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

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

References

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13

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

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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.