Nature chemistry最新文献

The structural anisotropy necessary to distinguish clockwise from counterclockwise motions in motor-molecules continuously rotating about a covalent single bond has previously been supplied by chiral fuelling systems or by enzymes. Here we report a class of rotary motors in which, like motor proteins, structural asymmetry in the motor itself causes directional rotary catalysis. A single stereogenic centre in azaindole-phenylethanoic acid motors is sufficient to produce diastereomeric intermediates of atropisomeric conformations in the catalytic cycle, generating 8:1 clockwise:counterclockwise directional bias in the motor's rotary catalysis of diisopropylcarbodiimide hydration (motor substituent PhCH₂-). One enantiomer of a chiral hydrolysis promoter increases the directionality to 30:1 for clockwise rotation (motor substituent CH₃-), while the other enantiomer reverses the direction to 1:2 clockwise:counterclockwise. The experimental demonstration that a chiral molecular motor can be powered by a chemical fuel to rotate either with, or counter to, the motor's dominant power stroke informs the understanding of how chemical energy is transduced through catalysis, the fundamental process that powers biology.

α-Oxy-metallocarbenes exemplify Fischer carbenes and find use in the synthesis of diverse materials. Most, however, arise from the addition of reactive organometallics to toxic metal carbonyls. Here we report a method to access α-siloxycarbenes from thioesters via the reductive silylation of cobalt acyls. The reaction results in carbonyl dimerization with high hetero- and stereo-selectivity to yield unsymmetrical tetrasubstituted disiloxyalkenes, while avoiding competitive decarbonylation. These products can be further elaborated to new functionalized fragments, heterocycles and challenging enolsilanes. Several different reactivity patterns combined with mechanistic interrogation converge on α-oxycarbenes as fleeting catalytic intermediates, indicating a way to generate and exploit these reactive species under mild conditions. This method provides a general platform to harness carbene reactivity from carboxylates via metal acyls and enables a range of diverse reactivities.

Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2^KLHDC3, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce the formation of kynurenine by both inhibition and induced degradation of the enzyme and thus also modulate the non-enzymatic functions of IDO1. This unique mechanism of action may open up alternative therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

Systematic evaluation of homologous series plays a pivotal role in synthetic and medicinal chemistry. Despite their structural resemblance, the preparation of homologues often requires individual synthetic planning tailored to distinct precursors and reactions. Here we introduce a strategy that integrates single-carbon insertion into established methods, specifically redirecting alkene vicinal difunctionalization towards direct routes for 1,3-difunctionalized products. This transformation is enabled by a designer methylene dication reagent, iodomethylthianthrenium salt, which facilitates the photocatalytic conversion of alkenes into linchpin 1,3-dielectrophilic intermediates, allowing seamless incorporation of nucleophiles at distal positions. Mechanistic studies suggest that the reaction proceeds via an α-thianthrenium methyl radical with unusual ambiphilic reactivity governed by multiple stereoelectronic effects. This approach shows high compatibility in pharmaceutical and late-stage settings, providing broad access to diverse 1,3-difunctionalized products, including azetidines, 1,3-diazides and 1,3-dihalides. This work establishes 'homologative alkene difunctionalization' as a powerful platform for repurposing ubiquitous alkenes as meritorious synthetic intermediates to unveil heretofore unknown 1,3-substitution patterns.

Metal-mediated chemistries now find increasing application in in vitro biomolecule modification. However, the perceived and potential toxicity of some metals has limited the application of organometallic reagents in more complex biological settings such as inside living cells. Ligands play a crucial role in modulating both the reactivity and availability of transition metals. Here we reveal that organonickel-mediated S-arylation tolerates flexible chelation with biocompatible ligands without destroying the chemical reactivity of corresponding aryl-nickel reagents, enabling the creation of safe, site-selective C-S-bond-forming arylation manifolds. These balanced systems prove sufficiently benign for use on diverse protein substrates in vitro and in living prokaryotic and eukaryotic cells. This, in turn, enables deep chemical surveys of reactive cysteines in human cells with sensitivity sufficient to detect covalently targetable proteins from emerging intracellular viral and bacterial pathogens. Biocompatible ligand balancing thus offers a path to the broader use of transition metals in living systems.