Total synthesis of potent antibacterial natural products with unique chemical structures and their structure-activity relationship studies

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H02920
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Kuwahara Shigefumi 東北大学, 農学研究科, 教授 (30170145)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: amycolamicin / nonthmicin / aplasmomycin / 抗菌物質

Outline of Final Research Achievements

The total synthesis of amycolamicin, an antibiotic with a unique hybrid molecular structure consisting of five ring systems (A-E units) and potent antibacterial activity against a wide range of drug-resistant bacteria, has been achieved from a known D-lactic acid derivative by a 20-step sequence that features: (1) highly diastereoselective construction of the C ring via a protecting group-free Lewis acid-promoted intramolecular Diels-Alder cyclization of a teraenal-type acyclic precursor; (2) preparation of the D unit via an extremely diastereoselective nucleophilic addition of a vinyllithium derivative to an α-azidoketone intermediate; (3) efficient stereoconvergent N-acylation of an A unit derivatives (α-anomer/β-anomer = 1:1.1) with the CDE unit (thioester derivative). We have also succeeded in synthesizing the western, northern, and southwestern parts of nonthmicin as well as the preparation of the C12-C17 segment of aplasmomycin.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

AmycolamicinのCユニットの調製で用いたヒドロキシ基無保護の分子内Diels-Alder反応は，それまでの類似反応では実現されていなかったequatorialヒドロキシ基を持つtrans-デカリン系の高ジアステレオ選択的構築を達成したものであり，今後の天然物合成に対する貢献は大きい。また，アノマー混合物である二環性N-グリコシドをチオエステルでN-アシル化すると，単一のN-アシル化生成物を収束的に与えるという新知見は，類似天然物の合成における立体制御を大幅に簡略化できることを意味している。各種合成品の構造活性相関研究により，有用な抗菌剤等の開発につながる可能性がある。