资源环境科技发展态势分析平台

Functionalization of the beta-C-H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions(1-5). Despite efforts for beta-C-H functionalization in carbon-carbon and carbon-heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope(6-13). Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed beta-C(sp(3))-H lactonization of aliphatic acids enabled by a mono-N-protected beta-amino acid ligand. The highly strained and reactive beta-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the beta position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(IV) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.

Shugoshin and MAD2 regulate separase-mediated chromosome separation during mitosis, in parallel to a previously identified mechanism involving the anaphase inhibitor securin.

Separation of eukaryotic sister chromatids during the cell cycle is timed by the spindle assembly checkpoint (SAC) and ultimately triggered when separase cleaves cohesion-mediating cohesin(1-3). Silencing of the SAC during metaphase activates the ubiquitin ligase APC/C (anaphase-promoting complex, also known as the cyclosome) and results in the proteasomal destruction of the separase inhibitor securin(1). In the absence of securin, mammalian chromosomes still segregate on schedule, but it is unclear how separase is regulated under these conditions(4,5). Here we show that human shugoshin 2 (SGO2), an essential protector of meiotic cohesin with unknown functions in the soma(6,7), is turned into a separase inhibitor upon association with SAC-activated MAD2. SGO2-MAD2 can functionally replace securin and sequesters most separase in securin-knockout cells. Acute loss of securin and SGO2, but not of either protein individually, resulted in separase deregulation associated with premature cohesin cleavage and cytotoxicity. Similar to securin(8,9), SGO2 is a competitive inhibitor that uses a pseudo-substrate sequence to block the active site of separase. APC/C-dependent ubiquitylation and action of the AAA-ATPase TRIP13 in conjunction with the MAD2-specific adaptor p31(comet) liberate separase from SGO2-MAD2 in vitro. The latter mechanism facilitates a considerable degree of sister chromatid separation in securin-knockout cells that lack APC/C activity. Thus, our results identify an unexpected function of SGO2 in mitotically dividing cells and a mechanism of separase regulation that is independent of securin but still supervised by the SAC.

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences(1). Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements(2). These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles(3-13). The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, alpha-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

A one-step, three-component radical coupling of [1.1.1]propellane by a photoredox reaction mediated by a copper catalyst produces drug-like bicyclopentanes.