CN112430183B - 一种轴手性4-取代亚环己基芳基醋酸酯类化合物的制备方法 - Google Patents

一种轴手性4-取代亚环己基芳基醋酸酯类化合物的制备方法 Download PDF

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CN112430183B
CN112430183B CN202011198556.8A CN202011198556A CN112430183B CN 112430183 B CN112430183 B CN 112430183B CN 202011198556 A CN202011198556 A CN 202011198556A CN 112430183 B CN112430183 B CN 112430183B
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张俊良
马纯
孙悦
郭浩
杨俊锋
李志铭
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Zhuhai Fudan Innovation Research Institute
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Abstract

本发明属有机化学技术领域，具体为一种轴手性4‑取代亚环己基芳基醋酸酯类手性化合物的制备方法。本发明以顺式4‑取代环己基‑α‑羟基重氮酯类化合物为原料，在钯源与手性配体配位形成手性钯物种为催化剂下，与芳基碘化物反应制得轴手性4‑取代亚环己基芳基醋酸酯类手性化合物。本发明优势在于反应原料简单易得，反应条件温和，产率高，反应的区域选择性和立体选择性好，底物的适用范围广，便于分离提纯。本发明制备的轴手性化合物官能团兼容性好，可灵活转化，该骨架是制备手性药物中间体和手性配体的重要手性砌块，具有重要的应用价值和广阔的应用前景。

Description

一种轴手性4-取代亚环己基芳基醋酸酯类化合物的制备方法
技术领域
本发明属有机化学技术领域，具体涉及一种轴手性4-取代亚环己基芳基醋酸酯类化合物的制备方法。
背景技术
轴手性骨架存在于许多天然产物、生物活性分子和优势的手性催化剂中。[(a)Kumarasamy,E.；Raghunathan,R.；Sibi,M.P.；Sivaguru,J.Chem.Rev.2015,115,11239.(b)Smyth,J.E.；Butler,N.M.；Keller,P.A.Nat.Prod.Rep.2015,32,1562.(c)Zask,A.；Murphy,J.；Ellestad,G.A.Chirality 2013,25,265.(d)Toenjes,S.T.；Gustafson,J.L.Future Med.Chem.2018,10,409.(e)Privileged chiral ligands and catalysts；Zhou,Q.-L.,Ed.；Wiley-VCH:Weinheim,Germany,2011.(f)Ma,Y.-N.；Li,S.-X.；Yang,S.-D.Acc.Chem.Res.2017,50,1480.]因此，该类骨架的催化不对称构建引起了化学工作者的强烈兴趣。而在众多的轴手性骨架中，亚烷基环烷烃是一类特殊结构的轴手性骨架。虽然作为手性液晶的前体有一些应用，但在圆二色性研究中，很少有人注意到它们。[(a)Eelkema,R.；Feringa,B.L.Org.Biomol.Chem.2006,4,3729.(b)Solladié,G.；Zimmermann,G.Angew.Chem.,Int.Ed.Engl.1984,23,348.(c)Brewster,J.H.；Privett,J.E.J.Am.Chem.Soc.1966,88,1419.(d)Duraisamy,M.；Walborsky,H.M.J.Am.Chem.Soc.1983,105,3252.(e)Zhang,Y.；Schuster,G.B.J.Org.Chem.1995,60,7192.(f)Bradford,R.F.；Schuster,G.B.J.Org.Chem.2003,68,1075.]而事实上，4-甲基亚环己基醋酸已成功地于1909年拆分出两个光学活性异构体以来，至今发展仍然缓慢。该骨架的不对称合成主要是手性辅基、化学计量的催化以及手性拆分，[(a)Nakamura,S.；Ogura,T.；Wang,L.；Toru,T.Tetrahedron Lett.2004,45,2399.(b)Dai,W.-M.；Wu,J.；Huang,X.Tetrahedron:Asymmetry 1997,8,1979.(c)Erdelmeier,I.；Below,G.；Woo,C.-W.；Decker,J.；Raabe,G.；Gais,H.-J.Chem.Eur.J.2019,25,8371.(d)Denmark,S.E.；Chen,C.-T.；J.Am.Chem.Soc.1992,114,10674.(e)Hanessian,S.；Delorme,D.；Beaudoin,S.；Leblanc,Y.J.Am.Chem.Soc.1984,106,5754.(f)Lemieux,R.P.；Schuster,G.B.J.Org.Chem.1993,58,100.(g)Zhang,Y.；Schuster,G.B.J.Org.Chem.1994,59,1855.(h)Nakamura,S.；Aoki,T.；Ogura,T.；Wang,L.；Toru,T.J.Org.Chem.2004,69,8916.(i)Mizuno,M.；Fujii,K.；Tomioka,K.Angew.Chem.,Int.Ed.1998,37,515.(j)Iguchi,M.；Tomioka,K.Org.Lett.2002,4,4329.]而不对称催化作为高效合成手性化合物的方法，而发展较少，仅有几例是通过不对称催化实现的，而这些方法实现的手性控制都不太理想，[(a)Fiaud,J.C.；Legros,J.Y.Tetrahedron Lett.1988,29,2959.(b)Fiaud,J.C.；Legros,J.Y.J Organomet Chem 1989,370,383.(c)Arai,S.；Hamaguchi,S.；TShioiri.Tetrahedron Lett.1998,39.2997.(d)Gramignaa,L.；Duce,S.；Filippini,G.；Fochi,M.；Franchini,M.C.；Bernardi,L.Synlett 2011,2011,2745.(e)Agudo,R.；Roiban,G.-D.；Reetz,M.T.J.Am.Chem.Soc.2013,135,1665.(f)Mei,H.；Lin,L.；Wang,L.；Dai,L.；Liu,X.；Feng,X.Chem.Commun.2017,53,8763.(g)Crotti,S.；Iorio,N.D.；Artusi,C.；Mazzanti,A.；Righi,P.；Bencivenni,G.Org.Lett.2019,21,3013.]所以迫切需要发展一种新的方法来实现其高对映选择性。
近年来，钯催化重氮化合物的交叉偶联反应作为一种新型的交叉偶联反应，常通过β-H消除来构建碳碳键，而被人们熟知。[(a)Xia,Y.；Qiu,D.；Wang,J.Chem.Rev.2017,117,13810.(b)Xia,Y.；Wang,J.J.Am.Chem.Soc.2020,142,10592.]而在金属有机化学中，β-OH消除作为一种常见的消除反应，也经常用于构建碳碳键，而钯催化的β-OH消除则很罕见。在之前的报道中，钯催化β-OH消除大多是在酸性条件下实现的。[(a)Huang,J.-M.；Zhou,L.；Jiang,H.-F.Angew.Chem.,Int.Ed.2006,45,1945；(b)Zhu,G.；Lu,X.J.Organomet.Chem.1996,508,83.]实验研究和理论研究都表明β-OH消除在钯化学中并不是一个有利的过程，[(a)Zhang,Z.；Lu,X.；Xu,Z.；Zhang,Q.；Han,X.Organometallics.2001,20,3724.(b)Zhao,H.；Ariafard,A.；Lin,Z.Organometallics.2006,25,812.]仅有一例是在碱性条件下实现的β-OH消除(Zhou,L.；Liu,Y.；Zhang,Y.；Wang,J.Chem.Commun.2011,47,3622.),而实现其对映选择性则未曾有报道。
在此，我们希望通过钯催化β-OH消除策略来实现轴手性亚烷基环烷烃的催化不对称合成。通过钯和手性配体的结合，实现芳基碘化物与4-取代环己基-α-羟基重氮酯类化合物的交叉偶联反应，实现轴手性4-取代亚环己基芳基醋酸酯类化合物的催化不对称合成，从而丰富轴手性化学。
发明内容
本发明目的在于提供一种简便、高效的轴手性4-取代亚环己基芳基醋酸酯类手性化合物的制备方法。
本发明提供的轴手性4-取代亚环己基芳基醋酸酯类手性化合物的制备方法，是利用4-取代环己基-α-羟基重氮酯类化合物和芳基碘化物，在钯源和手性配体的催化下，在还原剂和碱的促进下，在氮气氛围下，30-100℃且转速为1300-1500转的油浴下，发生金属催化的β-OH消除反应，高效合成轴手性4-取代亚环己基芳基醋酸酯类手性化合物。而该反应的具体历程为，首先钯源与手性配体配位形成的手性钯物种与芳基碘化物发生氧化加成，得到二价钯物种与顺式4-取代环己基-α-羟基重氮酯类化合物反应形成钯卡宾物种，接着芳基发生迁移插入，再发生β-OH消除，从而产生烯烃，便可以得到轴手性4-取代亚环己基芳基醋酸酯类化合物，与此同时，二价钯物种进行还原消除变成零价钯，从而完成其催化循环。其反应式为：
Figure BDA0002754709020000031
式中，Ar为吸电子或给电子的苯基或杂环取代基，吸电子基团有氟、氯、溴、氰基、醛基、乙酰基、酯基，三氟甲基取代基团，给电子基团为C1～C10烷基和烷氧基以及C1～C7保护的氨基基团，杂环可为C4～C16的含N、O或S的杂芳基。R为C1～C10烷基和烷氧基，C6～C13的芳基以及C6～C13保护的氨基，R1为C1～C10的烷基。
优选地，其特征在于，所述手性配体为具有如下结构的手性膦配体的一种。
Figure BDA0002754709020000032
优选地，所述有机溶剂选自正戊烷、正己烷、环己烷、四氢呋喃、甲苯、1,2-二氯乙烷、三氯甲烷、乙酸乙酯、乙腈、丙酮、甲醇、乙醇、异丙醇、叔丁醇、叔戊醇或二甲基乙酰胺，以及其中几种的混合有机溶剂。
优选地，所述钯源选自Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、Pd(OAc)2、PdCl2、PdBr2、Pd(TFA)2、[Pd(allyl)Cl]2或Pd(dppe)2Cl2。
优选地，所述碱选自三乙胺、二乙胺、二环己基胺、N,N-二异丙基乙胺、三乙烯二胺、碳酸钾、碳酸铯、乙酸铯、乙酸钠、磷酸钾、碳酸氢钾或甲酸钠。
优选地，所述还原剂选自锌粉、锰粉、镁粉、铁粉、铟或四羟基二硼。
优选地，所述芳基碘化物、4-取代环己基-α-羟基重氮酯类化合物、钯源、手性配体、碱、还原剂的摩尔比为1:(1～3):(0.01～0.075):(0.025～0.3):(0～10):(0～4)。
所述芳基碘化物、4-取代环己基-α-羟基重氮酯类化合物、钯源、手性配体、碱、还原剂的摩尔比更优选为:1:(1～3):(0.01～0.075):(0.025～0.3):(1～10):(0.5～4)。
本发明所述的轴手性4-取代亚环己基芳基醋酸酯类化合物的制备方法，其特征在于，具体操作步骤为：
(1)在室温下，向干燥的封管中加入0.30-6mmol的芳基碘化物、0.54-10.8mmol顺式4-取代环己基-α-羟基重氮酯类化合物、0.60-12mmol还原剂，0.015-0.3mmol的金属催化剂，0.06-1.2mmol手性配体，然后将封管用氮气进行抽换气，并置于高纯氮气中，使体系处于无水无氧条件，最后在鼓气下，加入3-60mL干燥的有机溶剂，再加入0.90-18mmol碱，移至30-100℃且转速为1300-1500转的油浴中进行反应，直至完全反应为止；
(2)用TLC监测至反应结束后，将反应液过滤，滤液旋干，并采用石油醚和乙酸乙酯的混合液作为流动相进行柱层析分离，即得到相应的轴手性4-取代亚环己基芳基醋酸酯类化合物，反应收率为43-92％，对映选择性为80-96％。
与现有技术相比，本发明具有如下有益效果：
1.本发明通过金属钯和手性配体的催化，制备4-取代亚环己基芳基醋酸酯类化合物，高效且环境友好，其优势在于反应原料简单易得，反应条件温和，产率高，反应的区域选择性和立体选择性好，底物的适用范围广，便于分离提纯；
2.本发明为这类化合物的催化不对称合成提供了一种简洁高效的途径。本发明合成的一系列4-取代亚环己基芳基醋酸酯类化合物是一类多官能团的轴手性化合物，其官能团兼容性好，可灵活转化，该骨架是制备手性药物中间体和手性配体的重要手性砌块，具有重要的应用价值和广阔的应用前景。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
轴手性4-苯基亚环己基对甲基苯基醋酸酯Iaa或IIaa的制备，其中给出了利用不同手性配体进行制备的结果。
向干燥的封管中加入0.18mmolcis-4-苯基环己基-α-羟基重氮乙酸乙酯cis-IIIa、0.1mmol对甲基碘苯、0.005mmol(5mol％)金属催化剂Pd2(dba)3，0.02mmol(20mol％)手性配体，50mg的无水硫酸镁和0.2mmol锌粉，然后用氮气将封管进行置换气，使得体系处于无水无氧条件，再在鼓气下，加入1.0ml超干的正己烷以及0.5mmol三乙胺，置于70℃且转速为1400转的油浴中进行反应，TLC监测反应，待反应结束后，加入10微升正十四烷进行定标，利用GC测得产率，利用HPLC测定ee值。
本实施例的反应式以及利用不同手性配体进行制备的结果如下：
Figure BDA0002754709020000051
实施例2
轴手性4-苯基亚环己基对甲基苯基醋酸酯Iaa的制备，其中给出了利用不同溶剂进行制备的结果。
向干燥的封管中加入0.18mmol cis-4-苯基环己基-α-羟基重氮乙酸乙酯cis-IIIa、0.1mmol对甲基碘苯、0.005mmol(5mol％)金属催化剂Pd2(dba)3，0.02mmol(20mol％)手性配体，50mg的无水硫酸镁和0.2mmol锌粉，然后用氮气将封管进行置换气，使得体系处于无水无氧条件，再在鼓气下，加入1.0ml溶剂以及0.5mmol三乙胺，置于70℃且转速为1400转的油浴中进行反应，TLC监测反应，待反应结束后，加入10微升正十四烷进行定标，利用GC测得产率，利用HPLC测定ee值。
本实施例的反应式以及利用不同溶剂进行制备的结果如下：
Figure BDA0002754709020000052
Figure BDA0002754709020000053
Figure BDA0002754709020000061
实施例3
轴手性4-苯基亚环己基对甲基苯基醋酸酯Iaa的制备，其中给出了利用不同温度进行制备的结果。
向干燥的封管中加入0.18mmol cis-4-苯基环己基-α-羟基重氮乙酸乙酯cis-IIIa、0.1mmol对甲基碘苯、0.005mmol(5mol％)金属催化剂Pd2(dba)3，0.02mmol(20mol％)手性配体和0.2mmol锌粉，然后用氮气将封管进行置换气，使得体系处于无水无氧条件，再在鼓气下，加入1.0ml甲苯以及0.3mmol三乙胺，置于不同温度下且转速为1400转的油浴中进行反应，TLC监测反应，待反应结束后，加入10微升正十四烷进行定标，利用GC测得产率，利用HPLC测定ee值。
本实施例的反应式以及利用不同溶剂进行制备的结果如下：
Figure BDA0002754709020000062
序号 温度(℃) GC-产率(％) ee(％)
1 70 88 86
2 60 82 89
3 50 84 89
4 40 65 90
。
实施例4、轴手性4-取代亚环己基芳基醋酸酯I的制备
向干燥的封管中加入0.54mmol cis-4-取代环己基-α-羟基重氮乙酸酯cis-III、0.3mmol芳基碘化物、0.015mmol(5mol％)金属催化剂Pd2(dba)3，0.06mmol(20mol％)手性配体和0.6mmol锌粉，然后用氮气将封管进行置换气，使得体系处于无水无氧条件，再在鼓气下，加入1.5ml无水甲苯和1.5ml超干正己烷以及0.9mmol三乙胺，置于50℃下且转速为1400转的油浴中进行反应，TLC监测反应，待反应结束后，过滤，旋干滤液，通过柱层析得到相应的产物，利用HPLC测定ee值。
以下是不同的轴手性4-取代亚环己基芳基醋酸酯的1H NMR、13C NMR的谱图数据，所有化合物可以利用实施例1～3的任意方法制备，相应的产率和对映选择性有一定的差异。
Figure BDA0002754709020000071
化合物例Iaa的结构表征：1H NMR(400MHz,CDCl3)δ7.32–7.27(m,2H),7.25–7.05(m,7H),4.19(q,J＝7.1Hz,2H),3.16–3.08(m,1H),2.83–2.73(m,1H),2.61–2.54(m,1H),2.36(s,3H),2.25–2.18(m,1H),2.13–2.05(m,1H),2.05–1.94(m,2H),1.80–1.71(m,1H),1.26–1.22(m,4H)；1C NMR(100MHz,CDCl3)169.4,146.9,146.3,136.9,134.3,129.3,129.0,128.5,126.9,126.2,60.7,44.4,35.4,35.3,32.4,31.8,21.3,14.3；HRMS(EI):m/z:[M]+Calcd for C23H26O2:334.1931,found 334.1927；HPLC conditions:Chiralcel OD-Hcolumn,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝11.222min,tminor＝10.423min,91％ee.。
Figure BDA0002754709020000072
化合物例Iab的结构表征：1H NMR(400MHz,CDCl3)δ7.45–7.37(m,2H),7.37–7.30(m,4H),7.30–7.27(m,2H),7.27–7.18(m,2H),4.24(q,J＝7.1Hz,2H),3.30–3.16(m,1H),2.89–2.76(m,1H),2.65–2.54(m,1H),2.34–2.23(m,1H),2.20–2.11(m,1H),2.10–1.95(m,2H),1.87–1.74(m,1H),1.68–1.57(m,1H),1.28(t,J＝7.1Hz,3H)；1C NMR(100MHz,CDCl3)169.2,147.5,146.2,137.4,129.5,128.5,128.2,127.2,126.9,126.2,60.7,44.3,35.4,35.3,32.4,31.9,14.3；HRMS(EI):m/z:[M]+Calcd for C22H24O2:320.1772,found320.1771；HPLC conditions:Chiralcel AD-H-AD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝21.910min,tminor＝22.766min,93％ee.。
Figure BDA0002754709020000081
化合物例Iac的结构表征：1H NMR(400MHz,CDCl3)δ7.68–7.61(m,4H),7.50–7.45(m,2H),7.41–7.32(m,5H),7.31–7.23(m,3H),4.33–4.21(m,2H),3.30–3.18(m,1H),2.91–2.79(m,1H),2.76–2.63(m,1H),2.37–2.24(m,1H),2.22–1.98(m,3H),1.90–1.75(m,1H),1.72–1.60(m,1H),1.33–1.29(m,3H)；1C NMR(100MHz,CDCl3)169.3,147.7,146.2,140.8,140.0,136.3,129.9,128.9,128.5,127.4,127.1,127.0,126.9,126.3,60.8,44.3,35.4,35.3,32.5,31.9,14.3；HRMS(EI):m/z:[M]+Calcd for C28H28O2:396.2083,found396.2084；HPLC conditions:Chiralcel AD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝19.281min,tminor＝17.068min,91％ee.。
Figure BDA0002754709020000082
化合物例Iad的结构表征：1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.90(d,J＝8.2Hz,2H),7.44(d,J＝8.1Hz,2H),7.35–7.30(m,2H),7.26–7.21(m,3H),4.22(q,J＝7.1Hz,2H),3.40–3.30(m,1H),2.89–2.78(m,1H),2.54–2.44(m,1H),2.33–2.21(m,1H),2.20–2.13(m,1H),2.12–2.05(m,1H),2.03–1.96(m,1H),1.86–1.73(m,1H),1.64–1.53(m,1H),1.25(t,J＝7.1Hz,3H)；1C NMR(100MHz,CDCl3)191.9,168.2,150.4,145.9,144.1,135.2,130.3,129.7,128.5,126.8,126.3,60.9,44.1,35.3,35.2,32.3,14.2；HRMS(EI):m/z:[M]+Calcd for C23H24O3:348.1721,found 348.1720；HPLC conditions:Chiralcel AD-Hcolumn,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝27.842min,tminor＝30.185min,95％ee.。
Figure BDA0002754709020000091
化合物例Iad的结构表征：1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),7.31–7.28(m,2H),7.24–7.17(m,3H),4.19(q,J＝7.1Hz,2H),3.38–3.23(m,1H),2.86–2.76(m,1H),2.62(s,3H),2.51–2.45(m,1H),2.32–2.21(m,1H),2.19–2.09(m,1H),2.09–1.95(m,2H),1.80–1.74(m,1H),1.62–1.52(m,1H),1.23(t,J＝7.1Hz,3H)；1CNMR(100MHz,CDCl3)197.8,168.3,149.9,145.9,142.7,135.9,129.8,128.5,128.3,126.8,126.3,60.8,44.2,35.3,35.2,32.3,32.2,26.7,14.2；HRMS(EI):m/z:[M]+Calcd forC24H26O3:362.1879,found 362.1876；HPLC conditions:Chiralcel AD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝32.638min,tminor＝36.719min,95％ee.。
Figure BDA0002754709020000092
化合物例Iad的结构表征：1H NMR(400MHz,CDCl3)δ8.03–7.97(m,1H),7.95(s,1H),7.49–7.42(m,2H),7.30(d,J＝7.4Hz,2H),7.25–7.19(m,3H),4.39(q,J＝7.1Hz,2H),4.20(q,J＝7.1Hz,2H),3.38–3.21(m,1H),2.87–2.72(m,1H),2.55–2.43(m,1H),2.33–2.20(m,1H),2.19–2.10(m,1H),2.09–2.00(m,1H),1.99–1.92(m,1H),1.85–1.70(m,1H),1.66–1.51(m,1H),1.41(t,J＝5.7Hz,3H),1.24(t,J＝7.1Hz,3H)；1C NMR(100MHz,CDCl3)168.6,166.5,149.5,146.0,137.8,134.0,130.6,128.5,128.4,128.3,126.9,126.2,61.1,60.8,44.2,35.3,32.2,32.1,14.4,14.2；HRMS(EI):m/z:[M]+Calcd for C25H28O4:392.1983,found 392.1982；HPLC conditions:Chiralcel OD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝18.199min,tminor＝16.378min,95％ee.。
Figure BDA0002754709020000101
化合物例Iag的结构表征：1H NMR(400MHz,CDCl3)δ7.63–7.57(m,1H),7.56(s,1H),7.51–7.44(m,2H),7.32–7.28(m,2H),7.25–7.20(m,3H),4.19(q,J＝7.1Hz,2H),3.42–3.31(m,1H),2.86–2.75(m,1H),2.56–2.47(m,1H),2.42–2.34(m,1H),2.29–2.21(m,1H),2.17–2.10(m,1H),2.10–2.02(m,1H),1.99–1.92(m,1H),1.82–1.71(m,1H),1.61–1.50(m,1H),1.23(t,J＝7.1Hz,3H)；1C NMR(100MHz,CDCl3)167.9,151.3,145.8,138.9,134.1,133.2,130.9,129.1,128.6,128.5,126.8,126.7,126.6,126.3,118.8,112.5,61.0,44.1,35.3,35.2,32.3,32.1,14.2；HRMS(EI):m/z:[M]+Calcd for C23H23NO2:345.1726,found345.1723；HPLC conditions:ChiralcelAD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝20.122min,tminor＝21.560min,94％ee.。
Figure BDA0002754709020000102
化合物例Iah的结构表征：1H NMR(400MHz,CDCl3)δ8.91(dd,J＝4.2,1.5Hz,1H),8.20–7.99(m,2H),7.71(d,J＝1.7Hz,1H),7.63(dd,J＝8.7,1.9Hz,1H),7.40(dd,J＝8.3,4.2Hz,1H),7.33–7.27(m,2H),7.25–7.17(m,3H),4.20(q,J＝7.1Hz,2H),3.36–3.25(m,1H),2.88–2.75(m,1H),2.59–2.51(m,1H),2.35–2.22(m,1H),2.20–2.12(m,1H),2.11–2.01(m,1H),2.00–1.92(m,1H),1.87–1.74(m,1H),1.66–1.53(m,1H),1.23(t,J＝7.1Hz,3H)；1CNMR(100MHz,CDCl3)168.8,150.5,149.5,147.4,146.0,136.2,135.9,131.6,129.3,128.5,128.1,128.0,127.7,126.8,126.3,121.3,60.8,44.2,35.4,35.3,32.3,32.2,14.2；HRMS(EI):m/z:[M]+Calcd for C25H25NO2:371.1883,found 371.1880；HPLC conditions:Chiralcel AD-H column,254nm,flow rate:1.0ml/min,iPrOH/hexanes＝10/90,tmajor＝12.752min,tminor＝17.857min,88％ee.。
Figure BDA0002754709020000111
化合物例Ibi的结构表征：1H NMR(400MHz,CDCl3)δ7.48(d,J＝8.4Hz,2H),7.14(dd,J＝8.4,6.9Hz,4H),6.85(d,J＝8.6Hz,2H),4.19(q,J＝7.1Hz,2H),3.79(s,3H),3.23(dd,J＝13.6,2.2Hz,1H),2.83–2.68(m,1H),2.48(dd,J＝13.6,2.2Hz,1H),2.22(td,J＝13.4,4.2Hz,1H),2.14–1.91(m,3H),1.77–1.65(m,1H),1.57–1.45(m,1H),1.24(t,J＝7.1Hz,3H)；1C NMR(100MHz,CDCl3)168.6,158.0,149.2,138.2,136.4,131.4,131.2,127.7,127.2,121.3,113.8,60.8,55.3,43.3,35.6,35.5,32.3,32.1,14.2；HRMS(EI):m/z:[M]+Calcd for C23H25BrO3:428.0984,found 428.0982；HPLC conditions:Chiralcel AD-Hcolumn,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝19.256min,tminor＝25.968min,95％ee.。
Figure BDA0002754709020000112
化合物例Ici的结构表征：1H NMR(400MHz,CDCl3)δ7.51–7.46(m,2H),7.35–7.27(m,5H),7.26–7.15(m,5H),7.14–7.10(m,2H),5.18(s,2H),3.33–3.21(m,1H),2.85–2.72(m,1H),2.56–2.42(m,1H),2.27–2.16(m,1H),2.14–2.06(m,1H),2.04–1.91(m,2H),1.79–1.65(m,1H),1.61–1.53(m,1H)；1C NMR(100MHz,CDCl3)168.2,150.5,146.0,136.3,136.0,131.4,131.3,128.5,128.4,128.1,127.9,126.8,126.3,121.4,66.4,44.2,35.3,35.2,32.2,32.1；HRMS(EI):m/z:[M]+Calcd for C27H25BrO2:460.1038,found 460.1032；HPLCconditions:ChiralcelOD-H column,254nm,flow rate:0.5ml/min,iPrOH/hexanes＝3/97,tmajor＝19.345min,tminor＝16.677min,94％ee.。
本技术领域中的技术人员应当认识到，以上的实例仅是用来说明本发明，而非用作为对本发明的限定，只要在本发明的实质精神范围内，对以上所述实施例的变化，变形都将落在本发明的权利要求范围内。

Claims (4)

1.一种轴手性4-取代亚环己基芳基醋酸酯类手性化合物的制备方法，其特征在于，利用4-取代环己基-α-羟基重氮酯类化合物和芳基碘化物，在钯源和手性配体的催化下，在还原剂和碱的促进下，在氮气氛围下，于30-100℃且转速为1300-1500转的油浴下，发生金属催化的β-OH消除反应，合成轴手性4-取代亚环己基芳基醋酸酯类手性化合物；其反应式为：
Figure DEST_PATH_IMAGE002
式中，Ar为吸电子或给电子的苯基，吸电子基团选自氟、氯、溴，氰基，醛基，酯基，三氟甲基取代基团，给电子基团选自C1~C10烷基和烷氧基以及C1~C7保护的氨基基团；R选自C1~C10烷基和烷氧基，C6~C13的芳基以及C6~C13保护的氨基，R1选自C1~C10的烷基；
所述手性配体为
Figure DEST_PATH_IMAGE004
；
所述钯源选自Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、Pd(OAc)2、PdCl2、PdBr2、Pd(TFA)2、[Pd(allyl)Cl]2或Pd(dppe)2Cl2；
所述有机溶剂选自正己烷、甲苯、1,2-二氯乙烷、乙酸乙酯、乙腈、甲醇、二甲基乙酰胺中的一种。
2.根据权利要求1所述的制备方法，其特征在于，所述碱选自三乙胺、二乙胺、二环己基胺、N,N-二异丙基乙胺、三乙烯二胺、碳酸钾、碳酸铯、乙酸铯、乙酸钠、磷酸钾、碳酸氢钾或甲酸钠。
3.根据权利要求1所述的制备方法，其特征在于，所述还原剂选自锌粉、锰粉、镁粉、铁粉、铟或四羟基二硼。
4.根据权利要求1所述的制备方法，其特征在于，所述芳基碘化物、4-取代环己基-α-羟基重氮酯类化合物、钯源、手性配体、碱、还原剂的摩尔比为：
1:(1~3):(0.01~0.075):(0.025~0.3):(1~10):(0.5~4)。
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