CN115466215A - 一种基于螺二氢茚骨架的手性胺-方酰胺类化合物及其制备方法和应用 - Google Patents
一种基于螺二氢茚骨架的手性胺-方酰胺类化合物及其制备方法和应用 Download PDFInfo
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Classifications
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- C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0237—Amines
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
本发明公开了一种基于螺二氢茚骨架的手性胺‑方酰胺类化合物及其制备方法和应用。所述的手性胺‑方酰胺类化合物是具有通式(I)所示结构的对映体化合物,可用于不对称催化有机反应,催化活性、对映选择性效果好。该手性胺‑方酰胺类化合物以式(II)化合物与方酸酯加成得到式(I)化合物,合成反应路线简单,易规模化应用。本发明开发的新型的手性胺‑方酰胺类有机催化剂具有经济实用性和工业应用前景。
Description
技术领域
本发明涉及不对称合成催化剂领域,具体涉及一种基于螺二氢茚骨架的手性胺-方酰胺类化合物及其制备方法和应用。
背景技术
不对称催化的核心科学问题之一是发展新型高效手性催化剂。尽管手性催化剂的设计合成已经取得快速发展,但仍然存在包括催化剂的适用范围有限,对反应底物依赖度高等问题,还没有任何一种手性催化剂是通用的。因而寻求新型手性催化剂,特别是具有新型骨架的手性催化剂,一直是不对称催化领域中的永恒主题。
公开号为CN108659046A的中国发明专利申请公开了一种基于四甲基螺二氢茚骨架的单膦配体,用于包括不对称加成、不对称氢化、不对称偶联和不对称烯丙基烷基化等许多手性催化反应。
具有多氢键给体的叔胺-方酰胺类双功能有机催化剂具有多种催化用途,文献报道了不同骨架的叔胺-方酰胺类双功能有机催化剂,并成功应用于多种不对称反应;相关文献有:(a)Applications of Chiral Squaramides:From Asymmetric Organocatalysis toBiologically Active Compounds.Chem.Rec.2016,16,897.(b)Squaramide-CatalyzedAsymmetric Reactions.Chem.Rec.2017,17,994.(c)Rec ent Advances in Squaramide-Catalyzed Asymmetric Mannich Reactions.Adv.Synth.Catal.2020,362,4487.(d)Squaramide-Based Catalysts in Organic Synthesis(A Review).Russ.J.Gen.Chem.2022,92,287。
但是,手性双功能叔胺/方酰胺催化剂在催化同一反应时候,对反应底物的依赖度很高,参见文献Organocatalytic Asymmetric Domino Michael/Acyl Tran sferReaction betweenγ/δ-Hydroxyenones andα-Nitroketones.J.Org.Chem.2018,83,5301;Organocatalytic Enantioselective Cycloaddition of O-Quinone Methides withOxazolones:Asymmetric Synthesis of Dihydrocoumarins.Chemistry Select,2020,5,13259。因此开发更多带有新骨架的手性双功能叔胺/方酰胺催化剂,具有很大必要性。
同时,不对称催化3-三氟亚乙基吲哚啉酮衍生物和吡唑-3-酮的不对称共轭加成反应具有较大的挑战性;不对称加成产物三氟甲基化吲哚啉-2-酮衍生物在医药、化工等领域具有广泛的用途。提供更多选择的高效的手性催化剂,实现手性三氟甲基化吲哚啉-2-酮衍生物的多样性合成,非常重要。
发明内容
本发明提供了一种基于螺二氢茚骨架的手性胺-方酰胺类化合物,可不对称催化吲哚啉酮衍生物和吡唑-3-酮的不对称共轭加成反应。
一种基于螺二氢茚骨架的手性胺-方酰胺类式(I)化合物、其对映体、其消旋体或其非对映异构体:
其中,
X为H、CH3;
R1、R6、R3、R4为H;
R2、R5为H或CH3;
R9为苯基、取代的苯基、苯基亚甲基或苯基亚乙基,所述的取代的苯基为1~5元取代,取代基可以是F、Cl、Br、I、NO2、CN、C1-4烷基、C1-4全氟烷基、C1-4烷氧基、C1-4全氟烷氧基。
进一步的,所述的手性胺-方酰胺类式(I)化合物为:
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、X如前所定义。
进一步的,所述的手性胺-方酰胺类式(I)化合物为:
本发明还提供了一种式(I)化合物的制备方法,包括如下步骤:将式(II)化合物、式(II-e)化合物加入有机溶剂中,加成反应得到式(I)化合物:
其中,X和R1、R2、R3、R4、R5、R6、R7、R8、R9如前所定义。
所述的有机溶剂为二氯甲烷、氯仿或四氢呋喃。
所述的加成反应的条件为0~60℃搅拌反应1~36小时。
本发明式(I)所示的基于螺二氢茚骨架的手性胺-方酰胺类化合物用于不对称催化加成反应。
所述的不对称催化加成反应为不对称催化3-三氟亚乙基吲哚啉酮衍生物和吡唑-3-酮的共轭加成反应。
应理解,在本发明范围中,本发明的上述各种技术特征和在下文实施例中具体描述的各种技术特征之间都可以互相组合,从而构成新的或优先的技术方案。限于篇幅,在此不再一一累述。
本发明的有益效果主要体现在:
(1)本发明式(I)所示的基于螺二氢茚骨架的手性胺-方酰胺类化合物用于催化有机反应,催化活性或对映选择性效果好,具有经济实用性和工业应用前景。
(2)本发明式(I)所示的基于螺二氢茚骨架的手性胺-方酰胺类化合物用于不对称催化3-三氟亚乙基吲哚啉酮衍生物和吡唑-3-酮的不对称共轭加成反应,催化剂活性远远超越已知的催化剂效果,即使用1%的催化剂,仍然可以不对称催化3-三氟亚乙基吲哚啉酮衍生物和吡唑-3-酮的不对称共轭加成反应,获得高产率和高对映选择性。
(3)本发明式(I)所示的基于螺二氢茚骨架的手性胺-方酰胺类化合物以廉价易得的螺二氢茚二酚为原料,合成反应路线简单,易规模化应用。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。这里所采用的术语"药学上可接受的",是针对那些化合物、材料、组合物和/或剂型而言。它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或者多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,术语“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
本发明化合物依据本领域常规命名原则或者使用软件命名,市售化合物采用供应商目录。相关的原料来源可以是商品化试剂,或参考相关文献合成,例如(a)Synthesis and Application of Hexamethyl-1,1′-spirobiindane-Bas edPhosphine-Oxazoline Ligands in Ni-Catalyzed Asymmetric Arylation of Cycl icAldimines.J.Org.Chem.2018,83,4034;(b)Synthesis and Application of A NewHexamethyl-1,1’-spirobiindane-based Chiral Bisphosphine(HMSI-PHOS)Ligand inAsymmetric Allylic Alkylation.Org.Biomol.Chem.2018,16,2239;(c)Iron-CatalyzedEnantioselective Si–H Bond Insertions.Org.Lett.2018,20,6544;(d)Rhodium-Catalyzed Asymmetric Addition of Organoboronic Acids to Aldimines UsingChiral Spiro Monophosphite-Olefin Ligands:Method Develop ment and MechanisticStudies.J.Org.Chem.2018,83,11873;(e)Synthesis and Optical Resolution of 3,3,3',3'-Tetramethyl-1,1'-spirobiindane-7,7'-diol.Synthesis 2018,51,557;(f)Atroposelective Phosphoric Acid Catalyzed Three-Component Cascade Reaction:Highly Enantioselective Synthesis of Axially Chiral N-ArylindolesAngew.Chem.Int.Ed.2019,58,15824;(g)Iron-catalyzed asymmetric intramolecularcyclopropanation reactions using chiral tetramethyl-1,1′-spirobiindane-basedbisoxazoline(TMSI-BOX)ligands Org.Biomol.Chem.2019,17,1154;(h)Preparation andapplication of bisoxazoline ligands with a chiral spirobiindane skeleton forasymmetric cyclopropanation and allylic oxidation Tetrahedron:Asymmetry 17(2006)634;(i)Synthesis and application of chiral spiro Cp ligands in rhodium-catalyzed asymmetric oxidative coupling of biaryl compounds withalkenes.J.Am.Chem.Soc.2016,138,5242。
具体实施方式
下面通过实施例对本发明进行详细阐述,下述说明仅为解释本发明,并不对其内容进行限定。本发明化合物可以通过本领域技术人员熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其它化合物合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式,也可以可经市售获得。优选的实施方式包括但不限于本发明的实施例。对本领域技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。
实施例1(Ra,R,R)-II-1的合成。
(R)-II-c1(1.56g,3.2mmol)和(R,R)-II-d1(12.8mmol,(R,R)-1,2-二氨基环己烷)以及K2CO3(1.33g,9.6mmol)溶解在70毫升乙腈中,氮气保护下加热回流12小时,然后冷却到室温,减压脱除溶剂。残留物加入50毫升乙醚,接着水洗,有机相干燥浓缩后柱层析(EtOAc/PE=1/6,另加5%三乙胺)得到白色固体(Ra,R,R)-II-1(737mg,收率52%)。
M.p.84-86℃;[α]D 20=+183.9(c=1.00,CH2Cl2).1H NMR(400MHz,CDCl3)δ6.87(d,J=8.4Hz,4H),3.85(d,J=12.9Hz,2H),3.26(d,J=13.1Hz,5H),2.97–2.85(m,1H),2.49(t,J=9.8Hz,1H),2.36(d,J=15.9Hz,2H),2.34(s,6H),2.12(d,J=9.6Hz,1H),1.90(d,J=12.5Hz,2H),1.66(s,2H),1.49(s,6H),1.24(s,6H),1.19–1.12(m,2H)ppm;HRMS(ESI+)calcd for[C31H43N2]+,m/z 443.3421,found 443.3421。
实施例2(Ra,S,S)-II-2的合成。
参照实施例1的过程,用(S,S)-II-d2(12.8mmol,(R,R)-1,2-二氨基环己烷)代替(R,R)-II-d1,则可以得到(Ra,S,S)-II-2(790mg,56%产率)。
M.p.88-90℃;[α]D 20=+201.2(c=1.00,CH2Cl2);HRMS(ESI+)calcd for C31H42N2,m/z 443.3421,found 443.3422。
实施例3(Ra,R,R)-II-3的合成。
参照实施例1的过程,用(R,R)-II-d3(12.8mmol,(R,R)-1,2-二氨基-1,2-二苯基乙烷)代替(R,R)-II-d1,则可以得到(Ra,R,R)-II-3(886mg,51%产率)。
M.p.96-99℃;[α]D 20=+58.2(c=1.00,CH2Cl2);HRMS(ESI+)calcd for[C39H44N2+H]+,m/z 541.3512,found 541.3573。
实施例4(Ra,S,S)-II-4的合成。
参照实施例1的过程,用(S,S)-II-d4(12.8mmol,(S,S)-1,2-二氨基-1,2-二苯基乙烷)代替(R,R)-II-d1,则可以得到(Ra,S,S)-II-4(743mg,43%产率)。
M.p.98-102℃;[α]D 20=+17.4(c=1.00,CH2Cl2);HRMS(ESI+)calcd for[C39H44N2+H]+,m/z 541.3512,found 541.3577。
实施例5(Ra,R,R)-I-1的合成。
(Ra,R,R)-II-1(0.2mmol)溶解在5毫升二氯甲烷中,加入3-((3,5-双(三氟甲基)苯基)氨基)-4-甲氧基环丁-3-烯-1,2-二酮(67.8mg,0.2mmol)室温搅拌反应48小时,然后过滤使用乙腈洗涤获得产物(Ra,R,R)-I-1(139mg,93%产率)。
M.p.234-236℃;[α]D 20=62.5(c=1.00,CH2Cl2);1H NMR(600MHz,DMSO-d6)δ10.09(s,1H),8.02(s,2H),7.67(s,1H),7.63(s,1H),6.81(d,J=10.6Hz,3H),4.23(s,1H),3.59(d,J=13.0Hz,2H),3.29(d,J=13.0Hz,2H),2.72–2.65(m,1H),2.50(d,J=1.5Hz,6H),2.31–2.23(m,2H),2.19(s,4H),2.03(d,J=12.8Hz,1H),1.67(dd,J=36.9,12.7Hz,3H),1.57(d,J=7.9Hz,1H),1.40(s,6H),1.34–1.22(m,2H),1.14(s,6H)ppm;HRMS(ESI+)calcdfor[C43H46F6N3O2]+,m/z 750.3489,found 750.3489。
实施例6(Ra,S,S)-I-2的合成。
按照实施例5的过程,把(Ra,R,R)-II-1(0.2mmol)用(Ra,S,S)-II-2代替,可以得到(Ra,S,S)-I-2(133mg,89%产率)。
HRMS(ESI+)calcd for[C43H46F6N3O2]+,m/z 750.3489,found 750.3487。
实施例7(Ra,R,R)-I-3的合成。
按照实施例5的过程,把(Ra,R,R)-II-1(0.2mmol)用(Ra,R,R)-II-3代替,可以得到(Ra,R,R)-I-3(737mg,87%产率)。
HRMS(ESI+)calcd for[C51H47F6N3O2+H]+,m/z 848.3606,found 848.3605。
实施例8(Ra,S,S)-I-4的合成。
按照实施例5的过程,把(Ra,S,S)-II-1(0.2mmol)用(Ra,S,S)-II-4代替,可以得到(Ra,S,S)-I-4(770mg,91%产率)。
HRMS(ESI+)calcd for[C51H47F6N3O2+H]+,m/z 848.3606,found 848.3608。
应用例1
(E)-2-氧代-3-(2,2,2-三氟亚乙基)二氢吲哚-1-羧酸叔丁酯(37.6mg,0.12mmol,1.2eq)和2,5-二苯基-2,4-二氢-3H-吡唑-3-酮(0.1mmol,1eq)溶解在1毫升1,2-二氯乙烷中,加入有机催化剂(Ra,R,R)-I-1(0.01mmol,0.1eq),然后室温搅拌反应16小时至反应完全,之后加入三氟乙酸(1mmol,10eq)反应2小时,接着使用制备色谱板(乙酸乙酯:正己烷=1:4)分离纯化得到的不对称加成产物(R,R)-12a(91%产率,95%ee,94:6d.r.)。
1H NMR(600MHz,CDCl3)δ12.20(s,1H),8.49(s,1H),7.92(d,J=7.9Hz,2H),7.61(d,J=7.3Hz,2H),7.53(t,J=7.4Hz,2H),7.50–7.42(m,3H),7.29(dd,J=14.7,7.4Hz,2H),7.12(t,J=7.4Hz,1H),7.08(d,J=7.2Hz,1H),6.91(d,J=7.7Hz,1H),4.32(q,J=9.3Hz,1H),4.05(s,1H)ppm。
HPLC条件:手性色谱柱IC-3(己烷/i-PrOH=95/5,流速1.5mL/min,λ=210nm),tR((R,R)-12a)=8.28min,tR((S,S)-12a)=6.60min;。
对比例
参照应用例1的过程,用文献Mechanochemically Activated AsymmetricOrganocatalytic Domino Mannich Reaction-Fluorination.ACSSustain.Chem.Eng.2020,8,14417.中基于金鸡纳碱胺的手性氨-方酰胺催化剂(化合物2,构型(R))代替(Ra,R,R)-I-1,可以得到不对称加成产物(S,S)-12a(63%产率,88%ee,97:3d.r.)。
其中化合物2的结构如下:
应用例2
参照应用例1的过程投入原料,但是减少催化剂用量,即使用有机催化剂(Ra,R,R)-I-1(0.001mmol,0.01eq),然后室温搅拌反应16小时后加入三氟乙酸(1mmol,10eq)反应2小时,接着直接使用制备色谱板(乙酸乙酯:正己烷=1:4)分离纯化得到的不对称加成产物(R,R)-12a(67%产率,88%ee,96:4d.r.)。
结论:催化剂活性远远超越已知的催化剂效果,即使用1%的催化剂,仍然可以催化不对称共轭加成反应,获得高产率和高对映选择性。
应用例3
参照应用例1的过程,用2-苯基-5-(对甲苯基)-2,4-二氢-3H-吡唑-3-酮代替2,5-二苯基-2,4-二氢-3H-吡唑-3-酮,得到不对称加成产物(R,R)-12b(74%产率,93%ee,>99:1d.r.)。
1H NMR(400MHz,CDCl3)δ12.12(s,1H),7.96(s,1H),7.91(d,J=7.7Hz,2H),7.47(dd,J=17.6,8.0Hz,4H),7.32(dd,J=18.3,7.7Hz,4H),7.19–7.10(m,2H),6.96(d,J=7.7Hz,1H),4.33(q,J=9.7Hz,1H),4.06(s,1H),2.46(s,3H)ppm。
HPLC条件:手性色谱柱IC-3(己烷/i-PrOH=90/10,流速1mL/min,λ=254nm),tR((R,R)-12b)=7.91min,tR((S,S)-12b)=6.56min。
应用例4
参照应用例1的过程,用2-(4-氯苯基)-5-苯基-2,4-二氢-3H-吡唑-3-酮代替2,5-二苯基-2,4-二氢-3H-吡唑-3-酮,得到不对称加成产物(R,R)-12c(66%产率,90%ee,96:4d.r.)。
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.77(d,J=8.8Hz,2H),7.60–7.52(m,5H),7.45(d,J=8.8Hz,2H),7.32(t,J=7.7Hz,2H),7.16(t,J=7.5Hz,1H),7.06(d,J=7.5Hz,1H),6.97(d,J=7.8Hz,1H),4.28(q,J=8.8Hz,1H),4.06(s,1H)ppm。
HPLC条件:手性色谱柱IC-3(己烷/i-PrOH=95/5,流速1mL/min,λ=254nm),tR((R,R)-12c)=7.09min,tR((S,S)-12c)=6.02min。
应用例5
参照应用例1的过程,用(E)-4-甲基-2-氧代-3-(2,2,2-三氟亚乙基)二氢吲哚-1-羧酸叔丁酯代替(E)-2-氧代-3-(2,2,2-三氟亚乙基)二氢吲哚-1-羧酸叔丁酯,得到不对称加成产物(R,R)-12d(52%产率,>99%ee,94:6d.r.)。
1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.84(d,J=7.9Hz,2H),7.63–7.44(m,7H),7.34(t,J=7.4Hz,1H),6.94(s,1H),6.77(s,1H),4.27(dd,J=18.4,9.0Hz,1H),4.03(s,1H),2.36(s,3H)ppm。
HPLC条件:手性色谱柱IC-3(己烷/i-PrOH=90/10,流速1mL/min,λ=254nm),tR((R,R)-12d)=4.12min,tR((S,S)-12d)=6.18min。
Claims (5)
4.一种根据权利要求1所述的基于螺二氢茚骨架的手性胺-方酰胺类式(I)化合物、其对映体、其消旋体或其非对映异构体的用途,其特征在于,所述的基于螺二氢茚骨架的手性胺-方酰胺类式(I)化合物、其对映体、其消旋体或其非对映异构体用于不对称催化加成反应。
5.根据权利要求4所述的用途,其特征在于,所述的不对称催化加成反应为不对称催化3-三氟亚乙基吲哚啉酮衍生物和吡唑-3-酮的共轭加成反应。
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