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Remote oxidation of natural products Hunter, David J. 1974

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REMOTE OXIDATION OF NATURAL PRODUCTS By DAVID J . HUNTER B.Sc. Univers i ty of Leeds, England, 1972 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 September, 1974 In p resent ing t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the 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 reference and study. I f u r t h e r agree tha t permiss ion fo r e x t e n s i v e copying o f t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s e n t a t i v e s . It i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be a l lowed without my w r i t t e n p e r m i s s i o n . Department of The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada Date - X I -ABSTRACT Remote oxidat ion at the C-5 pos i t i on of isobornyl acetate (37) by chromium t r i o x i d e i n g l a c i a l acet ic ac id /ace t i c anhydride, and the appl ica t ion of t h i s oxidat ion to monoterpenes having the b icyc lo [2 .2 .1 ] heptane framework i s described. Subsequent con-vers ion of 5- ketoisobornyl acetate (38) to 5-ketocamphene (42) and the relevance of th i s sequence to the proposed synthesis o f the sesquiterpenes, culmorin (95), helminthosporol (99) and helmintho-sporal (97) i s discussed. The oxidat ion of dihydroisocampherenyl acetate (87) at C-5 and subsequent conversion to b-ketodihyriro-p-santalene (90) i s also described. The postulate that "ce r t a in compounds are suscept ible to oxidat ion at pos i t ions remote from func t iona l i t y " i s further tested by the oxidat ion of fa t ty acid es ters . The formation of a mixture of mono-ketoesters from the oxidat ion of methyl stearate (72;n=16), methyl docosanoate (72;n=20), methyl myristate (72;n=12), methyl palmitate (72;n=14), and methyl decanoate (72;n=8) by Cr0 3 -Ac 2 0/AcOH, and the procedure used to obtain a quant i ta t ive estimation of the r e l a t i v e amounts o f isomeric ketoesters present i n the product mixtures, i s reported. Evidence i s given for the v a l i d i t y of the a n a l y t i c a l method used to estimate the r e l a t i v e amounts of isomeric ketoesters. TABLE OF CONTENTS Page Abstract • • • 1 1 Table o f Contents i i i L i s t of Figures i v Acknowledgements v i i Preface v i i i Introduction 1 Discussion 17 • Exper imen ta l . . . . -. ... • .75 Bibliography • • • 100 i v -LIST OF FIGURES Figure Page 1. Photo-oxidation of the C-14 ester 2. Photo-oxidation of the C-18 ester 3. Oxidation of Methyl Stearate [Data from the low reso lu t ion (15 eV) spectrum of acetals] 36 4. Oxidation of Methyl Stearate [Data from the low reso lu t ion (70 eV) spectrum of acetals] 37 5. Oxidation of Methyl Stearate [Data from low reso lu t ion (70 eV) spectrum of th ioaceta ls ] 38 6. Oxidation of Methyl Stearate [Data from high reso lu t ion (70 eV) spectrum of a c e t a l s ] . . 39 7. Oxidation of Methyl Docosanoate [Data from low reso lu t ion (15 eV) spectrum of th ioaceta ls] 40 8. Oxidat ion .of Methyl Docosanoate [Data from low reso lu t ion (70 eV) spectrum of th ioaceta ls] 41 9. Oxidation of Methyl Docosanoate [Data from low reso lu t ion (15 eV) spectrum of acetals] 42 10. Oxidation of Methyl Docosanoate [Data from high reso lu t ion (70 eV) spectrum of acetals] 43 11. Oxidation of Methyl Palmitate [Data from low reso lu t ion (70 eV) spectrum of a c e t a l s ] . . . . . . . 44 - V -12. Oxidation of Methyl Palmitate [Data from low reso lu t ion (70 eV) spectrum of t h i o a c e t a l s ] . . 45 13. Oxidation of Methyl Palmitate [Data from low reso lu t ion (15 eV) spectrum of acetals] 46 14. Oxidation of Methyl Myris ta te [Data from low reso lu t ion (15 eV) spectrum of th ioaceta ls] 47 15. Oxidation of Methyl Myris ta te [Data from low reso lu t ion (70 eV) spectrum of t h i o a c e t a l s ] . . . . . . . . . . . . . . . . 48 16. Oxidation of Methyl Myris ta te [Data from high reso lu t ion (70 eV) spectrum of a c e t a l s ] . . . . ' . 49 17. Oxidation of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of th ioaceta ls] 50 i o r i v i J n f 4 n . ~ £ i.u+u vi n m„4.„ — T AW. OJ-Uli V_i _i_ I'lC ^liy i L i W U O i l U a i . C ' IUO.L.CL X J. Will lUlV . reso lu t ion (70 eV) spectrum of t h i o a c e t a l s ] . . . . 51 19. Mass spectra l data from th ioace ta l of methyl 9- and 10- ketostearate 52 20. Mass spect ra l data from aceta l of methyl 9- and 10- k e t o s t e a r a t e . . . . . . . 53 21. Oxidation of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of th ioace ta l s , Frac t ion A J . . . . 54 22. Oxidation of Methyl Decanoate [Data from low reso lu t ion (70 eV) spectrum of th ioace ta l s , Frac t ion A ] . . . . 55 23. Oxidation of Methyl Decanoate [Data from high reso lu t ion (70 eV) spectrum of ace ta ls , Frac t ion A] 56 - v i -24. Oxidation of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of ace ta ls , Fract ion B ] . . . . . . . . 57 25. Oxidation o f Methyl Decanoate [Data from low reso lu t ion (70 eV) spectrum o f ace ta l s , Frac t ion Bj 58 26. Oxidation of Methyl Decanoate [Date from high reso lu t ion (70 eV) spectrum of ace ta l s , Frac t ion BJ 59 27. Oxidation of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of th ioace ta l s , Frac t ion B ] . 60 28. Oxidation of Methyl Decanoate [Data from low reso lu t ion (70 eV) spectrum of th ioace ta l s , Frac t ion B ] . . . . 61 29. Oxidation of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of ace ta l s , Frac t ion C] 62 30. Oxidation of. Methyl Decanoate [Data from low-reso lu t ion (70 eV) spectrum of ace ta ls , Frac t ion C ] . . . . . . . . 63 31. Oxidation o f Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of th ioace ta l s , Frac t ion C ] . . . . 64 32. Oxidation of Methyl Decanoate [Data from low reso lu t ion (70 eV) spectrum of th ioace ta l s , Frac t ion C ] 6 5 33. Two hour oxidat ion of Methyl Decanoate [Data from low reso lu t ion (15 eV) spectrum of th ioaceta ls] 66 34. Two hour oxidat ion of Methyl Decanoate [Data from low reso lu t ion (70 eV) spectrum of th ioaceta ls ] 67 - V l l -ACKNOWLEDGEMENTS I wish to express my deepest grati tude to Dr. Thomas Money for h i s guidance and encouragement throughout the course of t h i s work. Grateful appreciat ion i s a l so extended to Dr. C. R. Eck for his suggestions and technica l advice, and to Dr. G. Eigendorf for useful discussions. A spec ia l expression of grat i tude i s due to Grace Wood who has aided so great ly with her excel lent typing assistance. v i i i -PREFACE Unless otherwise spec i f i ed the fol lowing are impl ied . Mel t ing points were determined on a Kofler apparatus and are un-corrected. Infrared spectra (TR) were recorded on a Perkin-Elmer model 137, spectrophotometer and ca l ib ra ted by means of the 1601 cm~* band of polystyrene. Nuclear magnetic resonance spectra (NMR) were recorded on a Var ian Associates model T-60 or Varian Associates model XL-100. Signal pos i t ions were reported on the T-sca le , with CCl^ as solvent and tetramethylsi lane as an in te rna l standard. Mass spectra were obtained on At las CH-4 and A . E . I . MS902 instruments. Microanalyses were performed by Mr. P. Borda, Microanalysis Laboratory, Univers i ty of B r i t i s h Columbia, Vancouver, B. C. Gas - l iqu id chromatography ( g . l . c . ) was ca r r i ed out on a Varian Aerograph, Model 90-P, using the fo l lowing columns. Length Stat ionary phase Support Mesh 10 f t x h i n . 3% SE 30 Varoport 30 100/120 Car r i e r gas (helium) flow rate was 60 ml/min. Solvents employed were e i ther Reagent grade or C e r t i f i e d grade. The term "petroleum ether" refers to the low b o i l i n g f rac t ion of C e r t i f i e d grade petroleum d i s t i l l a t e (b.p. ca . 3 0 - 6 0 ° ) . - i x -The fol lowing abbreviat ion have been made i n the presentat ion of NMR data. broad s broad s ing le t bd broad doublet d doublet dd doublet of doublets dq doublet of quartets m mul t ip l e t q quartet s s i n g l e t t t r i p l e t - 1 -INTRODUCTION Although many of the reactions which occur i n nature have analogies i n the laboratory there are others, notably those invo lv ing reg iospec i f i c oxidat ion of molecules at "unreactive" pos i t i ons , which are inaccess ible to the organic chemist. C la s s i c examples of reactions i n th i s l a t t e r category are the oxidat ion of s t ea r i c acid to o l e i c acid and the oxidat ion of terpenoids and s teroids at pos i t ions remote from other func t i ona l i t y . CH_(Cfl o ) ' ,C0 o H Mycobacterium ^ CH„(CH„)_CH = CH(CH_)_C0.H o i lb £ p h l e i •> ^ I z / z s tea r ic acid — o l e i c ac id Several laboratory techniques have been developed to achieve reg iospec i f ic func t iona l i za t ion of molecules at unreactive pos i t ions . The f ree - rad ica l chain decomposition of a C^g-N-chloroamine (Hofmann-LOffler-Freytag r e a c t i o n ) 1 to a p y r o l l i d i n e , as shown below, i s the f i r s t well-known example of reactions on "nonactivated carbon atoms." In 1958 th i s method was used to func t iona l ize 18-methyl RCH2CH2CH2CH2NR'C1 + HCl R» 2 groups i n s teroids and the synthesis of dihydroconessine (2) by i r r a d i a t i o n of a s u l f u r i c ac id so lu t ion of 33-dimethylamino-20a-methylchloroaminoallopregnane (1) with u l t r a - v i o l e t l i g h t i s a s p e c i f i c example o f t h i s process. Cl) (2) - .3 -3 I t was postulated by Barton that photolysis of a l k y l n i t r i t e s might furnish excited alkoxy r ad ica l s with su f f i c i en t energy, i n excess of that found i n thermally generated r a d i c a l s , t o permit in te rna l hydrogen transfer according to scheme 1 (X = NO, Y = chain of carbon atoms). Later work showed that transformations of t h i s type take, place only when the chain of carbon atoms (Y) i s no more or no less than two, i e . one of the prerequis i tes for the "Barton reac t ion" i s the a v a i l a b i l i t y of a six-membered, c y c l i c t r a n s i t i o n s ta te . The react ion i s not l imi t ed to n i t r i t e s ; hypochlori tes (X = Cl) and hypoiodites (X = I) behave s i m i l a r l y . OX H OH I I I _ C — Y — C - • —C — Y i i i Scheme 1 The major app l i ca t ion of the Barton react ion has been i n the s te ro id f i e l d , where i t has been used to funct ional ise C-18 and C-19 methyl groups. Thus, photolysis of 38-acetoxy-5a-pregnan -20ct-yl n i t r i t e (3) i n benzene gave an isomeric oxime (4), 3B-acetoxycholestan-6g-yl n i t r i t e (5) on photolysis i n toluene gave the C19-nitros.o 3 dimer (6) which was r ead i ly converted to the corresponding oxime (7) . I r r ad ia t ion of c o r t i c o s t e r o n e - l l - n i t r i t e (8), followed by ni t rous ac id 4 treatment, gave aldosterone (10) . — C -5 -(8) CH2OAc OH CH^OAc (9) (10) Photolysis of simple a l i p h a t i c ketones i n saturated hydro-carbon solvents was found by Yang*' to lead to the formation of cyclobutanols e.g. i r r a d i a t i o n of 2-pentanone (11) i n cyclohexane gave acetone, ethylene and 1-methycyclobutanol (12). As i n the Barton reac t ion , t h i s photolysis involves the production of a CH, H R \ • / 0 CH II \ • C ^ CH C H 2 H hv CH 3C*V CH CH / C H 2 CH • -> 3 OH I C CH — R f I TH ' L M 2 ^ - C H 2 (11) (12) - 6 -react ive heteroatom r a d i c a l i n a molecule which then, by intramolecular attack on a hydrogen atom located s i x atoms away, i n i t i a t e s functiona-l i s a t i o n of a pos i t i on which i s not chemically act ivated i n the usual sense. I t has been shown^ that primary and secondary a l i p h a t i c alcohols containing unactivated <S-carbon atoms can be converted in to the corresponding tetrahydrofurans by oxidat ion with lead tetraacetate i n benzene, e i ther under thermal or u . v . - p h o t o l y t i c condi t ions . On the other hand, secondary and t e r t i a r y alcohols i n which one or both react ing centers are geometrical ly f ixed (e.g. s t e ro id alcohols) undergo intramolecular r i n g closure to c y c l i c 1,4-ethers when treated e i ther with iodine and mercuric oxide ( in carbon t e t r ach lo r ide , chloroform or methylene ch lor ide at room temperature i n the presence 7 of u . v . l i g h t or at r e f lux temperature i n the dark) , or with bromine and s i l v e r sa l t s (oxide or acetate) i n pentane (at room temperature i n the dark) . The act ion of s i l v e r oxide-bromine and mercuric oxide-iodine on primary and secondary unbranched a l i p h a t i c a lcohols 9 with unactivated 6-carbon atoms has been studied and both reagents were found to effect intramolecular r i ng closure to the corresponding tetrahydrofurans. Oxidat ions 'wi th s i l v e r oxide-bromine do not require - 7 -8 the absence of l i g h t (as stated previously ) . Reactions of th i s type f ind app l ica t ion i n many natural product syntheses. For example, with lead tetraacetate i n re f lux ing benzene, l o n g i f o l o l (13) and i s o l o n g i f o l o l (14) may be converted to the corresponding c y c l i c ethers, (15) and (16), i n ca. 30% y i e l d . 1 0 (13) " (15) (14) (16) S i m i l a r l y , methylnopinol (17), when treated with mercuric oxide-bromine i n carbon te t rach lor ide i n the presence of u .v . l i g h t , gives 40% of the expected t r i c y c l i c ether ( 1 8 ) . 1 1 - 8 -The processes described above normally involve i n t r a -molecular react ion between a hereroatom r a d i c a l i n the molecule with a saturated hydrocarbon centre (usually a methyl group) i n close proximity to i t . More recent ly ,Bres low,Baldwin and t h e i r respective co-workers have extended synthetic methodology i n th i s area by i r -12 13 rad ia t ing appropriate esters of benzophenone carboxyl ic ac ids . ' The benzophenone carboxyl ic ac id esters have the great advantage that benzophenone can be photo-excited to i t s t r i p l e t s ta te , i n which i t i s able to react with unactivated methylene and methine groups, to produce the corresponding t e r t i a r y a l coho l . Thus, a series of s t ra igh t -cha in esters of benzophenone carboxyl ic acid were 14 photolysed i n carbon te t rach lor ide . To determine the p o s i t i o n which had been funct ional ised, the r e s u l t i n g alcohol was dehydrated and the new double bond to the funct ional ized carbon cleaved with ozone (Scheme 2) . Af ter hydro lys i s , the r e su l t i ng carbonyl group was converted into a th ioace ta l and the mass spectrum of the r e su l t i ng product mixture examined. I t was reported that at low i o n i z a t i o n voltages mass spect ra l fragmentation occurred l a rge ly at the carbon carrying the th ioace ta l group, and from the pattern of mass spect ra l peaks the d i s t r i b u t i o n of oxidat ion s i t e s could be determined. The resu l t s obtained with a fourteen-carbon and an eighteen-carbon chain are shown i n figures 1 and 2 respec t ive ly . / hv, CClu. COOC. , H „ , io o 3 Me(CHJ i , H0Ac , I 2 i i , 0 3 i i i , KOH M o r r u -> — r .—(TH."* —-OH + — v - " 2 ' 1 4 - x " • 2 ' x Scheme 2 I t was suggested that i f the carbon chain was made longer the f l e x i b i l i t y of the system could resu l t i n a less regio-spec i f i c react ion and i t was also suggested that the absence of attack on the methyl group was the resu l t of the.chemical s e l e c t i v i t y of the benzophenone t r i p l e t , since the methyl hydrogens are less react ive than are methylene hydrogens. - 10 -0 8 9 10 11 12 13 14 Si tes of Oxidation Figure 1. Photo-oxidation of the C... ester . 0 2 ~To"- 11 l l 13 "TV"!? 16" 17 18 Si tes of Oxidation - 11 -This method of se lec t ive func t iona l i za t ion has also been applied to s te ro ids . Thus, i r r a d i a t i o n of the benzophenone-4-propionic 15 14 ester of cholestan-3a-ol (19) i n benzene gave A -cholest-3a-enol (20) as the only unsaturated s te ro id product. The carbonyl oxygen of the benzophenone t r i p l e t removes the hydrogen at C-14 and the carbon atom of the benzophenone t r i p l e t then removes a neighbouring hydrogen at C-15. The same d i r a d i c a l also undergoes some col lapse , forming a new carbon-carbon bond at C-14 to give (21). In add i t ion , there i s attack at C-12 and C-7 with subsequent coupling to give the alcohols which can be dehydrated by cleavage with ruthenium te t ra -oxide and sodium periodate to 12-ketocholestan-3a-ol (22) and 7-ketocholestan-3ot-ol (23). (21) - 12 -(19) (23) I r r ad ia t ion of the benzophenoneacetic ac id ester of cholestan-13 3<x-ol (24) gave cholest-14-enol (25), i n 55% y i e l d , as the only detectable s te ro id product. The shorter l i n k between the two r i g i d systems means that col lapse to form a new carbon-carbon bond i s apparently too s t ra ined , so the d i r a d i c a l undergoes hydrogen atom transfer exc lus ive ly . - 13 -I f benzophenonehexanoic acid i s attached at C-17 of r i ng D (26), the benzophenone t r i p l e t attacks hydrogens at C-9 and C-14 to give the.cholest-14-enol d i r e c t l y and a new carbon-carbon bond to C-9. Lead tetraacetate cleavage and hydrolys is gives the cholest-9(11)-enol thus introducing the 9-11 double bond in to a s te ro id and gaining entry into the important 11-oxygenated co r t i cos te ro id se r ies . 0 C = 0 (26) I r r ad ia t ion of compounds such as (24) i n the presence of 0.1M BrCClj gave a bromosteroid which on treatment with base gave cholestenols i n which the predominant isomer, 66% of the product mixture, was 17 15 9 ( l l ) - cho le s t en -3a -o l . (An e a r l i e r observation had been that photo-chemical remote oxidat ion of s teroids i n carbon te t rach lor ide lead to some ch lo r ina t ion of the s t e ro id ) . Bromination. of C-9 occurs by an independent f ree - rad ica l process, and can be ca r r i ed out by i r r a d i a t i o n of s teroids with B r C C l , i n solvents such as benzene without the - 14 -necessity of attached benzophenone. Thus, i r r a d i a t i o n of 3a-cholestanyl acetate (27) i n benzene with 0.1M BrCCl^ gave 75% s ta r t ing material and the A 9 ^ 1 1 ^ acetate (28) i n 48% y i e l d . Reasonable y i e lds of o lef ins can only be obtained when the react ion i s car r ied out to low conversion, since the product undergoes further complex reactions with BrCCl . More a t t r a c t i v e l y , P h l C ^ performs se lec t ive ch lo r ina t ion of cholestenyl acetate (27) to give a 75% y i e l d of a 1:1 mixture of 17 the 9-chloro- and 14-chloro-s teroids . Further s e l e c t i v i t y has recent ly been achieved by the use of appropriate substituent 18 effects . Thus, the most convenient and ef fec t ive group for suppressing halogenation at C-14 i s the C-17 carbonyl group (probably a combined polar and conformational e f f ec t ) , and C-5 halogenation can be diminished by an electron-withdrawing group at C-3. - 15 -i - 16 -I r r ad ia t ion of the t r i f luoroace ta te of androsterone (29) with 2 equivalents of P h l C l ^ i n benzene gave, after dehydrochlorination, saponif ica t ion and ace ty la t ion , 49% of 3a-acetoxy-5a-androst-9(l l)-en one (30) and a trace of the isomer. The p-iodophenylacetic ester of 3a~cholestanol was converted to the d ich lo r ide (31) and i r r ad ia ted i n chlorobenzene at -25° to give, after work-up as above, 53% of A ^ - c h o l e s t e n y l -3a-acetate (32). In add i t ion , only 5% of the A 9 ^ ^ isomer and 0.8% of the A^ isomer were detected. The d ich lo r ide of 3cx-cholestanyl m-iodobenzoate (33) was i r rad ia ted i n benzene at room temperature to give 43% of A 9 ' - 1 1 ^ -cholestenyl-3a-acetate (34). (Only 9% of the A 1 ^ isomer and 2% of the A** isomer were formed). The chlor ine atom i n the intermediate derived from (31) i s e s sen t i a l l y i n the same place as the abstract ing oxygen i n the p-benzophenoneacetic ester of 3a-cholestanol which on 14 17 photo lys i s , also produced a A -3a-cholestanol de r iva t ive . The approach described i n t h i s thesis d i f f e r s from those previously described i n th i s area since i t i s based on the postulate that ce r t a in molecules are i n t r i n s i c a l l y susceptible to oxida t ion at centres which are generally considered to be unreactive. - 17 -DISCUSSION 1. Remote Oxidation of Monoterpenoids: New Synthetic Route to  5-ketocamphene As part of our general synthet ic studies i n the sesquiterpene area we assumed that ce r t a in transformations, invo lv ing oxidat ion at remote unreactive centres, would enable us to convert some of our 19 syn the t i ca l ly accessible sesquiterpenes to na tu ra l ly occurring ear ly report which described the low-y ie ld d i rec t conversion of bornyl acetate (35) to 5-ketobornyl acetate (36) with chromium t r i -oxide i n g l a c i a l acet ic a c i d . This remarkable transformation has also —: 21 been accomplished more recen t ly , under re f lux condi t ions , i n y i e ld s varying from 15-35%. We were encouraged i n t h i s b e l i e f by an lAc AcOH 0 lAc (35) (36) - 18 -There has been l i t t l e inves t iga t ion in to the mechanism of th i s r eac t ion . . I t i s generally observed i n chromium t r i o x i d e oxidat ion of hydrocarbons that methylene groups react much more r e a d i l y than methyl groups, but the reason for the enhanced r e a c t i v i t y of the C-5 methylene over the C-6 methylene i n bornyl acetate i s unknown. However, experimentally, i t i s only the C-5 methylene which i s e f f ec t i ve ly oxid ized r e su l t i ng almost exc lus ive ly i n 5-ketobornyl acetate (36). The mechanism involved i n the chromic ac id oxidat ion of alcohols 22 to ketones i s out l ined below. A chromate ester i s r eve r s ib ly formed, CH CH, 0 — C r \ - 3 / ( / \ X C H — O H + HCrO," + 2H + —* X C 3 OH 3 C HX C H 3 ^ ^ " ^ r B CH3 OH \ . + / C = 0 + BH + 0 = Cr CH 3 X 0 H and i n the rate-determining step there i s an e l imina t ion with loss of a Cr (IV) species. Through a ser ies of other rap id reactions th i s i s converted to Cr ( I I I ) , j t he stable f i n a l oxidat ion s ta te . I n i t i a l l y i t was suggested that the solvent , ace t i c a c i d , was involved i n the oxidat ion of bornyl acetate (35) to 5-ketobornyl acetate (36). I f , for example, the ace t ic ac id attacked C-2 from the exo-p o s i t i o n , thereby ac t iva t ing the C-5 p o s i t i o n as shown below, invers ion at C-2 would occur and the mechanism of the reac t ion would be s i m i l a r to - 19 -that described previous ly . This was tested by using propionic acid 23 as the solvent; however, no ester interchange occurred and the products of the react ion were found to be i d e n t i c a l i n a l l respects to the o r i g i n a l oxida t ion . Thus, i t was concluded that no invers ion of configurat ion at the C-2 carbon atom had taken place and- that the solvent was not d i r e c t l y involved i n the reac t ion . The corresponding oxidat ion of i sobornyl acetate (37) using 24 chromium t r i o x i d e i n ace t ic anhydride has also been reported. We were able to improve the y i e l d of t h i s react ion to 65% by carrying out the oxidat ion of isobornyl acetate (37) i n a 1:1 mixture of g l a c i a l acet ic ac id /ace t i c anhydride. Chromium t r i o x i d e i n ace t ic anhydride was added slowly to a so lu t ion of isobornyl acetate i n g l a c i a l ace t ic ac id /ace t i c anhydride and the so lu t ion s t i r r e d at room temperature for 8 days. The NMR spectrum of 5-ketoisobornyl acetate (38) showed resonances at - 20 -x 9.23 (s, 3H, t e r t i a r y methyl), 9.14 (s, 3H, t e r t i a r y methyl), 8.97 (s, 3H, t e r t i a r y methyl), 8.08 (s, 3H, acetate methyl), and 5.26 (dd, IH, - CHOAc). In addi t ion, the expected molecular ion peak at m/e 210 and the peak due to loss of ace t ic ac id at m/e 150 were observed i n the mass spectrum. Unreacted s t a r t i ng mater ia l and camphor (39) (6%) were also i so la t ed from the reac t ion . [NOTE: the o x i d i z i n g so lu t ion (Cr0 3 - Ac^O) can be explosive, e spec ia l ly i n large quan t i t i e s , and must be made up and used under cont ro l led conditions ( < 2 5 ° ) ] . I t i s in te res t ing to note tha t , under the conditions used for the oxidat ion of bornyl acetate, i sobornyl acetate (37) i s not oxidized with chromium t r i o x i d e i n g l a c i a l acet ic ac id (Only camphor (39) and s t a r t i ng 23 material are i so la ted i n the r a t i o 63:37). Chromium t r i o x i d e i n ace t ic anhydride gives an orange so lu t ion of chromyl acetate, (AcO^CrG^. Presumably, i t i s th i s which i s responsible for the oxidat ion of isobornyl acetate (37) to 5-ketoisobornyl acetate (38). Hydrolysis of (38) with sodium carbonate i n methanol/water gave 5-ketoisoborneol (40). The inf rared spectrum (CCl^) showed a broad absorption band at 34.90 cm 1 (hydroxyl) and a sharp band at 1745 cm" 1 (carbonyl) . No resonance corresponding to the acetate methyl protons remained i n the NMR spectrum. The s tructure o f 5-ketoisoborneol (40) was further confirmed by oxidat ion (Jones' reagent) to 5-ketocamphor (41) [m.p. 209-211° (from pet. e ther ) ] . - 21 -(42) (43) Dehydration of (40) with methanesulfonyl chlor ide i n pyr id ine at 90°C for 24 hours gave a mixture of 5-ketocamphene (42) and 3-keto t r icyclene (43) i n the r a t i o 4 :1 . Column chromatography of the mixture over aluminium oxide (neutral Grade IV) completed a simple 3-step s tereospeci f ic route to 5-ketocamphene (42)* i n 50% o v e r a l l * The previous synthesis o f t h i s compound consisted of 9 s teps. - 22 -y i e l d from isobornyl acetate (37). The infrared spectrum (CCL^) of 5-ketocamphene showed absorption bands at 1745, 1650 and 890 cm v The NMR spectrum exhibi ted resonances at x 8.98 (s , 3H, t e r t i a r y methyl) , 8.89 (s, 3H, t e r t i a r y methyl), 6.95 (broad s, IH, a l l y l i c bridgehead proton) and 5.12 (d, 2H, Cti^=). In add i t ion , the correct molecular ion peak at m/e 150 was observed i n the mass spectrum. The po ten t ia l s igni f icance of t h i s monoterpene sequence, and of subsequent transformations of 5-ketocamphene, to the sesqui-terpene area w i l l be discussed l a t e r (cf . p.70 ) . Scheme 3 • • - 23.-Having obtained 5-ketocamphene i n good y i e l d , we attempted to introduce func t iona l i t y at C-6 wi th a view to cleaving the carbon-carbon bond between C-5 and C-6 to produce compounds such as (46) and (48) which are the monoterpene analogues of the sesqui-terpenes, helminthosporal (98) and helminthosporol (100) (cf . p . 70). We f e l t that selenium dioxide oxidat ion of 5-ketocamphene i n acet ic anhydride would give the desired a-diketone (44). Reduction of the diketone (44) to the d i o l (45) and subsequent cleavage with per iodic acid would give (46). In add i t ion , reduction of (46) to the d i o l (47) followed by se lec t ive oxidat ion of the un-saturated alcohol with manganese dioxide would be expected to produce (48) [Scheme 3]. However, selenium dioxide oxidat ion of 5-ketocamphene (42) gave a number of products, none of which contained a double-bond, and i t was l a t e r discovered that oxidat ion of camphene (49) with selenium dioxide gave the b i c y c l i c ketone (50) and subsequently the b i c y c l i c a-diketone (51). OSeOH (51) (50) - 24 -Attempts to oxid ise 5-ketocamphene hydrochloride (52) with selenium dioxide i n ace t ic anhydride were s i m i l a r l y unsuccessful due to the i n s t a b i l i t y o f 5-ketocamphene hydrochloride (52) which r e a d i l y converted back to 5-ketocamphene (42). (52) (42) Func t iona l i sa t ion was eventual ly achieved at C-6 of 5-keto-camphene (42) by the in t roduct ion of a bromine atom. Butyl l i t h ium was added to a so lu t ion of 5-ketocamphene and dicyciohexylamine i n tetrahydrofuran. After 15 minutes at room temperature, bromine i n methylene chlor ide was added at -78°C and the so lu t ion quenched af ter 1 minute with saturated sodium bicarbonate s o l u t i o n . Work-up provided 6-bromo-5-ketocamphene (53) i n ca. 50% y i e l d . The inf rared spectrum showed absorption bands at 1745, 1650, and 895 c m - 1 . The NMR spectrum exhibi ted resonance at x 8.85 (s, 3H, t e r t i a r y methyl) , 8.73 (s, 3H, t e r t i a r y methyl), 6.73 (broad s, IH, a l l y l i c bridgehead hydrogen), 6.53 (d, IH, endo-CHBr), 6.20 (d, IH, exo-CHBr), 4.87 (d, 2H, CH_2 =). - 25 -Subsequent transformations, as ou t l ined below (and i n Scheme 3 ) , should provide access to (46) and (48). However, the remainder of t h i s react ion sequence has yet to be ca r r i ed out i n the laboratory. The reg iospec i f i c oxidat ion of isobornyl acetate (37) seems to indicate that the C-5 pos i t i on i n t h i s molecule i s i n t r i n s i c a l l y vulnerable to oxida t ion . In an attempt to discover the extent of t h i s v u l n e r a b i l i t y we studied the chromyl acetate, Cr02-Ac20, oxidat ion of various monoterpenes having the b i c y c l o [2.2.1] heptane framework. Oxidation of fenchyl acetate (54) (a mixture of exo and endo acetates i n the approximate r a t i o 5:3) with chromium t r i o x i d e i n a 1:1 mixture of g l a c i a l ace t ic ac id /ace t i c anhydride gave, af ter 4 days at room temperature, a mixture of 5- and 6-ketofenchyl acetate (55a,b) i n the approximate r a t i o 3:1 . Subsequent hydrolys is to 5- and 6-ketofenchol (56a,b)^followed by oxidat ion (Jones' reagent) gave - 26 -5- and 6-ketofenchone (57,58) i n the r a t i o 3 :1 . Column chromatography of the mixture over aluminium oxide (neutral Grade I) gave a pure sample of 5- and 6-ketofenchone. The NMR spectrum of 5-ketofenchone (57) exhibi ted resonances at x 9.04 (s, 3H, t e r t i a r y methyl), 8.92 (s, 3H, t e r t i a r y methyl), 8.82 (s, 3H, t e r t i a r y methyl) , 8.04 (m, 4H) and 7.56 (broad s, IH, bridgehead hydrogen). The NMR spectrum of 6- ketofenchone (58) exhibi ted resonances at x 9.05 (s, 3H, t e r t i a r y methyl), 8.98 (s, 3H, t e r t i a r y methyl), 8.95 (s, 3H, t e r t i a r y methyl), 8.02 (s, IH, bridgehead hydrogen, 7.86 ( t , 2H) and 7.58 ( t , 2H). (56b), R 2=0, •R1=H2 The formation_of 5- and 6-ketofenchyl acetate was expected 25 since i t had been reported that the oxidat ion of camphenilyl acetate (59) with chromium t r i o x i d e i n g l a c i a l ace t ic ac id gave 5-ketocampheriilyl acetate (60); whereas, oxidat ion with chromium t r i o x i d e i n acet ic anhydride gave 6-ketocamphenilyl acetate (61). - 27 -We were prompted to attempt the oxidat ion of fenchone (62), 26 under our usual oxidat ion condi t ions , by an ear ly report which described the oxidat ion of fenchone (62) to 5-ketofenchone (63) by chromium t r i o x i d e i n g l a c i a l ace t ic a c i d , and to 6-ketofenchone by chromium t r i o x i d e i n ace t ic anhydride ( i . e . by chromyl acetate) . As expected, oxidat ion of (-)-fenchone (62) with chromium t r i o x i d e i n a 1:1 mixture of g l a c i a l acet ic ac id and acet ic anhydride gave, after 3 days at room temperature, a 1:1 mixture of 5- and 6- ketofenchone (63,64) i n ca. 25% y i e l d . CrO 3 -Ac 2 0 AcOH v • • (63) +. (64) - 28 -Bornane (65) appears to be oxidized only at C-5 with chromyl 27 acetate to give epicamphor (66) , and a further in t e res t ing chromyl (65) (66) (67) " (68) (69) acetate oxidat ion i s that of t r i cyc locc tane (67) tc give t r i c y c l e [3 .3.0.0.] octan-3-one (68) and t r i c y c l o [ 3 . 3 . 0 . 0 . ] - o c t - 3 - y l acetate 28 (69) i n the r a t i o 9 :1 , and an o v e r a l l y i e l d of ca . 60%. I t i s in te res t ing to note that i n the presence of. ce r ta in mammalian and microb io log ica l systems camphor (39) i s also oxidized at the C-5 posi t ion. . In dogs, camphor i s oxidised to 3-hydroxycamphor 29 (70) and 5-hydroxycamphor (71). A pseudomonad, s t r a i n P, i so la ted from sewage and grown-on a medium containing camphor (39) y ie lded 30 5-ketocamphor (41) and both 5-exo and 5-endo-hydroxycamphor (71). The occurrence of cytochrome P-450 i n the (+)-camphor monooxygenase 31 from Pseudomonas putida has been reported. This enzyme i s present i n high concentrations i n the c e l l s of a s t r a i n of Pseudomonas putida grown on camphor, and i s responsible for the f i r s t hydroxylating step i n - 29 -the degradation of camphor to 5-hydroxycamphor. (71) I t seems probable that the laboratory and natural trans-formation of bicyclo[2.2.1.]heptane der ivat ives may be due, i n par t , to a general molecular property which, h i t he r to , has not been f u l l y recognised: namely, that ce r ta in compounds are vulnerable to oxidat ion at saturated centres remote from func t i ona l i t y . - 30 -2. Remote Oxidation of Fat ty Acid Esters As a c r u c i a l test of the above hypothesis we examined the oxidat ive v u l n e r a b i l i t y of fa t ty acid esters . The oxidat ion of fa t ty acids leads to a va r i e ty of well-known na tu ra l ly occurring compounds such as prostaglandins, polyacetylenes, fungal metabolites and unsaturated fa t s . However, i t i s probably v a l i d to state that i n the absence of some b e l i e f i n "oxidat ive s u s c e p t i b i l i t y at remote centres" one would predic t that the simple d i r ec t oxidat ive mono-functionaliza-t i o n of fa t ty acids i n the laboratory would be d i f f i c u l t to achieve. 33 However, we have found that treatment o f pure methyl stearate (72; n=16) i n g l a c i a l acet ic ac id / ace t i c anhydride with chromium t r i -oxide i n acet ic anhydride ( i . e . chromyl acetate) at room temperature for 24 hours provided a mixture o f methyl ketostearates (73; x+y=15) ** and s t a r t ing mater ia l . The ketoesters were separated from s t a r t i ng material by column chromatography ( s i l i c a g e l ; 98:2 pet. ether:ether) and t h e i r i d e n t i f i c a t i o n as methyl mono-ketostearates i s based on ana lys i s , mass spectrum, infrared and NMR data. The inf rared spectrum (CCl^) showed absorption bands at 1750 and 1720 cnf*. The NMR spectrum -exhibi ted resonances-at T 9.07 ( t , 3H, C H ^ - ( C H ^ ) , 8.75, 8.45 (broad s, m, 24H, CH 3 - (CH_ 2 ) 1 2 ) , 7.73 (3 overlapping t r i p l e t s , 6H, -CH 2 C0 2 CH 3 , - CH 2C0CH 2-) and 6.40 (s, 3H, -C0 2 CH 3 ) . In add i t ion , the correct molecular ion peak at m/e 312 was observed i n the mass spectrum. The y i e l d of recovered methyl x-ketostearates was ca. 65% based on consumed s t a r t ing mate r ia l . G . L . C . examination of the crude react ion product indicated a much higher y i e l d . - 3 1 -- 32 -Anal . Calcd. for C ^ H ^ C y C, 73.07, H, 11.54. Found: C, 72.91; H, 11.60. This structural.assignment was supported by sodium borohydride reduction to the corresponding hydroxyesters (75), which were i n turn converted to the acetoxy esters (74) and the unsaturated esters (76). The r e l a t i v e amounts and i d e n t i f i c a t i o n of each of the monoketo der ivat ives of methyl stearate present i n the product mixture was deduced from the mass spectra** of the corresponding ethylene acetals 34 (77, x+y=15) and ethylene th ioaceta ls (78,x+y=15). In the low and high reso lu t ion spectra of (77) and (78) measured at 15eV and 70 eV the only s i g n i f i c a n t peaks are due to fragments (79a,b) and (80a,b). However, the fragmentation process was non-random when the aceta l or th ioace ta l group was located towards the end of the chain and th i s i s re f lec ted i n the differences between the two sets o f resu l t s displayed i n figures 3-6. In sp i te of these l i m i t a t i o n s i t seems reasonable to conclude that methyl stearate i s susceptible to oxidat ion and that there i s modest s e l e c t i v i t y for attack at b i o l o g i c a l l y in te res t ing pos i t i ons . Subsequent studies have shown that methyl decanoate (72; n=8), methyl myristate (72;n=12), methyl palmitate (72;n=14) and methyl doco-sanoate (72;n=20) are also converted to a mixture o f monoketo der iva-t ives when treated with chromyl acetate so lu t i on . In each case the charac ter isa t ion and estimation of the r e l a t i v e amounts of isomeric ketoesters was accomplished by the procedures described above. The t o t a l § The low and high reso lu t ion mass spectra were recorded at 15eV and 70eV on At las CH-4 and A . E . I . MS902 instruments. - 35 -r e s u l t s , summarised i n figures 3-18, indicate that the oxidat ion of methyl stearate (figures 3-6) and methyl docosanoate (figures 7-10) i s more r eg iospec i f i c than that of the lower homologs (figures 11-18). The ana ly t i c a l method described previously i s only v a l i d i f we can assume that the r e l a t i v e i n t e n s i t i e s of the peaks i n the mass spectra of the ethylene acetals (77) and ethylene th ioaceta ls (78) are a true representation of the r e l a t i v e amounts of isomeric ketoesters present i n the product mixture. We bel ieve th i s to be a reasonable assumption provided that the i n t e n s i t y of the parent peak i n the mass spectrum i s not greater than 3-4% of the t o t a l i n t ens i ty of the peaks corresponding to fragments (79a,b) and (80a,b) i . e . provided that the acetal (77) or th ioace ta l (78) i s t o t a l l y fragmented. I t i s i n t e res t ing to note that i n a s i t ua t i on where the parent peak i s quite large (figure 9) there i s a considerable decrease i n the i n t e n s i t y of the peaks corresponding to fragments (79a) and (80a) and t h i s i s re f lec ted i n f igure 9 as compared to figures 7,8 and 10. However, the shape of the curve i n f igure 9 remains s i m i l a r - t o those i n figures 7,8 and 10. Several pieces of evidence provide some support for the v a l i d i t y of the a n a l y t i c a l method used to estimate the r e l a t i v e amounts of isomeric ketoesters.—Diborane i n tetrahydrofuran was added to a so lu t ion o f methyl oleate.(81) i n tetrahydrofuran, af ter 24 hours at room temperature sodium hydroxide and hydrogen peroxide were added to g ive , after a further 24 hours, a mixture of methyl 9- and 10-hydroxystearate (82a,b). Jones' oxidat ion o f (82a,b) gave an approximately 1:1 mixture of methyl 9- and 10-ketostearate (83a,b). The mass spectra of the mixture of acetals and th ioaceta ls derived from - 34 -OH CH (CH •) CH = CH(CH 2 ) y C0 2 CH 3 * CH 3 (CH 2D x CH(CH 2 ) y C0 2 CH 3 (81) (82a);x=8,y=7 0 II (82b),x=7,y=8 C H 3 ( C H 2 ) x - C - ( C H 2 ) y C 0 2 C H 3 (83a);x=8,y=7 (83b),x=7,y=8 the 1:1 mixture of methyl 9- and 10- .ketostearate (83a,b) showed c lear fragmentation and provided a quant i ta t ive estimation i n reasonable agreement with the known composition of the mixture (figures 19 and 20). In the oxidat ion of methyl decanoate (72;n=8) careful chromatography ( s i l i c a g e l ; 98.2 pet. ether:ether) of the product provided three fract ions (A, B and C) with g . l . c . (3% SE 30, 155°) retent ion times of 2 .1 , 2.5 and 2.7 minutes respec t ive ly . The separate f ract ions were converted to the corresponding acetals and -thioacetalSjand the r e l a t i v e proport ion of p o s i t i o n a l isomers i n each f rac t ion determined by the mass spectroscopic method described above. The resu l t s are displayed i n f igures 21-32 and c l e a r l y show that f r ac t ion A (figures 21-23) i s mainly a mixture o f methyl 4- and 5- ketodecanoate, f rac t ion B (figures 24-28) i s a mixture o f methyl 6- , 7- and 8- ketodecahoates and f rac t ion C (figures 29-32) i s methyl 9-ketodecanoate. These resu l t s support the conclusion (cf. figures 17 and 18) that oxidat ion of methyl decanoate (72;n=8) occurs at - 35 -posi t ions 4-9. The acetal mixtures derived from fract ions A, B and C were separately examined by g . l . c . (3% SE 30, 155°) and, although complete reso lu t ion was not achieved, i t was noted that f rac t ion A consisted of 2 peaks (retention times, 4 and 5.5 minutes), f r ac t ion B showed 2 peaks, one broad, (retention times 5.5 and 6.5 minutes) and f rac t ion C was a s ingle peak (retention time 7 minutes). -These r e su l t s , coupled with the mass spect ra l data (figures 21-32), provide some support for the v a l i d i t y of the a n a l y t i c a l method we have used to estimate the r e l a t i v e amounts of isomeric ketoesters. Attempts to increase the s e l e c t i v i t y of the oxidat ion by decreasing the react ion time to 2-3 hours were unsuccessful for methyl decanoate (72;n=8). This i s c l e a r l y shown by figures 33 and 34 which are very s i m i l a r to the r e su l t s obtained from the 24 hour oxidat ion of methyl decanoate (figures 17 and 18). I t i s possible that more success w i l l be achieved with methyl stearate (72;n=16) and methyl docosanoate (72;n=20), and inves t iga t ions are continuing i n th i s area. While the mechanism of these reactions remains uncer ta in , i t seems reasonable to suggest that the p a r t i a l l y se lec t ive oxidat ion of fa t ty acid esters may be associated with the preferred conformation(s) of these compounds i n the react ion medium. 20 36 -i a 16 14 12 10 1 2 3 4 7 8 9 10. 11 12 13 14 1 5 16 17 18 Si tes o f Oxidation F i g . 3. OXIDATION of METHYL STEARATE [Data from low reso lu t ion (15 eV) spectrum of acetals (77; x+y=15): -x x- based on fragment (79a) -o ,—o- based on fragment (80a)]. -37-o • __g • by 1 2 3 4 ...5 6 7 8 9 10 11 12 13 14 15 16 17 18 Si tes of Oxidation F i g . 4. OXIDATION of METHYL STEARATE [Data from low reso lu t ion (70 eV) spectrum of acetals (77; x+y=15): -x x- based on fragment (79a): - o — o - based on fragment (80a)]. - 38 -x -—-x 4 5 6 7 8 9 . 10 11 12 13 14 15 16 Si tes of Oxidation OXIDATION of METHYL STEARATE [Data from low reso lu t ion (70 eV) spectrum of thioacetals (78; x+y=15): -x x- based on fragment (79b) - o — o - based on fragment (80b)]. - 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Si tes o f Oxidation F i g . 6. OXIDATION of METHYL STEARATE [Data from high reso lu t ion (70eV) spectrum of acetals (77; x+y=15): -x x- based on fragment (79a) - o — o - based on fragment ( 80a)]. 20 - 40 -18 16 14 12 10 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Si tes of Oxidation F i g . 7. OXIDATION of METHYL DOCOSANOATE [Data from low reso lu t ion (15 eV) mass spectrum of th ioaceta ls (78; x+y=19): - x — x - based on fragment (79b) - o — o - based on fragment (80b)]. - 41 -5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Si tes of Oxidation OXIDATION of METHYL DOCOSANOATE [Data from low reso lu t ion mass spectrum (70 eV) of th ioaceta ls (78; x+y=19: - x — x - based on fragment (79b): -o o- based on fragment (80b)]. - 42 -5 6 7 8 -9 10 11 12 1 3 14 15 16 17 18 19 20 Si tes of Oxidation OXIDATION of METHYL DOCOSANOATE [Data from low reso lu t ion mass spectrum (15 eV) of acetals (77; x+y=19: -x x - based on fragment (79a): _o o- based on fragment (80a)]. - 43 -Si tes of Oxidation OXIDATION of METHYL DOCOSANOATE [Data from high reso lu t ion mass spectrum (70 eV) of acetals (77; x+y=19) : -x—x- based on fragment (79a): _ 0 . — o - based on fragment (80a)]. - 44 -L2 : ; a 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Si tes of Oxidation OXIDATION of METHYL PALMITATE [Data from low reso lu t ion (70 eV) spectrum of acetals (77; x+y=13); - x — x - based on fragment (79a) - o — o - based on fragment (80a)]. - 45 -3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Sites of Oxidation OXIDATION of METHYL PALMITATE [Data from low resolution (70 eV) spectrum of thioacetals (78; x+y=13): -x—x- based on fragment (79b): -o—o- based on fragment (80b)]. - 46 -3 4 5 6 7 8 9 10 11 12 13 - 14 15 16 Si tes o f Oxidation OXIDATION of METHYL PALMITATE [Data from low reso lu t ion CIS eV) spectrum of acetals (77; x+y=13): -x x- based on fragment (79a): _ 0 — o - based on fragment (80a)]. 8 9 10 11 Sites of Oxidation 13 14 17 18 Fig. 14. OXIDATION of METHYL MYRISTATE [Data from low resolution CIS eV) spectrum of thioacetals (78; x+y=ll): - x — x - based on fragment (79b): - o — o - based on fragment (80b)]. - 48 -3 4 5 6 , 7 8 9 10 11 12 13 • 14 .. 15 16 17 Sites of Oxidation OXIDATION of METHYL MYRISTATE [Date from low resolution (70 eV) spectrum of thioacetals (78; x+y=ll): -x x- based on fragment (79b) -o — o - based on fragment (80b)J. - 49 -44 - 5 0 -30 Si tes of Oxidation F ig - 17> OXIDATION of METHYL DECANOATE [Data from low reso lu t ion ( 1 5 eV) spectrum of th ioaceta ls (78; x+y=7): -x x- based on fragment (79b) - o — o - based on fragment (80b)]. - 51 -3 4 5 6 7 8 9 Si tes of Oxidat ion OXIDATION of METHYL DECANOATE [Data from' low r e s o l u t i o n (70 eV) . spectrum of th ioace ta l s (78; x+y=7): -x x - based on fragment (79b) -o o- based on fragment (80b)]. - 52 -C H 3 ( C H 2 ) x s s" Sites of Relat ive % D i s t r i b u t i o n Oxidation Intensi ty HIGH RESOLUTION 9(x=8) 70.8 10(x=7) 70.1 50.2% 49.8% LOW RESOLUTION AT 15 eV 9(x=8) 1.10 47.8% I0(x=7) 1.20 52.2% LOW RESOLUTION AT 70 eV 9(x=8) 11.65 51.0% 10(x=7) 11.20 49.0% +S S ( C H 2 ) y C0 2CH 3 Si tes of Rela t ive \ Oxidation Intensi ty HIGH RESOLUTION 9(y=7) 58.6 10(y=8j 50.8 D i s t r i b u t i o n 53.5% 46.5% LOW RESOLUTION AT 15 eV 9(y=7) 1.15 51.2% 10(y =S) 1.10 LOW RESOLUTION AT 70 eV 9(x=7) 12.00 51.4% 10(y=8) 11.35 48.6% F i g . 19 Mass spect ra l data from th ioace ta l of methyl 9- and 10- ketostearate - 53 -I \ 0 0 + C H 3 ( C H 2 ) X - C Si tes of Rela t ive % D i s t r i b u t i o n Oxidation Intensi ty HIGH RESOLUTION 9(x=8) 26.7 48.5% 10(x=7) 28.3 51.5% LOW RESOLUTION AT 15 eV 9Cx=8) 1.10 52.4% n nn ± , uu LOW RESOLUTION AT 70 eV 9(x=8) 11.45 48.8% 10(x=7) 12.00 51.2% I 1 C —(CH 2 ) C0 2 CH 3 Si tes of Relat ive % D i s t r i b u t i o n Oxidation In tens i ty HIGH RESOLUTION 9(y=7) 19.8 48.0% 10(y=8) 21.4 52.0% LOW RESOLUTION AT 15 eV 9(y=7) 1.10 48.8% I i n r Q-\ " - V 1 1 C LOW RESOLUTION AT 70 eV 9(y=7) 11.00 48.5% 10(x=8) 11.65 51.5% F i g . 20 Mass spect ra l data from acetal of methyl 9-and 10- ketostearate 2 3 4 5 6 7 8 Si tes of Oxidation F i g . 21. OXIDATION of METHYL DECANOATE [Data from low reso lu t ion (15 eV) spectrum of th ioaceta ls (78; x+y=7) [FRACTION A ] : -x x- based on fragment (79b): -o o- based on fragment (80b)]. - 55 -40 t 30 20 H o •H « J •M H OT •H Q 10 Sites of Oxidation Fig. 22. OXIDATION of METHYL DECANOATE [Data from low resolution (70 eV) spectrum of thioacetals (78; x+y=7) [Fraction A]: -x-—x- based on fragment (79b): - o — o - based on fragment (80b)]. - 56 Si tes of Oxidation F i g . 23. OXIDATION of METHYL DECANOATE [Data from high r e so lu t ion (70 eV) spectrum of acetals (77; x+y=7) [Fract ion A] : - x — x - based on " fragment (79a): - o — o - based on fragment (80a)]. 40 - 57 -2 3 4 5 6 7 8 9 Si tes of Oxidation F i g . 24. OXIDATION of METHYL DECANOATE [Data from low reso lu t ion (15 eV) spectrum of acetals (77; x+y=7) [FRACTION B ] : -x x- based on fragment (79a); - o — o - based on fragment (80a)]. - 58 S i tes of Oxidat ion F i g . 25 OXIDATION of METHYL DECANOATE [Data from low r e so lu t i on (70 eV) spectrum of aceta ls (77; x+y=7) [Frac t ion B ] : - x — x - based on fragment (79a): -o o- based on fragment (80a)]. - 59 -40 30 20 J3 O •H •P 3 .o •p tn 10 _0_ 2 3 4 5 6 7 8 9 S i t e s o f O x i d a t i o n F i g . 26. OXIDATION o f METHYL DECANOATE [Data f r o m h i g h r e s o l u t i o n (70 eV) spectrum o f a c e t a l s (77;x+y=7) [ F r a c t i o n B ] : - x — x - b a s e d on frag m e n t (79a): -o o- b a s e d on fragment ( 8 0 a ) ] . Si tes of Oxidation OXIDATION of METHYL DECANOATE [Data from low reso lu t ion CIS eV) spectrum of th ioaceta ls (78; x+y=7) [FRACTION B ] : - x — x - based fragment (79b): -o o- based on fragment (80b)]. 40 - 6 1 -X Sites of Oxidation Fig. 28. OXIDATION of METHYL DECANOATE [Data from low resolution (70 eV) ' spectrum of thioacetals (78; x+y=7) [Fraction B]: - x — x - based on fragment (79b); - o — o - based on fragment (80b)]. - 62 -4 5 8 ? 8 9 Si tes of Oxidation OXIDATION of METHYL DECANOATE [Data from low reso lu t ion ( 1 5 eV) spectrum of acetals (77; x+y=7) [FRACTION C ] : -x x - based on fragment (79a): -o o- based on fragment (80a)]. - 63 -2 3 4 5 6 7 8 Sites of Oxidation Fig. 30. OXIDATION of METHYL DECANOATE [Data from low resolution (70 eV) spectrum of acetals (77; x+y=7) [FRACTION C]: - x — x - based on fragment (79a): - o — o - based on fragment (90a)]. 100 6 4 -o-x o X -O. 2 3 4 5 6 7 8 Si tes of Oxidation F i g . 31: OXIDATION of METHYL DECANOATE [Data from low reso lu t ion CIS eV) spectrum of th ioaceta ls (78; x+y=7) [FRACTION C] : -x x - based on fragment (79b): -o o- based on fragment (80b)]. Sites of Oxidation Fig, 32. OXIDATION of METHYL DECANOATE [Data from low resoltuion (70 eV) spectrum of thioacetals (78;x+y=7) [Fraction C] ; - x — x - based on fragment (79b): - o — o - based on fragment (80b)]. - 66 -^ * : : : 9. 2 3 4 5 6 7 8 9 Site of Oxidation Fig. 33. TWO HOUR OXIDATION of METHYL DECANOATE [Data from low resolution (15 eV) spectrum of thioacetals (78;x+y=7): -x x- based on fragment (79b): - o — o - based on fragment (80b)]. - 67 -40 30 20 c o 3 Xi •H u •p tn •H a 10 2 3 4 5 6 . 7 Sites of Oxidation Fig. 34. TWO HOUR OXIDATION of METHYL DECANOATE [Data from low resolution (70 eV) spectrum of thioacetals (78;x+y=7): - x — x based on fragment (79b): - o — o - based on fragment (80b)]. - 68 -3. Remote Oxidation of Sesquiterpenes In e a r l i e r inves t iga t ions of monoterpene acetates i t was demonstrated that isobornyl acetate (37) could be converted to the 5-keto der iva t ive and that the l a t t e r compound could then be rearranged to 5-ketocamphene (42) (40) (42) This react ion sequence forms the basis of current studies i n the sesquiterpene area and i n an i n i t i a l i nves t iga t ion i t was demonstrated that dihydroisocampherenyl acetate (87) could be trans-formed i n a s i m i l a r fashion to 5-ketodihydro -B-santalene (90) [Scheme 4 ] . Campherenone (84) was treated with 10% Pd-C and hydrogen to give dihydrocampherenone (85) which provided dihydroisocampherenol (86) on reduction with l i t h ium aluminium hydride. Dihydroisocampher-enol (86) i n pyr id ine and ace t ic anhydride was heated at 90°C for - 69 -24 hours to give;, after chromatography over aluminium oxide (neutral Grade IV) , dihydroisocampherenyl acetate (87) as a colourless o i l . Appl ica t ion of the usual oxidat ion conditions (cf . p 19) to dihydroisocampherenyl acetate (87) provided l i t t l e or no product after several days. However, when chromyl acetate was added, i n the usual fashion, to dihydroisocampherenyl acetate (87) i n g l a c i a i ace t ic ac id /ace t ic anhydride and the so lu t ion heated at 90°C for Scheme 4 1 hour, the product was a mixture of s t a r t i ng material (10%) and one product (90%). Column chromatography of the mixture over aluminium oxide (neutral Grade IV) gave, by e lu t i on with pentane, 5-ketodihydro-- 70 -isocampherenyl acetate (88) i n ca. 25% y i e l d . The infrared spectrum of (88) showed absorption bands at 1745, 1730 and 1240 cm" 1 . The NMR spectrum of 5-ketodihydroisocampherenyl acetate (88) showed resonances at r 9.18 (s, 3H, t e r t i a r y methyl), 9.16 (s , 3H, t e r t i a r y methyl), 8.06 (s, 3H, acetate methyl), 7.67 ( m, 3H, -CH_2C0-, bridgehead H) and 5.36 (dd, IH, -CHOAc). In add i t ion , the expected molecular ion peak at m/e 280 was observed i n the mass spectrum. Hydrolysis and rearrangement of 5-ketodihydroisocampherenyl acetate (88), as for 5-ketoisobornyl acetate (38) (cf . p .20) , gave 5-ketodihydro-B-santalene (90). The infrared spectrum of (90) showed absorption bands at 1735, 1660 and 880 c m - 1 . The NMR spectrum of 5-ketodihydro-S-santalene (90) showed resonances at T 8.94 (s, 3H, t e r t i a r y methyl). 7;68 ( t , ?H - CH^m-), 7,32 (broad s, IH, " H y l i c bridgehead H) and 5.43 (d, 2H, CH^ = J • I n add i t ion , the expected molecular ion peak at m/e 220 was observed i n the mass spectrum. The app l i ca t ion of the oxidat ion procedure described above to i so longibornyl acetate (92) could provide a simple synthet ic route to 35 culmorin (95). Isolongibornyl acetate (92) has been oxidised with chromyl acetate, CrO^-A^O, and the product i s a mixture of s t a r t i ng material and two isomeric keto-acetates whose structures remain to be determined. The helminthosporanes are a group of sesquiterpenes elaborated - 71 -(91) ; (92) OH . (93) (94) (95) 36 by Helminthosporium sativum and H. v i c t o r i a e . In the o r i g i n a l reports heiminthosporal (98) and helminthosporol (100) were i so la t ed from H. sativum but subsequent inves t iga t ions indicated that these are artefacts derived from the true metabolites, prehelmin-thosporal (97) and prehelminthosporol (99). A s t r u c t u r a l l y re la ted sesquiterpene a l k a l o i d , v i c tox in ine (101) has been i so l a t ed from the 37 cul ture f i l t r a t e of H. v i c t o r i a e . Heiminthosporal (98) i s a t o x i n , which along wi th the fungus, i s responsible for widespread seedling b l i g h t , foot and root ro t and l ea f spot of cereals . One reason for the attempted synthesis of (46) and (48) (cf. p. 23) , the monoterpene analogues of heiminthosporal (98) and helminthosporol (100), was the hope that these monoterpenes might prove to be an t i t ox ins . - l i -lt has been suggested that sativene (102) could be the b i o l o g i c a l precursor of prehelminthosporal (97) and preheiminthosporol (99), and ce r t a in ly the co-occurrence of these compounds would tend to support t h i s postulate . While the cleavage of the appropriate bond i n sativene may be poss ible i n an enzyme catalysed react ion there i s no laboratory precedent for such a process and a synthetic approach based on th i s b iosynthet ic proposal presents considerable problems. However, i f a su i tab le de r iva t ive o f sativene i s considered as a synthet ic intermediate the C-C bond cleavage becomes more reasonable. Many der iva t ives are of course poss ib le but i t was considered that ketosativene (103) might be admirably su i ted to i t s ro l e as a synthet ic precursor of heiminthosporal and de r iva t ives . The i n t i t i a l ob jec t ive , therefore, i s the development o f a s tereospeci f ic synthesis of ketosativene (105) and one of the approaches under consideration involves adaption of the sequence of reactions 19 (Scheme 5) developed for the synthesis of sat ivene. C l e a r l y , the key reac t ion i n the proposed route to ketosativene (103) would be to introduce oxygen func t iona l i ty in to the 5-posi t ion of i so longibornyl acetate (106) and the p o s s i b i l i t y of accomplishing th i s by d i r ec t oxidat ion wi th CrO^-Ae^O/AcOH i s being inves t igated. The oxidat ion of isobornyl acetate (37) and of dihydroiso-campherenyl acetate (87) at the 5-pos i t ion wi th chromyl acetate i n - 74 -g l a c i a l acet ic ac id suggests that the d i r ec t oxidat ion of isoylango-bornyl acetate (106) may be poss ib le . I n i t i a l studies have shown that isoylangobornyl acetate (106) i s indeed oxidised by chromyl acetate i n g l a c i a l acet ic ac id . However, isoylangobornyl acetate appears to be extremely susceptible to oxidat ion (oxidat ion i s complete wi th in a matter of hours at room temperature) and the product i s a mixture of a number of compounds. Studies are continuing i n t h i s area i n an attempt to character ize the products and to increase the s e l e c t i v i t y of the oxidat ion process, poss ib ly by carrying out the react ion at low temperature and/or by various solvent e f fec ts . - 75 -EXPERIMENTAL , 5-Ketoisobornyl acetate (38) Chromium t r i o x i d e (90 g.) was ca re fu l ly added to ace t ic anhydride (145 ml.) cooled i n an ice-ba th . The r e su l t i ng so lu t ion was added dropwise over a period of two days to an i c e - c o l d so lu t ion of i sobornyl acetate (37) (66 g . , 0.314 moles) i n g l a c i a l ace t i c acid (280 ml) and acet ic anhydride (125 ml.) and af ter 8 days at room temperature saturated sodium bicarbonate so lu t ion was caut iously added tc the reac t ion mixture. Excess ace t ic anhydride was removed under reduced pressure and the r e s u l t i n g green so lu t ion extracted with ether (4 x 200 ml) . The combined extracts were washed successively with 5% sodium hydroxide, saturated sodium bicarbonate so lu t ion and water. Af ter drying (anhydrous sodium s u l f a t e ) , removal of solvent provided a pale yellow o i l (53 g.) which was shown by g . l . c . (3% SE 30) to consis t of 5-ketoisobornyl acetate (38) (59%), isobornyl acetate (37) (34%) ancTcamphor (39) (6%). The y i e l d of product based on consumed s t a r t i ng mater ia l was 66%. F rac t iona l d i s t i l l a t i o n of the o crude o i l provided pure 5-ketoisobornyl acetate (38), b .p . 108-114 (1.0 mm): v (CC1J 1750, 1385, 1365, 1420, 1230 cm" 1 , T (CC1., 60 MHz) max 4 . • • v 4 J 9.23 (s , 3H, C H 3 _ ) , 9.14 (s, 3H, CH_3_), 8.97 (s, 3H, CH_ 3-), 8.08 (s, 3H, CH 3 C0 2 _) , 5.26, (dd, IH, - CHOAc); m/e 210 (M+) - 76 -5-Ketoisobomeol (40) 5-ketoisobornyl acetate (38) (9g. , 0.043 moles) was treated i -with a so lu t ion of sodium carbonate (6 g.) i n water (150 ml) and methanol (90 ml.) for 48 hours at 40-50° C. After coo l ing , the reac t ion mixture was extracted wi th ether (4 x 150 ml . ) and the combined extracts dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided a white s o l i d (6.9 g, 95%) which was r e c r y s t a l l i z e d from benzene-petroleum ether to give pure 5-ketoisoborneol (m.p. 142-144°) . v (CC1,) 3490, 1745, 1410, 1385, 1365 c m - 1 ; T ( C C 1 , , 60 MHz) max 4 4 9:31 (s, 3H, CH 3 _) , 9.19 (s , 3H, C H ^ ) , 9.09 (s, 3H, CH-) , 6.70 (dd, IH, - CHOH), 5.51 (broad s, IH , - OH); m/e 168 (M + ) . Ana l . Calcd. for C - . H ^ O . : C, 70.42; H, 9.53. Found: C, 70.33; H, 9.63. 5-Ketocamphor (41) Jones' reagent (CrO^-H^O^-^O) was added dropwise to 5-ketoisoborneol (40) (160 mg., 0.001 moles) i n acetone (15 ml . ) u n t i l oxidat ion was complete._ Removal of acetone under reduced pressure and work up i n the usual way provided 5-ketocamphor (41) as a white s o l i d (135 mg., 85%) m.p. 209-211° (from pet. e ther) . Vmax ( C C V 1 7 5 0 ' 1 3 8 5 ' 1 3 6 5 c m ~ 1 , T ( C C 14> 6 0 fflz) 9.05 (s, 3H, C H 3 - ) , 9.00 (s , 3H, C H 3 - ) , 8.95 (s , 3H, CH_ 3-). - 77 -5-Ketocamphene (42). Methanesulfonyl chlor ide (15 g . , 0.013 moles) was added to a so lu t ion of 5-ketoisoborneol (40) (7 g . , 0.029 moles) i n pyr id ine (315 ml.) and the reac t ion mixture was s t i r r e d , under n i t rogen, at 90-95° for 24 hours. After coo l ing , the so lu t ion was d i l u t ed with water and extracted with ether (4 x 150 m l . ) . The combined extracts were washed with d i l u t e hydrochlor ic a c i d , saturated sodium chlor ide so lu t ion , and dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided a dark coloured o i l (6.2 g.) which was shown by g . I . e . to be a mixture of two components (approximate r a t i o 3:1) . Column chromatography of the mixture over aluminium oxide (neutral Grade IV) gave, by e lu t ion with pet. ether, 2.7 g. of 5-ketocamphene (42) (62%) and 0 . 8 g. of a mixture o f the two components. Further chroma-tography provided a pure sample of the minor component (43). 5-ketocamphene exhibi ted the fol lowing cha rac t e r i s t i c s : v (CC1.) 3050, 1745, 1650, 890 cm" 1 , x (CC1., 60 MHz) 8.98 (s, 3H, max 4 v 4 " ' V ' ' C H 3 - ) , 8.89 (s, 3H, C H 3 - ) , 8.4-7.6 (m, 5H), 6.95 (broad s, IH, a l l y l i c bridgehead H) , 5.12 (d, 2H, J=13 Hz; CH_2= ) ; m/e 150 (M+) : The minor component exhibi ted cha rac te r i s t i c s consistent with those of 3-ketotr icyclene (43). v (CC1.) 1745, 1385, 1365 cm" 1 J v . • max v 4' ' ' x ( C C l 4 , 60 MHz) 9.07 (s , 3H, CH_ 3-), 9.03 (s, 3H, CH 3 -) 8.83 (s , 3H, - 78 -5-Ketocamphene hydrochloride (52) Anhydrous calcium chlor ide (22 g.) was added to a so lu t i on of 5-ketocamphene (42) (1.1 g . , 0.073 moles) i n ether (88 ml ) . The mixture was cooled i n an ice-bath and dry hydrogen chlor ide bubbled through the mixture for 3 hours. After 3 days at room temperature the so lu t ion was f i l t e r e d and the ether extracts washed with saturated sodium bicarbonate s o l u t i o n , saturated sodium chlor ide s o l u t i o n , and dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided 5-ketocamphene hydrochloride (52) as a white s o l i d (800 mg., 65%) m.p. 149-153° (from methanol) v x (CC14) 1750, 1385, 1365 cm" 1 ; T (CC1 4,.60'MHZ) 9.00 (s, 3H, CH_ 3-), 8.72 (s, 3H, Cti^-), 8.36 Anal . Calcd. for C 1 Q H 0C1: . C, 64.34; H, 8.03; C l , 19.04. Found: C, 64.22; H, 7.88; C l , 19.15. 6-bromo-5-ketocamphene (53) Butyl l i t h ium (2 m l . , 2 mmoles) was added to a so lu t ion of 5-ketocamphene (42) (300 mg., 2 moles) and dicyclohexylamine (380 mg., 2 mmoles) i n tetrahydrofuran (2 ml) under ni t rogen. After 15 minutes at room temperature, bromine (320 mg, 2 mmoles)in methylene chlor ide - 79 -(1 ml.) was added at -78°C. After one minute, the so lu t ion was quenched with saturated sodium bicarbonate so lu t ion and extracted with pet. ether (3x). The combined extracts were washed with saturated sodium bicarbonate so lu t ion and saturated sodium chlor ide so lu t ion . After drying (anhydrous sodium s u l f a t e ) , removal of solvent provided a yellow o i l (335 mg.) which was shown by g . l . c . (3% SE 30) to be a mixture of s t a r t i ng mater ia l and one product (approximate r a t i o 1:4). Column chromatography of the mixture over aluminium oxide (neutral Grade I) gave, by e lu t ion with pet . ether, 6-bromo-5-ketocamphene (53) (230 mg, 50%). v (CC1.) 1745, 1650, 895 cm" 1 , T (CC1„, 60 MHz) 8.85 max K AJ K 4 (s , 5H, C H , - ) , 8.75 (s, 3K, CH^-) , 7.70 (m, 311)., 6.73 (broad s, IH, bridgehead), 6.53 (d, IH, J=10 Hz, endo-CHBr-), 6.20 (d, IH, J=3Hz, exo-CHBr-), 4.87 (d, 2H, J=14 Hz, OLy' = .-) - 80 -Oxidation of fenchyl acetate (-54) Chromium t r i o x i d e (7 g.) was ca re fu l ly added to ace t ic anhydride (11.ml.) and the r e su l t i ng s o l u t i o n added dropwise over a * period of one day to a cold mixture of fenchyl acetate (54) (5 g, 0.025 moles) i n g l a c i a l ace t ic ac id (20 ml) and ace t ic anhydride (9 m l . ) . After 4 days at room temperature saturated sodium bicarbonate so lu t ion was added caut iously to the reac t ion mixture. Excess ace t ic anhydride was removed under reduced pressure and the r e s u l t i n g green so lu t ion extracted wi th ether (4 x 100 m l . ) . The combined extracts were washed successively wi th 5% sodium hydroxide., saturated sodium bicarbonate so lu t ion and water. After drying (anhydrous sodium s u l f a t e ) , removal of solvent provided a colourless o i l (3.5 g. 65%) which exhibi ted two peaks, i n the approximate r a t i o 3 :1 , on g . l . c . (3% SE 30, 140° , re tent ion times 4.6 and 7 minutes). v (CC1.) 1750 (broad), 1240 c m - 1 , max 4 * The n.m.r . spectra of fenchyl acetate (54) ind ica ted that i t consisted of a mixture of exo and endo acetates i n the approximate r a t i o 5:3. - 81 -5- and 6- ketofenchol (56a,b) A mixture of 5- and 6- ketofenchyl acetate (55a,b) (1 g , 0.0042 moles) was treated wi th a so lu t ion of sodium bicarbonate (0.7 g) i n water (17 ml.) and methanol (10 ml) for 3 days at 40-50°C. After coo l ing , the reac t ion mixture was extracted with ether (4 x) and the combined extracts dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided a colourless o i l (700 mg, 85%). v ( C C 1 J 3500, 1745, 1380, 1360 cm" 1 , max v 4 5- and 6-ketofenchone (57,58) Jones' reagent (CrO^-H^SO^-^G) was added dropwise to a mixture of 5- and 6-ketofenchol (56a,b) (700 mg., 0.0041 moles) i n acetone (50 ml.) u n t i l oxidat ion was complete. Removal of acetone under reduced pressure and work up i n the usual way provided a colourless o i l (630 mg, 90%) which exhibi ted two peaks, i n the approximate r a t i o 3 :1 , on g . l . c . (3% SE 30, 140°, re tent ion times 2.0 and 2.8 minutes). Column chromatography of the mixture over aluminium oxide (neutral Grade I) gave, by e lu t ion with pet. ether, a pure sample of each component. The major component exhibi ted cha rac te r i s t i c s consistent with those of 5-ketofenchone (57). v ( C C 1 J 1750, 1380, 1360 *• . max 4' cm" 1 , x (CC1 4 , 100 MHz) 9.04 (s, 3H, CH_3~), 8.92 (s, 3H, CH_3~), - 82 -8.82 (s, 3H, CH_ 3-), 8.04 (m, 4H), 7.56 (broad s, IH, bridgehead). The minor component exhibi ted cha rac te r i s t i c s consistent with those of 6-ketofenchone (58). v (CCTJ 1750, 1385, 1365 ^ 3 max 4 c m - 1 x (CC1 4 , 100 Mz) 9.05 (s, 3H, CH_ 3-), 8.98 (s , 3H, CH_ 3-), 8.95 (s, 3H, CH_ 3-), 8.02 (s , IH, bridgehead), 7.86 ( t , 2H), 7.58 ( t , 2H). Oxidation of (-)-fenchone (62) Chromium t r i o x i d e (7 g.) was ca re fu l ly added to ace t i c anhydride (11 ml.) and.the r e s u l t i n g so lu t ion added dropwise over a period of one day to a cold mixture of (-)-fenchone (62) (5 g . , 0.033 moles) i n g l a c i a l acet ic acid (20 ml) and ace t ic anhydride (9 m l . ) . After 3 days at room temperature, work up, as described for fenchyl acetate (cf . p . 80) provided a colourless o i l (1.24 g . , 23%). G . l . c . analysis (3% SE 30) indicated a 1:1 mixture of 5-and 6-ketofenchone (57,58) plus several minor products which were -not character ized. v (CC1.) 1750, 1385, 1365 cm" 1 , max v 4 Oxidation of methyl stearate (72; n=16) Chromium t r i o x i d e (7 g.) was ca re fu l ly added to ace t i c anhydride (11 ml) and the r e su l t i ng so lu t ion added dropwise over a period of one hour to a cold mixture o f methyl stearate (72; n=16) - 83 -(5 g . , 0.017 moles) i n g l a c i a l acet ic acid (20 ml.) and ace t ic anhydride (9 m l . ) . After 24 hours at room temperature saturated sodium bicarbonate so lu t ion was caut iously added to the react ion mixture. Excess acet ic anhydride was removed under reduced pressure and the r e su l t i ng green so lu t ion extracted with ether (4 x 100 m l . ) . The combined extracts were washed successively wi th 5% sodium hydroxide, saturated sodium bicarbonate so lu t i on and water. After drying (anhydrous sodium su l f a t e ) , removal of solvent provided a c r y s t a l l i n e s o l i d (4*5 g.) which was shown by g . l . c . (3% SE 30) to consis t of methyl stearate (50%) and a mixture of methy ketostearates (50%) (unresolved on g . l . c ) . Careful column chromatography of the mixture over s i l i c a gel gave, by e lu t ion with pet. ether/ether (98:2), a pure mixture o f methyl ketostearates (73; x+y=15) (1.9 g . , 65% based on consumed s t a r t i ng ma te r i a l ) . m a x (CC1 4 ) : 1750, 1720 cm" 1 : (CC1 4 > 100 MHz) 9.07 ( t , 3H, C H 3 - ( C H 2 ) n ) , 8.75, 8.45 (broad s, m, 24 H, C H 3 - (CH_2) n ) , 7.73 0 (3 overlapping t r i p l e t s , 6H, CH 2 C0 2 CH 3 , -CH^C-CJHy, 6.40 (s , 3H, - C O 2 C H 3 ) . Ana l . Calcd. for C i n H , , 0 7 : C, 73.07; H, 11.54. Found: i y 3D O C, 72.91; H, 11.60. ~ - 84 -Methyl hydroxystearates (75) Sodium borohydride (50 mg.) i n water... (1 ml.) was added dropwise to a so lu t ion of methyl ketostearates (73;x+y=15) (56 mg. 0.0002 moles) i n methanol (3 ml.) After 2-1/2 hours at room temperature, excess sodium borohydride was destroyed by the addi t ion of d i l u t e hydrochloric acid and the so lu t ion extracted with ether (3x). The combined extracts were washed with saturated sodium chlor ide so lu t ion and, after drying (anhydrous sodium su l f a t e ) , removal of solvent provided a quant i ta t ive y i e l d of a c lear o i l (56 mg.) which c r y s t a l l i z e d on standing. Vmax ( C C V 3 4 0 0 > 1 7 4 0 c m _ 1 ; T ( C C 1 4> 6 0 m z ' 9 - 1 4 (*» 3 H > C H 3 - ( C H 2 ) n ) , 8.72 (broad s, 28H, CH 3 - ( a y ) , 7.80 (m, 3H, -Methyl acetoxystearates (74) Methyl hydroxystearates (75) (125 mg., 0.0004 moles) i n pyr id ine (4 ml.) and acet ic anhydride (0.75 ml.) was heated at 80° for 24 hours. Af ter cool ing the so lu t i on was d i l u t ed with water and extracted with ether (3x). The combined extracts were washed with d i l u t e hydrochloric a c i d , saturated sodium chlor ide s o l u t i o n , and dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided a mixture of methyl acetoxystearates (74) (116 mg. 92%). vmax ( C C V 1 7 5 0 , 1 2 4 0 C m ~ 1 ; T ( C G 1 4 ' 1 0 0 m Z j 9 , 1 2 m > CH 3 - ( C H 2 ) n ) , 8.74 (broad s, 28H, CH 3 - (CH_ 2 ) 1 4 ) , 8.05 (s, 3H, -- 0 2 CCH 3 ) , 7.78 ( t , 2H, - CH_ 2C0 2CH 3), 6.40 (s, 3H, - C 0 2 C H 3 ) , 5.20 (m, IH, CHOAc). - 8 5 -Methyl octodecenoate (76) A mixture of methyl hydroxystearates (75) (650 mg., 0.002 moles) i n benzene (26 ml.) was treated with p-toluene su l fon ic ac id (350 mg.) at r e f lux i n a Dean-Stark apparatus for two days. After coo l ing , saturated sodium bicarbonate so lu t ion was added and the so lu t ion extracted with ether (3x). After drying (anhydrous sodium su l f a t e ) , removal of solvent gave an orange o i l (560 mg., 90%). v (CC1J 1750, 1660, 725 cm" 1 , x (CC1., 60 MHz) 9.10 max 4 v 4 ( t , 3H, C H 3 - ( C H 2 ) n ) , 8.72, 8.10 (broad s, m, 26H, CH 3 (CH_ 2 ) 1 3 ) , 7.60 (m, 2H, - CH_2C02Me), 6.40 (s, 3H, - C0 2CH_ 3), 4.63 (broad s, 2H, - CH=CH-)> m/e 296 (M + ) . Methyl ketostearate acetals (77;x+y=15) Ethyl orthoformate (2 m l . ) , ethylene g l y c o l (1 ml) and p-toluenesulfonic ac id (5 mg.) were added to methyl ketostearate (100 mg.). After 1 hour at 90° , the so lu t ion was heated at 150° for 2 hours while excess ethyl orthoformate d i s t i l l e d of f . After coo l ing , saturated sodium bicarbonate so lu t ion was added and the so lu t ion extracted with ether (3x). The combined extracts were washed with saturated sodium chlor ide so lu t i on . After drying (anhydro sodium su l f a t e ) , removal of solvent .provided a quant i ta t ive y i e l d of acetals (77,x+y=15). - 86 " v (CC1J 1745, 1150 cm" 1 , T (CC1., 100 MHz) 9.12 ( t , 3H, max 4 4 C H 3 - ( C H 2 ) n ) , 8.76, 8.48 (broad s, m, 28H, C H 3 - (CH_2) 1 4 ) , 7.77 ( t , 2H, J=7Hz, - CH 2 C0 2 CH 3 ) , 6.40 (s, 3H, -C0 2CH ) , 6.18 (s, 4H, - OCH^CJ^O-) . Methyl ketostearate th ioaceta ls (78,x+y=15j Methyl ketostearate (73) (100 mg.) and ethanedi thiol (0.25 ml.) i n g l a c i a l ace t ic acid (3.2 ml.) were warmed to 50° and boron t r i f l u o r i d e etherate (0.25 ml.) added. After 3 hours at room temperature, the so lu t ion was d i l u t ed with water and extracted with ether (3x). The combined extracts were washed with saturated sodium bicarbonate so lu t ion and saturated sodium chlor ide so lu t i on . After drying (anhydrous sodium s u l f a t e ) , removal of solvent provided a quant i ta t ive y i e i d of th ioaceta ls (78,x+y-15). v (CC1J 1745 cm" 1 x (CC1„, 100 MHz) 9.14 ( t , 3H, CH_-max v 4 v 4 v —3 ( C H 2 ) n ) , 8.74, 8.48 (broad s, m, 28H, CH 3 -(CH 2 ) ) , 7.80 ( t , 2H, -CH 2 C0 2 CH 3 ) , 6.82 (s, 4H, - SCH^CH^S-), 6.43 (s, 3H, - C O ^ H ^ ) . Oxidation of methyl myristate (72:n=12) Chromium t r i o x i d e (8 g.) was ca re fu l ly added to ace t ic anhydride (14 ml) arid the r e su l t i ng so lu t ion was added dropwise over a period of one hour to a cold mixture o f methyl myristate (72; n=12) (5 g . , 0.020 moles) i n g l a c i a l ace t ic acid (24 ml.) and acet ic anhydride (10 m l . ) . After 24 hours at room temperature, work up, as described for methyl stearate (cf . p . 8 2 ) , provided a green o i l (4.6 g.) - 87 -which was shown by g . l . c . (3% SE 30) to consist of methyl myristate (44%) and a mixture of methyl ketomyristates (55%) (unresolved on g . l . c ) . Chromatography, as described for methyl s tearate, provided a pure mixture of methyl ketomyristates (73;x+y=ll) (1.3 g . , 30% based on consumed s t a r t i ng mate r i a l ) . v ( C C 1 J : 1750, 1720 cm" 1 : x (CC1„, 100 MHz) 9.10 ( t , 3H, max1 4J ' 4 • CH - ( C H J J , 8.74, 8.50 (broad s, m, 16 H, CH - ( C H 0 ) 0 ) , 7.76 (3 —j Z 6 —Z o overlapping t r i p l e t s , 6 H, - CH_ 2C0 2CH 3, -CH^-CH^-), 6.43 (s, 3 H, - C 0 2 C H 3 ) . Anal . Calcd .. .for C 1 C H 0 0 0 7 : C, 70.31; H, 10.94. i b Zo 6 Found: C, 70.21; H, 10.79. Oxidation of methyl palmitate (72,n=14) Chromium t r i o x i d e (8 g.) was ca re fu l ly added to acet ic anhydride (14 m l . ) . The r e su l t i ng so lu t ion was added dropwise over a period of one hour to a cold mixture of methyl palmitate (72,n=14) (5.6 g . , - 0.020 moles) i n g l a c i a l ace t ic ac id (24 ml.) and ace t ic anhydride (10 m l . ) . After 24 hours at room temperature, work up as described above provided a c r y s t a l l i n e s o l i d (4 g.) which was shown by g . l . c . (3% SE 30) to consist of methyl palmitate (39%) and a mixture of methyl ketopalmitates (59%) (unresolved on g . l . c ) . Chromatography, as described for methyl s tearate, provided a pure mixture of methyl keto-palmitates (73,x+y=13) (1.3 g, 31% based on consumed s t a r t ing mate r i a l ) . - 88 -v ( C C 1 J : 1750, 1725 cm" 1 : T (CC1. , 100 MHz) 9.15 ( t , 3H, max 4 s 4 CH„-(CH 2 ) n ) , 8.76, 8.50 (broad s, m, 20H, Cti^CH^) 1 Q ) , 7.76.(3 over-lapping t r i p l e t s , 6H, -CH C02CH , - C H 2 - C - C H 2 - ) , 6.44 (s, 3H, -C0 2CH_ 3). Ana l . Calcd. for C^^Oy C, 71.82; H, 11.27. Found: C, 71.78; H, 11.46. Oxidation of methyl docosanoate (72;n=20) Chromium t r i o x i d e (8 g.) was ca re fu l ly added to ace t i c anhydride (14 ml.) and the r e s u l t i n g so lu t ion was added dropwise over a period of one hour to a cold mixture of methyl docosanoate (72, n=20) (5 g . , 0.014 moles) i n g l a c i a l ace t ic acid (24 ml.) and ace t ic anhydride (10 m l . ) . Af ter 24 hours at room temperature, work up as described above provided a c r y s t a l l i n e s o l i d (4.8 g.) which was shown by g . l . c . (3% SE 30) to consist o f methyl docosanoate (55%) and a mixture of methyl ketodocosanoates (45%) (unresolved on g . l . c ) . Chromatography, as described for methyl ketostearate, provided a pure mixture of methyl ketodocosanoates (73,x+y=19) (1.3 g . , 48% based on consumed s t a r t i ng mate r ia l ) . Vmax CCC14) 1750, 1715 cm" 1 : x (CC1 4 , 100 MHz) 9.12 ( t , 3H, CH -(CH ) ) , 8.76, 8.50 (broad s, m, 32 H, C H , - ( C H _ ) . , ) , 7.77 (3 —o l n 0 overlapping t r i p l e t s , 6 H, - C H 2 C 0 2 C H 3 > -CH -C-CH - ) , 6.44 (s, 3H, -C0 2 CH 3 ) Anal . Calcd. for C 2 3 H 4 4 0 3 : C, 75.00; H, 11.95. Found: C, 75.18; H, 11.96. - 89 -Oxidation of methyl decanoate (72;n=8) Chromium t r i o x i d e (8 g.) was ca r e fu l l y added to ace t ic anhydride (14 ml) and the r e s u l t i n g so lu t ion added dropwise over a period of one hour to a co ld mixture of methyl decanoate (72,n=8) (5 g . , 0.025 moles) i n g l a c i a l acet ic acid (24 ml.) and acet ic anhydride (10 ml) . After 24 hours at room temperature, work up, as described above, provided a green o i l (4.7 g.) which was shown by g . l . c . (3% SE 30) to consis t o f methyl decanoate (50%) and a mixture o f methyl ketodecanoates (50%) (unresolved on g . l . c ) . Chromatography, as described for methyl s tearate , provided a pure mixture of methyl ketodecanoates (73,x+y=7) (2.4 g, 65% based on consumed s t a r t i ng mate r i a l ) . v m a x ( C C l 4 ) : 1750, 1725 cm" 1 : T (CC1 4 > 100 MHz) 9.10 ( t , 3H, C H 3 - ( C H 2 ) 4 ) , 8.70, 8.45 (broad s, m, 8H, CH 3 (CH_ 2 ) 4 , 7.98 (s, 3H, C H 3 - C - ( C H 2 ) n ) , 7.74 (3 overlapping t r i p l e t s , 6H, - . ,9 " CH 2 C0 2 CH 3 , - C H 2 - C - C H 2 - ) , 6.44 (s , 3H, - C O ^ j y . Anal . Calcd. for C 1 1 H 2 Q 0 3 : C, 66.00; H , 10.00. Found: C, 66.11; H, 9.91. - 90 -Acetals of methyl ketodecanoate (73;x+y=7), methyl ketomyristate (73;x+y=ll), methyl ketopalmitate (73;x+y=13, methyl ketodocosanoate (73;x+y=19). The oxidat ion products (100 mg) from methyl decanoate (72;n=8), methyl myristate (72;n=12), methyl palmitate (72;n=14), and methyl docosanoate (72;n=20) were converted to the acetals as described for methyl ketostearate. The I .R . and N.M.R. character-i s t i c s of these acetals were s i m i l a r to those of methyl ketostearate acetal (77;x+y=15). Thioacetals of methyl ketodecanoate (73;x+y=7), methyl ketomyristate (73;x+y=19). The oxidat ion products (100 mg.) from methyl decanoate (72;n=8), methyl myristate (72;n=12), methyl palmitate (72;n=14), and methyl docosanoate (72;n=20) were converted to the th ioace ta l s , as described for methyl ketostearate. The I .R. and N.M.R. character-i s t i c s of these thioaceta ls were s i m i l a r to those of methyl ketostearate th ioaceta l (78;x+y=15). - 91 -Methyl 9- and 10-ketostearate (83a,b) A so lu t ion of diborane i n tetrahydrofuran (IM; 15 ml.) was added to a so lu t ion of methyl oleate (81) (2.96 g . , 0.01 moles) i n tetrahydrofuran (100 ml) at 0°C and the reac t ion mixture subsequently s t i r r e d for 24 hours at room temperature. Aqueous sodium hydroxide (IM; 20 ml.) and hydrogen peroxide (30%; 5 ml.) were added and after 24 hours at room temperature tetrahydrofuran was removed under reduced pressure. Ext rac t ion with ether (3 x 100 ml.) and work up i n the usual way provided methyl 9- and 10-hydroxystearate (82a,b) (3.4 g.) which, without further p u r i f i -cat ion was dissolved i n acetone (100 m l . ) . Jones' reagent (CrC^-M ? S0 4 -H 7 C) v;as added dropwise u n t i l oxidat ion was complete. Removal of acetone under reduced pressure and work up . in the usual way provided a mixture of methyl 9- and 10-ketostearate. (83a,b). Vmax ^ C C 1 4 ^ 1 7 5 0 , 1 7 2 0 c m _ 1 T ( C C 1 4 » 1 0 0 MHz). 9.12 ( t , 3H, C H 3 - ( C H 2 ) n ) , 8.74, 8.48 (broad s, m, 24H, C H 3 - (CH_2) u ) , 7.74 (3 overlapping t r i p l e t s , 6H, - CH 2 C0 2 CH 3 , - CH2C0CH_2~), 6.41 (s, 3H, - C 0 2 C H 3 ) . Methyl 9- and 10-ketostearate acetal Ethyl orthoformate (2 m l . ) , ethylene g l y c o l (1 ml.) and p-toluenesulfonic acid (5 mg.) were added to a mixture of methyl 9- and 10 ketostearate (83a,b) (100 mg.). After 1 hour at 90° , - 92 -the so lu t ion was heated at 150° for 2 hours while excess e thyl orthoformate d i s t i l l e d of f . After coo l ing , saturated sodium b i -carbonate so lu t ion was added and the so lu t ion extracted with ether (3x). The combined extracts were washed with saturated sodium chlor ide so lu t ion . After drying (anhydrous sodium su l f a t e ) , removal of solvent provided a quant i ta t ive y i e l d o f aceta ls . vmax ( C C V 1 7 4 5 ' 1 1 5 0 c m _ 1 ' T ( C C 1 4 » 1 0 0 m Z j ( - t ' 3 H * C H 3 - ( C H 2 ) n ) , 8.76, 8.48 (broad s, m, 28 H, CH (CH_2) 4 ) , 7.77 • ( t , 2H, J=7 Hz, - CH 2 C0 2 CH 3 ) , 6.40 (s , 3H, - C0 2CH ) , 6.18 (s, 4H, - OCH 2CH_ 20-).-Methyl 9- and 10-ketostearate t h ioace t a l . A mixture of methyl 9- and 10-ketostearate (83a,b) (100 mg.) and ethanedi thiol (0.25 ml.) i n g l a c i a l ace t ic acid (3.2 ml.) was warmed to 50° and boron t r i f l u o r i d e etherate (0.25 ml.) added. After 3 hours at room temperature, the so lu t ion was d i l u t e d with water -and extracted with ether (3x). The combined extracts were washed with saturated sodium bicarbonate s o l u t i o n , saturated sodium chlor ide so lu t i on . After drying (anhydrous sodium su l f a t e ) , removal of solvent provided a quant i ta t ive y i e l d of th ioace ta l s . Vmax ( C C V 1 7 4 5 c m ~ 1 ' T (CC1 4 , 100 MHz) 9.14 ( t , 3H, C H 3 - ( C H 2 ) n ) , 8.74, 8.48 (broad s, m, 28H, CH 3~ (CH_2) 1 4 ) , 7.80 ( t , 2H, -CH 2 C0 2 CH 3 ) , 6.82 (s, 4H, - SCH2CH_2S- ) , 6.43 (s, 3H, - C 0 2 C H 3 ) . - 93 -Oxidation of Methyl decanoate (72;n=8) Chromium t r i o x i d e (8 g.) was ca re fu l ly added to acet ic anhydride (14 ml.) and the r e s u l t i n g so lu t ion was added dropwise over a period of one hour to a cold mixture of methyl decanoate (72;n=8) (5 g . , 0.025 moles) i n g l a c i a l acet ic acid (24 ml.) and ace t ic anhydride (10 ml.) After 24 hours at room temperature, work up, as described above, provided a green o i l (3.7 g.) which was shown by g . l . c . (3% SE 30) to consist of methyl decanoate (51%) and a mixture of methyl ketodecanoates (49%) ( p a r t i a l l y resolved on g . l . c ) . Chromatography, as described for methyl s tearate, provided three fract ions (1.65 g. 38% based on consumed s t a r t i ng mater ia l ) . Frac t ion A (retention time 2.1 min . ; 3% SE 30, 155°) v (CC1J 1745, 1720 cm" 1 , x (CC1„, 100 MHz) 9.14 ( t , 3H, C1L-max v 4 ^ 4 —3 (CH_) ) , 8.72, 8.45 (broad s, m, 8H, CH_(CH_).), 7.74 (m, 6H, £ n 0 — - CH 2 C0 2 CH 3 , - CH -C-CH 6.44 (s, 3H, - C O ^ j y , Fract ion A (100 mg.) was converted, i n quant i ta t ive y i e l d , as described for methyl ketostearate (cf. p .85) , to the acetal (77;x+y=7) which exhibi ted two peaks on g . l . c . (3% SE 30, 155°) (retention times, 4 and 5.5 minutes), v (CC1.) 1745, 1180 cm 1 , J max K 4J ' ' x (CC1., 100 MHz) 9.12 ( t , 3H, CH - (CHJ ) , 8.60 (m, 12H, C H , ( C H J J , 7.76 ( t , 2H, - CH 2 C0 2 CH 3 ) , 6.44 (s, 3H, - C02CH_3) , 6.18 (s, 4H, - 0CH_2CH20-). The resu l t s from the mass spectra l analysis of the acetal of f rac t ion A are shown i n f i g . (23). - 94 -Fract ion A (100 mg.) was converted, i n quant i ta t ive y i e l d , as described for methyl ketostearate (cf . p . 8 6 ) , to the th ioace ta l (78;x+y=7). (CC14) 1745 cm" 1 , x (CC1 4 , 100 MHz) 9.12 ( t , 3H •CH -(CH ) ) , 8.40 (m, 12H, CH 3 (CH_ 2 ) 6 ) , 6.80 (s, 4H, - . SCH2CH_2S-) , 6.44 (s, 3H, - C02CH_3) . The resu l t s from the mass spectra l analysis of the th ioace ta l of f r ac t ion A are shown i n f i g s . (21), (22). Frac t ion B (retention time 2.5 min, 3% SE 30, 155°) v (CC1J 1745, 1720 cm" 1 , x (CC1J 9.12 ( t , 3H, CH - C H J ) 8.58 max 4 4 —3 2 r\J (m, 8H, CH -CH ) ) , 7.72 (3 overlapping t r i p l e t s , 6H, -CH CO CH , Q J z 4 Z Z o - C H 2 - C - C H 2 - ) , 6.44 (s, 3H, - C O ^ ) . Fract ion B (100 mg.) was converted i n quant i ta t ive y i e l d , to the acetal (77;x+y=7) which exhibi ted two peaks on g . l . c . (3% SE 30, 155°) (retention times. 5.5 and 6.5 minutes), v (CC1 .) 1745. v - max v . H 1170 cm" 1 , x (CC1 4 , 100 MHz) 9.12 ( t , 3H, CH - C H ^ ) , 8.60 (m, 12H, C H 3 - ( C H 2 ) 6 ) , 7.79 ( t , 2H, J=7Hz, - CH_ 2C0 2CH 3), 6.44 (s, 3H, - C 0 2 C H 3 ) , 6.22 (s, 4H, - OCH_2CH20-). The resu l t s from the mass spect ra l analysis of the acetal of f r ac t ion B are shown i n f i g s . (24), (25), (26). Fract ion B (100 mg) was converted i n quant i ta t ive y i e l d , to the th ioace ta l (73;x+y=7) v m & x (CC14) 1745 cm" 1 , x (CC1 4 > 100 MHz) 9.12 ( t , 3H, C H - ( C H _ ) " ) , 8.40 (m, 12H, CH,(CH„),) , 7.79 ( t , 2H, —o z n 6 —l o J=7Hz, - CH 2 C0 2 CH 3 ) , 6.82 (s, 4H, -SCH_2CH_2S-) , 6.44 (s, 3H, - C0 2CH_ 3). The resu l t s from the mass spect ra l analysis of the th ioace ta l of f rac t ion B are shown i n f i g s . (27), (28). - 95 -Fract ion C (retention time 2,7 mins . , 3% SE 30, 155°) v (CC1J 1750, 1725 cm" 1 , T (CC1., 100 MHz) 8.70, 8.42 max v AJ 4 ' 0 (broad s, m, 10H, C H 3 ( C H 2 ) 5 ~ ) , 7.98 (s, 3H, CH - C - C H 2 ) n ) , 7.82 3 o n ( t , 2H, J=8Hz, - CH 2 C0 2 CH 3 ) , 7.69 ( t , 2H, J=7Hz, CH 3-C-CH_ 2-) , 6.44 (s, 3H, - C0 2 CH 3 ) . Fract ion C (100 mg.) was converted, i n quant i ta t ive y i e l d , to the acetal (77;x+y=7) which exhibi ted one peak on g . l l c . (3% SE 30, 155°) (retention time, 7 minutes) v (CC1.) 1750, 1175 cm" > j v. > J m a x ^ 4; x (CC1 4 , 100 MHz) 8.80 (s, 3H, CH_ 3-C-OCH 2CH 20-), 8.70, 8.44 (broad s, m, 12H, CH 3 (CH_ 2 ) 6 ) , 7.78 ( t , 2H, - CH_ 2C0 2CH 3), 6.44 (s, 3H, - C 0 2 C H 3 ) , 6.20 (s , 4H, - OCH2CH_20-). The resu l t s from the mass spectra l analysis of che acetal of f r ac t ion C arc chcv.T. i n f i g s . (29), (30). Frac t ion C (100 mg.) was converted, i n quant i ta t ive y i e l d to the th ioaceta l (78;x+y=7). (CC14) 1750 c m - 1 T (CC1 4 , 100 MHz) 8.66, 8.50 (broad s, m, 12H, C H , ( C F L ) J , 8.32 (s, 3H, CH_-6 —Z o —J C-SCH 2 CH 2 S-), 7.78 ( t , 2H, -CH 2 C0 2 Me), 6.78 (s, 4H,-SCH_2CH_2S-), 6.44 (s , 3H, -C0 2CH_ 3). The resu l t s from the mass spect ra l analysis of the th ioaceta l of f r ac t ion C are shown i n f i g s . (31), (32). - 96 -Dihydrocampherenone (85) Campherenone (84) (1 g . , 0.0045 moles) i n ethyl acetate (100 ml.) was treated with 10% Pd-C (150 mg.) and hydrogen for 4 hours. After f i l t r a t i o n of the so lu t i on , removal of solvent provided dihydrocampherenone (85) as a colourless o i l (940 mg. 94%). v (CC1J 1740. cm" 1 , max 4 Dihydroisocampherenol (86) Dihydrocampherenone (85) (940 mg., 0.0042 moles) i n dry ethyl ether (150 ml.) was treated with excess l i t h ium aluminium hydride at ref lux for 24 hours. After coo l ing , e thyl acetate was added to destroy excess l i t h ium aluminium hydride and the so lu t ion chlor ide so lu t ion , and dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided dihydroisocampherenol (86) as a colourless o i l (780 mg., 84%). v (CC1.) 3500 cm" 1 , max 4 Dihydroisocampherenyl acetate (87) Dihydroisocampherenol (86) (780 mg. 0.0035 moles) i n pyr id ine (3 ml.) and acet ic anhydride (0.5 ml.) was heated at 90° for 24 hours. After coo l ing , the so lu t ion was d i l u t ed with water and extracted with' ether (3x). The combined extracts were washed successively with d i l u t e hydrochloric ac id , saturated sodium bicarbonate so lu t ion and - 97 -saturated sodium chlor ide s o l u t i o n . After drying (anhydrous sodium su l fa t e ) , removal of solvent provided a dark coloured o i l . . Column chromatography over aluminium oxide , (neutra l Grade IV) gave, by e lu t ion with pet. ether, dihydroisocampherenyl acetate (87) (740 mg; 75%) as a colourless o i l - homogeneous by - g . l . c . analysis (3% SE 30, 170°) , [ a ] 2 2 - 31.3 (c. 3.61, CHC1 ) . v (CC1J 1745, 1240 cm" 1 . x (CC1., 60 MHz) 9.16 (s, 6H max v 4J ' v 4 ' K ' 2 CH - ) , 9.07 (s, 3H, CH 8.10 (s, 3H, - 0 2CCH_ 3), 5.40 (dd, IH, -CHOAc). Oxidation of dihydroisocampherenyl acetate (87) Chromium t r i o x i d e (840 mg.) was added to acet ic anhydride (8 ml.) and the r e su l t i ng so lu t ion added dropwise over a period of one hour to a cold mixture of dihydroisocampherenyl acetate (87) (430 mg., 0.0016 moles) i n g l a c i a l ace t ic ac id (7.2 ml.) and acet ic anhydride (2.8 m l . ) . The so lu t ion was heated at 90° for 1 hour and, after coo l ing , saturated sodium bicarbonate so lu t ion was caut iously -added to the react ion mixture. Excess acet ic anhydride was removed under reduced pressure and the r e s u l t i n g green so lu t ion extracted with ether (4x). The combined extracts were washed successively with 5% sodium hydroxide, saturated sodium bicarbonate so lu t ion and saturated sodium chlor ide so lu t ion . After drying (anhydrous sodium su l f a t e ) , removal of solvent gave a yellow o i l (187 mg.) which was shown by g . l . c . analysis (3% SE 30, 170°) to consist of dihydroisocampherenyl acetate (87) (10%) and one product (90%) (retention time 7.1 minutes). - 98 -Column chromatography of 120 mg, of the mixture over aluminium oxide (neutral Grade IV) gave, by e lu t ion wi th pentane, 5-ketodihydroisocampherenyl acetate (88) (70 mg., 24%). v (CC1J 1745, 1730, 1240 cm" 1 , x (CC1., 100 Hz) max A 4 9.18 (s, 3H, CH - ) , 9.16 (s, 3H, CH - ) , 8.06 (s, 3H, -0 CCH ) , • 0 / 6 7.67 (m, 3M, - CH^-C-, bridgehead H) , 5.36 (dd, IH, -CHOAc); m/e 280 (M + ) . 5-Ketodihydroisocampherenol (89) 5-ketodihydroisocampherenyl acetate (88) (48 mg., 0.0002 moles) was treated with a so lu t ion of sodium carbonate (25 mg.) i n water (1 ml) and methanol (0.6 ml.) for 24 hours at 40-50° . A i t e r coo l ing , the react ion mixture naz extracted ",'ith ether (4x) and the combined extracts dr ied (anhydrous sodium su l f a t e ) . Removal of solvent provided 42 mg. of a yellow o i l , homogeneous by g . l . c . analysis (3% SE 30, 170°, re tent ion time 11.3 minutes). v (CC1J 3450, 1725, 1410 cm" 1 , x (CC1., 60 MHz) 9.17 max 4 . 4 . ; ; ; (s, 3H, C H 3 - ) , 9.10 (s, 3H, CH^-) , 6.42 (dd," IH, - CHOH)-."'"' 5-ketodihydro-g- santalene (90) Methane su l fonyl chlor ide (90 mg.) was added to a so lu t ion of 5-ketodihydroisocampherenol (89) (42 mg. 0.00018 moles) i n pyr id ine (1 ml . ) ' and the react ion mixture was heated at 100°, - 9 9 -under ni t rogen, for 48 hours. After coo l ing , the so lu t ion was d i lu ted with water and extracted with ether (4x). The combined extracts were washed with d i l u t e hydrochloric acid and saturated sodium chlor ide so l tu ion and dried (anhydrous sodium su l fa te ) , Removal of solvent and column chromatography over aluminium oxide (neutral Grade I) gave, by e lu t ion with pet . ether/ether (90:10), 24 mg. (64%) 5-ketodihydro-B-santalene (90): homogeneous by g . l . c . analysis (3% SE 30, 170°; re tent ion time 3.8 minutes). v (CC1J 1735, 1660, 880 cm"1." x (CC1., 100 MHz) 8.94 max -4 4 0 n (s, 3H, C H 3 - ) , 7.68 ( t , 2H, -CH^C- ) , 7.32 (broad s, IH, • a l l y l i c bridgehead H) , 5.43 (d, 2H, J=13 Hz; CH_2=); m/e 220 (M + ) . - 100 -BIBLIOGRAPHY• A. W, Hofmann, Ber . , 16, 558 (1883); K. Lbf f l e r and C, Freytag, i b i d , 42, 3427 (1909). E. J . Corey and W.R. Her t l e r , J . Am. Chem. Soc. , 80, 2913 (1958) and 81_, 5209 (1959); P. Buchschacher, J . Kalvoda, D. Ar igon i and 0. Jeger, i b i d , 80, 2905 (1958). D.H.R. Barton, J . M . Beaton, L . E. Ge l l e r and M. M. Pechet, J . 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R. Breslow, Chem. Soc. Rev. , 1_, 553 (1972), 14. R. Breslow and M. A. Winnik, J . Am. Chem. Soc . , 91, 3083 (1969). 15. R. Breslow and S. W. Baldwin, J . Am. Chem. Soc . , 92, 732 (1970) 1.6. R. Breslow and P. K a l i c k y , J . Am. Chem. Soc . , 93, 3540 (1971). 17. R. Breslow, J . A. Dale, P. K a l i c k y , S. Y. L i u and W. N. Washburn, J . Am. Chem. S o c , 94, 3276 (1972). 18. R. Breslow, R. Corcoran, J . A. Dale, S. L i u and P. K a l i c k y , J . Am. Chem. S o c , 96, 1973 (1974). .19. G. L . Hodgson, D. F . MacSweeney, T. Money, J . C . S . Perkin I , 2113 (1973); i b i d , 1974, i n press. 20. J . Bredt and A. Goeb, J . Prakt . Chem, 101, 273 (1921) 21. J . Meinwald, J . C. Shelton, G. L . Buchanan and A. Cour t in , J . Org. rfce™ xx OQ r iQARi' • » — ** > v. j -22. R. Breslow, "Organic Reaction Mechanisms," W. A. Benjamin, Inc.New York, 1969 pp.210-212. R. Stewart, "Oxidation Mechanisms" (W.A.Benjamin, New York, 1964 23. E. Sigurdson, B . 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Comm., 1974 submitted for pub l i ca t i on . 34. We are grateful to Professor R. Breslow (Columbia) for h i s advice on t h i s method of analysing mixtures o f s t ra igh t -cha in ketones. 35. (a) D. H. R. Barton and N . H. Werstiuk, J . Chem. S o c , £ , 148 (1968); (b) B. W. Roberts, M. S. Poonian and S. C. Welch, J . Am. Chem. S o c , 91, 3400 (1969). 36. (a) P. de Mayo, R. Robinson, E. Y . Spencer and R. W. White, Experimentia, 1_8, 359 (1962); (b) P. de Mayo and R. E. Wi l l i ams , J . Am. Chem. S o c , 87, 3275 (1965); (c) P. de Mayo, R. E . Will iams amd E. Y. Spencer, Canad. J . Chem., 43, 3517 (1965) and references c i t e d ; (d) E\ J . Corey and S. Nozoe, J . Am. Chem. Soc . , 87, 5728 (1965). 37. F . Dorn and D. A r i g o n i , Chem. Comm., 1342 (1972). 

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