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UBC Theses and Dissertations

A new synthesis of enantiomerically pure bicyclic ketones. Total synthesis of the diterpenoids (-)-Kolavenol and (-)-Agelasine B Roberge, Jacques Y.

Abstract

This thesis describes the synthesis of a series of enantiomerically pure cis-fused bicyclic trimethylstannyl ketones 124, 132 and 133. The bicyclic ketones were prepared by means of a methylenecyclohexane, methylenecyclopentane or anethylidenecyclopentane annulation sequence using the bifunctional conjunctive reagents 12, 110 and 115 and the novel, optically active trimethylstannyl enone 64,in which the trimethylstannyl moiety acts as a readily removable "anchoring" group. The trimethylstannyl group has a pronounced effect on the circular dichroism of the optically active ketones. A discussion of these effects is presented. A new, general destannylation procedure was developed and used to prepare a series of enantiomerically pure bicyclic alcohols 165, 175 and 176 from the ketones 124, 132 and 133. The generality of the method was demonstrated with the destannylation (Li, t-BuOH, NH3) of a series of trimethylstannyl alcohols, ethers and alkenes. The alcohol 165 was used as an intermediate for the total syntheses of the optically active clerodane diterpenoids (-)-kolavenol (65) and (-)-agelasine B (31). (-)-Kolavenol (65) was prepared in 14 steps and 19.4% overall yield from the enone 64. Thus, the alcohol 165 was oxidized and the resulting ketone 47 was converted to the nitriles 215. The nitriles 215 were stereoselectively alkylated to produce thenitrile 216. Functional group manipulations yielded the iodide 213 via the ether 214. A novel palladium-catalyzed coupling of an organozinc reagent (prepared from 213) with the vinyl iodide 265 produced the ether 282. (-)-Kolavenol (65) was obtained by removal of the silyl protecting group. (-)-Agelasine B (31) was obtained in three steps from the ether 282. Thus, 282 was converted directly into the bromide 300, and the resulting product was alkylated with the methyl adenine derivative 301 to give the methoxy-protected adenine _v "'SnMe3 -R= H, 132 R R = Me, 133 CCI Me3Sn 1 2 CI Me3Sn 110 R R= H, 175 R = Me, 176 H OH 165 OH 65 OMe___/ 214 derivative 302. A new, mild electrochemical deprotection of 302 was used to prepare (-)-agelasine B (31). This compound was prepared in 16 steps and 5.6% yield from the enone 64. A new procedure for the synthesis of compound 233, the enantiomer of theactive component of the commercially useful perfume lonoxide® 251, was discovered. The ether 214 was efficiently converted into 233 using acidic reaction conditions.

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