CN112694376A - 一种手性磷酸催化的烯丙基叔醇动力学拆分方法 - Google Patents

一种手性磷酸催化的烯丙基叔醇动力学拆分方法 Download PDF

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CN112694376A
CN112694376A CN202011562155.6A CN202011562155A CN112694376A CN 112694376 A CN112694376 A CN 112694376A CN 202011562155 A CN202011562155 A CN 202011562155A CN 112694376 A CN112694376 A CN 112694376A
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毛斌
高庆
张朝焕
孟鑫
王建飞
李蒙
俞传明
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Abstract

本发明公开了一种手性磷酸催化的烯丙基叔醇动力学拆分方法，在有机溶剂及添加剂存在的条件下，式I所示(E)‑烯基取代二醇类化合物在II所示的手性磷酸催化剂的催化下，经过动力学拆分反应得到式III所示的手性烯丙基叔醇(E)‑烯基取代二醇衍生物和式IV所示的(E)‑2‑烯基取代四氢呋喃类化合物，反应式如下：

Description

一种手性磷酸催化的烯丙基叔醇动力学拆分方法
技术领域
本发明涉及一种手性磷酸催化的烯丙基叔醇动力学拆分方法。
背景技术
手性叔醇在碳手性中心上含有三种不同的取代基团和一个羟基，是一类重要的结构单元，广泛存在于具有生物活性的天然化合物、非天然化合物和医药中，是合成各种天然产物和手性药物的重要中间体，例如广泛应用于临床的抗真菌类药物京纳康唑、雷夫康唑、泊沙康唑等，均含有手性叔醇的结构单元[Acetti,D.；Brenna,E.；Fuganti,C.；Gatti,F.G.；Serra,S.Tetrahedron:Asymmetry 2009,20,2413–2420.]。尤其是手性烯丙基叔醇的不对称合成仍然是一个非常具有挑战性的研究领域。而消旋烯丙基叔醇的动力学拆分是合成手性烯丙基叔醇类化合物最为有效以及可靠的方法之一。2006年，Shin-ya Tosaki使用手性1,1’-联萘酚(BINOL)和镧-锂双金属配合物的动力学拆分方法，得到的手性硝基叔醇具有80-90％的ee值[Tosaki,S.；Hara,K.；Gnanadesikan,V.；Morimoto,H.；Harada,S.；Sugita,M.；Yamagiwa,N.；Matsunaga,S.；Shibasaki,M.J.Am.Chem.Soc.2006,128,11776–11777.]。2008年，Ryo Shintani以(R)-2,2'-双(二苯基膦酰基)-5,5',6,6',7,7',8,8'-八氢-1,1'-联二萘作为手性配体，过渡金属铑为催化剂，对烯丙基叔醇进行动力学拆分，产物的ee值达97％[Shintani,R.；Takatsu,K.；Hayashi,T.Org.Lett.2008,10(6),1191–1193.]。2018年，Ma课题组以手性1,1’-联萘酚的衍生物作为手性配体，利用金属钯/氢离子共催化外消旋叔炔醇与一氧化碳和甲醇进行羧基化反应，并经过动力学拆分，提供了多取代的烯丙醇酸酯和ee值为90-99％的炔丙基叔醇[Zhang,W.；Ma,S.Chem.Commun.2018,54,6064–6067.]。
相对于金属催化的三级醇动力学拆分，非金属催化三级醇动力学拆分应用同样广泛。2010年，Benjamin等以新型手性螺环磷酸作为催化剂，通过乙酰化反应的逆反应，实现了对γ-羟基羰基化合物的高对映选择性的动力学拆分，以97％的ee值获得末端手性叔醇[
Figure BDA0002859675920000011
I.；Müller,S.；List,B.J.Am.Chem.Soc.2010,132,17370–17373.]。2013年，Zhao Yu等通过手性酰基偶氮化合物—N-杂环卡宾(NHC)催化的氧化酯化反应，首次实现了3-羟基-3取代的羟吲哚化合物的高度对映选择性动力学拆分，产物ee值达98％[Lu,S.；Poh,S.B.；Siau,W.-Y.；Zhao,Y.Angew.Chem.Int.Ed.2013,52,1731–1734.]。2018年，Maruoka课题组在手性季铵盐与非手性硼酸的协同作用下，成功实现了邻二醇的烷基化动力学拆分，该策略也成功应用于苄基叔醇的动力学拆分[Pawliczek,M.；Hashimoto,T.；Maruoka,K.Chem.Sci.2018,9,1231–1235.]。除此之外，手性1,1’-联萘酚衍生物催化剂以其优越的手性控制性能也备受关注。2019年，Yang课题组以手性磷酸作为催化剂，通过催化分子内的酯交换反应，动力学拆分实现叔2-烷氧基甲酰胺基取代烯丙醇的动力学拆分[Rajkumar,S.；He,S.；Yang,X.Angew.Chem.Int.Ed.2019,58,10315–10319.]。
在过去的几十年里，手性叔醇类特别是手性烯丙基叔醇类化合物的合成方法仍十分有限，其中通过动力学拆分来获得手性烯丙基叔醇的策略存在挑战：(1)相对于外消旋仲醇通过动力学拆分来获得手性仲醇，由于叔醇碳上有三个不同的取代基团导致空间位阻较大，反应性较低，相应的动力学拆分研究还较少，仅报道了少数手性磷酸和金属联合催化案例，单独使用手性磷酸催化的尚无报道案例；(2)现有文献报道的通过动力学拆分来获得手性叔醇的方法主要以金属催化或金属与手性配体联合催化为主，反应条件比较苛刻，底物适用性较窄，也与绿色化学相悖；(3)手性叔醇由于前手性碳中心非氢取代基的空间和电子差异较小而导致的对映体表面分化减小，以及不利的空间位阻和极强的碳正离子中间体倾向，其本身容易通过酸催化或碱催化的逆反应进行外消旋化。因此，适用于光学活性仲醇的合成策略不易推广到叔醇，开发一种绿色、反应条件简单且催化体系适用的底物范围广泛，高对映选择性合成手性叔醇的方法是本发明着力解决的技术问题。
发明内容
本发明的目的是针对现有技术的不足，开发了一种手性磷酸催化的烯丙基叔醇动力学拆分方法，它以手性磷酸为催化剂，以分子筛为唯一添加剂，在较简单的条件下实现了对外消旋烯丙基叔醇的动力学拆分，得到高光学活性和产率的手性烯丙基叔醇(E)-烯基取代二醇衍生物和(E)-2-烯基取代四氢呋喃类化合物。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于以手性磷酸为催化剂，在有机溶剂及添加剂存在的条件下，式I所示的(E)-烯基取代二醇类化合物在II所示的手性磷酸催化剂的催化下，经过动力学拆分反应得到式III所示的手性烯丙基叔醇(E)-烯基取代二醇衍生物和式IV所示的(E)-2-烯基取代四氢呋喃类化合物，反应式如下：
Figure BDA0002859675920000031
R1选自下列之一：C6～C20芳基或取代芳基、具有1-3个选自N、S和O的杂原子的C4～C16杂芳基；其中R1中，所述的C6～C20芳基或取代芳基优选为C6～C14芳基或取代芳基，所述的具有1-3个选自N、S和O的杂原子的C4～C16杂芳基优选为含有一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C15杂芳基；
R2选自下列之一：C1～C6烷基、C3～C6烯基、C3～C8环烷烃基、C6～C18芳基或取代芳基、C7～C12苄基、具有1-3个选自N、S和O的杂原子的C4～C12杂芳基；其中R2中，所述的C1～C6烷基优选为C1～C4烷基；C3～C6烯基优选为C3～C4烯基；所述的C3～C8环烷烃基优选为C3～C6环烷烃基；所述的C6～C18芳基或取代芳基优选为C6～C12芳基或取代芳基；C7～C12苄基优选为C7～C9苄基；所述的具有1-3个选自N、S和O的杂原子的C4～C12杂芳基优选为含一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C11杂芳基；
R3选自C2～C6烷基或取代烷基，优选为C2～C5烷基或取代烷基；
Ar选自下列之一：2,4,6-三异丙基苯基、三苯基硅基、萘基、菲基、蒽基、2,4,6-三环己基苯基、2,4,6-三苯基苯基和2,4,6-三环戊己苯基，优选为2,4,6-三环戊己苯基；
X选自下列之一：氢、硝基、三异丙基硅基，优选为氢。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于所述R1中，C6～C14芳基或取代芳基为苯基、氟苯基、甲氧基苯基、甲基苯基、联苯基、萘基、菲基或蒽基，含有一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C15杂芳基为苯并呋喃、噻吩、取代噻吩、取代吲哚或二苯并呋喃；所述R2中，C1～C4烷基为甲基或异丙基，C3～C4烯基为异烯丙基，C3～C6环烷烃基为环己基，C6～C12芳基或取代芳基为甲基苯基、氟苯基、甲氧基苯基或萘基，C7～C9苄基为苄基，含一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C11杂芳基为取代吡咯或噻吩；所述R3中，C2～C5烷烃基为乙基、丙基、正丁基或正戊基，C2～C5取代烷烃基中的取代基为苄氧基甲基、甲基、乙烯基或羟甲基。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于式I所示(E)-烯基取代二醇类化合物选自下列之一：
Figure BDA0002859675920000051
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于反应温度为-40℃～50℃，优选为-20℃～35℃；所述有机溶剂为二氯甲烷、甲苯、1,2-二氯乙烷、四氯化碳、乙醚、乙腈、三氟甲苯、氯仿或正己烷，优选为1,2-二氯乙烷。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于催化剂与式I所示的(E)-烯基取代二醇类化合物的物质的量比为0.5～50:100，优选为15:100；式I所示的(E)-烯基取代二醇类化合物的物质的量与有机溶剂的体积之比为0.05～0.5:1，优选为0.01:1，物质的量单位为mmol，体积单位为mL。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于所述添加剂为分子筛，分子筛型号为
Figure BDA0002859675920000061
分子筛、
Figure BDA0002859675920000062
分子筛或
Figure BDA0002859675920000063
分子筛，优选为
Figure BDA0002859675920000064
分子筛；所述分子筛的质量与式I所示的(E)-烯基取代二醇类化合物的物质的量之比为1～1.5:1，质量的单位为g，物质的量单位为mmol。
所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于式II所示的手性磷酸催化剂选自下列之一：
Figure BDA0002859675920000071
与现有技术相比，本发明具有如下创新点：
(1)相对于以金属催化或金属与手性配体联合催化的动力学拆分来获得手性烯丙基叔醇的方法，本发明只需用到催化量的手性磷酸作为催化剂，采用分子筛为唯一添加剂，实现了通过对外消旋烯丙基叔醇动力学拆分来获得手性烯丙基叔醇，减少了金属的使用，反应条件也相对简单，具有经济、环保的优点，顺应绿色化学发展的大趋势。
(2)本发明通过采用手性磷酸催化剂对外消旋烯丙基叔醇进行动力学拆分，作为产物之一的手性烯丙基叔醇结构在天然产物中较为常见，是具有较高价值的有机合成砌块；反应得到的另一种多取代手性呋喃类化合物也是重要的药物中间体，具有较好的应用前景和社会价值。
(3)本发明的催化底物范围相对于现有文献报道的催化体系来说，不再局限于特定的底物类别，无论是脂肪族类烯丙基叔醇，还是芳香族类烯丙基叔醇，产物均具有较高的对映选择性和转化率，范围十分广泛。
(4)本发明报道了一种高对映选择性合成手性烯丙基叔醇的方法，反应步骤简便，只需一步反应即可得到，底物适用范围广，反应条件简单，所得到的两种高光学活性的产物可进一步转化为多种药物中间体和多种天然产物。总而言之，本发明在原子经济性、步骤经济性、绿色性和多样性导向合成等方面具有较大的优势。
具体实施方式
下面结合具体实施例对本发明作进一步说明，但本发明的保护范围并不限于此。
分析仪器：使用BüchiB-540毛细管熔点仪测定熔点。包括1H NMR，13C NMR，19F NMR光谱在内的NMR数据是在Bruker 400MHz或600MHz仪器上记录的。所有的13C NMR光谱都是宽带质子去耦的。1H NMR相对于溶剂的残留信号以ppm为单位报道化学位移。19F NMR使用全氟苯作为内标。使用ESI作为离子源，在Agilent 6210TOF LC/MS上记录了高分辨率质(HRMS)。使用AUTOPOLV自动旋光仪测定旋光度。通过使用配备有Daicel Chiralpak IA，IC，IE，IF，IG色谱柱的Agilent 1100HPLC分析确定对映体过量值(ee)。
实施例1：产物III-1和IV-1的合成
Figure BDA0002859675920000081
实验步骤：在N2保护下，将反应体系密闭进行无水无氧处理，并调整温度为5℃，在25mL的反应瓶中依次加入I-1化合物(0.05mmol，1.0equiv)、手性联萘酚催化剂(R)-L2(0.0075mmol，0.15equiv)、添加剂(添加剂为：
Figure BDA0002859675920000082
分子筛(75mg))、溶剂为1,2-二氯乙烷(5.0mL)，进行反应。通过HPLC分析监测反应直至反应完成后，将反应体系通过硅藻土过滤并浓缩，所得浓缩物进行分离纯化后能够分别得到目标化合物III-1和目标化合物IV-1。
所得浓缩粗产品用柱层析分离纯化，(洗脱剂：石油醚：乙酸乙酯＝2：1(v/v))得到目标化合物III-1为白色固体，收率45％，ee值90％。[α]D 20＝–4.0(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.49(dd,J＝8.4,1.4Hz,2H),7.43–7.37(m,2H),7.29(td,J＝7.6,4.8Hz,4H),7.23–7.12(m,2H),6.61(d,J＝16.2Hz,1H),6.56(d,J＝16.2Hz,1H),5.31(s,1H),4.36(t,J＝5.2Hz,1H),3.33(m,2H),1.92–1.81(m,2H),1.46(m,1H),1.28(m,1H).13CNMR(100MHz,DMSO–d6)δ147.2,137.6,137.0,128.6,127.8,127.1,126.2,126.0,125.9,125.4,75.4,61.2,27.1.HRMS(ESI)m/z calcd.for C18H20NaO2[M+Na]+:291.1365；found291.1362.
所得浓缩粗产品用柱层析分离纯化，(洗脱剂：石油醚:乙酸乙酯＝20:1(v/v))目标化合物IV-1为无色油状液体，收率53％，ee值80％。[α]D 20＝+8.0(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.65–7.46(m,2H),7.29–7.13(m,4H),7.13–6.93(m,4H),6.71(d,J＝16.0Hz,1H),6.44(d,J＝16.0Hz,1H),3.91(td,J＝8.0,5.6Hz,1H),3.82(td,J＝8.0,6.5Hz,1H),2.12–1.94(m,2H),1.74–1.57(m,1H),1.58–1.43(m,1H).13C NMR(100MHz,C6D6)δ146.3,137.6,135.6,128.7,128.5,128.5,128.0,127.5,126.9,125.9,86.7,67.8,38.7,25.7.HRMS(ESI)m/z calcd.for C18H19O[M+H]+:251.1430；found 251.1428.
实施例2：产物III-2和IV-2的合成
实施例2的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-2所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-2和IV-2。
Figure BDA0002859675920000091
得到产物III-2为白色固体，产率42％，ee值为96％。[α]D 20＝–5.0(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.53–7.47(m,2H),7.45–7.39(m,2H),7.38–7.27(m,4H),7.24–7.16(m,2H),6.63(d,J＝16.0Hz,1H),6.58(d,J＝16.1Hz,1H),5.32(s,1H),4.38(t,J＝5.2Hz,1H),3.36–3.20(m,2H),1.98–1.77(m,2H),1.98–1.80(m,1H),1.34–1.20(m,1H).13CNMR(100MHz,DMSO–d6)δ161.7(d,J＝243.6Hz),147.2,137.5,133.5(d,J＝3.0Hz),128.1(d,J＝7.9Hz),127.8,126.1,125.4,124.7,115.4(d,J＝21.5Hz),75.4,61.2,27.2.19F NMR(376MHz,DMSO–d6)δ–117.63.HRMS(ESI)m/z calcd.for C18H19FNaO2[M+Na]+:309.1261；found 309.1261.
得到产物IV-2为无色油状液体，产率49％，ee值82％。[α]D 20＝+22.0(c 1.0,CHCl3)。1H NMR(400MHz,CDCl3)δ7.46(m,2H),7.39–7.29(m,4H),7.28–7.21(m,1H),6.97(t,J＝8.6Hz,2H),6.48(d,J＝16.0Hz,1H),6.34(d,J＝16.0Hz,1H),4.16–4.07(m,1H),4.07–3.97(m,1H),2.41–2.19(m,2H),2.10–1.98(m,1H),1.97–1.85(m,1H).13C NMR(100MHz,CDCl3)δ162.1(d,J＝246.4Hz),145.1,134.5(d,J＝2.3Hz),133.0(d,J＝3.3Hz),128.2,128.0(d,J＝7.9Hz),126.8,126.7,125.5,115.3(d,J＝21.6Hz),86.5,68.0,38.6,25.5.19FNMR(376MHz,CDCl3)δ–161.76.HRMS(ESI)m/z calcd.for C18H18FO[M+H]+:269.1336；found269.1342.
实施例3：产物III-3和IV-3的合成
实施例3的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-3所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-3和IV-3。
Figure BDA0002859675920000101
得到产物III-3为白色固体，产率42％，ee值为93％。[α]D 20＝–7.0(c 1.0,CHCl3)。1H NMR(400MHz,Benzene-d6)δ7.56(dd,J＝8.4,1.3Hz,2H),7.32–7.18(m,4H),7.16–7.00(m,1H),6.84–6.67(m,3H),6.37(d,J＝16.0Hz,1H),3.42–3.32(m,3H),3.28(s,3H),2.10–1.90(m,3H),1.65–1.32(m,2H),1.04–0.82(m,1H).13C NMR(100MHz,C6D6)δ159.7,147.1,134.8,130.3,128.5,128.3,127.9,126.8,126.1,114.4,76.6,63.0,54.8,40.1,27.2.HRMS(ESI)m/z calcd.for C19H22NaO3[M+Na]+:321.1461；found 321.1460.
得到产物IV-3为无色油状物，产率44％，ee值为84％。[α]D 20＝+15.0(c 1.0,CHCl3)。1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.4Hz,2H),7.35(t,J＝7.6Hz,2H),7.29(d,J＝8.8Hz,2H),7.24(d,J＝7.2Hz,1H),6.82(d,J＝8.8Hz,2H),6.45(d,J＝16.0Hz,1H),6.29(d,J＝16.0Hz,1H),4.11(m,1H),4.02(m,1H),3.79(s,3H),2.41–2.21(m,2H),2.12–1.97(m,1H),2.00–1.83(m,1H).13C NMR(100MHz,CDCl3)δ159.1,145.5,132.7,129.8,128.2,127.8,127.5,126.8,125.6,114.0,86.6,67.9,55.4,38.5,25.5.HRMS(ESI)m/z calcd.forC19H21O2[M+H]+:281.1536；found 281.1535.
实施例4：产物III-4和IV-4的合成
实施例4的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-4所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-4和IV-4。
Figure BDA0002859675920000111
得到产物III-4为白色固体，产率42％，ee值为98％。[α]D 20＝–3.4(c 1.0,CHCl3)。1H NMR(600MHz,DMSO–d6)δ7.47(d,J＝8.0Hz,2H),7.36(d,J＝5.0Hz,1H),7.32(t,J＝7.4Hz,2H),7.20(t,J＝7.4Hz,1H),7.05(d,J＝3.6Hz,1H),6.99(m,1H),6.73(d,J＝15.8Hz,1H),6.32(d,J＝15.8Hz,1H),5.35(d,J＝1.2Hz,1H),4.37(t,J＝5.0Hz,1H),3.35(m,2H),1.88(m,2H),1.47(m,1H),1.28(m,1H).13C NMR(150MHz,DMSO–d6)δ147.3,142.4,137.5,128.3,128.1,126.5,126.1,125.8,124.8,120.2,75.6,61.6,39.0,27.5.HRMS(ESI)m/z calcd.for C16H17NaO2S[M+Na]+:297.0920；found 297.0918.
得到产物IV-4为无色油状物，产率50％，ee值为90％。[α]D 20＝+4.4(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.47(d,J＝7.6Hz,2H),7.20(d,J＝7.6Hz,2H),7.08(t,J＝7.2Hz,1H),6.83(d,J＝15.6Hz,1H),6.71–6.58(m,3H),6.42(d,J＝15.6Hz,1H),3.89–3.81(m,1H),3.80–3.72(m,1H),1.95(t,J＝7.2Hz,2H),1.67–1.54(m,1H),1.52–1.40(m,1H).13CNMR(100MHz,C6D6)δ146.0,142.7,135.3,128.5,127.5,126.9,126.0,125.9,124.1,121.6,86.4,67.9,38.9,25.6.HRMS(ESI)m/z calcd.for C16H17OS[M+H]+:257.0995；found257.0994.
实施例5：产物III-5和IV-5的合成
实施例5的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-5所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-5和IV-5。
Figure BDA0002859675920000121
得到产物III-5为白色固体，产率47％，ee值为92％。[α]D 20＝–11.0(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.55–7.44(m,2H),7.29(d,J＝8.2Hz,2H),7.18–7.04(m,4H),6.54(d,J＝16.0Hz,1H),6.50(d,J＝16.0Hz,1H),4.36(t,J＝5.2Hz,1H),3.35(m,2H),2.25(s,3H),1.95–1.76(m,2H),1.53–1.36(m,1H),1.32–1.16(m,1H).13C NMR(100MHz,DMSO–d6)δ161.1(d,J＝241.3Hz),143.9(d,J＝2.9Hz),136.9,136.7,134.5,129.6,127.9(d,J＝7.9Hz),126.7,126.4,114.8(d,J＝20.9Hz),75.6,61.6,39.4,27.6,21.2.19F NMR(376MHz,DMSO-d6)δ–119.85.HRMS(ESI)m/z calcd.for C19H21FNaO2[M+Na]+:323.1418；found 323.1423.
得到产物IV-5为无色油状物，产率50％，ee值为90％。[α]D 20＝+18.0(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.34–7.28(m,2H),7.18(d,J＝8.4Hz,2H),6.93(d,J＝7.8Hz,2H),6.90–6.83(m,2H),6.65(d,J＝16.0Hz,1H),6.35(d,J＝16.0Hz,1H),3.91–3.83(m,1H),3.79–3.72(m,1H),2.08(s,3H),2.03–1.82(m,2H),1.71–1.57(m,1H),1.54–1.41(m,1H).13C NMR(100MHz,Benzene-d6)δ162.2(d,J＝244.3Hz),142.1(d,J＝3.0Hz),137.3,134.7,134.2,129.5,128.1,127.7(d,J＝8.2Hz),126.9,115.2(d,J＝21.1Hz),86.3,67.8,38.8,25.7,21.2.19F NMR(376MHz,C6D6)δ–118.63.HRMS(ESI)m/z calcd.for C19H20FO[M+H]+:283.1493；found 283.1494.
实施例6：产物III-6和IV-6的合成
实施例6的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-6所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-6和IV-6。
Figure BDA0002859675920000131
得到产物III-6为白色固体，产率44％，ee值为94％。[α]D 20＝–0.6(c 1.0,CHCl3)。1HNMR(400MHz,DMSO–d6)δ7.57(dd,J＝7.8,1.8Hz,1H),7.26–7.14(m,3H),7.08(d,J＝7.8Hz,2H),7.02–6.86(m,2H),6.77(d,J＝16.0Hz,1H),6.50(d,J＝16.0Hz,1H),5.16(s,1H),4.31(t,J＝5.2Hz,1H),3.78(s,3H),3.32–3.21(m,2H),2.24(s,3H),2.11(m,1H),1.85(m,1H),1.51–1.32(m,1H),1.26–1.05(m,1H).13C NMR(100MHz,DMSO–d6)δ155.8,136.1,135.3,134.5,134.4,129.1,127.7,126.6,125.9,125.6,120.1,111.7,75.1,61.4,55.5,36.4,27.4,20.7.HRMS(ESI)m/z calcd.for C20H24NaO3[M+Na]+:335.1618；found335.1612.
得到产物IV-6为无色油状物，产率47％，ee值为94％。[α]D 20＝+10.3(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ8.10–8.02(m,1H),7.27(d,J＝8.0Hz,2H),7.14–7.07(m,1H),6.98(td,J＝7.6,1.2Hz,1H),6.95(s,2H),6.91(d,J＝7.8Hz,2H),6.59(d,J＝8.0Hz,1H),4.04–3.95(m,1H),3.89–3.78(m,1H),3.32(s,3H),2.57–2.45(m,1H),2.31–2.18(m,1H),2.06(s,3H),1.83–1.70(m,1H),1.64–1.51(m,1H).13C NMR(100MHz,C6D6)δ156.2,136.7,135.5,135.0,133.5,129.4,128.2,127.4,126.9,126.6,121.1,111.6,85.5,67.6,54.9,38.5,25.9,21.1.HRMS(ESI)m/z calcd.for C20H23O2[M+H]+:295.1693；found295.1698.
实施例7：产物III-7和IV-7的合成
实施例7的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-7所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-7和IV-7。
Figure BDA0002859675920000132
得到产物III-7为白色固体，产率47％，ee值为80％。[α]D 20＝–50.8(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.23–7.17(m,6H),7.13(m,1H),7.09(d,J＝7.8Hz,2H),6.35(d,J＝16.0Hz,1H),6.17(d,J＝16.0Hz,1H),4.61(s,1H),4.35(t,J＝5.8Hz,1H),3.33(m,2H),2.88–2.71(m,2H),2.25(s,3H),1.63–1.31(m,4H).13C NMR(100MHz,DMSO–d6)δ137.9,136.1,135.5,134.4,130.6,129.1,127.4,126.6,125.9,125.7,74.2,61.3,47.8,36.7,27.1,20.7.HRMS(ESI)m/z calcd.for C20H23NaO2[M+Na]+:319.1669；found319.1667.
得到产物IV-7为无色油状物，产率50％，ee值为80％。[α]D 20＝+2.8(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.29–7.23(m,2H),7.22–7.16(m,2H),7.15–7.10(m,2H),7.10–7.04(m,1H),6.94(d,J＝7.8Hz,2H),6.69(d,J＝15.8Hz,1H),6.12(d,J＝15.8Hz,1H),3.79–3.71(m,1H),3.70–3.62(m,1H),2.96(d,J＝13.2Hz,1H),2.83(d,J＝13.2Hz,1H),2.08(s,3H),1.72–1.43(m,3H),1.42–1.25(m,1H).13C NMR(100MHz,C6D6)δ138.3,136.9,135.1,134.3,131.1,129.5,128.1,126.8,126.5,85.3,67.9,47.0,35.3,25.6,21.1.HRMS(ESI)m/z calcd.for C20H23O[M+H+]:279.1743；found 279.1742.
实施例8：产物III-8和IV-8的合成
实施例8的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-8所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-8和IV-8。
Figure BDA0002859675920000141
得到产物III-8为白色固体，产率47％，ee值为95％。[α]D 20＝–5.4(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.43(dd,J＝5.0,3.0Hz,1H),7.35–7.27(m,3H),7.18–7.06(m,3H),6.52(s,2H),5.31(s,1H),4.37(t,J＝5.2Hz,1H),3.38–3.35(m,2H),2.27(s,3H),1.94–1.76(m,2H),1.54–1.28(m,2H).13C NMR(100MHz,DMSO–d6)δ149.3,136.3,135.8,134.1,129.1,126.6,126.1,125.7,125.4,119.5,74.5,61.2,27.2,20.7.HRMS(ESI)m/zcalcd.for C17H20NaO2S[M+Na+]:311.1076；found 311.1078.
得到产物IV-8为无色油状物，产率47％，ee值为71％。[α]D 20＝+6.2(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.18(d,J＝8.0Hz,2H),7.09–7.00(m,2H),6.96–6.87(m,3H),6.72(d,J＝15.8Hz,1H),6.42(d,J＝15.8Hz,1H),3.92–3.83(m,1H),3.82–3.76(m,1H),2.08(s,3H),2.03–1.86(m,2H),1.73–1.49(m,2H).13C NMR(100MHz,C6D6)δ147.5,137.1,134.7,133.8,129.5,128.1,126.9,126.8,125.8,120.4,85.2,67.8,38.7,25.8,21.2.HRMS(ESI)m/z calcd.for C17H19OS[M+H+]:271.1151；found 271.1153.
实施例9：产物III-9和IV-9的合成
实施例9的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-9所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-9和IV-9。
Figure BDA0002859675920000151
得到产物III-9为白色固体，产率44％，ee值为90％。[α]D 20＝–7.4(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.67(td,J＝9.0,6.8Hz,1H),7.32(d,J＝8.8Hz,2H),7.18–7.01(m,2H),6.87(d,J＝8.8Hz,2H),6.53–6.47(m,1H),6.47–6.41(m,1H),5.47(s,1H),4.27(t,J＝5.1Hz,1H),3.73(s,3H),3.39–3.18(m,2H),2.11–1.97(m,1H),1.93–1.79(m,1H),1.46–1.26(m,3H),1.12–0.91(m,1H).13C NMR(100MHz,DMSO–d6)δ161.2(dd,J＝245.0,12.5Hz),158.7(dd,J＝247.5,11.9Hz),158.6,132.8,129.9(dd,J＝12.9,3.6Hz),129.2,129.0(dd,J＝9.2,6.3Hz),127.3,126.4,113.9,110.6(dd,J＝20.4,2.9Hz),103.9(dd,J＝27.9,25.8Hz),74.2,60.7,55.0,40.3,32.8,20.0.19F NMR(376MHz,DMSO–d6)δ–109.70,–115.83.HRMS(ESI)m/z calcd.for C20H22F2NaO3[M+Na+]:371.1429；found 371.1425.
得到产物IV-9为无色油状物，产率51％，ee值为76％。[α]D 20＝+5.2(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.72(q,J＝8.8Hz,1H),7.17(d,J＝8.6Hz,2H),6.70(d,J＝8.6Hz,2H),6.67–6.59(m,2H),6.52(t,J＝10.3Hz,1H),6.32(d,J＝16.2Hz,1H),3.87–3.71(m,1H),3.68–3.55(m,1H),3.27(s,3H),2.38–2.21(m,1H),2.01–1.85(m,1H),1.64–1.47(m,1H),1.47–1.20(m,3H).13C NMR(100MHz,C6D6)δ162.5(dd,J＝218.1,11.7Hz),160.0(dd,J＝220.6,11.9Hz),159.9,130.8,130.6,130.1,130.0(dd,J＝11.5,3.9Hz),129.0(dd,J＝9.2,6.0Hz),114.4,111.1(dd,J＝20.4,3.4Hz),104.4(dd,J＝27.7,25.1Hz),76.7,76.7,62.7,54.8,34.8,34.7,26.3,20.5.19F NMR(376MHz,C6D6)δ–110.40,–115.15.HRMS(ESI)m/z calcd.for C20H21F2O2[M+H+]:331.1504；found 331.1508.
实施例10：产物III-10和IV-10的合成
实施例10的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-10所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-10和IV-10。
Figure BDA0002859675920000161
结合本申请全文可以看出，式I-10所示化合物中的取代基R1为4-甲基苯基，取代基R2为苯基，R3为正戊烷基。式III-10、式IV-10结构式中的取代基R1、R2、R3均与式I-10结构式中相同。
得到产物III-10为白色固体，产率47％，ee值为66％。[α]D 20＝–19.2(c 1.0,CHCl3)。1H NMR(400MHz,DMSO–d6)δ7.58–7.42(m,2H),7.35–7.25(m,4H),7.18(t,J＝7.2Hz,1H),7.11(d,J＝7.8Hz,2H),6.55(d,J＝16.0Hz,1H),6.54(d,J＝16.0Hz,1H),5.24(s,1H),4.31(t,J＝5.2Hz,1H),3.32(td,J＝6.6,5.2Hz,2H),2.26(s,3H),1.94–1.77(m,2H),1.53–1.15(m,5H),1.15–0.99(m,1H).13C NMR(100MHz,DMSO–d6)δ147.3,136.6,136.3,134.2,129.2,127.8,126.2,126.0,125.6,125.4,75.5,60.7,42.4,32.6,25.9,23.2,20.8.HRMS(ESI)m/z calcd.for C21H26NaO2[M+Na+]:333.1825；found 333.1826.
得到产物IV-10为无色油状物，产率40％，ee值为80％。[α]D 20＝+11.3(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ7.57(d,J＝7.1Hz,2H),7.25(t,J＝7.8Hz,2H),7.20(d,J＝8.0Hz,2H),7.14–7.09(m,1H),6.92(d,J＝8.0Hz,2H),6.87(d,J＝15.8Hz,1H),6.31(d,J＝15.8Hz,1H),3.73–3.58(m,1H),3.49–3.38(m,1H),2.27–2.13(m,1H),2.08(s,3H),2.04–1.94(m,1H),1.70–1.39(m,5H),1.33–1.17(m,1H).13C NMR(100MHz,C6D6)δ147.5,136.9,135.9,135.0,129.4,128.5,127.6,126.9,126.8,126.5,81.8,64.2,39.5,31.8,29.7,22.2,21.1.HRMS(ESI)m/z calcd.for C21H25O[M+H+]:293.1900；found 293.1903.
实施例11：产物III-11和IV-11的合成
实施例11的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的如式I-11所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-11和IV-11。
Figure BDA0002859675920000171
得到产物III-11为白色固体，产率27％，dr>50％。[α]D 20＝–16.4(c 1.0,CHCl3)。1HNMR(400MHz,DMSO–d6)δ7.58(dd,J＝7.8,1.8Hz,1H),7.38–7.25(m,5H),7.25–7.16(m,3H),7.10(d,J＝7.8Hz,2H),7.02–6.89(m,2H),6.79(d,J＝16.0Hz,1H),6.51(d,J＝16.0Hz,1H),5.12(s,1H),4.51(d,J＝5.0Hz,1H),4.43(s,2H),3.78(s,3H),3.62–3.47(m,1H),3.24(dq,J＝9.7,5.2,4.5Hz,2H),2.34–2.28(m,1H),2.26(s,3H),1.94–1.79(m,1H),1.59–1.40(m,1H),1.11–0.96(m,1H).13C NMR(100MHz,DMSO–d6)δ155.8,138.5,136.0,135.4,134.5,134.4,129.1,128.0,127.7,127.3,127.1,126.5,125.9,125.6,120.1,111.8,75.1,74.6,72.0,69.4,55.5,35.8,28.4,20.6.HRMS(ESI)m/z calcd.for C28H32NaO4[M+Na+]:455.2193；found 455.2196.
得到产物IV-11为无色油状物，产率67％，dr>50％。[α]D 20＝+12.5(c 1.0,CHCl3)。1H NMR(400MHz,C6D6)δ8.18(dd,J＝7.8,1.8Hz,1H),7.31(d,J＝6.8Hz,2H),7.26(d,J＝8.0Hz,2H),7.21–7.17(m,1H),7.13–7.07(m,2H),7.03–6.85(m,5H),6.58(d,J＝8.0Hz,1H),4.54–4.47(m,1H),4.44(s,2H),3.61(dd,J＝9.6,5.4Hz,1H),3.44(dd,J＝9.6,5.4Hz,1H),3.32(s,3H),2.65–2.55(m,1H),2.34–2.22(m,1H),2.07(s,3H),2.02–1.92(m,1H),1.77–1.65(m,1H).13C NMR(100MHz,C6D6)δ155.9,139.4,136.7,135.5,135.5,133.5,129.4,128.5,128.3,127.6,127.4,126.9,126.9,121.1,111.4,86.3,77.9,73.6,73.4,55.0,37.5,28.4,21.1.HRMS(ESI)m/z calcd.for C28H31O3[M+H+]:415.2268；found415.2264.
实施例12-37
本发明具有广泛的底物实用性，按照实施例1中的反应条件，许多底物能参与该反应，高收率、高立体选择性地获得含有一个手性中心的手性烯丙基叔醇(E)-烯基取代二醇衍生物和(E)-2-烯基取代四氢呋喃类化合物。
实施例12-37的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的(E)-烯基取代二醇类化合物”，其余操作步骤同实施例1，最终得到相应的化合物手性烯丙基叔醇(E)-烯基取代二醇衍生物和(E)-2-烯基取代四氢呋喃类化合物，反应式如下：
Figure BDA0002859675920000181
上述反应式中，式III、式IV结构式中的取代基R1、R2、R3均与式I结构式中相同。
其中，实施例12-37中使用的(E)-烯基取代二醇类化合物的分子结构式分别如I-12～I-37所示，反应结果如表1所示。
在本申请的表1中，以式I化合物为原料，能够制得相应的两种化合物式，即III结构式的化合物和式IV结构式的化合物。例如，本申请的实施例12的实验方法重复实施例1，不同之处仅在于“将实施例1中的如式I-1所示的化合物替换为同等摩尔量的以式I-12所示化合物”，其余操作步骤同实施例1，最终得到相应的化合物III-12和IV-12，其反应结果汇总于表1中，化合物III-12和IV-12的产率分别为43％和52％。
表1
Figure BDA0002859675920000182
Figure BDA0002859675920000191
最后，还需要注意的是，以上列举的仅是本发明的具体实施例子。显然，本发明不限于以上实施例子，还可以有许多变形。本领域的技术人员能从本发明公开的内容直接导向或联想到的所有变形，均应以为是本发明的保护范围。

Claims (7)

1.一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于以手性磷酸为催化剂，在有机溶剂及添加剂存在的条件下，式I所示的(E)-烯基取代二醇类化合物在II所示的手性磷酸催化剂的催化下，经过动力学拆分反应得到式III所示的手性烯丙基叔醇(E)-烯基取代二醇衍生物和式IV所示的(E)-2-烯基取代四氢呋喃类化合物，反应式如下：
Figure RE-FDA0002956163100000011
R1选自下列之一：C6～C20芳基或取代芳基、具有1-3个选自N、S和O的杂原子的C4～C16杂芳基；其中R1中，所述的C6～C20芳基或取代芳基优选为C6～C14芳基或取代芳基，所述的具有1-3个选自N、S和O的杂原子的C4～C16杂芳基优选为含有一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C15杂芳基；
R2选自下列之一：C1～C6烷基、C3～C6烯基、C3～C8环烷烃基、C6～C18芳基或取代芳基、C7～C12苄基、具有1-3个选自N、S和O的杂原子的C4～C12杂芳基；其中R2中，所述的C1～C6烷基优选为C1～C4烷基；C3～C6烯基优选为C3～C4烯基；所述的C3～C8环烷烃基优选为C3～C6环烷烃基；所述的C6～C18芳基或取代芳基优选为C6～C12芳基或取代芳基；C7～C12苄基优选为C7～C9苄基；所述的具有1-3个选自N、S和O的杂原子的C4～C12杂芳基优选为含一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C11杂芳基；
R3选自C2～C6烷基或取代烷基，优选为C2～C5烷基或取代烷基；
Ar选自下列之一：2,4,6-三异丙基苯基、三苯基硅基、萘基、菲基、蒽基、2,4,6-三环己基苯基、2,4,6-三苯基苯基、2,4,6-三环戊己苯基，优选为2,4,6-三环戊己苯基；
X选自下列之一：氢、硝基、三异丙基硅基，优选为氢。
2.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于所述R1中，C6～C14芳基或取代芳基为苯基、氟苯基、甲氧基苯基、甲基苯基、联苯基、萘基、菲基或蒽基，含有一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C15杂芳基为苯并呋喃、噻吩、取代噻吩、取代吲哚或二苯并呋喃；所述R2中，C1～C4烷基为甲基或异丙基，C3～C4烯基为异烯丙基，C3～C6环烷烃基为环己基，C6～C12芳基或取代芳基为甲基苯基、氟苯基、甲氧基苯基或萘基，C7～C9苄基为苄基，含一个氧杂原子或一个硫杂原子或一个氮杂原子的C4～C11杂芳基为取代吡咯或噻吩；所述R3中，C2～C5烷烃基为乙基、丙基、正丁基或正戊基，C2～C5取代烷烃基中的取代基为苄氧基甲基、甲基、乙烯基或羟甲基。
3.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于式I所示(E)-烯基取代二醇类化合物选自下列之一：
Figure RE-FDA0002956163100000031
4.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于反应温度为-40℃～50℃，优选为-20℃～35℃；所述有机溶剂为二氯甲烷、甲苯、1,2-二氯乙烷、四氯化碳、乙醚、乙腈、三氟甲苯、氯仿或正己烷，优选为1,2-二氯乙烷。
5.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于催化剂与式I所示的(E)-烯基取代二醇类化合物的物质的量比为0.5～50:100，优选为15:100；式I所示的(E)-烯基取代二醇类化合物的物质的量与有机溶剂的体积之比为0.05～0.5:1，优选为0.01:1，物质的量单位为mmol，体积单位为mL。
6.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于所述添加剂为分子筛，分子筛型号为
Figure RE-FDA0002956163100000041
分子筛、
Figure RE-FDA0002956163100000042
分子筛或
Figure RE-FDA0002956163100000043
分子筛，优选为
Figure RE-FDA0002956163100000044
分子筛；所述分子筛的质量与式I所示的(E)-烯基取代二醇类化合物的物质的量之比为1～1.5:1，质量的单位为g，物质的量单位为mmol。
7.如权利要求1所述的一种手性磷酸催化的烯丙基叔醇动力学拆分方法，其特征在于式II所示的手性磷酸催化剂选自下列之一：
Figure RE-FDA0002956163100000051
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CN113788756B (zh) * 2021-10-12 2023-08-11 青岛科技大学 一种双酸催化绿色合成光学纯的烯丙醇类化合物的方法
CN113979975A (zh) * 2021-11-05 2022-01-28 浙江工业大学 一种手性磷酸催化的芳基烯丙基叔醇动力学拆分方法

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