Synthesis of regio- and stereoselectively deuterium-labelled derivatives of L-glutamate semialdehyde for studies on carbapenem biosynthesis.
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.
Ducho
Christian
C
University of Oxford, Department of Chemistry, Chemistry Research Laboratory, Mansfield Road, Oxford, United Kingdom OX1 3TA.
Hamed
Refaat B
RB
Batchelar
Edward T
ET
Sorensen
John L
JL
Odell
Barbara
B
Schofield
Christopher J
CJ
D015780:Carbapenems / Q000096:biosynthesis* / Q000737:chemistry; D003903:Deuterium / Q000737:chemistry*; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006865:Hydrogenation; D007553:Isotope Labeling; D008968:Molecular Conformation; D013237:Stereoisomerism
D015780:Carbapenems; D005971:Glutamates; C021199:glutamic acid gamma-semialdehyde; D003903:Deuterium