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Subrahamanian A DISSERTATION Submitted to Michigan State University in partiaT fquiTTment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1978 {*x \ .x I (j/ / ”(i 1/ ABSTRACT PART I RING OPENING REACTIONS OF FUSED CYCLOPROPANOL DERIVATIVES PART II TOTAL SYNTHESIS OF SPIROVETIVANE SESQUITERPENES By K.P. Subrahamanian PART I Fused cycTopropanoT derivatives % - 2 were prepared from the Tithium—ammonia reduction of WieTand Mischer ketone l, foTTowed by simpTe chemicaT transformations (equation 1). HO 0 T) Li, NH3, THF 3 / (1) E / 2) (NH4)2C03 o / O 4/ ‘e on I g g=R=H,‘ Z=H, OH 4=R=-Si+1 2—0 N I I, _ g—R——sc+g Z—H, OH _ _ I. g—R—-Srf, Z—H, H 7=R=—0Ac, Z=O ’\; 8=R=-0Ac, Z=H, 0H ’\1 9=R=-0Ac, Z=H, H 'b K.P. Subrahamanian Ring opening reactions of a — a with electrophiles such as H+ and H92+ and bases such as 0H" and guanidine have been studied. A correlation of regioselectivity with stereoselec- tivity has been noted. Products from 'a' bond cleavage are formed with predominant retention of configuration whereas products obtained from 'b‘ bond cleavage are formed with in- version of configuration. Mineral acid catalyzed reactions of cyclopropanol %, g, ' g, and % showed high regioselectivity ('a' bond cleavage) 4‘ and stereoselectivity (retention of configuration). Compound 2 is somewhat Tess regioselective possibly due to steric hin— drance of the t—butyl dimethyl silyl group. Acid catalyzed cleavage of a, i, and l proceeded with moderate regioselec- tivity (bond 'b' repture), the major products forming with inversion of configuration. Although cyclopropanol % and Q showed very poor regioselectivity on reaction with strong bases, very high regioselectivity were observed for compar- able reactions of compound a and A possibly due to carbonyl group participation. Remarkable regioselectivity and stereo- selectivity were noted in the reaction of cyclopropanol % with guanidine. Cyclopropanols % and i did not show much 2+ stereoselectivity in reaction with Hg , even though good regioselective cleavage of bond 'b' was observed for R' K.P. Subrahamanian PART II Two important sesquiterpenes having a spiro[4.5]decane skeleton are B-vetivone l and hinesol g. The spiroketone g and Q obtained from ring opening reactions of cyclopropanols 3 and % respectively have proven to be versatile intermediates in the synthesis of these natural products (equation l). o s S H H T 2 '\J ’\1 " CH3 (1) —‘) OH H 3=R=CH3 5=R=CH3 7=R=CH3 4L:R=H Q=R=H q=R=H Spiroketone 2, first prepared by Marshall and Johnson in their synthesis of B—vetivone, has been obtained from ketol I in 40—50% yield by a l,2—carbonyl transposition followed by dehydration. K.P. Subrahamanian 9 m A highly stereoselective synthetic approach to hinesol from enone l9 (obtained from E) has been studied. Conjugate addition of bisisopropenyl copper lithium to enone l9 pro- ceeded with high stereoselectivity to a single isomer ll. The conversion of TI to (i) hinesol has been partially com- pleted and follows established chemical transformation. ‘ """(i) Hinesol DEDICATION This dissertation is dedicated to the memory of my father. ACKNOWLEDGEMENT The author is deeply grateful to Professor William H. Reusch for his expert guidance, enthusiasm, and encouragement during the course of this work. To friends past and present, in the lab and elsewhere, the author extends his gratitude. Special thanks are also extended to my wife, Indira, and my daughter, Chitra, whose love, encouragement, inspira- tion, patience, perspiration, and understanding over the years have made this opportunity possible. The author acknowledges the financial support from the National Institutes of Health and the Department of Chemistry at Michigan State University. INTRODUCTION TABLE OF CONTENTS PART I RESULTS AND DISCUSSION EXPERIMENTAL General Preparation Tricyclo— Preparation Preparation Preparation Preparation Preparation Reaction of of [4. of of of of of cyclopropanol silyl ether with. (IR4, %, G)- 5- Hydroxy- 6- MethyT-. 4.0.0 5]decan— 9- one g cyclopropyl silyl ether 4 silyl ether T . cyclopropano acetate . trans- 9- methyldecalene- 1 IS cis- 9- -methyldecalene- l 4 hydrochloric acid . Reaction of cyclopropanol acetate 9 with hydrochloric acid Preparation of cyclopropanol silyl ether g and reaction with hydrochloric acid Preparation of cyclopropyl acetate “g and reaction with hydrochloric acid Preparation of cyclopropanol % and reaction with hydrochloric acid . . Reaction of cyclopropyl silyl ether 4 with hydrochloric acid. . . Reaction of cyclopropyl acetate 1 with hydrochloric acid. . Reaction of cyclopropanol g with hydrochloric acid 'b Reaction of 9 with methanolic potassium hydroxide Reaction of g with potassium tert. butoxide t- butanol. Reaction of cyclopropyl acetate Q with potassium hydroxide. Base catalyzed reaction of epimeric diol 9 Reaction of acetate 1 with potassium hydroxide Page 40 41 41 43 43 43 44 TABLE OF CONTENTS--Continued Reaction of leith guanidine . . Reaction of Q with mercuric acetate . Reaction of Q with mercuric acetate followed by demercuration with sodium borohydride. APPENDIX: SPECTRA PART II INTRODUCTION. RESULTS AND DISCUSSION. A. SYNTHESIS OF B-VETIVONE PRECURSOR B. STUDIES TOWARDS TOTAL SYNTHESIS OF HINESOL. EXPERIMENTAL. General. . Preparation of cyclopropanol illi..... Preparation of spiroalcohol igéand subsequent oxidation to spiroketone Preparation of ketal . Preparation of the a— phenyl sulphide . Preparation of isomeric vinyl sulphides QQ and l . . . Preparat1on of isomeric ketones Q and IQQ. Preparation of silyl ether Q . Preparation of spiroalcohol Q. Preparation of olefin . . . Preparation of spiroalcohol Q . Preparation of spiroketone . Preparation of unsaturated ketone . Preparation of d- bromoketone QQ with PHT and dehydrobromination to prepare enone QQ. Preparation of a— bromoketone QQ. Preparation of spiroketal QQ. . Preparation of enone Q via a- selenation Preparation of spiroa oxidation to spiroketone Preparation of enone QQ by a- sulfoxide elimination . . Preparation of ketal QQ. APPENDIX: SPECTRA APPENDIX: ABBREVIATIONS REFERENCES. cohol Q and subsequent. Page 45 45 48 49 128 129 LIST OF FIGURES Figure # PART I l. Infrared spectrum of Q . 2. Infrared spectrum of Q . 3. Infrared spectrum of Q . 4. Infrared spectrum of Q . 5. Infrared spectrum of AQ' 6. Infrared spectrum of l5. ’b’\; 7. a) }H NMR spectrum of 4. b) H NMR spectrum of Q. 8. a) 1H NMR spectrum of . b) 1H NMR spectrum of . 9. a) }H NMR spectrum of 4 b) H NMR spectrum of Q 10. a) Mass spectrum of 4. b) Mass spectrum of Q. ll a) Mass spectrum of . b) Mass spectrum of . l2. a) Mass spectrum of 4 b) Mass spectrum of Q l3. Infrared spectrum of QQ. . l4. Infrared spectrum of QQ. . . 15. Infrared spectrum of QQ. . . PART II vi Page 49 50 51 52 53 54 55 55 56 56 57 57 58 58 59 59 6O 60 96 97 98 LIST OF FIGURES--Continued Figure # 16. Infrared 17. Infrared l8. Infrared 19. Infrared 20. Infrared 21. Infrared 22. Infrared 23. Infrared 24. Infrared 25. Infrared 26. Infrared 27. ,Infrared 28. a) QH NMR b) H NMR 29. a) 1H NMR b) 1H NMR 30. a) 1H NMR b) 1H NMR 31. a) 1H NMR b) 1H NMR 32. a) 1H NMR b) 1H NMR 33. a) 1H NMR b) 1H NMR 34. a) 1H NMR b) 1H NMR spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum spectrum of spectrumo spectrum of spectrum of pectrum 1 s ( spectrum of . of axial alcohol QQ. spectrum spectrum spectrum spectrum spectrum 0 spectrum of of QQ. 80 MHz) spectrum of Q. 44 - KI - Q. equatorial alcohol 13. ’\:'\1 axial alcohol 13 ’b’b 8w 800 800 8m 8w 8N gm RN 801 84> aw 80 8&0 80° 1% ii: of equatorial alcohol QQ. of QQ. °¥ ii: °T= ii: spectrum 0 Page 99 100 TOT 102 103 104 LIST OF FIGURES--Continued Figure # Page 35. a) 1H NMR (180 MHz) spectrum of 33. 118 b) 1H NMR spectrum of 35.. . 118 36. a) }H NMR (180 MHz) spectrum of 31.119 b) H NMR spectrum of QQ.119 37. a) Mass spectrum of l . 120 b) Mass spectrum of Q . 120 38. a) Mass spectrum of QQ. 121 b) Mass spectrum of mm. 121 39. a) Mass spectrum of Q. 122 b) Mass spectrum of . 122 40. a) Mass spectrum of axial alcohol . 123 b) Mass spectrum of equatorial alcohol .QQ. 123 41. a) Mass spectrum of . 124 b) Mass spectrum of . 124 42. a) Mass spectrum of . 125 b) Mass spectrum of . 125 43. a) Mass spectrum of . 126 b) Mass spectrum of . 126 44. Mass spectrum of QQ 127 LIST OF TABLES 1. Products derived from the base and acid catalyzed cleavage of cyclopropano1 and their derivatives Q.- Q . . . . . . . . . . . . 10 Products derived from the reaction of cyclopropanol and with mercuric acetate acid, followed y demercuration with different reagents. . . . . . . . . . . . . . . . . . . . 16 viii PART I REACTIONS OF FUSED CYCLOPROPANOL DERIVATIVES INTRODUCTION During the past two decades organic chemists have developed an increasing interest in the chemistry of cyclo- 1,2,3,4,5 have been developed propanols. Several good methods for the synthesis of cycloprOpanols, including an ingenious and potentially very useful synthesis of the tricyclopropanol Q by reduction of l—methy1bicyclo[4.4.0]dec-6—ene-2,8-dione with lithium and ammonia6’7’8’9’m’H (eq. 1). (1) 1) L1, NH3, THF\ 8. 2) ( I 0 NH ) C0 1 Ring-opening reactions of cyclopropanols and their deri- vatives may be induced by electrophiles or bases. There are two important aspects of such cyclopropanol ring opening reactions: (1) To what degree is the cleavage of 'a' bond to the 'a' and 'b' side regioselective? (2) What is the degree of stereoselectivity in the protonation stage? (eq. 2) H H R (DH .1/ a + .é”: (2) 0A., Acid or Base 7xnj>95 An exceptional case in which inversion at the site of electrophillic attack was observed and could be explained by 12 steric hindrance (eq. 5). Furthermore, an interesting sol- vent effect on the stereochemistry of protonation has been reported in another case.13C Cyclopropanols and their derivatives react readily with mercuric acetate in either acetic acid or methanol.Ha The stereochemistry of these reactions depends strongly upon the substitution pattern of the cyclopropanol. Electrophillic attack occurs most readily at the least substituted bond in the molecule to give a B-mercurio aldehyde or ketone. If the a-bonds are equally substituted, attack on a cis substituted bond proceeds more readily than on a trans bond (eq. 6 and 7). I H3C ‘ C6|-l5 4. I49 (OAC)2 ———-) : (6) ACOH //C\ H o 9 H OH H' CH3 (90% Inversion) c6H5 CH3 H A H + H9(°A¢)2 _—————> (7) ‘CH3 ‘3" (90% rotation) The mercuric acetate ring opening of cyclopropanols is more sensitive to steric hindrance than is proton induced openingHb (eq. 8). CH2HgoAC H (DH (8) . Hg(oAc)2 ; H3C T <|:=o Pl (3 H CH3 C6"5 6 5 Base catalyzed ring openings of cyclopropanols may be regarded as SEl reactions and they generally proceed with high ll,l4 regioselectivity (eq. 3 and 5). Furthermore, the c- protonation step is usually characterised by inversion of con- llb,l3 figuration at the B-carbon atom. However, it is known that the solvent and the nature of the substituents on the 15 Base ring can alter the stereoselectivity of the reaction. catalyzed cleavage of 2-phenyl-l-methyl cyclopropanol in heavy water proceeds with inversion of configurationH (eq.3). On the other hand, Wharton and Bair‘3a noted the 7-hydroxy-l,6- dimethylbicyclo[4,4,0] heptane opened with retention of con- figuration on treatment with potassium t-butoxide in t-butyl- alcohol. However, the same system reacted with inversion of configuration when an ethylene glycol solvent was used. These results are consistent with the observations and interpretations suggested by Cram,15 for electrophillic substitution of car- banion intermediates. One exception to the above rule16 is the ring opening reaction of l-hydroxynortricyclene with ex- clusive inversion of configuration in t-butanol solution (eq. 9). This was rationalised as another case of favored exo attack in the norbornyl system. (9) ’ (CH3)3COD A D \ H OH I k KOC (C "3):, C) H In the first part of this dissertation, I will discuss the ring opening reactions of tricyclopropanols g, g, Q, Q, g, z, a, and g with electrophiles like H+ and HgZ+ and bases like OH" and guanidine. It is important to recognise that cyclopro- panols g - Q are closely related to the compound l9 studied by Wharton and Bair.13a / / / / // e '4 10 (DH ~ (DR H N H O u x H I II N II I V O I 50 II I II II N N II II I o o :0 I ll v -m un-lo :0 .+ II m. c—lo II N II CD 30 II D 0 8K0 800 8V 80‘ 801 84> 800 EN II II N N II II I I O I I v " 30 E II H U) ]> ..a ° + II N n I I Do I 3; O From the above structures we see that the key difference between our system and that of Wharton is the presence of a two-carbon bridge from one methyl group to the carbinol carbon and a carbonyl function in E, 3 and 1. In compounds 3 and 2 only the two-carbon bridge perturbs the symmetry of £8, so that the results of ring opening reactions of these cyclopro- panols should clearly show the influence of their structural feature. Furthermore, a parallel exists between this study and work of Nickon in which a two-carbon bridge perturbed the symmetry of nor-tricyclic acetate,Hd ll and l2. ’L’b ’b’b ococw3 ococu3 ll 12 RESULTS AND DISCUSSION RESULTS The cyclopropanol, 6-methyl-5-hydroxytricyclo[4,4,O,0]’5]- decan—9-one 2, used in this study was prepared by lithium— ammonia reduction of bicyclo dec—6—ene-2,8-dione l (equation l), in 50-90% isolated yield.6’7’8’9 HC) (1) 1) Li,NH3,THF ‘. I .9 2) (””4)2C03 ‘ o o 1 Z Cyclopropanql derivatives 3 - 9 were obtained from 2 in excellent yields by simple chemical transformations. Thus diol % was prepared as an epimeric mixture by reduction of 2 with lithium-ammoniua or sodium borohydride (equation 9). Li, NH , THF 0 Or NaBH ' 4 Treatment of 2 with tert—butyl dimethylchlorosilane in dimethylformamide containing imidazole as a catalyst proceeded to Q in 98% yield.]7 Reduction of 3 with sodium borohydride at —78°C (equation l0) was followed by conversion of alcohol 3 into silylether Q by the excellent procedure I HO +S:i— +S' _° 3 :,1 O OH 2 Q ~ reported by Y. Fugimoto and T. Tatsuno. 0 Thus, the tosyl- ate of g was treated with 5 equivalent of sodium iodide and l0 equivalent of zinc powder in refluxing glyme, and Q was obtained in 90% yield (equatlion ll). Quantitative conversion of cyclopropanol 2 to the acetate 1 was achieved by stirring 2 with acetic anhydride and pyri— '\J dine. Reduction of z with sodium borohydride then gave an epimeric alcohol mixture 8 in very good yield (equation l2). ’b “0—) “(a do... Conversion of this alcohol mixture into the deoxy deri- vative 2 was accomplished in 80% yield by the same method used in the preparation of 6 (equation l3). ’b (13)“? “ms_ 2 9 N N The products obtained from g - 3 on treatment with several different acids and bases are listed in Table I. These reactions were monitored by a combination of TLC (si- lica gel) and GLC (QF—l), and pure samples of each major component were isolated by preparative GLC and/or crystal- lization. Identification of these compounds was achieved by a combination of mass spectrometric, infrared and 1H NMR measurements. lO m cowuommg oz :0 :u .xox $2.5, 3w. e u m mum: mm mom: mm :0 O ucmmmmm ooetov we away we moeoq get; euxo .2; m . . .008 .Iomzu .8: 0...we _ o m m mumsuv we I o_ ” om or om .Ao_v Q% .Aomv a Iomxeo-e-mzeu-e-ox w _ a ... . buomspv Wk .msz a mm L m mm m .Ammv ea .Amv mp .oomm .Iomzu .xog " e E we ...; e. as ex m om meets max .Aooetev ea .Aomv a .oomm .Iomzo .PQI m . :o :u zox a om , Om mm mm M .MLfi M _ .008 .10qu .8: 0LT mmm>mm~u mmm>mmpu cowmsm>cH cowpcmpmm ccon.n_ ucon.m. Aupmw» av mpuzuosd mco_uwucou mucmpummm xyw>wpumpmmowmmm apwuwewomamomsmpm - cowuoomm «a i w mm>mpm>wsmu swmgp use FoamQOLQOPUaU ac mmm>mmru nm~xrmpmo ovum use omen we“ Eosw nm>wswu mpuanosd .H mFDmP ll . .8. 83 WW 8 8...: N o :8 m :8 m .Aamv we .A88 .8088 .:8 :8 .:8: A888 we .mL: 8 8 2 8 2 .8... E: 8: 3 .8088 if .8: 0u< e8888e8mae: :88:8 .:8: w :88 o a: _N a: _N Hflgme 0 .mL: N a $3 3 .23 3 .8088 LE .8: 0...? a 88 88 88 88 8: .3 .888 3 :38 892: S :o m .8 mm .:8 :8 .:8: . eooemww aw. eexo m.mt: 8_ gamuammu 8_ 88 8_ 88 .A888 w a .8 mm .:8 :8 _8: 3n. .cexom..8...: 8.20 w. 88 mm 88 mm 3 .33 3 .808 88 :8 :8 :88. 8 88mLu we :vxo ..mcg 08 o ooeee 88 888:8 :8 .:88a:8 w; .Ammw we. 8 mm .:om:8. 88: .a mam>mmF8 mmm>mwF8 co_m:m>:H cowucmum: econ in. 8:88 .8. Aquwx xv mpozuogd mConwucou mpcmuomwm xpw>wuum_mmowmmm xpwuww_8mqmom:mgm cowpummm A.8.8:888 8 8_8ee l2 A888 2 .8:: 8 88. 8 88_ 8 .:888 w: .:88 + .8088 .:88:8 .:8: A888 .A_wy aw .A8_8 W 8.0:: 88 88 888:8 88 880:8 .:888 8 .:888L88 _ .8088 .:8 :8 ._8: e m w 88 m8 888:» 88888 m8 . a m 8:: 8 .u: a .8088 .:8 :8 .88: w .08: 8 mm mm mm mm .8088 .818 .88: 888>88~8 8m8>8888 888888>8H 8888:8888. 8888.8. uconitm. A8F888 88 88888888 8888888888 88888888: 888>8888P8888888 8888888888888888m 8888888: A.U_u:oov H anmh l3 Authentic samples of cis and trans decalin dione l7 and ”Vb l9 lg were prepared by established methods and their configu- rations were confirmed by the linewidth of their angular methyl 1H NMR signals.20 Spirodiketone lg was identified by its characteristic spectra and its conversion into spiro- ketone l% which had been independently synthesized by cataly- tic reduction of the Diels-Alder adduct from trans-Z-ethyl- 20,2l idene cyclopentanone and l,3-butadiene (equation 14 and 15). The structure of T2 was unambiguously established by x—ray crystallographic analysis of its bromoderivative25 20. ’\;’b l4 C15 and trans-9-methyl decalone—l, IQ and lg were pre- pared by roughly the same procedure used for making cis and trans decalin diones l7 and l819 (equation l6). ’L’L ’L’b 0 H0) .9. — (D I) ,1, 2.2 Reduction of l with NaBH4 gave very good yield of alco- ’b hol 22,21 which was converted to its acetate derivative 2% on treatment with acetic anhydride and pyridine. Hydrogenation of the acetate 2% with Pd-SrCO followed by Wolf-Kishner 3 reduction and Jones oxidation gave the cis ketone lg in moderate yield. The trans ketone l3 was prepared by reducing 22 with lithium and ammonia, followed by Wolf-Kishner reduc- tion and oxidation with Jones reagent. The identity of these two isomers was confirmed by the characteristic peak shape of the angular methyl 1H NMR20 signals and by comparison of their properties with those reported by W.S. Johnson.22 Products derived from reactions of cyclopropanols 2 and g with mercuric acetate in acetic acid, followed by de— mercuration with different reagents are given in Table II. l6 m :0 N 3 .8: NW 88.8 8.3.8 0.8888, m .«o u 8: 88 w: .8828; :88:8.. 8:882. .:88: icon :0 :3 z... .0: A888 vww m :888888xo 88:88 88. 8 A88-888 w: .:8.. 8: :8 :8 ._8: .8:8:80z 8m mmv vww m:888W88x8 88:88 N 888 8 A_N-8N we. :8- 88 :8 :8 . :88: .:88: 88: 8 8.88.80: .8.: 5 .888 .8 808 .:88:8 .:80: m u o ... ... .0, :83 :8. 3%.: 88. 8 :88 we .::8 N: .:888 _ 808 .:8 :8 ._8: 88. 8 :82... 8..: 8828 0%: 9% g g: 3888 8.88888 888: mmm>mm~u mmw>mmpu 8:88 .8. 8:88 .8. A8888» NV 88888:: 88:888 8:888:8888588 88:88888: 888>8888F8888888 .88:8888: 8:888» P8 :8.2 :888888888588 88 88388_88 .8888 888888 8:8 8888888 88:88:85 :88: 8:8 w _8:888:88.888 88 :888888: 8:» 58:8 88>P:88 88888888 .88 88888 DISCUSSION The homoketonisation reactions of cyclopropanol deriva— tives Q and a can be satisfactorily explained by examining plausible conformational interactions in these systems. It can be assumed that an equilibrium exists between two cyclo- hexane chair forms A and B (equation l7). Approximate measurements made with the aid of Dreiding models suggest that a strong nonbonded interaction between the C-S-OR group and the C-8 axial hydrogen favors conformation A over B. The corresponding 0R; C-9-H interaction in A is less severe. If we assume that "A" is the preferred conformation for Q and 2, the following arguments can be made. 1. The 'b' side of the cyclopropane ring is more hindered than 'a' due to the three carbon bridge from C—l-C-S. There- fore electrophilic cleavage of bond 'b' with retention of configuration is not as favorable as the corresponding cleav- age of bond 'a'. 2. Since the 'a side of the cyclopropane ring is the more 17 l8 accessible bond for electrophilic attack by "edge cordina- tion”, we expect that reaction here will give products having retention of configuration at C-6. Reaction of cyclopropanol acetate 2 with aqueous hydro- chloric acid in methanol gave more than 90% spiroketone lg along with a small amount of trans ketone l2 (equation l8). Aci’ a. __...c. CH3OH (18) 9 This result is in agreement with the general principle that "in acid media almost all homoenols and homoenol acetates undergo ketonization with high stereochemical retention (usually 90-l00%) irrespective of the substituents or of the solvents”.Hb’]6’]3a Silylether Q underwent acid catalysed ring opening reac- tion with significantly lower regioselectivity than 3 (equa- tion 19). The formation of cis decalone l3 in 22% with in- version of configuration can be attributed to increased steric hindrance of both the 'a' and 'b' bonds by the bulky t-butyl- dimethylsilyl group. Since the endo side of the bicyclo [4,l,0]heptane system is blocked, exoprotonation at C-l begins to compete with the normally facile attack on bond 'a'. 19 Base catalysed ring opening reactions of these cyclo- propanol derivatives have been studied with g (Q is not reactive). A dramatic change in the regiospecificity and stereospecificity of these reactions was observed when the reaction condition changed from potassium hydroxide in aqueous methanol to potassium t-butoxide in t-butanol (equation l9). Acu I l ROH \ Base (19) ,2, L. 15 R = CH3, m5% 95% R = C(CH3)3, 90% mlO% These results are in accordance with Cram's findings in a general study of electrophilic substitution at carbon, namely predominant retention in low dielectric and nondis- sociating solvents like t-butyl alcohol and inversion in high dielectric and dissociating solvents like water, methanol and ethylene glycol. Even though the stereospecific retention in t-butanol is well documented,15’13a the change in regio- selectivity (formation of spiroketone lg) with the change of base and solvent requires explanation. The alkoxide base derived from 2 probably exists as a solvated ion pair in non- l5 dissociating solvents. Due to steric hindrance from the three carbon bridge, the solvated ion pair will be oriented 20 over the a side of the cyclopropane ring. This orientation favors collapse to spirocompound with a high degree of reten- tion of configuration. It will be instructive at this stage to compare and con- trast the reactions of 9 with those of Nickon's compound11d 12. 9 12 N NM On treatment with acid, lg gives 69% of the product resulting from cleavage of bond 'b' with inversion of configuration and 31% of the product from cleavage of bond 'a' with retention of configuration (equation 20). In this case Nickon suggests ‘~ Catalyst x Q CHBOD 7 ... (MflMCH 3 (a brexane) (a brendane) (20) Catalyst= 02304 3l% 69% = NaOCH3 0 >95% that the regioselectivity favoring bond breakage is due to the formation of the more stable brendane structure (2.25- 3.l3 Kcal/mole more stable than brexane). The stereospecifi- city was attributed to steric hindrance from C-8, C-9 bridge. 21 This interpretation does not fit the results obtained with 9. Heat of combustion measurements indicates that the spiro[5,4]- decane is less stable than either cis or trans decalin by 23 Nevertheless acid treat— 4.5-7.0 Kcal/mole, respectively. ment of 9 gives more 90% spiro compound lg with high stereo- selective retention of configuration. Since the 'a' bonds in both 9 and l2 have about the same degree of steric hindrance and since the 'b' bond appeared to be more hindered in l2 than 9, it is difficult to explain the predominance of the brendane ..., product from l2. Base catalysed reation of 9 and l2 in methanol show a remarkable similarity. High regioselectivity, favoring the thermodynamically more stable bicyclic isomer and high stereo- selectivity (inversion of configuration) are found in each case. The acid and base catalysed reactions of 9 agree well with the observation made by Wharton and Bair for the corres- ponding reactions of compound l0 (equation 21). HCl, aqueous glyme 7 (pomplete or KO—t-C4H , t-C4H90H Retention) 0n treatment with acid, cyclopropanols g, g, and g gave more than 95% spirocompound lg (equation 22). 22 R0' 1) CH30H, Hcl (22) \ , i (”1 9) (0} %: 2:21..~ w ”90%) a ='R = Ac The high regioselective cleavage of the 'a' bond and stereo- specific retention of configuration can be explained in terms of the inductive effect of the C-9-alcoholic group, which inhibits attack of a proton on the nearest cyclopropane bond. Homoketonisation of g and Q with methanolic potassium hydrox- ide gave about 40% inverted products ll and 60% spirocompound with retention of configuration (equation 23). 15 rule, but The former product is in accordance with Cram's the latter is difficult to explain. The products obtained by the treatment of cyclopropanols 2, l and l with acid can be explained by the interaction of the cyclopropane 'b' bond and the carbonyl group (equation 24). (24) 23 HCITHF ———-> 16 (19-22%) It (55-59%) lg (24%) xxx nun MI 0:]:- ENE-53v This interaction is evident, for example, in the rapid formation of methoxy ketone 22 on treatment of 2 with methano- lic hydrochloric acid. In order to rationalize the results of several related experiments of this kind, it is helpful to consider the equilibrium shown in scheme I. The bracketed cations with the partial bonds are intended to represent either a dynamic bond-switching interconversion of oxycar- bonium ions or a nonclassical delocalized cation. In either case the carbon atom designated by an asterisk undergoes on treatment with cold (0°C) methanolic hydrochloric acid for l h, 2 was partially converted (ca. 50%) to 20, this being the only significant product other than 2. After 5 h, 2 was still the major product, but substantial amount of the isomer El was also obtained. More vigorous conditions 24 Scheme I 25 (25°C, longer reaction times) not only gave roughly equiva— lent amount of 29 and ll, but also yielded products such as l6, l7 and 19. These results point to a very rapid hemi- mq, ’Vb 0A, ketalization reaction followed by a slower isomerisation of the three—membered ring (via the bracketed cations?) and an even slower ring cleavage of the stable methoxy derivatives 20 and 21. Hence the predominant inversion (80%) and regio- ’\/\/ ’b’b selective 'b' bond cleavage of 2, l, and l in acid media appears to be due to facile carbonyl group participation. The formation of 20% spirocompound l6 agrees with the gen— eral principle of retention in acid media. The highly stereospecific and regioselective cleavage of the 'b' bond in 2 and l (95%) on treatment with base is also due to carbonyl group interaction as shown in equation l v I "0““ Since no products incorporating the tricyclic skeleton of B were obtained, J. Yordy25 trapped the conjugate bases A 26 and B in apriotic medium by acetic anhydride and lithium di-isopropyl amide base (equation 26). 1) RZNLi 25°,t(min) 3—9 (25)2) (CH3C0)20 t = 45: 72% 18% 8% trace 90: 40% 30% 16% 11% A remarkable change in stereospecificity and regio— selectivity can be observed in cyclopropane ring opening reaction of E with guanidine as a base (equation 27). A catalytic amount of guanidine in hexamethyl phosphoamide gave the spirocompound (76%) and trans—decalindione l§ (51%), both with retention of configuration, in contrast to the inversion normally observed with base. HO 0 (FH2)2C=NH (0.01 eq. H 8,76% (l g|6960 I'.. THFzHMPA e (9 H2N=C(NH2) +l51' 15% z“ =|III| 27 This stereochemistry undoubtedly reflects the fact that guanidinium cation, formed as a result of proton abstraction from the Cyclopropanol, is the only proton source for the ring opening step and is necessarily oriented beneath the six membered ring. Treatment of E with a large excess of guanidine gave a product mixture similar to that obtained from methanolic potassium hydroxide. De Puy and co-workers have noted that mercury (II) ace- tate cleavage reactions of cyclopropanols proceed with vari- 11 , able stereoselectivity, a b sometimes giving inversion and other times retention of configuration. Steric hindrance seems to be an important controlling factor. Cyclopropanol 2 is cleaved by mercury (II) acetate with high regioselec- tivity (equation 28). CH COZH O 2) heat , L 'a’ —% 9 % trace 1trace (steam bath) NaOH 90% 2% 8% ——-> CH3OH 2) NaBH4 20% 20% 54% Jones oxidation 2) NaBH3CN, CH30H }10-15% 20-25% 65% 3) Jones oxidation 28 The fate of the mercury containing group depends on the method of work-up. (Thermal decomposition gives elimination, and reductive C-Hg cleavage gives a mixture of cis and trans— decalin derivatives, the latter predominating. It is not possible from this data to determine the stereoselectivity of mercury attack on the three membered ring, because the demer- curation step may not be stereoselective.26’27 Cyclopropanol l shows low regioselectivity in mercury (11) induced ring opening (equation 29). This probably reflects the low of homoconjugation of the three-membered ring with the carbonyl function. (29) \ CH3C00H ‘. 2) NaBH4, OH NaOH 3 3) Jones A! oxid. EXPERIMENTAL GENERAL Except as indicated, all reactions were conducted under dry nitrogen or argon, using solvents purified by distilla- tion from suitable drying agents. Magnetic stirring devices were used for most small scale reactions; larger reactions were agitated by paddle stirrers. Organic extracts were always washed with water and brine and dried over anhydrous sodium sulfate or anhydrous magnesium sulphate before being concentrated or distilled under reduced pressure. The pro- gress of most reactions was followed by thin layer chromato- graphy (TLC) and/or gas liquid phase chromatography (GLPC). Visualization of the thin layer chromatograms was effected by spray reagents such as 5% p-anisaldehyde in ethanol and 30% sulfuric acid with subsequent heating. Analysis by GLPC was conducted with A-90-P3 or 1200 Varian-Aerograph instruments. Preparative layer chromato- graphy was carried out on 2 mm silica gel F-254 adsorbent on 20 x 20 cm glass plates. Visualization of the preparative plates was effected by ultraviolet light and/or charring with a hot wire. Melting points were determined on either a Hoover- Thomas apparatus (capillary tube) or on a Reichert hot-stage microscope and are uncorrected. Infrared spectra (ir) were recorded on a Perkin-Elmer 237B grating spectrophotometer. Proton magnetic resonance spectra (pmr) were taken in deu- terochloroform or CCl4 solutions with a Varian T-6O 29 30 spectrometer and are calibrated in parts per million (6) downfield from tetramethylsilane as an internal standard. Ultraviolet spectra (UV) were recorded on a Unicam SP-800 spectrophotometer. Mass spectra (ms) were obtained with a Hitachi RMU 6 mass spectrometer. Carbon magnetic resonance spectra (cmr) were taken in deuterochloroform solution with a Varian CFT-20 spectrometer and are calibrated in parts per million (6) downfield from tetramethylsilane as an internal standard. Microanalyses were performed by Spang Microanalytical Labs, Ann Arbor, Michigan. Preparation of (IR*,5,6):5-Hydroxy-6-Methy1-Tricyclo- [4.4.0.01’5]decan-9-0ne, E In a one liter, three neck, round bottom flask containing a small lump of sodium metal, was condensed 500 m1 of ammonia. The ammonia was then distilled through Tygon tubing into a carefully dried two liter, three neck, round bottom flask containing 1.78 g (0.25 M) of lithium ribbon. The reaction flask was equipped with a paddle stirrer, a dry ice condenser, a dry ice-acetone bath, and an addition funnel to which a nitrogen gas line was attached. A solution of 17.8 g (0.1 M) of the enone g dissolved in 250 ml of THF was placed in the addition funnel and added dropwise over a one hour period. The blue color of the reaction was discharged by dropwise addition of ethylene dibromide, following which 10 g of finely ground ammonium carbonate was added in one portion. 31 The cooling bath was removed and the ammonia was evaporated into the hood under a stream of nitrogen by hot water bath. The residue was taken up in 300 ml of water and this mixture was extracted four times with 200 m1 of ether. The extracts were washed sequentially with water and brine, and then dried. After removal of the solvent, 18.00 g of light yellow oil was obtained, which was triturated with 10 ml of ether and placed in the refrigerator. Crystallization yielded 12.00 g (66%) of the white, crystalline cyclopropanol. An analytical sam- ple had mp 98-100° (ether). Preparation of cyclopropyl silyl ether l To a solution of 2.7 g (0.015 mol) of g in 150 ml of dimethylformamide was added 4.5 g (0.030 mol) of dimethyl tert-butyl silylchloride and 2.5 9 (0.0375 mol) of imidazole and the solution was stirred at 45°C for 7 h. The reaction mixture was diluted with ether and washed with water and brine and dried by anhydrous magnesium sulphate. The oil, after evaporation of the solvent, on bulb to bulb distilla- tion at 109°C in 0.0025 mm Hg gave 4.33 g of pure l (98%). 1 _ 1 IR (neat) 1710 cm ; H NMR (CCl 60.06 (s, 3H), 0.15 (s, 4) 3H), 0.9 (s, 9H), 1.06 (s, 3H), 1.2-2.4 (m, 12H); and mass spectrum (70 ev) m/e (relative intensity) 294 (20), 279 (100), 237 (99), 181 (52), 145 (60), 58 (99). Anal. calcd. for C H 0 Si: C, 69.33; H, 10.26 17 30 2 Found: C, 69.35; H, 10.27 32 Preparation of silyl ether 6 A solution containing 2.303 9 (0.0078 mol) of 4 in 25 mL ethanol was treated with 227 mg (0.006 mol) of sodium boro- hydride at 0°C. The reaction was quenched after 2 hours at room temperature by the addition of water/ethyl acetate mix- ture, and extracted with methylene chloride. The combined methylene chloride extract was washed with water and brine and dried by anhydrous magnesium sulphate. Removal of the solvent gave 2.384 g of an oil which was found to be an epi- meric mixture of two isomeric alcohol g in the ratio 65:35. -1, 1 IR (0014) (3600-3100) cm , H NMR (001 60.2 (bs, 6H), 4) 0.9 (s, 9H), 1.0 (s, 3H), 2.2-1.2 (m, 12H), 3.2 (bs, 1H), 3.6 (bs, 1H). The crude product from above (2.384 g = 0.0078 mol) was treated with 2.23 9 (0.0117 mol) of p-toluene sulphonyl chlo- ride in 25 mL of pyridine for 10 h at room temperature. ,The reaction mixture was poured into water and extracted with ether. After the usual work-up, these extracts yielded 3.619 g of white crystals having a very broad melting point (61-83°C). IR (coc13) 1175 cm"; 1 H NMR (00013) 60.15 (S, 3H), 0.2 (S, 3H), 0.9 (S, 12H), 2.2-1.4 (m, 12H), 2.5 (5, 3H), 4.6 (m, 1H), 7.5 (d, J=8 Hz, 1H), 7.8 (d, J=8 Hz, 1H). A mixture of 3.6 9 (0.0078 mol) of the tosylate from above, 7.5 g (0.05 mol) of sodium iodide and 6.5 g (0.01 mol) of zinc powder in 100 mL of glyme was heated at 85°C for 2 h. 0n cooling, the mixture was filtered, diluted with water and extracted with ether. The ether extract, after washing and 33 drying, yielded an oil which was distilled at 65°C (0.0025 mm of Hg), yielding 2.09 g (93%) of 6. IR (CC14) 2900, 1245, 1120 cm-]; 1H NMR (CC14) 60.15 (bs,- 6H), 0.9 (s, 9H), 1.0 (s, 3H), 2.2-1.2 (m, 14H); mass spec- trum (70 ev) m/e (re1 aboundance) 280 (6), 265 (51), 251 (11), 238 (12), 220 (34), 147 (100), 76 (99). Ana1. ca1cd. for C H32051: C, 72.78; H, 11.49 17 Found: C, 72.86; H, 11.46 . --iihn'l. Preparation of cyclopropanol acetate 7 g A solution containing 3.6 g (0.02 mol) of 2 and 10 mL of freshly purified acetic anhydride in 50 mL of pyridine was stirred for 10 h at room temperature. This reaction mixture was diluted with water and extracted with ether. After the ether extract was washed and dried, it yielded 4.1 g (92.3%) of 7 as pale yellow crystals. An analytical sample was ob- tained by crystallization from ether-pet. ether mixture; mp 53-54°C. IR (CC1 ) 1745, 1710 cm']; 1 4 (s, 3H), 1.9 (s, 3H), 2.6-1.4 (m, 12H); mass spectra (70 ev) H NMR (CC14) 61.2 (s, 3H), 1.9 m/e (re1ative intensity) 222 (10), 214 (15), 181 (96), 179 (34), 166 (92), 152 (100). Anal. calcd. for C13H180 C, 70.24; H, 8.16 3: Found: C, 70.27; H, 8.07 Preparation of cyclopropylacetate 9 A solution containing 4.0 g (0.018 mol) of z in 50 mL of absolute ethanol was treated with 740 mg (0.02nmfl) of sodium 34 borohydride at -78°C. After 3 hr, the reaction was quenched with a water ethyl acetate mixture and extracted with ether. The ether extract yielded 4.086 g of an oil (98%), assigned structure 8 on the basis of the following spectroscopic evi- dence: 1 IR (neat) (3600-3200), 1750 cm'1; H NMR (001 51.0 (s, 3H), 41 2.4-1.2 (m, 15H), 2.6 (bs, 1H), 3.6 (m, 1H). This epimeric alcohol mixture was converted to a tosylate derivative by treatment with 5.7 g (0.03 mol) of p-toluene sulphonyl chloride in 50 mL of pyridine for 10 h at room tem- perature. The reaction mixture was poured into water and ex- tracted with ether. The ether layer was washed with water, dilute hydrochloric acid and brine and dried by anhydrous magnesium sulphate. The ether layer gave 5.642 g of an oil which was used for the subsequent step without further puri- fication. 1 IR (001 ) 1745 cm"; H NMR (00013) 51.0 (s, 3H), 2.2-1.4 (m, 4 15H), 2.4 (s, 3H), 4.4 (m, 1H), 7.2 (d, J=8 Hz, 1H), 7.8 (d, J=8 Hz, 1H). Reduction of the crude tosylate to 2 was effected by the procedure of Y. Fugimoto and T. Tatsuno.18 A mixture of 5.642 9 (0.0149 mL) of tosylate, 9.75 g (0.15 mol) of zinc dust and 11.25 g (0.075 mol) of sodium iodide in 100 mL of glyme was heated at 85° for 3 h. This mixture was cooled, filtered, diluted with water and extracted with ether. The ether layer was washed with water and brine and dried over anhydrous mag- nesium sulphate. The oil obtained after evaporation of the 35 ether layer was distilled at 75°C in 0.0025 mm of Hg. Yield: 2.6 g (84%). An analytical sample was prepared by prepara- tive TLC (SiO eluted by 10% ethylacetate and hexane). 2 IR (neat) 1745 cm"; 1H NMR 51.1 (s, 3H), 2.4-1.2 (m, 17H); mass spectrum (70 ev) (relative intensity) 166 (8) (M+-42), 151 (60), 148 (100), 133 (50), 119 (37), 105 (45), 91 (50). Ana1. calcd. for C13H2002: C, 74.96; H, 9.68 Found: C, 74.86; H, 9.68 Preparation of trans-9-methy1decalene-1 15 d A solution of 1.1 g (0.006 mol) of hydroxyenone 2219 in N 20 mL of tetrahydrofuran was added dropwise (30 minutes) to a stirred solution of 0.445 g of lithium in redistilled liquid ammonia (100 mL). After the blue color was discharged by the addition of ammonium carbonate, the ammonia was evaporated and the residue was dissolved in water and extracted with ether. The ether extracts yielded 0.94 g of a colorless oil, which was deoxygenated by heating with 22.4 mL (0.462 mol) of hydrazine hydrate (99%) and 5.8 g (0.056 mol) of hydrazine hydrochloride in 126 mL of triethylene glycol at 110°C for 3 h, followed by the addition of 7.84 g (0.14 mol) of potassium hydroxide and additional heating at 210°C for 6 h. This reac- tion mixture was poured into ice cold water and extracted with methylene chloride. The oil obtained from the methylene chlo- ride layer was oxidised by Jones' reagent to give 465 mg (47%) of 15. The properties of a sample purified by preparative GLPC (4% QFI, 160°C) were: 36 IR (CDC1 1700 cm']; 1H NMR (C0013) 61.0 (s, 3H), 2.6-1.2 3) (m, 15 H); mass spectrum (70 ev) (relative intensity) 166 (61), 151 (18), 148 (51), 133 (20), 122 (100). A 2,4-DNP derivative of this compound was prepared and recrystallized from ethyl acetate methanol mixture, mp: 170- 171°C (171 5-172°0 reported by w.s. Thomson).22 Preparation of cis-9-methyldeca1ene-l 14 . A mixture of 1.7 g (0.009 mol) of the enone alcohol 2239 £ 6 mL of freshly distilled acetic anhydride and catalytic amount (170 mg) p-toluene sulphonic acid in 25 mL carbon tetrachloride was stirred for 10 h at room temperature. The solution was diluted with water, washed with dil. hydrochloric acid and brine and dried over anhydrous magnesium sulphate. Removal of the solvent gave 1.8 g of crude product as an oil. Chromatography of the oil on 200 g silica (eluted with ether) provided 920 mg of pure crystals. An analytical sample had mp 83-85°C (87-89°C 1it.‘9). To a solution of 100 mg (0.45 mmol) of the above acetate in 10 mL ethanol, was added 50 mg of 2% palladium on strontium carbonate and the resulting solution was hydrogenated at room temperature and atmospheric pressure. Hydrogen uptake ceased after 2 h and the catalyst was then removed by filtration. Removal of the solvent gave 100 mg of pure gig acetate. Ana- lytical sample obtained by recrystallisation from pentane had mp 48-50°C (so-51°c‘9). 37 A 125 mg (0.5 mmol) sample of the acetate was heated at 110°C with 3.2 mL (66 mmol) of 99% hydrazine hydrate and 840 mg (8 mmol) of hydrazine hydrochloride in 18 mL of tri- ethylene glycol for 2 h, followed by the addition of 1.12 g (20 mmol) potassium hydroxide and further heating (6 h, 210° C). This reaction mixture was poured into ice water and extracted with methylene chloride. The oil obtained from methylene chloride after the usual work up was oxidized by Jones reagent to give 70 mg of pure 14. An analytical sample d collected by preparative GLPC (4% QF-l, 160°C) displayed the A following properties. -1, 1 IR (CDC1 1710 cm , H NMR (C0013) 61.1 (5, 3H), 2.4-1.2 3) (m, 15H); mass spectrum (70 ev) (relative intensity) 166 (24), 15 (18), 148 (9), 124 (58), 111 (100). A 2,4-DNP of the above compound was prepared and re- crystallised from ethyl acetate and methanol, mp: 158-160°C ‘9 159-160°C26). (lit. 164-165°C, Acid treatment of cyclopropanols and their derivatives A general procedure for acid catalysed ring opening of cyclopropanols and their derivatives is illustrated by the reaction of cyclopropanol silylether 6 with hydrochloric acid and aqueous methanol. (a) Reaction of cyclopropanol silylether 6 with hydrochloric acid. To a solution of cyclopropanol silylether 6 (100 mg, 38 0.35 mmol) in 5 mL of aqueous methanol (1:1) was added six drops of concentrated hydrochloric acid at room temperature. The reaction mixture was stirred for 3 h under nitrogen, while being monitored by TLC. After quenching the reaction mixture with aqueous sodium bicarbonate, the methanol was evaporated at reduced pressure, and the aqueous suspension was extracted with ether. The washed and dried ether extracts yielded 60 mg of an oil, which proved to be a mixture of 13 (70%), 14 (22%) and 15 (8%). This product identification was made by comparing the GLPC retention times (4% QF-l, 100°C), infrared and 1H NMR spectra with authentic samples of 13, 14 and 12. Spiroketone 13 was prepared by the procedure re- 21 ported by Kurt Girm and the preparations of 14 and 15 are given earlier in this thesis. (b) Reaction of cyclopropanol acetate 9 with hydrochloric acid. Acid treatment of 22 mg (0.1 mmol) cyclopropanol acetate 9 with two drops of concentrated hydrochloric acid in 1 mL of methanol/water (1:1) gave, after 40 h at room temperature, 12 mg of an oil which proved to be a mixture of 13 (90%), 14 (trace) and 15 (8%) (GLPC analysis, 4% QF-l, 100°C). (0) Preparation of cyclopropanol silylether 5 and reaction with hydrochloric acid. A solution of 200 mg (0.68 mmol) of cyclopropyl silyl- ether 4 in 10 mL of ethanol was reduced by 37 mg (1 mmol) of sodium borohydrode at -78°C. To this was added 5 mL of 39 concentrated hydrochloric acid and was stirred for 5 h at 25°C. The usual work-up followed by Jones oxidation gave 68 mg of an oil, which proved to be 99% spiro diketone 16 con- taining traces of cis and trans decaline diones 17 and 18 (GLPC analysis and infrared spectroscopy). (d) Preparation of cyclopropyl acetate 8 and reaction with hydrochloric acid. A solution of 79 mg (0 35 mmol) cyclopropyl acetate 7 in 10 mL of ethanol was reduced by 37 mg (1 mmol) of sodium borohydride at -78°C. After 4 h the reaction mixture was treated with 5 mL of concentrated hydrochloric acid and stirred for 40 h at room temperature. The usual work-up followed by oxidation with Jones reagent gave 40 mg of an oil. Analysis by GLPC indicated this material to be chiefly 99% spiro diketone l6. . ’b'h (e) Preparation of cyclopropanol 3 and reaction with hydro- chloric acid. i) A solution of cyclopropanol 2 (180 mg, 1 mmol) in 10 mL of methanol was treated with 32.6 mg (16 meq) of sodium boro- hydride at -78°C. After 3.5 h the reaction was quenched with a few drops of acetic acid and permitted to warm to room tem- perature. This solution of 3 epimers was then treated with aqueous hydrochloric acid (0.5 mL conc. HCl in 4 mL water) overnight. Extraction with ether yielded after appropriate washing, ca. 145 mg of an oil which GLPC analysis (QF-l, 185°C) indicated to be a 85:15 mixture of two components. ——— ~- m:.-s-~..-a.:_~...,._..._..._.- ~ 40 Jones oxidation of this mixture gave spiro diketone 16 in 90% yield. Less than 10% 17 and 18 were present in the oxidation mixture. Identification of 16 as the major product was achieved by a comparison of chromatographic retention times and infrared spectrum with an authentic sample. ii) A solution of cyclopropanol 2 (360 mg, 2 mmol) in 50 mL of THF was added to a solution of lithium (ca. 3 mmol) in 50 mL of freshly distilled ammonia cooled to -78°C- Following a 2 h period, during which the temperature of the reaction mix- ture increased to the point of reflux, the remaining lithium was quenched by a few drops of ethylene dibromide (blue color is discharged). Work-up in the usual fashion yielded 350 mg of 3 epimers, portions of which were subjected to acid and base-catalyzed ring-cleavage. Thus, a 170 mg portion, on treatment overnight with methanolic hydrochloric acid, gave a 65:35 mixture of isomeric ketols. Oxidation of this mix- ture with Jones reagent yielded 160 mg of spiro diketone 16 containing no discernible amounts of 17 and 18 (GLPC analysis). (f) Reactions of cyclopropyl silylether 4 with hydrochloric acid. A solution of 294 mg (1 mmol) of silylether 4 in 10 mL THF/water (1:1) was treated with 5 mL of 6 N hydrbchloric acid for 2 h at room temperature. 0n work-up, this mixture gave 165 mg of an oil, which by GLPC analysis proved to be a mixture of 16 (25%), ll (55%) and 19 (24%). ’14 41 (9) Reaction of cyclopropyl acetate 1 with hydrochloric acid. A solution of 46 mg (0.2 mmol) of acetate 1 in 2.5 mL of THF/water (1:1) was treated with 10 drops of concentrated hydrochloric acid at 66°C for 6 h. The usual work-up yielded 30 mg of an oil, which by GLPC analysis was found to be a mixture of 16 (19%), 11 (58%) and 19 (23%). (h) Reactions of cyclopropanol 2 with hydrochloric acid. i) In aqueous THF solution Treatment of 100 mg (0.55 mmol) of g in 7 mL of THF/ water (1:1) with 10 drops of concentrated hydrochloric acid gave, after 2 h at 66°C, 80 mg of an oil. This oil proved to be a mixture of 16 (22%), 11 (54%) and 19 (24%) by GLPC analysis. ii) In aqueous methanol solution A solution of cyclopropanol g (60 mg, 0.33 mmol) in 10 mL of methanol was cooled to 0°C and treated with six drops of conc. hydrochloric acid. The reaction mixture was per- mitted to warm to room temperature, while being monitored by TLC. After 4 h at room temperature, the starting material was consumed and the reaction was quenched in aqueous bicar- bonate solution. Removal of the methanol at reduced pressure followed by extraction with ether yielded 50 mg of an oil, which proved to be a mixture of 20 (64%) and g1 (32%) along with traces of 16, 11, 18 and 19 (GLPC analysis, 4% QF-l, 160°C). Analytical samples of 20 and 21 were obtained by ’b’b ’b'b 42 preparative GLPC and characterized by the following measure- ments:25 20, (13*, 3, 6)-3-Methoxy-6-methy1tricyc10[4.4.0.0]’3]- decan-7-one; 1r (f11m) 1705, 1439, 1234, 1045 cm-1; 1H NMR (CDC13) 60.34 (d, J=5.5 Hz, 1H), 0.74 (d, J=5.5 Hz, 1H), 1.32 (s, 3H), 1.36-2.80 (m, 10H), 3.37 (s, 3H); mass spectrum (70 ev) m/e (rel. intensity) 194 (14), 179 (100), 151 (26), 138 (27), 123 (80), 110 (35), 91 (36). Anal. calcd. for C12H 02: C, 74.19; H, 9.34 18 Found: C, 73.92; H, 9.45 21, (1R*, 5, 6)-5-Methoxy-6-methyltricyclo[4.4.0.0]’5]- decan-9—one; ir (film) 1710 cm"; 1H NMR (00013) 51.12 (s, 3H), 1.2-2.80 (m, 12H), 3.37 (s, 3H); mass spectrum (70 ev) m/e (rel. intensity) 194 (12), 179 (100), 151 (15), 137 (88), 123 (31), 105 (34), 93 (38), 91 (50). Anal. calcd. for C12H1802: C, 74.19; H, 9.34 Found: C, 74.00; H, 9.41 Compound 20 was also prepared25 by methylation of the conjugate base of 2. Reaction of 1.0 g (5.6 mmol) of 1 with a suspension of 0.24 g of sodium hydride in a 1:1 mixture of benzene and DMF (940 mL total volume) gave, after quenching with 3 g (21 mmol) of methyl iodide and conventional work-up, 0.6 g of an oil. Analysis by GLPC indicated this material to be chiefly compound 20 and the pmr spectrum supported this conclusion. A semicarbazone derivative was prepared, mp 212- 213°C. 43 A similar reaction of 90 mg (0.5 mmol) of 2 in 10 mL of methanol/water (1:1) containing six drops of conc. hydrochlo- ric acid for 10 h at room temperature yielded 87 mg of an oil, which proved to be a mixture of 16 (10%), 17 (20%), 18 (4%), ’b’b "b’b ’b’b 19 (16%), 20 (21%) and 21 (29%) by GLPC analysis. ’b’b ’b’b ’b’b Base catalysed reactions of cyclopropanols and their deriva- .t_i_v_e_e (a) Reaction of 9 with methanolic potassium hydroxide A solution of 41 mg (0.19 mmol) of cyclopropyl acetate 9 in 5 mL methanol/water (1:1) was treated with excess of potassium hydroxide (70 mg) for 4 h at room temperature. The reaction mixture was quenched with dilute hydrochloric acid and extracted with methylene chloride. The methylene chlo- ride extracts were then washed with water and brine and dried by anhydrous magnesium sulphate. Evaporation of the solvent gave 28 mg of an oil, which was found to be a mixture of 11 (5%), 14 (95%) and 15 (trace) by GLPC analysis. ’b'b "Vb (b) Reaction of 9 with potassium tert. butoxide in t-butanol Treatment of 20 mg (0.096 mmol) of 2 with 112 mg (1 mmol) of potassium tert. butoxide in 5 mL of tert. butanol for 12 h at 25°C gave, after the usual work-up, 15 mg of an oil which proved to be a mixture of 11 (90%), 11 (10%) and 11 (trace) by GLPC analysis. (0) Reaction of cyclopropyl acetate 8 with potassium hydroxide A solution of 90 mg (0.4 mmol) of cyclopropyl acetate 1 44 in 1 mL of ethanol was reduced by 37 mg (1 mmol) of sodium borohydride for 4 h at -78°C. This reaction mixture was then treated with 70 mg (excess) of potassium hydroxide and stirred at room temperature for 4 h. After the usual work-up followed by oxidation with Jones reagent, this reaction gave 50 mg of an oil, which proved to be a mixture of 16 (85%) and 11 (45%) by GLPC analysis. (d) Base-catalysed reaction of epimeric diols 1 A 300 mg sample of 1 (1.6 mmol), prepared by sodium boro- hydride reduction of g was dissolved in 15 mL of methanol con- taining sufficient potassium hydroxide to raise the pH 13. After an overnight reaction period at room temperature, the mixture was diluted with water and extracted with ether. The residue from the ether extracts was oxidized by Jones reagent and worked up in the usual fashion. Analysis of the crude pro- duct by GLPC (QF-l, 185°C) showed it to be a 58:42 mixture of spirodiketone 16 and cis-decalin 11. These products were separated and identified by their characteristic spectra and appropriate mixed mp measurements. (e) Reaction of acetate 1 with potassium hydroxide A solution of 41 mg (0.18 mmol) of cyclopropyl acetate 1 and 70 mg (excess) of potassium hydroxide in 5 mL methanol/ water (1:1) was stirred for 4 h at 25°C. The usual work-up gave 28 mg of an oil which proved to be 11 (13%), 11 (29%) and 19 (68%) by GLPC analysis. 45 Reaction of 1 with guanidine Treatment of a suspension of guanidine carbonate in etha- nol with an equivalent amount of sodium ethoxide, followed by filtration of the insoluble sodium carbonate and evaporation of the solvent, gave crude guanidine. Residual ethanol was re- moved by repetitive shaking with anhydrous THF, in which guani- dine is relatively insoluble. The resulting anhydrous guani- dine was a colorless solid, mp ca. 50°. A stock solution of 0.01 M guanidine in 1:1 THF:HMPA was prepared, and 0.5 mL of this solution was added to a solution of 1 (90 mg, 0.5 mmol) in 10 mL of THF:HMPA. After 10 h at room temperature, the reaction mixture was quenched in ice water, acidified with dilute HCl and extracted with ether. The ether extracts yielded 90 mg of an oil, which proved to be a mixture of 16 (76%), 11 (8%) and 18 (15%) by GLPC analysis (4%QF-l, 160°C). The major product 16 was isolated by preparative GLPC, and proved to be identical (mp, ir, pmr) with the major product from heterogeneous protonation of the sodium salt of 1.25 Compounds 11 and 11 were identified by spiking the GLPC analy- sis with authentic samples. when the guanidinezcyclopropanol molar ratio was in- creased to 20:1, the above reaction yielded a mixture of 11 (20%), 11 (trace) and 11 (79%) in good yield. Only a trace of 17 was observed. ’b’b Reaction of 2 with mercuric acetate ’U To a suspension of 330 mg (1.1 mmol) mercuric acetate in 2‘mL of acetic acid was added dropwise a solution of 180 mg 46 (1 mmol) of cyclopropanol 1 in 3 mL of acetic acid. After stirring overnight at room temperature, the reaction mixture was neutralized by bicarbonate at 0°C. The resulting solu- tion was extracted with methylene chloride, washed with water and brine and dried over anhydrous magnesium sulphate. Eva- poration of the solvent gave 430 mg of a white solid which was found to be very unstable (even at room temperature). This solid was completely decomposed by heating on steam bath, and the residue, on extraction with methylene chloride, gave 99% Hieland Mischer ketone. Subsequent demercuration reactions were effected without isolating the intermediate organomercurial species. (a) Demercuration reaction with acid The mercury compound prepared by the above procedure from 180 mg (1 mmol) of cyclopropanol 1 in 10 mL of methanol was treated with 0.8 mL of concentrated hydrochloric acid at 0°C. The reaction was quenched with bicarbonate after 4 h, and the methanol was removed under reduced pressure. The residue was extracted with methylene chloride, and the usual work-up gave 180 mg of an oil which was proved to be a mix- ture of Hieland Mischer ketone 95%, 11 (1%) and 11 (4%) by GLPC analysis (4% QF-l, 180°C). (b) Demercuration with sodium hydroxide The mercury compound prepared from 180 mg (1 mmol) of cyclopropanol 1 in 10 mL of methanol was treated with an ex- cess of sodium hydroxide until the solution became strongly 47 alkaline. After 4 h stirring, the methanol was removed under reduced pressure and extracted with methylene chloride and the usual work-up gave 170 mg of an oil which was a mixture of 1 (90%), 17 (1-2%) and 18 (8-9%) by GLPC analysis. ’L ’L’L ’b'b (c) Demercuration with alkaline sodium borohydride The mercury compound from 180 mg (1 mmol) of cyclopro- panol 1 was treated with 2 mL of 4 M sodium borohydride solu- tion (sodium borohydride 4 molar in 14 molar sodium hydrox- ide, Alfa product). After 4 h at 25°, the reaction was quenched with acetic acid and the solvent was removed under reduced pressure. The residue was dissolved in water, ex- tracted with methylene chloride, and the oil obtained from the extracts after removal of the solvent was oxidized by Jones reagent. Work-up gave 144 mg of an oil which proved to be a mixture of 1 (20-21%), 11 (20-21%) and 11 (53-54%) by GLPC analysis. (d) Demercuration with sodium cyanoborohydride The mercury compound from 180 mg (1 mmol) of cyclopro- panol 1 was treated with 200 mg of sodium cyanoborohydride in 10 mL of methanol at 0°C (pH 5—6). After stirring over- night, the solvent was removed under reduced pressure, and the residue was extracted with methylene chloride. The oil obtained from the extracts was oxidized by Jones reagent to give 140 mg of an oil which was found to be a mixture of 1 (10-15%), 11 (20-25%) and 18 (65%) by GLPC analysis. 48 Reaction of g with mercuric acetate, followed by demercuration with sodium borohydride Cyclopropanol % was prepared from 180 mg (1 mmol) of cyclopropanol 2 by sodium borohydride (37 mg, 4 mmol) reduc- tion at -78°C. Mercuration of g was effected by the same procedure given earlier for 2, using 396 mg (1 mmol) of mer- curic acetate in 10 mL acetic acid. The crude mercury com- pound was demercurated by treatment with 2 mL of 4 M sodium borohydride solution (4 M sodium borohydride in 14 M sodium hydroxide solution) in 10 mL of methanol. An overnight reac- tion period was followed by an acetic acid quench, and the solvent was removed under reduced pressure. The oil obtained after extraction of the residue with methylene chloride was oxidized by Jones reagent to give 100 mg of an oil which was proved to be a mixture containing lg (30%), l; (46%) and lg (23%) by GLPC analysis. APPENDIX: SPECTRA 100 80 a? E' U 6’0 2 < p— t 5 Z 40 < E 20 0 i ' 9 f ' : ‘ : : 7 ' : z : ' : ; 4000 3500 3000 2500‘ 2000 1500 FREQUENCY (CM ') 100 100 80 § 5’ U 2 60 60 ( p— Z 2 ‘2 < 40 40 a .— 20 20 0 ' I Q I ‘ ' 1 ‘ ‘ . o 2000 1 800 1600 1400 1 200 1000 800 wtouem'v {I M ', Figure 1. Infrared spectrum of 4 "b 100 TRANSMITTANCE(%) , m‘hflgcb‘vrfig‘akc ,, , .-.: .4. . -.. - ..4 50 20 O ; : 3 . ' : : 3 ' ' . ' _ ‘ ' 4000 3500 3000 2500 2000 1500 FREQUENCY (CM '1 I . . . . . . . - . I D l » Q - s r e U h I I O D . . . . - . c u . . . a . . a . . . . . . . . . . . . . . . c . . 3 u v I 1 ~ C 0 0 ~ ' P ' ' U A (*0 TRANSMITTANCE 80 8 8 L O I . 0 I . . SI 7 - a l e I l I I h o I - . . . u v . . t I I . > . . u o n o . t n I a l n o o - 3 n I o I . p - . . . . n . o o n 0 ~ » ~ g u t u u r a . I . u . I v 0 ~ > y u a I I 0 ~ .. , . n g I b - 0 — . - - -~ » - - » -~ A I 1 O- - . - - . . . .. . I - ; ~ - o D 1 - - - .... . . . .. . . . .. .. . r . I = - -- — - o A . . - .. . . . . . . . . _ . - . -. . . .2. . . .- - _. .. . .. . . i. . - . . . . . - A ... t a o n - -- - ~ « . - o — . , « o I | , -4. - , V. . O o . o a t I - - 1 p O - . 9 D O , . - O o a . . b c o - .. 9- .n .- _ . . u a O I 4 - I . 2O . . . . . . . . . . 20 n « . - u . . a - . - a I 0 . . ‘ o . v n . - ~ ‘ , . . . a ~ 0 . a , I n ‘ c . o . y . . O O I | ~ . n a 1 . I ~ 5 - o t . ~ 3 . . - ~ - c I n s . 1 . . . . . . . a . u . . . . . . . l . . . u . . u . . . . . n - . n n u I - o n a n u o . . . . - . . I - 1 . - . 4 4 v u . p u r n n p . u n . . n n c . n . c n . . a v u u c o . a o a . n n I . - 1 400 1 200 1000 800 FREQUENCV ICM . 0 - a 5 F 5 2000 1 800 1600 Figure 2. Infrared spectrum of g TRANSMITTANCE(%) TRANSMITTANCE 51 100 a) O 8 . L o N O 6000 3500 3000 2500 2000 1500 FREQUENCY (CM ') 100 100 0%) 80 80 60 60 40 40 20 2%00 ' 1800 1600 1400 1 200" I 1000 800 IRI'JL'EKKV ‘U‘ 1 Figure 3. Infrared spectrum of 7 ’b 52 100' 8 8 TRANSMITTANCE(%) a. C 20 40000 3500 3000 2500 2000 1 500 FREQUENCY (CM '1 100 80 - 80 g 5' U 2 60 60 < .— Z 2 ‘2 < 40 40 a .— 20 20 O . . 2000 1800 1600 1400 1200 1000 800 vosouwr v 'M Figure 4. Infrared spectrum of 2 53 0 Q C O TRANSMITTANCE(%) ‘ O 20 4000 3500 3000 2500 2000 1500 FREOUINC‘I (CM '1 TRANSMITTANCE(%) 2000 1800 1600 1400 1200 1000 800 [REQUINCY (M '1 Figure 5. Infrared spectrum of 14 v“ ..n—dx _'-r -.. 54 1 .cc..... Samuzitzngp 15 25 2 FREQUENCY (CM ') 3000 35 o 8 6 4 Aimuzipingh 1600 1400 12 10 8 PREOUENCY (CM ‘1 1800 2000 ’\/’\.o Infrared spectrum of 15 Figure 6. .-w-u % L l A A l g 4_. i L A I L A A WI L A A I L A L L_l 4 J A T 1 A A A_L L A A I I A L A I 4*] J : v 3 L M» ' 4 J 0 2.0 L0 0 Figure 7b. 1H NMR spectrum of g A . , .- ..“u .m— ‘r v V v V v ‘7’ W V ‘r v j 1 v v y y r V7 V v v T fim f f vi 7 V 1 l ' I l 1 I j 1., T 7* v I *7 V V 1' v I v V’ V I— * 1" V V fi # T ' ' V T a V , i ' l' W m m I” 0 N Ac'O 1-. .14.1 A 1. 14124.1 1.. Al 1..1#1_.A- . -1 A A l L A A A I A L A_4 I L A 4 A J 1 A A A A L 1 A A A A —l A J—kAJ l L A A A‘I .A no 70 to so pm “1 co so h to to o . 1 Figure 8a. H NMR spectrum of z r v I’ V T V T r V Y Y 1-; T V T ‘7 fif T v L Y Y V v l v v v l v v v v I I 1 1 1 ' 1 ' 1 ' ' r T we too om 51X: 6m ”1. AC'O —— Mi A LL ____. A 1 A + _L _- ._ __- _.___,__ 4 __~ L L A l A; .+___ RA 1 ALL 4 A A A I L A L T A; A L L L L A 1 1 A l l #A A A l A p L T A L A J A | .H, 1 .: Figure 8b. 1H NMR spectrum of 2 I 1 i “HAL“ . 1 1 1 _. . 1 _ 1 l A A A I A A A 4 I A A LA J _L A A A I L A A A I A LL 1 I- 1 AA A Li A 1‘ In 1': . 11'] . ‘v ['1 Figure 9a. 1H NMR spectrum of 1% ...;J--.‘ ,j2;s.;__l-,.'_1'_n;.-'_-l .'--'__.L'___1f_'. ..'_.L_'. LL; '7' 1 ' ' ' ' I 1 A I J A J 1 A A A l J . J A 1 A A A A I A 4 #_ A I A A L A 1 L A A A l A j A A 1 J A A A I A . 5 ( pm 4 w .30 no . 1 Figure 9b. H NMR spectrum of 13 ..- 01—11-— 58 4 m- u, a . . 4 . {I r \- .. I d m . I l r a . v” M. AI LF ”‘3le v. 1m . f..... L. .. m . n M . ~ . Ill '4! .u p r u u . . . _ ....II. .ll.!. :11... - - 91.... w - 9 . — .IOII'IJn“IIW.’I.I'WI’tY-'uollll.. .1 _ . h s r . v ‘letllor-|- .lb u » ll II + . L . I. ‘ It I. | II S l .4 --.. ......I. -: ...... .- WI? 3 p0 «but ' l . 0. w. 7 .fl & )v‘htfihtN Q 76 Figure 10a. Mass spectrum of 4 _ . . . . - ...... ..IJ: ... .1! .o.-,|.. I... «Ila. I. .I ILIJV. i; . . . . . u . . . . A . r . _ .. . m. . l . ”64v .. u . u I n+3"; _. u ._ . 4 . .- . M ., - .. . . . n . . n .... n u 4 . . I 1.1”! “II-I.P.- 1|+-| 55+ -AIIPIITIWIOIL ! ll.ll. bIITl llolu OIL. . tout: ... o . a. m u . w o . .. 4.}! AILJ..A. . - .4 h . m . .fi- . m. m .-- . . 1.: . 4 .H , _ _ _ . . A m . V. In .l' Al I... . V ' 1+...I '1: lb Ill Illllnllbnll.o 0...... .a ...r. — u . u . - y p o o ..L. .. ~ .9. .. t. . . I'll! .vIIIIQ --. 1...- ilo;lioltiriq-lt til I... - n . . - . ; _ + m A . . w . w r a .i..- ..nlllvlzlrzs - x: v .. £91-- .. «El 1. . , H .. n 1.. .1 , . . . . . . ' ‘ Al '! It'r. '1’ ‘II l'll ' II! II. ‘1' ' . . ., . . t .3 . . _ . In 4 II II It. - .- h -_I ll ~ 9» Vials" ml! O :9. ' II s .I I ll til! .IIIIIII 0"!“ l b‘oi.’ ’b Mass spectrum of 6 Figure 10b. 59 pi. o «if? .I . .Ii Ii‘i | Ac'o ‘ mvpflanuwmw D. V>h\h\v~>fi $..Rfiu& .33. I, I ..I i .iOItr , .lnlllo . L... .l. .... 7.. .--llllllnl aaaaa ’b Mass spectrum of 7 Figure 11a. 210 Job - _. Ii _ 1 if.rl I1 : t _ m . -.m -— ‘I‘fii’r‘l I I I- .lt. I I ll.‘ I u x. 0 .w.® p.1F V n,.p u A» m i .--. I -.- - i N‘uxp\w§uw§-§§3hm ..K- II. .I. -viiv Ali"): .I... I Ilvl’“Ilu.I..Dlu...l....l I £0; "b Mass spectrum of 9 Figure 11b. q. 90 10 £5 1.; 7w: '5”)?er 1)‘ - E 60 l H i 11 II ‘9 Figure 12a. 3 s i 1y-S b V‘ O O 2:...» 7w; INTENS/TV (Z) 't‘ Figure 12b. 1. p I,“ (w No ‘1' '59 luv (1", “’0 fifi Mass spectrum of lg h “ML 1 ‘.'u m p r» w «nsv a M/e Mass spectrum of 15 ’b’» PART II TOTAL SYNTHESIS OF SPIROVETIVANES INTRODUCTION The sesquiterpenes provide a rich storehouse of diverse carbocyclic-structural types whose complexity has challenged the talent and imagination of synthetic chemists since the beginning of this century. In recent years, much attention has been directed toward the total synthesis of members of a rapidly expanding class of sesquiterpenes known as the spirovetivanes. This class is characterized by the spiro- [4.5]decane skeleton, seen in such representative members as B-vetivone {.28 hinesol g,29 B-vetispirene 3,30, a-vetispi- 4.31’303 anhydro-B-rotunol Q32 and agrospirol Q. rene 33,34 6T 62 All the above spirovetivanes can be envisioned as originating from a eudesmane intermediate. This is illus- trated for hinesol g by the following idealized carbonium ion rearrangement30a (eq. l). (Natural sources of hinesol 1.35) usually contain B-eudesmol as wel Although agarospirol Q was the first sesquiterpene to be recognized as a spiro[4.5]decane derivative, B-vetivone l and hinesol % have received most of the attention of chem- ists over the past ten years. Marshall and co-workers28 conclusively proved that B-vetivone l, obtained from the essential oil of vetiver, and hinesol g obtained from 'atrac- tylis'36 oil of Chinese origin, possess the spiro[4.5]decane skeleton rather than the previously assigned hydrazulenic structure.37 Many syntheses of spirovetivane sesquiterpenes have been reported over the past eight years. Most of these efforts have been directed at lB-vetivone28’30b’31a’b’32c’38 and hinesol.30b’33b’38‘5’C’d’39 In the landmark synthesis of B-vetivone by Marshall and Johnson,28 the intermediate ' N~W 63 enone Q was prepared in 36% overall yield from a decalin starting material (eq. 2). Other preparations of intermediate Q have been reported,40’4] but they do not match the ori- ginal in either convenience or yield. It is interesting to note that all these approaches to g involve a cyclopro- panone precursor (eq. 3 and 4). several steps ~V Ila .AC (NEH 64 Enone 3, an isomer of Q, has also served as an intermediate in spirovetivane synthesis. 9 I, I I 3 Many of the spirovetivane syntheses reported to date suffer from poor overall yield and/or lack of stereospecifi- city. The approach of Stork et al.,38a Yamada et al.,31a and Dauben and Hart38c are among the best. In this part of my dissertation, I will describe an efficient synthesisofspirovetivanesprecursor g from the versatile cyclopropanol intermediate lg (eq. 5), 1 will CH3 (5) lQ' R=CH3 It R=CH3 ll' R=H IQ R=H also describe a highly stereospecific approach to the syn- thesis of hinesol g by an independent route. RESULTS AND DISCUSSION Spiro[4.5]decane intermediates that might serve as precursor to the spirovetivanes are readily prepared by acid catalysed ring opening of cyclopropanols l0 and ll “A: ’b’» (eq. 5). The predominantly equatorial hydroxyl function in ketol l2 and 13 may be oxidised to spirodiketone l4 and ’b’» ’VL \ "J’b l2, and also obtained directly from the corresponding keto- cyclopropanols.10 (“H3 ll Li,NIIl3 A ZNNIIWM; I (5) IQ' R=CH3 IQ R=CH3 1% R=CH3 I& R=CH3 ll' R=H ll R=H I; R=H lg R=H A. Synthesis of a B-Vetivane Precursor Spiroenone Q was a key intermediate in Marshall's syn- thesis of B-vetivone. Methods for transforming dione lg into g were explored, in part to demonstrate the potential usefulness of IQ as a synthetic intermediate, and also to confirm its configuration. The first approach to this trans- formation is outlined in Scheme I. A key feature of this synthesis is an application of the l,2-carbonyl transporta- tion procedure devised by Trost.42 65 66 (CI-'20“) ,H + “’16 33 u. l) LiAiH4 Ill/”Q A; I ’1’, 2)CH3SOZCl ,pyr. ‘5 / 3 I3 Sulfenylation of ketal 16 with diphenyl disulphide and potassium hydride proceeded in quantitative yield. Subse- quent hydrolysis with dil. hydrochloric acid gave the di-‘ ketone lg, which was then reduced by lithium aluminum hydride. Since five membered ketone was very resistant to reduction (steric hindrance), the hydride reaction required 48 h. The diol thus obtained was converted into a dimeysalate deriva- tive by reaction with methane sulphanylchloride and pyridine. Bis-elimination was then effected, either by treatment with potassium t-butoxide or better by heating in pyridine solu- tion. Instead of a single isomer (l6), as suggested by Trost, the elimination product was found to consist of two isomers, IQ and $2 (1H NMR analysis and subsequent chemical reaction). This can be explained by a neighboring group participation by sulfur, as shown in the equation 6. (6) “S L .. I e ¢ /""' I ~ This type of aryl sulphide participation with inter- conversion of isomeric vinyl sulphides has been well docu- mented in the literature.43’44 Hydrolysis of the isomeric vinyl sulphides by a refluxing soltuion of mercuric chloride in aqueous acetonitrile gave a 60% yield of the target mole- cule g and its isomer QR in approximately a l:l ratio. This isomeric mixture was difficult to separate by the usual ana- lytical methods, but the 2,4-DNP derivatives of these ketones were separated by column chromatography (SiO2 and l0% ethyl- acetate/hexane). The melting point of an isomer was found to be l05-l07°C which is in agreement with the melting point reported for this compound 2 by Marshall and Nenkert.28 An authentic sample of £2 was prepared by dehydration of lg and its 2,4-DNP derivative proved identical to that of the 68 other isomer (BS-87°C). 1H NMR also showed that the epimeric mixture is in the ratio of l:l by the approximate measure- ment of the peak at 60.8-8 region Since the first approach was not satisfactory, another attempt was made, following Scheme II. Scheme II H «H3Ecs1(cngzc1 ”I . “..H Imidazolz ”’1 ““H \\ 2] (>90% from lg) 12 I. l) LiAlH4 A “n “““lflhexylboraz'e ”I, “N" 2> 7 ...“Ligga’ .. C5H5N,A Cr03, C5H5N 7 (Tos=(CH3)3c5i(CH3)2-I' 69 The axial epimer of ketol I6 was used for this synthesis, since it undergoes the final elimination much more effectively than the equatorial isomer. Preparation of the axial alcohol (lg) was readily achieved in 92% yield by sodium borohydride reduction of the diketone 14.2] The stereoselectivity of this reduction contrasts with the alternative preparation of lg from hydroxycyclopropanol l2 (equation 5). The equatorial epimer is favored by a 4:1 ratio in this latter synthesis. Conversion of spiro alcohol lg into its silylether ii was effected in quantitative yield by treatment with tert-butyl dimethyl chlorosilane in dimethyl formamide containing imida- zole. Silylation of the axial epimer was found to be very slow (48 h at 60°C), but the product was stable to subsequent reactions (unlike the equatorial analog). Conversion of silyl- ether gl into the olefin %4 was achieved (80%) by reducing the ketone with lithium aluminum hydride, followed by dehy- dration with methanesulphenyl chloride and pyridine. Hydro- boration of £4 with thexylborane45 followed by oxidation with hydrogen peroxide gave alcohol $6 in excellent yield (quanti- tative). Alcohol 36 was then oxidized to the corresponding ketone (gz) in 75% yield by the action of Sarett's reagent. Hydrolysis of the silyl ether function followed by acid- catalyzed dehydration gave enone 2 in 80% yield. The spec— troscopic properties of g (]H NMR, IR and mass spec) together with the 2,4-DNP melting point were in agreement with the data reported for this compound by Marshall (lit28 DNP l07- lO9°C, observed 105—107°C). 70 B. Studies Toward Total Synthesis of Hinesol The synthesis of B-vetivone precursor Q reported here not only proved that compound I4 is a useful intermediate in the total synthesis of spirovetivane sesquiterpenes, but also established the stereochemistry at C-lO during the ring opening reaction of cyclopropanol lg (equation 5). In this reaction the potential usefulness of intermediates lg through lg in a synthesis of hinesol will be explored. The most important step in such a synthesis is the stereo- selective introduction of a three carbon side chain at C-3. It is known from earlier studies that even though the spiro alcohol lg appears to be an ideal intermediate for a hinesol synthesis, very poor selectivity is achieved during the intro- duction of a side chain at C—3.21 The two methyl groups on the six-membered ring bracket the five-membered ring, making the steric hindrance to ap- proach from either side about the same. Intermediates lack- ing one of these methyl groups (e.g., gg and £3) would strongly favor approach of a reagent from the unsubstituted side. .Reagent gg R=CH3, Z=OH, gg R=H, Z=OH 71 In order to attach a side chain at C-3 in compound Li it is necessary to introduce a conjugated double bond, so that a l,4-addition can be effected. Several well-documented methods are known by which a double bond may be introduced a,B to a ketone. One straightforward method involves a a-bromination fol- lowed by dehydrobromination (equation 7). Direct bromination ;) Br Chm (DH L3 of l3 by the recently reported reagent 2-pyrrolidone hydro- ’b’b tribromide (PHT) was tried but gave limited success. The main problem seemed to be dihalogenation at the a-position of the ketone in large scale reactions (Zg). The monobromina- ted compound £0 was prepared in 80% yield in small scale reactions run at 0°C. Subsequent dehydrobromination of 3% under different conditions (lithium carbonate-toluene, diazo- bicyclo undecane (0BU)-toluene or DMSO, or lithium chloride- lithium carbonate-DMF) gave only moderate yields of $2 on a small scale. Very poor yields were obtained in larger scale reactions. Another approach to double bond insertion would be to prepare a B-halo ketone. Such compounds undergo facile 72 dehydrobromination. The reaction sequence outlined in Scheme II was therefore examined. Scheme 11 OFMW '3: “I” "I,” G \ -HBr .21..) a \ (TDS=(CH3)3CSi(CH3)2-) Compound 30 was prepared in quantitative yield from potassium hydride and tert-butyl dimethyl chlorosilane. However, allylic bromination with N-bromosuccinamide gave the vinylic bromide 33 instead of the expected allylic bro- mide 3%. This may be due to the addition of bromine from NBS to the electron-rich vinyl silyl53 ether double bond. Hydrolysis of 3% was difficult, but gave a very good yield 73 of the a-bromide g6. Unfortunately, this improvement in the a-bromination step could not be matched by an_improve- ment in the dehydrobromination step (equation 8). A third approach to the introduction of a conjugated double bond involved B-seleneylation48 followed by oxidative elimination to the a,B—unsaturated ketone. For this study ketone lg was used as the starting material, as outlined in equation 9. 0' «o I”, I \ \ 15 ( 9 ) ~ + Starting Material 60:40 74 Conversion of diketone lg to ketal 24 took place in quantitative yield. Transformation of 34 to enone 32 in 60% overall yield was then effected by treatment with lithium diisopropyl amide and various seleneylating agents (diphenyl diselenide, phenyl selenium bromide and phenyl selenium chlo- ride), followed by oxidative elimination with 30% hydrogen peroxide. The main problem associated with this approach was the separation of the 30% starting material along with the product. From the.above results it appeared that a very strong base was required to convert the five-membered ketone com- pletely into its enolate salt possible due to steric hin- drance and the strain of a double bond in the five-membered ring. The best reagent for this purpose proved to be potas- sium hydride, which is known to be useful in the formation of strained enolates.49 Indeed, enol silyl ether 30 was formed in quantitative yield after reaction of 13 with KH. A fourth method of double bond insertion, developed by Trost et al.,50 was then applied to 34. The potassium enolate salt from 34 was treated with diphenyldisulfide followed by oxidative elimination with sodium periodate. This reaction sequence (equation 10) was found to form the enone 36 in quantitative yield. In this system it appears that phenyl—‘ sulfide elimination is more effective than the corresponding selenide reactions. 75 H” toluene 36 1;. (100%) With the enone 36 in hand, it was decided to introduce a three-carbon unit at C-3, by l,4-addition. The l,4- addition of lithium dialkylcuprate reagents to a,B-unsaturated ketones has been extensively studied by House and co-workers,51 and this useful reaction has proven to be effective in this synthesis. Thus, enone 36 underwent a l,4-addition with li- thium diisopropenyl cuprate (ether solution at -78°C) giving an excellent yield of 31 as a single isomer (equation ll). (ll) The penultimate stage in this synthesis of hinesol requires the removal of the carbonyl group at C-l and the introduction of a methyl group at C-6. From previous work with ketones l4 and IQ it was known that this carbonyl function 76 is badly hindered, and its removal is not as easy as Trost 52 Various modifications of suggests in one of his papers. the Wolff-Kishner reduction were studied; however, starting material 3; was recovered in poor yield. A stepwise reduc- tion of the carbonyl function was therefore undertaken, as described in Scheme III. Elimination of the corresponding alcohol with methanesulphenyl chloride and pyridine was effected as before, the isopropenyl side chain being protec- ted as a primary alcohol. In the first application of this reaction sequence, a modest yield of compound 2% was obtained. Further study is needed to optimize this yield. Scheme III 0" 77 The final stage of this hinesol synthesis requires methylation of the six-membered ketone at C-6, followed by conversion of the ketone to a A6 double bond. Concurrent or subsequent reformation of the isopropenyl group should give hinesol. EXPERIMENTAL GENERAL 1H In addition to the general described in Part 1, NMR spectra were taken on Bruker NH -l80 and high resolu- tion mass spectra were taken on Varian, MAT, CH-5 mass spectrometer. Preparation of cyclopropanol 10. In a one liter, three neck, round bottomed flask containing a small amount of sodium metal, was condensed 500 mL of ammonia. The ammonia was then distilled through Tygon tubing into a carefully dried two liter three neck flask containing 1.78 g (0.25 mol) of lithium ribbon. The reaction flask was equipped with a paddle stirrer, a dry ice condenser, a dry ice,actone bath and an additional funnel to which a nitrogen gas line was attached. A solution of 13.0 g (0.067 mol) of the enone ($01) dissolved in 250 mL of THF was added dropwise over a one hour period. The blue color of the reaction was dis- charged by dropwise addition of ethylene dibromide, follow- ing which 10 g of finely ground ammonium carbonate was added in one portion. The cooling bath was removed and the ammonia was evaporated into the hood under a steam of nitro- gen. The residue was taken up in 300 mL of water and the mixture was extracted three times with 200 mL of ether. The ether extracts were combined, washed sequentially with 78 79 water and brine, and then dried by anhydrous magnesium sul- phate. After removal of the solvent 13 g of an oil was obtained which gave 7.3 g (60%) crystals from ether/pentane, mp = 96-98°C. Preparation of spiroalcohol 1% and subsequent oxidation to spiroketone 14; To a solution of 6 g (0.03 mol) of cyclo- propanol (10) in 50 mL of absolute ethanol at -l8°C was added a solution of 6 g (excess) of sodium borohydride in absolute ethanol. The reaction mixture was stirred at 0°C for 4 h N while monitoring the reaction by TLC. The reaction was quenched by dropwise addition of 20 mL of concentrated hydro- chloric acid in 20 mL ethanol, and the reaction mixture was stirred at room temperature for 10 h (overnight). Precipi- tated salt was filtered and ethanol was removed from the filtrate under reduced pressure. The residue was dissolved in ether, washed sequentially with sodium bicarbonate, water and brine, and dried over anhydrous magnesium-sulphate. Re- moval of the solvent gave 5.98 g of epimeric alcohols in the ratio 1:4. This mixture was separated by column chro- matography (silica eluted with ether) to give 3.1 g of pure equatorial alcohol mp 76-77° and l g of axial alcohol mp 78-79°C (IR and 1H NMR were in agreement with Kurt Grim's description of these compounds). The epimeric alcohol was oxidized quantitatively into the diketone 14 mp = 64-66°C (1it.2] 64-66°C). 80 Preparation of ketal 16; A solution of 2.0 9 (0.0103 mol) of the diketone 14 in 150 mL dry benzene containing 20 mL ethylene glycol and 100 mg of p-toluene sulphonic acid was refluxed through a Dean Stork trap. The reaction appeared to be finished after a half hour period (GLPC 4% QF-L 160°C), and the benzene solution was washed with sodium bicarbonate water and brine and dried over anhydrous magnesium sulphate. This solution yielded 2.367 g (97%) of pure ketal 16. IR (neat) 1735 cm']; 1H NMR (CC14) 60.7 (d, J=4.5 Hz, 3H), 0.8 (d, J=4.5 Hz, 3H) l-2.4 (m, 12H), 3.8 (m, 4H); mass spectrum (70 eV) m/e (relative intensity) 238 (8), 210 (2), 182 (3), 126 (53), 99 (100), 86 (77), 55 (38). Anal. calcd. for C14H2203: m/e 238.15636. Found: m/e 238.15688. Preparation of the a-phenyl sulphide 17; A solution of 2.6 9 (0.0109 mol) of the ketal 16 and 10 g (excess of potassium hydride in 100 mL of glyme was refluxed under argon for two h. The mixture was cooled to room temperature followed by the sequential addition of 8 mL of HMPA and 2.6 g (0.012 mol) ofdiphenyl disulphide in 10 mL of glyme. After 3 h, the excess potassium hydride was quenched by dropwise addi- tion of water at 0°C and the mixture was then treated over- night with 30 mL of concentrated hydrochloric acid. The reaction mixture was neutralized with sodium bicarbonate wn_~_‘_m . 81 and extracted with ether. The combined ether layers gave an oil which was percolated through 50 gm of silica to remove the mineral oil and other non-polar materials. The pure sulphide was eluted by ether as an oil (3.3 g, <95%) which solidified on cooling. An analytical sample was ob- tained by crystalization from ether/pentane, mp = 75-78°C; IR (neat) 1700, 1730 cm“; 1H NMR (coc13) 60.8-9-(m, 6H) 1.2-2.8 (m, 10H), 3-6 (m, 1H), 7.3 (m, 5H) and mass spec- trum (70 eV) m/g relative intensity 304 (5), 303 (14), 302 (65), 193 (9), 136 (100), 110 (12), 91 (11), 77 (8). Anal. calcd for C O S: m/e 302.13571. 18H22 2 Found: m/e 302.13403. Preparation of isomeric vinyl sulphides _18 and 12; A sOlu- tion of 100 mg (0.32 mmol) of the diketone 1% in 10 ml of ether was reduced with 37 mg (1 mmol) of lithium aluminum hydride over a period of 48 h at room temperature. The reaction mixture was quenched by dropwise addition of sodium hydroxide solution and then extracted with ether. The ether extract, after the usual work up, gave 98 mg of the diol (checked by IR). The diol was dehydrated by treatment with a solution of 1 mL of methyl sulphonyl chloride in 10 mL pyridine for 6 h at room temperature (bis-mesylate formation), followed by refluxing for 9 h. Removal of the pyridine left a residue which was extracted with methylene chloride. Purification 82 by preparative TLC ($10 10% EtOAC/Hexane) yielded 53 mg of 2. an oil (60%). IR (neat) 1600, 1625 cm'];]HNMR(CC14)60.8-0.95 (m, 3H) I.2-2.4 (m, 12H), 5.1—5.4 (m, 2H), 7.25 (m, 5H) and mass spectrum (70 eV) m/e (relative intensity) 272 (3), 271 (5), 270 (22), 228 (90), 218 (77), 202 (I00), 109 (98), 91 (58), 77 (97). Preparation of isomeric ketonesa and 20; To a solution of 108 mg (0.4 mmol) of the vinyl sulphide in 4 mL of aqueous acetonotrile (13) was added 300 mg (1 mmol) mercuric chlo— ride, and this mixture was refluxed for 78 h (the reaction was monitored by GLPC, 4% QF-180°C). The solvent was removed under reduced pressure and a pet ether solution of the resi- due was filtered through silica using petroleum ether as elutent. Removal of the solvent gave 40 mg of an oil (56%). IR (0614) 1750 Cm'];]H NMR(CCl )60.8-l (m. 6H),].4-2.8(m, 1H), 4 5.4 (m, 1H) and mass spectrum (70 eV) m/e (relative inten- sity) 179 (8), 178 (51), 163 (14), 150 (8), 145 (11), 136 (18), 122 (50), 110 (33), 107 (100). A 2,4-DNP derivative of this mixture was prepared and purified by column chroma- tography ($102 and 10% EtoAC/Hexane as elutent). The first fraction was recrystalized from ethanol, mp 85—87°C (BS-86°C observed in DNP of authentic sample of 20). The second fraction was recrystalized from ethanol, mp 105-107°C (lit28= 107-109°C). 83 Preparation of silyl ether 21; To a solution of 1.1 9 (0.0056 mol) of the axial alcohol 12 in 50 mL of dimethyl formamide was added 1.26 9 (0.0084 mol) of dimethyl tert butyl silyl chloride and 952 mg (0.014 mol) of imidazole, and the soltuion was stirred at 45°C for 48 h. The reaction mixture was diluted with ether, washed with water and brine and dried by anhydrous magnesium sulphate. Removal of the solvent gave 1.8 g of pure silyl ether 21 (99%). IR (CDC13) 1730 cm—1; 1H NMR (CDC1 60.034 (5, 6H), 0.8-1 (m, 6H), 3) 0.9 (s, 9H), 1 2-2.4 (m, 12H) 3.8 (m, 1H); and mass spec- trum (70 eV) m/e (relative intensity) 310 (6), 295 (5), 253 (97), 200 (12), 199 (10), 185 (18), 161 (43), 75 (100). Anal. calcd for C]8H34025e: m/e 310.23514. Found: m/e 310.23279. Preparation of spiro alcohol 22; A solution of 1.54 g (0.00496 mol) of silyl ether 21 in 100 mL of ether was treated with 500 mg (excess) of lithium aluminum hydride at room temperature. The reaction was quenched after 6 h by dropwise addition of sodium hydroxide solution, and the precipitate was filtered and wasned several times with ether. The organic layer after the usual work up gave 1.43 1:1H NMR 9 pure alcohol 22 (92%). IR (CC14) 3500—3200 cm- (CC14) 60.034 (s, 6H), 0.9 (m, 15H), 1.2-2.4 (m, 13H), 3.7 (m, 1H) 4.0 (m, 1H) 84 Preparation of olefin 24; A solution of 1.43 9 (0.0045 mol) of the alcohol 22 and 1.7 g (1 mL, excess) of methyl sulphonyl chloride in 10 mL of pyridine was stirred for 10 h and then refluxed for another 8 h. The pyridine was re- moved under reduced pressure and the residue was dissolved in ether, washed with water and brine and dried. Removal of the solvent gave 1.075 g of a single product 24 (80%). 1 IR (CC1 1480 cm" ; 1H NMR (cc14) 50.034 (s, 6H) 0.8-l (m, 4) 15H),1.2-2.4 (m, 10H), 3.8 (m, 1H), 5.1 (m, 1H), 5.6 (m, 1H), and mass spectrum (70 eV) m/e (relative intensity) 294 (4), 279 (3), 237 (45), 161 (24), 107 (22), 75 (100). Anal. calcd for C18H34OSe: m/e 294.23932. Found: m/e 294.23788. Preparation of spiro alcohol 26. To a solution of 0.72 mL (6 mmol) of 2,3—dimethyl-2-butene in 10 mL of THF at 0°C was added 3 mL (3 mmol) of 1 molar solution of diborane in THF. The solution was stirred at this temperature for 2 h. To this mixture was added dropwise 800 mg (2.72 mmol) of olefin 24 in 10 mL of THF and the reaction mixture was stirred at 0°C for 6 h followed by 5 h at room temperature. Oxidation of this borane mixture was effected by adding 12 mL of 10% sodium hydroxide followed by 12 mL of 15% hydro- gen peroxide. After 3 h stirring, the aeuqous layer was saturated with sodium chloride and the THF layer was separated. After working up the THF layer, 0.84 gm of an 85 -1 oil (98%) was obtained. IR (CC14) 3100-3600 cm ; 1H NMR (6614) 60.034 (5, 6H), 0.8—1 (m, 15H), 1.1 (s, 1H ex- changeable), l.2—2.4 (m, 12H), 3.8-4.2 (m, 2H). Preparation of spiroketone 21; Pyridine chromium trioxide compound was prepared by adding 1.2 g (4 mmol) of chromium trioxide to 30 mL of ice cold pyridine and the mixture was stirred for half an hour. To this solution was added 800 mg (2.56 mmol) of alcohol 26 in 10 mL of pyridine and was stirred at room temperature overnight. The brown solution was diluted with excess of water and neutralized by dilute hydrochloric acid and extracted several times with methelene chloride. The organic layer after the usual work up gave 600 mg of a simgle compound 27 (76%). IR (C014) 1735 cm'1; 1H NMR (CC1 60.034 (5, 6H) 0.9—1.1 (m, 15H), 1.2-2.2 (m, 4) 8H), 2.2-2.7 (m, 4H) 3.8 (m, 1H) and mass spectrum (70 eV) m/e (relative intensity) 310 (3), 295 (2), 253 (34), 195 (12), 161 (42), 75 (100). Anal. calcd for C18H34023i: m/e 310.23422. Found: m/e 310.23279. Preparation of unsaturated ketone 8; The silylether 27 was hydrolysed by stirring 181 mg (0.58 mmol) of it with 5 mL 6 N hydrochloric acid in 10 mL of THF. After overnight stirring the alcohol was dehydrated by refluxing in benzene solution containing a little p-toluene sulphonic acid. After 86 the usual work up the benzene layer gave 65 mg of unsatu- rated ketone 8 (80%). IR (cc14) 1735 cm'l, 1660 cm“; 1H NMR (60613) 60.92 (3H, d, J=7.2 Hz), 1.65 (3H, d, J=3.2 HZ), 1.7-2.2 (m, 9H) 2.03 (d, J=18 Hz, 1H), 2.32 (d, J=18 Hz, 1H), 5.3 (m, 1H); mass spectrum (70 eV) m/e (relative intensity) 178 (53), 163 (15), 150 (13), 149 (10), 137 (12), 136 (24), 123 (15), 108 (22), 107 (100), 93 (85), 68 (40), 55 (25). Preparation of a-bromoketone 28 with PHT and dehydrobromina- tion to prepare enone 29; To a solution of 4.6 g (0.025 ml) of ketoalcohol 13 in 200 mL dry tetrahydrofuran was added 15.19 g (0.3 ml) of 2-pyrrolidone hydrotribromide, PHT. The resulting organic solution was stirred at room temperature for 12 h in complete darkness, during which time a white crystalline solide precipitated. Following filtration, 100 mL of ether was added to the filtrate and the organic solution was washed with aqueous sodium bicarbonate, water and brine. Removal of the solvent gave an oil which proved to be a mix- ture. An analytical sample of the major component was isola- ted by GLPC (4% QF-180°C) and displayed the following pro- perties. IR (CC14) 3200-3500, 1750 cm'l; 1H NMR (00013) 80.8 (3H, d, J=6Hz) 1.2-2.5 (m, 12H) 3.4-3.8 (m, 1H), 4-4.4 (m, 1H) and mass spectrum (70 eV) m/e (relative intensity) 262 (10), 260 (10), 163 (70), 93 (100). Anal. calcd for C11H170 Br: C, 50.59; H, 6.56. 2 Found: C, 50.58; H, 6.52. 87 A solution of crude bromoketone 28 in 20 mL of dry DMSO containing 20 mL of 1,5-diazobicyc1o[5.4.0]undec-5- ene was heated overnight under nitrogen. The resulting dark solution was diluted with 300 mL of ice water and ex- tracted several times with ether. The ether extract was washed with 10% hydrochloric acid, water and dried over anhydrous magnesium sulphate. Removal of the solvent gave 2.5 g of an oil which on distillation at 125°C (0.0025 torr) gave 1 9 oil that crystallised from ether and pentane. The enone alcohol 29 displayed the following properties, mp ‘1 90-91°C, IR (CDCl 3600, 1690, 1603 cm'1, 1H NMR (CD613) 3) 60.68 (3H, d, J=6.8 HZ), 1.2-2.1 (m, 7H), 2.6 (1H, ddd, J=20, 3, 2 HZ), 3.0 (1 H, ddd, J=20, 3, 2 Hz), 4.2 (bs, 1H), 6.1 (1H, dt, 0:6, 2 Hz), 7.6 (1H, dt, J=6, 3 Hz) and mass spectrum (70 eV) m/e (relative intensity) 180 (22), 162 (45), 147 (3@, 133 (26), 95 (100). Anal. calcd for C11H1602: Found: C, 73.35; H, 9.08. C, 73.30; H, 8.9. Preparation of a-bromoketone 28; To a suspension of 6 g (0.033 mol) of 22.1% potassium hydride in 50 mL glyme was added 1.82 g (0.01 M) of ketoalcohol 13 in 10 mL of glyme, and this mixture was refluxed for 90 min under argon. This mixture was cooled and then treated with 4 mL of triethyl- amine and 4 g (0.026 mol) of tert-butyl dimethyl chlorosi- lane in 5 mL of glyme. After 15 min the excess potassium hydride was quenched by adding water dropwise (0°C) under 88 an argon atmosphere. The aqueous layer was extracted three times with ether, and the ether extracts, after washing with water and brine and drying with anhydrous magnesium sulphate, gave a colorless oil which was used for the subse- quent step without further purification. An analytical sample, collected by GLPC (4% QFl-180°C) showed the follow- ing properties. IR (CC1 1675 cm'1;111NMR.(CDCl3) 60.0 ($.6H) 4) 0.2 (s, 6H), 0.8 (s, 9H), 0.9 (s, 9H), 1.2-2.3 (m, 11H), 3.2-3.8 (m, 1H), 4.4 (1H, t, 0:2, 1 Hz) and mass spectrum (70 eV) m/e (relative intensity) 410 (23), 353 (74), 237 (77), 149 (100). To a refluxing solution of the above oil in 100 ml of carbon tetrachloride was added 1.8 g (0.01 M‘of N-bromosuccin- amide. Analysis by GLPC (4% QF-l, 160°C) showed the occurance of a very rapid reaction. The succinamidewas filtered from the cooled (0°) mixture, and the carbon tetrachloride layer was washed with sodium bicarbonate solution, water and brine and dried by anhydrous magnesium sulphate. Removal of the solvent gave light yellow oil which was utilized for the subsequent step without further purification. An analytical sample collected by GLPC (4% QF1-200°C) exhibited the follow- ing properties: IR (CC14) 1675 cm’1; 1H NMR (CDC13) 60.0 (s, 6H), 0.3 (s, 6H), 0.8 (s, 9H), 0.95 (s, 9H), 1.2-2.4 (m, 11H) 3.2-3.8 (m, 1H) and mass spectrum (70 eV) m/e (relative in- tensity) 490 (12), 488 (12), 433 (39), 431 (39), 147 (100). The crude product from above was hydrolysed by refluxing 89 in a solution of 20 mL of 4N hydrochloric acid and 50 mL of methanol overnight. After removing the solvent, the residue was dissolved in water and neutralized with aqueous soidum bicarbonate. The aqueous layer was extracted several times with methylene chloride, and washed with water and brine and dired by anhydrous magnesium sulphate. Removal of the solvent and residual oil (from KH) by pentane gave 2.03 g (80%) of a o-bromoketone 28. The GLPC retention 1 time, IR and H NMR were identical to those reported earlier for 28 prepared from spiroalcohol 13 and PHT: IR (CC1 ) 'b’b ’b'b 4 3200-3500, 1750 cm-], 1H NMR (60613) 60.8 (d, J=6 Hz, 3H), 1.2-2.6 (m, 12H), 3.4-3.8 (m, 1H), 4-4.4 (m, 1H) and mass spectrum (70 eV) m/e (relative intensity). 262 (10), 260 (10), 163 (70), 93 (100). Preparation of spiroketal_34; A solution of 0.48 9 (0.0026 mol) of diketone 15 in 100 mL of dry benzene and 20 mL of dry ethylene glycol, together with 20 mg of p-toluene sul- phonic acid, was refluxed through a Dean Stork trap. The reaction appeared to be finished after a half hour period (GLPC analysis, 4% QF-l, 160°C), and the benzene solution was then washed with sodium bicarbonate, water and brine, and then dried over anhydrous magnesium sulphate. This solution yielded 600 mg (100%) of a colorless oil which dis- played the following properties. IR (CCl4), 1730, 1150, 1100 cm-1; 1H NMR (0014) 60.8-O.9 (3H, d, J=8 Hz), 2.5-1.2 90 (m, 13H), 3.9 (bs, 4H), and mass spectrum (70 eV) m/e (rela- tive intensity) 224 (6), 196 (3), 150 (2), 126 (45), 99 (100). Anal. calcd for C13H2003: C, 69.61; H, 8.99. Found: C, 69.62; H, 8.93. Preparation of enone 35via o-selenation. A solution of 1.1 mmol of lithium diisopr0py1 amide was prepared under an argon atmosphere by adding 0.45 mL (1.1 mmol) of a 2.4 molar solution of n-butyllithium in 10 mL of THF to a solution of 0.175 mL (1.2 mmol) of freshly distilled diisopropyl amine in 10 mL of THF at -78°C. After 15 min, a solution of 224 mg (1 mmol) of ketal 34 in 10 mL of THF was added dropwise and was stirred for l h at room temperature. To this was added a solution of 1.2 mmol phenyl selenium bromide, prepared by mixing 197 mg (0.6 mmol) of diphenyl diselinide and 0.02 mL (0.6 mmol) of bromine in 5 mL THF. After stirring for 8 h, the reaction was quenched by the addition of ammonium chlo- ride, and the aqueous layer was extracted with ether. The ether layer, after the usual work up, gave a yellow oil which was oxidized by 2 mL of 15% H202 in 5 mL of methylene chloride and 0.2 mL of pyridine at room temperature. After one hour the reaction mixture was diluted with sodium bicar- bonate solution and extracted with methylene chloride. The methylene chloride layer, after the usual work up, gave 145 mg of an oil which was found to be a mixture of enone 35 and 91 starting material in the ratio 60:40 by GLPC analysis and IR and 1H NMR spectra. Preparation of spiroalcohol 13 and subsequent oxidation to the spirodiketone 15; To a solution of 9.0 g (0.05 mol) of cyclopropanol 11 in 100 mL of absolute ethanol at -78°C was added 6.25 g (0.17 mol) of sodium borohydride, and this mix- ture was stirred under nitrogen for 5 h at 0°C. The result- ing solution at -78° was treated with a solution of 30 mL of concentrated hydrochloric acid in 30 mL of ethanol, ..," added dropwise, followed by an overnight reaction period. Precipitated salts were filtered and the solvents were re- moved under reduced pressure. The residue was dissolved in water and neutralized with sodium bicarbonate, following which the aqueous layer was extracted several times with ether. The combined ether layers were washed with water and brine and dried over anhydrous magnesium sulphate. Re- moval of the solvent gave 9.047 g of an oil, which was found to be an epimeric mixture of axial and equatorial alcohol in the ratio 14:85. The major isomer was crystallised from ether and pentane, 7.3 g (81%). The major alcohol in this case was identical with the minor alcohol obtained from lithium/ ammonia reduction of cyclopropanol followed by acid treat- ment (60:40). The equatorial alcohol 13 displayed the following properties: mp, 76-78°C, IR (C014) 3600 (sharp), 1 3200-3500, 1725 cm"; H NMR (0014) 60.8 (3H, d, J=8 Hz), 92 1.1-2.3 (m, 13H), 2.8 (s, 1H, exchanged), 3.3- 3.8 (m, 1H) and mass spectrum (70 eV) m/e (relative intensity) 183 (5), 182 (40), 164 (56), 93 (100), 81 (37), 74 (56). Anal. calcd for C11H1802: C, 72.49; H, 9.95. Found: C, 72.56; H, 9.93. The minor (axial) alcohol showed the following pro- perties: mp, 81-83.5°C, IR (CC14) 3600 (sharp), 3200—3600, 1 1730 cm' ; 1H NMR (001 60.8 (3H, d, J=8 Hz), 1.2-2-2 4), (m, 13H), 2.4-2.6 (bs, 1H, exchanged), 3 8-4.0 (m, 1H) and mass spectrum (70 eV) m/e (relative intensity) 182 (10), _‘,,.4 164 (5), 137 (8), 124 (70), 111 (100), 93 (25), 79 (20). A 6.8 g (0.037 mol) sample of alcohol 13 was oxidized by Jone's reagent in acetone to give 6.5 g (98%) of an oil, from which 4.01 g of crystalline 15 was isolated (crystalli- zation from etherzpentane). The mp (60-62°C), IR and 1H NMR of this compound agreed with the corresponding properties for 15 reported by Kurt Grimms.2] Preparation of enone 35 by a-sulfoxide elimination. To a suspension of 20.0 g (0.12 mol) of 24% potassium hydride in 100 mL of glyme was added 4.942 9 (0.0022 mol) of ketal 34 in 20 mL of glyme, and this mixture was refluxed for 90 min under argon. After this reaction mixture was cooled to room temperature, it was treated with 1.6 mL hexamethyl phospho- amide followed by 5.45 g (0.025 mol) of diphenyl disulphide in 10 mL of glyme, and allowed to react for l h. Excess 93 potassium hydride was quenched by adding water dropwise at 0°C, and the aqueous layer was extracted several times with ether. The combined ether layers, after washing with water and brine, were dried by anhydrous magnesium sulphate. The crude product, contaminated with oil from the potassium hydride, was found to contain no starting material by GLPC analysis (4% QF-l, 180°C). The product from the above step was oxidized overnight by 5.35 9 (0.0025 mol)sodium periodate in 100 mL aqueous methanol. A precipitate which formed was filtered and ‘ washed with ether. Solvents in the combined filtrate and wash were removed under reduced pressure and the resulting oil was dissolved in ether and washed with water and brine and dried by anhydrous magnesium sulphate. The crude pro- duct (sulfoxide) obtained by removal of the solvent was refluxed for 2 h in 100 mL toluene containing 2.1 9 (0.0025 mol) of anhydrous solid sodium bicarbonate. The organic layer was washed with water and brine and dried by anhydrous magnesium sulphate. Removal of the solvent gave an oil which was purified by percolation through 50 g of silica. An initial pet ether eluted fraction contains the oil from potassium hydride and other products from diphenyl disul- phide. Enone 35 was eluted with ether, as an oil (8 g) which exhibited the following properties: IR (neat) 1710, —1_ 1 1600 cm , H NMR (CDC1 ) 60.68 (3H, d, J=6, 8 Hz), 1.35- 3 1.94 (m = 7H), 2.57 (1H, ddd, J=19.8, 3, 2 Hz), 2.91 (1H, 94 ddd, J=19.8, 3, 2 Hz), 3.93 (m, 4H), 6.18 (1H, dt, J=6, 2H2), 7.7 (1H, dt, J=6, 3 Hz) and mass spectrum (70 eV) m/e (rela- tive intensity) 222 (61), 207 (5), 194 (5), 193 (11), 166 (83), 126 (100), 99 (75), 77 (90), 66 (20). Anal. calcd for C13H1803: m/e 222.12675. Found: 222.12558. Preparation of ketal 37; To a suspension of 1.0 g (0.071 mol) of 50% lithium sand (washed three times with pentane) in 20 mL of ether was added 1.6 g (0.013 mol) of freshly dis— tilled isopropenyl bromide under argon. Vigorous reaction was observed in a few minutes and external heat was applied to induce reflux for 20 min after the initial reaction subsi- ded. To the above solution at -78°C was added 1.14 g (0.006 mol) of copper (I) iodide, and this mixture was allowed to warm until a yellow color was observed (£3; —40°C). This solution was cooled to -78°C, following which 630 mg (0.0028 mol) of enone 35 in 10 mL of ether was added dropwise. After an hour at -78°C, the reaction mixture was warmed to 0°C and quenched by dropwise addition of saturated ammonium chloride solution. Solids which formed were filtered and washed several times with ether. The combined ether layers were washed with 10% solution of ammonium hydroxide, water and brine, and dried over anhydrous magnesium sulphate. Re- moval of the solvent gave 732 mg (100%) of 31 which showed the following properties: IR (neat) 1750, 1660 cm'1; 1H NMR (00013) 60.79 (3H, d, J=8 Hz), 1.8 (s, 3H), 1.2-2.8 (m, 12H), 95 3.79 (m, 4H), 4.63 (2H, d, J=4 Hz) and mass spectrum (70 eV) m/e (relative intensity) 264 (8), 208 (2), 207 (6), 126 (52), 119 (6), 99 (100). Anal. calcd for C16H2403: m/e 264.17471. Found: m/e 264.17255. APPENDIX: SPECTRA 96 100 A “A 100 80 - -..“. --.W , , «--—~ -- - *' “*3 .. - ”5': 30 ‘- ..-/“"11, 1 -‘ 2 .5": 3 1.’ m g a; I? U 60 i : . : : 5: 60 ‘ . . ' : 1 Z 3 i 17 <' E .=' $5 a. 1 1 E : 240 = 4 ' ‘ 40 < 1’1 5' ' m "I” 3) i '— 1) if v - :1 20 j 20 0 4000 3500 3000 2500 2000 1500 FREQUENCY (CM'l 100 100 80 80 2‘; I.“ u . 260 60 < ... t 5. z (40 40 M .— 20 2O 0 ' : 2000 1800 Figure 13. I a. I 1000 1400 IIIOIJENc v th ‘) 1200 Infrared spectrum of 16 800 100 80p" 0 O TRANSMITTANCE (7'5) A C) 20 97 0 4000 ) TRANSMITTANCE(% ‘. O N O 0 7 . 2000 1800 Figure 14. 3500 3000 2500 FREQUENCY (CM ') 1600 1400 1200 FIEQUENC Y (CM 'l Infrared spectrum of 17 mm 2000 10X) 1500 8ND IUU 80 60 40 20 100 §ao 40 20 98 100 ' 100 fi____~____fl_-_n_~ __fi / '~ *j/’“" “ flunk .. 80 ‘1‘ 1" " 1‘! i i 80 l ' l- "T ‘ 1 i; V 1 E ) 1 1* I" 1 l 1. I woo =. _ 60 % 1'5 4 < l ”H 3 l. ‘ :1 ‘240 11 ‘g 4o E ‘1‘} r 20 20 0 o 4000 3500 3000 2500 2000 1500 maumcv (cu-I1 1 100 TRANSMITTANCE(%) O 2000 Figure 15. 1800 1400 ikEUUtN(1 1fM‘1 1600 Infrared spectrum of 21 ’b'b 1200 1000 800 99 (96) 8 . ' - . . 0 TRANSMIYYANCE ; O N O 2000 1800 1600 1400 1200 MOUENCV (CM '1 —_—_—._ L——.. _. Figure 16. Infrared spectrum of 24 2.5 ' 3.0 3.5 . M'CRONS . 8.0 4 J L 1 i llLJlLl-LJiLlllllllJ 100 100 , 1 1 — W11WM11 ‘ 80 1 80 E 360 60 z ( E Hm, 240 —, /"" 40 < M1 as 20 20 o 4000 3500 3000 2500 PRIOUINCY (CM" ) 5.0 1 4" 6.0 7.0 ~ 3.0 M'CWNS 10.0 11.0 12.0 16.0 '..100 80 40 20 100 100 “ 100 . ..9. 1111' ... .. _ ...... __ __' ~- .-» fflflniri‘lnilii'.“ 7.1., 1 ,. | 1 1.1 ' 80 1’1 . 80 1 ‘1 1 . A 1 3 z 360 60 Z < )— 1: 5 1 m . . .. Z 40 1 1 1‘ 40 :5. 1.1 l— i 1 20 20 1 0 4000 3500 3000 2500 2000 1500 8 8 8 TRANSMITTANCE(%) M O mxm 1800 1600 Figure 17. mouencv (CM '1 10( 80 40 20 1400 1 200 l 000 800 "£00!ch «M '1 Infrared spectrum of 27 ’b’» 101 10 100 1 J ‘ 80 1 ;1 11 ‘80 1 ‘ ' 1 $50 1‘ 60 E 2 H, 1 e ‘2 40 g; 1 40 < '1 1 1 t E 5 1 1 " 1 20 1 20 \‘ . 1 1‘ 0 4000 3500 3000 2500 2000 1500 moumcv 101111 TRANSMITTANCE(%) 1800 1600 1400 1200 1000 800 1 moumcv 1c» '1 Figure 18. Infrared spectrum of 8 102 100- O 8 o TRANSMITTANCEBS) a. o 20 " ' 4000 3500 3000 2500 2000 1500 MOUENCY (CM 1) 100 80 i “J U 260 60 < p— Z 2 _ (40. ‘40, g _ p- N O .__M.20 a ‘ 1400 1200 1000 800 FREQUENCY (CM '1 2000 1 800 l 600 Figure 19. Infrared spectrum of equatorial alcohol 13 ’1: 103 100 100 80 80 i w “’60 60 Z. ( .... :1 ‘2 m 40 2:40 < m p— '20 N 0 £000 3500 3000 2500 2000 ' 1500 FREQUENCV (CM ‘1 100 ,‘ -« -—~ ~-- _ - . _ . f , ' 3 . 101 TRANSMITTANCE(%) 2000 1800 1600 1400 12 leOUENCY 1CM'1 § ‘000 Figure 20. Infrared spectrum of axial alcohol 1% 104 1500 2000 2500 FIOOUENCY (CM 1) 3000 3500 4000 M9. .W 0 O m 0 ..... 80 4 20 ..0 Actmuz r REM.“ Em. Figure 39a. 'b Mass spectrum of 8 Figure 39b. .. 7. . . .2. L... .-.-... .. - III IImlIIuIn... » CH}? :2. (tea .3: p ‘4 b< a a 13 mm Mass spectrum of axial alcohol Figure 40a. sci F10 II N Il‘. , I no IN a Q; I” [IO fl' We to do ‘70 5' c .... 0 U 0 ... a y .. t ? ,. u .~.I\ov kr IIbttutx K); (4&1. Mass spectrum of equatorial alcohol IQ- Figure 40b. 124 i 0 ZA’If/VS/T/( 1' 3° ‘6 A O [35,1 A T / i/E % Z ‘8 E if — O p- ”— m — p-_ - $———— I 0 m..— «I W/c Figure 4la. Mass spectrum of £2 PE/n we .LNTE/V-Si‘ry (VJ 4. .- loo Wk Figure 4lb. Mass spectrum of £2 F90 125 - ... a -..... . ...... H. “I .I ‘ I ma — — . d . . .. H . 41.....«19 «+I4II4IIWEIIL .. A T I1 . a . o . . A . . III. I I I I . IIfil.I I II VI I . . . . I . r IIIIII I. . I . A . . . . u _ O I 'QIII III III.oIl .III I. IISIIflIIA1I «I o I. I . . a I I I I I . . Lt- . +- ...... m. I v. 1..ij J- ” _ _ . III I.‘III.I.II . .w «.mw r h «Ru xtfieteN a w v ¢ NEZQX an .I II . I .anII. . .I II I I.I I I ..I PI.I.III..II-II-I-.IITII . . w u u . . . l I .. ... I TI. I... I I 1- I — . . . .~ I III III I I IIIII II I O m . _ . u . a . f . I .. .. I. rItmII “ . _ m h . I. II "l‘. I" I .1 .. _ _ c u ”I p O a . .I I .. . IIIII IIII I I I II III IIII4II I . - _ A I l I I19 ..I. In .I U I u ..I? I .M I“ I I I. II II II . m. II. I «I I ..I I I I A JI . . U. I t . I ,- I A M M u ._ I II I I III I II 7...... I . . . I. I I I I‘m .- . t A — m I I- I . _ . o I I II III I In 1‘ . - III], I ML. ’b’» Mass spectrum of 30 Figure 42a. .N O I I u up u n \\ :;\w>\§\