LongLarf

Nature Catalysis, Published online: 20 September 2022; doi:10.1038/s41929-022-00849-5

Nature Catalysis, Published online: 15 September 2022; doi:10.1038/s41929-022-00841-z

Mechanisms: A comprehensive review of the catalytic mechanisms of imine reductase (IRED)-catalyzed imine reduction (IR), reductive amination (RA), recently reported conjugate reduction (CR), and stepwise CR-RA. Mechanistic insights from protein engineering were also included.

Abstract

The synthesis of chiral amines is significant in the pharmaceutical industry. Imine reductase (IRED), a promising biocatalyst that was previously known to only catalyze asymmetric imine reduction (IR), was revealed to achieve direct asymmetric reductive amination (RA) of ketones with excess amines, producing secondary and tertiary amines. Moreover, conjugate reduction (CR) and RA activity by a single IRED has been reported for the preparation of valuable amine diastereomers. IREDs catalyzing these different reactions share the same standard quaternary structure, but possess varying active sites, indicating correlations and differences between their catalytic mechanisms. In this review, we trace the catalytic mechanisms reported for IRED-catalyzed IR, RA, and CR-RA. Insights obtained from structural and protein engineering in understanding the IRED-catalyzed asymmetric synthesis are also included. This review will help readers acquire comprehensive insights into the catalytic mechanism of IREDs and ultimately inspire the engineering of IREDs for industrial applications.

This Review highlights single-atom catalysis on covalent triazine frameworks (CTFs), thus focusing on the available insights on factors influencing nuclearity and coordination environment of metal species on CTFs and the effect on catalytic performance.

Abstract

Heterogeneous single-site and single-atom catalysts potentially enable combining the high catalytic activity and selectivity of molecular catalysts with the easy continuous operation and recycling of solid catalysts. In recent years, covalent triazine frameworks (CTFs) found increasing attention as support materials for particulate and isolated metal species. Bearing a high fraction of nitrogen sites, they allow coordinating molecular metal species and stabilizing particulate metal species, respectively. Dependent on synthesis method and pretreatment of CTFs, materials resembling well-defined highly crosslinked polymers or materials comparable to structurally ill-defined nitrogen-containing carbons result. Accordingly, CTFs serve as model systems elucidating the interaction of single-site, single-atom and particulate metal species with such supports. Factors influencing the transition between molecular and particulate systems are discussed to allow deriving tailored catalyst systems.

The Cover Feature illustrates how dual catalysis between a photocatalyst and an enzyme accomplishes the synthesis of chiral γ-lactones from simple starting materials. In their Research Article, D. Ravelli, S. Schmidt and co-workers explored a decatungstate photocatalyst that, upon near-UV light irradiation, promotes the radical hydroacylation of α,β-unsaturated esters or acids with aldehydes. Subsequently, an alcohol dehydrogenase reduces the intermediate keto esters/acids to the corresponding chiral alcohols, which undergo lactonization to the desired chiral γ-lactones. This study highlights the powerfulness of merging photo- with biocatalysis for building molecular complexity to access high-value added chiral compounds from simple, cheap, and largely available starting materials. More information can be found in the Research Article by D. Ravelli, S. Schmidt and co-workers.

Although aryl thioamides are often used to assess the pharmacological effects of H₂S, their reactivity is extremely sluggish and their release of H₂S is highly inefficient. Herein, we report that H₂S liberation from this donor class can be augmented with intramolecular nucleophilic assistance. We envision this new chemistry serving as a general design strategy for accessing efficient donors that selectively respond to various biological stimuli.

Abstract

Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H₂S). From this class of donors, however, extremely low H₂S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H₂S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H₂S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide- and diselenide-linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H₂S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.

Nature Catalysis, Published online: 11 August 2022; doi:10.1038/s41929-022-00821-3

A distinct alkoxycarbonylation pattern via an in situ generated Fe²⁻ catalyst is reported. This low-valent iron catalyst activates alkyl halides via a two-electron transfer (TET) process, unlike previous reports where alkyl halides underwent a single electron transfer (SET). This reaction provides easy and efficient access to esters, and its mechanism will provide new ideas for the activation of alkyl halides in the field of carbonylation.

Abstract

Transition metal-catalyzed carbonylative cross-coupling reactions are some of the most widely used methods in organic synthesis. However, despite the obvious advantages of iron as an abundant and low toxicity transition metal catalyst, its practical application in carbonylation reaction remains largely unexplored. Here we report our recent study on Fe-catalyzed alkoxycarbonylation of alkyl halides. Mechanistic studies indicate that the reaction is catalyzed by an in situ generated Fe²⁻ complex. This low-valent iron species activates alkyl bromides via a distinctive two-electron transfer (TET) process, whereas it proceeds via a single electron transfer (SET) process for alkyl iodides which is consistent with literature.

Choosing the outcome: A silyl group at the alkyne terminal of secondary propargyl alcohols temporarily inverted the enantio-recognition of natural lipases. Using this phenomenon, the lipase/oxovanadium co-catalyzed dynamic kinetic resolution (DKR) of racemic alcohols achieved enantiodivergent production of R and S enantiomers in high yield and with high enantiomeric excess.

Abstract

Natural lipases typically recognize enantiomers of alcohols based on the size differences of substituents near the carbinol moiety and selectively react with the R enantiomers of secondary alcohols. Therefore, lipase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols produces only R enantiomers. We report herein a method for obtaining S enantiomers by DKR of secondary 3-(trialkylsilyl)propargyl alcohols by using a well-known R-selective Pseudomonas fluorescens lipase in combination with a racemization catalyst VMPS4, in which the silyl group reverses the size relationship of substituents near the carbinol moiety. We have already reported R-selective DKR of the corresponding propargyl alcohols without substituents on the ethynyl terminal carbon, and the presence of an easily removable silyl group has enabled us to produce both enantiomers of propargyl alcohols in high chemical yields and with high enantiomeric excess. In addition, immobilization of the lipase on Celite was found to be important for achieving a high efficiency of the DKR.

5-Sulfonyl and 5-sulfinyl substituted 1,2,4-thiadiazoles (TDZ) are very rapid and selective modifiers of solvent-accessible free-thiol groups on proteins. TDZs can be used in ESI-MS/MS studies or conventional biotin-switch assays to analyze fast oxidation processes of distinct cysteines in a protein.

Abstract

The study of cysteine modifications has gained much attention in recent years. This includes detailed investigations in the field of redox biology with focus on numerous redox derivatives like nitrosothiols, sulfenic acids, sulfinic acids and sulfonic acids resulting from increasing oxidation, S-lipidation, and perthiols. For these studies selective and rapid blocking of free protein thiols is required to prevent disulfide rearrangement. In our attempt to find new inhibitors of human histone deacetylase 8 (HDAC8) we discovered 5-sulfonyl and 5-sulfinyl substituted 1,2,4-thiadiazoles (TDZ), which surprisingly show an outstanding reactivity against thiols in aqueous solution. Encouraged by these observations we investigated the mechanism of action in detail and show that these compounds react more specifically and faster than commonly used N-ethyl maleimide, making them superior alternatives for efficient blocking of free thiols in proteins. We show that 5-sulfonyl-TDZ can be readily applied in commonly used biotin switch assays. Using the example of human HDAC8, we demonstrate that cysteine modification by a 5-sulfonyl-TDZ is easily measurable using quantitative HPLC/ESI-QTOF-MS/MS, and allows for the simultaneous measurement of the modification kinetics of seven solvent-accessible cysteines in HDAC8.

A single multifunctional enzyme is reported that can promote biocatalytic cascades based on multiple stereoselective steps. Specifically, a 4-oxalocrotonate tautomerase (4-OT) enzyme can form enamine and iminium ion intermediates from aldehydes and enals to promote both a two-component reaction and a triple cascade characterized by different mechanisms and activation sequences.

Abstract

Asymmetric catalytic cascade processes offer direct access to complex chiral molecules from simple substrates and in a single step. In biocatalysis, cascades are generally designed by combining multiple enzymes, each catalyzing individual steps of a sequence. Herein, we report a different strategy for biocascades based on a single multifunctional enzyme that can promote multiple stereoselective steps of a domino process by mastering distinct catalytic mechanisms of substrate activation in a sequential way. Specifically, we have used an engineered 4-oxalocrotonate tautomerase (4-OT) enzyme with the ability to form both enamines and iminium ions and combine their mechanisms of catalysis in a complex sequence. This approach allowed us to activate aldehydes and enals toward the synthesis of enantiopure cyclohexene carbaldehydes. The multifunctional 4-OT enzymes could promote both a two-component reaction and a triple cascade characterized by different mechanisms and activation sequences.