In the first part of this thesis an 8-step synthesis of (±)-4-demethylaristolone 16 is described. This synthetic sequence was eventually to provide the basis for the total synthesis of (±)-aristolone 11. Alkylation of the known 2-methyl-6-n-butylthiomethylenecyclohexanone 77 with methallyl chloride gave, after removal of the blocking group, ketone 79. Treatment of 79 with p-toluenesulfonic acid in refluxing benzene yielded a mixture of olefinic ketones, 79 and 80. Reaction of 80 with diethylcyanomethylphosphonate yielded a mixture of nitriles, 81 and 82, which upon base hydrolysis afforded in good yield, the β,γ-unsaturated carboxylic acid 83 as the sole product. The latter was converted into the crucial diazoketone 86 via the acid chloride 84. Intramolecular cyclization of 86 in the presence of cupric sulfate gave a mixture of (±)-4-demethylaristolone 16 and (±)-5-epi-4-demethylaristolone 88 in a ratio of 2:1. Employing, in each case, two successive Birch reductions, compounds 16 and 88 were converted into decalones 90 and 111, respectively. An alternate synthesis of compound 90 involved the 1,4-conjugate addition of isopropenylmagnesium bromide to the known octalone 91, followed by catalytic hydrogenation of the addition product 97. The compound obtained from this sequence was identical with 90 prepared from (±)-4-demethylaristolone, thus establishing the stereochemistry of the latter. That the predicted stereochemical outcome of the conjugate addition (to 91) was correct, was shown as follows. Ketalization of 97 yielded compound 104, which was converted into its more stable epimer 107, via keto ketal 106. The olefinic ketal 107 upon catalytic hydrogenation followed by acid catalyzed hydrolysis yielded decalone 108. Since compound 108 was clearly different from decalone 111, prepared from (±)-5-epi-4-demethylaristolone 88, it was established that the Birch reduction of the latter had yielded a product with a cis ring junction. In the second part of this thesis an efficient and very stereoselective 16-step synthesis of (±)-seychellene 13 is described. Conjugate addition of lithium dimethylcuprate to the known α,β-unsaturated ketone 142, followed by trapping of the intermediate enolate anion 150 with acetyl chloride, gave in high yield, the enol acetate 151. Epoxidation of the double bond of 151, and thermal rearrangement of the resulting crude product, gave the keto acetate 154. Reaction of 154 with methylenetriphenylphosphorane yielded the olefinic acetate 156. Successive subjection of 156 to hydrogenation [tris(triphenyl-phosphine)chlororhodium], base hydrolysis and Sarett oxidation afforded ketone 144. Reaction of ketone 144 with methyllithium gave the tertiary alcohol 170 which upon dehydration with thionyl chloride in pyridine afforded the olefin 169. Hydroboration-oxidation of the latter gave alcohol 173 which upon treatment with p-toluenesulfonyl chloride gave the tosylate 174 in high yield. Successive treatment of 174 with p-toluenesulfonic acid in methanol and with chromium trioxide in pyridine afforded the crucial keto tosylate 136. Cyclization of 136 in the presence of methylsulfinyl carbanion yielded (±)nor-seychellanone 117. Treatment of the latter with methyl lithium followed by dehydration of the resulting alcohol with thionyl chloride in pyridine afforded, in high yield, (±)-seychellene 13. The latter gave spectra identical with those obtained from the natural product. / Science, Faculty of / Chemistry, Department of / Graduate

An efficient, 8-step synthesis of (+)-∝-cyperone 168 from (-)-∝-santonin 107 is described. Epimerization of 107 followed by hydrogenolysis of the resulting product 174 gave the acid 175, which was esterified by treatment with diazomethane. Conversion of the resulting keto ester 176 into the substituted octalone 184 was achieved by hydrogenation of the former in the presence of the homogeneous catalyst tris(triphenylphosphine)-chlororhodium. Lithium aluminum hydride reduction of 184, followed by oxidation of the product with 2,3-dichloro-5,6-dicyanobenzoquinone gave keto alcohol 189. Pyrolysis of the corresponding keto carbonate 191 afforded (+)-∝-cyperone 168 in good yield. Photochemical rearrangement of a number of cross-conjugated dienones (192, 193, 200, and 176) into hydroguaiazulene derivatives (194, 195, 195, and 221, respectively) by the irradiation of the former compounds in 45% aqueous acetic acid is also described. Conversion of 194 into 5-epi-∝-bulnesene 216 was achieved by the following sequence. Birch reduction of 194, followed by chromium trioxide-pyridine oxidation of the resulting product afforded ketone 201. The stereochemistry of the latter was established by means of optical rotatory dispersion (o.r.d.). Wolff- , Kishner reduction of 201 and subsequent dehydration gave 5-epi-∝-bulnesene 216. In a similar reaction sequence, 195 was converted into 4-epi-∝-bulnesene 218. Conversion of compound 221 into ∝-bulnesene 7 was accomplished, according to the following scheme. Stereoselective catalytic hydrogenation of the acetate derivative of 221 gave 223 as the only product. The stereochemistry of the latter was established by an o.r.d. study and by chemical evidence. Sodium borohydride reduction of 223, followed by tosylation of the resulting product, gave a mixture of the olefin 230 and the tosylate 229. Hydrogenation of the former in the presence of the homogeneous catalyst, tris(triphenylphosphine)chlororhodium, followed by lithium aluminum hydride reduction, gave the diol 235. The same diol was also obtained by lithium aluminum hydride reduction of the tosylate 229. Successive treatment of the diol 233 with methyl chloroformate and thionyl chloride in pyridine afforded the monocarbonate 235. Pyrolysis of 235 gave ∝-bulnesene 7. The described stereoselective synthesis of the sesquiterpene ∝-bulnesene 7 fully corroborates the structure and stereochemistry assigned to this compound and indicates a general approach to the synthesis of guaiane-type sesquiterpenes. / Science, Faculty of / Chemistry, Department of / Graduate

Part of this thesis describes the investigation of several synthetic approaches to the cadinane group of sesquiterpenes. The first approach investigated the preparation of a possible key intermediate of type 118 using the known octalone 114 as starting material. However all attempts to obtain octalone 116, a necessary intermediate in this sequence were unsuccessful. This precluded further use of this approach. The second approach involved preparation of several cross-conjugated dienone systems (125, 133, 139 and 141) and the study of 1,4-conjugate addition of an alkyl group by means of cuprous ion catalyzed Grignard reagents and lithium dialkylcuprate reagents. Use of reagents in which the alkyl group was methyl or primary effected the desired 1,4-conjugate addition. However when isopropylmagnesium bromide or lithium diisopropylcuprate reagents were tried no addition products were detected. Evidence is presented which indicates that enolization of the keto system was the main reaction pathway in these cases. The final and most successful approach described is the condensation-annelation approach where condensation between a vinyl ketone such as 144 and a substituted cyclohexanone derivative of type 143 was investigated. Octalones 162 were prepared by the enamine-annelation reaction employing vinyl ketone 144 and the enamine of keto alcohol 158. The stereochemistry of octalones 162 was then established. The mixture of epimeric octalones 162 was degraded to decalones 165a and 165b. The stereochemistry of these decalones was unambiguously shown by a combination of chemical and spectroscopic methods. Octalones (162a + 162c) were converted into thioketal 166 by treatment with ethanedithiol and boron trifluoride etherate. Thioketal 166 was converted into alcohol 167 by desulphurization employing Raney nickel. Treatment of alcohol 167 with chromium trioxide in pyridine afforded octalone 168. Octalone 168 was converted into (+)-cadinene dihydrochloride by treatment of the former with methyllithium followed by treatment of the resultant 3° alcohol with anhydrous hydrogen chloride in ether. The Birch reduction of octalones of type 170 is described. The octalones were prepared by 1,4-conjugate addition of lithium dialkyl- cuprate reagents to the cross-conjugated dienones of type 171. The preparation of the corresponding authentic cis- and trans-fused decalones is described. The results of Birch reduction of octalones 188 to 192 revealed a higher percentage of cis-fused decalone product than normally obtained in other substituted Δ¹•⁹-2-octalone systems. The results also indicated that as the bulk of the C₄ substituent was increased the product ratio of cis-fused decalone to trans-fused decalone also increased. The substituent at the C₁₀ position also effected the ratio of cis:trans decalone obtained. Possible explanations for these results are presented. / Science, Faculty of / Chemistry, Department of / Graduate

An efficient, 10-step synthesis of (±)-aristolone (7) from 2,3-dimethylcyclohexanone (86) is described. Alkylation with methallyl chloride of 86, via the corresponding n-butylthiomethylene derivative 119, followed by removal of the n-butylthiomethylene blocking group, gave the two ketones 121 and 122. Acid catalyzed isomerization of 121 gave the ketone 136 which, upon treatment with diethyl cyanomethylphosphorane, followed by base hydrolysis of the resulting nitriles 139 and 140, gave carboxylic acid 141. The latter was converted into the corresponding diazoketone 144 which, upon heating with cupric sulfate in cyclohexane, afforded (±)-aristolone (7) and (±)-6,7-epi-aristolone (145) in good yield. The stereochemistry of the ketone 121 was proven unambiguously by converting it into the alkane 133. Authentic 133 was prepared by an alternate route. Thus, ozonolysis of the known octalin 125, followed by chromic acid oxidation and esterification with diazomethane gave the keto ester 126. Baeyer-Villiger oxidation of 126 gave the diester 127, which was treated with methyllithium to afford the diol 128. Dehydration of 128 followed by hydrogenation of the resulting hydroxy alkenes 130 gave the alcohol 131, which was converted to the tosylate 132. Reduction of 152 with lithium aluminum hydride afforded authentic 133. The stereochemistry of aristolone (7) was proven by an unambiguous synthesis of the Birch reduction product of dihydroaristolone (53). Thus, treatment of the known octalone 92 with isopropenylmagnesium bromide in the presence of cuprous chloride afforded the decalone 159 which upon hydrogenation gave 160 identical with the product of the lithium-ammonia reduction of dihydroaristolone (53). An efficient, 12-step synthesis of (±)-ϐ-cubebene (14)from d,l-menthone (171) is described. Thus, 171 was converted into the aldehyde 175, via the corresponding n-butylthiomethylene derivative 173. Thus, sodium borohydride reduction of the latter and acid catalyzed hydrolysis of the resulting ϐ-hydroxy-thioenol ether 174, produced aldehyde 175. Reduction of 175 with sodium borohydride gave the epimeric alcohols 177a,b which were separated via their trimethylsilyl ether derivatives. Pure 177a was converted to the bromide 181 with phosphorous tribromide. Treatment of 181 with carbethoxymethyltriphenylphosphorane, followed by base hydrolysis, gave the acid 186. Acid 186 was converted into the diazoketone 170 which, upon heating with cupric sulfate in cyclohexane, gave (±)-ϐ-cubebene norketone (104) and the epimeric ketone 189. Treatment of 104 with methylenetriphenylphosphorane gave (±)-ϐ-cubebene (14) in quantitative yield. The stereochemistry of the intermediate alcohol 177a was proven by converting 177a into the bromide 181, followed by lithium aluminum hydride reduction of the latter to the alkene 190. Authentic 190 was prepared in the following manner. Treatment of (-)-trans-caran-2-one (108) with methyllithium followed by pyrolysis of the resulting alcohol 195 gave the diene 196. Regioselective hydrogenation of the disubstituted double bond of 196 with the homogeneous catalyst tris(triphenylphosphine)-chlororhodium gave authentic alkene 190. The efficiency of the intramolecular cyclization of the two olefinic diazoketones 144 and 170 illustrates the utility of this synthetic method in the synthesis of natural products. / Science, Faculty of / Chemistry, Department of / Graduate

This thesis describes work leading to the completion of a total synthesis of (±)-stemodin 3 and (±)-maritimol 5, as well as a formal total synthesis of (±)-stemodinone 4 and (±)-2-desoxystemodinone 6. The tricyclic enone 66 was prepared, in a series of steps, from the Weiland-Miescher ketone 68. Photoaddition of allene to this enone provided equal amounts of two photoadducts, 79 and 80. Ozonolysis, followed by treatment of the resulting 1,3-dione with sodium methoxide in methanol, generated the same keto ester 65 from both photoadducts. Two possible mechanisms for the unexpected conversion of the oc-photoadduct 80 into the keto ester 65 are presented. The keto ester 65 was elaborated, in a series of steps, into the tetracyclic dlone 63. The key step in this reaction sequence was a Thorpe-Ziegler condensation of the dinitriles 77. The gemlnal methyl groups required at C-4 in the target natural products 3 - 6 were introduced using a 5-step sequence. Treatment of the resulting alkylated dione 62 with methyltriisopropoxytitaniura afforded the keto alcohol 61, admixed with its C-13 epimer, in the ratio of 5:1. This keto alcohol 61 was subsequently converted into (±)-maritimol 5, and also into (±)-stemodin 3, via compound 55. Since the keto alcohol 61 has previously been converted into (±)-2-desoxystemodinone 6, and 55 has been converted into (±)-stemodinone 4, the work described here also constitutes a formal total synthesis of compounds 4 and 6. / Science, Faculty of / Chemistry, Department of / Graduate

This thesis describes a stereoselective total synthesis of (±)-ishwarone 12 and (±)-ishwarane 13 via the trans-fused octalone 226 as the key intermediate. The first synthetic attempt toward the octalone 226 involved a Lewis acid-catalyzed Diels-Alder reaction between 1,3-butadiene and the unsaturated keto ester 258, obtained from the known diene ester 261 by selective hydrogenation and allylic oxidation. Two isomeric Diels-Alder adducts, 272 and 273, were isolated in moderate yield. The relative stereochemistry of these adducts was determinated by chemical correlation with compounds of known structure and stereochemistry . In a second approach to the synthesis of the octalone 226, 3,4-dimethyl-2-cyclohexen-1-one (227) was treated with vinyl magnesium bromide in the presence of cuprous iodide and dimethylsulfide to afford the adduct 142, which was converted into the aldehyde 304. Reaction of the latter with dibromomethylenetriphenylphosphorane afforded the dibromo olefin 305. Trapping the lithium acetylide generated from the dibromo olefin 305 with gaseous formaldehyde provided the ketal propargylic alcohol 306 which was elaborated into the keto allylic alcohol 291 by acid hydrolysis and hydrogenation. Mesylation of the keto allylic alcohol 306, followed by treatment of the resultant mesylate with excess potassium tert-butoxide gave the desired octalone 226. The ketone group of 226 was protected as the corresponding 5,5-dimethyl-1,3-dioxane derivative 324. Addition of dibromocarbene to the latter compound gave the dibromocyclopropane derivative 325. Model studies were carried out with 7,7-dibromonorcarane (185) and its derivatives. Subjection of 185 to a sequence involving lithium-halogen exchange and alkylation afforded the benzyl ether 329. This compound was converted by hydrogenolysis into the bromohydrin 331, which upon mesylation gave the bromo mesylate 332. Treatment of 7-exo-bromo-7-endo-methylnorcarane 336 (obtained from dibromonorcarane 185) with an alkyllithium and methyl chloroformate produced the monoester 338. The latter, upon reduction, provided the exo-hydroxymethyl derivative 339. Mesylation of this primary alcohol proved to be unsuccessful. When dibromonorcarane 185 was treated with two equivalents of an alkyllithium, followed by methyl chloroformate, the diester 359 was obtained. Reduction of this compound, followed by mesylation of the resultant diol 361 gave the dimesylate 362. The latter was converted into the dichloride 363 by treatment with lithium chloride in hexamethylphosphoramide. Conversion of the dibromocyclopropane derivative 325 into the benzyl ether 327 (R=PhCH₂) or the diester 369 by means of reaction conditions used in the model studies were unsuccessful. However, compound 325 could be monomethylated to afford a mixture of exo and endo isomers 366 and 372. The exo-isomer 366 was converted into the endo-monoester 367. Reduction of the latter, followed by deprotection of the ketone yielded the desired keto alcohol 368. Mesylation of 368 could not be achieved without decomposition. However, this alcohol underwent ester formation with p-nitrobenzyl chloride to give the p-nitrobenzoate derivative 380. Attempted intramolecular alkylation of this keto p-nitrobenzoate 380 to give (±)-ishwarone 12 was unsuccessful. The ketal olefin 324 reacted stereoselectively with the carbenoid derived from dimethyl diazomalonate to give the diester 369 as the only adduct. This compound was reduced to the diol 389. Hydrolysis of the ketal functionality, followed by mesylation of the resulting diol 383 afforded the keto dimesylate 384. Intramolecular alkylation of this keto dimesylate gave no recognizable product. When the dimesylate 384 was treated with anhydrous lithium chloride, the crystalline dichloride 391 was obtained. Base-promoted intramolecular alkylation of the latter provided the keto chloride 392 which was reduced immediately by means of lithium triethylborohydride. Oxidation of the resulting alcohol 393 gave (t)-ishwarone 12 which upon Wolff-Kishner reduction furnished (±)-ishwarane 13. / Science, Faculty of / Chemistry, Department of / Graduate

No description available.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

published_or_final_version / Chemistry / Master / Master of Science

No description available.