Abstract
Photolysis of alpha-diazo-N-methoxy-N-methyl (Weinreb) beta-ketoamides derived from enantiomerically pure (EP) alpha-amino acids affords the corresponding EP beta-lactams via an intramolecular Wolff rearrangement. The photochemistry is promoted with either standard UV irradiation or through the use of a 100 W compact fluorescent light; the latter affords a safe and environmentally friendly alternative to standard photolysis conditions. A continuous-flow photochemical reactor made from inexpensive laboratory equipment reduced reaction times and was amenable to scale-up. The diastereoselectivity (cis or trans) of the product beta-lactams has been shown to vary from modest to nearly complete. An extremely facile, atom-economical method for the epimerization of the product mixture to the trans isomer, which is generally highly crystalline, has been developed. Evidence for C3 epimerization of Weinreb amide structures via a nonbasic, purely thermal route is presented. Subsequent transformations of both the Weinreb amide at C3 (beta-lactam numbering) and the amino acid side chain at C4 are well-tolerated, allowing for a versatile approach to diverse beta-lactam structures. The technology is showcased in the synthesis of a common intermediate used toward several carbapenem-derived structures starting from unfunctionalized aspartic acid.
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