Asymmetric Synthesis of Unnatural α-Amino Acids: Applications to Natural Products

非天然α-氨基酸的不对称合成：在天然产物中的应用

• 批准号: 9232407
• 负责人: Stephane P Roche
• 金额: $ 43.29万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232407
• 关键词: Address; Alanine; Amino Acid Motifs; Amino Acids; Anions; Anti-Bacterial Agents; Antibiotics; Architecture; Binding; Biological; Biomedical Research; Carbon; Catalysis; Chemicals; Collaborations; Communities; Complex; Data; Environment; Esters; Evaluation; Glycine; Goals; Hydrogen Bonding; Investigation; Ions; Laboratories; Letters; Ligands; Methods; Natural Products; Peptide Synthesis; Peptides; Play; Production; Property; Public Health; Pyruvate; Reaction; Reporting; Research; Role; Route; Science; Silver; Therapeutic Agents; Urea; antineoplastic antibiotics; catalyst; design; drug discovery; drug market; innovation; inorganic phosphate; novel; nucleophilic addition; personalized medicine; programs; small molecule; synthetic peptide; unnatural amino acids

7. Project summary. Given their unique structural features, non-proteinogenic α-amino acids (Xaas) are prominent building blocks in biologically active molecules, non-ribosomal peptides and other marketed drugs. Even so, numerous classes of non-canonical amino acids remain untapped and their asymmetric syntheses complicated, which make them an exciting starting point for a rich discovery program. Despite enormous advances in the enantioselective synthesis of -amino acids, there is still no general and practical solution to the synthesis of enantiopure ,-disubstituted Xaas. Hence, we will address this issue by establishing novel maneuvers to synthesize different classes of non-proteinogenic Xaas in a straightforward one-pot fashion (overall aim). Preliminary findings in our laboratory validated two distinct asymmetric strategies to synthesize Xaas from -haloglycines: anion-binding catalysis and asymmetric counteranion-directed catalysis. The synthesis of -haloglycines was optimized to become operationally simple, practical and amenable to asymmetric functionalizations in the same pot as the main vantage point. This proposal seeks to provide innovative synthetic solutions for the synthesis of unusual -amino esters through enantioselective induction using hydrogen bond-donor catalysts and silver phosphates catalysts on glycine- and alanine-like iminium surrogates (aim 1). The asymmetric synthesis of α,α-disubstituted Xaa to craft a tetrasubstituted -stereocenter via arylation is also proposed in a one-pot approach, catalyzed by some designed (thio)ureas anion-binding catalysts. These strategies will ultimately serve to synthesize some biologically active small-molecule natural products in the most expedient way: (+)-sorbicillactone A and (−)-fumimycin (aim 2). Both natural products are architecturally framed around a privileged -arylated alanine unit and represent a valid starting point for the biological investigations of anti-leukemic and antibacterial agents. It is anticipated that these studies will establish simple, catalytic and highly enantioselective methods for synthesizing several major classes of non-canonical -amino acids (and -disubstituted Xaas). Our novel one-pot tactic expands the synthetic toolbox of asymmetric catalysis in a platform for reaction discovery towards -amino acids. By providing broader access to these critically important building blocks, we seek to impact antibiotic peptides synthesis which will likely find important applications in biomedical research.

7. 项目总结。鉴于其独特的结构特征，非蛋白 α-氨基酸 (Xaas) 生物活性分子、非核糖体肽和其他市售产品的重要组成部分 药物。即便如此，许多类别的非规范氨基酸仍未得到开发，而且它们的不对称性 综合起来很复杂，这使它们成为丰富的发现计划的令人兴奋的起点。尽管 尽管α-氨基酸的对映选择性合成取得了巨大进展，但目前还没有通用的、通用的方法。 合成对映体纯 α,α-二取代 Xaas 的实用解决方案。因此，我们将解决这个问题 通过建立新的方法来合成不同类别的非蛋白Xaas来解决这个问题 简单的一锅时尚（总体目标）。我们实验室的初步研究结果验证了两种不同的 从 α-卤代甘氨酸合成 Xaas 的不对称策略：阴离子结合催化和不对称 抗衡阴离子定向催化。 α-卤代甘氨酸的合成经过优化，可操作化 简单、实用且适合在同一锅中进行不对称功能化作为主要优势。 该提案旨在为合成不寻常的α-氨基酯提供创新的合成解决方案 通过使用氢键供体催化剂和磷酸银催化剂进行对映选择性诱导 甘氨酸和丙氨酸样亚胺替代物（目标 1）。 α,α-二取代Xaa的不对称合成 还提出通过一锅法催化芳基化来制作四取代的α-立体中心 一些设计的（硫代）脲阴离子结合催化剂。这些策略最终将用于综合 最便捷的一些具有生物活性的小分子天然产物：(+)-山梨内酯A 和 (−)-烟霉素（目标 2）。这两种天然产品在结构上都围绕着特权的α-芳基化 丙氨酸单位并代表抗白血病和抗白血病生物学研究的有效起点 抗菌剂。 预计这些研究将建立简单、催化和高度对映选择性的方法 合成几类主要的非经典 α-氨基酸（和 αα-二取代 Xaas）。我们的小说 一锅法扩展了反应发现平台中不对称催化的合成工具箱 朝向α-氨基酸。通过提供对这些极其重要的构建模块的更广泛的访问，我们寻求 影响抗生素肽的合成，这可能会在生物医学研究中找到重要的应用。