青藤碱N-四氮唑和N-噁二唑杂环衍生物的设计与合成

doi:10.6023/cjoc202211009

摘要/Abstract

建立了两个新的合成路线, 在青藤碱D环的N原子上构建了N-四氮唑和N-1,3,4-噁二唑取代的杂环衍生物, 共获得了34个新的青藤碱杂环衍生物. 以青藤碱为原料, 通过溴化氰取代生成N-CN青藤碱, 再与叠氮化钠通过1,3-偶极环加成反应, 生成了N-四氮唑青藤碱. 苄氯类试剂与四氮唑发生取代反应生成青藤碱N-四氮唑杂环衍生物; 酰氯类试剂与四氮唑通过酰化反应和惠思根重排反应生成青藤碱N-1,3,4-噁二唑杂环衍生物. 方法简单, 条件温和, 产率优良. 此工作为天然产物结构修饰提供了新的方法, 扩大了青藤碱衍生物库, 为潜在的青藤碱药物活性研究提供了药物分子设计方法.

关键词: 青藤碱, 四氮唑, 噁二唑, 衍生物

Two new synthesis methods were established, N-tetrazole and N-1,3,4-oxadiazole substituted heterocyclic derivatives of sinomenine were constructed on the N atom of D-ring, and 34 new sinomenine heterocyclic derivatives were synthesized. N-CN sinomenine at 17-position was generated by substituted reaction between cyanogen bromide and sinomenine, and then N-tetrazole sinomenine was achieved by 1,3-dipolar cycloaddition reaction with NaN₃. The reaction of tetrazole with benzyl chloride produced N-tetrazole heterocyclic derivatives of sinomenine. N-1,3,4-Oxadiazole heterocyclic derivatives of sinomenine were obtained by acylation reaction and the Huisigen rearrangement reaction of tetrazole with acyl chloride reagents. These methods with mild condition gave good to excellent yields. This method provides new methods for structural modification of natural products, the synthesized compounds expand the library of sinomenine derivatives, and this work provides a basis study for drug molecular design and potential activity study.

Key words: sinomenine, tetrazole, oxadiazole, derivative

引用此文

武学丹, 徐瑞祥, 方霄龙, 张克华, 金杰. 青藤碱N-四氮唑和N-噁二唑杂环衍生物的设计与合成[J]. 有机化学, 2023, 43(7): 2506-2518.

Xuedan Wu, Ruixiang Xu, Xiaolong Fang, Kehua Zhang, Jie Jin. Design and Synthesis of N-Tetrazole and N-Oxadiazole Heterocyclic Derivatives of Sinomenine[J]. Chinese Journal of Organic Chemistry, 2023, 43(7): 2506-2518.

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图/表 10

图1. 青藤碱

Figure 1. Sinomenine

图式1. 青藤碱N-四氮唑杂环衍生物的合成

Scheme 1. Synthesis of N-tetrazole heterocyclic derivatives of sinomenine

Entry	Catalyst	Solvent	t/h	T/℃	Yield^b/%
1	NH₄Cl	DMF	8	125	35
2	NH₄Cl	MeCN	12	80	47
3	ZnCl₂	DMF	8	125	60
4	ZnCl₂	Ethylene glycol	12	120	None
5	ZnCl₂	iso-Propanol	24	50	39
6	ZnCl₂	MeCN	12	80	90

表1. N-四氮唑青藤碱合成条件优化a

Table 1. Optimization of reaction conditions for N-tetrazole sinomenine

Entry	Benzyl chloride/mmol	Base	Yield^b/%
1	1.2	NaHCO₃	42
2	1.2	KHCO₃	65
3	1.5	KHCO₃	70
4	2	KHCO₃	81
5	3	KHCO₃	83

表2. 反应条件优化a

Table 2. Optimization of reaction conditions

Compd.	R	Yield^b/%	Compd.	R	Yield^b/%
5a	H	81	5j	3-Cl	89
5b	2,6-Me₂	86	5k	3-F	80
5c	2,6-Cl₂	82	5l	3-OMe	81
5d	2,6-F₂	85	5m	4-Br	87
5e	2-Me	80	5n	4-CMe₃	80
5f	2-Cl	83	5o	4-CF₃	85
5g	3,4-F₂	84	5p	4-CH₃	81
5h	3-Br	87	5q	4-CN	89
5i	3-Me	86	5r	4-NO₂	82

表3. 青藤碱N-四氮唑杂环衍生物的合成a

Table 3. Synthesis of N-tetrazole heterocyclic derivatives of sinomenine

图2. 化合物5r的HMBC谱分析

Figure 2. HMBC analysis of the target product 5r

图式2. 青藤碱N-1,3,4-噁二唑杂环衍生物的合成

Scheme 2. Synthesis of N-1,3,4-oxadiazole heterocyclic derivatives of sinomenine

Entry	Benzoyl chloride/mmol	Base	Yield /%
1	1.2	KHCO₃	52
2	1.2	NaHCO₃	63
3	1.5	NaHCO₃	67
4	2	NaHCO₃	83
5	2.5	NaHCO₃	81

表4. 反应条件优化a

Table 4. Optimization of reaction conditions

Compd.	R	Yield/%	Compd.	R	Yield^b/%
6a	H	83	6i	4-CF₃	86
6b	2-Me	84	6j	4-CH₂Cl	91
6c	2-Cl	89	6k	4-Me	92
6d	2-NO₂	80	6l	4-OMe	83
6e	3,4-Cl₂	85	6m	4-Cl	93
6f	3-Me	92	6n	4-CN	86
6g	3-Cl	85	6o	4-F	87
6h	4-Br	88	6p	4-NO₂	92

表5. 青藤碱N-1,3,4-噁二唑杂环衍生物的合成a

Table 5. Synthesis of N-1,3,4-oxadiazole heterocyclic derivatives of sinomenine

图式3. 青藤碱N-1,3,4-噁二唑杂环衍生物的形成机理

Scheme 3. Reaction mechanism of N-1,3,4-oxadiazole derivatives sinomenine

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