Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs.

Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics

Structural diversification of pillar[n]arene macrocycles

Despite the fact that pillar[n]arenes receive major interest as building blocks for supramolecular chemistry and advanced materials, their functionalization is generally limited to the modification of the hydroxy or alkoxy units present on the rims. This limited structural freedom restricts further developments and has very recently been overcome. In this article, we highlight three very recent studies demonstrating further structural diversification of pillar[n]arenes by partial removal of the alkoxy substituents on the rims, which can be considered as the next generation of pillar[n]arenes

Selective C(sp2)−H Halogenation of "click" 4-Aryl-1,2,3-triazoles

Selective bromination reactions of “click compounds” are described. Electron-neutral and electron-deficient arenes selectively undergo unprecedented Pd-catalyzed C–H ortho-halogenations assisted by simple triazoles as modular directing groups, whereas electron-rich arenes are regioselectively halogenated following an electrophilic aromatic substitution reaction pathway. These C–H halogenation procedures exhibit a wide group tolerance, complement existing bromination procedures, and represent versatile synthetic tools of utmost importance for the late-stage diversification of “click compounds”. The characterization of a triazole-containing palladacycle and density functional theory studies supported the mechanism proposal.We are grateful to Gobierno Vasco (ELKARTEK_KK-2015/0000101; IT_1033-16) and UPV/EHU (GIU15/31) for financial support. A. C. thanks MINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action is also acknowledged

New approaches to heterocyclic scaffolds using Diels-Alder chemistry

Isatin-derived 1,2,4-triazines were employed as electron deficient azadienes in inverse electron demand Diels-Alder (IEDDA) chemistry with tethered alkynyl dienophiles, leading to biologically interesting heterocyclic lactam- and lactone-annulated α-carbolines in excellent yields under microwave promotion. The chemistry scope was probed using various alkynyl amines and alcohols, and the impact of the tether length between the triazines and the dienophiles was also investigated. This IEDDA methodology was subsequently applied to the synthesis of an α-carboline library, producing eighty-eight members starting with various isatin-derived triazines, indole-derivatives, and propargylamine derivatives. In a related project, a regioselective Lewis acid catalyzed amidation of dimethyl 5H-pyridazino[4,5-b]indole-1,4-dicarboxylate was established to selectively direct the amidation to occur at either the C1 or C4 ester positions. This chemistry was then applied to tether dienophiles to the pyridazinoindole ring via an amide linkage. Subsequent IEDDA cycloadditions of these pyridazinoindole/dienophile pairs afforded carbazoles in excellent yields under thermal conditions. The scope of this chemistry scope was also thoroughly probed, leading to a library of one hundred and eighty-eight members. The synthesis of a third heterocyclic scaffold using Diels-Alder chemistry was also accomplished. Asymmetric cycloadditions of anthrone with various maleimides were successfully achieved using different chiral organocatalysts. The identity of the optimal catalytic system depended upon the dienophile, with good enantioselectivities achieved (78-83% ee). This chemistry was successfully applied as the stereocontrol element in a Diels-Alder/Functional Group Transformation/retro-Diels-Alder sequence to prepare alkaloidal scaffolds in an optically enriched form

Halogenases:a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation

Authors thank ERC GenoChemetics (FP7/2007-2013/ERC consolidator grant GCGXC grant agreement no. 614779 RJMG) for funding, BBSRC Follow on Funding, Synthetic Biology Highlight award. RSE Enterprise Fellowship (SVS), China Scholarship Council and EPSRC CRITICAT EP/L016419/1 for studentship support (Y. Z. & S. M. respectively).The enzymatic generation of carbon–halogen bonds is a powerful strategy used by both nature and synthetic chemists to tune the bioactivity, bioavailability and reactivity of compounds, opening up the opportunity for selective C–H functionalisation. Genes encoding halogenase enzymes have recently been shown to transcend all kingdoms of life. These enzymes install halogen atoms into aromatic and less activated aliphatic substrates, achieving selectivities that are often challenging to accomplish using synthetic methodologies. Significant advances in both halogenase discovery and engineering have provided a toolbox of enzymes, enabling the ready use of these catalysts in biotransformations, synthetic biology, and in combination with chemical catalysis to enable late stage C–H functionalisation. With a focus on substrate scope, this review outlines the mechanisms employed by the major classes of halogenases, while in parallel, it highlights key advances in the utilisation of the combination of enzymatic halogenation and chemical catalysis for C–H activation and diversification.Publisher PDFPeer reviewe

Modular allylation of C(sp³)-H bonds by combining decatungstate photocatalysis and HWE olefination in flow

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp(3))–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner–Wadsworth–Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules

Rare Gold-Catalyzed 4-exo-dig Cyclization for Ring Expansion of Propargylic Aziridines toward Stereoselective (Z)‑Alkylidene Azetidines, via Diborylalkyl Homopropargyl Amines

We report an uncommon 4-exo-dig cyclization of N-tosyl homopropargyl amines, catalyzed by [AuCl(PEt3)]/AgOTf, to prepare stereoselective (Z)-2-alkylidene-1-tosylazetidine compounds. The reaction outcome contrasts with the gold-catalyzed cyclization of N-tosyl homopropargyl amines containing a methyl group at the propargylic position that provides substituted 2,3-dihydropyrroles via a 5-endo-dig mechanism. The access to N-tosyl homopropargyl amines is possible by the regioselective nucleophilic attack of α-diboryl alkylidene lithium salts to propargylic aziridinesThe authors thank Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) through Projects PID2022-141693NB-I00, PID2020-113797RB-C21, and RED2022-134074-T, founded by MCIN/AEI/10.13039/ 501100011033 and “ERDF-A Way of Making Europe

Boron-Mediated Regioselective Aromatic C−H Functionalization via an Aryl BF2 Complex

An efficient regioselective functionalization of 2-aryl-heteroarenes and aryl aldehydes via an azaaryl BF2 complex has been developed. Mechanistically the reaction comprises fluoride to bromide ligand exchange on an aryl boron species and consecutive C−B bond cleavage to deliver a broad range of functionalized products. The reaction is high yielding, has a broad substrate scope where several different heteroarenes can be functionalized with chloro, bromo, iodo, hydroxyl, amine and BF2 in a highly regioselective fashion. The method can be applied for late-stage functionalization or for rapid skeleton remodeling with for instance cross-couplings

Recent advances in Flavin-dependent halogenase biocatalysis : sourcing, engineering, and application

The introduction of a halogen atom into a small molecule can effectively modulate its properties, yielding bioactive substances of agrochemical and pharmaceutical interest. Consequently, the development of selective halogenation strategies is of high technological value. Besides chemical methodologies, enzymatic halogenations have received increased interest as they allow the selective installation of halogen atoms in molecular scaffolds of varying complexity under mild reaction conditions. Today, a comprehensive library of aromatic halogenases exists, and enzyme as well as reaction engineering approaches are being explored to broaden this enzyme family’s biocatalytic application range. In this review, we highlight recent developments in the sourcing, engineering, and application of flavin-dependent halogenases with a special focus on chemoenzymatic and coupled biosynthetic approaches