Recent Advances in Metallated Azomethine Ylides for the Synthesis of Chiral Unnatural α-Amino Acids

Abstract

The development of efficient methods for the preparation of unnatural amino acids has long been an important goal since their widely application in synthetic and medicinal chemistry. The asymmetric α-functionalization of nucleophilic metalated azomethine ylides, which could be in situ-generated from readily-available aldimine esters, has been recogonized as a powerful strategy to synthesize unnatural amino acids. Over the past 20 years, tranistion metal-catalyzed asymmetric construction of unnatural amino acids using azomethine ylides have been extensively studied. In this review, the progress on metallated azomethine ylides invovled aymmetric transformation for the synthesis of unnatural amino acids is summarized according to eletrophilic reagents. Keywords azomethine ylide; asymmetric catalysis; unnatural α-amino acid 氨基酸是构成生命体蛋白质并同生命活动息息相 关的最基本的物质. 根据其存在形式, 氨基酸可分为天 然氨基酸和非天然氨基酸两大类. 自然界中天然存在的 氨基酸大约有 180 多种 [1] . 非天然氨基酸则是通过人工 合成的氨基酸, 结构与天然氨基酸存在着差异, 有的是 在天然氨基酸中引入一些官能团, 用以改善其性能, 有 的则与天然氨基酸结构完全不同, 是分子设计合成的结 果.具有光学活性的非天然 α-氨基酸是一些新的生物 活性肽的手性合成单元, 研究其合成也是探索蛋白质结 构和功能及功能性多肽的一种有效工具 [2] . 同时非天然 α-氨基酸及其衍生物还是合成许多药物、添加剂和精细 化学品的重要中间体 [3] . 近年来随着其越来越多的用途 被发现, 对氨基酸特别是具有特殊结构的光学纯 α-氨基 酸的需求量越来越大, 非天然 α-氨基酸的不对称合成已 经成为一个非常活跃的研究领域 [4] .

Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences

“…Initially, our investigations were focused on asymmetric allylic alkylation reaction between allyl carbonate 1 and alanine-derived aldimine ester 2a . In consideration of that metallated azomethine ylides are kind of stereochemically tunable nucelophiles 70 , 71 and no allyl stereogenic center will be generated in the expected coupling product, we firstly studied the feasibility of the reaction with the dual chiral Cu/achiral Pd co-catalyst system established in our previous work 49 . The intermediacy of α-allylic substituted aldimine ester 3a was obtained in 56% yield and unsatisfactory 80% ee in the presence of [Cu(I)/( S , S p )- L1 + Pd(PPh 3 ) 4 ] catalyst combination, together with Cs 2 CO 3 as the base and CH 2 Cl 2 as the solvent (Table 1 , entry 1).…”

New pharmaceuticals approved by FDA in 2020: Small‐molecule drugs derived from amino acids and related compounds

“…In this regard, we would like to stress the growing need in availability and affordability of various tactual types of AAs. Indeed, the interest in the development of synthetic approaches for the preparation of tailor‐made AAs in enantiomerically pure form is currently at an all‐time high 82–135 . Some impressive developments have been made in the area of dynamic kinetic resolution of unprotected AAs, 136–139 a methodology which is best suited for large‐scale production and can rival biocatalytic approaches in affordability and low‐cost structure.…”

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ‐Hydroxy α‐Amino Acids and Small Peptides

“…Taking atom and step economy and redox neutrality into account, it is extremely appealing to explore novel cascade strategies on the basis of the judicious selection and appropriate combination of dual metal relay catalysis for the borrowing-hydrogen reaction and azomethine ylide (AMY) chemistry. In continuation of our interest in asymmetric transformations with metalated azomethine ylides, [38,39] we supposed that stereochemically tunable metallated azomethine ylides derived from diphenyl ketoimine esters or amides would be an eligible nucleophile type [40,41] to react with an enone intermediate, a Michael receptor generated in situ by a borrowing-hydrogen strategy, with a racemic vinyl carbinol and a chiral metal catalyst. [42,43] Thus, as shown in Scheme 1c, an atom-and step-economical and redox-neutral cascade reaction enabled by bimetallic relay catalysis merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition would be realized in a stereodivergent manner.…”