A versatile synthesis of "tafuramycin A": a potent anticancer and parasite attenuating agent.
An improved and versatile synthesis of tafuramycin A, a potent anticancer and parasite-attenuating agent, is reported. The three major improvements that optimized yield, simplified purification and allowed the synthesis of more versatile duocarmycin analogues are: a first-time reported regioselective bromination using DMAP as catalyst; the control of the aryl radical alkene cyclization step to prevent the dechlorination side reaction; and the design of a new protection/deprotection method to avoid furan double bond reduction during the classical O-benzyl deprotection in the final step. This alternative protection/deprotection strategy provides ready access to duocarmycin seco-analogues that carry labile functionalities under reducing reaction conditions. Tafuramycin A (3) was prepared in either 8 steps from intermediate 6 or 7 steps from intermediate 17 in 52% or 37% yield respectively. Our strategy provides a significant improvement on the original procedure (11% overall yield) and greater versatility for analogue development.
Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia. i.el-deeb@griffith.edu.au m.vonitzstein@griffith.edu.au.
Ibrahim M
IM
El-Deeb
Faith J
FJ
Rose
Peter C
PC
Healy
Mark
M
von Itzstein
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C527858:centanamycin; C000597292:tafuramycin A