Highly effective and enantioselective α-amination of aldehydes promoted by chiral proline amide-thiourea bifunctional catalysts

A series of secondary amine-thiourea catalysts derived from l-proline and chiral diamine were prepared and successfully applied to the highly effective and enantioselective α-amination of unmodified aldehydes with various azodicarboxylates in excellent yields (up to 99%) and enantioselectivities (up to 99% ee) within a few minutes.     

Calixarene-based chiral primary amine thiourea promoted highly enantioselective asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides

Calix[4]arene based chiral bifunctional thiourea-primary amines have been shown to act as effective catalysts for the Michael addition of aldehydes to maleimides for the first time. The corresponding adducts were generally obtained preferentially in (R)- or (S)-forms with high yields (up to 99%) and with high to excellent enantioselectivities (up to 98% ee).     

Enantioselective α-vinylation of aldehydes via the synergistic combination of copper and amine catalysis

The enantioselective α-vinylation of aldehydes using vinyl iodonium triflate salts has been accomplished via the synergistic combination of copper and chiral amine catalysis. These mild catalytic conditions provide a direct route for the enantioselective construction of enolizable α-formyl vinylic stereocenters without racemization or olefin transposition. These high-value coupling adducts are readily converted into a variety of useful olefin synthons.     

Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts

Highly asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by chiral primary amine thiourea bifunctional catalysts was developed and a series of Michael adducts were obtained in excellent yields (up to 97%) and enantioselectivities (up to 95% ee). Optically pure S-warfarin was easily obtained in 99% ee after single recrystallization.     

Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts

Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.     

The versatile roles of ammonium salt catalysts in enantioselective reduction and alkylation of α,β-unsaturated aldehydes: iminium catalysis, enamine catalysis and acid catalysis

A novel strategy for highly efficient utilization of chiral ammonium salt catalysts has been described in this paper. Three kinds of catalytic functions including iminium catalysis, enamine catalysis, and acid catalysis of chiral ammonium salt catalysts, have been achieved in the enantioselective reduction and alkylation reaction of α,β-unsaturated aldehydes with alcohols.     

Highly enantioselective Friedel-Crafts alkylation of indole and pyrrole with β,γ-unsaturated α-ketoester catalyzed by chiral dicationic palladium complex

The chiral dicationic Pd complexes, bearing sterically demanding diphosphine ligands as Lewis acid catalysts, are shown to catalyze the asymmetric Friedel-Crafts (F-C) alkylations of indoles and pyrroles with β,γ-unsaturated α-ketoesters, to provide the F-C alkylation products with benzylic stereocenters in high yields and enantioselectivities. The reactive chelated structure, formed by the chiral dicationic Pd complex and the electrophile, would be important to gain a high level of asymmetric induction in the F-C alkylation. The F-C products can be readily functionalized to give α-hydroxy esters via catalytic asymmetric ene sequences.     

General and highly α-regioselective zinc-mediated prenylation of aldehydes and ketones

A simple, efficient, and general α-prenylation approach for the synthesis of a variety of α-prenylated alcohols has been successfully developed. A wide range of α-prenylated alcohol derivatives could be obtained in good yields by highly α-regioselective zinc-mediated prenylation of various aldehydes and ketones with prenyl bromide at 120 °C in HMPA. By simply altering the reaciton solvent and temperature, the method allows the achievement of a highly notable opposite regiocontrol, providing the expected regiochemical product. The method provides a convenient route for the direct α-prenylation of carbonyl compounds in a highly α-regioselective manner using a cheap and convenient mediator. Two possible pathways are proposed to account for the formation of these synthetically difficult-to-obtain molecules.     

An enantioselective biginelli reaction catalyzed by a simple chiral secondary amine and achiral brønsted acid by a dual-activation route

An enantioselective Biginelli reaction that proceeds by a dual‐activation route has been developed by using a combined catalyst of a readily available trans‐4‐hydroxyproline‐derived secondary amine and a Brønsted acid. Aromatic, heteroaromatic, and fused‐ring aldehydes were found to be suitable substrates for this multicomponent reaction. The corresponding dihydropyrimidines were obtained in moderate‐to‐good yields with up to 98 % ee under mild conditions. Based on the experimental results and the observed absolute configurations of the products, a plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.     

Asymmetric hydroazidation of α-substituted vinyl ketones catalyzed by chiral primary amine

We report herein the first example of asymmetric hydroazidation of α-substituted vinyl ketones by using chiral primary amines as the catalysts.A simple chiral primary-tertiary diamine catalyst derived from lphenylalanine was found to readily promote this aza-Michael addition reaction with enamine protonation as the key stereogenic step,thus enabling the effective synthesis of α-chiral β-azido ketones with good yields and moderate enantioselectivities.     

Stereoselective alkylation of chiral glycine enolate synthons. The enantioselective synthesis of α-amino acid derivatives.

The highly stereoselective alkylation (% de=99.6 to 97.6) of a new chiral glycine enolate synthon derived from D-2-phenylglycinol is described. Deprotection of the alkylation adducts in a one-pot three-step procedure provides the ethyl ester hydrochloride salts of the corresponding α-amino acids with no attending racemization.     

Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts

Highly enantioenriched (R)-4-bromo-1-cyanobutyl acetate and (R)-5-bromo-1-cyanopentyl acetate were prepared by acetylcyanation of 4-bromobutanal and 5-bromopentanal, respectively, catalyzed by (S,S)-[(4,6-bis(t-butyl)salen)Ti(μ-O)]₂ and triethylamine followed by enzymatic hydrolysis of the minor enantiomer. A cyclic procedure employing the same two chiral catalysts provided inferior results due to a slowly reached steady state and, in reactions with the former substrate, to ring-closure of the free cyanohydrin formed as an intermediate in the reaction. Hydrolysis of the acylated cyanohydrins followed by AgClO₄-promoted cyclization provided (R)-2-cyanotetrahydrofuran and (R)-2-cyanotetrahydropyran in essentially enantiopure form.     

One-pot highly enantioselective catalytic Mannich-type reactions between aldehydes and stable α-amido sulfones: asymmetric synthesis of β-amino aldehydes and β-amino acids

A highly enantioselective catalytic route to carbamate- and benzoate-protected β-amino aldehydes and β-amino acids is presented. The amino acid-catalyzed one-pot asymmetric reaction between unmodified aldehydes and α-amido sulfones gives the corresponding β-amino compounds with up to 95:5 dr and 97->99% ee.     

A highly regio-, diastereo- and enantioselective intramolecular cyclopropanation reaction of a racemic α-diazo ketone catalyzed by chiral ortho-metalated dirhodium(II) compounds

A series of racemic dirhodium(II) compounds with two ortho-metalated aryl phosphine ligands in a head-to-tail arrangement Rh₂(O₂CR)₂(pc)₂ (pc=ortho-metalated aryl phosphine) (1a–k) were tested in the regio- and stereoselective cyclopropanation of racemic 1-diazo-6-methyl-3-(2-propenyl)-5-hepten-2-one 2, which possesses two different reactive CC double bonds for a five-membered-ring formation. The complexes Rh₂(O₂CCH₃)₂(pc)₂ {pc=[(C₆H₄)P(C₆H₅)₂], [(p-CH₃C₆H₃)P(p-CH₃C₆H₄)₂], and [(C₆H₄)P(C₆H₅)(C₆F₅)]} (1a–d) successfully enhanced the cyclopropanation of trisubstituted versus monosubstituted CC bonds to give an 80:20 selectivity ratio. The reaction occurred with excellent diastereoselectivity; the syn-products were the only stereoisomers observed in the whole series of the catalysts. Enantioenriched products were obtained when enantiomerically pure dirhodium(II) complexes were used.     

Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral π-cation catalysts

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular π-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to β-lactams via reductive cleavage of the N-O bond using SmI(2).     

Highly asymmetric Michael additions of α,α-disubstituted aldehydes to β-nitroalkenes promoted by chiral pyrrolidine-thiourea bifunctional catalysts

A series of secondary amine-thiourea catalysts derived from l-proline and chiral diamine were prepared and first applied to the Michael addition of α,α-disubstituted aldehydes to trans-β-nitroalkenes. Moderate yields (47-75%) and excellent enantioselectivities (up to 96% ee) were obtained for a variety of aryl and heteroaryl nitroalkenes.