No abstract

Scheme 11. Synthesis of butenolides and isocoumarins by gold-palladium dual catalysis; dba = trans,trans-dibenzylideneacetone.

Amines are critical functional groups that are incorporated into many biologically active compounds and functional materials of importance to the biomedical, agrochemical and fine-chemical industries. [1] An idealized synthetic approach for the preparation of this important class of compounds would take advantage of the direct and byproduct free conversion of feedstock alkenes directly into unprotected amines with good regio-and stereoselectivity under mild reaction conditions. These goals could be realized with early transition metal catalyzed hydroaminoalkylation (Scheme 1), a CÀH functionalization reaction a to nitrogen that results in selective C À C bond formation. [2, 3] However, to date, all promising Group 4 and 5 metal complexes for this transformation demand harsh reaction conditions. [4,5] The identification of a system that can be used with mild reaction conditions is desirable. Here we show that by using a sterically demanding, N,O-chelating, electron-withdrawing phosphoramidate as an easily installed auxiliary ligand, room-temperature alkene hydroaminoalkylation can be achieved for the first time.Unlike late transition metal catalysts (Ir, Ru) [6,7] for this reaction, early transition metal catalysts (Ti, [4] Zr, [4a] Ta, [5] Nb, [5e-g] ) do not require a removable directing group or activated alkene substrates. Hydroaminoalkylation results in unprotected amines ready for further functionalization. This transformation gives selectively substituted amines in a single and atom-economic catalytic reaction, using inexpensive early transition metals of low toxicity. Thus, hydroaminoalkylation is an excellent reaction to target for advances in green chemistry.Ligand screening investigations by Herzon and Hartwig have shown that electron-withdrawing chloride ligands enhance reactivity, such that select substrate combinations yield products at 90 8C. [5b] Notably, the more challenging dialkylamine substrates required temperatures of 150 8C and thermally polymerizable styrene derivatives were not reported. [4b] Herein, we show that our phosphoramidate-ClTaMe 3 precatalyst is easily synthesized and can achieve roomtemperature hydroaminoalkylation with a broad range of substrates.

Eukaryotic-like serine/threonine kinases (eSTKs) with extracellular PASTA repeats are key membrane regulators of bacterial cell division. How PASTA repeats govern eSTK activation and function remains elusive. Using evolution- and structural-guided approaches combined with cell imaging, we disentangle the role of each PASTA repeat of the eSTK StkP from Streptococcus pneumoniae. While the three membrane-proximal PASTA repeats behave as interchangeable modules required for the activation of StkP independently of cell wall binding, they also control the septal cell wall thickness. In contrast, the fourth and membrane-distal PASTA repeat directs StkP localization at the division septum and encompasses a specific motif that is critical for final cell separation through interaction with the cell wall hydrolase LytB. We propose a model in which the extracellular four-PASTA domain of StkP plays a dual function in interconnecting the phosphorylation of StkP endogenous targets along with septal cell wall remodelling to allow cell division of the pneumococcus.

Iron-sulfur (Fe-S) clusters are ubiquitous co-factors essential for life. It is largely thought that the emergence of oxygenic photosynthesis and progressive oxygenation of the atmosphere led to the origin of multiprotein machineries (ISC, NIF, and SUF) assisting Fe-S cluster synthesis in the presence of oxidative stress and shortage of bioavailable iron. However, previous analyses have left unclear the origin and evolution of these systems. Here, we combine exhaustive homology searches with genomic context analysis and phylogeny to precisely identify Fe-S cluster biogenesis systems in over 10,000 archaeal and bacterial genomes. We highlight the existence of two additional and clearly distinct "minimal" Fe-S cluster assembly machineries, MIS and SMS, which we infer in the Last Universal Common Ancestor (LUCA), and we experimentally validate SMS as a bona fide Fe-S cluster biogenesis system. These ancestral systems were kept in Archaea whereas they went through stepwise complexification in Bacteria to incorporate additional functions for higher Fe-S cluster synthesis efficiency leading to SUF, ISC, and NIF. Horizontal gene transfers and losses then shaped the current distribution of these systems, driving ecological adaptations such as the emergence of aerobic lifestyles in archaea. Our results show that dedicated machineries were in place early in evolution to assist Fe-S cluster biogenesis, and that their origin is not directly linked to Earth oxygenation.

Most bacterial cells are surrounded by an essential cell wall composed of the net-like heteropolymer peptidoglycan (PG). Growth and division of bacteria are intimately linked to the expansion of the PG meshwork and the construction of a cell wall septum that separates the nascent daughter cells. Class A penicillin-binding proteins (aPBPs) are a major family of PG synthases that build the wall matrix. Given their central role in cell wall assembly and importance as drug targets, surprisingly little is known about how the activity of aPBPs is controlled to properly coordinate cell growth and division. Here, we report the identification of MacP (SPD_0876) as a membrane-anchored cofactor of PBP2a, an aPBP synthase of the Gram-positive pathogen We show that MacP localizes to the division site of, forms a complex with PBP2a, and is required for the in vivo activity of the synthase. Importantly, MacP was also found to be a substrate for the kinase StkP, a global cell cycle regulator. Although StkP has been implicated in controlling the balance between the elongation and septation modes of cell wall synthesis, none of its substrates are known to modulate PG synthetic activity. Here we show that a phosphoablative substitution in MacP that blocks StkP-mediated phosphorylation prevents PBP2a activity without affecting the MacP-PBP2a interaction. Our results thus reveal a direct connection between PG synthase function and the control of cell morphogenesis by the StkP regulatory network.

Methane is one of the most important greenhouse gases on Earth and holds an important place in the global carbon cycle. Archaea are the only organisms that use methanogenesis to produce energy and rely on the methyl–coenzyme M reductase complex (Mcr). Over the last decade, new results have significantly reshaped our view of the diversity of methane-related pathways in the Archaea. Many new lineages that synthesize or use methane have been identified across the whole archaeal tree, leading to a greatly expanded diversity of substrates and mechanisms. In this review, we present the state of the art of these advances and how they challenge established scenarios of the origin and evolution of methanogenesis, and we discuss the potential trajectories that may have led to this strikingly wide range of metabolisms.

Unprotected secondary amines are directly alkylated by C-H functionalization adjacent to nitrogen, thereby opening new routes toward the synthesis of α- and β-alkylated N-heterocycles. α-Alkylated piperidine, piperazine, and azepane products are prepared from heterocycles and alkenes in an atom-economic reaction with excellent regio- and diastereoselectivity. β-Alkylated N-heterocycles are synthesized via a scalable one-pot alkylation/cyclization procedure generating 3-methylated azetidines, pyrrolidines, and piperidines.