'WW'W'WW'W1 77W” “\r u):l't'zf'lmflliwgt’h‘prhy'1’.‘fian‘f} I." ‘ ' I 3‘ I' L" " "3". Ir“ ‘u' - . ,1 4 I ll 1‘.‘51."%”t" '. w.*\.'-v51'.’;r"{H‘i.‘!~“*’"r" .u'. :51 Mn -' m m»: -. § V“ J... M‘- ‘ .5"! film“ W I (‘ “1' Liv" ‘0: b 1' "J'o' :0 ‘r \' PIS-11"?!“ 3 ,— M u "T." n "’7 M A . ~r . "TI-:V‘F‘" _..'n" u A ($1, .‘ 3m: ‘. A" .hJ . 111‘ “'5'..le S}. . A" A ”it no. i 2 z {131‘ L M i 1 ., I" ' mi .. l . :: \ ‘ 9".“ 1‘ mac. v . ....... « -'.. I. n I fail. “£0‘111,.-..L J‘I -,“ I. *' . .h {‘ L'. ' "I “ ‘ ‘ v"': ,-2 nu, ‘ , .l‘ T 1‘: "'1 .‘x';' u ‘-“1_ "1' “' NEW-1 r. ' '7.“ I. -‘3t1;-‘..t..1lfl‘x 3‘ _ ,1 1‘. {V ‘l I‘Uf’f.‘ ' ,yu ‘. ' v-I.‘ “vi“.‘H: f2. ! .1: “.‘T 7" 1‘ ‘ '1} 4 "' Ml It! {hr}. " ll 1’ W‘ "w" '1‘ . Mm“; 1.1m .' "2.;‘3.2«:':.,:'1*;;~_ .' :“1 |'.u:;1ii: If: 1 “I":‘Vllylll-Lu' ":1th H" - 72L“ - .I'o' ‘.‘ 1“"an 1;. ‘I‘. ain’t“ . "3 -1' f v 'V: "._ ’ H ":17 “1“" it I'm “‘1 ‘ I: »' '0'. “W. 4" . ' 0' "all : vamdlmli “.1 1'le Stir MIMI hutmrkfifm?!‘h'l’n‘lmfllbl ' lnhnflfpm‘N'hyfiflghMl Wests This is to certify that the dissertation entitled A MODEL FOR TETRACYCLIC TRITERPENE SIDE CHAIN SYNTHESIS presented by Joseph Renato Gibson has been accepted towards fulfillment of the requirements for degree in Chemi Strl Mn W Major professor Doctoral Date (If/Kg '12! ”81 012771 MS U is an Affirmative Action/Equal Opportunity Institution MSU LIBRARIES m V RETURNING MATERIALS: Place in book drop to remove this checkout from your record. FINES will be charged if book is returned after the date stamped below. A MODEL FOR TETRACYCLIC TRITERPENE SIDE CHAIN SYNTHESIS By Joseph Renato Gibson A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1982 ABSTRACT A MODEL FOR TETRACYCLIC TRITERPENE SIDE CHAIN SYNTHESIS By Joseph R. Gibson Although the hindered carbonyl function in Bragg-1,6- dimethyl-2-methoxybicyclo[A.3.0]nonan-7-one é resists nucleo- philic addition and is prone to enolate formation, good yields of addition products from trimethylsilyl cyanide, methylenetriphenylphosphorane and crotyl magnesium bromide were obtained. Partial success in controlling the stereo- selectivity of the latter reaction was achieved by lowering the temperature to -lOO°. Efforts to transform the methallyl adduct 3 to a 08H17 terpenoid side chain failed because of a facile methyl shift in the course of dehydration of the tertiary alcohol. The nature of this rearrangement was demonstrated by conversion of the rearranged olefin IQ to the unsaturated ketone Ix. All efforts to transform the trimethylsilyl cyanide adduct IQ failed to produce a useful product. Introduction of the terpenoid side chain Joseph R. Gibson was eventually accomplished by conversion of § to the @- ethylidene derivative 28, from there to the ZB-acetyl inter- mediate gg, and finally to a mixture of side chain epimers gfi by a Wittig condensation followed by hydrogenation. The ratio of epimers in the mixture was found to be 2:1 by carbon-l3 NMR and gas chromatography. Interesting stereo- chemical differences in reactions of a and its derivatives compared with the steroid analogs are noted. For my parents, for their love and support even when they didn't really understand. ii ACKNOWLEDGMENTS The author wishes to express his deepest apprecia- tion to Dr. William Reusch for his guidance and friend- ship. His suggestions were invaluable and he always seemed to be present when needed. He has contributed greatly to my professional development. Thanks are extended to my colleagues for their friendship and humor; it made the going easier. Especially enjoyable were the lunch time round table discussions about life, chemistry, and whatever, that often extended into the afternoon. Finally, the author would like to thank Michigan State University for financial support. iii TABLE OF CONTENTS Chapter LIST OF TABLES. LIST OF FIGURES INTRODUCTION. RESULTS AND DISCUSSION. EXPERIMENTAL. General 6-methy1- 5- -hydroxytricyclo- [A.A .0. OJdecan-9- -one. trans- 1,26- dimethylbicycloEA. 3. O]- nonane- b7 dione I. . trans-1,6- dimethyl- -2- -hydroxybicyclo- [A.3.0]nonan-7-one g. . . . . . trans-l,6-dimethyl-2-methoxybicyclo- [A.3.0]nonan-7—one I. Homoallylic Alcohol I . . . . . Isomeric diols g. Methoxy alcohol 6 . Aldehyde I. . . . . . Alcohol Q . . . . . . . . . . . Mesylate 2. . . Methoxy olefin IQ Alcohol II. . . . . Methoxy ketone Ig . Diene I3. . . . . Monoolefin IA . . . . . . . Alcohol IQ. Methoxy ketone I6 iv Page vi . vii 17 AA “5 A6 A6 A7 A7 A8 A9 A9 50 50 51 51 51 52 52 53 53 5A Chapter Page Methoxy enone II. . . . . . . . . . . . . . 5A trans-1,6-dimethyl-7-c ano—7—trimethyl- siloxy-2-methoxybicyclo[A.3.0]nonane Q. . . 55 trans-l,6-dimethyl-7-methylene-Z- methoxybicycloEA.3.0]nonane I2. . . . . . . 56 E-7-ethylidene-trans-1,6-dimethyl- 2—methoxybicycloEA.3.0]nonane g8. . . . . . 56 Alcohol II. . . . . . . . . . . . . . . . . 57 Methoxy ketone g3 . . . . . . . . . . . . . 57 Olefin g3 . . . . . . . . . . . . . . . . . 58 Methoxy alkane IA . . . . . . . . . . . . . 59 APPENDIX I . . . . . . . . . . . . . . . . . . . . 60 APPENDIX II . . . . . . . . . . . . . . . . . . . . 62 REFERENCES. . . . . . . . . . . . . . . . . . . . . 119 Table LIST OF TABLES Transition States That Lead to A.. Low Temperature Experiments. . Attempted Reactions of IQ. . . . vi Page 20 23 33 LIST OF FIGURES Figure Page 1 Representative tetracyclic triterpenes . . 3 2 Representative side chains . . . . . . . . 9 3 Stereospecific side chain syntheses. . . . 15 A Possible stereoisomers of A. . . . . . . . 21 5 Euphenol 130 chemical shifts . . . . . . . A0 6 Dihydrolanosterol 13(3chemical shifts . . . . . . . . . . . . . . . . . . Al 7 130 chemical shifts of g5. . . . . . . . . A2 8 Mass spectrum of I . . . . . . . . . . . . 63 9 Proton NMR of I. . . . . . . . . . . . . . 63 10 Mass spectrum of 2 . . . . . . . . . . . . 6A 11 Proton NMR of g. . . . . . . . . . . . . . 6A 12 IR of I. . . . . . . . . . . . . . . . . . 65 13 Mass spectrum of 3 . . . . . . . . . . . . 66 1A Proton NMR of 3. . . . . . . . . . . . . . 66 15 IR of Q. . . . . . . . . . . . . . . . . . 67 16 Mass spectrum of I . . . . . . . . . . . . 68 17 Proton NMR of I. . . . . . . .V. . . . . . 68 18 IR of §g . . . . . . . . . . . . . . . . . 69 19 Mass spectrum of 2%“ . . . . . . . . . . . 70 20 Proton NMR of fig . . . . . . . . . . . . . 7O vii Figure 21 22 23 2A 25 26 27 28 29 30 31 32 33 3A 35 36 37 38 39 A0 A1 A2 A3 AA A5 Carbon-l3 NMR of 2a. IR of IQ . . . Mass spectrum of IR. Proton NMR of IQ . . Carbon-l3 NMR of IR. IR of Q. . . Mass spectrum of 6 . Proton NMR of 6. Carbon-l3 NMR of 6 . IR of I. . . Mass spectrum of I . Proton NMR of I. . . IR of 8. Mass spectrum of 8 . Proton NMR of 8. . . Carbon-13 NMR of 8 . Proton NMR of 2. . . IR of IQ . . . . Mass spectrum of IQ. Proton NMR of IQ . . IR of II . . . Mass spectrum of II. Proton NMR of II . . Carbon-13 NMR of II... IR of II . . . . viii Page 71 72 73 73 7A 75 76 76 77 78 79 79 80 81 81 82 83 8A 85 85 86 87 87 88 89 Figure Page A6 Mass spectrum of II. . . . . . . . . . . . 90 A7 Proton NMR of II . . . . . . . . . . . . . 90 A8 Carbon-13 NMR of II. . . . . . . . . . . . 91 A9 IR of II . . . . . 92 50 Mass spectrum of II. . . . . . . . . . . . 93 51 Proton NMR of I3 . . . . . . . . . . . . . 93 52 IR of II . . . . . . . . . . . . . . . . . 9A 53 Mass spectrum of II. . . . . . . . . . . . 95 5A Proton NMR of II . . . . . . . . . . . . . 95 55 IR of IQ . . . . . . . . . . . . . . . . . 96 56 Proton NMR of I5 . . . . . . . . . . . . . 97 57 IR of IQ . . . . . . . . . . . . . . . . . 98 58 Mass spectrum of IQ. . . . . . . . . . . . 99 59 Proton NMR of IQ . . . . . . . . . . . . . 99 60 IR of IQ and II. . . . . . . . . . . . . . 100 61 Mass spectrum of IQ and II . . . . . . . . 101 62 Proton NMR of IQ and II. . . . . . . . . . 101 63 IR of IQ . . . . . . . . . . . . . . . . . 102 6A Mass spectrum of IQ. . . . . . . . . . . . 103 65 Proton NMR of I8 . . . . . . . . . . . . . 103 66 IR of I2 . . . . . . . . . . . . . . . . . 10A 67 Mass spectrum of I9. . . . . . . . . . . . 105 68 Proton NMR of I9 . . . . . . . . . . . . . 105 69 Carbon-13 NMR of I9. . . . . . . . .‘. . . 106 70 IR of IQ . . . . . . . . . . . . . . . . . 107 ix Figure 71 72 73 7A 75 76 77 78 79 80 81 82 83 8A 85 Mass spectrum Proton NMR of Carbon-13 NMR IR of II . . Mass spectrum Proton NMR of IR of II . . Mass spectrum Proton NMR of Carbon-13 NMR Mass spectrum Proton NMR of Mass spectrum Proton NMR of Carbon-13 NMR Page of II. . . . . . . . . . . . 108 88 ... . . . . . . . . . . . 108 of IQ. . . . . . . . . . . . 109 . 110 of II. . . . . . . . . . . . 111 II . . . . . . . . . . . . . 111 112 of II. . . . . . . . . . . . 113 gg . . . . . . . . . . . . . 113 of II. . . . . . . . . . . . 11A of II. . . . . . . . . . . . 115 g; . . . . . . . . . . . . . 115 of II. . . . . . . . . . . . 116 II . . . . . . . . . . . . . 116 of II. . . . . . . . . . . . 117 INTRODUCTION "Organic chemistry nowadays almost drives me mad. To me it appears like a primeval trOpical forest full of the most remarkable things, a dreadful endless Jungle into which one does not dare enter, for there seems no way out." Friedrich Woehler (1800-1882) INTRODUCTION Tetracyclic triterpenes are primarily thirty carbon isoprenoid compounds found mainly in the plant kingdom, with a few (e.g. lanosterol) also occurring in animals (Figure 1). Tetracyclic triterpenes are sometimes called methylsteroids because of their strong structural resem- blance to steroids. Like many of the steroids, some tetra- cyclic triterpenes possess a physiological activity. Cucurbitacins are present in many medicinal plants that are used as narcotics, purgatives, and emetics, and other cucurbitacins possess anti—tumor activityl’2. In nature, the tetracyclic triterpenes are formed by enzymatic cyclization of squalene 2,3-oxide followed by carbocation initiated rearrangements3. The product of the cyclization depends upon the conformation the enzyme imparts to the squalene chain. A chair-boat-chair-boat orientation leads to lanosterol, whereas a chair-chair- chair-boat conformer leads to euphol (1). The main difference between steroids and lanostane tetracyclic triterpenes is the presence of three extra methyl groups, two at 0-H and one at 0-1“, in the latter. Despite this great similarity, very little work has been done on the total synthesis of tetracyclic triterpenes, é HO Lanosterol Euphol H O Cucurbitacin G Kulinone Figure 1. Representative triterpenes. (1) /\ Lanosterol Euphol especially when compared to the great mass of work on steroid total synthesis. To date, the successful total synthesis of a tetracyclic triterpene has been accomplished only twice. One approach, developed by R. B. Woodward's group at Harvard, prepared lanosterol by adding methyl groups to cholesterol; and the other, developed by van Tamelen, used a biogenetic type polyene cyclization. In the Woodward approach“, an important step was the alkylation of a cholesterol derivative to introduce the 1“ a-methyl group (2). This overall reaction scheme achieved lanosterol in approximately twenty steps and in a low overall yield. (L (2) HO \V Lanosterol Lewis acid induced cyclization of a squalene like epoxide derivative was studied by van Tamelen gt al.5, and yielded either parkeol or isotirucallol depending on the configuration at C-3 (3). S‘ parkeol . isoflrucouol A similar cyclization using a polyene epoxide with a preformed C and D rings gave a dihydrolanosterol pre- 6 cursor (u). C) C8Hl7 A z» dihydrolanosterol As can be seen from the above examples, only the lano- stane skeleton has been successfully synthesized. There have been no reported syntheses of the euphane or cucurbi- tacin skeletons. It is unlikely that a polyene cycliza- tion approach would be successful in generating the euphane skeleton because of its facile rearrangement to the 130 system2 Several years ago the synthesis of the bicyclic di- ketone I was reported from this laboratory7. Inspection reveals that it should be ideally suited for elaboration to tetracyclic triterpenes. It incorporates the C and D rings, the C-13 and 0-1“ methyl groups in the required trans configuration, and functionality in both rings that should allow construction of the desired structures. oHoch side chain 0/ olloch ringsAondB O 1 Fortunately, the carbonyl group in the six membered ring is more reactive than the other8. This is important be- cause it allows selective transformations to be carried out. An important advantage of diketone I is that it can be used as a synthon for the lanostanes, euphanes, or cucurbitacins, depending on the position and configura- tion of the angular methyl group introduced with the A and B rings. Introduction of a 9 B-methyl group leads to the cucurbitacin skeleton, a C—10 a-methyl group leads to the euphanes, and a C-10 B-methyl group leads to the lanostanes. Many of the side chains found at 0-17 in the tetra- cyclic triterpenes are very similar; the cucurbitacins are an exception. Therefore, a versatile general side chain synthesis would be applicable to most of the tetra- cyclic triterpenes. Before proceeding to this end, it was necessary to evaluate previous methods or approaches that have been used in side chain synthesis. In the past, a primary interest in steroid side chains focused on the synthesis of the two carbon side chains of the corticosteroids and pregnanes (Figure 2). This was due largely to their biological activity and also to a scarcity of knowledge about the more elaborate side chains present in other systems. This void was quickly filled by the discovery and characterization of cholesterol metabolites, marine sterols, insect hormones, brain sterols and many others (Figure 2). As a result, steroid side chain chemistry entered a new age, so to speak, in which attention was focused on the newly discovered side chains with eight or more carbons and away from the two carbon ones that had been in the limelight. A large proportion of side~chainsyntheses use one of the following substrates due to their availability from naturally occurring compounds (5). A and B are products 0 . O C02H o I,” H of a chromic acid oxidation of cholesterolg, C is derived from plant sapogenins such as diosgeninlo, and D is the product of an ozonolysis of stigmasterol or ergosterolll. Progesterone Fucsterol OH H “OH Ecoysone Cortisone Figure 2. Representative side chains. 11 Starting in the late 1930's, A and B were used for the synthesis of the two carbon pregnane type side chainl2. The common reactions at the C—17 carbonyl include addition 13 1A of hydrogen cyanide12, acetylenes , and Wittig reagents (6), while the C-20 carboxylic acid is transformed through its acid chloride12 or by direct addition of alkyl lith— iums15 (7). An example is the synthesis of progesterone from an- drostenolone by Butenandtl6 (8). C) CH CN Progesterone é? The main approaches that have been used to elaborate the pregnane sidecfluxh1(substrate C) are the addition 17,18 of Grignard or lithium reagents and the addition of 12 . OH 3 095 9 SW (10) < AcO ' / Cholesterol \ A¢ fiz —A \ l3 Wittig reagentsl7’19 (9). Woodward's synthesis of choles- terol20 made use of the addition of a Grignard reagent to a C-20 ketone (10). The C—22 aldehyde (substrate D) may be transformed in much the same way; namely, the addition of Wittig 17,21 17,22 (11). reagents and Grignard or lithium reagents The use of this approach can be seen in Djerassi's recent synthesis of the sidetflmflflof the plant sex hor- mone oogoniol23 (12). A crucial aspect of sidecflmflmlsynthesis, be it steroid or tetracyclic triterpene, is the control of stereochem- istry, especially at C-17 and 0-20. Unfortunately, all of the methods listed above fail to give good stereochemical control, particularly at 0-20. The 1,2-addition to ketones and the reduction of olefins produces an epimeric mixture at 0-20 which may be difficult to separate to obtain pure compounds. Even though substrate D has the configuration at C-17 and C-20 fixed, care must be taken to avoid epi- merization at C-20, due to the neighboring a1dehydel7. Recently, several groups have developed stereospecific syntheses of sterol side chains. The ene reaction2u, 25 the oxy-Cope and Claisen26 rearrangements, nucleophilic attack at n-allylpalladium complexes27, 1,“ addition of alkyl cyanocuprates28, and nucleophilic displacement29 have been used as the key stereodirecting processes. The key steps in each approacheuwashown in order in Figure 3. 114 , M “H .1 J \\\ 0T5 3. Base ’ . Figure 3. Stereospecific side chain syntheses. 16 Close scrutiny of the literature reveals little in- formation concerning the synthesis of tetracyclic tri- terpene side chains that is comparable in any way to the body of work outlined above. In particular, there is reason to believe that the presence of a 1M a-methyl group will perturb the stereospecificity of many of these trans- formations to a significant degree. The work described in this dissertation was undertaken to explore the problem' of stereospecific sidecfluthlsynthesis on a model of the triterpene C, D ring moiety. RESULTS AND DISCUSSION "Without fantasy there is no science. Without fact there is no art." Nabokov l7 RESULTS AND DISCUSSION In our studies on the synthesis of tetracyclic tri- terpene side chains,the methoxy ketone I has been used as a model compound. Unfortunately, the 5—membered carbonyl is relatively unreactive towards reagents that normally add to ketones. An initial study by J. Martin and J. Tou8 showed that stabilized ylides, organometallic reagents, and enolate salts failed to add to I. It was also de- termined that part of the problem with these nucleOphilic addition reactions was due to a facile enolization of the ketone by strong bases. Since then, several reagents have been found to give adducts with ketone I. They are shown in Scheme 1, and each will be discussed in the following pages. Reaction of I with crotyl magnesium bromide in ether produces a high yield of I. The success of this reaction is believed to be the result of a cyclic mechanism with the magnesium coordinating with the ketone oxygen30. There is the possibility of forming four stereoisomeric products since two new chiral centers are being intro- duced into the molecule. The equilibrium between cis and trans crotyl magnesium bromide is very rapid even at low temperatures33 (13). 18 l9 Scheme 1. Additions to I. 20 Therefore, both the cis and trans crotyl Grignard reagents will form the six membered cyclic transition state which /::\_M gBr‘ MMgBF‘ can be either in the boat or chair form. Also, the addi— tion can take place from the a or 8 face of the molecule. Figure I shows the four possible stereoisomers and Table 1 shows the different transition states that can lead to their formation. Table 1. Transition States That Lead to I. 8 Attack a Attack 01sa bChair + I Chair + IV Boat + II Boat + III Trans Chair + II Chair + III Boat + I Boat + IV aRefers to geometrical isomer of Grignard reagent. bRefers to boat or chair transition state. 21 Figure I. Possible stereoisomers of I. 22 Examination of the proton and carbon-13 NMR spectra revealed that I was a mixture of only two isomers with a ratio of approximately 1:1. Hydroboration followed by dehydration yielded an olefinic product which was shown to still be a mixture. Therefore, I is epimeric at C-20 and the mixture must consist of either I and II or III and IV. On the basis of molecular models and the chemical shifts of the angular methyl groups, I appeared to consist of I and II. Because of the potential synthetic usefulness of this adduct, a study was undertaken to increase the stereo- selectivity of the addition. In the reaction of allylic organometallic reagents with simple aldehydes it is known that the stereoselectivity of the reaction does not vary much with the temperature or the solvent; but it increases as the steric hindrance of the aldehyde increases, and with the electronegativity of the metal: Mg < Zn < Cd31. Unfortunately, both dicrotylzinc and dicrotylcadnfllmlfailedto react with I. This was also 32 the case with Hiyama's crotyl chromium reagent, but crotylaluminum sesquibromide did react to give adduct I or II, depending on the conditions of the workup. When I was the product, it was formed in high yield as a 1:1 mixture of isomers; identical to the mixture obtained from crotylmagnesium bromide. Partial success in improving the stereospecificity of 23 the reaction was achieved by lowering the temperature of the reaction. A value of about 2:1 (determined by proton NMR) in the isomer ratio was obtained at the lowest tem- peratures (Table 2). Since the equilibrium between the Table 2. Low Temperature Experiments. Conditions Ratio Ether, 23°C 1:1 Ether, 0°C 1:1 Benzene, 23°C 1:1 Ether, -78°C 2:1 Ether, Toluene, -110°C 2:1 cis and trans crotyl Grignard reagents is very rapid33, the change in stereoselectivity is presumed to reflect slight differences in the energies of the cyclic transi- tion states. Hydroboration of I yielded diol I as a mixture of isomers which could be cleanly separated by recrystalliza- tion from ether. The crystalline diols were obtained in a 3:1 ratio with an overall yield of 75%. This indicated that the actual isomer ratio is a little better than that 2“ determined by proton NMR. Unfortunately, mild Lewis acid- 3“ catalyzed dehydration of either epimer of I failed to give the desired olefin A (14). Instead, the rearranged olefin I (Scheme 2) was obtained. This rearrangement was not discovered until ketone II was synthesized from I, and its IR spectrum was examined. Carbonyl adsorption occurred at 1700 cm”1 and not at 1735—1750 cm‘l, as expected for a carbonyl group in a 5-membered ring, such as that in the desired compound B. Ketone II was synthesized as shown in Scheme 2. Oxi- dation of alcohol I by pyridium chlorochromate35 yielded the unstable aldehyde I, which was immediately treated with isobutylmagnesium bromide to give the alcohol I as a mix- ture of isomers. The hydroxyl group in I was removed by lithium aluminum hydride reduction of the corresponding mesylate I to form the olefin II. The hindered nature of the double bond in II was revealed by its inertness to hydrogenation under several different sets of conditions. Alcohol II was generated by hydroboration of olefin II in 25 PCC 26 Scheme 2. Synthesis of ketone lg. 27 ether solution using diborane generated in_situ from boron trifluoride etherate and lithium aluminum hydride36. Oxidation with pyridium chlorochromate35 produced ketone l%, the IR spectrum of which provided conclusive evidence that a rearrangement had occurred. There is precedent in the steroid field for rearrange- ments of this kind37’38. Steroids bearing a secondary C-l7 hydroxyl group were found to give a 1,2-methyl shift only when the methyl and hydroxyl groups have a trans-diaxial orientation to each other (15). H OH (15) .IOHw > b 5”” .H However, if the C-17 carbinol is tertiary the orientation of the methyl group to the hydroxyl group is not impor- tant (16). Thus, the geometrical selectivity appears to be counter-balanced by the greater stability of the tertiary carbocation. As mentioned previously, reaction of Q with crotyl- aluminum sesquibromide yielded either 5 or lg, depending upon the conditions used in the workup. Compound lé was assumed to be formed via 3 by a dehydration-rearrange- ment induced by aluminum bromide. This was confirmed 28 OH 0 ”OH 0 (16) . . by treating a known sample of Q with aluminum bromide in ether. Compound l; was obtained quantitatively after stirring at room temperature for only two minutes. Con- version of the olefin to a carbonyl group was effected in order to further corroborate the rearrangement (Scheme 3). Hydrogenation of l; saturated only the side chain double bond, as the double bond in the ring is hindered and does 36 not reduce. Hydroboration of la then yielded alcohol lg which was oxidized by pyridium chlorochromate35 to ketone lg. Once again the IR spectrum of lg showed a carbonyl absorbance at 1700 cm.1 revealing that the ketone was indeed in the six membered ring. Further evidence for the loca- tion of the carbonyl group in lg was obtained by introduc- tion of a double bond39 to form the unsaturated ketone ii. If the rearrangement had not occurred, the ketone would be in the five membered ring and it would be impossible to introduce a conjugated double bond. 29 , 8H2 PCC v I)§25282,LDA \ 2)[o] ’ 3) A Scheme 3. Synthesis of unsaturated ketone l1. 30 The trans ring Junction was assigned to alcohols ll and l§ for several reasons. Examination of molecular models revealed that the a face of the double bond is‘ severly hindered by the a side chain at C-l7 and the a methyl group at C-lu. As a result, cis addition of di- borane should occur from the 8 face, giving the trans ring Junction. Additional evidence for the trans ring Junction can be obtained from the proton NMR of compounds II and IQ. Examination of Dreiding models of the compounds with the cis (A) and trans (B) ring Junction revealed that the coupl- ing constants for the carbinol proton would be of no use in predicting the correct structure, as they both have two diaxial and one axial equatorial coupling and would give the same splitting pattern. The diagnostically useful proton is the one attached to the carbon bearing the methoxy group. In A that proton should be axial, and the model suggests that a doublet of doublets with coupling constants of 12-13 Hz and 3-u Hz should be observed. In the case 31 having a trans ring Junction (B), the corresponding hydrogen is equatorial and a triplet with J = 3-5 Hz is predicteduo. In fact, the proton NMR of 11 displays a signal for that hydrogen which is a triplet with J = 4.3 Hz, lending support to the trans ring Junction. In the ketones, lg and IQ, the situation is a little more complex due to the possibility of epimerization at the ring Junction. However, the proton NMR evidence still tends to indicate that the ring Junction is trans. Carbon—l3 NMR also proved useful in assigning the con- figuration of the ring Junction. For cyclohexane systems it is known that a carbon bearing a methoxy group under- goes a “-6 ppm downfield shift when the methoxy group goes from axial to equatorialul. In compound 3, the methoxy group is known to be axial8 and it has a chemical shift of 83.6 ppm. The carbon-l3 NMR spectra of compounds g, g, IQ, ll, lg, lg, IQ and IQ revealed that the chemical shift of the methoxy-bearing carbon was always in the range 82- 8A ppm. Clearly, a downfield shift has not occurred and the conclusion is drawn that the ring Junction is trans. While the preceding NMR evidence is good, it is not compelling due to the possibility of non-chair conformations. These could ariseifimm1distortion introduced into the system by interaction of the C-lu methyl group with the a side chain at C~l7. Treatment of ketone 3 with trimethylsilyl cyanideLl2 32 and zinc iodide yielded the silyl cyanohydrin kg in excel- lent yield (17) as a 1:1 mixture of isomers at C-l7. It (17) is known that methylmagnesium bromide adds to protected cyanohydrins to form a hydroxy ketones in good yield (18). OTHP O (18) . CN MeMQr 9 . OH However, all attempts to apply this reaction to l§, using either methylmagnesium iodide or methyl lithium failed (Table 3). Either no reaction occurred or the reagent attacked the silicon atom, and the ketone 3 was regenerated by loss of cyanide ion. Oda gt al. have developed a method“3 for the dehydra- tion of trimethylsiloxy nitriles to a, B-unsaturated nitriles (19). However, when this procedure was attempted 33 Table 3. Attempted Reactions of IQ. Conditions Product MeMgI, Et20, 23°C l8 MeMgI, Et20, 35°C l8 MeMgI, Benzene, 80°C 3 + I8 MeLi, Et2O, 23°C 1g MeLi, THF, 23°C g on l8 no reaction occurred and starting material was re- covered. In light of these failures, the rearrangement FKDCH that occurred with Q, and the success of the Wittig re- action, further work in this area was postponed. The Wittig reaction of ketone 3 with methylenetri- phenylphosphorane, using the Corey modificationuu, yielded olefin $2 in good yield. However, substitution of the ethylidene analog produced the synthetically more useful olefin g9 in only 35% yield. This lower yield is probably due to increased steric interactions caused by the presence 3“ of an additional methyl substituent in the reagent that must add to the hindered ketone. Fortunately, the addi- tion of ten equivalents of sodium iodide to the Wittig reagent solution increased the yield of £9 to 61%. It is not entirely clear why the sodium iodide improved the yield. It could complex with the carbonyl group to de- crease enolization and thereby facilitate addition, or it could act by increasing the ionic strength of the medium. The configuration about the double bond of 39 was assigned on the basis of its proton NMR spectrum. Steroid analogs in which the l7—ethylidene groups are known to have E and/or Z configurations have distinct and characteristic chemical shifts for the vinyl proton and the vinyl methyl group of this function27’Ll5 (20). 4.99 ~5.095 I70-l.785 “9H al.57-l.6|5 C» H ( . . ( .322—5255 < < Z E In eg, the chemical shift of the vinyl proton is 5.06 ppm and that of the vinyl methyl group is 1.61 ppm. These values agree very well with the configuration (E) in which the methyl group is anti to the ring system of the mole- cule, and do not match the corresponding signals for the 35 Z isomer. It is interesting to note that the E configuration obtained in the conversion of 3 to 29 does not correspond to that obtained when the same Wittig reaction is per- formed on l7-keto steroids!46 (21). In the case of 17- keto steroids, it is proposed that the Z isomer arises O (21) . 5 g. 12. A molec- from ylide attack at the less hindered a face ular model of 3 reveals that there is very little differ- ence in the steric environment of the a and B faces. It also suggests that attack from the a face would yield the Z isomer and attack at the 8 face would yield the E isomer. The observed stereoselective formation of 29 from 3 may reflect a lesser hindrance of the 8 face, despite the similarities indicated by the model. Hydroboration of 22 with diborane (Scheme u) yielded alcohol 2% as a mixture of isomers; probably from attack of diborane on both the a and B faces of the double bond. Steroids having a Z l7-ethylidene group react with di- borane predominantly at the a face (22), yielding the 17 A6 B—isomer, containing about 5% of the C-17 epimer An 36 Scheme 4. Synthesis of side chain. 37 attempt was made to improve the selectivity of the hydro- boration by using 9-BBN. However, no reaction occurred H \\\\OH (22) g . 8H3 7‘ NIH with 29 and the starting material was recovered. Again, this result contrasts with corresponding reactions of 29 steroids, which are known to occur with excellent stereo- selectivity. Oxidation of the mixture of alcohols 21 with pyridinium chlorochromate yielded a 1:1 mixture of ketones, which was epimerized with base to give a single isomer, 22. The 8 configuration was assigned to the pregnane side chain in 22 on the basis of steric hindrance estimates and the proton NMR spectrum. Since the mixture of ke- tones is epimeric at C-17, base-catalyzed epimerization interconverts the two possible configurations for the side chain: a and 8. Molecular models indicate that the B-epimer should be the more stable, since the a epimer wouldtnaseverely compressed due to interaction between the C-lu a methyl group and the C-17 a side chain. There— fore, epimerization should favor the more stable 6 side 38 chain. Coupling constants for the C-17 hydrogen atom can be predicted from a molecular model and the Karplus equa- A0, and are known in steroid analogs. For the B side tion chain, the C-17 hydrogen is predicted to be a triplet with J = 8-10 Hz and for the a side chain, a doublet of doublets with J = 7-9 Hz and “-5 Hz. The proton spectrum of the mixture of ketones had a triplet (J = 8.5 Hz) at 2.72 ppm and a doublet of doublets (J = 9.1 Hz, “.4 Hz) at 2.55 ppm. The latter disappeared upon epimerization, leaving only the triplet. This confirms the 8 configuration assigned to the side chain in 22. The remaining carbons of the terpenoid side chain were then introduced by a Wittig reaction, using a modification 147 of McMorris' procedure Addition of isohexylphosphorane to ketone 22 produced olefin 23 in fair yield. The E con- figuration of this olefin was indicated by the chemical shift of the C-21 methyl signal at 1.6 ppm. This is within the range expected for the E isomer (1.6-1.65 ppm), whereas the range for the Z isomer is 1.68-1.71 ppmua. Hydrogenation of the double bond with platinum oxide in dioxane: acetic acid (50:1) produced 23 as a 2:1 mixture epimeric at C-20. The 2:1 isomer ratio was determined by carbon-13 NMR and confirmed by gas chromatography. Hydro- genation of the 20(22) double bond has been widely studied, 17 but the results vary considerably The reaction seems to be extremely sensitive to both the substrate and the 39 reaction conditions; however, platinum oxide in dioxane: acetic acid is reported to give the best stereoselectivity. Since g’is racemic, the mixture 2% is actually com- posed of two pairs of enantiomers. Therefore, referring to the newly introduced chiral center at C-20 as R or S is improper, because in each pair of enantiomers C-20 will be both R and S. By using two chiral centers, C-20 plus one other, it should be possible to unambiguously designate all four of the isomers. For example, if C-l7 is used as the reference site, then one enantiomeric pair of 2% would be R,R and 8,8 and the other would be S,R and R,S. In order to use carbon-13 chemical shifts to determine the configurations of these isomers, it is important to have good reference standardsug (Figure 5 and 6). In this instance, dihydrolanosterol and euphenol serve as excellent models. Using the system described above, natural dihydrolanosterol is R,R and its unknown enantiomer is S,S; euphenol is R,S and its enantiomer is S,R. In an achiral solvent the carbon-13 NMR chemical shifts of the side chain carbon atoms of the R,R and 8,8 enantiomers in 35 should correlate with the corresponding signals in the spectrum of dihydrolanosterol. Similarly, the R,S and S,R enantiomers in 2% should correlate with the side chain signals in the euphenol spectrum. From the chemical shifts reported for these natural products (Figure 5 and 6), the assignments proposed for the diastereomers in 23 are 40 .mpmfinm HonEmno OMH Hosmnasm .m mpsmfim m.:m (I. oém / Ham 9% Hi i w.NN m.mz In mW//////(\\\\\\J H H Ham m.mm H H o.wm L 5.3 I 52 m.mm m.mm H.em H as Ml m.mm m.mm m.mm appease assesses om m.wm m.zm m.mm H or; i \ Hopmpmocmaopomnfia .m opswfim I) /. :I' IIIIIIIN m.m= n.0m m.mH 42 w:w.mm MHm.mN mmw.mm .ww to seesaw assesses om Nmo.:m *mwm.:m osfi.sm m wHNN.wN l Nom.mm *mom.mm mHH.m: *zmw.fim :mw.mm :Hm.mm *mmm.mH *z~.mm mow.wa NHwomm meowm Nmflomfl *wom.wa H .5 mhswfim owm.mm mmm.~m OoZ m>:.mm www.mm www.mw m:>.mm OCh OT: ““0 OWN NCU moo.mH *mmm.wa ‘43 shown in Figure 7. The starred numbers indicate the more intense peak of the pair, and presumably the more abundant isomer. Based on these assignments, the maJor isomer ap- peared to be 17R, 20R which is analogous to dihydrolano- sterol. However, this assignment cannot be considered firm because in two instances, C-13 and C-18, the more intense peak was not the predicted one. In fact, a definitive assignment may have to wait until the entire tetracyclic triterpene is assembled. Even though the promising crotyl adduct 3 could not be carried on to the terpenoid side chain, due to its facile rearrangement, the initial obJective of this proJect was reached. The terpenoid side chain was introduced by con- version of 3 to the E-ethylidene derivative 20, from there to the 7 B-acetyl intermediate 22, and finally to a mixture of side chain epimers 2% by a Wittig condensation followed by hydrogenation. While the synthesis is straight forward, it would be desirable to increase the stereoselectivity of the hydrogenation. EXPERIMENTAL "The chemists are a strange class of mortals who seek their pleasures among soot and flame, poisons and poverty, yet among all these evils, I seem to live so sweetly that I may die if I would change places with the Persian King." John Joachim Becher NH General Except as indicated, all reactions were conducted under dry nitrogen or argon, using solvent purified by distillation from suitable drying agents. Magnetic stirrers were used for small scale reactions; larger reactions were agitated 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 deuterochloroform solutions with either a Varian T—60 or a Bruker 250 MHz spectrometer and are calibrated in parts per million downfield from tetramethyl- silane as an internal standard. Carbon-l3 NMR spectra were taken in deuterochloroform solutions on the Bruker 250 MHz spectrometer using tetramethylsilane as an internal stan- dard. Mass spectra were obtained with a Finnigan M000 GC/ MS spectrometer. “5 N6 6-Methyl-5-hydroxytricyclo[u.A.0.0]decan—9-one A 2 liter three neck round bottom flask was dried, purged with dry nitrogen and fitted with a mechanical stirrer, a dry ice condenser and a dry ice acetone cool- ing bath. To this flask was added 1 liter of ammonia, 50 mL of dry THF and sufficient lithium metal to Just main- tain a blue solution. To this stirred solution at -78°C was added 3.5 g (0.5 mol) of lithium wire, followed over a 50 minute period by a solution of the Wieland—Miescher ketone (3N.5 g, 0.19” mol) in THF (250 mL). The resulting blue solution was stirred at -78°C for 1.5 hours and then quenched by addition of anhydrous ammonium chloride (30 g). After evaporation of the ammonia with a warm water bath (50°C), water (200 mL) and ether (200 mL) was added. The water layer was extracted with ether (3 x 100 mL). The combined ether layers were washed with water (100 mL) and brine (100 mL) and these washes were then reextracted with ether (2 x 50 mL). The ether extracts were dried (MgSOu) and the ether was removed under vacuum at room temperature to yield an oil which crystallized to yield 23.8 g (68%) of pure cyclopropanol. trans-l,6-dimethylbicyclo[4.3.0]nonane-2,7-dione I A solution of potassium hydroxide (6.2“ g, 0.111 mol) in 1:1 methanol-water (80 mL) was deoxygenated by bubbling in nitrogen through it for 15 minutes. The solution was then cooled to 0°C and the cycloprOpanol (20 g, 0.111 mol) was added. After stirring for 5 hours at 0°C, the solution was allowed to warm to room temperature and the stirring was continued for 8 hours. The solution was filtered and the resulting solid was washed with water and dried to yield 1“ g (70%) of hydrindandione 2: mp 166-167°C; MS, m/e 180(M+). trans-1,6-dimethyl-2-hydroxybicyclo[A.3.0]nonan-7-one 2 To a stirred solution of 2 (21.1 g, 0.117 mol) in ethanol (700 mL) at 0°C was added over a 15 minute period a solution of sodium borohydride (u.u3 g, 0.117 mol) in 3N sodium hydroxide (100 mL). After stirring for A hours at 0°C, this mixture was neutralized with 3N hydrochloric acid and the ethanol was removed. Ether and water was added to the residue and the aqueous layer was extracted with ether. The combined ether extracts were washed with water, brine, and then dried. Removal of the solvent yielded 18.5 g (87%) of the alcohol 2: mp 173—175°C; MS, m/e 182 (M+). trans—l,6-dimethyl-2-methoxybicyclo[u.3.0]nonan-7—one,3 A mixture of sodium hydride (1.6 g, 67 mmol) and dimethylsulfoxide (180 mL) was heated at 65°C for 1 hour. The resulting solution of dimsyl sodium was cooled to room temperature, the alcohol 2 (6.6 g, 36 mmol) was added and U8 stirring was continued for 1 hour. Following the addition of methyl iodide (7.72 g, 5“ mmol), the solution was stirred overnight (14 hours), water was added and the resulting mixture was extracted with ether. The combined organic layers were washed with water, brine, and dried. Removal of the solvent yielded 7.9 g of an oil which was submitted to Kugelrohr distillation, yielding 5.1 g (72%) of methyl ether 2. The remaining oil contained mainly alcohol 2 which could be recycled. IR (001“) 17uo cm’l; MS, m/e 196 (M+). Homoallylic Alcoholg To magnesium (10 g, 0.417 mol) in ether (50 mL) was slowly added (6 hr) a solution of crotyl bromide (31.5 g, 0.233 mol) in ether (150 mL). The metallic gray solution was stirred for 1 hour, toluene (90 mL) was added, and the resulting solution was cooled to —78°C. A solution of the methoxy ketone 3 (7.” g, 38 mmol) in ether (50 mL) was added over “5 minutes and this mixture was stirred for 5 hours at -78°C. After warming to room temperature, saturated ammonium chloride was added, and the mixture was filtered. The aqueous layer was extracted with ether, and the combined ether extracts were washed with water, brine, and dried. Removal of solvent yielded 9.5 g (99%) of homoallylic alcohol 5: IR (001“) 3605, 3550, 1625 cm’l; MS, m/e 252 (M+). “9 Isomeric diols 5 To a solution of 2 (8 g, 32 mmol) in THF (70 mL) at 0°C was added a solution of diborane in THF (32 mmol, 32 mL of a 1 M solution) over a period of 20 minutes. After stirring for 30 minutes at 0°C, the cooling bath was removed and the stirring continued for 1.5 hours at room tempera- ture. Sufficient water was added to quench the excess diborane, and then 3N sodium hydroxide (12 mmol) and 30% hydrogen peroxide (120 mmol) was added. After stirring for 18 hours, the THF was removed and the residue was extracted with ether. The ether extracts were washed with water and brine, and dried. Removal of the solvent yielded a viscous oil which was recrystallized from ether to yield two isomeric diols 5; 1.6 g (19%) mp 1uz.5—1uu.5°c, n.82 g (56%) mp 118-119°C; IR (001“) 3600, 3375 (br) cm’l; MS m/e 252 (M-18), 220 (M-SO). See Appendix I. Methoxy alcohol 6 A solution of diol g (2.6 g, 9.6 mmol) in benzene (U0 mL) and THF (10 mL) was heated to 50°C (oil bath tempera- ture) and boron trifluoride etherate (1.5 mL, 12 mmol) was added. After stirring for 35 minutes at 50°C, the solution was poured into ice-water, extracted with ether, and the combined ether extracts were then washed with brine and dried. Removal of the solvent followed by column chromatography (silica gel, 25% ethyl acetate/ hexane) of the crude product yielded 1.97 g (81%) of 50 olefin 6. An identical procedure was used for the other isomer and the yields were equivalent. IR (CClu) 3610, 3h00 (br) cm’l; ms, m/e 252 (M+). A1dehyde,2 To a suspension of pyridinium chlorochromate (0.5 g, 2.3 mmol) in methylene chloride (3 mL) was added a solu- tion of alcohol 6 (0.39 g, 1.5 mmol) in methylene chloride (2 mL). After stirring for 1 hour the reaction mixture was diluted with ether and filtered through a short column of Florisil. Removal of the solvent yielded 0.333 (86%) of a clear oil which appeared pure by TLC and NMR. The aldehyde 2 is unstable and is always used immediately in the following reaction. IR (CClu) 1720 cm-1 ; MS, m/e + 250 (m ). Alcohol 8 A solution of sec-butyl bromide (0.5 mL, “.6 mmol) in ether (5 mL) was slowly added to a suspension of magnesium turnings (0.131 g, 5.“ mmol) in ether (10 mL). The result- ing metallic gray solution was stirred for 30 minutes, and then a solution of aldehyde 1 (0.333 g, 1.3 mmol) in ether (7 mL) was added over a 20 minute period. After stirring this reaction mixture for 30 minutes, water was added and the solution was extracted with ether. The ether ex— tracts were washed, dried and evaporated to yield 0.3“8 g (85%) of Q as a clear oil: IR (001“) 3620, 3“80 cm‘l; MS, m/e 258 (M-SO). 51 Mesylate9 To a cold (0°) solution of alcohol § (0.312 g, 1.01 mmol) in pyridine (5 mL) was added methane sulfonyl chloride (0.12 mL, 1.51 mmol). After stirring for 1 hour at 0°C, cold water was added and the resulting solution was ex- tracted with ether. The ether extracts were washed with cold 5% hydrochloric acid, dilute sodium bicarbonate, water, brine and then dried. Removal of the solvent gave 0.37 g (95%) of mesylate 9. Methoxy olefin 2Q To a suspension of lithium aluminum hydride (0.208 g, 5.5 mmol) in THF (5 mL) was added a solution of mesylate 2 (0.39 g, 1.02 mmol) in THF (10 mL). After refluxing for 2“ hours, aqueous sodium sulfate was added, the mixture was filtered, and the aqueous filtrate was extracted with ether. The ether extracts were washed and dried. Re— moval of the solvent, followed by column chromatography (silica gel, 15% ethyl acetate/hexane) of the crude oil yielded 0.2 g (67%) of olefin 22 plus 62 mg (20%) of alcohol 2: MS, m/e 292 (M+). Alcohol 22 To a cold (0°C) solution of olefin 22 (0.35 g, 1.2 mmol) in ether (25 mL) was added boron trifluoride etherate 52 (3 mL, 2“ mmol), followed 10 minutes later by slow addi- tion of a suspension of lithium aluminum hydride (0.“55 g, 12 mmol). The stirring was continued for “ hours at room temperature, and water was then added to quench the excess diborane. The aqueous layer was extracted with ether, and the residue remaining after removal of the solvent was dissolved in ethanol (20 mL). This solution was treated with 3N sodium hydroxide (3 mL) and 30% hydrogen peroxide (1 mL), stirred for 3 hours, and water was added. After extraction with ether, the ether extracts were washed with water, brine, and dried. Removal of the solvent yielded 0.315 g (85%) of alcohol 33: IR (001,) 3630 cm‘l; MS, m/e 278 (M-32). Methoxy ketone 32 To a suspension of pyridium chlorochromate (0.183 g, 0.8“ mmol) in methylene chloride (3 mL) was added a solution of alcohol 33 (0.175 g, 0.56 mmol) in methylene chloride (2 mL). After stirring for 2 hours, the reaction mixture was diluted with ether and filtered through a short column of silica gel. Removal of the solvent yielded 0.156 g (90%) of 32 which appeared homogeneous by TLC and NMR: IR 1 (001“) 1695 cm” ; MS, m/e 308 (M+). Diene 33 To a suspension of aluminum powder (1.25 g, “6 mmol) in ether (10 mL) was added mercuric chloride (0.3 g) and 53 crotyl bromide (1 mL, 9.7 mmol). After stirring this mix- ture for 10 minutes, a solution of crotyl bromide (6 mL, 58 mmol) in ether (20 mL) was added over a 1.25 hour period. Following a 3 hour reaction period, a solution of ketone 3 (3 g, 15.3 mmol) in ether (20 mL) was added to the result- ing dark gray solution of crotyl aluminum. After stirring for 5.5 hours, the reaction mixture was quenched with water, filtered to remove solids, and the organic layer was washed with water, brine, and dried. Removal of the solvent, followed by column chromatography (silica gel, 10% ethyl acetate/hexane) of the resulting oil yielded 2.82 g (79%) 1; MS, m/e 23“ (M+). of 33 as an oil: IR (CClu) 1630 cm- See Appendix I. Monoolefin33 A solution of diene 33 (0.533 g, 2.28 mmol) in ab- solute ethanol (50 mL) was mixed with 10% Pd on carbon (97 Mg), and shaken under hydrogen (“0 psi) using a Parr apparatus. The solution was filtered and the solvent was removed to yield 0.53“5 g (99%) of 33 as an oil: MS, m/e 236 (M+). See Appendix I. Alcohol 33 To a cold (0°C) solution of olefin 33 (0.23 g, 0.97 mmol) and boron trifluoride etherate (2.6 mL, 21.2 mmol) in ether (10 mL) was added a suspension of lithium alumin- um hydride (0.“ g, 10.7 mmol) in ether (15 mL). After 5“ stirring this mixture at room temperature for “ hours, the reaction was quenched with water, filtered, and the organic layer was washed and dried. Removal of the solvent yielded 0.2“ g (98%) of té‘ IR (001“) 3590 cm'l. Methoxyketone3é To a suspension of pyridium chlorochromate (0.“5 g, 2.1 mmol) in methylene chloride (5 mL) was added a solu- tion of alcohol 33 (0.2“ g, 0.9“ mmol) in methylene chlor— ide (2 mL). After stirring for 3 hours, the reaction mixture was diluted with ether and filtered through a short column of silica gel. Removal of the solvent fol- lowed by column chromatography (silica gel, 10% ethyl acetate/hexane) of the residue yielded 0.1“1 g (60%) of 1; MS, m/e 252 (M+). See ketone 3g: IR (CClu) 1695 cm- Appendix I. Methoxy enone 31 A solution of diisopropylamine (0.156 mL, 1.1 mmol) and butyl lithium (1.1 mmol) in THF (5 mL) was stirred at —78°C for 30 minutes. Ketone 3Q (0.139 g, 0.55 mmol) was added and the stirring was continued for 1 hour at —78°C. After warming to 0°C, diphenyl disulfide (0.1“ g, 0.6“ mmol) was added, the reaction mixture was stirred at room temperature for “ hours, and then poured into ether and 10% hydrochloric acid. The ether extracts were washed with saturated sodium bicarbonate and dried. After the 55 solvent was removed, the residue was dissolved in methanol (8 mL), cooled to 0°C, and sodium periodate (0.13“ g, 0.63 mmol) dissolved in a minimum amount of water was added. The reaction mixture was stirred for 1“ hours, filtered, and the solvent was removed. The residue was dissolved in ether and dried. Evaporation of the ether yielded a residue which was dissolved in xylene (10 mL), calcium carbonate (100 mg) was added, and the mixture was refluxed for 12 hours. After filtration, the xylene was evaporated and column chromatography (silica gel, 5% ethyl acetate/hexane) of the residue yielded 92 mg of an oil containing the methoxy enone 22 and the ketone 22. This was determined by NMR, MS, and IR: IR (CClu) 1695, 1 1670 cm' ; MS, m/e 252 (M+), 250 (M+). trans-1,6-dimethyl-7-cyano-7-trimethylsiloxy-2-methoxy- bicycloE“.3.0]nonane,2§ To a solution of methoxy ketone 3 (1.99 g, 10.2 mmol) in methylene chloride (50 mL) was added trimethylsilyl- cyanide (3.9 mL, 30.5 mmol) and zinc iodide (0.35 g). After refluxing for “8 hours, TLC showed the reaction was complete. The solution was filtered, the solvent was removed, and the resulting dark oil was subJected to column chromatography (silica gel, 10% ethyl acetate/ hexane) to yield 2.8 g (93%) of silylcyanohydrin 22; mp 90-92°C. The proton NMR at 250 MHz clearly shows this product to be a roughly equimolar mixture of C-7 diasteromers: MS, m/e 295 (M+). See Appendix I. 56 trans-1,6-dimethy1—7-methy1ene-2-methoxybicyclo[“.3.0]- nonane 23 A solution of dimsyl sodium was prepared by heating a suspension of sodium hydride (0.“1 g, 17.1 mmol) in di- methyl sulfoxide (20 mL) at 65°C for “5 minutes. After cooling to room temperature, a solution of methyltri- phenylphosphonium bromide (6.3 g, 17.6 mmol) in DMSO (10 mL) was added followed “5 minutes later, by the ketone 3 (0.57“ g, 2.9 mmol) in DMSO (3 mL). The yellow orange solution was then heated at 60°C for 60 hours, cooled to room temperature, poured into water, and extracted with hexane. The hexane extracts were washed with water, the solvent was evaporated and the residue was dissolved in petroleum ether (30-60°C) and filtered through an alumina column to yield 0.““16 g (77%) of 23 as a clear oil: IR 1 (001“) 1650 cm‘ ; MS, m/e 19“ (M+). E-7-ethylidene-trans-l,6-dimethyl-2-methoxybicyclo[“.3.0] nonane 2Q A solution of dimsyl sodium was prepared by heating a suspension of sodium hydride (0.612 g, 25.5 mmol) in DMSO (60 mL) at 65°C for 1 hour. After cooling to room tem- perature, ethyltriphenylphosphonium bromide (9.5 g, 25.5 mmol) was added and the resulting red solution was stirred for “5 minutes. Sodium iodide (7.6 g, 51 mmol) was added, followed by a solution of ketone 3 (1 g, 5.1 mmol) in DMSO (5 mls), and the resulting mixture was heated at 60°C 57 for 65 hours, cooled, poured into water and extracted with hexane. The hexane extracts were washed with water, brine, and dried. Evaporation of the solvent, followed by column chromatography (silica gel, hexane) yielded 0.63“5 g (61%) of olefin 22 plus 0.25 g (25%) of ketone 3 as oils. The proton and carbon-13 NMR spectra show 20 to be solely one isomer: MS, m/e 208 (M+). See Appendix I. Alcohol 22 To a cold solution of olefin 29 (0.182 g, 0.88 mmol) in THF (10 mL) was added a solution of diborane (2 mmol) in THF. After stirring this mixture at room temperature for 3 hours, water was added to quench the excess diborane. Following addition of 3N sodium hydroxide (3 mmol) and 30% hydrogen peroxide (10 mmol), the reaction mixture was stirred for 2 hours, the solvent was removed and the aqueous residue was extracted with ether. The combined organic layers were washed with water, brine, and dried. Evaporation of the solvent yielded 0.186 g (93%) of 22 as a mixture of alcohols: IR (001“) 3610, 3375 (br) cm'l; MS, m/e 226 (M+). Methoxy ketone22 To a suspension of pyridinium chlorochromate (0.355 g, 1.65 mmol) in methylene chloride (3 mL) was added a solu- tion of the alcohol mixture 22 (0.186 g, 0.82 mmol) in 58 methylene chloride (2 mL). After stirring for 1.5 hours, this reaction mixture was diluted with ether and filtered through a short column of silica gel. Removal of the solvent yielded 16“ mg of an oil identified by NMR as a mixture of ketones epimeric at C-17. This epimer mixture in ethanol (3 mL) was added to a solution of sodium ethoxide prepared by dissolving sodium (93 mg, “ mmol) in ethanol (10 mL). After stirring for 3 hours, water was added, the solution was extracted with ether, and the combined organic layers were washed and dried. Evaporation of the solvent followed by column chromatography (silica gel, 20% ethyl acetate/hexane) of the residue yielded 1 0.122 g (65%) of 22: IR (001“) 1705 cm‘ ; MS, m/e 224 (M+). See Appendix I. Olefin 23 A solution of dimsyl sodium was prepared by heating a suspension of sodium hydride (0.08“ g, 3.“8 mmol) in DMSO (10 mL) at 65°C for “5 minutes. After cooling to room temperature, isohexyltriphenylphosphonium bromide (1.“9 g, 3.“8 mmol) was added followed, 30 minutes later, by a solu- tion of ketone 22 (0.195 g, 0.87 mmol) in DMSO (3 mL). The red solution was then heated at 60°C for 18 hours, cooled, poured into water, and extracted with hexane. The hexane extracts were washed with water, brine, and dried. Evaporation of the solvent, followed by column chromatography (silica gel, hexane) yielded 0.1 g (“0%) 59 of 23 as a volatile liquid: MS, m/e 292 (M+). See Appendix I. Methoxy alkane 22 A solution of olefin 23 (39 mg, 0.13 mmol) in 50:1 dioxane/acetic acid (2.5 mL) was mixed with platinum oxide (10 mg) and stirred for “ hours under an atmosphere of hydrogen. More platinum oxide (10 mg) was added and the stirring continued for 5 hours under a hydrogen atmos- phere. Filtration, and evaporation of the solvent yielded 35 mg (89%) of 22 as an oil. Gas chromatography and carbon- 13 NMR shows it to be a 2:1 mixture of isomers: MS, m/e 29“ (M+). See Appendix I. 60 APPENDIX I "All that is gold does not glitter; not all those that wander are lost." J. R. R. Tolkien The Fellowship of the Ring 61 Compound Calculated Found 5a C, 71.10 70.80 H, 11.19 11.21 5b C, 71.10 71.14 H, 11.19 11.17 14* C, 81.29 78.50 i 0.4 H, 11.75 11.29 i 0.04 18 C, 65.03 64.64 H, 9.89 9.85 20 C, 80.71 80.62 H, 11.61 11.53 22 C, 74.95 75.52 H, 10.78 10.98 23 C, 82.13 82.24 H, 12.41 12.29 * The found value is an average of three determinations, due to sample volatility. However, the calculated and found C/H ratios are 6.918 and 6.926:0.045 respectively, well within experimental error. APPENDIX "....when you have excluded the impossible, whatever remains, however improbable, must be the truth." Sherlock Holmes 62 63 a... , O'duo ...|-|V’P ml u on..... .1! I «-.. 3-. .ll.. 3” 5‘? .11 i- 1 I q a- I : A: II. II»; otiilllit It.” :14!HWH In: I l :d 7 ill I. I illitli- 30...! .5 I. II. V . I'll-Ila I 9 g I --.—- — ._ -... 01'] {IL . 11:1 ' [l.l0l..u-ul|l. -..," .-p ”—w. . n ’- . '4 ' . I 1 'I . I .QO“#W~“-'. _-.—.-- .-.- .— . -~ ‘T ‘7 I ffi T 1 . 1 I -, . IA . -....- -— . .- Mass spectrum of 2. Figure 8. Proton NMR of 2. Figure 9. 6“ p I! ..Ilub'cu. .. .IL.I'I.IIII-I. I .... l.’ 'l’l"l.ll I ' ... Q m.|ul|aIlII.I.I.i. ... I: gr.» p... ..I I I - IIIIIIIIIIII I I 9.. .5 I b I CI 0 -- i IIrII .I.. I... .... - ..- .15 .A . . . n _ . o . g o . .u I . ”WW-o; u—vd ~.-—‘ho-...- ..-. I . . Mass spectrum of 2. Figure 10. -.A L L'A q Proton NMR of 2. Figure 11. 65 £ I A. Ill-ll. If}. I‘ll ‘III 100:! I. «He'll Ill! I'll III I. I [A lllll'lv‘l ul ' I I: ‘I III: 'liuu.llctvll I ‘Il‘l I1 I III! I .'l.' 1 II. ‘llulll‘l I 100 60 40 2500 2000 1500 Inequeucv CM 3000 3500 ‘ l 300 1400 J G! 3C1 1200 “F“ 1800 1600 --41 EMT” in ‘IEGv. IR of ,3. Figure 12. 66 m 57 a; If ‘W «I who u a q, 5! ru l“ I" ‘ '| Jul 111']! 14' l I] l “ ‘1. I I I I I ‘1 go I» no no I» 10 no Figure 13. Mass spectrum of g. "*I*'*f11'+' 'vvv vv w T ‘3‘ ' { I {I I: T i i E E 1 rr' = ..a/ ; J k !2 a I . , ’l _____.__.._~..__——J- . ..__,JU y > F I; l i L. A! ’! _ii i; 1444 AAAA1 AAAAAAAAA T1+ rd Figure l”. Proton NMR of g 67 ’ "—W“ . ; - : ' —"“"f‘—— '“ *’ 9 , '_, - i * ._..__:.___.__-._ _ - - _A;i_._... - 1 '3 n 1304 I400 1200 H ‘C' 1 vUE’toE‘A Figure 15. IR of g. 68 7! W7 1! - a" n V .12 q‘ u! I37 In ’T’ u I I ' I ' 1P 1 .m I00 do 300 Figure 16. Mass spectrum of 5. MeO m“ —”*—— 5 ix I 1 it u .‘l A 4W. ,1; #1ka ”‘4' v v V wk llIjLiilllllillllllllllllllllllliiLillLJiJillLLilllilllLiJliLlllll b 7 ‘1 J' 1 I 0 ml- Figure 17. Proton NMR of Q. 69 .... . u .5...- -19.-.. - w . i ,. . .. .«a.ooaQI. :_9.IO.~:.v.a _ . . h . ‘. . . . .. . . . JHHHQ..uI _ . . D 0 . - .......'u.oo..- » V" . ,_ ..*.... _.4 .. ..Qic...o*1. -. . .. . . .~ . _ . . .. M. - .M .. ... ... . . . . . u . , so. _ IlcOOu. .-...J.IAI¢. . .-c'ollr.-io.l" . _ i u . _ _ _ .14.... .. _..-rat: .. A _... _...-..., -. .... m . _ _ . . _ _ . :.._. . .. i . . .h _ _ m . H _ _ _ m . . m m . w W , . . ... a . ILL" cum . . . . _ n _. . u u _ . _ .h fl . w . A..:a_ _ . _ . . . . . .. ... .... v v . , . _ 11:04 . _ _ i. H _ _.. _.-M 3 ... ._ .o w .. O . ._ .. m ”D v.9:ol‘016lo. .OOninllk.u - V.”'b .u H n _ m . _ ,. 3 H , , .. .. .. . .. . . _ . _ H _ . . . . .... ...: .... .... H . . _ i _ . _ . .u . ._ _ 2:. . . . . . _ ,. _ _ 3 'll. .. . .o . . . . ..d. . . . .. Int v.. .. . u .... .... ...-..._ .. 1 m. 3. p . . .. . a J! TIL - .. _ _ - .. a 0109'- ol’. III..IIOQ. o.-. . up. u o ... . ... .M: “ _~ M . , ” _.-.; . 7 _ fl _ .. . .Vo. c—h. .. . .. . ..—_. . o v ...a . .. * a _ ~ . —< . . ..u u — "Aw ...... 9.”. .... ..-. .... .. ..*. _. . ... . ... m .0...” . .5 ...N ... H . _ itl.OYO.ot 0Ln0* s. .... . .v “I V‘ctuw n . _ . _ ....“ ii . i . . . u . . . . . m , .. .. q . . . .. .41 . _.... ... ._. w . r b .w ”m ..fi .— . w .4 m . 140:0“ . .0. ~ .I 0.. .. . .... .... . . v V _ w . . - _. .. .all.l.o .4190 . 1..ol In... no 9.. .961 . . . 1!. . . . - y .W m :Q: _...... _ _ _ .. M “pf-T . ... .... . . m .— .... ... . . _ . . . u a .. .. o . _ F . On I‘llr :___ : _ . _ __ ... . .-.. _ "re-.3... .. ._ .-. . .:. -- 1:1.-33...- . . _. -. ; .. ”--.-.12}.-. 3.3+.- .. . . .. ..fl w —. ‘ ... m m . w . "ecu T...v....b. ....~._9..1‘ u. .. .Ma.. rs..oA I: I 1 _ a .. . .. .1... . . m-.. . .r . ... iv.” ..u u a . . . ‘_ .w .. w .— _ _ _ _ , . . - . .. .. .__ .. _ . _ .... . _ .4. .. _. ... u. . . . . ..-. . a. .- .m.. ... Jduusll - .p. .. ... . . ” ... ....H... _. ..h . .M. . w . _ . w nl..... ...u. c:.nwona m m . _ n . 1.3o._ fl . a , . vtocaiv..- ..0.+9¢ .-..O_ . ... . . . “0"“..1fluiflvwd ‘Qllr‘vbm loll. _ “.. .M“.. .H9/. _ A ..~.. ._ _ . . _ . . _ n u.‘ ..‘k.v-. ' Ploni?-l.il 0o .. .. ”_... ....w. . . m... 47.». “ . .. o. “. n i . é . . ... . h . ._. ...". \A . . _ n _ _ r. 1. . . .4 _ 3“ _ _ . . . u . h- g . . . . _ 3 JA.«.. .m.. .4..w. . . v\.‘|T . . ... ... ..~.. .H. v. 4 . . . H .‘ k. _. . . . . 1.7 s» .114 i...e i . . . _3 .::::s:. :. -_:...;+i-.zé. .Hi. i .... . u , n . .n _ . _ . . .k'b 015.1. ...fi. . . .. .. *9: . ..u. ....0 -; .p..- . . . . .. * V _ _ _ _ . .. ”AX. ...; __ .. n .. fl ” _ . . . 5 .. . . ... . _ .._ a. .- . . 3.-.:3... m . _ . - . 2 : __; _ _ 3 _ _ .9.. y... ... u.. ..Q-QIHH‘ . . *. .M.. .. ... . . . w _ _ . . _ .. -... .... . _ I... .... ... .. . . .b... -.. ... . .. .. 33......- - _ i m - _. i i W m i .vio a... . ... . o .. .. . . . . u H r H . u ..w.”.”. _M. .N _ g. m _ . - h .. . .... 1.. - ..... .. .. * i;- . .... . W..._ . . -. _ . .. _ .. _ n . fl _ :17... . 3 3 _ n. _ _ _ _ .t+.. , . _ .. . .2-3-::.3:- :7 .;:. _. .7. ..w-. . , _ . W N _ . _. . .. ._ o . “ w _. . 4... 4.“. .... . ... _ . . ... . . . . * _ . . _ .—._ “n. t _ ~ . _ w M H . ,1. ‘ .~ .. . ... .. u — . _ ” ...“ w H w . _ . - -.._ -. . h. pi. -. .. . . .14 . .. . . v _ . ~ . - 0 0 O P. .3... O L 0.4Lr: s -..i.--._! . -rl..s-t__r..-- 1: . 8 .4- 0 8 1. ....KJ *.F\‘4 ..--.- - loCQ IR of QQ. . -__.—__‘ ...... \ <3 1 .._..~-————. Figure 18. Figure 19. Figure 20. 10! I00 ll I. 70 137 Mass spectrum of §Q' Proton NMR of éé' 71 _...— con—......“ —. .— ‘ uh . _--—_.. I _..—... .. ...-__— -_. ‘“ _-'~' -J. . 21.-71'”: 7 éiggrv'AiJJ J'L.-.5..‘§Ji-L'1.-w'ali§:l.ku. "J1: law}! ""513. A"?! .1". - . J3 “WWW" ‘ “I "n!“fi‘fi‘ 3333333333” 3" In '3 :a .315; :3 3: .;?:;:T-f"i:s 7?} 3253' 37731 _LLLJJJ'IOIJIIILIllllllllllllllilll!lillll'1‘01 1 6° ‘10 20 A A L10 Figure 21. Carbon-l3 NMR of ég. 72 003‘.-4lo "fl‘lw .O-IMIIJ..IA.... N .-. .. .I .0». _ uglol I“.’1.'ll‘a.]JOlo¢ .—|0.C4’J,d| | . .-..4 Iu.n"|l0s h .. _ . a —. .. ..... 7...... .....— . . .. . .. ... .. m-.. ....w. . _... .. 4- . L: *. ... 1 . u . . . 1 1. 1 . 1 _ . 1 1 1 . u 1 1 _ . . 1 . 1 . . . T. . .. . .. L. * . . vo.v4.90o.0 :0-“.t soc-d»... . ... .Itu . ...! 1 . .M. . 7”; W . m 1 xx} . 1. .M . _ g 1 _ ‘ ...-441.... : 1:: . 1. .- . . 1 .. _ - . -. . .... .. ... . .111 1 . - 1 1 1 m . _ . ..-u m . H \.u.+ 1 .“1_ 1 1. . 1 _ 1 .1\1\_ 1 1, w _ 1 . 1 *7 a lint-I’ll. . .. _- . . .. T . .. ... ...1-0. -Oo. .. .. u no“ .- -. v - .1... 1 .. ... 1 . 1 _ 1 1 1 . 1. . . , 1 . 1 _. 1 1 1 . . a w — m _ n .m at. no u. . . . ..4 ... . 1 u .:. ...-.1 _ a: . - 1 _ 1 1 . , . . 1 1 _ 1 - 1 _ c .o . ..... . . .. .u.. . . _.... o4.c u . . fl . . . ‘ “Ibc 0.... '9’! .Y’. -. ... ..ro.. ...w.o — ..H .. ... . . 1 ._ , .. . t . - _ H 32111.1! . 1 _ . _ . . . .... .. .5 —. h _ w 1 _ 1 nut 1 1M . . . 1 1 1 _ m . . .. .. _ . .7... 1. .1 _ . .. a _ . 1 . L . J . _ .. . nu-‘..1 . w _ 1 . av P _ a _ IkJ 1. 1 . u . - .1... .... v. 9' .0. o '1 v« o tin. . o F. c a o lo v olo. a. v v o .3“ .- . L ..4.v. . . . a a. W . 1 1 1 a. . _ .. . 1.. 1 . . _ . .- . .1 : . 1 1.11.. - I _ . ... _. I .4.. 0|. . ~ 91v-‘-!. ‘ . ~ ” . ‘ _ . .. Ab _ J on o '0 ow‘. ..a g. .. n . ”.9 I 0.. “ m a .. o 1 .AT'il. . — .. ... . . . \OJ .».1. .. . . '1. b fi . .II« . . . it c 14 3 0.? I vet‘A v05 . 0. 0'0 0‘. A 5.0 0600 vovbl 7050. cl v: . . . .... . co I . 1 .1 . ...1 _ 1 1 «U . 1 N . 1 1 1 3.1 1 u.. .. . 1. .. . .. .A . ; :5 . 1 .. , - _ . . 1 I o .... .0... 90.9-1gfs- cho 9.0 o c a I o' . .. . v .. o. .l\ A It. 0 c. at". 10 C. . u 4. ..~ . o n... .VA-w.o.ovot.vov.o a 1 . w ..d . 1 ~ . . _.. _ _ 1 R‘ o. . .. . . . — .. H.. 1 ~ 1 - 0‘ .. . 0 . . q 04? F 96: .. .. do... I v” 0 - ~90? Oi..L¢u v.00. ........ .-. . . £4. 1 . 1. 1 1 . 1 . L .... 1. . “ . .1 ‘u. . _ w . . _ 1 1 . 4.. 1 .... ok‘» ....... .» . - .L.... a- a 0. V‘.‘ to o ._ . . . .. 1 .. _ L : . 4.. .1 O 1 . . . . . ., 1" 4 . Q'l ’l 7.00on b . it... I A u.# . I r O . ..1 _ L 1 , 4 L ...p .L 1.. . . n ] _... . ” coo ”.9. p... u 0 6. 04.. o. . of .2 11:... 1 . . . I4 I . __ .-. 1 . _ L 1 «a ... . . _ . m 7 1 Yb —. 1 o; I... a O o a . . o . _ _s . H m . 1 n 1*. . . — 1 T IO... oryto..vboav 1600 . ‘ n 1 g . ..¢ *9 .... .n .... veto o...1;oou.. ...I_. .- .. ._. . . .1 - ._ . _ .- . — . ” vor'L. 01.7. o! 0.0.99 0.0. 1%.. {:_vfrv- O-.. ..5. I~llw. .pv. o. ...: 1 . a. . _ 1 . P04. 1. ...... . A; 0A on . .— 4 a. —Hq . A 9!. o a V b no 0 . . “ .fl.) . . . _-.. u . .. - w O . . _ h . . ... . .m. . . .H T o...‘ 00.09 9F (M1? 0010.; u: 1;; no a ¢ 0. a .10. x. «74. 0— 0 ..vv .. . .. .... _ 1 1 . .. .1 . 1 -. _ k 1 _. L. . _ V- _ 1. 1 . . _”+. .u. . . * w . . o. 1 .L on .4“ .1» +4.-. Pf. to I ..5 v. Y bYA . A.“1 . o o . . ... . . ..u. . n. . . .. - ‘ .‘ 1. _..~ .... .1 . 1 h _- .. ”40. 4k“ . .. Mu: . . 1 . é .. ‘ . .*.¢ .. fl . _. I H 0% 1 341 W}??? 36!. .900 05.. 0.6; 6110-61. ol..41. . lob 1a 1- o. . . 1 . . 1 . . _ . _ . 1 . 1 . . . 0 on” w v .. . .u _..v. ....._... . . M u L .. . .uc. .Oh.rnwo..19‘..1 1 .1... .... c*¢! ...: .... .. o... ...l .L.. .. .s . ....... ... -. . . . 1. - . .... . ... . 1 . . . 1 2 _a _ 1. . .. 1... 1 1 1 1. ; ;..:.:.1.:.1._.: . .- . ;. . -_ ._ 1nu r. i ...-ll! lrl ) I“? In Lrt‘i! I'r .1! III 1" \_r ‘....l p I .. _ V” ..r .11. Ll -r1|03bll. Ir... p. c.- .I |.- m 0 O 0 O C . .... 0 O 0 0 O 02 O 8 .o 4 71 0 8 6 4 2 ] '.. Y 2.! (4,: IR of ép. Figure 22. 73 W “1 '4” [”7 \'/\1/':."‘. (\L/Lrpn- i '1 / J ‘MeO = mu m! ' 17 q; f :73 " " Ii I I J! ”1,.1111Hllu'lm In” I [J .l‘f’ ’f" 50 to (an [in Iva 12;. ’50 259 150 Figure 23 . Mass spectrum of QR. ‘) if). k ) 11 Figure 24. Proton NMR of QR. 7N \ CH '. ’ , No.35 iaé'béfigk’ .- . . 6"” f". . ." a ~ _ ’ '«5 ‘2' 3?: "ff; 1"": . Ah. .7 - . fi- : ; :3 ET‘I“ ‘ hi ‘I ”’5” II “1 ‘; . ‘ 6‘ - .“ ‘ a: fit I .l ’. , IV V, llllLlllJillllllJll111111111llll4liLLLLJEl"LL '0‘? .0 o ‘r0 I. Figure 25. Carbon-l3 NMR of QR. 75 -14 -.-.: ...: 3!. . a: ....I- .h HUM . an}: fiWWJ ”H «U ..... AU 6 mm /o 1 I. - - - 53$}... If. 1-\. EHHHM q. 100 80 Q o 1500 2000 2500 A‘1 dub; CM‘: ‘IEOUENC' 100 a . . . c u n . . . . . . - _...... . . . n . , . I i - . . _...-.-...-— . . 0 . - o “__— ..._1..._- . . 5.1—— I t: I I | ‘ . . . . . . _..-—...- ...—_-. T 1L- 1 _.-. .. 1 t- (1”: 1000 1200 1400 1600 1800 “if? *N’i ' IR of Q. Figure 26. 76 r “f. ‘ 10‘ M80 53' 7 ‘" I71. LJLR’JMJHJJ “Huh m. I ET .2: Figure 27. Mass spectrum of Q. ;i4 __JL _J‘J‘JULJL‘J 05/ng 1L11v.+1L11411111i111-11-1 .4 1 3 4 0 Figure 28. Proton NMR of Q. 77 MeO . -..... 1 f1 :1." f . ... 1_--.-.. 1- 111.111.... .._._....1. . i I 1.111 .- _. 1 _ 1 : i .30 I I .1 60%. i I . 0 l l - a . | - - 0 . o ’1... -1_._..1_.1_..1_.- -1-.- -— .—..__ . b ‘ ~ - - . 0 ! 'r-- 40 C. Q- .1- 100. R $0 IR of Figure 33. 81 ‘ In 1 WV :35 .. ‘ i 3 MeO 1m 1?! I05 10‘ 2’1 Jl J1 [I111HJ l i L, u 2.03 If! —}b Mo Mb 2% 12; Figure 34. Mass spectrum of Q. ‘v‘eé - if i , : r1 ' ~ ' 0 i a .‘ ‘ AA. . WV 1. I" '5' .‘~." K ‘ i , 1.1/L1 JLJ “L4”; ‘ J 111 \\‘-Ji1 l l L 1 1L 1L 1 1 J. 1 l l j. ' 111 J 1 1L 1 l 1 J l i i L I. 4' 4 3 L I J Figure 35. Proton NMR of Q. 82 Figure 36. Carbon-l3 NMR of g. 83 _ «W'Kh Proton NMR of 2. Figure 37. 8h .UII‘V.‘ .V fi-;«:e; w.<.:i-.a.V ....:-~-:Ha-.:.:i -u . V V .m. V.. 4. ._ .. . _. ..a .. . .—.A.W . WNW er. . _ .4 T.-. .. . .. .00 I . _ , +6... 1:- ... . w . w: . . . . . .I- up ur.~. . , .- . . __ovr...-- . w ...... . _.. _ V_ ... ... _ “ . . _... . . . w 0 o . . . .. ..... to?) .... ... .; e _- .f h _ i . ii a M .V . ...h _.ot,u........ol.vo.luav I'll”"91..f.7 0 . . . _.. . 4. , q q. _ o- ... i . . . , ~ . . . W .V .w . u a n .. _ ... . . . . , . . i W . .o .... ...” VV._ m .Vw..w.... .. ..V i . ‘ o . .... :.. : . ._ ._ . i, . ._ . . . n _ M w . m . V _ . . 1.;5.. .: .9. . .w. . fl . ... n. _o ... _ V v . . .i i . _ , N . _ H _ U . . ... m . . _ _ _ n u. . h . . . _ _ _ ~ - . ._ _ . _ r . .H 1 u _ on. . o a... .. ... . . . n . t. Uocw. . V .AV . . . . _ _ _ , ..nuu . . . .0 , . . . h . _ . _ h . . 4 e. . *, _ _ _ _ i g _ _ : _ . -1V; :T.J1¢i _. . i. H n.. _ _ .. ..H. .. i 1 . _ . .._. .. ...— . “ :... V L _. - .-.:_ V ~ “ . _ flU . . .M.. ... _ . AHV “ .nu v . .. . .. .w . . a o« w . _..J » fi . w .._ m V. . _ 2 . . t ..u .s :7.....'. .6..— __. _ :i... m V . L . . .. . . . . m . .p w... . . . . . . .. .. .IILM. . ; _ ... 3+..:__ _ . . a .... W. .. .... ., .Jv._ _ .n . .... .. .. _.~. _ $10131- 'ud+l.1 . m . u. ._ M J 4!»; ......IILTL . . . _ .4. . ...... .... . _ . .. .. tornav... . . . .. ... ., ... .1 . w v _ _ a -..J” u I; . V n H a . . , t. o......-.|v. .orvuuivyoLlh _ .Iu.. V .. . . \Inl .In-._-o9 A. . brad” _ ‘ .fi 0 .d... ...w T. . LA it-9§ITII .0..1An .. _ :__K ._. ..___ V .h .... . ' * . ,.r.. ..d. ” ... . . . . ". _.. .. . w _ . ‘ o o _— v -.. -— _— ~—*-- —_ “~— 0 n . V . . . - - . u u - O A I Hm-——-- c . i z, . J . . _ _..V , . w , _ F m r _ a _ . n . T .n._ .. .. . ._ . _ ., _ ... ... . - .o. .-...V “I . .w . _. — . M H _ .. _‘U . ..w . . . . .. i.. .... . .V, . w. -r. .. .. v.. .. ... . . .. .., . _ _ M W ,_ i . _ . i . e... .__ W . ... . _ . _ — . _ u e y . .... .... .0... 90‘... . ... . .. .... “ ... .fi . “ ... u .u . . . . _.. . . .. V . _ . fl _ . .. “... ... _ .M . . .. . .. . A H H i _ :... ....- .r _k ,4 ~ m. M _ H _ . m . n .. W .1. r..:h..:+: V... 7;. _ U _ .:%:.:L t: f” . m w i m _ . J . _ _ V .. _ __ _ . * . _ . _ _...“! m fi ” ,L-: ..-uz: .... ,.._ _ i. ...V W; .M; ......-._-. --s._- 8 b 4 8 l --—n .----.g ..- -..—...- _ ._ V_. _...-- —. V . . ...—V _.... ..--..- _... ~" I“ _...—_..-.. . .... _.... .. _.... V_ ,- .-..--i __...-.‘_- .._ __ ...___.V_.. . ————. .... _-..—-.‘..._ _. . ...- -.—_- ~__,_._ g _ __ _ _ ' . --.-_ -._- _-_~fl_ _ .-.. IOCO IR of $Q° _— 18L") ”_.- -... O a Figure 38. TIT W\/ 66 ' m: l g Meu I6 m H I ’1“ " ill I 1 J 131‘! 7:3“ 1‘" 7'?" 50 no :9 250 Figure 39. Mass spectrum of $9' L ! 1 1 1 1 Y “I"! ' 1" n .1: : 4‘: ii: I 'v‘l : w s .P/‘F a", 1‘1! , h {'3 V 9" ‘J " i J I“ . __,/:.4 W VA I ”lax x..- .1.-——l:' 4W «W‘b : i 1 i 1 I 1- ' :i i A — iL—fl Figure No. Proton NMR of $9“ - _-_- _l 1 Figure “1. IR of ii. 87 avg H55 m5 Ul . Jim... I 1 .3 T I [DO 150 100 Figure “2. Mass spectrum of ii. 5.4 i r : 9 r‘ ‘I ; .5 ..i t , i)“ i 9 J U'n. v”! i ! A ,Il 4, u ~ v x P 1 1 A l L 1 L l J L 1 J 1 L 1 l l J i L J. ‘é 3 i ' 0 Figure N3. Proton NMR of ii. 88 J . 9 I i + a i . , V LIILLLLLLLIILJAAAILIlllllljllllllLllLJlllL'l' W 2C 3 Figure MN. Carbon-13 NMR of ii. 89 I 4..-: 1.3. au.t.w< . ... .u .c .....-l. I. ‘\ 0C a-« I I...AI .3. II . . .i a . _ _. N . _ H 1 J .... _ i i _ , ..u . . _ _ . ~ V . . _ . _ u . . i . _.. i _ i .. . . m . __ _ .w H. _ . _ m .H i _ _ . V . . i .,_ _ V _ _ . _ M _ . u . M V .. a. a ... ”u _ . a. .0. . ...-I. . _ _ — .. . - . N .... . V 1.... . . . . i _ . n _ . 1U H _ a. . . .n . * ...O. .. . . J ‘ . . ... ‘.. .. . a _ . _ . . . __ . H _ _ i. . ui.'. . ,h»... ... ... h. .. a w.- 113—I _ . . i . . V i _ o _ . . fl .. . . . .* I . . , . . . i-‘OV‘ n... ovoa tuv. .... . n . o ‘a ‘ I . {H.xtb a... ,Qu 'I.‘ . *. u _ _ _ . .. ,. . p. A.-. o... .n.,+0-t. ......lb‘. l-IO 0..-. v.01, i . _ V __ , . , _ A... . i .. . i g ..I _ fl . . . . . . . u no o . t v . . :4 . v . 5 o .. i _ . _ H _ . .r . _ . .. . . .. . r . __ r , _ w . . .. . fiAl .04 7'1. 0.00 .00. .... 0'0. Ilii'iZ v-14... .. . fl . . . . . .H . u 4 . . .v . .o. c... . v .<|. cc woo. ... . . . _ ., c _ .. . . . _ . _ . . . .. . T 00.V v0.0. ..1. I'f.L v.6. .. o .*..- . ....fl ...1 .05. v"< «VOWQv'o. Ina... _ . _ V . L. _ A . . . . . .. .. '0- ..b. V . I — ..-- V 1"\I va 1 J hit _ -__._.._._..___ _.... ... . I o i 9 ~ . 0.; _ .IV r: l . . . 7 * xtec TIL . _ N * . . ~ ~ 'n‘.. "9 ’5‘. 0|... 0., .005 .v..~..o ... . o I... c‘. cool.o'.. ul... 7\ , _ . . \J . ... .. . .. . .- .V W .. u “ .... .. L? .. ... .. 1L1. . , _ . I _m. . . _. _ . . . .7 . .— . _ . . .. . . . . _ . _ ...t o 0. o. 4++. cM.. .. .9. .. . o . v . awn” o. o O... . co, .- . o I’d-volol 1 '0“; :.. ....4.n0b .oov...' cAOI 0‘9“... .— .,. V. _ , , r» . . . . . ... .. .. . . vV‘ut .... --.-.— - _.— fl . w ; .l‘oii V0? 11 wv.’u . . ,. , .. .V V V V . . . .A . . . . a... .... ..w‘ 9'... .. .... .... .... . .. ... . . .... '6'. .«u. .. .W _ 35' ‘ ‘ )‘J 3‘ I L: , . i- - _ 7 l 600 o ._._.._...—. IR of Ag. YB'JO v . ..-—.....- - ---- _. .. ._ ...*. ”MW. w.. ”.m. .H... . _ . . i .g. .. ._ i H. .w w .aw. .¢t “*u w. .H. .... . u _. . .. . .‘ ... . u. o. . _ . .ntoivtn vibawoc . «‘0‘. u v .9 . .4 .M-vof .‘.< .7 _ n . — V .:., 4: .L {V :.. ..V, . . . _ . .. .0 _ _ _ fl .. . ,_ . u _ T. ..Q. ..4. oHLdo... “ on e .. .V . . . . . .. ‘ . . u . .. ... .... o .. ... ...u . .. %. . ... .w 5:; a; _.n . . . . u _ . . i V. _. . . :_ ..V . _ ....s .u-. u‘ *4.. ”A... . .. .u. .... .V... .... . . . . .... .... ” a k . 0.60 9.." VOL; .x.. 040. .V . ...ofl...vvl.. ... . ..h.nl ...»..t VDI.~ . ...». .mo ..0. cm. Fh+. . o. >_. . ... . :..... . .. . . . n n .. .. . .... .... i. . ... . .. . .... ”.. V._. :h .. V. l— W . . .1 w . M u _ . .H it? It‘ll’lrl .- 5 tb.‘ - .tlubilk'. r 'tI . I. : 80 Figure “5. 9O M m “F V! 5; MEO 10! 1f H" ' ’ Bi H .7. llhnm {Jig ”A L.‘f° I 11331” to ’ mo' " we ' "25:: 2%.. 3 32» Figure 46. Mass spectrum of $3. 7| MeO ” (V I a : ‘ I l s I; . . " x " ll IL...“ . J' t ) O a‘J"~ ‘M ‘ * I. ’ ...-.14.. \. U' U ‘ «244' I i J. k L r ’_ \-’ R“ u - — _."_ ' \U x \ ’ Li ’ ‘ ' 111LL_LA'..’_11"1‘ ' ' I J ‘ ; i 1 A i 1 1 ' 1 1 . x _L =_,_ 3 L4' i i 4 Figure “7. Proton NMR of kg. I'm? ;‘ 91 MeO i un-s-v; . .7— .fi 5... u l ! i wk. my»; A:g;j.,g~W5W,W v waré~¢= m —. ..V-..“ - . --.-_..— -u91l .. gi “w '33“ if?!“ ”EH-l ' 5 a J 3 —s--‘~L$’~ éWII', L111] ILJLLLLLIXIJLJ LilliALlJu1+U1111lLLLLlALLlLJJlLJli11.10LL1111llolljlllllilLllllll Figure #8. DO 100 Ila Carbon-l3 NMR of kg. 00 -- 92 , ._ Q 41].".-. v‘ -7 _ ~ — v , . w _ . ... . .l'totolytf'll ‘ H Onlullfl'u H _ _ m _ n _ _ N . _ w _. _ _ _ m w . _n _ .imi:«m .;; Egs+3 . m ., _ _ _ ~..s . .. r o. .... _ 4 g. . . .. o .V.o.~ p-— . . o __,_. ..- ..- - - a~ - u . a . , -— - -- ...._. w.— . o . . a -— >———-.-—.. - ‘ - O . -.. u. . . . . ‘9 ..M w. J .. _ _ . H _ _: _. H .i fithllLl. . .l. v.. . ... . ~.o..w..:....a . _ .V .. .. . 4 A . . .0 . . ... n .. ....v... .i. ... _ _ .... .. . , _ _ V .... _... .....m. .. 3...... _ _ _ .... .. . .... . i _ _ _ .... ..._ . . __ _ _ .H r_:.:; .,_.V:.. n CV. «to. Mot.“- .. cl .In*.14 , , ~ F .V . . V _ . _ m. . . .. . . . ... v. _ . m V. _ . _ . _ ... . . w. i _ . .,_ .V _ .._ --.- ’- --- _-. ....—.. ....olrns ‘C'lfi i. i“! 1' .VJ g _o w . _ . V . , _ . .. V _ . V ... _ s .V _ i.. . s ...;._.-V I a b ... _. . m . m Wu H _, 3 _.....— --..-. .. ...— olno v’h', . V..... u ..T- 20‘ . .__. __ V} “I ' .— -~- 1:90.. '- -l. ‘3‘“ "J .. J I‘vsr‘ ‘La 1 1600 3400 00 IR of $3. Figure “9. 93 33.3- m? I I 195 I ' 1:21 15.71 179 I U I I 9 , I J . I I I ‘ . I; I I I . I I I ' 161 ' I 41 I I "a II I: Jfl I I I I I i 5- I; II 1 I. ' 37 9 1.11"} +33: 4III- -I'_': ': ..QIII".I hI IL. IIIIIILII.9 IIIII II.. 1. II II 219* 2’14 ~ '36 :..” ' T ; ' Figure 50. Mass spectrum of i;. W MeO I I I I ”III III AV4A\U‘L’ I Jw w I'Kx. LILJLLLIIJIL4111+1LJIJII b 3’ 9 .3 Figure 51. Proton NMR of %§. 2 l 94 ..-. . M. _ W _ III... WWW. _ ._ tiniltifide. .. _. _ _ _ ... - WW--—q_ ~---‘.-W C A- ......- WW... , a JV‘ 1:. ‘ . . ... _--...WVWW. -W‘._- I200 .WWW-_. ....-—-. o 1400 — WW. .. 30 A v 6. M - I _ _ H la. Ilrl. SH-.- IIYVVIVWII’I. . .. . ... . . _ W " . i _ a W _ W W . . .. W . .. .W . . _ ._. . . W W W W W . .V . . . .W W n N . W . _ . » . .W _W., _ ... ..r W w . H. W , . . _ H . . W . W W W H . a W _ W .W W. . . W i W .H V.” ”V. . .. v _ _, : . . . . _ W .. W . W W W . A . W W W .V. . .o w. .I .... I1 W . . W ...... W W .-J .. _ W -1 .....W: W _ . . WV‘ W w W . _ W. W W W W . .H.. . u 0 VI . W. W M _ .fi . _. W W .. . . n W _. .. :... _ H n r. . .. . . . O _ i m _ .. e W W . .. W I .9 ...9.. ... o ..W . W . M .. W i W 1.:U W ..W . ...—.... ...W . . .W .IU . o .L.. .... .. ._ . _ W _ ... .W _ . . 3 v .. .H W ..W _ ... .....W . ... W . «.L . _ W . T... W W W... .. . ; _ I.-. . .11.“...f .. W . _ W W W W . . . . . . _. .. .. . . . ,. . . W .W W _ _ W W W _ .5. .. ., . ... ...... . W ...... .... .” _.. . ... .,. . , . _ _ i . . . . _ , . If... no... . II V1.6 On '. .W . n— . . v —. ... A60"..- . ... .... n ’0‘ 090 .... W n _ W _ _ . I74- vl‘l':o . . _H . .. $.33..- - +--.I¢1:-II--.:-- .:.s: x -#;+.. . . W . _ _ _ . ..4 A _ L ...W . _ W W . W WT. WW WW..“.. W . W W. H W . ...W . W. W . _ v acct v . “WW. v. . ...._ .W W W W . W . W . W U... .. W. . _ W _ _ W. .W.. W.. W . W. . . ...W W ..W W . . W '60.- 9-1%}! .. .._ . i V I f. _ . ._. . . W . .....W.. WEW W W. . .. _.... . . . v . .0... .v. ob. .. _ .M. . . — i . W W . .—..W . . . .W W . W . ’01 no. A. .I.W.. W W t.o‘*t.v. D b 0.. l . W“ ..W. van. t ..W.W. .. .. .. .W . W.. W. W _.W _ W . _ W . .. .... ... .. . . _ m . W W t.W. . or at.‘ vb.... W. m . W . W . H-. . a . ..... W W .*... o ... t W _ 4. W W n W W W . . W W W . W W . H: W. ...W. W W W W. _ _ . . . . . W . .. ...... :..... W. . W , . W. n ..01 to . ......, W . . .0 IW.‘ ... .. . .w ._ m . W . W _ . . W . . _n ..w . . W . .. W -.. W .. W W . ...... . . ... .M. oi” .W _ A W W . . . i W , n,” ...v.. .YIW.*. . . W W W W H W c O 4.3! 0 ... uh I . .fi W I .Y.ot o-O-....l. o . W U . W W . W . .. W W W. W _.. 1 . W _ W . _ . . _ . _ .. O o .W . o u ..W,. W W . — W W . ...W. . W . . W . W... .. . . .. _.. _. ~ W W . . . Lfi _ W . W . W _ . L . W- I .-.. W n- .. III _ -WI I..- --. I-.- . Ir I . . r l -t W 1003 mu 80I 60 .1. 1004- 8 6C 4 I V ‘ u u ~. _-..—-_ ...—“.-.... ”_...... .-.—..-. .. IR of kg. Figure 52. 95 . ‘ 147 100.0 P 4 D 121 1 b 58.84 . M80 _ '1 , - l e 3 § 1 .- ! E r «.5 f : 1 ’ . I. t z ; i 1‘3 E . 1‘: I . 3 “' r :. g 4.1 J? 11 '9 I I :1: .13 I 161 . . , 1 t A II? N :e4 'V-g ! H" H '2 LI 4' :3: I" ,t I '33 . ‘:_ L J f TA“ A‘Yf’LA * T “I w A“ T— “1"“ J Ll W ! rfi— . fT A; X hui V .‘ A ' LL f L‘— H E '4 It“? 159 J)“ Figure 53. Mass spectrum of $3. MeO Figure 5“. Proton NMR of i3. 96 ..-- A—A——-» ‘— -._‘ —. _..—_-7 .50 .193131143‘. '3... 5.-..-. : ...o ....-.i . . ¢ . a. -6349; --.”...l: ... . , ...: . . . . .. ..L,.Hs . “I . . .. .... .L . . . . . . . a; . .. . ... _ .U w M . _ .v_, . , ._ . . .. w. .. _. . ; a . . k _ . w w _ w . ._ ”Q'OM‘J41H\ . ..Cl... . ... . . . . . fl '1! no.m!5.. 0:“. .m . sf. .. .31.-.. ...... -..-..zL T , . . u . . . . ,M . . _ . 411:... 4.4.4.4...» . . .. n . _ Mn. N . , m . __ ” . . . .. _ . . . a. . .... . _ ~ . _ . _ - W 'W— — . W m H .- . U . . .. . . _.u . u _ a w _ _ .. ... I... 0. fig»?! 9 . . ... -.. .... . H. . .. . . . l lo%*1.0w“u.n. .1 AI.. . . .. .. u argJ'I ._ . f H ‘ 4 . . .. . .. .. _ N A, . _ _ _ _ a _ _ n . n . . ... . . .. .......1..~J . . o . o . A a. ...” . m . - . . .. . _ . H . . _ . H m . _ 7 15.1.31; 1...- . . . * ... . I] . . . ... _ 19.77.. . _ . . _ . . .. . .— ... c . o ____.. ,~—____.-_-_. . . o ___.—..-—--..--._ - g -. _— - --—. --. . __._ _ . ..; ._ _* . . ..o.. .9. at“- . .- .d _ . _ _ . _ v . o.r _ A ...I .99. ...l to. .910 . ._ . . ~ I‘ 0"! . . . u I. . . A m -\ n... ...: a... 4» a u 0‘ IVOV .4.o .. O. . ‘ __._ L...,--.—‘- I - 1 : . - - I O ._ . u h _ . _ . _ . .. _w . _ . r _ _ _ ... _ ... ...: ‘._ . . _ _ $3.41.. :..T. .-..r ~ .. . . .2. . . _ _ _ . , . ... n . _ . _.J . . — ... . ., _ O. .0 .... O w—‘c.w.b - o. h — w . . u. . v, On... A. a u a. .. P. p. . . . 0| . . . .. m _ ,_ _. .m . IF! a M_» . . . \... . . . w 3*.-. w m . . - _ u , .. . _.... .ag ...I .. ...... 21.. u . ,_. ._ _. .w M. r n... L. _ . it x... . . _ .. . ; . .r 1.... .. . . . . . ._ _ . m . , . w . ,. N . Va... -- a .t ... u . ... .oA— 'fik .. d . . H w .6 c. .A. Dr... .9... a... ~05... — L. . m ~ , . _ . . . w _ t . _ . .;.a . H .. . .4 . ... ._ .. a - . . . c . _ . N. ... _ ., I: . q. _ .1! . . . ,_ _ . ..H. 5-. a , av. . ... .. . .... -.4. .+.* ..... o. , ... ....4!" .OI'Q. . 090.... Il‘t"~A..l *‘ . no .., . 71.3.. . ., . _ ._ . _ ... . ».. . H. H. . ,1. 1 .. . _ , . .. .. ,. . _ _ . . _.. . . . .. . , “‘11.. .. . .c y M ’+’.. .... W...v.-._c 3*. .— m...o ..wf0u417.!.l h... .... . v30 9.5. u . .O.. .o... “claiw'rtfi . ."u . . ,_ . v. # . _ I... .. 1.. . I... . hm. . ... .H ... . _ .r. .._. .. d . .1. _ _ . _ j ‘ A ‘ ,F D| 0! 11 h M . r bL-l‘l 0".“ 'Ivl r _..N- o . . .... 59,” ...—... -. -..- __.- 1% n A . b ... Q Q I . _. a. ‘ I ‘ V . u I v I ' _--—.....- 7*- UJ{ O .1 _,_.-_.‘._. a .._..3_ . ..f WJr. 7.4+: I... . .. _ w . .- --* A. _- , ‘_ “pf—1:14.-- _.'_ :3- . - “7.4%. ...—_...... . “_.... - _ {... _.... .-.—*‘p 7g. :m. . .7. 3: .I .. .. ... . .A- .-11 ..-. -... .. -. 3- ., . , . , “1M”. ..., ... . _ .i H . .. . * _ nou . . _ 7 . ~ .~ . 701? v... o... n.ano. - not. 0.0. ..v.t v01 . u.. n v. .. .... I . .rl .t . ... ...”... . u. _. .3 . _ . . . _ .. _ _ . . V . . . . . . .a ... . . . . ‘ . . . . - - n . v . D u a o i "- . . o I . . . . v A . .. . . . , u o , . .4... . . . .— 5 -...-—..~_.-—-.__-_. -... - . . . .. . u . .. . - H O I! 1.00 v‘.aT¢ x5 00" 0. .~ YO- v'.-.,. .... '6‘ .c _ _.... , _ ... . u . . . _ _ _ a .. . .. . _ _ _ _ . . . . . .. . . .. .. .. .. o . . . , — . . . n . . . .n c... .9: o... . . . ... .T. . j . . . .J , . _ fl 7. _ _ a .\v .. .. _.g — . .: 1..-...1-»-_...l cl! _ . . . .- .. . 2 f .L... _l. ..-... -‘ IQCO ‘ A 'J l \J IR of ég. 3800 ,x,‘ I. ‘V A o .. *\ Figure 55. 2000 97 r‘ v' c ‘. \\ Jib) LLfl/ w \ 4 1 1 1 1 L 1 l 1 1 1 L I 1 1 L J 1 ; L I 1 3 l I 0 Figure 56. Proton NMR of %§' -- -- 98 -- *4. o 4‘...—« ..-t..“ I .4 nu!) ...-u o i 3.. J «In: «‘fltll9.‘. It . I. c.lla0‘l’ I. t c. it . .lnl. u. . . ._ . . .. . __._.h . . _ . .4 4- .:..: . . .g :4 . _.. 4 . . . h i _ . _ _ . ‘ . _ 0.. . .... . . .. _ .. . .w . Ira}-.. _ _ H H . . 4 . _ _ 4 . . . h _ .-- '5... .filwquwinil' _ . ‘ _ — A _ _ . _ h , f!" 4 _ . . ... '0. .... c...‘ n u. o . 4 ct I655 00- ...00 .‘u.. v A .m.‘ . i I -.-: ..l ’0‘...» , . . . . . . .. . ..v'. v c. s .- l-.|I‘I|.I‘|OOILI . , . u. .04” u . . 4 .Q . . . .MA:...._._ -rzus . i ._ _ . . . .. _ _ . _ . _ . _ _ .-zi.::.?:.Mzri-i;uw.m+3153:y. _ , . _..;:-+z H. . . 2,: -7 _ M .r: E rt... f,r.1.....--2 _. . _ _ i ._ . . . u . . _ .1 . . .. . .7 . .-.: -.L..- n . . _ . .” .... .... .. _..._ m _ 0 w. .uota .....‘I‘Ia bl . l. ..l .. ~ . _ _ . _..; ..u .irllv..vui.-»lonufioi.w .. . , , . . . . . ... 4 . 4 _ . 4 k . . . _ . _ M _ .N U _ , . _ _ . m w .... hi... v . 9... ... .. .... .. q . ... . ._ 4 . u .. u _ _ _ fi . _ . , _ . _ _ . .1 N .H . .. _. _ .. . . . . 4 . . . . . . ,i . . i . f . _ 4 _ . . fl . . 4 . . _ m ....J. . . . n _, . at.... . . . o . .. , . . . . _.... _ m y . w I _ 4 a i H ._ . . _ . fl . I‘._ _ . ~ u . . . n. _ . .. ... ... _.. ... . N . . x. M . . . —. . _ . H _ A I” _ n . e * H _ - m _I; A. _ _ .10. ,. . .. ..~ ...»: ._.,.. ..v- .... . .. .. . ..4 . . . .... I...“ .... ..U , . ...: ...._ . . . . . .. . . . . .. .u . n . I _ n .. . . _ .. . . . . .4 _ . . _ _ ..r... ... . . . .a . .. ... _.... ..o. . . . . . ~. . ._.. . _ . f n _ ‘ w v V \ . _ .. o-C .- ._. ._ . _. m. . _ ._ . . _. If... . . h 4 . . o. . “_..- -——-—-_. .‘-.----. I . o e h u . u o o l . - .. _._.‘ _ o - 0 . , . a - . .. 4—.“ ~~-‘.O—-.O———... ~.- 9 4 i I ; MeO _. O n D O‘ o > n P v o o a . i . ..I..-o.. ...... .. -..llrnrllolllvn .vl. .. . 'l I'bl _ i _ . . o. ..ow — u w _ _ u. . .... . . . .\v .- ... . . _.. u . 3.40.! . __.... ..vY ..., .. a “ . u . . _ 7. , b . . . q _ 4 i H . _ 7,2 . .. . . :..-L 1.4:. .14.»; ._ _. _ _ . ... . 3.7:! ..s. .9... :0.” m.“— w .-. -- ..I.+oo.-T 34 i . ._ . . . .. ... . ..U . M .. . .W: .. u." . ._ . _ u * . .. .. ..\ H . ... ... . m . _. .4” . ..~ 0. ... . . u.... ..s. H~*. e up .. .. . ._ . .L ...4 ”II.— “ ._... o .. l. . . 4 1111.13.91.01 ill}... ... 3, u w . . _ _ u . _1\ ”I . ...Hz. 7. ..Hw . m . 011. , I - v. ..c.o .... '0'] 9.1 . n .‘A . I u . .I .10.. t o IIII ‘9. I! .... . _ I. I ...o.. 331173;. . u‘cl-.. . I .. * _ _ a .\ u. u h A . u 1* A _ ...“ .l _ . .. ” ‘ -0 4. . b n . _ a .+ . . ... .. .4 .. .... 4.. . . . . o. o. ..A . vA.. .. . _.lc. .....I.no r. :.. , . .m 4. , . .- "AOL. ..u . _.. ... . . _. . .0 . . “1 4U * ’J . .. .1 9.1.1.44... ...}. ...: W... V... .r fluidizfi? ..~. _.L 8 Mar-.. -. f. :_. -. --. . . H _ . i A .. . . -. . .... 4.... -... 95.19 '4... v. . . ... .oe.T .41!“ v3. .-. .-. . 2r .4 H . .. i 213:: _. .. __ _ .. fl 3 i . ... M _ g . M _ .L. . ..... .u . v : .... . .+ ..r.L y. ... . .... . . . . _ . , . _ . fl. . . .4 H... :4... H: 4... 41;. .. .. ... I . . ...... _... . 4 ..M... .-.... . . . 4 g: .. ... _H .. 4. 2 _.. . .._ . . . .. . , _.4: .4 .n. ... .m ... f: 3.. ...- .. _. - _:. .. 4 M i. I“. . . :wIHiJJroT . _ . _ .. .... x... .. .-.T . .. _ ‘99.)" .. a . ...; _ _ _ . ; . _. r _ . . _ i . . i, . -...-. ....-- _ _ . , _ _ __ 4 _ . — . 3... . .. ..u. .. . ...~4 .4 .4.. .. _. . . ... . . f . .. 4/... . . .. . . .. . xe _ . 4 ts :gs _ u 0 m g i :“x...i:..:.: 4 .. . i .4... . ._ .. . ...: ... :.- . . . i .. F i . w . . ....l... i...) - 1. . w . . _ . o. .... zioiv'vl zit-... . . .. I . . . . ...v. . o. . p . . _:.:._, . .. . . .7. F . .. Au . _ .. _ . .s;;::x :.- m . ”a“. ...-.... ... .v.-» .0 .... v.... .o. 90:. . a «u . . n~a A'J . _ IITC‘I I0‘O.UD .- ‘q- u . . :.. . ....” . ... _... __ ... . _ u U. . ._ :...E. ..L. . . fl _. n x _ _ ~ i . . . _ m L... . fi _ a _ u o“ n A a. u 0 - o n. .- guy I I-Vn 0 A. o I. — _ . o x 1.. t t 0:: . . Out I ‘ all e. I In. 0-0 . u . . ._ i L A 4 . ._ w i _.... ... .”.. ... .... . . woo Iwub out 0..“ ..... — ..4,. . ... .u w . .. . H ., ._ ._ _u — .. . ..v. .... .. .v.. . . ._ .. .. .. . .. ;; . ., _ 4+ u _: . .. . m _ i . 4 .. . r. .m. 1 ~ . . u "r.;..: .: _;; . ;:.w.:..:. H.. w .. .:;::.:1;.::x....;s:-.._. .;.:.;:.-.:.s; . .. .4.. u .. . .k. m .i . . _ _ w _ . +4.. .... . ..*.o. o .. u . . at. ...-“1 - . o . i... . 4. ... . .. h _ | I L 100% .4...‘ —“_—-.“ Q l l- d P. IR of %Q' In! Tvl . '||I| ,Il .. .v'lL'. Figure 57. 99 195 l ‘ u A 4—4— | . 7 T T MeO L66 I : I I I I 3 .1 1.5L -4. , 163 I ! € a l I i 121 109 1 vs) 58 ‘QIO - Figure 58. Mass spectrum of gé. _L A L L L l L 1... Proton NMR of éé. Figure S9. 100 14.4 . m u. . 1 I _ Vd‘! * .. . . . . . . .... .... .— . +__ - _. .-—. __— .. $3.4. .. ..ctp...l....... . . .. . .‘I'O'QA*I c. '0‘ ..W Dlfiii‘ nt"! ... rol.’oLtlloubo... _— -———— -..--. ..—.‘___—.— _. a v - . . . . - ‘ . v.5..nt‘lr L oLan. _ . _... . . .. .. .. v1 — c . _ .. + .. _ . llr 0.» q inn... ...-.14.. _ fl- .h. .... .u. .... .. .. . .I ..... a... .or. :..?4 obi. .. . .M.. .. . .. _..4 . .H.. - o . _..—. .... _.-.~—_M.. 2,». Y _ _ . . w. u. ... _ ._ 4.. . m . m _ ... .Ia‘4.'.. ..-... ..-—.—~__._.__--—- ~-v-.- . . . . ..... 2500 .... _-——.._.-..-.. ‘fl- — _.—.—_.. i . t 5 ...-...... .__. -.- .' .I ‘. .... .a .¢. cv.. .x. . . - ... o. '- v .0.- .0 In: no... . .o. a 1 at o‘b. . ciao ....VQVOQ . 4.... .. . Q.A. . . ... no. . n. w c... i. . ~ _ V. ‘Oh . .30. 000‘ , ... -‘.. v'.o 0r. . .‘ c... +9!v.# ... ..v‘ . . .... . .~.4 .... .iv‘ .l. I 1... .....‘T. J l . h. ...”.OIO . . . . .. n... . . {- . *‘. .- .. . I'- .‘~. . . _. . ..V“. fl Mk“ . . , . u. v.‘ . v . c... -A V‘el . rul tiLr. v ---“...— - -, ...I. ..- . 1 . ‘— “allLo: all ““15..- ”t. ._ 4.. .0 .-oopvhl’ _ _ “ .... -. a 0 ~ I l . . . _ 4 . . _ .5 . . . _ . . . .. .n . . x . '97: . v . h _ . _‘ \I..\.6.. . . . . 3,. _ a u. ..va . v . H II ‘ W s .4 . . . Q... I. 1 fl ct ’l. n . a. . art . . . . .o _ - a..ll.. . _ _ 4 _4 .. h . . . . . . ~ . . _ ~ A . _ r . .1 — .4. n. c H . a . ... . _ _ . :... . . . h . _ . . . . . .,..:.:_ . _ . m _ . 4 M m . . u m . M . u . . . H H M . .. . w h... 4 , . . . . . . , . . . . . . ._ U . . . . . . . . . _ . H . — .. _ . . _ . . _c ...... 0.4-.:— I q H _ W. . w .. — . . . . h . _ . q . pl..L.‘IOTa . . ~ “ _ .30". I’ll! 1.0.. .. 4 r0 . .. . .4 . ..l....! on 1'." .7:-\ ari.rli.l‘l.‘l* 0.1.1 I F. u y . . _..-...nliJmal-.-.-...- . u .. . -.-? .-..-. .- ... _ , . w _ . , . 4.- . dimly...“ . _ . -a a. :..-O! - . . . .. . . . _. _: . . .. “av . . . o . fl . . . _ h a _ .o c. .'o 2.00 to.“ x m h ... , _ H _” ......; ... . . . ..-. .-. . - “...J ....M. T. . . . . . _ . _ . ....T::..+uLE. f... . O _ m _ovt‘OVQ _ Aol'u ‘5'. 0.. [to GA I n...“ ... ....» _.. .4. ._ U. . .. .. _ .‘.o . undiv.*4. .t .o a ..w , .. . _ . . ., _ . .. fllfunuhnn'. . _ _ .4 ii. ......I. unwAIrHOH .. ...;On.’ :..}II. ...-.40... 0|...“ ...4...»~. .. . . .. to . _ . _ . o 13* .41. '37:; ...... - .._.. 4 _ . ..-- ... U. J‘ r IDIOPHH. ...»..fi‘ u»”. . 7‘. vl'..j¢'y'i.. , . m . _ . ..4.. . .... .NO- .w.¢ . 4 v _ . : ._ b . ..o oo|t O¢~0Lflfo vo-1.. . 1.0 ~.. ..I . . _..; . _ n . .. ... M... ... f” . . . .. . .. Q O--IAVIO‘ 00‘» ’ m bl n ... ; .. . g . . . u . PJ a1. .I ....“ ‘qU fi~~. LJQ l !800 IR of éé and $Z' Figure 60. IQJ - I 4 ! i i A 1 9 u . I ; I ‘ i ! - LILIIIJJJIJIJJJJI 101 H m i s i 1,‘ g I 3 3i? 5% 'l ‘33 ' 23:23:14, I“ L!!! . .. ;m;»4uhiirimfingfij 95') {$3 '7 6 Figure 62. f 1 MeO Proton NMR of &Q and $1. a": I i; l 1 if ‘ _ 1‘ ML!“ M .I 1‘.) MI‘ .3" wk L11.-.,..~_L+_1 j 1 :4 '_L~L LLi_J 3 2 a 0 102 , o. .. ..QQQ‘.OAA].IJ_1C:|¢ -.¢041.| ‘3 0.. I. 0 t O 4 I _ .4. u H I! ... . .. ...... . 4 . ‘ .. W i. a . M . . .w . w: . .“q —. . ‘ . _ _. . .. . .. .. . .. _ . _ _. _ _ * . . A m4 . .4.. .40 ....Fcua .. .n u o d — .-.v _ _. . ._ _ _ _ . . -tp-$w: i-" _ . . . 1 i. . n .. ..-... .- 31.11.42! . ., . r.. u w. —. .~ 4 — — .4.. . . _ . _ . _... ...” .. _ i . _ . ..... .+ .. h . m m . . ..LH . . . _ _. w . .. ,4. r4¢l‘. 04. . * 4 — ... ... .LH”. “ m w . PMv . 4.. .95.. y L. . .. . . _ G __ é . _ _ . 2 .g .- u .i, . r, : . o _ _ .. w . _ 7 . 1 . . ..... _ .. ._ w.“ m .H .. _ ._ _ _ . _3 V4. . rt 4.” .. . _fi..» I _.... M .... w .‘. . ...-.. ...... 4“ w.“. 4. . .._.. _ _. . . m w 0 . M M4“ 0 144. v4. «.96 Oath ... 4.- .14.v . .. .. , . . . ... u‘ .L :9 ~ — 4 _. .fi“ 4”?“ u.” m ....® . . w. _ MN)“ . 4 o “L. 1.14.. .7. .. T. . ..-.m. , .“ h .v “v v _ .. . 1:-.. _. .. ._ ... 0 ..J. ..n .. .. .. ._ . _ . .. .. ...u . 4 . _ 4 _ ... .44“ ...»n. . . . u— ... . v.L ,.~., ... _ u o. . _ .. _ w . h . . _..;:+ .e e . . ._ J u . . _ C u ....4. .M.J.1J . . ‘.t.....y . ‘ . M .. o a w. (a _ ... "a. .“u” ..Olvga’vaO-fo onto” ....“ — . ‘ . H a 4~.. .4m. ””4 o 16. h..:~‘.'|.ao’.o¢.... ....fi . . _ H _.. :_f .u. . . M ._ ...—sz... _ h .1 w . __ _ . . 1.. . . 4 r ..V"... fiijfljffi! .. .1. . .. . . .. . . . _XLu a i . ._ .. . . .. .. W ., H .. ” WW _ 4 H.. .. _ . fl . . . .. . 4 4. .. . ... ....4 . . . _ _.... w. .. 4 m u — n ...:J .»_n 94 4“. u. .. . t _ . . _AH. _ if i t . .. _ _ . m n a . 4* ¢¢... H ._ 4 .4 _.. . . u . _ . ..U. .1. . . H... L. .. _ i v .4 .n4. .4“ .... . .... . a: 4+. v v. _.. _. . h . _. _.. _ . _ L. ... 4...... .. u “ F. m .v f... ...-.0. .44.; n 4 A . . fi. ..o.. v 8. 4 . bu w . _ .i _ . .. . :... w .;e. .tfq . . + M... 3 . . .0. w 4— o... .4,‘» 4.44. . ... .._. ~ n. u: .. .n It. . _ .u _.. _ . i N g 8 ..... ..H..:_.... . .... .... . . _ ._. . . l . ... _.. ”I ._ . _ ‘ u 4 ..4. *4. .4 4%4. ~ on. 4 . ‘ H. . f... . .. . . .0. _ _ fl. _. i . . . . _ . ;:_ .r.e. _; ..... . H H u m . U . o . w»... ...". +4.4 0 , . 4. d. ... . . m ~ .. .a .9 :_ . A_ _. .. . __ 1:1: . L 3.. 1.4.1.... .... .... N... ...... ...... . .4.... v m . _ .... . .- ; f .. ._ . . ., . ... .. . . _ . . _. m .mn.t.:.::_._:..... .7. .5. p— _ i ”I O . . . .r . ~ . . w 9 » >P_ L». _ : Fr _ r » .L.» r :blt-,.._.-o-.. ..-.»o'o ... C L . . .II. -- v.-rbl all.-. — --., . . . , -II. . . n). a» 100' 100F* IR of &§. Figure 63. 103 (I) /H 13 ”HI ,1‘1’..TIJL_ .-flf’m 2913’. r Figure 6b. Mass spectrum of ifi. i , i _jLN‘ uu #44:” -/ jj\~. ,/k‘i44 ‘ 1 L11L4L1L_LLL1111L14 3 Figure 65. Proton NMR of kg. 1014 Figure 66. IR of $2. 105 1r " ”b fl ’6; ‘ m! 5! v fi'i ‘ k 85 .l ‘ ill '_ l [87 . , - no (,0 x to [no no [In Figure 67. Mass spectrum of i2. MeO Figure 68. Proton NMR of $2. 106 ; . i i;w:i.;4 A-44444444jl44444i444L4444UJ4JL44444 [111lllllLlllllLLlllllLJLLllULllllllllllll11111114Ll~gj”H ” ’0 3: Gm [50 1'0 110 1‘ 0 Figure 69. Carbon-l3 NMR of i2. 107 9'-‘ ‘<~ - >"—-V' "— U '+‘_“ '— J, . ' . —-.'_'_.“ . W—f—"_'+_’_I. ‘ 7 '7" J C' V ' - ‘ — 2 C') “,4! 1600 1400 1200 h.‘) I Figure 70. IR of £9. 108 ”EN 71! i W U [1" m If “5 n1 7 a 1 :33 { K ”7 W7 1 20! «a I.» so I» m In no we do Figure 71. Mass spectrum of ag. l . M wig ..J'M—4._____. 4—4/ 0 1%; 3 L 1 l l J__L 1 #1 l L l L l l l l l l l l 1 1 l : 7 3 1 0 Figure 72. Proton NMR of £2. 109 Figure 73. Carbon-13 NMR of £8. i !1 I : i ! i LL__J ‘ L J 444J’ juJ - ---LAA 1 4 1-._.L L -A l- 10 no ‘10 4«4N.1< H .....adulal. .4.-'4. ..fiul .4 .11. ...Jo..va.. I. .. , 4. 4 12' .. . 1. ...-‘11....14‘9... 1.1- . . 4 . 4 . _ ..., 4 . ... . U . 4.... 4.4.w4 44.4...44 IL. ..*4. .... — .4.. ..4..... 4 4 4 m . 4 . .4 4 4 4. . 4 . . w . 4 4 4 .. . . . 4.4 4 _ 4 _ . . _ 4 4 ‘ 0.40.6'.-L0"¢|n| . . w u 4 .4 . - 4 4 . 112.: .1. :13”? . _. 4 4 . . . 4 4.44 .015'o‘ll 4 .4.... ..H". .._ . 4 _ . m. 4. 4. .4... ¢ . a _ _ 4 . .. 4 U QCVIo‘tII — H .J. 4 4 H .4 4 4 . 4 , _ . 14444311... .1» . . . . 4 4 4 4 . . 4 . . .4. 4 4. . . . 4 ... . . . . . . . 4 w . . . . .. 4 4 .. .. .4 _ 4 4‘ 4 , . 4 4 — 4 . 4 . %. 4 4 . . 4 sq . _ ..x. . 4. 4 . 4 V 4 . 4 o. :04. I.- .4.. .l 4. _ . ._ . 4 ..491 u- . 4 . 4 . '4 4 . _. . 4 4 . . 4 4 4 4 4... 4 fi . 4 4 4 4 H 4 4 . 1.. ... . .6. ... ..V . _ .. 4 4 4 u. ., .u. . 4 . 4 w 4 _ _ . . . .. . .1. . .. 4. 4.. 4 . 4 . _ 4 4 ...;J 4 . 4 . . u . 6 .4. .14. 44.43.. tvv.f‘|¢cwio..fl ... 4.. ...V. a.....0?. ..fl . . 4 . .4 . 4 m . _ e». .1. 4 _ m . H 4 4 . . .. . 4 .4. .. 4. . .-J 4 .. 4 4 4 . . 4 4 . 4 . . 4 .4 O 4 . .. .. 4 . 4 . . 4. . 4 4 4 . . 4.... .. ..w 4. ;.......4 ::4. . 4.. . . 4..; .. .4 -..4. ; . .. . . . 4 . n, 4 4 . 1.4. 4 4 4 .. .. "7‘ 4 4.. _ 8.... 4 . u 4 u. H .” - . m . . . .. ..4 . -mvvld v71$l v *2 .M.. 4 fl 4 _ _ 4 4 . . . u _ 4 . ~o1H.‘. . 4 w _ . 4 4 v 4 _ . _ .1619'1141 0.1... L. . u 4 . _ 4 ...}..Lviul V... {6... . 4 w. 4 74.. V 4 h“. a... 4 40.1“ n 4 .4 . .. . 4 ......1-- ..1 . . . .. . . 4 . 4 4 ._ 4 4 4 4 , . _ . 4.. .... .4.. 1'. F451I. I A...- . 4... . .4. m _ N W . n11 - .. .u 4 U u . 4 m . \l. . . h 14 . 4 4 . 4 N 4 4 .4 .. ......4111v.o.44.. ....wl 4h4. ...m . . ....w4 ....m-.. .. w H ”34 .. I 4 .. . . . 4 . .- _ , 4 4 4 4 . . 4 . 4 . t v _ .. . .4 4 .4, .4 4 .. 4 . 4 . . . 4 _ .3 4 . _ m . . 4 u . _ . . 4 _ 4 fi . f. m . 4 . 4 . .4 . ... 4,:. b... 444. '41... . r4 - . . 4.4 .. 4.0 . . y M 4 m 4 4.. 4 J 4.. n .. _ _ _4 n A. . A. . . .. 4.4"... 4.“ “AH.O.f m m . .. * 4. . n . . 4 . . 4 _ _ . 4 ._ “..-“.U. _ . . 4 . m 4 _ > 44..*0Y.4L.C4Iv0413 O'QI‘I. ‘0‘ .0 - 4 . .v- n ..o W..lt " 1 ‘1. 4 .. . 4 _ .4 . . _ ~51 {_.. 1 4 ~ . 4 M 4 1H .4 h. 4.. .4.. . .4.. ..._ .4 . . 41.10}. .. ... m. ~ .4. o ofii * ._. 1.4V . 04! #0.] 0+. OAY'O4 ’6 ....Q w .. 1‘. .c .4fio‘. . o. . .. 4 . 4k m _ _ 4 4 .. _ 4.4 .4 . 4 4 4 H .m.4 4. 4 ..n. QH44 40.4 4. ..IA‘ . .4 4 . ”4 , .4“.... ~ 4. W h . 4 . . 4 .4 LYQ.EX* .0: Q. a D m w ”to. — .. .. 00... ‘0’ 46-. 0-. 044”. . v44 4 _ , 4.. 4. 41. 4 . ... . . ._ -. 21...- 1. ...... .1... _ ..4 b 4 . _ _ . _ . — .‘. .4 4.64. 9.9”... .dtq 4.4.. .v: 4 . . w . . 44 ,0 . — _ . . . . . . 4 _ _ _ -. ..+. .I 4 .Ifin.4. .l- '00 151*... .4. I .0.» .47.4. . 4 4 . M4. . . . . U 4 O _ . .4 . . _ 4.. .4 . at. . . . .o.4 . 4. 4. .. .... . a . 4 . 4 4 . . 4 ”A“ 4 u .4 n 4 . . m . 4 Q 44' .0” I .ot.wv016 0'... ..V... i. ... .4.... 4 44k 14!... b 4 h on . n. . 8 .4. . . . . H — m 4' 4h. . .... v. .. .... . 4. 4 .4 . 4 _. — n . .4 4 .4. M 4“ a... vinLlLfi. 0.6.04. 1. . ... . 4 4. 4 4 . 4 o H 4 m4 . 4. .74 . L: — 4 4 . . 1. -5 h . L 4 1H.-. .4, .11.?111. 11L? ...1 1. 1.. AL... .V 4* .. 4 4 ..V 20 IR of a;. Figure 7H. I 1 111 p p .P. 11:11. 4.1.111ll4 L1|1 I -89 149 4 Q4! 11'. v0. '11.--.I'1lil1911 --.! .1111 .. a... 1"!" II’IIIII'1 01011 4 1.1 1.1!!!! r 'o u . III-I. -1 . 4.. l1|ll 1 .... ill- -n lfi. a 1| $.31 .11. 1 1.1. '1 I. .411... P1... .11 ‘ 4. 'A I. ..I \J IA 1.. .U 4.4 .11.. IL or. ‘4— .l V. | ill. I. '1" ll Ill ‘ 5! .. . I .. . v 9 -11.-- . ..1 fl. 1 .1. . !-.-.I“‘|" .II '. - l' 'l - l 5 1'1 1.. O I «I 0. - 11 I .1 . 1. .9 1 A 1. 13.1.. . 1 1 I4! 1., 1 71 Mass spectrum of 3;. 1 11.3'1‘7' " '- ‘ *1 Ifi‘ Y W J‘IIO'AI7‘ 1... ... '24.. ..a'-.. IIDI .II..11III..11 ‘9 1 ll...- 1 I1- I... l .4 31.11. 1. s 11 1 1111111111.! 4. 11 1 ' all VVYVIV.V 1m40-1 ”E Figure 75. 'U Proton NMR of fig. -L L_1_ J4 J4 1 4.1 Figure 76. O...- O ( ---——O 4 I , 1.1 ‘ l "I 1 ¢_._.. - uVIOI TI 1 _ . . . . ‘ . . A .1 .. mHanuJHL _. ... ... fi .. . . _ m. _“. “L... n .— .n ._ . m . q — — m ... ....o . . .... . _ ~ q . _ . . . . ..... ..‘o :10. . f . . _ . _ _ . .. .... “-...-- ...—-—_ .—_——.. .- --‘—...-- _. ‘- _.--- ..-.—_._..._. 5 , 112 ”UH I _ . " .fi . fl ; ..M \ . A- _... .. -. .k. . . . . n _ ._ _*~ ..._ . . . a _. .v.* I, . '.- o .0 .1 . _ . 1.... :4. _. a .N.. 4. . z:- N g t ....vil v..LoOo. #1:.“ T f”. . ._ .. j. . . ._. WU . .. 11,374. :1.... .T O . . _ ., L .. . .. - I... . ..1 . L e u 5 . . .. .... .fi. LT, w. .. m. 1 w NIL _. . . . « h _.. _ .N. . , . .. . o... . ...m~ .... . .. . . . . _ r . ,” _.. ..r . . . _ _ . _ — A. L..oa.jvv.vvéua 4 I: ... .... _. _. _ a ,. _ w y _ .. . . ._ fl — . . . .7... . _ u. ,. . . . , ; a a . . . *.; ..2 . _.. .. . “ . . a . _ _ .- > ..t. A . .«5. _ ...Afbrll c§¥.0.l0. M a . . ... . g . _.. _ , . _ .. v _v . u a v. .... ..L M a _ ‘ v. _ . .. ... . . . v . _. . .. . . .. . _‘v . ., . ._ j~¢n o‘.uv o. . s A. . _ .w. ~ N. ..l... h“. {fio‘Lr-O ... V... .50 .vut no! a... b L» L4 ltl n L , . _ . . u . 7.. . . .... . u . _ u 3 _ v . . ... ., : _ . ; ._ ... , A _ . 4'4. ......b «o . . .N a* . . . .H Y. .5. v1.0. ....6 t: 9.99 ... . ~... ... o.. u or... . A .0. ... . W . . 7 w ...M. ...: . . .. ....h. _ _ .m 4 ..M ...H «.1 .M. ._ . . ... o 5:. ..r. . a ..... .. .. . . 2 95‘ .3. vrtv'rlb O ”15.0 a 0. .t. ....4.. {A n ‘vlo‘b .A , o t." .. a . . _M A » .7 . . . Olv Ir .d.. . .4 “_f ..U. . . . o q.. ... .. — . . . .y.. . _. _g. .‘i‘. .w . _ .Fa‘ urc. ~o '_. . ‘ ... . . _A.. H.” ..u m . ..V. up.“ Ca.» '7... “...!o. . .MA... - w. .. ...: o§.|. I. m V ._ m . ~ ,_ _ . ._ . .. .. .. ... _ . .. .. .. . ..... . . .. . _ . . . _ ... . _.. .. _ . w s _ H _ , . .-..7---......_A . .. H. ,Y“*. ... I . . . . ... _, o . m IT‘ > fflfi'9‘; 0+5AAA. 4Y.V..To .. .A6 .I v ... :. . . . “a , _ , . ~ a. . .HA. Q. ... .. .tu.u ..“o. . . .. . ‘ .. . . m o. . n 1 . .xu . ._ .. .0 ..V. .... a. « .f”.d.~ a u ,. u ” . . av . .. ...“ ._“ "..~"_ .. — _ . _ cw..u..cqg .h.._. . .n . . . .. .... .. vntd It‘ibJ’oOL-o .n .... ... ...... ‘ o.| .olTu' p0». _...._._ . ”._ . .. _ _-.."... . _ h .t. :.. ..r...flq9#.. .... . _... .. . . . " ... l»....»..4,.o.»...‘.. .. A... _ ... . .... ..H ....M... h . _ _ . . _ . ._. . —_ _.LZ ..._ _ _ . _ . . . . l .. _ . . . q Jufi. .oo¢~1w. ”:..... ....fl... . _ .0... A... 2‘ . _ H M J...L.t01:ljf'lio t..........l§...o._ :0... 0... A... 05.. :..... . .. . , .. . . A. :: 5; _,. ,L .M f _ _ . Ivbahowo W... 1H. 0. :..—_.. . . .. . ......a. . . _ .¢ .0. -... v<...'. .. .. .0. c. .u .l o 1...; . H. u.. . .. _ u. u . . _ ... .. . m _ . ; , w ,L n _ . . _ . h . ». . .. _, ... _ . _ ._, ,., ...W _ . _ . v .5 ._ P . r b AD-A .. All Ill-.001! .vp I..vU ¥ » D‘P.tv|.ll.rr0|':'o.tlll.l. - . I“ 4 3000 IR of gg. Figure 77- 149 113 £39 ... an OA 197 INJ- w 'I.. .. ‘. , Iv: n; 0.. 1 ' A " '1 1 fi' v v I i 4:1. .llll IQIIIOIual'I4lc'I -.4! 41"! ¢ .. i 03 fl 0 I ‘a .‘J ' ‘1 h kw...- .\ i \J JLJLLLLII1;L~.L_LLLJ.L1L111L111L Mass spectrum of 3%. Proton NMR of ag. _.JL Leigh LLLI 1 L14 1 Figure 78. Figure 79. 1111 “I. II "I I. . .I I 1‘0 I 90 [60 no 1:» Figure 80. Carbon-13 NMR of fig- [00 '0 ca _-._.---.-—.—-_-A-.< . _.--.-- .————— ..._ _..., ......_.___ ‘! .‘L H Ii Wean 43%;; .. ||ll|||lllll|lllll||l!llll||ll-uu .LuJAiiliiilillLAiililAliA111-1;AAAiA. I 70 LA to L ngj 4, O 1N3“ Figure 81. Figure 82. 115 93 32 M 1“ 1:38 .- l I 3 ‘ 2 s 3 .! 1‘6? . :pmn.‘aa.:u- . 3 :5— MeO Mass spectrum of g%. Proton NMR of 3%- MeO 116 100.0 q 1"” 234 L - c 93 . :~:-r: :‘3 29a :59 35.3 Figure 83. Mass spectrum of gg. Figure 8A. Proton NMR of £5. 117 0 ca at .ww no mzz mancoppmo 3 .mm onswfim ow ul—ddqdflA—da—da__—44q4___——_ddd4d4444AA4udd4__qu 3 num<4 REFERENCES "A man would make but a very sorry chemist if he attended to that department of human knowledge alone." M. Waldman to Victor Frankenstein Frankenstein, Mary Shelley 118 REFERENCES l. G. Ourisson, P. Crabbe and O. R. Rodig, "Tetracyclic Triterpenes", Holden-Day, Inc., 196”. 2. L. Fieser and M. Fieser, "Steroids", Reinhold, New York, 1959. 3. T. A. Geissman and D. H. G. Crout, "Organic Chemistry of Secondary Plant Metabolism", Freeman, Cooper & Co., 1969. A. R. B. Woodward, A. A. Patchett, D. M. R. Barton, D. A. J. Ives and R. B. Kelly, J. Am. Chem. Soc., 72, 1131 (1957). 5. E. E. van Tamelen and R. J. Anderson, J. Am. Chem. Soc., 35, 8225 (1972). 6. E. E. van Tamelen and J. W. Murphy, J. Am. Chem. Soc., 23: 720“ (1970)- 7. (a) K. Grimm, P. S. Venkataramani and W. Reusch, J. Am. Chem. Soc., 92, 270 (1971). (b) W. Reusch, K. Grimm, J. Karoghan, J. Martin, K. P. Subrahamanian, Y. C. Toong, P. S. Venka- taramani, J. D. Yordy and P. Eoutendam, J. Am. Chem. Soc., 99, 1953 (1977). (c) W. Reusch, K. Grimm, J. Karoglan, J. Martin, K. P. Subrahamanian, P. S. Venkataramani and J. P. Yordy, J. Am. Chem. Soc., 3 , 1958 (1977); w. Reusch and J. D. Yordy, J. m. Chem. Soc., 99, 1965 (1977). 8. J. L. Martin, J. S. TouanuiW. Reusch, J. Org. Chem., 33, 3666 (1979). 9. K. Mieschler and W. H. Fischer, Helv. Chim. Acta, 3g, 155 (1939). 10. R. E. Marker and E. Rohrmanon, J. Am. Chem. Soc., 6%, 518 (1940). 119 ll. 12. 13. 1“. 15. 16. 17. 18. 19. 20. 21. 22. 23. 2H. 25. 54,1582 (1979). 120 (a) F. W. Heyl, A. P. Centolella and M. E. Herr, J. Am. Chem. Soc., 63,1957 (1977) (b) D. A. Shepherd, 93 31., J. Am. Chem. Soc., 11, 1212 (1955). E. P. Oliveto in "Organic Reactions in Steroid Chem— istry", Vol. 2, J. Fried and J. A. Edwards, Ed., Van Nostrand-Reinhold, New York, N.Y., 1972. V. VanRheenan and K. Paul Shephard, J. Org. Chem., R. R. Wroble and D. S. Watt, J. Org. Chem., 31, 2939 (1975)- S. Danishefsky, K. Nagasawa and N. Wang, J. Org. Chem. , 50,1989 (1975). A. Butenandt and J. Schmidt-Thomé, Chemische Beriehte, 11. 1&87 (1938); 12, 182 (1939). D. M. Piatak and J. Wicha, Chem. Rev., 18, 199 (1978) Y. M. Shiekh, B. Tursch, and C. DJerassi, Tet. Letts., 3721 (1972). S. R. Schow and T. C. McMorris, J. Org. Chem. , 5%, 3760 (1979). R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler and U. M. McLamore, J. Am. Chem. Soc., 13, 2903, 3597, 3598 (1951); 1%, 9223 (1952). G. R. Weihe and T. C. McMorris, J. Org. Chem., 33, 39u2 (1978). R. D. Walkup, G. D. Anderson and C. Djerassi, Tet. Letts., 767 (1979)- J. R. Wiersig, N. W. Sarcevié and C. DJerassi, J. Org. Chem. , A“, 337“ (1979). (a) W. G. Dauben and T. Brookhart, J. Am. Chem. Soc., $83, 237 (1981). (b) A. D. Batcho, D. E. Berger, M. R. Uskovovic and B B. B. Snider, J. Am. Chem. Soc., 193, 1293 (1981). M. Koreeda, Y. Tanaka and A. Schwartz, J. Org, Chem., 5;, 1172 (1980). 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. DO. 121 M. Tanak and K. Mayashi, J. Am. Chem. Soc., 102, 862 (1980). ”m” (a) B. M. Trost and T. R. Verhoeven, J. Am. Chem. SOC-.,$39, 3u35 (1978). (b) J. S. Temple and J. Schwartz, J. Am. Chem. Soc., ,183: 7381 (1980). J. P. Marino and H. Abe, J. Am. Chem. Soc., 18;, 2907 (1981). (a) Takahashi, H. Yamada, and J. Tsuji, J. Am. Chem. Soc., $99, 5259 (1981). (b) M. M. Midland and Y. C. Kwan, J. Org. Chem., R. A. Benkeser, W. G. Young, W. E. Broxterman, P. A. Jones and S. J. Piaseczynski, J. Am. Chem. Soc., 9%, 132 (1969). G. Courtois and L. Miginiac, J. Or anometallic Chem., 39. 1 (197“). Y. Okude, S. Hirano, T. Hiyama, and H. Nozaki, J; Am. Chem. Soc., 22, 3179 (1977). D. A. Hutchison, K. R. Beck, R. A. Benkeser, and J. . Grutzner, J. Am. Chem. Soc., 2Q, 7075 (1973). . A. Dickinson, Synthetic Communications, 8, A27 E. J. Corey and J. W. Suggs, Tet. Letters, 2697 (1975). B N. Cohen, B. L. Banner, W. F. Eichel, Z. Valenta, and R ( J. A. Marshall, M. T. Pike and R. D. Carroll, J. Org. Chem., 3%, 2933 (1966). G. Teutsch, C. Long, R. Smolik, J. P. Mornon and J. Delettre, Tet. Letters, 327 (1981). N. L. Wendler in "Molecular Rearrangements", P. de Mayo, Ed., Interscience Publishers, New York, 196“. B. M. Trost, T. N. Salzmann, and K. Hiroi, J. Am. Chem. Soc., 28, “887 (1976). A. J. Gordon and R. A. Ford, "The Chemists' Companion" John Wiley and Sons, 1972. A1. A2. “3. AA. “5. A6. A7. A8. A9. 122 (a) M. J. Schneider and V. Hoppen, Tet. Letters, 597 (1974). (b) J. D. Roberts, F. J. Weigert, J. I. Kroschwitz, and H. J. Reich, J. Am. Chem. Soc., 92, 1338 (1970)- D. A. Evans, G. L. Carroll, and L. K. Truesdale, J; Org. Chem., 39, 91A (197A). M. Oda, A. Yamamuro, and T. Watabe, Chemistry Letters, 1A2? (1979). R. Greenwald, M. Chaykovsky, and E. J. Corey, J; Org. Chem., 28, 1128 (1963). R. Rees, D. P. Strike, and H. Smith, J. Med. Chem., 1A. 783 (1967). (a) A. M. Krubiner and E. P. Oliveto, J. Org. Chem., 31, 2a (1966). (b) A. M. Krubiner, N. Gottfried, and E. P. Oliveto, J. Org. Chem., 33, 1715 (1968). S. R. Schow and T. C. McMorris, J. Org. Chem., AA, 3760 (1979). (a) R. B. Bates, R. H. Carnighan, R. O. Rakutis, and J. H. Schauble, Chem. Ind., 1020 (1962). (b) B. M. Trost, Acc. Chem. Res., 3, 120 (1970). (a) S. A. Knight, Tet. Letters, 83 (1973). (b) G. Lukacs, F. Khuong-Huu, and C. R. Bennett, Tet. Letters, 3515 (1972). A T S I ll IIHINWIH