A Challenging Synthesis of the Highly Functionalized Echinocandin ASP9726: A Successor of Micafungin

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• 作者：Shinya Yoshida ; Joji Hayashida ; Yasuhiro Morinaga ; Shoji Mizobata ; Akihiro Okada ; Kazumi Kawai ; Shinjirou Tanoue ; Tomohide Nakata ; Minoru Kitayama ; Atsushi Ohigashi ; Mitsutaka Matsuura ; Takumi Takahashi ; Shigeru Ieda ; Minoru Okada
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：June 20, 2014
• 年：2014
• 卷：18
• 期：6
• 页码：725-738
• 全文大小：602K
• 年卷期：v.18,no.6(June 20, 2014)
• ISSN：1520-586X

文摘

Here, we describe a practical, scalable, and challenging synthesis of the highly functionalized novel echinocandin ASP9726 (1) starting from the natural product FR901379 (3), which is a starting material of micafungin (2). The synthesis includes transformations that address significant synthetic challenges due to the need to control the chemoselectivity of the reactions during modification of the highly functionalized peptide core. In the present study, we discovered an efficient, high-yielding route to ASP9726 (1) that is suitable for large-scale production. Namely, dehydration of carboxamide (14) to nitrile (15) was accomplished by use of EDC路HCl with pyridine. Further, the transformation of nitrile (15) to primary amine (17) was conducted via hydrogenation with Sponge Nickel catalyst without decomposition, followed by one-pot debenzylation with Pd/C. Reductive amination between primary amine (17) with dihydroxyacetone (DHA) was accomplished using 2-picoline/borane complex as a reducing agent in MeOH, yielding 66.6 kg of peptide core unit (18). After the C₁₅H₃₁ chain cleavage by bioconversion, reductive amination between the core peptide unit (4) and side chain (10) was achieved in high yield by making use of tert-butyl amine/borane complex as a reducing agent. Consequently, highly pure ASP9726 (1) was obtained in a practical manner without using silica gel or ODS column chromatography purification in any step. Overall yield was drastically increased from 0.71% to 13.8% compared to that of the prior synthetic method.