Synthèse organique

De très nombreuses cibles biologiques restent encore orphelines (une centaine de RCPG), c'est-à-dire dépourvues de ligands permettant d’en explorer les diverses fonctions. La communauté scientifique et l’industrie pharmaceutique estiment encore nécessaire d’étendre la diversité et le nombre de molécules pouvant potentiellement interférer avec ces systèmes. L’objectif de la thématique est de concevoir sur des bases rationnelles des motifs structuraux originaux potentiellement porteurs d’activité (« Diversophores »), de mettre au point leur synthèse et de démontrer que l’on peut produire des chimiothèques dérivées (« Diversothèques ») originales, génériques ou ciblées, en solution ou sur support solide.

Versatile Synthetic Approach for Selective Diversification of Bicyclic Aza-Diketopiperazines

ACS Omega, 2018, 3 (11), pp 15182–15192

Herein, we report a convenient synthesis of unprecedented aza-diketopiperazines (aza-DKPs). The strategy is based on selective diversification of bicyclic aza-DKP scaffolds by click reaction, N-acylation, and/or N-alkylation. These scaffolds containing either azido or amino groups were obtained by a key Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation reaction of allyl-substituted aza-DKP. The methodology is readily amenable to the parallel synthesis of original aza-DKPs to enlarge the chemical diversity of aza-heterocycles.

A Comparative Study of the Synthesis, Structural and Physicochemical Properties of Diketopiperazines vs Aza-Diketopiperazines

J. Org. Chem., 2017, DOI: 10.1021/acs.joc.6b02895

Aza-diketopiperazines (aza-DKPs) represent an underprivileged motif obtained by scaffold hopping of 2,5-diketopiperazines (2,5-DKPs). Herein, we compare the synthesis and the structural and physicochemical properties of aza-DKP vs 2,5-DKK. Thus, X-ray and ¹H NMR studies show that aza-DKP is a rigid and nonflat scaffold like the 2,5-DKP. Moreover, the replacement of one Cα-stereogenic center by a nitrogen atom results in a significant improvement of both the water solubility and the microsomal stability.

A Step-Economical Multicomponent Synthesis of 3D-Shaped Aza-Diketopiperazines and Their Drug-like Chemical Space Analysis

Org. Biomol. Chem., 2016, 14, 8859-8863.

A rapid and atom economy multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(I)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, the analysis of their 3D molecular descriptors and “drug-likeness” properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential in medicinal chemistry

Diastereoselective Synthesis of Novel Aza-diketopiperazines via a Domino Cyclohydrocarbonylation/Addition Process

Chem. Commun., 2014, 50, 9657-9660.

Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino-acids. The strategy is based on a Rh(I)-catalyzed hydroformylative cyclohydro-carbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry.

Combinatorial Aid for Underprivileged Scaffolds: Solution and Solid-phase Strategies for a Rapid and Efficient Access To Novel Aza-diketopiperazines (Aza-DKP)

ACS Comb. Sci., 2012, 14, 323-334

An efficient solution-phase synthesis of aza-diketopiperazines (aza-DKP, triazinediones) is reported. A structurally diverse collection of c-[aza-alkylGly-Pro] derivatives and yet unreported 2,4,5-trisubstituted-1,2,4-triazine-3,6-diones has been synthesized starting from Fmoc-L-Pro-OH and various Fmoc-L-amino acids. To extend the practical value of this class of dipeptidomimetics, a general solid-phase synthesis approach amenable to library production was developed on both Wang-PS and HMBA-PS resins.

Preparation of a Pilot Library Derived from the 2,3,4,5-Tetrahydro-1H-benzo[b]azepin-5-amine Scaffold

J. Comb. Chem., 2007, 9, 487-500.

A convenient and reliable solid-phase strategy for the synthesis of di- and tri-substituted benzazepine derivatives was developed. 5-Amino-1-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine and 5-amino-1-tert-butoxycarbonyl-7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine GPCR-targeted scaffolds were efficiently synthesized in a six-step solution phase process, immobilized on the acid-labile FDMP-AM resin and further functionalized through acylation, sulfonation, reductive amination, alkylation, Suzuki or Buchwald-Hartwig cross coupling reactions. The efficacy of this strategy was exemplified by the preparation of an original pilot library of di- and tri-substituted benzazepines obtained in high purity as assessed by both ¹H NMR and LC/MS analysis.

Solid-phase organic tagging resins for labeling biomolecules by 1,3-dipolar cycloaddition: application to the synthesis of a fluorescent non-peptidic vasopressin receptor ligand.

Chem. Eur. J., 2008, 14, 6247-54.

“SPOrT” resins. Two novel “Solid Phase Organic Tagging” resins have been developed to facilitate the labelling of peptides and small organic compounds. The strategy has been successfully applied to the synthesis of the first non-peptidic fluorescent compound with nanomolar affinity for human vasopressin V₂ receptor subtype.

Convenient method to access new 4,4-dialkoxy- and 4,4-diaryloxy-diaza-s-indacene (BODIPY) dyes: Synthesis and spectroscopic evaluation

J. Org. Chem., 2007, 72, 269-272.

A straightforward method for the synthesis of original 4,4-dialkoxy or 4,4-diaryloxy-diaza-s-indacenes (BODIPY) derivatives obtained by treatment of BODIPY 1 with various alcohols in presence of AlCl₃ is described.The novel compounds are characterized by spectroscopic properties similar to those of the parent BODIPY 1, namely absorption and emission spectra with similar band shapes, high molar absorption coefficients (ε_λmax ~ 80000 M^-1 cm^-1) and for most of them high fluorescence quantum yields (Φ_exp from 0.52 to 0.71). Among all the new compounds synthesized, the dye 2h (R = 4-NO₂Ph) exhibits higher fluorescence quantum yield (0.71) and lifetime (4.09 ns) than compound 1 and a good chemical stability towards conditions compatible with biological cell-based assays.