手性磷酸催化α-全碳季碳醛的不对称烯丙基化动力学拆分

doi:10.6023/cjoc202304015

摘要/Abstract

手性全碳季碳立体中心的高效构建一直是不对称催化领域的难点和热点. 其中, α-全碳季碳非环状醛因具有立体环境拥挤和构象多变性等结构特点, 相关不对称合成方法一直发展缓慢. 本工作基于手性醛和高烯丙基醇化合物的合成应用重要性, 通过Antilla烯丙基化反应, 采用2,4,6-三异丙基苯基取代的联萘二酚型手性磷酸催化剂, 以较好的产率、立体选择性和选择性系数(最高达到37.0), 实现了外消旋α-全碳季碳非环状醛的动力学拆分, 为含α-全碳季碳的醛和高烯丙基醇两类手性化合物的合成提供了新思路.

关键词: 手性醛, 烯丙基硼化反应, 手性磷酸, 全碳手性季碳, 动力学拆分

Acyclic aldehydes containing a chiral all-carbon quaternary center at the α-position are important synthons for pharmaceuticals and natural products. The challenges such as steric congestion and conformational flexibility in acyclic systems must be overcome, which constitutes to be a hot and difficult topic in the field of asymmetric catalysis. Such type of structural motif is mainly accessed from the α-C—H functionalization of tertiary aldehydes via enamine catalysis or based on enolate chemistry. Desymmetric and tandem strategies have also been applied for the synthetic task. The discovery of novel synthetic methods is still highly demanding, especially in an organocatalysis manner. Binaphthol (BINOL)-derived chiral phosphoric acids have been demonstrated as efficient bifunctional catalysts in a wide range of organic reactions including the asymmetric allylboration of aldehydes (Antilla allylboration). We envisaged that if racemic α-all-carbon quaternary aldehydes were applied, kinetic resolution of aldehydes through the Antilla allylboration would provide chiral aldehydes and homoallylic alcohols containing an all-carbon quaternary center. The idea was eventually realized by employing 10 mol% (R)-3,3'-bis- (2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate (TRIP) in toluene at –70 ℃. 15 examples of racemic aldehydes bearing electron-rich, electron-neutral and electron-deficient substituents at the phenyl ring, as well as 2-naphthyl group were screened, affording moderate kinetic resolution performance (with an s-factor up to 37.0). The ee values of chiral aldehydes and homoallylic products reached up to 97% and 81%, respectively. This method provides a new route for the synthesis of chiral molecules bearing an all-carbon quaternary stereocenter.

Key words: chiral aldehyde, allylboration, chiral phosphoric acid, all-carbon quaternary center, kinetic resolution

引用此文

陈宇亮, 贺凤开, 王思云, 贾鼎成, 刘亚群, 黄毅勇. 手性磷酸催化α-全碳季碳醛的不对称烯丙基化动力学拆分[J]. 有机化学, 2023, 43(12): 4294-4302.

Yuliang Chen, Fengkai He, Siyun Wang, Dingcheng Jia, Yaqun Liu, Yiyong Huang. Kinetic Resolution of Aldehydes Bearing an All-Carbon Quaternary Stereocenter at the α-Position by the Antilla Allylboration[J]. Chinese Journal of Organic Chemistry, 2023, 43(12): 4294-4302.

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Entry	Catalyst (x mol%)	Solvent	Temp./℃	Time/h	Chiral-1a		3a			C/%^f	s^g
Entry	Catalyst (x mol%)	Solvent	Temp./℃	Time/h	Yield^b/%	ee₁^c/%	Yield^b/%	dr^d	ee₂^e/%	C/%^f	s^g
1	(R)-CPA-3 (6)	Toluene	–60	21	45	39	47	>20∶1	50	0.44	4.3
2	(R)-CPA-3 (6)	CH₂Cl₂	–60	29	55	9	41	19.6∶1	18	0.33	1.6
3	(S)-CPA-3 (6)	Toluene	–60	21	44	–37	26	11∶1	–13	0.74	1.8
4	(S)-CPA-3 (6)	CH₂Cl₂	–60	45	41	–9	49	>20∶1	–44	0.17	2.8
5	(R)-CPA-3 (10)	Toluene	–70	16	44	43	34	>20∶1	63	0.41	6.7
6	(R)-CPA-3 (10)	CH₂Cl₂,	–70	36	57	7	27	>20∶1	17	0.29	1.5
7	(S)-CPA-3 (10)	Toluene	–70	21	52	–22	36	>20∶1	–29	0.43	2.2
8	(R)-CPA-4 (10)	Toluene	–70	72	29	30	39	15∶1	44	0.41	3.4
9	(R)-CPA-5 (10)	Toluene	–70	4	35	0	37	9∶1	0	0	0

Entry	Catalyst (x mol%)	Solvent	Temp./℃	Time/h	Chiral-1a		3a			C/%^f	s^g
Entry	Catalyst (x mol%)	Solvent	Temp./℃	Time/h	Yield^b/%	ee₁^c/%	Yield^b/%	dr^d	ee₂^e/%	C/%^f	s^g
1	(R)-CPA-3 (6)	Toluene	–60	21	45	39	47	>20∶1	50	0.44	4.3
2	(R)-CPA-3 (6)	CH₂Cl₂	–60	29	55	9	41	19.6∶1	18	0.33	1.6
3	(S)-CPA-3 (6)	Toluene	–60	21	44	–37	26	11∶1	–13	0.74	1.8
4	(S)-CPA-3 (6)	CH₂Cl₂	–60	45	41	–9	49	>20∶1	–44	0.17	2.8
5	(R)-CPA-3 (10)	Toluene	–70	16	44	43	34	>20∶1	63	0.41	6.7
6	(R)-CPA-3 (10)	CH₂Cl₂,	–70	36	57	7	27	>20∶1	17	0.29	1.5
7	(S)-CPA-3 (10)	Toluene	–70	21	52	–22	36	>20∶1	–29	0.43	2.2
8	(R)-CPA-4 (10)	Toluene	–70	72	29	30	39	15∶1	44	0.41	3.4
9	(R)-CPA-5 (10)	Toluene	–70	4	35	0	37	9∶1	0	0	0