Developments in the chemistry and biology of 1,2,3-triazolyl-C-nucleosides.

In the last 50 years, nucleoside analogs have been introduced to drug therapy as antivirals for different types of cancer due to their interference in cellular proliferation. Among the first line of nucleoside treatment drugs, ribavirin (RBV) is a synthetic N-nucleoside with a 1,2,4-triazole moiety that acts as a broad-spectrum antiviral. It is on the World Health Organization (WHO) list of essential medicines. However, this important drug therapy causes several side effects due to its nonspecific mechanism of action. There is thus a need for a continuous study of its scaffold. A particular approach consists of connecting  d-ribose to the nitrogen-containing base with a C-C bond. It provides more stability against enzymatic action and a better pharmacologic profile. The coronavirus disease (COVID) pandemic has increased the need for more solutions for the treatment of viral infections. Among these solutions, remdesivir, the first C-nucleoside, has been approved by the Food and Drug Administration (FDA) for clinical use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It drew attention to the study of the C-nucleoside scaffold. Different C-nucleoside patterns have been synthesized over the years. They show many important activities against viruses and cancer cell lines. 1,2,3-Triazolyl-C-nucleoside derivatives are a prolific and efficient subclass of RBV analogs close to the already-known RBV with a C-C bond modification. These compounds are often prepared by alkynylation of the  d-ribose ring followed by azide-alkyne cycloaddition. They are reported to be active against the Crimean-Congo hemorrhagic fever virus and several tumoral cell lines, showing promising biological potential. In this review, we explore such approaches to 1,2,3-triazolyl-C-nucleosides and their evolution over the years.

Studies on the synthesis of 1'-CN-triazolyl-C-ribosides.

The search for broad-spectrum antiviral compounds is a continuous mandatory effort. The recent approval of the first C-nucleoside carrying a nitrile as a substituent at the C1' position of the ribose ring has raised interest in this underexplored substitution pattern. We have previously reported the development of different 1,2,3-triazolyl-C-ribonucleosides with anticancer and antiviral activities. Herein we report our results on the incorporation of a C1'-CN group in 1,2,3-triazolyl-C-ribonucleosides.

Anti-HCV and Zika activities of ribavirin C-nucleosides analogues.

Ribavirin is an unnatural nucleoside exhibiting broad spectrum of antiviral and antitumor activities, still very widely studied particularly in a repositioning approach. C-triazolyl nucleoside analogues of ribavirin have been synthesized, as well as prodrugs and glycosylated or peptide conjugates to allow a better activity by vectorization into the liver or by facilitating uptake into the cells. The antiviral properties of all synthesized compounds have been evaluated in vitro against two important human viral pathogens belonging to the Flaviviridae family: hepatitis C virus (HCV) and Zika virus (ZIKV). There are no therapeutic options for Zika virus, whereas those available for HCV can be still improved. Our results indicated that compound 2 carrying an N-hydroxy carboxamide function exhibits the most inhibitory activities against both viruses. This compound moderately inhibited the propagation of HCV with an IC50 value of 49.1 µM and Zika virus with an IC50 of 33.2 µM comparable to ribavirin in the Vero cell line. The results suggest that compound 2 and its new derivatives may be candidates for further development of new anti-HCV and anti-ZIKV antiviral drugs.

Emerging Organometallic Methods for the Synthesis of C-Branched (Hetero)aryl, Alkenyl, and Alkyl Glycosides: C-H Functionalization and Dual Photoredox Approaches.

Transition-metal-catalyzed C-H functionalization and photoredox nickel dual catalysis have emerged as innovative and powerful avenues for the synthesis of C-branched glycosides. These two concepts have been recently established and provide efficient and mild methods for accessing a series of valuable complex C-branched glycosides of great interest. Herein, recent developments in the synthesis of C-branched aryl/alkenyl/alkyl glycosides through these two approaches are highlighted.

Gold-catalyzed enantioselective functionalization of indoles.

Gold catalysis and indole chemistry are two mature and prolific fields. The gold-catalyzed functionalization of indoles has produced numerous results and paved the way for novel strategies in the building of molecular complexity. However - and curiously - though enantioselective gold catalysis is now a well-established field, it has been relatively little applied to the modification of indoles. This review highlights most of the enantioselective gold-catalyzed examples of the functionalization of indoles in order to emphasize the strengths and limitations of the method.

Access to C-aryl/alkenylglycosides by directed Pd-catalyzed C-H functionalisation of the anomeric position in glycal-type substrates.

Directed palladium-catalyzed C-H functionalisation of C2-amido glycals onto the anomeric position is described as a novel route to C-aryl/alkenylglycosides. An aminoquinoline-type directing group was used to successfully introduce diverse (hetero)aryl and alkenyl groups at position 1 of the sugar (20 examples). Its application to the synthesis of a dapagliflozin analogue is presented.

"CO" as a Carbon Bridge to Build Complex C2-Branched Glycosides Using a Palladium-Catalyzed Carbonylative Suzuki-Miyaura Reaction from 2-Iodoglycals.

Development of a palladium-catalyzed carbonylative Suzuki-Miyaura coupling reaction between 2-iodoglycal partners and diverse aryl- and alkenyl-boronic acids is presented, leading to original 2-ketoglycals. The newly formed carbonyl link could be exploited to access 2-aryl/alkenyl-methylene-α-glucopyranoside scaffolds via a three-step sequence including an indium-mediated Ferrier-type reaction.

Synthesis of C-pyrimidyl nucleosides starting from alkynyl ribofuranosides.

The synthesis of four C-pyrimidyl nucleosides is described by condensation of small nitrogen molecules (amidines and ureas) onto alkynyl riboside derivatives. These last compounds were obtained by indium mediated stereoselective alkynylation of suitably protected ribose derivatives and the condensation reaction conditions were studied in order to favor the N-attack of the nitrogen molecules leading to the pyrimidine ring formation.

Influence of the Headgroup of Azolium-Based Lipids on Their Biophysical Properties and Cytotoxicity.

A series of (un-)charged NHC derivatives bearing two pentadecyl chains in the backbone was studied in detail to find cooperative effects between the membrane and the NHC derivative. The tendency to show lipid-like behavior is dependent on the properties of the NHC derivative headgroup, which can be modified on demand. The surface activity was investigated by film balance measurements, epifluorescence microscopy, and differential scanning calorimetry. Additionally the cytotoxicity was evaluated against different cell lines such as eukaryotic tumor cell lines. These novel lipid-like NHC derivatives offer a broad spectrum for biological applications.

Access to Complex C2-Branched Glycoconjugates via Palladium-Catalyzed Aminocarbonylation Reaction of 2-Iodoglycals.

A convenient and straightforward synthesis of 2-amidoglycals through a palladium-catalyzed aminocarbonylation reaction between 2-iodoglycal partners and diverse amines in the presence of a "CO" source has been developed. Several amines such as aliphatics, benzylics, or aromatics are compatible with our reaction conditions as well as sulfonamides. Further deprotection steps have been successfully applied, leading to glycoside mimics. This method constitutes a new route to access original glycopeptide- and glycolipid-type analogues possessing a C-C bond at the C2-position.

When Phosphosugars Meet Gold: Synthesis and Catalytic Activities of Phostones and Polyhydroxylated Phosphonite Au(I) Complexes.

The synthesis and characterization of P-chiral phosphonite-, phosphonate- and thiophosphonate-Au(I) complexes are reported. These novel ligands for Au(I) are based on glycomimetic phosphorus scaffolds, obtained from the chiral pool. The catalytic activities of these complexes are shown in the cyclization of allenols and the hydroamination of 2-(2-propynyl)aniline combined with an organocatalyzed reduction to the corresponding 2-phenyl tetrahydroquinoline. All described gold complexes present excellent catalytic activities.

New Route to Stabilize Ruthenium Nanoparticles with Non-Isolable Chiral N-Heterocyclic Carbenes.

Ru nanoparticles (RuNPs) stabilized by non-isolable chiral N-heterocyclic carbenes (NHCs), namely SIDPhNp ((4S,5S)-1,3-di(naphthalen-1-yl)-4,5-diphenylimidazolidine) and SIPhOH ((S)-3-((1S,2R)-2-hydroxy-1,2-diphenylethyl)-1-((R)-2-hydroxy-1,2-diphenylethyl)-4,5-dihydro-3H-imidazoline), have been synthesized through a new procedure that does not require isolation of the free carbenes. The obtained RuNPs have been characterized by state-of-the-art techniques and their surface chemistry has been investigated by FTIR and solid-state MAS NMR upon the coordination of CO, which indicated the presence of free and reactive Ru sites. Their catalytic activity has been tested in various hydrogenation reactions involving competition between different sites, whereby interesting differences in selectivity were observed, but no enantioselectivity.

Heterogeneously catalyzed direct C-H thiolation of heteroarenes.

The first general methodology for the direct thiolation of electron-rich heteroarenes was developed by employing Pd/Al2 O3 , a recoverable and commercially available heterogeneous catalyst, and CuCl2 . This method represents an operationally simple approach for the synthesis of these valuable compounds. Preliminary mechanistic studies indicate a heterogeneous catalytic system, in which both metals play a complementary role in the formation of the thiolated products.

First enantioselective total synthesis and configurational assignments of suberosenone and suberosanone as potential antitumor agents.

The first enantioselective total syntheses of two marine sesquiterpenes (1R)-suberosenone and (1R)-suberosanone are achieved leading to revision of the AC of natural (1S)-suberosanone. Key elements of the synthesis include hyperbaric asymmetric Michael addition and highly efficient silver trifluoroacetate mediated α-alkylation for the formation of ring A.

Synthesis and evaluation of di- and trimeric hydroxylamine-based ß-(1→3)-glucan mimetics.

Di- and trimeric hydroxylamine-based mimetics of ß-(1→3)-glucans have been accessed by an asymmetric synthesis route featuring an iterative double ring-closing reductive amination reaction. These oligomeric hydroxylamines are demonstrated to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively, and to stimulate phagocytosis, all in a linkage-dependent manner suggestive of binding to the lectin domains of complement receptor 3 (CR3) and dectin-1. The ability of these relatively short mimetics to bind to CR3 and dectin-1, as compared to the greater degree of polymerization required in ß-(1→3)-glucans, is discussed in terms of the increased hydrophobicity of the α-face on replacement of the glycosidic bond by the hydroxylamine linkage.

Alternative synthesis of P-chiral phosphonite-borane complexes: application to the synthesis of phostone-phostone dimers.

An improved strategy for the synthesis of P-chiral gluco- and manno-phosphonite-borane complexes is described on the basis of the addition of diethyl phosphonite-borane to a glucal-derived aldehyde, followed by a cyclization coupled with an ethyl/methyl exchange. This direct P(III) strategy facilitates the obtention of various P-chiral phosphonite-boranes, of which further coupling reactions are described leading to the selective synthesis of two phostone dimers.

N-O bond as a glycosidic-bond surrogate: synthetic studies toward polyhydroxylated N-alkoxypiperidines.

A series of novel polyhydroxylated N-alkoxypiperidines has been synthesized by ring-closing double reductive amination (DRA) of highly functionalized 1,5-dialdehydes with various hydroxylamines. The required saccharide-based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two-step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3-deoxyisofagomine, and numerous other N-alkoxy analogues. The barrier to inversion in these polyhydroxylated N-alkoxypiperidine derivatives was found by variable-temperature NMR methods to be approximately 15 kcal mol(-1). With the exception of N-hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond ß-glucosidase.

Synthesis, characterization, and coupling reactions of six-membered cyclic P-chiral ammonium phosphonite-boranes; reactive H-phosphinate equivalents for the stereoselective synthesis of glycomimetics.

Stereoselective syntheses of P-chiral ammonium phosphonite-borane complexes in the gluco- and manno-like series have been developed from P(V) phostone derivatives. The coupling reactions of these phostone donors with alcohols have been investigated with particular emphasis on the influence of protecting groups and conditions on stereoselectivity. The phosphonite-borane complexes may be applied directly in the coupling reactions and the products oxidized in situ to give phostone-mimetics of disaccharides. On the basis of these studies, successful protocols were established for the synthesis of ß-gluco and α- and ß-manno-configured phostones of primary alcohols. Deprotection of the dimeric compounds leads to novel families of α- or ß-(1→6)-linked glycomimetics.