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.     

Gold(I)/Chiral N,N′‐Dioxide–Nickel(II) Relay Catalysis for Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement

A highly efficient asymmetric cascade reaction between alkynyl esters and allylic alcohols has been realized. Key to success was the combination of a hydroalkoxylation reaction catalyzed by a π‐acidic gold(I) complex with a Claisen rearrangement catalyzed by a chiral Lewis acidic N,N′‐dioxide–nickel(II) complex. A range of acyclic α‐allyl β‐keto esters were synthesized in high yields (up to 99 %) with good diastereoselectivities (up to 97:3) and excellent enantioselectivities (up to 99 % ee ) under mild reaction conditions. These products can be easily transformed into optically active β‐hydroxy esters, β‐hydroxy acids, or 1,3‐diols.     

Mimicking enzymatic transaminations: attempts to understand and develop a catalytic asymmetric approach to chiral alpha-amino acids

Attempts are made to build a bridge between asymmetric catalysis and enzymatic reactions by mechanistic investigations and the development of a catalytic and enantioselective approach to amination of alpha-keto esters by primary amines catalyzed by chiral Lewis acids as a model for transamination enzymes. Different Lewis acids can catalyze the half-transamination of alpha-keto esters using primary amine nitrogen sources such as pyridoxamine and 4-picolylamine. The mechanistic studies of the Lewis-acid catalyzed half-transamination using deuterium-labelled compounds show the incorporation of deuterium atoms in several positions of the alpha-amino acid derivative, indicating that the enol of the alpha-keto ester plays an important role along the reaction path. The catalytic enantioselective reactions are dependent on the pKa-value of the solvent since enantioselectivities were only obtained in solvents with high pKa-values relative to methanol. However, stronger acidic conditions generally gave better yields, but poor enantioselectivities. A series of chiral Lewis acids were screened as catalysts for the enantioselective half-transamination reactions and moderate yields and enantioselectivities of up to 46% ee were obtained.     

Catalytic asymmetric alkylations of ketoimines. Enantioselective synthesis of N-substituted quaternary carbon stereogenic centers by Zr-catalyzed additions of dialkylzinc reagents to aryl-, alkyl-, and trifluoroalkyl-substituted ketoimines

Catalytic enantioselective alkylations of three classes of ketoimines are reported. Reactions are promoted in the presence 0.5-10 mol % of a Zr salt and a chiral ligand that contains two inexpensive amino acids (valine and phenylalanine) and involve Me2Zn or Et2Zn as alkylating agents. Requisite aryl- and alkyl-substituted alpha-ketoimine esters, accessed readily and in >80% yield on gram scale through a two-step sequence from the corresponding ketones, undergo alkylation to afford quaternary alpha-amino esters in 79-97% ee. Aryl-substituted trifluoroketoimines are converted to the corresponding amines by reactions with Me2Zn, catalyzed by a chiral complex that bears a modified N-terminus. The utility of the catalytic asymmetric protocols is illustrated through conversion of the enantiomerically enriched alkylation products to a range of cyclic and acyclic compounds bearing an N-substituted quaternary carbon stereogenic center.     

Asymmetric direct aldol reaction of functionalized ketones catalyzed by amine organocatalysts based on bispidine

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including alpha-keto phosphonates, alpha-keto esters, as well as alpha,alpha-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction.     

Proline-based P, N ligands in asymmetric allylation and the Heck reaction.

A series of phosphine-oxazoline ligands based on proline are reported. These ligands are synthesized from commercially available trans-4-hydroxy-L-proline in four steps. The ability of this type of ligand to catalyze allylic alkylation in an asymmetric fashion as well as the asymmetric Heck reaction is reported. The best of these ligands gave a palladium complex, which catalyzed the addition of dimethylmalonate to cyclopentenyl acetate in excellent yield and up to 96% ee. This same system catalyzed the Heck reaction between dihydrofuran and cyclohexene in up to 86% ee. These ligands appear to differ from the traditional phosphine-oxazoline ligands in that the stereochemistry of the stereogenic carbon next to the oxazoline is not necessarily the dominant chiral center in the induction of selectivity.     

Enantioselective synthesis of optically active secondary amines via asymmetric reduction

The enantioselective synthesis of optically active secondary amines via the asymmetric reduction of N-substituted ketimines with various chiral hydride reagents, such as Itsuno's reagent (1), Corey's reagent (2), K glucoride (3), Sharpless' reagent (4), and Mosher's reagent (5) has been investigated. Among the hydride reagents examined, 1 gave the best results in terms of asymmetric induction. Thus, the reduction of N-phenylimine derivatives of aromatic ketones with 1 provided the corresponding amines in 96–98% yields with high optical induction, such as 73 % ee for acetophenone N-phenylimine (6a), 87 % ee for propiophenone N-phenylimine (6b), 88 % ee for bulyrophenone N-phenylimine (6c), and 71 % ee for isobutyrophenone N-phenylimine (6d). In the case of N-alkyl ketimine derivatives, the reduction afforded somewhat lower optical inductions as compared to those of N-phenyl derivatives, giving 46 % ee for acetophenone N-benzylimine (6f), 52 % ee for acetophnone N-ⁿ-heptylimine (6g) and 43 % ee for acetophenone N-cyclohexylimine (6h). However, the substitution of a bulky alkyl group on nitrogen of the ketimines increases remarkably the optical induction of product amine, such as 80 % ee for acetophenone N-tert-butylimine (6e). The reduction of N-substituted aliphatic ketimines gave very low optical inductions (7.4 – 24 % ee). The catalytic effects of oxazaborolidines (1a and 2a) in the reduction of ketimines with 1 and 2 were also examined.     

Organocatalytic functionalization of carboxylic acids: isothiourea-catalyzed asymmetric intra- and intermolecular Michael addition--lactonizations

Tetramisole promotes the catalytic asymmetric intramolecular Michael addition-lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition-lactonization of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).     

Structural requirements in chiral diphosphine-rhodium complexes—XIII: Steric and electronic factors in the asymmetric homogeneous hydrogenation of Z-α-acylaminocinnamic acids and esters catalyzed by rhodium(I) complexes

Z-α-acylaminocinnamic acids and esters were hydrogenated with rhodium(I) complexes containing (4R,5R) - trans - 4,5 - bis(diphenylphosphinomethyl) - 2,2 - dimethyl - 1,3 - dioxolan (DIOP). Increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) resulted in a lowered reduction of the si-re prochiral face to yield a decreasing excess of the (R)-amino acid derivatives. In the series of N-acylphenylalanine free acids (resulting from hydrogenation of Z-α-acylaminocinnamic acids) the optical purity decreased from 82% ee-(R) [Me]; 57% ee-(R) [i-Pr]; 52% ee-(R) [t-Bu]; to 46% ee-(R) [1-adamantyl]. Theα-benzamido, α-formamido and α-trifluoroacetamido substrates gave hydrogenation products having 68% ee-(R) [Ph]; 60% ee-(R) [H]; and 16% ee-(R)[CF₃]. In the corresponding methyl esters, increasing the steric bulk of the acyl function (NHCOR) resulted in a markedly greater decrease in enantioface differentiation. In the series of N-acylphenylalanine methyl ester products (resulting from hydrogenation of Z-methyl α-acylaminocinnamates) the optical purity decreased from 69% ee-(R)[Me]; 15% ee-(R) [i-Pr]; to 0% ee[t-Bu and 1-adamantyl]. The α-benzamido, α-formamido, and α-trifluoroacetamido substrates gave hydrogenation products having 36% ee-(R) [Ph]; 58% ee-(R) [H]; and 22% ee-(S) [CF₃]In the series of N-acetylphenylalanine alkyl ester products (resulting from hydrogenation of Z-alkyl α-acetamidocinnamate esters) trifluoro substitution in the alkyl alcohol moiety resulted in a decrease in optical purity to 52% ee-(R) [CH₂CF₃] compared to 72, 76 and 77% ee-(R) [Et, i-Pr and t-Bu, respectively].     

The first asymmetric esterification of free carboxylic acids with racemic alcohols using benzoic anhydrides and tetramisole derivatives: an application to the kinetic resolution of secondary benzylic alcohols

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alcohols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the best reagent to use in producing the corresponding esters in high ee when the reaction is catalyzed by (+)-benzotetramisole (BTM); by contrast, when non-substituted benzoic anhydride is used as a coupling reagent, the resulting optically active alcohols are obtained with high selectivities. This protocol directly produces chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the trans-acylation process to generate mixed anhydrides from acid components and benzoic anhydride derivatives under the influence of chiral catalysts.     

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.     

Catalytic asymmetric aziridination of α,β-unsaturated aldehydes

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,β-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure β-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,β-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected β-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.     

Catalytic, enantioselective alkylation of alpha-imino esters: the synthesis of nonnatural alpha-amino acid derivatives.

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of alpha-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.     

Highly stereoselective reductions of alpha-alkyl-1,3-diketones and alpha-alkyl-beta-keto esters catalyzed by isolated NADPH-dependent ketoreductases

[reaction: see text] The biocatalytic reduction of alpha-alkyl-1,3-diketones and alpha-alkyl-beta-keto esters employing 1 of 20 different isolated NADPH-dependent ketoreductases proved to be a highly efficient method for the preparation of optically pure keto alcohols or hydroxy esters.     

Highly Enantioselective Hydrogenation of β‐Alkyl and β‐(ω‐Chloroalkyl) Substituted β‐Keto Esters

Highly enantioselective hydrogenation of β‐alkyl and β‐(ω‐chloroalkyl) substituted β‐keto esters was achieved with Ru catalysts based on chiral diphosphines in EtOH at 50°C under 50‐bar initial hydrogen pressure, affording the corresponding β‐hydroxy esters in >98% ee.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

Asymmetric hydrogenation of di and trisubstituted enol phosphinates with N,P-ligated iridium complexes

The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.     

Asymmetric Henry reaction catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) complexes: metal-controlled reversal of enantioselectivity

[reaction: see text] C(2)-symmetric tridentate bis(oxazoline) and bis(thiazoline) ligands with a diphenylamine backbone have been investigated in the catalytic asymmetric Henry reaction of alpha-keto esters with different Lewis acids. Their Cu(OTf)(2) complexes furnished S enantiomers, while Et(2)Zn complexes afforded R enantiomers, both of them with higher enantioselectivities (up to 85% ee). Reversal of enantioselectivity in asymmetric Henry reactions was achieved with the same chiral ligand by changing the Lewis acid center from Cu(II) to Zn(II). The results show that the NH group in C(2)-symmetric tridentate chiral ligands plays a very important role in controlling both the yields and enantiofacial selectivity of the Henry products.     

Synthesis of chiral butenolides using amino-thiocarbamate-catalyzed asymmetric bromolactonization

The asymmetric cyclization of 4,4-disubstituted 3-butenoic acids is studied. Amino-thiocarbamates are used as the catalysts and N-bromosuccinimide is used as the stoichiometric halogen source. The resulting γ-butanolide products are readily converted into the corresponding γ-butenolides (up to 58% ee) derivatives in one-pot.     

Preparation of enantiopure biimidazoline ligands and their use in asymmetric catalysis

A convenient new method for the preparation of 2,2'-biimidazolines is reported. Amino alcohols were reacted with dimethyl oxalate, and the product hydroxy amides converted into chloroamides by reaction with thionyl chloride. Treatment with PCl5, followed by diamines (ethanediamine, propane-1,3-diamine, 2,2-dimethylpropane-1,3-diamine) furnished a series of enantiopure tricyclic biimidazolines. Complexes of two of the ligands with PdCl2 were prepared and their X-ray crystal structures were determined. The biimidazolines were tested as ligands for asymmetric Pd-catalysed allylations. Moderate enantioselectivity (up to 80% ee) was found for the reaction of dimethyl malonate with diphenylallyl acetate, with the 5,7,5 fused tricyclic systems outperforming the 5,6,5 analogues. The corresponding reaction of pentenyl acetate gave lower enantioselectivity (44-57% ee), and proved very sensitive to the donor strength of the ligands, the stronger donors giving lower yields. The results provide a further demonstration of the value of the 'tunability' of imidazoline ligands.