Yongzheng Chen

Organocatalytic Asymmetric Mannich Reaction of 3-Hydroxyoxindoles/3-Aminooxindoles with in Situ Generated N-Boc-Protected Aldimines for the Synthesis of Vicinal Oxindole–Diamines/Amino Alcohols

A highly efficient asymmetric Mannich reaction of 3-monosubstituted 3-aminooxindoles/3-hydroxyoxindoles with in situ generated N-Boc-protected aldimines catalyzed by the chiral bifunctional thiourea-tertiary amine catalyst has been developed. Under mild reaction conditions, a series of structurally diverse vicinal oxindole-diamines/amino alcohols were smoothly obtained in moderate to high yields (up to 99%) with good to excellent diastereoselectivities and enantioselectivities (up to 95:5 dr and 96% ee). The synthetic application of this protocol was also demonstrated by the versatile transformation of chiral vicinal oxindole-diamine/amino alcohol into spirocyclic oxindoles.

Palladium-Catalyzed Nucleophilic Substitution/C-H Activation/Aromatization Cascade Reaction: One Approach To Construct 6-Unsubstituted Phenanthridines.

A facile and practical palladium-catalyzed nucleophilic substitution/C-H activation/aromatization cascade reaction has been developed. A range of 6-unsubstituted phenanthridines could be obtained in moderate to good yields (31-85%) with readily prepared N-Ms arylamines and commercially available 2-bromobenzyl bromide derivatives as starting materials. The potential application of the protocol was also demonstrated by the expeditious synthesis of the natural alkaloid trisphaeridine.

RNA-seq transcriptome analysis of a Pseudomonas strain with diversified catalytic properties growth under different culture medium

Biocatalysis is an emerging strategy for the production of enantio‐pure organic molecules. However, lacking of commercially available enzymes restricts the widespread application of biocatalysis. In this study, we report a Pseudomonas strain which exhibited versatile oxidation activity to synthesize chiral sulfoxides when growing under M9‐toluene medium and reduction activity to synthesize chiral alcohols when on Luria‐Bertani (LB) medium, respectively. Further comparative transcriptome analysis on samples from these two cultural conditions has identified 1038 differentially expressed genes (DEG). Gene Ontology (GO) enrichment and KEGG pathways analysis demonstrate significant changes in protein synthesis, energy metabolism, and biosynthesis of metabolites when cells cultured under different conditions. We have identified eight candidate enzymes from this bacterial which may have the potential to be used for synthesis of chiral alcohol and sulfoxide chemicals. This work provides insights into the mechanism of diversity in catalytic properties of this Pseudomonas strain growth with different cultural conditions, as well as candidate enzymes for further biocatalysis of enantiomerically pure molecules and pharmaceuticals.

Biocatalytic α-Oxidation of Cyclic Amines and N-Methylanilines for the Synthesis of Lactams and Formamides

An environmentally friendly method for the synthesis of lactams and formamides through the biocatalytic α‐oxidation of amines was developed by employing Pseudomonas plecoglossicida ZMU‐T04 as a biocatalyst. In this biocatalytic process, the α‐oxidation of cyclic amines and N‐methylanilines proceeded smoothly to give the corresponding amides in low to high yields. Furthermore, it was demonstrated that synthetic 3,4‐dihydroquinolin‐2(1H)‐one could be used as a key precursor of antidepressant bioactive molecules. The mechanism of this biocatalytic α‐oxidation process was investigated by isotope‐ labeling experiments.

A Protocol for the Synthesis of CF2H-Containing Pyrazolo[1,5-c]quinazolines from 3-Ylideneoxindoles and in Situ Generated CF2HCHN2

Herein is disclosed a selective and facile approach for the construction of CF2H-containing pyrazolo[1,5- c]quinazolines from easily accessible 3-ylideneoxindoles and in situ generated CF2HCHN2. The reaction involving a [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade proceeded smoothly at room temperature in the absence of catalyst and additive. Moreover, this metal-free process along with mild conditions is desirable and valuable for the pharmaceutical industry. Importantly, this reaction features a broad substrate scope, good functional group tolerance, and gram-scale synthesis.

Biocatalytic Preparation of Chiral Sulfoxides through Asymmetric Reductive Resolution by Methionine Sulfoxide Reductase A

Here we report an environmentally friendly method for the preparation of chiral sulfoxides under high substrate concentration using recombinant methionine sulfoxide reductase A from Pseudomonas monteilii (pmMsrA) as a biocatalyst. Our results show that this enzyme can effectively accomplish the preparation of (R)‐sulfoxides with approximately 50 % yield and 94–99 % enantiomeric excess through asymmetric reductive resolution of racemic sulfoxide. With the establishment of the enzyme regeneration system, the initial substrate concentration could be increased 40–100 times compared to our original report. The (R)‐sulfoxides were obtained with high enantioselectivity under the substrate concentration up to 200 mm (approximately 32 g L−1), representing a quite high substrate concentration in biocatalytic preparation of chiral sulfoxides. Moreover, this system showed fairly good activity and enantioselectivity towards a series of ortho‐ and para‐substituted phenyl methyl sulfoxides under high substrate concentration.

Biocatalytical asymmetric sulfoxidation by identifying cytochrome P450 from Parvibaculum lavamentivorans DS-1

Cytochrome P450 monooxygenases (P450s) catalyzed asymmetric sulfoxidation represents a green route for the synthesis of valuable enantiopure sulfoxides, which are potentially interesting synthons in synthetic and pharmaceutical chemistry. Here the potential P450 and redox partner genes from Parvibaculum lavamentivorans DS‐1 are screened and co‐expressed in Escherichia coli host to construct twenty recombinant P450 strains. By testing the whole‐cell biooxidation of thioanisole, P450PL2 (CYP278A4) and P450PL7 (CYP108G3) are identified with excellent S enantioselectivity while P450PL1 (CYP111B1) and P450PL9 (CYP153A26) exhibit the complementary R enantioselectivity. Asymmetric sulfoxidation of sulfides 1 a–1 m is further investigated using the recombinant E. coli strain P450PL2‐2 based on the optimal conditions, producing the corresponding enantioenriched sulfoxides with up to 82 % isolated yield and 99 % ee.

Deracemization of Phenyl-Substituted 2-Methyl-1,2,3,4-Tetrahydroquinolines by a Recombinant Monoamine Oxidase from Pseudomonas monteilii ZMU-T01

A monoamine oxidase (MAO5) from Pseudomonas monteilii ZMU‐T01 was first heterologously expressed in Escherichia coli BL21(DE3) and then used as a biocatalyst for the deracemization of racemic 2‐methyl‐1,2,3,4‐tetrahdroquinoline derivatives to yield the unreacted R enantiomer with up to >99 % ee. Sequence alignment revealed that MAO5 shared 14.7 % identity toward the well‐studied monoamine oxidase (MAO‐N).

Identification and characterization of a highly S-enantioselective halohydrin dehalogenase from Tsukamurella sp. 1534 for kinetic resolution of halohydrins

Halohydrin dehalogenases are remarkable enzymes which possess promiscuous catalytic activity and serve as potential biocatalysts for the synthesis of chiral halohydrins, epoxides and β-substituted alcohols. The enzyme HheC exhibits a highly R enantioselectivity in the processes of dehalogenation of vicinal halohydrins and ring-opening of epoxides, which attracts more attentions in organic synthesis. Recently dozens of novel potential halohydrin dehalogenases have been identified by gene mining, however, most of the characterized enzymes showed low stereoselectivity. In this study, a novel halohydrin dehalogenase of HheA10 from Tsukamurella sp. 1534 has been heterologously expressed, purified and characterized. Substrate spectrum and kinetic resolution studies indicated the HheA10 was a highly S enantioselective enzyme toward several halohydrins, which produced the corresponding epoxides with the ee (enantiomeric excess) and E values up to >99% and >200 respectively. Our results revealed the HheA10 was a promising biocatalyst for the synthesis of enantiopure aromatic halohydrins and epoxides via enzymatic kinetic resolution of racemic halohydrins. Whats more important, the HheA10 as the first individual halohydrin dehalogenase with the highly S enantioselectivity provides a complementary enantioselectivity to the HheC.