Transaminases engineering and their cascade systems for natural product synthesis.

A biocatalytic platform for the stereoselective synthesis of diverse atropisomeric compounds using engineered metalloenzymes

Atropisomeric compounds are widely distributed in natural products and pharmaceuticals and serve as key scaffolds in asymmetric catalysis. Despite their remarkable structural diversity, current synthetic efforts have primarily focused on C–C biaryl atropisomers, while the synthesis of other classes of atropisomeric compounds has been much less explored. Biocatalysis offers precise control over the stereoselectivity of reactions, however, its application in the synthesis of atropisomeric compounds remains at an early stage. In this work, we report a versatile biocatalytic platform that integrates metalloenzyme-catalyzed reduction reactions to access a broad array of structurally diverse atropisomeric compounds, including C–N atropisomers, diaryl ethers, and styrene derivatives, with high yields and excellent enantioselectivities. Molecular dynamics simulations provided mechanistic insights into the origin of the high stereoselectivity, and this study expands the repertoire of metalloenzyme-catalyzed, new-to-nature transformations for the synthesis of valuable molecules.

Thiamine diphosphate-dependent enzymes: mechanistic principles, stereoselective C-C bond formation, and synthetic biocatalytic applications.

This review systematically elucidates the structural characteristics, classification, and diverse reactions catalyzed by ThDP-dependent enzymes, with a primary focus on their potential for stereoselective C-C bond formation and cleavage.

Exploration of the Substrate Diversity of the Amine Transaminase 3FCR‐4M and its Engineered Variants

Enantioselective transamination of prochiral ketones is an indispensable transformation in the pharmaceutical and fine chemical industries. Transaminases have emerged as valuable biocatalysts for the preparation of a wide range of chiral amines through either kinetic resolution or asymmetric synthesis. Here, we explored the synthetic potential of the engineered amine transaminase 3FCR‐4M through systematic evaluation of combinatorial variants in both kinetic resolution and asymmetric synthesis mode. This dual assessment not only revealed synergistic effects between individually beneficial mutations, but also offered insight into the limited predictive value of kinetic resolution activity for asymmetric synthesis efficiency. Notably, we report for the first time the transaminase‐catalyzed direct amination of a terminal alkyne‐bearing substrate. The transamination of 1‐(4‐ethynylphenyl)ethanone proceeded with >99% conversion and excellent enantioselectivity (>99%ee), opening a new perspective for the integration of transaminase catalysis into click chemistry‐based synthetic workflows.

Nitrene generation and transfer for unnatural biosynthesis in living cells.

Synthetic biology has enabled the production of natural and unnatural products from inexpensive sustainable feedstocks. Yet, the scope of available products has been limited largely to compounds accessible from nature's chemical reactions. Evolved enzymes can catalyse reactions of unnatural substrates or reactions not found in nature but often require the addition of synthetic reagents to purified enzymes or to resting cells containing those enzymes. Here we show that chemical reactions of metabolic intermediates produced intracellularly in living cells can include intermolecular nitrene transfers. The biosynthesis of N-acetoxyanilines, in combination with the generation and transfer of N-aryl nitrene intermediates from them catalysed by a cytochrome P450, generates amino alcohols, diamines, diarylamines and aminoalkyl arenes from simple carbon feedstocks. These products-common substructures of pharmaceuticals and agrochemicals-are challenging to synthesize by standard organic chemistry and were produced from inexpensive, renewable feedstocks. Evolution of the enzymes in this pathway showed that titres can be increased by engineering and that the products can be synthesized with high enantioselectivity.

Advances in the Enzymic Synthesis of Unnatural Chiral Amino Acids.

Recent advances in synthesis and medicinal chemistry of pyrrolodiazepines

Nitrogen-containing heterocyclic compounds represent fundamental structural elements in contemporary medicinal chemistry. Pyrrolodiazepines, which result from the fusion of pyrrole and diazepine rings, integrate the beneficial properties of both parent structures and have emerged as a significant area of research in synthetic chemistry and pharmaceutical development in recent years. This review provides a systematic overview of the synthetic methodologies for pyrrolodiazepine derivatives that have been developed recently, encompassing transition-metal catalysis, cascade cyclization, multicomponent reactions, photoredox catalysis, base-mediated cyclization, and environmentally friendly synthesis approaches. The advantages and limitations of each method are critically evaluated. Furthermore, the biological activities of pyrrolodiazepines are extensively reviewed, addressing their antitumor, antibacterial, antiviral, central nervous system regulatory, metabolic, and cardiovascular effects, along with corresponding structure–activity relationship analyses. Finally, the review identifies the current challenges in the synthesis and application of pyrrolodiazepines and explores potential future development directions.