Yan-Hong He

Hydrolase-catalyzed asymmetric carbon–carbon bond formation in organic synthesis

Enzyme catalytic promiscuity, in which the active site of an enzyme has the ability to catalyze more than one chemical transformation, has received widespread attention as more catalytic promiscuities of existing enzymes have been discovered. In this field, hydrolases have been mainly studied due to their commercial availability, high stability, broad substrate scope and high catalytic efficiency in media containing organic solvents. In this study, we review the hydrolase-catalyzed asymmetric carbon–carbon bond-forming reactions for the preparation of enantiomerically enriched compounds in organic synthesis. To date, these hydrolase-catalyzed asymmetric reactions include the direct asymmetric aldol, Michael, Mannich and Morita–Baylis–Hillman reactions. The hydrolase-catalyzed non-enantioselective examples were not included.

Protease-catalysed Direct Asymmetric Mannich Reaction in Organic Solvent

We reported the first enzyme-catalysed, direct, three-component asymmetric Mannich reaction using protease type XIV from Streptomyces griseus (SGP) in acetonitrile. Yields of up to 92% with enantioselectivities of up to 88% e.e. and diastereoselectivities of up to 92:8 (syn:anti) were achieved under the optimised conditions. This enzymes catalytic promiscuity expands the application of this biocatalyst and provides a potential alternative method for asymmetric Mannich reactions.

Enzyme catalytic promiscuity: The papain-catalyzed Knoevenagel reaction.

Papain as a sustainable and inexpensive biocatalyst was used for the first time to catalyze the Knoevenagel reactions in DMSO/water. A wide range of aromatic, hetero-aromatic and α,β-unsaturated aldehydes could react with less active methylene compounds acetylacetone and ethyl acetoacetate. The products were obtained in moderate to excellent yields with Z/E selectivities of up to 100:0. This case of biocatalytic promiscuity not only widens the application of papain to new chemical transformations, but also could be developed into a potentially valuable method for organic synthesis.

Enzyme-catalyzed direct three-component aza-Diels-Alder reaction using hen egg white lysozyme.

The direct three-component aza-Diels-Alder reaction of aromatic aldehyde, aromatic amine, and 2-cyclohexen-1-one was catalyzed by hen egg white lysozyme for the first time. Under the optimized conditions investigated in this paper, the enzyme-catalyzed aza-Diels-Alder reaction gave yields up to 98% and stereoselectivity of endo/exo ratios up to 90:10.

Biocatalytic one-pot three-component synthesis of 3,3′-disubstituted oxindoles and spirooxindole pyrans using α-amylase from hog pancreas

α-Amylase from hog pancreas displayed catalytic promiscuity in three-component reaction for the synthesis of 3,3′-disubstituted oxindoles and spirooxindole pyrans. The reactions between isatins, malononitrile and active methyl or active methylene compounds (acetone, nitromethane, indole, acetylacetone, 4-hydroxylcoumarin and dimedone) offered corresponding products via Knoevenagel/Michael reactions or Knoevenagel/Michael/cyclization reactions in one pot with high to excellent yields of up to 98% under mild reaction conditions. The α-amylase showed a broad spectrum of adaptability to various substrates. A possible mechanism of the α-amylase catalyzed three-component reaction was proposed.

Chlorophyll-Catalyzed Visible-Light-Mediated Synthesis of Tetrahydroquinolines from N,N-Dimethylanilines and Maleimides

Natural pigment chlorophyll was used as a green photosensitizer for the first time in a visible-light photoredox catalysis for the efficient synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides in an air atmosphere. The reaction involves direct cyclization via an sp3 C-H bond functionalization process to afford products in moderate to high yields (61-98%) from a wide range of substrates with a low loading of chlorophyll under mild conditions. This work demonstrates the potential benefits of chlorophyll as photosensitizer in visible light catalysis.

Ionic Liquid as Catalyst and Reaction Medium: A Simple and Efficient Procedure for Paal–Knorr Furan Synthesis

The ionic liquid 1-butyl-3-methyl-imidazolium hydrogen sulfate, [bmim]HSO4, efficiently catalyzes Paal–Knorr furan synthesis without any organic solvent. A wide range of aliphatic and aromatic 1,4-diketones easily undergo condensations to form furan derivatives, providing a general and convenient procedure. The Paal–Knorr reaction of ester-substituted 1,4-diketones is first reported. The ionic liquid can be recovered and reused for subsequent runs without any appreciable loss of efficiency.

Combining enzyme and photoredox catalysis for aminoalkylation of indoles via a relay catalysis strategy in one pot

We report a novel strategy for combining enzyme and visible-light for mild aminoalkylation of indoles. This method features a relay catalysis protocol consisting of enzyme-catalyzed hydrolysis, visible-light excited decarboxylation, and subsequent oxidization of α-amino radicals and the Friedel–Crafts reaction of the iminium ion with indoles. The α-amino-alkylation products were obtained in good to excellent yields (up to 96%) with a wide range of substrates. This work demonstrates the potential benefits of combining an enzyme and photocatalyst in a relay catalysis reaction.

Biocatalytic asymmetric Mannich reaction of ketimines using wheat germ lipase

A highly enantioselective Mannich reaction between 3-substituted-2H-1,4-benzoxazines and acetone catalyzed by lipase from wheat germ type I (WGL) is described. Enantioselectivity of up to 95% ee was achieved in DMSO at 25 °C. This research provides a new and simple method for the synthesis of β-amino ketone derivatives and promotes the development of enzyme-catalyzed Mannich reactions.

The α-chymotrypsin-catalyzed Povarov reaction: one-pot synthesis of tetrahydroquinoline derivatives

The three-component one-pot Povarov reaction for the synthesis of tetrahydroquinoline derivatives was catalyzed by α-chymotrypsin from bovine pancreas (BPC) for the first time. The products were obtained in moderate to good yields with a wide range of substrates. Based on the control and comparison experiments of natural and promiscuous activities, a tentative mechanism was discussed. Molecular docking and energy calculation of quantum chemistry were used to explain the experimental results in theory. As a novel case of enzyme catalytic promiscuity, this work expands the application of BPC. Exploring the untapped catalytic promiscuity of natural enzymes may also provide useful information about enzyme evolution.