UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Synthetic routes from camphor to longicamphane and picrotoxane derivatives Cachia, Paul Joseph 1980

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

Item Metadata

Download

Media
831-UBC_1980_A1 C33.pdf [ 10.71MB ]
Metadata
JSON: 831-1.0060805.json
JSON-LD: 831-1.0060805-ld.json
RDF/XML (Pretty): 831-1.0060805-rdf.xml
RDF/JSON: 831-1.0060805-rdf.json
Turtle: 831-1.0060805-turtle.txt
N-Triples: 831-1.0060805-rdf-ntriples.txt
Original Record: 831-1.0060805-source.json
Full Text
831-1.0060805-fulltext.txt
Citation
831-1.0060805.ris

Full Text

SYNTHETIC ROUTES FROM CAMPHOR TO LONGICAMPHANE AND PICROTOXANE DERIVATIVES by PAUL J . CACHIA B . S c . U n i v e r s i t y o f T o r o n t o , 1972 M . S c . U n i v e r s i t y o f T o r o n t o , 1974 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY / i n * f THE FACULTY OF GRADUATE STUDIES (Department o f C h e m i s t r y ) We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA F e b r u a r y , 1980 0 P a u l J . C a c h i a In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree ly ava i lab le for reference and study. I fur ther agree that permission for extensive copying of th is thesis for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i cat ion of th is thes is for f inanc ia l gain sha l l not be allowed without my writ ten permission. Department of C h e m i s t r y The Univers i ty of B r i t i s h Columbia 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 D a t e J u l y 14, 19 80 - i i -ABSTRACT Camphor has been f u n c t i o n a l i z e d at the C-(8) p o s i t i o n by t r e a t i n g (+)-3,3-dibromocamphor with bromine and c h l o r o s u l p h o n i c a c i d . A m e c h a n i s t i c r a t i o n a l i z a t i o n i s proposed f o r t h i s t r a n s -formation which accounts f o r the presence of the minor sid e products t h a t form d u r i n g 8- and 9-bromination. (+)-8-Bromo-camphor produced by t h i s method was subsequently used as a key intermediate i n s e s q u i t e r p e n o i d s y n t h e s i s . Approaches t o the s y n t h e s i s of both the longicamphane and pic r o t o x a n e carbon frameworks are d i s c u s s e d . Our approach to the s y n t h e s i s of the longicamphane framework i n v o l v e d i n t r a m o l e c u l a r M i c h a e l - a d d i t i o n ' o f 9-oxocampherenone. While i n v e s t i g a t i n g a proposed s y n t h e s i s of 9-oxocampherenone v i a Meyer-Schuster rearrangement of 8-(3-hydroxy-3-methyl-l-butynyl)camphor ethylene a c e t a l an i n t e r e s t i n g new r e a c t i o n o c c u r r e d p r o v i d i n g the p o l y c y c l i c r i n g system (+)-6,7-dimethyl-6 - ( l - o x o - 2 - m e t h y l p r o p y l ) t r i c y c l o Q 4 *2 -1 -O3 ' 7 J nonan-9-one whose s t r u c t u r e was determined by X-ray e r y s t a l l o g r a p h i c a n a l y s i s . A mechanism f o r i t s formations i s proposed. Attempts to synthe-s i z e 9-oxocampherenone by a l l y l i c o x i d a t i o n of 9-hydroxycam-pherenone and i t s ethylene a c e t a l d e r i v a t i v e are a l s o d i s c u s s e d . Our s y n t h e t i c approach t o the pi c r o t o x a n e framework i n v o l v e s B a e y e r - V i l l i g e r o x i d a t i o n - t r a n s l a c t o n i z a t i o n o f a s u i t a b l e copacamphor-type derivative. In our f i r s t approach the attempted synthesis of 4-hydroxycopacamphor via intramolecular epoxide cyclization of 8-(1 ,2-epoxy-3-methylbutyl)camphor provided the t r i c y c l i c ketol 1 , 6-dimethyl - 4 -(l-hydroxy - 2-methylpropyl)tri-cyclo Q 4 • 3 • 0 « 0 3 ' 7 ] nonan-2-one . This 5-membered ring cyclization product was formed exclusively during the reaction. The strategy was revised to exclude 5-membered ring formation; the cyclization would be performed on 8-acetoxycampherenone epoxide. The syn-thesis of 8-acetoxycampherenol methyl ether is discussed and i t s potential conversion to 8-acetoxycampherenone epoxide is descr ibed. - iv -TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v L I S T OF TABLES v i L I S T OF SPECTRA v i ACKNOWLEDGEMENT v i i i SECTION A FURTHER OBSERVATIONS ON THE BROMINATION OF CAMPHOR * A b s t r a c t 2 I n t r o d u c t i o n 4 D i s c u s s i o n . . . 22 E x p e r i m e n t a l 39 R e f e r e n c e s 45 SECTION B SYNTHETIC APPROACH TO THE LONGICAMPHANE FRAMEWORK A b s t r a c t 49 I n t r o d u c t i o n 51 D i s c u s s i o n 61 E x p e r i m e n t a l I l l R e f e r e n c e s . . . 1 3 6 SECTION C SYNTHETIC APPROACH TO THE PICROTOXANE FRAMEWORK A b s t r a c t 141 I n t r o d u c t i o n D i s c u s s i o n Exper i m e n t a l R e f e r e n c e s - v i -LIST OF TABLES SECTION A Table Dihedral Angles for Compounds 45 32 (Scheme 3A) and Page . 33 LIST OF SPECTRA SECTION B Spectrum SECTION C Spectrum 1 Page N.m.r.. Spectrum (100 MHz) of Compound (132a) in CC1 4 100 N.m.r. Spectrum (100 MHz) of Compound (140) in CC1 4 101 N.m.r. Spectrum (100 MHz) of Compound (132a) in C ^ N 103 N.m.r. Spectrum (100 MHz) of Compound (141) in C 5D 5N 104 Page N.m.r. Spectrum (100 MHz) of Compound (119a) in CC1 4 219 N.m.r. Spectrum (100 MHz) of Compound (119b) in CC1 4 2 20 N.m.r. Spectrum (270 MHz) of Compound (119b) in CC1 4 221 - v i i -Spectrum Page 4 N.m.r. Spectrum (270 MHz) of Compounds (118) t (143) in CC1 4 227 5 N.m.r. Spectrum (270 MHz) of Compounds (144) * (145) in CC1 4 (D20) .... 228 6 N.m.r. Spectrum (270 MHz) of Compounds (146) and (147) in CC1 4 230 7 N.m.r. Spectrum (270 MHz) of Compound (160) in CCl^ 243 8 N.m.r. Spectrum (270 MHz) of Compound (15 8) in CC1 4 245 - v i i i -ACKNOWLEDGEMENT I would l i k e t o e x p r e s s my a p p r e c i a t i o n t o D r . Thomas Money f o r h i s g u i d a n c e t h r o u g h o u t the c o u r s e o f t h i s work. I would a l s o l i k e t o thank D r . M a l c o l m A l l e n , D r . N i c h o l a s D a r b y , and D r . C u r t i s Welborn f o r t h e i r h e l p f u l d i s c u s s i o n s and encouragement. The s u c c e s s f u l c o m p l e t i o n o f t h i s t h e s i s has a l s o depended on the e x c e l l e n t a s s i s t a n c e which I have r e c e i v e d from the s t a f f o f the n . m . r . , mass s p e c t r o m e t r y and m i c r o a n a l y s i s l a b o r a t o r i e s o f the C h e m i s t r y Department at U . B . C . D r . M i c h a e l Dadson and D r . C u r t i s Welborn d e s e r v e s p e c i a l m e n t i o n f o r the many h o u r s they d e v o t e d t o p r o o f r e a d i n g both the rough and f i n a l d r a f t s o f t h i s t h e s i s . F i n a l l y , I would l i k e t o acknowledge the H . R . M c M i l l a n F o u n d a t i o n f o r i t s generous f i n a c i a l a s s i s t a n c e d u r i n g t h e p e r i o d 1975-1979. SECTION A FURTHER OBSERVATIONS ON BROMINATION OF CAMPHOR - 2 -ABSTRACT (+)-Camphor Camphor has been f u n c t i o n a l i z e d a t the C-(8) p o s i t i o n by t r e a t i n g (+)-3,3-dibromocamphor w i t h bromine and c h l o r o s u l p h o n i c a c i d . The m e c h a n i s t i c r a t i o n a l i z a t i o n p r o p o s e d f o r t h i s t r a n s -f o r m a t i o n a l s o a c c o u n t s f o r the p r e s e n c e o f the minor s i d e p r o d u c t s which form d u r i n g 8- and 9 - b r o m i n a t i o n . - 3 --96 a) WM 2,3Me exo (6) (+)-9-Bromocamphor WM 2,3Me exo (ID) Br via alkene WM V (11) (-)-9-Bromocamphor VM - Wagner-Meervein rearrangement; 2,6H - 2,6-hydride s h i f t ; 2,We - 2,3-methyl s h i f t ; 2,3Br - 2,3-bromine s h i f t Scheme 1 - 4 -INTRODUCTION In our laboratory C(9)-bromination of (+)-camphor (1) (Scheme 1) i n chlorosulphonic acid and bromine i s assumed to occur by protonation of the C-(2) carbonyl function i n camphor followed by Wagner-Meerwein rearrangement (Schemel; 1 2 3 ) to give the b i c y c l i c carbonium ion 2 . cf. Scheme 1 Migration of an exo-methyi group (2,3-exo-methyl s h i f t ) from the center adjacent to the carbonium ion then y i e l d s carbonium ion 3 or i t s alkene equivalent. Bromination of 3 and return of the exo-methyl group (Scheme 1 , 4 -»• 5 -*• 6 ) complete the sequence which introduces a bromine atom on the (6) ^ W • Hafner-Meervein rearrangement; 2,6H - 2,6-hydrlde etalft; 2,Mi - 2,3-Mthyl e h i f t ; 2,3Br - 2,3-brcmine a b i f t cf. Scheme 1 - 5 -carbon that w i l l eventually return to the position of the C-(9) methyl in camphor. Return of t h i s group to the C-(9) position in camphor i s envisaged as taking place from the bro-minated carbonium ion 4 . A retro Wagner-Meerwein rearrange-ment followed by subsequent regeneration of the carbonyl func-tion at C-(2) as the driv i n g force y i e l d s (+)-9-bromocamphor (6). When (+)-camphor (1) i s brominated under these conditions (CISO^H - Br 2) the product i s p a r t i a l l y racemic 9-bromocamphor, l a b (6) + (11) ' . The racemization process leading to the pro-duction of (-)-9-bromocamphor (11) can be explained by consider-ing the equilibrium involved in the Wagner-Meerwein rearrange-ment (Scheme 1) 4 "t 7 cf. Scheme 1 followed by the sequence (8) (9) ->- (10). cf. Scheme 1 Scheme 2 - 7 -The carbonium ion 7 i s an asymetrical species which can under -go a 2,6-hydride s h i f t to y e i l d the enantiomeric ion 9 . This ion may then undergo a Wagner-Meerwein rearrangement followed by a 2,3-exo-methyl s h i f t and Wagner-Meerwein rearrange -ment to give (-)-9-bromocamphor (11). The equilibrium between structures 4 and 7 i s therefore responsible for the p a r t i a l racemization of the product 9-bromocamphor and the extent of 2 racemization w i l l be determined by the energy difference be -tween the two structures 4 and 7 . The bromination of (+)-3-bromocamphor (12) i s assumed to occur v i a the route outlined i n Scheme 2. The ismoeri-zation of (+)-3,9-dibromocamphor (17) to 6-endo,9-dibromocamphor (22) (Scheme 2) can be explained v i a the equilibrium 15 * 18 as shown i n Scheme 2. The sequence 19 -> 20 21 leads to the the production of (-)-6-endo,9-dibromocamphor (22) with the o r i g i n a l camphor configuration inverted. When (+)-9-bromo-camphor (6) i s subjected to strong acid conditions the struc-tures 7 and 8 (Scheme 1) are enantiomeric and inversion occurs. On the basis of c f . Scheme 2 - 8 -(18, X=Br) I (19, X=Br) ( 7, X=H ) ( 8, X=H ) cf. Schemes 1 and 2 these mechanistic considerations (concerning the bromination of camphor and (+)-3-bromocamphor under strong acid conditions) i t was presumed that d i r e c t 8-bromination could only occur i f an unprecedented 2,3-endo-methyl migration accompanied the i n t r o -duction of bromine (c_f. 26 -*• 27 ; Scheme 3 , p.9) The sequence 27 •+ 28 ->• 29 would then y i e l d ( + )-8-bromocamphor (29) (Scheme 3) . cf. Scheme3 The Wagner-Meerwein rearrangement of camphane and methyl-norbornyl cations i s an active area of research. Much attention has been devoted to determining the preference for exo- vs. 9 -Scheme 3 - 10 -Scheme 3A Scheme 3 (26) (33) WM (36) (35) (34) (+)-1,7,10,10-Tetra-bromo-3,3-$imethylbicyclo-[2.2.1]heptan-2-one Scheme 36 Scheme 4 - 13 -endo-migration of v i c i n a l groups adjacent to cations in these systems. A review of some of these results would seem in order at t h i s point as a means of introducing the background upon which the present work i s based. 2 Miki, Nishikawa and Hagiwara have studied the mechanism of isomerization by sulphuric acid in the camphor se r i e s . Nishikawa found that 3,9-dibromocamphor (17)(Scheme 4) underwent isomerization, involving migration of the a-halogen atom to the C-(6) position as well as inversion of the parent nucleus, to form 6-endo,9-dibromocamphor (22). The mechanism of the isomer-iz a t i o n given in Scheme 4 i s proposed by the authors. In this mechanism they suggest attack of the a c i d i c reagent on the car-bonyl function of 17 followed by Wagner-Meerwein rearrangement and 2,3-methyi s h i f t to y i e l d the cation 15 . C-(8) migration is favoured over the migration of the C - ( 9 ) halomethyl group since in 17+ 16 (Scheme 4) the C<1)-C(G) bond and the C(7)-C(8) bond are trans a n t i - p a r a l l e l and the C-(8) methyl group i s favoured, on s t e r i c grounds, to undergo migration to C-(l) as the C(l)-C(6) bond weakens and C-(6) migrates to C-(2). cf. Scheme 4 - 14 -The r e s u l t i s cation 15 which undergoes a further Wagner-Meer-wein rearrangement followed by a 2,6-hydride s h i f t and another Wagner-Meerwein rearrangement to provide the cation 20. c f . Scheme 4 Again on s t e r i c grounds, i t i s argued that the methyl group s i t u -ated in the coplanar d i r e c t i o n r e l a t i v e to the weakening bond in 19 should p r e f e r e n t i a l l y migrate to the adjacent carbonium ion in 20 and the Wagner-Meerwein rearrangement 21 22 completes the isomerization. c f . Scheme 4 In the f i n a l product 2T2 the halomethyl group, C-(9), has now taken up a trans configuration with respect to the carbonyl and the o r i g i n a l configuration of the camphor nucleus has been i n -verted . - 15 -( - ) - l (-)-A (-)-B - 16 -Finch and Vaughan"5 have suggested a mechanism (Scheme 5) for the sulphonation-racemization of camphor which invokes exo-vs. endo-methyl migration and supports the mechanism of the 2 Japanese workers . Their mechanism for sulphonation-racemiza-tion of camphor i s given in Scheme 5. Although Miki l e f t the problem of endo- vs. exo-migration open, Finch and Vaughan propose i t as an e s s e n t i a l feature of the racemization process. Using (±)-camphor-8-1 "*C , racemization of camphor in chloro-sulphonic acid with or without sulphonation at the C-(9) po s i -tion was shown to involve two exo-methyl s h i f t s , one before and one after sulphonation, and a 2,6-hydride s h i f t in the actual racemization step. This results in the transposition of the 8- and 10-carbons when one enantiomer i s converted to the other, the 9-carbon (sulphonated or not) remaining fixed. To provide a d e f i n i t e description of the behaviour of the (+)-camphor system during the sulphonation-racemization process leading to the formation of (±)-camphor-9-sulphonic acid E (Scheme 5) an unambiguous pathway was devised leading to a s p e c i f i c a l l y l l*C-labeled camphor which was then sulphonated to y i e l d (±)-camphor-9-sulphonic acid E . S p e c i f i c degradation methods then permitted unequivocal i d e n t i f i c a t i o n of the posi-tions in which the l a b e l appeared in E . Early attempts to account for both sulphonation and race-4 mization include a ring opening mechanism which would d i s t r i b u t e any l a b e l equally between the 8- and 9-positions, and a d i r e c t - 17 -sulphonation which makes no provision for racemization and therefore cannot account for the isotope d i s t r i b u t i o n . A mech-,6a,b ism has been proposed which accounts for both C-<9) and C-(10) sulphonation, but the racemization aspects have been ruled 2 out by the study conducted by Miki and coworkers. Another mechanism can be written for the sulphonation-race-mization process but i t invokes both endo and exo-methyl migra-tions. This mechanism was ruled out because i t necessitated the migration of the is o t o p i c l a b e l from C-(8) i n (+)-camphor-ic 8- C to C-(10) i n (+)-camphor-9-sulphonic acid, which was contrary to Finch and Vaughan's observations. Their investiga-t i o n supports the preference for exclusive exo-methyl migration i n the norbornane seri e s . Experiments conducted by Berson's F i g . 1 (+) - 3-endo-Me thy 1-2-cxo-norbornyl acetate ^ ( e n a n t i o m e r i c L — a e r i e s Products from 2,3-exo-hydrlde s h i f t . (+)-J-exo-Methyl 2—endo—norborayl acetate v i a 2.3-endo-hydrlde a h l f t <+) same stereo-chemical series Product from 2.3-endo-hydride s h i f t 7 group also indicate that the rearrangement of (+)-3-exo-methyl-2-endo-norbornyl acetate (Figure 1) i n acetic acid-sodium acetate takes a cir c u i t o u s route involving a 2,3-exo-hydride S h i f t rather than a more straightforward pathway requiring a - 18 -2,3-endo-hydride s h i f t . This evidence would seem to sugest that 2, 3-endo-methyl migration would be even more unfavour-able. There i s also an apparent requirement that an endo hydrogen become exo before i t can undergo a 2,3-migration i n the norbornane system*. I t has been reported, however, that 9 a b i n the bornane system authentic endo-2,3-hydrogen ' and 9c endo-2,3-methyl migration can occur. The results of Finch and Vaughan's study (Scheme 5) shows that the C-(9) position of (+)-camphor ((+)-l) remains the C-(9) position in (-)-camphor ( ( - ) - l ) while the o r i g i n a l C-(8) l a b e l experiences exo-migration to become C-(10) in (-)-camphor ( ( - ) - l ) . In addition the o r i g i n a l C-(10)-methyl experiences exo-migration to become the C-(8)-methyl in (-)-camphor ( ( - ) - l ) . Racemization involves a 2,6-hydride s h i f t and transposition of the C-(8) lable to the C-(10) position in (-)-camphor ( ( - ) - l ) occurs v i a the rearrangement sequence (+)-C * (_)_C % (-)-B t (-)-A shown in Scheme 5. (Continued on p. 20) * C o l l i n s et al.,° found that 2-phenyl-2,3-cis-exo-diol (F) rearranges with intramolecular migration of hydrogen from C-(3) to C-(2); the configuration of the ketone K produced i s inverted with respect to the configuration of F , and the phenyl remains attached to the same carbon throughout the rearrange-ment. A mechanism which can be written to explain these r e s u l t s includes the formation of the carbonium ion G , followed by rearrangement through ions H and I (with accompanying 2,6-hydride s h i f t ) to the ion J , which yei l d s ketone K which contains an inverted parent norbornane nucleus. (Continued overleaf) - 19 -(G) Ph B u s h e l l and W i l d e r f o u n d , however, t h a t 3 - e n d o - p h e n y l - 2 , 3 -c i s - e x o - d i o l (L) r e a r r a n g e d i n a c i d i c s o l u t i o n i n a p p r o x i m a t e l y 80% y i e l d t o 3 - e x o - p h e n y l c a m p h o r (M) . I f the r e a c t i o n i s c a r r i e d o u t f o r more than 4 h o u r s a t room t e m p e r a t u r e the compound i s o -l a t e d i s 3 - e n d o - p h e n y l c a m p h o r ( N ) . They s u b j e c t e d a d e u t e r a t e d d i o l 0 t o the same c o n d i t i o n s t h a t a f f e c t e d r e a r r a n g e m e n t o f d i o l L and found t h a t the p r o d u c t ketone P c o n t a i n e d more than 90% o f the d e u t e r i u m a t the 3-endo p o s i t i o n . O n l y r a c e m i c were u s e d i n t h e s e i n v e s t i g a t i o n s and t h u s t h e r e s u l t s do n o t c o n c l u s i v e l y p r o v e t h a t a 2 , 3 - e n d o - h y d r i d e s h i f t t a k e s p l a c e i n t h i s s y s t e m , (0) (P) - 2 0 -(-)-l .= 1 « * C (-)-A cf. Scheme 5 When (±)-camphor-8-1 "*C i s used as starting material 50% of the la b e l i s found as (±)-camphor-9-sulphonic acid-S-^C and 50% as (±)-camphor-9-sulphonic a c i d - 1 0 - 1 . It appears that for com-plete racemization, the o r i g i n a l l a b e l i s equally di s t r i b u t e d between the 8- and 9-positions. These results determine the d i s t r i b u t i o n after sulphonation-racemization, but only by establishing that the C-(8) l a b e l in authentic (±)-camphor (1) experiences a s p e c i f i c d i s t r i b u t i o n after the sulphonation-race-mization and appears in a p a r t i c u l a r position in (+) or (-)-camphor-9-sulphonic acid (E) as opposed to racemic camphor-9-sulphonic acid can the precise course of the process be estab-l i s h e d . To t h i s end (±)-camphor-8-1''C was subjected to resolution which la r g e l y eliminated (-)-camphor-8-1*C from the substrate - 21 -and after sulphonation the resultant (±) -cam£>hor-9-sulphonic acid (E) was resolved. Resolved camphor-9-sulphonic acid (E) was then subjected to two methods of degradation: one designed to remove the 9-carbon and the other the 10-carbon of camphor-9-sulphonic acid. Using this method i t was shown that in (+)-camphor-9-sulphonic acid the percent of the l a b e l at C-(8) was the same as the percent at C - ( 8 ) in ( + ) -camphor-8- 1 **C, while the same percentage o r i g i n a l l y at C - ( 8 ) in (+)-camphor-8- 1 **C i s found in the 1 0 -position in (-)-camphor-9-sulphonic acid. These r e s u l t s imply that configurational (and optical) inversion involves transposition of C - ( 8 ) and C- (10), and that these transpositions are the resu l t of exo-methyl s h i f t s . - 22 -DISCUSSION It has been found that the bromination of (+)-camphor (1) (Scheme 1) in chlorosulphonic acid solution provides p a r t i a l l y racemic 9-bromocamphorlb (6) + (11) (Scheme 1) as the major pro-duct, while the same conditions convert (+)-3-bromocamphor (12) (Scheme 2) to (+)-3,9-dibromocamphor (17)(Scheme 2). In the l a t t e r case, sel e c t i v e debromination with Zn-HBr can be accom-plished to provide a convenient route to (+)-9-bromocamphor (23) (Scheme 2) with complete retention of c o n f i g u r a t i o n 1 3 . From the foregoing introduction i t can be concluded that the sulphonation of camphor (Scheme 5) with sulphuric or chlorosulphonic acid proceeds s i m i l a r l y , with (+)-camphor ((+)-l) providing (±)-cam-phor-9-sulphonic acid ((±)-E) and (+)-3-bromocamphor providing (+)-3-bromocamphor-9-sulphonic acid . These methods, however, functionalize camphor at the C-(9) position to the exclusion of any f u n c t i o n a l i z a t i o n at C-(8). Because of the importance of C-(8) functionalized camphor derivatives as intermediates in or-ganic s y n t h e s i s 1 ^ 3 c , m e c h a n i s t i c 1 3 ' ^ ' 1 1 3 , and spectroscopic 12 studies the study of fu n c t i o n a l i z a t i o n of camphor at the C-(8) position has been the subject of considerable investigation. 3 1 lb Synthetic routes ' to 8-bromocamphor and 8-iodocamphor have been developed but these involve eleven- and nine-step sequences and in some cases provide racemic mixtures. The only method previously available for the synthesis of o p t i c a l l y pure (41) (42) - 24 -8-bromo- or 8-iodocamphor involves a twelve-step stereospecific sequence (Scheme 6) starting from camphor'*" 3'^ a'. This route^" a' i s based on a key transformation involving the con-version of 2-oxobornan-9-oic acid (37) (Scheme 6) to the lactone (39) . 13a, (38) cf. Scheme 6 The method i s long and the o v e r a l l y i e l d of (-)-8-iodocamphor (42) from (+)-camphor i s ca. 6%; for this reason many attempts b e ' have been made to provide a shorter and more e f f i c i e n t route to 8-substituted camphor derivatives, but these have f a i l e d . In general these unsuccessful e f f o r t s have t r i e d to take advantage of the proximity of the C-(8) methyl group to the 2-hydroxy group in isoborneol to induce oxidation at the former p o s i t i o n . .8 10 Isoborneol The ease of 9-bromination of camphor and the absence of 8-bromination can be explained in terms of the mechanism proposed by Miki and coworkers and studied by Finch and Vaughan. The accepted mechanism for thi s reaction involves exo-methyl migra-tion in the b i c y c l i c intermediate 4 + 5 (Scheme 1), while - 25 -Scheme 3 - 26 -Scheme 3A - 2 7 -Scheme 3 (26) (33) WM (36) (35) (34) (+)-1,7,10,10-Tetra-bromo-3, SHTimethylbicyclo-[2.2.1]hep tan-2-one Scheme 38 - 28 -8-bromination may require a rare endo-methyl migration, 26 27 (Scheme 3 ) 1 4 a , b . (27) cf. Scheme 3 In the hope of reversing the preference for exo- over endo-methyi migration i t was decided to place a bulky group in the 7-syn position of the b i c y c l i c intermediate 4 (Scheme 1). Since t h i s required the use of a 3rexo-substituted camphor as s t a r t -ing material and also a group which could be e a s i l y removed, (+)-3,3-dibromocamphor (23)(Scheme 3) was chosen as st a r t i n g material*. (+)-3,3-Dibromocamphor (23)was synthesized from com-mercially available (+)-3-endo-bromocamphor and then subjected to the usual bromination conditions (B^-CISO^H) used to convert (+)-3-endo-bromocamphor to (+)-3-endo,9-dibromocamphor (17) (Scheme 2). It was found that the bromination of (+)-3,3-di-bromocamphor (23)yields a crude product mixture whose major * 3-exo-bromocamphor i s not rea d i l y a v a i l a b l e . - 29 -component could be isol a t e d and p u r i f i e d . The spectral charac-t e r i s t i c s of this compound were consistent with the structure of {+)-3,3,8-tribromocamphor (28)(Scheme 3). It was possible to take p u r i f i e d product 28 and subject i t to debrominating con-di t i o n s (Zn-HBr) and convert i t in almost quantitative y i e l d to (+)-8-bromocamphor (29)(Scheme 3). When (+)-3,3-dibromocamphor (23) was treated with chlorosul-phonic acid in the absence of bromine, ( + ) -3,3,8-tribromocamphor was again the major product formed in ca. 50% y i e l d . We can explain t h i s r e s u l t i f we assume that (+)-3,3-dibromocamphor i s acting as a brominating agent under these conditions. In this way intermediate 25 (Scheme 3) can be transformed into 26 and subsequently provide (+)-3,3,8-tribromocamphor (28). Two minor products are also formed when (+)-3,3-dibromocam-phor i s treated with bromine and chlorosulphonic acid. One of these, (+)-1,7-dibromo-3,3,4-trimethylnorbornan-2-one (32) (Scheme 3A) , has been previously r e p o r t e d 1 ^ 3 ' ^ ' ^ and is presumably formed v i a the intermediate 25 (Scheme 3 and 3A). Our investigations have i d e n t i f i e d a second minor product which has been i d e n t i f i e d as the tetrabromo structure 36 (Scheme 3B) on the basis of n.m.r. and mass spectral data and th i s conclusion - 30 -was confirmed by X-ray c r y s t a l l o g r a p h i c analysis" 1"". The forma-t i o n of 36 presumably i n v o l v e s the intermediate 33 (Scheme 3B) which i s s u b j e c t to the rearrangement sequence 33 -*- 34 35 36 . (36) T h i s i s analogous to the sequence proposed f o r the format ion of 32 from i n t e r m e d i a t e 25 ( 25 30 ->• 31 -»• 32 ; Scheme 3A) . Thus i n the bromination of (+)-3,3-dibromocamphor (23)(Scheme 3), the formation of the products 28 , 32 , and 36 can be e x p l a i n e d o n l y i f 25 and 26 are true i n t e r m e d i a t e s i n the r e a c t i o n se-quences shown i n schemes 3, 3A, and 3B. The evidence r e s u l t i n g from the s t u d i e s c a r r i e d out on 9-bromination of the camphor system l e d to s p e c u l a t i o n that bromi-n a t i o n i n (+)-3,3^dibromocamphor might y i e l d an 8-bromination product a r i s i n g from a r a r e 2,3-endo-methyl s h i f t i n a b i c y c l o Q2«2»l^] heptane system. The p r a c t i c a l r e s u l t of t h i s s p e c u l a -t i o n was a s h o r t , simple s y n t h e s i s of o p t i c a l l y - a c t i v e 8-bromo-camphor. The s u c c e s s f u l outcome o f these i n v e s t i g a t i o n s , how-ever, c o u l d not be c o n s i d e r e d as d i r e c t evidence f o r the occur-rence of a 2,3-endo-methyi s h i f t d u r i n g the bromination p r o c e s s . S e v e r a l arguments have been proposed to account f o r 2,3-exo-methyl s h i f t r e g i o s p e c i f i c i t y i n the 9-bromination pr o c e s s . The t r a d i t i o n a l reasoning has i n v o l v e d a bridged ion p o s t u l a t e ^ . - 31 -It i s argued that since a non-classical norbornyl cation i s at-tacked by external nucleophiles from the exo d i r e c t i o n , internal 2,3-rearrangements of thi s same ion should also favour exo-migration strongly. 18 Brown has offered an alternative answer to the problem, based on s t e r i c grounds. He proposes that the exo side of the norbornyl molecule i s known to be less crowded than the endo toward attack by external reagents, therefore 2,3-shifts should occur p r e f e r e n t i a l l y exo. 19 Torsional e f f e c t s , as well, have also been used to explain 2,3-exo r e g i o s p e c i f i c i t y . i — 2 4—1 T r i c y c l o L.3'2'1'0 ' J octane has been used as a model for the endo (A) and exo (B) (Fig. 2) t r a n s i t i o n states for 2,3 mi-gration in the norbbrnane system. In the structures (A) (Fig. 2) the configuration about both the C(l)-C(2) and C(3)-C(4) bonds are eclipsed whereas in structures (B) the configurations about these same bonds are skewed. The bond rotation barrier about - 1 2 0 a C-C bond i s estimated at ca. 3 kcal mole . The t r a n s i t i o n state for endo-2,3-migration would then be less F i g . 2 - 32 --1 stable than that for the exo-migration by up to 6 kca l mole J~. It i s argued that t h i s difference i n energy i s more than enough to account for the experimentally observed degree of r e g i o s p e c i f i c i t y encountered i n 2,3-hydride or -methyl s h i f t s i n the bicyclo[2.2.l]heptane system. 21 A recent investigation by Vaughan and coworkers suggests that a stereoelectronic factor may be the agent determining which methyl group undergoes migration. In the case of camphene (1) (Fig. 3) the preferred migration of the exo-methyl group has been attributed to the unequal dihedral angles (a and 6 ; c f . (2); F i g . 3) between the C(3)-C(9), C(3)-C(10) bonds and the - J 9 C(2)-C(8) bond. If a > Br the exo-methyl group w i l l be closer than the endo-methyl group to the ideal coplanar rela t i o n s h i p with the developing p - o r b i t a l at C(2) and w i l l therefore migrate p r e f e r e n t i a l l y . The converse,B > a , would resu l t in a 2,3-endo-methyl s h i f t . This proposal has not been tested with camphene (43)(Fig. 3) 21 but a recent X-ray crystallographic analysis of camphene-8-carboxylic acid (45) has shown that t h i s molecule i s twisted and that the dihedral angle a i s greater than p (see Table 1, p.33). Fig. 3 - 33 -(4 5) ( 3 2 ; Scheme 3A) Table I; Dihedral Angles for Compounds 45 and 32 (Scheme 3A) Compound Compound C(3) -C(9)/C(2)- C(8) a, 64° C(3) -C(8)/C(2) -0 57° C(3) -C(10)/C(2) -C(8) 0 56 C(3) -C (9)/C(2) -0 61° C(3) -C(9)/C(4)- C(7) 78° C(3) -C (8)/C(4) -C(7) 88° C(3) -C(10)/C(4) -C (5) 52° C(3) -C(9)/C(4) -C(5) 42° Returning to our 8-bromination scheme (Scheme 3), i t had been predicted that bromination of (+)-3,3-dibromocamphor (23) would r e s u l t in a 2,3-endo-methyl s h i f t during the formation of (+)-3,3,8-tribromocamphor (28) . ! f Vaughan's proposal i s in fact correct t h i s 2,3-endo-methyl s h i f t would have resulted from a d i s t o r t i o n in the geometry of the intermediate 24 (Scheme 3) (cf. Fig.4 ) in such a way as to increase the dihedral angle 8 at the expense of a (cf. 46 ; Fig.4 )• - 34 -BrvZ^Br 8 P r o j e c t i o n along C(3)-C(2) bond (24; Scheme 3) (46) Fig. 4 This prediction, derived from Vaughan's proposal, could not be tested d i r e c t l y but i n d i r e c t evidence for i t s v a l i d i t y was ob-tained from the structure of dibromoketone 32 (Scheme 3A) which can be regarded as a reasonably close s t r u c t u r a l analogue of the hypothetical intermediate 24 (Scheme 3). Dibromoketone 32 i s formed during the bromination of (+)-3,3-di-bromo-camphor (23). (Scheme 3A) and re-examination of the previous-22 ly reported X-ray crystallographic data revealed that the d i -hedral angle C(3)-C(8)/C(2) -0 (a) was less than the angle C(3)-C(9)/C(2)-0 (8) (cf. Table 1). It seems reasonable then to suggest that the occurrence of a 2,3-endo-methyl s h i f t during the 8-bromination of (+)-3,3-dibromocamphor could be due to favour able geometric alignment between the endo-methyl group and the C(2) p - o r b i t a l in the pro-posed intermediate 24 (Scheme 3) and that this geometric (32 ; Scheme 3A) (23) WM 2,3Me endo »,t • Deuterium label 8-Deutereocamphor The numbering system in this diagram refers to the original methyl groups in (23). Zn-HBr; 8 19 n-Bu.SnH 9-Deutereocamphor WM 2J,3Me endo - J r LO U l Cu O I o WM 2,3Me exo • ,t ° Deuterium label The numbering system in this diagram refers to the original methyl groups in (23). 1 0 9 10 p _ 10-Deutereocamphor Br Zn-HBr; WM 9 h JO n-Bu-SnH 9 t 10 2,3Me endo CO 8-Deutereocamphor Br^ .Br Br^^Br - 37 -alignment may be associated with the s t e r i c e f f e c t of the C(7)-syn-bromine atom. The evidence presented above for 2,3-endo-methyl migration in the mechanism for 8-bromination of (+)-3,3-dibromocamphor is circumstantial; therefore the proposed mechanism (Scheme 3) must remain speculative. In order to obtain d i r e c t evidence for the mechanism experiments using C-(8) and C-(9) deuterium labelled (+)-3,3-dibromocamphor have been planned. Thus i f the bromination of (+)-3,3-dibromocamphor involves two endo-methyl s h i f t s (Scheme 7; endo, endo mechanism), then 8-deutereo-3,3-dibromocamphor should eventually provide 8-bromo-8-deutereocam-phor and hydrogenolysis with t r i - n - b u t y l t i n hydride (n-Bu^SnH) would y i e l d 8-deutereocamphor (cf. Scheme 7). S i m i l a r l y 9-deu-tereo-3,3-dibromocamphor would y i e l d 8-bromo-9-deutereocamphor which on hydrogenolysis (n-Bu^SnH) would provide 9-deutereocam-phor. On the other hand, i f the mechanism involved an exo-methyl s h i f t followed by an endo-methyl s h i f t (Exo, endo mech-anism; Scheme 8) this would resu l t in the conversion of 8-deutereo-3,3-dibromocamphor to 10-deutereo-3,3-dibromocamphor which would provide 10-deutereocamphor upon zinc-hydrogen bromide debromination followed by treatment with n-Bu3SnH. 9-Deuteri-ated material would provide 8-deutereocamphor after debromina-tion and hydrogenolysis. The three methyl groups of camphor are e a s i l y distinguished by proton n.m.r. (270 MHz) spectroscopy and a l l three are well resolved s i n g l e t s (in CDCl^) which have been previously - 38 -assigned^ - 3. Deuterium substitution on any one of these methyl groups can be determined since the s i n g l e t would then appear as 24 a t r i p l e t ( J D_ H = ca. 2 Hz) with 1/3 reduction in the o r i g i n a l r e l a t i v e i n t e n s i t y . Thus by using 8- and 9-deutereo-3,3-dibromo-camphor as s t a r t i n g materials i t should be possible to obtain the information necessary to determine unambiguously the pathway of methyl group migration during the formation of (+)-3,3,8-tri-bromocamphor (6) (Scheme 3) and thereby provide d i r e c t evidence to confirm or invalidate the mechanistic proposals outlined in Scheme 3. Such a study i s in progress in our laboratory. - 39 -EXPERIMENTAL Unless otherwise stated the following are implied. Melting points (m.p.) were determined on a Kofler micro heating stage or a Thomas Hoover c a p i l l a r y melting point apparatus and are un-corrected. Vapour phase chromatography (v.p.c.) was performed on either a Hewlett-Packard Model 5831A (flame ionization detector) gas chromatograph using 6' x 1/8" columns and nitrogen as c a r r i e r gas, or a Varian Aerograph Model 90-P (thermal conductivity de-tector) with 5' x 1/4" columns and helium as c a r r i e r gas. The following columns were employed: Column Dimensions Stationary Phase Support Mesh A 6' x 1/8" 3% OV-17 Chromosorb W 80/100 B " 3% OV-101 " 80/100 C " 3% OV-210 " 80/100 (above columns A, B, and C were used on the Hewlett-Packard 5831A) D 5' x 1/4" 3% SE-30 Varaport 30 100/120 E 10' x 3/8" 30% SE-30 Chromosorb W 60/80 F 6' x 1/8" 8% OV-17 " 80/100 (columns D, E, and F were used on the Varian Aerograph Model 90-P) Carrier gas flow rate for 1/4" columns was ca. 60 ml min 1 and for 1/8" columns ca. 35 ml min 1 . The 60 MHz nuclear magnetic resonance (n.m.r.) spectra were recorded on a Varian Associates Model T-60, while 100 MHz spectra were recorded on a Varian Associates Model HA-100 (CW) or Model XL-100 (FT). Signal - 40 -positions are given on the delta (6) scale with tetramethyl-silane (TMS) as an inter n a l reference (<5 0 . 0 0 ) . Signal multi-p l i c i t y , integrated area and proton assignments are indicated in parentheses. Infrared spectra (ir) were recorded on a Perkin-Elmer 137 B INFRACORD Spectrophotometer. Solution spectra performed using a sodium chloride solution c e l l of 0 . 1 mm thick-ness. Absorption positions ( v m a x ) are given in the cm ^ unit and are calibr a t e d by means of the 1601 cm 1 band of polystyrene. U l t r a v i o l e t (u.v.) spectra were recorded i n methanol solution on a Unicam model S.P. 800 spectrophotometer. Optical rotations C°Q D w e r e measured with either a Perkin-Elmer model 141 p o l a r i -meter or a Perkin-Elmer model 241 MC polarimeter. Low resolution mass spectra were determined on the Kratos-AEI model MS 902 or model MS 50 instruments. Microanalyses were performed by Mr. P . Borda, Microanalytical Laboratory, University of B r i t i s h Columbia, Vancouver. A l l of the solvents used for n.m.r.,ir,u.v., and o p t i c a l rotation studies were of Spectral grade. Reaction s o l -vents and reagents used were of either Reagent grade or C e r t i f i e d grade. Solvents were d i s t i l l e d before use. The term 'petroleum ether ( 3 5 - 6 0 )' refers to the low b o i l i n g "fraction of Reagent grade petroleum d i s t i l l a t e (b.p. ca. 3 5 - 6 0 ° ) . Dry solvents or reagents, where indicated, were prepared as follows: d i e t h y l ether (ether) and tetrahydrofuran (THF) by refluxing over sodium wire or lithium aluminum hydride followed by d i s t i l l a t i o n ; d i -methylformamide (DMF) by d i s t i l l a t i o n from barium oxide followed by storage over molecular sieves (Type 4A); chloroform (CHCl^) - 41 -and dichloromethane (CH 2C1 2) by d i s t i l l a t i o n from phosphorous pentoxide; hexamethylphosphoramide (HMPA) and dimethylsulphoxide (DMSO) by d i s t i l l a t i o n from calcium hydride followed by storage over molecular sieves (Type 4A); diisopropylamine and t r i e t h y l -amine by d i s t i l l a t i o n from and storage over potassium hydroxide p e l l e t s ; acetone by storage over anhydrous magnesium sulphate; benzene by d i s t i l l a t i o n from calcium hydride; and pyridine by storage over potassium hydroxide. S i l i c a gel for column chroma-tography was S i l i c a Woelm 100-200, active (70-150 mesh). Alumi-num oxide (Woelm neutral) for column chromatography was also em-ployed. Both types of packing were purchased from ICN Pharma-c e u t i c a l s , Inc. as the a c t i v i t y Grade I material and were deac-tivated to various a c t i v i t y grades with d i s t i l l e d water according to the manufacturer's instructions. F l o r i s i l used was from the F l o r i d i n Company. A n a l y t i c a l thin layer chromatography ( t . l . c . ) plates were prepared according to Stahl (type 6) (E. Merck Co.) from S i l i c a Gel GF-254 for t . l . c , and Alumina Woelm Neutral t . l . c . for thin layer chromatography (without binder) from ICN Pharmaceuticals, Inc. Plates were v i s u a l i z e d under long and short wavelength u l t r a v i o l e t radiation and were developed by iodine or by spraying with eerie ammonium sulphate in concen-trated sulphuric acid followed by heating. (+)-3,3,8-Tribromocamphor (28) Method (A) (+)-3,3-Dibromocamphor (23) (5.0 g, 16 mmole) was added to cooled (ice-water) chlorosulphonic acid (25 mil). The - 42 -mixture was allowed to warm to room temperature immediately and was s t i r r e d at th i s temperature for 4 hours. On work-up the reaction mixture was c a r e f u l l y added to i c e -water (ca. 200 g). Excess acid was destroyed with sodium hydro-gen carbonate and the aqueous solution was extracted with diet h y l ether. Drying over anhydrous magnesium sulphate and evaporation of the solvent provided an orange o i l (3.7 g) which was d i s t i l l e d (176°/0.115 Torr) to provide (+)-3,3,8-tribromocamphor (2B)(1.3g, 53% y i e l d ) . Chromatography over alumina (Alumina Woelm Neutral; a c t i v i t y grade IV) (30 g) eluting with petroleum ether (35-60) provided a product, which after sublimation (42°/5 x 10 Torr) and r e c r y s t a l l i z a t i o n from mixed hexanes, gave pure (+)-3,3,8-tr ibromocamphor (28) (m.p. 35-41° ) ; [ V j £>5 + 71.53° (c 0.720 in CHC1 3); 6(60 MHz,CCl4) 1.00 and 1.30 (two s i n g l e t s , 6H, t e r t i a r y methyls), 3.80 (d, IH, J=4.0 Hz, bridgehead methine), 3.26 and 3.76 (doublet of doublets, 2H, JAfi=12.0 Hz, C-(8) bromomethyl AB quartet); v (CCl.), 1776 cm"1 (sharp, strong, vC=0); U l u ^ C fx m/e 392/390/388/386 (M +), 311/309/307 (M-79, M-81), and 230/ 228 (311-81, 307-79). Anal, calcd. for C 1 0H 1 3Br 3O: C, 30.80; H, 3.35; Br, 61.45. Found: C, 31.25; H, 3.40; Br, 60.80 Method (B) (+)-3,3-Dibromocamphor (23) (17.3 g, 55.8 mmole) was added to cooled (ice-water) chlorosulphonic acid (25 ml) -contain-ing bromine (14.0 g, 87.4 mmole). The mixture was allowed to warm to room temperature immediately and was s t i r r e d at this temperature for 4 hours. - 43 -On work-up the reaction mixture was c a r e f u l l y added to i c e -water (ca. 200 g). Excess acid and bromine were destroyed with sodium hydrogen carbonate and sodium b i s u l p h i t e , r e s p e c t i v e l y . Extraction with d i e t h y l ether and work-up in the normal manner provided an orange o i l (25.5 g) which after d i s t i l l a t i o n (176°/ 0.1 Torr ) and chromatography over alumina (Alumina Woelm Neutral; a c t i v i t y grade IV) eluting with petroleum ether (35-60) provided (+)-3,3,8-tribromocamphor (28) (13.4 g, 61% y i e l d ) . The spectral c h a r a c t e r i s t i c s of thi s compound were i d e n t i c a l with those of the compound produced by method (A). (+)-8-Bromocamphor (29) (+)-3,3,8-Tribromocamphor (28) (5.0g, 12 mmole) was d i s -solved in cooled (ice-water) .glacial acetic acid (25 m£). Zinc-dust (2.67 g, 40.8 mmole) was added and the mixture was s t i r r e d vigorously. The exothermic reaction subsided after 0.5 hours and the cooling bath was removed. S t i r r i n g was continued for 0.5 hours. The contents of the flask were decanted from the zinc s a l t into d i e t h y l ether (200 mH). The ethereal solution was washed with water and dried over anhydrous magnesium sulphate. Evaporation of the solvent, followed by c r y s t a l l i z a t i o n of the s o l i d (2.95 g) from petroleum ether (30-60), provided (+)-8-bromocamphor (29) (m.p. 82-83° ) i d e n t i c a l (spectra) to an authen-25 t i c sample - 44 -(-)-1,7-Dibromo-4-dibromomethyl-3,3-dimethylnorbornan-2-one (36) In the preparation of (+)-3,3,8-tribromocamphor (28) by method (B) a solution of the crude product in mixed hexanes at -8° deposited c r y s t a l s , r e c r y s t a l l i z a t i o n of which from carbon tetrachloride provided pure (-)-1,7-dibromo-4-dibromomethyl-3.,3-dimethylnorbornan-2-one (36) (m.p. 127-127 .5°) ; £a~] £5 o -56.09 (c 1.77 i n CHCl 3); 6(60 MHz,CDCl3) 1.38 and 1.53 (two s i n g l e t s , 6H, t e r t i a r y methyls), 2.32 (m, 4H, ABCD), 4.38 (s, IH, C-(7) bromomethylene), 6.07 (s, IH, C-(4) dibromomethyl); v ( C C l J , 1770 cm - 1 (strong, sharp, vC=0); m/e 391/389/387/ max 4 385 (M_79, M-81) . Anal calcd. for C 1 ( )H 1 2Br 40: C, 25.65; H, 2.60; Br, 68.35. Found: C, 25.60; H, 2.65; Br, 68.30. REFERENCES (a) W.L. Meyer, A.P. Lobo, and R.W. McCarty, J . Org. Chem., 32, 1754 (1967). (b) H. Nishimitsu, M. Nishikawa, and H. Hagiwara, Proc•  Japan Acad., 27, 285 (1951) . T. Miki, M. Nishikawa, and H. Hagiwara, Proc. Japan Acad., 31, 718 (1955). A.M.T. Finch, J r . and W.R. Vaughan, J . Am. Chem. Soc., 91, 1416 (1969). H.E. Armstrong and T.M. Lowry, j . Chem. Soc., 1469 (1902). A. Windaus and E. Kuhr, Ann., 532, 52 (1953). (a) Y. Asahina, Proc. Imp. Acad. (Tokyo), 13, 38 (1937). (b) P. Lipp and H. Knapp, Ber., 73, 915 (1940). J.A. Berson, R.G. Bergman, J.H. Hammons, A.W. McRowe, A. Remanic and D. Houston, J . Am. Chem. Soc., 87, 3246 (1965) . G.J. C o l l i n s , Z.K. Chema, R.G. Werth, and B.M. Franklin, J. Am. Chem. S o c , 86 , 4913 (1964). (a) A.W. Bushell and P. Wilder, J r . , J . Am. Chem. Soc., 89, 5721 (1967). (b) P. Wilder, J r . and W-C. Hsieh, J . Org. Chem., 36, 2552 (1971). (c) S. Rengaragu and K.D. B e r l i n , Tetrahedron, 27, 2399 (1971). (a) E.J. Corey, M. Ohno, S.W. Chow, and R.A. Scherrer, J. Am. Chem. S o c , 81, 6305 (1959) . (b) G.L. Hodgson, D.F. MacSweeney, R.W. M i l l s , and T. Money, J.C.S. Chem. Comm., 235 (1973). (c) O.R. Rodig and R.J. Sysko, J . Org. Chem., 36, 2324 (1971) . (a) G.C. Joshi and E.W. Warnhoff, J . Org. Chem., 37, 2383 (1972) . - 46 -(b) O.R. Rodig and R.J. Sysko, J . Am. Chem. S o c , 94, 6475 (1972) and references c i t e d therein; c f . C.J. C o l l i n s and C.K. Johnson, J . Am. Chem. S o c , 95, 4766 (1973) . 12. M.T. Hughes and J . Hudec, J.C.S. Chem. Comm., 805 (1971). 13. (a) W. Carruthers, "Some Modern Methods of Organic Syn-thesis", Cambridge University Press, Cambridge, (1971), pp. 184-185. (b) E.C. Woodbury, "Intramolecular Functionalizations in the Camphane System", Ph.D. Thesis, Harvard University, Cambridge, (1967), pp. 11-15. (c) E.R. Sigurdson, B.Sc Thesis, University of B r i t i s h Columbia, Vancouver, (1973). 14. (a) J.A. Berson, J.H. Hammons, A.W. McRowe, R.G. Bergman, A. Remanick, and D. Houston, J . Am. Chem. S o c , 89, 2590 (1967). (b) C.W. David, B.W..Everling, R.J. K i l i a n , J.B. Stothers, and W.R. Vaughan, J . Am. Chem. S o c , 95, 1265 (1973) and references c i t e d therein. 15. (a) CR. Eck,- R.W. M i l l s , and T. Money, J.C.S. Chem. Comm. , 911 (1973). (b) CR. Eck, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 251 (1975). 16. S.E.V. P h i l l i p s and J . Trotter, Acta Cryst., 1332, 1423 (1976). 17. J.D. Roberts and J.A. Yancey, J. Am. Chem. S o c , 7_5, 3165 (1953); W.R. Vaughan and R. Perry, J . Am. Chem. Soc., 75 3168 (1953); P.D. B a r t l e t t , E.R. Webster, C E . D i l l s , and H.G. Richey, Ann., 623, 217 (1959); D.C. K l e i n f e l t e r and P. von R. Schleyer, J . Am. Chem. S o c , 8_3, 2329 (1961). 18. H.C. Brown, Chem. B r i t . , 199 (1966). 19. P. von R. Schleyer, J . Am. Chem. Soc., 89, 699, 701 (1967). 20. Propylene oxide, 2.56 kcal. mole - 1: D.R. Hershbach and J.D. Swalen, J . Chem. Phys., 29, 761 (1958); Propylene sulphide, 3.25 kcal. mole - 1: W.G. Fateley and F.A. M i l l e r , Spectrochim. Acta, 19, 611 (1963). - 47 -21. P.C. Moews, J.R. Knox, and W.R. Vaughan, Tetrahedron Lett., 359 (1977); P.C.Moews, J.R.Knox, and W.R.Vaughan, J. Am.  Chem. S o c , 100, 260 (1978). 22. C.A.Bear and J. Trotter, Acta Cryst., 1331, 904 (1975). 23. J.D. Connolly and R. McCrindle, Chem. and Ind., 379 (1965); P.V. deMarco, J.C.S. Chem. Comm., 1418 (1969); K.M. Baker and B.R. Davis, Tetrahedron, 24, 1663 (1968). 24. R.M. S i l v e r s t e i n , C G . Bassler, and T.C. M o r r i l l , "Spec-troscopic I d e n t i f i c a t i o n of Organic Compounds", 3rd. ed., Wiley Internat. Ed., New York, (9174), p. 180. 25. (+)-3,3,8-Tribromocamphor has also been converted into (+)-8-bromocamphor by using zinc and hydrogen bromide i n dichloromethane c f . CR. Eck, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 251 (1975). - 48 -S E C T I O N B S Y N T H E T I C A P P R O A C H T O T H E L O N G I C A M P H A N E F R A M E W O R K - 49 -ABSTRACT Longicamphane . g i n 2,2,6-Trimethyltricyclo[5.4.0 ' .0 ' ] -undecane An attempt to synthesize the longicamphane system via c y c l i z a t i o n of the intermediate enedione 84a to the ( 8 4a ) ( 74 ) diketone 74 led us to investigate an alternative synthetic route to enedione 84a . During this investigation an i n t e r e s t -ing new reaction occurred providing the p o l y c y c l i c ring system 6 , 7-dimethyl - 6 -(l-oxo - 2-methylpropyl) t r i c y c l o Q 4 • 2 • 1 • 0 3 ' 7~2 -nonan-9-one (88) (cf. Scheme 8, p. 6 7 ) whose structure was determined by X-ray crystallographic analysis. A mechanism i s proposed which involves carbonium ion capture by an acetylenic bond. Subsequent rearrangement yie l d s the t r i c y c l i c diketone 88 . - 50 -(88) Two routes to the enedione 84a were investigated. One of these routes involed a l l y l i c oxidation of the hydroxy-3-methyl-2-butenyl moiety jLn the 9-hydroxycampherenone derivative 133a. Attempts to oxidize t h i s compound to the enone 84a using standard procedures for a l l y l i c oxidation w i l l be ( 7 4 ) ( 1 3 3 a ) (135) described. During these investigations an al t e r n a t i v e route to the t r i c y c l i c diketone 74 was examined. The key step i n t h i s strategy involves intramolecular photochemical annelation of-the enol acetate 135. This route i s presented as a proposal scince work on t h i s scheme-was-halted as a r e s u l t of our i n a b i l i t y to synthesize the enol acetate 135 V i a the route chosen. - 51 -INTRODUCTION The synthesis of the longicamphane skeleton and more pre-c i s e l y longicamphor (4) i s of synthetic importance since there is a s t r u c t u r a l r e l a t i o n s h i p between longicamphor (4) and several other naturally occurring substances in the longicamphane group of sesquiterpenoids (cf. 1 - 4 ) . Fig. 1 Compounds such as longiborneol (1), longifolene (2) and longicyclene (3) ( F i g . l ) co-occur in nature 1 in Pinus l o n g i f o l i a Roxb. A chemical conversion of longicyclene (3) to longifolene (2) has been achieved by Dev and Nayak 1. These two compounds have a similar r e l a t i o n s h i p to that which exists between t r i -cyclene (5) and camphene (6) (Fig.2 ). - 52 -F i g . 2 I t i s t h i s s i m i l a r i t y which s t r o n g l y s u g g e s t s t h a t l o n g i c y c l e n e (3) i s the t e t r a c y c l i c isomer o f l o n g i f o l e n e ( 2 ) . I t has a l s o been p r o p o s e d ' t h a t the l o n g i b o r n y l c a t i o n 7 may. be i n v o l v e d i n some way i n the b i o g e n e s i s o f l o n g i f o l e n e a n d , t h e r e -f o r e , l o n g i c y c l e n e may be i n d i c a t i v e o f an a l t e r n a t i v e pathway o f n e u t r a l i z a t i o n o f t h i s c a t i o n i n the n a t u r a l s y s t e m . (7) (3) - 53 -Scheme 1 (Longifolene Synthesis (Corey)^a) (15) (16) (2) l,BOCH 2CH 2OH- £-Toluenesulphonlc «eid;ii,CH 3CH-PPh 3;iii,0*0^ ; iv,£-Toluenetulphonyl c h l o r i d e ; v , L i C 1 0 ^ ; v i , 6N H C l j v i i , EtjN-HOCHjCHjOH - 225';viii,Ph 3PCH 2N«-MeI;ix,HSCH 2CH 2SH-BF 3; *,LAH;xi,H 2NNU 2-H«'-HOCH 2CH 2OH;xii,Cr0 3-HOAc;xiil,MeLl; K i v , S O C l 2 - P y r i d i n e . Scheme 2 (Longifolene Synthesis (McMurry) 3 b ) (2) (27) (26) i,M«MgI;ii,50X H 2S0 4-Cyclohex«ne;iii,85X B - C I - C J H ^ C C ^ H . i v , B«CH 2SOCH 3;v,50Z H j S O ^ - C y c l o h e x a n e M e t h y l e n e c h l o r i d e ( 1 : 1 ) ; v i , K f J t - B u / C H B r 3 ; v i i , A g C l 0^ ^ i i i . N a * / l i q . N H 3 ; i x , C o l l i n s a V a a g t n t j x . M e ^ C u L i t x i . N a B H ^ j x i i . M e t h a n e s u l p h o n y l c h l o r i d e ; x i i i , K0_t-Bu;xiv ,Tr l a t r i p h e n y l p h o s p h i n e r o d i u n c h l o r i d e / H^; x v , M e L i ; x v i , S O C l , - P y r i d i n e . - 5 5 -If s t r u c t u r a l s i m i l a r i t i e s can be used to propose biogenetic connections between compounds which co-occur in nature, then these same ideas may also lead to a successful synthetic route in the laboratory. There have been several successful syntheses of racemic longifolene which have depended on the i d e n t i f i c a t i o n of basic ring systems within the structure of longifolene. Schematic representations and b r i e f descriptions of these syn-theti c routes are given below. 3a In Corey's synthesis of (±)-longifolene (2) (Scheme 1) the basic t r i c y c l i c framework was produced by c y c l i z a t i o n of an appropriate bicyclo Q 5*4*cQ' undecane derivative 8a to provide 8b . McMurry's synthesis (Scheme 2) started from an appropri-ately functionalized b i c y c l o ^4*4 *0~] decane derivative 18 which was c y c l i z e d and then ring-expanded to give k e t o l 19. (18) (19) Scheme 3 (28) (29) (30) (31) i,HBr-HOAc;ii,KOH-CHjOH;ii1 ,101 Pd/C-H 2;lv,NaH-CH 3CHBrC0 2Et ; v,NaOAc-Ac 20;vi,^-Bu 2AlH;vii.HjO*;vii i.Methanesulphonyl c h l o r i i x , Collidine;x,Ph 3P-CHOCH 3;xi,HC10 A;xii,K 2CO -CHjOH;xiii,CrO 3 H 2 S 0 4 ; x i v , ( C 0 C 1 ) 2 ; x v , C H 2 N 2 ; x v i , C u - T H F ; x v i i , L A H ; x v i i i , P h 3 P - C H 2 ; x i x , B H 3 / T H F - H 2 0 2 / ~ O H ; x x , C o l l i n s Reagent;xxl,NaN(SiMe 3) 2; x x i l , C a ' / l i q . NH 3 > ( L o n g i b o r n e o l S y n t h e s i s (Welch and W a l t e r s ) 3 c ) - 57 -Scheme 4 3d (Longifolene Synthesis (Oppolzer and Godel) ) i , P h C H 2 O C O C l - P y r i d i n e ; i i , h v ; i i i , H 2 - P d / C - H O A c ; i v , C H 2 - P P h 3 , Z n / C u CH 2I 2,H 2-Pt0 2-HOA C;v,H«Li,80Cl 2-Pyridine. - 58 -Welch and Walters (Scheme 3) synthesized longiborneol (±1), longicamphor (±4) and longicyclene (±3) from the bicyclo[4.2.l] nonane derivative 32 by adding a two carbon ethylene bridge to form the basic t r i c y c l i c skeleton of longicamphor (4) and longiborneol (1). Two other syntheses of longifolene have involved novel one step c y c l i z a t i o n s to provide the t r i c y c l i c £5-4 '0 1 ' 70 2 ' 9~2 -undecane framework 45. (45) *3 j Oppolzer and Godel (Scheme 4) used the intramolecular photochemical addition-retroaldol reaction sequence (DeMayo 4 reaction ) depicted in Figure 4 . By i r r a d i a t i n g the enol-enone 41 they achieved a simple and e f f i c i e n t synthesis of a t r i c y c l i c diketone 43 which was r e a d i l y converted to (±)-longifolene (2). - 59 -Scheme 5 (51) (52) y (53) i x - x i i i i . C u L i [ - ( C H 2 ) 3 C = C C H 3 J 2 ; i i , C H 3 C O C l ; i i i , C H 3 L i - E t 2 0 ; i v , B r 2 -Methylene c h l o r i d e ; v , 2 , 4 , 6-(CH 3) C ^ C C ^ N (CH )" ; v i , LAH ; vii,CF 3C0 2H;viii,2nBr 2/N«BH 3CN;ix,£-Toluenesulphonic »cid; x,RuO2/502 H 20 i n t-BuOH/HjIO f c-Na10^;xi,LiN(i-Pr ) 2 ~MeI; x i i , C H , L i ; x i i i , S 0 C 1 , - P y r i d i n e . 3c (Longifolene Synthesis (Johnson) ) - 60 -Fig. 4 3c Johnson et a l constructed the same t r i c y c l i c system v i a an acid-catalyzed c y c l i z a t i o n of the enynol 49 to provide the t r i c y c l i c carbinol 52 (Scheme 5 ) . - 61 -DISCUSSION The synthetic scheme to the longicamphane system considered here i s an extension of previous studies^ concerned with the development of stereoselective synthetic routes from camphor to a variety of complex sesquiterpenoids. The s i m p l i c i t y of the 5 successful synthesis by Money and co-workers was based on the recognition of the s t r u c t u r a l connection between camphor and the s p e c i f i c target molecules and aided by the development, in our laboratory, of a new three-step procedure for brominating camphor at the C-(8)-position . Starting with an appropriately C-(8)-substituted camphor der i v a t i v e , the stereoselective synthesis of campherenone (58a) was accomplished using a complex 55 derived from 8-methylbut-7 2-enyl bromide and tetracarbonylnickel . I ( 5 8 a ) ( 57 ) - 62 -The substrates used for reaction with this ir-allyl-nickel complex 55 were optically-active 8- and 9-iodocamphor ethylene acetals, 54 and 56 ,respectively. Reaction of the acetal iodide 54 derived from (-)-8-idodocamphor with the nickel complex, followed by hydrolysis, provided (-)-campherenone (58a). Subsequent reduction of (-)-campherenone (58a) with sodium-propan-l - o l and with lithium hydridotrimethoxyaluminate provided (-)-campherenol (59) and ( + )-isocampherenol (60) (Scheme 6). (5.8a) ( 57 ) S c h e m e 6 - 65 -( + ) -Isocampherenol (60) on heating with toluene-p_-sulphonyl chloride in pyridine^ was converted to (-)-B_-santalene (61). In a similar fashion ( + )-epicampherenone (57) was synthesized from (•-) -9-iodocamphor ethylene ace t a i (56) and subsequently trans-formed into (+)-epi-g-santalene (63) (Scheme 6). Campherenone (58a) has also been converted to ylangocamphor (65) and copacam-phor (66) (Scheme 7) . Epoxidation of the t r i s u b s t i t u t e d double bond followed by base-catalysed c y c l i z a t i o n , dehydration of the resulting t e r t i a r y alcohol and then hydrogenation provides a mixture of ylango- and copa-camphor (C-(10) epimers). This provides access to two of the three groups of compounds in Figure 5 . As indicated, the two groups containing ylangocamphor (65) and copa-camphor (66) are related by the mode of formation of their t r i -c y c l i c skeletons. Furthermore stereoselective chemical trans-formations retain the epimeric relationship between corresponding members of these two groups. Our synthetic approach to the longicamphane skeleton (cf. 4 ) was based on the p o s s i b i l i t y that campherenone could be e f f i c i e n t l y converted to the longicamphane skeleton by c y c l i z a -tion onto the double bonds through the most highly substituted carbon of the jr-bond. The syntheses of ylango- and copa-camphor had shown that c y c l i z a t i o n of campherenone vi a i t s epoxide 58b (Scheme 7) occurs at the less substituted carbon and results in the exclusive formation of 6-membered ring products. This was the case even though both 6- and 7-membered ring formation was possible under the base-catalyzed c y c l i z a t i o n conditions employed. - 66 -To reverse t h i s preference i t would be necessary to activate the terminal carbon of the double bond. Thus the 9-oxo-derivative 10 84a of campherenone was synthesized. The presence of the 9-oxo group in 84a would make C - ( l l ) susceptible to nucleophilic attack. Generating the enolate anion at C-(3) and intramolecular Michael addition onto the enone at C - ( l l ) would then produce the desired t r i c y c l o [j> • 4 • 0 1 ' 7 • 0 2 ' u n d e c a n e compound 74. The two carbonyl groups in the t r i c y c l i c diketone 74 would be expected to have d i f f e r e n t r e a c t i v i t i e s . For example, during investigations on the structure of culmorin (73), Barton and Werstiuk 8 noted that the diketone 73a could be reduced r e g i o s p e c i f i c a l l y at the C-(10) p o s i t i o n . Scheme 8 - 69 -A similar r e g i o s e l e c t i v i t y could be expected for diketone 74 which has an i d e n t i c a l carbon framework to that of Barton's diketone 73a so that the C-(2) carbonyl function of 74 may also be s t e r i c a l l y hindered toward reduction. Because of th i s s t e r i c constraint and the readily accessible nature of the 7-membered ring ketone we considered that no special precautions would be necessary to protect the C-(2) carbonyl of 74 while the C-(6) carbonyl was being reduced. This projected syn - t h e t i c sequence (Scheme 8) could then provide a simple synthesis of o p t i c a l l y pure longicamphor (4). The reduction of the bicyclo Q2 • 2 • 1^ ] heptanone using metal-l i q u i d ammonia i s known to provide the endo-alcohol almost ex-c l u s i v e l y ' . This i s the method of choice in Welch and 3c Walter's synthesis of racemic longiborneol from racemic l o n g i -camphor, 4 + 1 (Scheme 3). F i n a l l y , the conversion of longiiso-borneol (78) (Scheme 9), formed by reduction of l o n g i -camphor (4) with lithium aluminum hydride, to longifolene (2) could be accomplished by Wagner-Meerwein rearrangement of 78 (Scheme 9). The synthesis of longifolene (2) from l o n g i i s o -borneol (78) in t h i s manner i s analogous to the conversion of iso-borneol (75) to camphene (6) (Scheme 9) and could be accom-plished using similar reaction conditions (TsCl/pyridine). The synthesis of the enedione 84a (Scheme 8) began by conversion of (+)-8-bromocamphor (82) to (+)-8-cyanocamphor ethylene acetal (81). Conversion of (+)-8-bromocamphor (82) to i t s corresponding ethylene a c e t a l ^ employed standard conditions, - 70 -i . e . e t h y l e n e g l y c o l and a c a t a l y t i c amount of para-toluene s u l p h o n i c a c i d i n r e f l u x i n g benzene. T h i s was f o l l o w e d by t r e a t -ment of the 8-bromo ethylene a c e t a l d e r i v a t i v e with potassium cyanide i n hexamethyl phosphoramide (HMPA) at 100° f o r 96 hours to provide 81 as a c l e a r c o l o u r l e s s o i l i n 88% y i e l d . N i t r i l e 81 was then reduced with d i i s o b u t y l a l u m i n u m hydride (DIBAL) i n hexanes at -50° to an int e r m e d i a t e iminium s a l t which was c a r e -f u l l y h ydrolyzed to the corresponding aldehyde 80 using a mixture o f R o c h e l l e s a l t (sodium-potassium t a r t r a t e ) and 6N hydro-c h l o r i c a c i d . Aldehyde 80 i s uns t a b l e at room temperature and r e a d i l y undergoes t r a n s k e t a l i z a t i o n t o p r o v i d e 89. (80) (89) The two compounds shown above can be r e a d i l y d i s t i n g u i s h e d by t h e i r i n f r a r e d ( i r ) s p e c t r a . Compound 80 e x h i b i t s a s t r o n g band a t 1721 cm" 1 (vC=0); the t r a n s k e t a l i z e d m a t e r i a l 89 ex-h i b i t s a normal c a r b o n y l band f o r a b i c y c l o Q2-2«l^] heptan-2-one system a t 1739 cm" 1 (vC=0) accompanied by a weak, but d i a g -n o s t i c , a b s o r p t i o n a t 1408 cm" 1 (6CH 2)• T h i s 1408 c m - 1 band i n d i c a t e s the presence o f an a c t i v a t e d methylene group a to the - 71 -carbonyl group of the b i c y c l o £2*2*l]] heptanone ring system. The aldehyde could be p a r t i a l l y p u r i f i e d by chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 10% d i e t h y l ether-90% pet ether (35-60) as eluant. In t h i s way we obtained an 88% y i e l d of the desired aldehyde 80 which was estimated to be greater than 90% pure by v.p.c. analysis (column D at 180°). Aldehyde 80 was used without further p u r i f i c a t i o n in a subsequent Grignard reaction with 2-methyl-2-propenylmag-nesium chloride. The Grignard reaction provided a colourless o i l which, after chromatography on s i l i c a gel ( S i l i c a Gel Woelm, 100-200, a c t i v i t y grade III) using 20% d i e t h y l ether-80% petro-leum ether (35-60) as eluant, provided 8-(l-hydroxy-3-methyl-3-butenyl)camphor ethylene acetal 83a in 66% y i e l d . The i r spectrum of the intermediate alcohol exhibited an hydroxyl absorption at 3472 cm 1 (vO-H) and absorptions at 1645 cm 1 (vC=C) and 893 cm 1 (6=CH2) ind i c a t i v e of a terminal methylene group. Removal of the ethylene acetal was accomplished using a mixture of dioxane and IN hydrochloric acid at room temperature. This deketalization resulted in a crude product which was a colourless o i l exhibiting i r absorptions at 1739 cm 1 (vC=0) and 1408 cm 1 (SCf^) indicating that the camphor carbonyl had been regenerated. The unsaturated side chain remained intact exhibiting absorptions at 3571 cm - 1 (vO-H), 1639 cm"1 (vC=C) and 901 cm - 1 (6C=CH2). F i n a l l y , the crude unsaturated alcohol was oxidized to the diketone 83b in 98% y i e l d by dissolving i t in acetone and treating t h i s acetone solution with Jones reagent 1 1 - 72 -u n t i l a permanent orange colour was obtained. The double bond was brought into conjugation with the side chain carbonyl group by dis s o l v i n g 83b in petroleum ether (35-60) containing a small quantity of wet d i e t h y l ether and treating t h i s solution with alumina (Alumina Woelm Basic; a c t i v i t y grade I ) . This t r e a t -12 . ment isomerized the double bond from the B_,x t o T N E G,J3 posi-t i o n , r e l a t i v e to the side chain carbonyl group, to provide 8-(3-methyl-l-oxo-2-butenyl)camphor (84a). The u l t r a v i o l e t (u.v.) spectrum of t h i s compound confirmed that the double bond was conjugated with the carbonyl group. The u.v. spectrum (methanol) exhibited a strong absorption at A M A X 238 nm (e = 12,800) which i s consistent with the frequency and intensity expected ( X ^ = ^ 239 nm, z = 13,000) for a disubstituted a,B-un-saturated ketone. The o v e r a l l y i e l d from 8-formylcamphor ethylene acetal (80) to 84a was 56%. 13 A study was undertaken in our laboratory to determine whether or not the t r i c y c l i c longicamphor framework (4) could be obtained by using an intramolecular Michael reaction on the b i -c y c l i c enedione 84a by the reaction sequence outlined in Scheme 13 8 (p. 67) . Several attempts to synthesize the t r i c y c l i c dike-tone 74 by treatment of enedione 84a with a variety of basic and a c i d i c reagents were unsuccessful. Nevertheless, i t was our intention to investigate other reaction conditions before t h i s synthetic approach was abandoned. In an attempt to shorten the synthesis of enedione 84a and increase the o v e r a l l y i e l d other synthetic approaches were i n -vestigated . - 7 3 -Chromium trioxide-pyridine complex (Collins reagent) oxidizes alcohols to aldehydes and ketones in high y i e l d and has been p a r t i c u l a r l y e f f e c t i v e in oxidizing acid-sensitive alco-hols. An improvement on the u t i l i t y of the o r i g i n a l reagent was 15 reported by R a t c l i f f e and Rodehorst who made the complex in s i t u in dichloromethane. This avoided the problems involved in i s o l a t i n g the c r y s t a l l i n e complex. Dauben, Lorber, and F a l l e r t o n 1 ^ found that the isolated complex i s e f f e c t i v e in a l l y l i c oxidations, i . e . in oxidizing o l e f i n s d i r e c t l y to enones. 17 Other workers found that they were able to oxidize alkynes to acetylenic ketones but in only low y i e l d s . We attempted to u t i l i z e t h i s complex to synthesize enone 84b d i r e c t l y from campherenone ethylene acetal (58c). (58a;R«0) (84a;R=0) (5 8c;R=-0(CH 2) 20-) (84b;R=-0(CH 2) 20-) In these experiments we chose to use an _in s i t u method for gen-erating the complex since t h i s procedure had been used pre-18 viously to carry out a l l y l i c oxidations. (-)-Campherenone ethylene acetal (58c) was synthesized by the published method 19 of Money e_t a l . A t y p i c a l oxidation involved adding a - 74 -solution of (-)-campherenone ethylene acetal (58c) (1 equivalent) in dichloromethane to C o l l i n s reagent (15 equivalents) d i s -solved in dichloromethane and allowing the reaction mixture to s t i r at room temperature for 24 hours. Several reactions were carri e d out but the n.m.r., i r and v.p.c. analyses indicated in each case that no oxidation had taken place. The expected a, B_-unsaturated carbonyl stretch at 1675 cm 1 (vC=0) was not pre-sent in the i r spectrum. In addition n.m.r. and v.p.c. char-a c t e r i s t i c s of the reaction products showed l i t t l e difference from those of the star t i n g material, (-)-campherenone . ethylene acetal (58c) . In l a t e r investigations the acetal function was removed and (-)-campherenone (58a) was subjected to a l l y l i c oxidation using several chromium-based oxi d i z i n g agents. C o l l i n s reagent 1^, pyridinium chlorochromate^,and pryidinium 21 dichromate were a l l employed i n 15 molar exess over the sub-strate, (-)-campherenone (58a). These reactions were carr i e d out i n dichloromethane at room temperature for 24 hours and the re s u l t s i n each case were negative. Sta r t i n g material 58a was i s o l a t e d from the reaction each time i n 90-100% y i e l d and i n greater than 90% purity as determined by v.p.c. analysis (column D at 150°). Further inves t i g a t i o n of the di r e c t a l l y l i c oxidation of campherenone to enedione 84a was therefore abandoned. Another alternative synthesis of enedione 84a was now considered, the key step i n t h i s synthsis consists of a Meyer 22 -Schuster rearrangement of the alcohol 86 (p. 75 ) to the - 75 " Meyer-Schuster R e a r r a irtfemetit (86) Rupe Rearrangement (90) enedione 84a. An isomeric enedione 90 may also be formed 23 v i a a Rupe rearrangement , the mechanism of which i s given i n Figure 6. The Meyer-Schuster rearrangement involves the isomeriza-tion of secondary and t e r t i a r y a-acetylenic alcohols to a,8_-unsaturated carbonyl compounds v i a a 1,3-hydroxyl s h i f t . When the acetylenic group i s terminal, the products are aldehydes; otherwise, they are ketones (Fig. 7 )• O H (SJD a" ( 9 2 ) a' (93) 19 6) (95) F i g . 6 , Rupe Rearrangement (94) _ 76 -R', R )+ " C = C — R ^ (98a) R\ R / ^ O H K (97) R 'X (10 0) R'" H - = c = r / ? / (99) «^  \ Fig. 7,Meyer-Schuster Rearrangement Thus, in our alternative approach, the synthesis of acety-le n i c alcohol 86 (p. 67) was carr i e d out i n the following manner. Conversion of (+)-8-bromocamphor (82) to the correspond-ing ethylene acetal followed by treatment with potassium iodide in HMPA at 100° provided (+)-8-iodocamphor ethylene acetal ( 5 4 ) 1 0 . This iodo compound 54 was then treated with lithium acetylide ethylenediamine complex in a 1:1 mixture of d i e t h y l ether:HMPA at room temperature for 24 hours. Work-up provided 8-ethynylcamphor ethylene acetal (85) as an orange o i l which could be p u r i f i e d by vacuum d i s t i l l a t i o n to y i e l d a colourless o i l 85 whose n.m.r. spectrum exhibited a signal at 62.90 (a broad singlet) i n d i -cating the presence of an acetylenic hydrogen. The i r spectrum of 85 exhibited an absorption at 2128 cm"1 (vC=C). Alkyne 85 was then treated with n-butyllithium i n d i e t h y l ether at 0° and the acetylide produced was quenched with - 77 -acetone to provide 8-(3-hydroxy-3-methyl-l-butynyl)camphor ethylene acetal (86) in 63% y i e l d after chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 50% d i e t h y l ether-50% petroleum ether (35-60) as eluant. The n.m.r. spectrum of t h i s compound ex h i b i t e d a sharp s i n g l e t at 61.43 p.p.m.(6 pro-tons) , which i s consistent with a gem-dimethyl group situated on an oxygen-bearing carbon, and an ethylene acetal absorption cen-tered at 63.82 p.p.m. (broad multiplet, 4 protons). The i r spectrum exhibited absorption bands at 22 32 cm 1 (\>-C=C-) and 3448 cm - 1 (vO-H). The acetylenic alcohol 86 was then subjected to the a c i d i c conditions normally used to induce Meyer-Schuster rearrangement of t e r t i a r y acetylenic alcohols. Thus treatment of 86 with 98% formic acid for 21 hours provided an orange o i l which was 79% pure by v.p.c. analysis (colum A at 150°). The product was p u r i f i e d by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) with petroleum ether (35-60) as eluant, providing a compound (70% yield) which c r y s t a l l i z e d on standing. A portion of t h i s material was r e c r y s t a l l i z e d twice from petroleum ether (35-60) at -20° to give colourless white rods (m.p. 51-51.8°; sealed tube). High resolution mass spec-trometry indicated a molecular formula ( ci5 H22°2^ consistent with the structure of an enedione . However, the u.v. spectrum (methanol) of t h i s compound did not exhibit the c h a r a c t e r i s t i c absorption of an a, B_-unsaturated carbonyl system and only - 78 -displayed end absorption in the region 200-225 nm. The i r spectrum indicated that two carbonyl functions were present in the compound and that one of these belonged to a bicyclo ^2 * 2 • X^ ] heptan-2-one system (1745 cm 1 (vC=0)). There was no evidence, however, of any 1408 cm""1 (SCr^) absorption due to the active methylene a to such a carbonyl group. The other carbonyl function was also that of a saturated ketone (1709 cm - 1 (vC=0)). It was now clear that neither a Meyer-Schuster nor a Rupe rearrangement . had taken place but that an unexpected acid-catalyzed transforma-tion had occurred. The low resolution fragmentation pattern i n -dicated that two of the major pathways for fragmentation in thi s molecule resulted in the ions M +-C 3H 7 (M+-43 = m/e 191) 102 and M +-C 4H 70 (M+-71 = m/e 163) 103 . These two ions are the result of a-cleavage of an iso-propyl ketone . f C I R M + - C 3 H 7 m/e 191 (102) *1 M+-C.H_0 4 7 m/e 163 (103) a - 79 -This mass spectral evidence coupled with the information from the i r spectrum suggested p a r t i a l structures for the molecule, v i z . a bic y c l o £2 • 2 • 1] heptan-2-one with an a-substituent 104 and an iso-propyl ketone moiety 105 . Fig. 8 The n.m.r. (270 MHz) spectrum indicate that four methyl groups are present in the compound; two methyl singlets at 61.02 and 1.08 p.p.m. (6 protons) and two doublets ( i . e . two p r o c h i r a l iso-propyl methyl groups, 6 protons) centered at 61.05 p.p.m. (doublet, 3 protons, J=7.0Hz) and 61.06 p.p.m. (doublet, 3 pro-tons, J=7.0Hz). The iso-propyl methyls are coupled to a one proton septet centered at 62.89 p.p.m. (J=7.0Hz). Irradiation of the septet collapsed the p r o c h i r a l iso-proply methyl groups to two si n g l e t s at 61.09. and J61.11 p.p.m. The pos i t i o n of the septet (62.89 p.p.m.) indicates that i t must be adjacent to an electron-withdrawing group. This evidence supports the i r and mass spectral data which suggests that an iso-propyl ketone i s present in the molecule. Based on the part structures shown in Figure 8 we were able to account for 11 out of 15 carbon atoms present in the unknown structure. Of the remaining four carbon atoms, two were - 80 -m e t h y l groups ( n . m . r . ) and most l i k e l y a s s o c i a t e d w i t h the b i c y c l o Q2*2*l3] h e p t a n e -2 - o n e s y s t e m . S i n c e the l a c k o f any i r a b s o r p t i o n at 1408 cm 1 (6CH2) i n d i c a t e d t h a t s u b s t i t u t i o n had taken p l a c e a to the b i c y c l i c ketone i t seemed r e a s o n a b l e to c o n c l u d e t h a t c y c l i z a t i o n had o c c u r r e d at t h i s p o s i t i o n and t h a t the r e m a i n i n g two c a r b o n s were i n v o l v e d i n a carbon c h a i n b r i d g -i n g C-(7) and the a - p o s i t i o n o f a b i c y c l o Q 2 ' ' 2 » l ] ] heptanone (106) system ( c f . 106) . Of t h r e e p o s s i b l e t r i c y c l i c d i k e t o n e s t r u c t u r e s f o r t h i s compound ( F i g . 9 ) , 74 was i n c o n s i s t e n t w i t h ( 7 4 ) F i g . 9 - 81 -the presence of the M +-C 3H 7 and M +-C 4H 70 peaks in the mass spectrum and the septet at .62.89 p.p.m. in the n.m.r. spectrum. Structure 108 was d i f f i c u l t to r a t i o n a l i z e on mechanistic grounds and was also inconsistent with the presence of the M +-C 4H 70 peak in the mass spectrum. F i n a l l y , structure 107 was rejected by the independant synthesis described below (cf. Scheme 10) . 8-Formylcamphor ethylene acetal (80) (c_f. p. 82/ Scheme 10) was treated with iso-butyltriphenylposphonium y l i d e (1.25 equiv -alents) i n tetrahydrofuran (THF) for 8 hours at room temperar-ture. Work-up and chromatography of the product on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade III) using 20% d i e t h y l ether -80% petroleum ether (35-60) as eluant provided 8-(3-methyl-l-butenyl) camphor ethylene acetal (109b)(80% yield) as a colour-less o i l which was further p u r i f i e d by d i s t i l l a t i o n (b.p. 82-83°/2 x 10 3 T o r r ) . The n.m.r. of t h i s compound exhibited a s i x proton doublet at 60.93 p.p.m. (J=7.0Hz) for the iso-propyl group, a four hydrogen multiplet at 63.80 p.p.m. for the acetal and a two hydrogen multiplet at 65.23 p.p.m. for the v i n y l hydrogens. Microanalysis was consistent with the molecular formula Cj_7H2802* T ^ e o l e^^- n 109b was deketalized i n a mixture of acetone and 6N hydrochloric acid and provided the ketone 109a (vc=0,1739 cm"1) qu a n t i t a t i v e l y . Epoxidation of 109a with meta-chloroperbenzoic acid i n benzene provided 8-(1,2-epoxy-3-methylbutyl)camphor (110) as a clear colourless o i l (quanti* titative). The i r spectrum of 110 exhibits bands at 1255, 948,and 881 cm-1. Scheme 10 - 8 3 (107) Scheme 11 - 84 -characteristic of the epoxide group'6'*. Cyclization of 110 was accomplished by r e f l u x i n g 110 i n a solution of potassium tert-butoxide i n t e r t - b u t y l alcohol for 8 hours, t h i s provided the alcohol 1,6-dimrthyl-2-oxo-4-(l-hydroxy-2-methylpropyl)tricyclo-[jl «3 *0 *0 3' 7"2 nonane (111) (Scheme 10) which was p u r i f i e d by chromatography on s i l i c i c acid (Malincrodt S i l i c i c Acid, 100 mesh) using chloroform and then 1.5% ethanol (95%)-98.5% chloro-form as eluants. The alcohol 111 was oxidized to a mixture of diastereomeric t r i c y c l i c diketones 107 using Jones reagent. The structure of the diketones 107 was confirmed by an unam-biguous synthesis outlined in Scheme 11 (cf_. Section C, p.130). The key step in th i s scheme was the exclusive formation of the five-membered ring ketols 114 by base-catalyzed c y c l i z a t i o n of the keto-epoxide 113 . The spectral data obtained from the diastereomeric mixture of diketones 107 which resulted from t h i s synthetic scheme were i d e n t i c a l to those of the t r i c y c l i c diketone mixture 107 (Scheme 10). The i r spectrum exhibited two ketone functions at 1739 and 1710 cm - 1 (vC=0) and no active methylene stretch at 1408 cm 1 (dCH^) which indicated that c y c l i -zation had occurred a to the carbonyl group of the bicyclo Q2'2'l^] heptan-2-one system. The n.m.r. contained only one doublet at 61.06 p.p.m. (J=7.0Hz), the r e l a t i v e integrated inten-s i t y of which indicated two methyl groups (6 protons). Two other methyl si n g l e t s were also present at 60.89 p.p.m. and 60.98 p.p.m.. The high resolution mass spectrum analysis of the mole-cular ion (M+234) showed the molecular formula to be Ci5 H22°2 - 85 -but the fragmentation pattern for the compound 107 (Scheme 10) was d i f f e r e n t from that of the unknown compound from formic acid c y c l i z a t i o n of the acetylenic alcohol 86 (Scheme 8). This evidence forced us to conclude that structure 107 (Fig.9,p.80) was not that of the unknown. As indicated e a r l i e r , of the two possible remaining structures for t h i s compound, 108 was re-jected on the grounds that i t was d i f f i c u l t to r a t i o n a l i z e on mechanistic grounds and was also inconsistent with the presence of a peak at m/e 163 (M-C4H70) and structure 74 was rejected because i t was inconsistent with both a peak in the mass spectrum at m/e 191 and the septet at 62.89 p.p.m. in the n.m.r. spectrum. The f i n a l solution of the s t r u c t u r a l problem was provided by 25 X-ray crystallographic analysis which demonstrated that the diketone 88 was a t r i c y c l o • 2 • 1 *03 r nonane derivative (Scheme 8). Thus treatment of acetylenic alcohol 86 with formic acid had resulted in c y c l i z a t i o n as well as rearrangement of the o r i g i n a l bicyclo [^2*2*1^ heptane framework. A possible mechan-ism for t h i s transformation i s shown below (cf. 116->117 and 118*119). Acetylenes are known to react with both el e c t r o p h i l e s and 2 6 nucleophiles . The mechanism proposed in Scheme 8 requires that the acetylenic linkage acts as a source of electrons which tends - 86 -to neutralize the positive charge developing at C - ( 2 ) , resulting in the generation of a v i n y l cation 117. This v i n y l cation i s then neutralized by the solvent (formic acid) to y i e l d an enol formate 118. Further reaction,as indicated below, occurs to give 119. The reaction of acetylenic (118) (119) bonds with carbanions has precedent i n the chemical 27 2 7 b l i t e r a t u r e / a - g . Peterson's study of the s o l v o l y s i s of 6-heptyn - 2-yltosylate (120) and 6-octyn - 2-yltosylate (122) indicates that t r i p l e bond p a r t i c i p a t i o n occurs i n competition with normal s o l v o l y s i s . The s o l v o l y s i s of 120 in poor nucleo-p h i l i c solvents, e.g. t r i f l u o r o a c e t i c acid, w i l l r e s u l t in the c y c l i c v i n y l cation 121 i f the t r i p l e bond acts to a s s i s t in the s o l v o l y s i s of the t o s y l group. A linear c a t i o n i c species i s ruled out in the s o l v o l y s i s of 120 since this would resu l t in a - 8 7 -primary v i n y l cation. The s o l v o l y s i s of 122 could proceed via a l i n e a r c a t i o n i c t r a n s i t i o n state giving intemediate 123 (in which the cati o n i c carbon i s exocyclic to a 5-membered ring) or by a'bent' cation 124 (in which the cati o n i c carbon i s part of a 6-membered r i n g ) . Both of these c a t i o n i c species are secondary cations and therefore the product d i s t r i b u t i o n (5- and 6-membered ring ketones) should r e f l e c t the r e l a t i v e s t a b i l i t i e s , due to hybridization e f f e c t s , of bent and linear v i n y l cations. E f f e c t s other than hybridization may contribute to the ease of c y c l i z a -tion; for example s t e r i c e f f e c t s and to r s i o n a l s t r a i n . Hybridiza-28 a tion e f f e c t s , however, are considered to be so large they would be expected to predominate. The results of Peterson's experiments show that 5-membered ring products predominate i n the s o l -v o l y s i s of tosylate 122 . These results suggest that the tran-s i t i o n states for s o l v o l y s i s of the tosylates 120 and 122 bear almost no resemblance to li n e a r and bent v i n y l cations and the suggestion i s made that a bridged ion 125 may be a more appropriate structure for the t r a n s i t i o n state during s o l v o l y s i s of acetylenic tosylates of the type shown above i n 125. Thus, i t i s argued that t h i s bridged ion species does not - 88 -collapse in a product-determining step to a v i n y l cation such as 123 since there i s not a strong preference for 5-membered ring 28 b formation. Baldwin has suggested that successful acetylenic c y c l i z a t i o n of the type shown in 125 depends upon a b i l i t y of the approaching elec t r o p h i l e to acquire the correct geometry in the t r a n s i t i o n state: angle a must be 120° for successful formation of a 6-membered ring to take place. S i m i l a r l y , the angle 8_ must be equal to 120° for 5-membered ring formation to take place. Whether or not these geometrical re-quirements can be met in the t r a n s i t i o n state for c y c l i z a t i o n w i l l depend on the length of the carbon chain connecting the acetylenic group and the po s i t i v e center. Baldwin's empirical observations have led him to conclude that both 5- and 6-membered ring forma-tion are favoured processes in systems such as 125. Acetylenic bonds a s s i s t the s o l v o l y s i s of sulphonate esters with concomitant ring formation. Johnson and co-workers explored the p o s s i b i l i t y of using acetylenic bonds in po l y o l e f i n c y c l i z a -tions . They found that the dienynol 126 (p.89 ) with a methyl group attached to the acetylenic moiety c y c l i z e d in the presence of formic acid to the enol formate 127 . Hydrolysis of the enol formate gave 128 as the predominant epimer,the C-(l) 8_-isomer analogous to the C-(17) 8_-epimer in the 20-keto preg-nane s e r i e s . This conversion of 126 to 128 provided a model for the formation of the C/D portion of the pregnane series 27c steroids and was adapted to a synthesis of dl-progesterone - 89 -(128) Up to this point the center of attack for the acetylenic bond has been a positive center developed by s o l v o l y s i s of an 2 7c 2 7 f ester. Weiler and Hanack , however, have both shown that protonated carbonyl groups are also susceptible to attack by acetylenic bonds. Weiler and Hanack worked independently on the same acetylenic ketone 129 (p. 90) and obtained s i m i l a r r e s u l t s . Products obtained from the acid-catalysed c y c l i z a t i o n of the ketone 129 arose from a v i n y l cation intermediate of the type 130 and not from 131 . Both Weiler and Hanack*s re s u l t s pertain to products formed from transannular interac-tions of a protonated ketone with an acetylenic bond. Their studies, though, would seem good models to r a t i o n a l i z e , at least 90 -( 1 2 9 ) H + CO OH (130) in part, the mechanism leading to the formation of the t r i c y c l i c diketone 88 in our work. We propose, therefore, that i n i t i a l l y the ketal protecting group of 86 i s lost and the (86) (88) carbonyl function is regenerated. Protonation of this group leads to attack by the acetylenic bond (cf.116, p.85). This attack is facilitated by the position of the bond with respect to the carbonyl function of the bicyclo Q2*2'l^] heptane system. - 91 -Once th i s i n i t i a l interaction has taken place and the resulting v i n y l cation 117 (p. 84) has been captured by solvent (formic acid) to y i e l d the enol formate 118, a second protonation takes place. Subsequent rearrangement to a ketone with concomitant (118) -U19) production of the isomeric formate 119 which hydrolyzed on work-up to (+)-3,7-dimethyl-l-(2-methyl-l-oxopropyl)tri-cyclo[4.2.1.0 3 , 7]nonan-2-one (88) . (88) - 92 -( 7 4 ) Scheme 12 - 93 -Photochemical Route to the Longicamphane System In the work described above we have considered routes to the longicamphor system which involve c y c l i z a t i o n v i a an activated (84a) position in an appropriately substituted campherenone derivative 8 4a. Another possible route to the 7-membered r i n g of longicamphor i s outlined in Scheme 12. The key step in t h i s 4 route i s an intramolecular enone photoannelation of enol ace-tate 135 (Scheme 12) to y i e l d the cyclobutane derivatives* 136 and 137 . Hydrolysis of the acetate group in 136 would release the alkoxide ion which would be expected to undergo ring cleavage v i a a re t r o - a l d o l reaction to provide the dike-tone 74 . The reaction sequence considered for the synthesis of enol acetate 135 involved formation of a l l y l i c alcohol ,132a and i t s subsequent conversion as shown in Scheme 13. 30 New methods for removing methyl ethersunder mild condi-tions now make i t possible to use the methyl group in a much * The photoaddition of enones to o l e f i n s to produce cyclo-butane derivatives has been known for some t i m e 2 y . Oppolzer and G o d e l 3 d (cf. Scheme 4, p. 57) used a similar route to achieve a simple entry into the t r i c y c l i c skeleton of longifolene. \ - 94 -(132b) (132a) (135) (134a) Scheme 13 - 95 -wider context in the area of synthetic organic chemistry. We considered that the synthesis of the enol acetate derivative 135 (Scheme 12 and 13) from the a l l y l i c alcohol 132a could u t i l i z e protection of the alcohol as the methyl ether 132b . Removal of the acetal and conversion of the ketone 133b to i t s enol acetate using n-butyllithium and acetic anhydride would then provide 134b . The methyl ether could then be re-moved using t r i m e t h y l s i l y l i o d i d e 3 0 in a c e t o n i t r i l e or chloroform releasing the a l l y l i c hydroxyl (134a) which could then be o x i -dized to 135 . A l t e r n a t i v e l y , the a l l y l i c alcohol 132a could also be oxidized d i r e c t l y to the enone 84b. Subsequent removal of the acetal protecting group would then provide the enedione 84a. (132a) ( 8 4b ) / / ( 8 4 a ) _ 96 -In our i n i t i a l studies we attempted to synthesize the re-31 quired a l l y l i c alcohol 132a v i a the alkenyl lithium method , i . e . condensation of 8-formylcamphor ethylene acetal (8 0) with iso-butenyllithium. We were unsuccessful, however, in producing t h i s reagent following Braude's procedure 3 1 in which iso-butenyl bromide 3 1 and lithium pieces are s t i r r e d together in dry d i e t h y l ether at room temperature under a nitrogen atmosphere. We then turned our attention to the use of the corresponding Grignard reagent. Iso-butenyl bromide reacted cleanly with magnesium mesh at room temperature in tetrahydrofuran (THF) to y i e l d i s o -32 butenylmagnesium bromide . Both the keto aldehyde 138 (R=0) and the acetal aldehyde 80 (R=-0(CH 2) 20-) (p. 97) reacted smoothly with t h i s reagent in THF to provide the a l l y l i c alco-hols 132a and 133a. Neither of these alcohols could be oxidized to the required enone system when treated with a l l y l i c o x i d i z i n g agents. The f i r s t compound to be made with the a l l y l i c Grignard reagent was the acetal a l l y l i c alcohol 132a . The alcohol was prepared in 60-80% y i e l d by the addition of the acetal aldehyde 80 (R=-0(CH 2) 20-) to an excess of the iso-butenyl Grignard reagent in THF. Work-up and chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) provided the a l l y l i c alcohol 132a which was i d e n t i f i e d by i t s n.m.r., i r , and mass spectra. The n.m.r. spectrum (100 MHz) exhibited four methyy resonances between 60.72 and 0.92 p.p.m. These can be grouped into two - 97 -pairs, a) 60.72 and 0.88 p.p.m., and b) 60.78 and 0.92 p.p.m. The r e l a t i v e i n t e g r a l intensity for the two pairs corresponds to two methyl groups. The pairs arise as a resu l t of two modes of addition to the aldehyde function. This provides a mixture of diastereomeric alcohols. A broad singlet at 61.68 p.p.m. containing 6 protons was assigned to the two v i n y l methyl groups. The acetal resonances were seen as a broad multiplet at 63.78 p.p.m. while the a l l y l i c alcohol and v i n y l protons . were found at 64.38 and 5.16 p.p.m., respectively. The i r spectrum exhibited hydroxyl stretch at 3448 cm - 1 (vO-H) and a weak double bond absorption at 1653 cm - 1 (vC=C). The mass spectrum was very informative. A strong molecular ion (M+) was exhibited at m/e 280 accompanied by a strong peak at m/e 180. This peak at m/e 180 corresponds to the loss of frag-ments of t o t a l mass 100 (C f iH 1 n + H.,0) and can be rationalized by (132a;R= -0(CH 2) 20-) (133a;R=0) - 98 -Rearrangement involving the a l l y l i c alcohol results in the loss of two neutral molecules, water and 4-methyl-l,3-pentadiene, leaving a charged fragment with a mass of 180. The high resolu-tion mass spectrum confirmed the molecular formula as C;L7 H28°3 for t h i s compound 132a . Attempts to oxidize a l l y l i c alcohol 132a with various 33 . . . a l l y l i c oxidizing agents (manganese dioxide , pyndinium chloro-20 34 chromate , pyridine-sulphur trioxide complex , and sodium 35 . dichromate in dimethyl sulphoxide ) were uniformly unsuccessful and conversion of the a l l y l i c alcohol to the desired enone sys-tem of compound 84b was abandoned. We considered, at t h i s point, that the acetal protecting group of 132a was i n h i b i t i n g oxidation of the a l l y l i c hydroxyl. The 1,3-dioxolane r i n g oxygens have lone pair electrons which could interact with the incoming reagents and perhaps prevent oxidation. We decided to test t h i s hypothesis by removing the acetal protecting group and trying the - 9 9 -oxidation conditions on the ketol i t s e l f . Removal of the acetal group proved to be impossible without causing either 1,3-hydroxyl 32 • rearrangement of the a l l y l i c system providing the isomeric structure 141 or dehydration to y i e l d the diene 140. (141) Thus treatment of the acetal 132a with a solution of ace-tone containing a few drops of 6N hydrochloric acid provided the ketodiene 140 . This compound was readily i d e n t i f i e d by i t s n.m.r. (100 MHz) spectrum which was compared with the n.m.r. (100 MHz) spectrum of the acetal 132a (cf. spectra p.lOOand p. 101) in the same solvent (CCl^). The 1,3-diene was structured in such a way that one of the double bonds was terminal and was i d e n t i f i e d by a broad s i n g l e t centered at 64.86 p.p.m. (2 protons). A methyl sig n a l at 61.80 p.p.m. was s l i g h t l y s p l i t (J=2.0Hz, a l l y l i c coupling) which suggested (continued p. 102) - 102 -that one of the v i n y l methyls in the star t i n g material had been converted to a terminal methylene group by the l r 4 - e l i m i n a t i o n of water from the a l l y l i c alcohol. The protons (H A and Hg) of the second double bond were found as a doublet (1 proton, HB' JBA = 1^*^ H z) centered at 66.12 p.p.m. and two overlapping t r i p l e t s (1 proton, H A, J A B=16.0Hz and J A C=7.0Hz) centered at 6 5.61 p.p.m. Cha r a c t e r i s t i c carbonyl and active methylene absorptions at 1739 (vC=0) and 1404 cm"*1 (6CH2) confirmed that the carbonyl group had been regenerated. In addition two absorp-tions unique to the terminal methylene group (C=CH2) at 1605 (vC=C) and 887 cm"1 (6CH2) were noted. Confirmation that the double bonds were conjugated was obtained from the u.v. absorp-tion spectrum (95% EtOH) which exhibited X m a x 227 (e, 13,000). The methyl ether 132b was prepared from 132a by treatment of the alcohol with sodium hydride and quenching the thus formed alkoxide with methyl iodide. However, even under mild hydrolysis 3 6 conditions (2:1- acetic acid:water at room temperature) 1,3-hydroxyl rearrangement and cleavage of the acetal group occurred. This provided the t e r t i a r y alcohol 141 which was also re a d i l y i d e n t i f i e d from i t s n.m.r. spectrum (100 MHz) by comparison with the n.m.r. of a l l y l i c alcohol .132a in the same solvent (C^DjN)( spectra p.103 and p.104 ) . The n .m.r . spectrum of the product 141 indicated that the diastereoisomerism associated with the a l l y l i c alcohol 132a had disappeared. The saturated methyl region (continued p. 105) - 105 -contained only two sharp singlets at 60.85 and 60.94 p.p.m. The double bond resonance, s h i f t e d down to 65.82 p.p.m., now appeared as a complex multiplet with a r e l a t i v e integrated in t e n s i t y equivalent to two protons. This downfield s h i f t of the position of the double bond signal was accompanied by an up f i e l d s h i f t in the v i n y l methyl signals. The v i n y l methyls had coalesced into a sharp s i n g l e t at 61.46 p.p.m. (an up f i e l d s h i f t of 60.21 p.p.m.) (6 protons). The i r spectrum confirmed the presence of a hydroxyl function at 3390 cm 1 (vO-H), a camphor-like carbonyl absorption at 1739 cm 1 (vC=0) and, asso-ciated with this ketone, an active methylene group at 1408 cm 1 ( 6 C H 2 ) . The low resolution mass spectrum of t h i s compound exhi-bited a molecular ion (M +) at m/e 236 and the high resolution spectrum confirmed the molecular formula for the compound as ^15H24^2* This spectral evidence in connection with the work 32 done by Braude and Timmons on the oxotropic rearrangement of a l l y l i c systems led us to the conclusion that t h i s new alcohol had structure 141 (p. 99). Scince our e f f o r t s to sta-b i l i z e the a l l y l i c system by way of the methyl ether had f a i l e d to prevent rearrangement, even under mild a c i d i c conditions, further investigations with the acetal 132a were abandoned. Instead, the ketol 133a (p. 97) was synthesized d i r e c t l y from 8-formylcamphor (138) in one step using the Grignard reagent prepared from iso-butenyl bromide and magne-sium. The y i e l d s , after chromatography, were 50-70%. We found i t unnecessary to protect the camphor carbonyl dur ing t h i s - 106 -Grignard reaction since the ketone group i s protected from attack by bulky reagents by the C-.(8) and C-(10) methyl groups and. by the C-(5), C-(6) ethylene bridge. The keto aldehyde 138 was obtained by deketalization of the acetal aldehyde 80 . This keto aldehyde 138 i s extremely air sensitive and a neat sample oxidizes cleanly at room temper-ature in the presence of atmospheric oxygen to provide the keto Several unsuccessful attempts were made to oxidize a l l y l i c alcohol 133a to the corresponding enone 84a {p. 9 2 ) . The ox - i d i z i n g agents used included Jones reagent, manganese dioxide, C o l l i n s reagent, and dichlorodicyanoquinone. Our r e s u l t s are i n agreement with the results of other w o r k e r s 3 7 3 , b who have found cases i n which a l l y l i c oxidation of s i m i l a r systems with these reagents resulted i n poor y i e l d s of the desired enones. Dauben and M i c h h o 3 7 a found that the oxidation of 142 (p. 107j with pyridinium chlorochromate resulted in only a 31% y i e l d of enone 143 . This compound i s derived by 1,3-hydroxyl s h i f t followed by oxidation and i s an example of a l k y l a t i v e carbonyl - 107 " (144) (145) transposition. Sundararaman and Herz^'" were unable to oxidize the a l l y l i c alcohol 144 to the enone 145 using manganese d i -oxide. Other chromium-based oxidizing agents were t r i e d (Jones reagent, C o l l i n s reagent, pyridinium chlorochromate, and chromium trioxide-3,5-dimethyl pyrazole) but they gave the desired product 145 i n only 14.5-38% y i e l d contaminated with products from a l k y l a t i v e carbonyl transposition and over-oxidation. Examination of models of the acetal 132a and ketone 133a (p. 97) from our own work do not suggest any obvious reason for the lack of r e a c t i v i t y of these two compounds towards a l l y l i c pxidation. .Even though the literature contains evidence suggesting Scheme 14 - 109 -that a l l y l i c oxidation i s not always easy to achieve we decided to undertake a short structure c o r r e l a t i o n to confirm that the hydroxyl group was a c t u a l l y i n the a l l y l i c p o s i t i o n i n alcohol 132a (Scheme 14). The acetal aldehyde 80 was reacted with three d i f f e r e n t Grignard reagents: iso-butylmaqnesium bromide, 2-methyl-2-propenylmagnesium chloride, and iso-butenylmagnesium bromide. These procedures provided three acetal alcohols 146b , 83b, and 132a respectively. The alcohols 132a and 83b on hydrogenation of their respective double bonds, deketalization, and Jones oxidation each provide the same diketone which i s i d e n t i c a l to the diketone 149 produced by Jones oxidation of the saturated alcohol 146a . Before hydrogenation, com-pound 83a was subjected to standard deketalization conditions (acetone-6N hydrochloric acid at room temperature). The i r spectra for both compounds 147 and 146a (derived from 146b) indicated the presence of a carbonyl absorption at 1739 cm - 1 (vC=0) as well as hydroxy groups at 3509 cm 1 and 3571 cm (vO-H). The alcohol 132a could not be deketalized by t h i s method since even mild hydrolysis caused rearrangement (see p. 99). Hydrogenation of the alcohol 147 over 5% palladium on carbon at atmospheric pressure in hexanes provided a saturated compound which was oxidized immediately to a diketone using Jones reagent. This provided a compound whose spectral data were i d e n t i c a l to those of the diketone 149 obtained by oxidation of the k e t o l 146a under the same conditions. - 110 -Their n.m.r. (100 MHz) spectra exhibited a s i n g l e t at 60.85 p.p.m. (6 protons), a doublet for the iso-propyl methyls centered at 60.97 p.p.m. (J=7.0Hz) (6 protons), and a t r i p l e t centered at 62.75 p.p.m. (J=4.0Hz) (1 proton) for the bridgehead methine hydrogen. The i r spectra were also super-. imposable and indicated the presence of two carbonyl groups at 1739 and 1709 cm 1 (vC=0) accompanied by an active methylene absorption at 1408 cm"1 (6CH 2). High resolution mass spectral analysis confirmed the molecular formula i n both compounds as C15 H24°2* F i n a H y / the acetal alcohol 132a was hydrogenated at 40 p . s . i . of hydrogen i n hexanes using Adam's cat a l y s t (Pt0 2). The saturated material was then subjected to standard deketalization conditions (acetone-6N hydrochloric acid) and oxidized to a diketone using Jones reagent. This diketone was i d e n t i c a l i n a l l respects to compound 149. Micro-analysis of the purfied compound indicated a molecular formula C15 H24°2' *~n a 9 r e e m e n t with the high resolution mass spectral analysis. These s t r u c t u r a l correlations are consistent with the structure 132a assigned to the a l l y l i c alcohol derived by reaction of acetal aldehyde 80 and iso-butenylmagnesium bromide. Therefore, we must accept that under the normal oxidiz ing conditions the a l l y l i c alcohol moiety in 132a f a i l s to react. At t h i s stage we decided to terminate our investigation of the synthesis of the longicamphane framework v i a the projected route outlined in Scheme 12 (p. 92 )• - I l l -EXPERIMENTAL 8-Formylcamphor Ethylene Acetal (80) (+)-8-Cyanocamphor ethylene acetal (81) (2.33 g, 10.6 mmole) was dissolved i n hexanes (30 mJl) and cooled (dry i c e -acetone) to -50°. Diisobutylaluminum hydride (DIBAL) (Alfa; 20% i n hexane, 1 molar solution, 13 mi, 13 mmole) was added vi a syringe under a nitrogen atmosphere. As soon as addition was complete the reaction was warmed to room temperature over 2 hours. On work-up the reaction was c a r e f u l l y added to a mixture of saturated Rochelle s a l t and water (1:1) (150 mi). Hydrochloric acid (6N) (5 ma) was added and the mixture was s t i r r e d vigor-ously for 2 hours. Saturated sodium bicarbonate (6 mi) was added causing the solution to separate into two d i s t i n c t layers. The organic layer was washed with saturated sodium chloride, dried (sodium sulphate), and the solvent was evaporated to provide 8-formylcamphor ethylene acetal (80) as a clear colourless o i l . The o i l was p u r i f i e d by chromatography on alumina ( Alumina Woelm Neutral; a c t i v i t y grade III) (50 gm). 8-Formylcamphor ethylene acetal (80) was eluted from the column (10% di e t h y l ether-90% petroleum ether (35-60) as eluant (200 m£) ) as a c l e a r colourless o i l - 9 0 % pure by v.p.c. analysis on column D at 180° (2.07 g, 88% y i e l d ) . This material was used immediately without further p u r i f i c a t i o n ; 6 (60 MHz, CC1 4) 0.74 (s, 3H), 0.90 (s, 3H), 3.76 (m, 4H), 9.74 (t, IH, J=3.0Hz); v m a x (CC14) 2717 cm"1 (weak, vC-H of CHO), 1721 cm"1 (strong, sharp, vC=0), - 112 -and 1404 cm 1 (weak, sharp, «SCH2) . (.+)-8-Cyanocamphor Ethylene Acetal (81) (+)-8-Bromocamphor ethylene acetal (ref. 19) (10.0 g, 36.4 mmole) was dissolved i n dry hexamethylphosphoramide (HMPA) (100 m£) containing sodium cyanide ( 10.7 g, 0.22 mole). The reaction mixture was heated at 100° for 96 hours under a nitrogen atmosphere. On work-up the reaction mixture was poured into water (200 m£) and was extracted with petroleum ether (35-60). The organic layers were combined and washed with water. Drying (sodium sulphate) and evaporation of the solvent yielded (+)-8-cyano-camphor ethylene acetal (81). This material was p u r i f i e d by high vacuum d i s t i l l a t i o n (85-87°/0.01 Torr) (7.0 g, 88% y i e l d ; QoT]26 = + 5 . O 6 (c 2, 35, 95% EtOH) : 6 (60 MHzl CC14> 0.76 (s, 3H) , 1.05 (s, 3H), 2.13 and 2.86 (doublet of doublets, 2H, J A B=17.0Hz, C-(8) cyanomethyl AB quartet), 3.79 (m, 4H); v m = v (CC1.) 2247 lTlcl X ft cm - 1 (weak, sharp, vC=N) and 1420 cm 1 (weak, sharp, 6CH 2); m/e 221 (M+), 181, 113, 95 (base peak); M.W. calcd. for C,,H,_N0o: 221.1415. Found (high resolution mass spectrometry): 221.1422. Anal, calcd. for C 1 3 H 1 9 N 0 2 : C ' 7 0 - 5 4 ? H ' 8.50; N, 6.20. Found: C, 70.44; H, 8.50; N, 6.20. (+)-8-Bromocamphor (82) Compound 29 , section A p. 43 • - 113 -8- Cl-Hydro^-3-methyl-3-butenyl) camphor Ethylene Acetal (83a) Methallylmagnesium chloride was prepared i n the following way: neat methallyl chloride (7.60 g, 84.0 mmole) was added dropwise to a suspension of magnesium powder suspended i n die t h y l ether (6 0 ml). The addition was carr i e d out under an atmosphere of nitrogen at 0° over 1 hour. The reaction was then allowed to warm to room temperature and was s t i r r e d at t h i s temperature for 1 hour. At the end of t h i s period a white p r e c i p i t a t e was present. The ketal aldehyde 80 (0.860 g, 3.84 mmole) i n dieth y l ether (10 ml) was added to the suspension of methallylmagnesium chloride at 0° i n di e t h y l ether (10 ml). The reaction mixture was allowed to warm to room temperature and s t i r r e d for 2.5 hours. Work-up i n the usual manner (cf. preparation of (146b)) provided a clear colourless o i l (2.95 g) which was p u r i f i e d by chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using i n i t i a l l y petroleum ether (35-60) to elute impurities followed by di e t h y l ether to elute the required product 8 - ( l -hydroxy-3-methyl-3-butenyl)camphor ethylene acetal (8 3a) (1.05 g, 97% yield) as a clear colourless o i l . The compound 8 3a was deketalized i n the usual manner. 8-(3-Methyl-l-oxo-3-butenyl)camphor (83b) 8-Formylcamphor ethylene acetal (80) (765 mg, 3.42 mmole) in d i e t h y l ether (10 ml) was added i n one portion to 2-methyl-- 114 -2-propenylmagnesium chloride Cl molar i n d i e t h y l ether) (15 nU; 15 molar equivalents) at 4° (ice-water). The reaction was s t i r r e d at 4° for 20 minutes and then for 45 minutes at room temperature. On work-up the reaction mixture was hydrolysed c a r e f u l l y by the dropwise addition of saturated ammonium chloride solu-t i o n (50 ml). The aqueous mixture was extracted with d i e t h y l ether. The organic layers were combined and washed with satu-rated sodium chloride and dried (magnesium sulphate). Evaporation of the solvent gave 8-(1-hydroxy-3-methyl-3-butenyl) camphor ethylene acetal (83a) as a colourless o i l (630 mg, 66% yield) a f t e r chromatography on s i l i c a gel ( S i l i c a Gel Woelm 100-200; a c t i v i t y grade III) using 20% d i e t h y l ether-80% petroleum ether (35-60) as eluant; 6 (60MHz, CC1 4) 0.73 and 0.83 (two s i n g l e t s , 3H), 0.88 and 0.96 (two s i n g l e t s , 3H), 1.77 (bs, 3H) , 3.78 (m, 5H, acetal and alcohol methine protons)*, v (film) 3472 cm 1 (medium, broad, vO-H), 1645 cm \ 4.80 max ' ' ' (bd, 2H, J(gem) = 8.0Hz); (weak, sharp, vc=C), and 893 cm - 1 (strong, broad, 6=0^)• 8-(l-hydroxy-3-methyl-3-butenyl)camphor ethylene acetal. (83a) was deketalized i n dioxane (15 ml) and IN hydrochloric acid (1.5 ml) for 17 hours at room temperature. This gave, on work-up a colourless o i l (515 mg, 97% y i e l d ) ; 6 (60MHz, CC1 4) 0.82 and 0.85 (two s i n g l e t s , 3H) y 0.96 and 1.09 (two s i n g l e t s , 3H), 1.74 (bs, 3H), 3.84 (bm, IH), 4.82 (bd, 2H J „ = 12.0Hz); v (CC1.) 3571 cm"1 (weak, broad, vO-H) , (gem) max 4 1739 cm 1 (strong, sharp, vC=0), 1639 cm"1 (weak, sharp, vC=C), - 115 -"1 ~~ X 1408 cm (weak, sharp, SCB^) and 901 cm (medium, broad, 6=CH2). This ketol was oxidized immediately by disso l v i n g i n acetone (50 ml) and treating with Jones reagent u n t i l an orange colour persisted i n the solution. Work-up i n the usual manner gave 8-(3-methyl-l-oxo-3-butenyl)camphor (83b) as a colourless o i l (500 mg, 98% yield) which exhibited the i n f r a r e d c h a r a c t e r i s t i c s of a diketone, v i z . v (film) 1740 cm 1 (.strong, sharp, vC=0) , 1725 cm 1 (strong sharp, vC=0), 1650 cm 1 (weak, sharp, vG=C), 1408 cm 1 (weak, sharp, SCH^) and 895 cm 1 (medium, broad, 6=^^) • 8-(3-Methy1-1-oxo-2-butenyl)camphor (84a, R=0) 8-(3-Methy1-1-oxo-2-butenyl)camphor (8 3b) (5 0 mg, 0.2 mmole) was dissolved i n petroleum ether (35-60) (6 ml) contain-ing wet d i e t h y l ether (10 drops) and was treated with alumina (Alumina Woelm Basic; a c t i v i t y grade I) (15 0 mg) for 19 hours at room temperature. On work-up the alumina was f i l t e r e d o f f and washed care-f u l l y with d i e t h y l ether. Evaporation of the solvent yielded 8-(3-methy1-1-oxo-2-butenyl)camphor (84a, R=0) (45 mg, 90% yield) as a colourless o i l which c r y s t a l l i z e d on standing. This material was p u r i f i e d by sublimation (90°/10 Torr) to y i e l d colourless c r y s t a l s (m.p. 43-55°); 6 (60MHz, CCl 4) 0.83 (s, 3H), 1.02 (s, 3H) , 1.87 (d, 3H, J=2.0Hz), 2.12 (d, 3H, J=2.0Hz), 2.70 (bt, IH, J=4.0Hz, bridgehead methine proton), 5.93 (m, IH); vmax ^ C c l4^ 1 7 3 9 c m _ 1 (strong, sharp, vC=0), 1692 cm"1 (strong, - 116 -sharp, vC=0), 1618 cm 1 (.strong, sharp, vC=C) , and 1408 cm 1 (weak, sharp, 6CH 0); X (MeOH) 238 nm (e=12,800); m/e 234 (M+) , 218, 206, 153, 136 (base peak), 95; Anal, calcd. for C 1 5 H 2 2 ° 2 ; C ' 7 6 - 8 8 ; H ' 9 - 4 6 - Found: C, 76.66; H, 9.53. 8-Ethynylcamphor Ethylene Acetal (85) 8-Iodocamphor ethylene acetal (54) (see reference 19 for preparation) (3.36 g, 10.4 mmole) was dissolved i n a mixture of HMPA-diethyl ether (1:1) (20 ml). This mixture was added i n one portion to lithium acetylide ethylenediamine complex (Foote Mineral Co., 1.30 g, 14.0 mmole) suspended i n 40 m£ of the same solvent mixture and under a nitrogen atmosphere. This reaction mixture was s t i r r e d at room temperature for 24 hours On work-up the reaction was poured into a mixture of water and saturated ammonium chloride (1:1) (100 ml) and was extracted with petroleum ether (35-60). The organic layers were combined and washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided 8-ethynylcamphor ethylene acetal (85) (2.45 g) as an orange o i l o 3 which was p u r i f i e d by high vacuum d i s t i l l a t i o n (b.p. 68 /5 x 10 Torr) (1.24 g, 54% y i e l d ) ; 6 (60MHz, CC1 4) 0.78 (s, 3H), 1.02 (s, 3H), 2.62 (bs, IH), 2.90 (bs, IH), 3.77 (bm, 4H); v m = v (CCl.) ITlclX fx 2128 cm - 1 (weak, sharp, V C E C ) ; m/e 220 (M +), 205, 195, 181, 126, 113, 95 (base peak). M.W. calcd. for C 1 4 H 2 o ° 2 : 220.1463. Found (high resolution mass spectrometry): 220.1459. - 117 -8- (3-Hydro:xy-3-methyl-l-butynyl) camphor E t h y l e n e A c e t a l (86) 8-Ethyny.lcamphor e t h y l e n e a c e t a l (85) (1.77 g, 8.05 mmole) was d i s s o l v e d i n d i e t h y l e t h e r (25 ml), c o o l e d t o 4° (ice-water) and the s o l u t i o n was t r e a t e d w i t h n - b u t y l l i t h i u m ( A l f a ; 2.45 molar i n hexanes; 3.9 ml, 9.6 mmole, 1.2 molar e q u i v a l e n t s ) over 5 minutes. The r e a c t i o n was s t i r r e d a t 4° f o r 45 minutes and acetone ( d i s t i l l e d from 4A molecular s i e v e s and s t o r e d over magnesium sulphate) (0.70 g, 12 mmole) was added. The r e a c t i o n was warmed to room temperature and s t i r r e d f o r 2.5 hours. On work-up the r e a c t i o n mixture was poured i n t o s a t u r a t e d ammonium c h l o r i d e (100 ml) and e x t r a c t e d w i t h d i e t h y l e t h e r . The o r g a n i c l a y e r s were combined and washed w i t h water and s a t u r a t e d sodium c h l o r i d e . D r y i n g (magnesium sulphate) and e v a p o r a t i o n o f the s o l v e n t y i e l d e d 8-(3-hydroxy-3-methyl-l-butynyl)camphor e t h y l e n e a c e t a l (86) (2.29 g) as a y e l l o w o i l . T h i s crude product was p u r i f i e d by column chromatography on alumina (Alumina Woelm N e u t r a l ; a c t i v i t y grade I I I ) . The product was a p p l i e d t o the column i n 5% d i e t h y l ether-95% petroleum e t h e r (35-60) and the percentage o f d i e t h y l e t h e r i n the e l u a n t was g r a d u a l l y i n c r e a s e d to 50% a t which time the p r o p a r g y l a l c o h o l was e l u t e d i n 150 ml o f t h i s s o l v e n t system. T h i s p r o v i d e d 8-(3-hydroxy-3-methyl-l-butynyl)camphor e t h y l e n e a c e t a l (86) (1.42 g, 63.4% y i e l d ) as a p a l e y e l l o w o i l ; 6 (60MHz, CC1 4) 0.77 (s, 3H), 0.98 (s, 3H), 1.43 (s, 6H), 3.82 (bm, 4H); v (CC1„) 3448 cm" 1 (medium, broad, vO-H) and 2232 cm" 1 (weak, max 4 sharp, vC=C); m/e 278 (M +), 260, 181, 95 (base peak). M.W. - 118 -calcd. for c i 7 H 2 6 ° 2 : 278.1882. Found ( high resolution mass spectrometry): 278.1879. Anal, calcd. for C 1 7H 2g0 3: C, 73.33, H, 9.42. Found: C, 73.04; H, 9.52. (+) - 3, 7-Dimethyl-1- (2-Methy 1- 1-oxopropy 1) - t r i c y c l o r 4'2' l^O 3' 7~] nonan-2-one (88) • 8-(3-Hydroxy-2-methyl-1-butynyl)camphor ethylene acetal (86) (1.70 g, 6.1 mmole) was refluxed for 21 hours i n 98% formic acid. On work-up the reaction mixture was poured into water (50 ml) and extracted with d i e t h y l ether. The organic layers were combined and washed with water, saturated sodium bicarbonate, water and, f i n a l l y saturated sodium chloride. Drying (magnesium sulphate) and evaporation o f the solvent yielded an orange o i l (1.24 g, 79% pure by glc on column A at 150°). ' This o i l was subjected to p u r i f i c a t i o n by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade I I I ) . E l u t i o n with petroleum ether (35-60) (400 ml) provided 88 (1.0 g, 70% yield) as a pale yellow o i l which c r y s t a l l i z e d on standing over-night. A portion o f t h i s material was r e c r y s t a l l i z e d twice from petroleum ether (35-60) at -20° to give colourless white rods 88 (m.p. 51-51.8; sealed tube) 6 (270MHz, CDC13) 1.02 (s, 3H) , 1.05 (d, 3H, J=7,0Hz), 1.06 (d, 3H, J=7.0Hz), 1.08 (s, 3H), 2.89 (septet, IH, J=7.0Hz); v a v (CCl.) 1745 cm"1 (strong, sharp, vC=0) and 1709 cm"1 (strong, sharp, VC=0); m/e 234 (M +), 191, 163, 145, 135, 107, 95 (base peak); M.W. calcd. for C 1 5 H 2 2 0 2 : 119 -234.1620. Found (high resolution mass spectrometry): 234.1625. Anal, calcd. for c i 5 H 2 2 ° 2 : c' 76.B8; H, 9.46. Found: C, 77.09, H, 9.48. 8-(2'-(1',3'-Dioxoly1))camphor (89) A neat sample of 8-formylcamphor ethylene acetal (80) l e f t at room temperature for several days transketalized to 8-(2'-(l', 3'-dioxoly1)camphor (89) with spectral data i d e n t i c a l to those reported for compound (89) i n the experimental section for 8-formylcamphor (138) (cf. p. 126 t h i s section). 1, 6-Dimethyl-4- (l-oxo-2-methylpropyl) t r i c y c l o ^ • 3» 0 • 0 3 > 7~\ nonan-2-one (107) 8-(1,2-Epoxy-3-methylbutyl)camphor (110) (1.09 g, 4.24 mmole) was treated i n t e r t - b u t y l alcohol (100 ml) with potassium tert-butoxide (6.70 g, 59.8 mmole, 14 molar equivalents) at ref l u x for 8 hours under a nitrogen atmosphere. On work-up the reaction was .poured into water (200 ml) and extracted with petroleum ether (35-60). The organic layers were combined and washed with water and saturated sodium chloride. Drying (sodium sulphate) and evaporation of the solvent pro-vided 1,6-dimethyl-4-(l-hydroxy-2-methylpropyl)tricyclo-[]4« 3* 0* 0 3 ' 7"1[ nonan-2-one (111) which was p u r i f i e d by chroma-tography on s i l i c i c acid (Malincrodt S i l i c i c Acid, 100 mesh) (40 g) using, i n i t i a l l y , chloroform (100 mil) and then 1.5% ethanol (95%)-98.5% chloroform (130 ml) as eluants. This - 120 -provided 986 mg of the diastereomeric alcohols; 6 (100MHz, CCl^) 0.82 Cd, 3H, J=7.0Hz), 0.88 (s, 3H), 0.96 (s, 3H) , 0.97 (d, 3H, J=7.0Hz), 2.24 (m, IH), 2.68 (bs, IH), 3.07 (bm, 2H); v in 3 x (CCl^) 3413 cm 1 (m-dium, broad, vO-H) and 1739 cm """ (strong, sharp, vC=0). A portion of t h i s diasteromeric mixture was oxidized i n acetone using Jones reagent u n i t l a permanent orange colour developed i n the solution. On work-up the excess reagent was destroyed with a few drops of methanol and the reaction mixture was poured into water (100 ml). The product was i s o l a t e d by extraction with d i e t h y l ether. The organic layers were combined and washed with saturated sodium bicarbonate and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded l,6-dimethyl-4- (l-oxo-2-methylpropyl) tricycloQ4- 3* 0* 0 3' 7~2 nonan-2-one (107); 6 (100MHz, CC14) 0.89 (s, 3H), 0.98 (s, 3H), 1.06 (d, 6H, J=7.0Hz), 2.14 (bm, IH), 2.50 (bs, IH), 2.76 (m, 2H); vmax ^ C C i 4 ^ 1739 cm "*" (strong, sharp, vC=0) and 1710 cm 1 (strong, sharp, vC=0); m/e 234 (M +), 163, 153, (base peak), 135, 107, 93, 79, M.W. calcd. for C 1 5 H 2 2 ^ 2 : 2 3 4 " 1 6 1 9 " F o u n d (high resolution mass spectrometry): 234.1612. 8-(3-Methyl-l-butenyl)camphor (109a; R=0) 8-Formylcamphor ethylene acetal (80) (2.07 g, 9.2 mmole) i n THF (40 mil) was added over 10 minutes to a clea r orange solution of iso-butyltriphenylphosphonium bromide (5.26 g, - 121 -13.2 mmole, 1.25 molar equivalents) and n-butyllithium (Alfa. 2.25 molar i n hexanes; 5.17 ml, 11.6 mmole, 1.25 molar equi-valents) i n THF (4 0 m£). The mixture was s t i r r e d at room temperature for 8 hours. On work-up excess y l i d e was destroyed with methanol (0.5 ml) and the entire reaction mixture preabsorbed on s i l i c a gel ( S i l i c a Gel Woelm, 100-200; a c t i v i t y grade III) (25 g). The product 109b (R=-0(CH2)2°~) w a s chromatographed on s i l i g a gel of the same a c t i v i t y (50 g) using 20% d i e t h y l ether -80% petroleum ether (35-60) as eluant to y i e l d 8-(3-methyl-l-butenyl) camphor ethylene acetal (109b; R=-0(CH 2) 2)~) a s a colourless o i l (1.94 g, 80% y i e l d ) . This material was p u r i f i e d by high vacuum d i s t i l l a t i o n (b.p. 82-83°/2 x 10~ 3 Torr); 6 (100MHz, CC14) 0.76 (s, 3H), 0.80 (s, 3H), 0.93 (d, 6H, J=7.0Hz), 3.80 (m, 4H), 5.23 (m, 2H): Anal, calcd. for C 1 7 H 2 8 ° 2 : C ' 7 7 ' 2 1 ; H ' 1 ° - 6 8 - Found: C, 76.93; H, 10.53. Deketalization was accomplished by d i s s o l v i n g the ketol 109b (R=-0(CH2) 20-) i n acetone (25 ml) and 6N hydrochloric acid (10 drops) and s t i r r i n g at room temperature for 8 hours. Pouring into water (100 ml) and extraction with d i e t h y l ether, washing the combined ethereal layers with saturated sodium bicarbonate and saturated sodium chloride, drying (mag-nesium sulphate), and evaporation of the solvent yielded 8-(3-methyl-l-butenyl)camphor (109a; R=0) as a colourless o i l (1.08 g, quantitative). Compound 109a (R=0) was p u r i f i e d by high - 122 -vacuum d i s t i l l a t i o n (b.p. 75°/10~ 3 Torr); 6 (100MHz, CC14) 0.90 (s, 6H) , 0.94 (s, 3H) , 0.9 7 (s, 3H) , 5.30 Cm, 2H) ; v m = i v (CC1.) 1739 cm 1 (strong, sharp, vC=0), 1408 cm 1 Cweak, sharp, iCE^) abd 1370 cm"1 (weak, doublet, <5CR"3) ; m/e 220 (M+) , 138, 137, 136, 135, 125, 124, 122, 109 (base peak); M.W. calcd. for C 1 5H 2 40: 220.1827. Found ( high resolution mass spectrometry): 220.1811. 8-(1,2-Epoxy-3-methylbutyl)camphor (110) 8-(3-Methyl-l-butenyl)camphor (109a; R=0) (1.3 g, 6 mmole) was dissolved i n benzene (30 m£) and cooled to 4° ) i c e -water) . meta-Chloroperbenzoic acid (1.12 g, 6.5 mmole, 1.1 molar equivalents, 85% pure) i n benzene (30 ml) was added over 30 minutes. The reaction was s t i r r e d at 4° for an additional 0.5 hours and then allowed to warm to room temperature over 2 hours. On work-up, the reaction mixture was transferred to a separatory funnel and washed with small portions of saturated sodium bis u l p h i t e (5 m£ portions) u n t i l the benzene layer gave a negative starch-iodide test. F i n a l l y , the organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, and dried (sodium sulphate). Evaporation of the solvent yielded 8-(1,2-epoxy-3-methylbutyl)camphor (110). This material was p u r i f i e d by high vacuum d i s t i l l a t i o n (b.p. 84°/ 10~ 3 Torr) (1.4 g, quantitative); 6 (100MHz, CC1 4) 0.83 (s, 3H), 0.90 (d, 3H, J=6.0Hz), 1.04 (d, 3H, J=6."0Hz), 1.05 (s, 3H) , 2.88 Cm, 2H) ; (CC1A) 1739 cm"1 (strong, sharp vC=0) , 1408 cm"1 - 12 3 --1 (weak, sharp, 6CH 2) f 1255, 948 and 881 cm (epoxide); m/e 236 (M +), 193, 153 (base peak), 137, 136, 135, 123, 121, 109, 108, 107, 95, 94, 93; M.W. calcd. for C 1 5 H 2 4 0 2 : 236.1775. Found (high resolution mass spectrometry): 236.1786. 8-(l-Hydroxy-3-methyl-2-butenyl)camphor Ethylene Acetal (132a; R=H), (9-Hydroxycampherenone Ethylene Acetal) 8-Formylcamphor (80) (2.0 g, 8.3 mmole) was added to iso-butenylmagnesium bromide (16.0 mmole) i n THF (10 ml). Iso-butenylmagnesium bromide was prepared by adding i s o -butyl bromide (2.41 g, 17.9 mmole) to magnesium turnings (0.384 g, 16.0 mmole) i n THF (15 ml). The mixture was refluxed for 3 hours under an atmosphere of nitrogen. The aldehyde was added to the re f l u x i n g solution of the Grignard reagent i n THF (5 mil) i n one portion and re f l u x i n g was continued for 18.5 hours. On work-up the reaction mixture was cooled to room temper-ature and was then hydrolyzed by the careful addition of saturated ammonium chloride solution. Just enough ammonium chloride solu-t i o n was added to produce a granular white p r e c i p i t a t e which was removed e a s i l y by vacuum f i l t r a t i o n . The f i l t r a t e was dried (magnesium sulphate) and evaporation was p u r i f i e d by column chromatography on s i l i c a ( S i l i c a Gel Woelm; a c t i v i t y grade III) using, i n i t i a l l y , petroleum ether (35-60) (100 mil), then 25% di e t h y l ether-75% petroleum ether (35-60) (700 mil) , and f i n a l l y 100% di e t h y l ether (500 mil) as eluants. This provided 8-(1-hydroxy-3-methy1-2-butenyl)camphor ethylene acetal (132a; - 124 -R=H) (1.70 g, 68% yield) (97% pure by v.p.c. on column A at 180°) as a diasteromeric mixture of two alcohols; 6 (100MHz, CCl^) 0.72 and 0.88 (two s i n g l e t s , 3H) 3.78 (m, 4H), 4.38 (m, IH), 5.16 Id, IH, J=8.0Hz); v m a x (CC14) 3448 cm"1 (strong, broad, vO-H) and 1653 cm"1 (weak, broad, vC=C); m/e 280 (M +), 180, 125, 108, 95 (base peak). M.W. calcd. for C 1 7 H 2 g 0 3 : 280.2038. Found (high resolution mass spectrometry): 280.2040. 8-(l-Methoxy-3-methyl-2-butenyl)camphor Ethylene Acetal (132b; R=CH->) , (9-Methyoxycampherenone Ethylene Acetal) 8-(l-Hydroxy-3-methyl-2-butenyl)camphor ethylene acetal (132a; R=H) (1.0 g, 4 mmole) was dissolved i n THF (20 m£) and treated with sodium hydride (322 mg, 50% suspension i n o i l . 6.71 mmole) ( the sodium hydride was washed with petroleum ether (35-60) (3x) under a nitrogen atmosphere p r i o r to use). The reaction mixture was refluxed under an atmosphere of nitrogen u n t i l hydrogen ceased to evolve (ca. 1.0 hour). Methyl iodide (1.90 g, 13.4 mmole) was then added and the reaction was re-fluxed for an additional 16 hours. On work-up the reaction mixture was poured into d i e t h y l ether (75 m£) and the ethereal solution washed with water and dried (magnesium sulphate). Evaporation of the solvent pro-vided 8-(l-methoxy-3-methyl-2-butenyl)camphor ethylene acetal (132b; R=CH3) as a colourless o i l (quantitative); 6 (60MHz, CC1 4) 0.75 (s, 3H), 0.90 (s, 3H), 1.68 (s, 3H), 1.77 (s, 3H), 3.08 (s, 3H), 3.30 (m, IH), 3.75 (m, 4H), 5.0 (d, IH, J=8.0Hz); - 125 -v (CCl.) 1093 cm"a (strong, broad, vC-O-C); m/e 294 (M'), 180, 99 (base peak), 95. M.W. caled. for C 1 8 H 3 0 O 3 : 294.2195 Found (nigh resolution mass spectrometry): 294.2194. 8-(l-Hydroxy-3-methyl-2-butenyl)camphor (133a; R=H), (9-Hydroxy-campherenone) The keto aldehyde, 8-formylcamphor (138) (2.70 g, 70% pure by v.p.c. on column F at 190°) was dissolved i n THF (20 mil) and cooled to 4° (ice-water). The Grignard reagent iso-butenyl-magnesium bromide (11.5 mil of a 1.3 molar solution i n THF, 15 mmole) was added v i a syringe to the THF solution of the keto aldehyde (138) . The reaction mixture was kept under a nitrogen atmosphere at room temperature for 24 hours. Work-up as before (cf. (132a; R=H)) provided a yellow o i l (3.63 g) which was p u r i f i e d by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) uisng, i n i t i a l l y , 4% d i e t h y l ether-96% petroleum ether (35-60) (100 m£) and then gradually increasing the percentage of diet h y l ether to 20% during the next 600 mil of eluant. The column was washed f i n a l l y with 100% d i e t h y l ether (400 mil) . This provided two compounds: 8-(2-(1,3-dioxolyl))camphor (89) (contaminating s t a r t i n g material) was eluted from the column using 12% ether-88% petroleum ether (35-60) (125 mil) (716 mg) and was i d e n t i f i e d from i t s n.m.r. and i r spectra, and then 8-(1-hydroxy-3-methy1-2-butenyl)camphor (133a; R=0, R^H) was eluted i n 100% d i e t h y l ether as a c l e a r colourless o i l ; <5 (CC14) 0.82 and 0.86 (two - 126 -sin g l e t s , 3H), 1.00 and 1.06 (two si n g l e t s , 3H) , 1.70 (m, 6H, J=1.5Hz), 4.43 (bm, IH) , 5.18 (bd, IH, J=7.0Hz); v (CC1J 3484 cm (weak, broad, vO-H), 1739 cm 1 (strong, sharp, vC=0), -1 + 1408 cm (weak, sharp, 6CH 2); m/e 236 (M ), 109, 85 (base peak). M.W. calcd. for c i 5 H 2 4 ° 2 : 236.1776. Found (high resolution mass spectrometry): 236.1773. 8-Formylcamphor (138) 8-Formylcamphor ethylene aceta (80) (5.87 g, 26.2 mmole) was dissolved i n hexanes (25 m£) and was treated with water (.25 ml) containing concentrated hydrochloric acid (1 ml). This reaction mixture was s t i r r e d vigorously for 24 hours at room temperature. On work-up the reaction mixture was allowed to separate into two d i s t i n c t layers i n a separatory funnel. The acid aqueous layer was discarded and the organic layer washed with water, sodium bicarbonate and saturated sodium chloride solu-tions. Drying (sodium sulphate) and evaporation provided a clear colourless o i l (3.62 g) which was 70% 8-formylcamphor (138) (v.p.c. analysis on column A at 150°). This material was used without further p u r i f i c a t i o n i n the Grignard reaction with iso-butenylmagnesium bromide to prepare the keto alcohol (133a; R=0). A small sample of the crude 8-formylcamphor (138) was subjected to further p u r i f i c a t i o n by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade I I I ) . I n i t i a l e l u t i o n with 6% d i e t h y l ether-94% petroleum ether (35-60) pro-- 127 -vided a, sample of 8- C2'-(1* ,3'-dioxoly 1)) camphor (89) as a clear colourless o i l ; 6 (100MHz, CC1 4) 0.82 (s, 3H), 0.98 (s, 3H), 3.78 (m, 4H), 4.84 (dd, 1H, J C A=6.0Hz, J C B=4.0Hz); v m a x (CC14) 1739 cm 1 (strong, sharp, vC=0) and 1404 cm 1 (medium, sharp, 6CH 2); m/e 224 (M +), 180, 73 (base peak); base peak calcd. for C^Hj-G^: 73.0289. Found (high resolution mass spectrometry): 73.0280. M.W. calcd. for C 1 3 H 2 Q 0 3 : 224.1413. Found (high resolution mass spectrometry): 224.1421. Further elu t i o n with 20% d i e t h y l ether-80% petroleum ether (35-60) provided a sample of 8-formylcamphor (138) which decomposed to the keto-acid (139) i n ca. 5 hours at room temperature on exposure to a i r . The keto-acid (139) exhibited the following spectra data; ( 60MHz, CCl.) 0.88 (s, 3H), 0.94 (s, 3H), 9.82 (t, IH, J=3.0Hz); v v (CC14) 1739 and 1718 cm - 1 (strong, sharp vC=0), 1408 cm - 1 (weak sharp, 6CH2) . The mass spectrum of t h i s keto-acid exhibited the following peaks: m/e 196 (M +), 178, 152, 109 (base peak). M.W. calcd. for C,,HlirO_: 196. 1100. Found (high resolution XJ. lb O mass spectrometry): 196.1102. (132a; R=H) to 8-(3-Methy1-1,3-butadienyl)camphor (140) 8-(l-Hydroxy-3-methyl-2-butenyl)camphor ethylene acetal (132a, R=H) (3.80 g, 13.6 mmole) was dissolved i n acetone (50 ml) containing 6N hydrochloric acid (1.5 ml). The reaction was s t i r r e d for 8 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography ( t . l . c . ) on s i l i c a plates using 33% d i e t h y l ether-67% petroleum ether - 128 -C 3 5 - 6 0 ) as eluant. The plates were v i s u a l i z e d by spraying with eerie ammonium sulphate i n concentrated sulphuric acid followed by heating. On work-up, the acid was neutralized with s o l i d sodium bicarbonate and the n e u t r a l i t y of the reaction mixture was confirmed by using universal pH paper. The reaction was then gravity f i l t e r e d and the f i l t r a t e poured into water (50 ml) and extracted with d i e t h y l ether. The organic phase was dried (magnesium sulphate) and evaporated to y i e l d 8-(3-methyl-1,3-butadienyl)camphor (140) as a colourless o i l (2.33 g, 73.5% yield) (b.p. 130°/5 x 10~ 3 Torr); 6 (100MHz, CC1 4) 0.87 (s, 3H), 0.96 (s, 3H), 1.80 (d, 3H, J=2.0Hz), 4.86 (bs, 2H), 5.61 (dt, IH, J =16.0Hz, J =7. 0Hz) , 6.12 (d, IH, J=16.0) v (CCl^) 1739 cm 1 (strong, sharp, vC=0), 1605 cm 1 (medium, sharp, vC=C), 1404 cm 1 (medium, sharp, dCH^), 887 cm 1 (strong broad, 6=CH„); A (95% EtOH) 227 nm (e 13,000); m/e 218 (M+) 2 max ' • > — ' — and 95 (base peak); M.W. calcd. for C X 5 H 2 2 0 : 218.1670. Found (high resolution mass spectrumetry): 218.1664. (132b; R=CH3) to 8-(3-Methy1-1,3-butadienyl)camphor (140) 8-(l-Methoxy-3-methyl-2-butenyl)camphor ethylene acetal (132b; R=CH3) (54 mg, 0.2 mmole) was dissolved i n acetone (.2 ml) containing 6N hydrochloric acid (5 drops) . The reaction was kept at room temperature f o r 8 hours and monitored by t . l . c . as before (cf. 132a + 140). - 129 -Work-up as before (cf. 132a -»• 14 0) provided a pale yellow o i l (38 mg) whose spectral c h a r a c t e r i s t i c s were i d e n t i c a l to those of 8-(3-methyl-l,3-butadienyl)camphor (140), (see p. 127). (,132b; R=CH3) to 8-Hydroxy-3-methyl- 1-butenyl) camphor (141) 8-(1-Methoxy-3-methyl-2-butenyl)camphor ethylene acetal (132b; R=CH3) (25 mg, 0.1 mmole) was dissolved i n a mixture of 33% water-67% acetic acid (0.5 m£). S u f f i c i e n t THF was added to bring the mixture to homogeneity and i t was then l e f t at room temperature for 71 hours. On work-up the reaction was poured into d i e t h y l ether (15 ial) and washed with water and saturated sodium bicarbonate. The organic phase was dried (magnesium sulphate) and evaporated to y i e l d a pale yellow o i l 8-(3-hydroxy-3-methyl-1-butenyl)camphor (141) (21 mg, quantitative); 6 (100MHz, CgDgN) 0.85 (s, 3H) , 0.94 (s, 3H), 1.46 (s, 6H), 4.96 (bs, IH), 5.82 (m, 2H); v „ a v (CCl^) 3390 cm 1 (weak, broad, vO-H), 1739 cm 1 (sharp, strong vC=0), 1408 cm - 1 (weak, sharp, 6CH 2); m/e 236 (M +), 221, 193, 137, 109, 95 (base peak); M.W. calcd. for C 1 5 H 2 4 0 2 : 236.1776. Found (high resolution mass spectrometry): 236.1764. 8-(1-Hydroxy-3-methyIbutyl)camphor (146a), (9-Hydroxydihydro- campherenone) 8-(1-Hydroxy-3-methyIbutyl)camphor ethylene acetal (146b) (655 mg) was dissolved i n acetone (20 m ) , 10 drops of 6N hydrochloric acid were added, and i t was l e f t at room temperature - 130 -for 8 hours. Work-up consisted of pouring the reaction mixture into d i e t h y l ether (100 mil) and washing with water, saturated sodium bicarbonate, and saturated sodium chloride solutions. Drying (magnesium sulphate) and evaporation provided 8-(1-hydroxy-3-methylbutyl)camphor (146a) (550 mg, qua n t i t a t i v e ) . A sample of t h i s material was p u r i f i e d by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using an e l u t i o n gradient changing from 4% di e t h y l ether-96% petroleum ether (35-60) to 100% di e t h y l ether i n 300 mil of eluant. This provided a 90% pure sample (v.p.c. analysis on column A at 180°) of 8-(l-hydroxy-3-methylbutyl)camphor (146a) as a clear colourless o i l ; 6 (100MHz, CCl^) 0.83 (d, 6H, J=2.0Hz), 0.90 (s, 3H), 1.04 (s, 3H), 3.72 (m, IH); v (CCl ) 3509 cm - 1 XuCL J\ fx (weak, broad, vOH); 17 39 cm 1 (strong, sharp, vC=0), 14 08 cm 1 (weak, sharp, 6CH 2); m/e 238 (M+) , 220, 109, 95 (base peak); M.W. calcd. for C,1_H„C' : 238. 1933. Found (high resolution lD ZD 2. mass spectrometry): 238.1933. 8-(1-Hydroxy-3-methylbutyl)camphor Ethylene Acetal (146b), (9-Hydroxydihydrocampherenone Ethylene Acetal) The k e t a l aldehyde (80) (0.50 g, 2.2 mmole) was dissolved i n d i e t h y l ether (5 mil) and was added at room temperature to a solution of iso-butylmagnesium bromide (4.5 mmole) i n di e t h y l ether (10 mil) under a nitrogen atmosphere. - 131 -The Grignard reagent was prepared by adding i s c — b u t y l bromide (0.61 g, 4.5 mmole) dissolved i n dieth y l ether (2 m£) to magnesium powder (0.22 g, 8.9 mmole) suspended i n di e t h y l ether (8 m£.) at room temperature and under a nitrogen atmos-phere. The rate of addition was such that a gentl r e f l u x was maintained throughout the addition (ca. 15 minutes). The Grignard reagent was refluxed for a further 15 minutes. The ketal aldehyde 80 was added d i r e c t l y to the soluti o n of the Grignard and the reaction stood at room temperature for 17 hours. On work-up the reaction mixture was hydrolyzed with satu-rated ammonium chloride and the resultant p r e c i p i t a t e was f i l t e r e d o f f to provide a dry colourless ethereal solution of the product. Evaporation of the solvent yielded 8-(1-hydroxy-3-methylbutyl)camphor ethylene acetal (146b) (655 mg) which was immediately deketalized i n acetone-6N hydrochloric acid. 8-(1-Hydroxy-3-methyl-3-butenyl)camphor (147) 8-(1-Hydroxy-3-methyl-3-butenyl)camphor ethylene acetal 83a (1.05 g, 3.8 mmole) was dissolved i n acetone (15 m£) and treated with 6N hydrochloric acid (1.5 m£) for 8 hours at room temperature. Work-up i n the usual manner (cf. preparation of (146a)) provided 8-(1-hydroxy-3-methyl-3-butenyl)camphor (147) (670 mg) as a colourless o i l , which was p u r i f i e d by chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using an - 132 -eluti o n gradient changing from 5% d i e t h y l ether<-95% petroleum ether (35-60 ( to 100% diethyl ether i n 450 mil of eluant. This provided a 90% pure sample (v.p.c. analysis on column A at 180°) of 8-(l-hydroxy-3-methyl-3-butenyl)camphor (147) (450 mg, 51% yield) as a clear colourless o i l ; 6 (100MHz, CC1 4) 0.82 and 0.85 (two s i n g l e t s , 3H), 0.96 and 1.09 (two s i n g l e t s , 3H), 1.74 (s, 3H), 3.84 (bm, IH) , 4.82 (bd, 2H, J =12. 0Hz) ; v m a x (CCl^) 3571 cm 1 (weak, broad, vO-H), 1739 cm 1 (strong, sharp, vC=0), 1639 cm - 1 (sharp, weak, vC=C), 1408 cm"1 (weak, sharp, 6CH 2), 901 cm"1 (medium, broad, 6=CH2); m/e 236 (M +), 181, 95 (base peak); M.W. calcd. f o r c i 5 H 2 4 ° 2 : 236.1776. Found (high resolution mass spectrometry): 236.1764. The Reduction of 14 7 to 146a 8-(1-Hydroxy-3-methyl-3-butenyl)camphor (147) (300 mg, 1.3 mmole) was dissolved i n hexanes (3 mi). This compound was hydrogenated at atmospheric pressure i n the presence of 5% palladium on carbon. The hydrogen uptake was recorded using a gas burette. The compound absorbed 2 3.0 mJl of hydrogen gas (theoretical calculated uptake 29.0 mil) over 1.5 hours at room temperature. On work-up the c a t a l y s t was f i l t e r e d o f f by gravity and the solvent evaporated to provide 8-(1-hydroxy-3-methylbutyl) camphor (146a) (223 mg, 74% yield) as a clear colourless o i l , which was p u r i f i e d by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) as before (cf. previous - 133 -preparation of 146a from 146b ; p. 129 ). This provided a 99% pure sample of 146a (v.p.c. analysis on column A at 180°) (207 mg, 70% yield) as a clear colourless o i l . The spectral properties (n.m.r., i r and m.s.) of 146a prepared i n t h i s manner were i d e n t i c a l to those reported previously (see p. 1 2 9 )• The Reduction of 132a to 8-(1-Hydroxy-3-methylbutyl)camphor  Ethylene Acetal (148), (9-Hydroxycampherenone Ethylene Acetal) 8-(1-Hydroxy-3-methy1-2-butenyl)camphor ethylene acetal (132a) (312 mg, 1.1 mmole) was dissolved i n hexanes (15 ml). Adam's catalyst (100 mg) was added and the mixture subjected to low pressure hydrogenation at 30 p . s . i . of hydrogen gas for 1 hour. On work-up the reaction mixture was f i l t e r e d by gravity to remove the cat a l y s t and evaporation of the solvent provided 8-(1-hydroxy-3-methyIbutyl)camphor ethylene acetal (148) as a colourless o i l . This material was immediately subjected to the usual deketalizing conditions. Conversion of 14 8 to 146a 8-(1-Hydroxy-3-methyIbutyl)camphor ethylene acetal (148) (200 mg, 0.7 mmole) was dissolved i n acetone ( 10 ml) containing 10 drops of 6N hydrochloric acid and l e f t at room temperature for 8 hours. Work-up i n the usual manner (cf. preparation of 146a; p. 129) provided 8-(1-hydroxy-3-methyIbutyl)camphor (146a) as a - 134 clear colourless o i l (152 mg, 90% yield) of 80% purity (v.p.c. analysis on column A at 180°). The spectral properties (n.m.r., i r and m.s.) of t h i s compound were i d e n t i c a l to those of 146a (cf. p. 129)• 8-(l-Oxo-3-methylbutyl)camphor (149), (9-0xocampherenone) 8-(1-Hydroxy-3-methylbutyl)camphor (146a) (70 mg, 0.3 mmole) dissolved i n acetone (2 ml) was treated at room temperature with Jones reagent u n t i l a permanent orange colour persisted i n the solution. On work-up a few drops of methanol were added to the reaction to destroy any excess Jones reagent and the reaction mixture was poured into d i e t h y l ether (10 m£). This ethereal solution was washed with water, saturated sodium bicarbonate and saturated sodium chloride solutions. Drying (magnesium sulphate) and evaporation of the solvent provided a 9 3% pure sample (v.p.c. analysis on column A at 180°) of 8-(l-oxo-3-methylbutyl)camphor (149) (50 mg, 72% yield) as a colourless o i l . This material was p u r i f i e d by high vacuum d i s t i l l a t i o n (b.p. 90°/5 x 10~ 3 Torr); 6 (CC14) 0.85 (s, 6H), 0.97 (d, 6H, J=7.0Hz), 2.75 (t, IH, J=4.0Hz); v (CCl.) 1739 and 1709 cm 1 (strong, sharp, vC=0) and 1408 cm 1 (weak, sharp, 6CH 2); m/e 236 (M +), 179, 137, 136, 109, 95 (base peak); M.W. calcd. for c i 5 H 2 4 ° 2 : 236.1776. Found (high resolution mass spectrometry): 236.1789. Anal, calcd. for C 1 5 H 2 4 0 2 : C ' 7 6-23; H, 10.24. Found: C, 76.00; H. 10.10. - 135 -The Oxidation of 146a (prepared from 14 7) to 14 9 8-(1-Hydroxy-3-methylbutyl)camphor (146a) (100 mg, 0.5 mmole) was dissolved i n acetone (5 ml) and treated with Jones reagent as before (cf. p. 134 ) • Work-up i n the usual manner provided 8-(l-oxo-3-methyl-butyl)camphor (149) as a clear colourless o i l (80 mg, 73% yield) of 96% purity (v.p.c. analysis on column A at 180°). The spectral properties ( n.m.r., i r , m.s. and v.p.c.) of this compound were i d e n t i c a l to those of 14 9 (cf. p. 134 ) . The Oxidation of '146a (prepared from 147) to 149 8-(l-Hydroxy-3-methylbutyl)camphor (146a) (152 mg, 0.6 mmole) was oxidized to the diketone 149 i n the usual way using Jones reagent i n acetone (10 ml) (cf. preparation of 149 p.134 ). The spectral properties (n.m.r., i r , m.s., and v.p.c.) of thi s compound were i d e n t i c a l to those of 149 (cf. p.134 )• \ - 1 3 6 -REFERENCES 1. U.R. Nayak and S. Dev, Tetrahedron L e t t . , 243 (1963). 2. (a) G. Ourisson, B u l l . Soc. Chim. Fr., 895 (1955). (b) J.B. Hendrickson, Tetrahedron, 7, 82 (1955). 3. (a) E.J. Corey, M. Ohno, R.B. Mitra, and P.A. Vatakencherry, J. Am. Chem. S o c , 86 , 478 (1964). (b) J.E. McMurry and S.J. Isser, J . Am. Chem. Soc., 94, 7132 (1972). (c) S.C. Welch and R.L. Walters, J . Org. Chem., 39, 2665 (1974). (d) W. Oppolzer and T. Godel, J . Am. Chem. S o c , 100, 2583 (1978). (e) R.A. Volkmann, G.C. Andrews, and W.S. Johnson, i b i d . , 97, 4777 (1975). 4. For recent reviews, see P. de Mayo, Acc. Chem. Res., A, 41 (1971); H. Meier, "Houben-Weyl, Methoden der Organischen Chemie", Vol. 4/56, E. MUller, Ed., Georg Thieme Verlag, Stuttgard, (1975), p. 924. 5. CR. Eck, G.L. Hodgson, D.F. MacSweeney, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 1938 (1974); c_f. G.L. Hodgson, D.F. MacSweeney, and T. Money, i b i d . , 2113 (1973). 6. CR. Eck, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 251 (1975); P. Cachia, N. Darby, CR. Eck, and T. Money, i b i d . , 359 (1976). 7. E.J. Corey and M.F. Semmelhack, J . Am. Chem. Soc., 89, 2755 (1967) ; c_f. K. Sato, S. Inoue, S. Ota, and Y. F u j i t a , J .  Org. Chem., 3_7, 462 (1972). 8. D.H.R. Barton and N.H. Werstiuk, J . Chem. Soc. (C), 148 (1968) . 9. (a) - E. Pier s , M.B. Geraghty, F. Kido, and M. Soucy, Syn. ' Comm., 3, 39 (1973). (b) W.S. Murphy and D.F. Su l l i v a n , J.C.S. Perkin I, 999 (1972). - 137 -(c) G. Ourisson and A Rassat, Tetrahedron L e t t . , 16 (1960). 10. C.R. Eck, G.L. Hodgson, D.F. MacSweeney, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 1938 (1974). 11. C. Dj e r r a s s i , R.R. Engle, and A. Bowers, J . Org. Chem., 21, 1547 (1956). 12. Cf. a-Atlantone synthesis, J.H. Babler, D.O. Olsen, and W.H. Arnold, J. Org. Chem., 39, 1656 (1974). 13. N. Darby and C. Eck, unpublished observations. 14. J.C. C o l l i n s , W.W. Hess, and F.J. Frank, Tetrahedron  Lett. , 3363 (1968) . 15. R. R a t c l i f f e and R. Rodehorst, J. Org. Chem., 35, 4000 (1970). 16. W.G. Dauben, M. Lorber, and D.S. Fulle r t o n , J. Org. Chem., 3_4, 3587 (1969). 17. J.E. Shaw and J. J . Sherry, Tetrahedron Lett., 4379 (1971). 18. D.S. Fulerton and C.-M. Cheng, Syn. Comm., 6_, 217 (1976). 19. G.L. Hodgson, D.F. MacSweeney, R.W. M i l l s , and T. Money, J.C.S. Chem. Comm., 235 (1973). c 20. E.J. Corey and J.W. Suggs, Tetrahedron Lett., 2647 (1975). 21. E.J. Corey and G. Schmidt, i b i d . , 399 (1979). 22. K.H. Meyer and K. Schuster, Chem. Ber. y 55, 819 (1922). 23. S. SWaminathan and K.V. Narayanan, Chem. Rev., 71, 429 (19 71) and references c i t e d therein. 24. K. Nakanishi, "Infrared Absorption Spectroscopy— P r a c t i c a l " , Holden-Day, San Fransisco (1962), p. 36 and p. 155. 25. Submitted for publication i n Can. J . Chem. 26. (a) E. Winterfelt, "Chemistry of the Acetylenes", H.G. Yieke and M. Dekker, Eds., New York, (1969), Chapter 4. (b) T.F. Rutledge, "Acetylenes and Allenes", Van Nostrand-Reinhold, New York, (1969), Chapter 5. - 138 -(c) S.I. M i l l e r and R. Tanaka, "Selective Organic Trans-formations", S. Thyagarajan, Ed., Wiley-Interscience, New York, (1970), Vol. 1, p. 143. 27. (a) G. Stork, S. Malhotra, H. Thompson, M. Uchibayashi, J . Am. Chem. S o c , 8_7, 1148 (1965). (b) P.E. Peterson and R.J. Kamat, J. Am. Chem. Soc., 91, 4521 (1969). (c) R.J. Balf, B. Rao, and L. Weiler, Can. J . Chem., 49, 3135 (1971). (d) W.S. Johnson et a l . , J . Am. Chem. Soc., 93, 4330 (1971). (e) W.S. Johnson, M.B. Gravestock, and B.E. McCarry, i b i d . , 93, 4332 (1971). (f) M. Hanack, C E . Harding, and Jean-Luc Dorocque, Chem.  Ber . , 105, 421 (1972). (g) S.W. Baldwin, J.C. Tomesch, Syn• Comm., 5, 445 (1975). 28. (a) The linear v i n y l cation i s estimated to be 77 kcal mole 1 more stable than the bent v i n y l cation; c f . reference 27b and references cited therein. (b) Cf. section C, pp.180 29. G. Biichi and I. Goldmann, J . Am. Chem. S o c , 79 , 4741 (1957); R.C. Cookson, E. Crundwell, and J . Hudec, Chem.  Ind. (London), 1004 (1958); S.J. C r i s t o l and R.L. S n e l l , J. Am. Chem. Soc., 76, 5000 (1954). 30. M.E. Jung and M.A. Lyster, J . Org. Chem., 42, 3761 (1977); M.E. Jung and T.A. Blumenkopf, Tet. Lett., 3657 (1978); G. Olah et a l w J . Org. Chem., 4 4 , 1247 (1979). 31. E.A. Braude and C.J. Timmons, J . Chem. S o c , 2000, 2007, 2012, (1950). 32. M. Bertrand and J . V i a l a , Tetrahedron Lett., 2575 (1978); h. Normant/ Compt.rend.240, 314 (1955). 33. J.Attehburrow, A.F.B. Cameron, J.H. Chapman, R.M. Evans, B.A. Hems, A.B.A. Jansen, and T. Walker, J . Chem. Soc., 1094 (1952); L.A. Caprino, J . Org. Chem., 3971 (1970). 3 4 . J.R. Parikh and W. von E. Doering, J . Am. Chem. S o c , 89, 5505 (1967). - 139 -35. Y.S. Rao and R. F i l l e r , J . Org. Chem., 39, 3304 (1974). 36. N.H. Andersen and H.-S. Uh, Syn. Comm., 3, 125 (1973). 37. (a) W.G. Dauben and D.M. Michno, J . Org. Chem., 42, 682 (1977). (b) D. Sundararaman and W. Herz, i b i d . , 42, 813 (1977). - 140 -SECTION C SYNTHETIC APPROACH TO THE PICROTOXANE FRAMEWORK - 141 -ABSTRACT B i o s y n t h e t i c s t u d i e s of the pic r o t o x a n e f a m i l y of s e s q u i -t e r p e n o i d s have shown t h a t copaborneol (27) i s an intermediate in the b i o g e n e s i s of t u t i n (5), a member of t h i s t e r p e n o i d sub-group. The b i o s y n t h e t i c t r a n s f b r m a t i o n s i n v o l v e d i n c o n v e r t i n g copaborneol i n t o t u t i n remain s p e c u l a t i v e . We have considered that the b i o g e n e s i s i n c l u d e s a copacamphor-type d e r i v a t i v e which undergoes enzyme-catalyzed B a e y e r - V i l l i g e r r e a c t i o n to provide the b a s i c carbon framework of the picrotoxane group. Work i n our l a b o r a t o r y has been concerned w i t h d e v i s i n g a s y n t h e s i s of the p i c r o t o x a n e carbon framework based on t h i s p o s t u l a t e . The progress i n t h i s s y n t h e t i c approach i s dscussed i n the f o l -lowing s e c t i o n . (5) - 142 -INTRODUCTION History and Occurrence The picrotoxane family of sesquiterpenoids consists essen-t i a l l y of the following group of compounds: pi c r o t o x i n i n , p i c r o t i n , coriamyrtin, t u t i n , dendrobine and nobilomethylene. Picrotoxinin ( 1 ) and p i c r o t i n ( 2 ) were f i r s t obtained by Boullay in 1 8 1 1 1 as a molecular compound picrotoxin ^ Q H ^ O ^ . Picro-toxin i s the toxic p r i n c i p l e in the berries of the plant Menispermum cocculus, a member of the Menispermaceae or moon-seed family, native to regions of India. It has also been found in the plants Cocculus indicus and Anamirta cocculus. In 1 8 8 0 p i c r o t i n was shown to be an equimolar mixture of two compounds: pi c r o t o x i n i n , C-^H^gOg ( 1 ) and p i c r o t i n , C^s^^gO^ ( 2 ) . - 143 ~ Reversible bromination of picrotoxinin (1) affords a mix-ture Of a- and jS-bromopicrotoxinin and one modification of the a-epimer 3 was used i n the X-ray crystalographic determin-3 ation of the absolute configuration of the parent compound 1 . Coriamyrtin (4) and t u t i n (5) occur as the p r i n c i p l e toxic substances in two d i s t i n c t plant species in separate parts of the world. Coriamyrtin, c i 5 H X 8 ° 5 ^ 4 was i s o l a t e d , i n i t i a l l y , from a European species of the Coriaraceae family (Coraria m y r t i f o l i a ) , and was subsequently (4) (5) - 144 -found in C o r i a r i a japonica. Tutin, ci5 Hi8°6 ^ w a s f i r s t isolated by E a s t e r f i e l d and Aston 5 from plants of the C o r i a r i a genus (commonly c a l l e d "tutu") found in New Zealand. Tutin was later isolated from Coriar ia j aponica^ and Hyenancha 7 globosa . Dendrobine, C 1 6 H 2 5 ° 2 N (6) i s the major basic component isolated from methanol extracts of Dendrobium nobile, LINDL . The crude Chinese drug Chin-Shih-Hu, a tonic antipyretic prepared from Dendrobium linawianum, D. nobile and possibly other members of the Orchidaceae family, was the f i r s t source of dendrobine. This sesquiterpenoid alkaloid has structure (6) in which a t e r t i a r y nitrogen atom instead of an oxygen atom bridges C-(2) and C-(14) of the picrotoxane skeleton. Another ( 6 ) ( 7 ) s t r u c t u r a l feature which distinguishes t h i s a l k a l o i d from the normal sesquiterpenoid compounds (e.g. p i c r o t i n , p i c r o t o x i n i n , and coriamyrtin) i s the absence of an epoxide r i n g . Nobilomethylene, C 1 5 H 2 Q 0 3 (7), i s a neutral non-nitrogenous compound which i s isolated from a basic extract of - 1 4 5 -the plant, Dendrobium nobile, LINDl/. It has been suggested^ that this compound may be an a r t i f a c t of the process by which t h i s group of compounds i s is o l a t e d . It has also been suggested that nobilomethylene (7) may arise from the degradation of the al k a l o i d nobilonine (8) (Scheme 1) which i s also a constituent of Dendrobium nobile, LINDL. Oxidation of nobilonine (8) using hydrogen peroxide (30% aqueous solution) produces the N-oxide 9 which, on pyrolysis at 150-200°, provides nobilomethylene (8 ) (9 ) (7 ) Scheme 1 Numbering System Because of the complexity and length of f u l l y schematic nomenclature most workers have used t r i v i a l names when referri n g to the picrotoxane group of compounds, i n Chemical Abstracts members of the picrotoxane group are c l a s s i f i e d under t h e i r t r i v i a l name with"a cross-reference based on t h e i r systematic - 146 -nomenclature as derivatives of the hexahydroindan (10). k 3 (10) Early workers in t h i s area used a numbering system which was based on a hypothetical open-chain p a r t i a l structure I devised before the true r i n g structure was known. L.A. Porter in his review a r t i c l e on p i c r o t o x i n i n 1 0 suggested that t h i s numbering system i s confusing when applied to the true ring structure and proposed a numbering system based on a hypothetical picrotoxane II. He further proposed that in systematic nomenclature the bicyclo picrotoxanes should be named as derivatives of the parent hexahydroindan structure. For those picrotoxanes which contain three fused rings he - 147 -proposed a nomenclature based on the parent structures deca-hydroindeno Q 7 ,1-bcf] f uran and decahydrocyclopenteno f""cd^ | indole . Since most of the l i t e r a t u r e referred to in th i s section retains the numbering system shown in I, i t i s t h i s system which I have chosen to use in th i s thesis to avoid un-necessary confusion. Thus the numbering schemes to be used in the two-ring and three-ring systems are shown in III and IV. X - N or 0 Biosynthetic Studies 11-13 Three biosynthetic proposals have been put forward concerning the _in vivo formation of the picrotoxanes. Conroy 1 1 in examining the skeleton of picrotoxinin found that, although i t was composed of 15 carbon atoms and was possibly a sesquiter-penoid, he was unable to r a t i o n a l i z e i t s mode of formation from 5-carbon isoprenoid units. He then rewrote the skeleton as shown in Figure l (p. 148 ) and proposed that i t was derived by - 148 -degradation of the s t e r i oda l precursor. This stimulated f u r -ther speculation on i t s b iosynthet ic o r i g i n . Conroy proposed that p i c ro tox in i n represented an intermediate stage i n phyto-s t e r o l synthesis or or ig inated from a s tero id by way of a b i o l o g i c a l ox idat ive process. F i g . .1 12 C r o s s suggested t h a t p i c r o t o x i n i n was a s e s q u l t e r p e n o i d whose carbon s k e l e t o n was d e r i v e d by c y c l i z a t i o n of a f a r n e s y l c h a i n f o l l o w e d by two [JL, 2]] C - m e t h y l m i g r a t i o n s ( F i g . 2 ) » o x i -d a t i o n , and l a c t o n i z a t i o n . (11) (12) (13) Fig. 2 - 149 -P a r k e r 1 3 1 0 proposed the idea that c y c l i z a t i o n of the terminal double bond of c i s - f a r n e s y l pyrophosphate (14) (Fig. 3 ) with the a l l y l i c center generated by dephosphorylation would provide two intermediate carbonium ions. One of these 16 was favoured e l e c t r o n i c a l l y while the other 17 was favoured on s t e r i c 14 grounds. Hendrickson postulated c y c l i z a t i o n of farnesyl pyrophosphate to the same two ca t i o n i c species* 16 and 17 Fig. 3 but discarded the cation 16 as a p o s s i b i l i t y on the grounds of the s t r a i n and non-bonded interactions i m p l i c i t in i t s formation. It was then e n v i s a g e d 1 3 5 that a Q l , 3"]-hydr ide s h i f t i n 16 to 18. * The carbonium ion description is an o v e r - s i m p l i f i c a t i o n ; in nature we are presumably dealing with enzymic groups attached at these positions which can leave and i n i t i a t e c y c l i z a t i o n . - 150 -f o l l o w e d by c y c l i z a t i o n would pr o v i d e the c a t i o n 19 * which r e p r e s e n t s the b a s i c carbon s k e l e t o n of the cadinane group of s e s q u i t e r p e n o i d s . I f c a t i o n 19 i s a c i s - d e c a l i n d e r i v a t i v e , f u r t h e r i n t e r n a l c y c l i z a t i o n to t r i c y c l i c s t r u c t u r e s can occur. For example, anti-Markownikoff attack of the double bond on the t e r t i a r y c e n t e r i n carbonium ion 19 g i v e s the secondary c a t i o n * I t i s a l s o p o s s i b l e t h a t c a t i o n 19 or i t s e q u i v a l e n t c o u l d have been formed v i a an anti-Markownikoff c y c l i z a t i o n of j-curcumene (20) ( F i g . 4 ), followed by a [JL, 2 ^ - h y d r i d e s h i f t . F i g . 4 The i s o l a t i o n of the muurolanes (22) c o n t a i n i n g such a c i s r i n g j u n c t i o n lends support t o t h i s p r o p o s a l . (22) - 151 -23 , which can undergo Wagner-Meerwein rearrangement followed by deprotonation to give 24 . The aldehyde functions (19) (23) (24) (25) 15 observed in helminthosporal (25) can be produced by oxidative cleavage of the bond indicated in 24 . The i s o l a t i o n of the unsaturated t r i c y c l i c hydrocarbon sativene 1^ (24) provides sup-port for these proposals. A l t e r n a t i v e l y , oxidative f i s s i o n of the bond indicated in 24 leads d i r e c t l y to the gross 17 structure and most of the stereochemical features of tut i n 18 19 (5; R=H), coriamyrtin (4; R=OH) and picrotoxinin (1). l ^ Assuming that t h i s biogenetic scheme i s followed, then the c atoms derived from [2- 1 kC^\ -mevalonate should be located at the starred positions in tu t i n (5; R=H) (Fig. 5) (£f. F i g . 6 ) -20 The biosynthesis of coriamyrtin (4; R=OH) and tuti n (5; 20 21 R=0H) ' has been investigated by administration of (±)-r - 2 _ i - c " ] - , (±) - Q 4 - 1 HC2-» and (±) - £2 ,2-3H2"] -mevalonic acid to plants of C o r i a r i a japonica. - 152 -I • (23) <26) (4;R=0H) (1) (5;R=H) Fig. 5 The results obtained from radioactive degradation studies 12 fc) are consistent with the biogenetic proposal which invoked oxidative f i s s i o n of a t r i c y c l i c intermediate 23 (Fig. 5) such as copaborneol* (27) (cf. p.153 ). Radioactive samples of coriamyrtin (4) and t u t i n (5) were isolated and subjected to degradative procedures to determine the positions of the radioactive label(s) in these compounds. (The known biosyn-t h e t i c pathway to farnesyl pyrophosphate (14) from mevalonic acid (28) (Fig. 6 , p.154 ) necessarily places the lhC labels in the positions shown.) * Copaborneol has been detected as a component of the oleoresin from Pinus s i l v e s t r i s 2 2 . - 153 -(27) These investigations indicated that the positions of the radioactive labels in coriamyrtin (4) and tut i n (5) are as shown in Figure 3 . Since extensive investigations have shown that mevalonic acid l a b e l l e d at C-(2) or C-(4) produces farnesyl pyrophosphate with the l a b e l l i n g pattern shown in 14 (Fig. 9, p. 161), i t was suggested that the biosynthesis of coriamyrtin (4) and t u t i n (5) involves the reaction sequence outlined i n Figure 9 . These re s u l t s are consistent with the biosynthetic ideas outlined i n Figure 5 ( i . e . bond cleavage as shown i n 23 to y e i l d an intermediate l i k e 26 ). At the time they also strongly 13b supported the postulated biogenesis of the b i c y c l i c and t r i c y c l i c sesquiterpenes which were thought to be derived from t r a n s - c i s - f a r n e s y l pyrophosphate (14). The formation of the bond between C-(l) and C-(6) i n the intermediate 18 (Fig. 3) or a s i m i l a r species would lead to a muurolane skeleton 19 from which copaborneol (27) can be derived b i o g e n e t i c a l l y . - 154 -( 5 ) [ 4 - X A C J l a b e l s T u t i n F i g . 6 - 155 -The scheme (F i g . , 3 ) , therefore, not only explains the formation of d i f f e r e n t sesquiterpenes but also their stereochemical features. With the exception of C-(3), the absolute stereochemistry of a l l the asymmetric centers in copaborneol (27) are the same as in t u t i n ( 5 )(see p.161). The inversion at C-(3) in tut i n (5) Qc-(13) in , 5 ] can be rat i o n a l i z e d by a C-(2), C-(3) bond cleavage in 27 leading to the formation of an intermediate alkene 29 Thus far the proposed biogenetic routes to the picrotoxanes, vide supra, remain hypothetical. The preliminary work of Yamazaki 1 3 a, A r i g o n i 2 0 , and Jommi 2 1 has indicated that the com-pound dendrobine (6) i s derived from farnesyl pyrophosphate. More detailed experiments, which have so far established the route from mevalonic acid to copaborneol, have also shown that copaborneol i s a t r i c y c l i c intermediate capable of being trans-formed into the picrotoxane carbon framework. - 156 -Three p o s s i b l e routes from "'CQ -mevalonic a c i d to the p i c r o t o x a n e s k e l e t o n have been proposed and are d e p i c t e d i n equations ^1~2 a n d Q2a,b'*] ( F i g . 7, p. 158 ). 12 Equation d e p i c t s a c y c l i z a t i o n o f t r a n s - c i s - f a r n e s o l (30) i n an unprecedented manner, followed by synchronous methyl X 3 ci b m i g r a t i o n s . The second suggestion ' , equation Q2a,b~], i n v o l v e s c y c l i z a t i o n of t r a n s - c i s - f a r n e s y l pyrophosphate (14) to an intermediate with a muurolane s k e l e t o n 34 , followed by cleavage and c y c l i z a t i o n (eq. Q2a*] ) or c y c l i z a t i o n to a t r i -c y c l i c d e r i v a t i v e 2 3 ' 2 4 36 and cleavage (eq. [~2bJ ) . T h i s c y c l i z a t i o n - c l e a v a g e sequence has a p a r a l l e l i n the p o s t u l a t e d 23 24 b i o s y n t h e s i s of h e l m i n t h o s p o r a l ' . The muurolane intermediate c o u l d a r i s e v i a two r o u t e s : (eq. "322]) by p r i o r formation of a ten-membered r i n g (germacrane d e r i v a t i v e ) 16 from t r a n s - c i s -f a r n e s y l pyrophosphate (14) f o l l o w e d by c y c l i z a t i o n t o the muurolane d e r i v a t i v e 34 o_r (eq. Q3""] ) by c y c l i z a t i o n of c i s -c i s - f a r n e s o l (38) to the muurolane d e r i v a t i v e 40 by way of the bisabolane d e r i v a t i v e 39 . F i n a l l y , equation Q4"] de-p i c t s a second p o s s i b l e route from t r a n s - c i s - f a r n e s y l pyrophos-phate (14) to the t r i c y c l i c i ntermediate 36 . The b i o g e n e s i s of dendrobine (6) s t u d i e d by Y a m a z a k i 1 3 a and co-workers showed t h a t the d i s t r i b u t i o n of r a d i o a c t i v i t y i n dendrobine (6) d e r i v e d from Q2- 1 kC^\~mevalonic a c i d was c o n s i s t e n t with a b i o s y n t h e t i c route i n v o l v i n g the i n t e r m e d i -acy of f a r n e s y l pyrophosphate. In a d d i t i o n Yamazaki - 157 -proposed that the dendrobine skeleton could be derived from a muurolane-type precursor 3 4 (Fig. 7 , p.158 ) by cleavage of the carbon-carbon bond between C-(5) and C-(6). I t was also-suggested that the N-methyl group i n 6 was derived from 25 ammonia or methylamine. Other workers i n t h i s area confirmed the r e s u l t s of Yamazaki, but pointed out that the r e s u l t s obtained from feeding £2-11*C^]-mevalonate to Dendrobium nobile plants could not d i f f e r e n t i a t e between the three possible bio-synthetic pathways. Feeding [J2-1 **CQ-mevalonate would result in the l a b e l l i n g of the iso-propyl group derived from a l l of the possible biosynthetic routes (cf. equations Ql^J 1 Q2D 1 a n d 2 5 £ 3 ] ) . Edwards and co-workers suggested that feeding \j^-x^Q~\-mevalonate would d i f f e r e n t i a t e between the three p o s s i b i l i t i e s . The predicted pattern of la b e l d i s t r i b u t i o n in dendrobine (6) pro-duced via the postulated pathways (eq.s £ 0 ' C 2I] ' a n d C3I1 ) a r © outlined in Figure 8 (p.159 ). However, i t would be impossible to make a d i s t i n c t i o n between the product from route and the product from route [ j Q under the conditions of this experiment. The results obtained - 159 -Fig. 8 - 160 -by Edwards showed that the d i s t r i b u t i o n of the lab e l in dendro-bine (6) was consistent with routes Q2a and b"J , and route ^4*] and that the alt e r n a t i v e sequences, routes C l ] ] and £X"], could be rejected. (28) Routes [2a,b] and [4] (6) These i n i t i a l biosynthetic studies indicated that a t r i -c y c l i c intermediate such as copaborneol (27) (cf. p.161 ) could be involved in the biosynthesis of the picrotoxane group of sesquiterpenoids. The observed incorporation of labelled meva-lonic acids into members of the picrotoxane group (coriamyrtin, t u t i n , and dendrobine) i s consistent with the operation of a biosynthetic scheme (cf. F i g . 6 ) involving ring cleavage of the t r i c y c l i c intermediate copaborneol (27). This suggestion was v e r i f i e d by the _in vivo conversion of a t r i t i u m - l a b e l l e d copa-borneol [^starred position in 27 (p. 161 ) "2 t o l a b e l l e d 2 6 tu t i n (5) . A further examination of the biosynthesis of t u t i n 2 7 showed that t u t i n (5) derived from (4R) - ["^-'Hj -mevalonic acid (28) (Fig. 9, p. 161 ) retained one t r i t i u m atom at the C-(4) position. The result is important in determining the - 161 -mode of formation of the intermediate cyclodecane (germacrane) 14 • c a t i o n 18 . I t has been suggested that c a t i o n 16 , i n order to c y c l i z e i n t e r n a l l y to the muurolane system shown as 19 , Fig. 9 - 162 -must f i r s t undergo an isomerization to the cation 18 . This can be accomplished by a simple Q l , 3^]-hydride s h i f t or by two consecutive Ql,2[]-hydride s h i f t s . I f the Q l » 3 3 s h i f t were to occur a proton would be transferred from C-(l) to C - ( l l ) and the l a b e l l i n g pattern of the t r i t i u m atoms i n 16 would remain undistrubed. I f , however, two [jL,23 s h i f t s were involved t r i t i u m from C-(10) would s h i f t i n a Ql,2^ manner to C - ( l l ) and a proton would s h i f t i n a s i m i l a r fashion from C-(l) to C-(10). The t r i t i u m on C-(4) i n t u t i n would be replaced by a proton and a l l t r i t i u m labels would then be removed from the f i n a l product by b i o l o g i c a l oxidation processes. Tritium atoms pre-sent at C-(6) and C-(15) i n t u t i n (5) are removed by biolog-i c a l hydroxilation at C-(6) and v i a oxidation to the lactone at C-(15). If the t r i t i u m l a b e l had moved from C-(10) to C - ( l l ) i n the germacrane cation 16 , then i t too would have been removed during the formation of the terminal methylene at C-(8) 27 i n t u t i n . Thus the l a b e l l i n g experiment (cf. F i g . 9) sug-gests that the probable germacrane intermediate 16 rearranges v i a a Q l , 3]]-hydride s h i f t rather than through consecutive LjL, 2^ 1 s h i f t s . Unlike t u t i n (5), which lacks a C-(8) hydrogen, dendrobine (6) i s more suitable substrate from which to obtain d i r e c t e v i -2 8 dence for a Ql,3^-hydride s h i f t . Jommi fed plants of Dendrobium nobile, LINDL. with (3RS) 1 , 5 - 3H 2J-mevalonate (28) (Fig. 10) and i s o l a t e d the radioactive dendrobine (6). The dendrobine - 163 -incorporated f i v e of the o r i g i n a l s i x t r i t i u m labels i n i t s structure. The loss of one t i r t i u m l a b e l may be explained by hydrxylation at C-(3) i n dendrobibe. Fig. 10 o The data indicated that of the two t r i t i u m atoms o r i g i n a l l y at C-(l) i n farnesol, one was located at the expected position in dendrobine (C-(5)) and the other had migrated to the t e r t i a r y carbon of the iso-propyl group (C-(8) of dendrobine). A l l the remaining t r i t i u m i n dendrobine was located at C-(3) and C - ( l l ) (one and two t r i t i u m atoms, r e s p e c t i v e l y ) . These re s u l t s exclude 29 both the formation of an intermediate cyclopropyl species 2 5 30 and the involvement of a bisabolane (39) or camphorane (41) ' (Fig. 7) intermediate during dendrobine biosynthesis. - 164 -C o n s i d e r i n g the geometry of 16 and 19 ( F i g . 10) we might conclude that a 2 - c i s , 6-trans c o n f i g u r a t i o n of the double bonds i n f a r n e s y l pyrophosphate (14) i s necessary f o r the forma-t i o n of the former compound. I n v e s t i g a t i o n s on the b i o s y n t h e s i s 31 of n e r o l (43) from g e r a n i o l (42) and 2 - c i s , 6 - t r a n s - f a r n e s o l 32 (30) from t r a n s , t r a n s - f a r n e s o l (44) support the proposed intermediacy of aldehydes during t r a n s - c i s i s o m e r i z a t i o n of the C-(2 ) , C-(3) double bonds. (42) (43) (44) (30) In the b i o s y n t h e s i s of 2 , 6 - t r a n s , t r a n s - and 2 - c i s , 6 - t r a n s -f a r n e s o l s from (3RS) - Q2- 1 *C , -5 - 3 H 2^]— mevalonate , Overton and 32 Roberts found that there was t o t a l r e t e n t i o n of t r i t i u m i n the t r a n s , t r a n s compound but l o s s o f one s i x t h o f the t r i t i u m i n the c i s , t r a n s isomer, as shown by the 3H:11*C r a t i o s . These r e s u l t s support t r a n s •*• c i s i s o m e r i z a t i o n v i a a l d e h y d i c i n t e r -mediates. The evidence a v a i l a b l e from the b i o s y n t h e t i c s t u d i e s on dendrobine s y n t h e s i z e d from [*J5- 3"^j"]-mevalonic a c i d ( c f . F i g . 10) excludes the intermediate formation of f a r n e s a l . Thus f i v e out of s i x of the t r i t i u m l a b e l s from three molecules of meva-l o n i c a c i d are r e t a i n e d i n dendrobine (6) and the 3H removed i s - 165 -known to be l o s t as a r e s u l t of b i o l o g i c a l h y d r o x y l a t i o n at the C-(3) p o s i t i o n . Three p r o p o s a l s can be made to e x p l a i n these r e s u l t s : (a) C-(2) t r a n s - c i s i s o m e r i z a t i o n o f f a r n e s o l can take p l a c e by a mechanism not i n v o l v i n g an a l d e h y d e , or (b) 2 - c i s , 6 - t r a n s - f a r n ' e s o l can be s y n t h e s i z e d through an independent b i o -g e n e t i c pathway, or (c) t r a n s - c i s i s o m e r i z a t i o n can occur v i a 14 the a l l y l i c c a t i o n 45 , the t r a n s - i s o m e r of the c a t i o n 18 ( c f . 4 5 ) o r i g i n a t i n g from 2 - t r a n s , 6 - t r a n s - f a r n e s y l p y r o p h o s -phate (46) . The l a t e r p r o p o s a l i s s u p p o r t e d by the f a c t t h a t 2 - t r a n s , 6 - t r a n s - f a r n e s o l (47) was shown t o be a p r e c u r s o r o f d e n d r o b i n e b u t not the 2 - c i s , 6 - t r a n s i s o m e r . ( 4 6 ) ( 45 ) ( 1 8 ) - 166 -Thus Q.- 3H 2 3 -2-trans,6-trans-farnesol (47) was fed by Jorami to Dendrobium nobile plants and chemical degradation showed t h a t 52% of the l a b e l was l o c a t e d at C-(5) and 47% at C - ( 8 ) . In marked c o n t r a s t , a d m i n i s t r a t i o n of [ ] l - 3 - 2 - c i s , 6-tr ans- f a r n e s o l r e s u l t e d i n a n e g l i g i b l e i n -c o r p o r a t i o n of r a d i o a c t i v i t y i n t o dendrobine. When (1S)-[JL- 3 H~]-2-trans, 6-trans- f a r n e s o l was used as the p r e c u r s o r , i t 29 was shown t h a t t r a n s f o r m a t i o n of the r e s u l t i n g dendrobine 6 i n t o 6a r e s u l t e d i n the l o s s o f 88% of the t r i t i u m from C - ( 5 ) . As expected, when (IS) - |^"l- 3H"| - 2 - c i s ,6-trans f a r n e s o l was used as pre c u r s o r there was no a p p r e c i a b l e l a b e l l i n g of dendrobine. - 167 -The experiment with 3 H^ T] - 2-trans , 6-trans- fame sol (47) unambiguously establishes that the hydrogen atom at C-(8) of dendrobine originates from C-(l) of farnesol and the incorpora-tion of (IS) - [^1-3H~] -2-trans ,6-trans- farnesol indicates that t h i s Ql,3] -hydride s h i f t has a high degree of s t e r e o s p e c i f i c i t y , i . e . the 1-pro-R hydrogen migrates (c_f. 47 -*• 48) . These results confirm that farnesal is not an intermediate 32 in the trans-cis isomerization of farnesol . The lack of incorporation of 2-cis,6-trans-farnesol into dendrobine i n d i -cates that the germacradiene 48 i s formed i n a trans,trans configuration and only i n the subsequent steps i s the config-uration or the position of the C-(2), C-(3) double bond mod-i f i e d to f u l f i l l the geometrical requirements for r i n g closure 34 to the muurolane intermediate 19 (Fig. 10) - 1 6 8 -DISCUSSION Copaborneol (27) has been e s t a b l i s h e d 0 3 as an intermediate in the biosynthesis of t u t i n (5) (c_f. p. 161 ). The i n -corporation of copaborneol (27) into this biogenetic scheme i s consistent with the proposal involving r i n g cleavage of a t r i c y c l i c intermediate as indicated in Figure 9 (p. 150). Rupture of the C - ( l ) , C-(2) bond may be envisioned to occur v i a the ketone copacamphor (50) or a suitable derivative. There i s precedence for t h i s type of oxidative cleavage i n the b a c t e r i a l oxidation of camphor (51) by the Pseudomonad, s t r a i n 3 fi CI. Oxidation (Fig. 11) proceeds by hydroxylation, dehydrogen-ation, and l a c t o n i z a t i o n to the 6-lactone of 5-hydroxy-3,4,4,-2 trimethyl - A -pimelic acid (56) . In t h i s way both carbocyclic rings of camphor are cleaved by oxidation with the conversion of a c y c l i c diketone 53 into the lactone 56 . An analogous -169 - . Fig. 11 reaction also occurs during the b a c t e r i a l degradation of Fenchone 37 (57) . Fenchone (5 7) when oxidized by a Corynebacterium species gives 1,2-fencholide (-58) and 2,3-fencholide (59) i n the r a t i o 9:1. - 170 -The microbial transformation of steriods has also supplied many examples of oxidative removal of side-chains from the 38 C-(17) position of the steroid nucleus to generate a 17-hydroxyl or 17-keto group. Much of the work that has been 39a_e> reported in t h i s area has been concerned with the oxidation of progesterone (60) to testosterone acetate (61). These bacteria which are capable of removing side-chains can also carry out additional oxidation on the 17-ketones to give l a c t o n e s 4 0 3 °\ P e n i c i l l i u m chrysogenuro, for example, oxidizes progesterone (60) to testololactone (62)(Fig. 12, p.171) in 70% y i e l d 4 0 3 . These oxidations are not limited to C-(17) side-chains and D-rings. Eburicoic acid (63) i s cleaved at the A-ring by Glomerella fusariosides to give 4-hydroxy-3,4-seco-ebur ica-8 , 24 (28)-diene-3 ,21-dioic acid (64)(Fig. 1 2 ) 4 1 . - 1 7 1 ~ F i g . 12 - 172 ~ Each of these microbial transformations involves an enzymatic cleavage of a carbon-carbon bond of an a l i p h a t i c or a l i c y c l i c ketone, presumably by a peroxidative attack at the carbonyl function as shown in Figure 13. Migration of an adjacent carbon to the oxygen of the added peroxide forms an ester or lactone with release of reduced peroxide. The same mechanism i s 42 proposed f o r the B a e y e r - V i l l i g e r conversion of ketons to esters or lactones by peracids. ^ Since t h i s mechanism is f a i r l y well-established and can be considered to represent a v a l i d model system for the enzymatic oxidative cleavage, i t seems clear that the function of the enzyme system i s to generate an active peroxide which attacks the keto function of the substrate. One enzyme system which catalyzes the conversion of ketones to lactones has been shown 43 44 ' to consist of an oxidase (E^) and an iron-containing ketolactonase (E 2) which are coupled through a f l a v i n mono-nucleotide (FMN) to catalyze lactonization (Scheme 2). In t h i s oxidative system electrons from reduced diphosphopyridine nucl-eotide (DPNH2) are c a t a l y t i c a l l y transferred, i n the presence of reduced diphosphopyridine + R C H p D 2 H F i g . 13 - 173 nucleotide oxidase (E^), to FMN and from FMN to the iron-con-taining ketolactonase ( E 2 ) , then f i n a l l y to 0 2 to generate the activated form of oxygen used in the lactonization reaction. The reduced form of 0 2 i s presumably bound at the iron atom. The exact nature of the reduced oxygen i s not known but several p o s s i b i l i t i e s have been suggested 4^' 4*'. Attack at the el e c t r o -p o s i t i v e carbonyl carbon in the oxidative step suggests that the active oxygen carr i e s a negative charge. This negatively-charged species might be generated either by a one-electron reduction of 0 2 to the superoxide ion (0 2 ) or a two-electron reduction to the hydroperoxide ion (H0 2~). Since i t i s believed that the hydroperoxide ion i s the better oxidizing agent of the two i t is thought that hydroperoxide i s the more l i k e l y form of 4 7 4 3-the activated oxygen . The fact that enzyme-bound iron i s ess e n t i a l for oxidation and the known capacity of iron to coordinate 0 2 imply that peroxide i s generated from an 0 2 mole-cule coordinated to an iron atom. A peroxide formed at an iron atom could be the actual active oxygen in oxidation. On the other hand, an iron-bound peroxide could generate a peracid by - 174 -interaction with the carbonyl group of an adjacent a c i d i c amino acid side-chain in much the same manner as peracids are gener-ated in the Baeyer-Villiger reaction by the reaction of hydrogen peroxide (H^C^) with an organic acid. The evidence suggests that Baeyer-Villiger-type reactions occur in nature and that the carbon framework of the picrotoxane sesquiterpenoids are possibly derived from copacamphor (50) or a suitable derivative by oxidative cleavage of the C - ( l ) , C-(2) bond. To complete the basic carbon framework common to a l l the picrotoxanes, a 5-membered ring lactone must be constructed by translactonization onto an hydroxyl group at C-(3) or a A 2' 3 double bond. (69) - 175 -The picrotoxanes possess oxygen functions which can be 36 derived by enzymatic a l l y l i c oxidation . Dehydration of the l 3 <• 11+ C-(13) hydroxyl group in 69 would provide a A double bond. Examination of the structure of t u t i n (5) and coriamyrtin suggests that p r i o r to epoxidation (4) (5) of the A 1 3' 1 double bond, a l l y l i c oxidation at C-(12) followed by dehydration could provide a double bond between carbons C - ( l l ) and C-(12). Further a l l y l i c oxidation would provide the hydroxyl function at C-(6). Stereoselective epoxidation of both the double bonds A 1 1 ' 1 2 and A 1 3' 1 1* would then provide the epoxide functions common to both structures (4) and (5). Enzymatic hydroxylation at C-(3) in 70 (Scheme 3) presents a d i f f e r e n t problem since the methyl group at C-(l) blocks the sequential a l l y l i c oxidation, dehydration, a l l y l i c oxidation sequence which would place an hydroxyl group at C-(3) in - 176 (5) (72a) Scheme 3 - 1 7 7 coriamyrtin (4) and t u t i n (5). The biosynthetic oxidation proposal must also account for the va r i a t i o n i n structure at C-(2) between t u t i n (5) and coriamyrtin (4). In the case of t u t i n (5) the proposal must also allow for the introduction of cis-hydroxyl functions at carbons C-(2) and C-(3); however, i n the structure of coriamyrtin (4) only one hydroxyl function i s found, at C-(3). One proposal which perhaps explains these s t r u c t u r a l variations i s shown i n Scheme 3. The enzymatic 36 dehydrogenation of a suitable intermediate 70 could pro-duce the o l e f i n 71 . Scheme 3 may then diverge i n one of two ways: (A) would r e s u l t i n an acid-catalyzed r i n g closure i n -2-3 volving the A double bond and the C-(15) carboxyl group to produce the required lactone at C-(3) (cf. 71 + 4 ); (B) would 2 - 3 require an intermediate step, an epoxidation of the A double bond, followed by an enzyme-mediated epoxide r i n g opening and lactone r i n r f ormation at C-(3) (cf. 71->-7272a5 ). Both dehydrogenation and o l e f i n i c epoxidation are common reactions i n microbial chemistry. These microbial oxidation studies, p a r t i c u l a r l y those concerned with the formation of lactones from 36 37 camphor (51) and fenchone (57) , coupled with the res u l t s of 35 Arigoni's study on the i n vivo incorporation of copaborneol (27) (cf. p. 161 ) into t u t i n (5), suggested a synthetic appr-oach to the picrotoxane framework. Our preliminary objective was the synthesis of the basic t r i c y c l i c lactone structure 73 (p. 178 ) common to the pi c r o -toxanes. An e s s e n t i a l feature of our synthetic plan involved - 178 -(73) B a e y e r - V i l l i g e r o x i d a t i o n o f the t r i c y c l i c k e t o l (74) f o l l o w e d by t r a n s e s t e r i f i c a t i o n and d e h y d r a t i o n t o the b a s i c l a c t o n e s t r u c t u r e (73) . I n i t i a l l y we c o n s i d e r e d an a p p r o a c h t o the s y n t h e s i s o f 4-hydroxycopacamphor (74) by an a d a p t a t i o n o f our p u b l i s h e d 48 r o u t e t o copacamphor (Scheme 4 ) . Thus t r e a t m e n t o f the a l d e -hyde (76) , d e r i v e d from 8-bromocamphor (c_f. S e c t i o n B , p . 67 ) , w i t h the y l i d e g e n e r a t e d from i s o - b u t y l t r i p h e n y l p h o s p h o n i u m b r o m i d e and n - b u t y l l i t h i u m i n THF, and deketalization of the product p r o v i d e d t h e k e t o o l e f i n 77 (80% y i e l d ) . E p o x i d a t i o n o f t h i s - 179 -(69) (82) Scheme A - 181 -0 o l e f i n with meta-chloroperbenzoic acid i n benzene at 0 y i e l d -ed the epoxyketone 78. C y c l i z a t i o n of 78 with tert-butoxide i n t e r t - b u t y l alcohol resulted i n the exclusive formation of the t r i c y c l i c 5-membered r i n g k e t o l 79 which was then oxidized to diketone 80 (Scheme 4) using Jones reagent. In an e f f o r t to determine whether the iso-propyl substitu-ent on the epoxide r i n g was forcing exclusive 5-membered rin g formation, we synthesized the terminal epoxide 83 and subject-ed i t to the same c y c l i z a t i o n conditions. Once again only products from 5-membered r i n g c y c l i z a t i o n could be detected i n the mixture. V.p.c. analysis of the product (column C at 140 ) revealed that the sample contained two compounds (ca. 1:1) and was 90% pure. This product mixture was oxidized immediately using C o l l i n s reagent (chromium tri o x i d e - p y r i d i n e complex) to provide a mixture of aldehydes as o (79) (83) (84) - 182 -determined from the n.m.r. (100 MHz) analysis. Two protons at 69.42 p.p.m. (d,0.36H,J=2.0Hz) and 69.62 p.p.m. (s, 0.64H) assigned to the diastereomeric aldehydes shown in Figure 14. One of the aldehydic protons, that assigned to compound (86b; H =6 9.62 p.p.m.) was a s i n g l e t , while the analogous proton cl in (86a;-Ha = 69.42 p.p.m.) was a doublet with J = 2.0 Hz. Area of the 1 ^ 2 Hz J^fOHz Carbonyl Group The i r (CC14) spectrum of this mixture exhibited absorption bands at 2825 cm - 1 and 2703 cm - 1 (vC-H of CHO and overtone or combination tone) as well as two bands at 1745 and 1724 cm 1 (vC=0) indicating the presence of both the ketone and aldehyde carbonyl groups,respectively. The v.p.c. analysis (column C at 135°) indicated that the C o l l i n s oxidation procedure had pro-vided a product mixture which was 93% pure and composed of two major components in a 1.8:1 r a t i o . This change i n the r a t i o of the components from that of the starting ketol (84) (ca. 1:1) most l i k e l y resulted from epimerization about C-(4) caused by the presence of pyridine i n the oxidation procedure. In an effort to show that the n.m.r. signals at 69.62 and 9.42 p.p.m. resulted from two caastereaierically-related aldehydes a sample of a mixture - 183 -containing 60% (86a) and 40% (86b) was treated, in an n.m.r. tube, with tr ie thylamine for 8 hours. On n.m.r. (60 MHz) ana-l y s i s i t was found that the percent of aldehyde 86b (80%) had increased at the expense of aldehyde 86a (20%) as determined by the r e l a t i v e integrated i n t e n s i t i e s of the protons at 69.62 p.p.m. and 69 .42 p.p.m. ,respectively. At room temperature aldehyde 86b would seem to be the more thermodynamically stable configuration. This mixture of 5-membered ring diastereomeric aldehydes 86 was then used in a structure proof of the diketone 80 (Scheme 4). The mixture of aldehydes 86 (Scheme 5) was treated with iso-butylmagnesium iodide in d i e t h y l ether to provide a ket o l 79 . The i r (CC14) spectrum of the product contained peaks at 3413 cm - 1 (vO-H) and 1740 cm - 1 (vC=0). The ketol 79 was oxidized d i r e c t l y to a diketone whose spectral properties (n.m.r., i r , m.s.) were i d e n t i c a l to those of the diketone 80 (Scheme 4) . The i r spectra of both samples ( 80 via Scheme 4 and (80) v i a Scheme 5) exhibited two strong carbonyl absorption bands at 1740 and 1709 cm"1 (vC=0) indicating the presence of both the a l i c y c l i c camphor carbonyl and the a c y c l i c iso-propyl ketone. The 1408 cm - 1 (6CH2) absorption was absent in both cases, indicating that the bicyclo ["2»2»l"[] heptan-2-one system was substituted o to the 1740 cm"1 carbonyl group. The n.m.r. (100 MHz) spectrum of (80) exhibited strong methyl resonances at 60.89 p.p.m. (s, 3H), 0.98 p.p.m. (s, 3H), and 1.06 (d, 6H, - 184 -J=7.0Hz) accompanied by signals at 62.50 p.p.m. (s, 1H, bridge-head) and 62.76 p.p.m. (m, 2H, a-methines). The high resolution mass spectrum confirmed the molecular ion (M+) at m/e 234 was consistent with the molecular formula ^1^22^2' T n u s we were able to conclude that the structures of compound (80) (Scheme 4) and compound (80) (Scheme 5) were i d e n t i c a l and that the i s o -propyl substitution on the epoxyketone (78) (Scheme 4) was not responsible for the exclusive formation of 5-membered ring c y c l i z a t i o n products. The c y c l i z a t i o n of a c y c l i c systems v i a S N2-type processes to form cyclopentanes i s known to proceed at a faster rate than the formation of the corresponding cyclohexanes by the same mechanism. An important factor which determines the ease of formation of a c y c l i c carbon framework i s the pro b a b i l i t y of 49 having the ends of the ring-forming chain approach each other This p r o b a b i l i t y decreases as the ring size increases and i s refle c t e d in an unfavourable activation entropy for the forma-tion of medium and large rings*. If we consider a ring-closing reaction in which the two groups which must interact are s i t u -ated at the ends of a 10-carbon chain, then in order for reaction to take place, the groups must encounter one another. A 10-carbon chain, however, has many conformations, and in only a few of these are the ends of the chain proximal, resulting in a V. Prelog and H.C. Brown (Ref. 50, footnote 21) c l a s s -f i e d r i n g compounds i n four categories, v i z . "small rings" (3- and 4-membered), "common rings" (5-, 6-, and 7-membered), "medium rings" (8- to 11-membered), and "large rings" (12-membered and l a r g e r ) . - 185 -g r e a t l o s s of entropy i n forming the t r a n s i t i o n s t a t e . T h i s f a c t o r i s p r e s e n t , though l e s s so, i n c l o s i n g r i n g s of 6-members or l e s s (except 3-merabered r i n g s ) t o the e x t e n t t h a t , f o r r i n g s of t h i s s i z e , the entropy l o s s i s l e s s than t h a t of b r i n g i n g two i n d a v i d u a l molecules t o g e t h e r . In epoxyketone 78 C-(3) through C-(7) are p a r t of the r i g i d b i c y c l o Q 2 . 2 . l[] heptane system and, as such are h e l d i n one conformation. Atom C-(8) i s a l s o bonded t o t h i s b i c y c l o system but r e t a i n s a degree of r o t a t i o n a l freedom about the C-(7), C-(8) bond and t h e r e f o r e , c o n t r i b u t e s t o the entropy of the c h a i n . Since three atoms are h e l d i n the optimum p o s i t i o n f o r r i n g f ormation, then the s i t u a t i o n t h a t a r i s e s d u r i n g bond formation i n epoxyketone 78 ( c f . 78b, p. 186, 5-membered r i n g formation) might be compared w i t h ; t h a t of a 3-carbon c h a i n where r i n g formation i s r e l a t i v e l y easy because the p r o b a b i l i t y f a c t o r i s h i g h . Bond formation between C-(3) and C-(10) (6-membered r i n g f o r -mation) r e q u i r e s t h a t the a t t a c k i n g (78) - 186 -nucleophile, C-(3), approach from the backside of the epoxide C-(10), 0 bond in a c o l l i n e a r fashion (cf. 78a). The epoxide ri n g , however, imposes a r i g i d i t y on the car-bon chain of 78a and thi s in turn causes some bond d i s t o r -t i o n 5 1 when the requirement for c o l l i n e a r i t y i s applied to G-(3) attack at C-(10). Thus base-catalyzed c y c l i z a t i o n leads to the formation of 5-membered ring ketols (cf. 78b) and Scheme 4). Similar results from the compound 83 i n which the 0(10) iso-propyl group i s absent indicates that the s t e r i c crowding at C-(10) was not responsible for the i n a b i l i t y of C-(3) to achieve c o l l i n e a r i t y with the C-(10), 0 bond. - 187 -Baldwin has devised a set of empirical rules to predict the r e l a t i v e f a c i l i t y of d i f f e r e n t c y c l i z a t i o n reactions. B r i e f l y , Baldwin describes a ring-forming process with the prefex Exo when the breaking bond i s exocyclic to the forming r i n g , and Endo when the breaking bond i s endocyclic to the form-ing r i n g as i n Figure 15. A numerical p r e f i x describes the size of the r i n g , the number being equal to the number of atoms F i g . 1 5 constituting the skeleton of the c y c l i c product. F i n a l l y , the suffixes t e t (tetrahedral), t r i g (trigonal) and dig (digonal) indicate the geometry of the carbon atom undergoing the r i n g -closure reaction (cf. (A) and (B), F i g . 15). The rules for ring closure are as follows: Rule 1: "Tetrahedral Systems (a) 3 to 7-Exo-Tet are a l l favoured processes. (b) 5 to 6-Endo-Tet are disfavoured. - 188 -Rule 2: Trigonal Systems (a) 3 to 7-Exo-Trig are a l l favoured processes. (b) 3 to 5-Endo-Tr ig are disfavoured; 6 to 7-Endo-Trig are favoured. Rule 3: Digonal Systems (a) 3 to 4-Exo-Dig are disfavoured processes; 5 to 7-Exo-Dig are favoured. (b) 3 to 7-Endo-Dig are favoured. \ (c) (dig) Fig. 16 - 189 -Baldwin argues that the physical basis for th i s set of empirical rules i s the stereochemical requirements of the t r a n s i t i o n states for the various tetrahedral, t r i g o n a l , and digonal r i n g -closure processes. The proposed geometric requirements for the t r a n s i t i o n states for closure at carbon are shown in Figure 16 In each case the subtended angle a between the three i n t e r a c t -ing atoms i s maintained during the reaction pathway, becoming the angle between these atoms in the product. Thus the favoured ring-closure processes are those in which the length of the chain enables the terminal atoms to achieve the required geometry depending on the nature of the carbon atom that i s being at-tacked. Disfavoured processes require that bond angles and d i s -tances be severely distorted to achieve such geometries and con-sequently the activation energy for the ring closure i s increased and the c y c l i z a t i o n w i l l be d i f f i c u l t . The rules governing the opening of 3-membered rings 87 to form c y c l i c stuctures are not well defined, but seem to l i e between those for tetrahedral and t r i g o n a l systems. We may look to Stork's work 5 3 ENDO (87) - 1 9 0 -on the cyanoepoxides of general structures 88 and 90 ( p.191 ) for some indication of the preferred mode (Endo or Exo) of opening in oxirane rings. The concept of c o l l i n e a r backside attack was originated by S t o r k 5 3 3 ' * 3 in two papers concerned with the base-catalyzed c y c l i z a t i o n of cyanoepoxides of the type 88 . y n n=1or2 u n (88) (89) Stork found that the rate at which the 5-membered ring compound (89, n=l) formed was slower than the rate at which the 6-mem-bered ring compound (89, n=2) formed. This res u l t was in con-tr a s t with other c y c l i z a t i o n s involving S N2 type t r a n s i t i o n 54 states . The explanation offered for thi s unexpected r e s u l t was based on the proposal that attack on the epoxide ring re-quires the carbanion to approach in a c o l l i n e a r fashion, i . e . along the dotted l i n e in 88. In the case of ( 88, n»l ) this requirement demands considerable bond d i s t o r t i o n , but with (88, n=2) the carbanion can align i t s e l f c o l l i n e a r l y without severe bond d i s t o r t i o n . For t h i s reason a r e l a t i v e rate enhancement i s observed for 6-membered rin g formation. Stork found that c y c l i z a t i o n of cyanoepoxides of the general - 191 -ENDO CN (90) structure ( 90, n=2, R 1 = R 2 = H } l e d t o P r° ducts a r i s -ing from 6-membered ring-closure v i a the Endo-mode, and that this ring-closure was faster than the 5-membered ring-closure v i a the Endo-mode in (90, n=l, R^=R2=H). When n=l, however, i t was curious that no 4-membered ring-closure products were formed since the backside c o l l i n e a r i t y requirement for carbanion attack on the oxirane ring could e a s i l y be achieved as i s shown in (91, R1=R:>=H). If 5-membered rin g formation required (91) •2 - 192 -bond angle and bond length d i s t o r t i o n to achieve the t r a n s i t i o n state, then surely 4-membered ring-closure should be preferred. The experiment was normalized by introducing methyl substituents at the terminal oxirane carbon (91, R^ =Me or H and R2=Me or H) and only products from 4-membered ring-closure were formed. This experiment also suggests that oxirane rings prefer the Exo-mode of ring opening when s t e r i c factors are not s i g n i f i c a n t * . In our own r e s u l t s the s t e r i c bulk of the iso-propyl substituent did not prove to be a factor in d i r e c t i n g the mode of oxirane ring opening and therefore our results must r e f l e c t the i n a b i l i t y of our systems ((78, Scheme 4) and (83, Scheme 5)) to achieve the necessary geometry required for the 6-membered ring t r a n s i -tion state. We abandoned our attempts to introduce oxygen f u n c t i o n a l i t y at C-(4) in the copacamphor system 74 by ring-closure of epoxyketone 78 (Scheme 4) and considered an (78) * Cf. also J . Org. Chem., 43, 3800 (1978). - 193 -X 9 2 ) (93) (94;R=H) (95;R=Ac) (81) (69) Scheme 6 - 194 -alternative route (Scheme 6) which required that the C-(4) hydroxyl function be in place prior to ring-closure. This alternative seemed promising since c y c l i z a t i o n of the parent desoxy-epoxyketone had already been accomplished in our labora-48 tory . The a l l y l i c alcohol 94 had been synthesized previous-ly (cf. Section B, p. 9 7 ) and the structure of i t s correspond-ing k e t a l (cf.l32a, Section B, p.108) had been established by chemical methods, the alcohol 94 was subjected to acetylation in pyridine containing acetic anhydride. The crude acetate 95 was subjected to p u r i f i c a t i o n by column chromatography on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using, i n i t i a l l y , petroleum ether (35-60) and then gradually r a i s i n g the p o l a r i t y with d i e t h y l ether from 4% d i e t h y l ether-96% petro-leum ether (35-60) to 10% di e t h y l ether-90% petroleum ether (35-60). The acetate 95 R=Ac) was characterized by i t s n.m.r., i r . , and mass spectra. The n.m.r. (100 MHz) spectrum of 95 (R=Ac) exhibited a sharp methyl s i n g l e t at 61.90 p.p.m. for the acetate methyl group as well as a broad multiplet at 65.58 p.p.m. for the a l l y l i c proton on carbon bearing an acetate group. The remainder of the spectrum was s i m i l a r to that of the s t a r t -ing alcohol 94 (R=H) with a v i n y l proton s p l i t i n t o a broad doublet (J=10.0Hz) at 65.02 p.p.m. and two doublets represent-ing the v i n y l methyl groups at 61.69 p.p.m. (J=2.0Hz) and 61.74 p.p.m. (J=2.0Hz). - 195 -The i r spectrum contained a strong, broad acetate asymmetric stretch at 1235 cm - 1 (vC-O-C). The camphor carbonyl and acetate car-bonyl were coincident, however, at 1739 cm """ (vC=0). The peak at 1408 cm - 1 (SCH^) for active methylene hydrogens a to a b i -cyclo ["[2*2,1"3 heptan-2-one carbonyl was taken as further e v i -dence for the presence of the camphor carbonyl group in this compound. F i n a l l y the low resolution mass spectrum indicated that the molecular ion (M+) had a mass of 278 and that the • major cleavage pattern indicated the elimination o f . a c e t i c acid to leave a diene of mass 218 (Structure 99). These two peaks are related by the metastable ion of mass 171 2 ((218) /278=171). The high resolution mass spectrum indicated that the molecular formula for 95 as C ± 7 H 2 6 0 3 * The acetate 95 (R=Ac) was epoxidized using meta-chloro-perbenzoic acid i n benzene at room teperature to y i e l d the - 196 -epoxyketone 96 (Scheme 6, p.193 ) as a clear colourless o i l which was used without further p u r i f i c a t i o n . V.p.c. analysis (column B at 180°) indicated that t h i s compound was 95% pure. The n.m.r. (100 MHz) spectrum exhibited two methyl singlets at 60.84 and 60.94 p.p.m. and two additional methyl signals (on oxygen-bearing carbon) which occurred in pairs at 61.18 and 1.22 p.p.m. (3 protons) and 61.26 and 1.30 p.p.m. (3 protons) (diastereomeric p a i r s ) . Two diastereomeric acetate methyl groups appeared as sharp singlets at 61.96 and 1.98 p.p.m. accompanied by a broad one proton multiplet centered at 64.92 p.p.m. i (H-C-OAc). The one epoxide ring proton exhibited a multiplet i centered at 62.50 p.p.m.. The expected i r c h a r a c t e r i s t i c s for the carbonyls (1739 cm - 1), acetate (1235 cm - 1), and active methylene (1408 cm - 1) were present but no c h a r a c t e r i s t i c epoxide 55 bands were present. The low resolution mass spectrum e x h i b i t -ed a molecular ion (M+) for t h i s compound of mass 29 4 and the molecular formula ci7 H26^4 w a s c o n f i r m e d by high resolution mass spectrometric analysis of the molecular ion. The attempt-ed c y c l i z a t i o n of t h i s epoxide 96 i n t e r t - b u t y l alcohol-potassium tert-butoxide at 90° for 18 hours provided a complex mixture of products (v.p.c. analysis on column A at 180°). The lack of any absorption at 1235 cm '''(vC-O-C) i n the i r coupled with a weak carbonyl stretch at 1739 cm"1 (vC=0) i n d i c -ated that the acetate moiety had been l o s t . This was - 197 -supported by the absence of any resonances due to acetate methyl at ca. 1.95-1.98 p.p.m. in the n.m.r. (60 MHz) spectrum. The quarternary methyls on oxygen-bearing carbon at 61.18-1.30 p.p.m. were also absent, indicating that the epoxide ring had opened. A medium int e n s i t y hydroxyl group absorption (vO-H) appeared in the i r spectrum of the product mixture at 3509 cm - 1. In an attempt to simplify the problem, the product mixture from the c y c l i z a t i o n reaction was subjected to dehydration conditions (thionyl c h l o r i d e - p y r i d i n e ) . This process, however, yielded an even more complex mixture (v.p.c. analysis on column A at 180°). Investigation of this route was abandoned at t h i s point. Intro-duction of the acetate group at C-(9) in the parent epoxyketone structure 100 apparently altered t h i s compound's r e a c t i v i t y when i t was subjected to the standard conditions which cleanly cyclized 100 to the ketol 101 . Our work suggests that when C-(9) i s substituted with a leaving group i t becomes susceptible to nucleophilic attack by the intramolecular enolate centered at C-(3). Nucleophilic attack with subsequent - 198 -C - ( 3 ) , C-(9) bond formation produces 5-membered r i n g compounds. Our experience i n the longicamphane work (Se c t i o n B) a l s o i n -d i c a t e d that oxygen f u n c t i o n a l i t y at C-(9) i n campherenone was very s u s c e p t i b l e to rearrangement or e l i m i n a t i o n even when pr o t e c t e d as a " s t a b l e " methyl e t h e r . Therefore we c o n s i d e r e d the p o s s i b i l i t y of moving the oxygen f u n c t i o n to C-(8) i n 102. The C-(8) p o s i t i o n i n 102 i s not as s u s c e p t i b l e to i n t r a m o l e c u l a r displacement by an e n o l a t e . Ring c l o s u r e by bond formation between C-(3) and C-(8) would r e q u i r e the forma-t i o n of a 4-membered r i n g , which i s l e s s l i k e l y i f a more f a c i l e mode of c l o s u r e i s a v a i l a b l e , e.g. between C-(3) and C-(10) producing a 6-membered r i n g product. C y c l i z a t i o n of the epoxy-ketone 102 under the c o n d i t i o n s which cause 101 to c y c l i z e (potassium tert-butoxide in tert-butyl alcohol) should provide the ketol 103 . Dehydration of the tertiary alcohol in 103 and catalytic hydrogenation would provide the keto acetate 105 (p. 199) . Hydrolysis of the keto acetate 105 would then yield ketol 106 . The regiospecific dehydration JO 3 (102) -199 -of t h i s k e t o l should y i e l d the A keto o l e f i n 107 . Baeyer-Villiger oxidation of 107 with in s e r t i o n of oxygen between C-(7) and C-(8) followed by translactonization onto the A double bond at.C-(4) would provide the l a c t o l 108 (see p. 200). Iodolactonization has been used to functionalize double bonds in a regio- and stereoselective manner in a large number of cyclic cases^. During this reaction a lactone ring is formed from a carboxylic acid and an olefin in the presence of 57 . iodine and aqueous bicarbonate solution. The mechanism is b e l i e v e d to i n v o l v e the f o r m a t i o n of an a c y l h y p o i o d i t e 109 f o l l o w e d by i n t r a m o l e c u l a r i o d i n e t r a n s f e r to the double bond to produce the iodomium ion 110 . A t t a c k by the c a r b o x y l a t e ion on 110 g i v e s the i o d o l a c t o n e 111 . (109) (110) (111) There are two i m p o r t a n t p o i n t s to be noted about t h i s r e a c t i o n : (a) t h a t i t i s s t e r e o s p e c i f i c ; the l a c t o n e i s formed i n a c i s f a s h i o n , and (b) t h a t 5-membered r i n g l a c t o n e f o r m a -t i o n i s f a v o u r e d over the 6-membered r i n g p r o d u c t 5 7 . These two r e s t r i c t i o n s a p p l i e d t o l a c t o n e 108 w i l l l e a d t o the f o r m a t i o n of the i o d o l a c t o l 112 (see p . 201 )• Because o f the - 201 -(113) diastereomeric nature of lactone 108 , two i o d o l a c t o l products are p o s s i b l e : 112 and 113 . However, the s t e r i c crowding produced by the pro x i m i t y of the g-i s o - p r o p y l group present i n 113 may prevent the formation of t h i s compound. This may a i d in the separation of 112 from the product-mixture by enhanc-ing the s t r u c t u r a l d i f f e r e n c e s between 112 and the biproduct(s) i n the r e a c t i o n mixture. The i o d o l a c t o l 112 ( c f . 112, p. 202) possesses a l l f i v e stereochemical centers associated with the compound nobilomethylene 7. The t e r t i a r y a l c o h o l at C-(13) can undergo e l i m i n a t i o n 1 3 - 1 4 to form the exo-methylene group (A ) and the i o d i n e sub-s t i t u e n t at C-(2) provides a 'handle' which can be used to introduce the 2-oxo group of nobilomethylene. - 202 -Our i n i t i a l synthetic route (Scheme 7, p. 203.) was con-cerned with the conversion of (+)-8-bromocamphor (114) to 8-hydroxycampherenone (118). Thus (+)-8-bromocamphor (114) was treated with potassium acetate in hexamethylphosphoramide (HMPA) at 115° for 50 hours to provide (+)-8-acetoxycamphor (115) in 70% y i e l d after chromatography. This acetate exhibited a char-a c t e r i s t i c acetate methyl resonance in the n.m.r. (100 MHz) spectrum at 61.98 p.p.m.. The C-(8) methylene group also ex-hibited a sharp s i n g l e t at 63.74 p.p.m.. The two remaining quaternary methyls were found at 60.88 and 1.02 p.p.m.. Infra-red analysis revealed that the two carbonyl functions in the keto acetate (115) were coincident at 1745 cm - 1 (vC=0), although there was further evidence for both the ketone and acetate car-bonyl groups. A sharp but weak peak at 1412 cm - 1 (60^) was indicative of an active methylene group a to a bicyclo ["[2*2,l"2 heptan-2-one carbonyl and a strong broad band at 1224 cm 1 was - 203 -(120) (119a;R=H) (119b;R=-0(CH2)20-) Scheme 7 - 204 -c h a r a c t e r i s t i c of the acetate asymmetric stretch (vC-O-C). The low resolution mass spectrum of t h i s compound exhibited a mole-cular ion (M ) at mass 210 and several other peaks representing major fragmentation pathways available to the molecular ion (Fig. 17). The d i r e c t connection between the molecular ion (M+ = 210) and the ions at m/e 167 and 168 can be inferred from 2 the presence of metastable peaks at m/e_ 132.8 ((167) /210 = 132.8) and 134.4 ((168) 2/210 = 134.4) respectively. Elemental m/e 168 Fig.17 - 2 05 '-analysis confirmed that the molecular formula for 115 was C12 H18°3* The keto acetate 115 was hydrolyzed with potassium car-bonate i n MeOH-water (80:20) to provide the hyroxy ketone 116 i n y i e l d s of ca. 90-96%. The i r spectrum of 116 exhibited a strong band at 3448 cm 1 (vO-H) as well as a carbonyl stretch at 1739 cm - 1 (vC=0) and an active methylene absorption at 140 8 cm 1 (6CH 2). The acetate asymmetric stretch at 1224 cm 1 (vC-O-C) was not present. Elemental analysis and high resolut-ion mass spectrometry gave a molecular formula for 116 of C10 H16^2" Oxidation of 116 was carried out using pyridinium chlorochrornate i n dichloromethane to y i e l d the k e t i aldehyde 117. This method routinely provided samples of the keto aldehyde 117 i n 90-100% y i e l d and i n 96-100% purity (v.p.c. analysis on column A at 150°). The n.m.r. (60 MHz) spectrum of 117 exhibited two quarternary methyl singlets at 61.00 and 61.16 p.p.m. and a one-proton s i n g l e t at 69.45 p.p.m. (CHO). The i r spectrum indicated the presence of two carbonyl functions withabsorption bands at 1718 and 1745 cm""1" (vC=0) as well as a weak absorption band at 2703 cm 1 (vC-H of CHO). A weak absorp-tion at 140 8 cm 1 (6CH2) i s associated with the active methylene group. This keto aldehyde 117 exhibits extreme s e n s i t i v i t y to a i r oxidation. On exposure to a i r the keto aldehyde 117 i s converted to a keto acid whose structure was determined from i t s n.m.r., i r , and high resolution mass - 206 -spectra to be that of compound 12 4 (see p. 266 ). For th i s reason the keto aldehyde 117 was used immediately without any attempts at further p u r i f i c a t i o n . (117) (124) Our f i r s t approach to the synthesis of 8-hydroxycampher-enone (118) (Scheme 7) involved the d i r e c t addition of a prenyl anion to the 8-oxo group of the keto aldehyde 117 . We en-visioned this addition step as a condensation between the Grignard reagent ^,^-dimethylallylmagnesium bromide and the keto aldehyde 117 . The high r e a c t i v i t y of aldehydes towards Grignard reagents and the hindered nature of the camphor carbon suggested that t h i s addition might be performed without protect ing the ketone function in 117 . Thus the Grignard reagent was synthesized from l-bromo-3-methyl-2-butene and magnesium powder in tetrahydrofuran (THF). The keto aldehyde 117 in THF was added to two molar equivalents of the Grignard reagent - 207 -at 0° and the reaction was warmed to room temperature and s t i r r e d for 50 hours. V.p.c. analysis (column A at 140°) re-vealed that the keto aldehyde had f a i l e d to react under these conditions. The reaction mixture was then heated at reflux for 20 hours, after, which i t was worked up in the usual manner. Both the n.m.r. (60 MHz) and v.p.c. (column A at 140°) analyses indicated that the product was a complex mixture* of compounds containing c_a. 10% unreacted keto aldehyde. Investigation of this reaction was abandoned at th i s point in favour of a' route (Scheme 7) involving the addition of the v i n y l Grignard, 2-methyl-l-propenylmagnesium bromide, to the epoxide of 8-meth-ylenecamphor (119a). Attack of the v i n y l Grignard at the methylene groupt of the terminal epoxide 120 would result in oxirane ring-opening and addition of the 2-methyl-l-propenyl moiety at the terminal carbon of the epoxide to provide 8-hydroxycampherenone (118). 8-Methylenecamphor (119a) was syn-thesized d i r e c t l y from 8-oxocamphor (117) by treatment of 117 with methyltriphenyl phos'phorane (two molar equival-ents) i n THF at room temperature for 17 hours. This pro-vided 119a. i n 80% y i e l d a f t e r p u r i f i c a t i o n by column * ^-substituted allylmagnesium Grignard reagents may react at both their a- and ^-positions. t "In general, nucleophiles attack at the less highly sub-stituted carbon atom of the epoxide ring in basic or neutral media, as would be anticipated for a normal SN2 process; in acidic media, the proportion of attack at the more highly substituted carbon is increased and may become the predominant reaction."58 - 208 -chromatography on alumina (Alumina Woelm Neutral? a c t i v i t y grade III) using 20% d i e t h y l ether-80% petroleum ether (35-60) as eluant. The i r . spectrum of 119a exhibited the expected terminal v i n y l group absorptions at 1639 cm - 1 (vC=C), 995 cm 1 (6CH out-of-plane), and 921 cm - 1 (6CH in-plane). A carbonyl band at 1739 cm 1 (vC=0) and an active methylene absorption at 1408 cm - 1 (6CH2) were also present. The n.m.r. (100 MHz) spec-trum (cf. p. 219) of 119a exhibited two quaternary methyl singlets at 60.88 p.p.m. and 61.02 p.p.m.. The X part of ABX systems associated with terminal v i n y l groups []c_f. insert (17 a - v i n y l e s t r a d i o l (125) ) in the spectrum of 119a p.219 ""] normally exhibits a simple 4 l i n e spectrum. In the 100 MHz spectrum of 119a an unusual coupling pattern was observed which was composed of 6 l i n e s ; two more than expected for c i s -and t r a n s - o l e f i n i c coupling. The AB portion of the spectrum exhibits only 6 instead of 8 l i n e s . Therefore, 4 l i n e s are coincident as i s i l l u s t r a t e d in the spectrum of 119a • The resonance of the proton which i s trans-oriented with respect to H^ i s centered at 64.98 p.p.m. and s p l i t into a quartet with J. =18.0Hz and J =2 . 0Hz. The proton H D which i s cis-o r i -tr ans gem B ented with respect to H v i s centered at 65.04 p.p.m. and s p l i t A into four l i n e s with J • =10.0Hz and J„„ =2.0Hz. The sextet c i s gem centered at 65.65 p.p.m. i s therefore assigned to the proton H^. This same 6-line pattern for the H x portion of the ABX system also occurred in the n.m.r. (100 MHz) spectrum of - 209 -compound 119b (cf. p. 220) . An explanation for t h i s phenom-enon w i l l be offered in that part of the discussion pertaining to this compound, v i z . 119b (cf. p. 220). The low resolution mass spectrum of 119a indicated a molecular ion (M+) of mass 164 and the high resolution mass spectrum gave a molecular f o r -mula for 119a of c l x H i g ° » which i s correct for the desired keto o l e f i n . Compound 119a was epoxidized using meta-chloro-perbenzoic acid in benzene at room temperature for 24 hours to provide 120 (quantitatively) as a colourless s o l i d . V.p.c. analysis (column A at 140°) indicated that the compound was a 97.6% pure mixture of diastereomers, i . e . two peaks were present in the chromatogram at retention times t=3.4 and t=4.0 minutes with r e l a t i v e integrated i n t e n s i t i e s equal to 80.3% and 17.4% respectively. The n.m.r. (270 MHz) spectrum of t h i s compound exhibited a s i n g l e t at 60.93 p.p.m. (6 protons) and a broad multiplet between 62.39 and 2.67 p.p.m. (3 oxirane ring pro-tons). There were no o l e f i n i c protons in the region between 64.5-6.0 p.p.m.. The i r spectrum contained a carbonyl band at 1739 cm - 1 (vC=6) and a weak absorption at 1408 cm - 1 (6CH 2). The epoxide r i n g stretches were also present as medium broad bands at 9 40 and 855 cm"1, the so-called " l l y " and "12y" 55 bands . The low resolution mass spectrum contained a molecular ion (M+) at mass 180-and high resolution mass spectral analysis indicated - 2 1 0 -(126) (127) , (130) /H i (131) Scheme 8 - 211 -that the molecular formula for compound 1 2 0 i s c i i H i 6 0 2 * T n e epoxide 120 was treated with 2-methyl-l-prbpenylmagnesium bromide 5 9'^ 0 (Iso-butenyl magnesium bromide) at room temperature for 15 hours. V.p.c. analysis (column A at 140°) indicated that 50% of the epoxide remained unreacted at t h i s point and that the remainder of the starting material had produced a complex mixture of products. The indications were that forcing conditions might have driven the reaction to completion but that the resultant products would have been too complex to analyse. We had found that the reaction of the keto aldehyde 117 and the keto epoxide 121 with a l l y l i c and v i n y l Grignard reagents, respectively, led to product mixtures probably a r i s i n g from reaction at both car-bonyl s i t e s in the substrates 1 1 7 and 1 2 0 • Protection of the carbonyl group in 117 and 120 by formation of the ketals 129 and 130 was achieved by the sequence shown in Scheme 8. These two compounds 129 and 130 were also subjected to treat-ment with the a l l y l i c and v i n y l Grignard reagents (Scheme 8). The aldehyde 129 on treatment with j,^-dimethylallylmagnesium bromide underwent hydride reduction to provide the alcohol 128 in 61% y i e l d as indicated by v.p.c. analysis (column A at 160°). On work-up and chromatography of the reaction products on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 10% d i e t h y l ether-90% petroleum ether (35-60) as eluant a compound (25% yield) was obtained whose spectral properties (n.m.r. and i r ) - 212 -were i d e n t i c a l to those of compound 128 which we had previous-l y prepared (cf. p. 203) . It i s proposed that t h i s product arises v i a a Q l ,4*]-elimination of hydride from the Grignard reagent. The reduction of ketones by R WgBr2 MgBr OMgBr H MgBr2 Grignard reagents has been examined by B i r t w i s t l e and co-work-e r s ^ 1 , who studied the asymmetric reduction of a l k y l phenyl ketones to their corresponding alkylphenylcarbinols with an o p t i c a l l y - a c t i v e Grignard reagent made from (+)-l-chloro-2-phenylbutane. Reduction in thi s system i s believed to resu l t from [3lf2"j] hydride transfer to the ketone from the Grignard reagent. The reaction of the epoxide 130 with iso-butenyl-magnesium bromide resulted in an intramolecular hydride s h i f t . This reaction provided the ketone 132 in 76% isolated y i e l d and 85% purity as determined by v.p.c. analysis (column A at 150°). Chromatography of 132 on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 10% d i e t h y l ether-90% petro-leum ether (35-60) as eluant provided an a n a l y t i c a l sample of 132 . The structure of t h i s ketone 132 i s based on the f o l -lowing spectral c h a r a c t e r i s t i c s . The n.m.r. (100 MHz) spectrum - 213 -exhibited three strong methyl resonances at 60.98, 1.02 and 2.00 p.p.m. (9 protons) as well as a broad multiplet centered at 63.72 p.p.m. which was assigned to the protons of the 1,3-dioxolane r i n g . A scan of the region 610.0-13.0 p.p.m. did not reveal a low f i e l d t r i p l e t due to an aldehyde proton. The i r spectrum exhibited one carbonyl band at 1701 cm-"1" (vC=0) . Char-a c t e r i s t i c a l l y an a c y c l i c ketone would be expected to exhibit a band.at 1715 cm 1 but because of this ketone's neopentyl po s i -t i o n , which re s u l t s in the deformation of the bonds about the sp carbon, the bond between the carbon and oxygen of the car-bonyl group i s weakened, re s u l t i n g in a s h i f t to longer wave-length and thus lower wave number. The spectrum lacked any active methylene band at 1408 cm 1 ( 6 C H 2 ) since the camphor car-bonyl was protected as the ethylene acetal. The low resolution mass spectrum of 132 contained a molecular ion ( M + ) at mass 224 accompanied by two ketone a-cleavage peaks at m/e 181 and 209 (cf_. F i g . 18). High resolution mass spectrometry and e l e -mental analysis both confirm the molecular formula for 132 as C'13H20°3* Acid-catalyzed rearrangement of epoxides i s of spe-c i a l interest to the organic chemist since the o v e r a l l reaction scheme provides a means of converting an o l e f i n to a carbonyl compound. This rearrangement has been studied by several work-63—65 ers and a mechanism for the rearrangement of epoxides in the presence of magnesium bromide has been proposed**5. House has shown 6 5 b that free bromohydrin i s not an intermediate i n - 214 -r t m/e 181 Fig. 18 the rearrangement. The proposed mechanism (Fig. 19) may follow one of two routes. Rearrangement v i a a carbonium ion i n t e r -mediate (B) (or a concerted migration of a group and cleavage of a carbon-oxygen bond of the oxirane ring) - 215 -leads to the formation of the same product 134 which results when bromohydrins and glycols undergo pinacol rearrangement, and the product i s the same regardless of the stereochemistry of the epoxide. The product obtained from the rearrangement of the s a l t of the bromo alcohol (A), however, i s dependent on the stereochemistry of the epoxide and may d i f f e r from the products of analogous pinacol rearrangement. We have found that rear-rangement of the keto epoxide 120 to the diketone 135 does not take place under the conditions which cause rear-rangement of ketal epoxide 130 to the ketal ketone 132. (135) (120) THF ; 66* (130) (132) Therefore we propose that the oxygen atom of the 1,3-dioxolane • protecting group of 130 i s p a r t i c i p a t i n g in the rearrangement of 130 and s t a b i l i z i n g the formation of a posi t i v e center at C-(9) in the manner shown (see p. 216). The carbonyl group of 120 , because of i t s greater distance from C-(9), i s unable to exert a similar s t a b i l i z i n g influence and the rearrangement f a i l s to occur in th i s system. - 216 ~ I MgBr ( 132). (137) At t h i s time a procedure" 0 became available to us for the synthesis of the v i n y l l i t h i u m compound iso-butenyllithium f i r s t reported by Braude^ 0. However, attempts to condense the epoxy ketal 130 with iso-butenyllithium f a i l e d . A 97% recovery (by weight) of unreacted epoxyketal was r e a l i z e d . F i n a l l y , two Grignard reactions were run using 3-methyl-butyl- and 2-methylpropylmagnesium bromide with compounds 129 and 130 , respectively. The ketal aldehyde 129 reacted clean-l y with 3-methylbutylmagnesium bromide in THF at reflux to y i e l d the alcohol 8-hydroxydihydrocampherenone ethylene acetal .(138) - 217 ~ i n 80% y i e l d . The epoxy k e t a l 130 when treated with 2- methyl-propylmagnesium bromide provided the ketone 132 (138) (46%) , alcohol 138 (42%), and unreacted st a r t i n g material 130 (12%) as determined by v.p.c. analysis (column A at 180°). These results suggest that the f a i l u r e of compounds 129 and 130 to react with the unsaturated Grignard reagents results from a conformational r e s t r i c t i o n imposed by the double bond in the l a t t e r on the formation of the t r a n s i t i o n state required for addition. E l e c t r o n i c factors may also hinder the addition of these unsaturated Grignard reagents. Although addition was observed in the case of epoxy ketal 130 , magnesium bromide, - 218 " which i s present in the reaction mixture, catalyzes the rear-rangement of the epoxy ketal 130 to the ketone 132 at a rate which i s comparable to that of the addition. The results of the above experiments indicated that lithium or magnesium organometallic prenyl (^,j-dimethyl a l l y l ) or iso-butenyl re-agents would not be suitable for the synthesis of 8-hydroxy-campherenone (131). As was mentioned (cf. p. 208), the n.m.r. (100 MHz) spectra of both the keto o l e f i n 119a and the ketal o l e f i n ' 119b ex-h i b i t unusual 6-line patterns for the X portion of their re-spective ABX systems (c_f. spectra on pages 219 and 220). This pattern r e s u l t s from a phenomenon known as v i r t u a l (effective) 6 7 spin-spin coupling . Let us examine the ABX system H ABX SYSTEM R' H B shown above and assign the chemical s h i f t s for the i n d i -vidual protons H A, Hfi, and H x such that and VA" VB is small. Then, i f VB" VX VB" VX is very large >>JBX' w e c o u l d treat the X portion of thi s ABX system in a simple f i r s t - o r d e r manner. In f a c t , simple f i r s t - o r d e r analysis of the X portion i s a p p l i -cable in many cases (c_f. insert 17 a - v i n y l e s t r a d i o l (125) p. 219) and a simple f i r s t - o r d e r 4-line spectrum appears for the - 222 -H x proton. However, f i r s t - o r d e r analysis w i l l f a i l in circum-stances where the proton in question (X) is coupled to one set of strongly coupled nuclei ( i . e . a set in which J i s greater than the chemical s h i f t d i f f e r e n c e ) . Since the l a t t e r situation depends on J A B and VA~ VB both being small and approximately equal, then increasing the magnetic f i e l d strength w i l l increase the value of VA" VB and the X portion of the ABX system w i l l return to a simple f i r s t - o r d e r spectrum. Thus the 100 MHz and 270 MHz spectra of the ke t a l o l e f i n 119b were recorded i n 6 8 CCl^ and the res u l t s are shown on pages 220 and 221- . As pre-dicted, in a 270 MHz magnetic f i e l d the X portion of this spec-trum returns to a f i r s t - o r d e r pattern. Lithium and magnesium sa l t s of a l l y l i c systems, i . e . prenyllithium and prenylmagnesium bromide, undergo f a c i l e [""1, 3*"] rearrangement of the anionic center (see below) Most of the reactions of unsymmetrical a l l y l i c Grignard reagents show a tendency to react at the internal carbon of the a l l y l i c 69 • • system rather than at the terminal carbon . Organosilicon — . — 1 B r M 9 K compounds, such as prenyl trimethylsilane, are useful sources of substituted a l l y l carbanions. Fluoride ion displays a high nucleophilic a f f i n i t y s p e c i f i c a l l y for the s i l i c o n atom in an - 223 -organosilicon compound due to the high s i l i c o n - f l u o r i n e bond -1 70 energy, viz. 140 kcal mole . The carbanxons produced by this method main-71 tain the anionic center on the primary carbon. Sakurai found that the a l l y l - s i l i c o n bond of a l l y l silanes i s e a s i l y cleaved in the presence of tetra-n-butylammonium fluoride (TBAF) and the a l l y l i c anion species thus formed adds to carbonyl compounds to afford homoallyl alcohols. The a l l y l i c anion i s also chemo-se l e c t i v e , adding to aldehydes and ketones in the presence of n i t r i l e s , epoxides, and esters. Prenyl trimethylsilane was therefore synthesized from prenylmagnesium chloride and t r i -m e t h y l s i l y l chloride. Examination of the n.m.r. (270 MHz) spectrum of the crude product indicated that i t contained ca. 4% of the isomer 1,1-dimethylallyl trimethylsilane. The keto aldehyde 117 , in THF, was treated with prenyl trimethylsilane and TBAF (4.0 molar equivalents) in the presence of 4A molecular sieves (see p. 224 ). The reaction was refluxed under argon atmosphere for 24 hours. Work-up provided an orange o i l which rapidl y deposited a white s o l i d on standing at room temperature. The s o l i d was separated from the o i l and examined by n.m.r., i r , and m.s.. The n.m.r. (270 MHz) spectrum of th i s s o l i d exhibited four methyl singlets at 61.02, 1.03, 1.06, and 1.17 p.p.m. (12 protons), a t r i p l e t at 62.56 p.p.m. (1 proton, J=4.0Hz) and two si n g l e t s at 63.64 p.p.m. (1 proton, broad, (3 - 224 -OH) and 63.96 p.p.m. (1 proton, CH-OH). The i r . spectrum con-' _1 tained a broad carbonyl absorption at 1739 cm (vC=0) accom-panied by a weak active methylene absorption at 1408 cm 1 (6CH2) and a weak, broad hydroxyl band at 3472 cm - 1 (vO-H). The low resolution mass spectrum exhibited a molecular ion ( M + ) at mass 332 and other ions at m/e 273, 167, and 95 (base peak). The ion at m/e 273 was related to the molecular ion m/e 332 by a metastable ion (M*) at m/e 224.5 ((273)2/332=224.5 ). The high resolution mass spectral analysis of the molecular ion indicated that the molecular formula for th i s compound i s ^ 2 ( ^ 2^0^. This spectral data suggested that the structure of the s o l i d was 139. Based on t h i s structure the metastable ion at m/e 224.5 can be ra t i o n a l i z e d i n terms of a McLafferty rearrange-ment of the molecular ion (m/e 332) leading to the loss of a - 225 " -59 - C 2 H 3 0 2 a/e 332 (139) fragment of mass 59, C18H25°2 m/e 273 M =224.5 We propose that t h i s structure 139 72 arises v i a a 'benzoin-type' condensation of two molecules of the keto aldehyde 117 i n i t i a t e d by fluoride ion* attack (cf, Scheme 9) on the aldehyde group i n 117. In the ( M l ) (MO) (117) ( M 2 ) (139) Scheme 9 The use of fl u o r i d e ion as a catalyst for the benzoin condensation appears to be without precedent i n the chemical l i t e r a t u r e . - 226 -absence of further evidence, however, structure 139 must remain speculative. Chromatography of the o i l isolated from the reaction provided a sample whose n.m.r. (270 MHz) spectrum (cf n.m.r. spectrum p. 227) exhibited two methyl singlets at 60.88 and 0.94 p.p.m. (6 protons) and two v i n y l methyl singlets at 61.64 and 1.72 p.p.m.. A broad resonance of 63.52 p.p.m. (1 proton) was assigned to a proton on an oxygen-bearing car-i bon atom (CH-0-) and a t r i p l e t at 62.19 p.p.m. (2 protons, i J=7.0Hz) was assigned to the a l l y l i c hydrogens of the prenyl moiety. The'vinyl hydrogen exhibited a broad, poorly resolved, t r i p l e t at 65.19 p.p.m. (1 proton, J=7.0Hz). This spectrum was tent a t i v e l y assigned to the structures of the hemi-ketai 143 and ketol 118 (cf. n.m.r. spectrum p. 227 in rapid e q u i l i b -rium on the n.m.r. time scale. The assignment was also based on the i r spectrum of thi s o i l which exhibited a weak carbonyl band at 1739 cm - 1 (vC=0). The presence of the hydroxyl group was indicated by a broad absorption at 3350 cm 1 (vO-H). The n.m.r. sample was treated with deuterium oxide (E^O) and the 270 MHz spectrum was re-examined (c_f. n.m.r. spectrum p.228 ). The two methyl singlets at 60.88 and 0.94 p.p.m. (6 protons) in the previous spectrum (anhydrous) had now been replaced by four broad methyl singlets between 60.84 and 1.03 p.p.m. (6 protons). The two v i n y l methyl singlets at 61.64 and 1.72 p.p.m. (6 protons) remained unchanged, as did the t r i p l e t at •62.19 p.p.m. (2 protons, J=7.0Hz) assigned to the a l l y l i c - 227 -- 229 -p r o t o n s of the p r e n y l m o i e t y . The broad one p r o t o n resonance a t 63.52 p . p . m . had now been r e p l a c e d by two broad peaks at 63.37 and 3.68 p . p . m . (h p r o t o n e a c h ) . The p o o r l y r e s o l v e d v i n y l t r i p l e t at 65.18 p . p . m . remained at the same c h e m i c a l s h i f t but had now l o s t a l l r e s o l u t i o n . Thus the i n t r o d u c t i o n o f D 2 0 i n t o the sample had a p p a r e n t l y slowed down the r a t e a t which the two compounds were i n t e r c o n v e r t i n g so t h a t the l i f e t imes of the two compounds were now on the n . m . r . time s c a l e . The low r e s o l u t i o n mass spectrum of t h i s o i l e x h i b i t e d a m o l e -c u l a r i o n (M +) at mass 236 as w e l l as i o n s at m/e 221, 167, and 95 (base p e a k ) . High r e s o l u t i o n mass s p e c t r a l a n a l y s i s of the m o l e c u l a r i o n e s t a b l i s h e d a m o l e c u l a r f o r m u l a f o r the k e t o l 118 o f c i 5 H 2 4 ° 2 " ^is k e t o l was s u b j e c t e d to a c e t y l a t i o n ( a c e t i c a n h y d r i d e - p y r i d i n e ) i n an at tempt to p r e p a r e the s e c o n -d a r y a c e t a t e 146 . V . p . c . a n a l y s i s (column B at. 1 5 0 ° ) o f the p r o d u c t f r o m t h i s a c e t y l a t i o n i n d i c a t e d t h a t two compounds were p r e s e n t i n the r a t i o of 2 : 3 . The n . m . r . (270 MHz) spectrum ( c f . n . m . r . spectrum p . 230) e x h i b i t e d two sharp a c e -t a t e m e t h y l s i n g l e t s a t 61.83 and 1.98 p . p . m . (3 pro tons ) - 231 -accompanied by four methyl singlets grouped into pairs of singlets at 60.77 and 0.86 p.p.m. and at 60.84 and 0.97 p.p.m. (6 protons). The v i n y l hydrogen appeared as two, well-resolved t r i p l e t s (J = 7.0Hz) at 64 .96 p.p.m. (3/1+ proton) and 65.16 p.p.m. (1/1+ proton). The v i n y l methyl signals were not as c l e a r l y separated and appeared as three singlets at 61.53, 1.60 and 1.64 p.p.m. (6 protons) . Two doublets of doublets at 63.73 (1/1+ proton) and 4.81 p.p.m. (3/1+ proton) were assigned to hydrogens on oxy-gen-bearing carbon atoms (CH-0-). The doublet of doublets cen-tered at 63.73 p.p.m. was assigned to the methine proton of the hemi-ketal 147 (cf. n.m.r. spectrum p. 230), while the doublet of doublets centered at 64.81 p.p.m. was assigned to the methine proton of the secondary acetate 146 (c_f. n.m.r. spectrum p. 228). These doublets of doublets exh i b i t i d e n t i c a l coupling constants of ca. 4 and 7 Hz which arise from v i c i n a l coupling ( 3J) between the methine proton and the two magnetically non-equivalent, p r o c h i r a l , a l l y l i c hydrogens present in both com-pounds 146 and 147 . Encouraged by thi s success and in an e f f o r t to protect the camphor carbonyl group at C-(2), we synthesized the ketal alde-hyde 129 (Scheme 8, p. 210) and subjected this compound to reaction with prenyl trimethylsilane in the presence of TBAF. However, the presence of the k e t a l protecting group in 129 completely blocked addition to the aldehyde group at C-(8) and the ketal aldehyde 129 was recovered quantitatively - 232 -NO REACTION from the reaction. In an attempt to circumvent this d i f f i c u l t y i t was decided to reduce the C-(2) carbonyl group stereoselec-t i v e l y to the endo alcohol in order to remove the C-(2) oxygen f u n c t i o n a l i t y from the v i c i n i t y of the aldehyde group. To this 73 end, reduction using calcium metal in l i q u i d ammonia , was at-tempted on the following series of 8-substituted camphor d e r i -vatives: 8-tert-butyldiphenylsiloxycamphor (148), 8-acetoxy-camphor (115) , and 8-oxocamphor-8-ethylene acetal (149) (Fig. 20). The 8 - t e r t - b u t y l d i p h e n y l s i l y l derivative 148 was unre-active towards metal-liquid ammonia reduction, while the 8-ace-toxy compound 115 produced an unresolved mixture of products. 8-Oxocamphor-8-ethylene acetal 149 was reduced with calcium-l i q u i d ammonia and acetylated. The n.m.r. (60 MHz) spectrum - 233 -•S. = C 6 H 5 F i g . 20 - 234 -of the r e s u l t i n g o i l exhibited a broad doublet at 64.90 p.p.m. (1 proton, J=8.0Hz) superimposed on the C-(2) methine s i n g l e t of the 1,3-dioxolyl r i n g at 64.87 p.p.m. (1 proton). A sharp methyl s i n g l e t also appeared i n the spectrum at 61.98 p.p.m. (3 protons)* and the compound was therefore t e n t a t i v e l y assign-ed the structure 151 . Chromatography on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade III) using 15% die t h y l ether-85% petroleum ether (35-60) as eluant provided a sample of the endo-acetate 151 which was 90% pure (v.p.c. analysis on column A at 180°). The compound 151 was deketalized (acetone-6N hydrochloric acid) to provide the aldehyde 152 (Scheme 10, p. 236 ). The n.m.r. (60 MHz) spectrum of t h i s compound exhibit -ed two methyl singlets at 61.03 and 1.06 p.p.m. (6 protons), a sharp s i n g l e t at 62.00 p.p.m. (.3 protons) for the acetate methyl group and a broad doublet centered at 64.82 p.p.m. (1 proton, J=10.0Hz) for the C-(2) methine hydrogen. The alde-hydic proton (-CHO) appeared i n t h i s spectrum as a sharp s i n g l e t at 69.63 p.p.m. (1 proton). The i r spectrum contained a strong broad carbonyl absorption band at 1730 cm 1 (vC=0), a weak aldehyde absorption at 2695 cm (vC-H of CHO) and a strong ace-tate asymmetric stretch at 1235 cm - 1 (vC-O-C). Past experience (cf. p. -206 ) indicated that t h i s aldehyde might be * The methyl s i n g l e t and methine proton of bornyl ace-tate74,75 appear at 61.99 p.p.m. and 64.90 p.p.m., respectively i n the same solvent (CC1 4). - 235 -a i r - s e n s i t i v e , so i t was treated immediately with prenyl t r i -methylsilane, TBAF (1.0 molar equivalent) and 4A molecular sieves in THF at reflux for 17 hours. Work-up and chromato-graphy of the reaction products on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using petroleum ether (35-60) as eluant provided prenyl trimethylsilane (215 mg; 55% recovery based on s t a r t i n g weight). Changing the composition of the eluant to 30% d i e t h y l ether-70% petroleum ether (35-60) pro-vided an unidentified compound (73 mg). F i n a l l y , elution with 100% d i e t h y l ether provided 8-hydroxycamphor (116) (32 mg; 35% y i e l d based on s t a r t i n g aldehyde 152 ). 8-Hydroxycamphor was i d e n t i f i e d by comparison of the n.m.r., i r , and v.p.c. data of t h i s sample with those of authentic material (cf. 116 Scheme 7, p. 203). 8-Hydroxycamphor i s probably formed in this reac-tion by a Ql#4^] hydride s h i f t , i . e . prenyl anion produced by attack of fluoride ion on prenyl trimethylsilane attacks the acetate carbonyl group in t h i s molecule releasing the alkoxide moiety which collapses v i a a Ql»4^| hydride s h i f t to provide 8-hydroxycamphor 116 (cf. p. 237 ) • Intramolecular [jl»n~] hydride s h i f t s of the general type [^lfOU shown in Figure 21, 76 p. 237 ) have been observed i n a wide variety of ketols pro-vided they possess the correct stereochemistry and conformation 7 7 necessary for hydride transfer Scheme 10 - 237 -( 1 5 2 ) ( 1 1 6 ) Since the acetate protecting group had proved unsatisfactory for our purpose we turned our attention to the potential use of Fig. 2 1 H methyl ether 156 as shown in the route outlined in Scheme 11 (P« 240)• In model studies the methyl ether of (-)-borneol (155) was synthesized by treatment of (-)-borneol with sodium hydride in THF and quenching the alkoxide thus formed with excess methyl iodide. This methyl ether 155 was then used to estab l i s h conditions for removal of the methyl group(cf.p. .238 ) - 238 -The conditions which provided a quantitative recovery of (-)-borneol (154) from methyl ether .155 were found to 78 79 be those reported by Jung and Olah , i . e . t r i m e t h y l s i l y l iodide in chloroform or a c e t o n i t r i l e . The alcohol 150 was therefore converted to the methyl ether 156 by treatment with sodium hydride in THF followed by addition of excess methyl iodide. The n.m.r. (270 MHz) spectrum of methyl ether 156 exihbited two methyl singlets at 60.78 and 0.96 p.p.m. (6 pro-tons). A si n g l e t at 63.24 p.p.m. (3 protons) was assigned to the methyl group of the ether. This was accompanied by a broad doublet at 63.52 p.p.m. (1 proton, J=8.0Hz) assigned to the C-(2) methine proton. A one proton singlet at 64.77 p.p.m. was ch a r a c t e r i s t i c of the methine proton of the 1,3-dioxolyl pro-tecting group. The i r spectrum of 156 contained only one strong band at 1093 cm 1 which was assigned to the ether asymmetric stretch (vC-O-C). The low resolution mass spectrum was p a r t i c u l a r l y informative (Fig. 22). Several fragmentation pathways are open to t h i s molecule as indicated by the ( 1 5 4 ) (MeKSil-CHCl.tfO* (155) - 2 39 -appearance of prominent ions at m/e 226 (M ), 211, 194, 168, 126, 108, 95 (base peak), and 73. High resolution mass spec-t r a l analysis of the molecular ion (M+) confirmed that the molecular formula for 156 i s cj_3 H22°3* T ^ e P e a k s a t £/£ 7^ and m/e 194 arise from loss of each protecting group. The ion at m/e 73 res u l t s from cleavage of the 1,3-dioxolyl ring (cf. path a) and the ion at m/e 194 arises from loss of a a (156) Fig. 2 2 molecule of methanol (M -32) from the molecular ion v i a path b, a proton being derived from some other p o s i t i o n i n the molecule. Ether 156 was deketalized (acetone-6N hydrochloric acid) to provide the aldehyde 157 which was used immediately in the next reaction. The n.m.r. (60 MHz) analysis of the aldehyde 157 was s a t i s f a c t o r y . Two methyl singlets at 61.00 and 1.17 p.p.m. (6 protons) were assigned to the two quaternary methyl groups in 157 . A singlet at 63.25 (3 protons; overlapped with a broad doublet cen-tered at 63.38 p.p.m. (1 proton, J=8.0Hz). These Scheme 11 - 241 -Scheme 12 -'242 -ii t signals were assigned to the methyl group of the methyl ether and i t s corresponding methine proton, respectively. F i n a l l y the spectrum lacked the single proton resonance at 64.77 p.p.m. assigned to the d i o x o l y l methine, but instead contained a sharp one proton si n g l e t at 69.53 p.p.m. which was assigned to the proton of the aldehyde function now present in thi s molecule. The i r spectrum exhibited a weak absorption band at 2703 cm 1 (vC-H of CHO) together with a strong aldehyde carbonyl stretch at 1724 cm - 1 (vC=0). This aldehyde 157 was reacted with prenyl trimethylsilane (2.0 molar equivalents) and TBAF (4.0 molar equivalents) in THF at room temperature for 2.5 hours. Work-up provided a clear colourless o i l which was shown by v.p.c. analysis (column A at 160°) to be mainly composed of two compounds in the r a t i o 3:1. Acetylation followed by column chromatography on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade III) provided acetate 160 as the major component and alcohol 158 as the minor product (c_f. Schemes 11 and 12) . The struc-tures of compounds 158 and 160 were readily apparent from their n.m.r. spectra (cf. n.m.r. (270 MHz) spectra p. 243 and 245). Acetate 160 (cf. n.m.r. spectrum p. 243) exhibited methyl singlets at 60.79 and 0.96 p.p.m. (6 protons). Two v i n y l methyl singlets appeared at 61.71 and 1.78 p.p.m. (6 protons) accompanied by a v i n y l proton centered at 65.11 p.p.m. (one proton, broad t r i p l e t , J=7.5Hz). The acetate and methyl ether groups appeared as si n g l e t s at 62.04 p.p.m. (3 protons) and 63.41 - 244 -p.p.m. (3 protons),respectively. The methine proton of the ether was present as abroad doublet centered at 63.48 p.p.m. (1 proton, J=8.8Hz), while the methine proton of the acetate group was observed as two doublets of doublets (diastereomers) (cf. insert in n.m.r. spectrum p. 243). The minor component exhibited a doublet of doublets centered at 65.20 p.p.m. with coupling constants J=10.0Hz and J=3.8Hz (one proton), while the major component of t h i s diastereomeric mixture exhibited a doublet of doublets centered at 65.26 p.p.m. with coupling con-stants of J=10.0Hz and J=5.0Hz. No attempt was made to assign the stereochemistry of either of these diastereomers. The i r spectrum of 160 exhibited an acetate carbonyl band at 1730 cm 1 (vC=0) accompanied by the acetate asymmetric stretching band at 1238 cm - 1 (vC-O-C). A methyl ether band was also present at 1120 cm 1 (vC-O-C). The high resolution mass spectrum of the compound gave a molecular formula of Ci8 H30^3* ^ e n , m * r ' (270 MHz) spectrum of 158 (c_f. n.m.r. spectrum p.245) exhibited only four s i n g l e t s . Three of these singlets at 60.87, 1.00, and 3.46 p.p.m. had r e l a t i v e integrated i n t e n s i t i e s equal to three protons each. The fourth si n g l e t at 61.09 p.p.m. had a r e l a -t i v e integrated intensity equal to six protons. There are, therefore, a t o t a l of f i v e methyl groups in t h i s molecule and two of them have the same chemical s h i f t (1.09 p.p.m.). The down f i e l d multiplets at 64.96, 4.98 p.p.m. (AB), and 66.15 p.p.m. (X) suggest that a terminal methylene (-CH=CH2) group if 1.3HS 6*.98 66.15 -+17.5HZ 17.5Hz 11.3Ht 63.46 63.73-10 .OH: 63.81 4 I 'H3° (158) (270 mz N.M.R. Spectrin!) 61.09 61.00 60, 87_ V ml - 246 -was present i n t h i s molecule, and the position of the s i n g l e t at 61.09 p.p.m. (two methyl groups) indicated that these methyl groups are attached to the a l l y l i c p o s ition adjacent to the terminal methylene group. This accounts for a l l the carbon atoms present i n the prenyl nucleophile and therefore i t i s reasonable to suggest that t h i s compound has arisen by attack of the y-position of the prenyl anion on the aldehyde 157. The fact that there are only f i v e methyl groups present in this molecule indicated that the molecule had f a i l e d to undergo acetylation and i s the parent alcohol 15 8 . This hypothesis i s supported by the pos i t i o n of a one proton singlet at 63.73 p.p.m. which was assigned to the ire thine proton of the alcohol function in 158 This alcohol group being adjacent to two quaternary carbon cen-ters i s too s t e r i c a l l y hindered to undergo acetylation under the given conditions. The presence of a hydroxyl group i n compound 15 8 was confirmed by a broad absorption band at 3610 cm 1 (vO-H) in the i r spectrum. The spectrum also exhibited bands at 1639 cm"1 (vC=C) and 913 cm"1 (6CH2) i n support of the terminal methylene group (-CH=CH2) indicated by the n.m.r.data. The methyl ether was i d e n t i f i e d by a strong asymmetric ether band at 1117 cm 1 (vC-O-C). High resolution mass spectral analysis of thi s compound confirmed that i t s molecular formula i s c i 6 H 2 8°2* T ^ e a c e t a t e 160 was treated with sodium iodide and t r i m e t h y l s i l y l chloride i n a c e t o n i t r i l e at 85° ^ o r 2 n o u r s to remove the • methyl ether protecting group. This treatment provided - 247 -the iodo alcohol 162 which was i d e n t i f i e d by i t s n.m.r., i r , and mass spectra. The n.m.r. (270 MHz) spectrum of 162 exhibited singlets at 60.76 p.p.m. (3 protons), 1.02 p.p.m. (3 protons), 1.87 p.p.m. (3 protons), 1.93 (3 protons), and 2.00 p.p.m. (3 protons). The singlets at 61.87 and 1.93 p.p.m. were assigned to methyl groups on carbon bearing iodine. They arediasterecrneric methyls and have d i f f e r e n t chemical s h i f t values. The si n g l e t at 62.00 p.p.m. was assigned to the acetate methyl group and the two remaining singlets at 60.76 and 1.02 p.p.m. were assigned to the two quaternary methyl groups of the bicyc l o n"2*2*l"] system. A broad doublet at 64. 24 p.p.m. with a coupling constant of 8.0 Hz indicated that the methyl ether had been cleaved to reveal the alcohol. A deuterium oxide exchange experiment did not i d e n t i f y the hydroxyl proton signal The spectrum lacked the broad t r i p l e t at 65.11 p.p.m. (J=ca. 7Hz) indicative of the v i n y l proton of the starting material 160 but did exhibit two doublets of doublets at 65.19 and - 248 ~ 5.21 p.p.m. (both doublets of doublets have coupling constants of ca. 10 and 4 Hz) which were assigned to the diastereomeric acetate methine proton in 162 . The i r spectrum contained a weak hydroxyl stretch at 3546 cm 1 as well as two strong ace-tate absorptions at 1739 and 1242 cm ^. The low resolution mass spectrum exhibited a weak molecular ion at mass 408. The high resolution mass spectral analysis of the molecular ion confirmed that the molecular formula for compound 162 i s C 1 7 H 2 9 ° 3 1 , 8 0 As Jung has pointed out even though care may be taken to exclude a l l water from reactions involving t r i m e t h y l s i l y l iodide there i s always the p o s s i b i l i t y of advantitious water being present and thus r e s u l t i n g i n generation of hydrogen iodide. The addition of hydrogen iodide across::the double bond i n the alcohol 161 yi e l d s the iodide 162. The compound b i s - s i l y l cyclohexa-diene 16 3 appears to scavenge hydrogen iodide very ( C H 3 ) 3 5 i ~ \ _ y ~ S i ( C H 3 ) 3 * (T^J + 2(CH3^5iI \ / aprotic solvent 0 - 25* (163) 8 0 read i l y . This compound 163 in the presence of iodine in an aprotic solvent at temperatures ranging from 0 to 25° produces t r i m e t h y l s i l y l iodide and benzene. Hence by using 163 in s l i g h t excess i t is possible to guarantee the absence of - 249 -hydrogen i o d i d e i n the r e a c t i o n m i x t u r e and thus a v o i d the p r o -d u c t i o n o f the i o d i d e 162 . I t may a l s o be p o s s i b l e t o employ boron t r i b r o m i d e t o c l e a v e the e ther 160 . T h i s reagent has found g r e a t u s e f u l n e s s i n c l e a v i n g a r y l m e t h y l e t h e r s c o n s i s -81 t e n t l y y i e l d i n g a p h e n o l and m e t h y l bromide . The reagent can 81 a l s o be used t o c l e a v e d i a l k y l e t h e r s but m i x t u r e s of a l k y l -bromides r e s u l t when u n s y m m e t r i c a l d i a l k y l e t h e r s are e m p l o y e d . In our c a s e , however, boron t r i b r o m i d e s h o u l d c l e a v e the m e t h y l e t h e r r e g i o s p e c i f i c a l l y t o y i e l d methyl, bromide and the b o r n y l a l c o h o l m o i e t y . Format ion of the secondary bromide 164 seems u n l i k e l y s i n c e t h i s would r e q u i r e bromide . i o n t o 8 2 a t t a c k from the exo f a c e of the b i c y c l o Q2 • 2 • l ] system of (160) (164) These are the exper iments which have been completed d u r i n g our i n v e s t i g a t i o n o f the s y n t h e s i s of the p i c r o t o x a n e group of s e s q u i t e r p e n o i d s . F u r t h e r i n v e s t i g a t i o n s are p r o c e e d i n g i n our l a b o r a t o r y a c c o r d i n g to the o u t l i n e shown i n Scheme 13 (p. 250). - 251 ~ In conclusion, we propose that the oxidation of the alcohol 161 to the keto acetate 165 and c y c l i z a t i o n v i a epoxide 166 should provide the t r i c y c l i c ketols 10 3. Dehydration of 10 3 followed by hydrogenation, 103 104 -»• 105, might then provide the t r i c y c l i c acetates 105. At t h i s point Baeyer-Villiger oxidation across the C-(7), C-(8) bond i n 105 followed by de-iodolactonization (path a) could then provide 112. Dehyd-rat i o n of 112 to form the exo-methylene group i n 16 8 and reductive dehalogenation might then y i e l d 2-desoxynobilo-methylene (73). A l t e r n a t i v e l y , displacement of the iodine atom in 16 8 by acetate, hydrolysis and oxidation may provide nobilomethylene (7). Nobilomethylene (7) might also be derived from the acid 169 v i a path b of Scheme 13 (see p. 250 ). Epoxidation of the double bond i n 169 may pro-vide the epoxide 171 and oxirane ring-opening and l a c t o n i z -ation at C-(4) i n 171 might then y i e l d the lactone 172. Oxidation of t h i s lactone and dehydration of the t e r t i a r y hydration to form the A double bond i n 108 and trans-(170a;R=Ac) (170b;R=H) ( c f . Scheme 13, path a) - 252 -a l c o h o l c o u l d t h e n p r o v i d e n o b i l o m e t h y l e n e (7 ) . A p r e c e d -e n t f o r path, b can be found i n Borch and c o w o r k e r s ' s y n t h e s i s of ( ± ) - 8 - e p i d e n d r o b i n e . In t h i s s y n t h e s i s the e p o x i d a t i o n , c y c l i z a t i o n , and o x i d a t i o n o f the o l e f i n 173 p r o v i d e s the k e t o l a c t o n e 174 which has a s t u r c t u r e analogous t o t h a t o f n o b i l o m e t h y l e n e (7) . (173) (174) - 253 -Baeyer-Villiger Oxidation Preliminary experiments have been conducted on the Baey e r - V i l l i g e r oxidation of the camphor system. Camphor (51) has been oxidized to a mixture of lactones, 175 and 84 176, according to the procedure published by Sauers 2 .5 Camphor (51) was oxidized using Sauers 1 method (40% pera-c e t i c acid-sodium acetate at room temperature for 14 days). After 14 days v.p.c. analysis (on column F at 130°) of the reac-ti o n mixture indicated that the camphor had been converted i n 77% y i e l d , to a mixture of two compounds i n the r a t i o 2.5:1. The more abundant material i n the product mixture was i d e n t i f i e d as the lactone 175 by a sharp s i n g l e t at 61.28 p.p.m. (3 pro-85 tons) i n the n.m.r. (60 MHz) spectrum of the mixture. The minor component, o-campholide (176), also featured character-i s t i c proton resonances i n i t s n.m.r. spectrum. The two pro-tons H. and H of 176, appear as an AB quartet centered at A a 64.22 p.p.m. - 254 ". F i g . 2 3 - 255 -(J A B=11.0Hz). We attempted to oxidize camphor under a variety of conditions: 30% hydrogen peroxide (H^C^)-glacial acetic acid at 5 0 ° ^ , 30% J^C^-aqueous sodium hydroxide** 7, meta-chloroperbenzoic acid in methylene chloride, peroxytrifluoro-8 8 acetic acid-disodiumhydrogenphosphate in methylene chloride , eerie ammonium sulphate in 2:1 water-acetonitrile mixture at 1 0 0 ° 8 9 , and benzeneperoxyseleninic acid in THF 9^. Of the reac-tion conditions surveyed only benzeneperoxyseleninic acid was capable of oxidizing camphor to the lactones 175. and 176 . This reagent also proved to be s i g n i f i c a n t l y more selective in the formation of the lactone 175 over 176 . V.p.c. analy-s i s (column A at 130°) of the reaction mixture isolated from benzeneperoxyseleninic acid oxidation of camphor in THF at 66° for 72 hours showed that the oxidation was 95% complete and provided a mixture of both the lactone 175 and a-campholide (176). The r a t i o of 175 to 176 in this oxidation was 11.5:1. Benzeneperoxyseleninic acid i s therefore the reagent of choice for producing the lactone 175 and w i l l be used in attempts to convert t r i c y c l i c keto acetate ,105 (Fig. 23) (cf. Scheme 13) to the lactone 167a It i s possible, however, that t h i s t r i c y c l i c keto acetate (105) may not show the s e l e c t i v i t y ex-hibited by camphor. Arguments based on e l e c t r o n i c considerations suggest that during the Baeyer-Villiger oxidation the more high-ly substituted carbon atom w i l l migrate during the rearrange-ment. S t e r i c constraints, however, modify the e l e c t r o n i c demands - 256 -and hence a mixture of the lactone 175 and 176 r e s u l t s from the oxidation of (+)-camphor. In the keto acetate 105, the e l e c t r o n i c difference between the two migrating centers i s less defined, 1.e. a quaternary versus a t e r t i a r y center compared with a quaternary versus a secondary center i n (+)-camphor, and consequently the degree of s e l e c t i v i t y i n the oxidation of the keto acetate 105 may be less s a t i s f a c t o r y for our pur-poses. I f such i s the case, we f e e l i t w i l l be possible to preform the Ba e y e r - V i l l i g e r oxidation before we c y c l i z e onto the side-chain, i . e . 166 -»- 10 3 (Scheme 13) , and thereby take advantage of the e l e c t r o n i c differences between migration of the secondary and quaternary groups during the Baeyer-V i l l i g e r oxidation of the ketone. C y c l i z a t i o n would then be ca r r i e d out from the lactone 17 8 as shown i n Figure 23. Dehydration of the t e r t i a r y alcohol i n 179 and hydrogenation might then provide 16 7a (R=Ac) (Scheme 13). - 257 -EXPERIMENTAL 8-Formylcamphor Ethylene A c e t a l (76) Compound 80 , s e c t i o n B, p. 111. 80(3-Methyl-l-butenyl)camphor (77) Compound 109 (R=0), s e c t i o n B, p. 120. 8-(1,2-Epoxy-3-methylbutyl)camphor (78) Compound 110 , s e c t i o n B, p. 122. 1, 6-Dimethyl-4- (l-Hydroxy-2-methylpropy 1) t r i c y c l o [ ~ 4 • 3- 0 • 0 3 ' 7~| nonan-2-one (79) Contained i n the experimental f o r compound 10 7 , s e c t i o n B, p. 119. 1, 6-Dimethyl-4- (l-oxo-2-methylpropyl ( t r i c y c l o [ ~ 4 • 3- 0 • 0 3 ' 7^] nonan-2-one (80) (Compound 107, s e c t i o n B, p. 119). iso-Propylmagnesium i o d i d e was prepared by r e a c t i n g i s o -p r o p y l i o d i d e (680 mg, 4.0 mmole) and magnesium powder (BDH, 60-80 mesh) (240 mg, 10 mmole) i n d i e t h y l e t h e r (50 ml) at room temperature f o r 3 hours. The aldehyde, 1, 6 - d i m e t h y l - 4 - f o r m y l t r i c y c l o Q l • 3* 0-0 3 ' 7]] nonan-2-one (86), was added to, the G r i g n a r d reagent i n d i e t h y l e ther (4 ml). The r e a c t i o n was s t i r r e d f o r 8 hours a t room temperature. - 258 -On work-up the reaction mixture was quenched by the addition of saturated ammonium chloride (4 mJl) . The p r e c i p i -tates were f i l t e r e d by gravity and the solvent evaporated to y i e l d a colourless o i l , 1,6-dimetnyl-4-(l-hydroxy-2-methyl-propyl) tricyclo^-3-0--0 3' 73nonan-2-one (79) (161 mg, 82% yield) . A sample of t h i s o i l was oxidized i n acetone (25 mJl) using Jones reagent, to a diketone whose n.m.r. and i r data were i d e n t i c a l to those of compound 107 section B, 1,6-dimethyl-4- (1-oxo-2-methylpropyl) t r i c y c l o Q l • 3-0*0 3' 7]]nonan-2-one (80) . 8-Vinylcamphor Epoxide (8 3) 8-Vinylcamphor (85) (856 mg, 4.81 mmole) was dissolved i n benzene (50 ml) at room temperature and was treated with meta-chloroperbenzoic acid (1.55 g, 85% pure, 7.6 mmole; 1.6 molar equivalents). This mixture was s t i r r e d for 8 hours. On work-up the mixture was treated with 20% sodium b i -sulphite, saturated sodium bicarbonate, and saturated sodium chloride. Drying (sodium sulphate) and evaporation of the solvent yielded a colourless o i l , 8-vinylcamphor epoxide (83) (1.06 g), which was p u r i f i e d by high vacuum d i s t i l l a t i o n (bp. 88-94°/l x 10~ 3 Torr) (873 mg; 94% y i e l d ) ; 6 .(100MHz, CCl 4) 0.84 (s, 3H), 1.06 (s, 3H), 2.60 (m, 2H); 2.87 (bm, IH); vm (CC1.) 1742 cm"1 (strong, sharp, vC=0) , 14 08 cm - 1 (medium, sharp, 6CH 2), 1214, 914, 845 cm"1 (epoxide bands); m/e 194 ( M + ) , 151, 137, 95 (base peak). M . W . calcd. for C 1 2 H l g 0 2 : 194,1307. Found (high resolution mass spectrometry): 194.1303. - 259 -Anal, calcd, for c 1 2 H i 6 ° 2 : C ' 7 3 ' 2 9 ? H ' 8 - 9 5 - Found: C, 73.26; H. 9.00. I, 6-Dimethyl-4-Hydroxymethyltricyclol~4 • 3- 0 • 0 3 * 7~[nonan-2-one (84) 8-Vinylcamphor oxide (83) (1.0 g, 5.15 mmole) was d i s -solved i n t e r t - b u t y l alcohol (60 ml) containing potassium tert-botoxide (3.38 g, 30.2 mmole; 6 molar equivalents). The mixture was s t i r r e d at room temperature for 8 hours. On work-up the reaction mixture was evaporated under vacuum and the residue dissolved i n water (50 ml). The aqueous solution was extracted with d i e t h y l ether. The organic layer was washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded a clear yellow o i l (945 mg). V.p.c. analysis on column A at 180° indicated that t h i s o i l contained 8-vinylcamphor oxide (83) (12%) and compound 84 (88%). Chromatography of this o i l on s i l i c i c acid (Malincrodt S i l i c i c Acid, 200 mesh) using chloroform as eluant provided a pure sample of 1,6-dimethyl-4-hydroxymethyl-tricyclo[jl-3-0 «03'7]]nonan-2-one (84)'; 6 (100MHz, CC14) 0.82 (s, 3H), 0.91 (s, 3H), 2.06 (bs, IH), 3.30 (bm, 2H), 3.60 (bs, IH, OH); v (CCl.) 3390 cm"1 (medium, broad, vO-H), 1733 cm - 1 — max 4 ' (strong, sharp, vC=0); m/e 194 (M +), 176, 163, 94 (base peak). M.W. calcd. f o r c i 2 H l 8 ° 2 ; 1 9 4 " 1 3 0 7 * Found (high resolution mass spectrometry): 194.1304. - 260 -8-Vinyl camphor (.8 5) 8-Formylcamphor ethylene acetal (76) (1.80 g, 8.0 mmole) i n THF (10 ml) was added, i n one portion, to a THF solution (50 ml) of methyltriphenylphosphorane (1.25 molar equivalents). This mixture was s t i r r e d f or 8 hours after which time excess phosphorane was destroyed by the addition of methanol (0.5 ml). The product was i s o l a t e d i n the following manner. S i l i c a gel (30 g) ( S i l i c a Gel Woelm, a c t i v i t y grade III) was added to the reaction mixture and the solvent was removed under vacuum. The product, 8-vinylcamphor ethylene acetal, was eluted from the s i l i c a gel using 20% di e t h y l ether-80% petroleum ether (35-60) as eluant. This provided 1.31 g (74% yield) of a colourless o i l . The o i l was deketalized i n acetone (25 ml) containing 6N hydrochloric acid (10 drops) at room temperature for 8 hours. On work-up th i s acetone solution was poured into d i e t h y l ether (100 m£) and washed with saturated sodium bicarbonate and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded a colourless o i l (1.27 g) o * which was p u r i f i e d by high vacuum d i s t i l l a t i o n (bp. 50 / 1 x 10~ 3 Torr) to provide 8-vinylcamphor (85) (856 mg, 82% y i e l d ) ; 6 (100MHz, CC1 4) 0.86 (s, 3H), 0.94 (s, 3H), 2.16 (d, 2H, J= 3.0Hz), 4.98 (m, 0.9H), 5.10 (m, 1.IH), 5.83 (m, IH); v in 3.x (CC14) 1739 cm - 1 (strong, sharp, vC=0), 1639 cm"1 (weak, sharp, vC=C), 1406 cm - 1 (weak, sharp, 6CH 2), 917 cm"1 (strong, broad, 6«CH 2); m/e 178 (M +), 151, 137, 95 (base peak). M.W. calcd. - 261 -for C^2 H28 0 : 178.1358. Found (high resolution mass spectro-metry): 178.1358. 1, 6-Dimethyl-4-Formyltricyclor4 • 3» 0- 0 3 ' 7~|"onan-2-one (86) 1,6-Dimethyl-4-hydroxymethyltricyclo[]4 • 3* 0* 0 3 ' 7Jonan-2-one (84) (400 mg, 2.06 mmole) was oxidized i n the following manner. C o l l i n s reagent was made by di s s o l v i n g chromium t r i o x i d e (1.24 g, 12.4 mmole) i n dichloromethane (30 mil) containing pyridine (1.95 g, 24.7 mmole) This deep red solution was s t i r r e d at room temperature for 20 minutes. The alcohol 84 was added to the solution of C o l l i n s reagent i n dichloromethane (5 mil). Oxidation was carried out at room temperature over 2 0 minutes. On work-up the reaction mixture was concentrated under vacuum and poured into d i e t h y l ether (50 mil) . This ethereal solution was f i l t e r e d by gravity and washed successively with 5% hydrochloric acid, 5% sodium hydroxide, and saturated sodium chloride. Drying (magnesium sulphate) and evaporation yielded a colourless o i l , 1, 6-dimethyl-4-f ormyltricycloQ4 • 3* 0 • 0 3 / 7~^ \ nonan-2-one (86) (240 mg, 64% y i e l d ) ; 6 (100MHz, CCl 4) 0.88 and 0.89 (two s i n g l e t s , 3H), 1.00 (s, 3H), 9.42 (d, 0.36H, J=2.0Hz), 9.62 (s, 0.64H); v a<u, (CCl.) 2825 cm"1 (weak, broad, vC-H of CHO), max ^ 270 3 cm 1 (weak, broad, overtone or combination tone), 1745 cm 1, Cstrong, sharp, vC=0), 1724 cm"1 (strong, sharp, vC=0). A sample of 86 (2 0 mg) was dissolved in carbon t e t r a -- 262 -chloride (.350 p i ) i n a n.m.r. tube. Triethylamine (20 y£) was added and the sample was allowed to stand at room temperature for 8 hours. At t h i s point the 60 MHz n.m.r. spectrum was recorded; 6(CC1 4) 9.42 (d, 0.20H), 9.62 (s, 0.80H). The aldehyde 86 was used immediately without further p u r i f i c a t i o n . (.+ ) -8-Cyanocamphor Ethylene Acetal (92) Compound 81 , section B, p. 112. 8- Formylcamphor (9 3) Compound 138 , section B, p. 126. 9- Hydroxycampherenone (94) Compound 133a (R=H), section B, p. 125. 9-Acetoxycampherenone (95) 9-Hydroxycampherenone (1.15 g, 4.87 mmole) was dissolved i n pyridine (37 ml). The solution was heated to 90° and acetic anhydride (9.2 m£) was added. Heating was continued for 24 hours. On work-up the reaction was poured into water (300 ml). This aqueous solution was extracted with d i e t h y l ether. The extracts were combined and washed with water and 5% hydro-chloric, acid. Drying (magnesium sulphate) and evaporation of the solvent yielded 9-acetoxycampherenone (95) (1.07 g, 263 -79% crude y i e l d ) . This material was p u r i f i e d by column chromato-graphy on alumina (Alumina Woelm; a c t i v i t y grade III) using 10% d i e t h y l ether-90% petroleum ether (.35-60) as eluant. This provided pure 9-acetoxycampherenone (95) (v.p.c. analysis on column F at 220°) as a colourless o i l ; 6 (100MHz, CC14) 0.85 Cs, 3H), 1.00 (s, 3H), 1.69 (d, 3H, J=2.0Hz), 1.74 (d, 3H, J=2.0Hz), 1.90 (s, 3H) , 2.17 (bm, 2H) , 5.02 (bd, IH, J=10.0Hz), 5.58 (bm, IH); v (CCl.) 1739 cm - 1 (strong, sharp, vC=0), 1408 cm 1 (medium, sharp, 6CH 2), 1235 cm 1 (strong, broad, vC-O-C); m/e 278 (M+) , 218, 127, 95 (base peak); M.W. calcd. for C 1 7 H 2 6 ° 3 : 278.1882. Found (high resolution mass spectrometry): 278.1882. 9-Acetoxycampherenone Epoxide (96) 9-Acetoxycampherenone (95) was dissolved i n benzene (10 ml) and was treated at room temperature with meta-chloroper-benzoic acid (368 mg, 85% pure, 1.80 mmole) for 24 hours. on work-up the mixture was treated with 20% sodium b i -sulphite (0.5 ml). The benzene solution was then washed with saturated sodium bicarbonate and saturated sodium chloride. Drying (sodium sulphate) and evaporation of the solvent pro-vided pure 9-acetoxycampherenone epoxide (v.p.c. analysis on columb B at 180°) (500 mg, quantitative); 6 (100MHz, CC14) 0.84 (s, 3H), 0.94 (s, 3H), two pairs of diastereomeric oxirane methyl groups 1.18 and 1.22 (singlets, 3H), 1.26 and 1.30 (singlets, 3H), two overlapping diastereomeric acetate methyl - 264 -si n g l e t s , 1,96 and 1.98 (3H), the oxirane ri n g hydrogen appears at 2.50 (bm, IH) 4.92 (bm, 1H) ; v CCC1.) 1739 cm""1 (strong, sharp, vC=0), 1408 cm 1 (weak, sharp, 601^), 1235 cm 1 (strong, broad, vC-O-C); m/e 294 (M+) , 252, 234, 95 (base peak). M.W. calcd. for C X 7 H 2 6 ^ 4 : 294.1831. Found (high resolution mass spectrometry): 294.1822. (,+ ) -8-Bromocamphor (114) Compound 29 , section A, p. 4 3 . (,+) - 8-Acetoxycamphor (115) (+)-8-Bromocamphor (114) (9.0 g, 39.1 mmole) was dissolved i n HMPA (75 ml). Potassium acetate (17.0 g, 173 mmole; 4.4 molar equivalents).was added and the reaction was heated at 115° under an argon atmosphere f o r 48 hours. On work-up the reaction mixture was poured into d i e t h y l ether (125 ml) and washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded (+)-8-acetoxycamphor (115) as a pale yellow o i l (8.0 g, 89% crude y i e l d ) . A sample of t h i s o i l was p u r i f i e d by column chromatography on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade III) using 30% dieth y l e t h e r - 7 0 % petroleum ether (.35-60) as eluant. This provided an a n a l y t i c a l l y pure sample of (+)-8-acetoxycamphor (115); DOD"4 * 5 + 1 0 . 0 ° (c 2.49, CHC13) ; 6 (100MHz, CC14) 0.88 (s, 3H), 1.02 (s, 3H), 1.98 (s, 3H), 3.74 (s, 2H) ; (CC14) 1745 cm"1 (strong, broad, vC=0) , - 265 -1412 cm (weak, sharp, SCH^), 1224 cm (strong, broad, vC-O-C) ; m/e (M+) , 167, 150, 121, 108 (base peak), 95. Anal, calcd. for c i 2 H 1 8 ° 3 : C ' 6 8 , 5 5 ; H ' 8.63. Found: C. 68.66; H, 8.70. 91 (.+') - 8-Hydroxycamphor (116) (.+ )-8-Acetoxycamphor (115) (1.0 g, 4.7 mmole) was d i s -solved i n a solvent mixture composed of methanol-water (80:20) (25 ml). The acetate was treated with potassium carbonate (.2.62 g, 19.0 mmole; 4 molar equivalents) for 4 hours at room temperature. On work-up the mixture was a c i d i f i e d by the addition of 6N hydrochloric acid u n t i l the reaction mixture was s l i g h t l y a c i d i c to universal pH paper. Water (20 ml) and d i e t h y l ether (.20 ml) were added. The reaction separated into two colourless layers. The organic layer was separated and the aqueous layer was extracted twice with d i e t h y l ether. The organic layers were combined and washed with saturated sodium chloride. Dry-ing (magnesium sulphate) and evaporation of the solvent yielded a white waxy s o l i d , (+)-8-hydroxycamphor (116) (800 mg, quanti-o 3 t a t i v e ) . The waxy s o l i d was sublimed (85-90 /5 x 10 Torr) to provide a n a l y t i c a l l y pure material; (mp. 225-226°, softens 223°; sealed tube) ( l i t . 9 1 m p . 233-234°); [ V g 6 * 5 + 31.06° (c 3.12, abs. EtOH) ( l i t . 9 1 [ V ] * 8 -24.9° (c 1.07, 95% EtOH)); 6 (100MHz, CDC13) 0.92 (s, 3H), 1.07 (s, 3H), 2.00 (bs, IH, OH), 3.40 (s, 2H); v (CCL.) 3448 cm - 1 (medium, broad, 266 -vO-H), 1739 cm J" (strong, sharp, vC=0), 1408 cm J" Cweak, sharp, 5CH 2); m/e 168 (M+) , 108 (base peak), 95. M.W. calcd. for C 1 0 H 1 6 ° 2 : 168. 1150. Found (high resolution mass spectrometry): .168.1157. Anal, calcd. for C^H^O^. C, 71.39; H, 9.59. Found: C, 71.13; H, 9.46. 8-Oxocamphor (117) (+)-8-Hydroxycamphor (116) (500 mg, 2.98 mmole) was d i s -solved i n dichloromethane (5 ml) and was added i n one portion at room temperature to a s t i r r e d suspension of pyridinium chlorochromate (1.90 g, 8.82 mmole; 3 molar equivalents) i n dichloromethane (40 ml). S t i r r i n g was continued for 3.5 hours. On work-up the reaction mixture was poured into diethyl ether (200 ml) and th i s solution was f i l t e r e d through F l o r i s i l (2 0 g). Evaporation of the solvents provided 8-oxocamphor (117) as a waxy white s o l i d (500 mg, quantitative); 6 (60MHz, CC1 4) 1.00 (s, 3H), 1.16 (s, 3H), 9.45 (s, IH); v m a x (CC14) 2703 cm"1 (weak, sharp, vC-H of CHO), 1745 cm - 1 (strong, sharp, vC=0), 1718 cm 1 (strong, sharp, vC=0), 1408 cm 1 (weak, sharp, 6CH 2). The low and high resolution mass spectra of t h i s compound 117 were recorded on the corresponding acid 8-carboxy-camphor (124). Compound 124 was prepared by exposing a neat sample of 117 to the atmosphere for 8 hours; 6 (60MHz, CC1 4) 1.17 (s, 3H), 1.30 (s, 3H) , 9.00 (bs, IH) ; v '(CC1.) 3700-in 3.x ft 2350 cm 1 (medium, very broad, vO-H of C0 2H), 1739 cm 1 (strong, sharp, vC=0), 1695 cm 1 (strong, sharp, vC=0), 1404 cm 1 (weak, - 267 -sharp, 6CH 2); nj/e 182 (M+) , 154, 136, 125, 109, 95 (base peak). M.W. calcd. for C 1 0 H 1 4 ° 3 ; 182.0943. Found (high resolution mass spectrometry): 182.0940. 8-Hydroxycampherenone (118) 8-Oxocamphor (117) (630 mg, 3.80 mmole) was dissolved i n THF (30 ml) containing 4A molecular sieves and tetra-n-buty1 ammonium flu o r i d e (TBAF) (1.05 g, 4.02 mmole). j_ tY -Dimethyl-a l l y l t r i m e t h y l s i l a n e (593 mg, 4.17 mmole; 1.1 molar equiva-lents was added and the mixture was refluxed under argon for 24 hours. On work-up the reaction was poured into d i e t h y l ether (75 ml) and was washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded.a yellow o i l (400 mg). On standing this o i l deposited a white s o l i d (28 mg); 6 (270MHz, CDC13) 1.02 (s, 3H), 1.03 (s, 3H), 1.06 (s, 3H), 1.17 (s, 3H), 2.56 (t, IH, J=4.0Hz), 3.64 (bs, IH, OH), 3.96 (s, IH, HO-CH-CO); v (CHC1.) 3597 cm 1 (weak, sharp, vO-H), 3472 cm - 1 (weak, broad, v-OH), 1739 cm 1 (strong, sharp, vC=0) , 1408 cm "L, (weak, sharp, <5CH2) ; m/e 332 (M +), 314, 303, 273, 195, 167, 110, 95 (base peak). M.W. calcd. for C 2 o H28°4 : 332.1988. Found (high resolution mass spectrometry): 332.1984. This compound was t e n t a t i v e l y assigned the structure 139. The o i l was chromatographed on s i l i c a ( S i l i c a Gel Woelm; a c t i v i t y grade III) using 20% diet h y l ether-80% petroleum - 268 -ether (.35-60) as eluant. This provided 8-hydroxycampherenone (118) (70 mg, 8% y i e l d ) ; 6 (270MHz, CDC13) 0.88 (s, 3H), 0.94 (s, 3H), 1.64 (s, 3H), 1.72 (s, 3H), 2.19 (t, 2H, J=8.0Hz), 3.52 (bs, IH) , 5.19 (bt, IH, J=8.0Hz); 6 (CDC13 + D20) 0. 84, 0.88, 0.96, and 1.03 (4 broad s i n g l e t s , 6H), 1.64 (s, 3H), 1.72 (s, 3H), 2.20 (t, 2H,, J=8.0Hz), 3.37 (bs, 0.5H), 3.68 (bs, 0.5H), 5.18 (broad envelope, IH); v (CC1.) 3350 cm"1 1113. 4 (medium, broad, vO-H), 1739 cm 1 (weak, sharp, vC=0); m/e 236 (M+) , 221, 167, 95 (base peak). M.W. calcd. for C 1 5 H 2 4 ° 2 : 236.1789. Found (high resolution mass spectrometry): 236.1789. The alcohol 8-hydroxycampherenone (118) (30 mg, 0.13 mmole) was acetylated i n a mixture of pyridine (1.60 ml) and acetic anhydride (0.4 ml) at 90° for 24 hours. On work-up the reaction was poured into water (20 ml) and extracted, with diethyl ether. The ethereal solution of the product was washed with 5% hydrochloric acid, 5% sodium hydroxide and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided a yellow o i l . V.p.c. analysis of t h i s o i l on column B at 150° showed that the o i l was composed of two compounds (99% pure) i n the r a t i o 2:3; 6 (270MHz, CDC13) 0.77, 0.84, 0.86, and 0.97 (4 sin g l e t s , 6H), 1.53, 1.60, and 1.64 (three s i n g l e t s , 6H), 1.83 and 1.98 (two si n g l e t s , 3H), 3.73 (dd, 0.25H), J A X=7.0Hz, J B X=4.0Hz), 4.81 (d,d, 0.75H, J A X=7.0Hz, J B X=4.0Hz), 4.96 (t, 0.75H,J=8.0Hz), 5.16 (t, 0.25H, J=8.0Hz); v m a v (CC14) 1739 cm"1 (strong, sharp, - 269 -vC=0) , 1224 cm""1" (strong, broad, vOO-C); m/e 218 CM'-60), C 1 5 H 2 2 0 : 218.1671. Found (high resolution mass spectrometry): 218.1681. M.W. calcd. for m/e 16 7 ( M + - l l l ) , C 1 Q H 1 5 0 2 : 167.1072. Found (high resolution mass spectrometry): 167.1079. On the basis of t h i s spectral data the two compounds i n th i s mixture have been tenta t i v e l y assigned the structures 14 7 and 14 8 . Y., Y-Dimethylallyltrimethylsilane w a s prepared by adding Y ,Y_-dime thy lallylmagnesium chloride (95.6mmole) i n THF (30) to t r i m e t h y l s i l y l chloride (9.34 g, 86.0 mmole; 0.9 molar equivalents) i n THF (20 mJt) . The mixture was refluxed for 24 hours under an atmosphere of argon. Work-up i n the usual manner provided a colourless o i l (10 g, 82% y i e l d ) . This o i l was p u r i f i e d by high vacuum d i s t i l -l a t i o n (bp. 31-32°/5 x 10~ Torr); 6 (270MHz, CDC13) -0.06 (s, 9H), 1.35 (d, 2H, J=9.0Hz), 1.54 (s, 3H) , 1.68 (s, 3H) , 5.14 (t, IH, J=9.0Hz); v _ a v (CCl.) 1241 cm"1 (strong, sharp, 6Si ( C H 3 ) 3 ) , 1151 cm 1 (medium, sharp), 908 cm 1 (strong, sharp, vSi-C), no t r i s u b s t i t u t e d C=C absorptions were observed at ca. 1670 cm - 1 or at ca. 840-800 cm"1; m/e 142 (M +), 127, 109, 59, 45, 43, 41, 28 (base peak). M.W. calcd. for CgH^Si: 142.1178. Found (high resolution mass spectrometry): 142.1157. 8-Methylenecamphor (119a) Methyltriphenylphosphonium bromide (2.15 g, 6.0 mmole) was suspended i n THF (50 mJl) at room temperature. This suspension - 270 -was treated with n-butyllithium ( A l f a ; 2,60 molar i n hexanes; 1.73 ml, 4.50 mmole; 0.75 molar equivalents, based on methyl-triphenylphosphonium bromide) under an argon atmosphere. S t i r r i n g was continued for 3 hours. After t h i s time the aldehyde, 8-oxocamphor (117) (504 mg, 3.03 mmole), was added i n THF (2 mJl) to the solution of the y l i d e and s t i r r i n g was continued for an additional 8 hours. On work-up excess y l i d e was destroyed with methanol (0.5 ml). Alumina (Alumina Woelm Neutral; a c t i v i t y grade III) (25 g) was added and the solvent was removed under vacuum. The pro-duct, 8-methylenecamphor (119a) (392 mg, 80% y i e l d ) , was eluted from the alumina using 20% d i e t h y l ether-80% petroleum ether (35-60) as eluant; 6 (100MHz, CC14) 0.88 (s, 3H), 1.02 (s, 3H), 4.98 (dd, IH, J. _(gem)=2.0Hz, J_ v(trans)=18.0Hz), 5.04 (dd, IH, A J J A X — — — J„ D(gem)=2.0Hz, J„ v(cis=10.0Hz), 5.65 (6-line multiplet, IH); Ars D A — — v__ v (CC1.) 1739 cm - 1 (strong, sharp, vC=0), 1639 cm"1 (weak, XI I d H fx sharp, vC=C), 1408 cm 1 (weak, sharp, 6CH 2), 921 cm 1 (medium, broad, 5=CH2); m/e 164, 149, 136, 122, 121, 120, 107 (base peak). M.W. calcd. for C,,H,^0: 164.1201. Found (high resolution mass 11 16 spectrometry): 164.1215. Ke t a l i z a t i o n of 8-methylenecamphor (119a) (430 mg, 2.62 mmole) was car r i e d out i n benzene (20 ml). Ethylene gly c o l (554 mg, 8.94 mmole; 3 molar equivalents) and p_-toluenesulphonic acid (2 0 mg) were added and the mixture was refluxed for 8 hours. Water was removed using a Dean-Stark apparatus containing - 271 -4A molecular sieves. On work-up the reaction mixture was washed with 5% sodium hydroxide and saturated sodium chloride. Drying (sodium s u l -phate) and evaporation of the solvent provided 8-methylene-camphor ethylene acetal (119b) (5 38 mg, quantitative) as a colourless o i l which was 95% pure (v.p.c. analysis on column A at 130°); 6 (270MHz, CCl 4) 0.78 (s, 3H), 0.92 (s, 3H), 3.56-3.92 (bm, 4H0, 4.91 (dd, IH, J A £(gem) =2. 0Hz, J -(trans) = 18.0Hz) , 4.93 (dd, IH, . JEJ,(gem)=2. 0Hz, J .(cis) = 12. 0Hz) , 6.17 (dd, IH, J v.(trans)=18.0Hz, J V D(cis)=12.0Hz); v 1627 cm"1 (weak, X A - — — - X13 max sharp, vC=C), 914 cm 1 (medium, broad, 6=CH2). 8-Methylenecamphor Epoxide (120) 8-Methylenecamphor (119a) (372 mg, 2.26 mmole) was d i s -solved i n benzene (25 mi) and was treated with meta-chloroper-benzoic acid (576 mg, 85% pure, 2.84 mmole, 1.25 molar equiva-lents) at room temperature for 4 8 hours. On work-up the mixture was treated with 20% sodium b i -sulphite, saturated sodium bicarbonate, and saturated sodium chloride. Drying (sodium sulphate) and evaporation of the solvent yielded a colourless s o l i d 8-methylenecamphor epoxide (.120) (400 mg, 98% y i e l d ) . This material was p u r i f i e d by sublimitation (75°/5 x 10~ 3 Torr) ; (mp. 122-123°) (sealed tube); 6 (270MHz, CC1 4) 0.93 (s, 6H), 2.39-2.67 (m, 3H, oxirane r i n g protons); v m a y i (CCl^) 1739 cm 1 (strong, sharp, vC=0) , -1 -1 55 1408 cm (weak, sharp, 6CH 2), 940 and 855 cm (epoxide bands ) - 272 -m/e 180 (M +), 123, 108 (base peak), 95. M.W, calcd. for C,,Hn/r0^: 180. 1150. Found (high resolution mass spectro-11 lb 2 metry): 180.1155. Anal, calcd. for c 1 i H 1 6 ° 2 : C ' 7 3 - 2 8 ; H, 8.95. Found: C, 73.26; H, 9.00. 91 (+)-8-Benzoyloxycamphor (126) (+)-8-Bromocamphor (1.10 g, 4.76 mmole) was dissolved i n dimethylformamide (DMF) (25 mJl) and was treated with potassium benzoate (1.52 g, 9.52 mmole; 2 molar equivalents) at 115° for 63 hours. On work-up the reaction mixture was poured into d i e t h y l ether (75 ml) and the ethereal solution was washed with water, 5% sodium hydroxide, and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided a pale yellow s o l i d (+)-8-benzoyloxycamphor (126) (1.10 g, 85% y i e l d ) . This s o l i d was r e c r y s t a l l i z e d from a pentane-diethyl ether (2:1) mixture at -20° to provide pale yellow c r y s t a l s ; (mp. 102-103°) (sealed tube) ( l i t . 9 1 m p . 102.8-103.5°) ; [jTge + 24.7° (c 1.35, abs. EtOH) ( l i t . 9 1 [V]26 _ 21.3° (c 0.94 , 95% EtOH)) ; 6 (100MHz, CC14) 1.00 (s, 3H), 1.13 (s, 3H) , 4.04 (s, 2H) , 7.26-7.60 (m, 3H), 7.90-8.06 (m, 2H); v m a v (CC1.) 1739 cm"1 (strong, sharp, vC=0), 1724 cm"1 (strong, sharp, vC=0), 1408 cm"1 (weak, sharp, 6CH 2), 1258 cm"1 (strong, broad, vC-O-C), 1105 cm"1 (strong, broad, vC-O-C); m/e 272 (M +), 167, 150, 105 (base peak). M.W. calcd. for C 1 7 H 2 Q 0 3 : 272.1412. Found (high resolution mass spectrometry): 272.1423. - 273 -(.+ )-8-\Benzoyloxycamphor (12 6) (1.0 g, 3.68 mmole) was treated with ethylene g l y c o l (273 mg, 4.41 mmole; 1.2 molar equivalents) and p_-toluenesulphonic acid (20 mg) i n reflux i n g benzene (20 ml) for 16 hours. Water was removed from the reaction using a Dean-Stark apparatus containing 4A molecular sieves. On work-up the reaction was washed with 5% sodium hydroxide and saturated sodium chloride. Drying (sodium sulphate) and evaporation provided 8-benzoyloxycamphor ethylene acetal (12 7) (1.03 g, 89% yield) as a pale yellow o i l ; 6 (100MHz, CC1 4) 0.90 (s, 3H), 1.03 (s, 1. 03), 3. 79 (m, 4H) , 4.08 (d, IH, J_ =12. 0Hz) , 4.72 (d, IH, J o >=12.0Hz), 7.08-7'.54 (m, 3H), • 7.86-8.04 (m, 2H) : v (CCl.) 1718 cm 1 (strong, sharp,vC=0), 1269 cm 1 (strong, IHcL X f» broad, vC-O-C), 1110 cm - 1 (strong, broad, vC-O-C). (-)-8-Hydroxycamphor Ethylene Acetal (128) 8-Benzoyloxycamphor ethylene acetal (12 7) (4.7 g, 15.2 mmole) was dissolved i n 10% potassium hydroxide-ethanol solu-t i o n (80 ml) and refluxed for 1 hour. On work-up the reaction was poured into water (80 ml) and a c i d i f i e d to n e u t r a l i t y (universal pH paper). This aqueous mixture was extracted with diet h y l ether and the extracts were washed with water and saturated sodium chloride. Drying (mag-nesium sulphate) and evaporation of the solvent provided (-)-8-hydroxycamphor ethylene acetal (128) (2.25 g, 70% yield) as a pale yellow s o l i d . This s o l i d was p u r i f i e d by sublimation - 274 ^ (70°/l x 10~ 3 mm Hg) to provide a white powder; mp. 61-62.5" (sealed tube); [ a ] ^ - 22.5° (c 2.77, abs. EtOH); 6 (lOOMHz, CC1 4) 0.78 (s, 3H), 0.93 (s, 3H), 3.44 (d, IH, J=12.0Hz), 3.78 (m, 5H); v (CCl.) 3448 cm"1 (weak, broad, vO-H); m/e max 4 — — 212 (M +), 181, 125, 108 (base peak), 95. M.W. calcd. for C 1 2 H 2 0 ° 3 : 212.1412. Found (high resolution mass spectrometry): 212.1418. Anal, calcd. for C 1 2 H 2 Q 0 3 : C, 67.89; H, 9.50. Found: C, 67.60; H, 9.50. 8-Oxocamphor Ethylene Acetal (129) (-)-8-Hydroxycamphor ethylene acetal (128) (1.18 g, 5.57 mmole) was added, i n dichloromethane (5 mi), to a suspension of pyridinium chlorochromate (3.0 g, 14 mmole; 2.5 molar equivalents) i n dichloromethane (30 mi). This reaction was s t i r r e d at room temperature for 2.25 hours. On work-up the reaction mixture was poured into d i e t h y l ether (150 mi) and f i l t e r e d through F l o r i s i l (40 g). Evapo-r a t i o n of the solvent provided 8-oxocamphor ethylene acetal (12 9) (1.10 g, 94% yield) as a clear colourless o i l , 99% pure (v.p.c. analysis on column A at 160°); 6 (100MHz, CC1 4) 1.04 (s, 3H), 1.11 (s, 3H) , 3.93 (m, 4H) , 9.70 (s, 2H) ; v v (CCl.) 1718 cm"1 IUclX ft (strong, sharp, vC=0), 2740 cm"1 (weak, sharp, vC-H of CHO); m/e 210 (M +), 181, 127, 95 (base peak). M.W. calcd. for C,,H. 0,: 210. 1256. Found (high resolution mass spectrometry): 12 -Lo J 210.1264. - 275 -Reduction of 8-Oxocamphor Ethylene Acetal (129) with Y,'y- Dimethy 1 allylmagnesium Bromi de 8-0xocamphor ethylene acetal (129)(549 mg, 2.60 mmole) was treated with y_,x~diniethylallylmagnesium bromide (5.30 mmole; 2.0 molar equivalents) i n THF (25 m£) at re f l u x for 18 hours. On work-up the excess Grignard reagent was destroyed by the addition of saturated ammonium chloride. The r e s u l t i n g suspension of pre c i p i t a t e s was f i l t e r e d by gravity and the f i l t r a t e was evaporated to y i e l d a yellow o i l (670 mg). This o i l was analyzed by v.p.c. on column A at 160° and was shown to contain 61% (-)-8-hydroxycamphor ethylene acetal (128). A pure sample (134 mg, 25% i s o l a t e d yield) of 128 was obtained by chromatography of the crude o i l on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 10% di e t h y l ether-90% petroleum ether (35-60) as eluant. The n.m.r., i r , and v.p.c. analyses of the p u r i f i e d material were i d e n t i c a l to those of authentic (-)-8-hydroxycamphor ethylene acetal (128) (see p. 273). 8-Methylenecamphor Epoxide Ethylene Acetal (130) 8-Methylenecamphor ethylene acetal (119b) (2.15 g, 10.33 mmole) was dissolved i n benzene (60 mil) and was treated with meta-chloroperbenzoic acid (2.52 g, 85% pure, 14.6 mmole; 1.2 molar equivalents) at room temperature for 19 hours. On work-up the reaction was treated with 20% sodium b i -- 276 -sulphite, saturated sodium bicarbonate, and saturated sodium chloride. Drying (sodium sulphate) and evaporation of the solvent provided 8-methylenecamphor epoxide ethylene acetal (130) (2.01 g, 87% yield) as a colourless o i l ; 6 (270MHz, CC14) 0.5 8 and 0.78 (two methyl s i n g l e t s , one diastereomeric pair, 4.3 H), 0.69 and 0.90 (two methyl s i n g l e t s , one diastereomeric pa i r , 1.7H), 2.24, 2.52, 3.20 (three multiplets, 3H, oxirane rin g protons), 3.82 (m, 4H); m/e 224 (M +), 193, 181, 138, 125, 108, 95 (base peak). M.W. calcd. for c 1 3 H 2 o ° 3 : 224.1412. Found (high resolution mass spectrometry): 224.1431. The Reaction of 8-Methylenecamphor Epoxide Ethylene Acetal  (130) with is_o-Propylmagnesium Bromide 8-Methylenecamphor epoxide ethylene acetal (130) (1.13 g, 5.04 mmole) was treated with 2-methylpropylmagnesium bromide (7.56 mmole, 1.5 molar equivalents) i n THF (20 m£) at reflux for 16 hours. On work-up the excess Grignard reagent was destroyed by the addition of saturated ammonium chloride. The r e s u l t i n g p r e c i p i t a t e s were f i l t e r e d by gravity and evaporation of the f i l t r a t e yielded a yellow o i l (876 mg). V.p.c. analysis of t h i s o i l on column A at 180° revealed the presence of three compounds i n the reaction mixture. These compounds were ten t a t i v e l y i d e n t i f i e d by co-injection with authentic samples of the s t a r t i n g material 8-methylenecamphor epoxide ethylene acetal (131), (+)-1, 7-dimethyl-7-syn-acetylbicyclor2 - 2- l"]heptan-- 277 -2-one ethylene a c e t a l (132), and 8-hydroxydihydrocampherenone ethylene a c e t a l (138). In t h i s way i t was shown t h a t t h i s o i l was a mixture o f 12% 130, 46% 132, and 42% 138. ( + )-!, 7-Dimethyl-7-syn-Acetylbicyclor2 • 2 • l~|heptan-2-one  et h y l e n e a c e t a l (132) 8-Methylemecamphor epoxide ethylene a c e t a l (130) (46 0 mg, 2.05 mmole) was t r e a t e d with 2-methyl-l-propenylmagnesium bromide (4.10 mmole, 2.0 molar e q u i v a l e n t s ) i n THF (50 mJl) a t r e f l u x f o r 5 hours. On work-up the excess G r i g n a r d reagent was destroyed by the c a r e f u l a d d i t i o n o f s a t u r a t e d ammonium c h l o r i d e . The r e s u l t i n g suspension o f p r e c i p i t a t e s was f i l t e r e d by g r a v i t y and the f i l t r a t e was evaporated to p r o v i d e a c o l o u r l e s s o i l (436 mg, 76% crude y i e l d ) . T h i s o i l was p u r i f i e d by chromato-graphy on alumina (Alumina Woelm N e u t r a l ; a c t i v i t y grade III) us i n g 10% d i e t h y l ether-90% petroleum ether (35-60) as e l u a n t to pr o v i d e a sample of (+)-!, 7-dimethyl-7-syn-acetylbicyclol~2 '2 • 1~[ heptan-2-one ethylene a c e t a l (132) (mp. 55-56.5°); + 3 7 - i (c 0.77, abs. EtOH); 6 (100MHz, CC14) 0.98 (s, 3H), 1.02 (s, 3H), 2.00 (s, 3H), 3.72 (m, 4H); v (CC1.) 1701 cm" 1 (strong, sharp, vC=0); m/e 224 (M +), 209, 181, 127, 95 (base peak). M.W. c a l c d . f o r c i 3 H 2 0 ° 3 : 224.1413. Found (high r e s o l u t i o n mass sp e c t r o m e t r y ) : 224.1408. A n a l , c a l c d . f o r c 1 3 H 2 o ° 3 : G ' 6 9 - 6 1 ' H, 8.99. Found: C, 69.91, H, 8.91. - 278 -8-Hydroxydihydrocampherenone Ethylene Acetal (138) 8-Qxocamphor ethylene acetal (129) (526 mg, 2.36 mmole) was treated with 3-methylbutylmagnesium bromide (4.72 mmole; 2.0 molar equivalents) i n THF (25 mi) at reflux for 1.25 hours. On work-up the excess Grignard reagent was destroyed by the careful addition of saturated ammonium chloride. The re s u l t i n g suspension of pre c i p i t a t e s was f i l t e r e d by gravity and the f i l t r a t e was evaporated to provide 8-hydroxydihydro-campherenone ethylene acetal (138) (534 mg, 80% y i e l d ) , as a colourless o i l ; 5 (270MHz, CC1 4) 0.81 (s, 3H), 0.87 (s, 3H), 0.90 (d, 6H, J=8.0Hz), 0.96 (bs, IH, OH), 3.55 (bm, 5H, envelope contains acetal methylenes and -CH-OH methine proton); v (CC14) 3450 cm - 1 (weak, broad, vO-H); m/e 2 82 (M+) , 267, 227, 211 (base peak), 178, 154, 149, 121, 107, 95. M.W. calcd. for <"17^30<^>3: 282. 2195. Found (high resolution mass spectrometry): 282.2204. 8-Diphenyl-t-ButyIsiloxycamphor (148) (+)-8-Hydroxycamphor (2.65 g, 15.77 mmole) was dissolved i n dimethylformamide (DMF) together with imidazole (2.36 g, 34.70 mmole; 2.2 molar equivalents) and d i p h e n y l - t - b u t y l s i l y l chloride > (4.76 g, 17.35 mmole; 1.1 molar equivalents). This mixture was heated at 50° f o r 6 0 hours. On work-up the reaction was poured into d i e t h y l ether (50 mi) and washed with water and saturated sodium chloride. - 279 -Drying (magnesium sulphate) and evaporation of the solvent yielded 8-diphenyl-t-butylsiloxycamphor (148) (6.0 g, 94% y i e l d ) ; 6 (270MHz, CDCl-j) 0.85 (s> 3H) , 1.06 (s, 9H) , 1.09 (s, 3H) , 3.29 (d, IH, J=11.0Hz), 3.38 (d, IH, J=11.0Hz), 7.27-7.77 (m, 10H); v m a x (CC14) 1739 cm"1 (strong, sharp, vC=0); m/e 349 (M+-57), 256, 199, 161, 159, 150, 108, 95, 74, 73, 59 (base peak), 45. M.W. calcd. for m/e 34 9 (M +-57), C 2 2 H 2 5 0 2 S I : 349.1624. Found (high resolution mass spectrometry): 349.1617. ( + ).-8-Oxocamphor-8-Ethylene Acetal (149) 8-Oxocamphor (117) (2.45 g, 14.8 mmole) was dissolved i n benzene (25 ml) and was treated with ethylene g l y c o l (1.14 g, 18.5 mmole; 1.25 molar equivalents) and p_-toluenesulphonic acid (20 mg). The mixture was refluxed for 1.25 hours. Water was removed using a Dean-Stark apparatus containing 4A mole-cular sieves. Work-up i n the usual manner (cf. compound 119b) provided (+)-8-oxocamphor-8-ethylene acetal (149) (3.14 g, quantitative) as a yellow o i l . A pure sample was obtained for analysis by chromatography of the o i l on alumina (Alumina Woelm Neutral; a c t i v i t y grade III) using 5% d i e t h y l ether-95% petroleum ether (35-60) as eluant followed by high vacuum d i s t i l l a t i o n (bp. 80-85°/5 x 10~ 3 Torr); [ V ] 3 0 ' 5 + 19,38° (c 0.8, abs. EtOH); 6 0.90 (s, 3H), 0.94 (s, 3H), 3.83 (m, 4H), 4.44 (s, IH); Vmax ^ c c l4^ 1 7 3 9 c m _ 1 (strong, sharp, vC=0) , 14 04 cm"*1 (weak, - 280 -sharp, 6CH 2); m/e 210 (M+) f 195, 182, 167, 113, 95, 73 (base peak). M.W. calcd. for c 1 2 H i 8 ° 3 : 210.1256. Found (high resolution mass spectrometry): 210.1260. Anal, calcd. for C12 H18°3 : C ' 6 8 - 5 3 ; H ' 8 - 6 3 - Found: C, 68.29; H, 8.75. 8-Oxoborneol-8-Ethylene Acetal (150) (.+)-8-Oxocamphor-8-ethylene acetal (149) (1.30 g, 6.70 mmole) was dissolved i n diet h y l ether (10 mi) and t h i s solu-t i o n was added i n one portion to a s t i r r e d solution of calcium metal (536 mg, 13.4 mmole; 2 molar equivalents) i n l i q u i d ammonia (ca. 25 mi) at -75° (dry ice-acetone). S t i r r i n g was continued for 2 hours. On work-up the reaction mixture was treated with methanol (ca. 5 mi) to destroy excess calcium metal. The ammonia was evaporated at room temperature and water (40 mi) was added to the residue. A c i d i f i c a t i o n of t h i s aqueous solution of the product was c a r r i e d out with 6N hydrochloric acid. The solu-tion was extracted with d i e t h y l ether and the ether extracts were washed with saturated sodium bicarbonate and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded 8-oxoborneol-8-ethylene acetal (15 0) (1.0 g, 77% yield) as a clear yellow o i l ; 6 (60MHz, CC1 4) 0.83 (s, 3H), 0.95 (s, 3H), 3.77 (m, 4H), 4.03 (bd, IH, J=8.0Hz), 4.78 (s, IH) ; v (CCl.) 3597 cm"1 (medium, sharp, vO-H) , 3484 v , max 4 -1 * ' cm (medium, broad, vO-H). This o i l (1.0 g, 4.7 mmole) was immediately acetylated. - 281 -The o i l was dissolved i n THF (.10 mi) and added to a suspension of sodium hydride (274 mg, 50% dispersion i n o i l , 6.0 mmole; 1.15 molar equivalents) i n THF (50 mi). This mixture was refluxed for 1 hour after which time acetyl chloride (467 mg, 6.0 mmole; 1.25 molar equivalents) was added and reflux i n g was continued for 17 hours. On work-up the reaction was poured into d i e t h y l ether (50 mi) and washed with water and saturated sodium chloride. Dry-ing (magnesium sulphate) and evaporation of the solvent provided a yellow o i l (1.20 g). Chromatography on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade III) using 15% dieth y l ether~85% petroleum ether (35-60) provided a sample of 8-oxobornyl acetate-8-ethylene acetal (151) (90% pure; v.p.c. analysis on column A at 180°); 6 (270MHz, CC14) 0.82 (s, 3H), 0.93 (s, 3H), 1.98 (s, 3H), 3.83 (m, 4H), 4.87 (s, IH), 4.90 (d, IH, J=8.0Hz); v (CCl.) 1730 cm 1 (strong, sharp, vC=0), 1248 cm 1 (strong, in 3. x 4 broad, vC-O-C); m/e 254 (M +), 167, 150, 122, 108, 95, 94, 73, (base peak). M.W. calcd. for C 1 4 H 2 2 ° 4 : 254.1518. Found (high resolution mass spectrometry): 254.1518. 8-Oxobornyl Acetate (152) 8-0xobornyl acetate-8-ethylene acetal (151) (181 mg, 0.71 mmole) was dissolved i n acetone (2 mi) containing 6N hydro-c h l o r i c acid (5 drops). The mixture was kept at room temp-erature for 1 hour. On work-up the reaction was poured into d i e t h y l ether (20 - 282 -mil) and washed with saturated sodium bicarbonate and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided 8-oxobornyl acetate (152) (115 mg, 77% crude yield) as a clear colourless o i l . V.p.c. analysis of this o i l on column A at 180° indicated that i t was 95% pure; (60MHz, CC1 4) 1.03 (s, 3H), 1.06 (s, 3H), 2.00 (s, 3H), 4.82 I d , IH, J=10.0Hz), 9.63 (s, IH); v _ (CC1„) 2695 cm - 1 (weak, sharp, vC-H of CHO) , 1730 cm"1 (strong, broad, vC=0), 1235 cm"1 (strong, broad, vC-O-C). This material was used immediately without further p u r i f i c a t i o n . The Reaction of 8-0xobornyl Acetate (152) with y,Y-Dimethylallyl-trime thyIs1lane 8-0xobornyl acetate (152) (115 mg, 0.55 mmole) was d i s -solved i n THF (15 m£) containing y_, y-dimethylallyltrimethyl-silane (0.388 g, 2.74 mmole; 5 molar equivalents) and 4A mole-cular sieves. TBAF (0.715 g, 2.74 mmole; 5 molar equivalents) was added i n THF (5 mJl) and the mixture was re fluxed under an atmosphere of argon for 17 hours. On work-up the reaction was poured into d i e t h y l ether (50 m£) and was washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded an amber l i q u i d (372 mg). This material was chromato-graphed on alumina (Alumina Woelm Neutral; a c t i v i t y grade I I I ) . El u t i o n with petroleum ether (35-60) provided Y»Y-dimethylallyl-trimethylsilane (215 mg, 55% y i e l d ) . Changing the eluant to 2 83 -30% d i e t h y l ether-70% petroleum ether C35-60) provided 73 mg of un i d e n t i f i e d material. F i n a l l y , washing the column with 100% d i e t h y l ether provided a compound (32 mg, 35% yield) whose spectral data (v.p.c, n.m.r., and i r ) was i d e n t i c a l to those of (+)-8-hydroxycamphor (116). Borneol (154) from Bornyl Methyl Ether (155) Bornyl methyl ether (155) (100 mg, 0.60 mmole) was. dissolved i n chloroform (1 mi) and treated with iodotrimethyl-silane (0.262 g, 1.32 mmole; 2.2 molar equivalents) at room temperature for 18 hours. On work-up the reaction was poured into d i e t h y l ether (25 mi) and was washed with water, 20% sodium bi s u l p h i t e , and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvents provided a compound (9 8 mg) whose spectral data ( v . p . c , n.m.r. and i r ) was i d e n t i c a l to those of borneol (154). Bornyl Methyl Ether (155) (-)-Borneol (1.0 g, 6.5 mmole) was added i n THF (10 mi) to a suspension of sodium hydride (390 mg, 50% dispersion i n o i l , 8.1 mmole; 1.25 molar equivalents) i n THF (25 mi). The reaction was refluxed for 1 hour under an argon atmosphere. Methyl iodide (1.15 g, 8.11 mmole; 1.24 molar equivalents) was added neat v i a syringe and the reaction was refluxed for an additional 1.5 hours. - 284 -On work-up the reaction was poured into d i e t h y l ether (100 mi) and washed with water, 20% sodium b i s u l p h i t e , saturated sodium bicarbonate, and saturated sodium chloride. Drying (mag-nesium sulphate) and evaporation of the solvent provided bornyl methyl ether (155) (1.0 g, 91% yield) as a colourless l i q u i d ; 6 (270MHz, CC14) 0.89 (s, 9H), 3.44 (s, 3H), 3.57 (d, IH, J=10.0 Hz); \> (CC1.) 1120 cm"1 (strong, broad, vC-O-C); m/e 168 (M +), 153, 136, 121, 110, 108, 95 (base peak). M.W. calcd. for C l l H 2 0 O : 168.1514. Found (high resolution mass spectrometry): I68:i517. 8-Oxobornyl Methyl Ether-8-Ethylene Acetal (156) 8-Oxoborneol-8-ethylene acetal (150) (1.53 g, 7.2 mmole) was dissolved i n THF (10 mi) and was added to a suspension of sodium hydride (346 mg, 50% dispersion i n o i l , 7.2 mmole) i n THF ( 15 mil). The mixture was refluxed for 1 hour under an atmosphere of argon. Methyl iodide (2.05 g, 14.4 mmole; 2 molar equivalents) was added neat v i a syringe and the mixture was refluxed for an additional 1.5 hours. On work-up the reaction was poured into d i e t h y l ether (100 mil) and washed with water, 20% sodium b i s u l p h i t e , satu-rated sodium bicarbonate and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided 8-oxobornyl methyl ether ethylene acetal (156) (1.60 g, 98% crude yield) as a yellow o i l . This o i l was subjected to high vacuum d i s t i l l a t i o n (bp. 60-62°/5 x 10~ 3 Torr); 6 (270MHz, CC1 4) - 285 -0.78 (s, 3H), 0.96 (s, 3H) , 3.24 (s, 3H), 3.52 (d, IH, J=8.0Hz)f 3.80 Cm, 4H) , 4.77 (s, IH) ; v (CC1.) 1093 cm"1 (strong, broad, vC-O-C); m/e 226 (M+) , 211, 194, 168, 108, 95, 73 (.base peak). M.W. calcd. for C 1 3 H 2 2 ° 3 : 226.1569. Found (high resolution mass spectrometry): 226.1567. 8-Oxobornyl Methyl Ether (157) 8-Oxobornyl methyl ether-8-ethylene acetal (156) (115 mg, 0.51 mmole) was dissolved i n acetone (15 ml) containing 6N hydrochloric acid (5 drops). The mixture was kept at room temperature for 1.5 hours. Work-up i n the usual manner (cf. compound 152 p. 281) provided 8-oxobornyl methyl ether (157); 6 (60MHz, CCl^) 1.02 (s, 3H) , 1.12 (s, 3H) , 3.25 (s, 3H) , 3.38 (d, IH, J=8.0Hz), 9.53 (s,.lH); v (CC1.) 2703 cm"1 (weak, broad, vC-H of CHO). max 4 This material was used immediately without further p u r i f i c a t i o n . The Reaction of 8-Oxobornyl Methyl Ether (157) with ^,^-Dimethy1-a l l y l t r i m e t h y i s i l a n e and TBAF: The synthesis of 8-Acetoxy-campherenyl Methyl Ether (161) and 8-Hydroxy-8-(1,1-Dimethyl-2-Propenyl)bornyl Methyl Ether (158) 8-Oxobornyl methyl ether (157) (499 mg, 2.75 mmole) was dissolved i n THF (10 mil) containing y_,y-dimethylallyltrimethyl-s i l a n e (627 mg, 4.42 mmole; 1.6 molar equivalents) and 4A mole-cular sieves. TBAF (1.15 g, 4.42 mmole; 1.6 molar equivalents) was added i n THF (6 ml) and the mixture was s t i r r e d at room - 286 -temperature under an atmosphere of argon for 2.5 hours. On work-up the reaction was poured into d i e t h y l ether (25 mi) and washed with water and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded a clear colourless o i l (560 mg). V.p.c. analysis of th i s o i l on column A at 160° indicated i t was 75% pure and composed of two compounds i n the r a t i o 3:1. This o i l was acetylated i n pyridine (16 mi) containing acetic anhydride (.4 mi) for 6 hours at 95°. On work-up the reaction was poured into d i e t h y l ether (60 mi). This ethereal solution of the product was washed thorough-ly with water followed by 5% hydrochloric acid and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent yielded a clear orange o i l (943 mg). P u r i f i -cation of t h i s o i l was accomplished by column chromatography on s i l i c a gel ( S i l i c a Gel Woelm; a c t i v i t y grade I I I ) . Elution with 3% die t h y l ether-97% petroleum ether (35-60) provided 8-acetoxycampherenyl methyl ether (160) (255 mg; 32% y i e l d based on s t a r t i n g aldehyde 157 (mp. 41-43° (sealed tube)); 6 (270MHz, CC14) 0.79 (s, 3H), 0.96 (s, 3H), 1.71 (s, 3H), 1.78 (s, 3H), 2.04 (s, 3H), 3.41 (s, 3H) , 3.48 (d, IH, J=8.8Hz), 5.11 (t, IH, J=7.5Hz), 5.20 and 5.26 (two doublets of doublets assigned to the diastereomeric acetate methine proton: 5.20 (dd, J A X=10.0 Hz, J f i x=3.8Hz)), 5.26 tdd, J A X=10.0Hz, J B X=5.0Hz); v m a x (CC14) 1730 cm"1 (strong, sharp, vC=0), 1238 cm"1 (strong, broad, ester - 287 -vC-O-C), 1120 cm"1 (strong, broad, ether vC-O-C); m/e 294 (M +), 234 (base peak), 225, 183, 165, 151, 133, 125, 124, 123, 108, 95, 67, 43. M.W. calcd. for C 1 8 H 3 0 ° 3 : 294.2190. Found (high resolution mass spectrometry): 294.2192. Anal, calcd. for C 1 8 H 3 0 ° 3 : C ' 7 3 * 4 1 ; H ' 1 0 - 2 8 - Found: C, 73.54; H, 10.11. The solvent system was changed to 20% d i e t h y l ether-80% petroleum ether (35-60) and th i s provided 8-hydroxy-8-(1,1-dimethyl-2-propenyl)bornyl methyl ether (158) (22 mg); 6 (270MHz, CC14) 0.87 (s, 3H), 1.00 (s, 3H), 1.09 (s, 6H), 3.46 (s, 3H), 3.73 (s, IH), 3.63 (d, IH, J=10.0Hz), 4.96 (dd, J A X ( c i s ) = 11.3Hz, JAB(g_em)=2.5Hz) and 4.98 (dd, J p„ (trans) = 17. 5H z, J D A(gem)= 2.5Hz) (2H) , 6.15 (dd, IH, J. v (cis) = 11. 3Hz, J_ v(trans)=17.5Hz); A X D A v (CCl.) 3610 cm 1 (medium, broad, vO-H), 1639 cm 1 (weak, XHQ.X. »^ sharp, vC=C), 1117 cm 1 (strong, broad, vC-O-C), 913 cm 1 (medium, broad, 6=CH2); m/e 252, 234, 183, 181, 151, 123, 108, 95 (base peak), 70. M.W. calcd. for c i g H 2 8 ° 2 : 252.2089. Found (high resolution mass spectrometry): 252.2086. 8-Acetoxy-11-Iodo-Dihydrocampherenol (162) 8-Acetoxycampherenyl methyl ether (160) (64 mg, 0.22 mmole) was dissolved i n a c e t o n i t r i l e (3 mi) containing sodium iodide (168 mg, 1.12 mmole; 5 molar equivalents). T r i m e t h y l s i l y l chloride (121 mg, 1.12 mmole; 5 molar equivalents) was added neat via syringe and the solution was heated at 85° for 2 hours under an argon atmosphere. On work-up the reaction was poured into d i e t h y l ether (2 0 288 -ml) and was washed with water, 20% sodium bi s u l p h i t e , and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided 8-acetoxy-11-iodo-dihydro-campherenol (162) (80 mg, 88% yield) as a colourless o i l which was 97% pure by v.p.c. analysis on column A at 180° ( t h i s o i l darkens on standing). P u r i f i c a t i o n of 162 was accomplished by column chromatography on s i l i c a gel ( S i l i c a Gel Woelm, a c t i v i t y grade III) using 5% die t h y l ether-95% petroleum ether (35-60) as eluant. This provided a pure sample of 162 (100% pure by v.p.c. analysis on column A at 180°); 6 (270MHz, CC14) 0.76 (s, 3H), 1.02 (s, 3H), 1.87 (s, 3H), 1.93 (s, 3H), 2.00 (s, 3H), 4.24 (d, IH, J=8.0Hz), 5.19 and 5.21 (two doublets of doublets assigned to the diastereomeric acetate methine proton), 5.19 (d,d, J A X=10.0Hz, J B X=4.0Hz), 5.21.(d,d, J A X=10.0Hz, J B X=4.0Hz)); v (CC1.) 3546 cm 1 (weak, broad, vO-H), 1739 cm 1 (strong, max 4 r broad, vC=0), 1242 cm"1 (strong, broad, vC-O-C); m/e 408 (M +), 391, 349, 348, 282, 281, 263, 262, 222, 221, 151, 109, 95, 43 (base peak). M.W. calcd. for C^H^gC^I: 408.1161. Found (high resolution mass spectrometry): 408.1136. The Preparation of 2-Methyl-l-Propenyllithium (iso-Butenyllithium) A 30% dispersion of powdered lithium metal (containing 2% sodium metal) i n o i l (4.23 g, 181 mmole) was placed i n a dry three-neck loo ma round bottom fl a s k . The flask was flushed with argon and f i t t e d with an addition funnel, a thermometer, and a mechanical s t i r r e r . Diethyl ether (30 ml) was added to - 289 -wash the lithium dispersion free from o i l . This process was repeated twice. F i n a l l y the flask was charged with diet h y l ether (60 mJl) and ca. 150 of 1,2-dibromoethane was added to activate the lithium metal. l-Bromo-2-methyl-l-propene (7.0 g, 52 mmole) was dissolved i n diethyl ether (10 ml) and was added cautiously over 2 hours to the vigorously s t i r r e d lithium suspension. Gentle refluxing was maintained during t h i s addi-t i o n . On completion of t h i s addition the reaction was s t i r r e d for a further 1.5 hours. At the end of thi s time the now orange solution was f i l t e r e d under argon through glass wool to remove the excess l i t h i u m metal. The clear orange solution was assumed to be 0.74 molar i n iso-butenyllithium. Ba e y e r - V i l l i g e r Oxidation of Camphor (51) with 40% Peracetic 84 Acid and Benzeneperoxyseleninic Acid Camphor (3.0 g, 20 mmole), sodium acetate (1.0 g, 12 mmole) and 40% peracetic acid (6 m£, 32 mmole) were s t i r r e d together i n g l a c i a l acetic acid (20 ml) for 14 days at room temperature and protected from l i g h t . On work-up the reaction was poured into water (100 ml) and extracted with d i e t h y l ether. The di e t h y l ether extracts were washed with water, 20% sodium b i s u l p h i t e , saturated sodium bicarbonate, and saturated sodium chloride. Drying (magnesium sulphate) and evaporation of the solvent provided a white c r y s t a l l i n e material (1.5 g) which was analysed by v.p.c. on column G at 130°. This analysis revealed that the cry s t a l s - 290 -were a mixture of camphor (21%) and two other compounds i n the r a t i o 22:55 (77%) (ca. 1:2.5). The s o l i d was r e c r y s t a l l i z e d once from petroleum ether (35-60) at room temperature. The major 85 isomer 175 was i d e n t i f i e d from the n.m.r. (60 MHz) spectrum 6 (60MHz, CDC13) 1.00 (s, 3H), 1.07 (s, 3H), 1.28 (s, 3H). The minor isomer 176 exhibited peaks at 6 0.93 (s, 3H), 1.08 (s, 3H), 1.15 (s, 3H) and an AB quartet centered at 6 4.22 (6 4.01, d, J =10.0Hz and 6 4.42, d, J =10.0Hz); v (CCl.) (mixture of both isomers) , 1739 cm"'1' (strong, sharp, vC=0) and 114 3 cm 1 (strong, broad, vC-O-C lactone); m/e 168 (M +), 140, 126 (base peak), 111, 109, 108, 95. M.W. calcd. for C 1 0 H 1 6 ° 2 : 168.1150. Found (high resolution mass spectrometry): 168.1151. Camphor was also oxidized to a mixture of the lactones 175 and 176 using benzeneperoxyseleninic acid i n the following manner. Camphor (500 mg, 3.29 mmole) was dissolved i n THF (20 mi) containing benzeneseleninic acid (777 mg, 4.1 mmole; 1.25 molar equivalents) i n suspension. 30% hydrogen peroxide (3.0 mi, 35 mmole; 11 molar equivalents) was added and the mixture was refluxed for 72 hours. At t h i s time an aliquot of the reaction mixture was analysed by v.p.c. on column A at 130° and compared to a s i m i l a r v.p.c. analysis of the product mixture from the 40% peracetic acid oxidation. This analysis indicated that the reaction was 94% complete (5% s t a r t i n g material remained) and that two new compounds were present i n the reaction mixture i n the r a t i o 7.7:86.5 (94.2%) (ca. 1:11.1). 291 -Work-up as b e f o r e p r o v i d e d w h i t e c r y s t a l l i n e m a t e r i a l (400 mg). The major component was i d e n t i f i e d by n . m . r . (60 MHz) a n a l y s i s as the l a c t o n e 175 and the minor component as l a c t o n e 176 by c o - i n j e c t i o n , on column A a t 1 3 0 ° , w i t h the m i x t u r e o f l a c t o n e s o b t a i n e d f rom the f i r s t p r o c e d u r e . - 292 -REFERENCES 1. P.F.G. Boullay, Ann. Chim. Phys. (Paris), 80, 209 (1811). 2 . L. Bafth and M. Kretschy, Montash. Chem., 1, 99 (1880); E. Paterno and A. Oglialoro, Gazz. Chim. I t a i . , 11, 36 (1881). 3. B.M. Craven, Acta Cryst., 15, 387 (1962). 4. See reference 125 c i t e d i n reference 10 below. 5. T.H. E a s t e r f i e l d and B.C. Aston, J. Chem. Soc., 79, 120 (1901) . 6. T. Kariyone and T. Sato, J. Chem. Soc. Japan, 51, 134 (19 31) . 7. G. Jommi, F. Pe l i z z o n i , and C. Scolastico, Chim. Tnd. (Milan), 47, 406 (1965). 8. Y. Inubushi, H. I s h i i , B. Yasui, T. Konita, and T. Hara-yama, Chem. Pharm. B u l l . , 12, 1175 (1964). 9. T. Okomoto, M. Natsume, T. Onaka, F. Uchimaru, and M. Shimizu, Chem. Pharm. Bull. , 20, 418 (1972). 10. L.A. Porter, Chem. Rev., 67, 441 (1967) and references c i t e d therein. 11. H. Conroy, J. Am. Chem. Soc., 74, 2046 (1952). 12. A.D. Cross, Quart. Rev., 14, 317 (1960). 13. (a) M. Yamazaki, M. Matsuo, and K. Ar a i , Chem. Pharm. B u l l . , 14, 1058 (1966). (b) W. Parker, J.S. Roberts, and R. Ramage, Quart. Rev., 21, 331 (1967). 14. J.B. Hendrickson, Tetrahedron, 7, 82 (1959). 15. P. de Mayo, E.Y. Spencer, and R.W. White, Can. J . Chem., 41, 2996 (1963). 16. P. de Mayo and R.E. Williams, J. Am. Chem. Soc., 87, 3275 (1965). • • • 17. T. Okuda and T. Yoshida, Tetrahedron Lett., 2137 (1965). - 293 -18. T. Okuda and T, Yoshida, i b i d . , 439 (1964). 19. H. Conroy, J. AM. Chem. Soc., 79, 5550 (1957). 20. M. B i o l l a z and D. Arigoni, J.C.S. Chem. Comm., 633 (1969). 21. A. Corbella, P. Gariboldi, G. Jommi, and C. Scolastico, Chem. Comm., 634 (1969). 22. M. Kolbe and L. We s t f e11, Acta Chem. Scand., 21, 585 (1967). 23. P. de Mayo and R.E. Williams, J. Am. Chem. Soc., 87, 3275 (1965). (1965) . 24. P. de Mayo, J.R. Robinson, E.Y. Spenser, and R.W. White, Experientia, 18, 359 (1962). 25. O.E. Edwards, J.L. Douglas, and B. Mootoo, Can. J. Chem., 48, 2517 (1970) . 26. K.W. Turnbull, W. Acklin, and D. Arigoni, J.C.S. Chem. Comm., 598 (1972) . 27. A. Corbella, P. Gariboldi, and G. Jommi, J.C.S. Chem. Comm., 600 (1972). 28. A. Corbella, P. Gariboldi, G. Jommi, i b i d . , 729 (1973). 29. P. Bollinger, Dissertation No. 3595, ETH, Zurich; B. Muller, Dissertation No. 4000, ETH, Zurich. 30. G.P. Moss, " S p e c i a l i s t P e r i o d i c a l Reports, Terpenoids and Steroids", The Chemical Society, London, (1971), Vol. 1, p. 232. 31. P.J. Dunphy, Phytochem., 12, 1515 (1973). 32. K.H. Overton and'F.M. Roberts, J.C.S. Chem. Comm., 378 (1978) . 33. A. Corbella, P. Gariboldi, G. Jommi, and M. S i s t i , J.C.S. Chem Comm., 298(1975). 34. K. Yoshihara, Y. Ohta, T. Sakui, and Y. Hirose,Tetrahedron  Lett., 266 (1969). 35. K.W. Turnbull, W. Ack l i n , D. Arigoni, A. Corbella, P. Gari-b o l d i , and G. Jommi, J.C.S. Chem. Comm., 59 8 (19 72). - 294 -36. W. Bradshaw, H.E. Conrad, E.J. Corey, I.C. Gunsalus, and D. Lednicer, J. Am. Chem. S o c , 81, 5507 (1959); G. Fonken and R.A. Johnson, "Chemical Oxidations with Microorganisms", Marcel Dekker, New York, N.Y., (1972); K. K i e s l i c h , "Microbial Transformations of Non-steroid C y c l i c Compounds", Wiley-Thiene, Stuttgart, Germany, (1976). 37. J.D. Douros, J r . , and J.W. Frankenfeld, Appl. Microbiol., 16, 320 (196 8) . 38. W. Charney and H.L. Herzog, " Microbiological Transformations of Steroids", Academic Press, New York, (1967). 39. (a) G.S. Fonken, H.C. Murry, and L.M. Reineke, J . Am. Chem. Soc., 82, 5507 (1960). (b) K. Singh and S. Rakhit, Biochlm. Biophys. Acta, 144 139 (1967). (c) K. Carlstrom, Acta. Chem. Scand., 21, 1297 (1967). (d) N. Nakano, H. Sato, and B.I. Tamaoki, Biochim. Bio-phys. Acta, 164, 585 (1968). (e) K. Carlstrom, Acta Chem. Scand., 20, 2620 (1966). 40. (a) J. Fried, R.W. Thoma, and A. Klingsberg, J. Am. Chem. Soc., 75, 5764 (1953). (b) D.H. Peterson, S.H. Eppstein, P.D. Meister, H.C. Murray, H.M. Leigh, A. Weintraub, and L.M. Reineke, J. Am.  Chem. S o c , 75, 5768 (1953). (c) A. Bodanzsky, J. Kallonitsch, and G. Wix, Experientia, 11, 384 (1955). (d) A. Capek, 0. Hanc, K. Macek, M. Tadra, and E. R i e d l - r Tumova, Naturwis,43, 471 (1956). 41. A.I. Laskin, P. Grabowich, C. De L i s l e Meyers and J. Fried, J. Med. Chem., 7, 406 (1964). 42. J. Meinwald and E. Frauenglass, J. Am. Chem. Soc., 82, 5235 (1960). 4 3. H.E. Conrad, R. Dubus, M.J, Namtvedt, and I.C. Gunsalus, J. B i o l . Chem., 240, 495 (1965). 44. H.E. Conrad, R. Dubus, and I.C. Gunsalus, Biochem. Biophys. Res. Comm., 6, 293 (1961). 295 45. H.E. Conrad, K, Lieb, and I,C, Gunsalus, J . B i o l . Chem., 240, 4029 C1965) . 46. P. George and J.S. G r i f f i t h , "The Enzymes", P.D. Boyer, H. Lardy, and K. Myrback, Eds., 2nd Ed., Academic Press, o New York, Vol 1, (1959), p. 374. 47. I.C. Gunsalus, H.E. Conrad, and P.W. T r u d g i l l , "Oxidases and Related Redox Systems", T.E. King, H.S. Mason, and M. Morrison, Eds., J. Wiley and Sons Inc., New York, Vol. 1, (1965) , p. 436. 48. CR. Eck, G.L. Hodgson, D.F. MacSweeney, R.W. M i l l s , and T. Money, J.C.S. Perkin I, 1938 (1974). 49. E.L. E l i e l , "Stereochemistry of Carbon Compounds", McGraw-H i l l , New York, (1962), p. 198. 50. H.C. Brown, R.S. Fletcher, and R.B. Johannesen, J . Am. Chem. Soc. , 73_, 2 1 2 (1951). 51. Cf. L. Tenud, S. Farooq, J. S e i b l , and A. Eschenmoser, Helv. Chim. Acta, 53, 2059 (1970). 52. J.E. Baldwin, J.C.S. Chem. Comm., 734 (1976); J.E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, and R.C. Thomas, i b i d . , 736 (1976); J.E. Baldwin and L.I. Kruse, i b i d . , 233 (1977). 53. (a) G. Stork, L.D. Cama, and D.R. Coulson, J. Am. Chem. Soc., 96, 5268 (1974). (b) G. Stork and J.F. Cohen, i b i d . , 96i, 5270 (1974). 54. Cf. A.C. Knipe and C.J.M. S t i r l i n g , J. Chem. Soc., (B) 67, TT968) . 55. K. Nakanishi, "Infrared Absorption Spectroscopy - P r a c t i c a l " , Holden-Day, San Fransisco (1962), p. 36. 56. (a) J. Klein, J. Am. Chem. Soc., 81, 3611 (1959). (b) H.O. Houae, S.G. Boots, and V.K. Jones, J. Org. Chem., 30, 2519 (1965). (c) E.K. Corey, N.M. Weinshenker, T. Schaaf, and W. Huber, J. Am. Chem. Soc., 91, 5675 (1969). (d) E.J. Corey and R. Noyori, Tetrahedron Lett., 311 (1970). - 296 57. P.A. B a r t l e t t and J. Myerson, J. Am. Chem. Soc., 100, 3950 C1978). 58. H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin Inc., Menlo Park, C a l i f o r n i a , (1972), p. 302. 59. M. Bertrand and J. V i a l a , Tetrahedron Lett., 2575 (1978); H. Bormant and M. Delepine, Academie Des Sciences, 6 31 (1955); H. Nornant, Comptes rendus, 240, 314 (1955). 60. E.A. Braude and C.J. Timmons, J. Chem. Soc., 2000 (1950). 61. J.S. B i r t w i s t l e , K. Lee, J.D. Morrison, W.A. Sanderson, and H.S. Mosher, J. Org. Chem., 29, 37 (1964). 62. W.E. Bachmann, J.P. Horwitz, and R.J. Warzynski, J. Am.  Chem. Soc. , 75,. 3268 (1953). 63. S.M. Nagvi, J.P. Horwitz, and R. F i l l e r , i b i d . , 79, 6283 (1957). 64. H.O. House, i b i d . , 76, 1235 (1954). 65. (a) H.O. House, i b i d . , 77, 5083 (1955). (b) H.O. House, i b i d . , 77, 3070 (1955). 66. G. Linstrumelle, J.K. Krieger, and G.M.W. Whitesides, Org. Syn., 55, 103 (1976). 67. J . I . Musher and E.J. Corey, Tetrahedron, 18, 791 (1962); B.I. Ionin and B.A. Erschov, "N.M.R. Spectroscopy i n Organic Chemistry", Plenum Press, New York (1970), p. 34; E.D. Becker, "High Resolution N.M.R. Theory and Chemical Ap p l i -cations", Academic Press, New York (1969), p. 163. 68. We would l i k e to thank Dr. S.O. Chan for the U.B.C. Chemistry Department's n.m.r. laboratory for carrying out the n.m.r. studies on compound (120b). 69. H. Felkin and C. Frajerman, Tetrahedron Lett., 1045 (1970); G. Lindstrumelle, R. Lome, and H.P. Dang, Tet. Lett. , 4069 (1978); R.A. Benkeser, Synthesis, 347 (1971); F. Derguini-Boumechal, R. Lome and G. Lindstrumelle, Tetrahedron Lett., 1181 (1977). 70. L. Pauling, "General Chemistry", W.H. Freeman and Co., San Francisco, 3rd Ed., (1970), p. 913. 71. A. Hosomi, A. Shirahata, and H. Sakurai, Tetrahedron Lett., 3043 (1978). - 297 -72. J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", McGraw-Hill Book Co., New York £1968), p, 714, 73. E,M. Kaiser, Synthesis, 391 (1972); W.S. Murphy and D.F. S u l l i v a n , J.C.S. Perkin I, 999 (1972). 74. Reference Spectrum # 6023M, Stadler Standard Spectra, Stadler Research Laboratories, Inc., (1969), p. 6023M. 75. Reference Spectrum # 524M, i b i d . , p. 524M. 76. For examples, see R.S. Henry, F.G. R i d d e l l , W. Parker, and C.I.F. Watt, J.C.S. Perkin II, 1549 (1976). 77. E.W. Warnhoff, Can. J . Chem., 55, 1635 (1977). 78. M.E. Jung and M.A. Lyster, J. Org. Chem., 42, 3761 (1977). 79. G. Olah, S.C. Narang, B.G.B. Gupta, and R. Malhotra, J. Org. Chem., 44, 1247 (1979). 80. M.E. Jung and T.A. Blumenkopf, Tetrahedron Lett., 3657 (1978). 81. L.F. Fieser and M. Fieser, "Reagents for Organic Synthesis", John Wiley and Sons, Inc., New York, (1967), p. 66. 82. J.F. McOmie, M.L. Watts, and D.E. West, Tetrahedron, 24, 2289 (1968). 83. R.F. Borch, A.J. Evans, and J.J. Wade, J. Am. Chem. S o c , 97, 6282 (1975). 84. R.R. Sauers, i b i d . , 81, 925 (1959). 85. T. Hirata, T. Suga, and T. Matsuura, B u l l . Chem. Soc. Japan, 43, 2588 (1970). 86. A.E. Greene, J.P. Depres, H. Nagano, and P. Crabbe, Tetrahedron  Lett. , 2365 (1977)'; G. Mehta and P.N. Pandey, Synthesis, 404 (19 7 87. E.J. Corey, T.K. Schaaf, W. Huber, U. K o e l l i k e r and N.M. Weinshehker, J. Am. Chem. Soc., 92, 397 (1970). 88. W.D. Emmons and G.B. Lucas, i b i d . , 77, 2287 (1955). 89. G. Mehta, P.N. Pandey, and Tse-Lok Ho, J. Org. Chem., 41, 953 (1976). 90. P.A. Grieco, Y. Yokoyama, S. Gilman, and Y. Ohfune, J.C.S. Chem. Comm., 870 (1977). - 298 -W.L. Meyer, C. Capshew, J.H, Johnson, A.R. Klusener, A. Logo, and R.N. McCarty, J. : Org. Chem. , 42, 527 (1977). 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0060805/manifest

Comment

Related Items