钯配合物与手性方酰胺协同催化的乙烯基碳酸乙烯酯与醛的不对称脱羧环加成反应

引用本文: KhanIjaz, 李红芳, 吴学, 张勇健. 钯配合物与手性方酰胺协同催化的乙烯基碳酸乙烯酯与醛的不对称脱羧环加成反应[J]. 化学学报, 2018, 76(11): 874-877. doi: 10.6023/A18070291 shu

Citation: Khan Ijaz, Li Hongfang, Wu Xue, Zhang Yong Jian. Asymmetric Decarboxylative Cycloaddition of Vinylethylene Carbonates with Aldehydes by Cooperative Catalysis of Palladium Complex and Chiral Squaramide[J]. Acta Chimica Sinica, 2018, 76(11): 874-877. doi: 10.6023/A18070291 shu

钯配合物与手性方酰胺协同催化的乙烯基碳酸乙烯酯与醛的不对称脱羧环加成反应

KhanIjaz ^a, ,
李红芳 ^a,b, ,
吴学 ^b, ,
张勇健 ^{a,
,}

a.
上海交通大学化学化工学院上海 200240
b.
延边大学理学院化学系延吉 133002

通讯作者: 张勇健, E-mail: yjian@sjtu.edu.cn

基金项目:

项目受国家自然科学基金（No.21572130）资助

摘要: 利用金属钯与非手性膦配体原位生成的钯配合物和手性方酰胺为协同催化体系实现了乙烯基碳酸乙烯酯（VECs）与甲醛的不对称脱羧环加成反应，以良好的产率和对映选择性得到了手性叔醇类化合物.发现了有机小分子催化剂-手性方酰胺可实现该反应的不对称诱导，为通过两性离子烯丙基钯中间体的环加成反应的研究提供了新的思路.

关键词:

English

Asymmetric Decarboxylative Cycloaddition of Vinylethylene Carbonates with Aldehydes by Cooperative Catalysis of Palladium Complex and Chiral Squaramide

a.
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
b.
Department of Chemistry, Yanbian University, Yanji, Jilin 133002, China

Corresponding author: Zhang Yong Jian, yjian@sjtu.edu.cn

Received Date: 20 July 2018
Available Online: 15 November 2018
Fund Project:

Project supported by the National Natural Science Foundation of China (No. 21572130)

Abstract: Chiral tertiary alcohols are ubiquitous in medicinally relevant agents and biologically active natural products. Although some catalytic asymmetric approaches for the synthesis of chiral tertiary alcohols have been reported, the development of efficient methods for enantioselective construction of tertiary alcohols is still highly appealing. Most recently, we have developed Pd-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates (VECs) with formaldehyde to construct tertiary alcohol derivatives. The reaction was catalyzed by the chiral palladium complex with a chiral phosphoramidite to afford methylene acetal protected tertiary vinylglycols in high efficiency. Since the pioneer works by Gong and Takemoto respectively for the allylic substitution under cooperative catalysis of palladium complex and chiral phase-transfer catalyst, the asymmetric allylic substitution synergistically catalyzed by transition metal and organocatalyst has recently attracted a great deal of attention. However, there have been no reports on the combination of transition-metal and squaramide for the allylic alkylation. In this communication, we will report the asymmetric decarboxylative cycloaddition of VECs with formaldehyde under cooperative catalytic system of achiral palladium complex and chiral squaramide. With combination of palladium complex in situ generated from Pd₂(dba)₃·CHCl₃ (2.5 mol%) and achiral phosphine ligand L4 (10 mol%) and chiral squaramide OC2 (25 mol%) as cooperative catalysts, the reaction of VECs with paraformaldehyde (10 equiv.) proceeded smoothly to give desired tertiary alcohol derivatives in good yields (51%~65%) with moderate enantioselectivities (62%~79% ee). The reaction conditions are also suitable for the reaction of VEC with electronic deficient arylaldehydes to afford desired products in high yields with good enantioselectivities, although the catalytic system is less effective for the control of the diastereoselectivities. Although the enantioselectivity of the reaction is not significantly high, we firstly demonstrated that the chiral induction for the cycloaddition reaction could be achieved under the cooperative catalytic system of achiral palladium complex and chiral squaramide. The detail reaction mechanism and stereochemical outcome are currently underway, and will be reported in due course.

Key words:

1. 引言

手性叔醇作为重要的结构单元广泛存在于药物分子和天然产物中, 因此开发有效的合成方法制备手性叔醇类化合物是不对称催化领域的重要任务^[1].制备手性叔醇最常用的方法是手性过渡金属配合物催化或有机小分子催化的碳亲核试剂与酮的加成反应^[1a].然而该方法存在一些缺陷, 如因酮相对较弱的反应性, 往往需要活化酮羰基提高其亲电性或使用金属有机化合物等强的亲核试剂.而且为了得到优异的对映选择性, 酮上的两个取代基需要具有一定的立体差异性.对1, 1-二取代烯烃的不对称环氧化反应^[2]或不对称二羟基化反应^[3]也是构建手性叔醇类化合物的有效方法, 然而为了得到高对映选择性, 烯烃上的两个取代基也需要具有一定的立体差异.虽然近些年有一些制备手性叔醇的不对称催化方法相继被报道^[4], 开发高效、高对映选择性的制备手性叔醇类化合物的不对称催化合成方法学仍是有机合成领域的重要研究课题.

过渡金属催化的不对称烯丙基醚化反应是对映选择性地构建碳-氧键的重要方法之一^[5].然而该反应利用1, 1-或3, 3-二取代的烯丙基给体化合物区域选择性地制备手性叔醇类化合物却很难实现^{[6, 7]}. 1998年Trost等^[8]报道了钯催化的2-甲基-2-乙烯基环氧乙烷的不对称烯丙基醚化反应有效构建了手性叔醇类化合物, 然而该反应的反应底物仅局限于烷基取代的乙烯基环氧乙烷, 反应的普适性有待提高.最近我们课题组以乙烯基碳酸乙烯酯(VECs, 4-取代-4-乙烯基-1, 3-二氧杂戊环-2-酮, 4-substituted-4-vinyl-1, 3-dioxolan-2-one)为烯丙基给体, 实现了钯催化的VECs与各种不饱和亲电试剂的脱羧环加成反应, 成功构建了含有四取代手性中心的化合物^[9].我们以原位生成的手性亚磷酰胺配体L1-钯配合物为催化剂实现了VECs与甲醛的脱羧环加成反应高产率、高对映选择性地构建的手性叔醇类化合物2(Scheme 1a)^[9f].

图式 1

图式 1. VECs和甲醛的不对称脱羧环加成反应构建手性叔醇类化合物

Scheme 1. Asymmetric decarboxylative cycloaddition of VECs with formaldehyde for the construction of chiral tertiary alcohols

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近年来有机小分子-金属协同催化的策略广泛应用于不对称催化反应中^[10].自从2001年龚流柱课题组^[11]和Takemoto课题组^[12]分别报道了钯催化剂与手性相转移催化剂协同催化的不对称烯丙基取代反应, 有机小分子-金属协同催化的不对称烯丙基反应受到了广泛关注并取得了一些重要的研究成果^{[10, 13]}.基于这些研究成果, 我们设想VECs与甲醛的不对称环加成反应可以通过有机小分子-金属协同催化的策略实现.如Scheme 2所示, 我们认为两性离子烯丙基钯中间体A的氧负离子可以进攻被手性方酰胺活化的甲醛, 得到烯丙基钯中间体B.烯丙基钯中间体B的氧负离子被手性方酰胺稳定化并提供手性环境, 实现最后环加成反应的不对称诱导.本论文我们将实践我们的不对称催化策略, 报道非手性钯配合物与手性方酰胺协同催化的VECs与甲醛的不对称脱羧环加成反应(Scheme 1b).

图式 2

图式 2. 有机小分子-金属协同催化策略的不对称脱羧环加成反应

Scheme 2. Asymmetric decarboxylative cycloaddition under the cooperative catalysis strategy of organic small molecule and metal

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2. 结果与讨论

基于前期研究^[9], 以Pd₂(dba)₃•CHCl₃ (2.5 mol%), 非手性亚磷酰胺配体L2(10 mol%), 手性方酰胺OC1 ^[14] (20 mol%)为催化剂, 尝试了Ph-VEC 1a与甲醛(37%水溶液, 10 equiv.)的脱羧环加成反应(表 1).我们发现该协同催化体系可以诱导手性, 以13% ee的对映选择性得到产物2a(Entry 1).进一步筛选手性方酰胺催化剂(Entries 2~4), 我们发现利用手性方酰胺催化剂OC2可将反应的对映选择性提高到21% ee.我们进一步尝试了辛可尼丁衍生的方酰胺催化剂OC5和OC6(Entries 5 and 6), 但反应的对映选择性没有提升.利用双方酰胺催化剂OC7, 得到了几乎外消旋的产物(Entry 7).接下来基于手性方酰胺催化剂OC2, 我们进一步研究了非手性膦配体对反应的影响(Entries 8~14).当使用非手性单膦配体L4时, 反应得到了进一步优化(Entry 14, 83% yield, 35% ee).通过筛选反应溶剂(Entries 15~18), 我们发现该反应在甲苯中可以得到48%ee的对映选择性(Entry 18).增加手性方酰胺催化剂OC2到25 mol%, 我们可以以89%的产率和60% ee的对映选择性得到反应产物2a(Entry 19).考虑到甲醛水溶液的水对氢键的影响, 我们考察了利用多聚甲醛替代甲醛水溶液进行该反应的研究.我们发现虽然反应仅得到了32%的产率, 但对映选择性可以增加到76% ee(Entry 20).将该反应的反应温度提高到40 ℃, 反应时间延长到24 h, 我们可以以65%的产率和76% ee的对映选择性得到产物2a(Entry 21).

表 1

表 1 反应条件的优化^a

Table 1. Reaction conditions optimization^a

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Entry	Ligand	OC	Solvent	Yield ^b/%	ee ^c/%
1	L2	OC1	THF	70	13
2	L2	OC2	THF	79	21
3	L2	OC3	THF	73	16
4	L2	OC4	THF	80	19
5	L2	OC5	THF	65	19
6	L2	OC6	THF	83	3
7	L2	OC7	THF	91	7
8	PPh₃	OC2	THF	81	3
9	P(C₆F₅)₃	OC2	THF	NR	―
10	P(2-furanyl)₃	OC2	THF	77	13
11	DPPE	OC2	THF	NR	―
12	DPPB	OC2	THF	NR	―
13	L3	OC2	THF	64	17
14	L4	OC2	THF	83	35
15	L4	OC2	Et₂O	70	11
16	L4	OC2	MTBE	61	20
17	L4	OC2	CH₂Cl₂	87	3
18	L4	OC2	toluene	89	48
19^d	L4	OC2	toluene	89	60
20^{d, e}	L4	OC2	toluene	32	76
21^{d, e, f}	L4	OC2	toluene	65	76
^a Reaction conditions: 1a (0.2 mmol), formaldehyde (37% of aqueous solution) (2.0 mmol), Pd₂(dba)₃•CHCl₃ (0.005 mmol), ligand (0.02 mmol), organocatalyst (0.04 mmol), solvent (1.0 mL), 20 ℃, 15 h. ^b The yields are of isolated materials. ^c Determined by HPLC using a chiral stationary phase. ^d 25 mol% of OC2 was used. ^e Paraformaldehyde was used instead of aqueous solution of formaldehyde. ^f The reaction was carried out at 40 ℃ for 24 h. DPPE＝ 1, 2-bisdiphenylphosphinoethane; DPPB＝1, 4-bisdiphenylphosphinobutane; MTBE＝methyl tert-butyl ether.

在上述最优的反应条件下, 我们研究了该反应的适用范围.如表 2所示, 各种芳基取代的VECs可适用于该反应条件, 以中等的反应产率和良好的对映选择性得到了相应的环加成产物2b~2j. 4-(1-萘)取代的VEC也可以在该反应条件下以51%的产率和64% ee的对映选择性得到相应的产物2i.噻吩基也可以导入到反应产物中, 以70%的产率和62% ee的对映选择性得到了相应的产物2j.我们进一步研究了Ph-VEC 1a与醛的不对称环加成反应.在最优的反应条件下, 1a与苯甲醛不反应.但该反应与吸电子的对硝基苯甲醛或2-吡啶甲醛可以顺利地进行, 以高产率和良好的对映选择性得到相应的环加成产物3b和3c(图式 3).然而该反应条件无法控制反应的非对映选择性.

表 2

表 2 协同催化的VECs与多聚甲醛的不对称脱羧环加成反应^a

Table 2. Cooperative catalytic asymmetric cycloaddition of VECs with paraformaldehyde^a

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^a Reaction conditions: (0.2 mmol), paraformaldehyde (2.0 mmol), Pd₂(dba)₃•CHCl₃ (0.005 mmol), L4 (0.02 mmol), OC2 (0.05 mmol), toluene (1.0 mL), 40 ℃, 24 h. The yields are of isolated materials. The enantioselectivites were determined by HPLC using a chiral stationary phase.

图式 3

图式 3. 协同催化的Ph-VEC与醛的不对称脱羧环加成反应

Scheme 3. Cooperative catalytic asymmetric cycloaddition of Ph-VEC with aldehydes

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3. 结论

利用非手性钯配合物和手性方酰胺的协同催化体系实现了VECs与多聚甲醛的不对称脱羧环加成反应, 以良好的产率和对映选择性得到了手性叔醇衍生物.该协同催化体系也适用于VECs与缺电子的芳基醛的不对称脱羧环加成反应, 以高产率和良好的对映选择性得到了相应的产物, 但该反应条件无法控制反应的非对映选择性.虽然该反应的活性与对映选择性有待提高, 但我们首次发现了有机小分子催化剂-手性方酰胺可实现该反应的不对称诱导, 为通过两性离子烯丙基钯中间体的环加成反应的研究提供了新的思路.在今后的研究中, 我们将深入研究该协同催化反应的反应机理和立体选择性控制.

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图式 1 VECs和甲醛的不对称脱羧环加成反应构建手性叔醇类化合物

Scheme 1 Asymmetric decarboxylative cycloaddition of VECs with formaldehyde for the construction of chiral tertiary alcohols

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图式 2 有机小分子-金属协同催化策略的不对称脱羧环加成反应

Scheme 2 Asymmetric decarboxylative cycloaddition under the cooperative catalysis strategy of organic small molecule and metal

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图式 3 协同催化的Ph-VEC与醛的不对称脱羧环加成反应

Scheme 3 Cooperative catalytic asymmetric cycloaddition of Ph-VEC with aldehydes

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表 1 反应条件的优化^a

Table 1. Reaction conditions optimization^a


Entry	Ligand	OC	Solvent	Yield ^b/%	ee ^c/%
1	L2	OC1	THF	70	13
2	L2	OC2	THF	79	21
3	L2	OC3	THF	73	16
4	L2	OC4	THF	80	19
5	L2	OC5	THF	65	19
6	L2	OC6	THF	83	3
7	L2	OC7	THF	91	7
8	PPh₃	OC2	THF	81	3
9	P(C₆F₅)₃	OC2	THF	NR	―
10	P(2-furanyl)₃	OC2	THF	77	13
11	DPPE	OC2	THF	NR	―
12	DPPB	OC2	THF	NR	―
13	L3	OC2	THF	64	17
14	L4	OC2	THF	83	35
15	L4	OC2	Et₂O	70	11
16	L4	OC2	MTBE	61	20
17	L4	OC2	CH₂Cl₂	87	3
18	L4	OC2	toluene	89	48
19^d	L4	OC2	toluene	89	60
20^{d, e}	L4	OC2	toluene	32	76
21^{d, e, f}	L4	OC2	toluene	65	76
^a Reaction conditions: 1a (0.2 mmol), formaldehyde (37% of aqueous solution) (2.0 mmol), Pd₂(dba)₃•CHCl₃ (0.005 mmol), ligand (0.02 mmol), organocatalyst (0.04 mmol), solvent (1.0 mL), 20 ℃, 15 h. ^b The yields are of isolated materials. ^c Determined by HPLC using a chiral stationary phase. ^d 25 mol% of OC2 was used. ^e Paraformaldehyde was used instead of aqueous solution of formaldehyde. ^f The reaction was carried out at 40 ℃ for 24 h. DPPE＝ 1, 2-bisdiphenylphosphinoethane; DPPB＝1, 4-bisdiphenylphosphinobutane; MTBE＝methyl tert-butyl ether.

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表 2 协同催化的VECs与多聚甲醛的不对称脱羧环加成反应^a

Table 2. Cooperative catalytic asymmetric cycloaddition of VECs with paraformaldehyde^a




^a Reaction conditions: (0.2 mmol), paraformaldehyde (2.0 mmol), Pd₂(dba)₃•CHCl₃ (0.005 mmol), L4 (0.02 mmol), OC2 (0.05 mmol), toluene (1.0 mL), 40 ℃, 24 h. The yields are of isolated materials. The enantioselectivites were determined by HPLC using a chiral stationary phase.

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沈阳化工大学材料科学与工程学院沈阳 110142