CN112028753B - 一种钯催化1,3-二酮不对称氢化合成β-羟基酮的方法 - Google Patents

一种钯催化1,3-二酮不对称氢化合成β-羟基酮的方法 Download PDF

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CN112028753B
CN112028753B CN201910482596.6A CN201910482596A CN112028753B CN 112028753 B CN112028753 B CN 112028753B CN 201910482596 A CN201910482596 A CN 201910482596A CN 112028753 B CN112028753 B CN 112028753B
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余长斌
周永贵
李翔
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

一种钯催化氢化去对称化1,3‑二酮合成手性β‑羟基酮的方法。采用1‑5mol％钯催化剂，加入10‑100mol％的酸，对2取代1,3‑二酮化合物进行不对称氢化去对称化。得到相应的手性β‑羟基酮化合物，其对映体过量最多可达到98％。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

一种钯催化1,3-二酮不对称氢化合成β-羟基酮的方法
技术领域
本发明属于不对称氢化合成领域，具体涉及一种应用钯的均相体系高度对映选择性催化2取代1,3-二酮的氢化去对称化反应合成手性β-羟基酮的方法。
背景技术
光学活性的β-羟基酮化合物由于其具有官能团多样性的特点，可以通过进一步卤代、氢化、胺化等很方便地构建一系列具有生物活性的有机分子。(参考文献一：(a)Davis,F.A.；Chen,B.-C.Chem.Rev.1992,92,919.(b)Adam,W.；Lazarus,M.；
Figure BDA0002084323140000011
C.R.；Schreier, P.Acc.Chem.Res.1999,32,837.)如Calcitriol(骨化三醇)，是市面上销售维它命D的主要成分。而2-甲基-2-烯丙基-3-羟基环戊酮是合成天然产物Coriolin和Anguidine的关键起始原料。(参考文献二：(a)Attwood,M.R.；Francis,R.J.；Hassall,C.H.；
Figure BDA0002084323140000012
A.；Lawton,G.； Natoff,I.L.；Nixon,J.S.；Redshaw,S.；Thomas,W.A.FEBS Lett.1984,165,201.(b)Kawai,G.； Ikeda,Y.Schizophyllum Commune.Biochim.Biophys.Acta 1983,754,243.)。由此可见，发展一些高效的方法来合成具有光学活性的α-或β-羟基羰基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，去对称化反应是不对称合成中一种非常有效的方法，特别是对具有多个潜手性中心的底物进行去对称化反应可快速构建含有多个手性中心的产物。(参考文献三：(a) Spivey,A.C.；Andrews,B.I.Angew.Chem.Int.Ed.2001,40,3131.(b)Willis,M.C.J.Chem. Soc.,Perkins Trans.1 1999,1765.(c)Johnson,J.B.；Rovis,T.Acc.Chem.Res.2008,41,327.(d) Atodiresei,I.；Schiffers,I.；Bolm,C.Chem.Rev.2007,107,5683.)。进一步拓展底物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。通过化学家们的不懈努力，该领域取得了一些重要的进展。1981年，日本科学家Yoshikawa小组首次报道了以 Ru2Cl4(DIOP)3为催化剂，实现环状酸酐不对称氢化去对称化反应得到稳定的内酯化合物，但是只取得20％的对映选择性。(参考文献四：Osakada,K.；Obana,M.；Ikariyaf,T.；Saburi,M.； Yoshikawa,S.TetrahedronLett.1981,22,429.)。随后Ikariya小组使用钌催化剂，实现了环状酰亚胺的不对称氢化去对称化反应，最高获得98％对映选择性。(参考文献五：(a)Ito,M.； Sakaguchi,A.；Kobayashi,C.；Ikariya,T.J.Am.Chem.Soc.2007,129,290.(b)Ito,M.； Kobayashi,C.；Himizu,A.；Ikariya,T.J.Am.Chem.Soc.2010,132,11414.)2010年，Bergens 小组通过钌催化的转移氢化实现了环状酰亚胺的不对称氢化去对称化反应，该反应可以一次构建多个手性中心，反应的对映选择性和非对映选择性都可以得到很好的控制。(参考文献六：(a)Takebayashi,S.；John,J.M.；Bergens,S.H.J.Am.Chem.Soc.2010,132,12832.(b) John,J.M.；Takebayashi,S.；Dabral,N.；Miskolzie,M.；Bergens.S.H.J.Am.Chem.Soc.2013,135,8578.)。2013年，张绪穆等人用手性铱催化剂成功实现了环状酸酐化合物的不对称氢化去对称化反应，得到内酯化合物，最高获得99％对映选择性。(参考文献七：(a)Liu,T.-L.； Li,W.；Geng,H.-L.；Wang,C.-J.；Zhang,X.Org.Lett.2013,15,1740.)。综上所述，虽然基于氢化去对称化策略在不对称合成研究中取得了一些进展，但是其中仍然有许多问题值得进一步探讨。因此，发展一种高效、普适性更加广泛的不对称氢化体系具有非常重要的意义，也是一个充满挑战的方向。
发明内容
本发明的目的是提供一种钯催化均相体系高度对映选择性催化2取代1,3-二酮的氢化去对称化反应合成手性β-羟基酮的方法。为实现上述目的，本发明采用的技术方案如下：
本发明以钯的手性双膦P-P*配合物为催化剂，实现2取代1,3-二酮的氢化去对称化，反应式和条件如下：
式Ⅰ
Figure BDA0002084323140000021
式Ⅱ
Figure BDA0002084323140000022
式中：
R为H，C1-C2的烷基；Ar为苯环上不同取代的芳基基团。
基于以上技术方案，优选的，所述反应原料还包括酸添加剂。
基于以上技术方案，优选的，所述氢化反应包括催化剂制备和底物氢化两个阶段：
(1)催化剂制备，将钯金属前体和手性双膦配体加入丙酮后反应0.5-2小时，随后减压除掉丙酮，得到所述钯的手性双膦P-P*配合物催化剂；
(2)氢化反应，将所述钯的手性双膦P-P*配合物催化剂、有机溶剂加入1,3-二酮底物中，通入氢气反应得到所述手性β-羟基酮。释放氢气，先减压除去溶剂，再加入水，用二氯甲烷(20mL)分三次萃取，无水硫酸钠干燥，最后减压除去溶剂后直接柱层析分离得到纯的手性β-羟基酮产物。
所述催化剂制备中，钯的金属前体及双膦配体均为市售且无需任何处理。
所述催化剂制备和氢化反应中，所用的有机溶剂选自甲苯、二氯甲烷、三氟乙醇、六氟异丙醇中的一种，其中二氯甲烷和甲苯活性稍差，三氟乙醇、六氟异丙醇的活性和对映选择性好。
所述钯金属前体选自氯化钯、醋酸钯或三氟醋酸钯。
如权利要求1或2所述的方法，其特征在于：所述配体选自(R)-DTBM-SegPhos或(R)-SegPhos或(R)-MeO-Biphep或(R)-BTFM-GarPhos或(S)-SynPhos或(R)-BINAP或 (Rax,S,S)-C3-TunePhos或(R)-DifluorPhos。
基于以上技术方案，优选的所述双膦配体为(R)-SegPhos或(R)-MeO-Biphep或(S)-SynPhos。
所述反应投料：钯的金属前体、手性双膦配体、酸添加剂、底物摩尔比为：(0.01-0.05): (0.01-0.12):(0.1-1.0):1。
9、如权利要求1或2所述的方法，其特征在于：反应压力为100-800psi，优选300psi-400psi，反应温度为-10-80℃，反应时间为12-150h，步骤(2)中，反应底物浓度为0.025 -0.5mmol/mL。
基于以上技术方案，优选的，所述酸添加剂为乙酸，三氟乙酸，苯甲酸，五氟苯甲酸，酒石酸。
有益效果
1.反应活性和对映选择性高；
2.催化剂制备方便，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，本发明所用的钯的金属前体及手性双膦配体均为市售且无需任何处理，本发明所用的1,3-二酮底物参照文献合成 [a)J.Med.Chem.1968,11,342.b)J.Med.Chem.1985,28,1591.c)J.Org.Chem.1988,53,2699.d)Eur.J. Med.Chem.2015,102,310.e)Syn.Commun.2016,46,169.]。
实施例1
氢化反应条件的优化
氮气氛围下，向反应瓶中投入钯前体(底物用量的1mol％-5mol％)和手性双膦配体 (底物用量的1mol％-12mol％)，加入丙酮(1.0-2.0mL)，室温搅拌1h后减压除去丙酮，然后将此催化剂带入手套箱中，用氢化反应所用溶剂三氟乙醇和二氯甲烷将此催化剂溶解，转移至含有酸添加剂(底物用量的1.0-2.0equiv.)和底物0.2mmol)的反应瓶中，然后再将此反应瓶放入反应釜中，通入氢气(100psi-1000psi)，0-80℃下反应12-150小时；释放氢气，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，反应式和配体结构如下：
Figure BDA0002084323140000041
其产率为转化率，产物的对映体过量用手性液相色谱测定，详见表1。
表1. 1,3-二酮氢化去对称化条件优化a
Figure BDA0002084323140000042
Figure BDA0002084323140000051
实施例2
1,3-二酮1氢化去对称化合成手性β-羟基酮2
氮气氛围下，向反应瓶中投入钯前体(底物用量的1mol％-5mol％)和手性双膦配体 (底物用量的1mol％-12mol％)，加入丙酮(1.0-2.0mL)，室温搅拌1h后减压除去丙酮，然后将此催化剂带入手套箱中，用氢化反应所用溶剂将此催化剂溶解，转移至含有添加剂(底物用量的1.0-2.0equiv.)和底物0.2mmol)的反应瓶中，然后再将此反应瓶放入反应釜中，通入氢气(100psi-1000psi)，0-80℃下反应12-150h小时；释放氢气，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1,3-二酮底物中R和Ar的种类，得到不同的手性β-羟基酮，反应式如下：
Figure BDA0002084323140000052
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3
1,3-二酮3氢化去对称化合成手性β-羟基酮4
氮气氛围下，向反应瓶中投入钯前体(底物用量的1mol％-5mol％)和手性双膦配体(底物用量的1mol％-12mol％)，加入丙酮(1.0-2.0mL)，室温搅拌1h后减压除去丙酮，然后将此催化剂带入手套箱中，用氢化反应所用溶剂将此催化剂溶解，转移至含有添加剂(底物用量的1.0-2.0equiv.)和底物0.2mmol)的反应瓶中，然后再将此反应瓶放入反应釜中，通入氢气(100psi-1000psi)，0-80℃下反应12-150小时；释放氢气，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，反应式和配体结构如下：
Figure BDA0002084323140000061
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
1,3-二酮5、7氢化去对称化合成手性β-羟基酮6、8
氮气氛围下，向反应瓶中投入钯前体(底物用量的1mol％-5mol％)和手性双膦配体 (底物用量的1mol％-12mol％)，加入丙酮(1.0-2.0mL)，室温搅拌1h后减压除去丙酮，然后将此催化剂带入手套箱中，用氢化反应所用溶剂将此催化剂溶解，转移至含有添加剂(底物用量的1.0-2.0equiv.)和底物0.2mmol)的反应瓶中，然后再将此反应瓶放入反应釜中，通入氢气(100psi-1000psi)，0-80℃下反应12-150h小时；释放氢气，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，反应式和配体结构如下：
Figure BDA0002084323140000071
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。
Figure BDA0002084323140000072
(2R,3S)-(-)-3-Hydroxy-2-methyl-2-phenyl-2,3-dihydro-1H-inden-1-one(2a):55mg,92％ yield,new compound,white solid,mp102-103℃,96％ee,[α]20 D＝-124.86(c 1.48,CHCl3),Rf＝0.24(dichloromethane).1H NMR(400MHz,CDCl3)δ7.82 (d,J＝7.7Hz,1H),7.71(d,J＝4.0Hz,2H),7.54-7.50(m,1H),7.33-7.21(m, 5H),5.35(d,J＝6.0Hz,1H),2.63(d,J＝6.8Hz,1H),1.51(s,3H).13C NMR(100MHz,CDCl3) δ206.9,153.0,143.0,135.8,135.0,129.8,128.8,127.1,126.9,126.0,124.3,79.8,59.0,18.9. HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min, retention time6.8min and8.6min(major).HRMS Calculated for C16H15O2[M+H]+239.1067, found:239.1068.
Figure BDA0002084323140000073
(-)-3-Hydroxy-2-methyl-2-(o-tolyl)-2,3-dihydro-1H-inden-1-one(2b):62mg,98％yield, new compound,white solid,mp79-80℃,97％ee,[α]20 D＝-130.15(c1.25, CHCl3),Rf＝0.29(dichloromethane).1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.7Hz,1H),7.76-7.75(m,2H),7.58-7.54(m,1H),7.47-7.45(m,1H),7.26-7.21 (m,2H),7.18-7.17(m,1H),5.36(d,J＝5.0Hz,1H),2.28(d,J＝6.2Hz,1H),1.93(s,3H),1.51 (s,3H).13C NMR(100MHz,CDCl3)δ206.1,151.9,139.7,135.9,135.3,134.7,131.9,129.5,128.1,127.5,126.0,125.6,124.1,78.0,59.4,21.7,18.8.HPLC:Chiracel AS-H column,254nm, 30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time5.9minand8.8min (major).HRMS Calculated for C17H17O2[M+H]+253.1223,found:253.1227.
Figure BDA0002084323140000081
(-)-3-Hydroxy-2-methyl-2-(m-tolyl)-2,3-dihydro-1H-inden-1-one(2c):62mg,98％yield, new compound,colorless oil,95％ee,[α]20 D＝-151.59(c0.25,CHCl3),Rf＝ 0.30(dichlorome-thane).1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.6Hz, 1H),7.75-7.72(m,2H),7.56-7.51(m,1H),7.23-7.19(m,1H),7.10-7.05(m,3H),5.39-5.38(m,1H),2.35-2.32(m,4H),1.52(s,3H).13C NMR(100MHz,CDCl3)δ206.6,152.8,142.8,138.3,135.6,134.9,129.6,128.6,127.8,127.5,125.7,124.1,123.8,79.8,58.8,21.6, 18.7.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9 mL/min,retention time6.0min and7.6min(major).HRMS Calculated forC17H17O2[M+H]+ 253.1223,found:253.1224.
Figure BDA0002084323140000082
(-)-3-Hydroxy-2-methyl-2-(p-tolyl)-2,3-dihydro-1H-inden-1-one(2d):63mg,99％yield, new compound,colorless oil,94％ee,[α]20 D＝-104.81(c1.35,CHCl3),Rf＝ 0.32(dichlorome-thane).1H NMR(400MHz,CDCl3)δ7.81(d,J＝7.6Hz, 1H),7.73-7.69(m,2H),7.54-7.49(m,1H),7.16-7.09(m,4H),5.33(s,1H), 2.71(br,1H),2.29(s,3H),1.48(s,3H).13C NMR(100MHz,CDCl3)δ207.0,152.9,139.8, 136.6,135.6,134.8,129.6,129.4,126.6,125.8,124.1,79.7,58.7,21.0,18.7.HPLC:ChiracelAS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retentiontime 6.6min and8.0min(major).HRMS Calculated for C17H17O2[M+H]+253.1223,found:253.1223.
Figure BDA0002084323140000083
(-)-3-Hydroxy-2-methyl-2-(2-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(2e):65mg, 97％yield,new compound,white solid,mp117-118℃,97％ee,[α]20 D＝ -115.87(c1.65,CHCl3),Rf＝0.40(hexanes/ethyl acetate5/1).1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.6Hz,1H),7.72-7.70(m,2H),7.52-7.50(m,1H), 7.43(dd,J＝7.7,1.5Hz,1H),7.29(td,J＝8.0,1.6Hz,1H),7.03(td,J＝7.6,0.9Hz,1H),6.86(d, J＝7.7Hz,1H),5.41(s,1H),3.52(s,3H),2.33(s,1H),1.42(s,3H).13C NMR(100MHz,CDCl3) δ206.4,156.7,152.0,134.9,134.8,131.3,129.1,128.8,128.5,125.4,123.8,121.2,111.7,78.1, 57.2,55.4,17.2.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20, flow＝0.9mL/min,retention time6.5min and13.4min(major).HRMSCalculated for C17H17O3 [M+H]+269.1172,found:269.1169.
Figure BDA0002084323140000091
(-)-3-Hydroxy-2-methyl-2-(3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(2f):63mg, 94％yield,new compound,colorless oil,95％ee,[α]20 D＝-102.82(c1.45, CHCl3),Rf＝0.37(hexanes/ethyl acetate5/1).1H NMR(400MHz,CDCl3) δ7.83(d,J＝7.7Hz,1H),7.75-7.72(m,2H),7.55-7.50(m,1H),7.25-7.21 (m,1H),6.87-6.84(m,2H),6.79-6.77(m,1H),5.37(d,J＝3.2Hz,1H),3.76(s,3H),2.62(br, 1H),1.51(s,3H).13C NMR(100MHz,CDCl3)δ206.4,159.7,152.8,144.5,135.6,134.8,129.68,129.65,125.8,124.2,119.1,113.2,111.9,79.7,58.8,55.2,18.7.HPLC:Chiracel AS-Hcolumn, 254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retentiontime8.5min and10.8 min(major).HRMS Calculated for C17H17O3[M+H]+269.1172,found:269.1168.
Figure BDA0002084323140000092
(-)-3-Hydroxy-2-methyl-2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(2g):63mg, 94％yield,new compound,white solid,mp85-86℃,95％ee,[α]20 D＝ -83.53(c0.65,CHCl3),Rf＝0.26(dichloromethane).1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.6Hz,1H),7.72-7.71(m,2H),7.54-7.49(m,1H), 7.21-7.19(m,2H),6.85-6.82(m,2H),5.33(d,J＝6.9Hz,1H),3.76(s,3H),2.67(d,J＝7.1Hz, 1H),1.48(s,3H).13C NMR(100MHz,CDCl3)δ206.9,158.4,152.8,135.6,134.9,134.7,129.6, 127.8,125.7,124.1,114.0,79.7,58.3,55.3,18.9.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time9.5min and11.8min(major). HRMS Calculated for C17H17O3[M+H]+269.1172,found:269.1173.
Figure BDA0002084323140000093
(-)-3-Hydroxy-2-methyl-2-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-one(2h):61mg,95％ yield,new compound,white solid,mp106-107℃,96％ee,[α]20 D＝-111.30(c 1.60,CHCl3),Rf＝0.35(dichloromethane).1H NMR(400MHz,CDCl3)δ7.86 (d,J＝7.6Hz,1H),7.74-7.73(m,2H),7.54-7.52(m,1H),7.47-7.44(m,1H), 7.31-7.28(m,1H),7.21-7.18(m,1H),7.05-7.00(m,1H),5.42(d,J＝4.9Hz,1H),2.44-2.43(m,1H),1.48(s,3H).13C NMR(100MHz,CDCl3)δ205.1,160.5(d,J＝245.7Hz),151.9,135.4,134.0(d,JC-F＝1.2Hz),129.6(d,JC-F＝13.0Hz),129.5,129.2(d,JC-F＝8.7Hz),129.0(d,JC-F＝ 4.7Hz),125.5,124.3(d,JC-F＝3.2Hz),124.2,115.8(d,JC-F＝22.1Hz),78.3(d,JC-F＝3.1Hz), 56.7,17.2.19F NMR(376MHz,CDCl3)δ-111.09(s).HPLC:Chiracel AS-Hcolumn,220nm,30 ℃,n-Hexane/i-Propanol＝90/10,flow＝0.8mL/min,retentiontime13.6min and25.5min (major).HRMS Calculated for C16H14FO2[M+H]+257.0972,found:257.0971.
Figure BDA0002084323140000101
(-)-3-Hydroxy-2-methyl-2-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-one(2i):63mg,97％ yield,white solid,mp79-80℃,96％ee,[α]20 D＝-109.15(c1.55,CHCl3),Rf＝0.20(hexanes/ethyl acetate6/1).1H NMR(400MHz,CDCl3)δ7.86(d,J＝ 7.7Hz,1H),7.76-7.75(m,2H),7.58-7.53(m,1H),7.33-7.30(m,2H), 7.05-7.01(m,2H),5.38-5.37(m,1H),2.29-2.27(m,1H),1.53(s,3H).13C NMR(100MHz, CDCl3)δ206.5,161.7(d,J＝245.9Hz),152.7,138.6(d,JC-F＝3.3Hz),135.8,134.5,129.7, 128.4(d,JC-F＝8.0Hz),125.7,124.2,115.4(d,JC-F＝21.2Hz),79.5,58.3,19.2.19F NMR(376MHz,CDCl3)δ-115.80(s).HPLC:Chiracel AS-H column,220nm,30℃,n-Hexane/i-Propanol ＝90/10,flow＝0.8mL/min,retention time14.4min and17.6min(major).HRMSCalculated for C16H14FO2[M+H]+257.0972,found:257.0964.
Figure BDA0002084323140000102
(-)-3-Hydroxy-2-methyl-2-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-one(2j):66mg,97％ yield,new compound,white solid,mp110-111℃,97％ee,[α]20 D＝-87.72(c 1.85,CHCl3),Rf＝0.43(dichloromethane).1H NMR(400MHz,CDCl3)δ7.80-7.78(m,1H),7.74-7.67(m,2H),7.54-7.50(m,1H),7.27-7.19(m,4H), 5.28(s,1H),3.06-2.87(m,1H),1.46(s,3H).13C NMR(100MHz,CDCl3)δ206.3,152.8,141.3, 135.9,134.5,132.9,129.8,128.7,128.2,125.8,124.2,79.3,58.5,19.0.HPLC:Chiracel AS-Hcolumn,220nm,30℃,n-Hexane/i-Propanol＝90/10,flow＝0.8mL/min,retentiontime15.0 min and18.2min(major).HRMS Calculated for C16H14ClO2[M+H]+273.0677,found:273.0678.
Figure BDA0002084323140000103
(-)-3-Hydroxy-2-methyl-2-(naphthalen-2-yl)-2,3-dihydro-1H-inden-1-one(2k):72mg,99％ yield,new compound,white solid,mp141-142℃,94％ee,[α]20 D＝-76.35 (c1.40,CHCl3),Rf＝0.34(hexanes/ethyl acetate5/1).1HNMR(400MHz, CDCl3)δ7.78(d,J＝7.7Hz,1H),7.73-7.68(m,4H),7.65-7.60(m,2H), 7.47-7.39(m,3H),7.22-7.19(m,1H),5.33(s,1H),3.10(s,1H).13C NMR(100MHz,CDCl3)δ 207.1,153.0,140.1,135.7,134.7,133.3,132.3,129.6,128.5,128.1,127.5,126.2,126.0,125.8, 125.5,125.1,124.1,79.4,59.1,18.7.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time8.6min and11.0min(major). HRMS Calculated for C20H17O2[M+H]+289.1223,found:289.1223.
(-)-3-Hydroxy-2-methyl-2-phenylcyclopentan-1-one(2l):46mg,96％yield,new compound, colorless oil,91％ee,[α]20 D＝-37.86(c1.03,CHCl3),Rf＝0.50(hexanes/ethyl acetate2/1).1H NMR(400MHz,CDCl3)δ7.35-7.31(m,2H),7.26-7.21(m,3H),4.61(s,1H),2.56-2.52(m,1H), 2.38-2.29(m,1H),2.14-2.13(m,1H),2.07(br,1H),1.96-1.93(m,1H),1.37(s,3H).13C NMR
Figure BDA0002084323140000111
(100MHz,CDCl3)δ219.0,141.8,128.8,127.1,126.5,78.2,58.8,35.2,27.4,17.6. HPLC:Chiracel AS-H column,220nm,30℃,n-Hexane/i-Propanol＝95/5,flow ＝0.7mL/min,retention time31.1min and38.1min(major).HRMS Calculated for C12H15O2[M+H]+191.1067,found:191.1062.
Figure BDA0002084323140000112
(S)-(-)-1'-Hydroxyspiro[cyclopentane-1,2'-inden]-3'(1'H)-one(2m):The reaction conditions: substrate(0.25mmol),Pd(OCOCF3)2(5.0mol％),ligand(6.0mol％), trifluoroacetic acid(100mol％),H2(300psi),solvent(4.0mL),48h,70℃；34mg, 67％yield,(known compound7),colorless oil,61％ee,[α]20 D＝-27.50(c0.68, CHCl3),Rf＝0.40(hexanes/ethyl acetate5/1).1H NMR(400MHz,CDCl3)δ7.74-7.64(m,3H), 7.48-7.44(m,1H),4.95(s,1H),2.55(br,1H),2.03-1.98(m,2H),1.91-1.90(m,2H),1.89-1.78(m, 3H),1.76-1.74(m,1H).13C NMR(100MHz,CDCl3)δ208.9,153.5,135.7,135.3,129.6,126.0, 123.7,78.0,62.5,37.5,31.2,26.5,26.3.HPLC:ChiracelAS-H column,254nm,30℃, n-Hexane/i-Propanol＝85/15,flow＝0.8mL/min,retentiontime8.4min and10.1min(major).
Figure BDA0002084323140000113
(+)-Methyl-2-(-2,4-dioxo-2,3,4,8b-tetrahydro-3aH-indeno[1,2-b]furan-3a-yl)acetate(2n): The reaction conditions:substrate(0.25mmol),Pd(OCOCF3)2(5.0mol％), ligand(6.0mol％),trifluoroacetic acid(100mol％),H2(300psi),solvent(4.0 mL),48h,50℃；56mg,87％yield,new compound,colorless oil,91％ee, [α]20 D＝+34.19(c1.12,CHCl3),Rf＝0.33(hexanes/ethylacetate5/1).1H NMR(400MHz, CDCl3)δ7.86(d,J＝7.7Hz,1H),7.81-7.75(m,2H),7.64-7.60(m,1H),5.88(s,1H),3.65(s, 3H),3.09(dd,J＝43.6,17.5Hz,2H),2.70(q,J＝18.9Hz,2H).13C NMR(100MHz,CDCl3)δ 202.1,173.9,170.8,148.6,136.4,135.3,131.1,127.3,124.7,83.6,52.4,52.3,38.1,37.2.HPLC: Chiracel OD-H column,254nm,30℃,n-Hexane/i-Propanol＝70/30,flow＝0.6mL/min, retention time26.3min and33.1min(major).HRMS Calculated for C14H13O5[M+H]+261.0757, found:261.0753.
Figure BDA0002084323140000114
(+)-Methyl 3-(-2,5-dioxo-3,4,5,9b-tetrahydroindeno[1,2-b]pyran-4a(2H)-yl)propanoate (2o):The reaction conditions:substrate(0.25mmol),Pd(OCOCF3)2(5.0 mol％),ligand(6.0mol％),trifluoroacetic acid(100mol％),H2(300psi), solvent(4.0mL),42h,70℃；59mg,82％yield,new compound,colorless oil,84％ee,[α]20 D＝+80.16(c1.18,CHCl3),Rf＝0.51(hexanes/ethyl acetate5/1).1H NMR(400MHz,CDCl3)δ7.83-7.78(m,3H),7.62-7.58(m,1H),5.68(s,1H),3.65(s,3H),2.48-2.44(m,1H),2.37-2.28(m,3H),2.25-2.14(m,2H),1.97(td,J＝13.4,3.3Hz,1H), 1.84-1.80(m,1H).13C NMR(100MHz,CDCl3)δ205.5,173.0,171.2,150.1,136.9,136.5,131.1, 126.9,123.9,82.0,52.1,50.6,31.2,29.1,28.5,27.9.HPLC:Chiracel OD-H column,254nm,30 ℃,n-Hexane/i-Propanol＝70/30,flow＝0.6mL/min,retentiontime25.5min and33.3min (major).HRMS Calculated for C16H17O5[M+H]+289.1071,found:289.1070.
Figure BDA0002084323140000121
(-)-2-(3,5-Dimethoxyphenyl)-3-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one(2p):68mg, 91％yield,new compound,colorless oil,93％ee,[α]20 D＝-91.75(c1.08, CHCl3),Rf＝0.35(dichloromethane).1H NMR(400MHz,CDCl3)δ7.70 (d,J＝7.6Hz,1H),7.61(dd,J＝7.7,4.9Hz,2H),7.41(dd,J＝7.6,2.9Hz, 1H),6.33(d,J＝1.7Hz,2H),6.23(d,J＝1.4Hz,1H),5.23(s,1H),3.62(s, 6H),3.02(br,1H),1.37(s,3H).13C NMR(100MHz,CDCl3)δ206.7,161.0,153.2,145.4,135.8, 134.8,129.7,126.0,124.3,105.5,98.7,79.6,59.1,55.4,18.9.HPLC:Chiracel AS-H column,254 nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.7mL/min,retention time12.6min and17.1 min(major).HRMS Calculated for C18H19O4[M+H]+299.1278,found:299.1279.
Figure BDA0002084323140000122
(-)-3-Hydroxy-2-methyl-2-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-one(2q): 68mg,88％yield,new compound,colorless oil,dr.＝14:1,94％ee,[α]20 D＝ -89.89(c0.92,CHCl3),Rf＝0.40(dichloromethane).1H NMR(400MHz, CDCl3)δ7.86(d,J＝7.7Hz,1H),7.76(d,J＝5.0Hz,2H),7.61-7.54(m, 3H),7.47(d,J＝8.2Hz,2H),5.39(s,1H),2.39(s,1H),1.55(s,3H).13C NMR(100MHz,CDCl3) δ205.4,152.5,146.8,135.9,134.5,129.9,129.3(q,JC-F＝32.0Hz),127.2,125.6(q,JC-F＝4.0Hz),124.3,124.1(q,JC-F＝270.0Hz),58.8,19.1.19F NMR(376MHz,CDCl3)δ-62.59.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.7mL/min,retention time7.4min and8.0min(major).HRMS Calculated for C17H14F3O2[M+H]+307.0940, found:307.0943.
Figure BDA0002084323140000123
cis-3-Hydroxy-2-methyl-2-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-one(2q′): colorless oil,Rf＝0.50(dichloromethane).1HNMR(400MHz,CDCl3)δ 7.89(d,J＝7.7Hz,1H),7.80-7.71(m,2H),7.57(d,J＝8.0Hz,3H),7.33(d, J＝8.2Hz,2H),5.16(d,J＝7.4Hz,1H),1.74(s,3H),1.56(s,1H).13C NMR(100MHz,CDCl3)δ205.5,152.7,143.1,136.0,135.5,135.2,130.0,129.9(q,JC-F＝32.0 Hz),129.4(q,JC-F＝4.0Hz),128.6,126.4,125.4(q,JC-F＝4.0Hz),124.4,(q,JC-F＝40.0Hz), 124.0(q,JC-F＝279.0Hz),79.1,59.3,22.3.19F NMR(376MHz,CDCl3)δ-62.72.HRMS Calculatedfor C17H14F3O2[M+H]+307.0940,found:307.0931.
Figure BDA0002084323140000131
(-)-2-(3,5-Bis(trifluoromethyl)phenyl)-3-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (2r):colorless oil,conversion21％,dr.＝11:1,17mg,18％yield,new compound,98％ee,[α]20 D＝-78.51(c0.27,CHCl3),Rf＝0.50(dichloromethane).1H NMR(400MHz,CDCl3)δ7.89-7.87(m,3H),7.78(t, J＝8.0Hz,3H),7.61-7.57(m,1H),5.42(s,1H),2.41(s,1H),1.59(s,3H). 13C NMR(100MHz,CDCl3)δ204.5,152.3,145.6,136.4,134.3,132.2(q,JC-F＝33.0Hz),130.3, 127.5,126.1(q,JC-F＝281.0Hz),125.8,123.5(q,JC-F＝271.0Hz),121.4(q,JC-F＝4.0Hz),78.9, 58.8,20.3.19FNMR(376MHz,CDCl3)δ-62.75.HPLC:Chiracel AS-H column,254nm,30℃, n-Hexane/i-Propanol＝95/5,flow＝0.7mL/min,retention time8.4min and10.3min(major). HRMSCalculated for C18H13F6O2[M+H]+375.0814,found:375.0814.
Figure BDA0002084323140000132
cis-2-(3,5-Bis(trifluoromethyl)phenyl)-3-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (2r′):colorless oil,new compound,Rf＝0.55(dichloromethane).1H NMR (400MHz,CDCl3)δ7.89(d,J＝7.7Hz,1H),7.79(t,J＝7.3Hz,2H), 7.76-7.68(m,3H),7.60(t,J＝7.4Hz,1H),5.20(d,J＝6.0Hz,1H),1.79(d, J＝6.7Hz,1H),1.72(s,3H).13C NMR(100MHz,CDCl3)δ205.3,152.4, 142.0,136.6,135.1,131.6(q,JC-F＝33.0Hz),130.6,129.1(q,JC-F＝4.0Hz),126.8,123.5(q,JC-F＝270.0Hz),121.6(q,JC-F＝4.0Hz),121.5(q,JC-F＝4.0Hz),78.9,59.4,23.5.19F NMR(376 MHz,CDCl3)δ-62.75.HRMS Calculated for C18H13F6O2[M+H]+375.0814,found:375.0811.
Figure BDA0002084323140000133
(2R,3R)-(-)-3-Hydroxy-2-phenyl-2,3-dihydro-1H-inden-1-one(4a):51mg,90％yield,new compound,white solid,mp124-125℃,98％ee,[α]20 D＝-42.82(c0.78, CHCl3),Rf＝0.23(dichloromethane).1H NMR(400MHz,CDCl3)δ7.76(d,J ＝7.7Hz,1H),7.73-7.69(m,2H),7.53-7.48(m,1H),7.33-7.24(m,3H), 7.13-7.11(m,2H),5.24(d,J＝3.9Hz,1H),3.66(d,J＝4.1Hz,1H),3.28(br,1H).13C NMR (100MHz,CDCl3)δ202.4,153.3,137.2,135.7,135.6,129.6,128.9,128.6,127.5,125.6,123.7, 77.0,64.9.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time9.0min and19.5min(major).HRMS Calculated for C15H13O2[M+H]+225.0910,found:225.0911.
Figure BDA0002084323140000141
(2R,3R)-(-)-3-Hydroxy-2-o-tolyl-2,3-dihydro-1H-inden-1-one(4b):57mg,97％yield,new compound,white solid,mp100-101℃,96％ee,[α]20 D＝-51.70(c1.23, CHCl3),Rf＝0.37(dichloromethane).1H NMR(400MHz,CDCl3)δ7.79(d,J ＝7.7Hz,1H),7.71(d,J＝3.8Hz,2H),7.55-7.50(m,1H),7.20-7.02(m,3H), 6.90(d,J＝7.3Hz,1H),5.27(s,1H),3.94(d,J＝4.0Hz,1H),2.98(s,1H),2.28(s,3H).13C NMR(100MHz,CDCl3)δ202.8,153.4,137.3,136.2,136.1,135.6,131.0,129.8,128.9,127.7, 126.6,125.7,123.8,77.2,62.9,20.4.HPLC:Chiracel AS-H column,254nm,30℃, n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time7.1min and16.6min(major). HRMSCalculated for C16H15O2[M+H]+239.1067,found:239.1065.
Figure BDA0002084323140000142
(2R,3R)-(-)-3-Hydroxy-2-m-tolyl-2,3-dihydro-1H-inden-1-one(4c):54mg,91％yield,new compound,colorless oil,96％ee,[α]20 D＝-18.21(c1.23,CHCl3),Rf＝0.32 (dichloromethane).1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.7Hz,1H), 7.73-7.72(m,2H),7.54-7.50(m,1H),7.22(dd,J＝14.4,6.8Hz,1H),7.09(d, J＝7.6Hz,1H),6.97-6.93(m,2H),5.30(s,1H),3.71-3.64(m,1H),2.95(s,1H),2.31(s,3H).13CNMR(100MHz,CDCl3)δ202.3,153.3,138.6,137.1,135.8,135.5,129.6,129.3,128.9,128.3, 125.6,125.5,123.7,77.2,65.0,21.4.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time8.0min and17.3min(major). HRMS Calculated for C16H15O2[M+H]+239.1067,found:239.1069.
Figure BDA0002084323140000143
(2R,3R)-(-)-3-Hydroxy-2-p-tolyl-2,3-dihydro-1H-inden-1-one(4d):58mg,97％yield,new compound,colorless oil,89％ee,[α]20 D＝-5.74(c1.48,CHCl3),Rf＝0.30 (dichloromethane).1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.7Hz,1H), 7.73-7.69(m,2H),7.53-7.48(m,1H),7.13-7.11(m,2H),7.03-7.01(m, 2H),5.25-5.24(m,1H),3.65-3.64(m,1H),3.14(br,1H),2.31(s,3H).13C NMR(100MHz, CDCl3)δ202.4,153.3,137.1,135.7,135.5,134.1,129.63,129.55,128.4,125.5,123.6,77.1,64.7, 21.1.HPLC:Chiracel AS-H column,220nm,30℃,n-Hexane/i-Propanol＝85/15,flow＝0.8 mL/min,retention time13.1min and27.6min(major).HRMS Calculated forC16H15O2[M+H]+ 239.1067,found:239.1064.
Figure BDA0002084323140000144
(2R,3R)-(-)-3-Hydroxy-2-(2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-one(4e):59mg, 95％yield,new compound,white solid,mp155-156℃,95％ee,[α]20 D＝ -133.98(c1.33,CHCl3),Rf＝0.36(dichloromethane).1H NMR(400MHz, CDCl3)δ7.73(d,J＝7.7Hz,1H),7.70-7.64(m,2H),7.52-7.46(m,1H),7.05-7.02(m,2H), 6.94-6.92(m,1H),5.02(d,J＝4.1Hz,1H),4.08(d,J＝4.4Hz,1H),3.75(br,1H),2.43(s,3H), 1.73(s,3H).13C NMR(100MHz,CDCl3)δ202.1,152.6,138.5,136.3,135.7,135.3,134.3, 129.5,129.4,128.3,127.4,125.3,123.5,76.2,60.8,21.5,21.0.HPLC:Chiracel AS-H column, 254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time6.0min and14.0 min(major).HRMS Calculated for C17H17O2[M+H]+253.1223,found:253.1221.
Figure BDA0002084323140000151
(2R,3R)-(-)-3-Hydroxy-2-(2-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(4f):59mg,94％ yield,new compound,white solid,mp121-122℃,96％ee,[α]20 D＝-127.32(c 1.65,CHCl3),Rf＝0.29(dichloro-methane).1H NMR(400MHz,CDCl3)δ 7.80(d,J＝7.7Hz,1H),7.71-7.67(m,2H),7.51-7.47(m,1H),7.31-7.27(m, 1H),7.19-7.17(m,1H),6.97-6.93(m,1H),6.88-6.86(m,1H),5.31(s,1H),3.67(d,J＝4.1Hz,1H),3.61(s,3H),3.19(br,1H).13C NMR(100MHz,CDCl3)δ202.4,157.3,153.1,136.1,135.2, 131.5,129.3,129.1,126.4,125.6,123.5,121.2,111.3,76.2,62.4,55.6.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time9.0min and27.8min(major).HRMS Calculated for C16H15O3[M+H]+255.1016,found:255.1013.
Figure BDA0002084323140000152
(2R,3R)-(-)-3-Hydroxy-2-(3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(4g):58mg,91％ yield,new compound,white solid,mp156-157℃,97％ee,[α]20 D＝-21.87 (c0.80,CHCl3),Rf＝0.40(dichloro-methane).1H NMR(400MHz,CDCl3) δ7.81(d,J＝7.7Hz,1H),7.77-7.71(m,2H),7.56-7.51(m,1H),7.28-7.24(m,1H),6.85-6.82(m,1H),6.77-6.72(m,2H),5.34(d,J＝4.0Hz,1H),3.77(s,3H),3.71(d,J＝ 4.1Hz,1H),2.82(br,1H).13C NMR(100MHz,CDCl3)δ201.8,160.0,153.1,138.6,135.8,135.6,130.0,129.7,125.5,123.7,120.8,114.4,112.9,77.1,65.0,55.2.HPLC:ChiracelAS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retentiontime12.5 min and26.5min(major).HRMS Calculated for C16H15O3[M+H]+255.1016,found:255.1015.
Figure BDA0002084323140000153
(2R,3R)-(-)-3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one(4h):57mg,90％ yield,new compound,colorless oil,93％ee,[α]20 D＝-4.00(c0.80,CHCl3), Rf＝0.30(dich-loromethane).1H NMR(400MHz,CDCl3)δ7.77(d,J＝ 7.7Hz,1H),7.71-7.70(m,2H),7.52-7.48(m,1H),7.08-7.05(m,2H), 6.86-6.84(m,2H),5.28-5.24(m,1H),3.76(s,3H),3.64-3.62(m,1H),3.20(s,1H).13C NMR(100MHz,CDCl3)δ202.5,158.9,153.2,135.7,135.5,131.4,129.61,129.55,129.2,125.5,123.6, 114.4,77.1,64.3,55.3.HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝ 80/20,flow＝0.9mL/min,retention time17.1min and26.4min(major).HRMSCalculated for C16H15O3[M+H]+255.1016,found:255.1014.
Figure BDA0002084323140000161
(2R,3R)-(-)-3-Hydroxy-2-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-one(4i):The reaction was run at0℃for24h,58mg,96％yield,new compound,white solid,mp 59-60℃,93％ee,[α]20 D＝-68.30(c1.00,CHCl3),Rf＝0.30(dichlorome-thane).1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.7Hz,1H),7.75-7.73(m, 2H),7.55-7.52(m,1H),7.31-7.29(m,1H),7.21(td,J＝7.5,1.8Hz,1H),7.15-7.01(m,2H),5.37 (t,J＝4.5Hz,1H),3.84(d,J＝4.3Hz,1H),2.83(d,J＝5.8Hz,1H).13C NMR(100MHz,CDCl3) δ200.9,161.0(d,JC-F＝246.2Hz),152.9,135.6,131.4,129.6,129.5(d,J＝8.2Hz),125.4,124.6, 124.5,123.7,115.8(d,JC-F＝21.4Hz),76.3(d,JC-F＝1.8Hz),60.6.19F NMR(376MHz,CDCl3) δ-115.56(s).HPLC:Chiracel AS-H column,254nm,30℃,n-Hexane/i-Propanol＝80/20,flow ＝0.9mL/min,retention time8.5min and23.1min(major).HRMSCalculated for C15H12FO2 [M+H]+243.0816,found:243.0815.
Figure BDA0002084323140000162
(2R,3R)-(-)-3-Hydroxy-2-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-one(4j):Thereaction was run at0℃for24h,55mg,91％yield,newcompound,colorless oil, 92％ee,[α]20 D＝-36.53(c0.98,CHCl3),Rf＝0.33(dichloromethane).1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.7Hz,1H),7.74(d,J＝3.7Hz,2H), 7.58-7.49(m,1H),7.18-7.15(m,2H),7.06-7.02(m,2H),5.30(s1H),3.74(d,J＝4.2Hz,1H), 2.82(d,J＝5.5Hz,1H).13C NMR(100MHz,CDCl3)δ201.6,162.2(d,J＝244Hz),152.9, 135.7(d,JC-F＝7Hz),132.9,130.2,130.1,129.8,125.5,123.8,115.9(d,JC-F＝21Hz),77.1,64.2. 19F NMR(376MHz,CDCl3)δ-114.97(s).HPLC:Chiracel AS-H column,254nm,30℃, n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time9.3minand17.2min(major). HRMS Calculated for C15H12FO2[M+H]+243.0816,found:243.0814.
(2R,3R)-(-)-3-Hydroxy-2-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-one(4k):56mg,86％ yield,new compound,colorless oil,94％ee,[α]20 D＝-15.81(c0.93,CHCl3),Rf＝0.20(dichloro- methane).1H NMR(400MHz,CDCl3)δ7.80-7.73(m,3H),7.56-7.52(m,1H),7.31(d,J＝8.4 Hz,2H),7.12(d,J＝8.4Hz,2H),5.29(s,1H),3.72(d,J＝4.2Hz,1H),2.92(br,1H).13C NMR (100MHz,CDCl3)δ201.7,153.2,136.0,135.73,135.70,133.6,130.1,130.0,129.3,125.7,124.0, 77.1,64.4.HPLC:Chiracel AS-H column,220nm,30℃,n-Hexane/i-Propanol＝80/20,flow＝
Figure BDA0002084323140000171
0.8mL/min,retention time10.8min and18.5min(major).HRMS Calculated for C15H12ClO2[M+H]+259.0520,found:259.0518.
Figure BDA0002084323140000172
(2R,3R)-(+)-3-Hydroxy-2-(naphthalen-2-yl)-2,3-dihydro-1H-inden-1-one(4l):64mg,93％ yield,new compound,white solid,mp 85-86℃,96％ee,[α]20 D＝+14.89(c 1.35,CHCl3),Rf＝0.38(dichloro-methane).1H NMR(400MHz,CDCl3)δ 7.85-7.69(m,7H),7.57-7.53(m,1H),7.48-7.46(m,2H),7.23-7.20(m,1H), 5.42(d,J＝3.6Hz,1H),3.90(d,J＝4.1Hz,1H),2.82(br,1H).13C NMR(100MHz,CDCl3)δ 202.1,153.1,135.8,135.7,134.5,133.5,132.7,129.7,128.9,127.9,127.8,127.7,126.4,126.1, 126.0,125.6,123.8,77.1,65.2.HPLC:Chiracel AS-H column,254nm,30℃, n-Hexane/i-Propanol＝80/20,flow＝0.9mL/min,retention time11.6minand27.6min(major). HRMS Calculated for C19H15O2[M+H]+275.1067,found:275.1068.
Figure BDA0002084323140000173
(2R,3S)-(+)-3-Hydroxy-2-methyl-2-phenyl-2,3-dihydro-1H-phenalen-1-one(6a):27mg, 93％yield,new compound,white solid,mp157-158℃,dr＝13.8:1,95％ee, [α]20 D＝+88.76(c0.73,CHCl3),Rf＝0.24(dichloromethane).1H NMR(400MHz, CDCl3)δ8.28(dd,J＝7.2,1.0Hz,1H),8.03(d,J＝8.2Hz,1H),7.81(d,J＝8.3 Hz,1H),7.74(d,J＝6.9Hz,1H),7.62-7.58(m,1H),7.54-7.51(m,1H),7.22-7.20(m,2H),7.17-7.14(m,2H),7.11-7.09(m,1H),5.62(d,J＝6.1Hz,1H),1.93-1.92(br,1H),1.72(s,3H). 13C NMR(100MHz,CDCl3)δ200.1,141.4,134.5,133.8,133.2,129.1,128.9,128.5,128.1, 127.0,126.9,126.6,126.5,126.3,126.2,77.0,57.7,21.5.HPLC:Chiracel OD-Hcolumn,220nm, 30℃,n-Hexane/i-Propanol＝95/5,flow＝0.6mL/min,retentiontime50.3min(major)and54.3 min.HRMS Calculated for C20H17O2[M+H]+289.1223,found:289.1227.
Figure BDA0002084323140000174
(cis)-3-Hydroxy-2-methyl-2-phenyl-2,3-dihydro-1H-phenalen-1-one(6a’):Rf＝0.28(di- chloromethane).1H NMR(400MHz,CDCl3)δ8.28(dd,J＝7.2,0.9Hz,1H), 8.05(d,J＝8.1Hz,1H),7.83-7.81(m,2H),7.60-7.55(m,2H),7.39-7.37(m,2H), 7.18-7.09(m,3H),5.16(d,J＝5.8Hz,1H),2.56(d,J＝5.7Hz,1H),1.76(s,3H). 13CNMR(100MHz,CDCl3)δ199.3,139.4,135.0,134.0,132.9,128.9,128.7,128.3,128.2,127.6,127.1,127.0,126.6,126.2,125.1,77.0,57.4,22.8.HRMS Calculated for C20H17O2[M+H]+289.1223,found:289.1227.
(+)-3-Hydroxy-2-methyl-2-(m-tolyl)-2,3-dihydro-1H-phenalen-1-one(6b):20mg,67％
Figure BDA0002084323140000181
yield,new compound,white solid,mp165-166℃,dr＝13.8:1,96％ee, [α]20 D＝+84.82(c0.58,CHCl3),Rf＝0.31(dichloromethane).1H NMR (400MHz,CDCl3)δ8.27(d,J＝7.1Hz,1H),8.01(d,J＝8.1Hz,1H),7.80 (d,J＝8.2Hz,1H),7.73(d,J＝6.9Hz,1H),7.60-7.56(m,1H),7.54-7.49(m,1H),7.06-6.99(m, 3H),6.90(d,J＝7.0Hz,1H),5.60(s,1H),2.20(s,3H),1.98(br,1H),1.69(s,3H).13C NMR (100MHz,CDCl3)δ200.2,141.3,138.0,134.6,133.7,133.2,129.1,128.9,128.3,128.0,127.8, 127.7,126.6,126.5,126.2,126.1,123.9,76.9,57.6,21.6,21.3.HPLC:Chiracel OD-H column, 220nm,30℃,n-Hexane/i-Propanol＝95/5,flow＝0.6mL/min,retention time40.8min(major)and45.7min.HRMS Calculated for C21H19O2[M+H]+303.1380,found:303.1381.
Figure BDA0002084323140000182
(+)-3-Hydroxy-2-methyl-2-(p-tolyl)-2,3-dihydro-1H-phenalen-1-one(6c):24mg,80％yield, new compound,white solid,mp 65-67℃,dr＝14.5:1,95％ee,[α]20 D＝ +64.35(c0.58,CHCl3),Rf＝0.26(dichloromethane).1H NMR(400MHz, CDCl3)δ8.27(d,J＝7.1Hz,1H),8.02(d,J＝8.1Hz,1H),7.81(d,J＝8.3 Hz,1H),7.73(d,J＝6.9Hz,1H),7.61-7.57(m,1H),7.55-7.51(m,1H),7.11-7.09(m,2H), 6.97-6.95(m,2H),5.59(s,1H),2.18(s,3H),2.02(br,1H),1.71(s,3H).13C NMR(100MHz, CDCl3)δ200.2,138.4,136.6,134.6,133.7,133.1,129.2,129.1,129.0,128.0,126.7,126.6,126.5, 126.2,77.0,57.3,21.5,20.9.HPLC:Chiracel OD-H column,220nm,30℃,n-Hexane/i-Propanol ＝97/3,flow＝0.6mL/min,retention time78.7min(major)and86.1min.HRMS Calculated for C21H19O2[M+H]+303.1380,found:303.1383.
Figure BDA0002084323140000183
(+)-3-Hydroxy-2-methyl-2-(naphthalen-2-yl)-2,3-dihydro-1H-phenalen-1-one(6d):18mg, 53％yield,new compound,white solid,mp188-189℃,97％ee,[α]20 D＝ +58.00(c0.45,CHCl3),Rf＝0.22(dichloromethane).1H NMR(400MHz, CDCl3)δ8.33(d,J＝7.0Hz,1H),8.04-8.02(m,1H),7.82-7.80(m,2H), 7.71-7.59(m,5H),7.56-7.52(m,1H),7.40-7.38(m,3H),5.76(s,1H),1.99(br,1H),1.82(s,3H).13C NMR(100MHz,CDCl3)δ200.1,138.8,134.5,133.9,133.2,133.1,132.2,129.1,128.9,128.3,128.1,128.0,127.4,126.7,126.6,126.3,126.2.126.1,126.04,126.03,125.0,76.8,57.9, 21.1.HPLC:Chiracel IC column,220nm,30℃,n-Hexane/i-Propanol＝90/10,flow＝0.7 mL/min,retention time39.6min(major)and46.9min.HRMS Calculatedfor C24H19O2[M+H]+ 339.1380,found:339.1378.
(2R,3R)-(+)-3-Hydroxy-1,2,3-triphenylpropan-1-one(8a):51mg,85％yield,the known compound6,white solid,mp119-120℃,93％ee,[α]20 D＝+220.68(c1.30,CHCl3),Rf＝0.50
Figure BDA0002084323140000191
(dichloromethane).1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.7Hz,2H), 7.48-7.45(m,1H),7.36-7.32(m,2H),7.26-7.18(m,10H),5.54(d,J＝5.1Hz, 1H),4.82(d,J＝5.3Hz,1H),3.36(br,1H).13C NMR(100MHz,CDCl3)δ 201.4,142.1,137.1,135.0,134.1,130.6,129.6,129.44,129.38,128.9,128.5, 128.4,127.5,75.5,61.7.HPLC:Chiracel OD-H column,230nm,30℃,n-Hexane/i-Propanol＝ 90/10,flow＝0.7mL/min,retention time12.9min(major)and20.4min.
Figure BDA0002084323140000192
(2R,3R)-(+)-3-Hydroxy-1,3-diphenyl-2-(p-tolyl)propan-1-one(8b):57mg,90％yield,new compound,white solid,mp89-90℃,94％ee,[α]20 D＝+235.84(c1.40, CHCl3),Rf＝0.54(dichloro-methane).1H NMR(400MHz,CDCl3)δ7.83(d, J＝7.4Hz,2H),7.43(t,J＝7.4Hz,1H),7.33-7.29(m,2H),7.25-7.19(m, 5H),7.11-7.05(m,4H),5.49(d,J＝5.6Hz,1H),4.78(d,J＝5.6Hz,1H), 3.26(s,1H),2.28(s,3H).13C NMR(100MHz,CDCl3)δ189.0,137.4,136.7,133.7,132.6,130.4, 129.3,129.0,127.8,113.9,21.4.HPLC:Chiracel OD-H column,230nm,30℃, n-Hexane/i-Propanol＝90/10,flow＝0.7mL/min,retention time10.8min(major)and14.1min. HRMS Calculated forC22H20NaO2[M+Na]+339.1356,found:339.1359。

Claims (7)

1.一种钯催化1,3-二酮不对称氢化合成β-羟基酮的方法，其特征在于，所述方法的催化体系为钯的手性双膦P-P*配合物，所述方法的反应路线式Ⅰ和式Ⅱ，如下所述：
式Ⅰ
Figure FDA0003233099700000011
式Ⅱ
Figure FDA0003233099700000012
式中：
R为H，C1-C2的烷基；Ar为含有一个或多个取代基的芳基；所述取代基为C1-C5的烷基，卤素，甲氧基；
所述方法原料还包括酸添加剂，所述酸添加剂为乙酸，三氟乙酸，苯甲酸，五氟苯甲酸，酒石酸；
手性双膦配体选自(R)-DTBM-SegPhos或(S)-SegPhos或(S)-MeO-Biphep或(R)-BTFM-GarPhos或(S)-SynPhos或(R)-BINAP或(Rax,S,S)-C3-TunePhos或(R)-DifluorPhos。
2.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)催化剂制备：将钯金属前体和手性双膦配体加入丙酮后反应0.5-2小时，随后减压除掉丙酮，得到所述钯的手性双膦P-P*配合物催化剂；
(2)氢化反应：将步骤(1)所述催化剂、酸添加剂、有机溶剂加入1,3-二酮底物中，通入氢气反应得到所述手性β-羟基酮。
3.如权利要求2所述的方法，其特征在于：所述步骤(2)中，反应压力为100-800psi，反应温度为-10-80℃，反应时间为12-150h；所述步骤(2)中，底物的浓度为0.025-0.5mmol/mL。
4.如权利要求2所述的方法，其特征在于：钯的金属前体、手性双膦配体、酸添加剂、底物摩尔比为：0.01-0.05:0.01-0.12:0.1-1.0:1。
5.如权利要求2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、三氟乙醇、六氟异丙醇中的一种。
6.如权利要求2所述的方法，其特征在于：所述钯金属前体为氯化钯、醋酸钯或三氟醋酸钯。
7.如权利要求1所述的方法，所述手性双膦配体为(S)-SegPhos、(S)-MeO-Biphep或(S)-SynPhos。
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"Desymmetrization of cyclic 1,3-diketones via Ir-catalyzed hydrogenation: an efficient approach to cyclic hydroxy ketones with a chiral quaternary carbon";Quan Gong，et al.;《Chem. Sci.》;20190521;第10卷;6350-6353 *
"New Chiral Diphosphine Ligands Designed to Have a Narrow Dihedral Angle in the Biaryl Backbone";Takao Saito,et al.;《Adv. Synth. Catal.》;2001;第343卷(第5期);264-267 *
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