铜催化的α-亚胺酯不对称烷基化反应对映选择性合成(S)-BIRT-377

doi:10.6023/cjoc202603034

摘要/Abstract

报道了一种高效的铜催化α-亚胺酯不对称烷基化反应, 用于构建手性α-季碳氨基酸, 并成功实现了(S)-BIRT-377的高效对映选择性合成. 该方法具有广泛的底物适用范围, 可兼容烯丙基、炔丙基、苄基、烷基及官能团化烷基溴等多种卤代烃, 产物收率最高可达89%, 对映体过量值为90%~99%. 克级规模制备及下游衍生实验证明了其合成应用价值, 以三步59%总收率高效合成了(S)-BIRT-377, 并以两步69%总收率完成了抗高血压药物甲基多巴的合成. 该研究工作为手性α-季碳氨基酸的对映选择性合成提供了高效策略, 并展示了铜催化体系在药物分子后期修饰中的应用潜力.

关键词: 不对称烷基化, 铜催化, α-亚胺酯, BIRT-377, 甲基多巴

An efficient copper-catalyzed asymmetric alkylation of α-imino esters for the construction of chiral α-quaternary amino acids was reported, successfully enabling the enantioselective synthesis of (S)-BIRT-377. This method exhibits a broad substrate scope, tolerating a diverse range of alkyl halides including allylic, propargylic, benzylic, and functionalized alkyl bromides, affording the corresponding products in up to 89% yield with 90%~99% ee. The synthetic utility is further demonstrated by gram-scale preparation and downstream transformations, enabling the efficient synthesis of (S)-BIRT-377 in 59% overall yield over three steps, and the concise synthesis of the antihypertensive drug methyldopa in 69% overall yield over two steps. This work not only provides a practical route to (S)-BIRT-377 but also highlights the versatility of copper- catalyzed asymmetric alkylation of α-imino esters for the construction of chiral α-quaternary amino acids.

Key words: asymmetric alkylation, copper catalysis, α-imino ester, BIRT-377, methyldopa

引用此文

王弘毅, 周韦屹, 彭凌子, 郭昌. 铜催化的α-亚胺酯不对称烷基化反应对映选择性合成(S)-BIRT-377[J]. 有机化学, 2026, 46(7): 2779-2788.

Hongyi Wang, Weiyi Zhou, Lingzi Peng, Chang Guo. Enantioselective Synthesis of (S)-BIRT-377 via Copper-Catalyzed Asymmetric Alkylation of α-Imino Esters[J]. Chinese Journal of Organic Chemistry, 2026, 46(7): 2779-2788.

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图/表 7

Figure 1. Representative pharmaceuticals containing chiral qua- ternary α-amino acid cores

Scheme 1. Retrosynthetic analysis of (S)-BIRT-377

Scheme 2. Representative transition-metal-catalyzed asymmetric reactions of α-imino esters

Entry	L*	Base	Yield^b/%	ee^c/%
1	(R,R)-L1	Cs₂CO₃	nr	—
2	(R)-L2	Cs₂CO₃	29	8
3	(S,S_p)-L3	Cs₂CO₃	72	95
4	(S,S_p)-L4	Cs₂CO₃	76	97
5	(S,S_p)-L5	Cs₂CO₃	75	96
6	(S,S_p)-L6	Cs₂CO₃	60	38
7	—	Cs₂CO₃	nr	—
8^d	(S,S_p)-L4	Cs₂CO₃	nr	—
9	(S,S_p)-L4	—	nr	—

Table 1. Optimization of reaction conditionsa

Table 2. Substrate scope of alkyl halides and α-imino estersa

Scheme 3. Gram scale synthesis of (S)-BIRT-377

Scheme 4. Synthesis of (S)-methyldopa

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