Catalytic Asymmetric Synthesis of Deoxypropionates from Ketenes

乙烯酮催化不对称合成脱氧丙酸酯

• 批准号: 8770363
• 负责人: ROMAN DEMBINSKI
• 金额: $ 33.36万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770363
• 关键词: Acids; Alkaloids; Attention; Biological; Biological Factors; Calcium; Carboxylic Acids; Catalysis; Chloride Ion; Chlorides; Cytostatics; Development; Dimerization; Drug Targeting; Future; Health; Heterodimerization; Human; Hydrogenation; In Situ; Ionomycin; Ionophores; Lactones; Lipids; Malignant Neoplasms; Mediating; Methodology; Methods; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Process; Protocols documentation; Reaction; Reagent; Reporting; Scientist; Sex Attractants; Solutions; Stereoisomer; Structure; System; Therapeutic Agents; Tuberculosis; United States National Institutes of Health; Vaccines; Variant; Waxes; analog; base; catalyst; drug synthesis; ketene; method development; mycocerosic acid; public health relevance; stem; tuberculosis treatment

DESCRIPTION (provided by applicant): In this NIH R15 proposal we outline the development of sequential catalytic asymmetric ketene heterodimerization-reduction processes to provide stereodefined deoxypropionates suitable for natural product synthesis. The importance of deoxypropionate containing polyketides stems from the fact that they have a broad range of biological activities, e.g. as cytostatics (e.g. borrelidin and doliculide), or as potential conduis for tuberculosis therapy (as drug targets or vaccines). We recently reported that a catalytic asymmetric ketene heterodimerization could be accomplished through a stepwise mechanism promoted by an alkaloid nucleophilic catalytic system. 17 examples of ketene heterodimer ¿-lactones were prepared in ¿90% ee. Diastereoselective hydrogenolysis of the ketene heterodimers obtained would provide access to carboxylic acids bearing two chiral centers (deoxypropionate units) as the anti-deoxypropionate. An alternative approach would involve the asymmetric synthesis of a ¿-lactone through catalytic hydrogenation of a ketene heterodimer, followed by SN2 ring-opening of the ¿-lactone by a hydride reagent to provide access to the syn-deoxypropionate. The proposed sequential catalytic ketene heterodimerization-reduction sequences would therefore provide powerful and complementary asymmetric methods for deoxypolypropionate construction. Such methods possess great potential because deoxypolypropionates are frequently investigated as therapeutic agents for tuberculosis and cancer. The synthetic utility of the proposed methodologies will be validated through application to the synthesis of two biologically important deoxypropionate molecules, mycocerosic acid and (-)-mycolipanolic acid, which we expect to be assembled in significantly fewer steps than has previously been possible. Our specific aims for this NIH R15 AREA proposal are as follows: 1. Specific Aim no.1: To explore catalytic hydrogenolysis of ketene heterodimers for the synthesis of anti-deoxypropionates 2. Specific Aim no.2: To explore catalytic hydrogenation of ketene heterodimers for the synthesis of ¿-lactones bearing three chiral centers. 3. Specific Aim no.3: To explore hydride-mediated SN2 ring-opening of ¿-lactones for the synthesis of syn-deoxypropionate derivatives. 4. Specific Aim no.4: To investigate the utility of ketene heterodimer-derived deoxypropionates in the asymmetric synthesis of mycocerosic acid. 5. Specific Aim no.4: To investigate the utility of ketene heterodimer-derived deoxypropionates in the asymmetric synthesis of (-)-mycolipanolic acid.

描述（由申请人提供）：在这份 NIH R15 提案中，我们概述了连续催化不对称烯酮异二聚还原工艺的开发，以提供适合天然产物合成的立体定义的脱氧丙酸酯。含脱氧丙酸酯的聚酮化合物的重要性源于它们具有广泛的用途。一系列生物活性，例如作为细胞抑制剂（例如疏螺旋体素和多利库利特），或作为潜在的我们最近报道了催化不对称乙烯酮异二聚化可以通过生物碱亲核催化系统促进的逐步机制来完成 17 个乙烯酮异二聚体的例子。 -内酯是在 ¿ 中制备的获得的烯酮异二聚体的 90% ee 的非对映选择性氢解将提供带有两个手性中心（脱氧丙酸单元）的羧酸作为抗脱氧丙酸。另一种方法将涉及 ¿ 的不对称合成。 -内酯通过烯酮异二聚体的催化氢化，然后通过 ¿ 的 SN2 开环因此，所提出的连续催化烯酮异二聚还原序列将为脱氧聚丙酸酯的构建提供强大且互补的不对称方法，因为脱氧聚丙酸酯经常被研究作为治疗剂。所提出的方法的合成效用将通过应用于两种具有重要生物学意义的合成来得到验证。脱氧丙酸分子、霉菌蜡酸和 (-)-霉菌脂醇酸，我们预计其组装步骤将比以前少得多。 NIH R15 AREA 提案的具体目标如下： 1. 具体目标 1：探索乙烯酮异二聚体的催化氢解用于合成抗脱氧丙酸酯 2. 具体目标 2：探索乙烯酮异二聚体的催化氢化乙烯酮异二聚体用于合成 ¿ -带有三个手性中心的内酯 3. 具体目标 3：探索氢化物介导的 SN2 开环。 4. 具体目标 4：研究乙烯酮异二聚体衍生的脱氧丙酸酯在真菌蜡酸的不对称合成中的用途。 (-)-霉醇酸的不对称合成中乙烯酮异二聚体衍生的脱氧丙酸酯。

项目成果

Asymmetric Synthesis of Dipropionate Derivatives through Catalytic Hydrogenation of Enantioenriched E-Ketene Heterodimers.

通过对映体富集的 E-乙烯酮异二聚体的催化氢化不对称合成二丙酸酯衍生物。

• 发表时间: 2016-08
• 作者: Chen, Shi;Mondal, Mukulesh;Ibrahim, Ahmad A;Wheeler, Kraig A;Kerrigan, Nessan J
• 通讯作者: Kerrigan, Nessan J

Catalytic Asymmetric Synthesis of Ketene Heterodimer β-Lactones: Scope and Limitations.

乙烯酮异二聚体β-内酯的催化不对称合成：范围和局限性。

• 发表时间: 2016-09-02
• 作者: Chen, Shi;Ibrahim, Ahmad A;Peraino, Nicholas J;Nalla, Divya;Mondal, Mukulesh;Van Raaphorst, Maxwell;Kerrigan, Nessan J
• 通讯作者: Kerrigan, Nessan J

Recent Developments in Vinylsulfonium and Vinylsulfoxonium Salt Chemistry.

乙烯基锍和乙烯基锍盐化学的最新进展。

• 发表时间: 2018-03-23
• 作者: Mondal, Mukulesh;Chen, Shi;Kerrigan, Nessan J
• 通讯作者: Kerrigan, Nessan J

Asymmetric Synthesis of Deoxypropionate Derivatives via Catalytic Hydrogenolysis of Enantioenriched Z-Ketene Heterodimers.

通过对映体富集的 Z-乙烯酮异二聚体的催化氢解不对称合成脱氧丙酸酯衍生物。

• 发表时间: 2015-07-02
• 影响因子: 5.2
• 作者: Chen, Shi;Ibrahim, Ahmad A;Mondal, Mukulesh;Magee, Anthony J;Cruz, Adam J;Wheeler, Kraig A;Kerrigan, Nessan J
• 通讯作者: Kerrigan, Nessan J

Alkaloid-Catalyzed Enantioselective [3 + 2] Cycloaddition of Ketenes and Azomethine Imines.

生物碱催化的对映选择性 [3 2] 乙烯酮和甲亚胺亚胺的环加成。

• 发表时间: 2016-08-19
• 影响因子: 5.2
• 作者: Mondal, Mukulesh;Wheeler, Kraig A;Kerrigan, Nessan J
• 通讯作者: Kerrigan, Nessan J