LongLarf

Publication date: 10 August 2023

Source: Chem, Volume 9, Issue 8

Author(s): Kaitlin M. Hartung, Ellen M. Sletten

Nature Chemistry, Published online: 15 June 2023; doi:10.1038/s41557-023-01232-y

Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs are required for genetically encoding non-canonical amino acids into proteins, as well as for the encoded cellular synthesis of polymers and macrocycles; however, the scalable discovery of such pairs is challenging. A quintuply orthogonal set of pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pairs has now been generated through tRNA screening, engineering and directed evolution.

Computational modelling was employed to rationally guide protein engineering toward controlling the accessible conformations of a key lactone-carbene (LAC) intermediate in the enzyme active site by installing a new H-bond anchoring point. This H-bonding interaction controls the relative orientation of the fleeting carbene intermediate, orienting it for an enantioselective N-nucleophilic attack by the amine substrate.

Abstract

We report a computationally driven approach to access enantiodivergent enzymatic carbene N−H insertions catalyzed by P411 enzymes. Computational modeling was employed to rationally guide engineering efforts to control the accessible conformations of a key lactone-carbene (LAC) intermediate in the enzyme active site by installing a new H-bond anchoring point. This H-bonding interaction controls the relative orientation of the reactive carbene intermediate, orienting it for an enantioselective N-nucleophilic attack by the amine substrate. By combining MD simulations and site-saturation mutagenesis and screening targeted to only two key residues, we were able to reverse the stereoselectivity of previously engineered S-selective P411 enzymes. The resulting variant, L5_FL-B3, accepts a broad scope of amine substrates for N−H insertion with excellent yields (up to >99 %), high efficiency (up to 12 300 TTN), and good enantiocontrol (up to 7 : 93 er).

Transition metal catalysis is a powerful tool in synthetic chemistry; however, it has yet to reach its full potential in living cells. The hostile environment of cells towards metal complexes means that new strategies need to be developed to overcome poor reactivity.

Abstract

The importance of transition metal catalysis is exemplified by its wide range of applications, for example in the synthesis of chemicals, natural products, and pharmaceuticals. However, one relatively new application is for carrying out new-to-nature reactions inside living cells. The complex environment of a living cell is not welcoming to transition metal catalysts, as a diverse range of biological components have the potential to inhibit or deactivate the catalyst. Here we review the current progress in the field of transition metal catalysis, and evaluation of catalysis efficiency in living cells and under biological (relevant) conditions. Catalyst poisoning is a ubiquitous problem in this field, and we propose that future research into the development of physical and kinetic protection strategies may provide a route to improve the reactivity of catalysts in cells.

Nature, Published online: 14 June 2023; doi:10.1038/s41586-023-06087-4

A self-adjustive catalytic system with nickel under visible-light-driven redox reaction conditions provides a general method for carbon–(hetero)atom cross-coupling reactions and is demonstrated for nine different bond-forming reactions.

Nature Synthesis, Published online: 15 June 2023; doi:10.1038/s44160-023-00313-7

Piperidine heterocycles are widely prevalent in drug molecules; however, their synthesis remains challenging. Now, a general approach for N-(hetero)aryl piperidine synthesis using isolable iminium salts is reported. A variety of substituents are installed at the C2 and C3 positions, giving access to densely functionalized piperidines that are challenging to obtain using other methods.

Science, Volume 380, Issue 6650, Page 1147-1149, June 2023.

Science, Volume 380, Issue 6650, Page 1150-1154, June 2023.

Nature Catalysis, Published online: 08 June 2023; doi:10.1038/s41929-023-00963-y

Pyridoxal 5′-phosphate (PLP)-dependent enzymes that catalyse Mannich reactions were unknown. Now, it is reported that the PLP-dependent enzyme LolT catalyses a 5-endo-trig Mannich cyclization reaction during the pyrrolizidine core scaffold formation in loline biosynthesis, and its crystal structure is solved.

Nature, Published online: 14 June 2023; doi:10.1038/s41586-023-06087-4

A self-adjustive catalytic system with nickel under visible-light-driven redox reaction conditions provides a general method for carbon–(hetero)atom cross-coupling reactions and is demonstrated for nine different bond-forming reactions.

This review covers examples where C−H activation has been implemented on a preparative synthetic scale for the synthesis of drugs/drug candidates. Key features of the optimization process, challenges and potential of such methods in the pharmaceutical industry are discussed for various metals and transformations.

Abstract

C−H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established cross-coupling methods, C−H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C−H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C−H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in-depth understanding of the challenges and potential of C−H activation methodologies in the production of pharmaceuticals.

Science, Volume 380, Issue 6649, Page 1010-1011, June 2023.

Abstract

The employing visible light to drive organic transformations is the most promising choice to meet the needs for green synthesis, in which the reactions promoted by visible light may provide a more efficient and greener method. Currently, the most abundant methods for activation and functionalization of reaction substrates have relied on the direct single-electron transfer (SET) between the excited photocatalyst and substrates, and these wonderful works were summarized and docoumented in many reviews. As a complement to the above reactions, the photoredox-mediated atom transfer transformations (photocatalyst-to-HAT catalyst-to-substrates) to generate radical species are showing an explosively growing trend. In this review, we highlight recent significant developments in this rapidly growing area, mainly focusing on the photoinduced base-to-substrates charge transfer reactions.