Open Collections

Stereoselective total syntheses of tetracyclic sesquiterpenes: (±)-ishwarone and (±)-ishwarane

University of British Columbia

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.

Text

2010-02-26

For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

http://hdl.handle.net/2429/21158

Chemistry

University of British Columbia

Graduate