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Synthesis 2009(21): 3694-3707  
DOI: 10.1055/s-0029-1216980
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart ˙ New York

Structure Elucidation and Enantioselective Total Synthesis of the HMG-CoA Reductase Inhibitors FR901512 and FR901516

Masahiro Inoue, Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Fax: +81(3)52863240; e-Mail: mnakada@waseda.jp;
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Publication History

Received 24 June 2009
Publication Date:
28 August 2009 (online)

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Abstract

The enantioselective total synthesis of the potent HMG-CoA reductase inhibitors FR901512 (1) and FR901516 (2) is reviewed. FR901512 was prepared in 15 steps from commercially available compound via 2 in 16.3% overall yield (89% average yield). This study validated the applicability and reliability of the catalytic asymmetric Nozaki-Hiyama reactions that were developed by us. These reactions enabled the concise, efficient, and protecting-group-free enantioselective total syntheses of these new statins.

Key words

asymmetric catalysis - enantioselective synthesis - Nozaki-Hiyama reaction - structure elucidation - total synthesis

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The use of ent-12 afforded ent-34 accordingly.

16

CCDC 647745 contains the supplementary crystallographic data (excluding structure factors) for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

22

The specific rotation of 2 {[α]D ²5 -8.4 (c 0.35, MeOH)} differed significantly from the reported value {Lit.¹a [α]D ²³ -16 (c 0.40, MeOH)}. However, we soon found out that this difference was due to the methanolysis of 2 during the measurement of the specific rotation. That is, δ-lactone 2 was converted into the methyl ester of 1 by its reaction with MeOH, which was used as the solvent.