Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common Precursor

Org. Proc. Res. Dev., 8 (1), 92 -100, 2004. 10.1021/op034130e S1083-6160(03)04130-6
Web Release Date: December 4, 2003

Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common Precursor

Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Robert Daeffler, Adnan Osmani, Klaus Schreiner, Manuela Seeger-Weibel, Brigitte Bérod, Karl Schaer, and Remo Gamboni

Chemical and Analytical Development, Novartis Pharma AG, CH 4002 Basel, Switzerland

Stephen Chen, Weichun Chen, Christopher T. Jagoe, Frederick R. Kinder, Jr., Mauricio Loo, Kapa Prasad, Oljan Repi, Wen-Chung Shieh, Run-Ming Wang, Liladhar Waykole, David D. Xu, and Song Xue

Novartis Institutes for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, U.S.A.

Received for review September 16, 2003.

Abstract:

The synthetic strategy for producing multigram quantities of (+)-discodermolide (1) using a hybridized Novartis-Smith-Paterson synthetic route via common precursor 3 is described. In the first part of this five-part series, we present a multikilogram preparation of -methyl aldehyde 10 from Roche ester, its syn-aldol reaction with Evans boron enolate, removal of the chiral auxiliary, and the preparation of Weinreb amide 3 (Smith common precursor). The common precursor was produced without any chromatography.

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