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Chiral heterocyclic compounds are privileged structures in medicinal chemistry. Here, the authors report an in silico strategy for the enzymatic synthesis of pharmaceutically significant chiral N- and O-heterocycles via Baldwin cyclization of hydroxy- and amino-substituted epoxides and oxetanes using epoxide hydrolase mutants.

Connecting conformational dynamics and epistasis has so far been limited to a few proteins and a single fitness trait. Here, the authors provide evidence of positive epistasis on multiple catalytic traits in the evolution and dynamics of engineered cytochrome P450 monooxygenase, offering insights for in silico protein design.

Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — accommodates bulky substrates.

An intriguing advance in the rational protein engineering of a newly identified glycosyltransferase from Siraitia grosvenorii (UGT74AC2) has been accomplished by Zhoutong Sun, Yuanxia Sun and coworkers for the targeted pharmaceutically significant glucosylation of the polyhydroxy substrate silybin. Using an advanced version of Focused Rational Iterative Site-specific Mutagenesis (FRISM), they were able to evolve mutants that allow the formation of the 3-OH, 7-OH and the 3,7-O-diglycoside products with 94%, > 99% and > 99% regioselectivity, respectively. This can be viewed as a breakthrough because the wildtype UGT74AC2 delivers a difficult to separate mixture of products in a ratio of 22%:39%:39%. Even N- and S-glucosylations were achieved, a likewise unusual accomplishment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The majority of enzymatic Kemp elimination reactions proceed via a well-established acid-base mechanism. Here, the authors show that cytochrome P450 is able to metabolize the leflunomide drug via a redox Kemp elimination, offering new insights into enzyme catalysis.

Arbutin (also called β-arbutin) is a natural product occurring in the leaves of a variety of different plants, the bearberries of the Ericaceae and Saxifragaceae families being prominent examples. It is a β-glucoside derived from hydroquinone (HQ; 1,4-dihydroxybenzene). Arbutin has been identified in traditional Chinese folk medicines as having, inter alia, anti-microbial, anti-oxidant, and anti-inflammatory properties that useful in the treatment of different ailments including urinary diseases. Today, it is also used worldwide for the treatment of skin ailments by way of depigmenting, which means that arbutin is a component of many products in the cosmetics and healthcare industries. It is also relevant in the food industry. Hundreds of publications have appeared describing the isolation, structure determination, toxicology, synthesis, and biological properties of arbutin as well as the molecular mechanism of melanogenesis (tyrosinase inhibition). This review covers the most important aspects with special emphasis on the chemical and biocatalytic methods for the production of arbutin.

In the title compound, C16H14O, the cyclohexene ring has a half-chair conformation. The mean plane, calculated through all non-H atoms of the molecule, except for the central CH2 atoms of the cyclohexene ring, which deviate by 0.340 (3) and −0.369 (3) Å from this mean plane, has an r.m.s. deviation of 0.012 Å. In the crystal, there are C—H...π contacts present, resulting in the formation of zigzag chains propagating along the [010] direction.

The development of chiral catalysts for use in synthetic organic chemistry is traditionally associated with progress in asymmetric transition metal catalysis or organocatalysis. In addition to these options chemists have employed enzymes for a number of asymmetric transformations for a long time. However, limited substrate acceptance and insufficient enantioselectivity are the crucial factors which prevent the general exploitation of biocatalysis in organic chemistry. In order to solve this long-standing problem, we proposed some time ago the concept of directed evolution of enantioselective enzymes. This report constitutes a short overview of the principle involved, together with a description of the first examples and the illumination of the present and future challenges.

The electrocatalytic activity of Pt-nanoparticles used in fuel cells increases by 34% upon going from the usual Pt/Vulcan XC72 to support systems such as Pt/Printex XE2 which have a relatively rough surface structure.

A chiral phosphoric acid diester, specifically the BINOL-based derivative, has been used for the first time in Rh-, Ir-, and Pd-catalyzed hydrogenation of olefins and imines, giving ee-values of up to 85%.

The first step in applying the recently proposed concept concerning the application of directed evolution to the creation of selective hybrid catalysts is described, specifically the covalent attachment of Mn-salen moieties and of Cu-, Pd-, and Rh-complexes of dipyridine derivatives as well as the implantation of a diphosphine moiety in a protein, future steps being cycles of mutagenesis/screening.

The simultaneous use of a biocatalyst (lipase Candida antarctica) and a transition-metal catalyst (palladium) makes the dynamic kinetic resolution of racemic phenylethylamine possible, conversion to the enantiomerically pure N-acylated form being 75–77% (ee = 99%).

Borylated zirconocenes of the type (L2B–C5H4)2ZrCl2 and (L2B–C5H4)(C5H5)ZrCl2 are readily available in two steps. In the polymerization of ethylene and propylene in the presence of AlEt3 or methylalumoxan (MAO), these zirconocenes are more active than the unsubstituted reagent Cp2ZrCl2.

The lipase Candida antarctica catalyzes the enantioselective acetylation of chiral primary amines, kinetic resolution leading to an enantiomeric excess (ee) of 90–98%.

The [Ni(cod)2]/Ph2P(CH2)4PPh2-catalyzed reaction of hex-3-yne with CO2 under supercritical conditions affords tetraethylpyrone

The previously reported concept of using mixtures of monodentate ligands in a combinatorial manner in order to influence enantio- or regioselectivity of transition metal catalyzed processes has been extended to include diastereoselectivity. Accordingly, 1,2- and 1,3-asymmetric induction in the Rh-catalyzed hydrogenation of a chiral allylic alcohol and a chiral homo-allylic alcohol has been studied by using mixtures of monodentate P-ligands. It was found that appropriate 1:1 mixtures of two different P-ligands enhance the degree of diastereoselectivity relative to the use of the respective pure ligands themselves. Here, as in the previous cases regarding enantio- or regioselectivity, this type of combinatorial catalysis leads to improved catalytic profiles without the need to prepare new ligands.

A light-driven deazaflavin-dependent direct enzyme regeneration system has been developed for a P450-BM3 catalyzed CH-activating hydroxylation, thereby avoiding the need for the expensive NADPH cofactor. [ABSTRACT FROM AUTHOR]

As an alternative to screening in the directed evolution of enantioselective enzymes, a selection system has been implemented for a lipase-catalyzed hydrolytic kinetic resolution of a chiral ester. [ABSTRACT FROM AUTHOR]

Enantioselective mutants of the thermally robust phenyl acetone monooxygenase (PAMO) as catalysts in Baeyer–Villiger reactions have been evolved by utilizing saturation mutagenesis in which drastically reduced amino acid alphabets are employed at homologous enzyme positions. [ABSTRACT FROM AUTHOR]

Directed evolution of Pseudomonas aeruginosa lipase by the use of combinatorial active site saturation test (CAST) criteria provided a highly enantioselective mutant (Leu162Phe) for kinetic resolution of an axially chiral allene, p-nitrophenyl 4-cyclohexyl-2-methylbuta-2,3-dienoate (E = 111); the high enantioselectivity of the Leu162Phe mutant was rationalized by π–π stacking. [ABSTRACT FROM AUTHOR]