Asymmetric total synthesis of (-)-callystatin A and (-)-20-epi-callystatin A employing chemical and biological methods.
An efficient asymmetric total synthesis of the potent cytotoxic marine natural product (-)-callystatin A and its 20-epi analogue has been achieved. The synthetic pathway involved the preparation of three fragments to be coupled with each other at the end of the route. The first fragment 3 was obtained using a biocatalytic enantioselective reduction of a 3,5-dioxocarboxylate as the key step. For the second intermediate 4 the asymmetric alpha-alkylation of an O-protected derivative of 4-hydroxybutanal was performed exploiting the SAMP/RAMP hydrazone alkylation methodology, and followed by a highly Z-selective Horner-Wadsworth-Emmons reaction under modified conditions. For the synthesis of the polypropionate fragment 5 a diastereoselective syn-aldol reaction was employed between a chiral ethyl ketone and an alpha-substituted chiral aldehyde, both prepared in enantiopure form again by means of the asymmetric alkylation of their corresponding RAMP hydrazones. Finally, these three building blocks were coupled using highly E-selective Wittig reactions via allyltributylphosphonium ylides to afford the target compounds after a final oxidation/deprotection sequence.
Enders
Dieter
D
Institut für Organische Chemie Rheinisch-Westfälische Technische Hochschule Professor Pirlet-Strasse 1, 52074 Aachen, Germany. enders@rwth-aachen.de
Vicario
Jose L
JL
Job
Andreas
A
Wolberg
Michael
M
Müller
Michael
M
D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011161:Porifera / Q000737:chemistry; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; C421091:callystatin A