Direct asymmetric aldol reaction co-catalyzed by l-proline and group 12 elements Lewis acids in the presence of water

An approach based on combinations of various water compatible Lewis acids and l-proline co-catalysts has been evaluated for the direct asymmetric aldol reaction. From this broad screening, chloride salts from group 12 elements (ZnCl₂, CdCl₂, HgCl₂) lead to the highest stereoselectivities. Optimized catalytic conditions (catalytic system: l-proline: 20%/ZnCl₂: 10%; solvent mixture: DMSO/H₂O, 8:2) gave anti aldol products with improved enantioselectivity (>99% ee) compared to a moderately stereoselective procedure based on proline activation only.     

Asymmetric aldol reactions in poly(ethylene glycol) catalyzed by l-proline

A rapid l-proline catalyzed direct aldol reaction between various aldehydes and acetone was achieved using PEG as the solvent with comparable enantioselectivities and yields to those obtained in other solvents. Recycling the catalyst and solvent (PEG) was possible 10 times without loss of activity.     

Direct enantioselective aldol reactions catalyzed by calix[4]arene-based l-proline derivatives in the water

Two novel p-tert-butylcalix[4]arene-based chiral organocatalysts derived from l-proline have been developed to catalyze direct aldol reactions between cyclohexanone and aromatic aldehydes in water. Under the optimal conditions, high yields (up to 95%), enantioselectivities (up to 90%), and moderate diastereoselectivities (up to 65:35) were obtained. Considering the catalytic inefficiency of sole proline for the aldol reaction in water, these results clearly display the enormous effect of the hydrophobic part of calix[4]arene of compound A.     

Recyclable Merrifield resin-supported thiourea organocatalysts derived from l-proline for direct asymmetric aldol reaction

Four Merrifield resin-supported thiourea organocatalysts derived from l-proline were synthesized and found to be efficient catalysts for the direct asymmetric aldol reaction between ketone and aromatic aldehydes. The catalysts exhibited high catalytic activity, diastereoselectivity and excellent enantioselectivity at room temperature with a low loading (only 2 mol %). They also retained unchanged enantioselectivities even after being reused for at least four cycles.     

Direct asymmetric aldol reactions catalyzed by l-proline-2,4,6-trinitroanilide

Direct aldol reactions of several aromatic aldehydes with ketones using l-proline-2,4,6-trinitroanilide catalyst 2d were conducted. Under optimized conditions, high enantioselectivity (99% ee), regioselectivity (up to 95:5), and diastereoselectivity (up to 98:2) were achieved.     

l-Prolinamide derivatives as efficient organocatalysts for aldol reactions on water

A series of l-prolinamide derivatives have been evaluated as potential organocatalysts for aldol reactions. To synthesize these catalysts, a novel and simple route has been developed using proline N-carboxyanhydride (proline-NCA). A new catalyst with a trifluoromethyl-sulfonamide group has been found exhibiting excellent diastereoselectivity (anti/syn: 97/3) and enantioselectivity (99% ee) with 10 mol % loading and being easily recyclable in water.     

Novel stereocontrolled approach to conformationally constrained analogues of l-glutamic acid and l-proline via stereoselective cyclopropanation of 3,4-didehydro-l-pyroglutamic ABO ester

A new stereocontrolled approach to l-(carboxycyclopropyl)glycines (l-CCGs) and 3,4-methano-l-prolines, conformationally constrained analogues of l-glutamic acid and l-proline, respectively, was developed using a 3,4-didehydro-l-pyroglutamate derivative as a common chiral template. The unsaturated l-pyroglutamate derivative employed in this work is a novel chiral synthon in which the carboxyl functionality is protected as a 2,7,8-trioxabicyclo[3.2.1]octyl group (ABO ester). Stereospecific cyclopropanation of the olefin using diazomethane followed by appropriate functional group interconversion gave l-CCG-III and trans-3,4-methano-l-proline with complete stereocontrol. Synthesis of other diastereomers of l-CCG and cis-3,4-methano-l-proline was accomplished by alteration of the 3,4-methanoglutamic acid framework via carboxycyclopropanation of the olefin with sulfur ylide and subsequent Barton decarboxylation reaction of the original γ-carboxyl group included in the pyroglutamate skeleton.     

Domino synthesis of fused hexacyclic imidazoquinolinoacridinones catalyzed by CuI/l-proline

A three-component reaction of 2-halogenated aromatic aldehydes, 1H-benzo[d]imidazol-5-amine and cyclohexane-1,3-diones is described, and gives imidazoquinolinoacridinone derivatives in good yields catalyzed by CuI/l-proline. This Domino reaction constructs a fused hexacyclic skeleton in one-pot containing two new rings, six new bonds and an Ullmann-type C–N bond coupling reaction.     

Phase-transfer-catalyzed asymmetric Michael reaction using newly-prepared chiral quaternary ammonium salts derived from l-tartrate

The catalytic asymmetric Michael reaction of a glycine Schiff base was demonstrated using new PTCs and moderate to good ee's were achieved (up to 77% ee).     

Enantioselective synthesis of (−)-cytoxazone and (+)-epi-cytoxazone, novel cytokine modulators via Sharpless asymmetric epoxidation and l-proline catalyzed Mannich reaction

A short and efficient enantioselective synthesis of (−)-cytoxazone and its stereoisomer (+)-epi-cytoxazone, novel cytokine modulators, has been described with good yield and enantioselectivity. Ti-catalyzed Sharpless asymmetric epoxidation of allyl alcohol and l-proline catalyzed three-component Mannich reaction constitute the key steps in introducing stereogenicity into the molecule.     

New synthesis of flavanones catalyzed by l-proline

l-Proline is utilized as an efficient organocatalyst for the synthesis of substituted flavanones and chalcones in good yields. The efficiency of the catalyst was proved with a variety of substrates ranging from electron-deficient to electron-rich aryl aldehydes and 2-hydroxyacetophenones.     

Diastereoselective arylation of l-proline derivatives at the 5-position

Diastereoselective introduction of nucleophiles into l-proline derivatives at the 5-position was achieved with suitable selection of N-protecting group. N-Methoxycarbonylated or benzyloxycarbonylated l-proline derivatives reacted with arene to give cis-arylated products. On the other hand, N-benzoylated l-proline derivative preferentially gave trans-arylated product, which could be easily transformed into optically active C₂-symmetrical pyrrolidine derivative. Such derivative 5 worked well as an organic activator in the asymmetric reduction of aromatic imines by Cl₃SiH.     

Microbial screening in hydroxylation of l-proline

Microbial screening of 250 wild type strains resulted in identification of five strains with the activity of prolyl hydroxylase. All five strains hydroxylated regioselectively and enantioselectively l-proline into 4(R)-trans-hydroxy-l-proline 1. The best conversions were obtained with a wild type of Aeromonas caviae. 3-Hydroxylase activity was not detected.     

Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes with 4,5-methano-l-proline as organocatalysts

The 4,5-methano-l-prolines were used as chiral organocatalysts in asymmetric Michael addition of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with a cyclopropane and two H atoms attached to the bridgehead C atoms lying on the same side of the ring. They therefore showed high efficiency in asymmetric Michael addition of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 97/3 dr and 98% ee) were obtained in high yields for a series of aldehydes and nitroolefins using only 5 mol % catalyst loading. The methodology features easily available catalysts, high catalytic efficiency and environmentally friendly procedures.     

Catalytic asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and ketones

A copper(I)-catalyzed asymmetric borylative aldol reaction of 5,6-dihydro-2H-pyran-2-one and simple ketones (including aromatic ketones and an aliphatic ketone) was disclosed, which afforded a series of chiral diols after an oxidative work-up in moderate yields with moderate to high diastereoselectivity and excellent enantioselectivity. The lactone moiety was easily opened with methanol to generate a chiral triol in moderate yield.     

Synthesis of l,l-puromycin

l,l-Puromycin, a diastereomer of the natural peptidyl nucleoside antibiotic puromycin, has been synthesized from l-xylose in 13 steps.     

Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).     

Synthesis of l-aminohomohistidine (l-Ahh)

A short synthesis of l-aminohomohistidine (l-Ahh), which starts from readily available δ-hydroxy-l-lysine is described. The embedding of the basic guanidino moiety in the aromatic imidazole lowers the basicity of the side chain to a pK_a of 8.3. It is proposed that l-Ahh may be employed as an arginine-mimetic in medicinal chemistry.     

Intermolecular/interionic interactions in l-isoleucine-, l-proline-, and l-glutamine-aqueous electrolyte systems

Speed of sound and density values for ternary systems (amino acid + salt + water): l-isoleucine/l-proline/l-glutamine in aqueous solutions of 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ have been measured for several concentrations of amino acids at different temperatures (303.15, 308.15, 313.15, 318.15, and 323.15 K). Using speed of sound and density data, the thermodynamic parameters such as isentropic compressibility (κ_s), change in isentropic compressibility (Δκ_s) and relative change (Δκ_s/κ₀) in isentropic compressibility have been computed. The isentropic compressibility values decrease with increase in the amino acid concentration as well as with temperature. The decrease in κ_s values with increase in concentration of l-isoleucine/l-proline/l-glutamine in 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ has been ascribed to an increase in the number of incompressible zwitterions in solutions, and the formation of ‘zwitterions-ions’ and ‘zwitterions-water dipole’ entities in solutions. The decrease in κ_s values with increase in temperature has been attributed to the corresponding decrease of κ_relax (a relaxational part of compressibility), which is dominant over the corresponding increase of κ_∞ (an instantaneous part of compressibility). The trends of variation of Δκ_s and Δκ_s/κ₀ with variations in solute concentration and temperature have also been discussed in terms of solute-solute and solute-solvent intermolecular/interionic interactions operative in the systems.     

Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by l-proline-tetrazole ruthenium catalyst

A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)-2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler-Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing l-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis.