Journal of Organic Chemistry 2009-01-16

Stereoselective formation of a functionalized dipeptide isostere by zinc carbenoid-mediated chain extension.

Weimin Lin, Cory R Theberge, Timothy J Henderson, Charles K Zercher, Jerry Jasinski, Ray J Butcher

Index: J. Org. Chem. 74(2) , 645-51, (2009)

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Abstract

The application of a zinc carbenoid-mediated chain-extension reaction to a functionalized peptide isostere is reported. The cleavage site of human CVM protease was utilized as a target for testing the synthetic methodology. The utility of this chain-extension reaction is demonstrated in the preparation of an amino acid-derived alpha-unsubstituted gamma-keto ester, which is incorporated into a framework that mimics a tetrapeptide. The identification of a suitable protecting group strategy facilitated the application of a tandem reaction for the incorporation of an alpha-side chain, and the use of an oxazolidinone auxiliary provided excellent diastereocontrol in a tandem chain-extension-aldol reaction. Stereoselectivity of the tandem chain-extension-aldol reaction was determined through application of a CAN-mediated oxidative cleavage reaction.