Stereochemical Definition and Chirospecific Synthesis of the Peptide Deformylase Inhibitor Sch 382583

• Published in: Journal of organic chemistry 2004-03, Vol.69 (5), p.1734-1737
• Main Authors: Coats, Reed A, Lee, Sheng-Lian, Davis, Kari A, Patel, Kanu M, Rhoads, Elaine K, Howard, Michael H
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry; Cyclization; Dipeptides - chemical synthesis; Dipeptides - chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hexanones - chemistry; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Organic chemistry; Peptides; Pharmacology. Drug treatments; Preparations and properties; Pyridazines - chemical synthesis; Pyridazines - chemistry; Stereoisomerism; Succinates - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo035667t

The recently reported natural product Sch 382583 (1), an inhibitor of peptide deformylase, has been synthesized in 16 steps from commercially available starting materials. The three chiral centers were set by a combination of chiral auxiliary and chiral pool approaches. The succinate 5 and piperazic acid 9 moieties were obtained by Evans oxazolidinone imide enolate alkylation and hydrazination/cyclization, respectively, and the aminohexanone side chain 13 was prepared via Grignard substitution of the Weinreb amide derived from l-valine. Spectroscopic data for the resulting synthetic material, compared with the data reported for the natural product, established that the previously unassigned valine ketone stereocenter (C-4) has the S-configuration.