Synthetic study and structure-activity relationship of the broad-spectrum antibiotic amycolamicn, a hybrid molecular architecture

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20566
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0601:Agricultural chemistry and related fields
• Research Institution: Tohoku University
• Principal Investigator: Meguro Yasuhiro 東北大学, 農学研究科, 助教 (10912157)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: amycolamicin / 抗生物質 / 有機合成化学 / 全合成

Outline of Final Research Achievements

The total synthesis of amycolamicin, which exhibits potent antibacterial activity,has been achieved in a convergent manner.The DE unit was synthesized in 12 steps from methyl (R)-lactate. The preparation of C unit was achieved in 6 steps including an intramolecular Diels-Alder reaction.The synthesis of the A unit derivative was accomplished in 9 steps from L-fucose.Glycosylation of C unit with DE unit provide CDE unit, which was converted into β-keto amide with A unit derivative stereoconvergently as a single anomer. Finally, a four-step sequence involving the formation of the tetramic acid moiety (B unit) completed the total synthesis of 1. Syntheses of the A and AB units of 1 were performed for use in structure-activity relationship studies. The A unit was obtained from L-fucose via a regioselective acetylation. The syntheis of AB unit was completed with the construction of the B unit using Bestmann ylide as a key step.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

感染症治療の研究現場では,相次ぐ薬剤耐性菌の出現により,日々,新たな脅威が突き付けられている。今まさに,交差耐性を生じにくい新規な構造と作用機序を持ち,新しいカテゴリーの抗菌薬の起点となり得る薬剤の開発が急務となっている。申請者は構造的にも作用機序的にも全く新規な理想的抗菌薬リードとして大きな注目を集めているアミコラマイシン(1)の収束的合成経路を開拓した。現在、得られた1及び1の部分構造を用いて、構造活性相関研究を展開しており、画期的な感染症治療薬の開発に繋げることで、相次ぐ薬剤耐性菌の出現という閉塞状況を打破できると考えている。