Asymmetric one-pot synthesis of five- and six-membered lactones via dynamic covalent kinetic resolution: Exploring the regio- and stereoselectivities of lipase

Cascade lipase-catalyzed lactonization has been applied to dynamic hemithioacetal formation, leading to efficient five- and six-membered lactone synthesis as well as chiral discrimination. Solvent-dependent regioselectivity was observed for the selective formation of 1,3-oxathiolan-5-one and γ-butyrolactone derivatives.     

Asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives by organocatalyzed rearrangement of pyranones and enzymatic dynamic kinetic resolution

Dioxygenated cyclopentenones are versatile building blocks for the synthesis of several natural products. Herein we report a direct asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives through base-catalyzed rearrangement of pyranones followed by dynamic kinetic resolution. Milder conditions than previously reported for this rearrangement have been found regarding amine base catalysis, solvent and temperature effects. All data supports a mechanism involving cyclization of an intermediate formed by electrocyclic ring opening of a pyranone-derived enol. We have developed conditions for asymmetric synthesis of trans-4-tert-butoxy-5-hydroxycyclopent-2-enone, in 81% yield and 95% ee, and analogous dioxygenated cyclopentenones, via a lipase induced dynamic kinetic resolution.     

Practical enantioselective synthesis of lamivudine (3TC) via a dynamic kinetic resolution

A practical enantioselective synthesis of lamivudine 1 is described. A highly effective dynamic kinetic resolution of the 5-hydroxyoxathiolane, followed by chlorination and introduction of cytosine provides an efficient synthesis of lamivudine.     

Ruthenium and enzyme-catalyzed dynamic kinetic resolution of alcohols

Ruthenium acts as a good catalyst for the racemization reaction of secondary alcohols and amines. Ruthenium-catalyzed racemization is coupled with enzymatic kinetic resolution to prepare chiral compounds in 100% theoretical yield. Ten ruthenium complexes (1–10) act as a good catalyst the for racemization reaction and are also compatible with DKR process. Two other ruthenium complexes [RuCl₂(PPh₃)₃] and [Cp^*RuCl(COD)] are active for racemization reaction but their successful compatibility with DKR has not yet been reported. Ru/γ-Al₂O₃ and Ru–HAP are the heterogeneous catalysts used for the racemization reaction. They have also not been employed for DKR process. Polymer supported ruthenium is employed as a reusable racemization catalyst for aerobic DKR of alcohols.     

Stereoselective synthesis of syn β-hydroxy cycloalkane carboxylates: transfer hydrogenation of cyclic β-keto esters via dynamic kinetic resolution

The transfer hydrogenation of bicyclic and monocyclic β-keto esters using HCO₂H/Et₃N as the hydrogen source and TsDPEN-based Ru(II) catalysts proceeds with dynamic kinetic resolution to afford the corresponding cyclic β-hydroxy esters with moderate to excellent levels of diastereo- and enantioselectivities. The mild reaction conditions used make possible to preserve in most cases the syn relative configuration of the products, providing a complementary tool to known approaches to the synthesis of anti isomers.     

New air-stable iron catalyst for efficient dynamic kinetic resolution of secondary benzylic and aliphatic alcohols

We herein report a catalyst system for the dynamic kinetic resolution of secondary alcohols by combining the enzymatic resolution with an iron-catalyzed racemization. A new air-stable tricarbonyl (cyclopentadienone)iron complex is identified as the active racemization catalyst for this transformation without any additive. Various substrates including benzylic, heteroaromatic, aliphatic alcohols can be used and afford the corresponding esters in good yields and with excellent enantioselectivities.     

High yield synthesis of d-phenylglycine and its derivatives by nitrilase mediated dynamic kinetic resolution in aqueous-1-octanol biphasic system

A strategy of nitrilase mediated dynamic kinetic resolution toward the synthesis of d-phenylglycine was developed, using aqueous-1-octanol biphasic system. Due to the efficient suppression of the decomposition of phenylglycinonitrile, a maximum yield of 81% is obtained. This result indicates that the nitrilase mediated dynamic kinetic resolution is a promising method toward the synthesis of d-phenylglycine and its derivatives.     

Lipase-catalyzed dynamic kinetic resolution giving optically active cyanohydrins: use of silica-supported ammonium hydroxide and porous ceramic-immobilized lipase

Synthetically useful cyanohydrin acetates, ArCH(OAc)CN (Ar=C₆H₅, 3,4-methylenedioxyphenyl, 4-Me-C₆H₄, 4-Cl-C₆H₄, 4-F-C₆H₄, 4-CF₃-C₆H₄), were successfully synthesized in high enantiomeric purities (79-93% ee) via the lipase-catalyzed dynamic kinetic resolution (DKR) of cyanohydrins synthesized in situ from the corresponding aldehydes and acetone cyanohydrin. The combined use of silica-supported BTAH (benzyltrimethylammonium hydroxide) and porous ceramic-immobilized lipase under the optimized reaction conditions enabled the remarkable acceleration of the enantioselective DKR reactions.     

Dynamic kinetic resolution of secondary alcohols with a readily available ruthenium-based racemization catalyst

An easy to handle and stable racemization catalyst for secondary alcohols is obtained by an in situ mixture of readily available [Ru(cymene)Cl₂]₂ with chelating aliphatic diamines. Optimization of the reaction revealed that N,N,N′,N′-tetramethyl-1,3-propanediamine as ligand racemizes aromatic alcohols completely within 5 h. This easy to handle and stable catalytic system is combined with a lipase-catalyzed resolution to provide an efficient dynamic kinetic resolution of secondary alcohols.     

Efficient dynamic kinetic resolution of arylamines with Pd/layered double-hydroxide-dodecyl sulfate anion for racemization

A novel and efficient racemization catalyst, Pd/layered double-hydroxide-dodecyl sulfate anion, was prepared and used in the dynamic kinetic resolution (DKR) of arylamines. The undesired enantiomer was completely racemized at 55 °C, allowing the catalyst to be compatible with biocatalysts. DKR proceeded smoothly and showed a broad substrate scope, with good conversion and high product enantiomeric excesses (ee_p). The system could be reused more than 30 times without loss of conversion and ee_p value.     

Palladium catalysts on alkaline-earth supports for racemization and dynamic kinetic resolution of benzylic amines

Palladium catalysts on alkaline-earth supports were studied as new heterogeneous catalysts for racemization of chiral benzylic amines such as 1-phenylethylamine. Particularly 5 % Pd/BaSO(4) and 5 % Pd/CaCO(3) were able to selectively racemize amines, with minimal formation of secondary amines or hydrogenolysis to ethylbenzene. In contrast, these side reactions were pronounced on Pd/C. A reaction mechanism is proposed that is consistent with the reaction kinetics. The catalyst activity was found to depend on the number of available surface Pd atoms, determined by titration with CO. The selectivity crucially depends on the rate of condensation of the amine and the primary imine, which is highest on Pd/C. The racemization catalysts were combined in one pot with an immobilized lipase to perform dynamic kinetic resolution of chiral amines. High yields (up to 88 %) of essentially enantiopure amides were obtained in a single step. The chemo-enzymatic catalyst system proved to be stable and could be reused without losing the initial activity.     

Asymmetric synthesis of silylated alpha-amino acid esters through dynamic kinetic resolution

Esters of three types of silylated alpha-amino acids have been prepared from appropriate zirconaaziridines. Slow addition (syringe pump) of the (R,R) carbonate of trans-stilbene gave metallacycles with the maximum possible diastereomeric excess (as determined by the diastereomeric excess produced by the Hoffmann test-the same reaction but with racemic carbonate). Methanolysis gave esters (RO(2)C)CH(R')(NHPh) (R' = Me(3)Si, Me(3)SiCH(2), and p-Me(3)SiC(6)H(4)) with the same optical purity at the alpha carbon.     

A novel dynamic kinetic resolution accompanied by intramolecular transesterification: asymmetric synthesis of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives

Reaction paths of the one-pot reaction of (R)-2-(α-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate with DBU giving (4S,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(αR)-α-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane, the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford (4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution accompanied by intramolecular transesterification.     

Asymmetric syntheses of N-substituted α-amino esters via dynamic kinetic resolution of α-haloacyl diacetone-d-glucose

Diacetone-d-glucose or d-allose mediated dynamic kinetic resolution of α-halo esters in nucleophilic substitution reaction has been investigated. Reactions with various amine nucleophiles in the presence of TBAI and DIEA can provide the N-substituted α-amino esters up to 99:1 dr. Stereochemical models of transition states, taking into account a hydrogen bonding, are proposed on the basis of the observed results. Also, application of this mild and simple methodology to stereoselective preparations of 1,1′-iminodicarboxylic acid derivatives is demonstrated.