MRV

Nature, Published online: 26 April 2026; doi:10.1038/d41586-026-01361-7

1,2-Diazetidines are saturated four-membered heterocycles featuring two adjacent nitrogen atoms. Despite recent advances in their synthesis and promising potential in medicinal chemistry, the chemistry of these cyclic hydrazines remains underexplored. This review highlights their three-dimensional structure and explores various strategies for their preparation and functionalization.

1,2-Diazetidines are saturated four-membered heterocycles featuring two adjacent nitrogen atoms. Despite their promising potential as rigid molecular scaffolds for drug discovery, their synthesis and reactivity remain largely unexplored. This review summarizes their three-dimensional structural features, which have been characterized using various spectroscopic and crystallographic methods. Current synthetic approaches of 1,2-diazetidines fall into three main categories: (i) [2 + 2] cycloadditions between azo compounds and electron-rich olefins, (ii) photochemical ring contraction of dihydropyridazines, and (iii) intramolecular ring closure of hydrazine derivatives, the latter enabling stereocontrol at the four-membered ring. Finally, the reactivity and functionalization of these cyclic hydrazines are discussed, including derivatization at both nitrogen atoms.

The catalytic asymmetric allylic C–H alkylation of alkenes with NH₂ ⁻unprotected amino acid esters is achieved by light-induced chiral aldehyde/palladium combining catalysis. Various α,α-disubstituted amino acid esters bearing either allyl or conjugated enyne motifs are obtained with good experimental outcomes. Enantiocontrol arises from the synergistic action of the chiral aldehyde and the chiral phosphine ligand.

ABSTRACT

The catalytic asymmetric allylic C–H alkylation of alkenes with the α-carbon of readily available amino acid derivatives represents an ideal strategy for constructing chiral nonproteinogenic α,α-disubstituted amino acids. However, such synthetic methodologies remain unexplored. Herein, we report a light-induced, chiral aldehyde/palladium catalysis-enabled direct allylic C–H alkylation of allyl arenes and 1,4-enynes using NH₂-unprotected amino acid esters. The results demonstrate that competing allylic C–H amination is completely suppressed, and the desired alkylation products—bearing either allyl or conjugated enyne moieties—are obtained in 32%–93% yields with 80%–98% ee values. Mechanistic studies reveal that enantiocontrol is achieved through the cooperative action of the chiral aldehyde and the chiral ligand, and the latter primarily dictates the absolute configuration of the product by forming noncovalent C–H···π and C–H···O interactions with the chiral aldehyde-involved Zn complex.

This electrochemical methodology allows the preparation of bridged tricyclic scaffolds through a rapid increase in the molecular complexity of simple and readily accessible starting materials. Alcohols proved to be the most efficient nucleophiles, as well as 6-chloropurine. Plausibly, the process involves an anodic oxidative dearomatization to generate the key o-quinone-type intermediate.

The electrochemical methodology here reported allows the preparation of bridged tricyclic scaffolds through a rapid increase in the molecular complexity of simple and readily accessible starting materials. Standard conditions employing graphite as anode, nickel foam as cathode, and triflic acid as additive provided the target aza-caged structures in good yields. Alcohols proved to be the most efficient nucleophiles, affording the desired products in modest yields, while nitrogen-based nucleophiles generally resulted in decomposition, with the notable exception of 6-chloropurine, which gave the desired product in moderate yield. Plausibly, the process involves an anodic oxidative dearomatization that generates an o-quinone-type intermediate, which undergoes nucleophilic addition followed by an intramolecular Diels–Alder reaction. Cyclic voltammetry confirmed the aminophenol as the electroactive species, supporting the proposed mechanistic pathway.

Synthesis
DOI: 10.1055/a-2842-9696

Deuterium incorporation at metabolically labile C–H bonds is an appealing strategy for improving metabolic stability and pharmacokinetic attributes in drug design campaigns. However, conventional H/D exchange methods often suffer from significant reactivity and selectivity challenges, limiting access to diverse deuterated structures. Here, we introduce a deuterium-labeled iodomethylthianthrenium reagent, readily prepared via H/D exchange with D2O, that directly converts alkenes into deuterated azetidines or cyclobutanes via a common 1,3-dielectrophilic intermediate. This method is compatible with a wide range of functional groups and is operationally simple, providing a reliable way to install deuterium at targeted positions in strained-ring scaffolds with high molecular complexity.
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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Synthesis
DOI: 10.1055/a-2836-4476

The pentafluorosulfanyl (SF5) group has emerged as an attractive motif in drug design, yet access to SF5-containing molecules was long based on toxic or gaseous reagents with limited practicality. In this review, we summarize recent advances in novel SF5 transfer reagents, with emphasis on their design, synthesis, and reactivity. These advances provide a versatile toolkit to advance the accessibility of SF5 incorporation in organic synthesis and medicinal chemistry.
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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Nature Synthesis, Published online: 14 April 2026; doi:10.1038/s44160-026-01042-3

Nature Synthesis, Published online: 07 April 2026; doi:10.1038/s44160-026-01017-4

Synthesis
DOI: 10.1055/a-2835-2546

To address the escalating greenhouse effect driven by anthropogenic carbon dioxide (CO2) emissions, innovative strategies for CO2 utilization are required. The synthesis of amino acids from CO2 as a C1 building block is particularly attractive, given that these molecules are pivotal to both biological systems and synthetic chemistry as versatile synthons. Photochemical and electrochemical methods that leverage sustainable energy sources have recently emerged as powerful platforms for such valorizations. This review summarizes recent advances in the photochemical and electrochemical carboxylation with CO2 to access amino acids, including mechanisms, applications, and limitations. Finally, the persistent challenges and prospects of this burgeoning field are outlined.
[...]

Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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