Unprecedented, fully recyclable, solid-supported reagent for the kinetic resolution of racemic amines through enantioselective N-acetylation

The high-yielding synthesis and application of the first polymer supported reagent for the kinetic resolution (KR) of amines through enantioselective acetylation is described; this new supported chiral reagent allows the KR of primary amines with excellent selectivities at room temperature; moreover, this supported approach is highly efficient as the Merrifield-supported chiral scaffold can be quantitatively recovered and recycled.     

Organocatalytic enantioselective acyl transfer onto racemic as well as meso alcohols, amines, and thiols

Acyl transfer is at the heart of functional-group transfers utilized both in nature and in the chemical laboratory. Acylations are part of the natural assembly machinery for the generation of complex molecules and for energy transport in biological systems. The recognition of covalent acyl-enzyme intermediates led to both mechanistic studies as well as the development of biomimetic approaches. Consequently, chemists first used the tools of nature in the form of enzymes and naturally occurring alkaloids as catalysts, before eventually developing a large variety of synthetic small molecules for selective acyl transfer. In contrast to nature, chemists utilize acylation reactions as a practical way for stereoselection and functional-group protection. Indeed, the number of studies concerning acyl transfer has significantly increased over the last 15 years. This Review examines and highlights these recent developments with the focus as given in the title.     

Microbially mediated enantioselective hydrolysis of racemic acetates

The enantioselective hydrolyses of a series of racemic hydroaromatic acetates by $\text{Rhizopus}$$\text{nigricans}$ to produce optically active alcohols are described. A rule predicting the absolute stereochemistry of the resulting alcohols is proposed.     

Novel applications of chloroperoxidase: enantioselective oxidation of racemic epoxyalcohols

The CPO-catalysed enantioselective oxidations of racemic glycidol and cis-2,3-epoxyhexanol to the corresponding aldehydes were studied using tert-butyl hydroperoxide in the 9:9:1 and 18:1 mixtures of hexane:ethyl acetate:buffer and hexane:buffer, respectively. Temperature and pH (100 mM citrate buffer, pH 4.0–7.0) effects on enantioselectivity in the terms of ee for the less reactive alcohol enantiomers with conversion were studied.     

Catalytic enantioselective Negishi reactions of racemic secondary benzylic halides

This report describes the first enantioselective cross-couplings of racemic secondary benzylic halides, specifically, nickel-catalyzed Negishi reactions of bromides and chlorides. The catalyst components are commercially available and air-stable, and the reaction is not highly oxygen- or moisture-sensitive (it can be set up in the air). The method has been applied to the catalytic enantioselective synthesis of intermediates employed by others in the generation of bioactive compounds (e.g., trikentrin A and an androgen receptor agonist).     

Enzymatic kinetic resolution of racemic cyanohydrins via enantioselective acylation

Enzymatic kinetic resolution of a series of aromatic and aliphatic cyanohydrins in organic media has been investigated. The behavior of potential lipases, molecular sieves, acyl reagent, reaction temperature, and organic solvents on the kinetic resolution was studied. The influence of substrate structure, steric, and electronic nature and position of the aryl substituent on the enantioselectivity was discussed. Under the optimized reaction conditions, good enantioselectivity could be achieved for most of the investigated compounds. Specifically, substrates 1a, 1c, 1d, 1f, 1u could be resolved with the kinetic enantiomer ratio (E) higher than 200.     

Dimethylzinc-mediated, enantioselective synthesis of propargylic amines

A one-pot, enantioselective synthesis of N-aryl propargylic amines, using alkynylation reagents obtained from dimethylzinc and terminal acetylenes in combination with various aldehydes and o-methoxyaniline as starting materials, has been developed. Enantiopure beta-amino alcohols derived from norephedrine were used as non-covalent chiral auxiliaries, both in stoichiometric or substoichiometric amount. After optimization, propargylic amines were obtained in good to high yields (up to 93%) and with moderate to high enantiomeric excesses (up to 97% ee). The possibility to recover the chiral auxiliary after the reaction was demonstrated.     

Direct, enantioselective iridium-catalyzed allylic amination of racemic allylic alcohols

The direct route: Iridium-catalyzed direct conversion of branched allylic alcohols into enantioenriched branched primary allylic amines is highly regio- and enantioselective (see scheme; coe=cyclooctene).     

The thiopyran route to polypropionates: enantioselective synthesis of membrenone B from racemic fragments

(6S,7S,8S,9R,10S)-(--)-Membrenone B was synthesized in nine steps (9.4% overall yield) beginning with two-directional aldol coupling of tetrahydro-4H-thiopyran-4-one with racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde. The first aldol reaction occurs with dynamic kinetic resolution to give a single adduct (>98% ee). The second aldol reaction is highly diastereoselective (three of eight possible adducts), and both major products are converted to membrenone B. The route also constitutes a formal synthesis of membrenone A.     

Enantioselective separation of racemic secondary amines on a chiral crown ether-based liquid chromatography stationary phase

The first general enantioselective separation of racemic secondary amines on a crown ether-based liquid chromatography chiral stationary phase (CSP) is presented. The CSP is based on (+)- or (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel. A mobile phase containing methanol, acetonitrile, triethylamine and acetic acid was employed in these separations of secondary amines with crown ether CSPs. The separation mechanism is believed to be the secondary amine forming a complex which includes crown ether coordination and electrostatic interaction of the positively charged amine with a carboxylate anion of the immobilized crown ether.     

Mechanoenzymatic resolution of racemic chiral amines,a green technique for the synthesis of pharmaceutical building blocks

Very recently, several successful biocatalytic processes using mechanical activation to carry out enantioselective reactions have been reported. The present work describes the use of Candida antarctica Lipase B (CALB) in the kinetic resolution of racemic chiral amines by means of High-Speed Ball Milling (HSBM), minimizing the use of solvent and reducing reaction times. This approach provides an efficient and easily scalable strategy that was used for the green synthesis of enantiopure Rasagiline, as an illustrative example.     

Highly enantioselective oxidation of sulfides to sulfoxides by a new oxaziridinium salt

The new oxaziridinium salt 5 (R2 = TBDPS) is an effective reagent for the highly enantioselective oxidation of sulfides to sulfoxides with up to >99% ee and good yields. As such, it represents a new valuable nonmetallic alternative to the existing methods for asymmetric sulfoxidation.     

Copper-catalyzed enantioselective propargylic amination of nonaromatic propargylic esters with amines

The enantioselective propargylic amination of propargylic pentafluorobenzoates bearing an alkyl group at the propargylic position with amines in the presence of catalytic amounts of a copper complex and an optically active diphosphine such as BINAP has been found to give the corresponding propargylic amines in good yields with high enantioselectivity.     

Resolution of racemic 1-azido-3-aryloxy-2-propanols by lipase-catalyzed enantioselective acetylation

Kinetic resolution of racemic 1-azido-3-aryloxy-2-propanols 1a–g was performed using supported lipase of Candida antarctica-B (Novozym^® SP 435) in toluene at 4°C with isopropenyl acetate as the acyl donor to afford the optically active (S)-alcohols 2a–g and their corresponding (R)-acetates 3a–g with E values from 56 to 72.     

Kinetic resolution of racemic carboxylic acids by an L-histidine-derived sulfonamide-induced enantioselective esterification reaction

The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Br?nsted base such as O-protected alpha-hydroxy carboxylic acids and N-protected alpha-amino acids has been accomplished through an L-histidine-derived sulfonamide-induced enantioselective esterification reaction with tert-butyl alcohol for the first time. Highly asymmetric induction [S( k fast/ k slow) = up to 56] has been achieved under the equilibrium between a chiral catalyst and two diastereomeric acylammonium salts through an intramolecular hydrogen-bonding interaction.     

Nonenzymatic kinetic resolution of racemic 2,2,2-trifluoro-1-aryl ethanol via enantioselective acylation

Kinetic resolution of a series of 2,2,2-trifluoro-1-aryl ethanol with (R)-benzotetramisole as the catalyst has been investigated. The result showed that when the aryl group in the substrate was a phenyl (or a phenyl substituted by an electron-donating group) or a naphthyl (an extended phenyl) group, the system could give an s value higher than 20. Preparative KR examples demonstrated the applicability of this method in the preparation of some of enantiomerically pure 2,2,2-trifluoro-1-aryl ethanol or 2,2,2-trifluoro-1-aryl-ethyl iso-butyrate.