Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.     

An air-stable,storable chiral zirconium catalyst for asymmetric aldol reactions

Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields with high selectivity.     

Noncovalently supported heterogeneous chiral amine catalysts for asymmetric direct aldol and Michael addition reactions

A new strategy for the immobilization of asymmetric organocatalysts by combining polystyrene (PS)/sulfonic acids and chiral amines in situ through acid-base interactions is presented. The PS/sulfonic acids play a dual role as catalyst anchors and modulators for activity and stereoselectivity. Different types of polymeric sulfonic acids were examined and 1% divinylbenzene (DVB) cross-linked PS/sulfonic acid 1 e with a medium loading of sulfonic acid moieties was found to be the optimal support. Furthermore, the noncovalency of this system allows combinatorial screening of optimal catalysts for the targeted reactions. In this regard, highly efficient and enantioselective heterogeneous catalysts were identified for the asymmetric direct aldol and Michael addition reactions. The catalysts could be easily recovered by filtration and reused for six cycles with similar stereoselectivity but slightly decreased activity. Significantly, the deactivated catalysts could be regenerated following an acidic washing/amine recharging procedure.     

Organocatalytic direct asymmetric aldol reactions in water

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol products in excellent yield with high enantiomeric excess, even when only an equal molar ratio of the donor and acceptor was used. These results reveal an effective design strategy for the development of aqueous organocatalytic systems.     

Rational combination of two privileged chiral backbones: highly efficient organocatalysts for asymmetric direct aldol reactions between aromatic aldehydes and acylic ketones

A new class of organocatalysts has been designed by rational combination of proline with cinchona alkaloids. The chiral amine 3a, prepared from l-proline and cinchonidine, has been found to be an efficient catalyst for the direct aldol reactions of acetone or 2-butanone with a wide range of aldehydes (up to 98% ee). The cinchonidine backbone is essential to the reaction efficiency and enantioselectivity.     

Palladium-catalyzed asymmetric synthesis of axially chiral allenylsilanes and their application to SE2' chirality transfer reactions

Stepwise application of the Pd-catalyzed S(N)2' reaction and the desilylative S(E)2' reaction to the ambivalent 2-bromo-1-silyl-1,3-dienes provides a novel route to the highly enantioselective construction of tertiary and quaternary propargylic stereogenic centers via axially chiral allenylsilanes.     

An efficient, general asymmetric synthesis of carbocyclic nucleosides: application of an asymmetric aldol/ring-closing metathesis strategy

A general and efficient synthesis of carbocyclic and hexenopyranosyl nucleosides has been developed. The strategy combines three key transformations: an asymmetric aldol addition to establish the relative and absolute configuration of the pseudosugar, a ring-closing metathesis to construct the pseudosugar ring, and a Trost-type palladium(0)-mediated substitution to assemble the pseudosugar and the aromatic base. Carbovir, abacavir, and their 2'-methyl derivatives as well as hexenopyranosyl nucleoside analogues have been prepared by this sequence.     

Asymmetric organocatalytic direct aldol reactions of ketones with alpha-keto acids and their application to the synthesis of 2-hydroxy-gamma-butyrolactones

A variety of organocatalysts for the asymmetric direct aldol reactions of ketones with alpha-keto acids were designed on the basis of molecular recognition and prepared from proline and aminopyridines. The organic molecule 8e, derived from proline and 6-methyl-2-amino pyridine, was the best catalyst, affording excellent enantioselectivities (up to 98% ee) for the direct aldol reactions of acetone or 2-butanone with a wide range of alpha-keto acids and for the reactions of various acyclic aliphatic ketones with 3-(2-nitrophenyl)-2-oxopropanoic acid. The aldol adducts could be converted to 2-hydroxy-gamma-butyrolactones by reaction sequences of diastereoselective reduction and lactonization. Experimental and theoretical studies on the transition states revealed that the amide N-H and the pyridine N of the organocatalyst selectively form hydrogen bonds with the keto oxygen and the carboxylic acid hydroxy of the alpha-keto acid, respectively. These two hydrogen-bonding interactions are important for the reactivity and enantioselectivity of the direct asymmetric aldol condensation.     

Double diastereoselective SuperQuat glycolate aldol reactions: application to the asymmetric synthesis of polyfunctionalised lactones

Polyfunctionalised lactones with up to five contiguous stereocentres may be prepared with high stereocontrol by a double diastereoselective aldol protocol with protected homochiral alpha,beta-dihydroxy- or alpha,beta-gamma-trihydroxyaldehydes and a chiral glycolate oxazolidinone, followed by subsequent O-desilylation and lactonisation.     

Dipeptide-catalyzed direct asymmetric aldol reactions in the presence of water

The l-proline-based dipeptide has been discovered and developed as an efficient catalyst for the direct asymmetric aldol reactions of unmodified ketones with various aldehydes including aromatic, aliphatic, heteroaromatic, and unsaturated aldehydes in the presence of water at 0 °C. The resulted methodology and optimal conditions led to the corresponding aldol products with high yields (up to 94%) and good enantioselectivities (up to 97% ee).     

Synthesis of planar chiral [2.2]paracyclophane-based amino thioureas and their application in asymmetric aldol reactions of ketones with isatins

Several novel [2.2]paracyclophane-based amino thioureas have been designed and synthesized. The [2.2]paracyclophane-based amino thioureas were used as bifunctional catalysts for organocatalytic enantioselective aldol reactions between ketones and isatins, affording the desired adducts containing a chiral tertiary alcohol in high yields (up to 92% yield) and with good enantioselectivity (up to 88% ee). This is a successful example of employing planar chiral [2.2]paracyclophane-based amino thioureas in asymmetric aldol reactions.     

Synthesis of new ionic-liquid-tagged organocatalysts and their application in stereoselective direct aldol reactions

New amino acid—1,2,3-triazolium conjugates were synthesized by establishing a 1,2,3-triazolium unit to the amino acid through Cu-catalyzed alkyne-azide cycloaddition and subsequent N-methylation. These products were applied as ionic-liquid-tagged organocatalysts in asymmetric direct aldol reactions. Remarkably, a lysine-derived conjugate performed better than proline derivatives. Evidence was found that IL-tagging improved the catalytic performance. Recycling of the organocatalyst was easily possible by extraction of products.     

Non-linear effects in acyclic amino acid-catalyzed direct asymmetric aldol reactions

Non-linear effects were observed in acyclic amino acid-catalyzed direct asymmetric intermolecular aldol reactions. The non-linear effects are due to the equilibrium solid-liquid phase behavior of amino acids. The results suggest that the phase behavior of amino acids linked to asymmetric catalysis may have implications to the evolution of homochirality.     

Organocatalytic asymmetric syn-selective direct aldol reactions in water

A practical and convenient organocatalytic strategy is developed to provide a direct route to syn-selective aldol products in the presence of water. The siloxy serine organocatalyst mediates the direct aldol reaction of TBSO-protected hydroxyacetone with a variety of aldehydes to provide the aldol products in good yields and enantioselectivities up to 92%.     

Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions.

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.     

Telaprevir fragments as organocatalysts in asymmetric direct aldol reactions of aldehydes

We have demonstrated that the fragments of Telaprevir can act as organocatalysts for asymmetric aldol reactions between aromatic aldehydes and acetone under mild conditions. The reaction conditions have been optimized in terms of the catalyst nature, choice of temperature, solvent, additive, and the catalyst loading. Under proper conditions, fairly good yield and enantioselectivity have been achieved.     

Catalytic, asymmetric synthesis and diastereoselective aldol reactions of dipropionate equivalents

The dimer of methylketene can be conveniently prepared in one step and high enantiomeric excess from propionyl chloride, using a catalytic amount of a silylated cinchona alkaloid as a source of chirality. Opening of the dimer with a lithiated sulfonamide affords a beta-ketosulfonimide, which undergoes Sn(II)-mediated aldol reactions to diastereoselectively afford the anti,syn-aldol adduct. Alternatively, reduction of the dimer to the beta-hydroxy ketone, followed by acylation, affords a beta-acyloxyl ketone that undergoes diastereoselective, dialkylboron chloride-mediated aldol reactions to produce the anti,anti-aldol adduct.     

Highly stereoselective direct aldol reactions catalyzed by a bifunctional chiral diamine

The enantioselective organocatalytic direct aldol reactions of ketones with various aldehydes were developed by using chiral 1,2-cyclohexanediamine (DACH) based multifunctional ligands via a noncovalent catalysis mechanism. By using a catalyst, we also obtained functionalized 3-alkyl-3-hydroxyindolin-2-ones in high yields and with good to excellent enantioselectivities.