Asymmetric Syntheses V: Asymmetric Alkylation of D-Camphor Imine of 1-Aminomethyl Naphthalene

Alkylation of the D-camphor imine of 1-amino-methyl naphthalene with a variety of alkylating agents gave diastereoselectivities ranging from 20–64%. The de ratio in the alkylation could be determined by the chemical shift difference of ¹H-NMR signals of the C-8 methyl groups or by ¹³C-NMR signals in the C-7 of compound (6).     

联二萘酚衍生手性二胺催化的不对称Aldol反应

在10 mol%手性二胺和10 mol%手性磷酸的催化下,苯乙酮及其衍生物与三氟丙酮酸甲酯完成Aldol反应,得到80%的产率和73%ee的对映体过量产物,其结构经1H NMR和13C NMR表征.     

The Catalytic Asymmetric Aldol Reaction

The construction of C-C bonds with complete control of the stereochemical course of a reaction is of utmost importance for organic synthesis. The aldol reaction-the simple addition of an enolate donor to a carbonyl acceptor-is one of the most powerful reactions available to the synthetic chemist. In general, control of the relative and absolute configuration of the newly formed stereogenic centers has been achieved through the use of chiral starting materials or chiral auxiliaries. In recent years the search for catalytic methods that efficiently and effectively transfer chirality information has become a major effort in synthetic organic chemistry. Two different approaches have been taken toward the catalytic asymmetric aldol reaction: biocatalysis and catalysis with small molecules. Both approaches have specific advantages and limitations, and as a result are complementary to each other. The important efforts toward both approaches are reviewed in this article.     

Chiral Diamine-catalyzed Asymmetric Aldol Reaction

A highly efficient catalytic system composed of a simple and commercially available chiral primary diamine (1R,2R)-cyclohexane-1,2-diamine(6) and trifluoroacetic acid (TFA) was employed for asymmetric Aldol reaction in em-PrOH at room temperature. A loading of 10%(molar fraction) catalyst 6 with TFA as a cocatalyst could catalyze the Aldol reactions of various ketones or aldehydes with a series of aromatic aldehydes, furnishing Aldol pro- ducts in moderate to high yields(up to >99%) with enantioselectivities of up to >99% and diastereoselectivities of up to 99:1.     

Asymmetric Aldol Reaction with Formaldehyde: a Challenging Process

The asymmetric aldol reaction with formaldehyde is a fundamental carbon‐carbon bond‐forming reaction in organic synthesis, as well as in the quest of the origin of life, as it is thought to have been the first “molecular brick” involved in the synthetic path to complex sugars. Products of aldol reactions, i.e., the β‐hydroxy carbonyl compounds, are versatile building blocks used to access a great variety of functionalised molecules. The employment of formaldehyde, as a C1 symmetric electrophile, in aldol reactions can be likely considered the most challenging, yet simplest, process to introduce a hydroxymethyl group in an asymmetric fashion. In this account, an overview of the progress achieved in the asymmetric metal‐ and organocatalysed aldol reaction, using readily available formalin or paraformaldehyde sources, is illustrated. Our recent contribution to this area, with the application of asymmetric hydroxymethylation in cascade processes for the synthesis of γ‐butyrolactones, is also shown.

     

有机小分子催化的不对称羟醛缩合反应

总结了近年来用于不对称催化羟醛缩合反应的各种有机小分子催化剂, 简要阐述了每种类型的催化剂的催化机理以及它们的优缺点, 同时对有机小分子催化反应的发展进行了展望.     

Asymmetric Synthesis XIV: TiCl(Oipr)3-Promoted Asymmetric Coupling Reaction of D-Camphor Ketimine Anion

Optically active 1, 2-Diphenylethylendiamine(9) is obtained by asymmetric oxidative coupling reaction of d-camphor ketimine anion (4). Among various oxidating agents, TiCl(Oipr)₃ is better than l₂, Br₂, CuCl₂, FeCl₃ and BrCH₂CH₂Br.     

Redox Tuning of a Direct Asymmetric Aldol Reaction

Presented herein is a redox tuning strategy for asymmetric aminocatalysis with a designed chiral ferrocenophane. Under redox control, the ferrocenophane catalyst efficiently catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the redox‐active ferrocene moiety also served as phase‐tag to facilitate catalyst recovery and reuse. The catalyst can be reused for five cycles without much loss of activity. Ferrocenium of the oxidized ferrocenophane was proposed to serve as Lewis acidic site, thus accounting for the stereo control.     

L-脯氨酸催化的不对称Aldol缩合反应实验设计

介绍了L-脯氨酸催化的对硝基苯甲醛与丙酮的不对称Aldol反应的实验设计。室温反应2 h后,柱层析得到（R）-4-（4-硝基苯基）-4-羟基-2-丁酮,利用手性高效液相色谱测试得到产物的ee值。学生实验结果显示,收率范围为53%~74%,对映选择性范围为62%~69%。本实验方案将Aldol反应的研究成果设计成综合性实验,不仅强化训练了学生基本的实验技能和操作,同时拓宽了知识面,培养了学生分析问题、解决问题等方面的综合能力。     

脯氨酸二肽催化的不对称直接Aldol反应

以(S)-脯氨酸和(R)-脯氨酸为原料合成了二肽H-(S)-Pro-(S)-Pro-OH(1)和H-(S)-Pro(-R)-Pro-OH(2),分别以两种二肽催化了不对称直接A ldol反应,获得了相同立体构型(S)的产物,与(S)-脯氨酸催化所得的产物构型(R)相反.该催化剂的立体选择性不高(ee<21%).理论计算的结果与实验结果吻合.     

Asymmetric Syntheses IV: Enantioselective Synthesis of (R)-Benzylic Amines Via Alkylation of D-Camphor Ketimine

An efficient asymmetric synthesis of (R)-benzylic amines in optical purity 36–90% had been achieved by alkylation of a chiral ketimine prepared from D-camphor and benzylamine. Diastereoselectivity in the alkylation is dependent on the alkyl halides.     

Helical Polymer as Mimetic Enzyme Catalyzing Asymmetric Aldol Reaction

This Communication reports optically active helical substituted polyacetylenes which solely catalyzed asymmetric Aldol reaction between cyclohexanone and p‐nitrobenzaldehyde; more importantly the helical structures are found to play crucial roles in the asymmetric catalysis, with a remarkable yield and ee (both up to 80%). A synergic effect is observed between the helical structures in the polymer main chains and the pendent prolinamide moieties for successfully catalyzing the asymmetric reaction. The role of the helical polymer backbones is further verified by tuning the relative helical structure content.     

A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction

The direct catalytic asymmetric aldol reaction offers efficient access to β‐hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α‐sulfanyl 7‐azaindolinylamide, thus affording both aromatic and aliphatic β‐hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Brønsted base.     

Amino Acylguanidines as Bioinspired Catalysts for the Asymmetric Aldol Reaction

The binding and stabilizing effect of arginine residues in certain aldolases served as inspiring source for the development of a family of amino acylguanidine organocatalysts. Screening and optimization led to identify the threonine derivative as the most suitable catalyst for the asymmetric aldol addition of hydroxyacetone, affording the syn diastereomer in high ee. In contrast, the proline derivative yielded the anti diasteromer. MMFF models suggest the presence of an extensive hydrogen bonding network between the acylguanidinium group and the reaction intermediates.     

脯氨酸催化的甲基酮与a-酮酸酯间的不对称Aldol反应

以脯氨酸为催化剂，实现了甲基酮与a-酮酸酯间的不对称Aldol反应，以43%-93%的产率和最高达81％的ee得到多种a-羟基酸酯。空间效应看来是影响反应活性和选择性的一个重要因素。丙酮表现出比丁酮高的反应活性，而在某些情况下 丁酮则呈现更高的对映选择性。     

Asymmetric Aziridination by Reaction of Chiral Sulfinimine Derived From (+)-Camphor with Dimethyloxosulfonium Methylide

Addition of dimethyloxosulfonium methylide to chiral nonracemic pure (+)-camphor-derived sulfinimine I affords N-sulfinyl aziridine. which are easily separated The N-(+)-camphor-based-sulfinyl auxiliary was removed without ring opening by treatment with MeLi.     

三氟乙酸对氨基酸催化不对称直接Aldol反应的影响

研究了三氟乙酸(TFA)对各种L-α-氨基酸催化环己酮与对硝基苯甲醛的不对称直接Aldol反应的影响.结果表明:在TFA作用下,所测试的绝大部分氨基酸的催化性能都有显著变化,多数情况下能提高收率和对映选择性;对非对映选择性的影响无明显规律.     

L-脯氨酸催化α-酮酰胺与甲基酮的不对称直接Aldol反应

用L-脯氨酸催化α-酮酰胺与甲基酮的不对称直接Aldol反应, 获得了不同光学活性的α-羟基酰胺, 产率在21%～99%之间, 对映选择性最高达到43% ee. 加成产物的结构用元素分析、红外光谱和核磁共振进行了表征.