Marnix van der Kolk

Nature Synthesis, Published online: 01 June 2023; doi:10.1038/s44160-023-00332-4

Cross-coupling reactions are among the most widely used synthetic methods in medicinal chemistry; however, they typically form bonds with C(sp2)-hybridized atoms. The resulting molecules often have suboptimal physicochemical and topological properties. Here virtual and experimental libraries of products from benzylic C(sp3)–H cross-coupling are shown to access underpopulated 3D chemical space.

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.

Nature Synthesis, Published online: 15 June 2023; doi:10.1038/s44160-023-00341-3

Visible-light-driven dual photoredox catalysis often uses expensive metals, such as iridium. Now, a photocatalytic approach using a Ni single-atom carbon nitride catalyst is reported for the C–O cross-coupling of carboxylic acids and alkyl halides, demonstrating broad functional group tolerance, short reaction times, facile recovery and excellent stability.

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, Published online: 14 June 2023; doi:10.1038/s41586-023-06204-3

Behavioural electrophysiological and transcriptomic studies in mice show that psychedelic drugs reopen the social reward learning critical period and suggest that this involves reorganization of the extracellular matrix.

The mercury drop test is a widely used method for distinguishing between homogeneous and heterogeneous catalysis in organometallic systems. However, recent research has highlighted the limitations of this test due to the intrinsic reactivity of some organometallic compounds towards elemental mercury. In this study, we used real-time mass spectrometry with charge-tagged substrates to investigate the effect of elemental mercury on LnPd0 and PdIIArX intermediates common in palladium-catalysed cross-coupling reactions. Our findings demonstrate that mercury can interact with both species through redox-transmetallation and amalgamation processes, leading to a decrease in catalytic activity. This result further calls into question the fundamental assumption of mercury selectivity towards heterogeneous catalytic species. These results highlight the importance of careful consideration of the results the mercury drop test provides and encourages further research to gain a more comprehensive understanding of catalyst poisoning mechanisms.

A reliable method is introduced for the synthesis of branched α-arylated amines from simple linear N-sulfonyl amines and aryl boroxines utilizing dual palladium catalysis involving amine dehydrogenation. Bromobenzene serves as a hydride acceptor, and the ensuing imine intermediate undergoes a novel umpolung arylation. Given the wide availability of primary amines, this method can be expected to be useful for the synthesis of structurally complex amines with varied functionality.

Abstract

Functionalization of C(sp³)−H bonds adjacent to a nitrogen atom is an efficient means of preparing structurally complex amines and has long been of interest to synthetic chemists. Herein, dual palladium catalysis is used to achieve α-C−H arylation of linear N-sulfonyl amines with aryl boroxines, rather than N-arylation (C−N bond formation). This method has a broad scope with respect to both the amine and the boroxine, providing convenient access to α-branched amines. During the dehydrogenation step of the catalytic cycle, bromobenzene accepts a hydride from the α-carbon on the amine, producing an imine that subsequently undergoes Pd-catalyzed C-arylation with the boroxine. Mechanistic studies revealed that imine arylation proceeds through an unusual Pd⁰/Pd^II catalytic cycle, in which oxidative cyclization of a palladium η²-imine complex generates a three-membered palladacycle that subsequently undergoes transmetallation reaction with the boroxine.

Pt(II)−NHC complexes are used in alkene hydrosilylation reactions. Some of the examined compounds display excellent catalytic activity, outperforming Pt(0)−NHC pre-catalysts. Our study explores the catalyst structure-activity relationship and provides new mechanistic insights into this industrially important transformation. A sustainable protocol, featuring efficient platinum removal, allows us to access a series of organosilanes in very good to excellent yields.

Abstract

Herein, we report the catalytic activity of a series of platinum(II) pre-catalysts, bearing N-heterocyclic carbene (NHC) ligands, in the alkene hydrosilylation reaction. Their structural and electronic properties are fully investigated using X-ray diffraction analysis and nuclear magnetic resonance spectroscopy (NMR). Next, our study presents a structure-activity relationship within this group of pre-catalysts and gives mechanistic insights into the catalyst activation step. An exceptional catalytic performance of one of the complexes is observed, reaching a turnover number (TON) of 970 000 and a turnover frequency (TOF) of 40 417 h⁻¹ at 1 ppm catalyst loading. Finally, an attractive solvent-free and open-to-air alkene hydrosilylation protocol, featuring efficient platinum removal (reduction of residual Pt from 582 ppm to 5.8 ppm), is disclosed.

An overview of recent syntheses of enantiopure pharmaceutically relevant piperidines using Mannich reactions is presented. The asymmetric induction has been classified in three conceptual approaches using the chiral pool, chiral auxilliaries and asymmetric catalysis.

Abstract

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.

Nature Chemistry, Published online: 27 April 2023; doi:10.1038/s41557-023-01192-3

Functionalization of unsymmetrical internal alkenes usually takes place with low regioselectivity, giving a mixture of isomers. Now, a highly regio- and enantioselective remote 1,n-dioxygenation of internal alkenes using a palladium catalyst has been developed for the synthesis of chiral 1,n-diols. Regioselectivity tuning was demonstrated by altering the rate-determining step, enabled by the phenyl-substituted Pyox ligand.

Nature, Published online: 26 April 2023; doi:10.1038/d41586-023-01370-w

An archipelago constructed of sand and mud is bringing new life to a dead lake but can this bold experiment have a lasting impact?

Nature Chemistry, Published online: 24 April 2023; doi:10.1038/s41557-023-01189-y

The chemistry of polynitrogens has been enriched by a new isomer of N6 through the synthesis, in a laser-heated diamond anvil cell, of a charged aromatic [N6]4– ring that is recoverable at ambient temperature under high pressure.

Nature Synthesis, Published online: 20 April 2023; doi:10.1038/s44160-023-00275-w

Alkyl alcohols are attractive surrogates for alkyl halides in the Suzuki–Miyaura cross-coupling reactions, but methods to activate the C–O bond are underdeveloped. Now a Ni-catalysed arylation is reported that uses aryl boronic esters and tertiary alcohols, through in situ alcohol silylation.

Nature, Published online: 19 April 2023; doi:10.1038/s41586-023-06075-8

Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives

Nature, Published online: 19 April 2023; doi:10.1038/d41586-023-01296-3

Perceptions have shifted dramatically in the past few years on the therapeutic value of illicit drugs such as ecstasy. But questions still linger about what FDA approval might look like.

Nature Chemistry, Published online: 17 April 2023; doi:10.1038/s41557-023-01176-3

Methods for the direct construction of 1,3-disubstituted planar chiral ferrocenes are elusive. Now, a modular platform enables the construction of planar chirality in 1,3-disubstituted ferrocenes/ruthenocenes via enantioselective relay remote C–H arylation. The strategy involves an initial enantiodetermining ortho-C‒H activation enabled by a Pd(II)/chiral amino-acid ligand, followed by relay to the remote meta-position by a bridgehead-substituted norbornene mediator.