In silico correlation of enantioselectivity for the TADDOL catalyzed asymmetric hetero-Diels-Alder reaction

The reverse-docking of a TADDOL organocatalyst to rigid transition state models of catalyst-free reactions (TS-models) for an asymmetric hetero-Diels-Alder reaction is described. In previous reports, reverse-docking of similar organocatalysts to rigid TS-models showed promise for generating transition state models for the catalyzed reaction, and revealed clear energetic trends favoring the experimentally preferred product enantiomers. Although results indicated a mode of catalysis consistent with experimental data, relative docking energies between TS-model enantiomers were too great to allow for in silico correlation to experimentally observed enantiomeric excesses (ee). Several changes were made to the reverse-docking algorithm, EM-Dock, allowing for the first reported correlation to experimentally reported ee values based solely on reverse-docking and molecular mechanics energies.     

Reverse-docking as a computational tool for the study of asymmetric organocatalysis

A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment. Clear energetic trends emerged from docking the catalyst to both enantiomers of all six azidation TS models of this study. Structural analysis of the most favorable pose suggests a mechanism for enantioselective catalysis that is consistent with principles of molecular recognition, catalysis, and experimental data.     

Catalytic asymmetric three-component acyl-Strecker reaction

The first organocatalytic asymmetric three-component Strecker reaction, the urea-catalyzed acylcyanation of in situ generated imines, has been developed. Different alpha-amido nitriles are formed in excellent yields and enantioslectivities from aldehydes, amines, and acyl cyanides in the presence of Jacobsen's thiourea catalyst 5. Despite its obvious use for the synthesis of alpha-amino acids and their derivatives, our reaction may find use in diversity oriented synthesis and medicinal chemistry. [reaction: see text]     

C2-symmetric recyclable organocatalyst for enantioselective Strecker reaction for the synthesis of α-amino acid and chiral diamine--an intermediate for APN inhibitor

Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at -10 °C to give a high yield (95%) of α-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity.     

Construction of highly substituted pyrazole derivatives with P–C bond: access to racemic and enantioselective forms by conjugate addition of diarylphosphane oxides to α,β-unsaturated pyrazolones

The synthesis of organophosphorus compounds is of great importance to industrial, agricultural, and pharmaceutical chemistry. In this paper, we have reported the synthesis of highly substituted pyrazole derivatives through P–C bond formation under catalyst-free conditions. On the other hand, the first catalytic asymmetric version of this reaction has also been developed under catalysis by an isosteviol derived thiourea organocatalyst. The optically active phosphorus-containing compounds have been obtained in good chemical yields with moderate enantioselectivities.     

有机小分子催化的不对称Strecker反应研究进展

有机小分子催化的不对称合成反应是目前研究最为活跃的领域之一. 不对称Strecker反应是合成光学活性α-氨基酸衍生物的有效手段. 目前报道的催化不对称Strecker反应的有机催化剂主要有手性胍类、手性(硫)脲衍生物、氮-氧偶极化合物、手性Brønsted酸等, 取得了良好的催化活性和对映选择性. 对各类有机小分子催化剂在有机催化不对称Strecker反应中的应用研究进展, 以及催化剂结构与反应条件对催化活性和不对称诱导作用的影响进行了简要评述.     

Oxazoline‐Based Organocatalyst for Enantioselective Strecker Reactions: A Protocol for the Synthesis of Levamisole

A chiral oxazoline‐based organocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N‐benzhydrylimines with trimethylsilyl cyanide (TMSCN) as a cyanide source at ?20 °C to give α‐aminonitriles in high yield (96 %) with excellent chiral induction (up to 98 % ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organocatalyst in these reactions. The organocatalyst has been characterized by single‐crystal X‐ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.     

手性(硫)脲衍生物在不对称有机催化反应中的应用

手性(硫)脲衍生物是各种亲核试剂对亚胺、醛、缺电子烯烃加成反应的非常有效的有机催化剂之一, 已成功应用于对映选择性催化Strecker反应、Michael加成反应、Mannich反应、Baylis-Hillman反应、Henry反应等一系列重要的有机合成反应. 手性(硫)脲衍生物具有催化活性高、对映选择性和功能基相容性好、易于制备和修饰、适用范围广等优点, 成为近年来研究较多的不对称反应有机催化剂. 对手性(硫)脲衍生物在有机催化不对称合成中的应用研究进展进行了评述.     

Catalytic Strecker reaction: g-C3N4-anchored sulfonic acid organocatalyst for the synthesis of α-aminonitriles

Research on Chemical Intermediates - Efficient organocatalyst for enantioselective Strecker reaction was synthesized using g-C3N4 sheets (CN). CN-anchored sulfonic acid (CN-Bu-SO3H) was found to be...     

Chiral bisformamides as effective organocatalysts for the asymmetric one-pot, three-component strecker reaction

C2-symmetric chiral bisformamides have been shown to catalyze the asymmetric one-pot, three-component Strecker reaction, which produced the alpha-amino nitriles in excellent yields (up to 99%) with good enantioselectivities (up to 86% ee). Optically pure products could be obtained after a single recrystallization. A possible transition state (TS 1) has been proposed to explain the origin of asymmetric inductivity and reactivity according to the geometry of catalyst 2a optimized at the B3LYP/6-31G(d) level and the absolute configuration of product 4a.     

手性胺-质子酸催化剂在有机催化不对称合成中的应用

手性胺-质子酸是近年来发展起来的新型高效、高对映选择性的有机催化体系, 已成功应用于催化不对称Aldol反应、Michael加成反应、Diels-Alder反应和Strecker反应等许多重要的有机合成反应. 价廉易得的质子酸的引入不仅可促进活性中间体烯胺的生成, 并可通过形成的氢键稳定反应的过渡态, 从而显著提高该催化体系的催化活性和立体选择性. 对各类手性胺-质子酸催化剂在有机催化不对称合成反应中的应用、不对称诱导反应的机理、手性胺和质子酸的分子结构对其催化活性和不对称诱导活性的影响进行了评述.     

Asymmetric three-component Strecker reactions catalyzed by trans-4-hydroxy-L-proline-derived N,N'-dioxides

Novel trans-4-hydroxy-L-proline-derived N,N'-dioxides have been developed and used as efficient organocatalysts for the one-pot three-component Strecker reaction with an aldehyde, (1,1-diphenyl)methylamine, and TMSCN. Both aromatic and aliphatic aldehydes were found to be suitable substrates. The corresponding alpha-amino nitriles were obtained in high yields with up to 95 % ee (ee=enantiomeric excess) under mild conditions. Optically pure products could be obtained after a single recrystallization. The catalyst can be easily prepared from trans-4-hydroxy-L-proline and a diamine in three steps. Based on the experimental results and the observed absolute configurations of the products, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

醛亚胺的不对称Strecker反应研究进展

α-氨基腈不仅可以很容易地转化为α-氨基酸,而且是合成许多具有生物活性的天然产物和药物的重要中间体.醛亚胺的不对称Strecker反应作为制备光学活性α-氨基腈的直接而有效的方法之一,已被广泛接受.作者介绍了醛亚胺的不对称Strecker反应研究进展.     

不对称Strecker反应催化剂的研究进展

综述了不对称Strecker反应催化剂的研究进展,重点介绍了金属配合物催化剂、固体酸催化剂、有机小分子手性催化剂、路易斯酸和Brnsted酸催化剂在不对称Strecker反应中的应用。并对其未来发展进行了展望。参考文献44篇。     

Catalytic asymmetric synthesis of glutamate analogues

Utilizing our lateral metalation coupled with Jacobsen's catalytic asymmetric amino nitrile synthesis, we have demonstrated the ability to synthesize isoxazole-containing amino acid glutamate analogues in high yield and high enantiomeric excesses. Chiral centers alpha or beta at the C-5 position do not detract from diastereoselectivity of the Jacobsen-Strecker reaction. [reaction: see text]     

Conformational lock in a Brønsted acid–Lewis base organocatalyst for the aza-Morita–Baylis–Hillman reaction

(S)-3-(N-Isopropyl-N-3-pyridinylaminomethyl)BINOL has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction. The acid–base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol.     

Stereoselective synthesis of the macrolactone core of (+)-neopeltolide

A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis include asymmetric allylation using Krische' protocol, conjugate reduction using MacMillan's methodology, and an asymmetric hetero-Diels-Alder reaction using Jacobsen's catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction followed by Ireland-Claisen rearrangement, oxymercuration, and reductive lithiation are other key steps.     

手性助剂诱导催化不对称Strecker反应研究进展

亚胺的不对称Strecker反应是合成α-氨基酸化合物的重要途径之一,一般在手性助剂的诱导下进行.近年来,用于诱导不对称Strecker反应的各类手性助剂的研究受到广泛关注.本文综述了α-苯乙胺、α-氨基酸、α-氨基酸衍生的酰胺、α-苯甘氨醇、亚磺酰基亚胺、糖胺、肼等七类化合物作为手性助剂在不对称Strecker反应中的应用研究现状,就该研究领域存在的问题进行了分析,并对其前景进行了展望.     

New organocatalysts derived from tartaric and glyceric acids for direct aldol reactions

The synthesis of several new pyrrolidine based asymmetric organocatalysts derived from tartaric, glyceric acids and a pyrrolidine moiety is described with a study of their application in the development of an enantioselective aldol protocol. The influence of different proton donor groups, such as a primary hydroxyl or a carboxylic acid group, or their absence, on the efficiency of the organocatalyst was studied. The configuration of the tartrate derived catalysts and the presence of the rigid butane-2,3-diacetal were found to have a strong influence on the stereoselective outcome of the aldol reaction.     

有机催化不对称Michael加成反应

有机催化的不对称合成反应是目前研究最为活跃的领域之一. 不对称Michael加成反应是合成众多重要的手性合成子和药物中间体的有效手段. 目前报道的催化Michael加成反应的有机催化剂主要有脯氨酸及其衍生物、手性咪唑啉酮、手性(硫)脲、金鸡纳碱衍生物等. 对各类有机催化剂在有机催化不对称Michael加成反应中的应用, 以及不对称诱导反应的机理、催化剂分子结构及反应条件对其催化活性和不对称诱导作用的影响进行了评述.