Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions.
Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.
Keck
Gary E
GE
Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah, 84112, USA. keck@chemistry.utah.edu
Giles
Robert L
RL
Cee
Victor J
VJ
Wager
Carrie A
CA
Yu
Tao
T
Kraft
Matthew B
MB
D000438:Alcohols / Q000737:chemistry; D000838:Anions / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000138:chemical synthesis; D034261:Epothilones / Q000138:chemical synthesis*; D004952:Esters / Q000737:chemistry; D007202:Indicators and Reagents; D007783:Lactones / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy
D000438:Alcohols; D000838:Anions; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D034261:Epothilones; D004952:Esters; D007202:Indicators and Reagents; D007783:Lactones; C114026:desoxyepothilone B; C093788:epothilone B