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Studies related to the synthesis of eremopbilane sesquiterpenes Smillie, Robert Dean 1969

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STUDIES RELATED TO THE SYNTHESIS OF EREMOPHILANE SESQUITERPENES. THE SYNTHESIS OF RACEMIC FUKINONE BY ROBERT DEAN SMILLIE B.Sc. U n i v e r s i t y of B r i t i s h Columbia, 1966 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of Chemistry We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH'COLUMBIA June, 1969 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and S t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d b y t h e Head o f my D e p a r t m e n t o r b y h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . D e p a r t m e n t The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8, C a n a d a ( i i ) ABSTRACT The synthesis o f decalone (122) has been achieved by two a l t e r n a t i v e methods. S t e r e o s e l e c t i v e conjugate a d d i t i o n of li t h i u m dimethylcuprate to the k e t a l octalone (131) afforded the k e t a l decalone (129). Wolff-Kishner reduction o f the l a t t e r compound, followed by a c i d i c hydrolysis produced -decalone (122) contaminated with i t s epimer, decalone (148). A more - e f f i c i e n t procedure f o r the preparation of (122) involved an annelation of 2;3-dimethylcyclohexanone. The key step i n t h i s process was the rea c t i o n of the enol lactone (157) with methyllithium to produce, a f t e r appropriate a l d o l c y c l i z a t i o n , octalone (69a). Subsequent hydrogenation of t h i s compound afforded decalone (122) . A n a t u r a l l y occurring sesquiterpene, fukinone, has r e c e n t l y been i s o l a t e d and assigned structure (16). The t o t a l synthesis o f racemic fukinone, reported herein, was achieved by the following sequence. The hydroxymethylene d e r i v a t i v e of octalone (69a) was prepared. Hydrogenation of t h i s compound, followed by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone afforded a c r i t i c a l intermediate, keto aldehyde (167). Oxidation of the l a t t e r and e s t e r i f i c a t i o n of the r e s u l t i n g carboxylic acid (170) produced keto ester (171), which was subsequently hydrogenated to a f f o r d keto ester (172). Reaction of t h i s compound with methyllithium and dehydration o f the r e s u l t i n g alcohol afforded (1)-epi-fukinone (174). O l e f i n i c isomerization of the l a t t e r produced (1)-fukinone (16). The synthes of (±)-fukinone reported herein, establishes a s t e r e o s e l e c t i v e synthetic entry i n t o the eremophilane cl a s s of sesquiterpenes. ( i i i ) TABLE OF CONTENTS ' page T i t l e Page 7 (i) Abstract ..... ( i i ) Table of Contents ( i i i ) L i s t of Figures . ..; (iv) Acknowledgements •••• ( v) Introduction 1 Discussion * 24 Experimental 62 Bibliography 79 (iv) " . LIST OF FIGURES Figure . Page 1 Biosynthesis of terpenes 4 2 Biosynthesis of the eremophilane skeleton 5 . 3_ N.m.r. spectrum of ketal decalone (129) 32 4_ N.m.r. spectrum of decalone (122) 37 5_ Enamine alkylation 49 6^  N.m.r. spectrum of keto aldehyde (167) 53 7_ N.m.r. spectrum of fukinone (16) 60 (iv) ' LIST OF FIGURES Figure ' _ . • Page 1 Biosynthesis of terpenes 4 2_ Biosynthesis of the eremophilane skeleton 5 3^  N..m.r. spectrum of ketal decalone (129) 32 4_ N.m.r. spectrum of decalone (122) '37 5_ Emamine alkylation 49 6_ N.m.r. spectrum of keto aldehyde (167) 53 7_ N.m.r. spectrum of fukinone (16) 60 (v) ACKNOWLEDGEMENTS I would like to express my sincere thanks to my research director, Dr. Edward Piers, for his invaluable advice, guidance and enlightening discussions throughout the course of this research. I am also grateful for the financial support given me by the University of British Columbia, for the Queen Elizabeth Scholarship, and the University Graduate Fellowship, and to the National Research Council for a Bursary. My sincere appreciation is expressed to Mr. R.J. Keziere for his most helpful suggestions and criticisms in the preparation of this manuscript. INTRODUCTION Sesquiterpenes are a cl a s s of n a t u r a l l y occurring compounds normally containing f i f t e e n carbon atoms. They are one group i n the b i o g e n e t i c a l l y r e l a t e d terpene family, which also includes monoterpenes (ten carbon atoms), diterpenes (twenty carbon atoms), sesterterpenes (twenty-five carbon atoms), tr i t e r p e n e s ( t h i r t y carbon atoms) and carotenoids ( f o r t y carbon atoms). Terpenes are v i r t u a l l y ubiquitous i n the realm o f nature. Sesquiterpenes occur i n a large v a r i e t y o f plants and trees, and e x h i b i t a wide range o f structures from a c y l i c , monocyclic and b i c y c l i c to t r i - and t e t r a c y c l i c s t r u ctures. A b i o g e n e t i c a l l y i n t e r e s t i n g class of sesquiterpenes i s the eremophilane se r i e s which possesses the b a s i c carbon skeleton (1). Eremophilone (2) was i s o l a t e d by Simonsen (1) i n 1932 and represented the f i r s t eremophilane-type sesquiterpene to be found. Since then, approximately f i f t y eremophilane-type sesquiterpenes have been i s o l a t e d and i d e n t i f i e d (2). The most c h a r a c t e r i s t i c features of these compounds are the c i s -v i c i n a l methyl groups at C-4 and C-5 of r i n g A, and the isopropyl-type side chain o f r i n g B at C-7. The numbering system shown i n (1) i s that normally employed f o r t h i s c l a s s o f compounds. - 2 -(1) (2) These compounds are biogenetically interesting in that they pose a contradiction to the original isoprene rule which stated that, in the case of sesquiterpenes, three isoprene units (3) are joined by head to t a i l linkages. head ta i l (3) The isoprene rule was first formulated by Ruzicka (3) in the early 1920's, and states that a l l terpenes are derived from polymerization of units of isoprene. However, so many terpenes were found whose structures disobeyed the isoprene rule, such as the eremophilane class of sesquiterpenes, that the rule was revised (4) to include terpenes which have undergone carbon skeletal, rearrangments in the course of their biosynthesis. The basic precursor utilized in terpene biosynthesis is mevalonic acid (5,6,7) which is formed by the successive self condensation of three - 3 -molecules of a c e t y l eoenzyme A (4), a sugar metabolite. Phosphorylation of mevalonic,acid (5) and subsequent dehydration gives r i s e to the actual 3 isoprene u n i t , A -isopentenyl pyrophosphate (6). Isomerization of the terminal double bond o f (6) r e s u l t s i n the formation of d i m e t h a l l y l pyro-phosphate (7). Condensation of (6) with (7) y i e l d s geranyl pyrophosphate (8) which i s the biogenetic precursor of the monoterpenes. Condensation of another molecule of (6) with (8) leads to the formation of f a r n e s y l pyrophosphate (9), the biogenetic precursor of the sesquiterpenes. Reductive dimerization of f a r n e s y l pyrophosphate (9) produces squalene (10), the t r i t e r p e n o i d biogenetic precursor. Consecutive a d d i t i o n of two molecules of (6) to geranyl pyrophosphate (8) affords geranyl geranyl pyrophosphate (11) the diterpenoid biogenetic precursor. This i s represented diagramatically i n Figure 1_. The c e n t r a l double bond i s f a r n e s y l pyrophosphate (9) i s always trans, but the terminal double bond may be e i t h e r c i s (9a) or trans (9b) . C y c l i z a -t i o n of these compounds can lead to s i x c a t i o n i c species from which a l l sesquiterpenes can t h e o r e t i c a l l y be biosynthesized (7). The proposed biosynthesis o f the eremophilane skeleton i s outlined i n Figure 2. The eremophilane skeleton i s thought to a r i s e by C-10 to C-l c y c l i z a t i o n of t r a n s - f a r n e s y l pyrophosphate (9b) to produce ion (12). The double bonds of ion (12) are conveniently s i t u a t e d for a concerted c y c l i z a t i o n , which would y i e l d a b i c y c l i c product (13) . This ion (13) would be a d i r e c t precursor of the eudesmane family of sesquiterpenes (14) . However, ion (13) also has the i d e a l a n t i - p a r a l l e l geometry f o r a 1,2-shift of an angular methyl group to form ion (15) which has the basic eremophilane skeleton. The object of the work reported i n t h i s thesis was to e s t a b l i s h a general synthetic entry into the eremophilane class of sesquiterpenes, and i n - 4 -CO2 _ - — : — - B * - Photosynthesis Sugar Metabolism CH„C0SCoA — » Pyruvic Acid - 5 -) Figure 2_ p a r t i c u l a r , to synthesize unambiguously a number of members of t h i s class of compounds. S t r u c t u r a l E l u c i d a t i o n of Fukinone Since the work described herein culminated i n the t o t a l synthesis of racemic fukinone (16), i t i s pertinent to o u t l i n e the work which led to the s t r u c t u r a l e l u c i d a t i o n of t h i s eremophilane-type sesquiterpene. Fukinone (16) (8) was i s o l a t e d from the methanolic extract of the flower s t a l k s o f Petasites japanicus MAXIM (Japanese name, "Fuki") which grows wild throughout most of Japan. The ^^^2^ c o m P o u n i ^ w a s a colourless o i l with a fragrant smell., Its i n f r a r e d ( i . r . ) and u l t r a v i o l e t (u.v.) spectra i n d i c a t e d an a,B-unsaturated carbonyl system. The nuclear magnetic resonance - 6 -(n.m.r.) spectrum exhibited two singlets at T 8.10 and T 8.22 assigned to two methyl groups on a double bond, a singlet at T 9.05 for a t e r t i a r y methyl group, and a doublet ( J = 6 Hz) at T 9.16 which was assigned as a secondary methyl group. From t h i s and other data, the fukinone molecule was assumed to be a b i c y c l i c sesquiterpene having an a,3-unsaturated carbonyl system consisting of an isopropylidene group conjugated with a ketone. The presence of the isopropylidene group was confirmed i n two ways. F i r s t l y , c a t a l y t i c hydrogenation of fukinone (16) gave dihydrofukinone (17) which exhibited an i . r . spectrum t y p i c a l of a saturated six-membered ring carbonyl. The n.m.r. spectrum now lacked the v i n y l methyl signals, but two three proton doublets (J = 6.5 Hz) now appeared at x 9.15 and 9.17, indi c a t -ing an isopropyl group had been formed. Secondly, a l k a l i n e hydrolysis of fukinone afforded acetone and a decalone (18) by a retroaldol condensation. H H (18) The o p t i c a l rotary d i s p e r s i o n (o.r.d.) curves of fukinone (16), dihydro-fukinone (17) and decalone (18) exhibited negative Cotton e f f e c t s , which are c h a r a c t e r i s t i c of A/B c i s - f u s e d 3-keto steroid s (9). Many sesquiterpenes i s o l a t e d from Petasites species are of the cis-decalone type (10,11,12), and ex h i b i t a negative Cotton e f f e c t i n the o.r.d. Dihydrofukinone (17) was converted to the ethylene t h i o k e t a l (19), and upon d e s u l f u r i z a t i o n with Raney n i c k e l afforded hydrocarbon (20) which was i d e n t i c a l with the known 73-eremophilane (13) . • (17) (19) (20) F i n a l l y , i s o p e t a s o l (21) , an eremophilane sesquiterpene of known absolute c o n f i g u r a t i o n (10) was converted to dihydrofukinone (17) . Iso-petasol (21) was hydrogenated to provide tetrahydroisopetasol (22) which was ascertained to be a ci s - f u s e d decalone by the expected negative Cotton e f f e c t . The t o s y l a t e (23) of t h i s decalone was prepared, and then reduced with l i t h i u m aluminum hydride y i e l d i n g an al c o h o l . This alcohol was oxidized with Jones' reagent to y i e l d a decalone, which was i d e n t i c a l with dihydrofukinone (17). - 8 -H H Synthetic Approaches to the Eremophilane Sesquiterpenes Increased i n t e r e s t i n the eremophilanes i s evident from the number'of recent syntheses d i r e c t e d towards these compounds. The f i r s t t o t a l synthesis i n the eremophilane family was reported by Marshall, Faubl and Warne (14) with the synthesis of racemic isonootkatone (32). Previously r e f e r r e d to as a-vetivone (15), t h i s sesquiterpene had been regarded as an isomer of the agarospirenone, g-vetivone, u n t i l Marshall and Anderson's (16) s t r u c t u r a l e l u c i d a t i o n i d e n t i f i e d i t as an eremophilane sesquiterpene. In the presence o f a c a t a l y t i c amount of sodium methoxide, 2-carbomethoxy 4-isopropylidene-cyclohexanone (25) underwent Michael a d d i t i o n to trans-pent-3-en-2-one (24) a f f o r d i n g , a f t e r a l d o l c y c l i z a t i o n , a mixture of the c i s -and trans-octalones, (26) and (27), with the c i s - d e r i v a t i v e (26) predominating - 9 -{Marshall reasoned that s t e r i c and e l e c t r o n i c f a c t o r s i n the Michael a d d i t i o n would favour a t r a n s i t i o n s tate r e s u l t i n g i n the formation of the c i s -octalone (26), and t h i s was borne out experimentally. (24) (32) C02Me (25) (26) CH2X (29) >X = OH (30) ,X = OMs (31_),X = H = C02Me (27) C02Me (28) The keto group of (26) was protected as the ethylene k e t a l (28) and the ester group o f (28) was reduced with lithium aluminum hydride to produce al c o h o l (29). Hydrogenolysis (lithium-ammonia-ethanol) of the methanesulphon-.ate d e r i v a t i v e (30) y i e l d e d compound (31), which upon a c i d i c hydrolysis afforded racemic isonootkatone (32). The synthesis of (±)-nootkatone (42) was accomplished by two d i f f e r e n t groups o f researchers by quite d i f f e r e n t means. The f i r s t t o t a l synthesis - 10 -was reported by Peraro, Bozzato and Schudel (17). Condensation of 4-iso-propenylcyclohexanone (33) with ethyl formate afforded the hydroxymethylene d e r i v a t i v e (34) which was a l k y l a t e d with methyl iodide to give a mixture of keto aldehydes (35) and (36) and an enol ether (37). Condensation of keto aldehyde (35) with methyl acetoacetate followed by treatment with potassium hydroxide, and then e s t e r i f i c a t i o n , afforded dienone (38). Methylation of the l a t t e r with l i t h i u m dimethylcuprate (18) led e x c l u s i v e l y to the c r y s t a l -l i n e keto ester (59). Dehydrogenation with 2,3-dichloro-5,6-dicyanobenzo-quinone y i e l d e d the dienone-ester (40) which was s e l e c t i v e l y reduced with sodium borohydride i n py r i d i n e to give keto ester (41). Subsequent s a p o n i f i c a t i o n , followed by decarboxylation afforded racemic nootkatone (42). The second synthesis of (±)-nootkatone was achieved by Odom and Pinder (19), and was somewhat shorter than that reported by Schudel and coworkers. The key r e a c t i o n was the st e r e o s e l e c t i v e condensation of 4-isopropenyl-2-methylcyclohexanone (43) with trans-pent-5-en-2-one (24) . In the presence of sodium hydride, the ketone (43) underwent Robinson annelation with pentanone (24) to a f f o r d racemic nootkatone (42). It has been shown (20) that an a l t e r a t i o n i n annelation r e a c t i o n conditions can r e s u l t i n a marked change of c i s : t r a n s r a t i o i n the v i c i n a l dimethyl products. Odom and Pinder noted that from t h e i r annelation, and others reported i n the l i t e r a t u r e (14,20,21), the stronger the base, the greater the chance f o r the c i s - v i c i n a l methyl groups to be formed. Coates and Shaw have u t i l i z e d a s i m i l a r approach i n t h e i r synthetic studies. Condensation of the p y r r o l i d i n e enamine of 2-methylcyclohexane-1,3-dione (44) with trans-pent-3-en-2-one (24) afforded i n good y i e l d a - 11 -- 12 -mixture of the c i s and trans-octalones (45) (20). The c i s : t r a n s r a t i o of t h i s product was found to vary between 1:1 and 1:10, depending on the cyclohexanone reagent used and upon the exact re a c t i o n conditions that were employed. The 1:1 mixture of octalones was subsequently used i n the syntheses o f racemic - a r i s t o l e n e (calarene, g-gurjunene) (22) and ( t ) -eremoligenol and (±)-eremophilene (23). Treatment of the mixture of octalones (45) with 1,2-ethanedithiol i n the presence of a c i d afforded a mixture of the corresponding mono-thioketals (46). Desulphurization of the l a t t e r with Raney n i c k e l afforded the c i s - and trans-unsaturated ketones (47) and (48) which were separated by spinning-band column d i s t i l l a t i o n . The ci_s-unsaturated ketone (47) was an intermediate ketone common to both syntheses. -(24) (44) (45) + (48) - 13 -In the synthesis of ( l ) - a r i s t o l e n e (53) the cis-unsaturated ketone was treated with sodium hydride and diethylcarbonate to y i e l d the 8-keto ester (49). Treatment of compound (49) with methyllithium gave r i s e to the ke t o l (50) which was dehydrated to the isopropylidene d e r i v a t i v e (51). The s t e r e o s e l e c t i v e i n t r o d u c t i o n of the gem-dimethylcyclopropane moiety was e f f e c t e d by a p p l i c a t i o n of the thermal decomposition of pyrazolines. Reaction of the a,B-unsaturated ketone (51) with hydrazine produced an 2 unstable A -pyrazoline (52) which was then subjected to thermal decomposition with potassium hydroxide to a f f o r d a stereochemically homogeneous product, (±)-A 1 (- 1°' )-aristolene (53). (47) (53) The a r i s t o l a n e (calarane) family of which a r i s t o l e n e i s a member, i s generally regarded as a separate s k e l e t a l class of sesquiterpenes, but are c l o s e l y r e l a t e d to the eremophilanes i n that they are probably bio-g e n e t i c a l l y formed from the same intermediate ion (12) and possess the c i s - v i c i n a l methyl groups. - 14 -Coates and Shaw (23) i n t h e i r other synthetic sequence u t i l i z e d the same cis-unsaturated ketone (47). Reaction of the l a t t e r with sodium hydride and d i e t h y l carbonate again produced the g-keto ester (49), the sodium s a l t (54) of which was reacted with a c e t y l chloride to a f f o r d the enol acetate (55). Reduction of t h i s compound (55) with l i t h i u m i n ammonia •was the most c r i t i c a l step i n t h i s synthetic scheme. This reduction -removed both the conjugated double bond and the extraneous oxygen function, and most important, generated the required a x i a l configuration i n the ester (56). The a x i a l isomer was presumably the r e s u l t of a k i n e t i c a l l y c o n t r o l l e d protonation of the intermediate ester enolate anion from the les s hindered, e q u a t o r i a l s i d e . The r e a c t i o n of the ester (56) with ethereal methyllithium afforded (±) eremoligenol (57). Dehydration of eremoligenol with t h i o n y l chloride produced (i)-eremophilene (58) and i t s double bond isomer (59) i n a r a t i o of 2:1 r e s p e c t i v e l y . . Another means of entry into the eremophilane sesquiterpenes was explored by Pie r s and Keziere (24). Condensation of 3-isopropenylcyclo-hexanone (60) with ethyl formate afforded the hydroxymethylene d e r i v a t i v e (61), which upon treatment with l-diethylamino-3-pentanone methiodide (62), gave a f t e r c y c l i z a t i o n , octalone (63). In the key r e a c t i o n , s t e r e o s e l e c t i v e i n t r o d u c t i o n of an angular methyl group was accomplished by use of the li t h i u m dimethylcuprate (18) to a f f o r d the desired decalone (64). The tosylhydrazone (65), prepared from the decalone, was heated with sodium ethylene g l y c o l a t e (Bamford-Stevens reaction) to produce racemic eremophil-3,11-diene (66). Structure (66) was o r i g i n a l l y proposed as eremophilene, - 15 -(58) (59) but comparison with an authentic sample ( i . r . and n.m.r. spectra) showed them to be d i f f e r e n t . The structure of eremophilene was recently revised (25) to that of (58). Two completely d i f f e r e n t approaches to the t o t a l synthesis of ( t ) -a r i s t o l o n e have r e c e n t l y been reported. Berger, Franck-Neuman and Ourisson (26) , i n the f i r s t synthesis, condensed 2,3-dimethylcyclohexanone (67) with (66) (65) (64) methyl v i n y l ketone (68) i n the presence of sodium methoxide to obtain an epimeric mixture of octalones (69), i n a r a t i o of 3:2. Birch reduction (lithium-ammonia) of the octalones (69) produced the trans-fused decalones (70). Bromination of the l a t t e r produced a mixture of bromoketones, from which the desired compound (71) could be i s o l a t e d by s e l e c t i v e c r y s t a l l i z a -t i o n . Dehydrobromination of (71) y i e l d e d the unsaturated ketone (72), which when treated with diazoisopropane produced the pyrazoline (73). I r r a d i a t i o n of t h i s unstable pyrazoline (73) afforded (t)-trans-dihydro-a r i s t o l o n e (74) . Bromination of t h i s compound (75), followed by dehydro-bromination, y i e l d e d (±)-aristolone (76). In another synthesis of racemic a r i s t o l o n e , P i e r s , B r i t t o n and de Waal - 17 -(74) (75) (76) (27) chose a l k y l a t i o n of the 6-_n-butylthiomethylene d e r i v a t i v e of 2,3-dimethylcyclohexanone (77) with methyallyl chloride (78) to introduce the c i s - v i c i n a l methyl groups. This produced a mixture of two a l k y l a t e d products (79) i n a r a t i o of 4:1. A f t e r removal of the blocking group, the major isomer, which was the desired product (80), was separated by f r a c t i o n a l - 18 -d i s t i l l a t i o n . Acid catalyzed isomerization converted the methallyl group of (80) into the methylpropenyl moiety (82). Treatment of t h i s cyclohexanone d e r i v a t i v e (82) with d i e t h y l cyanomethylphosphate produced a mixture of the a, B-unsaturated n i t r i l e (83) and the 3, Y " u n s a t u r a t e c l n i t r i l e (84) . This mixture was hydrolyzed to produce the 3, y-unsaturated acid (85). The carboxylic a c i d (85) was converted into i t s sodium s a l t , and reacted with o x a l y l chloride to produce the acid chloride (86). This i n turn, was converted to the diazoketone (87) by treatment of the a c i d chloride (86) with diazomethane. Ring closure was accomplished by r e f l u x i n g the diazoketone (87) i n cyclohexane i n the presence of cupric sulphate to obtain (±)-•aristolone (76) and (+)-6,7-epiaristolone (88) i n a r a t i o of 2:1 r e s p e c t i v e l y . Sims and Selman (28) have investigated a new method of introducing an angular methyl group i n t o fused r i n g systems, a method that may well have a p p l i c a t i o n to the synthesis o f eremophilanes. The Birch reduction of 4-methyl-l-naphthoic a c i d (89) led to the formation of a mixture of tetrahydro acids (90) and (91), i n a r a t i o of 2:1 r e s p e c t i v e l y . The cis-tetrahydro acid (90), upon e s t e r i f i c a t i o n , followed by hydrogenation over Adam's c a t a l y s t , was converted i n t o the ester (93). The Simmons-Smith re a c t i o n on the ester (93) was st e r e o s e l e c t i v e and c i s - e s t e r (94), which upon s a p o n i f i c a t i o n gave the c r y s t a l l i n e a c i d (95). Decarboxylation by heating the a c i d (95) to i t s r e f l u x point produced the o l e f i n (96). Racemic tetrahydroeremophilone (111), a reduction product of eremophilone (2) was rec e n t l y synthesized by Brown and coworkers (29). The key step involved the a c i d catalyzed t r a n s - a n t i p a r a l l e i c y c l i z a t i o n of a t r i e n e (101) which introduced the c i s - v i c i n a l methyl groups d i r e c t l y . (85) , R = OH (76) (88) (86) , R = Cl (87) , R = CHN2 . - 20 -(95), R = H A l k y l a t i o n of the keto es t e r (97) with trans-l-bromo-pent-3-ene (98) afforded keto ester (99), which was hydrolyzed and decarboxylated to the unsaturated ketone (100). The mixture of trienes (101) was r e a d i l y obtained by treatment of (100) with methyllithium, followed by phosphorus oxychloride-pyridine dehydration of the r e s u l t i n g a l c o h o l . The trienes (101) were c y c l i z e d by treatment with anhydrous formic a c i d to produce two formates (102) and (104) epimeric at C-7, i n a r a t i o of 3:2 r e s p e c t i v e l y . Reductive cleavage of these formates with l i t h i u m aluminum hydride y i e l d e d the alcohols (105) and (105) which were separated by column chromato-graphy. - 21 -Oxidation of the desired epimer, alcohol (105) to the ketone (106) followed by Wolff-Kishnerreduction afforded olefin (107). Photo-oxygenation of olefin (107) followed by lithium aluminum hydride reduction gave a mixture of a l l y l i c alcohols (108). Cleavage of the exocyclic double bond •of (108) was effected by ozonolysis. The resulting ketol(109) was .acetylated and the corresponding acetate (110) was reduced with calcium and ammonia to give racemic tetrahydroeremophilone (111) . Br 0 0 0 (106) (104), R = CHO (102), R = CHO . ' •(105), R = H (103), R = H (109) , R = 0, R2 = H (110) , R1 = 0, R2 = Ac - 22 -Heathcock and coworkers have studied acid-catalyzed methyl migration i n 9-methyl decalins (30) as a possible entry into the eremophilane skeleton. A number o f l i t e r a t u r e examples (30) of 1,2-methyl migrations i n d i c a t e d that t h i s type of synthetic approach, patterned a f t e r the proposed b i o s y n t h e t i c pathway (7) might be f e a s i b l e . Of primary importance was the observation that the unsaturated a c i d (112), i n the presence of anhydrous formic a c i d , produced, presumably v i a the protonated intermediate (113), a mixture of the y-lactone (114) and the 6-lactone (115). (112) (113) (115) To make t h i s approach s y n t h e t i c a l l y u s e f u l , the methyl group at C-4 had to be introduced (31) so that methyl migration would form the c i s -v i c i n a l methyl groups of the eremophilane skeleton. To t h i s end, hydroxy-a c i d (120) was select e d . Lithium aluminum hydride reduction of the unsaturated acid (112) - .23 -y i e l d e d the alcohol (116) which was converted by m-chloroperbenzoic a c i d i n t o a mixture of epoxy-alcohols (117) and (118) i n a r a t i o of 2:3 r e s p e c t i v e l y . Treatment of epoxy-alcohol (118) with methylmagnesium bromide, afforded the d i o l (119) which was oxidized to produce the desired hydroxy-acid (120). It was hoped that r e l i e f of 1,3-diaxial s t e r i c i n t e r a c t i o n between the methyl groups would e n e r g e t i c a l l y enhance the f e a s i b i l i t y of the desired rearrangement, but treatment of the hydroxy-acid (120) with anhydrous formic a c i d r e s u l t e d only i n dehydration, to produce the unsaturated a c i d (121). The analogous r e a c t i o n at r e f l u x , afforded a complex lactone mixture c o n s i s t i n g of at least seven components. Thus, the methyl-migration approach to the" synthesis of eremophilanes as reported by Heathcock was not f r u i t f u l . (121) (120) (119) DISCUSSION The object o f the Work presented i n t h i s t hesis was the development of a general synthetic entry into the eremophilane class of sesquiterpenes. The stereochemical problems to be resolved were the introduction of c i s -v i c i n a l methyl groups at C-4 and C-5 of r i n g A, and also the establishment of a A/B c i s - r i n g j u n c t i o n . Another problem was the st e r e o s e l e c t i v e i n t r o d u c t i o n o f a " f u n c t i o n a l i t y " at C-7 of r i n g B, so as to enable the subsequent ela b o r a t i o n of an isopropyl-type side chain. A compound that seemed i d e a l f o r t h i s purpose was decalone (122) which had previously been synthesized by Church, Ireland and Schridhar (32). The synthesis of t h i s compound would r e s o l v e the stereochemical problems, and the " f u n c t i o n a l i t y " at C-7 could be introducted by means of the carbonyl at C-8. H (122) - 25 -Ireland and coworkers (32) began t h e i r synthesis by hydrogenation of the r e a d i l y a v a i l a b l e octalone (123) (33) to the ci s - f u s e d decalone (124), followed by k e t a l i z a t i o n of the l a t t e r compound to a f f o r d k e t a l alcohol (125) . Oxidation of (125) with Jones' reagent produced the keta l decalone (126) which was treated with ethereal methyllithium to a f f o r d the c r y s t a l l i n e k e t a l a l c o h o l (127) . The alcohol (127) was r e a d i l y dehydrated to o l e f i n (128). Hydroboration of the l a t t e r , followed by Jones' oxidation of the r e s u l t i n g alcohol produced the k e t a l decalone (129). Wolff-Kishner reduction of the carbonyl of (129) afforded the keta l d e c a l i n (130), which upon a c i d i c h y d r o l y s i s , produced the desired decalone (122). (129) " (130) (122) - 26 -Of special interest was the failure by Ireland and coworkers (32) to obtain ketal decalone (129) from the attempted conjugate methylation of octalone (131). (131) (129) The reaction of a Grignard with an a,8-unsaturated ketone generally affords a mixture of compounds resulting from 1,2- and 1,4-addition of the Grignard reagent to the unsaturated carbonyl system. Kharash and Tawney (34) were the first to observe that in the presence of a small amount of a copper (I) salt, predominately 1,4-addition would occur. For example, Ireland and coworkers (32) found that cuprous bromide catalyzed 1,4-addition of methylmagnesium bromide to octalone (132) led exclusively to the cis-fused decalone (133). However when the vinyl methyl group was introduced as in octalone (131) they found that, using a variety of experimental procedures, conjugated addition of methylmagnesium bromide was not possible. (132) (133) House, Respess and Whitesides (18) have extensively investigated the r o l e of copper i n conjugate Grignard additions. In the course of t h e i r i n v e s t i g a t i o n s , two ether soluble methyl copper complexes were prepared which exhibited a remarkable s e l e c t i v i t y toward p r e f e r e n t i a l conjugate addition (as opposed to 1,2-addition) of the methyl group to a,g-unsaturated carbonyl systems. These.reagents were methyl copper-tri-n-butylphosphine (134) and l i t h i u m dimethylcuprate (135). MeCuP(n-Bu) 3 Me 2CuLi (134) (135) From experience gained previously i n our laboratory (35), i t was f e l t that the use o f these reagents would r e s u l t i n the successful conjugate methylation o f octalone (131). Therefore the f i r s t objective of the present work was the preparation of compound (131), and t h i s was c a r r i e d out e s s e n t i a l l y by the method of Lukes, Poos and Sarett (36). - The s t a r t i n g m a t e r i a l f o r t h i s synthesis was commercially a v a i l a b l e f u r y l a c r y l i c a c i d (136). A s o l u t i o n of t h i s compound i n methanol was treated with hydrogen c h l o r i d e (36), thus opening the furan r i n g to produce the d i a c i d (137) . The d i a c i d was not p u r i f i e d , but was d i r e c t l y e s t e r i f i e d to produce, i n 84% y i e l d , the keto d i e s t e r (138). A broad absorption i n the i n f r a r e d ( i . r . ) spectrum at 5.80 y was assigned to ketone and d i e s t e r carbonyl absorptions. The nuclear magnetic resonance (n.m.r.) spectrum exhibited a six-proton s i n g l e t at x 6.33 assigned to the methyl ester protons, and a m u l t i p l e t at x 7.29 which was a t t r i b u t e d to the methylene protons. - 28 -The next step, k e t a l i z a t i o n of the ketone i n compound (138), turned out to be more d i f f i c u l t than indi c a t e d i n the reference (36). The keto d i e s t e r (138) was ref l u x e d i n benzene with one equivalent of ethylene g l y c o l and a c a t a l y t i c amount of p_-toluenesulphonic a c i d . A f t e r the correct amount of water had been c o l l e c t e d v i a a Dean Stark water separator, the re a c t i o n was worked up. D i s t i l l a t i o n , followed by r e d i s t i l l a t i o n of enriched f r a c t i o n s , afforded the desired k e t a l d i e s t e r (139) i n only 23% y i e l d . The remaining d i s t i l l a t e was shown by g a s - l i q u i d chromatographic (g.l.c.) a n a l y s i s to be a mixture of ketone and ketal d i e s t e r , (138) and (139) r e s p e c t i v e l y , and the mixture could be r e k e t a l i z e d . The d i s t i l l a t i o n residue, which was s u b s t a n t i a l , exhibited a strong hydroxyl absorption at 2.9 u i n the i n f r a r e d . The residue was thought to contain the trans-e s t e r f i c a t i o n products of the ketone d i e s t e r (138) and the ketal d i e s t e r (139), since t r a n s - e s t e r i f i c a t i o n (involving ethylene g l y c o l ) could be a competing r e a c t i o n with k e t a l i z a t i o n . This was confirmed by d e l i b e r a t e l y t r a n s - e s t e r i f y i n g the d i s t i l l a t i o n residue i n methanol and 10% sulphuric a c i d . Under these conditions, the only product i s o l a t e d was the s t a r t i n g m a t e r i a l , ketone d i e s t e r (138). Repetition of t h i s cycle several times brought the o v e r a l l y i e l d of the desired k e t a l d i e s t e r (139) to 44%. The i . r . spectrum of t h i s material indicated an ester carbonyl absorption at 5.77 y, while the n.m.r. spectrum showed c l e a r l y the ketal protons at x 6.04 and the methyl ester protons at T 6.30. Dieckmann condensation of the k e t a l d i e s t e r (159) i n ether with sodium hydride as the base afforded the cyclohexanone d e r i v a t i v e (140a) i n 69% y i e l d . The i n f r a r e d spectrum of t h i s compound showed c l e a r l y that the molecule existed p r i m a r i l y i n the en o l i c form (140b). There were weak - 29 -i n f r a r e d absorptions at 5.75 y and 5.85 y due to the saturated ester carbonyl and the ketone carbonyl r e s p e c t i v e l y , but the spectrum was dominated by strong absorptions at 6.03 y and 6.20 y of the unsaturated ester and enoli c double bond r e s p e c t i v e l y . The n.m.r. spectrum exhibited a four-proton s i n g l e t at x 5.97 which was assigned to the ketal protons, while the methyl ester protons gave r i s e to a three-proton s i n g l e t at x 6.23. (136) RO_ C C0„H 2 (137) , R = H (138) , R = Me (140b) (140a) C02Me A s l i g h t m o d i f i c a t i o n of the procedure of Ireland and coworkers (32) was employed i n the synthesis of the octalone (131). Robinson annelation (37) of compound (140) with l-diethylamino-3-pentanone methiodide (62) i n methanolic sodium methoxide at room temperature f o r seventy-two hours afforded the diketone (141) , which was not p u r i f i e d . Treatment of the dione (141) with aqueous potassium hydroxide i n i t i a l l y produced the carbomethoxy b i c y c l i c ketone (142) which, under these r e a c t i o n conditions, - 30 -was decarbomethoxylated i n s i t u to give the c r y s t a l l i n e k e t a l octalone (131) i n 59% y i e l d . The u l t r a v i o l e t (u.v.) spectrum exhibited an absorption maximum at 245 my (c = 14,400). The expected unsaturated carbonyl and o l e f i n i c i n f r a r e d absorptions appeared 6.03 and 6.24 y r e s p e c t i v e l y . The n.m.r. spectrum exhibited a four-proton s i n g l e t at T 6.02"which was at t r i b u t e d to the ethylene k e t a l protons, and also a three-proton m u l t i p l e t (width at half-height = 4 Hz) at T 8.21. This was assigned to the v i n y l methyl group which presumably, was h o m o a l l y l i c a l l y coupled (38) to the 2 a x i a l protons at C-6 and C-10. NEt 2MeI (129) . (131) Methylation of the ketal octalone (131) was accomplished by using the li t h i u m dimethylcuprate reagent (18). The preparation of t h i s reagent was effected by the ad d i t i o n of two equivalents of ethereal methyllithium to a 2 Unless otherwise noted, eremophilane numbering w i l l be henceforth employed. - 31 -s t i r r i n g ethereal s l u r r y of copper(I) iodide at 0°. An ethereal s o l u t i o n of the octalone was added slowly to the methylating reagent and the r e s u l t i n g r e a c t i o n mixture was s t i r r e d at 0° f o r one hour. The r e a c t i o n was quenched by adding the r e a c t i o n mixture to a s o l u t i o n of dry hydrogen c h l o r i d e d i s s o l v e d i n ethylene g l y c o l . Column chromatography of the crude product afforded the c r y s t a l l i n e decalone (129) i n 77% y i e l d . The product thus obtained exhibited the appropriate spectroscopic properties. The i . r . spectrum exhibited a strong saturated carbonyl absorption at 5.84 y. The n.m.r. spectrum (Figure 3) gave a four-proton s i n g l e t at T 6.03 due to the e t h y l e n e k e t a l protons, a quartet at T 7.20 (J = 6.5 Hz) assigned to the proton a to the carbonyl and secondary methyl group, a doublet ( J = 6.5 Hz) at T 9.08 designated as the secondary methyl group, and f i n a l l y a s i n g l e t at T 9.18 which was a t t r i b u t e d to the t e r t i a r y methyl group. There are three features of t h i s r e a c t i o n that require further comment: 1, the stereochemistry of the a l k y l a t i o n , 2, a proposed mechanism, and 3, the method of quenching the re a c t i o n . Dealing f i r s t with the stereochemistry involved, attack of the a l k y l a t -ing agent 1,4- to the unsaturated carbonyl must occur perpendicular to the IT e l e c t r o n system (39), as represented i n (131a). Attack at the 3-position a - 33 -may occur from the a- or B-side of the molecule. a-Attack would not be favoured due to the s i g n i f i c a n t s t e r i c i n t e r a c t i o n s of the a l k y l a t i n g reagent with the a x i a l C - l , C-7 and C-9 hydrogens. B-Approach on the other hand would be s i g n i f i c a n t l y less hindered. That the conjugate ad d i t i o n of lithium dimethylcuprate to octalones of the type (131) proceeds to give the corresponding c i s - f u s e d decalone system has c l e a r l i t e r a t u r e precedent (35). House.(18) postulated that the addition of lithium dimethylcuprate (135) to an a,B-unsaturated ketone proceeds v i a a one-electron t r a n s f e r mechanism. E i t h e r a p a r t i a l or complete electron tr a n s f e r from the copper (I) atom of complex (135) to the a,B-unsaturated carbonyl system of (131a) would lead to the formation of e i t h e r a charge-transfer complex or the ion-r a d i c a l (143). Subsequent t r a n s f e r of a methyl r a d i c a l from the transient dimethyl copper (II) species (144) to the B-position of the i o n - r a d i c a l (143), or the collapse of the charge t r a n s f e r complex would y i e l d the a l k y l a t e d enolate (145) and methyl copper (146). The gauche i n t e r a c t i o n between the incoming methyl group and the bridgehead hydrogen at C-10 would be a l l e v i a t e d as the system approached a t r a n s i t i o n state geometry as i n (145), i n which the t e r t i a r y methyl group i n e q u a t o r i a l l y oriented with respect to r i n g B. Protohation of the enolate (145) during workup would produce the f i n a l product, decalone (129). - 34 -(129) g 0 L l (145) (146) It was obvious from previous work c a r r i e d out i n our laboratory (35) that the quenching procedure used to terminate the above a l k y l a t i o n was c r i t i c a l . The quenching procedure c i t e d by House e t . a l . (18) required pouring the r e a c t i o n mixture into well s t i r r e d aqueous ammonium ch l o r i d e . They found that the reverse of t h i s procedure, a d d i t i o n of ammonium ch l o r i d e s o l u t i o n to the r e a c t i o n mixture led to a complex mixture contain-ing both mono- and d i a l k y l a t i o n products. It seemed reasonable to assume that protonation o f the enolate derived from 1,4-addition was competitive with the a c i d d e s t r u c t i o n of the organo-copper species. Hence the saturated ketone thus farmed rapidly underwent further alkylation by 1,2-addition of the residual methyl copper species to the carbonyl group. Piers and Keziere (24) overcame this problem by quenching a similar reaction with 10% aqueous hydrochloric acid. However, strong aqueous acids could not be used in our case because ketal hydrolysis would occur. " Quenching the reaction mixture with a weak acid such as acetic acid, which would not. hydrolyze the ketal resulted in a complex mixture of products. However, quenching the reaction mixture with a strong acid under anhydrous conditions proved successful. As noted previously, hydrogen chloride dissolved in dry ethylene glycol made up the quenching solution. Huang-Minion (40) modified Wolff-Kishner reduction was accomplished by reacting decalone (129) with excess hydrazine hydrate and potassium hydroxide in ethylene glycol. The infrared spectrum of the product thus obtained did not show an absorption due to a carbonyl group. G.l.c. analysis of the product showed two components, in a ratio of 5:1. The major component was collected by preparative g.l.c. and its n.m.r. spectrum was in accord with the assigned structure of the ketal decalin (130). The ketal protons gave a signal at x 6.09, a three-proton singlet at x 9.13 was assigned to the tertiary methyl group, while a three-proton doublet (J = 6.5 Hz) at x 9.13 accounted for the secondary methyl group. The only noticeable difference between the n.m.r. spectrum of the pure g.l.c. collected ketal decalin (130), and that of the crude reaction product was an "'extra" peak in the latter, at x 8.96. This "extra" signal was regarded as due to the tertiary methyl group of the trans-vicinal dimethyl decalin (147). From the n.m.r. spectrum, the ratio of (130) to - 36 -(147) also appeared to be approximately 5:1, r e s p e c t i v e l y . The secondary (130) (147) methyl group n.m.r. si g n a l of the minor isomer was*not observed as i t was buried i n the si g n a l s from the major isomer, or po s s i b l y had the same •chemical s h i f t and coupling constant as the secondary methyl group of the major isomer. Hydrolysis of the mixture of ketal decalins (130) and (147) with 10% hydrochloric a c i d afforded a mixture of decalones (122) and (148) . G.l.c. analysis of t h i s product again showed two components present, i n a r a t i o of 5:1. An a n a l y t i c a l sample of the major component, again obtained by preparative g . l . c , exhibited spectroscopic data i n f u l l accord with that of the assigned structure (122). The i . r . spectrum exhibited a strong saturated carbonyl absorption at 5.83 y. In the n.m.r. spectrum (Figure 4_), a s i n g l e t at T 9.04 accounted f o r the t e r t i a r y methyl group, while a doublet (J = 6.5 Hz) at T 9.13 was assigned to the secondary methyl group. The n.m.r.spectrum of the epimeric mixture (122) and (148) again exhibited an "extra" peak at x 8.75. This signal was assigned to the t e r t i a r y methyl of the decalone (148). Figure 4_. Nuclear Magnetic Resonance Spectrum of Decalone ( 1 2 2 ) . - 38 -H H (122) (148) The disadvantages of the above synthesis of decalone (122) were obvious. The o v e r a l l y i e l d of the r e a c t i o n sequence was low, and the desired product, decalone (122), was contaminated with i t s epimer, decalone (148). Moreover, the only separation technique that appeared to be app l i c a b l e was preparative g . l . c , as demonstrated by the i s o l a t i o n of an a n a l y t i c a l sample of decalone (122). However, t h i s technique proved impractical at t h i s j unction i n the synthesis, as the y i e l d of decalone (122) a f t e r p u r i f i c a t i o n was only 30-35%. In view of the above s i t u a t i o n , other methods were explored i n connection with the synthesis of decalone (122). Condensation of 2,3-dimethylcyclohexanone (67) with methyl v i n y l ketone (68) i n the presence of sodium methoxide led to the formation of an epimeric mixture of octalones (69) i n a r a t i o of 3:2, as had been previously reported by Ourisson and h i s colleagues (26) i n the synthesis of (±)-aristolone. It was hoped that the epimers could be separated and subsequent hydrogenation of the c i s - v i c i n a l dimethyl octalone (69a) would produce the desired decalone (122). - 39 -0 \ - 0 J7 (67) C6S) (69a) z (69b) (122) However, t h i s approach was abandoned f o r two reasons. F i r s t l y , the y i e l d o f the actalomes (69) from the above condensation was only 15%, and secondly, the aettalones, i n a r a t i o of 3:2 were very d i f f i c u l t to separate by e i t h e r spinning band column d i s t i l l a t i o n or g a s - l i q u i d chromato-graphy. C l e a r l y , the above synthetic approaches to the a l l - c i s decalone (122) were u n s a t i s f a c t o r y due to the apparently unavoidable presence of s i g n i f i c a n t amounts ©f the corresponding t r a n s - v i c i n a l methyl group isomer, decalone (148}- Apart from the two methods mentioned previously, another method o f s y n t h e s i z i n g decalone (122) could be based upon a d i r e c t - 40 -a l k y l a t i o n of a 2,3-dimethylcyclohexanone d e r i v a t i v e . As noted i n the Introduction, P i e r s and coworkers (27) i n t h e i r synthesis of (±)-aristolone, a l k y l a t e d 6-n-butylthiomethylene-2,3-dimethylcyclohexanone (77) with methailyl c h l o r i d e (78). The a l k y l a t i o n was reasonably s t e r e o s e l e c t i v e , since the major product (80%) contained c i s - v i c i n a l methyi groups. A l k y l a -t i o n of compound (77) with ethyl 3-bromopropionate would, by analogy, probably a f f o r d a compound with c i s - v i c i n a l methyl groups. Further elaboration of t h i s molecule would produce the desired decalone (122). This sequence i s examined i n the following pages. The 2,3-dimethylcyclohexanone (151) (41) was prepared by Paar hydrogena-t i o n of commerically a v a i l a b l e 2,3-dimethylphenol (149), followed by chromic a c i d o x i d a t i o n of the r e s u l t i n g alcohol (150). The 2,3-dimethylcyclohexanone (151) was treated with ethyl formate and sodium methoxide i n dry benzene, and a f t e r appropriate workup, yielded the hydroxymethylene d e r i v a t i v e (152). Reaction of the l a t t e r with n-butyl mercaptan i n benzene i n the presence of c a t a l y t i c amount of p_-toluene-sulphonic a c i d , i n a f l a s k equipped with a Dean Stark water separator (42), afforded 6-n-butylthiomethylene-2,3-dimethylcyclohexanone (153). A l k y l a t i o n o f (153) with ethyl 3-bromopropionate (154) i n t-butyl a l c o h o l , i n the presence o f potassium t_-butoxide, gave i n 86% y i e l d , an epimeric mixture of the a l k y l a t e d n-butylthiomethylene d e r i v a t i v e (155). The u l t r a v i o l e t spectrum with an absorption at 311 my (e = 14,900), was i n good agreement with the u l t r a v i o l e t spectra of s i m i l a r n-butylthiomethylene compounds (27). Furthermore, the i . r . spectrum, with absorptions at 5.79, 6.03 and 6.52 y, was also consistent with structure (155). - 41 -(155) (152), R = CHOH (153), R = CHS(CH 2) 3CH 3 Treatment of (155) with aqueous potassium hydroxide i n diethylene 1 g l y c o l removed the n-butylthiomethylene blocking group (42) and also hydrolyzed the ethyl ester to a f f o r d a mixture of the keto acids (156) i n 90% y i e l d . The i . r . spectrum was c h a r a c t e r i s t i c of a carboxylic a c i d , with a broad absorption from 2.7-4.2 y. The acid and ketone carbonyl absorptions were observed at 5.78 and 5.85 y r e s p e c t i v e l y . The keto acids (156) were refluxed i n a c e t i c anhydride containing sodium acetate, to produce a mixture of the corresponding enol lactones, i n 85% y i e l d . The n.m.r. and g . l . c . analysis of t h i s m a t e r i a l , suggested that i t contained a mixture of epimeric compounds (157) and (158) i n a r a t i o of approximately 9:1 r e s p e c t i v e l y . R e c r y s t a l l i z a t i o n from n-hexane - 42 -produced pure enol lactone (157). The i . r . spectrum of the major isomer (157) exhibited a carbonyl absorption at 5.72 y and a double bond absorption at 5.98 y. A one-proton t r i p l e t (J = 4.0 Hz) at T 4.72 i n the n.m.r. spectrum was assigned to the v i n y l proton, while a s i n g l e t at T 8.97 accounted f o r the t e r t i a r y methyl group and a.doublet (J = 6.5 Hz) at x 9.04 was assigned to the secondary methyl group. A pure sample of the minor isomer, enol lactone (158) was obtained from the mother liq u o r s of the above r e c r y s t a l l i z a t i o n by means of preparative g . l . c . The strongest absorptions i n the i . r . spectrum were i d e n t i c a l with those of the major isomer (157), although the f i n g e r p r i n t regions were quite d i f f e r e n t . The n.m.r. spectrum exhibited a t r i p l e t (J = 4.0 Hz) at T 4.68. The secondary methyl group of the minor isomer (158) exhibited exactly the same chemical s h i f t and coupling constant as the secondary methyl group of the major isomer. However, the t e r t i a r y methyl group gave r i s e to a s i n g l e t at T 8.79, some 18 Hz to lower f i e l d as compared with the corresponding signal of the major product (157). (155) (156) (157) (158) A number of methods were attempted f o r the conversion of the c r y s t a l -l i n e enol lactone (157) into the octalone (69a). A new procedure in v o l v i n g the r e a c t i o n of phosphoranes and phosphonate anions with enol - 43 -lactones (43) to prepare c y c l i c a,B-unsaturated ketones was employed, with (only marginal success. Although annelation by r e a c t i o n of the enol lactone ' W i t h methylmagnesium bromide (44,45), followed by a l d o l c y c l i z a t i o n of the r e s u l t i n g dione was su c c e s s f u l , the method f i n a l l y adopted by v i r t u e of its better yield was a mod i f i c a t i o n of t h i s procedure in v o l v i n g the use of ^methyllithium. To a s o l u t i o n of the enol lactone (157) i n ether, which was cooled to -25° by means of an external carbon t e t r a c h l o r i d e - d r y i c e slush bath, was added an ethereal s o l u t i o n of methyllithium, and the re a c t i o n was .'Stirred at -25° f o r two hours. The re a c t i o n was quenched with d i l u t e ihydrochloric acid to a f f o r d diketone (158) which was not p u r i f i e d . The crude diketone (158) was refluxed with potassium hydroxide i n aqueous methanol f o r two hours, and the octalone (69a) was i s o l a t e d from the •neutral layer in 70% y i e l d . Both the u l t r a v i o l e t and i n f r a r e d spectra of the product were c h a r a c t e r i s t i c of an a,B-unsaturated carbonyl system. "The u.v. spectrum showed an absorption maximum at 240 my (e = 12,100), while the i . r . spectrum exhibited an unsaturated carbonyl absorption at !5.98 y and an o l e f i n i c absorption at 6.19 y. In the n.m.r. spectrum, a broad s i n g l e t atT4.33 was designated as the v i n y l proton, a s i n g l e t at T 8.90 was a t t r i b u t e d to the t e r t i a r y methyl group while a doublet ( J = 6.5 Hz) at x 9.09 was assigned to the secondary methyl group. The b a s i c l a y e r from the above re a c t i o n was a c i d i f i e d and a keto acid was i s o l a t e d i n 10% y i e l d . Treatment of t h i s acid with sodium acetate in r e f l u x i n g a c e t i c anhydride gave the enol lactone (157). Thus, the enol lactone that had not reacted with methyllithium was hydrolyzed i n the subsequent step and the s t a r t i n g material was i s o l a t e d i n the form of the fceto a c i d (156), (cis-epimer). This was quite desirable as i t allowed a - 44 -f a c i l e separation of the octalone (69a) from the hydrolyzed s t a r t i n g m a t e r i a l . It should be noted that the success of the r e a c t i o n of the enol lactone (157) with methyllithium depended, to a large extent, upon a ju d i c i o u s choice of the r e a c t i o n temperature and r e a c t i o n time. That i s , use of. r e a c t i o n temperatures greater than -25°, or use of•longer r e a c t i o n times, r e s u l t e d i n the formation of a considerable amount of a l c o h o l -containing product, presumably due to " d i - a d d i t i o n " of methyllithium to the enol lactone. On the other hand, milder r e a c t i o n conditions (lower temperatures, shorter r e a c t i o n times) r e s u l t e d i n the recovery of s i g n i f i -cant amounts of s t a r t i n g m a t e r i a l , again i n the form of the corresponding keto a c i d (156), (cis-epimer). . . . . Conditions f o r the hydrogenation of the octalone (69a) were chosen to maximize the formation of the desired decalone (122). It was f e l t that the hydrogenation would occur from the less hindered side aff o r d i n g the desired c i s - r i n g j u n c t i o n . Palladium on charcoal has been shown (46) to be one of the b e t t e r c a t a l y s t s f o r t h i s purpose. The presence of acids and bases i n the r e a c t i o n mixtures employed f o r c a t a l y t i c hydrogenation i s known to a l t e r the s t e r i c course of many reductions. For example, i n the case of hydrogenation of octalones of the type (69a), there are reports i n the l i t e r a t u r e (46) which i n d i c a t e that the presence of base a s s i s t s the formation of a cis_-fused r i n g junction. The hydrogenation of octalone (69a) was c a r r i e d out i n ethanol under neutral conditions using 10% palladium on charcoal, and under basic conditions with the same c a t a l y s t . G a s - l i q u i d chromatographic analysis of the hydrogenation products indicated that the purest product was obtained - 45 -from the r e a c t i o n c a r r i e d out under basic conditions. This product was shown to be i d e n t i c a l ( i n f r a r e d spectra, g . l . c . r e t e n t i o n time) with the decalone (122) which had been previously prepared. Furthermore, the 2,4-dinitrophenylhydrazone d e r i v a t i v e s of these decalones were also shown to be i d e n t i c a l (melting point, mixed melting point, i n f r a r e d spectra). Thus, i t was c l e a r that the above r e a c t i o n sequence e f f i c i e n t l y .led to the r e a l i z a t i o n of a stereochemically homogeneous product contain-ing s o l e l y the desired a l l - c i s decalone (122). (122) Attempts to introduce a " f u n c t i o n a l " group at C-7 of the decalone (122) proved to be extremely d i f f i c u l t . Various a l k y l a t i o n procedures were employed, but to no a v a i l . A number of these methods that were t r i e d are o u t l i n e d b r i e f l y i n the following paragraphs. Direct a l k y l a t i o n of the decalone (122) i n t-butanol and potassium t_-butoxide with e i t h e r methyl bromoacetate or ethyl 2-bromopropionate as - 46 -the a l k y l a t i n g agent, produced i n each case a complex mixture of products, as shown by g . l . c . a n a l y s i s . The c h i e f disadvantage with t h i s type of a l k y l a t i o n i s that at equilibrium; most ketones are only p a r t i a l l y converted to t h e i r enolate anions, and a l d o l condensation may occur between the free ketone and i t s enolate anion (47). P o l y a l k y l a t i o n was another problem inherent with systems of t h i s type. In order to eliminate the f i r s t problem mentioned above, a stronger base was used, s p e c i f i c a l l y triphenylmethylsodium (48). The-addition of an enolizable ketone to a 1,2-dimethoxyethane s o l u t i o n containing the triphenylmethide anion r e s u l t s i n immediate formation of the corresponding enolate anion. Thus a 1,2-dimethoxyethane s o l u t i o n of decalone (122) was added dropwise to the basic s o l u t i o n u n t i l the intense red colour of the triphenylmethide anion had j u s t disappeared, i n d i c a t i n g that excess base and ketone were not present. However, a l k y l a t i o n of the enolate thus obtained with e i t h e r methyl bromoacetate or ethyl 2-bromopropionate yi e l d e d products whose spectra were not i n agreement with the expected s p e c t r a l data of the desired a l k y l a t i o n product. Another a l k y l a t i o n procedure that was attempted involved the enamine a l k y l a t i o n method (49). The enamine of the decalone was r e a d i l y prepared by re a c t i n g decalone (122) with p y r r o l i d i n e i n r e f l u x i n g benzene, and separating the water formed v i a a Dean Stark water separator. The n.m.r. spectrum of the enamine d e r i v a t i v e exhibited two d i f f e r e n t o l e f i n i c proton s i g n a l s , i n d i c a t i n g the formation of the two double bond isomers (159) and (160). - 47 -H O H 9 N (159) (160) A broad adsorption at x 5.S8 (width at half-height = 10 Hz) was assigned to the C-7 v i n y l proton of enamine (159), since t h i s proton would be coupled p r i n c i p a l l y with the two C-6 protons. The broad " s i n g l e t " at x 6.12 (width at half-height = 3 Hz) was a t t r i b u t e d to the v i n y l proton of enamine (160). The C-9 v i n y l proton of (160) would be coupled with the bridgehead hydrogen, but i t was apparent that the dlhedreal angle between these two protons was such that the coupling was very small.' The r a t i o of enamines (159) and (160) as determined by n.m.r. was 2:3 r e s p e c t i v e l y . The enamines proved very unstable and required cold storage under an atmosphere of dry nitrogen u n t i l use. Attempted a l k y l a t i o n of the mixture of enamines with ethyl 2-bromopropionate was unsuccessful. A l k y l a t i o n with methyl bromoacetate produced some of the desired product, but not enough to make t h i s a l k y l a -t i o n s y n t h e t i c a l l y u s e f u l . A v a r i a t i o n of the a l k y l a t i o n of an enolate i n the absence of excess ketone and base was examined. It i s known that the re a c t i o n of an enol acetate with methyllithium produces an enolate anion which can be alk y l a t e d (50). Hence, r e a c t i o n of decalone (122) with r e f l u x i n g isopropenyl acetate - 48 -and a c a t a l y t i c amount of p_-toluenesulphonic acid afforded a mixture of enol acetates (161) and (162). (161) (162) The broad s i g n a l at T 4.83 (width at half-height = 11 Hz) i n the n.m.r. spectrum was a t t r i b u t e d to the v i n y l proton at C-7 i n enol acetate (161), which was s p l i t p r i m a r i l y by protons at C-6. The broad s i n g l e t at T 4.98 (width at half-height = 3.5 Hz) was assigned to the v i n y l proton at C-9 of compound (162). The r a t i o of enol acetates (161) and (162) was 3:2 r e s p e c t i v e l y , as determined by n.m.r. and g . l . c . a n a l y s i s . A s o l u t i o n of methyllithium i n 1,2-dimethoxyethane, which also contained a c a t a l y t i c amount of triphenylmethane, was prepared. The s o l u t i o n possessed a red colour due to the presence of the triphenylmethide anion. The mixture of enol acetates was added to the above s o l u t i o n u n t i l the red colour had j u s t disappeared, i n d i c a t i n g that the corresponding enolates had been formed, i n absence o f excess ketone or base. Ethyl 2-bromopropionate was then added to the enolate mixture. However,.after appropriate workup, the spectra of the products obtained were not i n agreement with the predicted spectra of the desired product. It was evident from the above attempts that, although further experimentation might enable the desired a l k y l a t i o n of decalone (122), - 49 -regie-selective a l k y l a t i o n at the C-7 p o s i t i o n was extremely d i f f i c u l t because of the d i f f i c u l t y i n obtaining a pure enolate. .It was i n t e r e s t i n g to note that reactions of b i c y c l i c systems with t r a n s - r i n g junctions (51), or with unsaturation at the bridgehead (52) have been shown to a l k y l a t e only at the C-7 p o s i t i o n , as i l l u s t r a t e d i n Figure 5_. Figure 5_ Since a decalone with a trans-fused r i n g j unction would not be of use s y n t h e t i c a l l y , our a t t e n t i o n was focused on the u t i l i z a t i o n of octalone (69a). (69a) Reaction o f octalone (69a) with ethyl formate and sodium methoxide i n dry benzene gave, a f t e r s u i t a b l e workup, the desired c r y s t a l l i n e hydroxy-methylene d e r i v a t i v e (163) i n 89% y i e l d , based on unrecovered s t a r t i n g m a t e r i a l . An a n a l y t i c a l sample of the product (163) was obtained by vacuum sublimation, and the s p e c t r a l data obtained was i n f u l l accord with the assigned st r u c t u r e . The u l t r a v i o l e t spectrum showed absorption maxima at 248 my (e"= 9,280) and 311 my (e = 3,860). Upon addi t i o n of base the absorption maxima s h i f t e d to 242 my (e = 13,000) and 355 my (e = 9,620). The i . r . spectrum exhibited broad unsaturated carbonyl absorptions at 6.08 and 6.41 y i n d i c a t i n g the expected predominance of the keto enol (163b) and formyl-enol (163c) tautomeric forms. The n.m.r:. spectrum exhibited a one-proton s i n g l e t at x 4.23 corresponding to the v i n y l proton, a s i n g l e t at x 9.06, which was assigned to the t e r t i a r y methyl group and a doublet (J = 6.5 Hz) at x 9.08 which was a t t r i b u t e d to the secondary methyl group. A sharp one-proton s i n g l e t at x 2.62 and a very broad'one-proton m u l t i p l e t at x 0.0 were also evident. Enolic tautomers, e.g. (163b) and (163c), of (163a) (163b) (163c) hydroxymethylene d e r i v a t i v e s of ketones are normally predominant to the extent of approximately 99% (38). The equilibrium between the two possible e n o l i c forms i s f a s t , r e l a t i v e to n.m.r. spectra averaging (38). Accordingly, - 51 -the s i g n a l at T 2.62 was designated as the signal average of protons H & and of the enols (163b) and (163c). The broad x 0.0 signal was a t t r i b u t e d to the hydrogen-bonded hydroxyl hydrogens H £ and of (165b) and (163c) . Unfortunately, attempts to a l k y l a t e the hydroxymethylene d e r i v a t i v e (163) with e i t h e r methyl bromoacetate or ethyl 2-bromopropionate, using sodium hydride i n r e f l u x i n g benzene resu l t e d i n almost exclusive formation o f the O-alkylated products (164) or (165). (163) (164), R = CH2C02Me (165) , R = CH C'H-C02Et Since t h i s a l k y l a t i o n did not seem f r u i t f u l i t was decided to attempt the elaboration of the formyl group of compound (163). The f i r s t step was the hydrogenation of the hydroxymethylene d e r i v a t i v e (163). This was ca r r i e d out i n ethanolic sodium hydroxide over 10% palladium on charcoal af f o r d i n g hydroxymethylene d e r i v a t i v e (166). The i . r . spectrum was c h a r a c t e r i s t i c of t h i s type of compound with unsaturated carbonyl absorptions at 6.07 and 6.30 y. Of p a r t i c u l a r i n t e r e s t i n the n.m.r. spectrum was the absence of an a- v i n y l proton. The crude hydroxymethylene (166) was reacted with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) i n dioxane (53) for two hours. Chromatography and reduced pressure d i s t i l l a t i o n of the crude oxidation product afforded the c r y s t a l l i n e keto aldehyde (167) i n 60% y i e l d . The spe c t r a l data was i n 52 -H H (163) (166) (167) good accord with the proposed structure (167). The u l t r a v i o l e t spectrum showed an absorption maximum at 238 my (e= 7,740). The compound exhibited the expected-broad unsaturated carbonyl peak, centred at 5.95 y, and the double bond absorption at 6.23 y i n the i n f r a r e d spectrum. A one-proton si g n a l i n the n.m.r. spectrum (Figure 6) at T-0.32 was due to the aldehydic proton, while a one-proton s i n g l e t at t 2.20 was assigned to the g-vinyl proton. A s i n g l e t at T 8.74 was designated as due to the t e r t i a r y methyl group, while a doublet ( J = 6.5 Hz) at T 9.00 was a t t r i b u t e d to the secondary methyl group. The c r i t i c a l step i n the preparation of the keto aldehyde (167) was obviously the stereochemistry of hydrogenation. By analogy with the preparation of the decalone (122) from the octalone (69a) we were quite confident that the r i n g junction of the keto aldehyde (167) was indeed c i s . However, the p o s s i b i l i t y s t i l l existed that the presence of the hydroxymethylene moiety i n (163) had a l t e r e d the stereochemistry of hydrogenation and that, therefore, compound (167) contained a tr a n s - r i n g fusion. In order to unambiguously prove that the r i n g junction of keto aldehyde (167) was c i s , i t was decided to make the hydroxymethylene d e r i v a t i v e of decalone (122), >-H» j • Hi i - 54 -then oxidize the l a t t e r with DDQ and compare the r e s u l t i n g keto aldehyde with compound (167). Treatment of decalone (122) with ethyl formate and sodium methoxide i n dry benzene gave, a f t e r s u i t a b l e workup, the corresponding hydroxy-methylene d e r i v a t i v e i n 76% y i e l d . The i . r . spectrum exhibited a t y p i c a l d,3-unsaturated carbonyl system with absorptions at 6.07 y and 6.30 y. This material as in d i c a t e d by i t s n.m.r. spectrum, consisted of an isomeric mixture of hydroxymethylene d e r i v a t i v e s (166) and (168), i n a r a t i o of (166) approximately 3:2. This isomeric mixture was to be expected, as i t had been c l e a r l y demonstrated that upon treatment with base, the decalone (122) formed two d i f f e r e n t enolates v i a proton removal from the C-7 and C-9 p o s i t i o n s . The hydrogen-bonded hydroxy! protons of t h i s mixture were found at T -4.83 and -4.21 and were very broad. The absorptions of the enoli c protons of hydroxymethylene d e r i v a t i v e s (166) and (168) were observed as s i n g l e t s at x 1.42 and 1.52. The isomeric mixture of (166) and (168) was oxidized with DDQ i n dioxane f o r two hours, and the r e a c t i o n product was chromatographed on neutral alumina a f f o r d i n g a keto aldehyde i n approximately 15% y i e l d . This compound was found to be i d e n t i c a l with the previously prepared keto - 55 -aldehyde (167), (m.p., mixed m.p., i . r . and n.m.r. spectra). The reason that the mixture of hydroxymethylene d e r i v a t i v e s (166) and (168) produced only keto aldehyde (167) was presumably due to the f a c t that oxidation of (168) would not stop at the i n i t i a l keto aldehyde (169a) stage. That i s , oxidation of (168) would i n i t i a l l y give the keto aldehyde (169a) which could then tautomerize to the hydroxymethylene d e r i v a t i v e (169b). The l a t t e r would not be recovered from the column chromatography on alumina. (168) (169a) (169b) Once the f u n c t i o n a l i t y had been established at the C-7 p o s i t i o n of keto aldehyde (167) (a molecule that possessed the desired c i s - v i c i n a l methyl groups at C-4 and C-5, and A/B c i s - r i n g j u n c t i o n ) , the stereochemical problems of t h i s synthetic entry into the eremophilane cl a s s of sesquiter-penes seemed to be resolved. A measure of the u t i l i t y of t h i s compound would be i t s conversion to a known eremophilane sesquiterpene. This goal has been, r e a l i z e d i n the elaboration of the keto aldehyde (167) into racemic fukinone (16), and t h i s synthetic sequence i s presented i n the following pages. There are many methods a v a i l a b l e f o r mild oxidations of aldehydes to - 56 -carboxylic acids. One of the most e f f i c i e n t ways involves s i l v e r oxide oxidation (54) and t h i s method was adopted i n the present work. The keto aldehyde (167) and s i l v e r n i t r a t e were dissol v e d i n a s o l u t i o n of ethanol and water. When a sodium hydroxide s o l u t i o n was added to the above s o l u t i o n , oxidation of the aldehyde occurred a f f o r d i n g , a f t e r appropriate workup, the c r y s t a l l i n e keto acid (170), i n 92% y i e l d . The u.v. spectrum o f keto a c i d (170) was s i m i l a r to that of the keto aldehyde (167), e x h i b i t i n g a peak at 245 my (e = 6,780). A broad absorption at 5.75 y i n the i . r . was a t t r i b u t e d to the unsaturated acid carbonyl, while the unsaturated ketone carbonyl absorbed at 6.08 y. Also present was the o l e f i n i c double bond absorption at 6.26 y. The n.m.r. spectrum was i n good accord with the assigned structure (167). A one-proton s i n g l e t at T 2.55 was designated as the v i n y l proton, while a s i n g l e t at x 8.77 was assigned to the t e r t i a r y methyl group, and a doublet (J = 6.5 Hz) at x 9.02 was a t t r i b u t e d to the secondary methyl group. Reaction of the keto a c i d (170) with diazomethane (55) produced a complex mixture of products, as shown by g . l . c . a n a l y s i s . Therefore, another e s t e r i f i c a t i o n procedure was employed. The keto acid (170) was dissolved i n methyl iodide, and s i l v e r oxide powder was added to the s o l u t i o n (56). The r e a c t i o n mixture was f i l t e r e d , and the r e s u l t i n g s o l u t i o n was d i s t i l l e d under reduced pressure to a f f o r d the keto ester (171) i n 92% y i e l d . The u.v. spectrum of t h i s compound was s i m i l a r to that of the keto aldehyde (167) and keto acid (170), with an absorption maximum at 236 my (e = 7,740). The i . r . spectrum exhibited both unsaturated carbonyl absorp-t i o n s , the ester peak at 5.78 y and the ketone absorption at 5.96 y. The . o l e f i n i c absorption was observed at 6.20 y. The one-proton s i n g l e t atx 2.55 - 57 -i n the n.m.r. spectrum was assigned to the v i n y l proton, while the s i n g l e t at T 6.23 was a t t r i b u t e d to the methyl ester protons. The t e r t i a r y and secondary methyl groups afforded a s i n g l e t at T 8.82 and a doublet' (J = "6.5 Hz) at x 9.04 r e s p e c t i v e l y . Hydrogenation of the unsaturated keto ester (171) i n ethanol over Adam's c a t a l y s t r e s u l t e d i n the formation of the carbomethoxy decalone (172) i n 97% y i e l d . As noted before with carbomethoxy ketone (140) , compounds of t h i s type resid e mainly i n the enolic form. Accordingly, t h i s H H H (167) (170), R = H (172) (171) , R = Me compound showed a maximum at 257 my (e = 7,410) i n the u.v. spectrum. When base was added a bathochromic s h i f t to 285 my (e = 13,800) was observed. The i . r . spectrum exhibited weak saturated ester and ketone carbonyl absorptions at 5.78 y and 5.85 y r e s p e c t i v e l y , a strong unsaturated carbonyl absorption at 6.02 y and the o l e f i n i c double bond absorption at 6.17 y. The n.m.r. spectrum of compound (172) was p a r t i c u l a r l y informative. It was apparent that the enolic proton of (172) was hydrogen-bonded to the ester carbonyl group, r e s u l t i n g i n the observed broad x -2.11 s i g n a l . The appropriate methyl ester s i n g l e t appeared at x 6.28. In t e r e s t i n g l y the s i n g l e t due to the t e r t i a r y methyl group, and the doublet (J = 6.5 Hz) of the secondary methyl group, both appeared at x 9.12. - 58 -The carbomethoxy decalone (172) i s p o t e n t i a l l y a very useful compound in.that the carbomethoxy group s e l e c t i v e l y activates the C-7 carbon atom, and r e g i o s e l e c t i v e a l k y l a t i o n at t h i s p o s i t i o n might be p o s s i b l e . These p o s s i b i l i t i e s are c u r r e n t l y being explored. For the present synthesis however, the carbomethoxy f u n c t i o n a l i t y of compound (172) was u t i l i z e d i n a d i f f e r e n t manner. The carbomethoxy ketone (172) was reacted with methyllithium i n a procedure s i m i l a r to that used by Coates and Shaw (22) i n t h e i r synthesis of (±)-aristolene. However, several modifications were introduced. Even though compound (172) existed predominately i n the enolic form, i t was. considered that the tautomerically r e l a t e d keto ester form would be present to some extent. In the presence of methyllithium an undesired a d d i t i o n to the ketone carbonyl might occur competitively with a d d i t i o n to the ester carbonyl. To avoid t h i s , one equivalent of sodium hydride was added to an ethereal s o l u t i o n of compound (172), thus forming the sodium enolate s a l t (175) i n s o l u t i o n . To t h i s s o l u t i o n was then added an excess of an ethereal methyllithium s o l u t i o n . A f t e r a two hour r e f l u x period, the excess methyllithium and the enolate were quenched with water, to a f f o r d a f t e r s u i t a b l e workup, keto alcohol (174). The i . r . spectrum exhibited an absorption at 2.90 y which was due to the hydroxy1 group, and a saturated carbonyl absorption at 5.85 y. Without p u r i f i c a t i o n , the keto alcohol (174) as dehydrated by r e a c t i o n with 1% hydrochloric a c i d i n r e f l u x i n g methanol. G.l.c. analysis of the product indicated that the major component was the decalone (122). The l a t t e r undoubtedly arose from a r e t r o a l d o l type r e a c t i o n , and therefore i t was decided to a l t e r the dehydration procedure. Dehydration of the keto • - 59 -alcohol (174) using t h i o n y l c h l o r i d e i n pyridine re s u l t e d i n the formation of a product, ( i ) - i s o - f u k i n o n e (175), which c l e a r l y possessed a terminal double bond. The i . r . spectrum of t h i s compound exhibited a saturated carbonyl absorption at 5.85 y, and the expected o l e f i n i c absorptions at 6.10 and 11.27 y, the l a t t e r being c h a r a c t e r i s t i c of a terminal double bond The double bond of (±)-iso-fukinone (175) was then isomerized by tr e a t ment with p_-toluenesulphonic a c i d i n r e f l u x i n g dry benzene. G.l.c. an a l y s i s of the product obtained from t h i s r e a c t i o n showed i t to be a mixture of three components. The major component was (±)-fukinone (16) while one of the minor components was i d e n t i f i e d as decalone (122). The (16) (175) (122) racemic fukinone (16) was p u r i f i e d by preparative g . l . c . and exhibited s p e c t r a l data which was i n f u l l accord with the proposed structure, and which was i n very good agreement with the s p e c t r a l data reported by Naya, : - 61 -3 Hirose and coworkers (8) f o r fukinone i t s e l f . Thus, the u l t r a v i o l e t spectrum exhibited an absorption maximum at 251 my (e = 6,640) ( l i t . (8) A 251 my (e = 6,800)). The i n f r a r e d spectrum showed t y p i c a l a,6-in 3.x unsaturated carbonyl absorptions at 5.95 and 6.17 y ( l i t . (8) ^ m a x 5.94, 6.16 y ) . The n.m.r. spectrum (Figure 7) exhibited a p a i r of s i n g l e t s at T 8.08 and 8.24 corresponding to v i n y l i c methyl groups ( l i t . (8) T 8.10 and 8.22). Also present was a s i n g l e t at x 9.04 a t t r i b u t e d to the t e r t i a r y methyl group ( l i t . x 9.05) and a doublet (J = 6.5 Hz) at x 9.16 due to the s i g n a l of the secondary methyl group ( l i t . x 9.16, J = 6.5 Hz). Thus i n conclusion, the structure (16) proposed (8) as fukinone has been corroborated by the proceeding unambiguous synthesis of t h i s compound. This synthesis establishes a completely s t e r e o s e l e c t i v e synthetic entry into the eremophilane cl a s s of sesquiterpenes. An authentic sample of fukinone f o r comparison purposes has not been obtained. EXPERIMENTAL A l l melting points were determined on a Kofler block and are uncorrected. U l t r a v i o l e t spectra were measured i n methanol s o l u t i o n on a Unicam model SP 800 spectrophotometer. Routine i n f r a r e d spectra were recorded on a Perkin-Elmer Infracord model 137 spectrophotometer, while a l l comparison spectra were recorded on a Perkin-Elmer model 421 spectrophoto-meter. Nuclear magnetic resonance (n.m.r.) spectra were determined i n deuteriochloroform s o l u t i o n and recorded on a JEOLCO C-60-H spectrometer, or on Varian Associates spectrometers, model A-60 and/or model HA-100. Signal p o s i t i o n s are given i n the T i e r s x s c a l e , with tetramethylsilane as an i n t e r n a l standard; the m u l t i p l i c i t y , integrated peak areas, and proton assignments are ind i c a t e d i n parentheses. Gas-liquid chromatography was c a r r i e d out on an Aerograph Autoprep, model 700. The following columns (10 f t x 1/4 i n . , unless otherwise noted) were employed, with the i n e r t , supporting material being 60/80 mesh Chromosorb W i n each case: column A, 3% SE 30; column B (10 f t x 3/8 i n . ) , 30% SE 30; column C, 15% QF-1; column D (10 f t x 3/8 i n . ) , 20% Carbowax; column E (10 f t x 3/8 i n . ) , 30% FFAP. The s p e c i f i c column used, along with column temperature and c a r r i e r gas (helium) flow-rate ( i n ml/min), are indicated i n parentheses. Micro-analyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia. - 63 -The r e a c t i o n products were i s o l a t e d by repeated extractions with the solvent s p e c i f i e d and the combined extracts were consecutively washed and dried with the reagents ind i c a t e d i n parentheses. The reac t i o n products were then concentrated, i n i t i a l l y at water aspi r a t o r pressure, and f i n a l l y at vacuum pump pressure (0.1-1.0 mm). Dimethyl a-Ketopimelate (138) The procedure employed was that of Lukes, Poos and Sarett (36). A s o l u t i o n of 100 g (.725 mole) of f u r y l a c r y l i c a c i d (136) (Aldri c h Chemical Co., Inc.) i n 400 ml of methanol was placed i n a 1 l i t e r f l a s k f i t t e d with a magnetic s t i r r e r , r e f l u x condensor and gas i n l e t tube. Hydrogen c h l o r i d e was passed r a p i d l y into the s o l u t i o n u n t i l the s o l u t i o n reached the b o i l i n g p o i n t . The gas flow was reduced, and the so l u t i o n was maintained at the b o i l i n g point for 4 h. The so l u t i o n was concentrated under reduced pressure to one-fourth the volume. One 1 of benzene was added to the residue, and the d i s t i l l a t i o n continued at atmospheric pressure. When the vapour temperature reached 80°, the remainder of the benzene was removed under reduced pressure. To the residue was added 350 ml of methanol and one-third ml of 95% sulphuric a c i d and the mixture was refluxed for 18 h. At the end of t h i s time the methanol was removed under reduced pressure and the residue was dissolved i n 650 ml of benzene. The benzene s o l u t i o n was washed with 1 N sodium carbonate u n t i l b a s i c , dried (brine, MgSO^) and concentrated. D i s t i l l a t i o n afforded 122 g (84%) of dimethyl a-ketopimelate (158), b.p. 110-115° (.65-.7 mm), ( l i t (36) b.p. 90-93° at 0.1 mm), m.p. 49-50°, ( l i t . (36) m.p. 49-50°). Infrared (CHC1-), X 5.80, 6.97, 8.51 y;' n.m.r., T 6.33 ( s i n g l e t , 6H, COOCHp, 7.29 (multiplet, 8H, -CH2CH2~). - 64 -Preparation of Dimethyl y-ethylenedioxypimelate (139) The procedure used was a modified version of that used by Lukes, Poos and Sarett (36). In a 1 l i t e r f l a s k equipped with a Dean Stark water separator there was placed 120 g (.593 mole) of the keto d i e s t e r (138), 41.5 g (.642 mole) of ethylene g l y c o l and 220 mg of p-toluenesulphonic acid i n 600 ml of dry benzene, and the mixture was refluxed u n t i l the required amount of water (10.7 ml, .593 mole) had been c o l l e c t e d . The s o l u t i o n was washed with 1 N sodium carbonate u n t i l b a s i c , d r i e d (brine, MgSO^) and concentrated producing 130 g of a pale yellow o i l . D i s t i l l a t i o n of t h i s o i l , and r e d i s t i l l a t i o n of the enriched f r a c t i o n s afforded 33.6 g (23%) of dimethyl y-ethylenedioxypimelate (139), which was greater than 97% pure by g . l . c . a n alysis (column A, 220°, 85), b.p. 115-120° (.6mm), ( l i t . (36) b.p. 96-98° at 0.08 mm), n^ 0 1.4504, ( l i t . (36) ng5 1.4501). Infrared ( f i l m ) , X m a x 5.77, 7.00 y; n.m.r., i 6.04 ( s i n g l e t , 4H, k e t a l H), 6.30 ( s i n g l e t , 6H, C00CH 3). The pot residue a f t e r d i s t i l l a t i o n was thought to be a t r a n s - e s t e r i f i c a -t i o n product. This was confirmed by again t r a n s - e s t e r i f y i n g the pot residue i n methanol and sulphuric a c i d , to regenerate the keto d i e s t e r (138). This was combined with the keto d i e s t e r f r a c t i o n s of the d i s t i l l a t i o n and re k e t a l i z e d . Repetition of t h i s cycle several times brought the o v e r a l l y i e l d to 44%. 2-Carbomethoxy-4-ethylenedioxycyclohexanone (140) Using the procedure of Lukes, Poos and Sarett (36), 58.1 g (.238 mole) of the ketal (159) and 5.7 g (.238 mole) of sodium hydride i n 350 ml dry - 65 -ether was s t i r r e d with an overhead s t i r r e r , and the s o l u t i o n refluxed under a nitrogen atmosphere f o r 5 days. To t h i s mixture was added 20 ml of a c e t i c ac i d and 20 ml of water. The ether layer was washed with 1 N sodium carbonate u n t i l b a s i c , d r i e d (brine, MgSO^) and concentrated to y i e l d a yellow o i l , which upon d i s t i l l a t i o n (b.p. 124° at 0.35 mm)- afforded a colourless o i l which c r y s t a l l i z e d on standing. R e c r y s t a l l i z a t i o n from methanol afforded 34.8 g (69%) of the keto ester (140), m.p. 60-61° ( l i t . (36) m.p. 60-61°). Infrared (CHC1_), A 5.75, 5.85, 6.03, 6.20, 7.80, 9.52 p; n.m.r., T 5.97 j IQclX ( s i n g l e t , 4H, ketal H), 6.23 ( s i n g l e t , 3H, COOCHj). Preparation of Ketal Octalone (131) A s o l u t i o n of 7.3 g (34.1 mmoles) of the keto ester (140) and 2.0 g (36.8 mmoles) of sodium methoxide i n 60 ml of dry methanol was s t i r r e d at room temperature under a nitrogen atmosphere. To t h i s s o l u t i o n was added a so l u t i o n of 15.4 g (51.3 mmoles) of l-diethylamino-3-pentanone methiodide (62) i n 40 ml of dry methanol. A f t e r 72 h at room temperature the methanol was removed under reduced pressure and 0.5 g potassium hydroxide i n 100 ml of water was added to the residue. An a d d i t i o n a l 4.5 g of potassium hydroxide i n 75 ml of water was added dropwise over a period of 3 h, and then the s o l u t i o n was refluxed f or an a d d i t i o n a l 5 h. Af t e r cooling, the react i o n mixture was extracted with ether, washed (water), dried (brine, MgSO^) and concentrated to a f f o r d an o i l which was d i s t i l l e d at 117-120° (0.1 mm). The colou r l e s s o i l which was obtained, c r y s t a l l i z e d on standing, and was r e c r y s t a l l i z e d from 30-60 petroleum ether y i e l d i n g 4.4 g (59%) of the desired octalone (131), m.p. 61-62°, ( l i t . (32) m.p. 61-63°). U l t r a v i o l e t , A 245 mp (e = 14,400); i n f r a r e d (CHC1J, A 6.03, 6.24, - 66 -8.82, 9.40 y; n.m.r., T 6.02 ( s i n g l e t , 4H, k e t a l H), 8.21 (multiplet, 3H, v i n y l methyl, width at half-height = 4.0 Hz). Preparation of Ketal Decalone (129) A s l u r r y of 2.58 g (13.4 mmoles) copper(I) iodide and 60 ml of anhydrous ether was s t i r r e d at i c e temperature f o r 10 min under an atmosphere of dry nitrogen, then 16.9 ml (26.8 mmoles) of a 1.59 M ethereal methyl-l i t h i u m s o l u t i o n was added, r e s u l t i n g i n a tan-coloured s o l u t i o n of l i t h i u m dimethylcuprate (18). A s o l u t i o n of 1.00 g (4.47 mmoles) of octalone (131) i n 40 ml of dry ether was added dropwise to the above s o l u t i o n over a period of. 15 min, then the r e a c t i o n was s t i r r e d f o r an a d d i t i o n a l hour at 0°. The methylation r e a c t i o n was quenched by pouring the r e a c t i o n mixture into a 500 ml separatory funnel, which contained a s o l u t i o n of 5.4 g hydrogen ch l o r i d e d i s s o l v e d i n 100 ml of dry ethylene g l y c o l . The separatory funnel was shaken c a r e f u l l y f o r 1 min. The ethylene g l y c o l layer was drained o f f and the ether layer was washed immediately with 10% sodium carbonate, dri e d (brine, MgSO^) and concentrated. The r e s u l t i n g o i l was chromatographed on 20 g neutral alumina and eluted with benzene. The c r y s t a l s obtained were r e c r y s t a l l i z e d from hexane to a f f o r d 820 mg (77%) of the desired k e t a l decalone (129), m.p. 94.5-96° ( l i t . ( 3 2 ) m.p. 92-94°). Infrared (CHC1,) X 5.84, 6.90, 7.33, 9.12, 10.26 y; n.m.r., x 6.02 ( s i n g l e t , 4H, k e t a l H), 7.20 (quartet, IH, a to carbonyl and secondary methyl, J = 6.5 Hz), 9.08 (doublet, 3H, secondary methyl, J = 6.5 Hz), 9.18 ( s i n g l e t , 3H, t e r t i a r y methyl). Anal. Calcd. f o r C 1 4 H 2 2 0 3 : C, 70.56; H, 9.30. Found: C, 70.42; H, 9.21. - 67 Ketal Decalin (130) A s o l u t i o n containing 5.0 g of the keta l decalone (129), 6.0 ml of 85% hydrazine hydrate, and 6.0 g of potassium hydroxide i n 160 ml of ethylene g l y c o l was refluxed f o r 2 h, then the excess hydrazine was d i s t i l l e d o f f slowly by draining the water condensor and allowing the temperature to gradually increase to 200°. The system was heated at t h i s temperature f o r 4 h. The d i s t i l l a t e was cooled, and l a t e r combined with the cooled r e a c t i o n mixture, which had been d i l u t e d with 60 ml of water. The re a c t i o n mixture was extracted with ether, washed (water), dri e d (brine, MgSO^), concentrated and f i n a l l y d i s t i l l e d at 82-85° (0.28 mm) to a f f o r d 3.5 g (88%) of a colourless o i l which exhibited 2 components by g . l . c . analysis (column C, 180°, 85) i n a r a t i o of 5:1. The major component, k e t a l d e c a l i n (130) was obtained by preparative g . l . c . (column D, 240°, 170), and exhibited n£° 1.4961. Infrared ( f i l m ) , X 6.91, 7.35, 9.12 y; n.m.r., x 6.09 D max ( s i n g l e t , 4H, k e t a l H), 9.13 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.25 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C 1 4H 2 4C> 2: C, 74.95; H, 10.78. Found: C, 75.22; H, 10.91. The minor isomer while not characterized, was considered to be ketal d e c a l i n (147), a secondary methyl group epimer of the major isomer (130). A l k y l a t i o n of 6-n-butylthiomethylene-2,3-dimethylcyclohexanone (153) with Eth y l 3-propionate (154) The n-butylthiomethylene d e r i v a t i v e (153) (100 g, 0.44 mole) was added to 1800 ml of dry t^-butyl alcohol containing 144 g (1.40 moles) of potassium t-butoxide and the r e s u l t i n g s o l u t i o n was s t i r r e d at room - 68 -temperature f o r 10 min. Ethyl 3-bromopropionate (154) (250 g, 1.38 moles) was added slowly from a dropping funnel. The a l k y l a t i o n was exothermic and, a f t e r the ad d i t i o n was complete, the reac t i o n mixture was s t i r r e d f o r an ad d i t i o n a l 15 min. Most of the solvent was removed under reduced pressure and the residue was d i l u t e d with water. The resultant mixture was extracted with ether. The ether extracts were washed (water), d r i e d (brine, MgSO^), concentrated and d i s t i l l e d to a f f o r d 124 g (86%) of the keto ester (155) (mixture of epimers), b.p. 190-195° (0.2 mm), n^ 0 1.5261. U l t r a v i o l e t , X 311 my (e =14,900); i n f r a r e d ( f i l m ) , X 5.79, 6.03, 6.52 y. UlcLX DlcLX Anal. Calcd. f o r C.oH__0_S: C, 66.22; H, 9.26. Found: C, 66.14; H, 9.33. Preparation of Keto Acid (156) To a s o l u t i o n of the above a l k y l a t e d material (155) (124 g, 0.38 mole) i n 600 ml of diethylene g l y c o l was added 600 ml of 25% aqueous potassium hydroxide and the r e s u l t i n g s o l u t i o n was refluxed under a nitrogen atmosphere f o r 18 h. The s o l u t i o n was then cooled, d i l u t e d with water, and extracted . with ether. The ether washings were discarded. The aqueous layer was a c i d i f i e d with 6 N hydrochloric acid and extracted with ether. The ether extracts were washed (water) dri e d (brine, MgSO^) and concentrated. The re s i d u a l o i l was d i s t i l l e d under reduced pressure, giving 67.5 g (90%) of the keto acid (156) (mixture of epimers) as a c l e a r viscous o i l , b.p. 142-147° (0.15mm), n£° 1.4868. Infrared ( f i l m ) , X 2.7-4.2 (very broad), v • D • max 5.78, 5.85 y. Anal. Calcd. for C^H^O.: C, 66.64; H, 9.15. Found: C, 66.83; H, 11 18 o 9.07. - 69 -Preparation of Enol Lactones (157) and (158) A s o l u t i o n of the keto a c i d (156) (64.0 g, 0.323 mole) i n 140 ml of a c e t i c anhydride containing 14 g of sodium acetate was refluxed under an atmosphere of nitrogen f o r 2 h. The a c e t i c anhydride was removed under reduced pressure. The r e s i d u a l material was d i l u t e d with water and extracted with ether. The ether extracts were washed (water) and d r i e d (brine, MgSO^). Removal of the solvent, followed by d i s t i l l a t i o n of the r e s i d u a l o i l , afforded 49 g (85%) of c r y s t a l l i n e m aterial, b.p. 90-94° (0.15 mm). This m a t e r i a l , as judged by i t s n.m.r. spectrum, consisted of a mixture of compounds (157) and (158) i n a r a t i o of approximately 9:1 r e s p e c t i v e l y . R e c r y s t a l l i z a t i o n from hexane produced pure (157) (40 g). An a n a l y t i c a l sample was obtained by vacuum sublimation and exhibited m.p. 51-51.5°. Infrared (CS ), X 5.72, 5.98 y; n.m.r., x 4.72 ( t r i p l e t , IH, v i n y l H, c. nicLX J = 4.0 Hz),, 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, 3H, secondary 'methyl, J = 6.5 Hz). Anal. Calcd. f o r C.-H^O.: C, 73.30; H, 8.95. Found: C, 73.60; H, 8.93. An a n a l y t i c a l sample of the minor isomer (158) was obtained from the mother l i q u o r s of the above r e c r y s t a l l i z a t i o n by means of preparative g . l . c . (column E, 220°, 200), n^O 1.4910. Infrared ( f i l m ) , X 5.71, 5.98 y; n.m.r., x 4.68 ( t r i p l e t , IH, v i n y l H, J = 4.0 Hz), 8.79 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, 3H, secondary methyl, J =6.5 Hz). Mol. Wt. Calcd. f o r C 1 1 H 1 6 ° 2 : 180.113. Found (high r e s o l u t i o n mass spectrometry): 180.115. Preparation of Octalone (69a) i A s o l u t i o n of the c r y s t a l l i n e enol lactone (157) (19.6 g, 0.109 mole) i n 200 ml of dry ether was cooled to -25° by means of an external carbon t e t r a c h l o r i d e - d r y i c e slush bath. An ethereal s o l u t i o n of methyllithium (75 ml, 2.35 M) was added over a period of 3 min and the resultant s o l u t i o n s t i r r e d at -25°, under a dry nitrogen atmosphere, f o r 1.75 h. The r e a c t i o n mixture was poured into d i l u t e hydrochloric acid and the resultant mixture was extracted with ether. The ether extracts were washed (water) and concentrated under reduced pressure. To the r e s i d u a l o i l was added a so l u t i o n of potassium hydroxide (16 g) i n 120 ml of water and 1 l i t e r of methanol and the s o l u t i o n was refluxed under a nitrogen atmosphere f or 2 h. The methanol was removed under reduced pressure, the residue was d i l u t e d with water and extracted with ether. The ether extracts were washed (water) and d r i e d (brine, MgSO^). Removal of the ether gave a yellow o i l which upon d i s t i l l a t i o n under reduced presure, afforded 13.5 g (70%) of the octalone (69a), b.p. 96-98° (0.2 mm), n^ 0 1.5155. U l t r a v i o l e t , 240 my (e = 12,100); i n f r a r e d ( f i l m ) , X 5.98, 6.19 y; n.m.r., x 4.33 (broad IHcLX s i n g l e t , IH, v i n y l H), 8.90 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.09 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C._H 1 o0: C, 80.85; H, 10.18. Found: C, 80.96; 1.2. l o H, 10.29. The b a s i c aqueous layer from the above extraction was a c i d i f i e d with concentrated hydrochloric acid and the re s u l t a n t mixture was extracted with ether. The ether extract was drie d (MgSO^) and concentrated. D i s t i l l a t i o n of the r e s i d u a l material provided 2.1 g (10%) of a carboxylic acid which, upon treatment with sodium acetate i n r e f l u x i n g a c e t i c anhydride, as - 71 -described above gave the enol lactone (157). Preparation of Decalone (122) (a) By hydrolysis of k e t a l decaline (150). A s o l u t i o n of 5.0 g of the mixture of keta l decalins (150) and (147) i n 20 ml of acetone and 20 ml of 10% hydrochloric acid was heated on a steam bath f o r 10 min. To t h i s s o l u t i o n was added 100 ml of water, and the remaining acetone removed under reduced pressure. The aqueous layer was extracted with ether, dri e d (brine, MgSO^), concentrated and d i s t i l l e d at 88-90° (0.55 mm), ( l i t . (52) b.p. 75° at 0.15 mm) to a f f o r d 5.1 g (77%) of a colourless o i l , which by g . l . c . analysis (column C, 165°, 85) indicated 2 components i n a r a t i o of 5:1. An a n a l y t i c a l sample of the major component decalone (122) was obtained by preparative g . l . c . (column D, 240°, 170), and exhibited n£0 1.4955. Infrared ( f i l m ) , X 5.85, 6.91 y; n.m.r., T 9.04 D max ( s i n g l e t , 5H, t e r t i a r y methyl), 9.15 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r ^^^0: C, 79.94; H, 11.18. Found: C, 80.05; H, 11.19. The 2,4-dinitrophenylhydrazone prepared from t h i s ketone melted at 126-127° a f t e r r e c r y s t a l l i z a t i o n from ethanol. Anal. Calcd. f o r C ^ H ^ N ^ : C, 59.98; H, 6.71; N, 15.55. Found: C, 60.14; H, 6.94; N, 15.67. The minor isomer while not characterized, was considered to be decalone (148), a secondary methyl group epimer of the major isomer (122). - 72 -• (b) By hydrogenation of octalone (69a) A s o l u t i o n containing 1.0 g (5.62 mmoles) of octalone (69a) and 100 mg o f 10% palladium on charcoal i n 20 ml .3 N ethanolic sodium hydroxide was s t i r r e d at room temperature under hydrogen overnight. The r e a c t i o n mixture was f i l t e r e d and n e u t r a l i z e d with d i l u t e hydrochloric a c i d . The s o l u t i o n was concentrated, then extracted into ether, washed (water) and dri e d (brine, MgSO^). The ether extracts were concentrated and d i s t i l l e d to a f f o r d 920 mg (92%) of decalone (122) which, by g . l . c . analysis was greater than 98% pure. The s p e c t r a l data ( g . l . c . r e t ention time, r e f r a c t i v e index, i n f r a r e d , n.m.r.) was i d e n t i c a l with that of decalone (122) prepared by hydr o l y s i s of k e t a l d e c a l i n (130) above. The 2,4-dinitrophenylhydrazones of decalone (122) prepared both ways melted at 126-127° and the mixed m.p. was not depressed. The i n f r a r e d spectra (CHCl^) of these d e r i v a t i v e s were superimposable. Preparation of Hydroxymethylene Derivative (163) To a s t i r r e d suspension of 3.8 g (70.3 mmoles) sodium methoxide i n 25 ml dry benzene was added a s o l u t i o n of 5.2 g (70.3 mmoles) of ethyl formate i n 25 ml of dry benzene. The system was cooled i n i c e and 5.0 g (28.1 mmoles) of octalone (69a) i n 25 ml of dry benzene was added. The r e a c t i o n was s t i r r e d with an overhead s t i r r e r under a nitrogen atmosphere f o r 1.5 h and then l e f t standing at room temperature for an a d d i t i o n a l 14 h. To t h i s r e a c t i o n mixture was added 75 ml of water, and the basic layer was washed with ether. The organic layer was i n turn washed with 2% sodium hydroxide, the basic extracts were combined and a c i d i f i e d with d i l u t e hydrochloric acid. The aqueous layer was extracted with ether. The ether extracts were combined, d r i e d (brine, MgSO^), and concentrated to a f f o r d a dark o i l , which was d i s t i l l e d (b.p. 110-112° at 0.25 mm) to y i e l d 2.5 g (89% based on unrecovered s t a r t i n g material) of yellow c r y s t a l s of the hydroxymethylene d e r i v a t i v e (163). An a n a l y t i c a l sample was obtained by vacuum sublimation and exhibited m.p. 68-73°. U l t r a v i o l e t , X f f l a x 248 mp (e = 9,280), 311 my (E = 3,860), x N a 0 H 242 my (e = 13,000), 355 my (e = 9,620); i n f r a r e d (CHC1-), nicLX j X 6.08, 6.41, 8.42 y; n.m.r., T 0.0 (very broad m u l t i p l e t , IH, =CH0H), ind.x 2.62 ( s i n g l e t , IH, =CH0H), 4.23 ( s i n g l e t , IH, v i n y l H), 9.06 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.08 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C^H-.O.: C, 75.69; H, 8.79. Found: C, 75.99; H, 8.73. Preparation of Hydroxymethylene Derivatives (166) and (168) from Decalone (122) ' To a s t i r r e d s o l u t i o n containing .90 g (16.7 mmoles) sodium methoxide i n 5 ml dry benzene was added a s o l u t i o n of 1.24 g (16.7 mmoles) of ethyl formate i n 5 ml dry benzene. The system was cooled i n i c e , then 1.00 g (5.56 mmoles) of decalone (122) i n 5 ml of dry benzene was added. The rea c t i o n was s t i r r e d with a magnetic s t i r r e r at room temperature under a nitrogen atmosphere f o r 2 days. To t h i s r e a c t i o n mixture was added 20 ml of water and the basic layer was washed with ether. The organic layer was, i n turn, washed with 2% sodium hydroxide, the basic extracts combined and a c i d i f i e d with d i l u t e hydrochloric a c i d and extracted with ether. The ether extracts combined and then drie d (brine, MgSO^). Removal of the solvent, followed by d i s t i l l a t i o n of the r e s i d u a l o i l under reduced pressure, gave .88 g (76%) of the hydroxymethylene d e r i v a t i v e s , b.p. 105-110° (0.2 mm), - 74 -.which as judged by i t s n.m.r. spectrum, consisted of a mixture of compounds (166) and (168) i n a r a t i o of 3:2. U l t r a v i o l e t , X 285 my (e = 6,330), xNa0H 3 1 5 ^ £ £ = 1 7 i l 0 0 - ) . i n f r a r e d (film) x' 6.07, 6.30, 7.32 y; n.m.r., HlclX IIlcLX T -4.83 and -4.21 (very broad m u l t i p l e t s , IH, =CH0H), 1.42 and 1.51 (broad s i n g l e t s , IH, =CH0H). Anal. Calcd. f o r c 1 3 H 2 o 0 2 : C ' 7 4 - 9 6 » H> 9-68. Found: C, 75.05; H, 9.73. Preparation o f Keto Aldehyde (167) (a) From the hydroxymethylene d e r i v a t i v e (163) A s o l u t i o n o f 1.5 g (7.3 mmoles) of the hydroxymethylene d e r i v a t i v e (163) and 150 mg 10% Pd on charcoal i n 75 ml .3 N ethanolic sodium hydroxide was hydrogenated at atmospheric pressure, u n t i l the desired amount of hydrogen (163 ml, 7.3 mmoles) had been absorbed. The c a t a l y s t was removed by suction f i l t r a t i o n , the f i l t r a t e was n e u t r a l i z e d with d i l u t e hydrochloric a c i d , and the solvent was removed under reduced pressure. The residue was dissol v e d i n ether, washed (water), d r i e d (brine, MgSO^) and concentrated, a f f o r d i n g 1.5 g (> 95%) crude hydroxymethylene decalone (166), (infrared ( f i l m ) , X 6.07, 6.30, 7.30; n.m.r., showed no v i n y l proton). A s o l u t i o n IH3 . X of 200 mg (.972 mmole) of the above hydroxymethylene decalone (166) and 231 mg (1.13 mmoles) of 2,3-dichloro-5,6-dicyanobenzoquinone i n 15 ml dry dioxane was s t i r r e d at room temperature f o r 2 h under a dry nitrogen atmosphere. The r e a c t i o n was then quenched by addition of 35 ml methylene c h l o r i d e , and f i l t e r e d through 2.5 g of neutral alumina. The alumina was further eluted with methylene c h l o r i d e . The solvent was removed under reduced pressure and -.75 -the residue d i s t i l l e d , b.p. 180-190° (0.1 mm), a f f o r d i n g a yellow o i l which p a r t l y c r y s t a l l i z e d . R e c r y s t a l l i z a t i o n from hexane yi e l d e d 124 mg (62%) of the desired aldehyde (167), m.p. 81-83°. U l t r a v i o l e t , X m & x 238 mp (e= 7,740); i n f r a r e d (CHC1_), X 5.95, 6.23, 7.44 p; n.m.r., T -0.32 ( s i n g l e t , o nicix IH, -CHO), 2.20 ( s i n g l e t , IH, v i n y l H), 8.74 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.00 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C ^ H ^ O ^ C, 75.69; H, 8.79. Found: C, 75.92; H, 9.03. (b) From hydroxymethylene d e r i v a t i v e s (166) and (168) A s o l u t i o n of 200 mg (.972 mmole) of the mixture of hydroxymethylene d e r i v a t i v e s (166) and (168), and 225 mg (1.10 mmoles) 2,3-dichloro-5,6-dicyanobenzoquinone i n 15 ml of dry dioxane was s t i r r e d f o r 2 h under a dry nitrogen atmosphere. This s o l u t i o n was then quenched by addition of 35 ml methylene c h l o r i d e , and f i l t e r e d through 4.0 g neutral alumina. The alumina was furt h e r eluted with methylene c h l o r i d e . The solvent was removed under reduced pressure and the residue was r e c r y s t a l l i z e d from hexane y i e l d i n g 30 mg (15%) of the desired keto aldehyde (167). The i . r . and n.m.r. spectra were i d e n t i c a l with the spectra of the keto aldehyde from part (a) above. The keto aldehyde (167) prepared i n t h i s manner melted at 81-83° and the mixed melting point was not depressed. Preparation of Keto Acid (170) To a s t i r r e d s o l u t i o n of 548 mg (2.66 mmoles) of aldehyde (167) i n 7 ml ethanol, and 953 mg (5.60 mmoles) s i l v e r n i t r a t e i n 5 ml water, was added 436 mg (10.90 mmoles) of sodium hydroxide i n 15 ml water, over 15 min. - 76 -The r e a c t i o n was s t i r r e d f o r a t o t a l of 2 h. The s i l v e r oxide was then removed by suction f i l t r a t i o n , and the solvent removed under reduced pressure and replaced with 20 ml water. The basic layer was washed with ether and the ether washings were discarded. The aqueous layer was a c i d i f i e d with d i l u t e hydrochloric a c i d and extracted with ether. The ether extracts were dried (brine, MgSO^) and concentrated. R e c r y s t a l l i z a t i o n of the residue from hexane-ether afforded 542 mg (92%) of the desired a c i d (170): m.p. 65-67°; u l t r a v i o l e t , X 245 my (e = 6,780); i n f r a r e d (CHC1J, X 5.75, 6.08, 6.25, 7.00 y; n.m.r., T 2.55 ( s i n g l e t , IH, v i n y l H), 8.77 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.02 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C^H^O • C, 70.25; H, 3.16. Found: C, 70.31; ,H, > ... 8.22. Preparation o f Keto Ester (171) To a s t i r r e d s o l u t i o n of 262 mg (1.18 mmoles) of keto a c i d (170), d i s s o l v e d i n 10 ml methyl iodide, was added 1.10 g (4.72 mmoles).of s i l v e r oxide. The r e a c t i o n mixture was s t i r r e d at room temperature f o r 30 min, and then suction f i l t e r e d . The f i l t r a t e was concentrated and d i s t i l l e d , a f f o r d i n g 257 mg (92%) of the desired ester (171) b.p. 185-190° (0.1 mm), n£0 1.5208. U l t r a v i o l e t , X 236 my (e = 7,740); i n f r a r e d ( f i l m ) , u nicix X 5.78, 5.96, 6.20, 7.00, 7.86, 9.54, 9.98 y; n.m.r., T 2.55 ( s i n g l e t , nicLX IH, v i n y l H), 6.23 ( s i n g l e t , 3H, C00CH 3), 8,82 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.04 (doublet, CH 3, secondary methyl, J = 6.5 Hz). Anal. Calcd. f o r C ^ H ^ G y C, 71.16; H, 8.53. Found: C, 71.42; H, 8.32. - 77 -Preparation of Carbomethoxy Decalone (172) Hydrogenation of 250 mg of the unsaturated keto ester (171) i n 10 ml of ethanol at room temperature and atmospheric pressure over Adam's c a t a l y s t gave 242 mg (97%) of the carbomethoxy ketone (172) : n^° 1.5112; u l t r a v i o l e t , X 257 my (e = 7,410), x N a 0 H 285 my (e = 13,800); i n f r a r e d nicix nid.x ( f i l m ) , X 5.78, 5.84, 6.02, 6.17, 6.98, 7.75, 8.14, 8.30 y; n.m.r., IRclX T -2.11 ( s i n g l e t , IH, enol H), 6.28 ( s i n g l e t , 3H, COOCRj), 9.12 ( s i n g l e t , 3H, t e r t i a r y methyl), 9.12 (doublet, 3H, secondary methyl, J = 6.5 Hz). Anal. Calcd. for C ^ H ^ O ^ C, 70.56; H, 9.30. Found: C, 70.84; H, 9.30. £±)-Fukinone (16) To a s t i r r e d , i c e cooled s o l u t i o n of 200 mg (.841 mmole) of the carbomethoxy decalone (172) i n 2 ml of dry ether was added 20 mg (.841 mmole) of sodium hydride. The re a c t i o n was s t i r r e d f o r 10 min, then 2.15 ml (5.05 mmoles) of 2.35 M ethereal methyllithium was added over a period of 5 min. The r e s u l t i n g s o l u t i o n was refluxed f o r 2 h, then 15 ml of dry ether was added, and the re a c t i o n was quenched by pouring the so l u t i o n into 35 ml of water. The ether layer was separated, dried (brine, MgSO^) and concentrated t o a f f o r d 160 mg (80%) of alcohol (174). The i . r . (film) exhibited abosrbances at 2.90 and 5.85 y. To a s t i r r e d , i c e cooled s o l u t i o n of the crude alcohol (174) i n 10 ml dry pyri d i n e was added 100 y l of th i o n y l c h l o r i d e , and the s o l u t i o n was s t i r r e d f o r 15 min. The solvent was then removed under reduced pressure at 0°, and the residue extracted into benzene, washed (water), d r i e d (brine, MgSO.) and concentrated to a f f o r d 134 mg of a - 78 -pale yellow o i l . G.l.c. analysis (column A, 170°, 90) showed t h i s to be a mixture of three components. The i . r . (film) exhibited peaks at 5.85 y, 6.10 and 11.27 y. A s o l u t i o n of the dehydration product i n 15 ml benzene with a trace of p_-toluenesulphonic acid was refluxed f o r 20 h. The s o l u t i o n was washed with 10% sodium bicarbonate, d r i e d (brine, MgSO^) and concentra-ted. G.l.c. analysis (column A, 200, 85) showed the o i l to contain approximately 60% (i)-fukinone (16), 20% of decalone (122) and 10% of an u n i d e n t i f i e d peak. P u r i f i c a t i o n was eff e c t e d by preparative g . l . c . (column B, 230°, 180). The major component, (i)-fukinone (16) exhibited an u l t r a v i o l e t , . X , v .251 my (e = 6,640), [ l i t . (8) X E t 0 H 251 (e = 6,800)]. Infrared ( f i l m ) , X 5.95, 6.17 y- ( l i t . (8) X 5.94, 6.16 y ) ; n.m.r., x 8.08 ( s i n g l e t , 3H, v i n y l methyl), ( l i t . (8) 8.10 ), 8.24 ( s i n g l e t , 3H, v i n y l methyl), ( l i t . (8) 8.22), 9.04 ( s i n g l e t , 3H, t e r t i a r y methyl), ( l i t . (8) 9.05), and 9.16 (doublet, 3H, secondary methyl, J = 6.5 Hz), ( l i t . (8) 9.16, J = 6.0 Hz). Mol. Wt. Calcd. f o r C H 2 40: 220.183. Found (high r e s o l u t i o n mass spectrometry): 220.181. - 79 -BIBLIOGRAPHY -1. J . Simonsen. The Terpenes, 2nd Ed., Un i v e r s i t y Press, Cambridge, Vol. 3> p. 212 (1950) and references therein. 2. For an incomplete l i s t of twenty-four eremophilane sesquiterpenes see C H . Heathcock and T.R. Ke l l y . Tetrahedron, 24, 3753 (1968). See als o G. Ourisson, S. Munaralli and C. Ehret. International Tables of Selected Constants, 15, Data Relative to Sesquiterpenes, Pergamon Press, New York (1966). 3. L. Ruzicka. Experimenta, 9_, 357 (1953). 4. L. Ruzicka, A. Eshenmoser, 0. Jeger and D. Ar i g o n i . Helv. Chim. Acta. 38, 1890 (1955). ' 5. D.E. Wolff, C H . Hoffman, P.E. A l d r i c h , H.R. Skeggs, L.D. Wright and . K. Folkes. J . Am. Chem. Soc. 78, 4499 (1956). 6. 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