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CN111978276A - 钌催化2,2,5-三取代-1,3-环己二酮氢化去对称化合成多手性环己烷的方法 - Google Patents

钌催化2,2,5-三取代-1,3-环己二酮氢化去对称化合成多手性环己烷的方法 Download PDF

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CN111978276A
CN111978276A CN201910436747.4A CN201910436747A CN111978276A CN 111978276 A CN111978276 A CN 111978276A CN 201910436747 A CN201910436747 A CN 201910436747A CN 111978276 A CN111978276 A CN 111978276A
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ethyl acetate
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cyclohexanedione
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CN111978276B (zh
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余长斌
沈洪强
孙蕾
周永贵
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Dalian Institute of Chemical Physics of CAS
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Abstract

一种钌催化转移氢化去对称化2,2,5‑三取代‑1,3‑环己二酮合成多手性环己烷骨架的方法。采用0.5‑5mol％钌催化剂，对2,2,5‑三取代1,3‑环己二酮化合物进行不对称转移氢化去对称化。得到相应的多手性环己烷骨架化合物，其对映体过量最多可达到>99.9％％。本发明操作简便实用易行，收率高，环境友好，催化剂商业可得，反应条件温和，具有潜在的实际应用价值。

Description

钌催化2,2,5-三取代-1,3-环己二酮氢化去对称化合成多手 性环己烷的方法
技术领域
本发明属于有机合成领域，具体涉及一种应用钌的均相体系高对映选择性催化2,2,5三取代-1,3-环己二酮的转移氢化去对称化反应合成多手性环己烷骨架的方法。
背景技术
多取代手性环己烷衍生物广泛存在于具有生理活性的化合物、天然产物和药物分子中。(参考文献一：(a)Ciochina,R.；Grossman,R.B.Polycyclic polyprenylated acylphloroglucinols.Chem.Rev.2006,106,3963；(b)Li,G.；Kusari,S.；Spiteller,M.Naturalproducts containing‘decalin’motif in microorganisms.Nat.Prod.Rep.2014,31,1175.)。如oseltamivir phosphate(磷酸奥司他韦)是一种抗流感药物，对H5N1禽流感病毒有明显疗效。而脱落酸则表现出能够抑制大多数胚芽鞘生长的活性。(参考文献二：(a)Kim,C.U.；Lew,W.；Williams,M.A.；Liu,H.；Zhang,L.；Swaminathan,S.；Bischofberger,N.；Chen,M.S.；Mendel,D.B.；Tai,C.Y.；Laver,W.G.；Stevens,R.C.J.Am.Chem.Soc.1997,119,681；(b)Kim,C.U.；Lew,W.；Williams,M.A.；Wu,H.；Zhang,L.；Chen,X.；Escarpe,P.A.；Mendel,D.B.；Laver,W.G.；Stevens,R.C.J.Med.Chem.1998,41,2451；(c)Cimmino,A.；Masi,M.；Evidente,M.；Superchi,S.；Evidente,A.Nat.Prod.Rep.2015,32,1629；(d)Wang,C.Y.；Wang,S.Y.；Mellenthin,W.M.J.Agric.Food Chem.1972,20,451；(e)Takino,J.；Kozaki,T.；Sato,Y.；Liu,C.；Ozaki,T.；Minami,A.；Oikawa,H.J.Am.Chem.Soc.2018,140,12392.)。由此可见，发展一些高效的方法来合成具有光学活性的多取代环己烷骨架化合物并提升相关产业的技术水平具有重要的科学价值和应用前景。
众所周知，通过不对称氢化合成具有两个或三个连续手性中心化合物已得到广泛发展，但是，到目前为止，还没有文献报道通过不对称氢化合成具有多个非连续手性中心化合物的例子。(参考文献三：(a)Morris,R.H.Chem.Soc.Rev.2009,38,2282；(b)Li,X.；Zhang,P；Duan,K.；Wang,J.Chin.J.Org.Chem.2012,32,19；(c)Chen,Q.-A.；Ye,Z.-S.；Duan,Y.；Zhou,Y.-G.Chem.Soc.Rev.2013,42,497；(d)Xie,J.-H.；Bao,D.-H.；Zhou,Q.-L.Synthesis2015,47,460；(e)Zhang,Z.；Butt,N.A.；Zhang,W.Chem.Rev.2016,116,14769；(f)Liu,Y.-T.；Chen,J.-Q.；Li,L.-P.；Shao,X.-Y.；Xie,J.-H.；Zhou,Q.-L.Org.Lett.2017,19,3231；(g)Liu,Y.；Cheng,L.-J.；Yue,H.-T.；Che,W.；Xie,J.-H.；Zhou,Q.-L.Liu,C.；Xie,J.-H.；Li,Y.-L.；Chen,J.-Q.；Zhou,Q.-L.Angew.Chem.Int.Ed.2013,52,593.)。进一步拓展不对称氢化的应用范围一直还是该领域的重要研究方向之一，特别是通过该方法来构建含有多手性中心和多官能团产物仍然是该领域极具有挑战性的课题。如果能通过催化不对称氢化对含潜手性中心的底物去对称化，将极大推动传统不对称氢化反应的应用范围。
发明内容
本发明的目的是提供一种钌催化转移氢化去对称化2,2,5-三取代1,3-环己二酮合成多手性环己烷骨架的方法。为实现上述目的，本发明采用的技术方案如下：
本发明以钌的手性二胺配合物为催化剂，实现2，2,5-三取代1,3-二酮的转移氢化去对称化，反应式和条件如下，反应式包括两个，任意一个均可：
Figure BDA0002070755420000021
式中：
R为C1-C12的烷基、苯基或含有取代基的芳环；所述取代基为吸电子或供电子的不同基团至少一种甲基、乙基、甲氧基、三氟甲基，卤素；R’为C1-C12的烷基、烯基、炔基或苄基。
基于以上技术方案，优选的，所述吸电子或供电子的基团为甲基、乙基、甲氧基、三氟甲基或卤素。
基于以上技术方案，优选的，所述方法包括如下步骤：
(1)氮气气氛下，将催化剂、有机溶剂和氢源(甲酸/三乙胺共沸物)加入1,3-二酮底物中得到反应物溶液；
(2)将所述反应物溶液置于-10-70℃搅拌反应12-48h，得到单氢化的产物，然后减压除去溶剂三氟乙醇，再加入水，用二氯甲烷(20mL)分三次萃取，无水硫酸钠干燥，最后减压除去溶剂二氯甲烷后直接柱层析分离得到纯的产物。
基于以上技术方案，优选的，所述有机溶剂为甲苯、二氯甲烷、四氢呋喃、乙酸乙酯、乙醇、异丙醇中的一种。
基于以上技术方案，优选的，钌金属配合物、底物摩尔比为：0.01-0.05:1:80。
基于以上技术方案，优选的，所述底物在反应物溶液中的浓度为0.025-0.5mmol/mL。
基于以上技术方案，优选的，所述有机溶剂为甲苯、二氯甲烷、四氢呋喃、乙酸乙酯，乙醇和异丙醇的活性稍差，其余溶剂中的活性和对映选择性好。
基于以上技术方案，优选的，所述甲酸/三乙胺共沸物中有益效果
1.反应活性和对映选择性高；
2.催化剂来源方便，反应操作简便实用；
3.氢化反应条件温和。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例，本发明所用的催化剂为钌的二胺配合物，此催化剂为市售且无需任何处理，甲酸/三乙胺共沸物为市售且无需任何处理，底物2,2,5-三取代1,3-环己二酮参照文献方法合成(Tetrahedron 2013,69,10414；J.Med.Chem.1977,20,709；J.Med.Chem.1992,35,3429；Tetrahedron 2015,71,129。)。
实施例1
氢化反应条件的优化
氮气氛围下，向装有0.2mmol底物的反应瓶中投入钌的手性二胺配合物催化剂(底物用量的1mol％)、1ml溶剂和0.5mL甲酸/三乙胺共沸物(HCO2H/Et3N，甲酸和三乙胺的摩尔比为5:2)，于25℃下搅拌反应24小时。然后，停止反应，减压除去有机溶剂，加入碳酸氢钠水溶液，DCM萃取，合并有机层，减压除去萃取溶剂，柱层析分离得到纯的产物，反应式和配体结构如下：
Figure BDA0002070755420000031
其产率为转化率，产物的对映体过量用手性液相色谱测定，改变过程中有机溶剂的种类，详见表1。
表1. 1,3-二酮氢化去对称化条件优化a
Figure BDA0002070755420000032
Figure BDA0002070755420000041
实施例2
2,2,5-三取代1,3-环己二酮1氢化去对称化合成多取代手性环己烷衍生物2
氮气氛围下，向装有0.2mmol底物的反应瓶中投入钌的手性二胺配合物催化剂(底物用量的2mol％)和1ml溶剂、甲酸/三乙胺共沸物0.5mL(HCO2H/Et3N，甲酸和三乙胺的摩尔比为5:2)，于30下搅拌反应24小时。然后，停止反应，减压除去溶剂，加入碳酸氢钠水溶液，DCM萃取，合并有机层，减压除去溶剂，柱层析分离得到纯的产物，改变反应底物的种类，具体的反应条件和参数见反应式，其产率为分离收率，产物的对映体过量用手性液相色谱测定。反应式如下：
Figure BDA0002070755420000042
实施例3
2,2,5-三取代1,3-环己二酮4氢化去对称化合成多取代手性环己烷衍生物5
氮气氛围下，向装有0.2mmol底物的反应瓶中投入钌催化剂(底物用量的2mol％)和1ml溶剂、甲酸/三乙胺共沸物0.5mL，于30℃下搅拌反应24小时。然后，停止反应，减压除去溶剂，加入碳酸氢钠水溶液，DCM萃取，合并有机层，减压除去溶剂，柱层析分离得到纯的产物，反应式如下：
Figure BDA0002070755420000051
其产率为分离收率，产物的对映体过量用手性液相色谱测定。
实施例4
2,2,5-三取代1,3-环己二酮6氢化去对称化合成多取代手性环己烷衍生物7
氮气氛围下，向装有0.2mmol底物的反应瓶中投入钌催化剂(底物用量的2mol％)和1ml溶剂、甲酸/三乙胺共沸物0.5mL，于-30℃下搅拌反应24小时。然后，停止反应，减压除去溶剂，加入碳酸氢钠水溶液，DCM萃取，合并有机层，减压除去溶剂，柱层析分离得到纯的产物，其产率为分离收率，产物的对映体过量用手性液相色谱测定。反应式如下：
Figure BDA0002070755420000052
实施例5
2,2,5-三取代1,3-环己二酮8氢化去对称化合成多取代手性环己烷衍生物9
氮气氛围下，向装有0.2mmol底物的反应瓶中投入钌催化剂(底物用量的2mol％和1ml溶剂、甲酸/三乙胺共沸物0.5mL，于30℃下搅拌反应24小时。然后，停止反应，减压除去溶剂，加入碳酸氢钠水溶液，DCM萃取，合并有机层，减压除去溶剂，柱层析分离得到纯的产物，其产率为分离收率，产物的对映体过量用手性液相色谱测定。反应式如下：
Figure BDA0002070755420000061
(-)-Benzyl 2-(2,4-dioxo-6-phenylhexahydrobenzofuran-3a(4H)-yl)acetate(2a):71mg,94％yield,>99.9％ee,oil,[α]20 D＝-95.62(c 1.03,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H NMR
Figure BDA0002070755420000062
HPLC:AD-H,elute:n-hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time13.4min(major)and 15.2min；HRMS Calculated for C23H22NaO5[M+Na]+401.1365,found:401.1363.
(-)-Benzyl 2-(2,4-dioxo-6-(o-tolyl)hexahydrobenzofuran-3a(4H)-yl)acetate(2b):72mg,92％yield,>99.9％ee,white solid,mp 126-127℃,[α]20 D＝-98.96(c1.75,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),
Figure BDA0002070755420000063
135.3,131.0,128.9,128.8,128.4,127.1,126.9,124.9,83.4,67.3,51.6,44.8,40.2,37.0,36.5,30.8,19.4；HPLC:AD-H,elute:n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time 11.9min(major)and 12.9min；HRMSCalculated for C24H25O5[M+H]+393.1702,found:393.1698.
(-)-Benzyl 2-(2,4-dioxo-6-(m-tolyl)hexahydrobenzofuran-3a(4H)-yl)acetate(2c):75mg,96％yield,98％ee,white solid,mp 85-86℃,[α]20 D＝-116.72(c0.83,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,CDCl3)δ7.44-7.36(m,5H),7.26(d,J＝7.7Hz,1H),7.11(d,J＝7.5Hz,1H),7.02(d,J＝7.7Hz,2H),5.17(q,J＝12.2Hz,2H),4.94(dd,J＝11.1,6.2Hz,1H),3.34(d,J＝17.6Hz,1H),
Figure BDA0002070755420000071
HRMS Calculated for C24H24KO5[M+K]+431.1255,found:431.1255.
(-)-Benzyl 2-(2,4-dioxo-6-(p-tolyl)hexahydrobenzofuran-3a(4H)-yl)acetate(2d):71mg,91％yield,>99.9％ee,oil,[α]20 D＝-97.69(c 1.78,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H NMR
Figure BDA0002070755420000072
67.2,51.4,45.3,39.8,37.0,36.9,34.8,21.0；HPLC:AD-H,elute:n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time 13.4min(major)and14.8min；HRMS Calculated for C24H25O5[M+H]+393.1702 found:393.1722.
(-)-Benzyl 2-(6-(4-chlorophenyl)-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2e):76mg,92％yield,>99.9％ee,oil,[α]20 D＝-74.49(c 1.38,CHCl3),Rf＝0.40(hexanes/ethyl acetate＝5/1),new compound.
Figure BDA0002070755420000073
n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time16.6min(major)and 19.1min.HRMS Calculated for C23H21ClNaO5[M+Na]+435.0975,found:435.0952.
(-)-Benzyl 2-(6-(4-fluorophenyl)-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2f):70mg,88％yield,>99.9％ee,oil,[α]20 D＝-143.19(c 0.50,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.
Figure BDA0002070755420000074
128.9,128.5,128.2(J＝8Hz),116.0(J＝21Hz),83.1,67.5,51.5,45.5,40.1,37.2,37.0,34.7；19F NMR(376MHz,CDCl3)δ-115.28.HPLC:AD-H,elute:n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time 14.1min(major)and16.0min；HRMS Calculated for C23H21FNaO5[M+Na]+419.1265,found:419.1267.
(-)-Benzyl 2-(6-(2-methoxyphenyl)-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2g):76mg,93％
Figure BDA0002070755420000075
Hz,1H)；13C NMR(100MHz,CDCl3)δ207.9,173.3,170.9,157.2,135.3,130.2,128.9,128.7,128.5,128.4,127.1,121.0,110.9,83.4,67.3,55.5,51.8,43.2,39.9,37.2,35.4,30.4；HPLC:AD-H,elute:n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time 14.4min(major)and 16.8min；HRMS Calculated for C24H24NaO6[M+Na]+431.1465,found:431.1473.
(-)-Benzyl 2-(6-methyl-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2h):59mg,93％yield,>99.9％ee,oil,[α]20 D＝-174.58(c 1.48,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H
Figure BDA0002070755420000081
170.8,135.0,128.7,128.6,128.3,83.1,67.1,51.2,45.6,39.8,37.9,36.9,24.9,21.3；HPLC:AD-H,elute:n-Hexane/i-PrOH＝50/50,detector:210nm,30℃,flow rate:0.5mL/min,retention time 12.9min(major)and 14.4min；HRMS Calculated for C18H24NO5[M+Na]+334.1649,found:4334.1645.
(-)-Benzyl 2-(6-isobutyl-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2i):65mg,91％yield,>99.9％ee,oil,[α]20 D＝-150.52(c 1.50,CHCl3),Rf＝0.4(hexanes/ethyl acetate＝5/1),new compound.1H NMR
Figure BDA0002070755420000082
NMR(100MHz,CDCl3)δ207.8,173.0,170.7,135.1,128.7,128.6,128.3,83.1,67.1,51.7,45.3,44.2,39.7,36.9,36.2,27.5,24.8,22.8,22.6；HPLC:AD-H,elute:n-Hexane/i-PrOH＝90/10,detector:210nm,30℃,flow rate:0.5mL/min,retention time 27.1min(major)and 28.9min；HRMS Calculated for C18H30KO6[M+K]+381.1672,found:381.1684.
(-)-Ethyl 2-((3aR,6S,7aR)-2,4-dioxo-6-phenyloctahydrobenzofuran-3a-yl)acetate(2j):60mg，95％yield,>99.9％ee,white solid,mp 95-96℃,[α]20 D＝-143.04(c 1.18,CHCl3),Rf＝0.2(hexanes/ethyl acetate＝
Figure BDA0002070755420000083
126.6,83.1,61.5,51.3,45.3,40.0,36.9,36.8,35.2,14.1；HPLC:OD-H,elute:n-Hexane/i-PrOH＝35/65,detector:220nm,30℃,flow rate:＝0.5mL/min,retention time21.9min(major)and 38.7min；HRMS Calculated for C18H21O5[M+H]+317.1384,found:317.1382.
(-)-Ethyl 2-6-(4-chlorophenyl)-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2k):55mg,79％yield,>99％ee,white foam solid,[α]20 D＝-155.57(c 0.43,CHCl3),Rf＝0.18(hexanes/ethyl acetate＝5/1),
Figure BDA0002070755420000084
nm,flow rate:0.6mL/min,30℃,retention time 37.3 min and 41.9 min(major)；HRMSCalculated for C18H20ClO5[M+H]+351.0994,found 351.0992.
(-)-Ethyl 2-6-(4-methoxyphenyl)-2,4-dioxohexahydrobenzofuran-3a(4H)-yl)acetate(2l):61mg,88％yield,white foam solid,Rf＝0.25(hexanes/ethyl acetate＝3/1),>99％ee,[α]20 D＝-129.5(c 0.61,CHCl3)；1H
Figure BDA0002070755420000091
37.2,36.9,34.4,14.1；HPLC:OD-H,elute:n-Hexane/i-PrOH＝70/30,detector:220nm,flow rate:0.6mL/min,30℃,retention time 39.5min(major)and 42.3min；HRMSCalculated for C19H26NO6[M+NH4]+364.1755,found 364.1752.
(-)-3-Hydroxy-2,2-dimethyl-5-phenylcyclohexan-1-one(5a):40mg,91％yield,>99.9％ee,white solid,mp 68-69℃,[α]20 D＝-104.16(c 0.36,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new compound.1H
Figure BDA0002070755420000092
nm,flow rate:0.7mL/min,30℃,retention time 14.5min(major)and 18.7min；HRMSCalculated for C14H19O2[M+H]+219.1380,found:219.1383.
(-)-3-Hydroxy-2,2-dimethyl-5-(o-tolyl)cyclohexan-1-one(5b):44mg,96％yield,>99.9％ee,white solid,mp 97-98℃,[α]20 D＝-104.18(c 0.86,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,CDCl3)δ7.27-7.21(m,2H),7.18-7.13(m,2H),3.81-3.72(m,1H),3.09-3.00(m,1H),
Figure BDA0002070755420000093
and 20.0min；HRMS Calculated for C15H24NO2[M+NH4]+250.1802,found:250.1800.
(-)-3-Hydroxy-2,2-dimethyl-5-(m-tolyl)cyclohexan-1-one(5c):44mg,96％yield,99.1％ee,white solid,mp 82-83℃,[α]20 D＝-117.42(c 0.66,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new compound.1H
Figure BDA0002070755420000094
n-Hexane/i-PrOH＝85/15,detector:220nm,flow rate:0.7mL/min,30℃,retention time8.9min and9.4 min(major)；HRMS Calculated for C15H24NO2[M+NH4]+250.1802,found:250.1801.
(-)-3-Hydroxy-2,2-dimethyl-5-(p-tolyl)cyclohexan-1-one(5d):42mg,91％yield,99.3％ee,white solid,mp 100-101℃,[α]20 D＝-107.37(c 1.18,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new compound.1H
Figure BDA0002070755420000095
nm,flow rate:0.7mL/min,30℃,retention time 29.2min and 32.7min(major)；HRMSCalculated for C15H24NO2[M+NH4]+250.1802,found:250.1801.
(3R,5S)-(-)-3-Hydroxy-2,2-dimethyl-5-(2-methoxyphenyl)cyclohexan-1-one(5e):48mg,96％yield,>99.9％ee,white solid,mp 116-118℃,[α]20 D＝-102.93(c0.92,CHCl3),Rf＝0.20(hexanes/ethyl acetate＝5/1),
Figure BDA0002070755420000096
new compound.1H NMR(400MHz,CDCl3)δ7.26-7.18(m,2H),6.97-6.93(m,1H),6.88(d,J＝8.2Hz,1H),3.82(s,3H),3.75-3.72(m,1H),3.26-3.17(m,1H),2.85-2.78(m,1H),2.45-2.40(m,1H),2.24-2.09(m,2H),1.80(s,1H),1.21(s,6H)；13C NMR(100MHz,CDCl3)δ213.7,156.9,131.3,127.8,126.7,120.8,110.6,76.2,55.3,51.2,42.7,35.5,32.2,21.0,18.6；HPLC:AS-H,elute:n-Hexane/i-PrOH＝90/10,detector:220nm,flow rate:0.7mL/min,30℃,retention time 20.7min and 27.8min(major)；HRMS Calculated for C15H21O3[M+H]+249.1485,found:249.1489.
(-)-3-Hydroxy-2,2-dimethyl-5-(4-methoxyphenyl)cyclohexan-1-one(5f):45mg,90％yield,99.9％ee,white solid,mp 103-105℃,[α]20 D＝-103.17(c 0.88,CHCl3),Rf＝0.20(hexanes/ethyl acetate＝5/1),new
Figure BDA0002070755420000101
OD-H,elute:n-Hexane/i-PrOH＝85/15,detector:220nm,flow rate:0.7mL/min,30℃,retention time 14.2min(major)and 18.4min；HRMS Calculated for C15H24NO3[M+NH4]+266.1751,found:266.1753.
(-)-5-(4-Fluorophenyl)-3-hydroxy-2,2-dimethylcyclohexan-1-one(5g):44mg,94％yield,>99.9％ee,white solid,mp 127-129℃,[α]20 D＝-102.37(c 0.80,CHCl3),Rf＝0.40(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,CDCl3)δ7.21-7.17(m,2H),7.05-7.00(m,2H),3.74-3.70(m,1H),
Figure BDA0002070755420000102
detector:220nm,flow rate:0.7mL/min,30℃,retention time 18.4min and 20.4min(major)；HRMS Calculated for C14H21FO2[M+H]+254.1551,found:254.1557.
(-)-5-(4-Chlorophenyl)-3-hydroxy-2,2-dimethylcyclohexan-1-one(5h):49mg,96％yield,99.9％ee,white solid,mp 128-130℃,[α]20 D＝-95.99(c 0.60,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.
Figure BDA0002070755420000103
90/10,detector:220nm,flow rate:0.7mL/min,30℃,retention time 21.0min and23.8min(major)；HRMS Calculated for C14H17ClNaO2[M+Na]+275.0809,found:275.0804.
(-)-5-(4-Bromophenyl)-3-hydroxy-2,2-dimethylcyclohexan-1-one(5i):52mg,88％yield,99.8％ee,white solid,mp 103-105℃,[α]20 D＝-80.78(c 1.02,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.
Figure BDA0002070755420000104
90/10,detector:220nm,flow rate:0.7 mL/min,30℃,retention time 20.4min and23.3min(major)；HRMS Calculated for C14H21BrO2[M+NH4]+314.0750,found:314.0747.
(-)-2,2-Diallyl-3-hydroxy-5-phenylcyclohexan-1-one(7a):48mg,89％yield,99.4％ee,colorless oil,[α]20 D＝-76.66(c 0.84,CHCl3),Rf＝0.35(hexanes/EA＝10/1),new compound.1H NMR(400MHz,CDCl3)δ
Figure BDA0002070755420000105
2.33-2.12(m,4H)；13C NMR(100MHz,CDCl3)δ210.5,143.2,136.0,132.4,128.9,127.0,126.6,118.7,118.1,73.0,57.9,45.8,38.1,36.5,35.3；HPLC:AS-H,elute:n-Hexane/i-PrOH＝95/5,detector:220nm,flow rate:0.7mL/min,30℃,retention time 18.4min and19.6min(major)；HRMS Calculated for C18H23O2[M+H]+271.1693,found:271.1690.
(+)-10-Hydroxy-8-phenylspiro[4.5]dec-2-en-6-one(7b):46mg,94％yield,99.6％ee,color-less oil,[α]20 D＝+46.21(c 0.92,CHCl3),Rf＝0.25(hexanes/ethylacetate＝10/1),new compound.1H NMR(400MHz,CDCl3)
Figure BDA0002070755420000111
37.9,37.4,36.9；HPLC:OD-H,elute:n-Hexane/i-PrOH＝80/20,detector:220nm,flowrate:0.7mL/min,30℃,retention time 20.9min and 23.7min(major)；HRMS Calculatedfor C16H22NO2[M+NH4]+260.1645,found:260.1643.
(-)-3-Hydroxy-5-phenyl-2,2-di(prop-2-yn-1-yl)cyclohexan-1-one(7c):50mg,94％yield,>99.9％ee,colorless oil,[α]20 D＝-55.30(c 0.98,CHCl3),Rf＝0.40(hexanes/ethyl acetate＝5/1),new compound.1H NMR
Figure BDA0002070755420000112
85/15,detector:220nm,flow rate:0.7mL/min,30℃,retention time 25.7min and28.1min(major)；HRMS Calculated for C18H19O2[M+H]+267.1380,found:267.1382.
(-)-2,2-Dicinnamyl-3-hydroxy-5-methylcyclohexan-1-one(9a):70mg,97％yield,98.4％ee,colorless oil,[α]20 D＝-137.29(c 1.26,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,
Figure BDA0002070755420000113
127.4,127.3,127.2 126.2,126.1,124.2,72.7,58.3,46.7,38.0,35.8,34.7,27.7,22.0；HPLC:AD-H,elute:n-Hexane/i-PrOH＝80/20,detector:220nm,flow rate:0.7mL/min,30℃,retention time 10.2min and 12.6min(major)；HRMS Calculated for C25H28NaO2[M+Na]+383.1982,found:383.1979.
(-)-2,2-Dicinnamyl-3-hydroxy-5-isobutylcyclohexan-1-one(9b):68mg,85％yield,94.2％ee,colorless oil,[α]20 D＝-108.58(c 0.92,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,
Figure BDA0002070755420000114
MHz,CDCl3)δ211.3,137.2,137.0,133.4,132.8,128.6,128.5,127.39,127.35,127.3,126.24,126.15,124.2,72.8,58.7,46.1,45.0,36.1,35.8,34.7,30.1,24.8,22.64,22.61；HPLC:AD-H,elute:n-Hexane/i-PrOH＝90/10,detector:220nm,flow rate:0.7mL/min,30℃,retention time 12.2min and 15.8min(major)；HRMS Calculated for C28H38NO2[M+NH4]+420.2897,found:420.2896.
(-)-2,2-Dicinnamyl-3-hydroxy-5-phenylcyclohexan-1-one(9c):80mg,95％yield,99.9％ee,colorless oil,[α]20 D＝-60.25(c 1.36,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new com-pound.1H NMR(400MHz,
Figure BDA0002070755420000115
6.06-5.98(m,1H),4.13-4.11(m,1H),2.95-2.69(m,5H),2.54-2.42(m,2H),2.32-2.23(m,1H),2.16-2.13(m,1H),1.98(br,1H)；13C NMR(100MHz,CDCl3)δ210.6,143.2,137.3,137.0,133.7,133.1,128.9,128.63,128.59,127.5,127.4,127.2,127.0,126.6,126.3,126.2,124.1,72.7,58.7,45.9,38.0,36.9,35.7,35.0；HPLC:AD-H,elute:n-hexane/i-PrOH＝80/20,detector:220nm,flow rate:0.7mL/min,30℃,retention time 12.8min and 14.7min(major)；HRMS Calculated for C30H30NaO2[M+Na]+445.2138,found:445.2138.
(-)-2,2-Dicinnamyl-3-hydroxy-5-(m-tolyl)cyclohexan-1-one(9d):76mg,87％yield,98.4％ee,white solid,mp 45-46℃,[α]20 D＝-64.47(c 1.32,CHCl3),Rf＝0.35(hexanes/ethyl acetate＝5/1),new compound.1H NMR
Figure BDA0002070755420000121
137.3,137.0,133.7,133.1,128.8,128.61,128.58,,127.7,127.5,127.3,127.2,126.3,126.2,124.1,123.6,72.8,58.7,46.0,38.0,36.9,35.8,35.0,21.5；HPLC:AS-H,elute:n-Hexane/i-PrOH＝95/5,detector:220nm,flow rate:0.7mL/min,30℃,retention time28.0min and 31.7min(major)；HRMS Calculated for C31H36NO2[M+NH4]+454.2741,found:454.2743.
(-)-2,2-Dicinnamyl-3-hydroxy-5-(p-tolyl)cyclohexan-1-one(9e):84mg,97％yield,99.8％ee,colorless oil,[α]20 D＝-61.34(c 1.56,CHCl3),Rf＝0.40(hexanes/ethyl acetate＝5/1),new compound.1H NMR(400MHz,
Figure BDA0002070755420000122
140.2,137.3,137.0,136.6,133.6,133.1,129.6,128.61,128.57,127.5,127.3,127.2,126.4,126.3,126.2,124.1,72.7,58.7,46.0,37.6,37.0,35.8,35.0,21.1；HPLC:AD-H,elute:n-Hexane/i-PrOH＝80/20,detector:220nm,flow rate:0.7mL/min,30℃,retention time 13.2min and 15.1min(major)；HRMS Calculated for C31H32NaO2[M+Na]+459.2295,found:459.2300.
(-)-2,2-Dicinnamyl-3-hydroxy-5-(2-methoxyphenyl)cyclohexan-1-one(9f):85mg,93％yield,99.7％ee,white solid,mp 60-62℃,[α]20 D＝-68.13(c 1.50,CHCl3),Rf＝0.30(hexanes/ethyl acetate＝5/1),new
Figure BDA0002070755420000123
1.92-1.91(br,1H)；13C NMR(100MHz,CDCl3)δ211.2,157.0,137.4,137.1,133.5,132.9,131.1,128.60,128.56,127.9,127.4,127.3,126.7,126.3,126.2,124.3,120.8,110.7,72.9,58.8,55.3,43.9,35.8,35.0,34.96,32.3；HPLC:AD-H,detector:220nm,elute:n-Hexane/i-PrOH＝80/20,flow rate:0.7mL/min,30℃,retention time 17.6min and27.0min(major)；HRMS Calculated for C31H36NO3[M+NH4]+470.2690,found:470.2693.

Claims (7)

1.一种钌催化2,2,5-三取代1,3-环己二酮合氢化去对称化合成多手性环己烷骨架的方法，其特征在于，所述催化体系为钌的手性二胺配合物，所述方法的反应式包括式Ⅰ和式Ⅱ：
Figure FDA0002070755410000011
式中：
R为C1-C12的烷基、苯基或含有取代基的芳环；所述取代基为吸电子或供电子的基团至少一种；R’为C1-C12的烷基、烯基、炔基或苄基。
2.如权利要求1所述的方法，其特征在于，所述吸电子或供电子的基团为甲基、乙基、甲氧基、三氟甲基或卤素。
3.如权利要求1所述的方法，其特征在于：所述方法包括如下步骤：
(1)氮气气氛下，将催化剂、有机溶剂和甲酸/三乙胺共沸物加入1,3-二酮底物中得到反应物溶液；
(2)将所述反应物溶液置于-10-70℃搅拌反应12-48h，除去有机溶剂、萃取、干燥，最后除去萃取剂后直接柱层析分离得到所述多手性环己烷骨架。
4.如权利要求3所述的合成方法，其特征在于：所述有机溶剂为甲苯、二氯甲烷、四氢呋喃、乙酸乙酯、乙醇、异丙醇中的一种。
5.如权利要求3所述的方法，其特征在于：催化剂、底物和甲酸三乙胺摩尔比为：0.01-0.05:1:80。
6.如权利要求3所述的方法，其特征在于：底物在反应物溶液中浓度为0.025-0.5mmol/mL。
7.如权利要求4所述的方法，其特征在于，所述有机溶剂为甲苯、二氯甲烷、四氢呋喃、乙酸乙酯。
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CN115785031A (zh) * 2021-09-13 2023-03-14 中国科学院大连化学物理研究所 一种手性化合物及其制备方法和应用
CN119101040A (zh) * 2024-11-08 2024-12-10 杭州澳赛诺医药技术有限公司 一种通过去对称化合成芳基取代的手性四氢吡喃环的方法

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