The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analogue.
A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained epothilone derivative 42.
Martin
H J
HJ
Institut für Organische Chemie der Universität Wien, Austria. harry.martin@univie.ac.at
Pojarliev
P
P
Kählig
H
H
Mulzer
J
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis; D034261:Epothilones; D018942:Macrolides / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D034261:Epothilones; D018942:Macrolides; C093788:epothilone B