A smmmc APPROACH fro .. _ BEFANEDVANE SESQUITERPENES - e ' z mesis for the Degree of PIL De MICHIGAN STATE UNWERSITY KURT GEORGE GRIMM 1971 LIBRARY Michigan State University This is to certify that the thesis entitled A SYNTHETIC APPROACH TO BETA-VETIVANE SESQUITERPENES presented by KURT GEORGE GR IMM has been accepted towards fulfillment of the requirements for PH.D. Jame in CHEMISTRY Major professox lO--2-- I Date 7 0-7639 ABSTRACT A SYNTHETIC APPROACH TO BETA-VETIVANE SESQUITERPENES By Kurt G. Grimm The spiro[4,5]decane system plays an important role in sesquiterpene chemistry. Unfortunately, the methods available for the synthesis of these systems are limited in that little control is maintained over developing asymetric centers. An approach to spiro[4,5]decanes, based on cyclopropanol 2’6]decan-8- 1 ring opening reactions of 2-hydroxytricyclo[4.4.0.0 ones (1) was explored and found to be highly stereoselective. H (1) 2 (a) Using this valuable tool work was directed toward the synthesis of 8--vetivane sesquiterpenes. The l,7-dimethyl-2-hydroxytricyclo [4.4.0.02’6]decan-8-one (l,R]=R2=CH3) was transformed through Kurt G. Grimm a series of steps to dienone g which upon treatment with a cooper modified Grignard reagent2 gave dienone 3, a potential B-vetivane. REFERENCES l. Kurt Grimm, P.S. Venkataramani, w. Reusch, J. Amer. Chem. Soc., 3%, 270 (197l). 2. H. 0. House, R. Latham, C. Slater, J. Org, Chem., QT, 2667 (1966). A SYNTHETIC APPROACH TO BETA-VETIVANE SESQUITERPENES By Kurt George Grimm A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1971 DEDICATION To Jean Marie ii ACKNOWLEDGMENTS The author expresses his gratitude to Professor William H. Reusch for his guidance and assistance throughout the course of this investigation and for arranging financial support from January l970 to December 1971. This work was supported in part by National Institute of Health grant AM-10849 and National Science Foundation grant GP-l08l0. The author would also like to express his gratitude to M.E.T. and R.E.M. and most of all to J.M.G. for their help and moral support in the final weeks. EXPERIMENTAL TABLE OF CONTENTS General ....................... Preparation of cyclopentanone: pyrrolidine enamine (3,63) ...................... Trans-Z-ethylidenecyclopentanone ($2) ........ l0t-methyl-(5rC1)-spiro[4,5]decan-7-ene-l-one (50) 6t-methyl-(5rC1)-spiro[4,5]decan-l-one ($Z-DA). . l-methyl-2-hydroxytricyclo[4.4.0.0.2’6]decan-8-one (an) ...................... l0t-methyl-(5rC1)-spiro[4,5]decan-l,7-dione (QQ) lOt-methyl-(SrC1)-spiro[4,SJdecan-7-dithiolan-l-one (53) ...................... ”Vb 6t-methyl-(5rC1)-spiro[4,5]decan-l-one ($1-03). . . . 2-methyl-2-(3‘-oxopentyl)—l,3-cyclohexanedione (59) '\/'\1 A4-4,9-dimethyloctalin-3,8-dione (QQ) ........ l.7-dimethyl-2-hydroxytricyclo[4.4.0.02’6]decan-8- one (51) ..................... ’b’b 6t,lOt-dimethyl-(5rC])-spiro[4,5]decan-l,7-dione (Qg) ..................... 6t,lOt-dimethyl-(5rC])-spiro[4,5]decan-7t-ol—l-one (53) ...................... 6,lOt-dimethyl-(5rc1)-spiro[4,5]decan-6-ene-l-one (64) ...................... iv 33 33 33 34 35 36 36 38 39 40 41 42 43 44 45 46 TABLE OF CONTENTS - Continued 6t,lOt-dimethyl-(5rC1)-spiro[4,5]decan-7—acetoxy-l- one (12 R=Ac) .................. 47 6t,lOt-dimethyl-(5rC])-spiro[4,S]-7-decanol-2-ene-l- . one (as R=H) .................. 48 6t,lOt-dimethyl-(5rC1)-spiro[4,5]decan-7t-acetoxy-2- enePl-one (fig R=Ac) ............... 50 6,lOt-dimethyl-(5rC])-spiro[4,5]decan-2,6-diene-l- one (QQ) .................... 51 3-isopropenyl-6,lOt-dimethyl-(5rC1)-spiro[4,5]-6- decene-l-one (lg) ............... 53 FIGURES , , , ...................... 54 BIBLIOGRAPHY ....................... 103 Figure 10. ll. 12. l3. 14. LIST OF FIGURES Page Infrared spectrum of trans-Z-ethylidene- cyclopentanone (49) .............. 54 Vb Infrared spectrum of lOt-methyl-(SrC])- Spiro[4,5]decan—7-ene—l-one (SO) ....... 55 ’\/\.a Infrared spectrum of 6t-methyl-(5rC])- Spiro[4,5]decan-l—one (47) .......... 56 '\/L Infrared sgectrum of l-methyl-2-hydroxytricyclo [4.4.0.02, ]decan-8-one (44) ......... 57 Vb Infrared Spectrum of l0t-methyl-(5rC1)-spiro [4,5]decan-l,7-dione (45) ........... 58 "Vb Infrared spectrum of lOt-methyl-(SrC])-spiro [4,5]decan-7-dithiolan~l~one (53) ....... 59 'VC Infrared spectrum of 6t-methyl-(5rC])-spiro [4,5]decan-l-one (47) ............ 60 “4% Infrared sgectrum of l,7-dimethyl-2-hydroxytricyclo [4.4.0.02. ]decan-8-one (6]) ......... 6l ’Vb Infrared spectrum of 6t,lOt-dimethyl-(5rC])- spiro[4,5]decan-l,7-dione (62) ........ 62 m Infrared spectrum of 6t,lOt-dimethyl-(5rC1)- Spiro[4,5]decan-7t-ol-l-one (63) ....... 63 m Infrared spectrum of 6,lOt-dimethyl-(5rC])- Spiro[4,5]decan-6-ene-l-one (64) ....... 64 mm. Infrared spectrum of 6t,lOt-dimethyl-(5rC1)- spiro[4,5]decan-7t-acetoxy-l-one (72 R=COCH3) . 65 ’\/b Infrared spectrum of 6t,lOt-dimethyl-(5rC])- spiro[4,5]-7t-decanol-2-ene-l-one (55 R=H) . . 66 '\/b Infrared spectrum of 6t,l0t-dimethyl-(5rC1)- spiro[4,5]decan-7t-acetoxy-Z-ene-l-one (65 R=COCH3) ................. 67 ’VM vi LIST OF FIGURES (Cont.) Figures l5. l6. I7. 18. T9. 20. 21. 22. 23. 24. 25. 26. 27. 28. Infrared spectrum of 6,lOt-dimethyl-(5rC1)- Spiro[4,5]decan-2,6-diene-l-one (66) ..... Infrared spectrum of 3-isopropenyl-6,l0t- dimetnyi-(Srcl)-sp1ro[4,51-6-decene-1-one (it) Nmr spectrum of trans-2-ethylidenecyclopentanone (fig), (cc14) *“‘“‘ .............. Nmr spectrum of lOt-methyl-(SrC1)—Spiro[4,5] decan-7-ene—l-one (50), (CCl4) ..... "I/b ])-Spiro[4,5] l Nmr spectrum of 6t-methyl-(5rC decan-l-one (47-DA), (CCl4) OLA; ( ) Nmr spectrum of 6t—methyl- SrC )-spiro[4,5] decan-l-one (47-DA), (C6H ....... m 6 Nmr spectrum of l—methyl-2-hydroxytricyclo [4.4.0.Oze5Jdecan-8-one (44), (CDCl3) Nmr spectrum of lOt-methyl-(5r61)-Spiro[4,5] decan-l,7-dione (46), (CDCl3) ...... Nmr Spectrum of l0t-methyl-(5rC1)-spiro[4,5] decan-7-dithiolan-l-one (£3), (CDCl3) Nmr spectrum of 6t-methyl-(5rC1)-Spiro[4,5] decan-l-one (fig-OS), (CCl4) ....... Nmr spectrum of 6t-methyl-(5rC1)-Spiro[4,5] decan-l-one (47-DS), (C H ) ....... mm 6 6 Nmr spectrum of l,7-dimethyl-2-hydroxytricyclo [4.4.0.02.6]decan-8-one (6)), (CDCl3) Nmr specgrgm of l,7-dimethyl-2-hydroxytricyclo [4.4.0.0 . ]decan-B—one (6)), (C606) . Nmr spectrum of 6t,lOt-dimethyl-(5rC1)-Spiro [4,5]decan-l,7-dione (62), (C606) vii Page 68 69 7O 7) 72 73 74 75 76 77 78 79 8O 81 LIST OF FIGURES (Cont.) Figures 29. 30. 3T. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. Nmr Spectrum of 6t,lOt-dimethyl- (5rC])-spiro [4,5]decan-7t-ol-l-one (6%), (C6D6) Nmr Spectrum of 6,lOt-dimethyl-(5rC1)-Spiro [4,5]decan-6-ene-l-one (64), (CCl 'VL Nmr spectrum of 6t, lOt— -dimethyl- (5rC])- -spiro [4, 5]decan- 7t- -acetoxy- -l— -one (1% R: COCH 3) (c Nmr Spectrum of 6t,lOt-dimethyl-(5rC )- -spiro [4,5]-7-decanol-2-ene-l-one (66 R=H) (C606) Nmr spectrum of 6t,lOt-dimethyl-(5rC])-spiro [4,5]decan-7t-acetoxy-Z-ene-l-one (66 R=COCH3) Nmr Spectrum of 6,10t-dimethyl-(5rC1)-spir0 [4,5]decan—2,6-diene-l-one (66), (CCl4) Nmr spectrum of 3- iSOpropenyl- 6, lOt- dimethyl- (5rC])- spiro[4, 5]- 6- decene- 1- -one (78), (CCl4) Mass Spectrum of 6t-methyl-(5rC1)-Spiro[4,5] decan-l-one (fig-DA) ............. Mass Spectrum of l-methyl- 2- -hydroxytricyclo [4. 4. O. 02:6 ]decan- 8- -one (44) . ...... Mass spectrum of lOt-methyl-(SrC1)-Spiro[4,5] decan-l,7-dione (45) ............. ’V'L Mass spectrum of lOt-methyl-(SrC1)-Spiro[4,5] decan-7-dithiolan-l-one (53) . . ....... "UL Mass spectrum of 6t-methy1-(5rc‘)-sp1ro[4,5] decan-l-one (47-DS) ............. Mass Spectrum of l, 7— —dimethyl- 2 hydroxytricyclo [4. 4. 0. O2 6]decan-8 -one (6)) ......... Mass spectrum of 6t,lOt-dimethyl-(5rC1)-Spiro [4,5]decan-l,7-dione (62) . . . ........ ’V'b viii 4) ' ..... 6 D6) ' Page 82 83 84 85 86 87 88 89 9O 9) 92 93 94 95 LIST OF FIGURES (Cont.) Figures 43. 44. 45. 46. 47. 48. 49. Mass Spectrum of 6t,10t-dimethy1-(5rC1)-Spiro [4,5]decan-7t-ol-1—one (63) . . . . . ..... Mass Spectrum of 6t,10t-dimethyl-(5rC])-spiro [4,5]-7t-decanol~2-ene-l-one (66 R=H) Mass spectrum of 6,10t-dimethy1-(5rC1)-Spiro [4,5]decan-2,6-diene-1-one (66) . Mass spectrum of 3-isopropeny1-6,10t-dimethyl- (5r01)-Spiro[4,5]-6-decene-l—one (78) Ultraviolet Spectrum of trans-Z-ethylidene cyclopentanone (42) . . . . . . ....... Ultraviolet Spectrum of various 2-hydroxytricyclo [4.4.0.02,6]decanones . . . . . . ...... Ultraviolet Spectrum of various spiro[4,5] decan-2—ene-1-ones . . ........... ix Page 96 97 98 99 100 101 102 A SYNTHETIC APPROACH TO BETA—VETIVANE SESQUITERPENES INTRODUCTION Toutes Zes histoires anciennes, comme Ze Zisait unde nos beaux esprits, ne sont que des fables convenues. Francois-Marie Arouet (Voltaire) Jeannot et Colin Introduction During the last twenty-five years one of the most interesting developments in the field of terpene chemistry was the discovery that some sesquiterpenes contained the previously unknown Spiro[4,5]decane skeleton A' The first compound identified as having this novel l 2 3 ’b "b ”L I O U 0 I . structure was acorone g . The 1n1t1al structure eluc1dat1on was performed by Sorm and Herout? using a classical degradative approach. Since then other acorane derivatives have been noted in the sesquiterpene literature. A second class of Spiro[4,5]decane based sesquiterpenes can be regarded as derivatives of p-vetivone 3. Although all sesquiterpenes having a Spiro[4,5]decane skeleton could be classified in one family, 3 consideration of plausible biogenesis pathways for these compounds leads one to conclude that they fall into two categories. The acorane series can be envisioned as originating from a protonated bisabolene moiety 4, which is ultimately transformed into . 3g the bas1c Skeleton 6. 969 -—-= as o’ | G) 4 5 6 m ”b ’b Similar considerations of the B-vetivone group point to a common derivation by rearrangement of a eudesmane intermediate. This is 5 illustrated by the structure of hinesol Z, a compound believed to arise via a carbonium ion rearrangement of B-eudesmol 6 (natural sources 6 of hinesol usually contain B-eudesmol as well). Preliminary structural analyses of this kind help the chemist to plan rational synthetic approaches to these compounds. At the present time no Specific synthetic approaches to the acorane group have been reported, probably because the greater substitution of the five—membered ring poses a greater synthetic challenge. However, in recent years Several syntheses of the B-vetivane class have been described. In 1965 S. C. Bhattacharyya reported7 the isolation of agarospirol and assigned structure 1) to the compound on the basis of chemical 12% degradation and Spectroscopic analysis. Independent synthesis of the Spiro ketone )g, and comparison of this compound with an analogous substance derived from agarospirol revealed only minor differences, attributable to the stereochemical heterogeneity of the synthetic material. Indeed, the stereochemistry of structure L) was based on tenuous arguments regarding the nmr spectra of agarospirol and the reactivity of its hydroxyl group. The structure of agarospirol was unambiguously determined recently by a total synthesis by Deslongchamps8 and co-workers. The crucial step in this synthesis was the copper-catalized internal cyclization of diazoketone 13 to ketone 14 in a highly stereoselective manner IS «A (90% correct stereoisomer). On being subjected to the following sequence of reactions: carbomethoxylation, borohydride reduction, Grignard reaction, and aqueous acid treatment, ketone 14 gave the spiroketone 16 which on carbonyl reduction, monoacetylation, hydrogenolysis and lithium—ethyl amine reduction gave agarospirol in good yield. In 1967 Marshall9 and co-workers demonstrated that B-vetivone 3 possesses the Spiro[4,5]decan skeleton and not the previously acceptedl bicyclo[5.3.0]decane system 16. The clue leading to this reassignment of structure lay in the failure of the three epimeric synthetic 6,10-dimethy1-ci§;decahydroazulene—B-ones 17 to correlate with the epimeric desisoprOpylidenedihydro-B-vetivones prepared from B-vetivone}I In true Sherlok Holmes style Marshall showed that the original degradative studies on B-vetivone were also consistent with structure 3. Then through an elegant degradative study Marshall and Johnsongshowed that B-vetivone does in fact possess structure 3. As further proof of their assignment, Marshall and Johnsohzkgffected 14 a total synthesis of B-vetivone starting with the known cyclopropyl O ketone )8, which could be easily transformed into dieneone l2. After conversion to alcohol 20 (a mixture of C-2 epimers, one hinesol and the other agarOSpirol), racemic B—vetivone was obtained by the method used for the conversion of (-)-hinesol to (+)-8-vetivone}5 One of the most important results of Marshalls' work on B-vetivone was that it not only invalidated structure )6 for B-vetivone but it also cast a cloud of suspicion over the structural assignments of all bicyclic vetivane sesquiterpenes based on carbon skeleton fil- A few of the sesquiterpenes defrocked as a result are hinesol 7, the isovetivenes 22, bicyclovetivenol, and acorenone 33. Recently other spiro[4,5]decanes have come to light, notably a-vetispirene 24,5 B-vetispirene £55 o,-and B-alaskene 26,Aéand a 17 novel bromine containing compound called spirolaurenone 27. Of the above sesquiterpenes the one which has probably received the most attention is hinesol. This sesquiterpene was first isolated 1819 in 1961 by Sorm and co—workers, ' and Since then it has been the Subject of many investigationsmle including its conversion to B-vetivone.‘5 In 1969 Marshall and Brady fixed the spiro[4,5]decane structure of hinesol beyond all doubt by an unambiguous total synthesi522t23 Reaction of tricyclic dienone 28 with lithium dimethyl copper gave the expected saturated ketone as a mixture of anti_and syn_isomers. Unfortunately the desired product, enone 22, was the minor component. The carbonyl function was then shifted to C-8, and ketone 39 was converted to diol 31. Reaction with methane sulfonyl chloride (esterification of the secondary hydroxyl group) followed by base catalyzed fragmentation afforded compound 32, which was further elaborated to hinesol. CH 3 CH3. q: Br % 1 CH3 CH \H 31 "v’u Even though Marshall's work on hinesol was successful, it has several drawbacks: introduction of the C-2 methyl group in compound 29 gave mainly the wrong isomer, the carbonyl at C-4 had to be moved to a more effective position, and finally the synthesis was rather lengthy (32 steps). Among the synthetic approaches to compounds containing a spiro[4,5]decane skeleton we have noted diazoketone decomposition, photorearrangement of unsaturated ketones, and fragmentation of a suitably bridged tricyclic skelton. Recent additions to this list 24 should include annelation reactions described by Lawton (equation 1), 2b 9 Corey (equation 2),25 Patterson (equation 3) and Conia (equation 27 4) . Although these methods have not yet been used for the O 0 JR \\/1 i 7 +- \. e- t \'Br -““—-¢” / T//\ <:V;(E\~ 02CH3 cozcn3 OH Ht 1 ) c, 3 / —+- K 0C(Cxi3)3 ,,, cozcn3 BR 0 o + / Br__... .\ o ’ (3 CH “33 3 7’ A ———-—.u CH synthesis of Spiro sesquiterpenes they can clearly be adapted for such purposes. A weakness of many of these methods is their lack of control over developing asymmetric centers (asymmetric induction). RESULTS AND DISCUSSION It has long been an axiom of mine that the little things are infinitely the most important. Sir Arthur Conan Doyle A Case of Identity RESULTS AND DISCUSSION 28 Recent work from this laboratory has revealed the novel formation of cyclopropanol 35 during the Birch reduction of enone 34 and its subsequent ring opening to spiro[4,5]decane 36. This efficient sequence clearly has potential utility in the synthesis of spiro[4,5] decane sesquiterpenes, However, the Unknown stereochemistry of the cyclopropanol ring opening presents a major obstacle to the general usefulness of this approach. The stereochemistry of cyclopropanol ring opening reactions has been studied by a number of workers?9 Some excellent work, reported by DePuyIOindicates that ring Opening with dilute acid occurs with retention of configuration,while with base, inversion of configuration is the "modus operandi." This empirical rule is nicely illustrated using optically active trans—Z-phenyl-1—methylcyclopropanol 37 as the substrate. 11 12 1’ \\ CH ”Vb CoHs 3 % CH2 0 37 D 'j-qH ’Vb H 6H5 3 39 WW In 1966, Wharton and Blairaghowed that the dissociating power of the solvent plays an important role in the stereochemistry of ring opening. In their work, both exp; and gnggr7-hydroxy-l,6- dimethy1[4.l.Olbicycloheptane 40 were used to show that predominant retention 41 (90%) is observed upon base catalyzed opening in t-butyl ’Vb 13 alcohol and predominant inversion 42 occurs in ethylene glycol. In view of the above uncertainties regarding the stereo- chemistry of ring opening reactions it was necessary to demonstrate conclusively the stereochemistry of dione Q6 or its analogs. For sake of simplicity the comparison was made using the spirodiketone 233 J 3 45 which is readily prepared from the Wieland—Miescher ketone 43. Thus, reduction of ketone 43 by a solution of lithium in ether/ liquid ammonia, produces l-methyl-2~hydroxytricyclo[4.4.O.02’6] decan-8-one 44 in up to 80% yield. The infrared spectrum of 44 exhibits absorptions at 3411 and 1696 cm'] ; the nmr spectrum displays absorptions at T 6.82 (one hydrogen multiplet exchanged rapidly with deuterium oxide) and at 8.92 (three hydrogen singlet). Cyclopropanol 44 also exhibits a parent ion at m/e 180 in the mass spectrum, and strong fragment ions at m/e 165 and 55 (base) which are consistent with the transformations shown in Scheme 1. l4 Scheme 1 HC) 3. —~ <3? m/e 180 - CH5. 110 H o \ 4— «———- (5+ Six)'* m/e 55 m/e 165 The conversion of cyclopropanol 44 to 10t-methyl-(5rC1)-Spiro ’Vb [4,5]deca-1,7-dione 45 was accomplished in greater than 80% yield ’V'b by slowly adding methanol to a rapidly stirred suspension of the cyclopropanol sodium salt (prepared by reaction of 44 with sodium Vb hydride). The Spiro diketone 45, m.p. 6O - 62°, exhibits infrared "lb 1 absorption at 1735 and 1705 cm' , and a three-proton doublet at r 9.15 (J = 6.5 H3) in the nmr. It is important to note that diketone 45 is stereochemically homogeneous (glc, tlc, nmr line 'V'b widths, nmr solvent shifts). The success of this transformation apparently depends on the 15 heterogeneity of the reaction mixture, since similar treatment of a homogeneous benzene-DMF solution of the sodium salt gave the hydrin- 34 dandione 46. In his work regarding the alkylation of phenolate 'Vb 35 anions, Kornblum has noted a similar "heterogeneity effect," as Scheme 2 E/lc’ lllilllll+ lll‘iIIE::l CGHSOONa’ ("Jr 08 40% 54% + CH2=CHCH28R 6‘ r A \5 om03 99% illustrated in Scheme 2. A common method of effecting configurational correlations is to compare the unknown substance (or a derivative thereof) directly with 16 a compound having established stereochemistry. In the case of the Spiro[4,5]decane system under discussion here, it was envisioned that the stereospecific synthesis of ketone 47 by catalytic reduction of the Diels-Alder adduct of tran§;2-ethylidenecyclopentanoneks49 with 1,3butadiene would provide such a reference compound. I S O H N . --'- 6* —- f C” .. iii 99 m. Enone 49, preparedlby condensationuof the pyrrolidine enamine mm 37 of cyclopentanone 48 with acetaldehyde, was characterized by an absorption at Amax 2411nn (c=7850) in the ultraviolet, absorptions at 1721 and 1650 cm'] (equal intensity) in the infrared, and by its nmr Spectrum which displays a single vinyl hydrogen at T 3.62 as a quartet of triplets (J=7.0 Hz, J'=2.5 Hz), and a three proton doublet of triplets at T 8.22 (J=7.0 Hz and J'=2.5 Hz). A decalin solution of enone 49 was heated (200°) with excess 1,3-butadiene according to the prdzedurereported by Tanaka, Uda, and Yoshikoshi38 for the synthesis of the chamigrene skeleton. After extensive purification of the resulting gelatinous mixture a 28% yield of lOt-methyl-(SrC‘)-Spiro[4,5]-7-decene-l-one 50 was obtained. This ketone was characterized by infrared absorption at 1735 cm'] and an nmr spectrum showing a two-hydrogen doublet at T 4.47 (J=2.5 Hz) and a three-hydrogen doublet at 9.27 (J=6.0 Hz). Finally, catalytic reduction of enone 50 gave ketone gz-DA in 89.5% yield. Ketone;47-DA was characterized by an infrared absorption at 1733 cm'} by a three—proton doublet at T 9.34 (J=6.5 Hz) in the l7 nmr spectrum, and by a parent ion at m/e 166 and fragment ions at m/e 111, 97, and 95 (base) in the mass spectrum. Once the synthesis of a suitable reference compound was completed it was necessary to degrade diketone 45 to an equivalent structure so that a comparison could be made. At least two possible methods can be envisaged for this degradation. First, as seen in Scheme 3, one might effect reduction of the six-membered ring carbonyl to CH Scheme 3 51 52 47' M ’L'L ketol 51 followed by dehydration to a mixture of enones 52, which ’V‘b ’Vb could then be converted to ketone 47'by catalytic hydrogenation. "Vb A second approach involving desulfurization of thioketal 53 Scheme 4 has the advantage of brevity, and was therefore investigated first. Diketone 45 was converted in 82% yield to 10t-methyl-(5rC1)- Spiro[4,5]decan-7-dithiolan-l-one 33 (m.p. 92.5-94.0°) by a BF3 catalyzed reaction with ethanedithiol in acetic acid solution. The crystalline thioketal exhibited absorption at 1733 cm-1 in the infrared, a four-hydrogen singlet at T 6.73 and a three-hydrogen 18 doublet at 9.25 (J=6.0 Hz) in the nmr Spectrum. Desulfurization of thioketal 53 was effected by a slight modification tion of the conventional procedure. Freshly deactivated Raney- nickel (w-7) was added to a solution of thioketal 53 in n-propanol followed by a 59 hr reflux. After distillation and hydrogenation (to remove some induced unsaturation) of the crude ketone a 62% yield of pure 47-05 was realized. Ketone 47-05 was characterized by infrared absorption at 1733 cm"1 and an nmr Spectrum which contained a three-hydrogen doublet at 9.34 (J=6.5 Hz). During this investigation, the mass spectra of the various Spiro[4,5]decane derivatives were used primarily to determine molecular weights, since at first very few fragment ions could be rationalized. It seemed as though spiro[4,5]decanones did not follow the usual ketonic fragmentation routes.39 Recently some light has been shed on the fragmentation reactions of Spiro ketones by D. A. Lightner40. Using Professor Lightner's findings, the mass Spectra of the previously described Spiro[4,5]decanone derivatives are easily accountable. Some characteristic fragmentations are Shown in Scheme 5. Once QZ-DA and QZ-DS were in hand an absolute comparison could be made. The traditional approach would involve a comparison of the melting points of pure compounds and mixtures thereof. Unfortunately, no crystalline derivatives could be made from either ketone, and under forcing conditions (in the 2,4-dinitro- phenylhydrazone case) only tars were obtained. AS a result spectroscopic comparisons provided the major correlation. The 19 Scheme 5 m/e 97 m/e 111 m/e 95 infrared spectra of fil—DA and QZ-DS both exhibit absorptions at 20 1733 cm-], and are in fact virtually superimposable. The nmr spectra in both carbon tetrachloride and benzene were also identical, as were the mass spectral fragmentation patterns. From the chemical shift difference of the methyl doublet in carbon tetrachloride (T = 9.34) and benzene solution (T = 9.40) (Figure 20p73) and (Figure 25p78) it is apparent that there has been an induced upfield shift (3.60 Hz). This effect has been observeddl by other researchers and is explained by the formation of a collision complex in which the n electrons of the benzene ring interact with the partial positive charge of the carbonyl carbon atom. Structure 54 is a pictorial representation of this complex and it can be seen that the secondary methyl group is located in the shielding cloud of the aromatic ring causing an upfield shift. C H3 H ”mm A comparison of chromatographic retention times supports the 21 identity of 47-DA and 47-DS. Thus, silica gel TLC of the pure ’Vb ’\/\1 compounds and a mixture, in several different solvents, showed a single spot of identical Rf, and gas liquid chromatography of 47-DA ’Vb and 4705 (20% SE-30, 10' x l/8" and 4% QF—l, 5' x l/4") gave M the same results. Therefore, it was concluded from the above spectroscopic and chromatographic evidence that 47-DA and 47-DS are in fact identical ’V‘b ’VL 42 compounds. Once the stereochemistry of the C-lO methyl group was determined a rational synthetic plan could be formulated for the synthesis of the B-vetivane sesquiterpenes: hinesol 7 , agarospirol ll, and 'b ’Vb R1=R3=R4=H, R2 R2=R3=R4=H, R]=-C(OH)(CH3)2=agarospirol R1=R2= =C(CH3)2, R3=R4=O=B-vetivone =-C(OH))CH3)2=hinesol B-vetivone 2. This facile, stereospecific synthesis of substituted spiro[4,5]decanes holds obvious advantages for such syntheses. The most important remaining step in the synthesis of these sesquiterpenes would be the stereOSpecific introduction of a three carbon side chain at C-3. In this study we considered two methods for accomplishing this: the first involved introduction of the Side chain before formation of the spiro system, and the second, introduction later in this synthesis. For the first approach it appeared that a good starting material would be compound 57, M which could possibly be obtained from the l,3-dione 55 and ethyl ”Vb 22 vinyl ketone 56 in the usual manner. The configuration of the ester function posedma potential problem, but acting on the assumption that this could be worked out, efforts were made to implement this approach. In l957 Stetter43 reported the synthesis of 4-methyl-3,5-diketo- cyclohexane-l-carboxylic acid 55 (R=H) by alkylating the known44 3,5diketo—l-carboxycyclohexanemm with methyl iodide in 20% potassium hydroxide. Unfortunately Stetter's work could not be repeated on ten separate occasions operating under a variety of conditions, and this synthetic plan was drOpped in favor of the second general approach. The synthesis of 6t, lOt-dimethyl-(SrC‘)—spiro[4,5]decan-l,7- dione SE was accomplished via the cycloprOpanol 6l which in turn was prepared from 2-methylcyclohexane-l,3-dione and Ethyl vinyl ketone by the sequence Michael addition, aldol cyclization and lithium in ammonia reduction. CH 3 o +- co R 2 3% CH3 +- o 58 ’L’L H 0 CH3 .9 C 3 (u ('1 23 Thus A4-4,9-dimethyloctalin-3,8—dione 99, prepared in over 73% yield by established procedures45'46’47'48, was reduced to l,7-dimethyl- 2-hydroxytricyclo [4.4.0.02’6] decan-8-one Ql’ m.p. 96-l02°, in over 65% yield by the action of a solution of lithium in ammonia and ether. Cyclopropanol Q; was characterized by infrared absorptions at 3572, l695 cm.1 and nmr absorption (CDCl3) at r 6.58 (broad one proton singlet, rapidly exchanged with 020), 8.78 (three proton doublet, J=6.5 Hz) and a three proton singlet at r 8.95. When the nmr spectrum of cyclopropanol 61 was measured in benzene-d6 solution two doublets appeared at r 8.66 (J=7.0 Hz) and 8.89 (J=7.0 Hz). Integration of these signals indicated they were generated by the methyl group at C-7 which assumed a 72/28 mixture of equatorial/ axial epimers. Application of the previously described heterogeneous base catalyzed ring opening reaction of cyclopropanol Q1 gave after sublimation, pure 6t,l0t-dimethyl-(5rC1)-spiro[4,5]decan-l,7-dione 62 (m.p. 64-66°) in over 83%. The infrared spectrum of the spiro diketone 62 showed strong at l735 and l705 cm-1 ; the nmr spectrum (benzene-d6) exhibited two three—proton doublets at r 9.21 (J=6.5 Hz) and 9.49 (J=6.5 Hz),indicating that this compound was stereo- chemically homogeneous. With spirodione 9% in hand a method Of selectively transforming each ring in the desired manner had to be developed. Preliminary studies were directed toward the synthesis of enone 63. 9% —- 9% 44 Spirodione 64 was selectively reduced to 6t,l0t-dimethyl-(5rC])- ’Vb spiro[4,5]decan-7t-ol-l-one 63 in over 86% yield by excess sodium borohydride in methanol. Ketol 63 was characterized by infrared absorption at 36ll and 1726 cm"1 and an nmr spectrum (benzene-d6) which included two three-proton doublets at r 9.19 (J=7.0 Hz) and 9.37 (J=6.5 Hz). It also included a one-proton multiplet centered at T 6.48 with a width at one-half height of approximately 6.0 Hz. This splitting pattern indicates that the hydroxyl function is in an axial orientation. Among the various methods for dehydrating alcohols, thionyl chloride in pyridine is probably one of the most commonly employed. When this reaction was applied to 63; 6,10t-dimethyl-(5rC1)-spiro [4,5]-6-decene-l-one Qi’ was obtained in 73% yield. The infrared spectrum of enone 64 displayed absorptions at l723 and l659 cm-1 and its nmr spectrum showed a one-proton multiplet between T 4.45- 4.70, consistent with the assigned structure. Since the elimination seemed to proceed exclusively in the Saytzeff manner, this seemed to be an excellent method for the introduction of the A6 double bond. The next problem to be faced involved the introduction of a 25 three carbon side chain at C-3 in enone 64. Since C-3 is _beta to the ketone function it was decided to introduce a conjugated double bond between C-2 and C-3 in order to functionalize C-3, and to follow this by a conjugate addition to the cyclOpentenone. Efforts to prepare enone 85 and dienone 66 were then initiated, since the latter seemed to be an ideal intermediate for the synthesis of hinesol 7. Although the two methyl groups in 65 block the front ’Vb ’b r”\\ Scheme 6 r”‘>5 C) C) C) o .. BR BR _. 9.8 o «u . 81 8‘3 9% and back Sides of the enone system more or less equally, the introduction of a A6-olefin decreases the hindrance at that side of the cyclopentenone, thus offering the possibility of stereoselective conjugate addition. Various methods for the introduction of the A2 double bond were tried on ketoacetate ZS, without success. Some of these include dicyanodichloroquinone (DDQ)49, and chloranilso. Molecular bromine in both acetic acidsand carbon tetrachloride was tried in hopes dehydrobromination could be effected but these ideas ended in insufficient bromination. In 1962 Eatonsz, using a method similar to Jacques53'54 , reported the synthese of bi§;enone 69 (Scheme 5 ) from the corresponding “Vb ketone. This was accomplished by bromination of the corresponding 26 bisfketal with two equivalents of pyridinium bromide perbromidess , dehydrobromination with potassium t-butoxide in dimethylsulfoxide, and finally hydrolysis of the bis;ketal with aqueous acid. Since the over-all yield of this sequence was high, it seemed ideal for the synthesis of dienone 26. Efforts to prepare ketal ll from ketone 12 included the following reactions: ethylene glycol in benzene, toluene56 , and xylene57 ; trafls_ketalization with 2-butanone dioxolanes8 ; ethylene glycol- boron triflouride etherate in methylene chloride59 and ethylene glycol in triethylorthoformate53 . Unfortunately none of the above methods yielded the desired product ll. Direct bromination of the cyc10pentanone by the recently reportedaxb] reagent 2-pyrrolidone hydrotribromide (PHT) was first tried on acetate 72 ’V'b (R=COCH3) with limited success; however, when the bromination 27 procedure was applied to 6t, l0t-dimethyl-(5rC‘)-spiro[4,5]-7t— decanol-l-one 66(66, R=H) in tetrahydrofuran solution (complete darkness) a good yield (66%) of 6t, l0t-dimethyl-(5rC1)-spiro[4,5]- 7t‘decanol-2-ene-l-one 65 (R=H) was obtained upon subsequent dehydrobromination of ZEN(R=H) with l,5—diazabicyclo[5.4.0]undec- S-ene (DBU) in dimethylsulfoxideéz. Enone 66 (R=H) (m.p. 96.5-97.5°) was characterized by its infrared spectrum which included absorptions at 36l7, l69l and l585 cm" , and an nmr spectrum (benzene-d6) showing absorptions at r 2.l6 (quintet, lH, J=3.0 Hz), 3.75 (doublet triplets, lH, J=6.0 Hz, J'=2.0 Hz), 6.00-6.l8 (multiplet, lH), an AB quartet of triplets equvalent to two hydrogens at 6.89 and 7.59 (J=2l.0 Hz, J"=3.0 Hz), and two doublets each equivalent to three hydrogens at 9.23 (J=7.0 Hz) and 9.36 (J=6.5 Hz). Enone 66 (R=H) also exhibited ultraviolet absorption at Amax=223 nm (e=lO,500). Unfortunately, application of the thionyl chloride-pyridine dehydration procedure to hydroxyenone 66 (R=H) did not meet with the same success enjoyed in the previously described dehydration of 66 . Apparently the diene 66 is not stable to the reaction conditions and is destroyed upon forming. Treatment of alcohol 66 (R=H) with phosphorus oxychloride63 in pyridine gave low yields of double- bond isomers in several attempts. Finally, alcohol 66 (R=H) was dehydrated to enone 66 in 66% yield by refluxing with‘pétoluenesulfonyl chloride in pyridineror nine hours. Infrared absorptions at T709 and 1591 cm'1 in the spectrum of 66 are characteristic of cyclopentenones. The nmr spectrum included a one-proton quintet at r 2.3l (J=3.0 Hz), a one proton doublet of triplets at r 3.80 (J=6.0 Hz, J'=2.0 Hz), 28 a one-proton multiplet between T 4.37-4.67, a two-proton quintet at r 7.l0 (J=3.0 Hz) which arose from the merging of an AB quartet, a three-proton multiplet at r 8.60 and a three-proton doublet at T 9.29 (J=6.5 Hz). Enone 66 also exhibited absorption, A ax =224 nm '\/L m (e=lQ,600), in the ultraviolet. With dienone 66 in hand it was now necessary to decide how to effect the desired l,4 addition to the cyclopentenone system. Among the methods considered were hydrogen cyanide, diethylaluminum cyanide, a copper modified Grignard reaction, or a dialkyl copper lithium reagent. The conjugate addition of hydrogen cyanide was not seriously explored partly due to its obvious hazard and partly because the stereochemistry of addition might not be adequately controlled. In l966 Nagata reported65 an attractive new method for effecting l,4 hydrocyanation of enones using diethyl aluminum cyanide. This method was used to convert compound 12 into steroid 75 in excellent 'b’b yield, but unfortunately the reagent is very hazardous to prepare and store. This method was also eliminated from serious consideration, 29 since epimerization of the resulting nitrile might occur in a subsequent hydrolysis step. Extensive work on copper modified Grignard reactions was reported by House and Whitesidesbb . For example, the synthesis of 3—isopropenylcyclohexanone 77 from cyclohexanone 76 and the copper (I) an M . . . . . . 67 iodide modified Grignard reagent of 2-bromopr0pene is reported C) L? U CH2 to proceed in 68% yield. Despite serious concerns regarding the effect of steric hindrance, this approach seemed to provide the simplest solution to the problem of introducing a three carbon side chain. When the copper (I) iodide modified Grignard reagent of 2-bromopropene was reacted with dienone 66 a 67% yield of 3-isopropenyl- 6,lOt—dimethyl-(5rC])-spiro[4,5]6-decene—l-one 16 (a series shown) aw HC/\ 3 CH Lg 2 was obtained as a mixture (66/34) of epimers at C—3. Since the alpha 30 side of the cyclopentenone ring appears to be less hindered to attack, the major isomer was assumed to be that having an d- isopropenyl group 16. An even greater degree of stereoselectivity might be achieved by conducting the reaction at -78°. Dienone 16 was characterized (as a mixture) by its infrared spectrum which contained absorption at 1731, 1660 and 1638 cm'], and an nmr Spectrum having a broad two-proton singlet at r 5.22, a three- proton singlet at 1 8.21 and a pair of secondary methyl doublets at 1 9.14 (J=7.0 Hz) and 9.19 (J=6.5 Hz). The penultimate step in this synthesis of hinesol required the removal of the carbonyl at C-1 in dienone 16. From previous work with ketone 31 it was known that the carbonyl function was badly hindered. Consequently, forcing conditions were anticipated in purging the compound of its carbonyl group. Various modifications of the Wolff-Kishner reduction were studied first (e.g. the Lock modification68 and the Nagata modificationb9); however, only recovered dienone 16 was obtained in poor yield. With the failure of the Wolff-Kishner approach, the possibility of Haney—nickel catalyzed desulfurization of the corresponding thioketal was explored. Unfortunately, even after extended reaction times, only starting material could be recovered from the ethanedithiol—borontrif1uoride etherate solution. The Clemmensen reduction was not considered because it was felt that the acidic reaction conditions would cause rearrangement of the spiro system along with double bond isomerization. Since straightforward carbonyl reductions have failed it will 31 . . . . 20 now be necessary to use a more cirCUitous route to diene 79(hinesene ’VL One possibility (Scheme 7) would involve reduction of ketone 78 ’\J’\J Scheme 7 ;q 1 1.93 ———> by lithium aluminum hydride, followed by conversion of alcohol 80 ’VD to bromide 81 by the action of triphenyl phosphine dibromide, as ’Vb 70 reported by Wiley for the preparation of neopentyl halides. Bromination of the double bonds is not considered a serious problem 71 in light of work reported by Levy and Stevenson in which they converted cholesterol 82 to 36-bromocholest—5-ene 83 in over 80% ’\/\; '\/'\1 yield. In any event, the vicinal dihalides formed by halOgen addition to one or more double bonds would be eliminated in the .9 ___, HO’ ' \ Br I .3 ("‘0 C: (I) j w (J c final step of this sequence. ). 8N 32 Thus, the magnesium Grignard derivative of bromide 66 would be expected to give diene 16 on quenching with water. The 2e-isonropenyl-6,10c-dimethyl-(5rC])-spiro[4,5]-6—decene 1% could then be converted to hinesol 7 by way of the Brown oxymercurea- no 7273 tion reaction ’ . The required selectivity is anticipated from the fact that limonene 66 can be converted to a -terpineol 66 in good 74 yield by this method EXPERIMENTAL FiZth of a fenny snake, In the cauldron boil and bake; Eye of next and toe of frog, WboZ of‘bat and tongue of ice, Adier'e fbrk and blind—worm's sting, Lizard'n leg and ccht's mint, For a charm of powerful truublc, Like a heZZ-brcth boil and bubec. Ecuch, double tail and trouble; Fire burn and cauldron bubb 3. William Shakespeare Macbeth EXPERIMENTAL general Infrared spectra were recorded on a Perkin-Elmer 237B grating Spectrophotometer, using sodium chloride cells and discs. Nuclear magnetic resonance spectra were taken on either a Varian A—60 or a Varian T—60 high resolution spectrometer; tetramethylsilane was used as an internal standard in all solvents. The ultraviolet spectra were recorded on a Unicam SP 800 spectrOphotometer in either 95% or absolute ethanol. Mass spectra were recorded with either a Hitachi RMU~6 or a LKB gas chromatograph—Mass Spectrometer combination, the LKB data being analyzed by a PDP—8/e computer. Melting points were measured with a Koefler hot stage and are uncorrected. Micro-analyses were performed by either Spang Microanalytical Labs, Ann Arbor, Michigan, or Chemalytics, Inc., Tempe, Arizona. Saturated sodium chloride solution is referred to as brine. Cyclopentanone: pyrrolidine enamine (48) 'V‘u 37 The enamine 28 was prepared essentially by the method of Stork ‘b and co-workers. The enamine was obtained in 90% yield, boiling 37 point 97—98°/15 mm [Lit reported b.p. 88-92/15 mm, and b.p. 97—98°/ 75 20 mm]. The enamine was stored under nitrogen in the refrigerator. 34 Trans-Z-Ethylidenecyclopentanone (49): ’VD The title compound was prepared by a modification of the procedure described by Birkofer, Kim, and Engelsa.‘5 To a conslant- ly stirred solution (under nitrogen) of 68.61 g (500 mmol) of cyclopentanone enamine 66 in 550 ml of dry benzene was added dropwise a solution of 22.25 g (505 mmol) of acetaldehyde in 50 ml of benzene. The addition was conducted at room temperature and required 20 minutes. After being heated to 40° for 4.5 hr, the solution was cooled to ambient temperature and treated with 100 m1 of 50% hydrochloric acid. The organic phase was separated and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with water, saturated sodium bicarbonate, water, and brine and dried over anhydrous magnesium sulfate. The crude product remaining after the solvents were removed at reduced pressure was fractionated through a 15 cm. Vigreux column. A preliminary fraction (25-52°/30 mm) was taken to remove any low boiling contaminants, following which the temperature was reduced and the pressure lowered to 0.40 mm. Continued distillation then yielded a fraction A, 7.15 g (13%), boiling point 25-35°, (Lit?%.p. 58°/0.3 mm) and a second fraction 8, 0.429 g, 65-80°/0.30 inn. Fraction A was shown by nmr analysis to be the trans enone while fraction 8 proved to be the cis isomer. Enone 62 : IR (Figure 1, p54) (neat) 3010 (=CH), 1721, 1650 (a, B unsaturated carbonyl, peaks of equal intensity) and 750 cm"; nmr (Figure 17.P70) (CC14) r 3.62 [quartet of triplets, 35 1H, (J=7.0Hz, J'=2.5 Hz)], 7.25—8.08 (mul, 6H,8.22 [doublet of triplets, 3H, (J=7.0 Hz, J'=2.5 Hz)]; U.V. (Figure 47, p 100) (absolute EtOH) 24lrmi (e=7850). lOt-Methyl-(5rC])-spiro[4,5]decan-7-ene-l-one (66): The procedure given by Tanaka, Uda, and Yoshrhashimaas modified slightly for the preparation of the title Diels-Alder adduct. A solution of 2.7564 g (25.1 mmol) of enone 66 and excess 1,3-butadiene (about 20 g condensed into the reaction mixture at ice bath temperature) in decalin was heated in a sealed-tube at 200° for 7.5 hr. The gelatinous mixture isolated from the tube was partitioned with methylene chloride and water, and the dried organic extracts were concentrated at reduced pressure by a rotary evaporator to yield 39.460 9 of solution. This solution was chromatographed on 100 g of si1ica-gel beginning the elution with hexane followed by an 85:15 chloroform: ether mixture. Fractions 16-24 (50 m1 fractions) were combined to give 11.790 9 of adduct containing solution, which was distilled under vacuum yielding 1.1029 g (28%) of adduct 66: b.p. 63-66°/0.05 mm; IR (Figure 2, 655) (neat) 3017 (C=C-H), 1736 (carbonyl), 1650 (C=C) cm"; nmr (Figure 18p71) (CCl4) 1 4.47 (doublet, 2H, a=2.5 Hz), 7.33—8.50 (mul, 11 H), 9.27 (doublet, 3H, J=6.0 Hz). Adduct also shows a parent ion at m/e 164 and strong peaks at m/e 93 (base), 79, and 68 in the mass spectra an analytical sample was obtained by preparative glc on a 15% SE-30, 10' x 1/4" column at 175°. 36 Anal: Calcd for C11H160: C, 80.44; H, 9.83. Found: C, 79.08; H, 9.48. 6t-Methyl-(5rC])-spiro[4,5]decan-l-one (6Z-DA): Ketone 6Z-DA was prepared by catalytic reduction of 0.8541 g (5.19 mmol) of enone 66 with 0.1020 g of 10% Pd/C in 20 m1 of absolute ethanol. A total of 128.6 ml (calc 128.5 ml) of hydrogen was absorbed. The catalyst was removed by filtration on celite and the ethanol solution was evaporated at reduced pressure (rotary evaporator) to yield 0.8495 g of crude product (95% pure by glc). Purification of the ketone by preparative glc (4% QF-l, 5' x 1/4", at 125°) yielded 89.5% of pure ketone 61-0Ale (Figure 3, p 56) (neat) 1733 (carbonyl) cm']; nmr (Figure 19p72) (CC14) r 7.83-8.87 (mul, 15 H), 9.34 (doublet, 3H, J-6.5 Hz); the mass spectrum (Figure 36p89) includes a parent ion at m/e 166 and strong peaks at m/e 111, 97, 95 (base), and 67. An analytical sample was obtained by glc collection on a 4% QF-l column, 5' x 1/4" at 125°. flflgl; Calcd fbr C11H180: C, 79.46: H, 10.92. Found: C, 78.98; H, 10.90. l-Methyl~2-hydroxytricyclo[4.4.0.02’61decan-8-one (Qt)- Cyclopropanol 66 was prepared by the method of Reusch and Venkataramanizewith only slight modification. To a solution of Li (444 mmol, 1.18 g-atom excess) in 700 ml of liquid ammonia and 100 m1 of anhydrous ether in a 2 l. 3-neck flask equipped with an 37 overhead stirrer and a dry-ice condenser with a soda lime drying tube was added dropwise (20 minutes) and with stirring’a solution of 24.98 9 (140.3 mmol) of the Wieland-Miescheaziitone 66 in 150 ml of anhydrous ether. After addition the mixture was stirred for 4.75 hr at -33°, following which it was decomposed by the addition of solid ammonium chloride at -78°. The reaction mixture was transferred to a 4 l. beaker and the liquid ammonia was evaporated by a stream of dry air. Treatment of the resulting slurry with 200 ml of water followed by extraction of the aqueous mixture three times with ether gave, after washing, drying and evaporating the combined ether extracts 22.83 g of crude material. This was triturated with ether and cooled in the ice box (-10°) until crystallization was complete. A first crop consisted of 14.75 g of pure 66. A second crop of 2.64 g was also obtained to give a combined yield of 68.7%. In some preparations yields as high as 80% were realized. CycloprOpanol 66 can be kept in the refrigera- tor (-10°) for as long as two months without extensive decomposi- tion. Crystalline 66 exhibits the following properties m.p. 98-100°; IR (Figure 4135” (KBr) 3411 (-0H), 2955-2850 (C-H), 1696 (C=0), and 1030 (cyclopropane ring) cm'1; nmr (Figure 21, p 74) (CDC13) r 6.82 (mul, lH, exchanged rapidly with 020), 7.52-8.40 (mul, 12H), 8.92 (singlet, 3H); Amax (Figure 48, p 101) (95% ethanol 211 ( e=819), 290 ( E=67) m . Even after three recrystallizations from ether-pentane a good micro-analysis could not be obtained. due to the unstable nature of the cyclopropanol at room temperature. 38 However, cyclopropanol 66 exhibited a parent ion of m/e 180 in the mass spectrum (Figure 37p90). Other important peaks appeared at m/e 165, 110, 81, 67, 55 (base), 41, and 40. lOt-Methyl-(5rC1):spiro£4,Sldecan-l,7—dione (45): ’Vb To a 1 1. indented flask, containing a vigorously stirred suspension of 0.961 g (40.1 mmol) sodium hydride (from a 52.8%) pentane washed mineral oil suspension in 300 ml of dry benzene was added dr0pwise 4.0057 g (22.3 mmol) of cyclopropanol 66 in 100 m1 of dry benzene. The addition required 0.5 hr and was effected in a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at ambient temperature for 4.5 hr and then decomposed by cautious addition of methanol. Following the addition of 200 ml of water to the resulting light brown solution, the immiscible phases were separated and the aqueous phase was extracted three times with ether. The combined ether- benzene solution was washed three times with water and dried over anhydrous sodium sulfate. Evaporation of the solvent at reduced pressure yielded 3.754 g of a light yellow oil which solidified on cooling in the refrigerator. The crude dione was sublimed (65°/0.075 mm) and recrystallized from pentane to yield 3.2163 g (80.4%) of pure dione 66: m.p. 60-62°; IR (Figure 5, p 58) (CHC13) 2961, 2872, 1735 (5-membered ring carbonyl), and 1705 (6-membered 1 ring carbonyl) cm' ; nmr (Figure 22p75) (CDC13) r 7.35-8.70 (mul, 13H, methylene envelope), 9.15 (doublet, 3H, J=6.5 Hz); Diketone 66 39 exhibits a parent ion at m/e.180 and strong peaks at m/e 124, 97 81, 55 (base), and 41 in the mass spectrum (Figure 38, p 91). An analytical sample was obtained by several recrystallizations from pentane. final; Calcd for C H 0 ° C, 73.30: H, 8.95. Found: C, 11 16 2' 73.63; H, 8.94. lOt-Methyl-(5rC1)—spiro£4,5]decan-7-dithiolane-l-one (53): In a three-neck 50 ml flask equipped with a septum, condenser, and calcium chloride drying tube, a solution of 1.2420 g (6.92 mmol) of dione 45 in 25 ml of hot (100°) glacial acetic acid was treated with 2.231 g (24.7 mmol) of ethanedithiol followed by 2 m1 (33.2 mmol) of boron-trifluoride etherate. After the hot solution has cooled to ambient temperature (3 hr) it was transferred to a 250 ml separatory funnel, mixed with 50 m1 of ether and washed successively with water, 10% sodium carbonate solution, water and brine. The ether extract was dried with anhydrous sodium sulfate, and evaporated at reduced pressure. The yellow oil thus obtained (1.593 g) was chromatographed on 60 g silica-gel (elution with 1:1 benzene/carbon tetrachloride) and crystallized from pentane to give 1.4451 g (82%) of thioketal 22: m.p. 92.5-94.0°; IR (Figure 6. p 59) (0014) 1733 (carbonyl) cm']; nmr (Figure 23 p75) (00013) T 6.73 (singlet, 4H), 7.50-8.62 (mul, 13H), 9.25 (doublet, 3H, J=6 Hz); Thioketal 23.exhibits a mass spectrum (Figure 39, p 92) in which the parent ion (m/e 256) is the base peak. Other 40 significant peaks appear at m/e 200, 158, and 131. An analytical sample was obtained by two recrystallizations from pentane. Anal: Calcd for C13H20052: C, 60.89; H, 7.86: S, 25.01. Found: C, 60.76; H, 7.79; S, 25.05. 6t-Methy1-(5rC1)-spiro£4,5]decan-l-one (41-08): To a 125 m1 three-neck flask equipped with a mechanical stirrer and a reflux condenser was added 75 ml of n-propanol and 15.6 g of w-7 Raney Nickel (deactivated by refluxing in acetone for 1 hr and washing with ethanol). A solution of 0.7884 g (3.08 mmol) of thioketal 53 in 10 m1 of n-propanol was added in one portion and the mixture was refluxed for 59 hr (reaction monitored by TLC). The reaction mixture was cooled, filtered on celite and the filter cake washed several times with hot n-propanol and ether. The solvent was evaporated at reduced pressure on the rotary evaporator, yielding 0.5334 g of crude material which after fractionation gave 0.4662 g of material, boiling point l35-138°/25 mm. The distillate was catalytically reduced with 0.0650 g of 10% Pd/C in 10 ml of absolute ethanol for 1 hr at room temperature (25.8 ml of hydrogen absorbed). After filtration of the catalyst on celite and evaporation of the solvent at reduced pressure, the ketone was distilled in a micro molecular still giving 0.3158 g (62%) of pure ketone QZ-Ds:b.p. 150-158° (bath temperature)/25 mm; IR (Figure 24, 1 p77) (neat) 1733 (carbonyl) cm' ; nmr (Figure 7 p60) (CC14) T 7.83-8.87 (mul, 15H, 9.34 (doublet, 3H, J=6.5 Hz); Ketone 47:08 41 exhibits a parent ion at m/e 166 and strong peaks at m/e 111, 97, 95 (base), and 67 in the mass spectrum, (Figure 40, p 93). 2-Methyl—2-(3'-oxopenty1)-l,3-cyclohexanedione (g2): The triketone 59 was prepared using the method given for the preparation of 2-methyl-2-(3'-oxobuty1)-1,3-cyclohexanedione?3 Four pellets of potassium hydroxide were added to a solution of 63.10 g (0.5 mole) 2-methy1-l,3-cyclohexanedione leghé763.20 g (0.75 mole) ethyl vinyl ketone in 300 m1 of absolute methanol. The solution was heated to reflux for 3.75 hr, following which the reflux condenser was exchanged for a distillation head and the methanol and excess ethyl vinyl ketone were removed by distillation at atmospheric pressure. The crude trione 52 was cooled and diluted with 250 ml of ether. Unreacted 2-methy1-l,3-cyclohexanedione precipitated, and was filtered and washed once with ether. The combined filtrates were washed with water and brine, and after drying over anhydrous sodium sulfate, the solvent was removed at reduced pressure. Distillation of the crude Michael adduct (88.02 9) through a 15 cm Vigreux column yielded 83.46 g (79.3%) of adduct 32 : b.p. 108- lll°/0.03 mn (Lit45b.p. 129-13l°/l rrm); IR (neat) 1710, 1693 cm']; nmr (CDC13) r 7.13-8.30 (mul, 12H), 8.76 (singlet, 3H), 8.98 (triplet, 3H, J=7.0 Hz). 42 A4-4,9-Dimethyloctalin-3,8-dione (go): The title compound was prepared using a slight modification of the methods of Wieland48 and Kitaharad5 . To a stirred solution of 27.80 g (227 mmol) of benzoic acid and 19.90 g (197 mmol) of triethylamine in 300 ml dry xylene was added, in one portion, 31.83 g (152 mmol) of trione 59 in 150 m1 of xylene. The reaction mixture was refluxed for 48 hr during which time 2.70 ml (theory 2.74 ml) of water was collected with a Dean-Stark water separating apparatus. An ether solution of the resulting mixture was washed successively with water, saturated sodium bicarbonate solution, 10% hydrochloric acid, water, and brine. The washings were back extracted with ether, washed with water, combined and dried over anhydrous sodium sulfate. Removal of the solvent at reduced pressure yielded 26.67 g of crude material which was then fractionated through a 15 cm Vigreux column. Compound 69 was thus obtained as a pale yellow liquid with boiling point 118-124°/0.1 mm (Lit77 124-150°/ 0.05 mm, also 145-150°/3 mm?)8 in 92% yield. The enedione 69 crystallized overnight in the refrigerator giving pale yellow crystals with melting point 40-4l° (Lit 39-403‘5 , 41-42°77 , and also 45-46°78 ), and was used without further purification. Enedione Q0: IR (neat) 1708 (carbonyl, saturated), 1665 (conjugated carbonyl), 1612 (conjugated double bond); nmr (C0013) r 6.84-8.10 (mul, 10 H), 8.17 (singlet, 3H), 8.55 (singlet, 3H); Amax (95% ethanol) 252 rmi (5:12.100). The overall yield of enedione 69 from 2-methy1-1,3-cyclohexanedione is 73% (the largest reported yield to date). 43 1,7-Dimethy1-2-hydroxytricyclo[4.4.0.02’6]decan-8-one (61): The procedure given for the preparation of cyclopropanol 44 was followed with only slight modification. A solution of 20.13 9 (104.5 mmol) of enedione 60 in 200 m1 of anhydrous ether was added to a solution of 2.43 g (347 mmol) Li in 1000 m1 liquid ammonia and 250 m1 anhydrous ether at ~33°. The reaction mixture was stirred for 5 hr, decomposed with solid ammonium chloride, evaporated, and treated with water. The ether extracts were handled in the usual manner and yielded 19.734 9 of crude cyclopropanol, which was triturated with cold ether-pentane to give 13,29 9 (65.5%) of pure cyclopropanol 61: m.p. 96-102°; IR (Figure 8 p61) (CHCl3) 3572 (hydroxyl), 2990-2850 (carbon-hydrogen), 1695 (carbonyl) and 1050 cm’1 ; nmr (Figure 26p79) (CDC13) r 6.58 (broad singlet, 1H, rapidly exchanged with deuterium oxide), 7.23-8.60 (mul, 11H), 8.78 (doublet, 3H, J=6.5 Hz), 8.95 (singlet, 3H). The nmr (Figure 27 p 80 ) of cycloprOpanol 61 in benzene-d6 shows two doublets at 1 8.66 (J=7.0 Hz) and 8.89 (J=7.0 Hz) in a 72:28 ratio of 41 equatorial, axial methyl groups respectively :A (Figure 48 max p10])(95% ethanol) 205 (C=757), 284 (€=47)rm1 . Even after several recrystallizations from ether-pentane a satisfactory micro- analysis could not be obtained; however, cyclopropanol 61 exhibits a parent ion of m/e 194 and other important peaks at m/e 179, 111, 95, 55 (base), and 41 in the mass spectrum (Figure 41 p 94). 44 6t,10t-Dimethyl-(5rC])-spiro[4,5]decan-1,7-dione (62): The method used for the preparation of dione 45 was repeated without modification. A solution of 2.1801 9 (112.5 mmol) cyclopropanol $1, in 50 ml dry benzene, was added to a vigorously stirred suspension of 0.3370 9 (135.0 mmol) sodium hydride (from a 57% pentane washed mineral oil dispersion) in 150 m1 dry benzene, the addition being effected in a nitrogen atmosphere over a 20 minute period. After stirring at ambient temperature for 4.5 hr, the reaction mixture was decomposed by cautious addition of methanol (25 m1) followed by 50 m1 of water. Separation of the organic phase and extraction of the aqueous phase with ether followed by washing and drying the combined organic layers gave after evaporation of the solvents under reduced pressure 2.033 g of crude dione 6g. Sublimation at 75°/0.1 mm gave 1.8230 9 (83-7%) of pure dione 62 which was improved by recrystallization from pentane affording 1.495 g dione 62 : m.p. 64-66°; IR ’Vb (Figure 9 p62) (CHC13) 1735 (five—membered ring carbonyl), 1705 (six-membered ring carbonyl) cm"1 ; nmr (Figure 28p81) (CDC13) r 7.15 (quartet, lH, CH3-CH;C=0, J=6.5 Hz), 7.5-8.3 (mul, 11H), 9.15 (broad doublet, 6H, J=6.5 Hz); nmr (benzene-d6) r 7.47 (quartet, 1H, J=6.5 Hz), 7.72-8.33 (mul, 5H), 8.40-8.88 (mul, 6H), 9.21 (doublet, 3H, J=6.5 Hz, methyl next to six-membered ketone), 9.49 (doublet, 3H, J=6.5 Hz). Diketone 62 exhibits a parent ion at m/e 194 and significant peaks at m/e 179? 138, 111 (base), 95, 81, 83, 55, 41, and 28 in the mass spectrum (Figure 42p95). An analytical 45 sample was obtained by several recrystallizations for pentane. Anal: Calcd for C12H1802: C, 74.19; H, 9.34. Found: C, 74.04; H, 9.27. 6t, 10t—Dimethyl-(5rC])-spiro[4,51decan-7t-ol-1-one (66): Ketoalcohol 66 was prepared by a method similar to that reported by Boyce and Whitehurst.79 A solution of 3.46 g (91.4 mmol) of sodium borohydride in 150 m1 methanol was added dropwise to a solution of 8.86 g (45.7 mmol) diketone 66 in 300 ml of methanol at 0°. After completing the addition (30 minutes), the reaction mixture was stirred for 30 minutes, following which the excess sodium borohydride was decomposed by cautious addition of acetic acid. The residue remaining after evaporation of the solvent was dissolved in 250 ml ether, and this solution was washed with saturated sodium bicardonate solution, water, brine and dried over anhydrous sodium sulfate. Solvent evaporation at reduced pressure yielded 8.92 g crude alcohol which crystallized on standing. Alcohol 66 was recrystallized from ether-pentane at -10° to give 7.73 g (86.3%) colorless crystals, m.p. 75.5-77.5°. Glc analysis (15% SE-30, 10‘ x 1/4", 190°, 85 ml/min) showed that alcohol 66 was a 92/8 (axial/equatorial) mixture of C-6 epimers. The axial isomer was collected by preparative glc (column above), recrystallized from ether-pentane, m.p. 78.0-79.5°; IR (Figure 10p63) (CHC13) 3611 (hydroxyl), 1726 (five-membered ring carbonyl); nmr (Figure 29p82) (benzene-d6) T 6.48 (mul, 1H), 7.53-9.05 (mul, 13H), 9.19 (doublet, 46 3H, J=7.0 Hz), 9.37 (doublet, 6.5 Hz). Ketoalcohol 66 also exhibits a parent ion at m/e 196 and significant peaks at m/e 178, 124, 111 (base) and 55 in the mass spectrum (Figure 43p96). An analytical sample was obtained by several recrystallizations from ether- pentane at -10°. Anal: Calcd for C 02: C, 73.43; H, 10.27. Found: C, 12”2o 73.57; H, 10.28. 61_10t-Dimethy1—(5rC1)-spiro[4,5jdecan-6-ene-l-one (66): The title compound was prepared by dehydration of alcohol 66, using a method similar to that reported by Summerse.0 A solution of 0.7866 g (4.02 mmol) ketoalcohol 66 in 8 m1 dry pyridine was added dropwise to a chilled mixture of 16.55 9 (139.0 mmol) thionyl chloride in 12 m1 of dry pyridine. After completing the addition (10 min) the reaction mixture was stirred for 1 hr at 0°, followed by an additional 2 hr while warming to room temperature. The resulting reddish-brown solution was poured slowly onto 100 9 ice and was then thoroughly extracted with ether. The combined organic extracts were washed with cold 5% hydrochloric acid, water, saturated sodium bicarbonate solution, water and brine and then dried over anhydrous sodium sulfate. Evaporation of the solvent at reduced pressure yielded 0.693 g crude ketone. Glc analysis (5% SE-30, 6' x 1/8", 130°) showed the presence of a small amount of unreacted alcohol; consequently, the mixture was purified by preparative thin layer 47 chromatography (2 mm SIlica-Gel, eluting with methylene chloride), yielding 0.520 g (73%) pure ketone 66 as a pale yellow oil: IR (Figure 11p54) (CHC13) l723 (carbonyl), 1659 (carbon-carbon double bond), 3020 (vinyl hydrogens) cm"; nmr (Figure 30p83) (cc14) T 4.45-4.70 (mul, 1H), 7.57-8.40 (mul, 11H), 8.52 (quintet, 3H, J=2.0 Hz), 9.12 (doublet, 3H, J=7.0 Hz). Ketone 66 also exhibits a parent ion at m/e 178 and significant peaks at m/e 122, 107 (base), and 93 in the mass spectrum. 6t,10t-Dimethy1-(5rC1)-spiro£4,5]decan-7t-acetoxy-l-one (72, R=Ac): M A solution of 1.43 g (7.31 mmol) ketoalcohol 6; in 10 m1 dry pyridine was added dropwise to an ice cold mixture of 20 ml dry pyridine and 10 m1 of freshly distilled acetic anhydride. The resulting reaction mixture was stirred for 30 hr at ambient temperature, followed by decomposition of the excess acetic anhydride by stirring with 20 m1 of water at 0° for 2 hr. An additional 100 g of ice water was added, and this mixture was thoroughly extracted with ether. The combined extracts were washed with water, 5% hydrochloric acid, water, brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent at reduced pressure yielded 1.51 g of crude acetate as a thick syrup. Distillation in a molecular still (85-93°/0.15 mm) afforded 1.352 g (78%) of acetate as a mixture of epimers. The epimers could be separated by preparative glc (6% carbowax 20 M, 175°, 6' x 1/4" @ 100 ml/min); however, the mixture was used in subsequent reactions without further purification. Axial acetate zg, R=Ac 48 (major isomer) has the following physical properties: IR (Figure 12 p65) (CHC13) 1725 (broad absorption of five membered ring carbonyl and ester) cm'] ; nmr (Figure 31 p84) (benzene-d6) r 4.97-5.15 (mul, 1H), 7.78-9.15 (mul, 12H), 8.27 (singlet, 3H), 9.38 (doublet, 3H, J=7.0 Hz), 9.41 (doublet, 3H, J=6.5 Hz); a parent peak of m/e 238 and significant peaks at m/e 196, 178, 124 (base), 111, 107, 93, 55, 41, and 43 in the mass spectrum. An analytical sample was obtained as a clear oil by preparative glc (column above). 6331; Calcd for C14H2204: C, 70.57; H, 9.30. Found: c, 71.07; H, 9.32. 6t,10t-Dimethy1-(5rC])-spiro[4,5]-7t-decanol-2-ene-1-one ( 65, R=H): 'Vb The title compound was prepared by a bromination-dehydrobromina- tion sequence. To a solution of 1.0644 g (5.43 mmol) of ketoalcohol 66 in 50 m1 dry tetrahydrofuran was added, in one portion, 3.523 g (7.09 mmol) 2-pyrrolidonehydrotribromide, PHT. The resulting orange solution was stirred for 5 hr in complete darkness, during which time a white crystalline solid [bis-(Z-pyrrolidone)hydrotribromide] precipitated. Following filtration, 50 ml of ether was added to the filtrate and the organic solution was washed with saturated sodium bicarbonate, water and brine. The solvent was evaporated from the dried solution at reduced pressure, yielding 2.0143 g of crude bromoketone which was used without further purification. 49 To a nitrogen blanketed solution of 2.0143 g of crude bromoketone in 8 m1 dry dimethylsulfoxide was added dropwise 15 m1 of 1,5- diazabicyclo[4,5.0]undec-5-ene. The light brown solution was warmed to 90° for 3.5 hr, cooled, and poured into 100 g of ice water. The combined ether extracts of this mixture were washed with 5% hydrochloric acid and water, and dried over anhydrous sodium sulfate. Evaporation of the solvent at reduced pressure gave 0.8201 g of crude enone alcohol 66, R=H. This crude material was chromatographed by dry column chromatography on 300 g of silica- gel, elution with 1:1 ether/hexane and collecting fractions until complete. This afforded 0.699 g (66.3%) enone alcohol (m. p. 95-96°) which was further improved by recrystallization from ether: hexane at -10°, melting point 96.5-97.5°. Enone alcohol 66, R=H (Figure 13p66) (CHC13) 3617 (hydroxyl), 3000 (olefinic hydrogens), 1691 (unsaturated carbonyl), 1585 (carbon-carbon double bond) cm'l; nmr (Figure 32p85)(benzene-d6) r 2.16 (quintet, 1H, J=3.0 Hz) 3.75 (doublet of triplets, 1H, J1’2=6.0 Hz, J'=2.0 Hz), 6.00-6.18 (mul, 1H, hydrogen H3), 6.89 (this is Ha of an AB quartet further split by vinyl hydrogens, 1H, Ja,b=2]'0 Hz, J"=3.0 Hz), 7.59 (this is Hb of an AB quartet, 1H, Jab=21.0 Hz, J”=3.0 Hz), 7.83-8.77 (mul, H), 50 9.23 (doublet, 3H, J-7.0 Hz), 9.36 (doublet, 3H, J=6.5 Hz): enone alcohol exhibits a parent ion of m/e 194 and significant peaks at m/e 176, 161, 122, 109 (base), 41, and 18 in the mass spectrum (Figure 44p97). Enone 66, R=H has ultraviolet (Figure 49p102) absorption at Amax=223 (10,500). An analytical sample was obtained by several several recrystallizations from etherzhexane at -10°. 6331; Calcd for C H 0 ' C, 74.19; H,9.34. Found: C, 12 18 2' 73.71; H, 9.40. 6t,10t-Dimethyl-(5rC])-spiro£4,51decan-7t-acetoxy-2-ene-1-one (65, R=Ac): 'V'b The title compound was prepared by the same procedure as enone alcohol 66, R=H except that 1,S-diazabicyclo[4.3.0]non-5-ene (DBN) was used as the dehydrobrominating agent. Enone acetate 66, R=Ac was obtained in low yield (glc, < 40%) as a difficultly separable mixture; how- ever, pure material was obtained by preparative glc (20% carbowax 20 M, 10' x 1/4", @ 215°). Enone acetate 66, R=Ac displays the following properties: m.p. 84-88°; IR (Figure 14 p67) (CC14) 1739 (ester carbonyl), 1708 (unsaturated carbonyl), 1598 (carbon-carbon double bond), 1241 cm']; nmr (Figure 33p86 (benzene-d6) T 2.15 (quintet, 1H, J=3.0 Hz), 3.75 (doublet of triplets, 1H, J=6.0 Hz, J'=2.0 Hz), 4.83-5.07 (mul, 1H), 7.05 (this is 8 Ha of an AB quartet further split by vinyl hydrogens, 1H, Jab=-20.5 Hz, J'=3.0 Hz), 7.59. This is Hb of an AB quartet, 1H, Jab=-20.5 Hz, J'=3.0 Hz), 7.67 (mul, 6H), 7.93 (singlet, 3H), 9.32 (doublet, 3H, J=7.0 Hz), 9.36 (doublet, 3H, J=6.5 Hz); xmax (absolute Et0H)=219 mp (c=19,100). Enone acetate 66, R=Ac 51 exhibits a parent ion at m/e 236 and significant peaks at m/e 221, 194, 176 (base), 122, and 109 in the mass spectrum. 6t,10t-Dimethyl-(5rC])-spiro[4,5]decan-2,6-diene-1-one (66): The title compound was prepared by a method similar to that described by Hintersteiner and Moore?4 To a solution of 0.5176 g (2.67 mmol) of enone alcohol 66, R=H in 15 m1 dry pyridine was added, in one portion, 2.4634 g (13.01 mmol) of freshly recrystallized p-toluenesulfonyl chloride?l This solution was refluxed for 9.0 hr in a nitrogen atmosphere, following which the pyridine was removed by evaporation at reduced pressure. The resulting brown semi-solid was slurried with water, thoroughly extracted with hexane and the combined extracts were washed with water, ice cold 2.5% hydrochloric acid, water, brine, and dried over anhydrous sodium sulfate. Upon evaporation at reduced pressure, 1.1949 g of crude dienone 66(contains some tosyl chloride) was obtained. The mixture was disolved in a small quantity of pentane, cooled to -10°, and the precipitated tosyl chloride was removed by centrifugation. The solvent was removed at reduced pressure and the resulting light brown liquid was purified by dry-column chromatographyagn silica- gel (28" x 2" nylon column, eluting with methylene chloride), yielding 0.3067 g (65%) dienone 66: IR (Figure 15p68) (CC14) 3030-3000 (vinyl hydrogens), 1709 (unsaturated carbonyl), 1591 (conjugated carbon- 1 carbon double bond), 860 cm' ; nmr (Figure 34p87) (CC14) T 2.31 (quintet, 1H, J=3.0 Hz), 3.80 (doublet of triplets, 1H, J=6.0 Hz, 52 J'=2.0 Hz), 4.37-4.67 (mul, 1H), there is a merged AB quartet of triplets (quintet) centered at 7.46 with a small triplet at 7.10, 2H, J=3.0 Hz, 7.73-8.50 (mul, 5H), 8.60 (mul, 3H), 9.29 (doublet, 3H, J-6.5 Hz); A x (Figure 49p102)(95% ethanol) = 220 mu , (c=l9,600); ma the mass spectrum (Figure 45p66) of dienone was obtained using a LKB gas chromatograph-mass spectrometer combination, the data being analyzed by a PDP-8/e computer. Dienone 66 exhibits a parent peak at m/e 176 with significant peaks at m/e 161 (base), 146, and 133. 6331} Calcd for C12H160: (P+1)/(P)=13.26; (P+2)/(P)=1.01. Found: (P+1)/P=14.22, (P+2)/P=1.25. 3-i50pr0penyl-6,10t-dimethy1-(6rC])-spiro[4,51;6-decene-l-one (78): ’Vb Ketone 66 was prepared by using a method similar to that of House and Nhitesidesf)6 The Grignard reagent of 2-bromopropene was prepared by the dropwise addition of 2.84 g (23.4 mmol) of freshly distilled 2-bromopronene in 20 m1 of dry tetrahydrofuran to a mixture of 0.523 g (21.8 mmol) of magnesium turnings in 80 m1 tetrahydrofuran (plus a crystal of iodine). The addition required 20 minutes and was affected in a nitrogen atmosphere. After the magnesium had been consumed the solution was diluted with 80 ml tetrahydrofuran, cooled to 0°, and 1.035 g (5.44 mmol) cuprous iodide (washed with methanol and dried at 56°/1 mm for 24 hrs) was added in one portion. After stirring at 0° for 10 minutes 0.9576 g (5.44 mmol) of dienone 66, in 20 m1 of dry tetrahydrofuran, was added dropwise over 0.75 hr. The resulting mixture was stired at 0° for 2.0 hr and for 4.0 hr while warming to room temperature. 53 The mixture was decomposed by dropwise addition of saturated anmonium chloride solution (pH 8 by addition of conc. ammonium hydroxide). Following the addition of 50 ml water, the phases were separated and the blue aqueous phase was extracted several times with ether. The combined organic solution was washed with water, 0.5 M sodium thiosulfate solution, water, brine and dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure to yield 1.3137 g of crude ketone which was distilled in a molecular still to obtain 1.0513 g (b.p. 105-115°/0.115 mm) of purified material. After futher purification by preparative TLC (1.7 mm silica-gel, 1% ether/benzene) 0.7940 g (67%) of ketone 66 was obtained. Glc analysis (4% QF=1, 1.3% carbowax 20 M; 10' x 1/8 "; 100°) revealed ketone 16 to be a mixture of epimers with one predominating (66%). The epimeric mixture was not futher purified. Epimeric ketone 16: IR (Figure 15p59) (neat) 3090 (C=Cfl2), 3027 (vinyl hydrogen), 1731 (five-membered ring ketone), 1660 (trisubstituted double bond), 1638 (disubstituted double bond), and 885 cm“; nmr (Figure 35 p 88) (CC14) T 4.43-4.63 (mul, 1H), 5.22 (broad singlet, 2H, isopropenyl vinyl hydrogens), 8.21 (singlet, 3H, isopropenyl methyl), 8.33-8.41 (mul, 3H, allylic methyl), 7.24-8.83 (mul, 10H), and a pair of secondary methyls, 9.19 (J=6.5 Hz) and 9.14 (J=7.0 Hz), 3H. The epimeric mixture exhibited a parent ion at m/e 218 and fragment ions at 203, 200, 122 (base), 107, and 93 in the mass spectrum (Figure 45p99). Figures "I'd like to see Paris before I die - Philadelphia will do". w. C. Fields My Little Chickadee 54 51) AMCRCNHS 9 4.0 L4LJJA'JLII . :- s w ,w;. w . ., ot.1lolllllllll|lfl 111.11 I . . .. A . o 7.111. . . . _ 4 . --._. _.— --._—_._.- 2000 1500 '500 utNC'! (‘A'l 80 6 4 :3 Uz<:_,...mz...fi P4 O O 0 40011 3000 III4 11.0 12.0 a; 60 160~ 6% '1 A L A‘ 'A w m o LIL}! t... .L? -. ." " u; ._ _ L a _ ._ .. . 1 . “I .T.1..-1u -. w 24.1.11. _.1- - . _ . . . l 1 . . .. _ . ” . .l.| 1"L1l.llcl. 1,! .11)., 'Illll'l.. l lllrlll l . Ill 1 |1lut .0 14 C c _ u _ 0. .ll; 56 ,-\ o O .O 4 5 5725:5925 o 2 8C' 10th 1700 nt- (unto Ln". 1400 160’) ’1 A 1) gr. 0 20 Infrared spectrum of trans-2-ethylidenecyclopentanone 4 ). Figure l. 55 . . I1 1|‘0‘l‘llllll'10'tl Q C A . o u a. . o . s . p . A to . . n I: . . c .o . . ~ 0 .1 . _ . | o...lsu-ll«OOnll. .1. , . . . . — . . . 11L 1 o .. 9. - -i|||||l| . s . .0 .ul 1 I 2500 MtOuQ'dCI ((u', 3000 aux) . 3500 4000 m nucnows 7.0 moo’. 1200 umu 'CM ‘1 MOO MOO 18011 2000 Cal" methyl-(5rC1)-spiro [4,5]decan- (50). 'l/b Infrared spectrum of lOt 7-ene-1-one Figure 2. 56 100 ‘ J I 3o _ _ 2000 25 80+- A» 6 :3 325:... O I. 20r~ 1500 1()() K 2 3000 O 350 4009 INI'V IIOO' 8.0 MICRONS 71) .u1 . H. : _1. ..J, u .l l I. with. LIIFJ . .. II. .1111 1.. 211111; _ 1411." . 4.1.11 “111... -111. .1. 1 1 u 11.111 .. 1 T11 1 11 I 1 1 1 111111111 _ . a o . -‘ '* I I . .1. . 1 _ 1. c . 11 1 .II 11 11 l 41 _ . . u u . — . . . O.|. . . o lo . . {111111 . 1.. 1. 1v 1. . m o - . f 1. 1.1- .1 1.1.P111 . .. . . . ~ .10. o. I 11 o ._ m _ . “ a . , " O! i '1' I .01 o ’0’ A , on. V - . . n . , _ 1 w . a 1111 1111.11 '1 + . m _ . . _ . u . . . _ a 1 IO 1. 1.1 1 . ..1 . . r . _ _ . - 111. 11.1 41 . . .. . . . . lfi — — - - l1 2 — '1111 m . . o 1'14 0“... 1200 1100C! C» ‘1 1600 1000 1400 '1801) av 33 5244:2335 , 2000 800 .I.I Figure 3. Infrared spectrum of 6t-methy1-(5rC1)-spiro[4,5]decan- (47-DA). l-one ’Vb 57 o I L A 1 n 1500 1 O ‘ l16.0 0 . m1 1 A W _. L .. 0 1 1 I11- 1 1 1 11 II. 11 , o\\\ J 4 . I L 1 1 _ m m 0 IL- I'llll'l' 11 '1' |.‘11 I I H 1 2 m A. l ijl I. [I'll' I... a. 1". 1 I. S . 1 - m 11.1-1111- 1 1.1.1111! - 111i 1 R A.. 110.1111 111.1111 C L“ -, _ M 41.. - -- I11 - 11.111.111-11 11 m - a v.5 .m 01 . 1 I 111 1 11 1 1 L 2 I 01 u - 1111-11 11- 1.111 1 u 111111 w 1. m ., A 3000 3300 0'1 . 0 80 4000 50 C 6 20 0 40 20 0 .Wv 0 0 0 .l 8 6 A. .mkuquzsm24u» / ....\.._ mJ....<_ :..,.n. .3: 800 1 1000 12110 1CM'1 . 1"! «11111 1400 (3,3). 1600 |r 1d decan-8—0ne 20011 , , 2.6 F1gure 4. Infrared soectrum of 1-methy1-2-hydr0xytr1cyc10[4.4.O.0 ] 58 BI) I)... 10C 61) A 1500 1 .-m .31 .. L 2 <.1 N 1‘ O- a. R L m 1 M 1; 0g“. m 4 . 5 1 .5. .i1 1 0 n0 nu 3 n~1 3 1 .U - 0 5 1. 3 1,) 5 a; a w a: nu n0 «0 my my w. 2 04 6 4 “.5 524E223: 'IIQULNCV 'Cm '1 70 O 2 0 1IIIL mo “KRONS 100 110120 .1 11“. 1.114112! 1 1"1f1'11111'5 @1- 1600 1200 1000 800 Oh JINCV C111 '1 1400 180) 6 4 .5 wuz;gwewuuuop.uo mo sagpumam LEz .mm mgzmwm 0.0 0.» ex 3. ca — I I I I — I I I I _ I I I I — I I. I I h I [I 4 .10 _ a_ . - -Q—Q— .~-.--.. -~-—_—_- - -A-vR-v-.. .— .- o o c o n C O O I 0--..-. .‘n-——- o d I I I . I 4 q I I - I I‘ I 82 0.0— 0.0 J— .Amooov .Awev mco-_-Po-»~-=muoumm.euogwam-APugmv-_»cpmswu-po_.uo $0 saguumgm Ls: .mm mgamwm 0.0 ON 00 on I ‘I I I. — I I I I _ I I 4 I I 1_‘ «I I I I _ I I I u I 1_ 83 S .Aepuuv .Aemv mco-Puwcmamucmumumm.euogwamuapugmvupxsumswuuuop.o we Eagpumam LE: .om mgzmwm 8 2 od ow c... Q... 84 S .Aoomuv AogmeLHOF mo Eszumam mmmz 91 a : :: == O I. .0. LON .0m ‘0? 10m OJ apad aseg ;o abpluanad .mm mgzmwu 92 .Ame mco-Fucmpowgpvaunncmumvmm.egogwnmuflFugmv-F»;umE-uop mo Eagpumam mmwz .mm mgamwm <2 OPN 3N OHM 05v~ 8“ CNN O.“ 8“ 06- g or 3‘ Gas 0" 3‘ °N~ O: 8 8 8 2 g 0“ 0' On. 0“ a _ _ - .. . _._ , . . . _ ....-._._ _ . .... Liz-Mull"- .. - . - e . :0- . . . . . . -i.--...-T.. -- _- -.L.-_.-- -- - .oud ” “1.. m a , . . . m L. -ml.a|l.. . ion a . . u . 1+ L .0? O I: . 8 cm. 9 S a .oJ .d . a 0.. ror X. AMUfiHmwv .oo o w. .6? g 93 09‘ .Amonwwv wco-—Lcmumvmm.QQOLwomuA ogmvufixsmeme $0 Esgpumqm mmm: .oq mgzmwm e9 3. 3. 0! on. o! o: 02 ow cm 2. co om or om — 0- ON on 07 Om OJ xead 9598 J0 1uaoxad 0.. ca 00 00. 94 S .A_ . CON mcoumucmumvflo.m OZ 0? 0: 03 0.2 o.o.¢.¢HopuxquuxxogumcumuFxgumewvum.F mo Ezgpumnm mmm: «a. 2: an. 3. o: 02 at cm or as am 0: 0m 0 O. Ow On 0.. on 0.» need asea ;0 JUBDJad Or 00 oo 00. ._¢ 0.59.. 95 .flwwv m:o-m-:mumwmo.mo.o.¢.¢.opo>uPprxognxcnmuchpmevaN.F mo Eaguomom mmm: .mc mgzmwm as 8s 0‘ 0‘ 9...: 9: .0: a: 94 02 or 2 Or 3 oh 0) 3 ON .0 - . . .. . U 0‘ . . . on. d 8 J 3 on 8 U 3 O . or I: 8 p. S . ov a m. on. 9 an. 00 on em 00\ .Awwv mco-F-Feupfiucmumcmm,¢gogwamufi ugmv-~>;umewvuuo~.uo we Ezguumam mmmz .mc mgsmwu _. 00a: 9? 02 92 3‘ oh 9‘ 02 0‘: at o: oo 8 0r 0.. Q... a. an 96 _ . . _. .. . ._ _.. ._.._.. .__ ... _ -- . .. 9 . . H a H H J . . . D 8 w . 11 o... w. W S a d a a m. as a 9.. oo\ 97 .Aznm 00“ S m . O. \ mCOLPmemLN-Focmumuuuxnmm.¢.0LwamLA &\ 0: 3x P: 96\ 0.x Dds O§ 8\ P Q» 9w be 0. O.“ 0? On ON 0. ULm.-F»£umE.u-po_.pm *0 Ezguumam mmm: .7 oh. OJ or or 3‘ need aseg ;o QUBDJBd .¢¢ m.:mw. 98 S .Ao . mco-—-mcmwc-o.mncmumumm.¢gogwamafiPugmvu_xcpmewu-uop.o we Esgpomam mmmz .mv mgzmwm m\E 0+; OOH cm L. .. . _.__. LS. ._ .__.. .51. .1_=:F.’.fi.__ ....._.. -”_.. I. a. . - .1 [ON 1 10¢ . w L. 0 low m nm—w n. “n L Iom m. .l fi.IOOH .Awev mcouFumcmumuumumm.vuogwamnAFugmvuFxcpmswuuuo—.mupzchOLQOmw-m mo Ezgpumqm mmmz .m¢ mgzmwm 3.. o. m o: om. om om 99 _ F -L _ g r P ..- ._. L; z? _- .w p _ b _ L. g1w b. _ _ fl; :AL .13 d; 1;: A; .3: A 4A1 E .4. 1 4 u: _ TON HPad 8598 ;o zuaoJad 10m [00” 100 1000q 7500 500C;— Extinction Coefficient 250g .4 L L 200 225 250 275 300 r A(nm) Fiqure 47. U1trav101et spectrum of trans-2-ethy1idene cvc1opentanone Q3”). 101 .mmcocmumnmm.mo.o.¢.¢go~u>uwgu>xogw>;-m msowgm> $0 Eaguumam pm~ow>mguyz .we mgamwm Ascva Pomm mmm com mum omm mum com A . mm m. n m“ H . I 8m w m. _ my g ”u Q 3 . mu m “w . fir emu M- - - - - -. A_m. mco-m-coumumo.No.o.¢.¢.o_uauwgpxxoguxg-~-Fxgume_u-~.P . Ace. mco-m-=mumumo.~o.o.¢.«Hopu»0wgu»xoge»;-m-Fxguos.P coop 102 2000 . 6t,10t-dimethy1-(5rc1)-spiro[4,5]-7-decano1-2-ene-1L one (65 R=H) ( ----------- ) 6,10t-dimethy1-(5rC‘)-spiro[4,5]decan- 2,6-diene-1-one (66) 0————-——J 1500C- 4..) C Q) '8 a~\ 1: 10000. ,I \ q. 8 x ‘ u I \\ C O :3 / \ .E I \ *’ I .3: , x \ sooéL ’ / I I I I I I I \ I .‘.‘ 1 ! ‘r--~---- 200 225 250 275 3001 1(nm) Figure 49. Uitravioiet spectrum of various spiro[4,5]decan-2-ene-1-ones. 10. 11. 12. 13. 14. 15. 16. 17. 103 BIBLIOGRAPHY J. Vrkot, J. Jonas, V. Herout and F. Sorm, C011. Czech. Chem. Comm., $2, 539 (1964). F. Sorm and V. Herout, C011. Czech. Chem. Comm., 1%, 177 (1948). Nie1$ H. Andersen, Phytochemistry, g, 145 (1970). w. Parker, J. S. Roberts, and R. Ramage, Quart. Rev. (London), 331 (1967). N. H. Andersen and D. Syrda1, Tetrahedron Lett., 1759 (1970). I. Yoshioka, S. Takahashi, H. 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