Rhodium-catalyzed asymmetric addition of arylboronic acids to γ-phthalimido-substituted-α,β-unsaturated carboxylic acid esters: an approach to γ-amino acids

Efficient Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to ethyl-γ-phthalimidocrotonate by using bis-sulfoxide ligand affords γ-aminobutyric acid (GABA) derivatives with high enantioselectivities (90-96% ee) under mild conditions. Optically pure (S)-Baclofen and (S)-Rolipram have been prepared successfully through this synthetic route.     

Organocatalytic asymmetric Michael addition of 1-acetylindolin-3-ones to α,β-unsaturated aldehydes: synthesis of 2-substituted indolin-3-ones

A highly efficient asymmetric Michael addition of 1-acetylindolin-3-ones to α,β-unsaturated aldehydes is developed to afford 2-substituted indolin-3-one derivatives in high yields (up to 94%) with good stereoselectivities (up to 11:1 dr and 96% ee). The Michael adducts can be transformed into substituted cyclopentyl[b]indoline compounds conveniently without racemization.     

Enzyme mediated kinetic resolution of δ-hydroxy-α,β-unsaturated esters as a route to optically active δ-lactones

A novel synthetic route to optically active saturated and unsaturated δ-lactones based on enzymatic kinetic resolution and ring-closing metathesis reactions has been proposed. The influence of temperature, co-solvent, organic additives and the substrate structure on the catalytic behavior of selected hydrolases was studied. The substantial impact of the organic co-solvent and surfactant type on the enzymatic activity and enantioselectivity was observed providing enantiomerically pure δ-hydroxy-α,β-unsaturated esters. The established protocol combining enzymatic kinetic resolution with ring closing metathesis was successfully applied in the synthesis of the enantiomerically pure (6R)-phenyl-5,6-dihydro-2H-pyran-2-one which plays crucial role in the synthesis of the number of bioactive compounds.     

Double diastereoselection in asymmetric [2+3] cycloaddition of chiral oxazoline N-oxides: application to the kinetic resolution of a racemic α,β-unsaturated δ-lactone

The asymmetric [2+3] cycloaddition reaction between chiral oxazoline N-oxide 1 and α,β-unsaturated lactone 2 was studied. A double diastereoselection was observed, (1R)-1 and (R)-2 gave a mismatched pair with almost no cycloadduct obtained. A transition state model is proposed, accounting for the destabilization of transition state in the cycloaddition reaction. This result has led to kinetic resolution studies, in which both enantiomers of 1 were reacted with racemic lactone 2. The enantiomeric excess of the recovered lactone 2 was determined to be up to 70% ee, by ¹³C-{¹H} NMR analysis in a chiral liquid crystalline solvent. The experimental results are in agreement with predicted enantiomeric excesses and consistent with the transition state models.     

Double asymmetric induction in the osmylation of -γ-alkoxy-α,β-unsaturated esters

OsO₄ promoted cis-dihydroxylation of enantiomerically pure (E)-α,β- unsaturated esters derived from alkoxyaldehydes occurs with noticeable levels (up to⩾ 45:1) of stereoselection when carried out in the presence of alkaloid derived ligands. Matching and mismatching substrate-ligand pairs have been identified.     

Enantioselective synthesis of anti-β-amido-α-hydroxy esters via asymmetric transfer hydrogenation coupled with dynamic kinetic resolution

The asymmetric transfer hydrogenation of β-amido-α-keto esters providing the corresponding anti-β-amido-α-hydroxy esters via dynamic kinetic resolution is reported. The use of a commercially available, or simply prepared, chiral ruthenium catalyst results in good yields as well as high diastereoselectivities and enantioselectivities.     

Catalytic asymmetric chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones

Highly efficient catalytic chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones has been developed via a chloronium-based mechanism to deliver anti-regioselective vicinal chloroamines instead of the aziridinium intermediates delivered aminochlorides. The combination of TsNCl(2) and TsNH(2) as reagents made the transformation highly efficient, delivering the γ-carbonyl-β-chloro-α-amino acid derivatives and α-chloro-β-amino-ketone derivatives in nearly quantitative yields with up to 99% ee and 99:1 dr under 0.05-0.5 mol % catalyst loading. TsNHCl was demonstrated to act as the key reactive species to form a bridged chloronium ion intermediate in the presence of a chiral scandium complex. The method might provide useful information for further realization of other haloamination reactions.     

Silylene transfer to α-keto esters and application to the synthesis of γ-lactones

Disubstituted α-hydroxy acids have been synthesized by metal-catalyzed silylene transfer to α-keto esters. A range of substituents are tolerated in the transformation with the exception of branched groups at the vinylic position. The α-hydroxy acid products can be converted into γ-lactones using a variety of lactonization conditions.     

Rhodium-catalyzed asymmetric 1,4-addition of arylboron reagents to α,β-unsaturated esters

Reaction of arylboron reagents, arylboronic acids or arylborates, which are readily accessible by lithiation of aryl bromides followed by treatment with trimethoxyborane, with α,β-unsaturated esters in the presence of rhodium/(S)-binap catalyst proceeded with high enantioselectivity to give high yields of optically active β-aryl esters of up to 98% ee. The enantioselectivity depends on the steric bulkiness of the ester moiety.     

Efficient synthesis of α,β-unsaturated γ-lactones linked to sugars

A series of structurally diverse unsaturated sugar-derived lactones has been prepared. α,β-Butenolides were introduced to the sugar moiety starting from epoxides, while α-methylene-γ-lactones were constructed from a carbonyl precursor, either an aldehyde, a ketone or a lactone. In the last case, an unprecedented Reformatsky-type reaction has been developed.     

New polymer-supported phosphonate reagents for the synthesis of Z-α,β-unsaturated esters

New polymer-supported phosphonate reagents have been prepared and evaluated for the synthesis of Z-α,β-unsaturated esters. High Z-selectivity was obtained using the reagent having two o-t-BuC₆H₄ groups.     

Rhodium-catalyzed asymmetric 1,4-addition of sodium tetraarylborates to β,β-disubstituted α,β-unsaturated esters

A rhodium-catalyzed 1,4-addition of sodium tetraarylborates to β,β-disubstituted α,β-unsaturated esters has been developed. Highly efficient asymmetric catalysis has also been described to create quaternary carbon stereocenters at the β-position of esters by tuning the ester group of substrates and employing a readily available chiral diene ligand.     

Stereoselective allylation of acyclic and chiral α-amino-β-Hydroxy aldehydes part 2: Application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-Detoxinine

Stereoselective allylations of acyclic, chiral α-amino-β-hydroxy aldehydes mediated by BF₃·OEt₂ and its application to the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine are described. The reactions of syn-α-NHCbz-β-OTBS substrates mediated by BF₃·OEt₂ afforded syn-selective products. The same reaction conditions gave anti-selective products from syn-α-NCbzBn-β-OTBS substrates. A hydrogen-bonded transition state and Felkin-Anh model have been suggested to account for the stereochemical outcomes of the two reactions, respectively. One of the allylation products was used for the formal synthesis of the polyhydroxylated γ-amino acid (+)-detoxinine.     

Stereoselective cyanation of 4-formyl and 4-imino-β-lactams: application to the synthesis of polyfunctionalized γ-lactams

The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with cyanide-based reagents give β-lactam α-aminonitriles, which are chameleonic building blocks for the controlled synthesis of a variety of new compounds including functionalized γ-lactams, succinimide derivatives, and diamino-lactams derivatives in optically pure form.     

Interaction of derivatives of 7-amino-1,5-benzo-diazepin-2-ones with α,β-unsaturated ketones

Derivatives of new condensed heterosystems, the tetracyclic [1,4]diazepino[3,2,1-hi]pyrido-[4,3,2-cd]indoles and tricyclic [1,4]diazepino[2,3-g]- and -[2,3-f]quinolines have been synthesized by the interaction of 7-amino-4-phenyl(or methyl)-1,3,4,5-tetrahydro(or 1,3-dihydro)-2H-1,5-benzodiazepin- 2-ones with dimethyl 2-oxoglutaconate and methyl 4-oxo-2-pentenoate. The corresponding carboxylic acids of the new derivatives were synthesized by alkaline hydrolysis of the methyl esters. The direction of the cyclocondensation reaction was determined by both the structure of the diazepine ring of the initial amines and also by the structure of the α,β-unsaturated ketones. Quantum-chemical calculations have been carried out of the minimal values of the local energy of ionization and of the resonance stabilization energy on specific atoms of the initial amines.     

Lipase-catalyzed kinetic resolution of α,β-unsaturated α′-acetoxy ketones

The lipase-catalyzed kinetic resolutions of the α,β-unsaturated α′-acetoxy ketones 3a,b have been investigated. Of the lipases examined, CAL-B from Candida antarctica (fraction B) has been shown to be an efficient biocatalyst, which may be used effectively in preparative scale reactions.     

Organocatalytic asymmetric oxy-Michael addition to a γ-hydroxy-α,β-unsaturated thioester via hemiacetal intermediates

We report an asymmetric oxy-Michael addition to a γ-hydroxy-α,β-unsaturated thioester via hemiacetal intermediates in the presence of Cinchona-alkaloid-thiourea-based bifunctional organocatalysts. This method provides a novel enantioselective route to β-hydroxy carboxyl compounds, which in turn can be used to synthesize valuable chiral building blocks.     

A concise synthesis of highly functionalized α,β-unsaturated γ-butyrolactones through ring contraction of 2H-pyran-2-ones

2-Oxo-5-(1-arylvinyl)-4-piperidin-1-yl-2,5-dihydrofuran-3-carbonitriles 3 have been synthesized through ring contraction of suitably functionalized 2H -pyran-2-ones 1 by a carbanion generated in situ from nitromethane 2 in good yield. In some cases their counterpart tautomers 2-oxo-5-(1-arylethylidene)-4-piperidin-1-yl-2,5-dihydrofuran-3-carbonitriles 4 have also been isolated and characterized as minor products.