Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D.
The phosphonium salt 35, representing one of the two principal subunits of the epothilones, was prepared from propargyl alcohol via heptenone 22. A Wittig reaction of the phosphorane from 35 with aldehyde 33, obtained from aldol condensation of ketone 27 with aldehyde 28, afforded 37. Seco acid 42 derived from 37 underwent lactonization to give cis-9,10-dehydroepothilone D (43) which was selectively reduced with diimide to yield epothilone D (4) and, after epoxidation, epothilone B (2). An alternative route to epothilone D employed alkyne 39, obtained from 33, in a Castro-Stephens reaction with allylic bromide 34 to furnish enyne 40. The latter was semi-hydrogenated to provide 37. Alkyne 46, prepared from alcohol 45, was converted to trans-vinylstannane 47 which, in a Stille coupling with allylic chloride 50, gave 51. Seco acid 52 derived from 51 underwent lactonization to give trans-9,10-dehydroepothilone D (54). Bioassay data comparing the antiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, although both retain full antiproliferative activity against a paclitaxel-resistant cell line. No significant difference in potency was noted between cis analogue 43 and its trans isomer 54.
White
J D
JD
Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003, USA.
Carter
R G
RG
Sundermann
K F
KF
Wartmann
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D034261:Epothilones; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology; D013552:Swine; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
C442200:9,10-dehydroepothilone D; D000970:Antineoplastic Agents; D034261:Epothilones; D004852:Epoxy Compounds; D018942:Macrolides; D013844:Thiazoles; D014404:Tubulin; C114026:desoxyepothilone B; C093788:epothilone B