CN115991694B - 一种手性砜类化合物及其制备方法与应用 - Google Patents
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Abstract
一种手性砜类化合物及其制备方法与应用。所述化合物具有如下结构：R1、R2、R3和R4独立选自氢、C1～C10的烷基或含有取代基的C3～C10芳基、C3～C10杂芳基中的一种。制备方法为将含有底物、氢源和催化剂的原料与溶剂混合，反应，得到所述手性化合物，ee值大于90％；所述催化剂为[Ru(p‑甲基异丙苯)I2]2或Pd/C或Fe3(CO)12。所述氢源为环芳烷骨架手性可再生NAD(P)H模拟物CYNAM，不需要额外添加路易斯酸、布朗斯特酸以及脲等转移催化剂，反应活性高，原子经济性好，对映选择性及非对映选择性好，底物适用范围广，具有潜在的应用价值。
Description
技术领域
本申请属于有机合成领域，具体涉及一种手性化合物及其制备方法与应用。
背景技术
仿生科学是一门古老又年轻的学科，主要是研究生物体的结构和工作原理。根据这些原理发展出新的技术和设备，改善了人们的生活水平和生活质量。在生物体中，烟酰胺腺嘌呤二核苷酸(NADH)和烟酰胺腺嘌呤二核苷酸磷酸(NADPH)是一类非常重要的辅酶，在传递质子和电子方面起着至关重要的作用。其过程主要依赖于还原型NAD(P)H与氧化型NAD(P)+之间的相互转化。因此，基于辅酶NAD(P)H的仿生不对称还原长期以来引起了科学家的广泛兴趣。到目前为止，仿生不对称还原已经成为不对称氢化领域中重要的组成部分，科学家们仿生模拟辅酶参与的生物体转化过程，发展了不同类型的NAD(P)H模拟物。烟酰胺衍生物或者菲啶作为非手性NAD(P)H模拟物的代表，需要添加额外的手性试剂(文献：a)Xu,H.J.；Liu,Y.C.；Fu,Y.；Wu,Y.D.Org.Lett.2006,8,3449；b)Chen,Q.-A.；Chen,M.-W.；Yu,C.-B.；Shi,L.；Wang,D.-S.；Yang,Y.；Zhou,Y.-G.J.Am.Chem.Soc.2011,133,16432；c)Chen,Q-A.；Gao,K.；Duan,Y.；Ye,Z.-S.；Shi,L.；Yang Y.；Zhou,Y.-G.J.Am.Chem.Soc.2012,134,2442.)。因此，基于二茂铁骨架以及环芳烷骨架的手性可再生NAD(P)H模拟物被设计合成，并且实现了亚胺、含氮芳香杂环化合物以及缺电子四取代烯烃的仿生不对称还原(文献：a)Zhu,Z.-H.；Ding,Y.-X.；Wu,B.；Zhou,Y.-G.Chem.Sci.2020,11,10220；(b)Zhu,Z.-H.；Ding,Y.-X.；Zhou,Y.-G.Tetrahedron 2021,83,131968；(c)Wang,J.；Zhu,Z.-H.；Chen,M.-W.；Chen,Q.-A.；Zhou,Y.-G.Angew.Chem.Int.Ed.2019,58,1813；(d)Wang,J.；Zhao,Z.-B.；Zhao,Y.；Luo,G.；Zhu,Z.-H.；Luo,Y.；Zhou,Y.-G.J.Org.Chem.2020,85,2355；(e)Zhao,Z.-B.；Li,X.；Chen,M.-W.；Zhao,Z.K.；Zhou,Y.-G.Chem.Commun.2020,56,7309.)。另外，磺酰基在功能材料、药物和农用化学品中十分常见。例如，氨苯砜(用于治疗麻风病)，他唑巴坦(抗生素)和CX157(抗抑郁药)等药物均有磺酰基团。含有磺酰基的砜类化合物还参与许多合成转化，是有机合成中的通用中间体。因此，开发用于合成手性砜类化合物的有效方法是有机合成的挑战。
发明内容
基于上述背景，我们通过合理的底物设计，使用基于环芳烷骨架手性可再生NAD(P)H模拟物的仿生不对称还原体系对含有磺酰基的3,4-二取代香豆素进行不对称还原来构建两个连续立体中心。该反应为简洁、高效和快速地构建含有两个连续手性中心的砜类化合物提供了新的方法。
本申请的目的是提供一种通过对3,4-二取代香豆素的仿生不对称还原合成含有两个连续立体中心的砜类化合物方法。为实现上述目的，本申请采用的技术方案如下：
根据本申请的一个方面，提供一种手性砜类化合物，具有式I所示的结构；
式中“*”所标出的碳为手性中心；
所述R1、R2、R3和R4独立选自氢、C1～C10的烷基或含有取代基的C3～C10芳基、C3～C10杂芳基中的一种。
所述取代基选自C1～C10的烷氧基、C1～C10的烷基、卤素中的至少一种；
所述C1～C10的烷基选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基的同分异构体中的一种；
所述的芳基选自单环芳基、双环芳基、或三环芳基中的一种。
所述杂芳基选自单环杂芳基、双环杂芳基中的一种。
所述的杂芳基包含5至10个骨架成环原子，其中至少1个成环原子为杂原子，所述杂原子选自N、S或O中的至少一种；
可选地，所述杂芳基为含1～4个氮原子的5元单环、6元单环或包含所述5元单环或6元单环的稠环；
可选地，所述杂芳基为含1～2个氧原子的5元单环或6元单环或包含所述5元单环或6元单环的稠环；
可选地，所述杂芳基为含1～2个硫原子的5元环或6元环或包含所述5元单环或6元单环的稠环；
可选地，所述杂芳基选自吡啶基、吡咯基、呋喃基、噻吩基中的一种。
所述手性化合物的ee值大于90％。
根据本申请的另一个方面，提供一种上述的手性化合物的制备方法，包括以下步骤：将含有底物、氢源和催化剂的原料与溶剂混合，反应，得到所述手性化合物。
进一步地，所述混合过程为将底物与含有氢源和催化剂的原料混合，再加入溶剂。
进一步地的，所述方法包括如下步骤：(1)在空气下，向安培瓶中加入催化剂、氢源和底物；(2)将安培瓶转移至手套箱中，加入有机溶剂，放置于高压反应釜中，移出手套箱，充入高纯氢气；(3)将高压反应釜置于50～110℃的油浴或者金属砂浴中，搅拌反应22～28小时；(4)除去有机溶剂，柱层析分离，得到所述手性化合物。
所述底物具有式II所述的结构；
所述底物、氢源与催化剂的摩尔比为1:(0.05～0.1):(0.005～0.04)；
所述底物的摩尔量与溶剂的体积比为0.01mol/L～0.20mol/L。
所述氢源具有式III所示的结构；即为环芳烷骨架手性可再生NAD(P)H模拟物CYNAM；
所述R5和R6选自氢、氟原子、甲基或甲氧基中的至少一种。
所述催化剂选自[Ru(p-甲基异丙苯)I2]2或Pd/C或Fe3(CO)12中的至少一种。
所述溶剂选自二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳、甲苯、氯苯、三氟甲苯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、乙酸乙酯、甲醇、乙腈和二甲亚砜中的至少一种。
所述反应气氛为氢气气氛；所述氢气气氛的压力为500～1200psi。
根据本申请的另一个方面，提供一种上述的手性化合物或上述的方法制备的手性化合物的应用，其特征在于，所述手性砜类化合物用于烯丙基烷基化反应或直链手性砜的合成反应。
本申请的有益效果为：
1、对映选择性高，产率好，能高对映选择性地得到单一的手性产物。
2、反应操作简便实用
具体实施方式
下面通过实施例详述本申请，但本申请并不限于下述的实施例。
本申请所述的催化剂为为市售且无需任何处理。
氢气为市售且无需任何处理。
有机溶剂为市售且无需任何处理。
氢源参照文献方法合成(Zhu,Z.-H.；Ding,Y.-X.；Wu,B.；Zhou,Y.-G.Chem.Sci.2020,11,10220)。
底物参照文献方法合成(Ren,H.；Zhang,M；Zhang,A.Q.Tetrahedron2018,74,4435；Kanyiva,K.S.；Hamada,D.；Makino,S.；Takano,H.；Shibata,T.Eur.J.Org.Chem.2018,43,5905.)。
本申请的实施例中分析方法如下：
通过1H NMR测定非对映选择性和转化率，具体过程如下：
将反应体系溶剂减压蒸馏除去，随后加入0.5毫升的氘代氯仿，转移至核磁样品管中在BRUKER DRX 400MHz核磁共振波谱仪中进行核磁氢谱的测试。
用直径0.5mm的毛细管取少量产物溶解在异丙醇中，使用进样针抽取5微升产物的异丙醇溶液至Agilent Technologies 1260Infinity II高效液相色谱仪中进行测试。
对映体过量用手性液相色谱测定。
本申请的实施例中转化率、非对映选择性计算如下：
转化率为核磁氢谱中产物单氢特征峰峰面积除以原料单氢特征峰峰面积的比值。
非对映选择性为核磁氢谱中反式和顺式产物单氢特征峰峰面积的比值。
实施例1～21
空气下，向装有0.15mmol底物的安培瓶瓶中投入[Ru(p-甲基异丙苯)I2]2(底物用量的1.5mol％)和CYNAM 3d(底物用量的10mol％)，转移至手套箱中，加入3mL三氟甲苯，装入高压反应釜中，充入800psi氢气，于90摄氏度下搅拌反应28小时。然后，停止反应，减压除去有机溶剂，柱层析分离得到纯的产物。
其中1a、1b、1c、1d、1e、1f、1g、1h、1i、1j、1k、1l、1m、1n、1o、1p、1q、1r、1s、1t、1u为实施例1～21的底物。
2a、2b、2c、2d、2e、2f、2g、2h、2i、2j、2k、2l、2m、2n、2o、2p、2q、2r、2s、2t、2u为实施例1～21的产物，其中2u包括顺反异构体，无法相互分离。
氢源CYNAM 3d的结构如下：
其产率为分离收率，通过1H NMR测定非对映选择性，产物的对映体过量用手性液相色谱测定。
(+)-4-苯基-3-对甲苯磺酰基色满-2-酮(2a):
56毫克,99％收率,无色液体,Rf＝0.51(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+160.08(c 1.12,CHCl3),1H NMR(400MHz,CDCl3)δ7.71-7.64(m,2H),7.35-7.26(m,7H),7.21-7.16(m,1H),7.09-7.04(m,2H),7.00-6.94(m,1H),5.17(s,1H),4.41(s,1H),2.43(s,3H).13C NMR(100MHz,CDCl3)δ159.9,150.9,146.0,139.4,133.9,129.9,129.6,129.4,129.2,129.1,128.2,127.1,125.7,120.9,116.9,72.1,42.3,21.8.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝7.4min(minor)and 10.5min(major).HRMS(ESI)m/z:[M+NH4]+Calcd forC22H22NO4S 396.1264,found:396.1265.
(+)-4-苯基-3-苯磺酰基色满-2-酮(2b):
54毫克,99％收率,无色液体,Rf＝0.51(hexanes/ethyl acetate 5/1),d.r.＝32:1,98％ee,[α]20 D＝+145.18(c 1.08,CHCl3),1H NMR(400MHz,CDCl3)δ7.96-7.92(m,0.06H),7.83-7.76(m,1.94H),7.67-7.61(m,1H),7.53-7.46(m,2H),7.34-7.24(m,5H),7.23-7.16(m,1H),7.16-7.13(m,0.06H),7.09-7.05(m,1.94H),7.03-6.88(m,1H),5.19(s,0.97H),5.15(d,J＝6.0Hz,0.03H),4.66(d,J＝5.9Hz,0.03H),4.45(d,J＝0.6Hz,0.97H).13C NMR(100MHz,CDCl3)δ159.8,150.9,139.3,136.9,134.7,129.7,129.6,129.3,129.2,129.1,128.2,127.1,125.8,120.8,117.0,72.0,42.2.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝6.9min(minor)and11.4min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C21H20NO4S 385.1108,found:382.1108.
(+)-3-((4-甲氧基苯基)磺酰基)-4-苯基苯并二氢吡喃-2-酮(2c):
58毫克,98％收率,无色液体,Rf＝0.37(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+161.71(c 1.16,CHCl3),1H NMR(400MHz,CDCl3)δ7.75-7.62(m,2H),7.33-7.24(m,5H),7.20-7.15(m,1H),7.09-7.04(m,2H),6.99-6.94(m,1H),6.93-6.88(m,2H),5.16(s,1H),4.42(d,J＝0.5Hz,1H),3.87(s,3H).13C NMR(100MHz,CDCl3)δ164.5,160.1,150.8,139.5,131.3,129.6,129.5,129.2,128.1,128.1,127.1,125.7,121.0,116.9,114.5,72.2,55.8,42.4.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝9.0min(minor)and 13.7min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C22H22NO5S 412.1213,found:412.1213.
(+)-3-((4-氟苯基)磺酰基)-4-苯基苯并二氢吡喃-2-酮(2d):
57毫克,99％收率,淡黄色固体,熔点＝86-87℃,Rf＝0.52(hexanes/ethylacetate 5/1),d.r.＝32:1,98％ee,[α]20 D＝+131.83(c 1.14,CHCl3),1H NMR(400MHz,CDCl3)δ7.91-7.86(m,0.06H),7.84-7.73(m,1.94H),7.35-7.25(m,5H),7.23-7.18(m,1H),7.14(t,J＝8.5Hz,2H),7.07(d,J＝7.1Hz,2H),6.97(d,J＝8.2Hz,1H),5.19(s,0.97H),5.11(d,J＝6.0Hz,0.03H),4.67(d,J＝6.0Hz,0.03H),4.44(s,0.97H).13C NMR(100MHz,CDCl3)δ166.4(d,1JF-C＝257.0Hz),159.8,150.8,139.1,132.8(d,4JF-C＝3.1Hz),132.1(d,3JF-C＝9.8Hz),129.7,129.6,129.2,128.3,127.0,125.9,120.8,116.8(d,2JF-C＝19.5Hz),116.5,72.2,42.3.19F NMR(376MHz,CDCl3)δ-101.16,-102.69.HPLC(Chiralpak IAcolumn,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝6.8min(minor)and 9.7min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C21H19FNO4S 400.1013,found:400.1018.
(+)-3-((4-氯苯基)磺酰基)-4-苯基苯并二氢吡喃-2-酮(2e):
59毫克,99％收率,无色液体,Rf＝0.42(hexanes/ethyl acetate 5/1),d.r.＝32:1,98％ee,[α]20 D＝+149.90(c 1.18,CHCl3),1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.6Hz,0.06H),7.68(d,J＝8.6Hz,1.94H),7.41(d,J＝8.6Hz,2H),7.35-7.23(m,5H),7.21-7.15(m,1H),7.13(d,J＝7.9Hz,0.06H),7.04(d,J＝7.0Hz,1.94H),6.98(d,J＝8.0Hz,0.03H),6.94(d,J＝8.1Hz,0.97H),5.15(s,0.97H),5.08(d,J＝6.0Hz,0.03H),4.64(d,J＝6.0Hz,0.03H),4.40(s,0.97H).13C NMR(100MHz,CDCl3)δ159.7,150.7,141.7,139.1,135.2,130.5,129.7,129.7,129.6,129.2,128.3,127.0,125.9,120.7,117.0,72.1,42.2.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝7.3min(minor)and 10.2min(major).HRMS(ESI)m/z:[M+NH4]+Calcd forC21H19ClNO4S416.0718(35Cl)and 417.0755(37Cl),found:416.0715(35Cl)and 417.0745(37Cl).
(+)-3-((4-溴苯基)磺酰基)-4-苯基苯并二氢吡喃-2-酮(2f):
65毫克,98％收率,无色固体,熔点＝127-128℃,Rf＝0.43(hexanes/ethylacetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+145.22(c 1.30,CHCl3),1H NMR(400MHz,CDCl3)δ7.66-7.56(m,4H),7.31(m,5H),7.23-7.18(m,1H),7.07(d,J＝7.0Hz,2H),6.96(d,J＝8.2Hz,1H),5.17(s,1H),4.43(s,1H).13C NMR(100MHz,CDCl3)δ159.7,150.7,139.0,135.7,132.6,130.5,129.7,129.7,129.2,128.3,127.0,125.9,120.7,117.0,72.1,42.2.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝7.7min(minor)and 10.8min(major).HRMS(ESI)m/z:[M+NH4]+Calcd forC21H19BrNO4S 460.0213(79Br)and 462.0200(81Br),found:460.0214(79Br)and462.0196(81Br).
(+)-4-苯基-3-(间甲苯基磺酰基)苯并二氢吡喃-2-酮(2g):
56毫克,99％收率,无色液体,Rf＝0.51(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+147.85(c 1.12,CHCl3),1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.6Hz,1H),7.52(s,1H),7.42-7.32(m,2H),7.32-7.27(m,2H),7.26-7.20(m,3H),7.17-7.13(m,1H),7.04(d,J＝7.1Hz,2H),6.92(d,J＝8.1Hz,1H),5.15(s,1H),4.41(s,1H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ159.8,150.9,139.7,139.4,136.7,135.5,129.6,129.6,129.3,129.2,129.1,128.2,127.1,126.3,125.6,120.9,116.9,72.1,42.4,21.3.HPLC(ChiralpakIA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝80/20,flow rate＝0.8mL/min)tR＝9.2min(minor)and 12.8min(major).HRMS(ESI)m/z:[M+NH4]+Calcd forC22H22NO4S396.1264,found:396.1263.
(+)-4-苯基-3-(邻甲苯基磺酰基)苯并二氢吡喃-2-酮(2h):
40毫克,70％收率,无色液体,Rf＝0.51(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+178.71(c 0.78,CHCl3),1H NMR(400MHz,CDCl3)δ7.90-7.82(m,1H),7.54-7.49(m,1H),7.36-7.22(m,7H),7.20-7.15(m,1H),7.14-7.09(m,1H),7.06-7.01(m,2H),5.17(s,1H),4.40(d,J＝0.9Hz,1H),2.69(s,3H).13C NMR(100MHz,CDCl3)δ159.8,151.1,139.6,138.6,135.5,134.8,133.1,131.5,129.7,129.7,129.2,128.2,127.0,126.8,125.8,121.0,117.0,71.2,41.8,20.8.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝80/20,flow rate＝0.8mL/min)tR＝8.8min(minor)and 18.6min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C22H22NO4S 396.1264,found:396.1266.
(+)-4-(对甲苯基)-3-甲苯磺酰色满-2-酮(2j):
56毫克,95％收率,无色液体,Rf＝0.37(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+158.56(c 1.05,CHCl3),1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.3Hz,2H),7.28-7.21(m,5H),7.16-7.12(m,1H),7.08(d,J＝8.0Hz,2H),6.95-6.88(m,3H),5.10(s,1H),4.37(s,1H),2.40(s,3H),2.27(s,3H).13C NMR(100MHz,CDCl3)δ160.0,150.8,145.9,138.0,136.5,133.9,130.2,129.9,129.3,129.2,129.1,126.9,125.6,121.2,116.9,72.2,41.9,21.7,21.0.HPLC(Chiralpak ID column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝14.9min(major)and 18.0min(minor).HRMS(ESI)m/z:[M+NH4]+Calcd for C23H24NO4S 410.1421,found:410.1423.
(+)-4-(4-甲氧基苯基)-3-甲苯磺酰基色满-2-酮(2k):
55毫克,90％收率,淡黄色固体,熔点＝132-133℃,Rf＝0.30(hexanes/ethylacetate5/1),d.r.>20:1,98％ee,[α]20 D＝+156.08(c 1.10,CHCl3),1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.1Hz,2H),7.28-7.20(m,4H),7.17-7.12(m,1H),7.00-6.89(m,3H),6.79(d,J＝8.6Hz,2H),5.08(s,1H),4.36(s,1H),3.72(s,3H),2.39(s,3H).13C NMR(100MHz,CDCl3)δ160.0,159.3,150.8,145.9,133.9,131.4,129.9,129.3,129.1,129.0,128.2,125.7,121.3,116.9,114.9,72.3,55.3,41.6,21.7.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝11.1min(minor)and 13.5min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C23H24NO5S 426.1370,found:426.1370.
(+)-4-(4-氟苯基)-3-甲苯磺酰苯并吡喃-2-酮(2l):
59毫克,99％收率,淡黄色固体,熔点＝117-118℃,Rf＝0.37(hexanes/ethylacetate5/1),d.r.>20:1,98％ee,[α]20 D＝+151.60(c 1.18,CHCl3),1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.3Hz,2H),7.31-7.22(m,4H),7.19-7.14(m,1H),7.03-6.93(m,5H),5.13(s,1H),4.34(s,1H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ162.3(d,1JF-C＝246.3Hz),159.8,150.8,146.1,135.2(d,4JF-C＝3.5Hz),133.8,129.9,129.6,129.1,129.1,128.88,128.8(d,3JF-C＝8.1Hz),120.8,117.0,116.5(d,2JF-C＝21.6Hz),72.1,41.6,21.7.19F NMR(376MHz,CDCl3)δ-113.53.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝7.8min(minor)and 10.2min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C22H21FNO4S 414.1170,found:414.1165.
(+)-4-(4-氯苯基)-3-甲苯磺酰基色满-2-酮(2m):
61毫克,99％收率,无色液体,Rf＝0.50(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+147.37(c 1.22,CHCl3),1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.2Hz,2H),7.32-7.21(m,6H),7.19-7.14(m,1H),7.00-6.93(m,3H),5.12(s,1H),4.33(s,1H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ159.7,150.8,146.1,137.9,134.2,133.7,129.9,129.7,129.1,129.1,128.5,125.8,120.5,117.0,71.8,41.6,21.8.HPLC(Chiralpak IAcolumn,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flow rate＝1.0mL/min)tR＝10.1min(minor)and 13.0min(major).HRMS(ESI)m/z:[M+H]+Calcd for C22H18ClO4S 413.0609(35Cl)and 415.0592(37Cl),found:413.0609(35Cl)and 415.0576(37Cl).
(+)-4-(4-溴苯基)-3-甲苯磺酰基苯并二氢吡喃-2-酮(2n):
68毫克,99％收率,无色液体,Rf＝0.54(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+135.43(c 1.36,CHCl3),1H NMR(400MHz,CDCl3)δ7.63(d,J＝7.9Hz,2H),7.41(d,J＝8.0Hz,2H),7.31-7.20(m,4H),7.19-7.14(m,1H),6.97-6.86(m,3H),5.11(s,1H),4.34(s,1H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ159.7,150.8,146.1,138.4,133.7,132.7,129.9,129.7,129.1,129.1,128.8,125.8,122.3,120.4,117.0,71.7,41.7,21.8.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flow rate＝1.0mL/min)tR＝10.6min(minor)and 14.0min(major).HRMS(ESI)m/z:[M+Na]+Calcdfor C22H17BrNaO4S 478.9923(79Br)and 480.9910(81Br),found:478.9923(79Br)and480.9894(81Br).
(+)-4-(间甲苯基)-3-甲苯磺酰基色满-2-酮(2o):
58毫克,99％收率,淡黄色液体,Rf＝0.54(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+160.25(c 1.16,CHCl3),1H MR(400MHz,CDCl3)δ7.64(d,J＝8.2Hz,2H),7.29-7.21(m,4H),7.17-7.12(m,2H),7.03(d,J＝7.5Hz,1H),6.93(d,J＝8.1Hz,1H),6.85(s,1H),6.80(d,J＝7.7Hz,1H),5.10(s,1H),4.38(s,1H),2.39(s,3H),2.26(s,3H).13CNMR(100MHz,CDCl3)δ160.0,150.8,146.0,139.4,139.4,133.9,129.9,129.4,129.4,129.2,129.1,128.9,127.7,125.7,124.1,121.0,116.9,72.1,42.2,21.8,21.5.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flow rate＝1.0mL/min)tR＝7.0min(minor)and 8.4min(major).HRMS(ESI)m/z:[M+H]+Calcd for C23H21O4S393.1155,found:393.1154.
(+)-4-(邻甲苯基)-3-甲苯磺酰基苯并二氢吡喃-2-酮(2p):
14毫克,24％收率,无色液体,Rf＝0.52(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+113.92(c 0.28,CHCl3),1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.2Hz,2H),7.33-7.26(m,2H),7.25-7.21(m,2H),7.20-7.11(m,3H),7.04-6.97(m,2H),6.55(d,J＝7.7Hz,1H),5.39(s,1H),4.21(s,1H),2.54(s,3H),2.41(s,3H).13C NMR(100MHz,CDCl3)δ159.8,151.5,146.0,137.1,134.9,133.9,131.5,129.9,129.4,129.3,129.1,128.1,127.3,127.2,125.8,121.1,116.8,70.7,38.7,21.8,19.4.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flow rate＝1.0mL/min)tR＝6.7min(minor)and8.4min(major).HRMS(ESI)m/z:[M+H]+Calcd for C23H21O4S 393.1155,found:393.1152.
(+)-4-(萘-2-基)-3-甲苯磺酰基色满-2-酮(2q):
64毫克,99％收率,淡黄色液体,Rf＝0.55(hexanes/ethyl acetate 5/1),d.r.>20:1,97％ee,[α]20 D＝+156.55(c 1.28,CHCl3),1H NMR(400MHz,CDCl3)δ7.80-7.73(m,2H),7.70-7.63(m,3H),7.46-7.41(m,2H),7.37(s,1H),7.33-7.25(m,2H),7.22(d,J＝8.5Hz,3H),7.18-7.13(m,1H),6.98(d,J＝8.0Hz,1H),5.31(s,1H),4.50(s,1H),2.37(s,3H).13CNMR(100MHz,CDCl3)δ160.0,151.0,146.1,136.7,133.8,133.4,132.8,129.9,129.8,129.6,129.4,129.1,128.0,127.7,126.8,126.7,126.1,125.8,124.7,120.9,117.0,71.9,42.4,21.8.HPLC:(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flowrate＝1.0mL/min)tR＝12.2min(minor)and 14.7min(major).HRMS(ESI)m/z:[M+H]+Calcdfor C26H21O4S 429.1155,found:429.1151.
(+)-7-甲基-4-苯基-3-甲苯磺酰色满-2-酮(2r):
49毫克,83％yield,colorless oil,new compound,Rf＝0.50(hexanes/ethylacetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+156.62(c 0.98,CHCl3),1H NMR(400MHz,CDCl3)δ7.63(d,J＝7.9Hz,2H),7.31-7.18(m,5H),7.14-6.94(m,4H),6.73(s,1H),5.09(s,1H),4.36(s,1H),2.40(s,3H),2.32(s,3H).13C NMR(100MHz,CDCl3)δ160.2,150.8,145.9,140.0,139.6,134.0,129.8,129.5,129.1,128.9,128.1,127.1,126.5,117.8,117.3,72.2,42.0,21.8,21.2.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝7.5min(minor)and 9.9min(major).HRMS(ESI)m/z:[M+H]+Calcd for C23H21O4S 393.1155,found:393.1152.
(+)-6,8-二甲基-4-苯基-3-甲苯磺酰基苯并二氢吡喃-2-酮(2s):
58毫克,95％收率,无色液体,Rf＝0.53(hexanes/ethyl acetate 5/1),d.r.>20:1,99％ee,[α]20 D＝+128.61(c 1.16,CHCl3),1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.2Hz,2H),7.30-7.16(m,5H),7.03(d,J＝7.3Hz,2H),6.86(d,J＝4.3Hz,2H),5.03(s,1H),4.39(s,1H),2.38(s,3H),2.24(s,3H),2.09(s,3H).13C NMR(100MHz,CDCl3)δ160.3,147.1,145.8,139.5,134.9,133.9,131.6,129.6,129.5,129.0,128.1,127.1,127.0,125.9,120.1,72.5,42.8,21.7,20.7,15.4.HPLC(Chiralpak IA column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flow rate＝1.0mL/min)tR＝5.9min(minor)and 7.4min(major).HRMS(ESI)m/z:[M+H]+Calcd for C24H23O4S 407.1312,found:407.1305.
(+)-4-(噻吩-3-基)-3-甲苯磺酰基色满-2-酮(2t):
50毫克,87％收率,无色液体,Rf＝0.53(hexanes/ethyl acetate 5/1),d.r.>20:1,98％ee,[α]20 D＝+128.47(c 0.92,CHCl3),1H NMR(400MHz,CDCl3)δ7.64-7.59(m,2H),7.30-7.21(m,6H),7.18-7.13(m,1H),6.91-6.86(m,2H),6.84-6.76(m,1H),5.17(s,1H),4.46(s,1H),2.40(s,3H).13C NMR(100MHz,CDCl3)δ160.1,150.5,146.0,139.6,134.0,129.9,129.4,129.0,128.9,127.9,125.9,125.6,122.4,121.4,117.0,71.2,38.1,21.7.HPLC(Chiralpak AD-H column,λ＝230nm,30℃,n-Hexane/i-PrOH＝70/30,flowrate＝0.8mL/min)tR＝13.5min(minor)and 19.1min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C20H20NO4S2 402.0828,found:402.0829.
(+)-4-甲基-3-甲苯磺酰基苯并二氢吡喃-2-酮(2u):
34毫克,72％收率,无色液体,Rf＝0.45(hexanes/ethyl acetate 5/1),d.r.＝10:1,94％ee(trans),94％ee(cis),[α]20D＝+91.33(c 0.60,CHCl3),1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.2Hz,0.18H),7.58(d,J＝8.2Hz,1.82H),7.35(d,J＝8.2Hz,0.18H),7.25-7.11(m,4.82H),7.00(d,J＝8.1Hz,0.09H),6.81(d,J＝8.0Hz,0.91H),4.25(d,J＝4.7Hz,0.09H),4.16(s,0.91H),3.98-3.89(m,1H),2.44(s,0.27H),2.40(s,2.73H),1.59(d,J＝7.1Hz,0.27H),1.34(d,J＝7.4Hz,2.73H).13C NMR(100MHz,CDCl3)δ160.5,149.9,145.8,134.0,129.8,129.0,128.8,127.8,125.5,123.9,116.8,71.3,32.2,22.8,21.7.HPLC(Chiralpak AS-H column,λ＝230nm,30℃,n-Hexane/i-PrOH＝75/25,flowrate＝1.0mL/min)trans:tR＝17.9min(major)and 20.5min(minor)；cis:tR＝30.9min(minor)and 48.4min(major).HRMS(ESI)m/z:[M+H]+Calcd for C17H17O4S 317.0842,found:317.0839.
实施例22～30
空气下，向装有0.1mmol 1a底物的安培瓶中投入[Ru(p-甲基异丙苯)I2]2和CYNAM(底物用量的10mol％)，转移至手套箱中，加入2mL溶剂，装入高压反应釜中，充入800psi氢气，于相应温度下搅拌反应22小时。然后，停止反应，减压除去有机溶剂。氢源的结构如下：
产物非对映选择性用1H NMR测定，对映体过量用手性液相色谱测定，改变反应过程中温度、[Ru(p-甲基异丙苯)I2]2的用量以及CYNAM的种类，详见表1。
表1
应用例1
将无水碳酸钠(42.4mg,0.40mmol)、烯丙基碘(67.2mg,36.5μL,0.40mmol)、18-冠醚-6(7.9mg,6.8μL,0.03mmol)、实施例12得到的产物2l(39.6mg,0.10mmol)和四氢呋喃(2mL)添加至反应瓶中，室温下搅拌28小时。薄层色谱检测，反应完全，减压蒸馏除去溶剂，直接硅胶柱层析分离，洗脱剂为石油醚/乙酸乙酯(5/1)。反应式如下：
其产率为分离收率，通过1H NMR测定非对映选择性，产物的对映体过量用手性液相色谱测定。
(+)-3-烯丙基-4-(4-氟苯基)-3-甲苯磺酰基苯并二氢吡喃-2-酮(3):
43毫克,98％收率,无色液体,Rf＝0.41(hexanes/ethyl acetate 5/1),>99％ee,[α]20 D＝+176.03(c 0.86,CHCl3),1H NMR(400MHz,CDCl3)δ7.81-7.69(m,2H),7.40-7.27(m,3H),7.23-7.17(m 2H),7.15-7.05(m,3H),6.97-6.85(m,2H),5.83-5.68(m,7.3Hz,1H),5.15(d,J＝10.0Hz,1H),4.79(d,J＝16.9Hz,1H),4.70(s,1H),2.84-2.72(m,2H),2.39(s,3H).13C NMR(100MHz,CDCl3)δ163.5,162.5(d,1JF-C＝246.2Hz),149.4,145.2,134.8,133.1(d,4JF-C＝3.1Hz),131.3(d,3JF-C＝6.7Hz),131.1,130.0,129.2,129.2,128.7,125.6,125.0,121.7,116.7,115.7(d,2JF-C＝21.3Hz),74.6,48.0,37.5,21.7.19F NMR(376MHz,CDCl3)δ-113.68.HPLC:Chiralpak IC,230nm,30℃,n-Hexane/i-PrOH＝80/20,flow＝1.0mL/min,tR＝14.9min(major),16.2min(minor).HRMS(ESI)m/z:[M+NH4]+Calcd forC25H25FNO4S 454.1483,found:454.1486.
应用例2
0℃下向实施例12得到的2l(39.6mg,0.10mmol)的乙醚(3mL)溶液中加入四氢锂铝(5.7mg,0.15mmol)，搅拌反应3小时。薄层色谱检测，反应完全。用水(3mL)和1N盐酸水溶液(3mL)淬灭反应，乙酸乙酯(10mL×3)萃取水层，盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂。随后，室温下向上述粗产物的二氯甲烷(3mL)溶液中加入三乙胺(101.2mg,0.14mL,1.0mmol)、4-二甲基氨基吡啶(6.1mg,0.05mmol)和乙酸酐(51.1mg,47.3μL,0.5mmol)，搅拌过夜。薄层色谱检测，反应完全。用饱和氯化铵水溶液(10mL)淬灭反应，二氯甲烷(10mL×3)萃取水层，盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂后，硅胶柱层析分离，洗脱剂为石油醚/乙酸乙酯(2/1)。反应式如下：
(-)-2-(3-乙酰氧基-1-(4-氟苯基)-2-甲苯磺酰丙基)乙酸苯酯(4):
46毫克,95％收率,无色液体,Rf＝0.31(hexanes/ethyl acetate 2/1),>99％ee,[α]20 D＝-44.45(c 0.92,CHCl3),1H NMR(400MHz,CDCl3)δ7.48-7.42(m,2H),7.26-7.12(m,7H),7.06-7.01(m,1H),6.85-6.78(m,2H),4.94(d,J＝9.8Hz,1H),4.55-4.47(m,1H),4.30-4.21(m,2H),2.39(s,3H),2.38(s,3H),1.84(s,3H).13C NMR(100MHz,CDCl3)δ170.1,169.1,161.7(d,1JF-C＝244.8Hz),148.1,144.5,137.0,135.4(d,4JF-C＝2.9Hz),132.1,130.0(d,3JF-C＝8.1Hz),129.5,128.7,128.4,128.3,126.5,123.4,115.3(d,2JF-C＝21.5Hz),66.2,60.9,41.0,21.6,21.1,20.4.19F NMR(376MHz,CDCl3)δ-115.37.HPLC:Chiralpak AD-H,230nm,30℃，n-Hex-ane/i-PrOH＝60/40,flow＝1.0mL/min,tR＝9.7min(minor),15.2min(major).HRMS(ESI)m/z:[M+NH4]+Calcd for C26H29FNO6S 502.1694,found:502.1696.
以上所述，仅是本申请的几个实施例，并非对本申请做任何形式的限制，虽然本申请以较佳实施例揭示如上，然而并非用以限制本申请，任何熟悉本专业的技术人员，在不脱离本申请技术方案的范围内，利用上述揭示的技术内容做出些许的变动或修饰均等同于等效实施案例，均属于技术方案范围内。
Claims (11)
1.一种手性砜类化合物，其特征在于，具有式I所示的结构；
式I；
式中“*”所标出的碳为手性中心；
所述R1选自氢、C1～C10的烷基、含有取代基的C3～C10芳基、C3～C10杂芳基中的一种；
所述R2选自含有取代基的C3~C10芳基、C3~C10杂芳基中的一种；
所述R3选自氢、C1～C10的烷基中的一种；
所述R4选自氢、C1～C10的烷基中的一种；
所述取代基选自C1~C10的烷基、C1~C10的烷氧基、卤素中的至少一种；
所述C1~C10的烷基选自甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基的同分异构体中的一种；
所述的芳基选自单环芳基、双环芳基中的一种；
所述杂芳基选自单环杂芳基、双环杂芳基中的一种；
所述的杂芳基包含5至10个骨架成环原子，其中至少1个成环原子为杂原子，所述杂原子选自N、S或O中的至少一种。
2.根据权利要求书1所述的手性砜类化合物，其特征在于，
所述杂芳基为含1~4个氮原子的5元单环、6元单环或包含所述5元单环或6元单环的稠环。
3.根据权利要求书1所述的手性砜类化合物，其特征在于，
所述杂芳基为含1~2个氧原子的5元单环或6元单环或包含所述5元单环或6元单环的稠环。
4.根据权利要求书1所述的手性砜类化合物，其特征在于，
所述杂芳基为含1~2个硫原子的5元环或6元环或包含所述5元单环或6元单环的稠环。
5.根据权利要求书1所述的手性砜类化合物，其特征在于，
所述杂芳基选自吡啶基、吡咯基、呋喃基、噻吩基中的一种。
6.根据权利要求1~5中任一项所述的手性砜类化合物，其特征在于，所述手性化合物的ee值大于90%。
7.一种权利要求1~6中任意一项所述的手性砜类化合物的制备方法，其特征在于，包括以下步骤：将含有底物、氢源和催化剂的原料与溶剂混合，发生氢化反应，得到所述手性化合物；所述底物具有式II所述的结构；
式II；
所述底物、氢源与催化剂的摩尔比为1:0.05~0.1:0.005~0.04；
所述底物的摩尔量与溶剂的体积比为0.01mol/L~0.20mol/L；所述氢源具有式III所示的结构；
式III；
所述R5和R6独立地选自氢原子、氟原子、甲基或甲氧基中的至少一种；
所述催化剂选自[Ru(p-甲基异丙苯)I2]2或Pd/C或Fe3(CO)12中的至少一种。
8.根据权利要求7所述的方法，其特征在于，所述混合过程为将底物与含有氢源和催化剂的原料混合，再加入溶剂。
9.根据权利要求7所述的方法，其特征在于，所述溶剂选自二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳、甲苯、氯苯、三氟甲苯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、乙酸乙酯、甲醇、乙腈和二甲亚砜中的至少一种。
10.根据权利要求7所述的方法，其特征在于，所述氢化反应的气氛为氢气气氛；所述氢气气氛的压力为500~1200psi。
11.一种权利要求1~6中任意一项所述的手性砜类化合物或权利要求7~10中任意一项所述的方法制备的手性砜类化合物的应用，其特征在于，所述手性砜类化合物用于烯丙基烷基化反应或直链手性砜的合成反应。
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| Biomimetic asymmetric reduction of benzoxazinones and quinoxalinones using ureas as transfer catalysts;Zi-Biao Zh ao et al.;《Chem. Commun.》;第56卷;7309-7312 * |
| Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies;Jie Wang et al.;《J. Org. Chem.》;第85卷;2355-2368 * |
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