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DOI: 10.1055/s-0029-1217252
Synthesis of Zaragozic Acid C
Contributor(s):Philip Kocienski, Zofia KomstaUniversity of North Carolina at Chapel Hill, USA
Self-Consistent Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C via Controlled Oligomerization
J. Am. Chem. Soc. 2008, 130: 17281-17283
Publication History
Publication Date:
22 June 2009 (online)
Key words
zaragozic acid C - aldol reaction - oxidative kinetic resolution
Significance
The zaragozic acids are picomolar inhibitors of squalene synthase, an enzyme that catalyzes the first step in cholesterol biosynthesis. They also enhance radiochemotheraphy of acute myeloid leukemia cell lines. This formal synthesis features the use of silyl glyoxylate A as a geminal dipolar glyoxylate synthon in the diastereoselective synthesis of C.
Comment
The yield of the oxidative kinetic resolution of racemic C reached 48%. Diastereoselective aldol reaction in E afforded lactone G in good yield and selectivity. Opening of the lactone I with t-BuOK resulted in inversion of the C6 stereocenter. Intermediate L is an intermediate in Carreira’s synthesis of zaragozic acid (J. Am. Chem. Soc. 1995, 117, 8106).