Methodology in organic synthesis

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

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

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

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.

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

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.

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

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.

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

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.

Graphical abstract : 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

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 (ελmax ~ 80000 M-1 cm-1) and for most of them high fluorescence quantum yields (Φexp 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.

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