可见光催化N-芳基乙醛酸亚胺脱羧烷基化合成非天然氨基酸衍生物

doi:10.6023/cjoc202304020

摘要/Abstract

研究了可见光诱导乙醛酸亚胺的脱羧自由基烷基化反应制备α-烷基化的非天然氨基酸衍生物. 四氯-N-羟基邻苯二甲酰亚胺(TCNHPI)活性酯在可见光照射下产生的多种烷基自由基以良好的收率与亚胺加成. 金属铱配合物为光催化剂, 汉斯酯(HE)为必不可少的氢转移试剂, 氟硼酸(HBF₄)作为添加剂可显著提高产率. 反应条件温和, 显示了广泛的底物适用范围. 此外, 简单有效的一锅合成法, 包括乙醛酸乙酯、伯胺和TCNHPI活性酯的多组分反应也能够顺利进行, 该方案为α-烷基化的非天然氨基酸衍生物的合成提供了一种新的方法.

关键词: 光催化, N-芳基乙醛酸亚胺, 脱羧, 一锅法, 非天然氨基酸衍生物

A visible-light-mediated decarboxylative radical alkylation of glyoxylimines for preparing α-alkylated unnatural amino acid derivatives was developed. Various alkyl radicals generated by tetrachloro-N-hydroxyphthalimide (TCNHPI) active esters were added to imines in good yields under visible light irradiation. Iridium complex was selected as photocatalyst and also, Hantzsch ester (HE) as hydrogen transfer reagent was essential. Fluoboric acid (HBF₄) significantly improved the yield. Mild reaction conditions showed wide substrate scopes. In addition, the straightforward and efficient one-pot procotol, involved a multicomponent reaction of ethyl glyoxalate, primary amine and TCNHPI active ester occurred smoothly. This scheme provides a new method for the synthesis of α-alkylated unnatural amino acid derivatives.

Key words: photocatalysis, N-aromatic glyoxylimines, decarboxylation, one-pot, unnatural amino acid derivatives

引用此文

王永玲, 张铁欣, 张栩铭, 孙晗扬, 冷津瑶, 李亚明. 可见光催化N-芳基乙醛酸亚胺脱羧烷基化合成非天然氨基酸衍生物[J]. 有机化学, 2023, 43(12): 4284-4293.

Yongling Wang, Tiexin Zhang, Xuming Zhang, Hanyang Sun, Jinyao Leng, Yaming Li. Synthesis of Unnatural Amino Acid Derivatives by Visible- Light-Catalyzed Decarboxylative Alkylation of N-Aromatic Glyoxylimines[J]. Chinese Journal of Organic Chemistry, 2023, 43(12): 4284-4293.

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图/表 9

图1. 具有生物活性的非天然氨基酸衍生物或肽示例

Figure 1. Examples of unnatural amino acid derivatives or peptides with biological activity

图式1. 可见光催化非天然氨基酸衍生物合成

Scheme 1. Visible-light-catalyzed synthesis of unnatural amino acids derivatives

Entry	Catalyst	Additive	Solvent	Yield^b/%
1	Ru(bpy)₃Cl₂	—	DCM	30
2	4CzIPN	—	DCM	16
3	Eosin Y	—	DCM	<10
4	Ir(ppy)₃	—	DCM	41
5^c	Ir(ppy)₃	—	DCM	42
6^d	Ir(ppy)₃	—	DCM	n.d.^e
7f	Ir(ppy)₃	—	DCM	n.d.
8^g	Ir(ppy)₃	—	DCM	27
9	Ir(ppy)₃	K₂CO₃	DCM	61
10	Ir(ppy)₃	(NH₄)₂CO₃	DCM	60
11	Ir(ppy)₃	PhCOOH	DCM	56
12	Ir(ppy)₃	CF₃COOH	DCM	44
13	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DCM	76
14^h	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DCM	55
15ⁱ	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DCM	61
16^j	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DCM	75
17^k	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DCM	73
18	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DMF	78
19	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	MeCN	52
20	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DMSO	85
21^l	Ir(ppy)₃	ⁱPr₂NEt•HBF₄	DMSO	83
22	—	ⁱPr₂NEt•HBF₄	DMSO	32

表1. 乙醛酸亚胺脱羧烷基化反应条件优化a

Table 1. Optimization of reaction conditions for the decarboxylative alkylation of glyoxylimines

表2. N-芳基乙醛酸亚胺的底物拓展a,b

Table 2. Scope of N-aromatic glyoxylimines

表3. TCNHPI活性酯的底物拓展a,b

Table 3. Scope of TCNHPI activated esters

图式2. 一锅法合成3a

Scheme 2. One-pot protocol for synthesis of 3a

图式3. 3a的一锅法克级放大

Scheme 3. Gram-scale preparation of 3a by one-pot protocol

图式4. 亚胺与TCNHPI酯反应的控制实验

Scheme 4. Control experiments of imine with TCNHPI esters

图式5. 亚胺与TCNHPI酯反应可能的反应机理

Scheme 5. Possible reaction mechanism of imine with TCNHPI esters

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