and a minor constituent could have easily been overlooked during purification. It had been hoped that the diol 251 would be crystalline, in order to allow an X-ray structural determination, but this proved not to be the case. The diastereomeric purity did result in the NMR spectra being somewhat less confusing (see Appendices 2a,c), particularly the 1 3 C NMR spectrum, which clearly showed 23 different carbon signals, and was consistent with the structure 251 (Appendix 2b). The attached proton test (APT) indicated that 12 of the carbon atoms had an odd number of protons attached (methyl and methine groups) while 11 possessed an even number of protons (methylene and quaternary carbons). This result is in keeping with the structure 251, but importantly not with the dehydrated compound 254, for which 11 methyl/methine carbons and 12 methylene/quatemary carbons would be expected. Treatment of the diol 251 with acetic anhydride, DMAP and pyridine provided the monoacetate 252 in 77% yield. The identification of the product of acetylation as 252 was made on the basis of its IR and *H NMR spectra. The IR spectrum provided a clear indication that an acetate group was present, by the presence of a new carbonyl absorption at 1730 cm - 1 . That it was a monoacetate was not so obvious, although a weak peak at 3525 cm*1 and the presence of an apparently hydrogen bonded ketone absorption at 1695 cm*1 suggested that the tertiary alcohol at C(14) was still present The lH NMR spectrum (Appendix 2b) confirmed that the product was indeed a monoacetate; only one peak attributable to an acetate methyl group was observed, at 2.08 ppm (3H, s). In addition, the *H NMR spectrum confirmed that acetylation had taken place on the 121 C( l l ) hydroxyl group; a broad singlet at 3.21 ppm (IH) was assigned to the C(14) hydroxyl proton and the C( l l ) proton had shifted downfield to 5.40 ppm (1H, td, J = 11,4 Hz), as would be expected following acetylation46. 252 253 255 The acetate 252 proved to be crystalline and suitable for an X-ray crystallographic structural determination. The results of this experiment (Appendix 2d) confirmed our assignments of the absolute configurations of both the C( l l ) and C(14) centres as well as the hydrogen bonding of the C(14) hydroxyl group to the C(7) ketone. It remained to dehydrate 252 to provide the desired bis(enone) 253. A single experiment involving treatment of 252 with mesyl chloride, DMAP and Et 3 N appeared to result in dehydration, but it was apparent from the *H NMR spectrum that two products had been obtained, possibly the C(10) epimers 253 and 255 (Equation 16). Unfortunately, due to time and material constraints, it was not possible to complete this final step. 122 2.3 Conc lus ion The tetracyclic alcohol 252 was synthesised in 21 steps and 0.65 % overall yield from (-)-bomeol (229), (+)-5,6-dehydrocamphor (223) and trimethylsilylacetylene (Scheme 46). The chirai centres at C(13) and C(17) were derived direcdy from (-)-borneol (229), while those at C(5) and C(9) and the geminal dimethyl group at C(4) were derived via an anionic oxy-Cope rearrangement90'91 of the 5,6-dehydrocamphor derivative 241a. It is anticipated that 252 should be readily transformed to the bis(enone) 253, which can be considered to represent the basic carbocyclic skeleton of triterpenoids of the euphane and apo-euphane type, lacking only the angular methyl groups at C(10) and C(8) or C(14) and the sidechain at C(20). The introduction of the C(10) methyl group to similar systems has been an ongoing concern in our laboratory, although no solution to this problem has yet been found 9 9. The introduction of the C(8) (apo-euphane) methyl group could potentially be accomplished by 253 Scheme 4 6 123 alkylation of a suitable derivative of 253, such as 256 (Scheme 47); conjugate addition of a methyl group to 256 could provide the C(14) (euphane) methyl group as in 258. It is considered that both these processes would occur preferentially from the B-face to provide the desired methyl stereochemistry. The methoxyethyl sidechain at C(17) could potentially be elaborated or modified earlier in the synthesis to provide a (methoxycarbonyl)methyl sidechain, as in 259. It is expected that alkylation of this ester group would occur stereospecifically71 (cf. Chapter 1) to allow for introduction of a variety of sidechains with control of the C(20) stereochemistry. Since either an 1 2 4 isohexyl or a methyl group could be introduced at this stage (Scheme 47), access to derivatives of either euphol or tirucallol (eg. 262 and 260 respectively) is potentially available, while the introduction of a group which would enable die construction of a furan ring could lead to syntheses of the limonoids. The value of 253 as a potential triterpenoid synthon is enhanced by the presence of oxygen functionality at C(3), C(7) and C( l l ) , all of which can be oxygenated in the euphanes, apo-euphanes and the limonoids. In addition, the bis(enone) functionality of 253 potentially allows for the introduction of oxygen at a number of other sites. It is worthy of note that a similar synthetic route based on a D ring subunit derived from (+)-camphor (228) (Scheme 48) would provide the diastereomeric bis(enone) 263, a potentially useful intermediate in the synthesis of derivatives of lanosterol (185). OMe Scheme 48 125 2.4 Experimental Oxidation of (-)-borneol (229) to (-)-camphor (ent-228): 229 ent-228 A solution of (-)-bomeol (229,100 g, 0.65 mol) in acetone (300 mL) was stirred in a bath of cold water and a solution of C1O3 (52 g, 0.52 mmol) and cone. H2SO4 (45 mL) in water (155 mL) was added dropwise over 45 min. Following the addition, the mixture was stirred an additional 30 min before being diluted with Et20 (100 mL). The layers were separated and the aqueous phase was extracted with Et20 (2 x 100 mL). The combined organic phases were washed with brine (2 x 50 mL), NaHS03 (2 x 50 mL) and again with brine (50 mL), and dried over MgS04- Evaporation of the solvent provided (-)-camphor (ent-228) as a white solid which was used without further purification; yield: 100 g, 100%. A small amount of the product was recrystallised at low temperature from PE to afford white crystals; mp: 177 - 179 °C, (ht.100 178 -180°C); [a]22 -44° (c = 1.0, EtOH) (tit.1™ [a]20 -43°, c = 10, EtOH). C 1 0 H 1 6 O Calc. Mass: 152.1201 Meas. Mass: 152.1204 IR (CHCI3): "o = 2970,2915,2890 (C-H); 1735 cm-1 (C=0). MS (70 eV): m/z (%) = 152 (M+, 26.7); 110 (13.0); 109 (28.9); 108 (52.8); 95 (100.0). !H NMR (CDCI3): 8 = 0.84 (3H, s, C(8)H3); 0.92 (3H, s, C(10)H3); 0.96 (3H, s, C(9)H3); 1.29 -1.45 (2H, m, C(5) and C(6) endo H's); 1.69 (IH, td, J = 14,4 Hz, C(6) exo H); 1.86 (IH, d, J = 17 Hz, C(3) endo H); 1.92 - 2.01 (IH, m, C(5) exo H); 2.10 (IH, t, J = 5 Hz, C(4)H); 2.32 (IH, dt, J = 17, 5 Hz, C(3) exo H). 126 Bromination of (-)-camphor (ent-228) to (-)-enoo-3-bromocamphor (ent-117): A solution of (-)-camphor (ent-228, 47.4 g, 0.311 mol) in glacial AcOH (125 mL) was placed in a 250 mL, 3-necked rbf equipped with a pressure equalizing addition funnel, condenser, and gas trap. The solution was heated to 85°C and a solution of Br 2 (20 mL, 62 g, 0.39 mol) in glacial AcOH (20 mL) was added dropwise over 2.5 h, while stirring. After the addition was complete the solution was stirred overnight at 85°C, cooled, and quenched by pouring onto ice (250 mL), resulting in precipitation of the (-)-3-bromocamphor (ent-117). The crude product was collected by suction filtration and purified by recrystallization from EtOH to afford (-)-endo-3-bromocamphor (ent-117) as white needles; yield: 50.3 g, 70%; mp: 75-6°C (lit.1 0 1 75-7°C); [a] 2 4 -136° (c = 1.92, CHC13) (lit. 1 0 1 -1270, c = 5, MeOH). CioH 1 5BrO Calc: C 51.97 H 6.54 Br 34.57 % Anal.: C 51.76 H 6.49 Br 34.40 % Calc. Mass: 232.0287, 230.0307 Meas. Mass: 232.0291, 230.0315 JR (CHCI3): t> = 2975,2950,2895 (C-O); 1750 cm"1 (C=0). MS (70 eV): m/z (%) = 232,230 (M+, 11.5, 11.6); 189, 187 (1.0,0.8); 151 (37.5); 123 (100.0). iH NMR (CDCI3): 5 = 0.93 (3H, s, C(8)H3); 0.97 (3H, s, C(10)H3); 1.08 (3H, s, C(9)H3); 1.44 (IH, ddd, J = 14, 9, 5 Hz, C(6) endo H); 1.69 (IH, td, J = 13, 4 Hz, C(5) endo H); 1.84 - 1.94 (IH, m, C(5) exo H); 2.10 (IH, ddd, J = 14, 10, 4 Hz, C(6) exo H); 2.31 (IH, t, J = 4 Hz, C(4)H); 4.63 (IH, ddd, J = 4, 2, 1 Hz, C(3)H). 127 Bromination of (-)-c/iaV>-3-bromocamphor (ent-117) to (-)-3,9-dibromocamphor (ent-118): ent-117 ent-118 A solution of Br2 (18 mL, 55 g, 0.35 mol) in chlorosulphonic acid (40 mL, 70 g, 0.62 mol) was added to (-)-3-bromocamphor (ent-117, 50 g, 0.22 mol), while cooling in ice. After stirring for 5 min at 0°C, the solution was allowed to warm to rt and stirring was continued for a further 1 h. The solution was cautiously poured onto ice (250 mL) and NaHSO^ (25 g), resulting in the precipitation of crude (-)-3,9-dibromo-camphor. The solution was decanted and the solid triturated with water (4 x 100 mL), and finally collected by suction filtration. The crude product was dissolved in CH2CI2 (500 mL), washed with brine (2 x 50 mL) and dried over MgSC>4. MeOH (50 mL) was added and the solvents were removed by rotary evaporation until the first crystals appeared. The mixture was cooled to 5°C and the crystalline (-)-3,9-dibromocamphor (ent-118) was collected by suction filtration. The mother liquor was concentrated, cooled and filtered again to afford a second crop. The combined (-)-3,9-dibromocamphor (ent-118) was not purified further, yield: 49.4 g, 74%; mp: 157-8°C (lit.?8 158-9°C); [a] 1 8 -100° (c = 0.14, CHCI3), (lit.78 -99°. c = 1, CHCI3). C 1 0 H 1 4 Br 2 O Calc: C 38.74 H 4.55 Br 51.55 % Anal.: C 38.78 H 4.51 Br 51.36 % IR (CHCI3): D = 3000,2945 (C-H); 1740 cm-l (c=0). MS (70 eV): m/z (%) = 312, 310,308 (M+ 1.0, 2.2,1.1); 231,229 (8.6, 8.6); 203, 201 (14.0, 14.2); 68 (100.0). ! H NMR (CDCI3): 8 = 1.03 (3H, s, C(8)H3); 1.10 (3H, s, C(10)H3); 1.52 (IH, ddd, J = 16, 6,4 Hz, C(6) endo H); 1.74 (IH, td, J = 13,3 Hz, C(5) endo H); 1.85 - 1.94 (IH, m, C(5) exo H); 2.19 (IH, ddd, J = 16,9, 3 Hz C(6) exo H); 2.71 (IH, t, J = 4 Hz, C(4)H); 3.30, 3.66 (2H, qAB, J = 10 Hz, C(9)H2Br); 4.57 (IH, broad d, C(3)H). 128 Conversion of (-)-3,9-dibromocamphor (ent-118) to (-)-9,10-dibromocamphor (ent-120): Br Br ent-118 ent-119 ent-120 A solution of Br 2 (19.5 mL, 60.7 g, 0.38 mol) in chlorosulphonic acid (76.5 mL, 134 g, 1.15 mol) was added cautiously to (-)-3,9-dibromocamphor (ent-118, 79.0 g, 0.255 mol) while cooling in ice. After 5 min, the ice bath was removed and the mixture was stirred for 5 d. Further Br 2 (5 mL, 15 g, 0.1 mol) and chlorosulphonic acid (10 mL, 17 g, 0.15 mol) was added and the mixture was stirred another 24 h before being poured cautiously onto ice (500 mL) and NaHSC>3 (25 g), causing the crude product to separate as an orange tar. The aqueous solution was decanted, and extracted with Et 2 0 (3 x 100 mL), and the tar was dissolved in Et 2 0 (500 mL). The combined Et 2 0 was washed with water (3 x 100 mL), NaHCO^ (5 x 50 mL, until the washings were basic) and brine (50 mL), and dried over MgSO^. Evaporation of the solvents provided crude (-)-3,9,10-tribromocamphor (ent-119) as a viscous orange oil which was used without purification; yield: 94.0 g. The crude tribromocamphor ent-119 was dissolved in 1:1 Et20:glacial AcOH (400 mL) in a 1 L Erlenmeyer flask equipped with a thermometer and an overhead mechanical stirrer, and cooled to 0°C. Zn dust (36 g, 0.55 mol) was added in portions over 1 h, while stirring rapidly and maintaining the temperature below 20°C. The mixture was stirred for a further 30 min before Celite (10 g) was added and the solids were removed by suction filtration. The solution was diluted with Et 2 0 (200 mL) and washed with water (3 x 100 mL), NaHC0 3 (6 x 100 mL, until the washings were basic) and brine (100 mL), and dried over MgSC«4. Evaporation of the solvent provided a viscous orange oil which was triturated with MeOH to produce yellow crystals. Recrystallization from MeOH afforded pure (-)-9,10-dibromocamphor (ent-120) as off-white 129 needles; yield: 35.5 g, 45% over two steps; mp: 96-7°C (lit.39 97-9°C (120)); [a] 2 2 -70° (c = 0.50, MeOH) (lit 3 9 (120) +68°, c = 2, MeOH). C 1 oH 1 4 Br 2 0 Calc. Mass: 311.9371, 309.9391, 307.9411 Meas. Mass: 311.9374, 309.9394, 307.9424 IR (CHC13): v = 3015,2985,2895 (C-H); 1740 cm-l (C=0). MS (70 eV): m/z (%) = 312, 310, 308 (M+ 0.4,0.9,0.5); 231, 229 (32.6, 33.3); 203, 201 (1.4, 1.5); 121 (81.4); 107 (100.0). lH NMR (CDC13): 5 = 1.12 (3H, C(8)H3); 1.45 - 1.55 (2H, m, C(5) and C(6) endo H); 2.00 (IH, d ^ , J = 19 Hz, C(3) endo H); 2.02 - 2.11 (IH, m, C(5) exo H); 2.26 - 2.35 (IH, m, C(6) exo H); 2.40 (IH, d^t, J = 19,4 Hz, C(3) exo H); 2.61 (IH, t, C(4)H); 3.49 (IH, dAB. J = 12 Hz), 3.60 (IH, d ^ , J = 11 Hz) and 2.70 (2H, broad d ^ , J = 12 Hz, C(9)H2BrandC(10)H2Br). Grob fragmentation of (-)-9,10-dibromocamphor (ent-120) to bromoester ent-115: Br^Sf ^C02Me J 9 —~& ent-120 ent-115 Sodium (2.0 g, 87 mmol) was added in small portions to dry MeOH (150 mL) while stirring under Ar. Once the formation of NaOMe was complete, (-)-9,10-dibromocamphor (ent-120, 20.0 g, 64.5 mmol) was added in one portion and the mixture was stirred vigorously for 18 h. The solution was then poured into brine (100 mL) and water (100 mL), and extracted with Et 20 (100 mL, 2 x 50 mL). The combined extractions were diluted with PE (50 mL) causing the MeOH to separate, and the latter was removed. The remaining organics were washed with NH4CI (50 mL) and brine (50 mL), and dried over MgS0 4. Evaporation of the solvents provided a mobile, pale yellow oil which was purified by vacuum distillation to afford the bromoester ent-115 as a colourless mobile liquid; yield: 14.0 g, 84%; bp: 100°C (0.1 mm); [a] 2 0 33.0° (c = 1.86, CHC13). 1 3 0 C n H 1 7 B r 0 2 C a l c : C 5 0 . 5 9 H 6 . 5 6 B r 3 0 . 6 0 % A n a l . : C 5 0 . 6 4 H 6 . 6 7 B r 3 0 . 4 5 % I R ( n e a t ) : v = 3 0 9 0 ( = C - H ) ; 2 9 6 0 , 2 8 7 5 , 2 8 5 0 ( C - H ) ; 1 7 4 0 ( C = 0 ) ; 1 6 5 0 (C=CH2); 8 9 0 c n r * ( = C - H ) . M S ( 7 0 e V ) : m / z ( % ) = 2 6 2 , 2 6 0 ( M + , 0 . 2 , 0 . 1 ) ; 2 3 1 , 2 2 9 ( 2 . 2 , 2 . 0 ) ; 2 0 3 , 2 0 1 ( 0 . 1 , 0 . 1 ) ; 1 8 8 , 1 8 6 ( 4 . 8 , 4 . 9 ) ; 1 8 1 ( 4 . 4 ) ; 1 8 0 ( 3 . 6 ) ; 1 6 7 ( 8 6 . 3 ) ; 1 0 7 ( 1 0 0 . 0 ) . * H N M R ( C D C 1 3 ) : 8 = 1 . 0 6 ( 3 H , s, C H 3 ) ; 1 . 3 0 - 1 . 4 0 ( I H , dq, J = 1 3 , 9 H z ) ; 1 . 9 2 - 2 . 0 0 ( I H , m ) ; 2 . 1 6 ( I H , dd, J = 1 6 , 1 1 H z ) ; 2 . 3 1 - 2 . 5 0 ( 2 H , m ) ; 2 . 5 3 - 2 . 6 1 ( 2 H , m ) ; 3 . 4 1 , 3 . 4 8 ( 2 H , qAB, J = 1 1 H z , - C H 2 B r ) ; 4 . 8 6 , 5 . 0 1 ( I H e a c h , 2 t , J = 2 . 5 H z , 2 H z , = C H 2 ) . R e d u c t i o n o f e s t e r ent-115 t o a l c o h o l 2 3 0 : A s u s p e n s i o n o f L L A I H 4 ( 1 . 2 1 g , 3 1 . 9 m m o l ) i n d r y E t 2 0 ( 1 0 0 m L ) w a s s t i r r e d u n d e r A r a t 0 ° C , a n d a s o l u t i o n o f t h e e s t e r ent-115 ( 1 3 . 9 g , 5 3 . 2 m m o l ) i n d r y E t 2 0 ( 1 0 0 m L ) w a s a d d e d d r o p w i s e o v e r 2 . 5 h . A f t e r s t i r r i n g f o r a f u r t h e r 1 h , N a S C V I O H 2 0 ( 3 g ) w a s a d d e d c a u t i o u s l y a n d t h e s u s p e n s i o n w a s s t i r r e d f o r 1 h b e f o r e a n h y d r o u s M g S 0 4 ( s ) w a s a d d e d a n d t h e m i x t u r e w a s f i l t e r e d . E v a p o r a t i o n o f t h e s o l v e n t p r o v i d e d t h e a l c o h o l 2 3 0 a s a c o l o u r l e s s o i l w h i c h w a s n o t p u r i f i e d f u r t h e r , y i e l d : 1 2 . 4 g , 1 0 0 % ; b p : 1 0 5 ° C ( 0 . 1 m m ) . C 1 0 H 1 7 B r O C a l c . M a s s : 2 3 4 . 0 4 4 4 , 2 3 2 . 0 4 6 4 I R ( n e a t ) : v = 3 3 5 0 ( b r o a d , O - H ) ; 3 0 5 5 ( = C - H ) ; 2 9 4 5 , 2 9 2 5 , 2 8 5 5 ( C - H ) ; 1 6 5 0 ( C = C H 2 ) ; 1 0 5 5 ( C - O ) ; 8 9 5 c m - l ( = C - H ) . M S ( 7 0 e V ) : m / z ( % ) = 2 3 4 , 2 3 2 ( M + , 0 . 1 , 0 . 1 ) ; 2 1 6 , 2 1 4 ( 0 . 4 , 0 . 5 ) ; 1 8 8 , 1 8 6 ( 0 . 7 , 0 . 6 ) ; 1 5 2 ( 3 . 0 ) ; 1 3 9 ( 4 0 . 6 ) ; 9 5 ( 1 0 0 . 0 ) . I H N M R (CDCI3): 8 = 1 . 0 4 ( 3 H , s , C H 3 ) ; 1 . 2 9 ( I H , b r o a d s , e x c h a n g e s w i t h D 2 0 , - O H ) ; 1 . 2 6 -1 . 4 4 ( 2 H , m ) ; 1 . 8 0 ( I H , d t d , J = 1 4 , 9 , 4 H z ) ; 1 . 8 8 - 1 . 9 6 ( I H , m ) ; 2 . 1 7 ( I H , t d d , J = ent-115 230 M e a s . M a s s : 2 3 4 . 0 4 3 3 , 2 3 2 . 0 4 6 4 131 12, 8, 4 Hz); 2.27 - 2.37 (1H, m); 2.39 - 2.47 (IH, m); 3.43, 3.49 (2H, o^, J = 10 Hz, -CH2Br); 3.70 (1H, broad m, simplifies to d^t with D20, J = 12, 8 Hz) and 3.76 (IH, broad m, simplifies to d^dd with D20, J = 12,9,5 Hz, -CH2OH); 4.84 and 4.98 (IH each, 21, J = 2 Hz, 2 Hz, =CH2). Protection of alcohol 230 as methyl ether 231: A suspension of KH (1.74 g, 43.4 mmol) in dry THF (75 mL) was cooled under Ar to 0°C, and CH3I (2.70 mL, 6.16 g, 43.4 mmol) was added by syringe. A solution of the alcohol 230 (8.10 g, 34.7 mmol) in dry THF (60 mL) was added dropwise over 20 min, and the mixture was stirred for a further 40 min. Water (40 mL) was added, the layers were separated, and the organic phase was washed with water (30 mL), brine (30 mL), 10% Na2S203 (30 mL) and again with brine (30 mL), and dried over MgSO .^ Evaporation of the solvent provided an orange liquid which was purified by column chromatography (70-230 mesh Si02,6.5 x 8 cm), eluting with 19:1 PE:Et20 to afford the methyl ether 231 as a colourless mobile liquid; yield: 7.59 g, 88%; bp: 86°C (0.1 mm). C nH 1 9BrO Calc. Mass: 248.0601, 246.0621 IR (neat): x> = 3080 (=C-H); 2950,2860,2845 (C-H); 1650 (C=CH2); 1115 (C-O); 880 cm"1 MS (70 eV): m/z (%) = 216,214 (M+-CH3OH, 7.4,7.5); 201, 199 (0.1,0.2); 188, 186 (6.5, 6.5); 167 (9.5); 166 (19.6); 153 (36.1); 121 (100.0). OMe 230 231 Meas. Mass: 248.0595, 246.0621 (=C-H). 132 lH NMR (CDCI3): 8 = 1.04 (3H, s, CH3); 1.21 - 1.42 (2H, m); 1.82 (IH, dtd, J = 13, 8.5, 3.5 Hz); 1.86 - 1.94 (IH, m); 2.13 (IH, tdd, J = 10.5,7, 3 Hz); 2.26 - 2.36 (IH, m); 2.39 -2.47 (IH, m); 3.36 (3H, s, -OCH3); 3.40 - 3.55 (2H, m, -CH20-); 3.44, 3.48 (2H, o^, J - 10 Hz, -CH2Br); 4.84,4.98 (IH each, 21, J = 2 Hz, 2 Hz, =CH2). Conversion of bromide 231 to nitrile 232: A solution of the bromide 231 (7.59 g, 30.7 mmol) and NaCN (7.52 g, 153 mmol) in dry HMPA (75 mL) was heated under Ar to 95°C for 3 h. The mixture was cooled, poured into water (200 mL) and extracted with Et 20 (3 x 100 mL). The combined extractions were washed with water (3 x 50 mL) and brine (2 x 50 mL), and dried over MgSC»4. Evaporation of the solvent provided a colourless mobile oil which was purified by column chromatography (70-230 mesh Si02, 6.5 x 8 cm), eluting with 4:1 PE:Et20, to afford the pure nitrile 232 as a colourless liquid; IR (neat): 0) = 3050 (=C-H); 2950,2910,2850 (C-H); 2220 (CN); 1650 (C=CH2); 1120 (C-O); 890cm-1(=C-H). MS (70 eV): m/z (%) = 193 (M+, 2.1); 178 (2.2); 162 (2.0); 161 (4.3); 160 (3.9); 152 (66.7); 121 (100.0). ! H NMR (CDCI3): 8 = 1.00 (3H, s, CH3); 1.30 - 1.46 (2H, m); 1.78 (IH, dtd, J = 14, 8, 3.5 Hz); 1.90 - 2.00 (2H, m); 2.34 - 2.44 (IH, m); 2.45 - 2.51 (IH, m); 2.47, 2.48 (2H, qAB, J = 16 Hz, -CH2CN); 3.36 (3H, s, -OCH3); 3.40 - 3.51 (2H, m, -CH20-); 4.94, 5.01 (IH each, 2 t, J = 2.5 Hz, 2 Hz, =CH2). 231 232 yield: 5.06 g, 85%; bp 85°C (0.1 mm); [a]2 0 18.9° (c = 1.86, CHC13). C 1 2 H 1 9 NO Calc: C 74.57 H 9.91 N 7.25 % Anal.: C 74.44 H 9.80 N 7.09 % 133 Reduction of nitrile 232 to aldehyde 233: NC OHC / 'OMe 232 233 A solution of the nitrile 232 (8.78 g, 45.4 mmol) in dry Et20 (150 mL) was cooled to 0°C under Ar, and DIBAL (55 mL, lM/hexanes, 55 mmol) was added by syringe. The solution was stirred for 45 min, poured into saturated K,Na tartrate (150 mL), water (150 mL), and 1 N HCl (10 mL), and stirred for a further 1 h. The layers were separated and the aqueous phase was extracted with Et20 (3 x 50 mL). The combined extracts were washed with 0.1 N HCl (30 mL), NaHCC»3 (30 mL) and brine (30 mL), and dried over MgS04- Evaporation of the solvents provided a pale yellow, mobile oil which was purified by vacuum distillation to afford the pure aldehyde 233 as a colourless liquid; yield: 6.55 g, 73%; bp: 90°C (0.1 mm); [a] 2 0 57.8° (c = IR (neat): \) = 3085 (=C-H); 2945,2870,2850 (C-H); 2750 (0=C-H); 1720 (C=0); 1650 (C=CH2); 1115 (C-O); 880 cm-l (=C-H). MS (70 eV): m/z (%) = 196 (M+ 0.2); 164 (1.3); 152 (34.4); 122 (100.0). lH NMR (CDC13): 8 = 0.96 (3H, s, CH 3); 1.30 -1.44 (2H, m); 1.75 (IH, dtd, J = 14, 7.5, 3 Hz); 1.86 - 1.96 (IH, m); 2.45 (1H, d^d, J = 16, 3.5 Hz) and 2.53 (IH, d ^ d , J = 16,2 Hz, -CH 2CHO); 2.46 - 2.54 (IH m); 3.34 (3H, s, -OCH 3); 3.37 - 3.52 (2H, m, -CH 20-); 4.86, 4.99 (IH each, 21, J = 2.5, 2 Hz, =CH2); 9.71 (IH, dd, J = 3.5, 2 Hz, -CHO). 1.66, CHCI3). Ci2H 2o0 2 Calc: C 73.43 H 10.27 % Anal.: C 73.29 H 10.30% Calc Mass: 196.1463 Meas. Mass: 196.1466 134 Condensation of aldehyde 233 with lithium trimethylsilylacetylide to form trimethylsilyl alkynol 234: 233 TMS 234 A solution of trimethylsilylacetylene (4.70 mL, 3.25 g, 33.1.mmol) in dry THF (100 mL) was cooled under Ar to 0°C, and n BuLi (20.7 mL, 1.6 M/Hexanes, 33.1 mmol) was added by syringe. The solution was stirred for 30 min, when a solution of the aldehyde 233 (5.41 g, 27.6 mmol) in dry THF (50 mL) was added by cannula. After stirring an additional 1 h, NH4C1 (50 mL) was added and the layers were separated. The organic phase was washed with brine (2 x 25 mL) and the combined aqueous phases were extracted with Et^O (2 x 20 mL). The combined organic solvents were dried over MgS0 4 and evaporated to produce a viscous yellow oil. This was purified by column chromatography (70-230 mesh SiC>2, 6.5 x 8 cm), eluting with 4:1 PE:Et20, to afford the silyl alkynol 234 as a colourless oil, in a 2:1 mixture of diastereomers; yield: 7.92 g, 98%. C 1 7H3o0 2Si Calc: C 69.33 H 10.26 % Anal.: C 69.15 H 10.43 % Calc. Mass: 294.2015 Meas. Mass: 294.2024 IR (neat): u = 3400 (broad, O-H); 3050 (=C-H); 2945,2925,2880,2850,2825 (C-H); 2155 ( C C ) ; 1645 (OCH2); 1120 (C-O); 890 cm-1 (=C-H). MS (70 eV): m/z (%) = 294 (M+, 0.1); 279 (1.2); 221 (1.5); 219 (3.8); 218 (6.1); 217 (8.7); 122 (100.0). lH NMR (CDC13): 8 = 0.17 (6H, s, Si(CH 3) 3, major diastereomer); 0.18 (3H, s, Si(CH 3) 3, minor diastereomer); 0.88 (2H, s, C H 3 , major diasteroemer); 0.89 (1H, s, C H 3 , minor diastereomer); 1.20 - 1.42 (2H, m); 1.73 - 1.83 (IH, m); 1.85 - 1.95 (2H, m); 1.98 - 2.02 (IH, m); 2.03 - 2.12 (IH,in); 2.17 (0.33 H, broad d, J = 5 Hz, -OH, minor diastereo mer); 2.42 - 2.50 (IH, m); 2.52 (0.67 H, broad d, J = 5 Hz, -OH, major diastereomer); 135 3.34 ( 2H , s, - O C H 3 , major diastereomer); 3.35 (IH, s, - O C H 3 , minor diastereomer); 3.38 - 3.52 ( 2H , m, -CH 2OMe); 4.40 - 4.48 [ 1 H , m, simplifies with D 2 0 to: 4.42 (0.67 H, dd, J = 8, 3 Hz, RR'CHOH, major diastereomer) and 4.45 (0.33 H, t, J = 6 Hz, RR'CHOH, minor diastereomer)]; 4.77 and 4.93 (0.67 H each, 21, J = 2.5 Hz, 2 Hz, =CH 2, major diastereomer); 4.88 and 4.97 (0.33 H each, 21, J = 2.5 Hz, 2 Hz, =CH 2, minor diastereomer). Cleavage of trimethylsilylalkynol 234 to alkynol 235: A solution of KOH (4.02 g, 72 mmol) in MeOH (75 mL) was added to a solution of the trimethylsilylalkynol 234 (7.04 g, 23.9 mmol) in CH 2 C1 2 (120 mL) and the mixture was stirred for 45 min. After diluting with 1:1 PE:Et 20 (200 mL), the solution was washed with NH4CI (2 x 75 mL) and brine (50 mL), and dried over MgSO^ Evaporation of the solvents provided a viscous yellow oil which was purified by column chromatography (70-230 mesh S i0 2 , 4.5 x 18 cm), eluting with 2:1 PE:Et 20, to afford the alkynol 235 as a colourless oil, in a 2:1 mixture of diastereomers; yield: 5.30 g, 99%. IR (neat): v = 3400 (broad, O-H); 3290 (H-O); 3050 (=C-H); 1645 (C=CH2); 1120 (C-O); 895 cm-^sC-H). MS (70 eV): m/z (%) = 222 (M+, 1.3); 204 (2.0); 190 (2.0); 189 (6.2); 175 (6.6); 165 (17.6); 107 (100.0). *H NMR (CDCI3): 8 = 0.87 (2H, s, C H 3 , major diastereomer); 0.89 (IH, s, C H 3 , minor dia-stereomer); 1.25 -1.44 (2H, m); 1.72 - 1.82 (IH, m); 1.84 - 1.91 (IH, m); 1.93 (0.33 H, d, J = 8 Hz, H - O , minor diastereomer); 1.97 (0.67 H, d, J = 7.5 Hz, H - O , major dia-stereomer); 2.00 - 2.13 (2H, m); 2.25 (0.33 H, broad d, J = 6 Hz, exchanges with D 2 0 , -OH, minor diastereomer); 2.28 - 2.39 (IH, m); 2.43 - 2.52 (2H, m); 2.72 (0.67 H, d, J = TMS 234 H 235a,b C i 4 H 2 2 0 2 Calc: C 75.63 H 9.97 % Anal.: C 75.80 H 10.10% Calc Mass: 222.1620 Meas. Mass: 222.1622 136 6 Hz, exchanges with D2O, -OH, major diastereomer); 3.35 (3H, s, -OCH 3); 3.38 - 3.53 (2H, m, -CH 20-); 4.41 - 4.51 [IH, broad m, simplifies with D 2 0 to: 4.43 (0.67 H, dt, J = 7.5, 2 Hz, RR'CHOH, major diastereomer) and 4.47 (0.33 H, td, J = 8, 3 Hz, RR'CHOH, minor diastereomer)]; 4.76,4.94 (0.67 H each, 2 t, J = 2.5 Hz, 2 Hz, =CH 2, major diastereomer); 4.89,4.97 (0.33 H each, 21, J = 2.5 Hz, 2 Hz, =CH 2, minor diastereomer). Conversion of (+)-e/uto-3-bromocamphor (117) to (+)-5,6-Dehydrocamphor (223): B r 117 B r 223 A 500 mL rbf was charged with (+)-e/uio-3-bromocamphor (117, 55.0 g, 0.24 mol) and chlorosulphonic acid (180 mL) was added carefully. The solution was heated in a 50°C oil bath for 15 min, cooled in ice, and poured cautiously onto ice (500 g). The mixture was extracted with E t 2 0 (3 x 200 mL) and the combined extracts were washed with water (3 x 100 mL), NaHC03 (5 x 100 mL, until the washings were basic) and brine (100 mL), and dried over MgS0 4 . Evaporation of the Et 2 0 provided crude (-)-emi?-6-bromo-camphor as a dark yellow solid, which was not purified further, crude yield: 35 g, 64%. A small amount was purified by column chromatography (70-230 mesh Si0 2 ) , eluting with 10:1 PE:Et 2 0, to afford pure (-)-endo-6-bromocamphor as a white crystalline solid; mp: 54°C (lit.1 0 2 56°); [a] 2 5 -52° (c = 1.1, CHCI3), (tit.1 0 2 -51.60, c = 4.96, CH 2C1 2). C 1 0 H 1 5 BrO Calc. Mass: 232.0286, 230.0306 Meas. Mass: 232.0278,230.0302 IR (neat): o> = 2985,2950,2875 (C-H); 1745 cm"1 (C=0). MS (70 eV): m/z (%) = 232,230 (M + , 1.8,1.6); 167 (11.0); 151 (39.0); 149 (30.0); 109 (100.0). iH NMR (CDCI3): 5 = 0.92 (3H, s, C(8)H3); 0.98 (3H, s, C(10)H3); 1.00 (3H, s, C(9)H3); 1.90 (IH, dd, J = 14.5, 5 Hz, C(5) endo H); 2.06 (IH, d, J = 18.5 Hz, C(3) endo H); 2.22 (IH, dd, J = 6,4 Hz, C(4)H); 2.45 (IH, ddd, J F 18.5, 5, 4 Hz, C(3) exo H); 2.82 - 2.90 (IH, m, C(5) exo H); 4.23 (IH, dd, J = 10.5, 3.5 Hz, C(6) exo H). 1 3 7 The crude (-)-6-bromocamphor was dissolved in DMSO (600 mL), and a solution of KOH (42 g, 0.76 mol) in water (60 mL) was added. The solution was heated in a 110°C oil bath for 5 h, cooled, and poured into brine (500 mL). The solution was extracted with E t 2 0 (4 x 150 mL) and the combined extracts were washed with water (3 x 100 mL) and brine (100 mL), and dried over MgSC<4. Evaporation of the E t 2 0 provided a slushy yellow solid which was purified by sublimation (20 mmHg, 50°C) to afford pure (+)-5,6-dehydrocamphor (223) as a white waxy solid; yield: 4.75 g, 13% over two steps; mp: 148-150°C, (lit 103 149-151°C); [ a ] 2 2 +740° (c = 1.2, CHC13) (lit103 +756°, c = 0.50, C r ^ C l ^ . C 1 0 H 1 4 O Calc. Mass: 150.1045 IR (neat): v = 2980,2950,2895 (C-H); 1740 cm-l (c=0). MS (70 eV): m/z (%) = 150 (M+ 12.1); 93 (58.0); 85 (49.8); 71 (91.5); 69 (100.0). IH NMR (CDCI3): 8 = 0.91 (3H, s, C(8)H); 1.01 (3H, s, C(10)H3); 1.08 (3H, s, C(9)H3); 1.95 (IH, d, J = 17 Hz, C(3) endo H); 2.22 (IH, dd, J = 17, 4 Hz, C(3) exo H); 2.69 (IH, t, J = 4 Hz, C(4)H); 5.59 (IH, d, J = 6 Hz, C(6)H); 6.45 (IH, dd, J = 6, 4 Hz, C(5)H). Condensation of alkynol 235 with 223 to provide alkynyl diol 239: A solution of the alkynol 235 (1.69 g, 7.60 mmol) in dry THF (35 mL) was cooled under Ar to 0°C, and n BuLi (11.2 mL, 1.5 M/Hexanes, 16.7 mmol) was added by syringe. The solution was stirred at 0°C for 30 min and then cooled to -78°C. A solution of (+)-5,6-dehydrocamphor (223,1.37 g, 9.10 mmol) in dry THF (15 mL) was cooled to -78°C and added by cannula to the Meas. Mass: 150.1044 OMe 138 lithium acetylide. After stirring for 1 h at -78°C the mixture was allowed to warm slowly to it, and was stirred for a further 36 h before water (20 mL) and Et20 (100 mL) were added. The layers were separated, the aqueous phase was extracted with Et 2 0 (3 x 30 mL), and the combined organic solvents were washed with NH4CI (2 x 25 mL) and brine (2 x 25 mL), and dried over MgSC»4. Evaporation of the solvents provided a viscous, pale yellow oil which was purified by column chromatography (70-230 mesh SiO^, 3.5 x 15 cm), eluting with 9:1 PE:Et2<I) and increasing polarity to 1:1 PE:Et20, to afford the alkynol as a pale yellow oil; recovered yield: 402 mg, 18%. Further elution provided the diol 239 as a viscous oil in a 2:1 mixture of diastereomers; yield: 2.06 g, 88% based on recovered starting material. Small amounts of each diastereomer were obtained pure enough to obtain separate NMR spectra. C24H36O3 Calc. Mass: 372.2664 Meas. Mass: 372.2668 IR (neat): \> = 3400 (broad, O-H); 3050, 3010 (=C-H); 2945,2925,2885,2850 (C-H); 1650 (C=Ol2); 1120,1105 (C-O); 890 cm-1 (=CH2). MS (70 eV): m/z (%) = 372 (M+, 0.2); 354 (1.6); 344 (1.1); 326 (6.3); 312 (4.1); 297 (3.5); 93 (100.0). Major Diastereomer ! H NMR (CDCI3): 6 = 0.87 (3H, s, cyclopentane CH 3); 0.94 (3H, s) and 1.10 (6H, s, 3 x 2.2.1 CH 3 's); 1.22 - 1.38 (2H, m); 1.77 - 1.88 (IH, m); 1.87 (IH, d, J = 13 Hz, 2.2.1 C(3) endo H); 1.90,1.97 (2H, q^c l , JAB = 15 HZ, J D = 7 HZ and 4 HZ respectively, -CH2CH(OH)R); 2.11 (IH, tdd, J = 11, 6.5, 3 Hz); 2.24 (IH, dd, J = 13, 3 Hz, 2.2.1 C(3) exo H); 2.28 - 2.49 (3H, m); 2.30 (IH, broad s, exchanges with D 2 0 , 2.2.1 -OH); 2.39 (IH, broad d, J = 4 Hz, exchanges with D 2 0 , -CHROH); 3.35 (3H, s, -OCH 3); 2.38 - 2.53 (2H, m, - C H 2 O M e ) J 4 - 4 1 ( 1 H » dt, J = 7,4 Hz, simplifies with D 2 0 to dd, J = 7,4 Hz, -CHROH); 4.73,4.91 (IH each, 21, J = 2 Hz, 2 Hz, =CH2); 5.72 (IH, d, J = 6 Hz, 2.2.1 C(6)H); 6.07 (IH, dd, J = 6, 3 Hz, 2.2.1 C(5)H). Minor Diastereomer lH NMR (CDCI3): 8 = 0.85 (3H, s, cyclopentane CH3); 0.93,1.10,1.11 (3H each, 3 s, 3 x 2.2.1 CH 3 's); 1.19 - 1.36 (2H, m); 1.80 - 1.92 (2H, m); 1.86 (IH, d, J = 12.5 Hz, 2.2.1 C(3) endo H); 1.94,1.96 (2H, q^c i , J^B = 11 Hz, J D = 1 Hz and 2.5 Hz respectively); 2.18 - 2.27 (IH, m); 2.22 (IH, dd, J = 12.5, 3.5 Hz, 2.2.1 C(3) exo H); 2.28 - 2.36 (IH, m); 2.39 (IH, t, J = 3.5 Hz, 2.2.1 C(4)H); 2.42 - 2.50 (IH, m); 3.30 (IH, broad s, exchanges with D20,2.2.1 -OH); 3.35 (IH, d, J = 4 Hz, exchanges with D 2 0 , 139 -CHROH); 3.36 (3H, s, -OCH 3); 3.42 (1H, td, J = 10, 6 Hz) and 3.50 - 3.58 (IH, m, -CH 2OMe); 4.36 (1H, broad q, J = 5 Hz, simplifies with D 2 0 to t, J = 7 Hz, -CHROH); 4.83, 4.94 (IH each, 2 t, J = 2 Hz, 2 Hz); 5.74 (IH, d, J = 6 Hz, 2.2.1 C(6)H); 6.07 (IH, dd, J = 6, 3 Hz, 2.2.1 C(5)H). Reduction of alkynyl diol 239 to alkenyl diol 240: A suspension of L iAlH* (835 mg, 22 mmol) in dry THF (60 mL) was stirred under Ar, and a solution of the alkynyl diol 239 (2.05 g, 5.50 mmol) in dry THF (40 mL) was added slowly by cannula, resulting in vigorous bubbling. Once this ceased, the mixture was heated to 40°C and stirring was continued for 1.5 h, before Na2SO4°10 H 2 0 (1 g) was added cautiously. The suspension was stirred rapidly for 45 min, anhydrous MgS04 was added, and the solids were removed by suction filtration. Evaporation of the solvent provided a colourless glass which partially crystallised on standing. This was purified by column chromatography (70-230 mesh SiO^ 3.5 x 13.5 cm), eluting with 1:1 PE:Et 20 to afford the pure alkenyl diol 240 as a colourless glass, in a 2:1 mixture of diastereomers; yield: 1.64 g, 80 %. C24H 3 803 Calc. Mass: 374.2821 Meas. Mass: 374.2817 IR (CHa3): \) = 3600 (H-bonded O-H); 3425 (broad, O-H); 3025 (=C-H); 2980,2950,2930, 2890,2850 (C-H); 1650 ( O C H ^ ; 1605 (C=C); 1120 (C-O); 890 cm-l (=Crl£. MS (70 eV): m/z (%) = 374 (M+, 0.6); 356 (2.9); 341 (0,5); 338 (0.5); 324 (1.0); 108 (100.0). 140 !H NMR (CDCI3): 8 = 0.85 (2H, s, cyclopentane CH3, major diastereomer); 0.88 (IH, s, cyclo-pentane C H 3 , minor diastereomer); 0.89,0.91,1.00 (IH each, 3 s, 3 x 2.2.1 CH 3 's, minor diastereomer); 0.92,0.93,1.18 (2H each, 3 s, 3 x 2.2.1 CrLys, major diastereo-mer); 1.26 - 1.41 (2H, m); 1.53 (1H, broad s, exchanges with D 2 0 , -OH); 1.62 (IH, d, J = 12 Hz, 2.2.1 C(3) endo H); 1.71 (IH, dABd, J = 16, 8 Hz); 1.78 (IH, d ^ d , J = 16,4 Hz); 1.79 - 1.93 (2H, m); 2.06 - 2.12 (IH, m); 2.15 (1H, dd, J = 12, 4 Hz, 2.2.1 C(3) endo H); 2.44 - 2.51 (1H, m); 2.47 (IH, broad s, exchanges with D 2 0 , -OH); 3.34 (IH, s, -OCH3, minor diastereomer); 3.35 (2H, s, -OCH3, major diastereomer); 3.38 - 3.53 (2H, m, -CH 2OMe); 4.11 - 4.19 (1H, broad hump, simplifies to 2 m with D 2 0 , -CH(OH)R); 4.68 (0.33 H, t, J = 2.5 Hz, one of =CH 2, minor diastereomer); 4.73 (0.67 H, t, J = 2.5 Hz, one of =CH 2, major diastereomer); 4.91 (IH, t, J = 2 Hz, one of =CH 2, both diastereomers); 5.54 - 5.67 (3H, m, 2.2.1 C(6)H and RR'C(OH)CH=CH-); 5.99 (IH, dd, J = 6, 3.5 Hz, 2.2.1 C(5)H). Protection of alcohol 240 as silyl ether 241: A solution of the diol 240 (2.66 g, 7.10 mmol) in dry CH 2 C1 2 (70 mL) was stirred under Ar, and 2,6-lutidine (1.65 mL, 1.52 g, 14.2 mmol) and TBDMSOTf (1.95 mL, 2.25 g, 8.5 mmol) were added by syringe. The solution was stirred overnight and quenched by adding NaHC03 (15 mL). The layers were separated and the CH 2 C1 2 was washed with NaHC03 (15 mL), 0.1 N HCl (3 x 50 mL), and brine (25 mL), and dried over MgS04. Evaporation of the solvent provided an orange oil which was purified by column chromatography (70-230 mesh S i0 2 , 4.5 x 12 cm), eluting with 9:1 PE:Et 20 to afford the mono silyl ether 241 as a colourless oil, in a 2:1 mixture of diastereomers; yield: 1.86 g, 70 % based on recovered starting material. Further elution with 1:1 PE:Et 20 afforded the diol 240 as a viscous, pale yellow oil; recovered yield: 0.61 g, 23%. 141 C 3oH 520 3Si Calc. Mass: 488.3686 Meas. Mass: 488.3679 IR (neat): v = 3500 (O-H); 3075,3030 (=C-H); 2950,2870 (C-H); 1650 (C=CH2); 1115 (C-0); 880 cm-1 (=CH2). MS (70 eV): m/z (%) = 488 (M+, 2.4); 470 (0.5); 431 (9.6); 413 (5.9); 399 (0.7); 356 (4.6); 319 (17.7); 108 (100.0). IH NMR (CDC13): 8 = 0.00,0.02 (4H, 2 s, Si(CH 3) 2, major diastereomer); 0.03 (2H, s, Si(CH3)2, minor diastereomer); 0.85 (2H, s, cyclopentane C H 3 , major diastereomer); 0.87 (6H, s, 'Bu, major diastereomer); 0.88 (3H, s, tBu, minor diastereomer); 0.89 (IH, cyclopentane C H 3 , minor diastereomer); 0.90 (IH, s) and 0.93 (2H, s, 3 x 2.2.1 CH 3 's, minor diastereomer); 0.94,0.95 and 1.18 (2H each, 3 s, 3 x 2.2.1 CH 3 's, major diastereo-mer); 1.23 - 1.36, (2H, m); 1.61 -1.67 IH, m); 1.70 (IH, s, exchanges with D 2 0 , -OH); 1.73 - 1.85 (3H, m); 1.87 - 1.99 (IH, m); 2.04 - 2.11 (IH, m); 2.13 (IH, dd, 12, 4 Hz, 2.2.1 C(3) exo H); 2.21 - 2.32 (IH, m); 2.34 - 2.45 (IH, m); 2.38 (IH, t, J = 4 Hz, 2.2.1 C(4)H); 3.33 (3H, s, -OCH 3); 3.37 - 3.50 (2H, m, -CH 2OMe); 4.12 (0.33 H, td, J = 7.5, 5 Hz, -CHOSi, minor diastereomer); 4.23 (0.67 H, q, J = 6 Hz, -CHOSi, major diastereo-mer); 4.54, 4.88 (0.67 H each, 2 broad s, =CH 2, major diastereomer); 4.77, 4.92 (0.33 H each, 2 broad s, =CH 2, minor diastereomer); 5.47 (0.33 H, d^B- J = 16 Hz, RR'C(OH)CH=CHR", rninor diastereomer); 5.54 (0.67 H, d A B , J = 16 Hz, RR'C(OH)CIi=CHR", major diastereomer); 5.57 (0.67 H, dAfid, J = 16, 6 Hz, RR ,C(OH)CH=CHR", major diastereomer); 5.59 (0.67 H, d, J = 6 Hz, 2.2.1 C(6)H, major diastereomer); 5.62 (0.33 H, d, J = 6 Hz, 2.2.1 C(6)H, minor diastereomer); 5.67 (0.33 H, dAsd, J = 16 Hz, 7.5 Hz, RR'C(OH)CH=CHR", minor diastereomer); 5.95 (0.33 H, dd, J = 6, 3 Hz, 2.2.1 C(5)H, minor diastereomer); 5.99 (0.61 H, dd, J = 6, 3 Hz, 2.2.1 C(5)H, major diastereomer). Anionic oxy-Cope rearrangement of alkenol 241 to ketodiene 242: A solution of the alcohol 241 (1.10 g, 2.25 mmol) in dry THF (10 mL) was stirred under Ar, and KH (108 mg, 2.69 mmol) was added in one portion. The mixture was stirred for 2.5 h, 142 after which NH4CI (10 mL) was added and the mixture was diluted with Et20 (50 mL). The layers were separated and the organic phase was washed with NH4CI (10 mL) and brine (10 mL), and dried over M g S 0 4 . Evaporation of the solvents provided a viscous, dark brown oil, which was purified by radial chromatography (4 mm plate), eluting with 5:1 PE:Et20, to afford the ketodiene 242 as a viscous, pale yellow oil, in a 2:1 mixture of diastereomers; yield: 824 mg, 75%. C3oH5203Si Calc. Mass: 488.3686 Meas. Mass: 488.3682 IR (neat): v = 3075 (=C-H); 2955,2940; 2905,2855 (C-H); 1720 (C=0); 1650 (C=CH2); 1120 (C-O);880cm-1(=CH2). MS (70 eV): m/z (%) = 488 (M+, 15.2); 431 (27.9); 399 (1.7); 356 (13.1); 319 (100.0). *H NMR (CDCI3): 8 = 0.04 (2H, s, one of Si(CH3)2, major diastereomer); 0.10 (3H, s, one of Si(CH3)2, both diastereomers); 0.11 (IH, s, one of Si(CH3)2, minor diastereomer); 0.88 (IH, s, angular CH3, minor diastereomer); 0.89 (3H, s, lBu, minor diastereomer); 0.90 (2H, s, angular CH3, major diastereomer); 0.91 (6H, s, tBu, major diastereomer); 0.92 and 0.95 (IH each, 2 s, geminal CJ^'s, minor diastereomer); 0.99 and 1.00 (2H each, 2 s, geminal CH3S, major diastereomer); 1.19 -1.40 (2H, m); 1.55 - 1.63 (IH, m); 1.58 (3H, t, J = 3 Hz, allylic CH 3 ) ; 1.69 - 1.77 (2H, m); 1.84 - 1.91 (2H, m); 1.94 - 1.99 (IH, m); 2.06 - 2.53 (7H, m); 3.13 (IH, broad s); 3.32 (IH, s, -OCH3, minor diastereomer); 3.33 (2H, s, -OCH 3 , major diastereomer); 3.35 - 3.49 (2H, m, -CH 2OMe); 3.86 (0.67 H, dt, J = 11, 2.5 Hz, RR'CHOSi, major diastereomer); 3.95 (0.33 H, ddd, J = 7, 4, 3 Hz, RR'CHSi, minor diastereomer); 4.78 and 4.92 (0.33 H each, 2 broad s, =CH 2, minor diastereomer); 4.84 and 4.95 (0.67 H each, 2 broad s, =CH2, major diastereomer); 5.38 (0.33 H, broad s, ring =C-H, minor diastereomer); 5.66 (0.67 H, broad s, ring =C-H, major diastereomer). 143 Conversion of diene 242 to diketoenone 248 and dimethyl ketal 249: A solution of the ketodiene 242 (1.13 g, 2.31 mmol) in 1:1 MeOH:CH 2 Cl 2 (100 mL) was cooled to -78°C, and ozone was bubbled through the solution until a permanent blue colour was observed. Excess ozone was removed by bubbling 0 2 (g) through the solution until it was again colourless. After warming to rt, the solution was poured onto a mixture of Zn (3.61 g, 55.3 mmol) and AcOH (6.3 mL) and stirred rapidly for 1 h. The mixture was filtered, diluted with CH 2C1 2 (50 mL) and washed with NaHC03 (3 x 25 mL, until the washings were basic) and brine (25 mL), and dried over MgSO^ Evaporation of the solvents provided a viscous gum which was not purified further. The IR spectrum was consistent with this being the triketoaldehyde 246. IR (neat): 0) = 2970,2940,2900,2860 (C-H); 1735,1715,1705 (C=0); 1115 cm-l ( C - 0 ) . The crude triketoaldehyde 246 and TsOH (57 mg, 0.3 mmol) were dissolved in dry CgHg (75 mL) and refluxed overnight in a Dean-Stark apparatus. Evaporation of the solvent provided a brown foam which was purified by radial chromatography (4 mm plate), eluting with 3:1 PE:Et 20 and increasing polarity to 1:1 PE:Et 20. The two major compounds obtained were, in order of elution, the ketal 249, as a colourless glass, in a 2:1 mixture of diastereomers; yield: 265 mg, 144 21%, and the diketoenone 248 as a pale yellow foam, in a 2:1 mixture of diastereomers; yield: 600 mg, 51%. Ketal 249 C 3 1H540 6Si Calc. Mass: 550.3689 Meas. Mass: 550.3684 IR (CHC13): v = 3000,2970,2950,2905,2890,2850 (C-H); 1740 (cyclopentyl O O ) ; 1675 (enone C=0); 1120 cm-1 (C-O). MS (70 eV): m/z (%) = 550 (M+. 0.1); 520 (1.0); 519 (3.0); 518 (1.7); 503 (0.6); 493 (1.1); 461 (70.7); 231 (100.0). LH NMR (CDCI3): 8 = 0.04 and 0.08 (2H each, 2 s, Si(CH3)2, major diastereomer); 0.07 and 0.16 (IH each, 2 s, Si(CH3)2, minor diastereomer); 0.81 (2H, s, cyclopentane CH3, major diastereomer); 0.86 (IH, s, cyclopentane CH3, minor diastereomer); 0.87 (9H, s, tBu, both diastereomers); 1.04 and 1.33 (2H each, 2 s, geminal CH 3 's, major diastereomer); 1.06 and 1.21 (IH each, 2 s, geminal O^ ' s , minor diastereomer); 1.09 -1.17 (2H, m); 1.41 - 1.51 (3H, m); 1.52 - 1.62 (IH, m); 1.64 - 1.74 ((IH, m); 1.77 - 1.84 (IH, m); 2.08 - 2.24 (3H, m); 2.27 - 2.43 (2H, m); 3.07 and 3.14 (2H each, 2 s, ketal -OCH 3 's, major diastereomer); 3.09 and 3.15 (IH each, ketal -OQ^ 's , minor diastereomer); 3.33 (3H, s, ether -OCH3, both diastereomers); 3.36 - 3.52 (2H, -CH 2OMe); 3.90 (0.33 H, broad s, -GHOSi, minor diastereomer); 3.94 (0.67 H, broad m, -CHOSi, major diastereo-mer); 5.83 (0.67 H, dd, J = 11, 3 Hz, -C(0)CH=CH-, major diastereomer); 5.90 (0.33H, dd, J = 10.5,3 Hz, -C(0)CH=CH-, minor diastereomer); 6.88 (0.33 H, broad d, J = 10.5 Hz, -C(0)CH=CH-, minor diastereomer); 7.49 (0.67 H, broad d, J = 11 Hz, -C(0)CH=CH-, major diastereomer). Treatment of a solution of the ketal in acetone (5 mL) and water (2 mL) with 12 N HCl (0.25 mL), afforded, after workup and chromatography, the diketoenone 248 as a pale yellow, viscous oil, in a 65 % yield. Diketoenone 248 C29H4805Si Calc. Mass: 504.3271 Meas. Mass: 504.3266 IR (CHCI3): v = 2960,2940,2895 (C-H); 1735 (cyclopentyl C=0); 1710 (cyclohexyl C=0); 1680 cm*1 (enone C=0). MS (70 eV): m/z (%) = 504 (M+, 0.6); 491 (1.7); 479 (1.2); 459 (4.5); 447 (57.1); 429 (8.3); 415 (13.4); 295 (100.0). 145 J H NMR (CDCI3): 5 - 0.00 (2H, s, major diastereomer), 0.07 (3H, s, both diastereomers), and 0.17 (IH, s, minor diastereomer, Si(CH3)2); 0.80 (3H, s, cyclopropane CH3, both dia-stereomers); 0.84 (3H, fflu, minor diastereomer); 0.86 (6H, s, tfiu, major diastereomer); 0.99 (3H, s, both diastereomers), 1.23 (IH, s, minor diastereomer), and 1.36 (2H, s, major diastereomer, gerninal CH 3 's); 1.13 -1.21 (IH, m); 1.33 - 1.46 (2H, m); 1.51 (IH, dd, J = 15,4 Hz); 1.58 - 1.64 (IH, m); 1.67 - 1.90 (3H, m); 1.95 - 2.17 (4H, m); 2.24 (IH, d, J = 10 Hz); 2.28 - 2.39 (2H, m); 2.49 (IH, t, J = 13 Hz); 3.27 (IH, s, -OCH 3 , minor diastereomer); 3.30 (2H, s, -OCH3, major diastereomer); 3.34 - 3.47 (2H, m, -CH 2OMe, both diastereomers); 3.86 (0.67 H, dt, J = 11.5, 3 Hz, -CHOSi, major dia-stereomer); 4.04 (0.33 H, dt, J = 8, 2.5 Hz, -CHOSi, minor diastereomer); 5.93 (0.67 H, dd, J = 10.5, 3 Hz, -C(0)CH=CH-, major diastereomer); 5.98 (0.33 H, dd, J = 10.5, 3 Hz, -C(0)CH=CH-, minor diastereomer); 7.10 (0.33 H, broad d, J = 10.5 Hz, -C(0)CH=CH-, niinor diastereomer); 7.59 (0.67 H, broad d, J = 10.5 Hz, -C(0)CH=CH-, major diastereomer). Aldol condensation of 2 4 8 to keto alcohol 2 5 0 : A solution of KOH (196 mg, 3.5 mmol) in MeOH (2 mL) was added to a solution of the diketoenone 2 4 8 (179 mg, 0.35 mmol) in MeOH (2 mL) and E t 2 0 (1 mL) and the mixture was stirred for 4 h. The solution was diluted with Et 2 0 (15 mL), washed with NH4CI (2x5 mL) and dried over MgS0 4 . Evaporation of the solvents provided a pale yellow foam which was purified by radial chromatography (1 mm plate), eluting with 4:1 PE:Et 20 to afford the tetracyclic keto alcohol 2 5 0 in a 9:1 mixture of diastereomers, as a white foam; yield: 99 mg, 55 %. C^gS iOs Calc. Mass: 486.3165 (M-H 20) 447.2567 (M-<Bu) Meas. Mass: 486.3161 447.2569 IR (neat): M = 3525 (O-H); 3040 (=C-H); 2955,2940,2890,2860 (C-H); 1695 (ketone C=0); 1675 cnr 1 (enone C=0). 146 MS (70 eV): m/z (%) = 486 (M+-H2O f 1.0); 471 (0.5); 447 (15.5); 429 (8.9); 415 (37.9); 397 (7.5); 355 (15.0); 323 (100.0). *H NMR (CDCI3): 8 = 0.09 (3H, s, one of Si(CH 3) 2, both diastereomers); 0.10 (0.3 H, s, one of Si(CH3)2, minor diastereomer); 0.13 (2.7 H, one of Si(CH3)2, major diastereomer); 0.85 (2.7 H, angular C H 3 , major diastereomer); 0.88 (0.3 H, s, angular CH3, minor diastereo-mer); 0.89 (8.1 H, tBu, major diastereomer); 0.92 (0.9 H, s, tBu, minor diastereomer); 1.06 and 1.24 (0.3 H each, 2 s, geminal CH 3 's, minor diastereomer); 1.08 and 1.23 (2.7 H each, 2 s, geminal CH 3 's, major diastereomer); 1.34 -1.44 (2H, m); 1.49 (IH, dd, J = 13,10 Hz); 1.60 - 1.80 (5H, m); 1.84 (IH, t, J = 7 Hz); 1.86 - 1.93 (IH, m); 2.11 (IH, dAfid, J = 16, 6 Hz); 2.14 - 2.17 (IH, m); 2.23 and 2.31 (2H, O ^ B , J = 15 Hz); 2.43 (IH, d ^ d , J = 15,5 Hz); 3.34 (0.3 H, s, -OCH 3 , minor diastereomer); 3.37 (2.7 H, s, -OCH 3 , major diastereomer); 3.38 - 3.46 (2H, m, -CH 2OMe, both diastereomers); 3.59 (IH, broad s, -OH); 4.16 (0.9H, td, J = 12, 6 Hz, -CHOSi, major diastereomer); 4.30 (0.1 H, ddd, J = 12, 6, 4 Hz, -CHOSi, minor diastereomer); 6.07 (0.1 H, dd, J = 11, 4.5 Hz, -C(0)CH=CH-, minor diastereomer); 6.17 (0.9 H, dd, J = 11, 4.5 Hz, -C(0)CH=CH-, major diastereomer); 6.91 (0.9 H, dt, J = 11,2 Hz, -C(0)CH=CH-, major diastereomer); 7.23 (0.1 H, dt, J = 11,2 Hz, -C(0)CH=CH-, minor diastereomer). Hydrolysis of silyl ether 250 to diol 251: 250 251 A solution of the silyl ether 250 (362 mg, 0.74 mmol) in dry THF (5 mL) was stirred under Ar, and TBAF (3.7 mL, 1 M/THF, 3.7 mmol) was added by syringe. The solution was stirred for 1.5 h, diluted with Et 2 0 (20 mL), and washed with water (2x5 mL) and brine (5 mL), and dried over MgS04. Evaporation of the solvents provided an orange foam which was purified by radial chromatography (2 mm plate), eluting with 1:2 PE:Et 2 0, to afford the pure major diastereomer 251 as a pale yellow foam; yield: 171 mg, 62%. C^H^Os Calc. Mass: 372.2300 (M-H20) Meas. Mass: 372.2298 1 4 7 IR (neat): v = 3375 (broad, O-H); 2980,2935,2890 (C-H); 1695 (ketone C=0); 1680 cm-l (enone C=0). MS (70 eV): m/z (%) = 372 (M+-H20,35.9); 354 (34.0); 340 (16.7); 328 (7.2); 314 (6.5); 296 (17.3); 290 (19.5); 45 (100.0). lH NMR (CDC13): 6 • 0.86 (3H, s, angular CH 3 ) ; 1.07 and 1.26 (3H each, 2 s, geminal CH 3 's); 1.34 - 1.43 (2H, m); 1.48 (IH, dd, J = 14, 12 Hz); 1.68 - 1.93 (7H, m); 2.09 (IH, ddd, J = 14,10,5 Hz); 2.17 (IH, d ^ m , JAB = 14 Hz); 2.25 (IH, d ^ , J = 13 Hz); 2.34 (IH, dAB, J = 14 Hz); 2.44 (IH, d ^ d , J = 13,4 Hz); 3.32 - 3.47 (2H, m, -CH 2OMe); 3.36 (3H, s, -OCH3); 3.64 (IH, broad s, 3° -OH); 4.15 (IH, td, J = 12, 5 Hz, -CH(OH)-); 6.18 (IH, dd, J = 11,4 Hz, -C(0)CH=CH-); 7.04 (IH, dt, J = 11, 2 Hz, -C(0)CH=CH-). 13C NMR (CDC13): 8 = 17.166,21.148, and 24.360 (angular and geminal CH3's); 25.852; 30.250; 32.999; 34.723; 37.027; 38.647; 40.792; 45.712; 47.095 ( M e ^ R C ^ ) ; 47.916; 49.507; 53.901; 58.509 (2°C-OH); 64.805 (CH 30-); 71.208 (-CH2OMe); 79.400 (3° C-OH); 130.119 (-C(0)CH=CH-); 144.744 (-C(0)CH=CH-); 203.190 (ketone C=0); 213.709 (enone C=0). Acetylation of diol 251 to monoacetate 252: 251 A solution of the diol 251 (120 mg, 0.31 mmol) in dry pyridine (2.5 mL) was stirred under Ar, and A c 2 0 (0.060 mL, 65 mg, 0.64 mmol) was added by syringe. The solution was stirred overnight, after which TLC indicated that starting material was still present. A further portion of A c 2 0 (0.027 mL, 30 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) were added and the solution was stirred for a further 2 h, after which TLC indicated that no starting material remained. The solution was diluted with E t 2 0 (30 mL) and washed with 1 N HCl (4 x 10 mL), water (5 mL), NaHC0 3 (5 mL) and brine (10 mL), and dried over MgS04. Evaporation of the 148 solvent provided a pale yellow glass which was purified by radial chromatography (1 mm) plate, eluting with 3:2 PE:Et 20, to afford the acetate 252 as a white solid; yield: 103 mg, 77%; mp: 139-42°. Recrystallization from Et20/PE provided white crystals which were submitted for X-ray structural extermination. C 2 5 H 3 6 0 6 Calc: C 69.42 H 8.39 % Anal: C 69.56 H 8.43 % Calc. Mass: 432.2512 Meas. Mass: 432.2506 IR (CHC13): -o = 3525 (O-H); 2985,2950,2890 (C-H); 1730 (C=0, acetate); 1695 (C=0, ketone); 1680 cm' 1 (C=0, enone). MS (70 eV): m/z (%) = 414 (M+-H20,3.8); 400 (0.2); 382 (21.2); 372 (10.1); 354 (25.1); 322 (61.5); 156 (93.1); 97 (100.0). *H NMR (CDCI3): 6 = 0.86 (3H, s, angular CH 3); 1.07 and 1.22 (3H each, 2 s, geminal CH 3 's); 1.33 - 1.47 (2H, m); 1.52 (IH, dd, J = 12.5, 11.5 Hz); 1.59 (IH, broad s); 1.73 - 1.96 (6H, m); 2.08 (3H, s, CH3C02-); 2.17 (IH, d ^ m , = 13 Hz); 2.26 (IH, t, J = 13 Hz); 2.32 (IH, d^dd , J = 13.5,10, 4 Hz); 2.38 (IH, d A B , J = 13.5 Hz); 2.46 (IH, d A B dd , J = 13, 4, 1 Hz); 3.21 (IH, broad s, -OH); 3.36 (3H, s, -OCH 3); 3.42 (2H, dd, J = 8, 6.5 Hz, -CH 2OMe); 5.40 (IH, td, J = 11. 4.5 Hz, -CH(OAc)-); 6.17 (IH, dd, J = 10.5, 3 Hz, -C(0)CH=CH-); 6.95 (IH, dt, J = 10.5, 2 Hz, -C(0)CH=CH_-). Chapter 3 The Synthesis of a Chiral D Ring Synthon for the Intramolecular Diels-Alder Route to Steroids 1 5 0 3.1 Introduction During a previous discussion of the steroids and their synthesis (Chapter 1) it was mentioned that one of the four common multiple annulation approaches would be discussed in more detail in this chapter. The approach stems from a disconnection of the B and C rings n a [41 (Equation 4) to provide two monocyclic fragments. In general, the A ring fragment is the synthetic equivalent of an o-quinodimethane104, eg. 264, and the D ring fragment is a vinyl cyclopentane represented by 265, possessing appropriate functionality for both elaboration to the steroidal D ring and connection to the A ring fragment. Following connection of the two fragments and MeO + 264 265 MeO MeO X = Leaving Group G = Ketone or equivalent 267 Scheme 4 9 151 unveiling of the o-quincdimethane moiety, an intrarnolecular Diels-Alder reaction34 (Scheme 49) forms the B and C rings and regenerates the aromaticity of the A ring. Because of this latter aspect, this methodology has been most commonly used in the synthesis of A-aromatic steroids, such as estrone (3). Scheme 51 Because of its reactive nature the o-qumodimethane functionality of the Diels-Alder precursor is normally introduced in a disguised form 1 0 4. A number of suitable precursors have been developed, including benzocyclobutenes643'105, eg. 269 (Scheme 50), cyclic sulphones106, 1 5 2 Scheme 5 3 eg. 273 (Scheme 51), y-silyl epoxides1 0 7, eg. 278 (Scheme 52), and y-silyl amines1 0 8, eg. 282 (Scheme 53), all of which are readily transformed to o-quinodimethanes under appropriate conditions (cf. Schemes 50 - 53). The introduction of the D ring portion of the Diels-Alder precursor is often accomplished by alkylation of the A ring subunit. In the case of the sulphone 272 1 0 6 and the y-silyl amine 281 1 0 8 this requires no chemical modification; the required anions are stabilised and are readily formed upon treatment of 272 or 281 with base. Benzocyclobutenes require an electron-withdrawing substituent to stabilise the anion, often taking the form of an 153 acyloxy group (cf. 268) 6 4 a, which is readily removed by a decarboxylative sequence following the alkylation. The Y-silyl epoxide 278 was synthesised by a somewhat different strategy in which the steroidal C( l l ) and C(12) were part of the A rather than the D ring subunit107. Thus, 278 was derived from the allylic alcohol 276 and the cyclopentanone derivative 277 in two steps. Approaches to o-quinodimethane steroidal precursors in which C( l l ) and C(12) are part of the A ring subunit have also been reported by Kametani 1 0 5^ and Vollhardt105a. The major drawback of this methodology, relative to that in which C(l 1) and C(12) are part of the D ring subunit, is that control of the stereochemistry at C(13) is not always good. Because of this problem, the more popular synthetic strategy to o-qumodimethane steroidal precursors has been that in which C(l 1) and C(12) are part of the D ring subunit, in which case the C(13) stereochemistry is defined prior to, rather than during connection to the A ring subunit. Figure 6: Transition State Conformation of the o-Qumodimethane Intramolecular Diels-Alder Reaction 154 Because it is the portion that possesses most of the chiral centres of the steroidal target and, indeed, all the chiral centres of the Diels-Alder precursor (cf. 266), the synthesis of appropriate D ring subunits has attracted considerable attention. To emphasise the importance of the D ring subunit, it must be noted that the stereochemistries of C(14) and C(13) of the Diels-Alder precursor play a significant role in governing the conformation that the molecule adopts during the electrocyclic reaction, and hence the stereochemistries of the chiral centres at C(8) and C(9) which are formed during the reaction. It has been found that the preferred transition state (Fig. 6) for Diels-Alder reactions of this type is one in which the cyclopentyl vinyl dienophile approaches the diene in an exo fashion 1 0 6 0. One can see that this results in the correct steroidal orientation of the C(8) and C(9) hydrogens when C(14) and C(13) are also in the correct orientation. 0 265 X = Leav ing Group G = Ketone or e q u i v a l e n t Thus, the most popular D ring subunits have been of the general type 265 in which the key stereochemistries at C(13) and C(14) (steroidal numbering) are defined. The two-carbon sidechain at C(13) incorporates a terminal leaving group, to allow connection to the A ring subunit. In addition, C(17) is functionalised in such a way as to allow formation of a ketone or hydroxyl group, the most common substituents at this centre in A-aromatic steroids. The synthesis of a number of variants of 265 have been reported, employing a variety of methodologies. O -t5 18 RX [ 1 7 ] 285 ( 155 Many of the syntheses of D ring subunits have been based on 2-methylcyclopent-2-enone (18). Conjugate addition of a vinyl group (Equation 17) followed by introduction of the C(13) (steroidal numbering) sidechain by either direct trapping of the enolate 284 or by a subsequent alkylation affords the general subunit structure very quickly. This approach was used by Nicolau 1 0 6 b , Vollhardt1 0 5 a, Oppolzer1 0 6 a and Saegusa108 in their syntheses of the D ring synthons 286,287, 288 and 289 respectively. The control of the C(13) stereochemistry depended on the alkylating group approaching from the face opposite the B-oriented vinyl group, a selectivity which was found to be high in all three cases. The major disadvantage of this methodology is that the starting material, 18, is achiral, and thus the products (286 - 289) are racemic, although Oppolzer achieved the chirai synthesis of 288 by resolving an intermediate carboxylic acid as its ephedrine salt 1 0 6 a. Scheme 54 One solution to this problem was reported by Posner and co-workers, who discovered that it was possible to transform the chirai sulphoxide 290 1 0 9 to the chirai keto ester 293 (Scheme 54) 1 1 0 . The initial step, a conjugate addition of vinyl magnesium bromide provided only 291, with the desired steroidal C(14) configuration1103. Subsequent elaboration of the C(13) centre also 156 proceeded enantiospecifically, and provided 293 in 30% yield over the seven steps from the sulphoxide 290 1 1 0 b . The ester 293 was an intermediate in Oppolzer's synthesis of 288 1 0 6 a , and thus this represented an enantiospecific synthesis of the latter compound. Kametani and co-workers reported a chirai synthesis of the iodide 296 (Scheme 55) 1 1 1 , based on the bicyclic keto ether 294 developed by the Hoffman-LaRoche group19. The sequence required nine steps and afforded 296 in 24% yield from 294, which in turn was prepared in 44% yield over five steps from the chirai Hoffman-LaRoche keto enone 41. Scheme 55 Recently, Daniewski and Kiegiel 1 1 2 reported a synthesis of Saegusa's bromoketal 289 1 0 8 in chirai form (Scheme 56). The synthesis was based on the chirai diketoalcohol 46 1 7 , the immediate synthetic precursor of the Hoffman-LaRoche keto enone 41, which is readily available in quantity. The diketoalcohol 46 was converted in three steps to the unsaturated lactone 297, which was stereoselectively hydrogenated to provide 298 with the desired steroidal C(14) stereochemistry. Subsequent transformation to 289 required a further six steps, and provided the bromoketal in 30% overall yield from 46. 46 297 298 289 Scheme 56 157 3.2 Discussion Our interest in the synthesis of a D ring synthon for the intramolecular Diels-Alder route to steroids was prompted by the similarity of the bromo ester ent-115 to the steroidal D ring. As has been previously discussed (Chapter 2), ent-115 is readily available from the Grob-type cleavage89 of (-)-9,10-dibromocamphor (ent-120) with sodium methoxide37. We considered that the conversion of ent-115 to the hydroxy diene ent-299 (Scheme 57) would be straightforward, and would provide a new potentially useful chiral intermediate in steroid synthesis. At the time this study was undertaken, a large quantity of (+)-9,10-dibromocamphor (120) was available to us. Hence, it was decided to use this compound to prepare the enantiomeric hydroxy diene 299 1 1 3 . Since (-)-9,10-dibromocamphor (ent-120) is also readily available (cf. Chapter 2), this would represent a formal enantiospecific synthesis of ent-299. The synthetic route we took to 299 is shown in Scheme 58. Treatment of (+)-9,10-dibromocamphor (120) with sodium methoxide in methanol37 afforded the desired bromo ester 115 in 99% yield. After reduction to the primary alcohol ent-230, the vinyl sidechain was formed by dehydration of ent-230 using Grieco's methodology114. Thus, treatment of the alcohol ent-230 with o-nitrophenylselenocyanate and tri-nbutyl phosphine, followed by oxidation of the intermediate selenide, resulted in an excellent yield of the diene 300 (95% from the ester 115). The structure of 300 was confirmed by its IR and lH NMR spectra. Me02C ent-120 ent-115 ent-299 Scheme 57 158 i) NaOMe / MeOH, A, 3h, 99% ii) DJJBAL / Et20,0°C, 96% iii) o-N02-C6H4SeCN, Bu3P / THF, 3h; H 20 2 / H20,99% iv) NaCN, KI / DMSO, 110°C, 8h, 64% v) DIBAL / hexane, -78°C - rt; K,Na tartrate, HCl / H20,65% vi) DIBAL / Et20,0°C, 63%. Scheme 58 The IR spectrum clearly showed the presence of two different olefins, as evidenced by C=C stretching absorptions at 1650 and 1640 cm-1. The *H NMR spectrum exhibited five peaks in the region expected for vinyl protons. Two triplets at 4.85 (IH, J = 2.4 Hz) and 5.00 ppm (IH, J = 2 Hz) were assigned to the protons of the original exo-methylene substituent. Signals at 5.07 (IH, dd, J = 10.5 and 2 Hz) and 5.11 ppm (IH, dd, J = 17 and 2 Hz) were assigned to the terminal protons of the newly-formed vinyl group, as suggested by the mutual coupling of 2 Hz. The 17 Hz coupling constant is in the range expected for trans-vinyl protons, whereas that of 10.5 Hz is as expected for cis-vinyl protons46. These latter coupling constants are reflected in the signal of the third proton of the vinyl group, at 5.74 ppm (IH, ddd, J = 17, 10.5 and 8.5 Hz); the coupling of 8.5 Hz must therefore be to the ring proton next to the vinyl group. An AB quartet at 3.39 and 3.47 ppm (2H, J = 10 Hz) confirmed that the bromomethyl sidechain was still intact. The assignment of 300 was also supported by low resolution MS, which exhibited molecular ions at m/z = 216 and 214, as expected for CioH^Br. 159 Treatment of the bromide 300 with sodium cyanide and catalytic potassium iodide in DMSO at 110°C afforded the nitrile 301 in only 64% yield. It is probable that the low isolated yield of this compound can be partly attributed to its volatility, but it also seems likely that a rearrangement analogous to that observed for the bromo ether 231 (Chapter 2) was occurring. Unfortunately, at this stage we did not investigate the use of HMPA as the solvent for this reaction (cf. page 109). The identity of the product was confirmed by its IR, *H NMR and low resolution mass spectra. The IR spectrum displayed a characteristic nitrile CN stretch at 2230 cm*1, as well as absorptions atttributable to the two olefins at 1650 and 1635 cm - 1 . The *H NMR spectrum confirmed that displacement of bromine with cyanide had occurred; the characteristic AB quartet associated with the bromomethyl group had disappeared and was replaced by an AB quartet at 2.41 and 2.47 ppm (2H, J =16 Hz). The low resolution MS exhibited a molecular ion at m/z = 161, as expected for C u H ^ N . Reduction of the nitrile 301 with DIBAL in hexane at -78°C - room temperature and hydrolysis of the intermediate iminoalane afforded the aldehyde 302 in 65% yield 9 2. Again, the low yield was attributed to the volatility of both the starting material and the product, although may also have been due in part to the facility with which 302 was oxidised to the corresponding carboxylic acid 303 on exposure to atmospheric oxygen. Attempts to obtain an elemental analysis of 302 were unsuccessful; the observed analysis (C 73.80 H 9.00 %) was, however, close to that expected for 303 (C 73.30 H 8.95 %). That the isolated compound was indeed the aldehyde 302 was clearly shown by its IR and *H NMR spectra. The former displayed peaks at 2820 and 2715 cm*1, associated with the aldehyde C-H stretch, and a strong peak at 1720 cm - 1 ccrosponding to the aldehyde carbonyl group. Perhaps more significant was the absence of a broad peak in the region 2700 - 3400 cm - 1 , confirming that the isolated product was not a carboxylic acid. The ! H NMR spectrum displayed a triplet at 9.75 ppm (IH, J = 3 Hz), assigned to the aldehyde proton. 160 Finally, reduction of 302 with DIBAL in diethyl ether at 0°C afforded the alcohol 299 in 63% yield. Presumably the low yield was once again associated with the volatility of both the starring material and the product. The IR and *H NMR spectra (Appendices 3a and 3b) confirmed the identity of the product The absorptions attributed to the aldehyde group in the IR spectrum were replaced by a broad hydroxyl peak at 3325 cm - 1 . The low-field triplet in the *H NMR spectrum of 302 was also no longer observed, and triplets at 1.77 (2H, J = 7 Hz) and 3.73 ppm (2H, J = 7 Hz) were assigned to the hydroxyethyl sidechain. 161 3.3 Conclusion The hydroxydiene 299 was prepared in six steps and 25% overall yield from (+)-9,10-dibromocamphor (I20) 1 1 3 . The relatively low overall yield can be in part attributed to the volatility of intermediates late in the synthesis, and could potentially be improved by the use of techniques which would rninimise product loss due to this factor. In addition, the yield of the step involving displacement of bromine with cyanide could potentially be improved by the use of HMPA instead ofDMSO as solvent Scheme 59 The synthesis of 299 represents a formal enantiospecific synthesis of ent-299. The hydroxydiene ent-299 is considered to be a potentially valuable intermediate in the synthesis of steroids by the A-D --> ABCD intramolecular Diels-Alder route. The hydroxyl group should be readily transformed to a leaving group, enabling connection to an A ring subunit (eg. 26S 6 4 3) to 162 form 305 (Scheme 59). This could then be subsequendy transformed to 17-methylene steroids, such as 306, ozonolysis and deprotection of which would provide estrone (3). In addition, the exo-methylene group could potentially be elaborated to a variety of C(17) sidechains by hydroboration10'115, homologation, and stereoselective alkylation at C(20)71. 163 3.4 Experimental Grob fragmentation of (+)-9,10-dibromocamphor (120) to (-)-bromo methyl ester 115: Sodium (1.0 g, 0.43 mmol) was added in small portions to dry MeOH (100 ml) while stirring at 0°C under Ar. When the formation of NaOMe was complete, (+)-9,10-dibromocamphor 120 (10.0 g, 32 mmol) was added in one portion. The temperature was increased to reflux and stirring was continued for 3 h. After cooling to room temperature, the reaction was quenched by pouring into brine (100 ml) and 12 N HC1 (3.5 ml). The mixture was extracted with Et 2 0 (3 x 50 ml) and the combined extracts are washed with brine (50 ml) and dried over MgS04. Evaporation of the solvents yielded a yellow oil which was purified by vacuum distillation to give the bromo ester 115 as a colourless mobile liquid; yield: 8.37 g, 99%; bp: 75°C (0.1 mm); [a] 2 5 -32.5° (c = 0.714, CHCI3). C n H 1 7 B r 0 2 Calc: C 50.60 H 6.56 Br 30.59 % IR (neat): V = 3050 (=C-H); 2940 (-C-H); 1730 (C0 2 CH 3 ) ; 1645 (0=01^; 895 cm-l (=CH2). MS (70 eV): m/z = 262, 260 (M+, 0.1,0.1); 231,229 (0.6, 0.6); 230, 228 (0.1, 0.1); 188, 186 (2.8, 3.6); 167 (35.4); 107 (100.0). !H-NMR (CDCI3): 8 = 1.06 (3H, s, CH 3 ) ; 1.30 - 1.40 (IH, m); 1.91 -1.99 (IH, m); 2.15 (IH, dd, J = 16, 11 Hz); 2.32 - 2.47 (2H, m); 2.52 - 2.59 (2H, m, CH 2 C0 2 Me); 3.39 and 3.46 (2H, qAB, JAB = 10 Hz, -CH 2Br); 3.70 (3H, s, -C0 2 CH 3 ) ; 4.86 and 5.00 (IH each, 2t, J = 2 Hz, =CH2). Anal.: C 50.52 H 6.68 Br 30.45 % Calc. Mass: 262.0391, 260.0411 Meas. Mass: 262.0397, 260.0407 164 Reduction of ester 115 to alcohol ent-230: Br Br Me02C 1 1 5 ent-230 HO A solution of the ester 115 (8.37 g, 32 mmol) in dry Et20 (150 ml) was cooled to 0°C under Ar, and DIBAL (71 ml, lM/hexanes, 71 mmol) was added by syringe. The reaction was stirred at 0°C for 75 min and then quenched by the cautious addition of Na2SC>4olO H 20 (2 g). The suspension was stirred for 1 h, filtered, and the solvents dried over MgSC«4. Evaporation of the solvents yielded the alcohol ent-230 as a colourless oil which was used without further purification; yield: 7.20 g, 96%; bp 105°C (0.1 mm); [a]22 -37.4° (c = 0.594, MeOH). C1 0H1 7BrO Calc: C 51.51 H7.35 Br 34.26% IR (neat): v = 3325 (OH); 3050 (=C-H); 2920,2850 (-C-H); 1645 (C=CH2); 895 cm-l (=0^ 2). MS (70 eV): m/z = 234, 232 (M+, 0.7,0.8); 217,215 (0.3, 0.2); 216, 214 (0.7, 0.8); 189, 187 (0.7, 0.7); 188, 186 (1.6, 1.6); 153 (1.0); 152 (3.5); 139 (43.6); 95 (100.0). 1H-NMR (CDCI3): 8 = 1.04 (3H, s, CH3); 1.20 -1.46 (2H, m); 1.32 (IH, broad s, exchanges with D20, -OH); 1.80 (IH, dtd, J = 14, 8, 3.5 Hz); 1.88 - 1.97 (IH, m); 2.17 (IH, tdd, J = 11, 7, 3 Hz); 2.27 - 2.38 (IH, m); 2.43 (IH, dAfidq, J = 17, 8, 2.5 Hz); 3.43 and 3.49 (2H, qAB, JAB = 10 Hz, -CH2Br); 3.70 amd 3.77 (IH each, 2 m, CH2OH); 4.84 and 4.98 (IH each, 2 t, J = 2 Hz, =CH2). Anal.: C 51.40 H 7.20 Br 34.09 % 1 6 5 Dehydration of alcohol ent-230 to diene 300: Br Br ent-230 HO A solution of the bromoalcohol ent-230 (2.57 g, 11 mmol) and o-nitrophenyl selenocyanate (3.00 g, 13.2 mmol) in dry THF (50 ml) was stirred under a continuous flow of Ar. Tri-n-butyl phosphine (3.25 ml, 2.67 g, 13.2 mmol) was added by syringe and the reaction was stirred for 3 h. 30% H2O2 (6 ml) was then added and stirring was continued overnight. The reaction was diluted with Et20 (30 ml), filtered, and the solvents were washed with water (2 x 20 ml) and brine (20 ml), and dried over MgSC»4. The solvents were evaporated to yield an orange oil which was purified by column chromatography (230-400 mesh SiO ,^ 5x15 cm), eluting with PE, to provide the bromodiene 300 as a colourless mobile liquid; yield: 2.34 g, 99%; bp 75°C (10 mm); [a]22 -54.9° (c = 3.88, CHCI3). C 1 0H 1 5Br Calc: C 55.83 H 7.03 Br 37.14% MS (70 eV): m/z = 216, 214 (M+, 0.2,0.6); 188, 186 (0.2, 0.2); 162, 160 (0.6, 0.5); 135 (70.8); 79 (100.0). JH-NMR (CDCI3): 8 = 1.00 (3H, s, CH3); 1.54 - 1.63 (IH, m); 1.82 - 1.90 (IH, m); 2.32 - 2.42 (IH, m); 2.44 - 2.52 (IH, m); 2.78 (IH, dt, J = 8, 5 Hz); 3.39 and 3.48 (2H, q^, = 10 Hz, -CH2Br); 4.85 and 5.00 (IH each, 21, J = 2.4 Hz, J = 2 Hz, >C=CH2); 5.07 (IH, dd, J = 10.5, 2 Hz, -CH^HcHt); 5.11 (IH, dd, J = 17, 2 Hz, -CH=CHcHt); 5.74 (IH, ddd, J = 17, 10.5, 8.5 Hz, -CH=CH2). Anal.: C 55.74 H 7.01 Br 36.95 % Calc. Mass: 216.0337,214.0357 Meas. Mass: 216.0341, 214.0361 IR (neat): u = 3060 (=C-H); 2950,2850 (-C-H); 1650 (C=CH2); 1640 (O^CI^); 920, 890 cm"1 (=C-H). 1 6 6 Conversion of bromide 300 to nitrile 301: Br 300 NC 301 The bromodiene 300 (2.00 g, 9.3 mmol), NaCN (680 mg, 14 mmol) and KI (150 mg, 0.9 mmol) were stirred in dry DMSO (10 ml) under Ar at 110°C for 8 h. The mixture was cooled to room temperature and poured into brine (25 ml) and 1 N NaOH (0.25 ml), and extracted with Et20 (3 x 25 ml). The combined extractions were washed with 10 % Na2S203 (15 ml) and brine (15 ml), and dried over MgSO^ Evaporation of the solvents yielded an orange oil which was purified by column chromatography (230-400 mesh silica gel, 2 x 20 cm), eluting with 9:1 PE:Et20 to afford the nitrile 301 as a colourless mobile liquid; yield: 965 mg, 64 %; bp 85°C (15 mm); [a]25 -37.3° (c = 3.86, CHC13). IR (neat): v = 3050 (=C-H); 2950,2850 (-C-H); 2230 (CN); 1650 (C=CH2); 1635 (-CH=CH2); 925, 895 cm-l (=C-H). MS (70 eV): m/z = 161 (M+, 11.6); 160 (6.2); 146 (11.7); 134 (9.2); 133 (30.1); 132 (33.1); 121 (47.4); 93 (100.0). !H-NMR (CDCI3): 8 = 0.98 (3H, s, CH3); 1.57 - 1.69 (IH, m); 1.85 - 1.93 (IH, m); 2.39 - 2.57 (3H, m); 2.41 and 2.47 (2H, o^, = 16 Hz, -CH2CN); 4.95 and 5.02 (IH each, 21, J = 2.4 Hz, J = 2 Hz, >C=CH2); 5.12 (IH, dd, J = 10, 1.5 Hz, -CH=CHcHt); 5.16 (IH, dd, J = 17, 1.5 Hz, -CH-Ojjlj); 5.72 (IH, ddd, J = 17, 10, 9 Hz, -CH=CH2). C n H 1 5 N Calc: C 81.94 H 9.38 N 8.69 % Anal.: C 81.77 H 9.25 N 8.77 % Calc Mass: 161.1204 Meas. Mass: 161.1197 Reduction of nitrile 301 to aldehyde 302: 167 Il 301 II 302 A solution of the nitrile 301 (314 mg, 1.95 mmol) in dry hexane (10 ml) was stirred and the heterogeneous mixture was cooled to -78°C, at which temperature the nitrile solidified. DIBAL (2.4 ml, 1 M in hexanes, 2.4 mmol) was added by syringe, and the reaction was allowed to warm to rt over 2.5 h. It was quenched by pouring into 1:1 K,Na tartrate:water (30 ml), adding 6 N HCl (1 ml) and stirring for 1 h. NaHCC»3 (2 ml) was added and the layers were separated. The aqueous layer was extracted with PE (10 ml), and the combined organic solvents were washed with brine (10 ml) and dried over MgSC>4. After evaporating the solvents, the crude aldehyde was purified by column chromatography (230-400 mesh silica gel, 2 x 15 cm), eluting with 9:1 PE:Et20, to provide 302 as a pale yellow oil; yield: 195 mg, 65 %; bp 65°C (10 mm). This compound was found to be too susceptible to oxidation to obtain a reliable [a]o or microanalysis. C n H 1 6 0 Calc. Mass: 164.1201 Meas. Mass: 164.1193 IR (neat): o> = 3060 (=C-H); 2950,2850 (-C-H); 2820,2715 (OC-H); 1720 (HC=0); 1650 (>C=CH2); 1635 (-CH=CH2); 925,895 cm-l (=C-H). MS (70 eV): m/z = 164 (M+, 0.4); 163 (0.3); 149 (2.1); 135 (6.5); 122 (30.2); 120 (47.5); 107 (28.5); 41 (100.0). IH NMR (CDC13): 5 = 0.99 (3H, s, CH3); 1.59 - 1.69 (IH, m); 1.82 - 1.90 (IH, m); 2.46 and 2.51 (2H, qAfid, J = 12, 3 Hz, -CH2CHO); 2.36 - 2.59 (3H, m); 4.85 and 4.99 (IH each, 2 t, J = 2.4 Hz, J = 2.1 Hz, >C=CH2); 5.07 (IH, dm, J d = 17 Hz, -CH=CHcHt); 5.09 (IH, dm, J d = 10.5 Hz, -01=01^; 5.73 (IH, ddd, J = 17, 10.5, 8.5 Hz, -CH=CH2); 9.75 (IH, t, J = 3 Hz, -CHO). 168 Reduction of aldehyde 302 to alcohol 299: OHC ll 302 || 299 A stirred solution of the aldehyde 302 (120 mg, 0.73 mmol) in dry Et 20 (10 ml) was cooled to 0°C under Ar, and DIBAL (0.9 ml, 1 M in hexanes, 0.9 mmol) was added by syringe. The reaction was stirred for 45 min, quenched by the cautious addition of Na2SC«4olO H2O (0.1 g), and stirred vigorously overnight. The solid was removed by suction filtration, and the solvent was dried over MgSC»4, and evaporated to yield a pale yellow oil. Purification by column chromatography (230-400 mesh silica gel, 2 x 10 cm) eluting with 1:1 PE:Et20 afforded the alcohol 299 as a colourless oil; yield: 76 mg (63 %); bp 85°C (0.1 mm); [a]22 -71.8° (c = 1.31, • IR (neat): v = 3325 (OH); 3055 (=C-H); 2940, 2850 (-C-H); 1650 (>C=CH2); 1635 (-CH=CH2); 920, 885 cm-1 (=C-H). MS (70 eV): m/z = 166 (M+, 25.9); 165 (2.4); 151 (41.8); 149 (5.8); 148 (33.5); 138 (5.7); 137 (11.7); 135 (57.9); 133 (62.6); 93 (100.0). !H-NMR (CDCI3): 8 = 0.89 (3H, s, CH3); 1.38 (IH, broad s, exchanges with D20, -OH); 1.50 -1.61 (IH, m); 1.77 - 1.86 (IH, m); 1.77 (2H, t, J = 7 Hz, CH2CH2OH); 2.31 - 2.41 (IH, m); 2.42 - 2.53 (2H, m); 3.73 (2H, broad t, J = 7 Hz, CH2CH2OH); 4.81 and 4.93 (IH each, 2 t, J = 2.4 Hz, J = 2 Hz, =CH2); 5.02 (IH, s, -CH=CHcHt); 5.06 (IH, m, -CH^HcHt); 5.76 (IH, m, -CH=CH2). CHCI3). C n H 1 8 0 Calc: C 79.46 H 10.91 % Anal.: C 79.26 HI 1.09% Calc. Mass: 166.1358 Meas. Mass: 166.1353 Chapter 4 2-Methvlenebornane to 4-Methvlisobornvl Acetate: A Mechanistic Investigation 170 4.1 Introduction Our interest in the synthesis of triterpenoids possessing a 14-methyl group, such as lanosterol (185), prompted us to investigate the synthesis and reactivity of 4-methylcamphor (308) 1 1 6. It was hoped that 308 would undergo an analogous series of brominations to those of camphor (228) 3 9 - 5 8 b ' 1 1 7 , to eventually provide 9,10-dibromo-4-methylcamphor (309) (Scheme 60). A Grab-type cleavage of 309 would then be expected to provide substituted cyclopentanes such as 310, the similarity of which to the euphane D ring is plain. The results of these investigations have been reported elsewhere1163, and can be summarised by saying that while 4-methylcamphor (308) could be prepared simply and in good yield, bromination of 3-bromo-4-methylcamphor (311) (Scheme 61) provided 3,9-dibromo-4-(bromomethyl)camphor (312) rather than the expected 3,9-dibromo-4-methylcamphor (313). Scheme 60 The synthesis of 4-methylcamphor (308) which we developed is shown in Scheme 62. The key step was the acid-catalysed rearrangement of 2-methylenebornane (314) to provide 4-171 methyl-isobornyl acetate (315). The acetate 315 was then readily transformed to 4-methylcamphor (308) in two steps. Br Scheme 61 308 316 i) Ph 3P=CH 2 / THF ii) T iC l * Zn, CH 2 Br 2 / THF, CH 2C1 2 iii) H 2 S 0 4 / AcOH iv) L1AIH4 / Et zO v) PCC / CH 2C1 2. Scheme 62 It seemed likely that this rearrangement occurred by the mechanism shown in Scheme 63, analogous to mechanisms proposed for a number of similar processes including the racemizauon of camphor and the brornination or sulphonation of a number of camphor derivatives118. Thus, 172 protonation of 314 provides the tertiary carbocation 317, which then undergoes a Wagner-Meerwein rearrangement119, a 3,2-exo-methyl shift and a second Wagner-Meerwein rearrangement to provide the secondary carbocation 320. This can then be either trapped by the solvent to afford 4-methyhsobornyl acetate (315), or can undergo a 6,2-hydride shift to provide the enantiomeric secondary carbocation ent-320, trapping of which provides ent-315. When the rearrangement was performed, it was found that the product was not optically pure, but consisted of a ~4:1 mixture of 315:ent-315 as estimated by a variety of methods1163. This result suggested that while the 6,2-hydride shift (320 to ent-320) did occur, it was a somewhat slower process than the trapping of 320 by acetate, assuming the proposed mechanism to be correct. ent-315 ent-320 6,2-H = 6,2-hydride shift Scheme 63 173 In an attempt to shed more light on the mechanism of the rearrangement of 2-methylenebornane (314) to 4-methylisobornyl acetate (315) we decided to undertake a study using *H NMR spectroscopy of deuterium-labelled derivatives of 4-methylcamphor (308) to trace the fate of the 2-methylene and C(8) methyl groups of 2-methylenebomane (314). As can be seen from Scheme 63, if the proposed mechanism is correct, the 2-methylene group of 314 becomes the C( l l ) methyl group* of 315, while the C(8) methyl group is still C(8) in 315, but becomes C(9) if the 6,2-hydride shift occurs to provide ent-315. Thus, it was clear that a study of this type could provide valuable information about the rearrangement and hopefully support the proposed mechanism. * In order to minimise confusion, we have chosen to designate the additional methyl group of 308 as C(l 1). The other centres of this molecule are numbered 1 -10 as for camphor (228). 1 7 4 4.2 Discussion 4.2.1 The Assignment of the l H N M R Spectrum of 4-Methvlcamphor T3(W Because the J H NMR methyl signals of 4-methylcamphor (308) (Table 1, Appendix 4a,b) were more distinct than those of either 4-methylisobornyl acetate (315) or 4-methylisoborneol (316), it was decided to carry out the spectroscopic analysis on the deuterated derivatives of this compound (308) rather than 315 or 316. In order to interpret the results of the labelling study, it was first necessary to assign the four methyl signals of 308 unambiguously, a process which was not as trivial as might have been expected. None of the previous reports of the synthesis of 308 1 2 0 included such an assignment, so the preliminary part of this study was concerned with this problem. Table 1: iH-NMR Signals of the methyl groups of 4-methylcamphor (308) and 9-deuterio-4-(deuteriomethyl)camphor (322) recorded in CDCI3 and benzene-el^ . Compound Solvent Position (ppm) and Multiplicity C(8) C(9) C(10) C( l l ) 308 CDCl3a 0.71 (s) 0.83 (s) 0.92 (s) 1.04 (s) benzene-d6b 0.47 (s) 0.51 (s) 0.92 (s) 0.70 (s) 322 CDCl3c 0.71 (s) 0.82 (t) 0.92 (s) 1.03 (t) benzene-d6d 0.47 (s) 0.50 (t) 0.92 (s) 0.69 (t) a) Appendix 4a b) Appendix 4b c) Appendix 4c d) Appendix 4d During the earlier study of the bromination of 4-methylcamphor (308) 1 1 6 a , we had obtained 3,9-dibromo-4-(bromomethyl)camphor (312), the structure of which had been proved 175 unambiguously by X-ray crystallographic analysis74. This compound provided the starting point from which our assignment of the methyl signals could be made. A two step process (Scheme 64), afforded 9-deuterio-4-(deuteriomethyl)camphor (322), in the  lH NMR spectrum of which two pairs of methyl signals could be differentiated. Scheme 64 Thus, selective debrornination of 311 with Zn in ethereal acetic acid at 0°C 3 9 provided 9-bromo-4-(bromomethyl)camphor (321) in 92% yield. The MS indicated that a single debrornination had occurred, as indicated by the observed molecular ions at m/z = 326, 324, and 322 as expected for CnHigB^O. That the bromine lost was from the 3-position was confirmed by the *H NMR spectrum of 321, which showed only two methyl singlets at 0.99 and 1.03 ppm, and two AB quartets at 3.36 and 3.66 ppm (2H, J = 11 Hz) and 3.62 and 4.02 ppm (2H, J = 10 Hz) assigned to the two bromomethyl groups. Reduction of 321 with tri-n-butyltin deuteride94*'121 in refluxing benzene then provided the desired dideuterio compound 322 in 58% yield. The observed molecular ion, at m/z = 168, was as expected for C u H i ^ O and the measured exact mass of 168.1483 was identical with that calculated for 322. The ! H NMR spectrum of 322 in CDC13 (Appendix 4c and Table 1) exhibited two singlets at 0.71 and 0.92 ppm (3H each), assigned to the two methyl groups [C(8)/C(10)], 1 7 6 and two 1:1:1 triplets at 0.82 and 1.03 ppm (2H, J = 2 Hz), assigned to the two deuteriomethyl groups [C(9)/C(ll)]. It still remained to differentiate these pairs of methyl groups, i.e. C(8) from C(10) and C(9) from C( l l ) . This was accomplished by performing n.O.e. difference experiments on 4-methylcamphor (308). Irradiation of the methyl signal at 0.71 ppm (Appendix 4e) resulted in positive enhancement of the signal at 2.08 ppm, assigned to the C(3) exo-proton, indicating that the methyl signal was that of C(8), and hence that at 0.92 ppm was C(10), by default. The assignment of the signal at 2.08 ppm (IH, dd, J = 18 and 3 Hz) to the C(3) ea»-proton was made by analogy with camphor, supported by its position and multiplicity; the 18 Hz coupling constant is as expected for geminal coupling to the C(3) endo-proton and the 3 Hz coupling is due to W-coupling to the C(5) exo-proton. Irradiation of the methyl signal at 0.83 ppm (Appendix 4e) resulted in enhancement of the signals at 1.59 - 1.77 ppm, assigned by analogy with camphor to the C(5) and C(6) exo-protons. Thus, the signal at 0.83 ppm was assigned to the C(9) methyl group and, by default, that at 1.04 ppm must be due to the C(l 1) methyl group. A third experiment supported our assignment of the signal at 0.92 ppm to the C(10) methyl group. Connolly and McCrindle 1 2 2 reported that a comparison of the *H NMR spectra of camphor in CDCI3 and benzene revealed that the signals of the C(8) and C(9) methyl groups experienced benzene-induced upfield shifts (A8 = 0.23 and 0.32 ppm respectively), while that of the C(10) methyl group was essentially constant (AS = 0.02 ppm). It was suggested that benzene-induced shifts of the *H NMR signals of methyl groups on cyclic ketones could be predicted by considering the position of the methyl group relative to a plane passing through the carbonyl carbon and perpendicular to the C=0 bond. Those groups close to but behind (i.e. on the ring side of the plane) the plane should exhibit very small (A8 < 0.1 ppm) upfield shifts, as observed for the C(10) methyl group of camphor. Those groups further behind the plane should exhibit somewhat 177 larger upfield shifts (A8 = 0.25 - 0.55 ppm), as observed for the C(8) and C(9) methyl groups of camphor. The ! H NMR spectrum of 4-methylcamphor (308) recorded in CDCI3 exhibited methyl signals at 0.71,0.83.0.92 and 1.04 ppm, whereas that recorded in benzene-dg exhibited signals at 0.47,0.51,0.70 and 0.92 ppm (Table 1 and Appendix 4b). It appeared that the assignment of the signal at 0.92 ppm to the C(10) methyl group was correct. This was the only peak which did not undergo a benzene-induced upfield shift, assuming that the peak observed at 0.70 ppm in benzene-d 6 was not the same as that at 0.71 ppm in CDCI3 (assigned to the C(8) methyl group). To confirm this assumption, the ! H NMR spectrum of 9-deuterio-4-(deuteriomethyl)camphor (322) was also recorded in benzene-dg (Table 1 and Appendix 4d); the corresponding peak at 0.69 ppm was observed to be a broad singlet integrating to two protons, indicating that it was probably the C(l 1) deuteriomethyl group and certainly not the C(8) methyl group. The signal at 0.92 ppm was again observed to be a sharp singlet, lending support to the assignment of this peak to the unshifted C(10) methyl group. 4.2.2 An investigation of the rearrangement of 2-methvlenebornane (314) Having assigned the methyl region of the *H NMR spectrum of 4-methylcamphor (308), we were ready to proceed with the mechanistic investigation. Two deuterated derivatives of 2-methylenebornane (314): 2-(dideuteriomethylene)bornane (323) and 8-deuterio-2-methylene-bomane (324) were used in the study. The former, 323, was readily prepared from (+)-camphor (228) in a single step (Scheme 65). Addition of 228 to a suspension of Lombardo's methylenating reagent123 (prepared from Zn, TiClj and CT^B^) provided a 67% yield of 2-(dideuteriomethylene)bornane. The identity of the product was confirmed by its IR, *H NMR and mass spectra. The IR spectrum exhibited peaks at 2300 cm-1, assigned to the vinylic C-D stretch, and 1610 cm*1, assigned to the C=CD2 stretch. The occurrence of the latter peak at 40 178 cm*1 lower frequency than the corresponding C=CH2 stretch of 2-methylenebornane (314) (1650 cm-1) is consistent with the substitution of deuterium for hydrogen50. The lH NMR spectrum of 323 was identical to that of 314 with the exception that a pair of broad singlets at 4.64 and 4.69 ppm (IH each), assigned to the methylene protons, was absent The low resolution MS exhibited a molecular ion at m/z - 152, the measured exact mass of which was 152.1541, in good agreement with that of 152.1532 calculated for C n H 1 6 D 2 . 228 323 i) Zn, TiOj, CD2Br2 / THF, CH2C12, 67% Scheme 65 325 324 i) Zn, TiCl4, CH2Br2 / THF, CH2C12, 67% Scheme 66 8-Deuterio-2-methylenebornane (324) was prepared in a similar fashion by methylenation of 8-deuteriocamphor (325)124 (Scheme 66) with Lombardo's reagent123, this time prepared from CH2Br2. The precursor, 325, was prepared in four steps from (+)-camphor (228) as has been previously described. The identity of the 8-deuterio-2-methylenebornane (324) was confirmed by lH NMR and mass spectroscopy. The AH NMR spectrum differed from that of 314 only in that the C(8) methyl singlet at 0.77 ppm was observed to be a 1:1:1 triplet (J = 2 Hz) at 0.74 ppm, 179 consistent with a single deuterium substituent This would be expected to cause a small upfield shift of the resonance frequency and, having a nuclear spin 1=1, would produce the observed splitting pattern46; the coupling constant of 2 Hz is consistent with geminal deuterium-hydrogen coupling. The observed molecular ion, at m/z = 151, in the low resolution MS and the measured exact mass of 151.1470 were also consistent with the molecular formula C u H 1 7 D (calculated exact mass = 151.1470). 315 R = CH 3 328 R = CD 2H Scheme 67 When 2-(dideuteriomethylene)bornane (323) was treated with catalytic sulphuric acid in acetic acid (Scheme 67), it was evident from GC analysis that rearrangement to a 4-methylisobornyl acetate had occurred. The *H NMR spectrum indicated that the product was mainly 315, in which considerable loss of the deuterium label had occurred. Four methyl singlets, at 0.69 (C(8)), 0.83 (C(9)), 0.86 (C(10)) and 0.90 ppm (C(ll)), were observed, and all integrated to three protons. A small multiplet at 0.88 ppm, presumably due to a small amount of deuterium-labelled compound, was also seen, but was obviously minor. The initial protonation of 323 to 326 would be expected to be reversible, and apparently the rate of proton or deuteron exchange of 1 8 0 326 was faster than the Wagner-Meerwein rearrangement to 327, resulting in the loss of most of the label. Table 2: ^-NMR Signals of the methyl groups of 4-methylcamphor (308),4-(trideuterio-methyl)camphor (334) and 8-deuterio-4-methylcamphor (343) recorded in CDCI3. Compound Position (ppm) and Multiplicity C(8) C(9) C(10) C(ll) 308a 0.72 (s) 0.83 (s) 0.92 (s) 1.04 (s) 334^  0.72 (s) 0.83 (s) 0.92 (s) — 343c 0.70 (t) + 0.83 (s) + 0.92 (s) 1.04 (s) 0.72 (weak s) 0.82 (sh) a) Appendix 4a b) Appendix 4f c) Appendix 4g To avoid this problem the rearrangement was performed in deuterated acetic acid, CH3CO2D. In this case loss of the label did not occur, and the NMR spectrum of the product, 4-(trideuteriomethyl)isobornyl acetate (333), exhibited only three methyl singlets at 0.69,0.83 and 0.86 ppm. Conversion of 333 to 4-(trideuteriomethyl)camphor (334) proceeded as shown in Scheme 68. It was evident from the *H NMR and low resolution mass spectra of the product that, while 334 was the major component, considerable deuterium incorporation had also occurred at other sites, most obviously C(9) and C(10). The !H NMR spectrum (Appendix 4f, Table 2) exhibited singlets at 0.71 (3H, C(8) methyl), 0.83 (3H, C(9) methyl) and 0.92 ppm (3H, C(10) methyl), as well as small multiplets at 0.82,0.90 and 1.01 ppm. The latter peak was attributed to a small amount of proton leakage into the C(ll) methyl group and was not unexpected. The immediate result of this experiment was the confirmation that the methylene group of 181 2-rnethylenebornane (314) became the C( l l ) methyl group of 4-methylisobornyl acetate (315), as predicted by the mechanism proposed for the rearrangement (Scheme 63). ent-334 ent-333 ent-332 WM = Wagner-Meerwein rearrangement; 3,2-Me = 3,2-exo-methyl shift; 6,2-H = 6,2-hydride shift i) H 2 S 0 4 / CH 3 C0 2 D ii) LLAIH4 / THF iii) PCC / CH 2C1 2 Scheme 68 182 A consideration of the proposed mechanism also reveals that deuterium incorporation into the C(9) and C(10) methyl groups is also likely. The postulated intermediates 330 and 331 would be in equilibrium with the deprotonated methylene compounds 330a and 331a, which would be able to pick up deuterons from the solvent The methylene carbons of 330 and 331 are the future 4-methylcamphor C(9) and C(10) methyl groups respectively, and the small peaks observed at 0.82 and 0.90 ppm in the *H NMR spectrum of 334 reflect deuterium incorporation at these sites, lending support to the postulated existence of the intermediates 330 and 331, and therefore the mechanism in general. It is also significant that no peak attributable to deuterium incorporation into X 323 329 X = H 335 336 X - D t 337 Scheme 69 the C(8) methyl group was observed. One can see that none of the proposed intermediates is capable of equilibrating to a structure in which the future C(8) methyl group exists as a methylene substituent The low resolution MS of 334 exhibited a molecular ion at m/z = 169 (20.8%), corresponding to a molecular formula of C i i H 1 5 D 3 0 , as well as others at 170 (30.6%), 171 183 (33.6%) and 172 (28.2%), corresponding to the incorporation of one to three additional deuterium atoms. In addition, a peak at m/z =168 (8.2%) was assigned to 334 in which a proton rather than a third deuteron had been incorporated. It should be noted that deuterium incorporation at C(3) is also possible, as shown in Scheme 69, and this may be the location of a significant proportion of the "extra" deuterium. When monitoring the rearrangement of 323 by GC it was evident that it was proceeding more slowly than that of the unlabelled material 314. In addition, a minor CG peak noted while following the rearrangement of 314 was present to a much greater extent in the rearrangement of 323, but was eventually converted to 4-methylisobornyl acetate. It is possible that this intermediate was 335, although no other evidence corifirrriing its existence or structure was obtained. Treatment of 8-deuterio-2-methylenebornane (324) with catalytic sulphuric acid in acetic acid resulted in a smooth conversion to the desired 8-deuterio-4-methylisobornyl acetate (342) (Scheme 70), which was then converted to 8-deuterio-4-methylcamphor (343). The *H NMR spectrum of 343 (Appendix 4g, Table 2) exhibited a 1:1:1 triplet at 0.70 ppm (2H, J = 1.8 Hz) assigned to the C(8) deuteriomethyl group, and singlets at 0.83 (3H), 0.92 (3H) and 1.04 ppm (3H) assigned to the C(9), C(10) and C( l l ) methyl groups respectively. This result is consistent with the proposed mechanism for the rearrangement (Scheme 63), in which the C(8) methyl group of 2-methylenebornane (314) becomes the C(8) methyl group of 4-methylisobornyl acetate (315) in the absence of the 6.2-hydride shift which results in partial racemization. In the case of 8-substituted 2-methylenebomanes such as 324, the intermediates 341 and 344, interconverted by the 6,2-hydride shift, are structural isomers, rather than enantiomers. Thus, if the 6,2-hydride shift occurred one would expect to see peaks in the *H NMR spectrum of 343 corresponding to 9-deuterio-4-methylcamphor (346). Indeed, a small singlet at 0.71 ppm and a shoulder at 0.81 ppm were observed in the lH NMR spectrum of 343 (Appendix 4g) and were assigned respect-ively to the C(8) methyl group and C(9) deuteriomethyl group of 346. Unfortunately it was not possible to obtain an accurate integration of these peaks, relative to those of 343, but a rough 184 estimate is consistent with the ~4:1 ratio of enantiomers (308 and ent-308) obtained from the rearrangement of 2-methylenebornane. The fact that 8-deuterio-4-methylcamphor (343) is the major product of the rearrangement of 324 confirms that trapping of 320 (Scheme 63) by acetate is preferred to the 6,2-hydride shift, and therefore that the absolute configuration of the major enantiomer of 4-methylcamphor produced in this process is 308. i) H 2 S 0 4 / CH 3 C0 2 H ii) LiAUL, / THF iii) PCC / CH 2C1 2 Scheme 70 1 8 5 4.3 Conclusion The *H NMR spectrum of 4-methylcamphor (308) was assigned by a series of ! H NMR experiments, and used to trace the fate of deuterium when deuterated 2-methylenebornanes 323 and 324 were converted to deuterated 4-methylcamphors 334 and 343. The results of these experiments support the mechanism proposed for the rearrangement of 2-methylenebornane (314) to 4-methylisobornyl acetate (315) and its enantiomer (ent-315)116b. 186 4.4 Experimental Debromination of 3,9-dibromo-4-(bromomethyl)camphor (312) to 9-Bromo-4-(bromomethyl)-camphor (321): A solution of 3,9-dibromo-4-(bromomethyl)camphor 312 (580 mg, 1.44 mmol) in 1:1 Et20:AcOH was cooled to 0°C. While stirring vigorously, Zn (294 mg, 4.50 mmol) was added in portions over 30 min. Stirring was continued for a further 15 min, before Celite (500 mg) was added and the mixture was filtered. The solution was diluted with Et20 (25 mL) and washed with water (2x5 mL), NaHCO^ (3x5 mL, until the washings were basic) and brine (5 mL), and dried over MgSC«4. Evaporation of the solvents yielded a pale yellow slushy solid which was recrystallised from MeOH to afford 9-bromo-4-(bromomethyl)camphor (321) as white crystals; yield: 283 mg, 61%; mp 53-5°C. The mother liquor was concentrated and the residue purified by column chromatography (230-400 mesh SiO^, eluting with 19:1 PE:Et20 to provide a further 146 mg; total yield: 429 mg, 92%. C n H 1 6 Br 2 0 Calc: C 40.77 H4.98 Br 49.31 % Anal.: C 40.99 H 5.04 Br 49.09 % Calc. Mass: 325.9527, 323.9547, 321.9567 Meas. Mass: 325.9532, 323.9543, 321.9585 IR (CHC13): v = 3025,2980 (C-H); 1745 cm-1 (C=0). MS (70 eV): m/z (%) = 326, 324, 322 (M+, 3.3,7.0, 3.7); 311, 309, 307 (0.3,0.9,0.4); 245, 243 (22.6, 23.3); 41 (100.0). 187 1H-NMR (400 MHz, CDC13): 8 = 0.99 and 1.03 (3H each, 2 s,C(8)H3 and C(10)H3); 1.50 -1.59 and 1.70 - 1.79 (IH each, 2 m, C(5) and C(6) endo H); 1.87 - 2.03 (2H, m, C(5) and C(6) exo H); 2.32 (IH, dAB, J = 18 Hz, C(3) endo H); 2.35 (IH, dd A B, J = 18, 3 Hz, C(3) exo H); 3.36 and 3.66, 3.62 and 4.02 (2H each, 2 <JAB> J = 11 Hz, J = 10 HZ, C(9)H2Br and C(l l)H2Br). Reduction of 9-bromo-4-(bromomethyl)camphor (321) to 9-Deuterio-4-(deuteriomethyl)camphor 9-Bromo-4-(bromomethyl)camphor 321 (384 mg, 1.25 mmol) was dissolved in dry CgHg (7 mL) and AIBN (cat) and Bu3SnD (1.0 mL, 1.1 g, 3.7 mmol) were added. The solution was refluxed for 18 h. The solvent was evaporated to provide a yellow oil which was purified by column chromatography (70-230 mesh Si02, 3x11 cm), eluting with PE and increasing polarity to 9:1 PE:Et20 to afford a mixture of 9-deuterio-4-(deuterio-methyl)camphor (322) and Bu3SnBr. Further purification by sublimation provided pure 9-deuterio-4-(deuteriomethyl)-camphor (322) as a white crystalline solid; yield: 121 mg, 58%; mp: 149-50°C. CnH 1 6D 20 Calc. Mass: 168.1483 IR (CHC13): x> = 3010,2970,2900 (C-H); 2200 (C-D), 1735 cm"1 (C=0). MS (70 eV): m/z (%) = 168 (M+, 62.0); 140 (23.9); 84 (100.0). *H-NMR (CDC13): 8 = 0.71 (3H, s, C(8)H3); 0.82 (2H, 1:1:11, J = 2 Hz, C(9)H2D); 0.92 (3H, s, C(10)H3); 1.03 (2H, 1:1:11, J = 2 Hz, C(11)H2D); 1.35 - 1.43 (2H, m, C(5) and C(6) endo H); 1.57 - 1.77 (2H, m, C(5) and C(6) exo H); 1.88 (IH, d^, J = 18 Hz, C(3) endo H); 2.08 (IH, dd^, J = 18, 3.5 Hz, C(3) exo H). (322): Meas. Mass: 168.1483 188 IH-NMR (CgDg): 5 = 0.48 (3H, s, C(8)H3); 0.495 (2H, broad s, C(9)H2D); 0.69 (2H, broad s, C(11)H2D); 0.92 (3H, s, C(10)H3); 1.03 (IH, broad t, J = 10 Hz, C(5) endo H); 1.15 -1.40 (3H, m, C(6) endo H, C(5) and C(6) exo H); 1.62 (IH, d ^ , J = 18 Hz, C(3) endo H); 1.86 (IH, ddAB, J = 18, 3 Hz, CQ)exo H). Dideuteriomethylenation of camphor (228) to 2-(Dideuteriomethylene)bomane (323): 228 323 A 125 mL Erlenmeyer flask containing Zn dust (3.87 g, 59.3 mmol) was flame dried and cooled under Ar. Dry THF (50 mL) and freshly distilled CD 2 Br 2 (1.40 mL, 3.52 g, 20.0 mmol) were added by syringe, and the vigorously stirred suspension was cooled to -40°C. TiCl4 (1.63 mL, 2.81 g, 14.8 mmol) was added dropwise over 3 min, and stirring was continued for a further 30 min, allowing the temperature to increase to -25°C. The mixture was aged at 5°C for 3 d. A solution of camphor (228, 1.00 g, 6.57 mmol) in dry CH 2 C1 2 (10 mL) was then added to the reagent at 0°C under Ar, and stirred for 2 d at rt. The mixture was then poured into 50% NaHC0 3 (75 mL) and stirred for 20 min before being filtered to produce a colourless two-phase solution. The layers were separated and the aqueous solution was extracted with Et 2 0 (2 x 35 mL). The combined organic solvents were washed with brine (35 mL) and dried over MgSC«4. Evaporation of the solvents afforded a pale yellow liquid which was purified by column chromatography (70-230 mesh Si0 2 ,3 x 12 cm), eluting with PE to provide 2-(dideuteriomethylene)bornane (323) as a white solid; yield: 666 mg, 67%; mp: 69-71°C. C n H 1 6 D 2 Calc. Mass: 152.1532 Meas. Mass: 152.1541 IR (CHC13): x> = 2950,2875 (C-H); 2300 (=C-D); 1610 (C=C); 700 cm-l (=C-D). MS (70 eV): m/z (%) = 152 (M+, 14.6); 137 (25.8); 41 (100.0). 189 1H-NMR (400 MHz, CDCI3): 8 = 0.76 (3H, s, C(8)H3); 0.89 (3H s, C(10)H3); 0.92 (3H, s, C(9)H3); 1.15 -1.30 (2H, m, C(5) and C(6) endo H); 1.64 (IH, td, J = 13,5 Hz, C(6) exo H); 1.74 (IH, m, C(4)H); 1.78 (IH, m, C(5) exo H); 1.92 (IH, d, J = 16 Hz, C(3) endo H); 2.40 (IH, dt, J = 16,4 Hz, C(3) exo H). Rearrangement of 2-(dideuteriornethylene)bornane (323) to 4-(Trideuteriomethyl)isobornyl acetate (333): A solution of 2-(dideuteriomethylene)bornane (323, 39.2 mg, 0.257 mmol) in AcOD (1 mL) was stirred, cone. H2SO4 (1 drop) was added and stirring was continued for 4 h. The mixture was diluted with Et20 (10 mL) and water (5 mL), and the layers were separated. The water was extracted with Et20 (5 mL) and the combined organics were washed with water (5 mL), NaHC03 (2x5 mL, until the washings were basic) and brine (5 mL), and dried over MgS04. Evaporation of the solvents produced a colourless oil which was purified by column chromatography (230-400 mesh SiO ,^ 1x6 cm), eluting with PE and increasing polarity to 24:1 PE:Et20, to provide 4-(trideuteriomethyl)isobornyl acetate (333) as a colourless mobile liquid; yield: 19.6 mg, 36%. C 1 3H 1 9D 30 Calc. Mass*: 213.1808 Meas. Mass*: 213.1777 IR (neat): v = 2950,2880 (C-H); 2220 (C-D); 1740 (C=0); 1220,1020 cm"1 (C-O). MS* (70 eV): m/z (%) = 213 (M+, 0.8); 170 (2.4); 153 (29.2); 43 (100.0). *The masses listed are only those for the trideuterio compound. The low resolution MS also exhibits peaks at m/z (%) = 216 (0.5), 215 (0.8), 214 (0.5), and 212 (0.1), presumably to the picking up of up to three additional deuterons or, in the latter case, a proton during the rearrangement. The measured masses support these assignments. 323 333 190 1H-NMR (400 MHz, CDC13): 8 = 0.69 (3H, s, C(9)H3); 0.83 (3H,s, C(8)H3); 0.86 (3H, s, C(10)H3); 1.11 -1.20 (2H, m, C(5) and C(6) endo H); 1.37 - 1.55 (3H, m, C(5) and C(6) exo H, and C(3) exo H); 1.83 (IH, dd, J = 14, 8.5 Hz, C(3) endo H); 2.02 (3H, s, CH 3CO); 4.66 (IH, dd. J = 8.5, 3.5 Hz, CHOAc). The *H-NMR spectrum also exhibits small peaks due to deuterium leakage into the C(9) and C(10) methyl groups, at 8 = 0.67 and 0.85 ppm respectively. Conversion of 4-(trideuteriomethyl)isobornyl acetate (333) to 4-(Trideuteriomethyl)camphor (334): A solution of 4-(trideuteriomethyl)isobornyl acetate (333, 54.4 mg, 6.255 mmol) in dry Et20 (2 mL) was stirred under Ar and LLAIH4 (5.3 mg, 0.14 mmol) was added. The mixture was stirred for 45 min, after which Na2SO4-10 H2O (50 mg) was added, and stirring continued for a further 20 min. The solvent was filtered after adding MgSC>4 (s), and evaporated to provide 347 as a pale yellow oil which was not purified further. The crude 4-(trideuteriomethyl)isoborneol (347) was disolved in dry CH2CI2 (3 mL) and PCC (83 mg, 0.38 mmol) was added. The mixture was stirred under Ar for 1.5 h and then filtered through a pad of 70-230 mesh Si0 2 (5 g) and MgS0 4 (5 g), rinsing well with CH 2C1 2 (25 mL). Evaporation of the solvent afforded a pale yellow oil which was purified by column chromatography (230-400 mesh Si0 2 , 1 x 7 cm), eluting with 19:1 PE:Et 20, to afford 4-(trideuteriomethyl)camphor as white crystals; yield: 13.9 mg, 33%; mp: 150-1°C. 191 CnH 1 5D 30 Calc. Mass*: 169.1546 Meas. Mass*: 169.1543 IR (CHC13): V = 2970,2890 (C-H); 2210 (C-D); 1735 cm-l (C=0). MS (70 eV): m/z (%) = 169 (M+, 20.8); 141 (9.2); 85 (100.0). iH-NMR* (CDCI3): 5 = 0.71 (3H, s, C(8)H3); 0.83 (3H, s, C(9)H3); 0.92 (3H, s, C(10)H3); 1.35 - 1.45 (2H, m, C(5) and C(6) endo H); 1.58 - 1.77 (2H, m, C(5) and C(6) exo H); 1.88 (IH, d^, J = 18 Hz, C(3) endo H); 2.08 (IH; dd^, J = 18, 3 Hz, C(3) exo H). Methylenation of 8-deuteriocamphor (325) to 8-Deuterio-2-methylenebornane (324): 325 324 Zinc dust (1.9 g, 29 mmol) was placed in a 50 mL rbf and flame dried. Dry THF (25 mL) and freshly distilled CH2BT2 (0.69 mL, 1.7 g, 9.8 mmol) were added by syringe and the mixture was cooled under Ar to -40°C. Freshly distilled TiCl4 (0.80 mL, 1.4 g, 7.3 mmol) was added by syringe and the mixture was stirred virorously, allowing the temperature to increase to 0°C over 2 h, and then aged at 5°C for 3 d. The brown suspension was cooled to 0°C and 8-deuterio-camphor (325,500 mg, 3.26 mmol) in dry CH2CI2 (5 mL) was added dropwise by cannula, over 5 min, stirring vigorously. Stirring was continued for 2 d at rt, after which the mixture was poured into 50% NaHCO^ (40 mL) and stirred for 20 min before the layers were separated. The aqueous phase was extracted with Et20 (2 x 10 mL) and the combined organic solvents were washed with brine (10 mL) and dried over MgSC>4. Evaporation of the solvents produced a pale *The masses quoted are only those for the trideuterated compound. The low resolution MS also exhibits peaks at m/z (%) = 172 (28.2), 171 (33.6), 170 (30.6) and 168 (8.7), corresponding to the uptake of up to three more deuterons or, in the latter case, a proton during the rearrangement. *The signals quoted are only those for 4-(trideuterio-methyl)camphor. The 1H-NMR also exhibits a broad shoulder at 0.82 ppm, a 1:1:1 triplet at 0.90 ppm and a multiplet at 1.01 ppm, corresponding to C(9)H2D, C(10)H2D, and C(l 1)HD2 respectively. 192 yellow oil which was purified by column chromatography (230-400 mesh SiC«2,1 x 17 cm), eluting with PE, to afford 8-deuterio-2-methylenebomane (324) as a white solid; yield: 232 mg, 47%; mp: 170-1°C. C n H 1 7 D Calc. Mass: 151.1470 JR ( CHC I3 ) : D = 3075 (vinyl C-H); 2950,2875 (C-H); 1660 (OC) ; 880 cm-1 (vinyl C-H). MS (70 eV): m/z (%) = 151 (M+ 22.9); 136 (42.6); 79 (100.0). 1H-NMR (CDCI3): 8 = 0.74 (2H, 1:1:11, J = 2 Hz, C(8)H2D); 0.88 (3H, s, C(10)H3); 0.91 (3H, s, C(9)H3); 1.15 -1.30 (2H, m, C(5) and C(6) endo H); 1.63 (IH, td, J = 11.5,4 Hz, C(6) exo H); 1.71 - 1.83 (2H, m, C(4) H and C(5) exo H); 1.93 (IH, dt, J = 16,2 Hz, C(3) endo H); 2.40 (IH, dm, J = 16 Hz, C(3) exo H); 4.65 and 4.70 (IH each, 2 broad s, vinyl H). Rearangement of 8-deuterio-2-methylenebornane (324) to 8-Deuterio-4-methylisobomyl acetate (342) and 9-deuterio-4-methylisobornyl acetate (345): A solution of 8-deuterio-2-methylenebornane (324,120 mg, 0.79 mmol) in AcOH (1 mL) was stirred, and cone. H2SO4 (1 drop) was added. Stirring was continued for 35 min, when the solution was diluted with Et20 (15 mL) and H2O (2 mL). The layers were separated and the Et20 was washed with H2O (2 mL), NaHCO^ (2x2 mL, until the washings were basic), and brine (2 mL), and dried over MgSO^. Evaporation of the solvent afforded a pale yellow liquid which was purified by column chromatography (230-400 mesh Si02, 1 x 12 cm), eluting with PE and increasing polarity to 24:1 PE:Et20, to provide a mixture of 8-deuterio-4-methylisobornyl acetate Meas. Mass: 151.1470 193 (342) and 9-deuterio-4-methylisobomyl acetate (345) as a colourless mobile oil; yield: 125 mg, 75%. C13H21DO2 Calc. Mass: 211.1681 Meas. Mass: 211.1681 IR (neat): v = 2960,2885 (C-H); 2195 (C-D); 1740 (C=0); 1240,1025 cm-l (C-0). MS (70 eV): m/z (%) = 211 (M+ 7.7); 169 (16.5); 151 (85.5); 43 (100.0). 1H-NMR* (CDCI3): = 0.68 (3H, s, C(9)H3); 0.81 (2H, broad s, C(8)H2D); 0.86 (3H, s, C(10)H3); 0.90 (3H, s, C(l 1)H3); 1.11 -1.21 (2H, m, C(5) and C(6) endo H); 1.37 -1.47 (2H, m, C(5) and C(6) exo H); 1.50 (IH, dt, J = 14, 3.5 Hz, C(3) exo H); 1.84 (IH, dd, J = 14, 8.5 Hz, C(3) endo H); 2.03 (3H, s, CH3CO-); 4.65 (IH, dd, J = 8.5, 3.5 Hz, CHOAc). Conversion of 8-Deuterio-4-methylisobornyl acetate (342) and 9-deuterio-4-methylisobornyl acetate (345) to 8-Deuterio-4-methylcamphor (343) and 9-deuterio-4-methylcamphor (346): A solution of 8/9-deuterio-4-methylisobornyl acetate (342/345, 125 mg, 0.59 mmol) in dry Et20 was stirred under Ar, and LLAIH4 (12 mg, 0.30 mmol) was added. Stirring was * The peaks listed are those for 8-deuterio-4-methyl-isobornyl acetate (342). The NMR spectrum also shows a small broad peak at 8 = 0.67 ppm, and a small sharp singlet at 8 = 0.83 ppm, which are assigned to C(9)H2D and C(8)H3 respectively, of the 9-deuterio-4-methylisobornyl acetate (345). 194 continued for 45 min and Na2SC>4-10 H2O (100 mg) was then added. After stirring a further 20 min, MgSC<4 (s) was added and the mixture was filtered. Evaporation of the Et20 provided crude 8/9-deuterio-4-methylisoborneol (348/349) as white crystals, which were not purified further. PCC (190 mg, 0.88 mmol) was added to a solution of the 8/9-deuterio-4-methylisoborneol (348/349,100 mg, 0.59 mmol) in dry CH 2Cl2 (5 mL), and the mixture was stirred under Ar for 1.2 h. The solvent was filtered through a pad of 70-230 mesh S i0 2 and MgS0 4 (1:1 v:v) and the remaining solid triturated with CH 2Cl2 (3 x 10 mL), which was also filtered. The solution was evaporated to provide a pale yellow oil, which crystallised on standing. The crude product was purified by column chromatography (230-400 Mesh SiC>2,1x7 cm), eluting with 19:1 PE:Et20 to afford a mixture of 8-deterio-4-methylcamphor (343) and 9-deuterio-4-methylcamphor (346) as white crystals; yield: 53.2 mg, 54% from the acetate; mp: 150-1°C. C n H 1 7 D O Calc. Mass: 167.1420 Meas. Mass: 167.1425 IR (CHCI3): D = 3020,2980,2900 (C-H); 1740 cm-* (C=0). MS (70 eV): m/z (%) - 167 (M+, 95.0); 152 (3.2); 139 (47.8); 110 (100.0). 1H-NMR (CDCI3): 8 = 0.70 (2H, 1:1:11, J = 1.8 Hz, C(8)H2D); 0.83 (3H, s, C(9)H3); 0.92 (3H, s, C(10)H3), 1.04 (3H, s, C(11)H3); 1.35 - 1.45 (2H, m, C(5) and C(6) endo H); 1.59 -1.77 (2H, m, C(5) and C(6) exo H); 1.88 (IH, d ^ , J = 18 Hz, C(3) endo H); 2.09 (IH, ddAB, J = 18, 3 Hz, C(3) exo H). 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Tetrahedron Lett. 26,2579 (1985). 124. (a) W.M. Dadson and T. Money. Can. J. Chem 58, 2524 (1980) (b) T.M. AUay. M.Sc. Thesis. UBC, Vancouver, B.C. 1983. 206 Appendix 1: Selected Spectra from Chapter 1 la. X-Ray Crystal Structure of the Alcohol 175 207 lb . J H N M R Spectrum of the M T P A Ester 178 l c . 1 9 F N M R Spectrum of the M T P A Ester 178 I | I I I i — p n I I r i r V T i i i i i - |-1 -i - I - I | i i-i i [ i i-i i | i I T I | i I T I l i I I i | i i n - | i T - I - r - | - r - n - r f T T ' • | 10 8 6 4 . 2 0 - 2 -4 PPM 208 Appendix 2: Selected Spectra from Chapter 2 2a.  lH NMR Spectrum of the Tetracyclic Diol 251 — i — — r — — i 1 l 1 1.7 J.I 6.B S .6 t.l • • • •vJLU 2b. IH NMR Spectrum of the acetate 252 * — ' ' I »~ t ' I • l " - * f ' * • I 7.1 CB E .« C.l 6.1 S I 5.6 • ' • I • I • I ' I • I • 1 1 I ' 1 » '-T • 1 * •" f • I ' I • I ' 1 •' I •» 1 1 •»'-..T....n • T . . ^ | - T , t | S.6 5.4 5.2 S.I i l «.( 1.1 | . 7 I I S B S B 5.1 5 7 1.1 2.1 2.B 7.1 7.1 2.1 1 8 J . B I.i 1.1 I.I .1 -I .1 • • • 2c. 1 3 C NMR Spectrum and APT Brperiment of the Tetracyclic Diol 251 2d. X-Ray Crystal Structure of the Acetate 252 C23 04 C17 | C7 k03 ) HI C3 C23 04 C17 | 103 > HI C3 01 C18 211 Appendix 3: Selected Spectra from Chapter 3 3a. IR Spectrum of the hydroxydiene 299 3b. lH NMR Spectrum of the hydroxydiene 299 2 1 2 Appendix 4: Selected Spectra from Chapter 4 4a. IH NMR Spectrum of 4-Methylcamphor (308) in CDCI3 J J "PPK 4b. IH NMR Spectrum of 4-Methylcamphor (308) in Cg>6 4c. IH NMR Spectrum of 9-deuteric^(deuteriomethyl)camphor (322) in CDCI3 4d. IH NMR Spectrum of 9-deuterio-4-(dXuteriomemyl)camphor (322) inC6D 6 ?PK » » T " I 214 4e. n.0.e. Difference Experiments of 4-Methylcamphor (308) 215 4f. IH NMR Spectrum of 4-(trideuteriomethyl)camphor (334) 4g. IH NMR Spectrum of 8-Deuterio-4-methylcamphor (343) J U 

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