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

7.项目总结。鉴于其独特的结构特征，非蛋白性α-氨基酸(XaAs)是 生物活性分子、非核糖体多肽和其他上市产品中的重要组成部分 毒品。即便如此，许多种类的非正则氨基酸仍未被开发，它们的不对称 复杂的合成，这使它们成为一个丰富的发现计划的令人兴奋的起点。尽管 -氨基酸的对映选择性合成取得了巨大的进展，但目前尚无通用的 合成对映体，-二取代XAAS的实用方案。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来源的XaAs来解决这个问题 直截了当的一刀切时尚(总体目标)。我们实验室的初步发现证实了两种截然不同的 从-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 反阴离子定向催化。对-卤代甘氨酸的合成进行了优化，使其具有可操作性 简单、实用、易于不对称的功能化，与主要优势相同。 该提案旨在为合成特殊的-氨基酯提供创新的合成解决方案。 通过氢键供体催化剂和磷酸银催化剂的对映选择性诱导 甘氨酸和丙氨酸的替代物(目标1)。不对称合成α，α双取代的XAa 还提出了通过芳基化反应制备四取代立体中心的方法，该方法由 一些人设计(硫代)尿素作为阴离子结合催化剂。这些策略最终将用于综合 一些具有生物活性的小分子天然产物最便捷的方式：(+)-山梨内酯A 和(−)-伏米霉素(目标2)。这两种天然产品在建筑上都围绕着一种特权的-arylated 丙氨酸单位，是抗白血病和抗白血病生物研究的有效起点。 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 合成了几类主要的非规范-氨基酸(和-二取代的XaAs)。我们的小说 一锅策略在反应发现平台上扩展了不对称催化的合成工具箱 朝向-氨基酸。通过提供对这些至关重要的构件的更广泛的访问，我们寻求 影响抗菌肽的合成，这可能会在生物医学研究中找到重要的应用。

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.