Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and C—H Functionalization

DOI Web Site PubMed 被引用文献2件 オープンアクセス
  • Andrew N. Lowell
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Matthew D. DeMars
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Samuel T. Slocum
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Fengan Yu
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Krithika Anand
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Joseph A. Chemler
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Nisha Korakavi
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Jennifer K. Priessnitz
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Sung Ryeol Park
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Aaron A. Koch
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • Pamela J. Schultz
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States
  • David H. Sherman
    Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States

書誌事項

公開日
2017-06-05
DOI
  • 10.1021/jacs.7b02875
公開者
American Chemical Society (ACS)

この論文をさがす

説明

Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification. Synthetic chemistry was employed to generate the tylactone hexaketide chain elongation intermediate that was accepted by the juvenimicin (Juv) ketosynthase of the penultimate JuvEIV PKS module. The hexaketide is processed through two complete modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and functionalization of two ketide units followed by cyclization of the resulting octaketide into tylactone. After macrolactonization, a combination of in vivo glycosylation, selective in vitro cytochrome P450-mediated oxidation, and chemical oxidation was used to complete the scalable construction of a series of macrolide natural products in as few as 15 linear steps (21 total) with an overall yield of 4.6%.

収録刊行物

被引用文献 (2)*注記

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ