P-1 Total Synthesis of Antibiotic (R)-(+)-Thiolactomycin

• Ohata Kohei

  Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.

• Terashima Shiro

  Sagami Chemical Research Center

Bibliographic Information

Other Title

• P-1 抗生物質(R)-(+)-チオラクトマイシンの全合成(ポスター発表の部)

Abstract

Thiolactomycin (TLM) 1 isolated as a thiolactone antibiotic from a soil Nocardia spp., showed moderate in vitro activity against broad spectrum of pathogens (Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis) and anti-malarial activity. It was also disclosed that 1 exhibits inhibitory activity against fatty acid synthase (FAS). Accordingly, 1 and its analogues are expected to be the drug targets not only for infective diseases but also for cancer and obesity treatments. Although three total syntheses of 1 have hitherto been reported, a novel synthetic route was sought which can afford 1 and its analogues more efficiently than those reported. As outlined in Scheme 1, we have now succeeded in exploring an efficient synthetic scheme to 1 by employing deconjugative asymmetric α-sulfenylation of α,β,γ,δ-unsaturated carbonyl derivative 4 carrying a chiral auxiliary as a key step. Thus, α-sulfenylation of 4 with S-3,3-dimethoxypropyl methanethiolsulfonate as a sulfenylating agent smoothly took place using NaHMDS as a base in the presence of HMPA, affording α-3,3-dimethoxypropylsulfenyl β,γ,δ,ε-unsaturated carbonyl derivative 6 in 90% yield. This was converted to aldehyde 12 in 81% yield by sequential treatments with Ti(OBn)_4 for benzylester formation and with 6% HCl for hydroysis of dimethylacetal. Retro-Michael reaction of 12 was effected by treating with cesium bicarbonate. Subsequent acylation of the resulting thiol with propionyl chloride furnished S-acyl derivative 13 in 75% yield. Dieckmann cyclization of 13 with LiHMDS following the protocol reported by Townsend proceeded smoothly, giving rise to optically pure 1. Synthetic 1 exhibited spectral characteristics and optical rotation value identical to those reported for the natural product. Utilizing ent-4 in place of 4, the same synthetic operations as for the preparation of 1 afforded ent-1. When the enantiomeric thiols deriverd from 12 and ent-12, respectively, were acylated with acetyl chloride, an enantiomeric pair of 3-demethyl TLM(2 and ent-2) were similarly prepared after Dieckmann cyclization. Novel aspects for the biological activity of 1, ent-1, 2 and ent-2 will be also reported.

Journal

• Symposium on the Chemistry of Natural Products, symposium papers

  Symposium on the Chemistry of Natural Products, symposium papers 47 (0), 235-240, 2005

  Symposium on the Chemistry of Natural Products Steering Committee

Details

• CRID: 1390282681055396992
• NII Article ID: 110006682551
• DOI: 10.24496/tennenyuki.47.0_235
• ISSN: 24331856
• Text Lang: ja
• Data Source:
  • JaLC
  • CiNii Articles
• Abstract License Flag: Disallowed