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Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst‐controlled pyrazole alkylation by a cyclic two‐enzyme cascade. In this enzymatic system, a promiscuous enzyme uses haloalkanes as precursors to generate non‐natural analogs of the common cosubstrate S‐adenosyl‐l‐methionine. A second engineered enzyme transfers the alkyl group in highly selective C−N bond formations to the pyrazole substrate. The cosubstrate is recycled and only used in catalytic amounts. Key is a computational enzyme‐library design tool that converted a promiscuous methyltransferase into a small enzyme family of pyrazole‐alkylating enzymes in one round of mutagenesis and screening. With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale. [ABSTRACT FROM AUTHOR]

The squalene hopene cyclase from Alicyclobacillus acidocaldarius ( AacSHC) is a highly efficient enzyme catalyst for stereoselective Brønsted acid catalysis. We engineered AacSHC to catalyze the selective Prins cyclization of citronellal. Four active site variants were identified for the diastereoselective cyclization of ( S)-citronellal to stereoisomers (−)- iso-isopulegol, (+)-isopulegol and (−)- neo-isopulegol, respectively. The replacement of active site residues resulted in two triple variants that catalyzed the transformation of ( R)-citronellal to give the isomers (+)- neo-isopulegol and (−)-isopulegol with up to >99 % de, respectively. The newly designed library of functionally diverse active site geometries exhibits high selective control during citronellal cyclization, leading exclusively to a single diastereomer of the desired isopulegol. Whereas the cyclization of citronellal with chemical catalysts was observed to produce the isopulegol isomer with the lowest energy, the reaction with AacSHC variants proceeded with higher product selectivity. The results of this study show that variants of AacSHC are excellent catalysts for the highly selective formation of isopulegol stereoisomers. [ABSTRACT FROM AUTHOR]

Imine reductases (IREDs) have emerged as promising biocatalysts for the synthesis of chiral amines. In this study, the asymmetric imine reductase-catalyzed intermolecular reductive amination with NADPH as the hydrogen source was investigated. A highly chemo- and stereoselective imine reductase was applied for the reductive amination by using a panel of carbonyls with different amine nucleophiles. Primary and secondary amine products were generated in moderate to high yields with high enantiomeric excess values. The formation of the imine intermediate was studied between carbonyl substrates and methylamine in aqueous solution in the pH range of 4.0 to 9.0 by 1H NMR spectroscopy. We further measured the kinetics of the reductive amination of benzaldehyde with methylamine. This imine reductase-catalyzed approach constitutes a powerful and direct method for the synthesis of valuable amines under mild reaction conditions. [ABSTRACT FROM AUTHOR]

Polycyclizations constitute a cornerstone of chemistry and biology. Multicyclic scaffolds are generated by terpene cyclase enzymes in nature through a carbocationic polycyclization cascade of a prefolded polyisoprene backbone, for which electrostatic stabilization of transient carbocationic species is believed to drive catalysis. Computational studies and site-directed mutagenesis were used to assess the contribution of entropy to the polycyclization cascade catalyzed by the triterpene cyclase from A. acidocaldarius. Our results show that entropy contributes significantly to the rate enhancement through the release of water molecules through specific channels. A single rational point mutation that results in the disruption of one of these water channels decreased the entropic contribution to catalysis by 60 kcal mol−1. This work demonstrates that entropy is the key to enzyme-catalyzed polycyclizations, which are highly relevant in biology since 90 % of all natural products contain a cyclic subunit. [ABSTRACT FROM AUTHOR]

The use of enzymes as catalysts for the preparation of novel compounds has received steadily increasing attention over the past few years. High demands are placed on the identification of new biocatalysts for organic synthesis. The catalysis of more ambitious reactions reflects the high expectations of this field of research. Enzymes play an increasingly important role as biocatalysts in the synthesis of key intermediates for the pharmaceutical and chemical industry, and new enzymatic technologies and processes have been established. Enzymes are an important part of the spectrum of catalysts available for synthetic chemistry. The advantages and applications of the most recent and attractive biocatalysts-reductases, transaminases, ammonia lyases, epoxide hydrolases, and dehalogenases-will be discussed herein and exemplified by the syntheses of interesting compounds. [ABSTRACT FROM AUTHOR]

Review: recent advances in enzyme catalysis for the synthesis of challenging chemicals; 128 refs. [ABSTRACT FROM AUTHOR]