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Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents

Nicolaou, K.C.; Pulukuri, K.Kumar.; Rigol, S.; Buchman, M.; Shah, A.A.; Cen, N.; McCurry, M.D.; Beabout, K.; Shamoo, Y.

Journal of the American Chemical Society 139(44): 15868-15877

2017


ISSN/ISBN: 0002-7863
PMID: 29064688
DOI: 10.1021/jacs.7b08749
Accession: 059678447

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure-activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

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