The decarboxylative Strecker reaction

α-Amino acids react with aldehydes in the presence of a cyanide source to form α-amino nitriles in what can be considered a decarboxylative variant of the classical Strecker reaction. This unprecedented transformation does not require the use of a metal catalyst and provides facile access to valuable α-amino nitriles that are inaccessible by traditional Strecker chemistry.     

Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.     

Highly enantioselective Mannich reactions with α-aryl silyl ketene acetals and imines

Mannich reactions with chiral silicon Lewis acid activated acylhydrazones and α-aryl silyl ketene acetals and α-aryl,α-alkyl silyl ketene imines proceed efficiently and with good to excellent levels of both diastereoselectivity and enantioselectivity. The reactions provide access to α-aryl,β-hydrazido esters and α-aryl,α-alkyl,β-hydrazido nitriles, which are valuable analogs of β-amino acids.     

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.     

Catalytic enantioselective Michael addition of deconjugated butyrolactams to maleimides

The first catalytic enantioselective Michael addition of deconjugated butyrolactams to N-arylmaleimides is developed with the help of a bifunctional tertiary aminosquaramide catalyst. Unlike the widely explored and structurally related vinylogous nucleophile – deconjugated butenolides, deconjugated butyrolactams are found to be exclusively α-selective. The resulting highly substituted and densely functionalized products, bearing contiguous all-carbon quaternary and tertiary stereocenters, are formed in good yields with moderate diastereoselectivity and good to excellent enantioselectivity (up to 99:1 er).     

Organocatalyzed, enantioselective synthesis of bicyclo-[2.2.2]-octanes containing benzylic, all-carbon quaternary centers

Proline aryl sulfonamide-catalyzed, multi-component couplings have been developed for accessing densely functionalized [2.2.2] bicyclic ketones containing up to four contiguous chiral centers including an all-carbon benzylic quaternary center in high enantio- and diastereoselectivity. Application to the bicyclic core of the recently isolated alkaloid kopsonoline is illustrated.     

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C−C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C−C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C−C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.     

Enantio- and Diastereoselective Synthesis of Chiral Tetrasubstituted α-Amino Allenoates Bearing a Vicinal All-Carbon Quaternary Stereocenter with Dual-Copper-Catalysis

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.     

Asymmetric synthesis of α,β-diamino acid derivatives with an aziridine-, azetidine- and γ-lactone-skeleton via Mannich-type additions across α-chloro-N-sulfinylimines

The efficient asymmetric synthesis of new chiral γ-chloro-α,β-diamino acid derivatives via highly diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters across a chiral α-chloro-N-p-toluenesulfinylimine was developed. The influence of the base, LDA or LiHMDS, used for the formation of the glycine enolates, was of great importance for the anti-/syn-diastereoselectivity of the Mannich-type reaction. The γ-chloro-α,β-diamino acid derivatives proved to be excellent building blocks for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters, and subsequent ring transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives and α,β-diamino-γ-butyrolactones.     

Stereoselective Mannich-type reaction of chlorotitanium α-phenylseleno esters enolates with aromatic aldimines

The stereoselective Mannich-type reaction of α-phenylseleno chlorotitanium enolates with aromatic aldimines is described. The corresponding α-phenylseleno-β-amino esters were obtained in good yields and with moderate to good diastereoselectivity. A rationale for the predominant syn selectivity based on a chelated cyclic transition state is suggested. The obtained compounds are useful synthetic tools and direct precursors of new α-phenylseleno-β-lactams.     

Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis

Quaternary phosphonium ion-pair or a salt derived from amino acid has been developed to catalyze the Mannich-type reaction of α-substituted ethyl cyanoacetates and 2-(2-nitrophenyl) acetonitrile to N-Boc imines. Experiments shown that more active cyanoacetates could be catalyzed by the gentle phosphonium ion-pair catalysis, while 2-(2-nitrophenyl) acetonitrile as the substrate has to be activated by quaternary phosphonium salts and strong base. All the reactions gave the corresponding highly functionalized chiral β-amino nitriles products with good yields, high diastereo- and enantioselectivities in mild conditions.     

Catalytic asymmetric vinylogous Mannich-type (AVM) reaction of nonactivated α-angelica lactone

A direct highly diastereo- and enantioselective asymmetric vinylogous Mannich-type (AVM) reaction of aldimines with nonactivated natural α-angelica lactone has been successfully developed. It was demonstrated that the nonactivated natural α-angelica lactone is a useful vinylogous nucleophile to give the chiral δ-amino γ,γ-disubstituted butenolide carbonyl derivatives. The N,N'-dioxide L2-Sc(III) complex is efficient toward the obtention of a range of corresponding products with adjacent quaternary and tertiary stereocenters in excellent dr and ee values.     

Solventless DBU-promoted Mannich-type reactions of α-amido p-tolylsulfones with diethyl fluoromalonates and diethyl malonates

Mannich-type reactions of α-amido p-tolylsulfones with diethyl fluoromalonates and diethyl malonates, respectively in presence of catalytic amount of DBU have been developed. A variety of α-amido p-tolylsulfones prepared from aromatic and aliphatic aldehydes reacts with diethyl fluoromalonates and diethyl malonates, respectively under mild reaction conditions to afford α-fluoro β-amino esters and β-amino esters in moderate to good yield.     

Proline Sulfonamide-Based Organocatalysis: Better Late than Never

The history of proline sulfonamides for use in catalyzing highly enantioselective and diastereoselective C-C bond forming reactions is described. Highlighted is the development of N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide ("Hua Cat") and N-(carboxy-p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide ("Hua Cat-II") by Yang and Carter. Specific reactions covered include the aldol reaction, Mannich reaction, formal aza-Diels-Alder reaction, tandem Michael/Mannich reaction and Yamada-Otani reaction. The ability of proline aryl sulfonamides to construct all-carbon quaternary stereocenters in high enantioselectivity and diastereoselectivity is a notable feature of the reported work. The practicality of this chemistry for large scale and industrial applications is also included. Finally, a discussion of the future directions of proline sulfonamide organocatalysis is provided.     

l-Proline-catalysed three-component domino reactions for the diastereoselective synthesis of 5,6-disubstituted 3-thiomorpholinones

l-Proline-catalysed three-component domino reactions of ethyl 2-[(2-oxo-2-arylethyl)sulfanyl]acetate, aromatic aldehydes and ammonia provide a rapid and facile access to novel trans-6-aroyl-5-aryl-3-thiomorpholinones. This diastereoselective reaction presumably proceeds via a domino sequence comprising enamine formation, Mannich reaction and intramolecular amidation individual steps and resulting in the generation of one C-C and two C-N bonds in a one-pot operation. The reaction also creates two contiguous stereocenters with complete diastereoselectivity.     

Asymmetric synthesis of α,α-difluoro-β-amino phosphonic acids using sulfinimines

Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl α,α-difluoro-β-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl α,α-difluoro-β-amino phosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl afforded enantiopure α,α-difluoro-β-amino phosphonic acids.     

Organocatalytic Enantioselective Synthesis of Tetrasubstituted α-Amino Allenoates by Dearomative γ-Addition of 2,3-Disubstituted Indoles to β,γ-Alkynyl-α-imino Esters

The first asymmetric synthesis of tetrasubstituted α-amino allenoates by a chiral phosphoric acid catalyzed dearomative γ-addition reaction of 2,3-disubstituted indoles to β,γ-alkynyl-α-imino esters is reported. This method provides access to a series of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters in high yields, and with excellent regio-, diastereo-, and enantioselectivities under mild conditions without by-product formation. Representative large-scale reactions and diverse transformations of the products into various scaffolds with potential biological activities render are also disclosed. The mechanism of the reaction was elucidated by control reactions and DFT calculations.     

A highly enantio- and diastereoselective catalytic intramolecular Stetter reaction

A highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Subjection of alpha,alpha-disubstituted Michael acceptors to an asymmetric intramolecular Stetter reaction results in a highly enantioselective conjugate addition and a diastereoselective proton transfer. Available evidence suggests the diastereoselective protonation occurs via intramolecular delivery to the sterically more hindered face of the enolate. The scope of the trisubstituted Michael acceptors has been examined and found to be broad with respect to the size of the alpha-substituent and nature of the Michael acceptor. Aliphatic and aromatic aldehydes were examined and found to afford the desired product in good overall yield with high enantio- and diastereoselectivity.     

Asymmetric aldol reaction via memory of chirality

Asymmetric aldol reactions of α-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation.     

Decarboxylative benzylation and arylation of nitriles

Decarboxylative benzylation of nitriles is achieved via coupling of metallated nitriles with Pd-π-benzyl complexes that are generated in situ from cyanoacetic benzyl esters. In addition, decarboxylative couplings of α,α-disubstituted 2-methylfuranyl cyanoacetates can lead to either decarboxylative arylation or benzylation depending on the reaction conditions.