Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 132, Issue 32, Pages 11379-11385Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja1050023
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Funding
- NCRR NIH HHS [S10 RR019918, S10RR019918] Funding Source: Medline
- NIGMS NIH HHS [R25GM58903, R25 GM058903-12, R25 GM058903] Funding Source: Medline
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Photolysis of alpha-diazo-N-methoxy-N-methyl (Weinreb) beta-ketoamides derived from enantiomerically pure (EP) a-amino acids affords the corresponding EP /3-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 (fl-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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