Enantioselective Synthesis of (S)-BIRT-377 via Copper-Catalyzed Asymmetric Alkylation of α-Imino Esters

doi:10.6023/cjoc202603034

Abstract

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

Cite this article

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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Fig. & Tab. 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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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