Braca

Although alcohols are among the most abundant chemical feedstock, they remain vastly underutilized as coupling partners in transition metal catalysis. Herein, we describe a copper metallaphotoredox manifold for an open shell deoxygenative coupling of alcohols with N-nucleophiles forging C(sp3)–N bonds, a linkage highly sought in pharmaceutical agents but challenging to access via conventional cross-coupling techniques. N-heterocyclic carbene (NHC)-mediated conversion of alcohols into the corresponding alkyl radicals followed by copper-catalyzed C–N coupling renders this platform successful for a broad range of structurally unbiassed alcohols and 18 classes of N-nucleophiles.

The single component flavin-dependent halogenase AetF halogenates a range of 1,1-disubstituted styrenes, often with high stereoselectivity, and AetF and homologues of this enzyme also halogenate terminal alkynes. These findings expand the scope of FDH catalysis, and mutagenesis studies and deuterium kinetic isotope effects provide insight into the unique utility of single component FDHs for biocatalysis.

Abstract

Single component flavin-dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C−H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1′-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.

Science, Volume 383, Issue 6681, Page 438-443, January 2024.

Nature Synthesis, Published online: 26 January 2024; doi:10.1038/s44160-023-00477-2

Enzymatic C–Se bond forming reactions are rare. Now an enzymatic method for the synthesis of organoselenium compounds is reported using an ‘element engineering’ strategy. This method allows selenium analogues of cysteine, thiamine and a chuangxinmycin derivative to be produced using sulfur carrier proteins.

P450 enzymes naturally perform selective hydroxylations and epoxidations of unfunctionalized hydrocarbon substrates, among other reactions. The adaptation of P450 enzymes to a particular oxidative reaction involving alkenes is of great interest for the design of new synthetically useful biocatalysts. However, the mechanism that these enzymes utilize to precisely modulate the chemoselectivity and distinguishing between competing alkene double bond oxidations and allylic hydroxylations is sometimes not clear, which hampers the rational design of specific biocatalysts. In a previous work, a P450 from Labrenzia aggregata (P450LA1) was engineered in the laboratory using directed evolution to catalyze the direct oxidation of trans-b- methylstyrene to phenylacetone. The final variant, KS, was able to overcome the intrinsic preference for alkene epoxidation to directly generate a ketone product via the formation of a highly reactive carbocation intermediate. Here, additional library screening along the evolutionary lineage permitted to serendipitously detect a mutation that overcomes epoxidation and carbonyl formation by exhibiting a large selectivity towards allylic oxidation. A multiscalar computational methodology was applied to reveal the molecular basis towards this hydroxylation preference. Enzyme modelling suggests that introduction of a bulky substitution dramatically changes the accessible conformations of the substrate in the active site, thus modifying the enzymatic selectivity towards terminal hydroxylation and avoiding the competing epoxidation pathway, which is sterically hindered.

Nature Communications, Published online: 06 January 2024; doi:10.1038/s41467-023-44485-4

Authors develop an approach to distinguish between induced and triggered tectonic earthquakes. Seismicity at the Groningen gas field is solely induced. The probabilities to trigger tectonic earthquakes indicate the inherent stability of the field.

Nature Structural & Molecular Biology, Published online: 04 January 2024; doi:10.1038/s41594-023-01147-9

Here authors developed a computational method to design complicated all-α structures using typical helix–loop–helix motifs and canonical α-helices, and demonstrated the ability to create complicated all-α proteins.

A simple cobalt catalyst active for hydroformylation can also couple alkenes, amines, and carbon monoxide under photochemical conditions.

Nature Chemical Biology, Published online: 29 December 2023; doi:10.1038/s41589-023-01493-1

Peptide epimerization is a common but enigmatic post-translational modification found in antibiotics formed from ribosomally synthesized and post-translationally modified peptides. Now, crystallographic snapshots, spectroscopy and biochemical investigations have provided insight into the mechanism of peptide epimerization catalyzed by radical S-adenosyl-l-methionine epimerases.

Nature Synthesis, Published online: 02 January 2024; doi:10.1038/s44160-023-00446-9

An engineered ‘carbene transferase’ is shown to convert both Z and E isomers of silyl enol ethers in a stereoconvergent manner, yielding chiral α-branched ketones with high efficiency and excellent selectivity. This biocatalyst offers an efficient and high-yield method to functionalize these alkene mixtures.

We report the efficient and site selective modification of non-canonical dehydroamino acids in ribosomally synthesized and post-transationally modified peptides (RiPPs) by β-amination. The singly modified thiopeptide Thiostrepton showed an up to 35-fold increase in water solubility, and minimum inhibitory concentration (MIC) assays showed that antimicrobial activity was maintained.

Nature Chemistry, Published online: 20 December 2023; doi:10.1038/s41557-023-01388-7

Cysteine bioconjugation is an important method to modify biomolecules, but synthetic efforts to diversify reactive warheads and the low reactivity of introducible linchpins often impede application in biological laboratories. Now, a thianthrenium-based reagent permits site-selective installation of episulfonium on biomacromolecules, enabling one-step addition of bioorthogonal nucleophiles and further applications in quantitative proteomics and cross-linking.

Nature, Published online: 18 December 2023; doi:10.1038/s41586-023-06822-x

Enzyme-bound ketyl radicals derived from thiamine diphosphate are selectively generated through single-electron oxidation by a photoexcited organic dye and shown to lead to enantioselective radical acylation reactions.

Nature Catalysis, Published online: 18 December 2023; doi:10.1038/s41929-023-01065-5

Merging photoredox and biocatalysis provides opportunities to address challenges in synthetic chemistry. Now the combination of a ruthenium photocatalyst for oxidative radical formation and ‘ene’-reductases for radical interception enables an enantiodivergent decarboxylative alkylation reaction.