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.

1 β-甲基碳青霉烯类抗生素作为下一代β-内酰胺类抗生素的最有希望的候选者，近年来受到了广泛关注。本项目的主要目的是开发实用的方法用于不对称合成，1 β-甲基碳青霉烯关键衍生物。1.以市售的（R）-β-羟基丁酸甲酯为原料，采用高度立体控制的方法，不对称合成了1 β-甲基碳青霉烯的关键前体。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，该中间体可通过我们先前开发的方法从（R）-羟基丁酸酯容易地获得。以易得的（S）-β-羟基异丁酸甲酯为原料，以（S）-3-苄氧基-2-甲基丙醛与（三甲基硅基）乙酸乙酯的酮硅基缩醛为原料，通过螯合控制的羟醛缩合反应合成了1 β-甲基碳青霉烯关键前体.以（R）-羟基丁酸酯和（S）-羟基异丁酸酯为起始原料，开发了一种高效制备1 β-甲基碳青霉烯关键前体的新方法。关键步骤是螯合控制的双不对称羟醛缩合反应和立体化学纯羟醛产物的N-C_4环化反应.合成了一系列1 β-甲基碳青霉烯衍生物，并对其抗菌活性进行了评价。

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-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)。

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）。

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

Fumiyuki，Shirai：有机化学杂志。