Development of convergent synthetic strategies for nucleoside antibiotics based on the key three radical intermolecular C-C bond formations

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: Nagatomo Masanori 東京大学, 大学院薬学系研究科(薬学部), 講師 (70634161)
• Research Collaborator: Inoue Masayuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 有機合成 / 全合成 / 核酸系天然物 / ラジカル反応 / 高酸化度天然物 / 二量化 / テルリド / 人工類縁体

Outline of Final Research Achievements

Polyoxins J (1a) and L (1b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1a and 1b contain thymine and uracil nucleobases, respectively. We report the unified total synthesis of 1a, 1b, and their artificial analogues 1c and 1d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between alkoxyacyl tellurides and achiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside amino acid structures of 1a-d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1a-d. The two amino acid fragments were connected and elaborated into 1a-d (longest linear sequence:11 steps).
Compounds 1a and 1b assembled in this way exhibited potent activity against true fungi, while only 1d was active against Gram-positive bacteria.

Free Research Field

天然物合成化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、ポリオキシン類およびヒキジマイシンに代表されるヌクレオシドを母核構造として含む核酸系天然物の収束的合成戦略の確立を目指した。本研究過程で得られる成果はヌクレオシド合成化学の発展に大きく寄与する。また、核酸系天然物は抗がん、抗ウイルス、抗菌活性等の多彩な生物活性を有している。したがって本研究は、長期的には新たな医・農薬品のリード化合物の発見へと寄与し、広範な科学技術・公衆衛生分野に大きな影響を与える基礎研究である。