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Communication | Special issue | Vol 77, No. 1, 2009, pp.179-186
Published online, 26th June, 2008
DOI: 10.3987/COM-08-S(F)16
Synthesis of Chaetomellic Anhydride A, a Potent Inhibitor of Ras Protein Farnesyltransferase

Takehiko Yoshimitsu,* Yoshimasa Arano, Tomohiro Kaji, Tatsunori Ino, Hiroto Nagaoka, and Tetsuaki Tanaka*

*Medicinal and Organic Chemsitry, Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

Chaetomellic anhydride A, a potent inhibitor of Ras protein farnesyltransferase, was synthesized in 61% yield over four steps from methyl propionate. The synthesis features palladium-catalyzed carboxylation reaction under Cacchi conditions, efficiently incorporating carbon monoxide generated in situ from acetic formic anhydride into β-carbomethoxyalkenyl triflate, and giving rise to the maleic anhydride motif of chaetomellic anhydride A. Noteworthy is the remarkable reactivity of the carboxylation reaction that takes place at room temperature despite the fact that common palladium-catalyzed carboxylations generally require rather harsh conditions. The scope of the method is also presented.