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.     

Organocatalyzed highly enantioselective direct aldol reactions of aldehydes with hydroxyacetone and fluoroacetone in aqueous media: the use of water to control regioselectivity

An organocatalyst prepared from (2R,3R)-diethyl 2-amino-3-hydroxysuccinate and L-proline exhibited high regio- and enantioselectivities for the direct aldol reactions of hydroxyacetone and fluoroacetone with aldehydes in aqueous media. It was found that water could be used to control the regioselectivity. The presence of 20-30 mol% of the catalyst afforded the direct aldol reactions of a wide range of aldehydes with hydroxyacetone to give the otherwise disfavored products with excellent enantioselectivities, ranging from 91 to 99% ee, and high regioselectivities. Aldolizations of fluoroacetone with aldehydes mediated by 30 mol% of the organocatalyst in aqueous media preferentially occurred at the methyl group, yielding products with high enantioselectivities (up to 91% ee); however, these additions took place dominantly at the fluoromethyl group in THF. Optically active 3,5-disubstituted tetrahydrofurans and (2S,4R)-dihydroxy-4-biphenylbutyric acid were prepared by starting from the aldol reaction of hydroxyacetone. Theoretical studies on the role of water in controlling the regioselectivity revealed that the hydrogen bonds formed between the amide oxygen of proline amide, the hydroxy of hydroxyacetone, and water are responsible for the regioselectivity by microsolvation with explicit one water molecule as a hydrogen-bond donor and/or an acceptor.     

Asymmetric synthesis of quaternary alpha- and beta-amino acids and beta-lactams via proline-catalyzed mannich reactions with branched aldehyde donors

[reaction: see text] L-Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected alpha-imino ethyl glyoxylate with various alpha,alpha-disubstituted aldehydes affords quaternary beta-formyl alpha-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted to the corresponding quaternary alpha- and beta-amino acids and beta-lactams.     

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3, 3-Amino Acid Esters

Mukaiyama–Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama–Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β^{3, 3}-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.     

Amino acid-catalyzed direct enantioselective synthesis of β-amino-α-oxyaldehydes

The first direct amino acid-catalyzed asymmetric syntheses of α-oxy-β-aminoaldehydes are presented. The organocatalytic Mannich reactions between unmodified α-oxyaldehydes and anilines proceeded with excellent enantioselectivities. In most cases, the corresponding α-oxy-β-aminoaldehyde adducts were isolated in high yield with excellent chemo- and enantioselectivity. For example, orthogonally protected 3-amino-tetroses and α-amino acid derivatives were isolated in up to >99% ee.     

3-Pyrrolidinecarboxylic acid for direct catalytic asymmetric anti-Mannich-type reactions of unmodified ketones

We report the development of direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and alpha-imino esters under mild conditions. The reactions were performed using 5-10 mol % of (R)-3-pyrrolidinecarboxylic or (R)-beta-proline as catalyst in an environmentally benign solvent, 2-PrOH, at room temperature. The anti-Mannich products were obtained in good yields with high diastereo- and enantioselectivities (up to anti/syn >99:1, 99% ee). While (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid is an excellent catalyst for the anti-Mannich-type reactions of aldehydes, it did not efficiently catalyze the corresponding Mannich-type reactions of ketones; (R)-3-pyrrolidinecarboxylic acid did efficiently catalyze the Mannich-type reactions of ketones. (S)-Proline or (S)-2-pyrrolidinecarboxylic acid has been reported to catalyze the Mannich-type reactions of ketones to afford the syn-products. Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction, providing either syn- or anti-Mannich products.     

Direct asymmetric three-component organocatalytic anti-selective Mannich reactions in a purely aqueous system

The direct three-component Mannich reactions of O-benzyl hydroxyacetone with p-anisidine and aromatic or aliphatic aldehydes in the presence of an L-threonine-derived catalyst afforded anti-1,2-amino alcohols in good-to-excellent yields and with enantioselectivities of up to 97%. This study is the first demonstration that direct three-component Mannich reactions can be promoted by a primary amino acid in water.     

An organocatalytic direct Mannich-cyclization cascade as [3+2] annulation: asymmetric synthesis of 2,3-substituted pyrrolidines

A new method for asymmetric synthesis of 2,3-substituted pyrrolidines from N-PMP aldimines and succinaldehyde via formal [3+2] cycloaddition is reported. This reaction involves proline catalyzed direct Mannich reaction and acid catalyzed reductive cyclization with high yields (up to 78%) and excellent enantioselectivities (up to >99%).     

Asymmetric 1,3-dipolar cycloaddition reaction of nitrones and acrolein with a bis-titanium catalyst as chiral Lewis acid

A mu-oxo-type chiral bis-Ti(IV) oxide (S,S)-1 can be successfully utilized in the asymmetric 1,3-dipolar cycloaddition reactions between various nitrones 2 and acrolein to give the corresponding isoxazolidines with high to excellent enantioselectivities. For instance, the reaction between nitrone 2 (R = t-Bu) and acrolein in the presence of 10 mol % of bis-Ti(IV) catalyst (S,S)-1 in dichloromethane at -40 degrees C gave the corresponding endo cycloadduct with 97% ee.     

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.     

Chiral Cinchona Alkaloid‐Thiourea Catalyzed Mannich Reaction for Enantioselective Synthesis of β‐Amino Ketones Bearing Benzothiazol Moiety

Mannich reactions of imine with acetylacetone were effectively catalyzed by the modified chiral cinchona alkaloid‐derived thiourea. The reactions led to chiral β‐amino carbonyl compounds in high yields and good enantioselectivities. The study demonstrated for the first time that Mannich reactions of unmodified acetylacetone with heterocyclic imine derived from benzothiazole can be promoted by chiral bifunctional organocatalyst.     

Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid

The development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities under mild conditions and low catalyst loadings (1-5 mol %) is reported. Based on principles gained from the study of (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. Computational studies of the above reaction using HF/6-31G* level of theory suggested that this design would be highly effective. The catalyst was subsequently synthesized and studied in organocatalytic Mannich-type reactions between unmodified aldehydes and N-PMP-protected alpha-imino esters. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6 to 98:2, >97 to >99% ee).     

Enantioselective synthesis of anti- and syn-homopropargyl alcohols via chiral Brønsted acid catalyzed asymmetric allenylboration reactions

Chiral Br?nsted acid catalyzed asymmetric allenylboration reactions are described. Under optimized conditions, anti-homopropargyl alcohols 2 are obtained in high yields with excellent diastereo- and enantioselectivities from stereochemically matched aldehyde allenylboration reactions with (M)-1 catalyzed by the chiral phosphoric acid (S)-4. The syn-isomers 3 can also be obtained in good diastereoselectivities and excellent enantioselectivities from the mismatched allenylboration reactions of aromatic aldehydes using (M)-1 in the presence of the enantiomeric phosphoric acid (R)-4. The stereochemistry of the methyl group introduced into 2 and 3 is controlled by the chirality of the allenylboronate (M)-1, whereas the configuration of the new hydroxyl stereocenter is controlled by the enantioselectivity of the chiral phosphoric acid catalyst used in these reactions. The synthetic utility of this methodology was further demonstrated in highly diastereoselective syntheses of a variety of anti, anti-stereotriads, the direct synthesis of which has constituted a significant challenge using previous generations of aldol and crotylmetal reagents.     

anti-selective direct asymmetric Mannich reactions catalyzed by axially chiral amino sulfonamide as an organocatalyst

A direct asymmetric Mannich reaction using a novel axially chiral amino trifluoromethanesulfonamide (S)-3 has been developed in highly anti-selective and enantioselective manners. Thus, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and the alpha-imino ester 4 proceed smoothly to give the functional beta-amino aldehydes with significantly higher anti/syn ratio and enantioselectivity than previously possible.     

Highly diastereoselective asymmetric Mannich reactions of 1,3-dicarbonyls with acyl imines

[reaction: see text] The cinchona alkaloids catalyze direct asymmetric Mannich reactions of cyclic 1,3-dicarbonyl compounds with acyl imines to afford alpha-quaternary carbon-bearing reaction products in yields of up to 98%, a diastereomeric excess of 90% or greater, and enantioselectivities up to 99% ee. A model is proposed that accounts for both the observed diastereoselectivities and the enantioselectivities for the reactions.     

The development of scalemic multidentate niobium complexes as catalysts for the highly stereoselective ring opening of meso-epoxides and meso-aziridines

The discovery and development of a new Lewis acid system based on a complex formed from niobium(V) methoxide and (R)-3,3'-bis(2-hydroxy-3-isopropylbenzyl)-1,1'-binaphthalene-2,2'-diol, a novel tetradentate BINOL derivative, is presented. The system was shown to be extremely effective in promoting the desymmetrative ring opening of linear and cyclic meso-epoxides using anilines as nucelophiles, delivering the corresponding (R,R) anti-amino alcohols in good to excellent yields (up to quantitative) and excellent enantioselectivity (up to 96% ee). Furthermore, the catalyst system displays a remarkable sensitivity to steric bulk at the beta-carbon of the epoxide, selectively facilitating ring opening of smaller epoxides in the presence of more sterically hindered epoxides. This property was confirmed by a series of competition reactions using a mixture of meso-2-butene oxide and another aliphatic meso-epoxide, with the result that the former, less encumbered epoxide reacted preferentially with up to 98% chemical selectivity. While it was found to be most convenient to conduct the reactions with 10 mol % catalyst loading at 0.16 M, at higher overall concentration the reaction still proceeded efficiently with as little as 0.25 mol % catalyst to give the desired products with no significant reduction in yields or enantioselectivities. In addition, the current catalyst system was also found to mediate the asymmetric ring opening of nonsymmetrical cis-2-alkene oxides with anilines to give preferentially the corresponding (2R,3R)-2-amino-3-ols arising from ring opening at the methyl terminus, in excellent yields (up to quantitative) and good to excellent regio- and enantioselectivities (up to 18:1 and >99% ee, respectively). Intriguingly, it was discovered that the same catalyst system also promoted the ring-opening desymmetrization of aziridines with aniline nucleophiles to give the corresponding (S,S) vicinal diamines in good to excellent yields and enantioselectivity (up to 95% and 84% ee [>99% ee following a single recrystallization]). Catalyst systems that promote closely related reactions with opposite stereochemical outcomes in high selectivity such as the current niobium system are extremely unusual. To the best of our knowledge, this report constitutes not only the first example of the catalytic desymmetrization of both meso-epoxides and meso-aziridines but also a rare example of such complementary stereoselectivity in a catalytic reaction.     

Asymmetric Synthesis of a Quaternary Carbon Stereogenic Center by Organocatalysis Using a Primary Amino Acid and Its Salt

In this personal account, our recent developments on the asymmetric synthesis of a quaternary carbon stereogenic center by organocatalysis using a primary amino acid and its salt as a catalyst are described in three chapters: (1) conjugate addition to nitroalkenes and vinyl ketones, (2) nucleophilic addition to π-allyl palladium complexes, and (3) nucleophilic substitution reactions with allyl and propargyl halides. By these methods, asymmetric α-allylation of α-branched aldehydes and ketones smoothly proceeded to give γ-nitroaldehydes, ketoaldehydes, α-allylated aldehydes, and α-allylated β-ketoesters possessing a quaternary carbon stereogenic center in good yields with high enantioselectivities.     

Highly enantioselective Mannich reactions of imines with tert-butyl acetoacetate catalyzed by squaramide organocatalyst

Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl acetoacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corresponding benzothiazole β-keto ester derivatives were obtained in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee).     

Ag/ThioClickFerrophos-catalyzed enantioselective Mannich reaction and amination of glycine Schiff base

The AgOAc/ThioClickFerrophos complex catalyzed the asymmetric Mannich reaction of glycine Schiff base with N-tosylimines effectively to give a mixture of syn and anti adducts (syn/anti = 60/40-70/30) at high yields with high enantioselectivities (up to 98% ee). The complex also catalyzed the asymmetric amination of glycine Schiff base with di-tert-butyl azodicarboxylate with high enantioselectivity.     

Enantioselective and solvent-controlled diastereoselective Mannich reaction of isatin imines with hydroxyacetone: synthesis of 3-substituted 3-aminooxindoles

The diastereoselectively switchable enantioselective Mannich reaction of isatin imines with hydroxyacetone is reported. The chiral primary amino acid catalyzed this Mannich reaction to afford both anti- and syn-Mannich adducts in high yields, good diastereoselectivities, and enantioselectivities. The reason for the solvent control of the diastereoselectivity phenomenon was investigated.