Polarity-Reversal Strategy for the Functionalization of Electrophilic Strained Molecules via Light-Driven Cobalt Catalysis.

Strain-release-driven methodology is a powerful tool for accessing structural motifs, highly desirable by the pharmaceutical industry. The reactivity of spring-loaded cyclic reagents is dominated by transformations relying on their inherent electrophilic reactivity. Herein, we present a polarity-reversal strategy based on light-driven cobalt catalysis, which enables the generation of nucleophilic radicals through strain release. The applicability of this methodology is demonstrated by the design of two distinct types of reactions: Giese-type addition and Co/Ni-catalyzed cross-coupling. Moreover, a series of electrochemical, spectroscopic, and kinetic experiments as well as X-ray structural analysis of the intermediate alkylcobalt(III) complex give deeper insight into the mechanism of the reaction.

Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin.

Aging is associated with the accumulation of several types of damage: in particular, damage to the proteome. Recent work points to a conserved replicative rejuvenation mechanism that works by preventing the inheritance of damaged and misfolded proteins by specific cells during division. Asymmetric inheritance of misfolded and aggregated proteins has been shown in bacteria and yeast, but relatively little evidence exists for a similar mechanism in mammalian cells. Here, we demonstrate, using long-term 4D imaging, that the vimentin intermediate filament establishes mitotic polarity in mammalian cell lines and mediates the asymmetric partitioning of damaged proteins. We show that mammalian JUNQ inclusion bodies containing soluble misfolded proteins are inherited asymmetrically, similarly to JUNQ quality-control inclusions observed in yeast. Mammalian IPOD-like inclusion bodies, meanwhile, are not always inherited by the same cell as the JUNQ. Our study suggests that the mammalian cytoskeleton and intermediate filaments provide the physical scaffold for asymmetric inheritance of dynamic quality-control JUNQ inclusions. Mammalian IPOD inclusions containing amyloidogenic proteins are not partitioned as effectively during mitosis as their counterparts in yeast. These findings provide a valuable mechanistic basis for studying the process of asymmetric inheritance in mammalian cells, including cells potentially undergoing polar divisions, such as differentiating stem cells and cancer cells.

Reversal of regioselectivity in reactions of donor-acceptor cyclopropanes with electrophilic olefins.

Reactivity of donor-acceptor cyclopropanes towards nucleophiles and electrophiles is determined by the specific philicity of the carbon atoms originating from the strong polarization of the central C-C bond. Herein, we report that vitamin B12 catalysis enables the transformation of an initially electrophilic center into a nucleophilic radical that reacts with SOMOphiles. This radical-based strategy reverses the standard regioselectivity and thus complements the classical approaches.

Strain release - an old tool for new transformations.

Strain-release driven transformations give access to attractive bioisosteric motifs highly prized by medicinal chemists and they are characteristic of molecules possessing distorted bond lengths and angles. By broadening the chemical space in drug discovery, recently, these compounds have attracted a lot of interest. Their reactivity stems mainly from an increased energy and destabilization. As a result, the opening of the bridging bond occurs under the action of both nucleophiles and electrophiles as well as radical species and transition metals. Though the bridge bond dominates their reactivity, it is also influenced by the substitution pattern. This feature article focuses on strain-release driven strategies paying particular attention to the most recent (year > 2010) advances.

Photoinduced Vitamin B12-Catalysis for Deprotection of (Allyloxy)arenes.

Vitamin B12 is a natural cobalt complex that, while reduced to the "supernucleophilic" Co(I) form, can easily react with electrophiles via an SN2 mechanism. It is also shown to react via an SN2' mechanism with allylic compounds allowing for photochemical deprotection of (allyloxy)arenes. A sustainable alternative to commonly used noble metal-catalyzed deprotection reactions is presented.