MSU LIBRARIES u. RETURNING MATERIALS: Place in book drop to remove this checkout from your record. FINES wiII be charged if book is returned after the date stamped beIow. PART I PREPARATION AND REACTIONS OF l-HYDROXY-l,5a-CYCLOCHOLESTAN-7-ONE PART II APPROACHES TO THE TOTAL SYNTHESIS OF LACTARORUFIN A BY Joel Robert Christensen A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1983 ABSTRACT PART I PREPARATION AND REACTIONS OF l-HYDROXY-l,5a-CYCLOCHOLESTAN-7-ONE PART II APPROACHES TO THE TOTAL SYNTHESIS OF LACTARORUFIN A BY Joel Robert Christensen PART I Cholest-S-ene-l,7-dione, a new polyfunctional steroid, gave l-hydroxy-l,Sa-cyclocholestan—7-one (ll) on dissolving metal reduction. Acid and base-catalyzed isomerizations of ll were studied, and the results compared with corresponding reactions of the parent cyclopropanol g. The chief arrange- ment products from ll were the gig and trans l,7-diketones z& and gé, and the ring A spiro epimers £2 and gg. Surpris— ingly, no B-norsteroid products were obtained despite the isolation of an isomer of l1, 7-hydroxy—5,7B-cyclocholestan- l-one gl, from the base induced reaction of k1. Ring Joel Robert Christensen cleavage reactions of reduced derivatives of l1 and %l were also examined. PART I I Hydroazulenone éé has been prepared in three steps from enedione El. The possibility of using g% as a synthon for the total synthesis of Lactarorufin A was explored. A study of the reactivity of a% found that the enolate derived from g% (gé) was relatively unreactive. However, the silyl enol ether éé was obtained by reaction of 3% with trimethyl silyl chloride. Enol ether 3Q gave the keto-acetal ég upon alkylation with trimethyl orthoformate in the presence of zinc iodide. Nucleophilic additions to the carbonyl group of g% were complicated by 1,4 and 1,6-additions to the enone moiety. Oxidation of £3 with singlet oxygen gave endoperoxide 31 and hydroperoxide 3% in nearly a 1:1 ratio. Attempted catalytic reductions of $2 or ég, prepared by the base induced peroxide cleavage of £1: were complicated. Dienone g3 was selectively epoxidized with mgtg- chloro- peroxybenzoic acid. For my mother, whose love and support made this possible ii ACKNOWLEDGMENTS The author wishes to express his sincere appreciation to Professor William Reusch for his guidance and encourage- ment throughout the course of this work. Thanks are extended to my family, colleagues and friends, especially Rob and Pat, who made the going easier. Special thanks are also extended to my brother, Gerald, for his help and to Mr. Ernie Oliver for obtaining mass spectra. Finally, the author would like to thank Michigan State University for financial support. iii TABLE OF CONTENTS Chapter LIST OF TABLES. . . . . . . . . . . . LIST OF FIGURES . . . . . . . . . . . PART I INTRODUCTION. . . . . . . . . RESULTS AND DISCUSSION. . . . . . . . EXPERIMENTAL. . . . . . . . . . . . . General . . . . . . . . . . . . Preparation of Cholest-S-ene-l- one (3%) . . . . . . . . . . Preparation of Cholest-S-ene— l,7-dione (lg) . . . . . . . Preparation of l-hydroxy-l,5a- cyclocholestan-7-one (l1). . . Preparation of 58- -cholestane- l, 7- dione (ii) and Sa-cholestane- l, 7- dione ( . . . . . . Acid catalyzed opening of l1 . Base catalyzed opening of l1 . Preparation of 7-hydroxy-5,7B- cyclocholestan-l-one (4%). . . Base catalyzed opening of 4% . Preparation of a3. . . . . . Acid catalyzed ring opening of gg. Base catalyzed ring opening of £3. iv Page vii . . viii l 7 30 30 . . 31 32 . . 33 . . 34 . . 35 . . 36 . . 36 . . 37 . . 38 . . 38 38 Chapter Reduction and Subsequent Of 4%. O O O O O O O O O ’h APPENDIX I: SPECTRA PART I. . . REFERENCES. . . . . . . . . . . PART II INTRODUCTION. . . . . . . . . . RESULTS AND DISCUSSION. . . . . EXPERIMENTAL. . . . . . . . . . General . . . . . . . . . . Preparation of 2%. . . . Preparation of 2%. . . . Preparation of 38. . . . Methylation of 2%. . . . Formylation of 2%. . . . Reduction of 2%. . . .-. Preparation of 32. . . . Preparation of £1. . . . Photo-oxidation of 2%. . Base Treatment of £7 . . Acetalization of 3%. . . Reduction of Q5. . . . . Acid Treatment of §% . . Epoxidation of 2%. . . . Reaction Page 39 4O 71 74 82 116 116 117 118 118 119 120 120 120 121 121 122 123 123 123 124 Chapter Page APPENDIX II: SPECTRA PART II. . . . . . . . . . . . 125 REFERENCES. . . . . . . . . . . . . . . . . . . . . 196 vi LIST OF TABLES Table PART I 1 Observed and Calculated C(18) and C(19) Methyl Resonances for Compounds 23, lg, %Q and 28. . . . . . . . . . 2 Acid and Base Catalyzed Reactions of Cyclosterols I; and 2%. . . . . . 3 Acid and Base Catalyzed Reactions of 8 and Selected Derivatives. . . . 4 Observed and Calculated C(19) Shifts for a Series of 5,78- Cyclosteroids. . . . . . . . . . . . 5 Observed and Calculated C(19) Shifts for Two 5,7a-Cyclosteroids. . 6 Calculated C(19) Methyl Shifts for $1 and éé- . . . . . . . . . . . . . PART II 1 Solvent Effect in the Reaction of Singlet Oxygen with 2% . . . . . . . 2 Results of Attempted Catalytic Reductions of ag, ES, and SQ . . . vii Page 11 12 14 23 25 26 103 110 LIST OF FIGURES Figure Page Figure I-# 1 IR of 2% . . . . . . . . . . . . . . . . . . 4O 2 IR of 2% . . . . . . . . . . . . . . . . . . 41 3 Mass spectrum of 2%. . . . . . . . . . . . . 42 4 Proton NMR of 2% . . . . . . . . . . . . . . 43 5 Carbon-13 NMR of 23. . . . . . . . . . . . . 44 6 IR of 16 . . . . . . . . . . . . . . . . . . 45 7 IR of 16 . . . . . . . . . . . . . . . . . . 46 8 Mass Spectrum of 16. . . . . . . . . . . . . 47 9 Proton NMR of 16 . . . . . . . . . . . . . . 48 10 Carbon-13 NMR of 16. . . . . . . . . . . . . 49 11 IR of 17 . . . . . . . . . . . . . . . . . . 50 12 IR of 12 . . . . . . . . . . . . . . . . . . 51 13 Mass spectrum of 17. . . . . . . . . . . . . 52 14 Proton NMR of 17 . . . . . . . . . . . . . . 53 15 Carbon-13 NMR of 11. . . . . . . . . . . . . 54 16 IR of 2S . . . . . . . . . . . . . . . . . . 55 17 IR of gé . . . . . . . . . . . . . . . . . . 56 18 Mass Spectrum of 2%. . . . . . . . . . . . . 57 19 Proton NMR of 2S . . . . . . . . . . . . . . 58 20 IR of 26 . . . . . . . . . . . . . . . . . . 59 viii Figure 21 22 23 24 25 26 27 28 29 3O 31 Figure I-# IR of 26 . . . . . . . . . . . . . . . . Mass spectrum of 26. . . . . . . . . . . Proton NMR of 26 . . . . . . . . . . . . IR of 21 and 28. . . . . . . . . . . . . IR of 21 and 28. . . . . . . . . . . . . Mass spectrum of 21 and 28 . . . . . . . Proton NMR of 27 and 28. . . . . . . . . IR of 41 . . . . . . . . . . . . . . . . IR of 41 . . . . . . . . . . . . . . . . Mass spectrum of 41. . . . . . . . . . Proton NMR of 41 . . . . . . . . . . . . PART II II-# Representative Lactarane Sesquiterpenes. Biogenesis of selected humulene derived sesquiterpenes . . . . . . . . . Synthesis of velleral 16 and vellerolactone 5 . . . . . . . . . . . . IR of 23 . . . . . . . . . . . . . . . . IR of 23 . . . . . . . . . . . . . . . . Mass spectrum of 2%. . . . . . . . . . . Proton NMR of 23 . . . . . . . . . . . . Carbon-13 NMR of 23. . . . . . . . . . . ix Page 60 61 62 63 64 65 66 67 68 69 70 Page 75 76 79 125 126 127 128 129 Figure II-# 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 .32 33 IR of 24 . IR of 24 . . . Mass spectrum of Proton NMR of 24 . Carbon-13 NMR of IR of 36 . . . . IR of 36 . . Mass Spectrum of £33.- Proton NMR of 36 . Carbon-13 NMR of IR of 31 . . . . IR of 31 . . Mass spectrum of Proton NMR of 37 . IR of 38 . . IR of 38 . . . . Mass spectrum of Proton NMR of 38 . IR of 33 . . . IR of 32 . . . Mass spectrum of Proton NMR of 3% Carbon-l3 NMR of IR of fig . . . IR of 48 . . . r22- 562' Page 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 Figure II-# 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Mass spectrum of Proton NMR of 4Q Carbon—13 NMR of IR of 41 . . . IR of 41 . . . . Mass spectrum of Proton NMR of 41 Carbon-l3 NMR of IR of 41 . . . . IR of 41 . . Mass spectrum of Proton NMR of 47 Carbon-13 NMR of IR of 48 . . . . IR of 48 . . . Mass spectrum of Proton NMR of 48 Carbon-13 NMR of IR of 54 . . . . IR of 54 . . . . Mass spectrum of Proton NMR of 5% Carbon-l3 NMR of 54. IR of 55 . . . . IR of 55 . . . . . . xi Page 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 .170 171 172 173 174 175 176 177 178 179 Figure II-# 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 Mass spectrum of Proton NMR of 55 Carbon-13 NMR of IR of 56 . . . . IR of 56 . . . . Mass spectrum of Proton NMR of 56 IR of 57 . . . . IR of 57 . . . . Mass spectrum of Proton NMR of 57 IR of 52 . . . . IR of 59 . . Mass Spectrum of 55. . 55. . éé- - az- EQ- Proton NMR of 59 . . Carbon-l3 NMR of 45.2- xii Page 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 PART I PREPARATION AND REACTIONS OF 1-HYDROXY-1,5a-CYCLOCHOLESTAN-7-ONE INTRODUCTION The reduction of a,B-unsaturated carbonyl compounds by solutions of alkali metals in ammonia generates reactive nucle0philic intermediates. These intermediates are pre- sumed to be radical anions or dianions arising from the ad- dition of electrons to the enone moiety.l-3 Under suitable conditions, the resulting B-carbanion can attack electro- philic centers in either an intra or intermolecular fashion. One of the first examples of intramolecular attack occurred 1,9 in the reduction of lO-hydroxymethyl A -2-octalone tosylate described by Stork and Tsuji3 (Equation 1) CH 20T$ .. f .6 l 2 Cyclopropane formations of this kind, during alkali metal-ammonia reductions of multifunctional compounds have been noted in many other systems, as illustrated by Equa- tions 2-4. Thus, even relatively reactive compounds such (4) 8 2 R1: H3122: CH3 ‘3 R1: H3122: CH3 as cyc10propanols have been prepared by this method. The Wieland-Miesher ketone Z and simple alkyl derivatives of Z, such as compounds 9 and 11, have been prepared and subjected to lithium-ammonia reduction with similar re- sult56’7. The ring opening reactions of these cyclo- propanols8’9 have been studied in detail. In fact, oxy- cyclopropanes, including cyclopropanols have found con- siderable use in synthetic organic chemistrylo. Reaction of cycloprOpanes with acid may give rise to many ring opened or rearranged products. With cyclopropan- ols, the hydroxyl group controls and facilitates ring Opening by its ability to stabilize an adjacent positive charge. Stereochemical studies of acid-catalyzed cyclo- propanol ring openings indicate that they generally pro- ceed with retention of configuration at the protonation sitellb'l3. However, these reactions often do not show high regioselectivityll’lz. Thus, a mixture of products is usually observed from the acid catalyzed opening of unsym- metrical cyclopropanols, although the product resulting from proton attack at the least substituted carbon generally pre- dominates (Equations 5, 6, and 7). In a few cases cyclo- prepanol ring Opening With inversion has been observedlz’l4 (Equation 7). Base-catalyzed ring opening of cyclopropanols generally proceeds the more stable carbanionllb'15'16. Consequently, 11,15 these reactions often show high regioselectivity (Equa- tions 5 and 7). In addition, the C-protonation step is usually characterized by inversion of the B-(carbanionic) carbonllb’l3 CH D CatalystJ‘ H OH Dioxane-r MN + g CH3 (5) c H CH ”20 CH 6 5 Catalysts: DCl 60% 3 40% (Retention) = KOD Q% 100% Inversion §C H 3 ' HCl, aqueous glyme _ or 4' '9 KO-i-Cqu , E-CquOH C313 (Retention) D Catalyst - Q \'.o (7) 'H P‘. “*0 OCOCH3 o ‘ ’33 (a brexane) (a brendane) Catalyst = D230” 31% 69% : NaOCH3 0 9% (Retention) (Inversion) (Equation 5). However, the stereochemistry of these ring opening reactions appears to depend upon the solvent and the nature of the substrate being studied. In many instances, the stereochemistry of the ring-opened product is consistent with the observations and interpretations reported by Cram and coworkers for electrOphilic substitutions involving carbanionic intermediatesl7. CycloprOpanols such as 8 rearrange under acid- or base-catalysis to the synthetically useful intermediates 88, 18 and 88 in good yield. The formation of 88 from 8 has been shown to involve interaction of the cycloprOpane moiety with the C(7) carbonyl group, giving an isomeric cyclopropanol which is then cleaved to the hydrindandione (88). Products such as 88 arise from 8 by C(1)-C(10) bond cleavage, occurring with retention of configuration, whereas products 88 and 18 are formed by C(l)-C(5) cleavage which occurs with inversion of configuration. To extend the cyclopropanol studies of our research group8’9 to steroids, a preparation of steroid 88 (choles- tane series) was needed. Reduction of 88 with lithium in ammonia should yield cyclosterol 88. Since no steroid having the functionality shown in formula 88 has been re- ported in the literature, a portion of this thesis is de- voted to the synthesis of steroid 88. Subsequent reductive cyclization of 18 to 81 and a study of the acid and base- catalyzed ring opening reactions of 81, with comparisons to the parent system (8, 88 and 18), will also be discussed. CaHI7 RESULTS AND DISCUSSION Cholesterol 88 is an inexpensive starting material for the synthesis of 88 and was converted to la-hydroxy-S- cholestene 88 according to Okamural8 (Equation 8). CM? [g :9 (8) LAH ml Li.NH3 .9 S f} a 2.? Samples of 88 prepared in this manner and purified by 5 column chromatography were found to be a mixture of A and A4 isomers (roughly 3:1). Oxidation of 88 with pyridin- 19 ium chlorochromate or pyridinium dichromate20 gave the 7 unsaturated ketone 88 as an equivalent mixture of A5 and A4 isomers. Allylic oxidation 88 with Collins reagent, 21 according to Fullerton , gave a 25% yield of 88 (Equa- tion 9). Attempted allylic oxidations with sodium 1 chromatezz, t-butylchromate23, 3,5-dimethylpyrazole chromium trioxide complex24, or N-bromosuccinimide25 failed to im— prove this yield. Recycling recovered 88, from the allylic oxidation with Collins, reagent, gave an overall yield of 30% of 88. Dissolving metal reduction of 88 by lithium in am- monia/THE gave 88 in over 85% yield. Subsequent reduction of 88 by lithium in ammonia yielded diol 88 (Equation 10), which was used without purification in a parallel series of acid and base-catalyzed isomerizations. The only structural characterization for 88 was the absence of carbonyl stretch- ing absorption in its infrared spectrum. The gig and trans diketones 88 and 88 are potential products from the acid and base-catalyzed reactions of 88, \ LJ hUi3 I __l s. 1 A ,_J O v and were prepared independently by catalytic reduction of 88 (Equation 11). The known A/B-trans diketone 88 was separated from its cis isomer (88) by medium pressure liquid chromatography 1 x x *= 4- .é +1 (11) IS 25 2626 Compounds 88, 88, 88, and 88 have not been previously described, and their molecular formulae were confirmed by mass spectrometry and elemental analysis. Support for the assigned structures was obtained in part from calculations 10 of the angular methyl 1 27,28 H NMR chemical shifts. Bhacca and Williams have tabulated the effect of functional sub- stitution at various positions on the chemical shifts of the C(18) and C(19) protons in the 5d,l4d-androstane series. From the appropriate functional group increments, the cal- culated chemical shifts of the C(18) and C(19) protons for compounds £3! lg, gé, and gé were compared with the ob- served values (Table 1). Good correlations were found for the assigned structures. Table 2 lists the chief products from prolonged acid (hydrochloric acid in THF) and base (aqueous potassium hydroxide in THF) treatment of l1 and g3. They include gé, gé and a difficult to separate mixture of epimeric spiro-diketones g1 and %§. The products from acid and base-catalyzed reactions of £3 were subjected to Jones oxidation prior to chromatography and analysis. CaHn ll hammoumna m .oxonh .oxOIH mmv.a Nav.a hoo.o omw.o 1%wv mcwumouwcmnaqa.am hammonmsa » 6on 6.8% 234 8TH 30.0 2E6 Ammo mcmumouocmuava.mm A .( hammonmha .oxoun .m< .oxoua Nam.a oma.H Hos.o mmm.o Aw_v mcmumoupcmlava.am hammoumaa . < .oxo-H mmm.H m©N.H Hoa.o mam.o .z m Ammo wcmumOHUCMIa¢H.om # pom: AEdmv Asmmv AEQQV AEQQV UGDOQEOU ucmEmHocH cfloumum onmo who ooamo moo Amavu Amavu AmHVU Amavu .88 .88 .88 .88 . mm 0cm mm ma mm monsomfiou How mmocMGOmmm H>cumz Amavo cam Amavo cmumasoamu pcm ©w>uomno .H magma 12 AOMHOBV ”womv coflumvflxo mmCOh AN mN cam NN + Amomuuc 0N + Awoev mN an NH .omN .mONmo\mme .mom AH «N Aomuoav meHc NN cam NN + Awomuuv mN + “Nome mN M: NH .omN .mONmoxmme .mox Nw Remnant ANNNV coflumpflxo mmc0h Am mN cam NN + Amomupv mN + Amomuuv mN a u; NH .omN .mme .Hom AH «w Aomuoac ANmNV NN cam NN + ANNNV oN + ANNHV mN .u: o .omN .mme .Hom Na mposooum mcoHuncoo cowuowmm wumuumnzm .ww 6cm N¥ maoumumoHo>o mo mcofluommm cwnwamuMUImmmm can ©Ho¢ .N mHnme 13 The product distributions shown in Table 2 indicate that cyclosterols l1 and éé undergo acid and base-catalyzed ring opening isomerizations comparable to those reported earlier for g and some of its derivatives (Table 3). In particular, removal of the homo-conjugated carbonyl function (as in E3) changes the regioselectivity of these isomeriza- tions in similar ways. For example, both 3% and %Q give a spirodiketone (after Jones oxidation) as the chief product, upon treatment with acid. Two interesting differences be- tween the reactions of *1 and g may be noted. First, the stereoselectivity of the C-protonation (leading to EZ and gg) is poorer in the ring opening of l2 than in the equi- valent reaction of §- For example, spiro[5.4]decane pro- ducts such as lé are formed from g or 3Q! with exclusive retention of configuration; but 31 and gg appear to be formed together in roughly 70:30 ratio from both acid and base-catalyzed reactions of l1 and 3%. The major epimer, g1, has been assigned the axial methyl configuration l4 logy we ...... love we AONV we lmomuuv we ioHv NH Amomupc ww ioac «H Achww lame NH I u: OHuN .omN .:0mmo :H mox an CHIN omN .mONmo cH mos Mn CHIN .omN .mONmo cH Hum up mnN Moo .mme cH Hom .lo c? 08 M8 «9 a? g 9% In. 828 Achva muoscoua mcofluflpcoo newuommm mumuumnsm .mm>Hum>HHmQ pwuowawm 0cm w mo mcofluommm UmuhamuMUImmmm paw Uflofl .m mHQMB 15 .muospoum Home HMHsomHOEmuucH mdm 88 mm mHmmv NH HS CHIN oomN .mONmo cH mos .m . M. I 3 HS CHIN .omN .mONmo cH .mox vi Achva muoscoum mcoHpHocou coHuommm mumuumnsm .UmsaHpcoo .m mHnme l6 (retention of configuration) on the strength of the chemical shift difference observed for the methyl doublets: z 2 ’L (61.145 ppm, J = 7.0 Hz), %§ (50.935 ppm, J = 6.9 Hz). In this rigid framework an axial methyl group at C(10) (as in %Q) is deshielded by the carbonyl function at C(7)2 (assuming ring B adopts a chair conformation). A second difference between reactions of lz and g is the absence of aflnorsteroid product £3: equivalent to 1% in the parent system, among the tetracyclic isomers ob- tained from 11. The formation of 1%, by the action of CaHI7 lm )3 33 ~ ~ base on g, has been proposed to proceed through an isomeric cyclopropoxide 3%, which undergoes a regiospecific cleavage of the C(6)-C(7) bond to give 1% (Equation 12). The forma- tion gé involves an interaction of the carbonyl group with the cyclopropane ring, causing a shift of the C(l)-C(5) bond to the C(5)-C(7) position. A similar B-homoenolate l7 (00 o: A (A U1 (12) rearrangement has been proposed in the base promoted con- version of diketone %Q to the bicyclooctane 32?9 (Equation 13). 2 ‘ (l3) 18 The six-membered ring of 3% (or Q) can assume one of two possible boat conformations relative to the three membered ring. Thus two kinds of interaction between the cyclo- prOpane ring and the C(7) carbonyl group can be envision- ed (Equation 14 and 15). Neither the gigeindane 32' nor derivatives of %§, has ever been obtained as a product from g. Apparently, the inter- action leading to %§ does not occur. In fact, it has been noted that cyclopropyl interactions similar to those des- cribed here generally proceed with inversion of configura- tion of the carbon atom common to both three membered l9 . 30 . rings . Although the cyclopropanol corresponding to 35 (30%) has never been observed directly, 35 has been trapped as its acetate égb, which is rapidly converted to I; on 40d R=F1 b R = 0C0CH3 treatment with base.8 Substituents on Q which favor conformation Bl rather than BZ, or which cause subtle changes in the required cyclopropyl-carbonyl orientation and interaction would be expected to hinder formation of the trans-hydrindandione. This hypothesis is supported by the observation that base treatment of IQ gave exclusively the trans-hydrindandione 31, whereas lg was transformed exclusively to the gig- decalin 3% under similar conditions (Table 3). The more stable conformation of 10,(10Q), orients the methyl substi- tuent (R1 = CH3) in an equatorial-like position. On the other hand, conformational analysis predicts that the B1 type conformation, lga, would be favored in 1% because the methyl substituent (R2 = CH3) would occupy an equatorial- like position. 20 "I ) 1: “W” s. .. 0H 0H B'---~~- BOAT CONFORMATION ------~82 88 RI 7- H ; R2: H ° ‘éb (0a --------- R':CH3 ; R2: H “”‘”'"‘!Qb '33 ......... R| _ H ’ R2: CH3 humulgb This conformational argument cannot be used to explain the absence of norsteroid 3% from reactions of l1. Cyclo- sterol l1 can adopt only a B2 type boat conformation, be- cause ring C must necessarily be fused to ring B in a diequatorial fashion. Consequently, the cyclopropyl-car— bonyl group orientation necessary for the C(l)-C(5) to C(5)-C(7) bond shift is easily achieved by 11. Indeed, 21 OH E? in a B2 boat conformation this bond shift is observed. Mild base treatment of 11 gave the isomeric 5,78 cyclosterol $1 in 23% yield, together with 25 (16%), 21 and 2% (8%), and recovered 11 (33%). The configuration of the cyclopropane ring in $1 was 1 assigned by comparing the H NMR signals of the C(19) 22 methyl and the 6 (a and 8) cyclopropyl protons with the corresponding signals reported for known 5,7B-cycloster- oids and their 5,7a isomers31(a-C). Using the additive approach described by Zurcher27’28 for calculating the C(19) methyl shifts in steroids, the influence of the 5,7-cyclopropane moiety upon the C(19) methyl shift was determined. Thus, the C(19) methyl shifts for a series of known 5,7B-cyclosteroids were calculated ignoring the ef— fect of the cyclopropane ring. These calculated C(19) methyl shifts were subtracted from the observed C(19) methyl shifts and the resulting shift differences were averaged to obtain a value of 0.09:0.02 ppm (downfield). This value represents the downfield shift of the C(19) methyl resonance induced by the cyclopropane moiety of a 5,7B-cyclosteroid (Table 4). A similar analysis of two 5,7a-cyclosteroids, reported by Joska gt Elfin'c, indicates that the configurationally isomeric cyclopropane moiety in these cyclosteroids causes a -0.22:0.03 ppm (upfield) shift of the C(19) methyl signal (Table 5). In both of these computations the Sa-cholestane system was used as a ref- erence, since it more closely approximates the shape of both the 5,7a-and 5,7B-cyclosteroids than does SB-choles- tane. The 5,7-cyclopropyl group increments calculated in this fashion were then used to calculate the C(19) methyl shift in cyclosterol %1 (Table 6). The good correlation between the calculated C(19) methyl shift (51.262 ppm) and 23 Ou< oaolmm mmCC.o mmm.o mm.o oéOIam omC.C CCC.C mm.o melmm mmC.o mom.o mm.o mOIdm mCH.o mhh.o mm.o com: Hemmv Heady Heady pHouwumoHo>UImh.m unoEouocH UOHMUImQO< ponU mHU mno HU CHoumum m m.m©HoumumoHomUImh.m mo mmHHmm m new muanm AmHvU wwumHsono paw ©m>ummno .e mHnma 24 .Empmwm mcmummHonoIom any you msHm> mocwnmmmu Ema mhh.o m :0 pmmmmm .AmcHu mcwdoumoHo>UIh.mIo .mmmum>mv Edd ~.CHmC.C n .ConoImnO< .1 .9004. < H no.0 mm.o No.0 .0d0lom H H< NvH.o Nmm.o oo.H monmm < . . . H mmo o mmm C Hm C .m lam Comb Heady Heady Heady UHoumumoHo>UImb.m ucmEmHocH CUHMUImQO< CUHMU CH0 mno CHU UHoumum .Umscwucou .v anme 25 .Emum>w mcmummHonoIam may now msHm> mocmumwwu Ema mhh.C m co pommmm .HCCHH mammoumoHoonh.mIm .mmmum>mv Ema mC.CHNN.CI n .UUHMOI.mnO<« n1< omoImm mmm.ou mmm.o hm.o H .auI mouam mmHé- 23.0 $6 0. 2 Como Heady Hammv Heady UHonmvmoHo>UIoh.m ucmEmuocH COHMUImQO< ponu mHU mno mHU pHouwum m.m©HoumumoHo>UIah.m 039 now mpmHnm Acho cmHMHsono cam wm>ummno .m mHnme 26 Table 6. Calculated C(19) Methyl Shifts for 3% and gg.a C(19) Calcd. Steroid Increments Cyclosterol (ppm) Used 1.262 l-oxo, d-5,7-cyclopropane 0.992 l-oxo, B-S,7-cyclopropane aBased on a 0.775 ppm reference value for the 5a-cholestane system. the observed value of 51.245 ppm supports £1 as the assigned structure rather than the isomeric 5,7a-cyclosteroid 42. The geminal cyclopropyl protons in 41 appear as broad doublets at 60.23 and 1.00 ppm, J = 5.57 Hz, in its 1H NMR spectrum. Some long-range coupling is apparent on close inspection of these signals, and a model suggests that protons at C(8) and C(4)-(B) are ideally oriented for coupling with the 6B and 6d protons respectively. Also note that the relatively small chemical shift (60.23 ppm) 27 associated with one of the cyclopropyl protons, presum- ably 68, corresponds to observations made with authentic 5,7B-cyclosteroid531. Since the isomeric 5,7a-cyclosteroids 31c do not exhibit any 1H NMR signals at higher field than the C(18) methyl singlet (@ 60.70 ppm), this is additional sup- port for the assigned 5,7B-cyclosteroid configuration. Treatment of $1 with potassium hydroxide in a THF- methanol solution yielded a mixture of 25, 21 and 2% (Equa- tion 16) similar to that obtained from 17 (Table 2). It 4| awed?» 37 + 2.,8 ( IO‘I.) is clear that 17 and %1 must be interconverted under these reaction conditions, but the failure of the latter to isomerize to the B-norsteroid 3% remains unexplained. Such a product would be formed initially in a trans-anti-trans configuration of rings A, B, and C, and this appears to be more strained than the normal steroid ring system. Consequently, it is possible that reaction of £1 by cleav- age of the C(6)-C(7) bond is less favorable than the com- parable reaction of 40b. When %1 was reduced (Li in NH3), followed by base treatment and Jones oxidation, 25 was 28 the only product (Equation 17). Thus, both $1 and £3 react by cleavage of the C(5)-C(7) bond with retention of configuration. Cyclosterols 11 and 2% react by cleavage of the C(l)-C(10) bond with both retention and inversion of configuration (leading to 21 and 28) or by cleavage of the C(1)-C(5) bond with inversion of configuration. Under basic conditions, it is clear that 17 and 31 are interconverted (Equation 16). This interconversion appears to occur as well during the acid catalysis of 17, since 31 was detected by TLC as a transitory product. This behavior parallels that of the parent system 8, which upon mild treatment with hydrochloric acid in methanol yielded the isomeric 5,7-cyc10propyl-methyl ether 35 as the major product (Equation 18). One last difference between the reactivity of 11 versus 8 is that the acid catalyzed isomerization of ll (Table 2) generates a larger amount of the trans decalin 26, than does 8. Overall, the reactivity of 12 generally parallels that 29 (m of the parent system 8. As with 8, a cyclopropyl-carbonyl group interaction has been demonstrated in 17. As is often observed during acid-catalyzed opening of cyclopro- panols, cyclosterol 17 exhibits poor regioselectivity during the ring-opening, however, this reaction is compli- cated by the cycloprOpyl-carbonyl group interaction. Re- moval of the C(7) carbonyl group, as in 2%, followed by acid treatment, yielded (after oxidation) spiro-diketones 27 and 28 as the exclusive product. The absence of the B- norsteroid product 33 may be rationalized in terms of the trans—anti-trans configuration of rings A, B and C which appears to be more strained than the normal steroid system. EXPERIMENTAL General Except as indicated, all reactions were conducted under dry nitrogen or argon, using solvent purified by distilla- tion from suitable drying agents. Magnetic stirrers were used for small scale reactions; larger reactions were agi- tated by paddle stirrers. Organic extracts were always dried over anhydrous sodium sulfate or anhydrous magnesium sulfate. The progress of most reactions was followed by thin layer chromatography and/or gas liquid chromatography. Visualization of the thin layer chromatograms was effected by 30% sulfuric acid with subsequent heating. Analysis by GLPC was conducted with a Varian 1200 gas chromatograph. Melting points were determined on a Hoover- Thomas apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 237B grating spectrophotometer. Proton magnetic resonance Spectra were taken in deutero- chloroform solutions with either a Varian T-60 or a Bruker 250 MHz spectrometer and are calibrated in parts per mil- lion downfield from tetramethylsilane as an internal stan- dard. Carbon-13 NMR spectra were taken in deuterochloro- form solutions on the Bruker 250 MHz spectrometer using tetramethylsilane as an internal standard. Mass spectra 30 31 were obtained with a Finnigan 4000 GC/MS spectrometer. Preparation of Cholest-—5-ene-l—one23 To a stirred slurry of 1.05 g (4.9 mmol) of pyridinium chlorochromate in 3 mL of methylene chloride was added a solution of 1.0 g (2.59 mmol) of l-hydroxycholest-S-ene (2%) in 2 mL methylene chloride. This mixture was stirred for 2 hours, diluted with 20 mL of ether and decanted. The black precipitate was washed with ether and the combined ether solutions were filtered through a layer of florisil. Evaporation of the ether gave 0.8 g of a yellow oil which was crystallized from acetone-methanol to afford 0.72 g 5 4 (72/) of 23, mp 97-101°C. This mixture of A and A isomers (roughly 70:30) exhibited the following properties: IR (CHC13) 1700 cm'l; 1H NMR (c0013) 60.677 (5, 3H, C-l8), 0.862 (d, 3H, J = 6.55 Hz), 0.865 (d, 3H, J = 6.55 Hz), 0.911 (d, 3H, J = 6.55 Hz, c-21), 1.266 (s, 3H, C-19), c NMR (00013) 6195.03, 194.44, 146.57, 141.33, 122.86, 117.51, 56.81, 56.40, 53.76, 51.01, 42.64, 42.46, 39.76, 39.64, 38.11, 36.58, 36.34, 36.17, 35.94, 33.64, 31.99, 31.23, 28.23, 28.05, 27.56, 26.05, 24.34, 24.05, 22.86, 22.64, 19.06, 18.76, 15.12, 12.96, 12.06; ms (70 eV) m/e (rel. intensity) 384 (M+, 100), 369(15), 27(17), 176(45), 124(47). Anal. Calcd. for C27H44O : C, 84.31; H, 11.53 Found : C, 84.08; H, 11.61. 32 Preparation of Cholest -5-ene-1,7-dione_16 To a cold (0°) solution of 25.0 g (0.3 mmol) of pyridine in 300 mL of methylene chloride was added with stirring 15.0 g (0.15 mmol) of chromium trioxide. The resulting bur— gundy colored solution was slowly warmed to room temperature, following which a solution of 4.0 g (0.01 mmol) of 2%, dis- solved in 3 mL of methylene chloride, was added one portion. An additional portion of the chromium trioxide-pyridine com- plex (prepared as above) was added after a 24 hr reaction period, and this reaction mixture was stirred for an addi- tional 48 hours. The reaction mixture was decanted, the tarry precipitate was washed three times with 150 mL por- tions of methylene chloride and the combined solutions were evaporated to afford a dark oil which was then dis- solved in 500 mL of ether and filtered. This ether fil- trate was washed twice with 150 mL portions of 5% hydro- chloric acid, 150 mL of brine, and then dried. Evaporation of the solvent and chromatography of the resulting solid (silica gel, 35% ethyl acetate/hexane) gave 200 mg of re- covered 23 and 800 mg (25%) of 16 as a white solid. An analytical sample prepared by recrystallization from methanol, mp 81-82°C, exhibited the following properties: IR (CHC13) 1715, 1650 cm'l; 1H NMR (00013) 60.689 (3, 3H, J 6.55 Hz), 0.860 (d, 3H, J = 6.72 Hz), 0.863 (d, 3H, 6.57 Hz, C-21), 1.419 (s, 13 J 6.55 Hz), 0.915 (d, 3H, J 3H, C-19), 5.803 (d, 1H, J = 1.37 Hz); C NMR (CDC13) 33 6200.38, 196.92, 163.99, 126.10, 54.98, 50.36, 45.12, 43.39, 43.24, 39.49, 38.75, 37.01, 36.21, 35.65, 30.48, 28.46, 27.93, 26.18, 23.87, 23.18, 22.77, 22.53, 18.88, 16.65, 12.12; MS (70 eV) m/e (rel. intensity) 398 (M+, 2), 380 (22), 342(50), 55(100). A331. Calcd. for C H O : C, 81.35; H, 10.62 27 42 2 Found : C, 81.10; H, 10.70 Preparation of l-hydroxyl-l,Sa-cyclocholestan-Twnuilz In a fifty milliliter, three neck, round bottom flask, containing a small piece of sodium metal, was condensed 30 mL of ammonia. The ammonia was then distilled through tygon tubing into a carefully dried fifty milliliter, three neck, round bottom flask containing 30.0 mg (4.2 mmol) of lithium wire. This reaction flask was equipped with a mag- netic stir bar, a dry ice condenser, a dry ice-acetone bath, a nitrogen gas inlet, and a septum inlet. By means of a syringe, 5 mL of tetrahydrofuran was added to the ammonia solution, followed by a solution of 300 mg (0.75 mmol) of 16 dissolved in 4 mL of tetrahydrofuran, added dropwise. The reaction mixture was allowed to stir for 0.5 hr and was then quenched with approximately l.g of solid ammonium chloride. The cooling bath was removed and the ammonia evaporated under a stream of nitrogen. The residue was taken up in an ether and water mixture, and the organic layer was washed with water, brine and finally dried over 34 sodium sulfate. Evaporation of the solvent gave 267 mg (89%) of 11 as a white foam of purity >90%, which was used without purification for the subsequent ring opening re- actions. Thin layer chromatography (silica gel, 35% ethyl acetate/hexane) of the crude cyclopropanol showed it to be homogeneous, Rf = 0.39, except for a small amount of 16. An analytical sample, mp 113-118°C, was prepared by recrystallization from acetone, and exhibited the following properties: IR (CHC13) 1700, 3350 cm’l; 1H NMR (c0013) 60.718 (8, 3H, C-18), 0.856 (d, 3H, J 6.4 Hz), 0.860 (d, 3H, J = 6.75 Hz), 0.915 (d, 3H, J = 6.43 H 13 2! c-21)r 0.928 (s, 3H, c-19); c NMR (benzene d-6) 6194.46, 71.28, 55.60, 52.03, 47.36, 43.70, 40.04, 39.87, 39.54, 39.16, 36.60, 36.20, 33.92, 33.44, 32.33, 30.67. 28.56. 28.45, 26.03, 24.74, 24.31, 23.37, 23.02, 22.78, 19.14, 11.97. 8.27; MS (70 eV) m/e (rel. intensity) 400 (MT 15), 382 (10). 151(65). 124(100). Anal. Calcd. for C C, 80.94; H, 11.07 27H4402 ‘ Found : c, 81.23; H, 10.92. Preparation of 58-Cholestane-l,7-dione (25) and Sa-Cholestane- A solution of 50.0 mg (0.13 mmol) of 16 in 3.5 mL of ethyl acetate was hydrogenated over 10% palladium on char— coal for 20 hours (1 atm. H2). This solution was filtered and evaporated to afford 50 mg of an oil, which on 35 chromatography (silica gel, 25% ethyl acetate/hexane) yielded 22 mg (36%) of 22 and 28 mg (56%) of 22. Analytical sample of 2p, mp 110-111°c (lit. mp 110-111°C)5, was pre- pared by recrystallization from 95% ethanol. An analytical sample of 22, mp l48-l48.5°C, prepared by recrystallization from 95% ethanol exhibited the following properties: IR (CHC13) 1705 cm’l; 1H NMR (00013) 60.645 (3, 3H, C-18), 0.857 (d, 3H, J = 6.55 Hz), 0.862 (d, 3H, J = 6.55 Hz). 0.884 (d, 3H, J MS (70 eV) m/e (rel. intensity) 400 (M7 10), 382(2), 111 (30), 43(100). Anal. Calcd. for C27H44O2 : C, 80.94; H, 11.07 Found : C, 81.17; H, 11.08 Acid Catalyzed Opening of Cycloprgpanol 22 A solution of 60 mg (0.15 mmol) of 22 in 4 mL of tetra- hydrofuran, containing four drops of concentrated hydro- chloric acid, was stirred for 6 hours at room temperature. The reaction mixture was diluted with ether, washed with saturated bicarbonate, and dried. Evaporation of the sol- vent followed by chromatography of the resulting oil (silica gel, 25% ethyl acetate/hexane) gave 8 mg (13%) of 22, 23 mg (38%) of 22, 15 mg (25%) of 22 and 22 (70:30), mp 121- 128°C, and 3 mg of 22. Combining the remaining fractions gave 4 mg of an oil containing three unidentified products. The epimeric mixture of 22 and 22 exhibited the following 36 properties: IR (CHC13) 1710, 1760 cm_l; 1H NMR (CDC13) 60.656 (5, 3H, C-18, 22), 0.664 (s, 3H, C-18, 22), 0.859 (d, 3H, J = 6.55 Hz, 22 and 22), 0.864 (d, 3H, J = 6.7 Hz, 22 and 22), 0.906 (d, 3H, J = 6.55 Hz, C-21 22 and 22), 0.936 (d, 3H, J = 6.85 Hz, equatorial C-l9, 22), 1.146 (d, 3H, J = 7.03 Hz, axial C-l9, 22); MS (70 eV) m/e (rel. intensity) 400 (M, 10), 382(9), 290(20), 111(30), 55(48), 43(100). Base Catalyzed Ring Opening_of22 To a solution of 60 mg (0.15 mmol) of 22 in 4 mL of tetrahydrofuran at 0°C was added 0.35 mL (0.45 mmol) of a solution of 0.35 g (6.3 mmol) of potassium hydroxide in 8 mL of a deoxygenated mixture of methanol and water (1:1). This solution was stirred for 2 hours at 0°C and then overnight at room temperature. The reaction mixture was diluted with ether, washed successively with water and brine, and dried. Evaporation of the solvent followed by chromatography of the resulting oil (silica gel, 25% ethyl acetate/hexane) gave 40 mg (66%) of 22, 10 mg (16%) of 22 and 22 (70:30), and 3 mg of 22. Preparation of 7-hydroxy-S,7B-cyclocholestan-1—one To a stirred solution of 60 mg (0.15 mmol) of 22 in 4 mL of tetrahydrofuran was added 0.35 mL (0.45 mmol) of 37 the same KOH solution used in the previous experiment. The progress of this reaction, including the formation of Lflk, was followed by TLC analysis (silica gel, 35% ethyl acetate/hexane). After 5 hours, the reaction mixture was diluted with ether, washed successively with water and brine, and dried over sodium sulfate. Evaporation of the solvent, followed by chromatography of the resulting oil (silica gel, 25% ethyl acetate/hexane), gave 6 mg (10% of 25, 20 mg of 11, 3 mg of 21 and 28, 3 mg of 16, 3 mg of an oil containing two unidentified components, and 14 mg (23%) of 41, mp 92—94°C. This crystalline solid exhibited 1 1 the following properties: IR (CHC13) 1700 cm- ; H NMR (CDC13) 60.229 (d, 1H, J = 5.57 Hz), 0.673 (s, 3H, C-18), 0.863 (d, 3H, J 6.53 Hz), 0.879 (d, 3H, J = 6.7 Hz), 0.915 (d, 3H, J 6.58 Hz, C-21), 0.996 (d, 1H, J = 5.57 Hz), 1.245 (s, 3H, C-l9); MS (70 eV) m/e (rel. intensity) 400 (M, 11), 385(8), 151(30), 124(35), 55(60), 43(100). Base Catalyzed Ring Qpening of 41 To a solution of 10 mg (0.025 mmol) of 41 in 1 mL of tetrahydrofuran at 0°C was added 58 uL (0.075 mmol) of the previously described KOH solution. After 2 hours at 0°C and then overnight at room temperature, the reaction mixture was diluted with ether, washed with water and dried. Evaporation of the solvent followed by chromatography of the resulting oil gave 6 mg (60%) of 25 and 1 mg (10%) of 27 and 28 (70:30). 38 Preparation of 24 A solution of 200 mg (0.5 mmol) of 17 in 15 mL of tetra- hydrofuran was added to a cold (-78°C) solution of 28 mg (4.0 mmol) of lithium in 15 mL of freshly distilled ammonia. This solution was refluxed for 2 hours and then quenched with ammonium chloride. Workup as described earlier for the preparation of 11 gave 180 mg (90%) of 2% (epimeric mixture) as a white solid having no carbonyl absorption in the infrared. Acid Catalyzed Rinngening ofgé A solution of 60 mg (0.15 mmol) of 24 in 4 mL of tetra- hydrofuran containing 4 drops of concentrated hydrochloric acid was stirred overnight. The reaction mixture was diluted with ether, washed with saturated sodium bicarbonate, and dried. Evaporation of the solvent gave 55 mg of isomeric ketols which were oxidized with Jones reagent. Chroma- .tography of the crude oxidation product (silica gel, 25% ethyl acetate/hexane gave 47 mg (78%) of 21 and 28 (70:30). Trace amounts of 25 and 26 could be detected by TLC. Base Catalyzed Ring Openingyofgg To a solution of 60 mg (0.15 mmol) of 2% in 4 mL of tetrahydrofuran was added 0.35 mL (0.45 mmol) of the usual KOH solution. This solution was stirred overnight, and 39 workup in the usual manner gave 52 mg of a white solid, which was oxidized with Jones reagent. Chromatography of the crude oxidation product (silica gel, 25% ethyl acetate/ hexane) gave 28 mg (46%) of 25 and 18 mg (30%) of 21 and 28 (70:30). A trace of 26 was detected by TLC. Reduction and Subsequent Reaction of{fl% A solution of 4.0 mg (0.01 mmol) of fik in 1 mL of tetrahydrofuran was added to a solution of 4 mg (0.58 mmol) of lithium in 1 mL of freshly distilled ammonia, cooled to -78°C. This solution was refluxed for 2 hours and then quenched with ammonium chloride. Workup as described for the preparation of 17 gave 3 mg of a white solid, which was immediately dissolved in 1 mL of tetrahydrofuran. To this solution was added 29 uL (0.037 mmol) of the stan- dard base solution and was stirred overnight. Workup in the usual manner followed by Jones oxidation of the residue and chromatography of the crude oxidation product (silica gel, 25% ethyl acetate/hexane) gave 2.0 mg (50%) of 25. APPENDIX I: SPECTRA PART I 40 ocnp I l O N I I I I a— ——d. -.o« c—o— I o—— —- —_..4 I I I l I I _ ._ -__—.-..-— _ I . - -_.~._..-..§_-. . » I On 00 I V .._.-—4 -- - -4---‘7 l I I l ._..._.-.1 -_....._ ._...7 l 0 _ ._.;--.__.-;-- 1-4..- .3 mo E 22 98mg A. SC. > vaDCuzg OOON oonw ooom ._ -.--.--J- I _ .1— .-- _ .-- . ‘ g I +--—4.'-~~-5 1..-- .-._ _ - I I +.---_._.l_. 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I4 7 -.-u. .I _ 4 4 . - . . 4 4 4 4 4 4 4 4 _ _ 4 4 4 .- 4 4 N oo--e4 4,-I-¢-4I---- .-4- 4-:;---- 4- 1:; -4I.-I- 4-.4- 4 oo.J V 4 _ 4 4 _ 4 W 4 4 4 4 4 4 4 4 4 4 4 4 4 4 :4 4- 4 .- _. - .4 4 _ ..- 4 I .1 .4 -. 4 - - -4 4- -.4 4- x) i _ 4 . . 4 _ . . - . _ /o C . 4 - 4 . 4 . 4 4 4 4 U _ 4 _ 4 _ 4 4 / 4c 4 --_. 4.1-4 4- .42 - I. 415- 4 _ _ m- . 4 4 . 4 .- . 4 4 4 4 _ 4 4 4 4 4 _ 4 4 - 4 4 4 4 ..- .II le 4 - . I II?- 4II l4... laI II..:«-- I” ,4 4 4 4 4 4 4 _ 4 4 4 . 4 4 4 4 4 _ 4 4 - - . 4 4 4 4 .4 . 4 4 - 4 4 _ 4 2... F 4 4- 4-- . .- _-_- - -_---.--. .-I- II- -I -....-..-Q j 4 4 om . - . . . _ _ _ 4 . _ _ 4 - . .3 I; I4} -_- _ 4 4 4 _ 4 4 4 4 4 . , _ 4 4 \\ 4 4 4 4 - 4 4 4 4 4 -. -4 4 . 4 4\ 4 . 4 - 4.;4-II . . . -4: :4-- . - . 4 - - 4 - _ I 4 4 - - - 4 4 4 4 H . III. III. I..\; \I-- 4 4 4 -. 4 4 4 . I. ,. -_-4 . ,4. LJK- -44 4: ..4- .4.-- 4. - 4! I4-- 47- I----I4I-I4- 4 -H _ ..-..n- 4 _ _ 4 4 4f. 4 - 4 - 4 . _ . . 4 4 4 4 . 4 4 ,- 4 . . _ _ . . _ 4 _ 4 4 4 4 . 4 - , . - _ 4 4 4 h . 4s - H L. 4 -_ .- I-N- -. .4- . . 4 4 4 - 4 . _ 4 . 4 4 4 - 4 4 _ 4 . 4 _ 4 . _ - _ . 4 4 4 4 4 4 4 4 _ 4 so; 4 ... w .. 4.-. -- I.- --.-4-- -4- 84 II; .I .-.-r-I-I»I-. - . ri- n «.l II...-..-I_ -LIL 4 _ [F -_ LI]-.- -. 344:3}: I4 4444 _ 4 4 4 4 - “‘2 N oa- f . 1 Aw-wzxv—’..«~ A-.w In. m C m 4 68 ON CV 00 ow- oo_ 05: 4. (<4. 4. 42420.4“: 00m 000— CON— 4 4 - 4 - 4 4.4- cov— o-S Q: 3: $205.2 ohm _ .4411... 4 .9 mo E .omuH 88mg Doom (%)33NVJ.J.IWSNVHJ. 653 vnc_ PhPDD._bbr>bx—P\PPID ‘ owv Gav am. cur evm 0mm 79. mo 5:50me mwmz mom rtrbhbrhhbbkrilbh—Phhxhl¥r\—>PPP-LPPLPPL>bb-PPPPF>!bthFtF_rtb-PPDPL—r>bb— 3mm emu mvm qbrbthxPFtLb bPPhlrh*b .omuH mnsmwk w\ z _ Gav _— _ mmm mmm _ emu m8 $3 ....a U0 GNN Dom am“ am" a?“ ”Na 00 am am a? w\: bL.P¥,LL>->>LIPP+> —.b<‘_,kr*b.. —Prr.p _ pbflr—r“ » uthpI» n — bLhu R- mm mm; b“: ___ __1 ___: “41:: 2.: ____ __._ __ mm: _— «K« on: J c- ma~ “fl“ a mm 1 «m u .m 1 «b— m~ 1 : 9.3,. 70 \I‘ .H: mo mzz covoum .HMIH mnsmwh _- REFERENCES 10. ll. 12. REFERENCES G. Stork and S. D. Darling, J. Amer. Chem. Soc., 99, 1761 (1964). H. Burton and C. K. Ingold, J. Chem. Soc., 2022 (1929). G. Stork and J. Tsuji, J. Am. Chem. Soc., 99, 2783 W. Reusch and D. B. Pridday, J. Am. Chem. Soc., 99, 3677 (1969). H. R. Taneja, Ph.D. Dissertation, Michigan State Uni- versity (1977). P. S. Venkataramani, J. E. Karaglan, and W. Reusch, J. Am. Chem. Soc., 99, 269 (1971). W. Reusch, K. Grimm, J. E. Karaglan, J. Martin, K. P. Subramanian, Y.-C. Toong, P. S. Venkataramani, J. D. Yordy, and P. Zoutendam, J. Am. Chem. Soc., 99, 1953 (1977). W. Reusch, K. Grimm, J. E. Karaglan, J. Martin, K. P. Subrahamanian, P. S. Venkataramani, and J. D. Yordy, J. Am. Chem. Soc., 99, 1958 (1977). J. D. Yordy and W. Reusch, J. Am. Chem. Soc., 99, 1965 (1977). E. Wenkert, Acc. Chem. Res., 99, 27 (1980). (a) A. Deboer and C. H. Depuy, J. Am. Chem. Soc., 99, 4008 (1970). (b) C. H. Depuy, F. W. Breitbell, and K. Debruin, Ibid., 99, 3347 (1966). (c) C. H. Depuy and R. Vanlener, J. Org. Chem., 99, 3360 (1974). (d) D. F. Nickon, G. D. Covey, and J. J. Frank, Tet. Lett., 3681 (1975). Z. J. Barnies, R. J. Warnet, D. M. S. Wheeler, M. G. Waite, and G. A. Sim, Tetrahedron, 99, 4683 (1972). 71 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 72 (a) P. S. Wharton and I. I. Bair, J. Org. Chem., 99, 2480 (1966). (b) A. Nickon, and J. J. Frank, D. F. Covey, and Yun, J. Am. Chem. Soc., 99, 7574 (1974). (c) A. Nickon and J. J. Frank, Tet. Lett., 4335 (1975). R. J. Warnet and D. M. S. Wheeler, Chem. Comm., 547 (1971). C. H. Depuy, N. C. Arney, Jr., and D. H. Gibson, J. Am. Chem. Soc., 99, 1830 (1968). C. H. Depuy and F. W. Breitbeil, J. Am. Chem. Soc., 99, 2176 (1963). D. J. Cram, Fundamentals of Carbanion Chemistry, Academ- ic Press, New York.‘ M. N. Mitra, A. W. Norman, and W. H. Okaramura, J. Org. Chem., 99, 2931 (1974). E. J. Corey and J. W. Suggs, Tet. Lett., 2647 (1975). E. J. Corey and G. Schmidt, Tet. Lett., 399 (1979). D. S. Fullerton and C.-M. Chen. Syn. Comm., 9, 217 (1976). J. A. Marshall and P. C. Johnson, J. Org. Chem., 99, 192 (1970). W. G. Dauben and K. Takemura, J. Am. Chem. Soc., 99, 6302 (1953). W. G. Salmond, M. A. Barta, and J. L. Havens, J. Org. Chem., 99, 2057 (1978). B. W. Finucane and J. E. Thompson, Chem. Comm., 1220 (1969). T. Nakano and M. Hasegawa, Chem. Pharm. Bull, 99, 971 R. F. Zurcher, Helv. Chim. Soc., 99, 2054 (1963). N. S. Bhacca and D. H. Williams, Applications of NMR Spectroscopy in Organic Chemistry - Illustrations from the Steroid, Holden-Day, San Francisco, 1964, p. 19-23. N. H. Werstiuk and S. Yeroushalmi, Can. J. Chem., 99, 1601 (1980). 30. 31. (a) (C) (d) (e) (f) (a) (b) (C) 73 J. Haywood-Farmer, Chem. Rev., 99, 315 (1974). D. A. Lightner and W. A. Beavers, J. Am. Chem. Soc., 99, 2677 (1971). P. E. Schueler and Y. E. Rhodes, J. Org. Chem., 99, 2063 (1974). P. E. Schueler and Y. E. Rhodes, Abstracts, 164th National Meeting of the American Chemical Society, New York, N.Y., August 1972, No. ORGN-129. P. K. Freeman and D. M. Balls, Tet. Lett., 437 (1967). P. K. Freeman and J. N. Blazevich, Chem. Comm., 1357 (1969). P. K. Freeman, D. M. Balls, and J. N. Blazevich, J. Am. Chem. Soc., 99, 2051 (1970). P. Gassman and W. Hymans, Tet., 99, 4437 (1968). J. Fajkos, M. Budesinsky, and J. Joska, Coll. Czech. Chem. Comm., 99, 1406 (1973). J. Joska, J. Fajkos, and F. Sorm, Ibid., 99, 2049 (1968). PART II APPROACHES TO THE TOTAL SYNTHESIS OF LACTARANE SESQUITERPENES INTRODUCTION Nature provides a variety of terpenoid compounds, whose carbocyclic structures have challenged the skill and im- agination of synthetic chemists. One rich and diverse source of such substances is a rather highly specialized and advanced fungi known as Basidiomycetes, a class to which "mushrooms" and "toadstools" belong. A number of sesquiterpenes isolated from Basidiomycetesl, such as those f belonging to the marasmaneza- and hirsutaneBa"n classes, have received widespread attention due in part to their biological activity. In the last few years, eleven new members of a class of sesquiterpenes known as the lactar- anesl (from Basidiomycete "lactarius") have been isolated and identified. This class is characterized by a hydro- azulenic skeleton containing a geminally substituted di- methyl cyclopentane ring, representative members being e, furoscrobiculide B 95, lactarolide 5’7, vellerolactone 98a’b, and pyro- lactarorufin A 94a- A 96, furan ether A 9 b, Figure II-l. vellerolactone 98a' The biogenesis of these humulene derived sesquiter- penes is depicted in Figure II-Z. Humulene, which arises by the cyclization of farnesyl pyrophosphate (9), can under- go further cyclization to a variety of carbocyclic structures 74 75 5 6 Figure II-l. Representative lactarane sesquiterpenes. 76 < Hirsutane I O H .“ ) Q~ Km -- C \ 9096) \7 7 Humulene ” b O ~~j -- C m ‘ Z\' 0‘ =2 Lactarane Marasmane Protoilludane Figure II-2. Biogenesis of selected humulene derived sesquiterpenes. 77 ultimately leading to the lactarane, marasmane, hirsutane and other classes of sesquiterpenes. Several biosynthetic investigations support this scheme3C-e’9a-b'lo. Syntheses of hydroazulenic sesquiterpenes have been directed mainly at compounds of the guaine classll. Although there are approximately thirty members of the lactarane sesquiterpenes, only two syntheses of compounds in this class have been reported. Pyrovellerolactone 9 was synthesized in 1975 by Magnusson and coworkerslz. The key step in this synthesis involved a ring contraction initiated during the acetolysis of 9, which presumably pro- ceeds via carbocation 9. Loss of a proton from 9 afforded a mixture of products, from which olefin 99 was isolated and oxidized to pyrovellerolactone Q in poor overall yield (Equation 1). The solvolysis of apprOpriately function- H 4) 1" T (/,. SOZCH3 e "7 HOAc -H :’ No.0Ac / \ L _J g 2 (1) [OX] (‘I| __ _, '5 gm 78 alized bicyclo—[4.3.l]-decanes such as 9 to form hydro- azulenes was first demonstrated by Marsha1113. In 1978, Magnusson and Froborg reported a vastly im- proved synthesis of the lactaranes velleral and vellero- lactonel4. Cycloaddition of a functionalized acetylene with enamine 99 provided cyclobutene 99 which, without purification, underwent a clean thermal electrocyclic ring opening to afford 99. Deamination of 99 gave 99 which was converted to velleral 9915 and vellerolactone 9 (Figure II-3). In 1971, Reusch and co-workers reported the conversion of the Wieland-Miescher ketone 99 to the hydroazulene 99 by way of cyclopropanol 9916 (Equation 2). Since then it n L.,NH3,THF 4—t 29 hflt4CW (2) 79 —~ ‘0 2—2—1. ll |2 C/R I "’ // / (I)zc}t5 ___—4» R-—+ R A CO CH L 002mg, J 2 3 L33 '3 R R=CH<0CH;)2 CH0 '3 COZCHs 16 CHO leCHZOAc Figure II-3. Synthesis of velleral 99 and vellerolactone 9. 80 has been found that simple alkyl derivatives of lg also undergo analogous cyc10propanol formation during reduction with lithium in ammonia17. For example, lithium-ammonia reduction of %l proceeded smoothly to give cyclopropanol . Using the methodology employed for the conversion of to %8 it should be possible to convert %% to the gem- dimethyl hydrazulene %% (Equation 3). Even a cursory examination of dienone %% suggests that it could serve as a valuable synthon for the total synthesis of lactarane sesquiterpenes. Thus the requisite ggmfdi- methyl cyclopentane ring is present, and the diene portion incorporating carbons 3-2-9-8 (lactarane numbering, Scheme 1) provides suitable functionality for the introduction of the oxygen functional groups present at one or more of these carbon atoms in the majority of the lactaranes. The C-12 methyl group is present and the carbonyl function 81 activates carbons g and 1, providing a potential for furan, lactone or lactol annulation (Scheme 1). 12 14 Q. 5 15 13 Attach carbons Lactarane 2&4 5 and 13 which «a make up furan, lactone, or lac- tol ring. Oxidize diene moiety to provide requisite oxygen functionality and in addition es- tablish the proper ring fusion stereo- chemistry Scheme I A study of compound %3 as an intermediate for the syn- thesis of lactarorufin A was set as the initial goal of this project, and most of the chemistry described here was car- ried out with this goal in mind. This portion of the thesis describes an efficient synthesis of EQ! and the re- sults of several studies designed to convert it to lac- tarorufin A. RESULTS AND DISCUSS ION Cyclopropanol %% was prepared by lithium in ammonia re- duction of enedione gl17, which had been synthesized accord- ing to the procedure of Heathcocle. Reaction of 3% with methanesulfonyl chloride in pyridine containing a catalytic amount of dimethylaminopyridine19 gave the corresponding mesylate ester g3. Acetolysis of %% yielded dienone £3! accompanied by a higher molecular weight product believed to have structure %2 (Equation 4)20. (4) A¢0 82 83 The observance of %§ in roughly a 2:3 ratio with %% sup- ports a solvolysis mechanism in which carbonium ion gé is formed as the key intermediate (Equation 5). Thus gé may lose a proton to generate 3%, or suffer nucleophilic attack (- (£13 —-—- ~ 0 § C Q W?“ 2.5» (.5) V 23 24 by sodium acetate to give 3%. Varying the amount of sodium acetate used in the solvolysis or increasing the reaction temperature failed to effect a cleaner conversion. To circumvent this problem, the possibility that %% might undergo ring expansion under basic conditions was studied (Equation 6). Although amine bases had no effect on €31 stronger bases such as alkali metal alkoxides, sodium 84 2“: a I - H 9 (cm (6) b _J hydride, lithium diisopropyl amide and dimsylsodium were effective in promoting the conversion of g; to a4. Un- fortunately the yield was poor and the occurrence of side products complicated the reaction. Since neat acetic acid proved ineffective for the con- version of éé to g%, it was proposed that a stronger acid, with a less nucleophilic conjugate base would be an ideal solvent for this reaction. Trifluoroacetic acid fits this requirement, and a solution of a; in neat trifluoroacetic acid yielded g% in nearly quantitative yield. With an efficient synthesis of £3 established, it be- came necessary to investigate the viability of E% as a lactarane synthon. Two basic strategies were explored and are illustrated in Scheme 2. One approach, A, involves the introduction of missing carbons 5 and 13 (Scheme I) to obtain an intermediate of structure %§- The notation 85 "E" represents a one-carbon moiety added to 3% by reaction of a suitable electrophile (E+) with an enolate species derived from g%. The notation "Nu" represents a one-carbon moiety appended to the dienone skeleton by 1,2-addition of an appropriate nucleOphile (Nu-) to the carbonyl function of g1. These one carbon units must be suitable function- alized so that cyclization to the lactone, furan or lactol ring may be effected at a later stage. Oxidation of the diene system of gg should then provide a lactarane ses- quiterpene. Conversely, as in approach B, diene oxidation could be effected first, leading to intermediate g2. Lactone, furan, or lactol annulation would then proceed as in the case of gg. This is of course a simplified picture but it serves to illustrate three objectives which must be undertaken concerning the use of £4 as a functional lactarane synthon. 1. Reactions of the cycloheptatrienylate conjugate base of g% must be studied. 2. The reactivity of theketone.carbonyl present in %Z or ég towards nucleOphilic 1,2-addition must be examined. 3. Methods of oxidizing the diene moiety in %4 need to be studied, keeping in mind the stereoselec- tivity needed in these transformations. 86 I ) BASE 4 E 2) E e 25‘ .23 DIENE _ Noe OXIDATION I CC ‘O OH Nu 0' OXYGEN 2:? 2~ 8 ”82:": DIENE 2)E OXIDATION N..9 .a E a LACTARANES Q OXYGEN 339 Scheme II 87 1. Reactivity of the chloheptatrienylate Conjugate Base _gé) of Dienone %% The success of the lactone annulation will depend in part on how 8%, the cycloheptatrienylate conjugate base of £4, reacts with electrophilic reagents. The possibility that the bicyclic enolate ion will exist in equilibrium with a tricyclic enolate ion may pose a problem. This cyclo- heptatrienylate-norcaradienylate equilibrium was first studied by Corey21 (Equation 7). r _ __i, // ______, *__ I 3 O 0 // EUCARVONE L §! §? ‘ (7) RCOCI RX ” R OER / 3 a; 34 ~ Corey observed that when reactive electrophiles, such as acid chlorides, were added to the conjugate base derived 88 from eucarvone al, a cycloheptatriene product such as %% was obtained. However, reaction of i% with less reactive electrophiles, alkyl halides for example, gave the nor- carene product éé° In the present study, when %é was treated with lithium diisopropyl amide followed by addi- tion of trimethylsilyl chloride the expected cyclohepta- trienol silyl ether %9 was isolated. Similarly, reaction of 3% with methyliodide gave exclusively the alkylated hydroazulenic dienone %1 (Equation 8). TMSCI Mel —_’. CH3 (8) OeLiQ .' 36 35 37 ~ ~ ~ Although it is not possible to rule out a cyclohepta- trienylate-norcaradienylate equilibrium here, product an- alysis of %§ and £3 indicates that 8% reacts exclusively as the cycloheptatrienylate form at room temperature. The fusion of the geminally substituted dimethyl cyclopentane ring may impart sufficient rigidity or steric constraint so as to shift the proposed equilibrium to favor the cyclo- heptatrienylate isomer. 89 The reaction of 3% with trimethylsilyl chloride was rapid at 0°, but to achieve reaction with methyliodide it was necessary to reflux the reaction mixture for 0.5 hr. The lithium enolate gé, proved to be relatively unreactive with certain other electrophiles, failing to react with carbon dioxide, diethyl carbonate, ethylformate, and carbon disulfide. However, the sodium enolate, prepared by reac- tion of sodium hydride with g%, in glyme containing ethyl formate yielded the a-hydroxymethylene product 38 (Equa- tion 9). The formation of unidentified side products, Nah, glyme EtOCHO ’ .C— HOH (9) ‘O 2:3 as lack of reproducibility, and difficulties in product puri- fication complicated this reaction. Owing to the limited reactivity exhibited by gé, alkyla- tion reactions of the silyl enol ether %g were also studied. Alkylations of silyl enol ethers with trimethyl orthofor- mate in the presence of Lewis acids have been reported by numerous groupszza-C. In applying this method to the 90 present study, it was found that $8 reacts with trimethyl orthoformate in the presence of zinc iodide to give the B-ketoacetal %2 (Equation 10). Thus, in contrast to the HC(OCH3)2 / (10) . r CH(OCH ) OS?— l :5: 39 direct use of the enolate 8% as a nucleophile in reactions with a number of simple electrophiles, the alkylation of the silyl enol ether gé was an encouraging result. The synthesis of an intermediate of type gl, specifically product 8%, completed the first stage of this investigation. 2. Reactivity of the Unsaturated Ketonegé with Nucleophiles Following the introduction of carbon number 5 ("E" in Scheme II) by electrophilic attack on enolate 8% or enol ether éér the construction of the fused lactone or furan ring of the lactaranes requires a 1,2-addition of a suitably functionalized carbon nucleophile (Nu-) to £1, as shown in Equation 11. 91 N09 (11) IVU 27 OH Cyclization of the appropriately functionalized one carbon appendages "E" and "Nu" at some later stage of the synthesis completes the annulation. In order to examine the reactivity of this dienone system (21) towards nucleophiles, the unsubstituted dienone 2% was used as a model. It was found that 2% could be selectively reduced to allylic alcohol 3Q by the sodium 23 borohydride-cerium trichloride reagent (Equation 12) r —> 24 4O (12) 92 Addition of methyllithium to 2% also gave the 1,2-addition adduct 31 (Equation 13). CHBLi . ’ EtzC, -78 C CH3 (13) H 24 4I ~ ~ Unfortunately, stabilized nucleophiles, bearing sufficient functionality so as to be useful in the later planned cyclization, failed to add cleanly to 2%. Thus, addition of anions derived from phenyl chloromethyl sulfoxide24a-C, thioanisolezs, and dimethylsulfide26 to 2% gave only complex mixtures. The possibility of nucleo- philic 1,4- or 1,6-addition and enolization most likely complicate these reactions. 27is known to undergo Although dimethylsulfonium ylide exclusive 1,2-addition to unsaturated ketones, its reaction with 2% also proved complicated, perhaps due to instability of the resulting allylic epoxide. The reaction of tri- methylsilyl cyanide with 32 was equally disappointing. This reagent normally reacts with unsaturated ketones to give the corresponding unsaturated cyanohydrin TMS 93 derivatives28. However, no reaction was observed with 3% in the presence of a zinc iodide catalyst. These findings appear to limit the usefulness of approach A (Scheme II). Approach B, in which the diene system of 2% is modified prior to lactone annulation, was therefore investigated. Indeed, there is reason to believe that early transformation of the diene moiety in 2% may be ad- vantageous. For example, by establishing the proper oxi- dation state and stereochemistry of contiguous carbons 3-2-9—8 (Scheme I) as in lactarorufin A (1), the olefinic conjugation with the carbonyl group in 2% is removed, and nucleophilic additions to this function may be rendered less complicated. 3. Oxidations of the Diene Moiety ofgé and Attempts at Establishing the Ring Fusion Stereochemistry Three approaches for effecting oxidation of the diene system of 2% were investigated with varying degrees of 94 success: hydroboration with thexylborane, cycloaddition with singlet oxygen, and epoxidation with meta-chloroperoxy- benzoic acid. Cyclic hydroboration of 2% with thexylborane appeared to be an attractive method for converting the diene moiety into a cis 1,4-diol, with concommitant fixing of the ring fusion stereochemistry in the desired gig conformation. It has been shown that certain dienes react with thexyl- borane to yield cyclic boranes which can be oxidized to 1,4- diols, as shown in Equation 1429. A H H WBHZ 5 [0] \OH ’/’ (14) fi fi (CH2)20H a An equivalent cyclic hydroboration of 2%, after protec- tion of the carbonyl function, would provide an especially short and stereospecific procedure for establishing the desired configuration at four contiguous asymmetric carbons (Equation 15). In principle the protecting group in 32 (Z) should be as small as possible since models indicate that the gi§_ ring fusion forces the hydroazulenic skeleton to adopt a folded structure. Severe non-bonded interactions exist OH 1) Thexylborane Z4.“ ----- e ------------ 5 «U 2) Oxidation ‘2 Z :. protecting group OH 42 43 ~ ~ 09 --h?@2---. Knnulation l w between the methylene group of the cyclopentane ring and the protective group Z in such a compound (3%). %% Ketalization of 2% with ethylene glycol proceeded in an unsatisfactory fashion. The reaction of 2% in refluxing 96 benzene containing ethylene glycol and a catalytic amount of paraftoluenesulfonic acid gave a mixture (>3) of ketals. Double bond migration is often observed during the ketaliza- tion of unsaturated ketones, and is most likely occurring in this reaction. It has been reported that the use of weaker acid catalysts avoids this double bond migration. However, ketalization using fumaric acid30 as a catalyst also gave an unresolvable mixture of ketals. Since the carbonyl group of 2% could not be suitable protected, as in $2, the cyclic hydroboration of the un- protected ketone 2% was attempted. Thexylborane is known to react with ketones although at a rate slower than with olefins. However, reaction of 2% with thexylborane gave a complex mixture of products. Reaction of $1 with thexylborane was equally disappointing, again, a complex mixture of products was obtained. It has been reported that conjugated dienes are less reactive towards cyclic addition of thexylborane. In addition, the cyclic borane expected from reaction of thexylborane with a diene such as $2 results in the formation of a relatively strained intermediate. These two facts may account for the observed results with substrates 2% and 41. A promising alternative for the synthesis of gig 1,4- diols is the photo-sensitized oxidation of conjugated 31 dienes with singlet oxygen, first observed by Windaus . These reactions have been shown to proceed by 1,4-cyclo- 97 addition of singlet oxygen to give an endoperoxide inter- mediate (Equation 16). Subsequent reduction of this OH 6) '02 . [R] 4 4 \ o ( 1 6 ) OH intermediate provides a good general method for the intro- duction of cis hydroxyl groups at the terminal carbon atoms of a conjugated diene. Indeed, the role of endoperoxides in synthetic chemistry has increased dramatically in the last few decades32. Reactions of singlet oxygen with olefinic substrates often are complicated by alternative modes of reactivity. The three most common modes of reaction of singlet oxygen with olefins are: 1,4-cycloaddition (A) forming endoper- oxides, the ene reaction (B) leading to hydroperoxides, and [2+2] cycloaddition to activated olefins (C) resulting in the formation of 1,2-dioxetanes (Scheme III). In practice, competition among these three kinds of reactions is often observed, the structure of the substrate being an important factor in determining the product 98 1 ; I + 02 | ‘\\\ l,#-cycloaddition (D ‘V’ H ‘+’ H32 'The" 9' OOH Scheme III 99 distribution. It is generally accepted that for a conju- gated diene fixed in a cisoid fashion, the energy of activa- tion for 1,4-cycloaddition is near zero. The ene reaction appears to be electrophilic in nature, and as a rule, tetrasubstituted double bonds react nearly as rapidly as 1,3-cyclohexadienes, whereas tri-, di-, and monosubstituted double bonds react more slowly. Consequently, if a sub- strate incorporates both a conjugated diene and a tetra- substituted double bond, a mixture of hydroperoxide and endoperoxide products may be obtained. This situation is realized in the reaction of singlet oxygen with_dienone 2%. Cycloaddition to the diene moiety is desired in order to effect the gig hydroxylation needed for a synthesis of lactarorufin A. Such a reaction has in fact been observed 33 for the similar cycloheptadienone %% (Equation l7). (l7) HOO 100 The exclusive formation of the endoperoxide 49 is readily rationalized. The double bonds of the diene system in 3% are disubstituted and thus less likely to participate in an ene reaction. Furthermore, the only possible ene product, gé, has a strained double bond. Both 2% and 3% have an electron withdrawing carbonyl function conjugated with the diene system. This conjugation should in prin- ciple deactivate the diene systems in reactions with electrophilic reagents. In the present study, photo- oxidation of 2% in acetone, with hematophorphyrin as a sensitizer yielded two crystalline products, as shown in Equation 18. 24 47 (497. ) 43 (427.) Although endoperoxide $1 is the major product, the isomeric hydroperoxide $8 is formed in only slightly lower yield. Interestingly, 38 is only one of four possible 101 ene" products derived from reaction at the four different allylic sites available in 2% (gg-gl). 3 H00 ? HOO i ll '\ - HOO 3% 3% 22 We a» Hydroperoxide 38 comes from an ene reaction at the most electron rich double bond in 2% (i.e., the most sub- stituted and most removed from the carbonyl function). In addition, this hydroperoxide product (£8) maintains a fully conjugated dienone system unlike £2, SQ or 91. Thus, product stability helps to lower the energy of activation for the reaction leading to Q8. This conclusion is supported by the observation that photo-sensitized oxidation of alcohol 31 yielded only a mixture of ene products. Clearly, the CH3 H 5&0 102 the carbonyl function in 22 has a dramatic effect upon the reactivity of the diene system with singlet oxygen. The hypothesis that the carbonyl function would deacti- vate 2% towards participation in an ene reaction appears to be true to an extent. However, the established re- activity of tetrasubstituted double bonds in "ene" reac- tions continues to be a significant factor, as the forma- tion of $2 demonstrates. In 1981 Matsumoto34 reported an interesting solvent effect in reactions of acyclic conjugated dienes with singlet oxygen. Prior to this report, no study involv— ing the solvent dependency of the ene reaction versus the cycloaddition reaction had been published. For a number of simple acyclic dienes, Matsumoto found that carbon tetrachloride was the best solvent for the 1,4- cycloaddition reaction. It appears that the cycloaddi- tion process is more sensitive to the lifetime of singlet oxygen than the ene reaction, since singlet oxygen is known to have a considerably longer lifetime in carbon tetrachloride than in other solvents such as simple alcohols or ketones. In an effort to maximize the yield of endoperoxide 22, a study of the solvent dependency of the photo-sensitized oxidation of 2% was carried out (Table 1). Surprisingly, carbon tetrachloride favored the ene reaction. Overall, the photo-sensitized oxidation appeared to exhibit little dependency on the solvent or the sensitizer. 103 Table l. Solvent Effect in the Reaction of Singlet Oxygen With 2%. . . a Relative Ratio: Solvent Sensitizer 42 42 b Acetone None NR Acetone Hematophorphine (HP) 1.16 l Acetone Rose bengal (RB)C l 1 Carbon Tetrachloride HP 1 1.5 Carbon d Tetrachloride HP 1 2.3 Carbon Tetrachloride Tetraphenylphorphine l 1.5 Ether HP NR Ethyl Acetate HP 1 1.08 Methanol RB l l Methanol HP 1 1 aReaction times varied from 2-12 hours for completion. b was detected. After extended periods >24 hrs a small amount (<10%) of 22 CAn unidentified product (10%) was isolated. dReaction performed at 0°. 104 The yield of endoperoxide 22 is moderate but accep- table, considering that the terminal carbon atoms of the diene system have undergone the gig-oxidations. Unfor- tunately, efforts to reduce 22 to the corresponding diol proved unsatisfactory. Various methods exist for the reduction of endoperoxides and these can be classified into three types (Scheme IV). OH A o C (r : I ‘9 0H CATALYTIC o DIIMIDE o B CHEMICAL ‘7 OH. OH Scheme IV 105 Thus an unsaturated endoperoxide can be converted to the saturated 1,4-diol (A) by catalytic reduction, or to the unsaturated allylic 1,4-diol (B) by chemical reduction of the peroxide bond, or to the saturated endoperoxide (C) by selective reduction of the carbon-carbon n bond with di- imide35. In particular, the latter reaction seemed to offer an ideal first step in transforming £2 for a lactarane synthesis. Reduction of olefinic bonds with diimide, generated by the acid decomposition of potassium azodicarboxylate, has been extensively studied36. These reductions are presumed to proceed by a "synchronous transport" of hydrogen through 37a-c a cyclic transition state (Equation 19). H I \/ ‘F .H / W / N c 'f‘ (i/ H—C/ H + H ‘—"‘ i 3 -—'N2 + i (19) N c N“~H/’C\‘ H‘ t A / \ _ J Not surprisingly, the reduction with diimide is quite sensi- tive to steric factors. Models indicate that the oxygen bridged side of 32 is considerably less hindered than the carbon bridged side. Consequently, reduction from the 106 peroxide bridge side should establish the desired stereo- chemistry at the ring junction, leading eventually to a synthesis of lactarorufin A or another of the lactaranes (Equation 20). Diimide reductions are normally observed to be smooth and selective reactions. The presence of other functional groups, such as halogens, carbonyls, and esters do not normally interfere with olefin reductions. Unexpectedly, the endoperoxide 22 proved to be very sensitive to the conditions of diimide reduction, yielding only a complex mixture of products in methanol, dioxane, pyridine, or dimethylsulfoxide solutions.36 Owing to the reactive nature of 22, initial reduction of the peroxide linkage, as in approaches (A) and (B), was next explored in the hope of achieving an intermediate more amenable to subsequent manipulation. Catalytic re- duction of 32 over 10% palladium on charcoal in ethyl acetate 107 gave only an unresolvable mixture of compounds. This result was not altogether unexpected since the peroxide linkage in 22 would certainly undergo reductive cleavage before olefin reduction, and without an intact peroxide bridge both faces of the double bond will be accessible to the addition of hydrogen. Hydrogenolysis of the initially formed allylic l,4-diol and hemiketal formation may also be complicating factors in this reaction. Chemical reduc- tion of the peroxide bridge with triphenyl phosphine38 or thiourea was expected to give the unsaturated allylic l,4-diol, but this also proved unexpectedly complicated. It has been observed that peroxides are sensitive to base. Kornblum and de-la Mare first reported a base- catalyzed decomposition of a dialkyl peroxide in 195139. Bases such as potassium hydroxide, alkali metal alkoxides, or piperidine were found to catalyze the decomposition of l-phenylethyl-tert-butyl peroxide Q2 as shown in Equation 21. I“ e ’0’_ CjO-{P-C(CH3)3 —'* 58'0713 + 0—C‘CH3)3 (In lBH 9 B (21) 53’ HO-C(CH 393 Application of this mechanism to unsaturated endoperoxides would predict the formation of hydroxy-enones. This 108 potentially useful synthetic pathway has been confirmed for 40a-c. In the present case, treat- a variety of endoperoxides ment of endoperoxide 22 with triethylamine gave the bridged hemiketal 2% as a stable crystalline substance (Equation 22). CH3 ‘i ET3N 4 (22) ‘WOH 54 ~ It was hOped that this hemiketal (22) would lend itself to stereoselective double bond reduction more readily than the isomeric endoperoxide (22). Methods for the reduction of a,B-unsaturated ketones to saturated ketones are well documented41a'b. In the present case it was assumed that reduction of the double bond by diimide or the catalytic addition of hydrogen would proceed from the least hindered oxygen bridged side. Such reduc- tions were carried out, either with the free hemiketal (E3) or the acetate derivative (éé). The latter was prepared by the reaction of 2% with acetic anhydride in pyridine containing a catalytic amount of 4-dimethylaminopyridine (Equation 23). 109 %“3 g . (23> " VOAc. q 5'25} 55 Attempted diimide reductions of 2% or 22 in methanol or pyridine solution were ineffective, with only starting material being recovered. Likewise, numerous efforts to effect catalytic reduction of these compounds (Table 2) failed to give the desired dihydro gig-fused products. At some stage in any proposed lactarane synthesis pro- ceeding from intermediate 2%, it would be necessary to reduce the carbonyl group. Reduction of 22 with sodium borohydride-cerium trichloride reagent23 gave a single product 9Q, in which the hydroxyl group was assigned the a-configuration on the assumption that reduction took place from the less hindered oxygen bridged side of the carbonyl group. Although this is the wrong 110 .Umppm mmB mfiom oaumom mo mono Ho .Awomv mHmEomH powMflucwpflcs o3u m0 musuxflzn .COHuommH O: u mzm mz m = em moms Ha\nm ww mnsuxae xmamsdo m Sum H em oaoum O\pm woa ww m2 m ama om em oaoum O\cm woa ww mz v = em omomz . H<\nm ww mz m = am now: OIom\wm ww m2 m = come- em oHOm unwamumu mumuumnsm cofluommm 8 8 .88 .mw paw mw am mo mcofluospmm Oflumamumu pwumfimuu< mo muasmmm .N OHQMB 111 configuration for lactarorufin A, it was proposed that 56 might be useful as an intermediate in a synthesis of Furo- scrobiculide B, 2 (Equation 24). Unfortunately, the 55 56 HO 9'3 SCH?) . C -------- D \ ‘1 ‘7/ HO OAc ZN catalytic reduction of 22 proved to be exceedingly complex with 10% palladium on charcoal and ineffective with rhodium on alumina (Table 2). Before the preparation of 22 had been achieved, efforts were made to convert Q4 to a methyl ketal derivative. In refluxing methanol containing a little pftoluenesulfonic acid, 2% did not undergo any significant reaction. However éé did react in refluxing methanol containing one drop of sulfuric acid and yielded a single product having a A: '- 112 molecular weight of 178. The presence of a methyl doublet centered at 6 = 1.12 ppm (J = 7.2 Hz) and two singlets at 6 = 1.09 and 6 = 1.10 ppm, and in addition, a strong carbonyl absorption at 1650 cm.1 observed in the infrared spectrum supports the assignment of structure 92 for this product (Equation 25). 9 H3 H CH30H , ’ . (25) A I o 593} 5.3 In the presence of strong acid 2% appears to suffer the loss of carbon dioxide. A plausible mechanism for this novel transformation is illustrated in Scheme V. It is interesting to conjecture, based on the struc- tural similarity of Q2 with the recently discovered class of sesquiterpenes known as the alliacanes, the possibility of using 22 as an intermediate for the synthesis of a natural product such as alliacolide 2242 (Equation 26). Alliacolide 58 was isolated from the Basidiomycete Marasmium Alliaceus. The biogenesis of the alliacane skeleton has yet to be established but it is significant 113 I,2— SHIF fi (1 -C02 . —~ 57 RETRO ~ + HO [2 4] Scheme V CH3 gH3 ’ i CH3 (2m §"'Iz CH3 ALLIACOLIDE £18 114 that the alliacanes contain the same geminally substituted dimethyl cyclopentane ring commonly found in the sesquiter- penes isolated from Basidiomycetes. As with the lactaranes, evidence has been obtained which indicates that the allia- canes could arise from farnesyl pyrophosphate via a humulene intermediate43. The last oxidation method explored in this study was the selective epoxidation of the tetrasubstituted double bond of 22 with mfchloroperoxybenzoic acid to give 22 (Equation 27). MCPBA —> (27) CHC|3 Time permitted only a preliminary investigation involving the use of 22. It was proposed that 22 may be a useful intermediate for the synthesis of furoscrobiculide B (Equa- tion 28). A crucial step would invole the regio- and stereospecific reduction of 22 to the homoallylic alcohol 22. Attempted catalytic reductions with palladium on calcium carbonate or palladium on charcoal were complicated. Z = 0,protective group 59 ~ 115 HE‘S. ‘ ‘1 EXPERIMENTAL General Except as indicated, all reactions were conducted under dry nitrogen or argon, using solvent purified by distilla- tion from suitable drying agents. Magnetic stirrers were used for small scale reactions; larger reactions were agi- tated by paddle stirrers. Organic extracts were always dried over anhydrous sodium sulfate or anhydrous magnesium sulfate. The progress of most reactions was followed by thin layer chromatography and/or gas liquid chromatography. Visualization of the thin layer chromatograms was effected by 30% sulfuric acid with subsequent heating. Analysis by GLPC was conducted with a Varian 1200 gas chromatograph. Melting points were determined on a Hoover- Thomas apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 237B grating spectrophotometer. Proton magnetic resonance spectra were taken in deutero- chloroform solutions with either a Varian T-60 or a Bruker 250 MHz spectrometer and are calibrated in parts per mil- lion downfield from tetramethylsilane as an internal stan- dard. Carbon-l3 NMR spectra were taken in deuterochloro- form solutions on the Bruker 250 MHz spectrometer using tetramethylsilane as an internal standard. Mass spectra 116 117 were obtained with a Finnigan 4000 GC/MS spectrometer. Preparation of 23 fl’b One liter of ammonia was condensed in a carefully dried two-liter, three-neck, round bottom flask containing 75 mL of tetrahydrofuran, one-tenth gram of lithium wire, and equipped with a mechanical stirrer, an addition funnel, a dry ice condenser, and cooled by a dry ice-acetone bath. An additional 1.02 g (147 mmol) of lithium wire was added to the stirred blue solution, followed by dropwise addition of a solution of 12.0 g (59.3 mmol) of 2% dissolved in 150 mL of tetrahydrofuran: This reaction mixture was stirred an additional 0.5 hr and was then quenched by careful ad- dition of approximately 3 g of solid ammonium chloride. The cooling bath was removed and the ammonia was evaporated under a stream of nitrogen. The residue was diluted with 500 mL of ether and washed with water, saturated brine, and dried over sodium sulfate. Evaporation of the ether gave 1H NMR to be 90% 11.9 g of a yellow oil which was judged by pure, containing approximately 10% of enedione 22. This crude cyclopropanol was immediately dissolved in 35 mL of cold pyridine (0°C) and added to a solution of 7.0 mL (90 mmol) of freshly distilled methanesulfonyl chloride dissolved in 35 mL of cold pyridine, containing 0.5 g (4.0 mmol) of 4-dimethylaminopyridine. This mixture was stirred overnight at 0°C, poured into 400 mL of ice water, 118 and extracted twice with 500 mL portions of ether. The organic layer was washed successively with 2% hydrochloric acid and saturated sodium bicarbonate solution, and dried. Evaporation of the solvent gave a crude solid which was triturated with cold ether and filtered to give 11.0 g (65% from 22) of 22 as a white powder, mp 101-103 with de- composition (ether). Agal. Calcd. for C H O S : C, 58.71; H, 7.74; 14 22 4 Found : C, 58.54; H, 7.75. Preparation of 2% To 20 mL of trifluoroacetic acid was added 2.0 g (7.0 mmol) of 22. This solution was stirred for 0.5 hr at room temperature, poured into 100 mL of water and extracted with 100 mL of ether. The ethereal layer was washed with 100 mL portions of saturated sodium bicarbonate solution until carbon dioxide evolution ceased, and dried. Evapora- tion of the solvent followed by column chromatography (sili- ca gel, 25% ethyl acetate/hexane) gave 1.18 g (91%) of 24 as a light yellow oil, (Amax 95% EtOH = 315, e = 6250). Anal. Calcd. for C H O: C, 82.13; H, 9.53; 13 18 Found : C, 81.92; H, 9.47. Preparation of 36 ’b’b A solution of 2.4 mmol of lithium diisopropyl amide was prepared by addition of 0.26 mg (2.6 mmol) of diisopropyl 119 amine to a cold (0°C) solution of 1.6 mL (2.4 mmol) of 1.5 M n-butyllithium in 5 mL of hexane. This mixture was stirred at 0°C for 10 minutes, the ice-bath was removed, and the solvents and excess amine were evaporated under reduced pressure, leaving a white solid. After purging the product with argon and recooling to 0°C, the amide was dissolved in 2.5 mL of tetrahydrofuran, following which a solution of 418 mg (2.2 mmol) of 2% in 1 mL of tetrahydrofuran was added. After a ten minute reaction period, 0.32 mL (2.4 mmol) of trimethylsilyl chloride was added, the mixture was stirred 5 minutes and the solvent was removed under vacuum. The residue was dissolved in 20 mL of pentane, filtered, and evaporated to yield 536 mg (93%) of 22 as a yellow oil. Methylation of2g To 2.2 mL (0.88 mmol) of a 0.4 M solution of lithium diisopropyl amide in tetrahydrofuran cooled to 0°C was added a solution of 0.13 g (0.7 mmol) of 2% dissolved in 1 mL of tetrahydrofuran. After stirring 10 minutes, 140 mg (1.0 mmol) of methyliodide was added and the reaction mix- ture was warmed to room temperature and then refluxed for 30 minutes. After cooling, the reaction mixture was diluted with 30 mL of ether, washed successively with water and saturated brine, and dried. Evaporation of the solvent and column chromatography of the residue (silica gel, 20% ethyl acetate/hexane) gave 0.12 g (82%) of 22 as a yellow oil. 120 Formylation of 2% To a slurry of 51 mg (2.12 mmol) of sodium hydride in 2 mL of ethyl formate was added a solution of 100 mg (0.53 mmol) of 2% dissolved in 1 mL of dimethoxyethane. This reaction mixture was stirred for 1.5 hrs, poured into ammonium chloride solution, extracted with ether, and dried. Evaporation of the solvent gave a dark-red oil which was distilled (kugelrohr Bp.05mm = 150-160°C) to obtain 35 mg (30%) of 22 as a red oil. Proton NMR indicates 22 exists as a mixture of Z and E isomers in a 2:1 ratio. Reduction of 24 ._mm To 4.6 mL (1.84 mmol) of a 0.4 M solution of cerium(III) chloride in methanol was added 0.35 g (1.84 mmol) of 22. To this stirred solution was slowly added 69.3 mg (1.8 mmol) of sodium borohydride, and after stirring for 5 minutes, the reaction mixture was hydrolyzed, extracted with ether, and the ethereal layer washed with saturated brine and dried. Evaporation of the solvent followed by column chromatography of the residue (silica gel, 40% ethyl acetate/ hexane) gave 0.28 g (80%) of 22 as a colorless oil. Preparation ofp22 To a solution of 0.97 g (3.67 mmol) of 22 dissolved in 20 mL of dry trimethyl orthoformate was added 1.28 g (4.0 mmol) Tl===‘ifl 121 of zinc iodide. This mixture was stirred for 1 hr, diluted with 100 mL of ether, washed with 100 mL portions of water and brine, and dried. Evaporation of the solvent followed by chromatography (MPLC, silica gel, 25% ethyl acetate/ hexane) gave 0.86 g (85%) of 22 as a yellow oil. Anal. Calcd. for C H O : C, 72.69; H, 9.15; 15 24 3 Found : C, 72.31; H, 9.09. Preparation of $2 To a stirred solution of 90 mg (0.47 mmol) of 2% dis- solved in 1.5 mL of ether and cooled to —78°C was added 0.34 mL (0.51 mmol) of a 1.5 M solution of methyllithium in ether. The reaction mixture was warmed to room tempera- ture, stirred an additional one hour, and quenched with saturated ammonium chloride. The ethereal layer was washed with water and brine, and dried over sodium sulfate. Evap— oration of the solvent followed by chromatography (MPLC, silica gel, 25% ethyl acetate/hexane) gave 75 mg (77%) of 22 as a pale yellow oil. Photo-Oxidation of 22 To a solution of 190 mg (1.0 mmol) of 22 in 15 mL of acetone was added 10 mg of hematoporphyrin. This solution was irradiated with visible light (200 watt bulb), while oxygen was slowly bubbled through the solution. The re- action vessel consisted of a 25 mL side-arm test tube 122 fitted with two septa. Oxygen was introduced into this system through a syringe needle fitted through the top septum and bubbled directly into the acetone solution. An additional fine bore needle fitted through the side arm septum provided a vent for the escape of oxygen. Occasion- ally, acetone was added to the reaction mixture to replace that which had been lost to evaporation. After approxi- mately 10 hrs, the reaction mixture was evaporated under reduced pressure to yield 230 mg of a semisolid residue, which was chromatographed (silica gel, 50% ethyl acetate/ hexane) to give 110 mg (49%) of 22 as white solid, mp, 67.5-68°C (hexane), and 93 mg (42%) of 22 as a white crystal- line solid, mp, 133.5-134.5°C. 22 Apal. Calcd. for C H O : C, 70.24; H, 8.16; 13 18 3 Found : C, 70.34; H, 8.21. Base Treatment ofpéz To a solution of 100 mg (0.45 mmol) of 22 dissolved in 5 mL of methylene chloride was added 4.5 mg (0.45 mmol) of triethylamine. This solution was stirred at room tempera- ture for 1 hr, following which the solvent and amine were removed under reduced pressure, yielding 100 mg (100%) of 22 as a white solid, mp 106-108° (hexane-ethyl acetate). Apgl. Calcd. for C H O : C, 70.24; H, 8.16; 13 18 3 Found : C, 69.92; H, 8.16. 123 Acetalization of 54 11A; To a solution of 1.5 mL of acetic anhydride in 1.5 mL of pyridine, containing 5.0 mg of 4-dimethylaminopyridine, was added 100 mg (0.45 mmol) of 2%. This mixture was stirred for one hour at room temperature, poured into 20 mL of water and extracted with ether. The ethereal layer was washed successively with 2% hydrochloric acid and saturated sodium bicarbonate solutions, and dried. Evaporation of the solvent gave 105 mg (88%) of 2% as a white sOlid. Re- crystallization from hexane gave pure éér mp 112-113°C. Anal. Calcd. for C H O : C, 68.16; H, 7.62; 15 20 4 Found : C, 68.23; H, 7.66. Reduction of 5% To 5.6 mL (2.28 mmol) of a 0.4 M solution of cerium(III) chloride dissolved in methanol was added 200 mg (0.76 mmol) of 22. To this stirred solution was added 86.0 mg (2.28 mmol) of sodium borohydride over a 2 minute period. After stirring 5 minutes, the reaction mixture was hydrolyzed, extracted with ether, and the ethereal layer was washed with brine, and dried. Evaporation of the solvent gave 198 mg (99%) of 22 as a colorless oil. Acid Treatment of 22 A solution of 10.0 mg (0.045 mmol) of 2% dissolved in 20 mL of methanol containing one drOp of concentrated 124 sulfuric acid was refluxed for five hours. The reaction mixture was cooled, diluted with ether, washed with satu- rated sodium bicarbonate solution, and dried. Evaporation of the solventand chromatography of the residue (MPLC, silica gel, 25% ethyl acetate/hexane) gave 7.0 mg (87%) of 22 as a clear oil. Epoxidation of_2é To a solution of 4.8 g (25 mmol) of 2% dissolved in 100 mL chloroform was added 10.1 g (50 mmol) of m-chloro- peroxybenzoic acid (85%). This solution was stirred for one hour at room temperature, washed successively with water, 10% sodium sulfite and saturated sodium bicarbonate, and dried. Evaporation of the solvent followed by column chromatography of the residue (silica gel, 25% ethyl ace- tate/hexane) gave 4.1 g (80%) of 59 as a clear oil. Anal. Calcd. C H O : C, 75.69; H, 8.79; 13 18 2 Found : C, 75.51; H, 8.74. APPENDIX II: SPECTRA PART II .mm mo mH .auHH mnsmaa 1. S. .11 1.1211315. oer-N 00mm (O/OHDNVIIIWSNVHI 125 O .I. (411141 III-IIIIIJIII 114(th . a . a _ .IJ . 4 1 1 . .1 a .1 1. 1. fl 1.1 J_I c 1 . . . m . 1 1 . . a . . N 4 4 . . 4 u . 1 1 _ 1 . 1 1 1 _ 1 1 1 1 1 . . _ 1 1 1 . 1 1 1 . 1 . . . 1 1 . . 1 -1 .. -1. 1 1 .1 - ...-I: :1 1 _. 1 1 1 1 . 1 1 1 1 1 1 1 1 . 1 . . 1 _ 1 1 _ 1 .1 -1 .1. 1 4 - m 1...1-I...-1I .... I1 - I. . 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SC. > .2303. 00m ocop Dog 00: 000— com, ooom om ca 1 MO O7 ow w S w” n“ l V 00 co N D 3 mm am on om oo. - -1 - 1w ...1._71111 .1.oo_ od— o~_.v._ Qo. 2.0mu2<.vm ox c6 oh 193 Nmmv L com 09 am" .om mo enhpommm mmmz DthD F om Eb..- mam : q mu: PP PD—LIDPP?DDP—Prbbb11rPP l 1 ‘4 ‘ mm: m: mm: we: ow. fi_. 7: d _m . mm mm mm om .NBIHH mnsmwm mv >+F h m\: Iodm 10.03 194 .mn mo mzz nopoum .mmuHH musmwm .195 .mm mo mzz mflucopnmo .amuHH musmwa - «O1 111 1 11 1 1 On 09 Ean Omp OON — — — <4—1111—1114—1111—1111—1411—<111_1114—1111—1I1141111_1441—1111—1114—1111_<114—1111~1111_4111—. REFERENCES l. 2. REFERENCES For a comprehensive review of terpenoid mushroom metabolites isolated from Basidiomycetes see W. A. Ayer and L. M. Browne, Tetrahedron, 2199 (1981). (a) (b) (C) (d) (e) (f) (a) (b) (C) (d) (e) (f) (g) F. Kavanagh, A. Hervey, and W. J. Robbins, Pro. Natl. Acad. Sci. U.S.A., 3%! 343 (1949). J. J. Dugan, P. de Mayo, M. Nisbet and M. Anchel, J. Am. Chem. Soc., 82, 2768 (1965). J. J. 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