Enantioselective organocatalytic alpha-fluorination of aldehydes

The first direct enantioselective catalytic alpha-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate alpha-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis. The use of imidazolidinone 1 as the asymmetric catalyst has been found to mediate the fluorination of a large variety of aldehyde substrates with N-fluorobenzenesulfonimide serving as the electrophilic source of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.     

Direct organocatalytic asymmetric alpha-chlorination of aldehydes

The direct organocatalytic enantioselective alpha-chlorination of aldehydes has been developed. The reaction proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine. The alpha-chloro aldehydes are obtained in up to 99% yield and up to 95% ee. The synthetic utility of the enantioselective alpha-chlorination of aldehydes is demonstrated by transformation of the alpha-chloro aldehydes to the corresponding alpha-chloro alcohols (>90% yield) by standard reduction and further transformation to both a terminal epoxide and amino alcohol, both obtained without loss of optical purity. Oxidation of the alpha-chloro aldehydes followed by esterification gave optically active alpha-chloro esters without loss of optical purity. It is demonstrated that these optically active alpha-chloro esters can be converted into nonproteinogenic amino acids in overall high yields, maintaining the enantiomeric excess obtained in the catalytic enantioselective alpha-chlorination step.     

Direct and enantioselective organocatalytic alpha-chlorination of aldehydes

The first direct enantioselective catalytic alpha-chlorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective chlorination of aldehydes to generate alpha-chloro aldehydes, an important chiral synthon for chemical and medicinal agent synthesis. The use of imidazolidinone 3 as the asymmetric catalyst has been found to mediate the halogenation of a large variety of aldehyde substrates with the perchlorinated quinone 1 serving as the electrophilic chlorinating reagent. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. The capacity of catalyst 3 to override the inherent bias of resident stereogenicity in the chlorination of enantiopure beta-chiral aldehydes is also described. Catalyst quantities of 5 mol % were generally employed in this study.     

Enantioselective organocatalytic conjugate addition of aldehydes to nitrodienes

The asymmetric organocatalyzed Michael addition of aldehydes to alpha,beta-gamma,delta-unsaturated nitro compounds has been accomplished using only 5 mol % of (S)-diphenylprolinol silyl ether and 2 equiv of aldehyde in a mixture of ethanol and water (5% v/v). The Michael adducts were obtained in good yields, diastereoselectivities up to 94/6, and ee's up to 99%. This process provides synthetically useful compounds which can easily lead to more complex molecules, as exemplified with substituted tetrahydropyran or cyclohexene.     

The direct and enantioselective organocatalytic alpha-oxidation of aldehydes

The first direct enantioselective catalytic alpha-oxidation of carbonyls has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective oxyamination of aldehydes, to generate alpha-oxyaldehydes, important chiral synthons for natural product and medicinal agent synthesis. The use of l-proline as the asymmetric catalyst has been found to mediate the oxidation of a large variety of aldehyde substrates with nitrosobenzene serving as the electrophilic oxidant. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 2 mol % were generally employed in this study, successful oxidations conducted using catalyst loadings as low as 0.5 mol % are described.     

Microwave-assisted organocatalytic anomerization of alpha-C-glycosylmethyl aldehydes and ketones

The use of l-proline (30 mol %) and MW irradiation (13 W) with cooling promotes in a few hours the almost quantitative anomerization of alpha-C-glycosylmethyl aldehydes into beta-isomers. An open-chain enamine-based mechanism is postulated for this transformation. The anomerization of alpha-ketones was instead achieved by the pyrrolidine/TFA couple and MW irradiation at 120 degrees C (enamine mechanism) and by DBU as Br?nsted base (enolate mechanism).     

Direct, organocatalytic α-sulfenylation of aldehydes and ketones

A method for direct sulfenylation of aldehydes and ketones, catalyzed by a novel pyrrolidine trifluoromethanesulfonamide organocatalyst, has been developed. This process serves as an efficient and mild approach to the preparation of α-phenylthio-ketones and -aldehydes.     

Enantioselective organocatalytic aryloxylation of aldehydes with o-quinones

An enantioselective organocatalytic inverse electron demand hetero Diels-Alder reaction of in situ generated enamines with o-quinone reagents is reported. The method, which is optimal in wet acetonitrile at ambient temperature, provides a new and direct asymmetric route to the aryl alkyl ether motif and an alternative metal-free strategy to S_N2 substitutions with phenolate nucleophiles.     

Direct organocatalytic asymmetric α-hydroxymethylation of ketones and aldehydes

Direct organocatalytic asymmetric α-hydroxymethylation of ketones and aldehydes with formaldehyde has been developed, which furnished the corresponding α-hydroxymethylated adducts with high chemo- and enantioselectivity. The reaction is catalyzed by proline derivatives and is a simple method for the enantioselective synthesis of α-hydroxymethylated ketones and aldehydes, and C-2 symmetric diols.     

First enantioselective organocatalytic conjugate addition of aldehydes to vinyl phosphonates

Chiral amines catalyze the enantioselective conjugate addition of aldehydes to vinyl phosphonates in high yields and with enantioselectivities up to 97% ee. This novel process provides synthetically useful chiral gamma-geminal phosphonate aldehydes which can be easily converted in a few steps into chiral beta-substituted vinyl phosphonates with conservation of the optical purity.     

Direct organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes

The organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes with peroxides or sodium percarbonate is presented. Chiral pyrrolidine derivatives, proline and amino acid derived imidazolidinones mediate the asymmetric epoxidation of α,β-unsaturated aldehydes. For example, commercially available protected α,α-diphenyl-2-prolinol catalyzes the asymmetric formation of 2-epoxy-aldehydes in 81-95% conversion with up to 96:4 dr and 98% ee. The use of non-toxic catalysts, aqueous solvents and hydrogen peroxide or sodium percarbonate as the oxygen sources makes the reaction environmentally benign.     

Asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes with hydrogen peroxide

The first asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes is presented. A chiral bisaryl-silyl-protected pyrrolidine acts as a very selective epoxidation organocatalyst using simple oxidation agents, such as hydrogen peroxide and tert-butyl hydroperoxide. The asymmetric epoxidation reactions proceed under environmental friendly reaction condition in, for example, water mixtures of alcohols, and the scope of the reaction is demonstrated by the formation of optically active alpha,beta-epoxy aldehydes in high yields and enantioselectivities >94% ee. Furthermore, the direct synthesis of the sex pheromone from an acaric mite by asymmetric epoxidation of citral is presented.     

Dienamine catalysis: organocatalytic asymmetric gamma-amination of alpha,beta-unsaturated aldehydes

A new concept in organocatalysis is presented, the direct asymmetric gamma-functionalization of alpha,beta-unsaturated aldehydes. We disclose that secondary amines can invert the usual reactivity of alpha,beta-unsaturated aldehydes, enabling a direct gamma-amination of the carbonyl compound using azodicarboxylates as the electrophilic nitrogen-source. The scope of the reaction is demonstrated for the enantioselective gamma-amination of different alpha,beta-unsaturated aldehydes, giving the products in moderate to good yields and with high enantioselectivities up to 93% ee. Experimental investigations and DFT calculations indicate that the reaction might proceed as a hetero-Diels-Alder cycloaddition reaction. Such a mechanism can explain the "unexpected" stereochemical outcome of the reaction.     

The direct organocatalytic asymmetric mannich reaction: unmodified aldehydes as nucleophiles

The unprecedented application of unmodified aldehydes as nucleophilic donors in direct catalytic asymmetric Mannich-type reactions is disclosed in a full account. Our efforts in broadening the applicability of chiral pyrrolidine-based catalysts in direct asymmetric Mannich-type reactions led to the highly diastereo- and enantioselective and concise synthesis of functionalized alpha- and beta-amino acids, beta-lactams, and amino alcohols.     

Efficient organocatalytic cross-aldol reaction between aliphatic aldehydes through their functional differentiation

A chemo- and stereoselective asymmetric direct cross-aldol reaction between aliphatic aldehydes and α-chloroaldehydes has been developed as a method for the formation of the sole cross-aldol adduct with both enantio- and diastereocontrol, and either anti- or syn-aldol adducts were obtained in good to excellent stereoselectivities by use of proline or a novel axially chiral amino sulfonamide as catalyst.