CN104628730A - 一类光学纯手性环状n,n-缩醛的合成方法 - Google Patents
一类光学纯手性环状n,n-缩醛的合成方法 Download PDFInfo
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- CN104628730A CN104628730A CN201510035988.XA CN201510035988A CN104628730A CN 104628730 A CN104628730 A CN 104628730A CN 201510035988 A CN201510035988 A CN 201510035988A CN 104628730 A CN104628730 A CN 104628730A
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- naphthyl
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- 125000003118 aryl group Chemical group 0.000 claims description 46
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
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- FGTYTUFKXYPTML-UHFFFAOYSA-N 2-benzoylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 FGTYTUFKXYPTML-UHFFFAOYSA-N 0.000 abstract 2
- 239000007848 Bronsted acid Substances 0.000 abstract 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
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- 238000001819 mass spectrum Methods 0.000 description 14
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- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
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- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一类光学纯手性环状N,N-缩醛的合成方法，以手性Br?nsted酸或者手性双噁唑啉/金属盐作为催化剂，在有或没有分子筛存在的条件下，N取代基脂肪二胺与邻甲酰基苯甲酸酯发生串联不对称亚胺缩合-加成-酰胺化反应，合成目标化合物。反应产率高，对映选择性好，条件温和，操作简单，环境友好。同时底物具有适应范围广的特点，适用于各类取代的邻甲酰基苯甲酸酯类化合物和各种链取代和链长的脂肪二胺和芳香二胺，非常适合于医药及其中间体的合成。
Description
技术领域
本发明属于化学催化领域，具体地说，涉及不对称催化法合成一类光学纯手性环状N,N-缩醛的合成方法
背景技术
氮杂环手性化合物是药物分子和天然产物的重要组成部分，其中N,N-缩醛以其独特的结构广泛存在于海洋和陆生天然产物生物碱中和药物小分子中，这一类化合物往往具有较好的生物活性[(a)Zhang,M.；Huang,X.；Shen,L.；Qin,Y.J.Am.Chem.Soc.2009,131,6013.(b)Zi,W.；Xie,W.；Ma,D.J.Am.Chem.Soc.2012,134,9126.(c)Horning,B.D.；MacMillan D.W.C.J.Am.Chem.Soc.2013,135,6442.(d)Wang,Q.Z.；Liang,J.Y.；Feng,X.Chin.Chem.Lett.2010,21,596.(e)Snider,B.B.；Zeng,H.Org.Lett.2000,2,4103.(f)Shao,C.-L.；Xu,R.-F.；Wei,M.-Y.；She,Z.-G.；Wang,C.-Y.J.Nat.Prod.2013,76,779.(g)Sharma,M.；Chauhan,K.；Shivahare,R.；Vishwakarma,P.；Suthar,M.K.；Sharma,A.；Gupta,S.；Saxena,J.K.；Lal,J.；Chandra,P.；Kumar B.；Chauhan,P.M.S.J.Med.Chem.2013,56,4374.]。分子内不对称N,N-缩醛化反应作为一种能够高效构建N，N-缩醛的有机反应，在药物分子合成中具有极其重要的地位和广泛的应用[(a)Chinigo,G.M.；Paige,M.；Grindrod,S.；Hamel,E.；Dakshanamurthy,S.；Chruszcz,M.；Minor,W.；Brown,M.L.J.Med.Chem.2008,51,4620.]。例如近年来报道的分子内不对称N,N-缩醛化反应可以用手性酸作为催化剂，但是成功的例子仅仅限于邻氨基苯甲酰胺及其衍生物作为底物[(a)Cheng,X.；Vellalath,S.；Goddard,R.；List,B.J.Am.Chem.Soc.2008,130,15786.(b)Rueping,M.；Antonchick,A.P.；Sugiono,E.；Grenader,K.,Angew.Chem.Int.Ed.2009,48,908-910.(c)Cheng,D.-J.；Tian,Y.；Tian,S.-K.Adv.Synth.Catal.2012,354,995.]。同时，仅仅有一例是通过手性噁唑啉和金属组成Lewis酸直接催化合成[Prakash,M.；Kesavan,V.Org.Lett.2012,14,1896.]，但是底物也是仅限于邻氨基苯甲酰胺作为底物。文献检索发现，迄今为止，脂肪二胺作为底物的分子内不对称N,N-缩醛化仅仅只有两例报道[(a)Katritzky,A.R.；He,H.-Y.；Verma,A.K.Tetrahedron:Asymmetry2002,13,933-938.(b)Yamada,S.；Takahashi,Y.Tetrahedron Lett.2009,50,5395.]，且都是通过在脂肪二胺的结构中引入手性辅助基团，计量不对称反应生成手性环状N,N-缩醛产物。而通过直接催化的不对称N,N-缩醛化反应来合成该类化合物的例子尚未见报道。据报道，异吲哚酮结构的环状N,N-缩醛具有抗炎(anti-inflammatory)、抗痉挛(spasmolytic)、止咳(antitussive)、抗风湿(rheumatism)、镇痛(analgesic)、镇静(sedative)、降血压(bloodpressure lowering)等广泛的生物活性[(a)Geigy,J.；R.Neth.Appl.6,613,264,1967；Chem.Abstr.1967,67,82204q.(b)Graf,W.Swiss 481,123,1969；Chem.Abstr.1970,72,100709t.(c)Graf,W.Swiss 481,124,1969；Chem.Abstr.1970,72,100710m.]；也是一种很好的抗HIV病毒的化合物，并且抗HIV的活性取决于N,N-缩醛手性中心的构型[Mertens,A.；Zilch,H.；Koenig,B.；Schaefer,W.；Poll,T.；Kampe,W.；Seidel,H.；Leser,U.；Leinert,H.J.Med.Chem.1993,36,2526.]。而且，具有异吲哚酮结构的环状N,N-缩醛还是很重要的药物先导化合物[(a)Nielsen,T.E.；Quement,S.L.；Meldal,M.Org.Lett.2005,7,3601.(b)Mizutani,N.；Chiou,W.-H.；Ojima,I.Org.Lett.2002,4,4575.(c)Vink,M.K.S.；Schortinghuis,C.A.；Mackova-Zabelinskaja,A.；Fechter,M.；Pochlauer,P.；Castelijns,A.M.C.F.；van Maarseveen,J.H.；Hiemstra,H.；Griengl,H.；Schoemaker,H.E.；Rutjes,F.P.J.T.Adv.Synth.Catal.2003,345,483.]。以前光学纯异吲哚-5-酮结构的环状N,N-缩醛都是通过计量不对称合成方法获得，迄今为止，还没有应用不对称催化法获得光学纯异吲哚酮结构的环状N,N-缩醛的报道，为此我们发明了一种高效的催化不对称合成制备光学纯异吲哚酮结构的环状N,N-缩醛的方法。
发明内容
本发明的目的在于提供一种高效的不对称催化合成手性环状N,N-缩醛的方法。
为了实现上述目的，本发明采用如下技术方案：
一类光学纯手性环状N,N-缩醛的合成方法，包括以下步骤：在有或者没有或者分子筛存在的条件下，反应温度为-85-100℃的有机溶剂中，以邻甲酰基苯甲酸酯和N-取代的脂肪二胺为原料，以手性酸催化剂或者手性噁唑啉/金属盐作为催化剂进行缩合反应，生成亚胺后发生分子内N原子对亚胺加成同时酰胺化的串联反应，反应5分钟到72小时后，分离得到产物，所述的邻甲酰基苯甲酸酯、N-取代的脂肪二胺和手性催化剂的摩尔比为1：1.2-2：0.02-0.2；
所合成的光学纯环状N,N-缩醛化合物具有如下结构通式：
结构式中n＝0，1，2，3，4时，化合物分别代表1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮、1-取代-1,3,4,10b-四氢嘧啶[2,1-a]异吲哚-6(2H)-酮化合物、1-取代-2,3,4,5-四氢-1H-[1,3]二氮卓[2,1-a]异吲哚-7(11bH)-酮、1-取代-1,3,4,5,6,12b-六氢-[1,3]二氮杂辛环烷[2,1-a]异吲哚-8(2H)-酮、1-取代-2,3,4,5,6,7-八氢-1H-[1,3]二氮杂壬环烷[2,1-a]异吲哚-9(13bH)-酮；R1选自H、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、C2-C16羰基、芳基、芳香杂环、取代苄基；
R2、R3、R4、R5选自H、F、Cl、Br、I、C1-C16烷基、C1-C16烷氧基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、C2-C16氰基、NO2、CF3、SO3H、醛基、羟基、羧基、氨基、酰胺基、芳基、芳香杂环、取代苄基；
R6、R7、R8、R9选自H、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、氧烷羰基、氰基、取代苄基；
R10选自H、C1-C16烷基、C3-C16烯基、C3-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳基、芳香杂环、取代苄基；
其中R11、R12、R13、R14、R15选自H、C1-C16烷基、C1-C16烷氧基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、氰基、NO2、CF3、SO3H、醛基、羟基、羧基、氨基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；
所述的邻酰基苯甲酸酯的结构为：R16为任意选自C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环选自C5-C10的含氮、硫、氧原子的杂环基团；所述N-取代脂肪二胺结构式为：其中n＝0，1，2,3,4；
所述的手性催化剂结构选自： (R或S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R或S)(R或S)(R或S)(R或S)(R，R)或(S，S)(R或S)(R或S)(R或S)(R或S)(R或S)酒石酸；所述的手性双噁唑啉配体结构选自：(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R,R)或(S,S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R，R)或(S，S)(R,R，R)或(S,S，S)(Ra,R，R)或(Sa,S，S)(Ra,R，R)或(Sa,S，S)(Rp,R，R)或(Sp,S，S)(R，R)或(S，S)所用的金属盐为：Sc(OTf)3，Yb(OTf)3，La(OTf)3，Y(OTf)3，Cu(OTf)2或Zn(OTf)2；
其中R17选自H、C1-C16烷基、三(C1-C16烷基)硅基或三芳硅基；R18为任意选自H、F、Cl、Br、I、C1-C16烷基、三(C1-C16烷基)硅基、三芳硅基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；R19为任意选自OH、NH2、NHSO2R20、NHPO(R20)、NHPO(OR20)，其中R20为任意选自H、C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；R21为选自、C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团。
在上述合成方法中，所述的有机溶剂优选是苯、甲苯、二甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、石油醚、正己烷、四氢呋喃、二甲基甲酰胺、二甲基乙酰胺、乙醚、环己烷、正庚烷、正戊烷、二氧六环、乙二醇二甲醚、甲基叔丁基醚或乙腈，溶剂可以是其中的一种或者是两种或两种以上的混合溶剂。
在上述合成方法中，所得到的产物通过重结晶、柱层析、薄层层析或减压蒸馏加以分离。
在上述合成方法中，所述的邻甲酰基苯甲酸酯、N-取代的脂肪二胺和手性催化剂的摩尔比为1：1.2-2：0.02-0.2。
在上述合成方法中，所得到的产物的构型为R或S。
与现有技术相比，本发明具有如下有益效果：本发明以手性酸或者手性双噁唑啉/金属盐作为催化剂，在有或没有分子筛存在的条件下，N取代基脂肪二胺与邻甲酰基苯甲酸酯发生串联不对称亚胺缩合-加成-酰胺化反应，合成目标化合物。反应产率高，对映选择性好，条件温和，操作简单，环境友好。同时底物具有适应范围广的特点，适用于各类取代的邻甲酰基苯甲酸酯类化合物和各种链取代和链长的脂肪二胺和芳香二胺，非常适合于医药及其中间体的合成。
具体实施方式
下列实施例有助于对本发明的理解，但不限定本发明的内容。
实施例1：制备N1-烷基取代-1,2-乙二胺
将N1-叔丁氧羰基取代-1,2-乙二胺(30mmol)和等摩尔的醛溶于100mL甲醇中，搅拌下回流分水反应0.5-4h，然后冷却到室温，加入NaBH4(30mmol),反应1-5h，反应结束后用50mL二氯甲烷萃取三次，无水硫酸镁干燥，减压浓缩，柱层析得到产物(洗脱液：乙酸乙酯/甲醇)。将得到的纯产物溶于吸收HCl气体达到饱和的乙酸乙酯中，室温搅拌2-8h，加入氢氧化钠中和过量的酸，乙酸乙酯萃取。无水硫酸镁干燥，减压浓缩干得到底物N1-烷基取代-1,2-乙二胺。
实施例2：手性磷酸催化的N1-烷基-1,2-乙二胺和邻甲酰基苯甲酸甲酯发生分子内N,N-缩醛化反应制备光学纯1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮化合物
在干燥的反应管中加入高温活化后的分子筛(50mg),邻甲酰基苯甲酸甲酯(0.1mmol)和催化剂(0.01mmol)和1mL干燥的甲苯，冰浴搅拌下加入N1-(2,6-二异丙基苄基)-1,2-乙二胺，反应用TLC监测至原料消失，柱层析(洗脱液：石油醚/乙酸乙酯)得到产物。当本实施例用到的手性磷酸催化剂为：
手性1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮产物1：
31.1mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.119.0-120.1℃；(c＝1.5,CHCl3)；89％yield,96％ee；HPLC Analysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。1H NMR(300MHz,CDCl3)δ:7.84-7.82(m,1H),7.54-7.51(m,5H),4.90(s,1H),4.13(d,J＝12.3Hz,1H),3.87(d,J＝12.3Hz,1H),3.69-3.63(m,1H),3.47-3.21(m,4H),3.06-2.91(m,1H),1.11(d,J＝6.9Hz,6H),1.05(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:173.4,148.7,143.6,133.8,131.7,130.5,129.5,127.9,124.4,123.6,123.0,81.20,54.8,46.9,41.9,28.7,24.5,23.7；高分辨质谱(ESI)m/z计算值C23H29N2O[M+H]+324.2280,实测值324.2290.
34.0mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.121.3-122.1℃；(c＝1.7,CHCl3)；93％yield,95％ee；HPLC Analysis:Daicel Chiralpak OD-H columm:n-heptane:i-PrOH＝99:1,flow rate:1.0mL/min,λ＝225nm:tmajor＝16.13min,tminor＝14.76min；1H NMR(300MHz,CDCl3)δ:7.47(d,J＝7.2Hz,1H),7.28-7.10(m,5H),4.90(s,1H),4.13(d,J＝12.3Hz,1H),3.87(d,J＝12.3Hz,1H),3.69-3.64(m,1H),3.46-3.21(m,4H),3.05-2.97(m,1H),1.11(d,J＝6.9Hz,6H),1.07(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:172.0(d,J＝3.0Hz),163.5(d,J＝247.6Hz),148.5,139.3(d,J＝2.5Hz),136.1(d,J＝8.4Hz),130.4,128.1,124.9(d,J＝8.3Hz),123.1,119.0(d,J＝23.3Hz),111.1(d,J＝23.1Hz),80.7,54.9,47.2,41.8,28.8,24.5,23.7；高分辨质谱(ESI)计算值C23H28N2OF[M+H]+367.2180,实测值367.2188.
35.0mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.93.7-94.2℃；(c＝1.8,CHCl3)；92％yield,92％ee；HPLC Analysis:Daicel Chiralpak OD-H columm:n-heptane:i-PrOH＝99:1,flow rate:1.0mL/min,λ＝225nm:tmajor＝15.94min,tminor＝14.27min；1H NMR(300MHz,CDCl3)δ:7.78(d,J＝1.8Hz,1H),7.47-7.43(m,1H),7.28-7.23(m,1H),7.11(d,J＝7.8Hz,3H),4.90(s,1H),4.12(d,J＝12.6Hz,1H),3.87(d,J＝12.6Hz,1H),3.66(d,J＝9.9,8.1Hz,1H),3.46-3.20(m,4H),3.06-3.02(m,1H),1.11(d,J＝6.9Hz,6H),1.08(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:171.8,148.5,141.9,135.8,135.7,131.8,130.4,128.1,124.6,124.5,123.1,80.9,55.0,47.3,41.9,28.8,24.5,23.8；高分辨质谱(ESI)m/z计算值C23H28N2OCl[M+H]+383.1885,实测值383.1889.
39.5mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.97.9-98.8℃；(c＝2.0,CHCl3)；93％yield,92％ee；HPLC Analysis:Daicel Chiralpak OD-H columm:n-heptane:i-PrOH＝99:1,flow rate:1.0mL/min,λ＝225nm:tmajor＝17.36min,tminor＝15.11min；1H NMR(300MHz,CDCl3)δ:7.94(s,1H),7.60(d,J＝8.1Hz,1H),7.26-7.23(m,1H),7.12-7.03(m,3H),4.89(s,1H),4.12(d,J＝12.3Hz,1H),3.87(d,J＝12.3Hz,1H),3.72-3.63(m,1H),3.46-3.21(m,4H),3.02(dd,J＝17.7,9.9Hz,1H),1.11(d,J＝6.6Hz,6H),1.08(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:171.5,148.4,142.3,135.8,134.5,130.3,128.1,127.4,124.9,123.5,123.1,80.9,54.9,47.3,41.7,28.8,24.5,23.8；高分辨质谱(ESI)m/z计算值C23H28N2OBr([M+H]+)427.1379,实测值427.1386.
39.2mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.148.5-149.8℃；(c＝2.0,CHCl3)；92％yield,96％ee；HPLC Analysis:Daicel Chiralpak OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝10.30min,tminor＝16.91min；1H NMR(300MHz,CDCl3)δ:7.63(s,1H),7.35-7.22(m,3H),7.11(d,J＝7.8Hz,3H),4.90(s,1H),4.15(d,J＝12.3Hz,1H),3.83(d,J＝12.3Hz,1H),3.65(dd,J＝18.0,9.9Hz,1H),3.45-3.39(m,1H),3.32-3.23(m,3H),3.00(dd,J＝17.7,9.3Hz,1H),2.47(s,3H),1.13(d,J＝6.6Hz,6H),1.06(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:173.6,148.5,140.9,139.6,134.0,132.6,130.6,128.0,124.6,123.0,81.1,54.8,46.9,41.8,28.7,24.6,23.8,21.4；高分辨质谱(ESI)m/z计算值C24H31N2O([M+H]+)363.2436,实测值363.2438.
34.0mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝5:1),white solid:m.p.154.5-155.8℃；(c＝1.7,CHCl3)；90％yield,94％ee；HPLC Analysis:Daicel Chiralpak OJ-H columm:n-heptane:i-PrOH＝90:10,flow rate:1.0mL/min,λ＝225nm:tmajor＝21.28min,tminor＝15.49min；1H NMR(300MHz,CDCl3)δ:7.30-7.04(m,6H),4.87(s,1H),4.12(d,J＝12.6Hz,1H),3.87-3.80(m,4H),3.63(dd,J＝18.0,9.0Hz,1H),3.45-3.39(m,1H),3.29-3.23(m,3H),3.03-2.95(m,1H),1.12(d,J＝6.6Hz,6H),1.06(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:173.3,160.9,148.5,136.0,135.4,130.6,127.9,124.1,123.0,119.7,107.1,80.9,55.6,54.8,46.9,41.8,28.7,24.5,23.7；高分辨质谱(ESI)m/z计算值C23H28N2O2[M+H]+379.2380,实测值379.2391.
35.4mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝5:1),white solid:m.p.165.8-166.5℃；(c＝1.8,CHCl3)；90％yield,91％ee；HPLC Analysis:Daicel Chiralpak AS-H columm:n-heptane:i-PrOH＝90:10,flow rate:1.0mL/min,λ＝225nm:tmajor＝17.81min,tminor＝13.79min；1H NMR(300MHz,CDCl3)δ:8.59(s,1H),8.29(dd,J＝8.4,1.8Hz,1H),7.31-7.26(m,1H),7.14-7.07(m,3H),5.02(s,1H),4.18(d,J＝12.6Hz,1H),3.98(d,J＝12.6Hz,1H),3.81-3.72(m,1H),3.53-3.39(m,2H),3.31-3.22(m,2H),3.13-3.04(m,1H),1.11(d,J＝6.6Hz,6H),1.08(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:170.40,149.3,149.0,148.5,135.5,130.1,128.4,126.5,124.7,123.3,119.6,80.8,55.4,47.9,41.9,28.9,24.4,23.8；高分辨质谱(ESI)m/z计算值C23H28N3O3[M+H]+394.2125,实测值394.2132.
34.4mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.127.8-128.7℃；(c＝1.7,CHCl3)；94％yield,96％ee；HPLC Analysis:Daicel Chiralpak OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝12.99min,tminor＝17.18min；1H NMR(300MHz,CDCl3)δ:7.78(dd,J＝8.4,5.1Hz,1H),7.30-7.11(m,4H),6.79(dd,J＝8.4,1.8Hz,1H),4.90(s,1H),4.13(d,J＝12.3Hz,1H),3.89(d,J＝12.3Hz,1H),3.70-3.64(m,1H),3.46-3.23(m,4H),3.02(dd,J＝14.7,9.3Hz,1H),1.11(d,J＝6.9Hz,6H),1.08(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:172.3,165.1(d,J＝251.0Hz),148.5,146.2(d,J＝9.3Hz),130.4,129.7(d,J＝2.1Hz),128.2,126.2(d,J＝9.6Hz),123.1,117.0(d,J＝23.2Hz),111.1(d,J＝24.4),80.7,55.2,47.4,41.9,28.9,24.5,23.8；高分辨质谱m/z计算值C23H28N2OF[M+H]+367.2180,实测值367.2183.
35.1mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.175.2-175.8℃；(c＝1.76,CHCl3)；92％yield,96％ee；HPLC Analysis:Daicel Chiralpak OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝10.13min,tminor＝15.72min；1H NMR(300MHz,CDCl3)δ:7.72(d,J＝8.1Hz,1H),7.47(d,J＝8.1Hz,1H),7.30-7.25(m,1H),7.14-7.06(m,3H),4.91(s,1H),4.14(d,J＝12.6Hz,1H),3.89(d,J＝12.6Hz,1H),3.74-3.65(m,1H),3.46-3.20(m,4H),3.47-3.22(m,4H),3.07-2.98(m,1H),1.12(d,J＝6.9Hz,6H),1.09(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:172.3,148.5,145.3,138.2,132.1,130.3,129.9,128.3,125.4,124.1,123.1,80.6,55.3,47.5,41.9,28.8,.24.4,23.8；高分辨质谱m/z计算值C23H28N2OCl[M+H]+383.1885,实测值383.1889.
39.2mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.179.6-180.8℃；(c＝2.0,CHCl3)；92％yield,96％ee；HPLC Analysis:Daicel Chiralpak OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝10.30min,tminor＝16.91min；1H NMR(300MHz,CDCl3)δ:7.67-7.61(m,2H),7.28-7.12(m,4H),4.91(s,1H),4.14(d,J＝12.6Hz,1H),3.89(d,J＝12.6Hz,1H),3.74-3.65(m,1H),3.47-3.22(m,4H),3.08-2.99(m,1H),1.12(d,J＝7.2Hz,6H),1.09(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:172.4,148.5,145.5,132.8,132.5,130.3,128.3,127.1,126.5,125.6,123.1,80.6,55.3,47.5,41.9,28.8,24.4,23.8；高分辨质谱m/z计算值C23H28N2OBr([M+H]+)427.1379,实测值427.1386.
37.8mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.177.4-179.2℃；(c＝2.0,CHCl3)；91％yield,92％ee；HPLC Analysis:Daicel Chiralcel OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝7.81min,tminor＝11.83min；1H NMR(300MHz,CDCl3)δ:7.90(d,J＝8.1Hz,1H),7.78(d,J＝7.8Hz,1H),7.30-2.25(m,2H),7.12(d,J＝7.8Hz,2H),5.00(s,1H),4.18(d,J＝12.3Hz,1H),3.94(d,J＝12.3Hz,1H),3.80-3.71(m,1H),3.53-3.41(m,2H),3.30-3.21(m,2H),3.13-3.04(m,1H),1.08(d,J＝6.6Hz,12H)；13C NMR(100MHz,CDCl3)δ:171.6,148.4,144.3,137.0,133.6(q,J＝32.3Hz),130.2,128.4,126.7(d,J＝3.7Hz),124.7,123.6(q,J＝271.2),123.2,120.92(q,J＝3.8Hz)；高分辨质谱m/z计算值C24H28N2OF3([M+H]+)417.1950,实测值417.1948.
34.4mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝5:1),white solid:m.p.201.5-203℃；(c＝2.0,CHCl3)；91％yield,90％ee；HPLC Analysis:Daicel ChiralpakAS-H columm:n-heptane:i-PrOH＝90:10,flow rate:1.0mL/min,λ＝225nm:tmajor＝23.81min,tminor＝10.78min；1H NMR(300MHz,CDCl3)δ:7.72(d,J＝8.4Hz,1H),7.27-7.22(m,1H),7.13(d,J＝7.5Hz,2H),7.02(dd,J＝8.4,2.1Hz,1H),6.79(d,J＝2.1Hz,1H),4.89(s,1H),4.16(d,J＝12.3Hz,1H),3.87-3.82(m,4H),3.71-3.61(m,1H),3.43-3.26(m,4H),3.05-2.96(m,1H),1.13(d,J＝6.9Hz,6H),1.08(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:173.3,160.9,148.5,136.0,135.4,130.6,127.9,124.1,123.0,119.7,107.1,81.0,55.6,54.8,46.9,41.8,28.7,24.5,23.7；高分辨质谱m/z计算值C24H31N2O2([M+H]+)379.2380,实测值379.2376.
32.5mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:m.p.156.2-158.0℃；(c＝2.0,CHCl3)；90％yield,92％ee；HPLC Analysis:Daicel Chiralcel OJ-H columm:n-heptane:i-PrOH＝98:2,flow rate:1.0mL/min,λ＝225nm:tmajor＝10.68min,tminor＝14.45min；1H NMR(300MHz,CDCl3)δ:7.69(d,J＝7.5Hz,1H),7.32-7.22(m,2H),7.12-7.08(m,3H),4.89(s,1H),4.16(d,J＝12.6Hz,1H),3.84(d,J＝12.6Hz,1H),3.71-3.62(m,1H),3.45-3.23(m,4H),3.05-2.96(m,1H),2.42(s,3H),1.11(d,J＝6.6Hz,6H),1.06(d,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ:173.8,148.5,144.1,142.4,131.1,130.7,130.3,127.9,124.0,123.9,123.0,81.1,55.1,47.1,41.9,28.7,24.5,23.7,21.8；高分辨质谱m/z计算值C24H31N2O([M+H]+)363.2430,实测值363.2431.
当本实施例用到的手性磷酸催化剂为：
所得到产物所得到产物：36.5mg,(Flash column chromatographyeluent,petroleum ether:ethyl acetate＝10:1),white solid:90％yield,50％ee；HPLCAnalysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。
当本实施例用到的手性磷酸催化剂为：
所得到产物：36.5mg,(Flash column chromatography eluent,petroleum ether:ethyl acetate＝10:1),white solid:90％yield,52％ee；HPLC Analysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。
当本实施例用到的手性磷酸催化剂为：
所得到产物所得到产物：37.5mg,(Flash column chromatographyeluent,petroleum ether:ethyl acetate＝10:1),white solid:91％yield,65％ee；HPLCAnalysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。
当本实施例用到的手性磷酸催化剂为：
所得到产物
所得到产物所得到产物：35.5mg,(Flash column chromatographyeluent,petroleum ether:ethyl acetate＝10:1),white solid:89％yield,70％ee；HPLCAnalysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。
实施例3：手性噁唑啉/金属Lewis酸催化的N1-烷基-1,2-乙二胺和邻甲酰基苯甲酸甲酯发生分子内N,N-缩醛化反应制备光学纯1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮化合物
在干燥的反应管中加入高温活化后的分子筛(50mg),邻甲酰基苯甲酸甲酯(0.1mmol)和手性噁唑啉配体(0.01mmol)、Sc(OTf)3和1mL干燥的甲苯，常温搅拌下加入N1-(2,6-二异丙基苄基)-1,2-乙二胺，反应用TLC监测至原料消失，柱层析(洗脱液：石油醚/乙酸乙酯)得到产物。本实施例用到的手性噁唑啉配体为：
所得到的产物为：
26.8mg,(Flash column chromatography eluent,petroleumether:ethyl acetate＝10:1),white solid:77％yield,62％ee；HPLC Analysis:DaicelChiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tminor＝9.74min,tmajor＝10.75min。
实施例4：手性硫脲催化N1-烷基-1,2-乙二胺和邻甲酰基苯甲酸甲酯发生分子内N,N-缩醛化反应，制备光学纯1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮化合物：
在干燥的反应管中加入高温活化后的分子筛(50mg),邻甲酰基苯甲酸甲酯(0.1mmol)和手性硫脲(0.01mmol)以及1mL干燥的甲苯，常温搅拌下加入N1-(2,6-二异丙基苄基)-1,2-乙二胺，反应用TLC监测至原料消失，柱层析(洗脱液：石油醚/乙酸乙酯)得到产物。本实施例使用的手性硫脲催化剂为：
所得到的产物为：36.5mg,(Flash column chromatography eluent,petroleum ether:ethyl acetate＝10:1),white solid:93％yield,70％ee；HPLC Analysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝9.74min,tminor＝10.75min。
实施例5：手性方酰胺催化的N1-烷基-1,2-乙二胺和邻甲酰基苯甲酸甲酯发生分子内N,N-缩醛化反应制备光学纯1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮化合物：
在干燥的反应管中加入高温活化后的分子筛(50mg),邻甲酰基苯甲酸甲酯(0.1mmol)和手性方酰胺(0.01mmol)1mL干燥的甲苯，常温搅拌下加入N1-(2,6-二异丙基苄基)-1,2-乙二胺，反应用TLC监测至原料消失，柱层析(洗脱液：石油醚/乙酸乙酯)得到产物。本实施例使用的手性方酰胺为：(S)
所得到的产物为：35.5mg,(Flash column chromatographyeluent,petroleum ether:ethyl acetate＝10:1),white solid:91％yield,68％ee；HPLCAnalysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tminor＝9.74min,tmajor＝10.75min。
实施例6：手性磷酸催化的N1-烷基-1,2-丙二胺和邻甲酰基苯甲酸甲酯发生分子内N,N-缩醛化反应制备光学纯1-取代-2,3,4,5-四氢-1H-[1,3]二氮卓[2,1-a]异吲哚-7(11bH)-酮化合物：
在干燥的反应管中加入高温活化后的分子筛(50mg)，邻甲酰基苯甲酸甲酯(0.1mmol)和催化剂(0.01mmol)和1mL干燥的甲苯，冰浴搅拌下加入N1-(2,6-二异丙基苄基)-1,3-丙二胺，反应用TLC监测至原料消失，柱层析(洗脱液：石油醚/乙酸乙酯)得到产物。本实施例用到的手性磷酸催化剂为：
手性1-取代-2,3,4,5-四氢-1H-[1,3]二氮卓[2,1-a]异吲哚-7(11bH)-酮产物
32.5mg,(Flash column chromatography eluent,petroleum ether:ethylacetate＝10:1),white solid:m.p.126.0-128.1℃；(c＝1.5,CHCl3)；89％yield,66％ee；HPLC Analysis:Daicel Chiralpak OD-H columm，n-heptane:i-PrOH＝95:5,flow rate 1.0mL/min,λ＝225nm，tmajor＝7.28min,tminor＝9.75min。1H NMR(300MHz,CDCl3)δ:7.92-7.89(m,1H),7.62-7.50(m,3H),7.23-7.20(m,1H),5.06(s,1H),4.53-4.47(m,1H)4.08(d,J＝12.3Hz,1H),3.57(d,J＝12.3Hz,1H),3.59-3.08(m,3H),2.92(d,J＝12.3Hz,1H),2.74-2.65(m,1H),1.87-1.70(m,1H),1.77-1.55(m,1H)1.11(d,J＝6.9Hz,6H),1.05(d,J＝6.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:165.9,148.9,141.7,133.5,130.7,130.6,129.1,127.6,124.1,123.9,122.7,76.7,48.3,44.3,38.9,28.7,24.5,24.0,22.4；高分辨质谱(ESI)m/z计算值C23H29N2O[M+H]+363.2436,实测值363.2455。
Claims (5)
1.一类光学纯手性环状N,N-缩醛的合成方法，其特征在于包括以下步骤：在有或者没有或者分子筛存在的条件下，反应温度为-85-100℃的有机溶剂中，以邻甲酰基苯甲酸酯和N-取代的脂肪二胺为原料，以手性酸催化剂或者手性噁唑啉/金属盐作为催化剂进行缩合反应，生成亚胺后发生分子内N原子对亚胺加成同时酰胺化的串联反应，反应5分钟到72小时后，分离得到产物，所述的邻甲酰基苯甲酸酯、N-取代的脂肪二胺和手性催化剂的摩尔比为1：1.2-2：0.02-0.2；
所合成的光学纯环状N,N-缩醛化合物具有如下结构通式：
结构式中n＝0，1，2，3，4时，化合物分别代表1-取代-2,3-二氢-1H-咪唑[2,1-a]并异吲哚-5-酮、1-取代-1,3,4,10b-四氢嘧啶[2,1-a]异吲哚-6(2H)-酮化合物、1-取代-2,3,4,5-四氢-1H-[1,3]二氮卓[2,1-a]异吲哚-7(11bH)-酮、1-取代-1,3,4,5,6,12b-六氢-[1,3]二氮杂辛环烷[2,1-a]异吲哚-8(2H)-酮、1-取代-2,3,4,5,6,7-八氢-1H-[1,3]二氮杂壬环烷[2,1-a]异吲哚-9(13bH)-酮；R1选自H、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、C2-C16羰基、芳基、芳香杂环、取代苄基；
R2、R3、R4、R5选自H、F、Cl、Br、I、C1-C16烷基、C1-C16烷氧基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、C2-C16氰基、NO2、CF3、SO3H、醛基、羟基、羧基、氨基、酰胺基、芳基、芳香杂环、取代苄基；
R6、R7、R8、R9选自H、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、氧烷羰基、氰基、取代苄基；
R10选自H、C1-C16烷基、C3-C16烯基、C3-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳基、芳香杂环、取代苄基；
其中R11、R12、R13、R14、R15选自H、C1-C16烷基、C1-C16烷氧基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、氰基、NO2、CF3、SO3H、醛基、羟基、羧基、氨基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；
所述的邻酰基苯甲酸酯的结构为：R16为任意选自C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环选自C5-C10的含氮、硫、氧原子的杂环基团；所述N-取代脂肪二胺结构式为：其中n＝0，1，2,3,4；
所述的手性催化剂结构选自：
酒石酸；所述的手性双噁唑啉配体结构选自： 所用的金属盐为：Sc(OTf)3，Yb(OTf)3，La(OTf)3，Y(OTf)3，Cu(OTf)2或Zn(OTf)2；
其中R17选自H、C1-C16烷基、三(C1-C16烷基)硅基或三芳硅基；R18为任意选自H、F、Cl、Br、I、C1-C16烷基、三(C1-C16烷基)硅基、三芳硅基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；R19为任意选自OH、NH2、NHSO2R20、NHPO(R20)、NHPO(OR20)，其中R20为任意选自H、C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团；R21为选自、C1-C16全氟烷基、C1-C16烷基、C2-C16烯基、C2-C16炔基、C3-C16环烷基、C3-C16环烯基、C3-C16环炔基、芳杂环、芳基或共轭芳环，所述的芳基为取代苯基，所述的共轭芳环为1-萘基、2-萘基、菲基和蒽基；所述的芳杂环为C5-C10的含氮、硫、氧原子的杂环基团。
2.如权利要求1所述的合成方法，其特征在于，所述的有机溶剂是苯、甲苯、二甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、石油醚、正己烷、四氢呋喃、二甲基甲酰胺、二甲基乙酰胺、乙醚、环己烷、正庚烷、正戊烷、二氧六环、乙二醇二甲醚、甲基叔丁基醚或乙腈，溶剂是其中的一种或者是两种或两种以上的混合溶剂。
3.如权利要求1所述的合成方法，其特征在于，所得到的产物通过重结晶、柱层析、薄层层析或减压蒸馏加以分离。
4.如权利要求1所述的合成方法，其特征在于，所述的邻甲酰基苯甲酸酯、N-取代的脂肪二胺和手性催化剂的摩尔比为1：1.2-2：0.02-0.2。
5.如权利要求1所述的合成方法，其特征在于，所得到的产物的构型为R或S。
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