DEVELOPMENT OF PRACTICAL METHODS FOR ASYMMETRIC SYNTHESIS OF 1beta-METHYL ARBAPENEMS AS CANDIDATES FOR THE NEXT GENERATION OF ANTIBIOTICS

开发不对称合成 1β-甲基阿巴青霉烯作为下一代抗生素候选物的实用方法

• 批准号: 63850176
• 负责人: NAKAI Takeshi
• 金额: $ 2.69万
• 依托单位: TOKYO INSTITUTE OF TECHNOLOGY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-63850176/
• 关键词: Carbapenem; Antibiotic; Asymmetric synthesis; 1beta-Methylcarbapenem; beta-Lactam; Aldol reaction; beta-Hydroxybutyrates; Double-Asymmetric Synthesis; カルバペネム系抗性物質; 1βーメチルカルバペネム; βーラクタム; βーヒドロキシ酪酸; βーヒドロキシイソ酪酸; カルバペネム中間体; アルドール反応; βーヒドロキシ酪酸メ

Recently much attention has been focused on 1beta-methylcarbapenem antibiotics as the most promising candidates for the next generation of beta-lactam antibiotics. The main purpose of this project is to develop practical methods for asymmetric synthesis of the,1beta-methylcarbapenem key precursor.1. A highly stereocontrolled method has been developed for the asymmetric synthesis of the 1beta-methylcarbapenem key precursor from commercially available (R)-methyl beta-hydroxybutyrate. The key step is the aldol-type reaction of an achiral ketone Sn(II)-enolate with the chiral beta-acetoxy-beta-lactam intermediate which is easily accessible from the (R)-hydroxybutyrate via our previously-developed method.2. A new synthetic route to the 1beta-methylcarbapenem key precursor from easily available (S)-methyl beta-hydroxyisobutyrate has been developed which involves as a key step the chelation-controlled aldol reaction of (S)-3-benzyloxy-2-methylpropanal with the ketone silyl acetal of ethyl (trimethylsilyl)acetate.3. A novel, highly efficient approach to the 1beta-methylcarbapenem key precursor has been developed which employs the (R)-hydroxybutyrate and the (S)-hydroxyisobutyrate as the starting materials. The key steps are the chelation-controlled double-asymmetric aldol reaction and the N-C_4 cyclization of the stereochemically pure aldol product.4. A variety of 1beta-methylcarbapenem derivatives have been synthesized and their antibiotic activities have been evaluated.

最近，1β-甲基碳青霉烯类抗生素作为下一代 β-内酰胺类抗生素最有前途的候选药物受到了广泛关注。本项目的主要目的是开发1β-甲基碳青霉烯关键前体的不对称合成实用方法。 1．我们开发了一种高度立体控制的方法，用于从市售的 (R)-甲基 β-羟基丁酸酯中不对称合成 1β-甲基碳青霉烯关键前体。关键步骤是非手性酮Sn(II)-烯醇化物与手性β-乙酰氧基-β-内酰胺中间体的羟醛型反应，该中间体可以通过我们先前开发的方法从(R)-羟基丁酸酯轻松获得。2．开发了一种从容易获得的 (S)-甲基 β-羟基异丁酸酯合成 1β-甲基碳青霉烯关键前体的新路线，其中关键步骤涉及 (S)-3-苄氧基-2-甲基丙醛与(三甲基甲硅烷基)乙酸乙酯的酮甲硅烷基缩醛。3．开发了一种新型、高效的 1β-甲基碳青霉烯关键前体方法，该方法采用 (R)-羟基丁酸酯和 (S)-羟基异丁酸酯作为起始材料。关键步骤是螯合控制的双不对称羟醛反应和立体化学纯羟醛产物的N-C_4环化。 4．多种1β-甲基碳青霉烯衍生物已被合成，并对其抗生素活性进行了评估。

项目成果

Fumiyuki Shirai and Takeshi Nakai: "A New Approach to the Chiral Synthesis of the 1-beta-Methyl Carbapenem Key Precursor Using an Achiral Ketone Sn(II)-Enolate" Journal of Organic Chemistry. Vol.52. 5491-5493 (1987)

Fumiyuki Shirai 和 Takeshi Nakai：“使用非手性酮 Sn(II)-烯醇化物手性合成 1-β-甲基碳青霉烯关键前体的新方法”有机化学杂志。

Fumiyuki Shirai: "A Novel,Double-Asymmetric Aldol Approach to the Synthesis of a 1β-Methyl Carbapenem Antibiotic Precursor" Tetrahedron Letters. 29. 6461-6464 (1988)

Fumiyuki Shirai：“合成 1β-甲基碳青霉烯类抗生素前体的新型双不对称羟醛方法”四面体快报 29. 6461-6464 (1988)。

村田正好: "3ーピロリジニルチオー1ーアザビシクロ〔3,2,0〕ヘプトー2ーエンー2ーカルボン酸化合物" 公開特許公報(A). 783-852 (1988)

Masayoshi Murata：“3-吡咯烷基硫基-1-氮杂双环[3,2,0]庚-2-en-2-羧酸化合物”公开专利出版物（A）783-852（1988）。

村田正好: "3-ピロリジニルチオ-1-アザビシクロ[3.2.0.]ヘプト-2-エン・2-カルボン酸化合物およびその製造法" 公開特許公報(A). 837-864 (1989)

Masayoshi Murata：“3-吡咯烷基硫基-1-氮杂双环[3.2.0.]庚-2-烯2-羧酸化合物及其制备方法”公开专利申请(A)837-864(1989)。

Fumiyuki,Shirai: Journal of Organic Chemistry. 52. 5491-5493 (1987)

Fumiyuki，Shirai：有机化学杂志。