Approach For Asymmetric Synthesis Research Articles

Predicting the stereoselectivity of chemical reactions by composite machine learning method.

Stereoselective reactions have played a vital role in the emergence of life, evolution, human biology, and medicine. However, for a long time, most industrial and academic efforts followed a trial-and-error approach for asymmetric synthesis in stereoselective reactions. In addition, most previous studies have been qualitatively focused on the influence of steric and electronic effects on stereoselective reactions. Therefore, quantitatively understanding the stereoselectivity of a given chemical reaction is extremely difficult. As proof of principle, this paper develops a novel composite machine learning method for quantitatively predicting the enantioselectivity representing the degree to which one enantiomer is preferentially produced from the reactions. Specifically, machine learning methods that are widely used in data analytics, including Random Forest, Support Vector Regression, and LASSO, are utilized. In addition, the Bayesian optimization and permutation importance tests are provided for an in-depth understanding of reactions and accurate prediction. Finally, the proposed composite method approximates the key features of the available reactions by using Gaussian mixture models, which provide suitable machine learning methods for new reactions. The case studies using the real stereoselective reactions show that the proposed method is effective and provides a solid foundation for further application to other chemical reactions.

Stereocontrol via Propeller Chirality in FLP-Catalyzed Asymmetric Hydrogenation.

Utilization of chiral frustrated Lewis pairs as catalysts in enantioselective hydrogenation of unsaturated molecules represents a promising approach in asymmetric synthesis. In our effort to improve our current understanding of the factors governing the stereoselectivity in these catalytic processes, herein we examined the mechanism of direct hydrogenation of aromatic enamines catalyzed by a binaphthyl-based chiral amino-borane. Our computational analysis reveals that only one particular conformer of the key borohydride reaction intermediate can be regarded as a reactive form of this species. This borohydride conformer has a well-defined chiral propeller shape, which induces facial selectivity in the hydride transfer to pro-chiral iminium intermediates. The propeller chirality of the reactive borohydride conformer is generated by the axially chiral binaphthyl scaffold of the amino-borane catalyst through stabilizing π-π stacking interactions. This new computational insight can be readily used to interpret the high degree of stereoinduction observed for these reactions. We expect that the concept of chirality relay could be further exploited in catalyst design endeavors.

Immobilization of engineered E. coli cells for asymmetric reduction of methyl acetoacetate to methyl-(R)-3-hydroxybutyrate

The efficient asymmetric bio-synthesis of chiral β-hydroxy esters is of great importance for industrial production. In this work, a simple and productive engineered E.coli cell-immobilized strategy was applied for the asymmetric reduction of MAA to (R)-HBME with high enantioselectivity. Compared with the corresponding inactivated free cells, the alginate-immobilized cells remained 45% of initial activity at 50 ℃ and 65% after reuse of 10 times. After 60 days of storage at 4 ℃, the immobilized cells maintained more than 80% relative activity. Immobilization contributed significantly to the improvement of thermal stability, pH tolerance, storage stability and operation stability without affecting the yield of product. The immobilized recombinant E. coli cell had absolute enantioselectivity for the asymmetric reduction of MAA to (R)-HBME with e.e. > 99.9%. Therefore, microbial cell immobilization is a perspective approach in asymmetric synthesis of chiral β-hydroxy esters for industrial applications.Graphical

Visible‐Light‐Driven Catalytic Deracemization of Secondary Alcohols

AbstractDeracemization of racemic chiral compounds is an attractive approach in asymmetric synthesis, but its development has been hindered by energetic and kinetic challenges. Here we describe a catalytic deracemization method for secondary benzylic alcohols which are important synthetic intermediates and end products for many industries. Driven by visible light only, this method is based on sequential photochemical dehydrogenation followed by enantioselective thermal hydrogenation. The combination of a heterogeneous dehydrogenation photocatalyst and a chiral molecular hydrogenation catalyst is essential to ensure two distinct pathways for the forward and reverse reactions. These reactions convert a large number of racemic aryl alkyl alcohols into their enantiomerically enriched forms in good yields and enantioselectivities.

Visible-Light-Driven Catalytic Deracemization of Secondary Alcohols.

Deracemization of racemic chiral compounds is an attractive approach in asymmetric synthesis, but its development has been hindered by energetic and kinetic challenges. Here we describe a catalytic deracemization method for secondary benzylic alcohols which are important synthetic intermediates and end products for many industries. Driven by visible light only, this method is based on sequential photochemical dehydrogenation followed by enantioselective thermal hydrogenation. The combination of a heterogeneous dehydrogenation photocatalyst and a chiral molecular hydrogenation catalyst is essential to ensure two distinct pathways for the forward and reverse reactions. These reactions convert a large number of racemic aryl alkyl alcohols into their enantiomerically enriched forms in good yields and enantioselectivities.

Efficient production of (R)-(-)-2-hydroxy-4-phenylbutyric acid by recombinant Pichia pastoris expressing engineered D-lactate dehydrogenase from Lactobacillus plantarum with a single-site mutation.

(R)-2-hydroxy-4-phenylbutyric acid (R-HPBA) is a valuable intermediate for the synthesis of angiotensin-converting enzyme inhibitors. The asymmetric reduction of 2-oxo-4-phenylbutyric acid (OPBA) by oxidoreductases is an efficient approach for its synthesis. Here, we report a novel biocatalytic approach for asymmetric synthesis of R-HPBA using recombinant Pichia pastoris expressing the Tyr52Leu variant of D-lactate dehydrogenase (D-LDH) from Lactobacillus plantarum. The recombinant yeast cells showed impressive catalytic activity at a high concentration of NaOPBA (380mM, 76g/L) and achieved full conversion starting with 40g/L NaOPBA or even at higher concentration. Under optimized reaction conditions (pH 7.5, 37°C, and 2% glucose), a full conversion with > 95% reaction yield and ~ 100% product enantiomeric excess (ee) was achieved for the preparation of R-HPBA on a 2-g scale. The findings of this study promote both the biotransformation of R-HPBA and an extension of the application of recombinant yeast as biocatalysts.

ChemInform Abstract: New Approaches for Asymmetric Synthesis of Sulfoxides

Abstract Recent progress in asymmetric oxidation of sulfides is passed in review, and the various possibilities of using chiral sulfites for asymmetric synthesis of sulfoxides are discussed

The Chemistry of C2‐Symmetric Bis(sulfoxides): A New Approach in Asymmetric Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Chemistry of C2-Symmetric Bis(sulfoxides): A New Approach in Asymmetric Synthesis

The preparation of various racemic or enantiopure C2-symmetric bis(sulfoxides) has been developed over the last decades. Numerous applications in organic synthesis (anionic condensation, cycloadditions) as well as in coordination chemistry have been worked out. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A New Approach for Asymmetric Synthesis of (R)-3-Methylpyrrolidine Alkaloids from (S)-Malic Acid

Diastereoselective methylation of dimethyl (S)-malate 7, followed by two, three-step reductive de-hydroxylation procedures afforded dimethyl (R)-2-methylsuccinate 11 in 80.2% e.e. and 84.7% e.e., respectively. The latter compound was further transformed into the natural enantiomers of the ant venom alkaloids (R)-leptothoracine 1 and (R)-3-methyl-N-(2-phenylethyl)-pyrrolidine 2.

Enantiopure N-sulfonylamino alcohols and their copolymers as chiral auxiliaries for the highly enantioselective allylboration of aldehydes

Enantioselective synthesis of homoallylic alcohols by nucleophilic addition of chirally modified allylboron reagents to aldehydes was investigated. Reaction of enantiopure N-sulfonylamino alcohols ( 1a, 1b, 3a, 4a) with triallylborane gave the chiral allylboration reagents. Aldehydes were converted to enantioenriched homoallylic alcohols with the reagents. Polymer-supported chiral allylboron reagents were also prepared from triallylborane and crosslinked polymers having chiral N-sulfonylamino alcohol moieties ( 5–8). These polymeric reagents reacted with aldehydes to give optically active homoallylic alcohols in high chemical yield with high enantioselectivities. Optical yield up to 92% ee was obtained by the use of polymeric chiral ligand 7 derived from d-camphor. The potential of this type of approach in asymmetric synthesis is discussed.

Asymmetric Diels-Alder reaction of cyclopentadiene with methacrolein using polymer-supported chiral catalysts

Polymer-supported chiral Lewis acids were prepared from bromoboranes and crosslinked polymers having chiral amino alcohol or diol moieties. These polymers were used as chiral catalysts for Diels-Alder reactions of cyclopentadiene with methacrolein to give optically active cycloadduct in high chemical yield with high exo selectivity. Optical yield up to 54% ee was obtained by the use of polymeric chiral catalyst derived from ( S)-proline. The potential of this type of approach in asymmetric synthesis is discussed.

Asymmetric synthesis by reduction or by oxidation of prochiral substrates absorbed into chiral polymer supports

Prochiral ketones absorbed into chiral polymer supports were reduced with aqueous potassium borohydride. 2-Substituted naphthoquinones absorbed into chiral polymer supports were epoxidized using aqueous alkaline hydrogen peroxide. In both systems asymmetric synthesis was achieved. Best results were obtained with microcrystalline cellulose triacetate as the polymer support: 8.6% ee in a reduction, 4.5% ee in an epoxidation. Use of tetra- n-butylammonium bromide as a phase transfer catalyst tended to improve chemical yields and ees. The potential of this type of approach in asymmetric synthesis is discussed.