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.项目摘要。鉴于其独特的结构特征，非蛋白原性α-氨基酸（Xaas）是 生物活性分子、非核糖体肽和其他市售的 毒品即便如此，许多种类的非规范氨基酸仍然没有开发，它们的不对称性也是未知的。 合成复杂，这使他们成为一个令人兴奋的起点，丰富的发现计划。尽管 尽管β-氨基酸的对映选择性合成取得了巨大进展，但仍然没有通用的和 合成对映体纯的β，β-二取代的Xaas的实际解决方案。因此，我们将解决这个问题， 通过建立新的策略来合成不同类别的非蛋白原性Xaas， 简单的一锅时尚（总体目标）。我们实验室的初步发现证实了两种不同的 β-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 反阴离子导向催化。对β-卤代甘氨酸的合成进行了优化，使其操作简便， 简单、实用并且适合于在与主要Vantage位置相同的罐中的不对称官能化。 该提案旨在为合成不寻常的β-氨基酯提供创新的合成解决方案 通过使用氢键给体催化剂和磷酸银催化剂的对映选择性诱导， 甘氨酸和丙氨酸样亚胺替代物（AIM 1）。α，α-二取代Xaa的不对称合成 还提出了通过芳基化来制备四取代的β-立构中心的一锅法， 一些设计的（硫）脲阴离子结合催化剂。这些战略最终将有助于综合 一些具有生物活性的小分子天然产物：（+）-山梨内酯A 和（-）-烟曲霉素（aim 2）。这两种天然产物都是围绕着一个特权的α-芳基化的 丙氨酸单位，并代表了一个有效的起点，生物学研究的抗白血病和 抗菌剂 预计这些研究将建立简单，催化和高对映选择性的方法， 合成几种主要类别的非规范β-氨基酸（和β-二取代的Xaas）。我们的新型 一锅法在反应发现平台中扩展了不对称催化的合成工具箱 向β-氨基酸转化。通过更广泛地提供这些至关重要的组成部分，我们力求 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。