Diastereoselective access to C,C-glycosyl amino acids via iron-catalyzed, auxiliary-enabled MHAT coupling.

Access to C,C-glycosyl amino acids as a novel class of glycomimetics is reported by means of radical generation, intermolecular addition and stereoselective reduction via a metal-induced hydrogen atom transfer (MHAT) sequence. The 'matched' coupling of exo-D-glycals with an enantiopure dehydroalanine bearing a (R)-configured benzyl oxazolidinone enables a singular case of two-fold diastereocontrol under iron catalysis. In the common exo-D-glucal series, the nature of the C-2 substituent was found to play a key role from both reactivity and stereocontrol aspects.

Deconstructing Best-in-Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition.

Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non-polymeric glycosidase inhibitor have been obtained with cyclopeptoid-based inhibitors of Jack bean α-mannosidase (JBα-man). Here, we report a structure-activity relationship (SAR) study based on the top-down deconstruction of best-in-class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate-binding, resulting from the formation of a cross-linked complex between a multivalent inhibitor and two dimeric JBα-man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors.

Towards a General Access to 1-Azaspirocyclic Systems via Photoinduced, Reductive Decarboxylative Radical Cyclizations.

A convenient and versatile approach to important 1-azaspirocyclic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.

Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells.

EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.

Single-Scan Selective Excitation of Individual NMR Signals in Overlapping Multiplets.

2D NMR is an immensely powerful structural tool but it is time-consuming. Targeting individual chemical groups by selective excitation in a 1D experiment can give the information required far more quickly. A major problem, however, is that proton NMR spectra are often extensively overlapped, so that in practice only a minority of sites can be selectively excited. Here we overcome that problem using a fast, single-scan method that allows selective excitation of the signals of a single proton multiplet even where it is severely overlapped by other multiplets. The advantages of the method are illustrated in a selective 1D NOESY experiment, the most efficient way to determine relative configuration unambiguously by NMR. The new approach presented here has the potential to broaden significantly the applicability of selective excitation and unlock its real potential for many other experiments.

Stereoselective Synthesis of C,C-Glycosides from exo-Glycals Enabled by Iron-Mediated Hydrogen Atom Transfer.

We describe herein a convenient strategy for the construction of C,C-glycoside building blocks via the intermediacy of tertiary pseudoanomeric radicals. Application of an iron-mediated hydrogen atom transfer/Michael-Giese coupling enables the anomeric quaternization of readily available exo-glycals with good to complete stereocontrol in the pyranose and furanose series. Carefully optimized conditions allow the use of challenging trisubstituted derivatives prone to undergo further elaboration to stable neoglycoconjugates. Preliminary results for direct C-disaccharide synthesis are also discussed.

Stereocontrolled synthesis of polyhydroxylated bicyclic azetidines as a new class of iminosugars.

We report herein the development of a stereodivergent route towards polyhydroxylated bicyclic azetidine scaffolds, namely 6-azabicyclo[3.2.0]heptane derivatives. The strategy hinges on a common bicyclic ß-lactam precursor, which is forged by way of a rare example of a cationic Dieckmann-type reaction, followed by IBX-mediated desaturation. Substrate-controlled diastereoselective oxidations then allow the divergent preparation of novel iminosugar mimics.

Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals.

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthesis. Enantioselective radical cyclization cascades have the potential to deliver complex, densely packed, polycyclic architectures, with control of three-dimensional shape, in one step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI2. Here, we demonstrate that enantioselective SmI2-mediated radical cyclizations and cascades that exploit a simple, recyclable chiral ligand can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocentres with high enantio- and diastereocontrol. A computational study has been used to probe the origin of the enantioselectivity. Our studies suggest that many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

Gold(I)-Catalyzed N-Desulfonylative Amination versus N-to-O 1,5-Sulfonyl Migration: A Versatile Approach to 1-Azabicycloalkanes.

Valuable 1-azabicycloalkane derivatives have been synthesized through a novel gold(I)-catalyzed desulfonylative cyclization strategy. An ammoniumation reaction of ynones substituted at the 1-position with an N-sulfonyl azacycle took place in the presence of a gold cation by intramolecular cyclization of the disubstituted sulfonamide moiety onto the triple bond. Depending on the size of the heterocyclic ring and substitution of the substrates, two unprecedented forms of nucleophilic attack on the sulfonyl group were exploited, that is, a N-desulfonylation in the presence of an external protic O nucleophile (37-87 %, 10 examples) and a unique N-to-O 1,5-sulfonyl migration (60-98 %, 9 examples).

Robust synthesis of N-sulfonylazetidine building blocks via ring contraction of α-bromo N-sulfonylpyrrolidinones.

A simple and robust one-pot nucleophilic addition-ring contraction of α-bromo N-sulfonylpyrrolidinones has been achieved toward α-carbonylated N-sulfonylazetidines. In the presence of potassium carbonate, various nucleophiles, such as alcohols, phenols or anilines, have been efficiently incorporated into the azetidine derivatives. Moreover, the α-bromopyrrolidinone precursors could be selectively obtained in good yields by monobromination of cheap and easily available N-sulfonyl-2-pyrrolidinone derivatives.

Gold(I)-catalyzed rearrangement of N-aryl 2-alkynylazetidines to pyrrolo[1,2-a]indoles.

Various N-aryl-2-alkynylazetidines were very efficiently converted to pyrrolo[1,2-a]indoles with gold catalysts, especially the 2-biphenyl-dicyclohexylphosphino-gold(I) hexafluoroantimonate, in dichloromethane at room temperature. Additionally, two formal syntheses of bioactive non-natural compounds, i.e. 7-methoxymitosene and an 5-HT(2C) receptor agonist, have been achieved.

Silver(I)-catalyzed deprotection of p-methoxybenzyl ethers: a mild and chemoselective method.

The p-methoxybenzyl protecting group (PMB) on various alcohols and an acid was efficiently and selectively cleaved by the action of a catalytic amount of silver(I) hexafluoroantimonate combined with 0.5 equiv of 1,3,5-trimethoxybenzene in dichloromethane at 40 °C.

Coinage metals-catalyzed cascade reactions of aryl alkynylaziridines: silver(I)-single vs gold(I)-double cyclizations.

Alkynylaziridines carrying an aryl group could be efficiently converted into aminoallenylidene isochromans, isoquinolines, or tetrahydronaphtalenes with silver(I) salts and into 1-azaspiro[4.5]decane derivatives with gold(I) complexes. Mechanistic investigations revealed that both Ag- and Au-catalyzed reactions involved a Friedel-Crafts type intramolecular reaction leading to an allene and that Au also rapidly promoted a second intramolecular cyclization of the aminoallene intermediate to the corresponding spiro derivative. Stereochemical investigations suggested an anti-SN(2)'-type pathway for the first cyclization leading to a stereodefined allene, which could then be cyclized to the corresponding stereodefined spiro product. These results highlight the duality between oxo- or azaphilicity and alkynophilicity of Ag and Au as well as their complementarity in terms of reactivity.

Gold(I)-catalyzed rearrangement of aryl alkynylaziridines to spiro[isochroman-4,2'-pyrrolines].

Alkynylaziridines carrying an aryl group could be efficiently converted to spiro[isochroman-4,2'-pyrrolines] with gold salts as catalysts. This new rearrangement involved a Friedel-Crafts type intramolecular reaction followed by cyclization of the aminoallene intermediate, both initiated by the dual σ and π Lewis acidities of gold.