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Synthesis of Regio- and Stereoselectively Deuterium-Labelled Derivatives of L-Glutamate Semialdehyde for Studies on Carbapenem Biosynthesis

Research Authors
Christian Ducho, Refaat B. Hamed, Edward T. Batchelar, John L. Sorensen, Barbara Odell, Christopher J. Schofield
Research Department
Research Journal
Org. Biomol. Chem., DOI: 10.1039/B903312B
Research Rank
1
Research Vol
Vol. 7
Research Year
2009
Research Member
Research Abstract

L-Glutamate semialdehyde (L-GSA) is an intermediate in biosynthetic pathways including those leading to the carbapenem antibiotics. We describe studies on asymmetric deuteration or hydrogenation of appropriate didehydro-amino acid precursors for the stereoselective synthesis of C-2- and/or C-3-[2H]-labelled L-GSA suitable for use in mechanistic studies. Regioselective deuterium incorporation into the 5-position of L-GSA was achieved using a labelled form of the Schwartz reagent (Cp2Zr2HCl). 4,4-Dideuterated and fully backbone deuterated L-GSAs were prepared. The application of the labelled L-GSA derivatives to biosynthetic studies was exemplified by the chemo-enzymatic preparation of selectively deuterated trans-carboxymethylprolines using two different carboxymethylproline synthases (CarB and ThnE), enzymes that catalyse early steps in the biosynthesis of two carbapenems: (5R)-carbapenem-3-carboxylate and thienamycin, respectively.