Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation. The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of triethylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectivities (up to 91% ee). The products could be further converted to the heteroatomic mimics of prostaglandins via reaction with primary amines.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

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.     

Asymmetric synthesis of (-)-nupharamine and (-)-(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizidine from beta-amino ketones and the intramolecular Mannich reaction

The asymmetric synthesis of the 2,3,6-trisubstituted piperidine core of the antitumor Nuphar alkaloids was readily achieved by using the intramolecular Mannich reaction and a sulfinimine-derived beta-amino ketone.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

Tandem reactions of Pd‐catalyzed cross‐coupling of 3‐(2‐isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich‐type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich‐type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich‐type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.     

Acyclic chiral amines and amino acids as inexpensive and readily tunable catalysts for the direct asymmetric three-component Mannich reaction

The direct three-component asymmetric Mannich reaction catalyzed by acyclic chiral amines or amino acids is presented. Simple acyclic chiral amines and amino acids--such as alanine-tetrazole (9), alanine, valine, and serine-catalyzed the three-component asymmetric Mannich reactions between unmodified ketones, p-anisidine, and aldehydes with high chemo- and stereoselectivity, furnishing the corresponding Mannich bases with up to >99 % ee. This study demonstrates that the whole range of amino acids in nature, as well as nonproteogenic amino acid derivatives, can be considered in the design and tuning of novel, inexpensive organocatalysts for the direct asymmetric Mannich reaction.     

固定化脯氨酸及其衍生物用于催化不对称有机合成

脯氨酸及其衍生物作为有机手性催化剂,在不对称有机合成中得到广泛应用。该类催化剂具有结构简单、来源丰富和选择性高等优点,但仍存在催化剂用量大、难以回收以及无法重复利用等不足。近年来,随着固定化技术的发展,固定化脯氨酸及其衍生物受到广泛关注。固定化脯氨酸及其衍生物催化剂可以简化不对称催化中产物的分离过程,实现催化剂的便利回收与循环使用。本文综述了固定化脯氨酸及其衍生物的制备及在催化不对称有机合成(如Aldol反应、Michael加成反应、Mannich反应等)中的研究进展。     

Carbohydrates as Chiral Auxiliaries in Stereoselective Synthesis. New Synthetic Methods (90)

Carbohydrates are inexpensive natural products in which numerous functional groups and stereogenic centers are combined in one molecule. By directed regio-and stereoselective formation of derivatives they can be converted into efficient chiral auxiliaries for controlling asymmetric syntheses. Stereoelectronic effects and pre-orientation of the reactive and shielding groups through formation of complexes can often be used for effective diastereofacial differentiation. In aldol reactions and alkylations on carbohydrate ester enolates intramolecular complexation promotes simultaneous elimination with formation of ketene. The steric, stereoelectronic, and coordinating properties of carbohydrate templates can also be used selectively to attain high levels of asymmetric induction in processes such as Diels–Alder reactions, hetero-Diels–Alder reactions, [2 + 2] cycloadditions, cyclopropanations, and Michael additions. It was possible with bicyclic, strongly stereodifferentiating carbohydrate auxiliaries to achieve a diastereoselective synthesis of carboxylic acid derivatives branched in the β position by a new 1,4-addition of alkylaluminum halides to α,β-unsaturated N-acylurethanes, in which methylaluminum halides and higher alkyl- or arylaluminum compounds behave mechanistically in a strikingly different manners. As complex ligands in chiral reagents and promoters, carbohydrates allow highly stereoselective reductions and aldol reactions that lead, amongst others, to chiral alcohols and β-hydroxy-α-amino acids in excellent enantiomeric excesses. Glycosylamines offer the possibility of versatile stereoselective applications: in the presence of Lewis acids the corresponding aldimines permit high-yielding syntheses of enantiomerically pure α-amino acids by Strecker and Ugi reactions, controlled by steric and stereoelectronic effects and by complex formation. They can be used with equal efficiency for asymmetric syntheses of chiral homoallylamines and for asymmetric Mannich syntheses of β-amino acids and chiral heterocycles, for example alkaloids.     

Asymmetric Disulfonimide‐Catalyzed Synthesis of δ‐Amino‐β‐Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions

An organocatalytic asymmetric synthesis of δ‐amino‐β‐ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama–Mannich reaction of readily available dioxinone‐derived silyloxydienes with N‐Boc‐protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new C? C bond‐forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (?)‐lasubin.     

Titanocene(III)‐Catalyzed Three‐Component Reaction of Secondary Amides,Aldehydes, and Electrophilic Alkenes

An umpolung Mannich‐type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one‐pot formation of C N and C C bonds by a titanocene‐catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N‐substituted γ‐amido‐acid derivatives and γ‐amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α‐amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.     

Titanocene(III)‐Catalyzed Three‐Component Reaction of Secondary Amides,Aldehydes, and Electrophilic Alkenes

An umpolung Mannich‐type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one‐pot formation of C? N and C? C bonds by a titanocene‐catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N‐substituted γ‐amido‐acid derivatives and γ‐amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α‐amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.     

The proline-catalyzed direct asymmetric three-component Mannich reaction: scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols

We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide beta-amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, and chemoselectivities. The scope of each of the three components and the influence of the catalyst structure on the reaction are described. Reaction conditions have been optimized, and the mechanism and source of asymmetric induction are discussed. We further present application of our reaction to the highly enantioselective synthesis of 1,2-amino alcohols.     

Addition reactions of ROPHy/SOPHy oxime ethers: asymmetric synthesis of nitrogen containing compounds

Oxime ethers prepared from (R)- or (S)-O-(1-phenylbutyl)hydroxylamine (ROPHy or SOPHy) are versatile intermediates for the asymmetric synthesis of a range of nitrogen containing compounds including simple amines, 1,2-aminoalcohols, alpha- and beta-amino acids, heterocyclic building blocks of natural products, piperidine alkaloids, lactams, 5- to 8-membered ring nitrogen heterocycles, imino-sugars, and chiral ferrocene based receptors.     

Synthesis of Chiral 2-OXO- and 2-THIO-1,3,2-Oxazaphospholidines via the Asymmetric Cyclization of L-Serinoates with (Thio)Phosphoryl Dichlorides

In this paper is described the asymmetric cyclization of L-serine derivatives with phosphoro(no-)dichloridates or their thio-analogues, and investigated the asymmetric induction effect of chiral carbon centre on the forming chiral phosphorus centre. Some cyclization products have been separated as a pure diastereomer and their configuration is preliminarily discussed.     

Asymmetric total syntheses of (-)-antofine and (-)-cryptopleurine using (R)-(E)-4-(tributylstannyl)but-3-en-2-ol

The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.     

不对称Reformatsky反应的研究

分别将催化计量和化学计量的(1R, 2S)或(1S, 2R)-2-氨基-1,2-二苯基乙醇衍生的手性氨基醇配体1应用于催化不对称Reformatsky反应, 研究了手性配体的结构及其用量与反应对映选择性的关系, 溶剂和底物改变对e.e.值的影响; 并设计与研究了双手性体系, 使该反应在催化量(25mol%)手性配体的作用下, 得到中等对映选择性; 另外, 还比较了不同的实验方法对反应的对映选择性的影响, 提出了手性催化循环机理和反应过渡态模型, 能较好地解释一系列实验事实。     

联二萘酚配合物催化的不对称异原子Diels-Alder反应研究进展

光学活性的联二萘酚及其衍生物作为优良的手性配体在不对称催化反应中的研究已经取得重大进展,本文概述了近些年来以联二萘酚及其衍生物为手性配体和各种金属盐形成的配合物作为手性催化剂在不对称催化的异原子Diels-Alder反应中的应用.总结了各种基于联二萘酚及其衍生物的用于异原子Diels-Alder反应的新的催化剂,以及能有效不对称催化该反应的新条件及新方法.     

3-苯基异香豆冉酮衍生物的不对称Mannich反应研究

研究了双功能手性硫脲-叔胺催化剂催化的3-苯基异香豆冉酮衍生物与N-保护亚胺的不对称Mannich反应,高收率、高对映选择性(88%~98%)地合成了一系列具有连续季碳叔碳手性中心的新化合物,其结构经1HNMR和13C NMR表征。     

Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis

A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford 3-tetrasubstituted oxindole derivatives which are key structures for biological activities. The products are formed with a quaternary carbon and featured with two adjacent chiral centers. Various N-EDG(electron-donating group) and N-EWG(electron-withdrawing group) protected oxindoles, including 3-aryl and 3-alkyl substituted ones, have been evaluated with aromatic and aliphatic imines under this catalytic system, smoothly giving desired products in good yields as well as excellent diastereo- and enantioselectivities.