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

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:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2019-12-31

项目摘要

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中文摘要
翻译
7. 项目总结。非蛋白质原性α-氨基酸(Xaas)具有独特的结构特征
英文摘要
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.
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