Organocatalytic asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids and derivatives

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.     

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.     

Enantioselective organocatalytic Mukaiyama-Michael addition of silyl enol ethers to alpha,beta-unsaturated aldehydes

[reaction: see text] A highly enantioselective, organocatalytic Mukaiyama-Michael addition reaction of silyl ethers and alpha,beta-unsaturated aldehydes has been developed. The process, catalyzed by MacMillan's chiral imidazolidinone, affords delta-keto aldehydes in high yields (56-87%) and high enantioselectivities (85-97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and alpha,beta-unsaturated aldehydes and, as such, provides access to a range of important synthetic building blocks.     

Organocatalytic asymmetric 5-hydroxyisoxazolidine synthesis: a highly enantioselective route to beta-amino acids

The highly chemo- and enantioselective organocatalytic tandem reaction between N-protected hydroxyl amines and alpha,beta-unsaturated aldehydes is presented; the reaction provides access to 5-hydroxyisoxazolidines and beta-amino acids in high yields and with 90-99% ee.     

Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to alpha,beta-unsaturated aldehydes

An organocatalytic asymmetric multicomponent domino and a conjugated addition reaction to alpha,beta-unsaturated aldehydes are presented. The development is based, first, on an organocatalyzed highly enantioselective nucleophilic thiol addition to the beta-carbon atom in the iminium ion intermediate, followed by an electrophilic amination of the alpha-carbon atom to the enamine intermediate. The multicomponent reactions proceed to give enantiopure amino-thiols in moderate to good yields. Furthermore, the organocatalyzed thiol addition to alpha,beta-unsaturated aldehydes takes place in good yields and excellent enantioselectivities.     

Organocatalytic and direct asymmetric vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes

The first highly regio-, chemo-, diastereo- and enantioselective direct vinylogous Michael addition of alpha,alpha-dicyanoolefins to alpha,beta-unsaturated aldehydes is described, employing readily available chiral alpha,alpha-diarylprolinol salts as iminium organocatalysts.     

Enantioselective organocatalytic double Michael addition reactions

[reaction: see text] A novel organocatalytic, enantioselective domino double Michael addition reaction of alpha,beta-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate has been developed. The process is promoted by chiral diphenylprolinol TMS ether to give chiral tetrahydrothiophenes in high to excellent levels of enantioselectivities.     

The first enantioselective organocatalytic Mukaiyama-Michael reaction: a direct method for the synthesis of enantioenriched gamma-butenolide architecture

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.     

Enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indoles

An enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indolyl alpha,beta-unsaturated aldehydes has been developed. This powerful new strategy allows enantioselective access to THPIs and THBCs in a straightforward and atom-economical manner.     

Enantioselective organocatalytic amine conjugate addition

The first enantioselective organocatalytic amine conjugate addition has been successfully developed. The application of LUMO-lowering iminium catalysis has enabled the highly chemo- and enantioselective 1,4-addition of a rationally designed N-silyloxycarbamate nucleophile (HOMO-raised) to alpha,beta-unsaturated aldehydes. Imidazolidinone 2*pTSA was found to catalyze the addition of various orthogonally N-protected silyloxycarbamate nucleophiles to a range of alpha,beta-unsaturated aldehydes, affording synthetically useful beta-amino aldehyde intermediates. The synthetic utility of the protocol was demonstrated in the rapid synthesis of enantioenriched beta-amino acids in one operation and 1,3-amino alcohol derivatives in three operations.     

Enantioselective organocatalytic intramolecular aza-Michael reaction: a concise synthesis of (+)-sedamine, (+)-allosedamine, and (+)-coniine

The intramolecular aza-Michael reaction of carbamates bearing remote alpha,beta-unsaturated aldehydes under organocatalytic conditions took place with good yields and excellent ee's when J?rgensen catalyst IV was used in the process, giving rise to the enantioselective formation of several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.     

Enantioselective organocatalytic hydride reduction

The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated aldehydes to generate beta-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol.     

Tetrazolic acid functionalized dihydroindol: rational design of a highly selective cyclopropanation organocatalyst

Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of alpha,beta-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted alpha,beta-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.     

A simple asymmetric organocatalytic approach to optically active cyclohexenones

Optically active 2,5-disubstituted-cyclohexen-2-one derivatives have been prepared in a one-pot process consisting of five reaction steps: an organocatalytic asymmetric conjugated addition of beta-ketoesters to alpha,beta-unsaturated aldehydes that proceeds in aqueous solutions or under solvent-free conditions has been implemented in a multi-step process.     

The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to alpha,beta-unsaturated aldehydes

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described.     

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.     

One-pot organocatalytic domino Michael/alpha-alkylation reactions: direct catalytic enantioselective cyclopropanation and cyclopentanation reactions

The development of one-pot organocatalytic domino Michael/alpha-alkylation reactions between bromomalonates or bromoacetoacetate esters and alpha,beta-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99 % ee. The catalytic domino Michael/alpha-alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cyclopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of beta-malonate esters (91-97 % ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.     

tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts for the asymmetric aldol reaction in aqueous or organic medium

The enantioselective aldol reaction between ketones and aldehydes constitutes one the most common reaction models for the evaluation of novel organocatalysts. The last few years, it has been shown that the organocatalytic aldol reaction can be performed in water. A family of tripeptides consisting of proline, phenylalanine, and tert-butyl esters of amino acids was successfully employed in this asymmetric transformation. The products of the reaction between various ketones and aldehydes were obtained in high yields (up to 99%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee). The C-terminal amino acid determines the ability of the tripeptide (Pro-Phe-AA-O^tBu) to act efficiently in aqueous or organic medium.     

Organocatalytic enantioselective aza-Michael reaction of nitrogen heterocycles and alpha,beta-unsaturated aldehydes

The asymmetric organocatalytic aza-Michael reaction of several nitrogen heterocycles and alpha,beta-unsaturated aldehydes has been studied in detail; under the optimised conditions, the conjugate addition products have been obtained in high to excellent enantioselectivities.     

Catalytic asymmetric reductive Michael cyclization

A highly efficient and chemo-, regio-, diastereo-, and enantioselective organocatalytic tandem conjugate reduction-Michael cyclization of enal enones has been developed. Accordingly, treating the enal enone with a Hantzsch dihydropyridine in the presence of a catalytic amount of an imidazolidinone organocatalyst provides cyclic keto aldehydes in high yields and enantiomeric excesses. The reaction works well with aliphatic and aromatic substrates in the synthesis of five- and six-membered carbacyclic derivatives.