Asymmetric Synthesis of Amino Acids and Amino Phosphonic Acids

氨基酸和氨基膦酸的不对称合成

• 批准号: 7477591
• 负责人: FRANKLIN A DAVIS
• 金额: $ 28.32万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-07-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477591
• 关键词: Acids; Alkaloids; Amides; Amines; Amino Acids; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Antiviral Agents; Attention; Aziridines; Biological; Biological Factors; Cancer cell line; Chemicals; Chemistry; Complex; Condition; Cyclization; Diamines; Diels Alder reaction; Drug Industry; Esters; Evaluation; Excision; Facility Construction Funding Category; Funding; Goals; Heterocyclic Compounds; Human; Imines; Isomerism; Ketones; Lead; Ligands; Marines; Methodology; Object Attachment; Pharmaceutical Preparations; Pharmacologic Substance; Phosphonic Acids; Preparation; Procedures; Proline; Protocols documentation; Pyrrolidines; Rana; Reaction; Reagent; Research; Route; Scheme; Skin; Solvents; Structure; Technology; analog; aziridine; aziridine-2-carboxylate; base; carboxylate; design; diene; improved; molecular recognition; novel; nucleophilic addition; phosphonate; piperidine; programs; pyrrolidine; receptor; scaffold; small molecule libraries

The objective of this research program is to design and synthesize new sulfmimine (N-sulfinyl imine)-derived chiral building blocks, and to invent related methodologies for the asymmetric synthesis of amine structures that are presently difficult to prepare but necessary for the synthesis of biologically important anticancer, antiviral, antibacterial, antifungal, and other bioactive molecules of medicinal relevance. Examples include novel a- and (¿-amino acids, pyrrolidine, and piperidine alkaloids. These amine types are also widely used as chiral building blocks for the enantioselective construction of bioactive materials, including drug and drug candidates. Four sulfinimine-derived chiral building blocks (a-substituted (¿-amino ketones, d-amino (¿- ketophosphonates, 2,¿-diamino esters, and 2-substituted 2H-azirine ¿-carboxylates) will be employed to accomplish our objectives. a-Substituted (¿-amino Weinreb amides, prepared by addition of prochiral Weinreb amides to sulfinimines, on reaction with Grignard reagents, represent a general solution.to the problem of a-substituted (¿-amino ketone synthesis. Using our intramolecular Mannich cyclization protocol, these new (¿-amino ketones will be employed in syntheses of toxic frog skin polysubstituted piperidines not previously prepared. d-Amino (¿-ketophosphonates will be used in new stereocontrolled syntheses of cis- 2,5- and trans-2,5 disubstituted ring functionalized pyrrolidine alkaloids from a common ¿-oxo pyrrolidine 2- phosphonate intermediate. Sulfinimine derived syn- and anti-2,¿-diamino esters are expected to provide access to several biorelevant diamino compounds including the unknown anti isomer of (+)-CP99,994, a potent neurokinin substrate P receptor antagonist. Analogues of the architecturally unique marine antibiotic (-)-agelastatin A will be prepared for biological evaluation. (-)-Agelastatin A has significant activity against a variety of human cancer cell lines, but its mechanism of activity remains undetermined. The reaction of new sulfinimine-derived 2-substituted 2H-azirine ¿-carboxylates with nucleophiles and with dienes in aza-Diels-Alder reactions, will provide unique routes to enantiopure 2-substituted aziridine 2- carboxlates and bicyclic and tricyclic aziridine carboxylates. Stereoselective ring opening of these aziridines affords novel a- and (¿-amino acids not easily assessable by other means. The photodesulfmylation of sulfinamides represents an important new protocol, not requiring acids or bases, for the removal of the valuable amine N-sulfinyl protecting group.

本研究计划的目的是设计和合成新的亚磺酰亚胺衍生物 手性结构单元，并发明用于胺结构的不对称合成的相关方法 这些化合物目前难以制备，但对于生物学上重要的抗癌药物的合成是必需的， 抗病毒、抗细菌、抗真菌和其它与医学相关的生物活性分子。实例包括 新的α-和β-氨基酸、吡咯烷和哌啶生物碱。这些胺类型也被广泛使用 作为对映选择性构建生物活性材料（包括药物和药物）的手性构建块 候选人 四个亚磺酰亚胺衍生的手性结构单元（α-取代的（<$-氨基酮，d-氨基（<$-氨基酮）， 酮膦酸酯、2，<$-二氨基酯和2-取代的2 H-吖丙啶<$-羧酸酯）将用于 实现我们的目标。α-取代的（ω-氨基Weinreb酰胺，通过加成前手性 Weinreb酰胺到亚磺亚胺，在与格氏试剂反应时，代表了一般的solution.to α-取代的（ω-氨基酮的合成问题。使用我们的分子内曼尼希环化方案， 这些新的（ω-氨基酮将用于合成有毒的蛙皮多取代哌啶， 以前准备的。d-氨基（ω-酮基膦酸酯将用于顺式- 2，5-和反式-2，5-二取代的环官能化的吡咯烷生物碱，从常见的<$-氧代吡咯烷2- 膦酸酯中间体预期亚硫亚胺衍生的顺式和反式2，η-二氨基酯提供 获得几种生物相关的二氨基化合物，包括未知的（+）-CP 99，994的反异构体，a 有效的神经激肽底物P受体拮抗剂。结构独特的海洋抗生素的类似物 将制备（-）-琼脂糖蛋白抑制素A用于生物学评价。（-）-Agelastatin A具有显著的抗肿瘤活性， 多种人类癌细胞系，但其活性机制尚未确定。 新的亚磺酰亚胺衍生的2-取代的2 H-氮杂环丙烷<$-羧酸酯与亲核试剂的反应， 在氮杂-Diels-桤木反应中与二烯反应，将提供独特的路线来制备对映体纯的2-取代氮丙啶2- 羧酸酯和双环和三环氮丙啶羧酸酯。这些氮杂环丙烷的立体选择性开环 提供了通过其它方法不易获得的新的α-和β-氨基酸。的光敏化 亚磺酰胺代表了一种重要的新方案，不需要酸或碱， 有价值的胺N-亚磺酰基保护基。