Aryl transition metal chemical warheads for protein bioconjugation.

The past seven years have witnessed the burgeoning of protein bioconjugation reactions highlighting aryl transition metal reagents as coupling partners. This new bioorthogonal organometallic chemistry, which sets the scene for stoichiometric processes in place of the catalytic procedures that developed in parallel, already enabled the forging of C-S and C-C bonds onto protein substrates, respectively in their native state or equipped with pre-installed non-natural terminal alkene or alkyne appendages. Although not yet applied to proteins, related transformations pointing to the creation of C-N bonds have, in addition, just been disclosed by targeting peptide lysine residues. Central to this research was the selection of ligands attached to the transition metal, in order to confer to metal complexes, not only their stability in aqueous medium, but also the desired chemoselectivity. We summarize here this body of work, which has already put in the limelight elaborated palladium and gold complexes equipped with biologically relevant appendages, such as fluorescent and affinity tags, as well as drug molecules. This research holds much promise, not only for the study of proteins themselves, but also for the design of new protein-based biotherapeutics, such as protein-drug conjugates or constrained analogs resulting from macrocyclisation reactions.

Modular total syntheses of mycolactone A/B and its [2H]-isotopologue.

A modular total synthesis of mycolactone A/B, the exotoxin produced by Mycobacterium ulcerans, has been achieved through the orchestration of several Pd-catalyzed key steps. While this route leads to a mixture of the natural product and its C12 epimer (4 : 1 ratio), this was inconsequential from the biological activity standpoint. Compared to the previously reported routes, this synthetic blueprint allows the late-stage modification of the toxin, as exemplified by the preparation of [22,22,22-2H3]-mycolactone A/B.

Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.

Inverse Electron-Demand [4 + 2]-Cycloadditions of Ynamides: Access to Novel Pyridine Scaffolds.

Functionalized polycyclic aminopyridines are central to the chemical sciences, but their syntheses are still hampered by a number of shortcomings. These nitrogenated heterocycles can be efficiently prepared by an intramolecular inverse electron demand hetero Diels-Alder (ihDA) cycloaddition of ynamides to pyrimidines. This ihDA/rDA sequence is general in scope and affords expedient access to novel types of aminopyridinyl scaffolds that hold great promise in terms of exit vector patterns.

Stereodivergent hydrogermylations of α-trifluoromethylated alkynes and their applications in cross-coupling reactions.

The hydrometalation of alkynes with group 14 elements such as tin- or silyl hydrides is a classical transformation in organic synthesis. Strangely, among the group 14 elements, the use of germanium hydrides is rarely seen. Two efficient, stereodivergent, and broadly applicable routes to (Z)- and (E)-α-CF3-vinylgermanes by regio- and stereoselective hydrogermylation of α-trifluoromethylated alkynes under radical or transition-metal-catalyzed conditions are reported. Furthermore, we demonstrate that the resulting stereodefined fluorinated building blocks are remarkable cross-coupling partners, provided that the vinylgermane is appropriately tuned electronically, as demonstrated by the synthesis of trisubstituted (Z)- and (E)-α-trifluoromethylated alkenes.

Boron chemistry in a new light.

Photocatalysis has recently opened up new avenues for the generation of radical species under visible light irradiation conditions. A particularly fascinating class of photocatalyzed transformations relies on the activation of stable boron species with visible-light since it allows the creation of boryl and/or carbon radicals through single electron transfer or energy transfer without the need for specific and costly equipment. This new paradigm has found numerous applications in synthetic organic chemistry, catalysis, and macromolecular chemistry. In this minireview, the concepts underlying photoactivation of boron-species as well as applications to the creation of C-H, C-C, C-O, B-C and B-S bond are discussed.

Taming sulfur dioxide: a breakthrough for its wide utilization in chemistry and biology.

Although sulfur dioxide (SO2) has been used as a reagent for organic chemistry for more than one hundred years, being endowed with quite a distinct and varied reactivity profile, which allows the synthesis of a large range of compounds, its notorious toxicity as well as its gaseous state have impeded its frequent utilization by chemists. We summarize recent studies in this emerging area aimed at stimulating its utilization in organic (including organometallic) chemistry thanks to the development of innocuous, bench-stable reliable SO2 donors. Proof-of-concept experiments have also been recently performed in biology with the design of organic SO2 donors having controlled release profiles under physiological conditions, either active against mycobacteria or used for clarifying the role of endogenously produced SO2 in living cells.

Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis.

Aryl acid adenylation domains are the initial enzymes for aryl-capping of catecholic siderophores in a plethora of microorganisms. In order to overcome the problem of iron acquisition in host organisms, siderophore biosynthesis is decisive for virulence development in numerous important human and animal pathogens. Recently, it was shown that growth of Mycobacterium tuberculosis and Yersinia pestis can be inhibited in an iron-dependent manner using the arylic acyl adenylate analogue 5'-O-[N-(salicyl)-sulfamoyl] adenosine that acts on the salicylate activating domains, MbtA and YbtE [Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LEN (2005) Nat Chem Biol1, 29-32]. The present study explores the behaviour of the 2,3-dihydroxybenzoate activating domain DhbE (bacillibactin synthesis) and compares it to that of YbtE (yersiniabactin synthesis) upon enzymatic inhibition using a set of newly synthesized aryl sulfamoyl adenosine derivatives. The obtained results underline the highly specific mode of inhibition for both aryl acid activating domains in accordance with their natively accepted aryl moiety. These findings are discussed regarding the structure-function based aspect of aryl substrate binding to the DhbE and YbtE active sites.

Copper-mediated cross-coupling of H-phosphonates with vinyliodonium salts: a novel very mild synthesis of 2-arylvinylphosphonates.

We report a novel, very mild, highly stereoselective preparation of 2-arylvinylphosphonates at room temperature that involves the copper iodide-mediated cross-coupling of H-phosphonates with vinyliodonium tetrafluoroborates. [Structure: see text]