Synthetic studies for antimicrobial stalobacin I

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16310
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Tohoku University
• Principal Investigator: Kosuke Ohsawa 東北大学, 薬学研究科, 助教 (20774417)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 全合成 / 天然物 / ペプチド抗生物質 / N,O-アセタール / グアニジン含有特殊アミノ酸 / カルノサジンラクタム

Outline of Final Research Achievements

Synthetic studies for antibiotic stalobacin I were investigated. Amide/carbamate-linked N,O-acetal formation with bulky amides and alcohols was efficiently performed via a highly reactive and sterically less-hindered acyliminium cation species, which were generated from the corresponding o-alkynylbenzoic acid ester in the presence of a catalytic amount of cationic Ph3PAuOTf. Our developed methodology was effective to construct bridged substructure between cyclopropaneamino acid and 3-hydroxyvaline to give desired N,O-acetal product in good yield.
In addition, step-economical synthesis of optically active cyclopropane derivative , which is a synthetic intermediate of carnosadines as a componetnt of stalobacin I, was achieved by aziridine formation followed by double alkylation of diethyl malonate in an one-pot operation. Thus, short-step and divergent synthesis of three carnosadine derivatives were achieved from common intermediate.

Free Research Field

薬系化学

Academic Significance and Societal Importance of the Research Achievements

中性条件下での触媒的N,O-アセタール形成反応を開発し、かさ高いアミノ酸の連結法を確立することができた。ジペプチド化合物にも適用できるため、枝分かれ構造をもつペプチド天然物やミメティクスへの展開も期待できる。また、立体選択的かつ短工程で供給されたカルノサジン類は、配座自由度が制限されたアルギニン等価体として、カチオン性ペプチド抗生物質の構造活性相関研究に必要なフラグメント供給に大きく貢献できる。