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The evaluation of 4-methylcamphor as an intermediate in Triterpenoid synthesis Li, Diana L. F. 1989

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The E v a l u a t i o n of 4-Methylcamphor as an Intermediate In T r i t e r p e n o i d S y n t h e s i s By DIANA L.F. LI B . S c , The U n i v e r s i t y of B r i t i s h Columbia, 19,85 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA March 1989 © Diana L.F. L i , 1989 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. The University of British Columbia Vancouver, Canada Department DE-6 (2/88) A B S T R A C T A new s y n t h e t i c route to (-)-4-methylcamphor H Is d e s c r i b e d which i n v o l v e d i n i t i a l c o n v e r s i o n of (+)-camphor 1 to (-)-2-methylenebornane H. A c i d - c a t a l y z e d rearrangement of 41 p r o v i d e d ( +)-4-methylisobornyl a c e t a t e 10. which was reduced to (+)-4-methylisoborneol 12. F i n a l l y , o x i d a t i o n of 12. produced (-)-4-methylcamphor 12.. The o p t i c a l p u r i t y of compounds 40 and 12. was determined by a c h i r a l l a n t h a n i d e s h i f t r e a g e n t , [ E u d i f c ^ ] 15. while the o p t i c a l p u r i t y of 12 was determined by the Anderson-Shapiro reagent 48. Based on a m e c h a n i s t i c r a t i o n a l e , a d i f f e r e n t approach to the s y n t h e s i s of o p t i c a l l y pure ASL was attempted which i n v o l v e d the s y n t h e s i s of a C ( 5 ) - s u b s t i t u t e d 2-methylenebornane d e r i v a t i v e 5_8_ from ( + ) -endo-3-bromocamphor 5a . The p o t e n t i a l of (-)-4-methylcamphor 11 as a u s e f u l intermediate i n the s y n t h e s i s of t r i t e r p e n o i d s b e l o n g i n g to the lanostane 19_ s t r u c t u r a l sub-group was i n v e s t i g a t e d . Through a s e r i e s of bromination r e a c t i o n s f o l l o w e d by r e g i o s e l e c t i v e C-3 debrominat i o n , 12. was converted to 9,10-dibromo-4-(bromomethyl)camphor 7_5_ which was c l e a v e d to give 7_6_, a p o s s i b l e p r e c u r s o r of a p o t e n t i a l l y u s e f u l intermediate 6_5_ i n t r i t e r p e n o i d s y n t h e s i s . TABLE OF CONTENTS Page A b s t r a c t H Table of Contents i v L i s t of Tables v L i s t of F i g u r e s v i Contents of Appendix 1: v i i Contents of Appendix 2: v i i i L i s t of A b b r e v i a t i o n s and Terminology i x Acknowledgements x i General I n t r o d u c t i o n 1 A. Some Aspects of Camphor Chemistry 2 B. Determination of O p t i c a l P u r i t y by NMR Methods ....13 D i s c u s s i o n 17 A. P o t e n t i a l Use of 4-Methylcamphor i n T r i t e r p e n o i d S y n t h e s i s 17 B. A New S y n t h e t i c Route to 4-Methylcamphor 18 C. A l t e r n a t i v e S y n t h e t i c Routes to E n a n t i o m e r i c a l l y Pure (-)-4-Methylcamphor 4J. 43 D. Use of 4-Methylcamphor i n a New S y n t h e t i c Approach to T r i t e r p e n o i d s 53 Experimental . 60 B i b l i o g r a p h y 102 Appendix 1: IH NMR Spectra of S e l e c t e d Compounds 106 Appendix 2: Stereoview of Endo-3f9-dibromo-4-(bromomethyl) camphor 7_p_ 117 V LIST OF TABLES Table Page 1 L i t e r a t u r e v a l u e s of s p e c i f i c r o t a t i o n s 19 2 A summary of the r e s u l t s of the [ E u ( h f c ) 3 l study u s i n g (±)- i s o b o r n y l a c e t a t e and ( - ) - i s o b o r n y l a c e t a t e 24 3 A summary of the r e s u l t s of the [ E u f h f c ^ ] study u s i n g d i f f e r e n t samples of (+)-4-methylisobornyl a c e t a t e 29 4 The enantiomeric p u r i t y of (+)-4-methylisobornyl a c e t a t e s y n t h e s i z e d under d i f f e r e n t r e a c t i o n c o n d i t i o n s 33 5 A summary of the r e s u l t s of the [ E u ( h f c ) 3 l study u s i n g a s p e c i f i c sample of (-)-4-methylcamphor 34 6 R e s u l t s of the study of enantiomeric p u r i t y of the three a l c o h o l s u s i n g the Anderson-Shapiro reagent 39 LIST OF FIGURES Figure Ease. 1 R e s u l t s of the [ E u C h f c ^ l study u s i n g (±)- I s o b o r n y l a c e t a t e 26 2 R e s u l t s of the [ E u ( h f c ) 3 l study u s i n g (-)-Isobornyl a c e t a t e 27 3 R e s u l t s of the [ E u ( h £ c , 3 ] study using a s p e c i f i c sample of ( + )-4-methylisobornyl a c e t a t e 40a 30 4 R e s u l t s of the t E u ( h f c ) 3 l study u s i n g a s p e c i f i c sample of (+)-4-methylisobornyl a c e t a t e 40b 31 5 R e s u l t s of the [EuthfcJ-j] study u s i n g a s p e c i f i c sample of ( + )-4-methylisobornyl a c e t a t e 40c 32 6 R e s u l t s of the [Eu(hfc>3] study using a s p e c i f i c sample of (-)-4-methylcamphor 36 7 R e s u l t s of the model study u s i n g (±)- i s o b o r n e o l and ( - ) - i s o b o r n e o l 40 8 The 3 1P NMR spectrum of the d e r l v a t i z e d sample of ( +)-4-methyllsoborneol 42 v i i C O N T E N T S O F A P P E N D I X 1 Appendix 1 contains the 400 MHz *H NMR Spectra of the following compounds: Compound Page (-)-2-methylenebornane 41. . 107 ( + )-4-methylisobornyl acetate 40c ..107 (+)-4-methylisoborneol 42. 108. (-)-4-methylcamphor 42 109 ( ± )-lsobornyl acetate (±)-2JL . . . . . . . 1 0 9 (-)-isobornyl acetate ent-21 110 endo-3-bromo-4-methylcamphor 67 110 endo-3 f 9-dlbromo-4- ( bromomethyl Vcamphor 70 I l l 9,10-dibromo-4-(bromomethyl )camphor 7_5_ 112 9-bromo-4-(bromomethyl)camphor 21. 112 dibromoester 7_6_ 113 3, 3,9-tr ibromo-4-(bromomethyl)camphor 22. 114 ( + J-3, 3-dibromocamphor 2JL 114 perlcyclocamphanone 2_4 115 ejio.-5-bromocamphor 21 115 exo-5-bromo-2-methylenebornane 5.5. . 116 v i i i CONTENTS OF APPENDIX 2 Appendix 2 contains the stereoview of endo-3.9-dibromo-4-(bromo-methyl) camphor 7_0 page 117 LIST OF ABBREVIATIONS AND TERMINOLOGY (a) Terminology Since many of the compounds referred to in this thesis are opt ical ly active, in order to differentiate between enantiomers the term "ent" is used. "Ent" refers to the enantiomer of the compound given, eg. (+)-camphor 1. has the structure: O 1 (-)-camphor is thus denoted as ent-1. (h) Abbreviations The following abbreviations are used in this thesis: Ac Acetyl br broad (!H NMR) But t-Butyl c. concentration in g/100 mL of solvent calcd. calculated d doublet (!H NMR) DMAP 4-(Dimethylamlno)pyridine Et Ethyl [Eu(hfc) 31 Tris 13-(heptafluoropropylhydroxymethylene)-d-camphoratoleuropium(III) GLC Gas Liquid Chromatography HMPA Hexamethylphosphoramide IR i n f r a r e d J c o u p l i n g constant (Hz) LAH L i t h i u m Aluminum Hydride LDA L i t h i u m D l l s o p r o p y l a m l d e LSR Lanthanlde S h i f t Reagent m m u l t i p l e t (1H NMR) Me Methyl m/e mass to charge r a t i o mp m e l t i n g p o i n t NMR Nuclear Magnetic Resonance PCC P y r i d l n i u m Chlorochrornate ppm p a r t s per m i l l i o n i s o p r o p y l q q u a r t e t (*H NMR) s s i n g l e t (*H NMR) t t r i p l e t (1H NMR) THF T e t r a h y d r o f u r a n TLC Thin Layer Chromatography TMS T e t r a m e t h y l s i l a n e WM Wagner-Meerwein Rearrangement I O ]D S p e c i f i c R o t a t i o n at 589 nm 2,3 exo Me 2r3-exo-Methvl s h i f t 2,6 H 2,6-Hydrlde s h i f t 5 chemical s h i f t In ppm from t h v Wavenumbers (cm-*-) ACKNOWLEDGEMENTS I would l i k e to take t h i s opportunity to thank my research supervisor Professor Thomas Money for his guidance and advice throughout the course of my graduate study. Special thanks go to my colleagues Andrew Clase, Garney Gracey and Dr. David Kuo whose help and advice during the course of t h i s challenging project i s very much appreciated. I am grateful to Professor J. Trotter and Dr. S. Rettig for carrying out the X-ray crystallographic analysis of endo-3,9-dlbromo-4-(bromomethyl)camphor. I would also l i k e to express my appreciation to Andrew Clase for proofreading t h i s t h e s i s . F i n a l l y , I am thankful to God for a l l that He has done for me and for my parents for their ever-present love and support throughout my l i f e . 0 Lord, I am an unworthy servant possessing no merit, I have merely done what was my duty to do. May t h i s thesis be an acceptable and pleasing s a c r i f i c e of thanksgiving in Your sight. 1 INTRODUCTION Camphor, although not widespread in Nature, has been known for many centuries because of i t s ease of i s o l a t i o n . [ l a ] Most of the work leading to the elucidation of i t s structure was carried out In the nineteenth century.[lb] While the dextrorotary form of camphor occurs primarily in ^ the wood of the camphor l a u r e l which is Indigenous to Formosa, Central China, and Japan and is cu l t i v a t e d elsewhere, the laevorotary form (which is a constituent of the o i l of sagebrush) and racemic form are much less common in Nature.[la] Extraction of (+)-camphor 1 is achieved by steam d i s t i l l a t i o n of the chopped trunk and branches of the camphor l a u r e l . [ l a ] (-)-Camphor ent-1 can be prepared cheaply in the laboratory by oxidation of commercially available (-)-borneol 2.. [ 21 Nowadays, camphor is used in medicine and as a p l a s t i c i z e r in the manufacture of explosive, c e l l u l o i d and photographic f i l m , and most of the world's requirements are supplied by the synthetic products derived from a -plnene 3_. l i b ] 1 SBkl 1 1 Interest in the chemistry of camphor has been larg e l y motivated by the fact that i t undergoes a var i e t y of fascinating transformations.[3a] Much of this chemistry has had a significant impact . on theoretical and mechanistic organic chemistry and various derivatives of camphor have been employed as key Intermediates in organic synthesis.[3a] In fact, the use of camphor as chiral starting material In the enantiospecific synthesis of natural products is largely due to the ava i lab i l i ty of camphor in both optical ly pure enantiomeric forms and the ava i lab i l i ty of methods for the direct or indirect introduction of functionality at C(3), C(5), C(6), C(8), C(9), and C(10).[3a] Moreover, useful synthetic intermediates are obtained by cleavage of the C(l)-C(2) , C(2)-C(3) and C(l)-C(7) bonds in camphor and i ts derlvatIves.I 3a] The functionalization of camphor and Its use in natural product synthesis has been extensively reviewed by Money[3a] so only a brief outline of its react ivi ty and use in synthesis which are relevant to the present work wi l l be given. A. Some Aspects of Camphor Chemistry: 1. C(3)-Functionalization Position 3 in camphor displays a degree of react ivi ty that would normally be expected for active methylene groups, and a large number of C(3)-substituted camphor derivatives have been reported.I 3a1 l a . C(3) Methylation Recent investigations have shown that sequential treatment of (+)-camphor 1 in THF with lithium diisopropylamide (1 mole equivalent) and with methyl iodide (excess) at 0°c provides a product (~75% yield) which was shown by 1 H NMR (400 MHz) and capi l lary GLC to be a mixture (~4:1) of exo-3-methylcamphor 4a and endo-3-methylcamphor lb_[ 4 ] (Scheme 1). Subsequent treatment of this mixture with NaOMe in MeOH or with HCl and HOAc provides a mixture (~9:1) in which the major component is endo-3-methyl-camphor 4b. Similarly, protonation of 3-methylcamphor enolate results in the formation of endo-3-methylcamphor 4b and a small amount of the exo-3-methyl epimer 4a. ( (endo ] : [ exo ] = 9:1).[5] iii or iv H Me I 4a 4b. R e a g e n t s : i , L l N P r ^ , T H F - H M P A (20:1), a t 0°C; i i , M e l , a t 0°C; i i i , NaOMe, MeOH, h e a t ; i v , H C l , H O A c , h e a t . Scheme 1 l b . C(3) M o n o b r o m i n a t l o n B r o m l n a t i o n o f ( + ) - c a m p h o r 1 w i t h b r o m i n e i n a c e t i c a c i d t o y i e l d ( + ) - e n d o - 3 - b r o m o c a m p h o r 5a was f i r s t a c c o m p l i s h e d b y K i p p i n g a n d P o p e i n 1893.16] S i n c e t h e n , i t h a s b e e n e s t a b l i s h e d t h a t t r e a t m e n t o f ( + ) - c a m p h o r 1. w i t h b r o m i n e i n a c e t i c a c l d [ 7 ] , e t h a n o l [ 8-10 ], o r c h l o r o f o r m ! 8-10 ] p r o v i d e s (+) -e_njio_-3-bromo-c a m p h o r 5_a_ a s t h e m a j o r p r o d u c t (~92%). T h i s i s a l s o t h e m o s t s t a b l e d e r i v a t i v e s i n c e treatment with a base (NaOMe or KOBuM does not change the r e l a t i v e p r o p o r t i o n s of C(3)-epimers ([endo]:[exo] = 92:8). Bromination of (+)-camphor 1 with p y r i d i n i u m bromide perbromide or of camphor enol t r i m e t h y l s i l y l ether £ with bromine i n dioxane-pyrIdine leads to approximately equal amounts of exo-3-bromocamphor 5b and endo-3-bromocamphor 5a,. t i l ] Subsequent e q u i l i b r a t i o n of t h i s mixture with base (NaOMe i n MeOH) pr o v i d e s the thermodynamic mixture ([endo]:[exo] = 92:8). Reagents: i , Br2, HOAc; i i , NaOMe, MeOH; i i i , C5H5NHBr3, HOAc; i v , KOBuS HOBut; v, H C l , HOAc, heat; v i , Br2/ di o x a n e - p y r i d I n e . Scheme 2 2. C(9) and C(10)-Bromlnations Treatment of (+)-endo-3-bromocamphor 5a with bromine and c h l o r o s u l p h o n l c a c i d p r o v i d e s ( + )-endo-3 f9-dibromocamphor 1 5 and a small amount of ( +)-endo-3,9,9-trlbromocamphor 8_[12,133 (Scheme 3). The mechanism of C(9)-bromination of (+)-endo-3-bromocamphor 5_a. is shown in scheme 4. Br Br Br Br l a 2 £ Scheme 3 Confirmation of the mechanism of bromination at C-9 that is shown in scheme 4 has been obtained by using endo-3-bromo-8-deuteriocamphor (5a. A =2H) in the bromination react ion.[14] The product, ( + )-endo-3 f 9-dibromocamphor 7. has deuterium located only at C-8. Note that, according to the mechanistic proposals shown in scheme 4, the presence of an endo-bromo-substituent at C-3 in camphor ensures that C(9)-bromination provides 3,9-dl-substituted derivatives with retention of configuration. Prolonged treatment of ( +) -endo-3 f 9-dibromocamphor 2. with bromine and chlorosulphonic acid (5 days) gives (+)-endo-3,9,10-tribromocamphor 9_. [15] Selective debromination of 9_ with zinc and acetic acid provides ( + )-9,10-dibr omocamphor 10 . . The mechanism!151 of the bromination of ( +)-endo-3 f 9-dlbromocamphor X has been postulated to involve a Wagner-Meerwein rearrangement to provide the camphene intermediate H . (Scheme 5). Reaction Br of i l w i t h bromine and subsequent rearrangement back to the camphor framework p r o v i d e s the t r i b r o m o camphor 9_. W M 2,3 exqMe A 2,3 exo Me 2,3 exo Me Scheme 4 Scheme 5 3 . Cleavage of C ( l ) - C ( 2 ) Bond i n Camphor and Camphor D e r i v a t i v e s Cleavage of the C ( l ) - C ( 2 ) bond i n camphor and i n v a r i o u s camphor d e r i v a t i v e s r e s u l t s i n the formation of a f u n c t i o n a l i z e d 5-membered r i n g . (+)-Camphor 1 i t s e l f undergoes cleavage upon p h o t o - i r r a d i a t i o n ! 1 6 - 2 0 ] to g i v e the aldehyde 12. while (+)-9,10-dibromocamphor JLQ. can be clea v e d t o provide the c y c l o p e n t a n o i d r i n g systems 12., 14., and 1 5 . [ 2 1 , 2 2 1 The C ( l ) - C ( 2 ) r i n g cleavage r e a c t i o n i n camphor and i t s d e r i v a t i v e s has been u t i l i z e d i n routes from camphor to the C/D r i n g system of s t e r o i d s with c o n t r o l of s t e r e o c h e m i s t r y at the C ( 1 3 ) , C ( 1 7 ) and C ( 2 0 ) carbon c e n t r e s of the s t e r o i d a l s k e l e t o n . The u t i l i z a t i o n of the r i n g cleavage products of camphor d e r i v a t i v e s as c h i r a l synthons i n t e r p e n o i d and s t e r o i d s y n t h e s i s has been i n t e n s i v e l y i n v e s t i g a t e d i n our laboratory.I 221 hv O X ^ B r IQ Reagents: i , NaOMe, MeOH; i i , KOH, THF, H20; i i i , KOH, DMSO, H20. or in \ C—OR // O Products: 13 X=Br, R=Me 14 X=Br, R=H 15. X=OH, R = H Scheme 6 21 \ / 2 2 ^ / 2 4 ^ ^ 2 6 20 23 25 18 j 15 16 / 7 27 Steroidal Skeleton 4. C(5)-Functionalization Two conventional approaches are available for the synthesis of C(5)-substituted camphor.I 3a] In the f i r s t approach (Scheme 7 ) , (-)-bornyl acetate 1£ Is oxidized with CrC^ and HOAc or with C r 0 3 , HOAc, and A C 2 O to provide a mixture of 5-oxobornyl acetate H (24-40% yie ld) , 6-oxobornyl acetate 18_ (5-15% yie ld) , and other minor products (15_ . and 20.). [ 3b] Remote oxidation of (+)-isobornyl acetate 2JL with Cr03, HOAc, and Ac 20 provides a mixture of (4:1) 5-oxoisobornyl acetate 22 and i ts 6-oxo-lsomer 23 in 55% yield.[3c-e] In fact, this one-step synthesis of (-)-5-oxoisobornyl acetate 22 from (+)-isobornyl acetate 21 is the most eff icient way to prepare this compound and has been used in various synthetic studies.[3d-f] 21 22 21 Reagents: i , Cr03, HOAc, A C 2 O ; i i , C r 0 3 , HOAc Scheme 7 An alternative route to C(5)-substituted camphors such as compounds 27 R 28 and 22. involves ring-cleavage of pericyclo-camphanone 24123-30] which can be prepared from 3-diazocamphor 25 or 3,3-dibromocamphor 26.. As shown in scheme 8, the ring-cleavage product e_xo_-5-bromocamphor 22 can be transformed to two other C(5) derivatives of camphor (2JL and 29). HBr; iv , AgOAc, HOAc; v, aluminum amalgam, D2O. Scheme 8 5. C(4)-Functionalization C( 4)-substituted camphor derivatives 22. (Scheme 9) can be prepared in modest yield using (+)-camphor 1 or fenchone 31 as starting material.t8,10,23,32-34,47] In the most conventional procedure (Scheme 9), C(4)-substituted camphor 39 is prepared by f i r s t converting ( + )-camphor 1. to a C(2)-isoborneol derivative 12. or a C(1)-camphene derivative 33 which rearranges to the C(4)-bornane derivatives (24.-22). In one variation of this approach, camphor nitrimine 2S. is converted to camphehe-l-carboxylic acid (22; R=C00H)l33a] and eventually to 4-carboxycamphor 22. (R=COOH). As shown in scheme 9, 1-methylcamphene (12.; R=Me) can be prepared from fenchone 21. R R 24 R'WVc 22 25. R'-NOj 2fiR'-coca, SZR'^HO Reagents: 1, RM; i i , MeMgl; i i i , K H S O 4 , heat; i v , HOAc, H2SO or 65% H N O 3 ; v , CCI3COOH or HCOOH or HOAc, H 2 S O 4 ; v i , NH2OH V i i , NaN02, H 2 S 0 4 ; V i i i , KCN, EtOH. Scheme 9 The mechanistic rationalization of these earl ier Investigations prompted research in our laboratory which led to the development of a more convenient route (Scheme 10) to ( + )-4-methyl Isobornyl acetate 10_ which involves direct acid-catalyzed rearrangement of (-)-2-methylenebornane 1 1 . This compound H a n d Its enantiomer are readily prepared[12,14] in -77% yield by Wlttig reaction on (+)- and (-)-camphor, respectively. Preliminary investigations[31] in our laboratory showed that when (-)-2-methylenebornane l i was treated with HOAc / H2SO4 (20:1 ) for 15 minutes at room temperature, ( + )-4-methyllsobornyl acetate IQ. {[alp 5 +35.79 (c.2.28, EtOH)} was produced in ~75% yie ld . Subsequent conversion of 40. to (+)-4-methyllsoborneol 12 {[a ]25 +20.40 (c .9 .0 , EtOH)} and (-)-4-methylcamphor H {[a ] - 1 6 . 7 0 (c.1.5, EtOH)} was then accomplished in ~62% overall y ie ld . Although the specific rotations of (+)-4-methylisobornyl acetate 1P_, (+)-4-methyl-lsoborneol 12 and (-)-4-methylcamphor 13_ prepared in this way were comparable to those recorded in the l i terature (cf. Table 1, p. 19), the optical purity of our compounds or those described in the l i terature had not been established. 1 11 42 Reagents: i , CH3PPh3Br, n-BuLi, THF; 11, HOAc, H 2 S0 4 (20:1), 15 min., 25°C. Scheme 10 B_, Determination of Optical Purity bv NMR Methods: 1. Use of Chiral Lanthanide Shift Reagents The f i r s t chiral lanthanide shift reagent (LSR), t r i s [3 - ( t -butylhydroxymethylene)-d-camphorato]europium(III) 4_4_ was reported by Whitesides and Lewis[35] who showed that i t was quite effective in separating the signals of the enantiomers of a-phenylethylamine 47_ and of several other amines. However, this LSR was not found useful for functional groups other than amines. 4£R-CF2CF2CFi 46R-CF, Soon after, Fraser[36] and Goering[37] independently introduced other chiral shift reagents, tris[3-(heptafluoro-propylhydroxymethylene)-d-camphorato]europium(III), [Eu(hfc)3] 45 and tris-[3-(trifluoromethylhydroxymethylene)-d-camphorato]-europium( III) , [Eu(facam)3] 4JL. Both were shown to be effective for many different functional groups. Although 4_5_ and 4_6_ have been by far the most widely used, other chira l LSRs have also been reported.[36,38-40] An overview of the types of structures for which chiral LSRs have been successfully ut i l i zed can be found in a detailed review by Sul l ivan.[41 ] It is apparent that v i r tua l ly any chiral molecule containing a functional group capable of binding to an achiral LSR is a possible substrate for enantiomeric purity determination with a chira l LSR. by acting as Lewis acids, forming a complex with the substrate under analysis, which acts as a nucleophile. Induced shifts are attributed to a pseudo-contact, or dipolar, interaction between the shift reagent and the nucleophile. It is believed that the magnetic f ie ld produced by summation of the magnetic moments of the six unpaired electrons of the europium ion combines with that resulting from the orbital motion of the europium electrons and generates an anisotropic magnetic f ie ld In the v i c in i ty of the shift reagent.[38] As a result , the protons of the nucleophile coordinated to the europium atom reflect this f ie ld in their chemical shif ts . Under normal conditions, the equilibrium between the substrate and the LSR is rapid on the NMR time scale: Lanthanide p-diketone shift reagents such as 44-46 function D (R)-substrate .(S) -substrate + 2(R)-LSR {11 (S)-substrate.(R)-LSR (R)-substrate.(R)-LSR Thus, only a single time-averaged spectrum results from the average of complexed and uncomplexed substrate molecules. R a p i d l y e q u i l i b r a t i n g complexes are formed by an e n a n t i o m e r i c a l l y pure c h i r a l LSR b i n d i n g to each of two enantiomers. Note tha t the c h i r a l LSR ( a r b i t r a r y assumed i n equation {1} to have R c o n f i g u r a t i o n ) i s a c t u a l l y a mixture of four diastereomers i n r a p i d e q u i l i b r i u m by v i r t u e of the c h i r a l i t y of the o c t a h e d r a l europium. These d i a s t e r e o m e r i c complexes can have d i f f e r e n t averaged chemical s h i f t s due to (1) the e q u i l i b r i u m constants (K R, kg) may be d i f f e r e n t f o r d i a s t e r e o m e r i c complexes, t h u s , causing l a r g e r s h i f t s f o r the complex having the l a r g e r b i n d i n g constant; and (2) the two d i a s t e r e o m e r i c complexes (A.,E) formed may d i f f e r i n t h e i r geometry, t h u s , c a u s i n g a d i f f e r e n c e i n the induced s h i f t f o r corresponding s i g n a l s i n the two complexes.[38] The use of c h i r a l LSR o f f e r s a d i r e c t approach f o r d e t e r m i n a t i o n of enantiomeric p u r i t y by NMR. Since resonances of enantiomers undergo d i f f e r e n t chemical s h i f t s i n a c h i r a l environment, the enantiomeric r e l a t i v e abundances can be determined by s i m p l y choosing one or more s i g n a l s t h a t show s u f f i c i e n t response to the s h i f t reagent and are adequately separated from other s i g n a l s . A good d i s c u s s i o n of p r a c t i c a l a s pects of use of these LSRs has been given by McCreary et a l . [38] In g e n e r a l , the f a s t e s t and e a s i e s t technique f o r o b t a i n i n g induced s h i f t s i s to add a few m i l l i g r a m s of s h i f t reagent d i r e c t l y to the n u c l e o p h i l e d i s s o l v e d i n s o l v e n t . Then one or more s i g n a l s are chosen to monitor enantiomeric s h i f t d i f f e r e n c e s or d i f f e r e n t i a l s h i f t s , AA8 . A d d i t i o n a l amounts of shift reagent can be added unt i l sufficient resolution is attained. 2. Use of Anderson-Shapiro Reagent 4JL o / / P o A This chiral derlvatlzing agent was introduced by Anderson and Shapiro in 1984[42) and is characterized by three advantages: (1) easy to use: 4JS. is capable of the direct in s i tu determination of enantiomeric purity of both primary and secondary alcohols; (2) analysis bf enantiomeric purity is performed by J AP NMR, a nucleus readily available In NMR systems having broad-band capabi l i t ies; and ( 3 ) due to the C 2 symmetry of the chiral glycol ligand on phosphorus, either retention or inversion at phosphorus during derivatization of an enantiomerically pure alcohol yields a single diastereomer. Thus, i f the sample under examination contains enantlomers, two diastereomers having some degree of 3!p NMR nonequlvalence (A8) are expected after derivatization. A variety of alcohols have been studied using this reagent and In general, the 31p chemical shift range of a l l of the derivatlzed alcohols studies is between 12 and 15 ppm while the reagent 4JL is found at 17.4 ppm. [42] 17 DISCUSSION Potential US_£ £2i 4-Methylcamphor 43 In Tr l t e r p e n o l d Synthesis: Among the C ( 4 ) - s u b s t l t u t e d camphor d e r i v a t i v e s 34-37 mentioned e a r l i e r ( c £ . Scheme 9 ) , (-)-4-methylcamphor 4 1 and i t s enantiomer (ent-43) are p o t e n t i a l l y u s e f u l i n t e r m e d i a t e s In the s y n t h e s i s of t r i t e r p e n o l d s belonging to the lanostane 49 and euphane 5_5_ s t r u c t u r a l sub-groups. The development of s y n t h e t i c routes to t r I t e r p e n o l d s belonging to these two s t r u c t u r a l sub-groups has been the o b j e c t i v e of e x t e n s i v e i n v e s t i g a t i o n s by Reusch and co-workers.[44] A key intermediate i n these s y n t h e t i c routes i s the b i c y c l i c diketone 5_1 i n which the c h a r a c t e r i s t i c £iajis_ arrangement of the angular methyl groups i n the C,D r i n g system of lanostane 49. t r i t e r p e n o l d s i s a l r e a d y i n p l a c e . In a d d i t i o n , Reusch and co-workers[44] demonstrated tha t by u s i n g a photo-epimer i z a t i o n r e a c t i o n ! 4 5 ] , diketone 5_1 has p o t e n t i a l as an Intermediate i n the s y n t h e s i s of the C,D r i n g system of the euphane 5_0_ f a m i l y of t r i t e r p e n o l d s . Diketone 51 has a l s o been used as a key intermediate i n the s y n t h e s i s of 14-methyl-19-norsterolds.[46] 2Q 51 B_ A New S y n t h e t i c Route to 4-Methvlcamphor 43: 1. L i t e r a t u r e Routes: L i t e r a t u r e procedures[47] f o r the s y n t h e s i s of ( - ) -4-methylcamphor ±2. g e n e r a l l y i n v o l v e i n i t i a l c o n v e r s i o n of ( + )-camphor 1. to (-)-2-methylisoborneol 5_2_ or 1-methylcamphene 53 f o l l o w e d by a c i d - c a t a l y z e d rearrangement to ( + )-4-methylisoborneol 42.[47c/g]/ (+ )-4-methylisobornyl a c e t a t e 10_[47h,i], or ( + ) - 4-methylisobornyl n i t r a t e 5_4J47d,f] (Scheme 11). In no c a s e , however, was the o p t i c a l p u r i t y of these products or the d e r i v e d 4-methylcamphor 4_3_ determined and, hence, o n l y an estimate of r e l a t i v e enantiomeric p u r i t y can be gauged from l i t e r a t u r e values of s p e c i f i c r o t a t i o n s l i s t e d i n t a b l e 1. A c c o r d i n g l y , the i n i t i a l o b j e c t i v e of the r e s e a r c h d e s c r i b e d i n t h i s t h e s i s was to determine the o p t i c a l p u r i t y of s y n t h e t i c ( + )-4-methylisobornyl a c e t a t e 4JL d e r i v e d from (-)-2-methylenebornane 41. 51 Scheme 11 19 Table 1: L i t e r a t u r e values of s p e c i f i c r o t a t i o n s Compound S p e c i f i c R o t a t i o n [oc]2° Reference U L + 1 8 . 9 0 ° + 3 5 . 8 4° 47a 47g, i 12. + 1 4 . 8° + 2 2 . 6 9 ° (EtOH) + 2 5 . 2 0 ° (c.10.0, EtOH) 47a 47g 47c,f 11 - 1 4 . 5 ° (c.10.0, EtOH) 47c,f 2. Development of a New S y n t h e t i c Route to 4-Methylcamphor 11: The i n i t i a l work of t h i s r e s e a r c h p r o j e c t which i s o u t l i n e d i n scheme 12 was accomplished by Linda Lo, a summer student i n our l a b o r a t o r y . Since i t Is known tha t r e a c t i o n s i , i l l and i v i n scheme 12 occur with r e t e n t i o n of c o n f i g u r a t i o n , the enantiomeric p u r i t y of (-)-4-methylcamphor H depends on t h a t of ( + )-4-methyl i s o b o r n y l a c e t a t e 10.. The formation of (+)-4-methylisobornyl a c e t a t e 10 from (-)-2-methylenebornane 41 as shown i n scheme 13 probably i n v o l v e s a s e r i e s of Wagner-Meerwein rearrangements (WM) and a 2,3-exo-methyl s h i f t (2,3 exo Me). P r e l i m i n a r y i n v e s t i g a t i o n s have shown t h a t t h i s r e a c t i o n Is extremely temperature s e n s i t i v e . For example, at 70°C and f o r one hour, two products were produced: 4-methylisobornyl a c e t a t e and an u n i d e n t i f i e d s i d e product (which c o u l d be any one of those shown i n scheme 13). Moreover, at t h i s temperature, the 2,6-hydride s h i f t ( c f . A. — » B_, Scheme 13) occurred so r e a d i l y t h a t an equlmolar mixture of 4-methyl i s o b o r n y l a c e t a t e 4_0_ and ent-40 was produced. A more d e s i r a b l e outcome was observed when t h i s r e a c t i o n was c a r r i e d out at room temperature f o r 15 minutes as 4-methylisobornyl a c e t a t e was , formed i n y i e l d . When the r e a c t i o n time was i n c r e a s e d to 30 minutes, the y i e l d of a c e t a t e 4JI was 13% but the product was racemic. When conducted at 0°C, the r e a c t i o n was too slow to be p r a c t i c a l . 1 41 4Q iii Reagents: i , CH3PPh3Br, n-BuLi, THF i i , HOAc, H2SO4 (20:1), 15 min., 25°C i i i , LAH, THF i v , PCC. CH 2Cl2 Scheme 12 1 Scheme 13 gnt-40 At t h a t p o i n t , the enantiomeric p u r i t y of the (-)-4-methylcamphor i l d e r i v e d from (+)-4-methylisobornyl a c e t a t e 40 ( c f . Scheme 12) was e v a l u a t e d by comparing i t s s p e c i f i c r o t a t i o n with l i t e r a t u r e v a l u e s ( c f . Table 1 ) . Thus, the f i r s t o b j e c t i v e of the present work was d i r e c t e d toward the s y n t h e s i s of e n a n t i o m e r i c a l l y pure (+)-4-methylisobornyl a c e t a t e 10_ i n a reasonably good y i e l d and to i n v e s t i g a t e convenient methods to determine the enantiomeric p u r i t y of (+)-4-methylisobornyl a c e t a t e IU, ( + )-4-methylisoborneol 12 and (-)-4-methylcamphor 1 2 . 3. Determination of O p t i c a l P u r i t y of S y n t h e t i c 4-Methyllso-b o r n y l Acetate 40, 4-Methylisoborneol 12 and 4-Methylcamphor 13: During the course of t h i s s t u d y , two convenient methods were employed to determine the enantiomeric p u r i t y of the samples of i n t e r e s t . A c h i r a l l a n t h a n i d e s h i f t r e a g e n t , namely t r l s - [ 3 -( heptafluoropropylhydroxymethylene)-d-camphorato]europlum(III), [ E u ( h f c ) 3 l 15 was used to determine the enantiomeric p u r i t y of the ( + )-4-methylisobornyl a c e t a t e 1P_ samples produced under d i f f e r e n t experimental c o n d i t i o n s . In a d d i t i o n , a s p e c i f i c a c e t a t e sample 40a was reduced to (+)-4-methyllsoborneol 1 2 , the enantiomeric p u r i t y of which was then determined by the Anderson-Shapiro reagent IS. and was c o r r e l a t e d to the enantiomeric p u r i t y of the a c e t a t e precusor 40a determined by the l a n t h a n i d e s h i f t r e a g e n t . F i n a l l y , t h i s s p e c i f i c (+)-4-methylisoborneol sample was o x i d i z e d and the enantiomeric p u r i t y of the product (-)-4-methylcamphor 42 was evaluated by the l a n t h a n l d e s h i f t r e a g e n t . 3a. Determination of Enantiomeric P u r i t y Using C h i r a l Lanthanide S h i f t Reagent, [ E u ( h f c )3l 45: The t h e o r y of the use of c h i r a l l a n t h a n i d e s h i f t reagents f o r the d e t e r m i n a t i o n of enantiomeric p u r i t y i s b r i e f l y covered i n the i n t r o d u c t i o n of t h i s t h e s i s and t h e r e f o r e , the d i s c u s s i o n i n t h i s s e c t i o n w i l l be focused s p e c i f i c a l l y on the r e s u l t s . The c h i r a l l a n t h a n i d e s h i f t reagent [ E u C h f c )3] 4_5_ was used to determine the enantiomeric p u r i t y of the samples of the f o l l o w i n g four compounds: (1) racemic i s o b o r n y l a c e t a t e (±)-21, (2) ( - ) - i s o b o r n y l a c e t a t e e n t - 2 1 ( 3 ) s y n t h e t i c (+)-4-methyllsobornyl a c e t a t e 42. and (4) (-)-4-methylcamphor 42 d e r i v e d from 12a. F i r s t , (±)- i s o b o r n y l a c e t a t e (±)-21 and ( - ) - i s o b o r n y l a c e t a t e ent-21 were used i n a model study to t e s t the e f f e c t i v e n e s s and r e l i a b i l i t y of [ E u ( h f c ) 3 l . The procedure i s d e s c r i b e d In the experimental s e c t i o n on page 76. Table 2 summarizes the r e s u l t s and the 400 MHz *H NMR s p e c t r a recorded are i n c l u d e d below i n f i g u r e s 1 and 2. H ent-21 21 24 Table 2: A summary of the results of the [Eu(h£c)3l study using (t)-isobor-nyl acetate (±)-2i (Sample A) and (-)-isobornyl acetate ent-21 (Sample B) Sample Equiv. of [Eu(h£c)3] Markers (multiplicities & chemical sh i f t s ) * MS (HZ) C-9Me C-8Me C-lOMe C-9Me C-8Me C-lOMe 0 C-9 & C-8: s, 0.85 s, 0.98 0 0 0 A 0.10 s, 0.97 1.21 1.22 1.26 1.27 0 4 4 0.25 s, 1.11 1.59 1.61 1.64 1.67 0 8 10 0.50 1.32 1.33 2.08 2.12 2.30 2.35 2 16 20 0 C-9 & C-8: s, 0.85 s, . 0.98 0 0 0 0.10 s, 0.96 s, 1.19 s, 1.25 0 0 0 B 0.25 s, 1.11 s, 1.60 s, 1.63 0 0 0 0.50 s, 1.32 s, 2.10 s, 2.37 0 0 0 * s = singlet, 8 in ppm The spectra of ( ± ) - I s o b o r n y l acetate ( ± ) - 2 J L from this model study showed that: (1) as the concentration of [Eu(hfc) 3 l increased, the resonances of the substrate shifted (in most cases, downfield) and separated into two signals due to the presence of enantlomers in the racemic sample. The line width increased with increased chemical shift and with increasing concentration of the shift reagent; (2) part icularly useful markers are the C-8 and C-10 methyls where 0.5 mole equivalence of the shift reagent allowed accurate determination of enantiomeric purity from signal integrations which was found to be 1:1; (3) the values of AA8 (enantiomeric shift differences) increased as the concentration of the shift reagent increased. The useful markers exhibited AA8 up to 20 Hz with 0.5 mole equivalence of the shift reagent. When a sample of (-)-isobornyl acetate ent-21 was studied under the same experimental conditions, the resonances of the substrate shifted (in most cases, downfield) but did not separate. However, i t was interesting to note that in the presence of [Eu(hfc)3l, the singlet of C-8 and C-9 methyls separated, suggesting that the C-8 methyl was Influenced differently by the presence of the lanthanide shift reagent than the C-9 methyl. As mentioned in the introduction, lanthanide p-diketone shift reagents function by acting as Lewis acids, forming a complex with the substance under study, which acts as a nucleophile. Induced shifts are attributed to a pseudo-contact, or dipolar, interaction between the shift reagent and the nucleophile and the "shifted spectrum" represents the averaged environments of the nuclei in the complexed and uncomplexed nucleophiles. Although the nature of the Interaction between l E u t h f c ^ l and Isobornyl acetate was not investigated in the present work, i t appeared to be reasonable to speculate that the acetyl functionality in isobornyl acetate interacted 26 Figure 1: Results of the [Eu(hfc) 3 l study using ( ± ) - l s o b o r n y l acetate (±)-2JL . a. The 400 MHz -""H NMR spectrum of a 0.1M sample concentration of ( ± ) - i s o b o r n y l acetate b. The spectrum of the same sample after the addition of 0.10 mole equivalence of [Eu(hfc) 3 l c. The spectrum recorded after the amount of [Eu(hfc) 3 l was increased to 0.25 mole equivalence d. The spectrum recorded after the amount of [Eu(hfc) 3 l was increased to 0.50 mole equivalence Figure 2: Results of the [Euthfc^] study using (-)-isobornyl acetate ent-21 a. The 400 MHz ^ H NMR spectrum of a 0.1M sample concentration of (-)-isobornyl acetate b. The spectrum of the same sample after the addition of 0.10 mole equivalence of . [Eu(hfc)3] c. The spectrum recorded after the amount of [Eu(hfc)3l was increased to 0.25 mole equivalence d. The spectrum recorded after the amount of [Eu(hfc)3l was increased to 0.50 mole equivalence with the shift reagent in such a way that the C-8 and C-10 methyls were brought close to the shift reagent. At this point, from the results of this model study, i t can be concluded that [Euthfc^] was useful in determining the enantiomeric purity of isobornyl acetate and that i t may be used to determine the enantiomeric purity of the samples of two other related compounds: (+)-4-methylisobornyl acetate 4JL and (-)-4-methylcamphor 43. The procedure used for the determination of enantiomeric purity of three different samples of (+)-4-methylisobornyl acetate 4_0_ is described on page 76 in the experimental. Table 3 summarizes the results and the 400 MHz *H NMR spectra recorded are included In figures 3, 4, and 5. The spectra from the enantiomeric purity study of the three different samples of ( + )-4-methylisobornyl acetate J_0_ showed that: (1) as the concentration of tEuthfc)^] increased, the resonances of the substrate shifted (in most cases, downfield) and separated into two signals due to the presence of enantiomers in the sample. The line width increased with increased chemical shift and with increasing concentration of the shift reagent; (2) part icularly useful markers are the C-8, C-10 and C-4 methyls where 0.5 mole equivalence of tEu(hfc)3l allowed accurate determination of the enantiomeric purity; (3) the values of AA8 Increased as the concentration of the shift reagent Increased. The useful markers exhibited AA8 up to 18 Hz with 0.5 mole equivalence of the shift reagent. Table 3: A summary of the results of the [Euthfc^l study using different samples of (+)-4-methylisobornyl acetate £fia s Equiv. of (Eu(hfc)3) (multipl Markers Icities & chemical s h i f t s )b AA8 (HZ) C-9Me C-8Me C-lOMe C-4Me C-9Me C-8Me C-lOMe C-4Me A 0 s, 0.70 s, 0.85 s, 0.88 s, 0.91 0 0 0 0 0.10 s, 0.79 s, 0.95 s, 1.04 s, 1.14 0 0 0 0 0.25 s, 0.92 1.02 1.03 1.36 1.37 1.54 1.56 0 4 6 8 0.50 s, 1.14 1.16 1.17 1.91 1.94 c2.24 2.28 0 4 12 18 B 0 s, 0.70 s, 0.85 s, 0.88 s, 0.91 0 0 0 0 0.50 sf 1.12 1.12 1.14 1.82 1.85 d2.12 2.16 0 8 12 17 C 0 s, 0.70 s, 0.85 s, 0.88 s, 0.91 0 0 0 0 0.50 s, 1.12 1.12 1.14 1.82 1.85 e2.12 2.16 0 8 12 17 a. Sample A: IQa. produced under the conditions of 25 C, 15 minutes; Sample B: 40b produced under the conditions of 25°C, 10 minutes; Sample C: 40c produced under the conditions of 0°C, 30 minutes. b. s = singlet, 5 in ppm c. integration ratio 4.5:1 d. integration ratio 3.7:1 e. integration ratio 5.0:1 U) 30 •(b) (c) -Cx4) (x4) Cx4) 4 (x2) (x4) "(X2) (x2) C 4.5:1 0 ppm Figure 3: Results of the lEu(hfc)3l study using (+)-4-methyllsobornyl acetate 40a produced under the conditions of 25°C, 15 minutes. a. The 400 MHz 1H NMR spectrum of a 0.1M sample concentration of (+)-4-methylisobornyl acetate b. The spectrum of the same sample after the addition of 0.10 mole equivalence of CEu(hfc)3] c. The spectrum recorded after the amount of (Eu(hfc)3l was increased to 0.25 mole equivalence d. The spectrum recorded after the amount of [Eu(hfc)3] was increased to 0.50 mole equivalence 31 (a) 5 4 3 2 1 0 ppm 5 4* ~3 2 1 : u~ppn Figure 4: Results of the [Eu(hfc)3l study using (+)-4-methylisobornyl acetate 40b produced under the conditions of 25°C / 10 minutes. a. The 400 MHz *H NMR spectrum of 0.1M sample concentration of (+)-4-methylisobornyl acetate b. The spectrum of the same sample after the addition of 0.5 mole equivalence of tEu(hfc) 3] 32 (a) (x4) 0 ppm 0 ppm Figure 5: Results of the [Eu(hfc)3l study using (+)-4-methylisobornyl acetate 40c produced under the conditions of 0°C, 30 minutes. a. The 400 MHz 1 H NMR spectrum of 0.1M sample concentration of (+)-4-methylisobornyl acetate b. The spectrum of the same sample after the addition of 0.5 mole equivalence of [Eu(hfc)3] The above r e s u l t I n d i c a t e d t h a t ( E u ( h £ c ) 3 l was e f f e c t i v e i n the d e t e r m i n a t i o n of the enantiomeric p u r i t y of ( + ) - 4 - m ethylisobornyl a c e t a t e 4JL. The enantiomeric p u r i t y of 40 s y n t h e s i z e d under d i f f e r e n t r e a c t i o n c o n d i t i o n s i s summarized i n t a b l e 4. One can see t h a t among these three s e t s of r e a c t i o n c o n d i t i o n s , the c o n d i t i o n s of 30 minutes at 0 ° c produced a c e t a t e 40c with the best o p t i c a l p u r i t y . Table 4: The enantiomeric purity of ,(+)-4-methylisobornyl acetate 4JL synthe-sized under different conditions3 Compound Experimental Conditions Yield % lain oi the Acetate Product Optical Purityb Time(min.) Temperature 40a 15 25°C 60 +35.79 (c.2.28, 95% ethanol) 64% 40b 10 25°C 62 +32.12 (c.3.12, 95% ethanol) 57% 40c 30 0 °C 73 +39.23 (c.2.20, 95% ethanol) 67% a. Reagents: acetic acid / sulphuric acid (20:1) b. from [Eu(hfc)3l study: based on the integration ratio obtained when 0.5 mole equivalence of [Eufhfc^l was used (cf. table 3). A g a i n , although the nature of the i n t e r a c t i o n between (Eu(hfc)3) and ( + )-4-methylisobornyl a c e t a t e 4J3. was not i n v e s t i g a t e d i n the present work, i t appeared to be reasonable to s p e c u l a t e t h a t the a c e t y l f u n c t i o n a l i t y In t h i s s u b s t r a t e i n t e r a c t e d with the s h i f t reagent i n such a way t h a t the C-8, C-10 and C-4 methyls were brought c l o s e to the s h i f t r eagent. Among these three "markers", C-4 methyl appeared to be i n f l u e n c e d most e x t e n s i v e l y and t h e r e f o r e most u s e f u l In the d e t e r m i n a t i o n of the enantiomeric p u r i t y of (+)-4-methylisobornyl a c e t a t e ASL. The use of tEu(hfc) 3] was extended to determine the enantiomeric purity of (-)-4-methylcamphor 4_3_. A specific sample of (-)-4-methylcamphor 4_3_ was obtained by reducing a (+)-4-methyllsobornyl acetate 40a sample (cf. table 4), then oxidizing alcohol A2. to (-)-4-methylcamphor 4_3_. The procedure used for the determination of the enantiomeric purity of this sample is described on page 77 In the experimental. Table 5 summarizes the results and the 400 MHz ! H NMR spectra recorded are included In figure 6. Table 5: A summary of the results of the [Eu(hfc)3l study using a specific sample of (-)-4-methylcamphor H a Equiv. of tEu(h£c)3] (multipl Markers Lcitles & chemical shifts)b AA5 (Hz) C-9 Me C-8Me C-lOMe C-4Me C-9Me C-8Me C-lOMe C-4Me 0 s, 0.72 s, 0.84 s, 0.93 s, 1.05 0 0 0 0 0.10 s, 1.04 1.06 1.08 s, 1.18 s, 1.46 0 7 0 0 0.30 s, 1.41 1.42 1.43 1.66 1.71 s, 2.39 0 2 18 0 0.60 s, 1.89 1.73 1.75 c2.45 2.53 s, 3.60 0 7 32 0 a. obtained by reducing a (+)-4-methylisobornyl acetate 40a (cf. table 4), then oxidizing the alcohol 4JL-b. s = singlet, g *n PPm c. integration ratio 4.3:1 The s p e c t r a i n f i g u r e 6 showed t h a t : (1) as the c o n c e n t r a t i o n of [ E u C h f c ^ ] i n c r e a s e d , the resonances of the s u b s t r a t e s h i f t e d ( i n most c a s e s , downfield) and separated i n t o two s i g n a l s due to the presence of enantiomers i n the sample. The l i n e width i n c r e a s e d with i n c r e a s e d chemical s h i f t and with I n c r e a s i n g c o n c e n t r a t i o n of the s h i f t reagent; (2) p a r t i c u l a r l y u s e f u l markers are the C-8 and C-10 methyls where 0.6 mole equivalence of the s h i f t reagent allowed accurate d e t e r m i n a t i o n of the enantiomeric p u r i t y which i s ~62% for t h i s sample; (3) the v a l u e s of AA8 i n c r e a s e d as the c o n c e n t r a t i o n of the s h i f t reagent i n c r e a s e d . The u s e f u l markers e x h i b i t e d AA8 up to 32 Hz with 0.6 mole equ i v a l e n c e of [ E u ( h f c ) 3 l . The major reason f o r the e x t e n s i o n of the [ E u ( h f c ) 3 ] study from ( + )-4-methylisobornyl a c e t a t e 40_ to (-)-4-methylcamphor 43 was to c o n f i r m the r e l i a b i l i t y of t h i s s h i f t reagent i n determining the enantiomeric p u r i t y of two r e l a t e d compounds where one i s the p r e c u r s o r of the other i n a chemical s y n t h e s i s . As mentioned e a r l i e r , s i n c e r e a c t i o n s i i i and i v i n scheme 12 (p. 20) occur with r e t e n t i o n of c o n f i g u r a t i o n and the enantiomeric p u r i t y of (-)-4-methylcamphor 13_ depends on that of (+)-4-methylisobornyl a c e t a t e 40, the i n d i v i d u a l [ E u ( h f c ) 3 l s t u d i e s of these two compounds were expected to provide comparable values of t h e i r o p t i c a l p u r i t y . In f a c t , i t was found t h a t the o p t i c a l p u r i t y of the p r e c u r s o r (+)-4-methylisobornyl a c e t a t e 40a ( c f . t a b l e 4) was ~64% which 36 Ca) (b) C O Cd) 5 4 3 2 1 0 ppm Figure 6: Results of the [Euthfc^l study using a specific sample of (-)-4-methylcamphor 4_3_ a. The 400 MHz 3-H NMR spectrum of a 0.1M sample concentration of (-)-4-methylcamphor b. The spectrum of the same sample after the addition of 0.10 mole equivalence of [Eudifc)^] c. The spectrum recorded after the amount of [Eu(hfc)3l was Increased to 0.30 mole equivalence d. The spectrum recorded after the amount of [Eufhfcjg] was increased to 0.60 mole equivalence was comparable to t h a t of (-)-4-methylcamphor £2. which was ~62%. In a d d i t i o n , i t was found t h a t although the C-4 methyl was a good "marker" i n a c e t a t e 4JL, i t was not u s e f u l i n (-)-4-methylcamphor 13_. T h i s suggested th a t the two compounds i n t e r a c t d i f f e r e n t l y , from a s p a t i a l p e r s p e c t i v e , with [ E u ( h £ c )3I . In c o n c l u s i o n , the o p t i c a l p u r i t y of our s y n t h e t i c ( + )-4-methylisobornyl a c e t a t e 4M { l a l ^1' 5+35 . 79 ( c . 2 . 28, EtOH)} was e s t a b l i s h e d to be ~64% u s i n g t h i s technique of enantiomeric p u r i t y d e t e r m i n a t i o n . In a s i m i l a r f a s h i o n , the o p t i c a l p u r i t y of (-)-4-methylcamphor H { [ c c l ^5 -16.70 (c.1.5, EtOH)} d e r i v e d from 40a was determined to be ~62%. A comparison of the s p e c i f i c r o t a t i o n s quoted i n the l i t e r a t u r e ( c f . Table 1) and those recorded i n our l a b o r a t o r y leads to the c o n c l u s i o n t h a t a l l of the c u r r e n t methods of p r e p a r i n g 4-methylisobornyl a c e t a t e 40 provide product which i s not e n a n t i o m e r i c a l l y pure. From the mechanism proposed f o r the c o n v e r s i o n of (-)-2-methylenebornane 4JL to ( + )-4-methylIsobornyl a c e t a t e 4JL (Scheme 13, page 21), i t i s obvious t h a t o p t i c a l l y pure 4 - m e t h y l i s o b o r n y l a c e t a t e 4JL can only be obtained i f the 2,6-hydride s h i f t which converts A. to E. i s i n h i b i t e d . As a r e s u l t , two approaches to the s y n t h e s i s of e n a n t i o m e r i c a l l y pure 4-methylisobornyl a c e t a t e 4JL were attempted and w i l l be d e s c r i b e d l a t e r (page 43). 3b. Determination of Enantiomeric Purity of 4-methylIsoborneol 42 Using Anderson-Shapiro Reagent 48: The theory of the use of the Anderson-Shapiro reagent, 2-chloro-4 (R), 5 (R)-dimethyl-2-oxo-l, 3,2-dloxapholane 4_8_/ in the study of enantiomeric purity by NMR Is br ie f ly covered in the Introduction and therefore, the discussion here w i l l focus on the results . This ch ira l derivatizing agent 4JL was used to determine the enantiomeric purity of the samples of the following three compounds: (1) racemic isoborneol (±)-5JL, (2) (-)-isoborneol 5_5_ and (3) ( + )-4-methylisoborneol 42. 4S 51 F i r s t , ( ± ) - i s o b o r n e o l (±)-5_5_ and (-)-isoborneol 55 were used in a model study to test the effectiveness and r e l i a b i l i t y of the Anderson-Shapiro reagent. The procedure Is described in the experimental on page 71. Table 6 summarizes the results and the 121.4 MHz 3 1 P NMR spectra recorded are shown in figure 39 Table 6: Results of the study of enantiomeric purity of the three alcohols ( ( ± ) -55, 55 and 42.} using the Anderson-Shapiro reagent. Spectrum Sample Markers* ( 5 in ppm) A8(Hz) I . R . b Fig.7(a) ( ± ) - i s o b o r n e o l 8 13.341, 13.404 7.89 1:1 Fig.7(b) (-)-isoborneol 8 13.478 F ig . 8 (+)-4-methyl-isoborneol c 8 13.628, 13.667 4.85 . 2 . 1 : l d a. The J J-P chemical shifts of the derivatlzed alcohols. The Anderson-Shapiro reagent was observed at 8 17.480 and 17.375 in spectra F ig . 7(a) and F ig . 7(b) respectively. b. I.R. = Integration Ratio c. This particular sample of (+)-4-methylisoborneol 4 2 was obtained by reducing a specific sample of (+)-4-methylisobornyl acetate 40a (cf. table 4). d. The signal separation was too small to provide more than an approximate estimation of relative signal areas. As mentioned ear l ier , the Anderson-Shapiro reagent reacted with the enantiomers in the racemic alcohol sample, that i s , ( ± ) - i s o b o r n e o l (±)-5_5 to yield diastereomers 5_6_ and 5_7 which exhibited: (1) a significant degree of 3 1 P NMR nonequivalence ( A S 7.89 Hz); and (2) an Integration ratio of 1:1 which was the same as the ratio of enantiomers in the racemic sample. With the enantiomer i c a l l y pure (-)-isoborneol 5_5_, a single diastereomer was observed ( 8 13.478 ppm) as expected after derivatization with the reagent. In both spectra, the excess reagent was observed at ~ g 17 ppm which agreed with the literature.142] 40 fa) 1 : 1 , 1 i (b) Figure 7: Results of the model study using ( ± ) - i s o b o r n e o l (±)-5J3_ and (-)-Isoborneol 5JL a. The 121.4 MHz 3 1 P NMR spectrum of the derivatized ( ± ) - i s o b o r n e o l . b. The 121.4 MHz 3 1 P NMR spectrum of the derivatized (-)-isoborneol. Based on the success of the above model study, the Anderson-Shapiro reagent was used to determine the enantiomeric purity of a specific sample of (+)-4-methylisoborneol 12. { [ a l p 5 +20.40 Cc. 9.0, EtOH)}. The procedure is described in the experimental on page 72. The results is shown in table 6 while the 121.4 MHz 3 1 P NMR spectrum recorded.is shown In figure 8. In this spectrum, the two signals observed at 8 13.628 and 8 13.667 were believed to come from the diastereomers 5_8_ 31 and 5_9_ produced. As shown in table 6, the P NMR nonequivalence ( 4.85 Hz) between the two diastereomeric phosphate esters was too small to provide a rel iable estimate of optical purity. Me Me Me Me 56 SZ 42 2.1:1 14. 0 i 1 1 r-13 b i 1 i r-13.0 PPM / -A i i I i i i i • i 30 10 i x «n l l | i l i i | i- i i u | i i i i | i i l vi l vi L i. i i i t | i » i i I 20 -10 -30 PPU Figure 8: The 121.4 MHz 3 1 P NMR spectrum of the derlvatized sample of ( + )-4-methylisoborneol 42 (obtained by reducing 40af cf. table 4) . C_, Alternative Synthetic Routes £0. Enantiomer Ically Pure (-1-4-Methylcamphor 43: 1. Route A: The f i r s t alternative approach to the synthesis of enantiomerically pure 4-methylisobornyl acetate JJL was an extension of the i n i t i a l work described ear l i er , that i s , (-)-2-methylenebornane 4JL was reacted with acetic acid / sulphuric acid (20:1) and i t was found that the experimental conditions of 30 minutes at 0°C appeared to give the most desirable results . At a lower temperature, -10°C and for 85 minutes, many side reactions occurred, producing 4-methylisobornyl acetate 4J). in less than 15% y ie ld . Scheme 14 shows the improved synthesis of (-)-4-methyl-camphor 4_3_ from ( + )-camphor 1.. As shown in scheme 14., a modification of the method used by Oshima et al.. [48] (CF^B^/ Zn, T i C l 4 ) was found superior to a modification of the method used by Gream e_t_ a l . [ 49 ] (CH 3PPh 3Br, BuLi, THF). Methylenat ion with a system consisting of C^Br 2~Zn-TiCl 4 was f i r s t introduced by Oshima ai. al.. (1978) [50] and has since shown to be a useful alternative (characterized by high yields and mild conditions) for the Wittlg carbonyl methylenatlon.[48,50] However, l i t t l e is known about the chemistry of this method of methylenatlon. Although the synthesis of (-)-4-methylcamphor 13. from (+)-camphor 1. was achieved with good yields, the attempt to maximize the optical purity of acetate 4J). by varying the reaction time and temperature appeared to be unsatisfactory for the system using acetic acid / sulphuric acid (20:1). Therefore, a different approach was attempted and is described below. I 41 40 iv 41 42 Reagents: i , CH3PPh3Br, BuLl, THF (87%) 11, CH2Br2, Zn, TiCl4 (99%) 111, HOAc / H 2 S O 4 , 20:1; 30 min., 0°C (73%) iv,- L1A1H4, THF (99%) v, PCC, CH 2Cl2 (99%) Scheme 14 2. Route B: The second approach was based on the assumption that the formation of (-)-4-methylIsobornyl acetate ent-40 (shown in scheme 15) was the result of a 2,6-hydride shift (cf. Scheme 15). Thus, either inhibiting this crucial 2,6-hydride shift to suppress the formation of ent-40 or enhancing the same step to favor the formation of ent-40 should produce enantiomerIcally pure product. We considered the poss ib i l i ty that the presence of an electronegative substituent replacing a hydrogen on C(5) in 4 1 (scheme 15) would inhibit the 2,6-hydrlde shift which leads to ent-40. Therefore, e.xo-5-br omo-2-methylenebornane 58 was synthesized in 69% overall yield by the reaction sequence outlined in scheme 16. This involved treatment of commercially available (+)-e_Mo_-3-bromocamphor jja. with bromine and acetic acid to provide (+ )-3,3-dibromocamphor 2JL which was subsequently reacted with diethylzinc in benzene(28] to yield per icyclocamphanone 24.. It has been suggested [ 28 ] that this reaction involves intermediate formation of ketocarbene 6_1 followed by Insertion into the C(5)-H bond (Scheme 17). Ejto.-5-bromocamphor 22. was obtained subsequently by treating pericyclocamphanone 2 4 . with hydrobromlc acid (48%) and acetic anhydride for 3 hours at 65°C. Exo-5-bromocamphor 27 has been prepared previously[24] in 82% yield by treating pericyclocamphanone 2 4 . with dry hydrogen bromide and acetic acid for 24 hours at room temperature. Scheme 18 shows a possible mechanism for this transformation of 24L into 21-46 Scheme 15 47 5J 2Z Reagents: i , HOAc, B r 2 , 55°C, 4 hours (92%) i i , E t 2 Zn, benzene, refluxed, 24 hours (94%) i i i , 48% HBr, A c20, 650c, 3 hours (93%) iv , TiCl4, Zn, CH 2 Br 2 , 25°C, 1 day (86%) Scheme 16 Scheme 17 48 24 2Z Scheme 18 The synthesis of e_x_Q.-5-br omo-2-methylenebornane 5_8_ from ejco_-5-bromocamphor 22. was attempted by using a modification of the method used by Gream e_t a_L.[49] (CH^PPh^Br, BuLi, THF) for the conversion of (+)-camphor 1 to (-)-2-methylenebornane 41. However, i t was found that under these conditions, §_xo_-5-bromocamphor 22. reverted to per icyclocamphanone 2_4 in 99% yield (Scheme 19)! An alternative carbonyl methylenation reported by Oshima e i a_L. [48] (CH2Br2, Zn, T i C l 4 ) is known to work well for the methylenation of easi ly enolizable ketones[48,50] and the use of this methodology led to the successful conversion of exo-5-bromocamphor 27 to ej£o_-5-bromo-2-methylenebornane 5_8_ in 86% yield (Scheme 16). Scheme 19 Treatment of exo-5-bromo-2-methylenebornane 58 with acetic acid / sulphuric acid (20:1) at 0°C for 35 minutes and then at room temperature for 3 hours provided starting material and heating the reaction mixture to ~80°C produced extensive decomposition. In a separate run, the reaction mixture was st irred at room temperature for 21 days. GLC and TLC anaylses showed that the starting material 5_8_ slowly underwent decomposition and that no major reaction products were observed. It was speculated that the failure of exo-5-bromo-2-methylenebornane 58. to undergo acid-catalyzed rearrangement was due to the fact that the electronegative bromine substituent on C(5) inhibited the second Wagner-Meerwein rearrangement in scheme 20. Since the acid-catalyzed rearrangement of 58. was found to be unsuccessful, this approach to the synthesis of enantiomerically pure 4-methylcamphor 4J. was terminated. Scheme 20 3. Future study: Since i t is assumed that the formation of (-)-4-methyliso-bornyl acetate ent-40 (shown in scheme 15) was the result of a 2,6-hydride shift (cf. Scheme 15), future work wi l l be concerned with the synthesis of a C(5)-disubstituted 2-methylenebornane derivative that lacks a C(5) proton. An immediate synthetic target w i l l be the thloketal 22. of 5-keto-2-methylenebornane 28_ i f this could possibly be derived from (+)-endo-3-bromocamphor 5a by the sequence outlined in scheme 21. It is hoped that treatment of thioketal 22. with acetic acid / sulphuric acid (20:1) wi l l provide compound £0. and then subsequent treatment of compound JLP_ with Raney nickel w i l l provide enantiomerically pure (+)-4-methylisobornyl acetate &SL. scheme 21 EL. U£L& £Lf 4 . - M e t h y I c a m p h o r 4J In a New Synthetic Approach to Trlterpenolds: While efforts were spent in attempting to synthesize enantiomer i c a l l y pure (+)-4-methylisobornyl acetate 4j0_ (and hence, enantiomer i ca l l y pure (-)-4-methylcamphor 4_3_), the potential of (-)-4-methylcamphor 4_3_ and its enantiomer ent-43 as intermediates In the synthesis of trlterpenolds belonging to the lanostane 4JL and euphane 5J}. structural sub-groups was investigated. Previous investigations in our laboratory have shown that (+)-9,10-dibromocamphor U L [ 1 5 ] or i ts enantiomer ent-10 can be converted to intermediates 64. and ent-64 in steroid synthes i s . [21,431 We realized that i f the same kind of chemical transformations could be accomplished with the enantiomers of 4-methylcamphor J_2 and ent-43 , then a simple route (Scheme 22) to potentially useful intermediates 6J5_ and ent-65 in triterpenoid synthesis would be available. The retrosynthetic analysis shown in scheme 22 is based on two assumptions, v i z : (1) 4-methylcamphor can be prepared readily in either enantiomeric form; and (2) 4-methylcamphor can be converted to 9,10-dibromo-4-methyl-camphor 6_6_ / ent-66 by the same type of rearrangement / bromination sequence as that used in the conversion of camphor to 9,10-dibromocamphor 10_ /ent 1 0 . [151 Our present Investigations were designed to test the va l id i ty of these assumptions and the results are described below. 54 1R=H 10R=H M R = H ent-43 R=Me ent-66 R=Me ent-65 R=Me R ent-1 R=H 43_R=Me Scheme 22 When (-)-4-methylcamphor ±3_ was treated with bromine and acetic acid endo-3-bromo-4-methylcamphor 67 was produced in 99% y ie ld . Subsequent treatment of endo-3-bromo-4-methylcamphor 67 with 2.3 equivalents of bromine In chlorosulphonic acid did not provide the expected endo-3,9-dlbromo-4-methylcamphor 69. Spectroscopic evidence (400 MHz *H NMR, IR and mass spectrometry) led us to conclude that the product was e_njlo_-3/9,10-tribromo-4-methylcamphor £JL. The formation of £DJlo_-3 /9 / 10-tribromo-4-methylcamphor £JL from endo-3-bromo-4-methylcamphor JL7_ was completely unexpected although i t was possible to rationalize ent-10R=H ent-64 R=H £6 R=Me £5_R=Me i t s f ormation by the mechanism shown i n scheme 23. Thus we s p e c u l a t e d t h a t a f t e r a 2 r 3-exo-methyl s h i f t of i n t e r m e d i a t e X. (Scheme 23), a second bromination occurred r e a d i l y and t h i s was f o l l o w e d by a Wagner-Meerwein rearrangement to produce the tribromo compound 68. R e g i o s e l e c t i v e debromination of proposed 6_8_ with z i n c / a c e t i c a c i d y i e l d e d a dibromo compound with *H NMR and mass s p e c t r a c o n s i s t e n t with our e x p e c t a t i o n t h a t t h i s product was 9,10-dibromo-4-methylcamphor 6_6_. A c h a r a c t e r i s t i c f e a t u r e of 10-bromocamphor and d e r i v a t i v e s i s the ease with which they undergo r i n g cleavage of the C ( l ) - C ( 2 ) bond when t r e a t e d with base. The f a i l u r e of s o - c a l l e d 9,10-dibromo-4-methylcamphor 66 to undergo C ( l ) - C ( 2 ) bond cleavage when t r e a t e d with sodium methoxide l e d to the c o n c l u s i o n t h a t t h i s compound d i d not c o n t a i n a bromo s u b s t i t u e n t at C( 1 0 ) . The only other a l t e r n a t i v e s t r u c t u r e * c o n s i s t e n t with the NMR evidence was the tribromo compound 20 . (Scheme 24) and t h i s was l a t e r confirmed by X-ray c r y s t a l l o g r a p h i c a n a l y s i s * * . Thus, the tribromo compound was shown to be endo-3,9-dlbromo-4 - (bromomethvl) camphor 2 0 . and the d e r i v e d dibromo compound was t h e r e f o r e 9-bromo-4-(bromomethyl)camphor 21 . . A mechanism which e x p l a i n s the formation of tribromo compound 2P_ i s shown i n scheme 24. Thus, in t e r m e d i a t e X.. undergoes a Wagner-Meerwein rearrangement * I am g r a t e f u l to Mr. Andrew Clase f o r t h i s s u g g e s t i o n . ** I am g r a t e f u l to P r o f e s s o r J . T r o t t e r and Dr. S. R e t t i g f o r t h i s a n a l y s i s . 56 Scheme 23 (Scheme 24) instead of undergoing a second 2,3-exo-methyl shift (cf. Scheme 23). And this is followed by bromination, Wagner-Meerwein rearrangement, 2 f3-exo-methyl shi f t , and Wagner-Meerweln rearrangement to give product 70. 57 Scheme 24 In an attempt to promote C-10 bromlnatlon, £ijjio_-3,9-dlbromo-4-(bromomethyl)camphor 7_0_ was treated with bromine and chlorosulphonlc acid (Scheme 25) for 5 days at room temperature, followed by heating at 80°C for 2.5 days, but 3,3,9-tribromo-4-(bromomethyl)camphor 22. was produced. When 20. was treated with bromine and chlorosulphonlc acid at room temperature for 12 days, approximately half of the starting material was converted to endo-3 f9 f10-trlbromo-4-(bromomethyl)camphor 74. Since attempts made to isolate and purify JA. by column chromatography and recrystal ization were unsatisfactory, the crude product mixture was treated with zinc and acetic acid to give 9,10-dlbromo-4-(bromomethyl)camphor 7_5_ (96% f rom 7_4J . treatment of 7_5_ with sodium methoxlde in methanol (Scheme 26), resulted in C(l)-C(2) bond cleavage as expected, to give dibromoester 76. It is hoped that this compound can be converted to b icycl lc enone 65., a potentially useful intermediate in triterpenoid synthesis. Reagents: i , C I S O 3 H , B r 2 , 2.5 days at 80°C (62%) i i , C I S O 3 H , B r 2 , 25°C, 19 days i i i , C I S O 3 H , B r 2 , 12 days at 25 C (50%) iv , Zn / HOAc, 0°C, 2 hours (96%) Scheme 25 59 Br Br O NaOMe Br MeOH (86%) - O Br 21 Br C02Me Scheme 26 Thus, the r e s e a r c h d e s c r i b e d above has shown t h a t (-)-4-methylcamphor 4.2. can be converted to an intermediate 7_6_ which co u l d be of value i n the s y n t h e s i s of t r i t e r p e n o i d s belonging to the lanostane 19_ s t r u c t u r a l sub-group. O b v i o u s l y enantiomer ent-43 w i l l undergo the same type of chemical t r a n s f o r m a t i o n to give ent-76 as a p o t e n t i a l l y u s e f u l intermediate In the s y n t h e s i s of t r i t e r p e n o i d s belonging to the euphane 5_D_ s t r u c t u r a l sub-group. 60 EXPERIMENTAL gene ral M e l t i n g p o i n t s (mp) were determined on a K o f l e r micro h e a t i n g stage and are u n c o r r e c t e d . I n f r a r e d (IR) s p e c t r a were recorded on a Perkin-Elmer model 710B spectrophotometer and were c a l i b r a t e d u s i n g the 1601 cm~l band of p o l y s t y r e n e . A b s o r p t i o n p o s i t i o n s ( v max) are given i n cm-*. O p t i c a l r o t a t i o n s (((X)D) were measured on a Perkin-Elmer 141 p o l a r i m e t e r at ambient temperature. The proton nuclear magnetic resonance (*H NMR) were taken i n d e u t e r o c h l o r o f o r m and recorded at 400 MHz on a Bruker WH-400 spectrometer. S i g n a l p o s i t i o n s are gi v e n i n p a r t s per m i l l i o n (ppm) downfield from t e t r a m e t h y l s i l a n e (TMS) u s i n g the 8 s c a l e . S i g n a l m u l t i p l i c i t y , c o u p l i n g constants and assignments of s e l e c t e d s i g n a l s are i n d i c a t e d i n 31 parentheses. P NMR s p e c t r a were obtained i n benzene and determined on a V a r i a n XL-300 spectrometer at 121.421 MHz with s i g n a l p o s i t i o n s given i n p a r t s per m i l l i o n d ownfield from H3PO4 (used as an e x t e r n a l r e f e r e n c e standard) with an I n t e r n a l CgDg l o c k . Low r e s o l u t i o n mass s p e c t r a were obtained u s i n g a V a r i a n MAT CH-4B spectrometer and exact masses were obtained by high r e s o l u t i o n mass spectroscopy on a Kratos MS-50 mass spectrometer. A l l compounds c h a r a c t e r i z e d by high r e s o l u t i o n mass spectrometry e x h i b i t e d one spot on a TLC ( t h i n l a y e r chromatography) p l a t e . Low r e s o l u t i o n gas l i q u i d chromatography / mass s p e c t r a (GC/MS) were obtained on a C a r l o Erba 41 60 / Krato MS 80 RFA instrument using a 0.25 mm X 15 m column with helium as the carrier gas. Gas-liquid chromatography (GLC) was performed on either a Hewlett Packard model 5830A gas chromatograph with a 6 ft X 1/8 in . column of 3% OV-17 or a Hewlett Packard model 5880A gas chromatograph using a 50 m or 12 m X 0.2 mm column of Carbowax 10 M or a 12 m X 0.2 mm column of OV-101. The carrier gas was nitrogen for the 5830A and helium for the 5880A. In a l l cases a flame ionization detector was used. X-ray crystallographic analysis was carried out by Dr. S. Rettig and microanalyses were performed by Mr. P. Borda, Microanalytical Laboratory, University of Bri t i sh Columibia. A l l reactions involving moisture sensitive reagents were performed under an atmosphere of dry argon using either oven or flame dried glassware. A l l reaction products were dried by allowing the solutions to stand over anhydrous magnesium sulphate. The solvents and reagents used were purified as follows: tetrahydrofuran (THF) was d i s t i l l e d from calcium hydride and then from lithium aluminum hydride (LAH). Diethyl ether was d i s t i l l e d from LAH and hexamethylphosphoramlde (HMPA), benzene, methylene chloride, diisopropylamine, trlethylamlne, and pyridine were d i s t i l l e d from calcium hydride. Methanol was d i s t i l l e d from dry magnesium and iodine following reflux. Petroleum ether (the hydrocarbon fraction of boil ing range ~30-60 °C) was d i s t i l l e d prior to use. Flash Chromatography was performed using Merck s i l i c a gel 60, 230-400 mesh and TLC using Merck s i l i c a gel 60 F 2 5 4 sheets. A l l chemicals were supplied by Aldrich Chemical Company unless otherwise stated. Preparation of (-)-2-methylenebornane 41 O 1 41 ( i ) Method A * Methyltriphenylphosphonium bromide (154.73 g, 0.43 mol) was vacuum pumped f o r 3 hours to remove any t r a c e of moisture before i t was d i s s o l v e d i n pure THF (400 mL). n - B u t y l l i t h i u m (0.43 mol, 270.7 mL of a 1.6 M s o l u t i o n ) was added dropwise at room temperature and the r e s u l t a n t mixture was s t i r r e d at 50°C f o r 2 hours under argon. (+)-Camphor 1 (41.21 g, 0.27 mol) i n pure THF (160 mL) was then added dropwise to the W i t t i g reagent and the r e a c t i o n mixture was r e f l u x e d f o r 15 hours at 65°C under argon. Upon completion of the r e a c t i o n , h a l f of the THF was removed by r o t a r y e v a p o r a t i o n and the r e s t was d i l u t e d with water and e x t r a c t e d with pentane (3X). The pentane e x t r a c t s were combined and washed with water (3X) and d r i e d over anhydrous magnesium s u l p h a t e . E v a p o r a t i o n of the s o l v e n t y i e l d e d a v i s c o u s y e l l o w o i l which was p u r i f i e d by column chromatography ( s i l i c a g e l 230-400 mesh, e l u t i o n with 100% petroleum e t h e r ) to provide (-)-2-methylenebornane 41 as a white c r y s t a l l i n e s o l i d (35.5 g, 87%), mp 70-71 °C ( s e a l e d tube; l i t . r e f . mp 68-70 °C); [ a )2n3 -52.88 ( c . 2.67, benzene) ( l i t . * T h i s i s a m o d i f i c a t i o n of the method used by Gream §_£ a_L.[49] I a ] 2 D 6 -48.5 (c. 2.12, benzene) H 49 ]; v max (CHC13): 1650 cm"1, 885 c m - 1 ; 5 (CDC13, 400 MHz): 0.76 (3H, s, C-8 methyl), 0.89 (3H, s, C-10 methyl), 0.92 (3H, s, C-9 methyl), 1.16-1.30 (2H, m, C-5 and C-6 endo protons), 1.64 (IH, ddd, J=12 Hz, 12 Hz and 4 Hz, C-6 exo proton), 1.73 (IH, dd, J=8 Hz and 4 Hz, C-4 proton), 1.78 (1H, m, C-5 exo proton), 1.91 (IH, bd, J=16 Hz, C-3 endo proton), 2.38 (IH, bd, J=16 Hz, C-3 exo proton), 4.63 (d) and 4.69 (d) (2H, AB quartet, J=22 Hz, exo-methylene protons); m/e (relative intensity): 150 (M + , 10.2), 135 (8.6), 69 (80.6), 55 (26.9), 41 (52.4). Exact mass calcd. for C 1 1 H l g : 150.1409; found 150.1413. Anal. calcd. for C i ; L H 1 8 : C 87.93, H 12.07; found: C 87.71, H 12.10 . ( i i ) Method B ** Titanium tetrachloride (0.48 mL, 4.37 mmol) was added dropwise to a st irred suspension of zinc dust (1.18 g, 18.0 mmol) and dibromomethane (1.04 g, 0.42 mL, 6.0 mmol) in THF (20 mL) at -40°C . The reaction mixture was allowed to warm to 5°C and kept in the refrigerator for 3 days to give a thick brown s lurry. The ice-cold s lurry was added portionwise to a st irred solution of (+)-camphor 1. (0.30 g, 2.0 mmol) in dichloromethane (2.0 mL) and the resultant mixture was st irred at room temperature for 18 hours under argon. The reaction ** This is a modification of the method used by Oshima g i al.[48] mixture was then quenched with saturated sodium bicarbonate solution, extracted with ether (3X) and the combined ether extracts washed with water (3X), and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded pure (-)-2-methylenebornane • H as a white crystal l ine sol id (0.30 g, 99%) exhibiting spectral data comparable to those above. 66 Preparation of (+)-4-methylisobornyl acetate 40c Concentrated sulphuric acid (1.31 mL, 0.016 mol) was added dropwise to (-)-2-methylenebornane 41 (12.64 g, 0.084 mol) in glacial acetic acid (54.4 mL). The reaction mixture was st irred at 0°C for 30 minutes, quenched in water and extracted with ether (3X). The ether extracts were combined, washed with saturated soduim bicarbonate solution (3X), water (2X), and dried over anhydrous magnesium sulphate. Evaporation yielded a l ight yellow o i l (12.58 g) which was purified by column chromatography ( s i l i ca gel 230-400 mesh). Elution with petroleum ether / ether 98:2 provided pure (+)-4-methylisobornyl acetate 40c as a clear colorless o i l (9.54 g, 73%), ( a ) 1 9 • 5 +39.23 (c. 2.20, 95% ethanol) ( l i t . [ a ] D +35.84)[47g,1]; V m a x (film): 1740 cm"1, 1250 c m - 1 , 1040 cm"1; 8 (CDC13, 400 MHz): 0.69 (3H, s, C-9 methyl), 0.83 (3H, s, C-8 methyl), 0.86 (3H, s, C-10 methyl), 0.90 (3H, s, C-4 methyl), 1.10-1.19 (2H, m, C-5 and C-6 endo protons), 1.36-1.54 (3H, m, C-6 exo, C-3 endo, and C-5 exo protons), 1.82 (IH, dd, J=14 Hz and"8 Hz, C-3 exo proton), 2.01 (3H, s, acetyl) , 4.65 (1H, dd, J=9 Hz and 3.5 Hz, C-2 proton); mZfi. (relative intensity):. 210 (M + , 2.0), 150 (50.9), 135 (48.3), 109 (82.3). 43 (100.0). EjiajLt mass, calcd. for Ci3H22°2 : 210.1620; found 210.1622. 67 Anal. c a l c d . for C1 3H22° 2: c 74.24, H 10.54; found: C 74.82, H 10.70 . 68 Preparation of (+ )-4-methylisoborneol 12 40c OAc OH Lithium aluminum hydride (3.1 g, 0.082 mol) was added to a solution of dry ( + )-4-methylisobornyl acetate lfic_(9.54 g, 0.045 mol) In pure THF (160 mL) and the reaction mixture was st irred at 0°C for 4 hours. The reaction mixture was then quenched in water, extracted with ether (3X), and the ether extracts washed with 1M HCl solution (3X), brine (2X), and water (2X), and dried over anhydrous magnesium sulphate. Evaporation of the ether yielded (+)-4-methylisoborneol 1 2 as white needles (7.56 g, 99%), mp 193-194 °C (sealed tube; l i t . ref. mp 195-196.5 °C) ; [ C U 3 0 ' 5 +19.47 (c.10.0, 95% ethanol) { l i t . [a]D+25.2 (c. 10.0, EtOH)}[47c,f]; v max (CHC13): 3600 c m - 1 , 1210 cm"1; 8 (CDC13, 400 MHz): 0.67 (3H, s, C-9 methyl), 0.87 (3H, s, C-8 methyl), 0.90 (3H, s, C-10 methyl), 0.93 (3H, s, C-4 methyl), 0.94-1.11 (2H, m, C-5 and C-6 endo protons), 1.34-1.46 (2H, m, C-6 exo and C-3 endo protons), 1.51 (IH, ddd, J=8 Hz, 8 Hz and 4 Hz, C-5 exo proton), 1.74 (IH, dd J=14 Hz and 8 Hz, C-3 exo proton), 3.52 (IH, dd, J=8 Hz and 4 Hz, C-2 proton); m/e (relative intensity): 168 (M + , 2.1), 150 (14.4), 109 (100.0), 41 (70.6). Exact mass calcd. for C u ^ g O : 168.1514; found 168.1514. Anal, calcd. for C11H20O: C 78.51, H 11.98; found: C 78.57, 69 H 11.99 70 Preparation of (-)-4-methylcamphor 42 OH O (+)-4-Methylisoborneol 4 2 (7.50 g, 0.045 mol) was dissolved in pure methylene chloride (150 mL) and the solution added dropwise to PCC (14.4 g, 0.067 mol) in methylene chloride (150 mL) and then st irred at room temperature for 3.5 hours. The reaction mixture was f i l tered through a layer of s i l i c a gel and anhydrous magnesium sulphate and washed with ether. Evaporation of the solvent provided (-)-4-methylcamphor 43 as a white crystal l ine sol id (7.45 g, 99%), mp 150-151 ° C (sealed tube; l i t . ref. mp 167-168 ° C ) ; [a J 2 1 -16.05 (c. 2.04, 95% ethanol) ( l i t . [ a ] D -14.50 (c. 10.0, EtOH)H47f]; v m a x ( C H C I 3 ) : 1730 cm"1; 5 ( C D C I 3 , 400 MHz): 0.71 (3H, s, C-9 methyl), 0.83 (3H, s, C-8 methyl), 0.92 (3H, s, C-10 methyl), 1.04 (3H, s, C-4 methyl), 1.35-1.43 (2H, m, C-5 and C-6 endo protons), 1.57-1.75 (2H, m, C-5 and C-6 exo protons), 1.87 (IH, d, J=18 Hz, C-3 endo proton), 2.08 (IH, dd, J=18 Hz and 3 Hz, C-3 exo proton); mZfi. (relative intensity): 166 (M + , 39.8), 138 (13.9), 109 (94.8), 83 (92.6), 82 (100.0). Exact mass calcd. for C n H ^ s 0 1 166.1358; found 166.1360. Anal. calcd. for C n H i e O : C 79.47, H 10.91; found: C 79.67, H 11.03 . Determination of Optical Purity Using the Anderson-Shapiro Reagent AS. (1) Model study using ( ± ) - i s o b o r n e o l (±)-£5_ and (-)-isoborneol 5_£: The alcohol (±)-5_5_ or 5_5_ (308.5 mg, 2.0 mmol) was dissolved in dry benzene (2.0 mL) and dry triethylamine (0.42 mL, 303.6 mg, 3.0 mmol) and 4-(dimethylamino)pyridine (24.4 mg, 0.20 mmol) were added. The Anderson-Shapiro reagent 4JL (358.1 mg, 2.10 mmol) was then added and the v i a l was shaken for 30 seconds. After allowing the reaction mixture to stand for 15 minutes, a small amount of C 5 D 5 was added for NMR locking purposes, and the mixture was f i l tered through a cotton plug Into a 5-mm NMR tube and a 121.4 MHz 3 1P NMR spectrum was recorded using H 3 P O 4 as the external reference standard: (a) Using ( ± ) - i s o b o r n e o l (±)- .£5_as substrate, 5 : 13.404, 13.341 (two diastereomerlc Anderson-Shapiro derivatives, relative intensity ~ 1:1, A6 7.89 Hz), 17.480 (Anderson-Shapiro reagent). (b) Using (-)-isoborneol £5_ as substrate, 5: 13.478 (Anderson-Shapiro derivative), 17.375 (Anderson-Shapiro reagent). ( i i ) Examination of (+)-4-methylisoborneol 42 prepared by the LAH reduction of 40a*: (+)-4-Methylisoborneol 42 U a l 3 D ° ' 5 +19.47 (c. 10.0, 95% ethanol), 334.5 mg, 2.0 mmol} was treated in the manner described 31 above and a 121.4 MHz P NMR spectrum of the Anderson-Shapiro derivatives was recorded: 5 : 13.667, 13.628 (two diastereomeric derivatives, relative intensity -2.1:1, A 8 4.86 Hz. ) . The signal separation was too small to provide more than an approximate estimation of relative signal areas. * 40a was prepared by a similar procedure as described on page 6 6 with the temperature and time of reaction changed to room temperature and 15 minutes. 73 Preparation of ( ± ) - i s o b o r n y l acetate ( ± ) - 2 1 (±>S1 (±)-21 4-(Dimethylamino)pyrldine (3.7 g, 30.0 mmol) and dry acetic anhydride (2.84 mL, 30.0 mmol) were added to a solution of ( ± ) - i s o b o r n e o l (±)-5_5_ (1.54 g, 10.0 mmol) in dry pyridine (50 mL) under argon at room temperature. The reaction mixture was then st irred at room temperature overnight, quenched with water and extracted with ether (3X). The ether extracts were combined, washed with IM HCl solution (3X), saturated sodium bicarbonate solution (3X), water (2X), and dried.over anhydrous magnesium sulphate. Evaporation of the solvent yielded an orange o i l (2.1 g) which was purified by column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 95:5) to provide ( ± ) - i s o b o r n y l acetate (±)-,2JL as a clear colorless o i l (1.63 g, 83%), ( a l ^ 9 , 5 0.00 (c. 12.1, 95% ethanol); v max (film): 1735 cm"1, 1250 c m - 1 , 1035 c m - 1 ; 8 (CDC13, 400 MHz): 0.85 (6H, s, C-8 and C-9 methyls), 0.98 (3H, s, C-10 methyl), 1.04-1.19 (2H, m, C-5 and C-6 endo protons), 1.51-1.83 (5H, m, C-6 exo, C-3 endo, C-5 exo, C-4 and C-3 exo protons), 2.03 (3H, s, acetyl) , 4.67 (IH, dd, J=8 Hz and 4 Hz, C-2 proton); m/e (relative intensity): 196 (M + , 0.6), 136 (66.2), 121 (63.0), 95 (98.4), 43 (94.3). Exact maaa. calcd. for C 1 2 H 2 0 ° 2 : 196.1463; found 196.1454. 74 Anal, calcd. for C 1 2 H 2 0 O 2 : C 73.43, H 10.27; found: c 73.63, H 10.29 . Preparation of (-)-isobornyl acetate ent-21 A mixture of (-)-isoborneol £5_ and ( + )-borneol ent-2 (1.54 g, 10.0 mmol; 9:1 by capi l lary GLC [OV-101, 100°C]) was acetylated with acetic anhydride / pyridine using the procedure described above (page 73) for ( ± ) - i s o b o r n e o l (±)-5_5_. A mixture of (-)-isobornyl acetate ent-21 and (+)-bornyl acetate ent-16 (85.7% ent-21 r 14.3% ent-16 by capi l lary GLC [OV-101, 100°Cl) was obtained as a clear colorless o i l (1.57 g, 80% yield based on recovered starting materials), v max (film): 1738 c m - 1 , 1240 c m - 1 , 1050 cm' 1 ; 8 (CDCl 3 , 400 MHz): 2.06 (s, • C H 3 C 0 2 - ) , 4.89 (dd, J=10 Hz and 4 Hz, C-2 exo-hydrogen) were observed; m/e (relative intensity): 196 (M+, 1.6), 136 (50.1), 121 (41.0), 95 (94.1), 43 (100.0). Exact mass calcd. for C i 2 H 2 0 O 2 : 196.1463; found 196.1456. Anal. calcd. for C 1 2 H 2 Q 0 2 : C 73.43, H 10.27; found: C 72.61, H 10.08 . Determination of Optical Purity using Tris[3-(heptafluoropropyl-hydroxyroethylenej-drcamphoratoleuropium (III) 4_5_ (i) Model study using ( ± ) - i s o b o r n y l acetate (±)~2X and (-)-isobornyl acetate ent-21: The acetate ( ± ) - 2 i . or ent-21 (19.63 mg, 0.10 mmol) was weighed in a pipette and transferred to a 5-mm NMR tube. The volume of the sample In the tube was made up to 1 mL with C D C I 3 . A 400 MHz 1H NMR spectrum (with TMS as the Internal reference standard) was recorded at room temperature before the addition of [Eu(hfc) 3 J. [Eu(hfc) 3 l . (11.94 mg, 0.010 mmol) was then added direct ly to the NMR tube and a second spectrum was recorded. Additional spectra were obtained after the concentration of [Eu(hfc) 3 r was increased to 0.025 mmol/mL (addition of 17.9 mg) and 0.050 mmol/mL (addition of 29.85 mg) respectively. ( i i ) Synthetic (+)-4-Methylisobornyl acetate ASL (cf. p.66): Sample Experimental Conditions [al D 40a 25°C, 15 min. + 35. 79 (c. 2 .28, 95% ethanol) 40b 25°C, 10 min. + 32. 12 (c. 3 .12, 9 5% ethanol) 40c 0°C , 30 min. + 39. 23 (c. 2 .20, 95% ethanol) ( + )-4-Methyllsobornyl acetate ASL (21.03 mg, 0.10 mmol) was treated in the same manner and a series of four 400 MHz *H NMR spectra were recorded as described above. ( i i i ) Synthetic (-)-4-Methylcamphor 4_3_ derived from 40a: (-)-4-Methylcamphor 4_3_ (16.63 mg, 0.10 mmol) was dissolved in CDC13 (1 mL) and a 400 MHz IH NMR spectrum (with TMS as the internal reference standard) was recorded at room temperature before addition of (Euthfc)^]. Three additional spectra were recorded after sequential addition of 11.94 mg (0.01 mmol), 23.87 mg (0.02 mmol) and 35.81 mg (0.03 mmol) of [ E u ( h £ c ) 3 ) . Preparation of ejidj2.-3-bromo-4-methylcamphor £2 4 i SL A solution of (-)-4-methylcamphor 4 1 (6.37 g, 0.038 mol) in g lacial acetic acid (28 mL) was warmed to 80°C and bromine (2.29 mL, 6.87 g, 76.6 mmol) in g lacial acetic acid (2.29 mL) was added dropwise. The mixture was st irred at 80°C for 31 hours, then cooled, poured into ice-water. The resulting solid was f i l tered off, washed with water to yield endo-3-bromo-4-methylcamphor £7 as a white crystal l ine sol id (9.30 g, 99%), mp 119.5-120.5 °C (sealed tube); V max (CHC13): 1750 cm"1; 5 (CDCl3, 400 MHz): 0.81 (3H, s, C-9 methyl), 0.98 (3H, s, C-8 methyl), 1.00 (3H, s, C-10 methyl), 1.06 (3H, s, C-4 methyl), 1.40 (IH, m, C-6 endo proton), 1.55-1.67 (2H, m, C-5 endo and C-6 exo protons), 2.07 (1H, m, C-5 exo proton), 4.31 (IH, d, J=1.5 Hz, C-3 proton); m/e (relative Intensity): 246/244 (M + , 5.0/4.9), 165 (48.1), 137 (52.1), 123 (45.0), 109 (75.7), 83 (100.0). Exact mass calcd. for C n H ^ O B r : 246.0442/244.0462; found 246.0439/244.0467. Anal. calcd. for CnH^ O B r : C 53.89, H 6.99, Br 32.59; found: C 53.81, H 6.86, Br 32.80. Preparation of fiuid_o_-3,9-dibromo-4-(bromomethyl)camphor IQ. Endji-3-bromo-4-methylcamphor 6_1 (7.36 g, 0.030 mol) and bromine (3.47 mL, 0.069 mol) were added to a single-neck flask. Chlorosulphonlc acid (5.48 mL, 0.082 mol) was added slowly to the reaction mixture. After being st irred at room temperature for 19 hours, the reaction mixture was added to ice-cold bisulphite solution and extracted with ether (3X). The ether extracts were combined, washed with saturated sodium bicarbonate solution (2X) and water (2X), and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a yellow sol id which was washed with ice-cold ether to provide endo-3.9-dibromo-4-(bromomethyl )camphor 7_0_ as a white crystal l ine sol id (6.20 g, 51%), mp 142.5-143.5 °C (sealed tube); v max (CHCl 3 ): 1750 c m - 1 ; 8 (CDCl3, 400 MHz): 1.07 (3H, s, C-8 methyl), 1.27 (3H, s, C-10 methyl), 1.53 (IH, ddd, J=14 Hz, 9 Hz and 4 Hz, C-6 endo proton), 1.72 (IH, ddd, J=14 Hz, 14 Hz and 4 Hz, C-5 endo proton), 1.85 (IH, dddd, J=14 Hz, 14 Hz, 4 Hz and 2.5 Hz, C-5 exo proton), 2.22 (IH, ddd, J=14 Hz, 9 Hz and 4 Hz, C-6 exo proton), 3.45 (d, J=ll Hz), 3.74 (d, J=ll Hz) (2H, AB quartet, C-9 methylene), 3.52 (d, J=11.5 Hz), 4.05 (d, J=11.5 Hz) (2H, AB quartet, C-4 methylene), 4.92 (IH, d, J=2.5 Hz, C-3 proton); mZfi. (relative intensity): 406/404/402/400 (M + , 0.4/1.8/2.0/0.7), 325/323/321 (17.1/41.7/18.8), 245/243 (14.0/18.8), 201/199 (28.7/22.2), 163 (16.9), 121 (36.3), 107 (50.8), 105 (37.8), 93 (66.7), 91 (69.2). Exact mass, calcd. for C i i H l 5 O B r 3 : 405.8612/403.8632/401.8652/399.8672; found 405.8605/403.8637/401.8667/399.8675. Ana 1. calcd. for. C n H i 5 0 B r 3 : C 32.79, H 3.75, Br 59.49; found: C 33.05, H 3.78, Br 59.22. The structure and absolute configuration of this compound was confirmed by X-ray analysis.* * I am grateful to Professor J . Trotter and Dr. S. Rettig for carrying out this analysis. Preparation of 9,10-dibromo-4-(bromomethyl)caraphor 15. 10. 24 11 Ejidj2.-3,9-dibromo-4-(bromomethyl )camphor IQ. ( 0 . § 0 g, 0.0020 mol) and bromine (0.17 mL, 0.0034 mol) were added to a single-neck flask. Chlorosulphonic acid (0.70 mL, 0.010 mol) was added slowly to the reaction mixture which was then s t irred at room temperature under nitrogen and followed by capi l lary GLC (OV-101, 190°C) . After 6 days, more bromine (0.17 mL, 0.0034 mol) and chlorosulphonic acid (0.35 mL, 0.0052 mol) were added. After another 6 days, capi l lary GLC analysis indicated that approximately half of the starting material IQ. was brominated and that bromination failed to proceed further. Thus, the reaction mixture was added to cold sodium bisulphite solution and extracted with ether (3X). The ether extracts were combined, washed with saturated sodium bicarbonate (3X) and water (3X), and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a yellow sol id (0.84 g). Capil lary GLC analysis (OV-101, 190°C) of the crude product indicated the ratio of the starting material 7_0_ to the product l i to be 1:1. The crude product was subsequently treated with zinc / acetic acid in a procedure described below. Zinc dust (235.8 mg, 3.61 mmol) was carefully added to a solution of the crude tetrabromo product (0.84 g) in acetic acid (3.37 mL, 58.87 mmol) at 0°C. The reaction mixture was st irred for 2 hours at 0°C, added to water, and extracted with ether (3X). The ether extracts were combined, washed with saturated sodium bicarbonate solution (2X), brine (2X), and water (2X), and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a yellow o i l (0.83 g). Column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 98:2) yielded 9-bromo-4-(bromomethylJcamphor H as a clear o i l (0.30 g, 47% yield from 10_) (cf. p.84) followed by 9,10-dlbromo-4-(bromomethyl )camphor 7_5_ as a white crystal l ine sol id (0.39 g, 48% yield from lp_), mp 158-159 °C (sealed tube); V max ( C H C I 3 ) : 1745 c m - 1 ; 5 ( C D C I 3 , 400 MHz): 1.15 (3H, s, C-8 methyl), 1.62 (IH, ddd, J=14.5 Hz, 9.5 Hz and 5.5 Hz, C-6 endo proton), 1.92-2.08 (2H, m, C-6 exo and C-5 endo protons), 2.25 (IH, ddd, J=14.5 Hz, 11 Hz and 5 Hz, C-5 exo proton), 2.35-2.45 (2H, m, C-3 endo and exo protons), 3.47 (d, J=12 Hz), 3.71 (d, J=12 Hz) (2H, AB quartet, C-9 methylene), 3.67 (d, J=11.5 Hz), 3.72 (d, J=11.5 Hz) (2H, AB quartet, C-10 methylene), 3.59 (d, J=10.5 Hz), 4.02 (d, J=10.5 Hz) (AB quartet, C-4 methylene); mZe_ (relative intensity): 406/404/402/400 (M+, 0.1/0.3/0.3/0.1), 325/323/321 (21.9/45.8/23.2), 243/241 (27.3/21.3), 215/213 (33.4/30.5), 201/199 (95.0/100.0), 163 (18.7), 121 (26.7), 107 (25.7), 105 (35.8), 93 (49.6), 91 (49.8). ExacjL maas. calcd. for CnHisOBrs: 405.8612/403.8632/401.8652/399.8672; found 405.8568/403.8621/401.8679/399.8667. Anal , c a l c d . f or C 1 1 H 1 5 O B r 3 : C 32.79, H 3.75, Br 59.49; found C 32.64, H 3.71, Br 59.32. Preparation of 9-bromo-4-(bromomethyl)camphor 21. IQ 21 Zinc dust (30.59 mg, 0.47 mmol) was carefully added to a solution of endo-3f9-dibromo-4-(bromomethyl)camphor 70 (100 mg, 0.25 mmol) in acetic acid (0.44 mL, 7.63 mmol). The reaction mixture was st irred for 90 minutes at 0°c, added to water, and extracted with ether (3X). The ether extracts were combined, washed with saturated sodium bicarbonate solution (2X), brine (2X), and water (2X), and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a viscous yellow o i l (88.1 mg). Column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 95:5) yielded 21. as a clear o i l (60.5 mg, 75%), v max (CHCl 3 ): 1740 cm"1; 8 (CDCI3, 400 MHz): 1.00 (3H, s, C-8 methyl), 1.04 (3H, s, C-10 methyl), I. 54 (IH, m, C-6 endo proton), 1.75 (IH, ddd, J=14.5 Hz, 11 Hz and 5 Hz, C-5 endo proton), 1.87-2.02 (2H, m, C-5 and C-6 exo protons), 2.28-2.39 (2H, m, C-3 exo and endo protons), 3.35 (d, J=ll Hz), 3.65 (d, J=ll Hz) (2H, AB quartet, C-9 methylene), 3.61 (d, J=10.5 Hz), 4.00 (d, J=10.5 Hz) (2H, AB quartet, C-4 methylene); m/e (relative intensity): 326/324/322 (M +, II . 4/23.9/12.7), 245/243 (56.2/56.2), .217/215 (35.5/35.2), 201/199 (83.9/76.6), 163 (50.3), 135 (85.8), 121 (77.8), 107 (69.6), 93 (90.0), 81 (97.4), 41 (100.0). Exact mass, calcd. for C 1 1 H 1 6 O B r 2 : 325.9527/323.9547/321.9567; found 325.9532/323.9543/321.9585. Preparation of the Dibromoester 7_6_ 26 9,10-Dlbromo-4-(bromomethyl )camphor 7_5_ (74.5 mg, ;0.18 mmol) in dry methanol (1.0 mL) was added to a solution of sodium methoxide in methanol {prepared from sodium (6.4 mg, 0.28 mmol) and methanol (0.8 mL)} under argon at 0°C. After 4 hours at room temperature, the reaction mixture was acidif ied with IM HCl solution and extracted with ether (3X). The combined ether extracts were washed with brine (3X) and water (2X), dried (anhydrous magnesium sulphate), and the solvent removed to yield the crude product as a l ight yellow o i l (0.143 g). Column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 99:1) yielded 7_6_ as a clear colorless o i l (56.3 mg, 86%); v max (CHCl 3 ): 1720 cm"1, 1640 cm"1; 8 ( C D C 1 3 , 400 MHz): 1.28 (3H, s) , 1.80-1.96 (2H, m), 2.38-2.50 (3H, m), 2.82 (IH, dd, J=15.5 Hz and 1 Hz), 3.47 (d, J=10 Hz), 3.59 (d, J=10 Hz) (2H, AB quartet, CH 2 Br), 3.68 (3H, s, C O 2 C H 3 ) , 3.76 (d, J=ll Hz), 3.90 (d, J=ll Hz) (2H, AB quartet, CH 2 Br), 4.94 (IH, t , J=2 Hz), 5.05 (IH, t , J=2 Hz); m/e (relative intensity): 356/354/352 (M + , 0.1/0.2/0.1), 275/273 (3.1/3.7), 201/199 (28.2/30.9), 154 (0.5), 133 (41.8), 119 (100.0), 105 (52.5), 91 (4 8.3) . Anal. calcd. for C i 2 H 1 8 0 2 B r 2 : C 40.71, H 5.12, Br 45.13; found: 87 C 40.64, H 5.03, Br 45.06 A t t e m p t e d c l e a v a g e o f 9 - b r o m o - 4 - ( b r o m o m e t h y l ) c a m p h o r 21 21 9-Bromo-4-(bromomethyl)camphor H (60.0 mg, 0.19 mmol) In dry methanol (1.0 mL) was added to a solution of sodium methoxide in methanol {prepared from sodium (6.4 mg, 0.28 mmol) and methanol (0.8 mL)} under argon at 0°C. The starting material remained unchanged after 10 hours at 50°C. Preparation of 3,3,9-tribromo-4-(bromomethyl)camphor 12 7JQ 22 Chlorosulphonic acid (2.10 mL, 0.031 mol) was added slowly to a mixture of endo-3f9-dibromo-4-(bromomethyl)camphor 70 (2.4 g, 0.0060 mol) and bromine (0.51 mL, 0.010 mol). After s t i rr ing at room temperature for 5 days, the reaction mixture was heated to 80°C and terminated after 2.5 days. The reaction mixture was cooled and quenched with water, and sodium bisulphite was added to destroy excess bromine. Extraction with ether (3X), followed by washing with saturated sodium bicarbonate (3X) and water (3X), drying over anhydrous magnesium sulphate, and evaporation of the solvent yielded a yellow sol id which on tr i turat ion with Ice-cold ether provided tetrabromo compound 12 as a white crystal l ine sol id (1.80 g, 62%), mp 182-183 °C (sealed tube); v max (CHCI3): 1755 c m - 1 ; 8 (CDCl3, 400 MHz): I . 12 (3H, s, C-8 methyl), 1.30 (3H, s, C-10 methyl), 1.70-1.85 (2H, m, C-5 and C-6 endo protons), 2.27 (IH, ddd, J=14.5 Hz, II . 5 Hz and 6.5 Hz, C-5 exo proton), 2.89 (IH, ddd, J=14.5 Hz, 9 Hz and 3.5 Hz, C-6 exo proton), 3.38 (d, J=ll Hz), 3.71 (d, J=ll Hz) (2H, AB quartet, C-9 methylene), 3.91 (d, J=ll Hz), 4.28 (d, J=ll Hz) (2H, AB quartet, C-4 methylene); m/e (relative intensity): 486/484/482/480/478 (M+, 0.6/5.2/7.5/4.8/1.4), 405/403/401/399 (1.8/4.9/4.3/1.5), 325/323/321 (26.1/54.3/29.1), 90 243/241 (16.5/18.5), 161 (30.5). Exact ma3s calcd. for C 1 1 H 1 4 O B r 4 : 485.769 7/483.7717/481.77 37/479.7757/477.7777; found 485.7747/483.7729/481.7727/479.7774/477.7820. Anal. calcd. for CiiH^OBr^j: C 27.42, H 2.93, Br 66.33; found: C 27.23, H 2.87, Br 66.58. 91 Attempted C-10 bromination of 3,3 /9-tribromo-4-(bromomethyl)-camphor 72 Chlorosulphonic acid (1.31 mL, 0.019 mol) was added slowly to a mixture of 3,3,9-tribromo-4-(bromomethylJcamphor 22. (1.80 g, 0.0037 mol) and bromine (0.32 mL, 0.0063 mol) and the reaction mixture st irred at room temperature for 19 days. Workup as described above (page 89) provided starting material. 92 Preparation of (+)-3,3-dibromocamphor 2L Br 5a Br Br 26 Bromine (40.0 g, 12.5 mL, 0.25 mol) was added dropwise to a solution of (+)-endo-3-bromocamphor 5a (46.2 g, 0.20 mol) in g lac ia l acetic acid (200 mL) and the reaction mixture was heated at 55°C for an hour followed by three more additions of bromine (10 mL, 0.20 mol each) at one-hourly intervals. After the last addition of bromine, the reaction mixture was further heated for an hour before i t was cooled, poured into ice-water, neutralized with sol id sodium bicarbonate and excess bromine destroyed by sol id sodium bisulphite. The mixture was then extracted with ether (3X), washed with brine (3X) and water (3X), and dried over anhydrous magnesium sulphate. Removal of the solvent yielded a yellow sol id which was crystalized from ether in the refrigerator to provide (+)-3,3-dlbromocamphor 2L as a white crystal l ine sol id (57.0 g, 92%), mp 60-61 °C (sealed tube; l i t . ref . mp 64°C); v max ( C H C I 3 ) : 1755 cm"1; 8 ( C D C I 3 , 400 MHz): 1.02 (3H, s, C-8 methyl), 1.11 (3H, s, C-10 methyl), 1.25 (3H, s, C-9 methyl), 1.60-1.67 (2H, m> C-5 and C-6 endo protons), 2.08 (IH, m, C-6 exo proton), 2.33 (1H, m, C-5 exo proton), 2.82 (IH, d, J=4 Hz, C-4 proton); m/e (relative intensity): 312/310/308 (M + , 1.4/2.5/1.2), 284/282/280 (3.3/6.0/2.7), 232/230 (3.1/3.0), 203/201 (18.9/19.8), 123 (22.0), 83 (100.0). Exact mass calcd. for CioHi40Br2: 311.9371/309.9391/307.9411; found 311.9363/309.9386/307.9413. Anal. calcd. for C ^ Q H J ^ O B ^ : C 38.74, H 4.55, Br 51.55; found C 38.46, H 4.62, Br 51.33. 94 Preparation of Pericyclocamphanone 24. Br O Br 26 24 Diethyl zinc (50.0 mL of a 15% wt. solution in toluene; 0.05 mol) was added to a solution of dry (+)-3,3-dibromocamphor 26 (15.5 g, 0.05 mol) in dry benzene (500 mL). The reaction mixture was refluxed for 24 hours, quenched with ice-water (the white emulsion produced was destroyed by the addition of 1M HCl solution), and extracted with ether ( 3 X ) . The ether extracts were combined and washed with water ( 3 X ) , dried over anhydrous magnesium sulphate. Removal of the solvent yielded a yellowish crystal l ine sol id (8.3 g). The crude product which on column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 95:5) provided pericyclocamphanone 24 (7.1 g, 94 %) as a white crystal l ine so l id , mp 168-170 °C (sealed tube; l i t . ref . mp 168-170 °C); v max ( C H C 1 3 ) : 1720 c m - 1 ; 6 ( C D C I 3 , 400 MHz): 0.81 ( 3 H , s, C-8 methyl), 0.90 ( 3 H , s, C-10 methyl), 0.97 ( 3 H , s, C-9 methyl), 1.44 (IH, t , J=5.5 Hz, C-3 proton), 1.72 (IH, d, J=ll Hz, C-6 endo proton), 1.94 (IH, dd, J=ll Hz and 1.5 Hz, C-6 exo proton), 1.97 (IH, t , J=5.5 Hz, C-4 proton), 2 . 0 1 (IH, bt, J=5.5 Hz, C-5 proton); m/e (relative intensity): 151 (M++l, 2 1 . 6 ) , 150 (M + , 24.1), 123 (60.0), 107 ( 1 0 0 . 0 ) . Exact mass calcd. for Ci0 H 14 O : 150.1045; found 150.1054. Anal. calcd. for C 1 0 H 1 4 O : . c 79 . 96 , H 9 . 3 9 ; found C 78.50, H 95 9.26 96 Preparation of ej£o_-5-bromocamphor 21 2A 21 Hydrobromic acid (48%, 100 mL) was added carefully to a solution of pericyclocamphanone 24. (5.00 g, 0.033 mol) in acetic anhydride (15 mL). The reaction mixture was s t irred at 65°C for 3 hours, cooled and poured into ice-water. The resulting sol id was f i l tered off, dissolved in ether, washed with saturated sodium bicarbonate solution, then with water (2X), and the ether solution dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a l ight yellow sol id which was purified by column chromatography ( s i l i ca gel 230-400 mesh, elution with petroleum ether / ether 98:2) to afford exo-5-bromocamphor 27 as a white crystal l ine compound (7.15 g, 93%), mp 110.5-111.5 ° c (sealed tube; l i t . ref. mp 111-111.5 °C); v max (CHCI3): 1735 cm"1; 5 (CDCI3, 400 MHz): 0.90 (3H, s, C-8 methyl), 0.96 (3H, s, C-10 methyl), 1.38 (3H, s, C-9 methyl), 1.84 (IH, d, J=18.5 Hz, C-3 endo proton), 2.15 (IH, dd, J=15.5 Hz and 8.5 Hz, C-6 endo proton), 2.28 (IH, dd, J=15.5 Hz and 5 Hz, C-6 exo proton), 2.47 (IH, dd, J=18.5 Hz and 5 Hz, C-3 exo proton), 2.53 (IH, d, J=5.5 Hz, C-4 proton), 4.70 (IH, dd, J=8.5 Hz and 5 Hz, C-5 proton); m/e (relative intensity): 232/230 (M+, 4.5/4.5), 151 (18.8), 123 (38.4), 109 (100.0). Exact mass calcd. for C 1 0 H 1 5 O B r : 232.0286/230.0306; found 232.0292/230.0309. Anal. calcd. for C 1 0 H 1 5 O B r : C 51.97, H 6.54, Br 34.57; found C 51.67, H 6.64, Br 34.40. 98 Attempted p r e p a r a t i o n of ftxo_-5-bromo-2-methylenebornane 5JL 22 5£ Methyltriphenylphosphonium bromide (1.73 g, 0.0048 mol) was vacuum pumped for 1.5 hours to remove any trace of moisture before It was dissolved in pure THF (4.5 mL) and flushed with argon. n-Butyllithium (3.88 mL of the 1.25M solution, 0.0048 mol) was added dropwise and the resultant mixture was st irred at 50°C for 2 hours under argon. A solution of exo-5-bromo-camphor 21 (0.70 g, 0.0030 mol) in d i s t i l l e d THF (1,8 mL) was added dropwise to the Wittig reagent and the reaction mixture was refluxed at 65°C under argon. After 1 hour, capi l lary GLC and TLC analyses indicated that a single product had been formed. The reaction mixture was cooled, diluted with water, extracted with pentane (3X) and the pentane extracts were combined and washed with water (3X) and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a white crystal l ine compound (0.45g, 9 9 % ) . Capil lary GLC (OV-101, 120°C) and TLC analyses, the low resolution mass spectrum and the *H NMR spectrum ( C D C I 3 , 400 MHz) of this compound confirmed that the product was pericyclocamphanone 24! 99 Preparation of £xo_-5-bromo-2-methylenebornane 5jB_ O; Br Br 22 52. Titanium tetrachloride (4.8 mL, 4 3 . 7 mmol) was added dropwise to a s t irred suspension of zinc dust (11.8 g, 180 mmol) and dibromomethane (10 . 4 g, 4.2 mL, 60.0 mmol) in THF (200 mL) at -40°C . The reaction mixture was allowed to warm to 5°C and kept in the refrigerator for 3 days to give a thick brown s lurry. The ice-cold slurry was added portionwise to a st irred solution of exo-5-bromocamphor 27 ( 2 . 3 g, 10 . 0 mmol) in dichloromethane (20 mL) and the resultant mixture was st irred at room temperature for 1 day under argon. The reaction mixture was then quenched with saturated sodium bicarbonate solution, extracted with ether ( 3 X ) and the ether extracts were combined and washed with water ( 3 X ) , and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded pure exo-5-bromo-2-methylenebornane i i as a white crystal l ine sol id (1.98 g, 86%), mp 88-89.5 °C (sealed tube); v max ( C H C 1 3 ) : 1645 c m - 1 , 880 cm"1; 8 ( C D C I 3 , 400 MHz): 0.80 ( 3 H , s, C-8 methyl), 0.97 ( 3 H , s, C-10 methyl), 1.28 ( 3 H , s, C-9 methyl), 1.91 (IH, d, J=18 Hz, C-3 endo proton), 2 .02 (IH, dd, J=14 Hz and 8.5 Hz, C-6 endo proton), 2.18 (IH, d, J=6 Hz, C-4 proton), 2.27 (IH, dd, J=14 Hz and 4.5 Hz, C-6 exo proton), 2.50 (IH, bd, J=18 Hz, C-3 exo proton), 4.01 (IH, dd, J=8.5 Hz and 4.5 Hz, C-5 endo 1 0 0 proton), 4.74 (d) and 4.79 (d) (2H, AB quartet, exo-methylene protons); m/e (relative intensity): 230/228 (M+, 1.2/1.1), 215/213 (1.5/1.6), 149 (86.2), 107 (72.3), 80 (100.0). Exact mass calcd. for C i j H ^ B r : 230.0493/228.0513; found 230.0497/228.0512. A n a l . calcd. for C 1 1 H 1 7 B r : C 57.65, H 7.48, Br 34.87; found: C 57.75, H 7.56, Br 34.79. 101 Attempted acid-catalyzed rearrangement of ejso_-5-bromo-2-methylenebornane 5JL Concentrated sulphuric acid (0.013 mL, 0.17 mmol) was added to a solution of exo-5-bromo-2-methylenebornane 58 (0.20 g, 0.86 mmol) in g lac ia l acetic acid (0.55 mL) at 0°C and the reaction mixture s t irred at 0°C for 35 minutes. GLC (OV-101, 120°C) and TLC analyses indicated that no reaction had taken place and further s t i rr ing at room temperature for 3 hours made no difference. F ina l ly , the reaction mixture was heated to about 80°C which caused the starting material 5_8_ to decompose. In a separate run, concentrated sulphuric acid (0.12 mL, 1.54 mmol) was added to exo-5-bromo-2-methylenebornane 5JJ. (1.83 g, 7.91 mmol) in g lac ia l acetic acid (5.0 mL) at 0°C. The reaction mixture was s t irred at room temperature and followed by GLC and TLC for 21 days, GLC and TLC analyses showed that the starting material 5JL slowly underwent decomposition and that no major products were observed. 102 BIBLIOGRAPHY 1. W. Templeton, "An Introduction to the Chemistry of Terpenoids  and Seroids", Butterworths, London, 1969, (a) p.63; (b) p.64. 2. R.V. Stevens, K.T. Chapman and H.N. Weiler, J. Org. Chem., 1980, 1 6 , 2030. 3. (a) T. Money, Natural Product Reports, 1985, 2, 253 and references cited therein; (b) M.S. Allen, N. Darby, P. Salisbury, E.R. Sigurdson and T. Money, Can. J. Chem., 1979, 57, 733; (c) N.J. Toivonen and A. Halonen, Suomen Kemlstil. Bf 1946, 19., 1 (Chem. Abstr. . 1947, 4_1, 5487i); (d) M.S. Allen, N. Lamb and T. Money, Can. J. Chem.r1979r 57 P 742; (e) M.S. Allen, N. Lamb, T. Money and P. Salisbury, J. Chem. Soc. Chem.  Commun.f 1979, 112; (f) J. Meinwald, J.C. Shelton, G.L. Buchanan and A. Courtin, J. Org. Chem. , 1968, 33., 99. 4. J.H. 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