Selective Reductive Elimination at Alkyl Palladium(IV) by Dissociative Ligand Ionization: Catalytic C(sp3 )-H Amination to Azetidines.

A palladium(II)-catalyzed γ-C-H amination of cyclic alkyl amines to deliver highly substituted azetidines is reported. The use of a benziodoxole tosylate oxidant in combination with AgOAc was found to be crucial for controlling a selective reductive elimination pathway to the azetidines. The process is tolerant of a range of functional groups, including structural features derived from chiral α-amino alcohols, and leads to the diastereoselective formation of enantiopure azetidines.

Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction.

The Sondheimer dialkyne reagent has previously been employed in strain-promoted double-click cycloadditions with bis-azide peptides to generate stapled peptide inhibitors of protein-protein interactions. The substituted variants of the Sondheimer dialkyne can be used to generate functionalized stapled peptide inhibitors with improved biological properties; however, this remains a relatively underdeveloped field. Herein, we report the synthesis of new substituted variants of Sondheimer dialkyne and their application in the stapling of p53-based diazido peptides to generate potent stapled peptide-based inhibitors of the oncogenic p53-MDM2 interaction. The functionalized stapled peptide formed from a meta-fluoro-substituted Sondheimer dialkyne was found to be the most potent inhibitor. Furthermore, through experimental studies and density functional theory calculations, we investigated the impact of the substituent on the strain-promoted double-click reactivity of Sondheimer dialkyne.

Mechanistic investigation into the C(sp3)-H acetoxylation of morpholinones.

The study of a selective palladium(ii)-catalyzed C(sp3)-H acetoxylation reaction on a class of cyclic alkyl amines is reported. Computational modelling and kinetic studies were used to provide support for a mechanism involving selective C-O bond formation from a γ-aminoalkyl-Pd(iv) intermediate. The C-O bond forming step was computed to occur by a dissociative ionization mechanism followed by an SN2 process involving external acetate attack at the C-Pd(iv) bond. This pathway was computed to be of lowest energy with no competing C-N products observed. Additionally, with a few modifications to reaction conditions, preliminary studies showed that this process could be rendered enantioselective in the presence of a non-racemic BINOL-phosphoric acid.

An iron-catalysed C-C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks.

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.

Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy.

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

A general catalytic ß-C-H carbonylation of aliphatic amines to ß-lactams.

Methods for the synthesis and functionalization of amines are intrinsically important to a variety of chemical applications. We present a general carbon-hydrogen bond activation process that combines readily available aliphatic amines and the feedstock gas carbon monoxide to form synthetically versatile value-added amide products. The operationally straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium anhydride to transform aliphatic amines into ß-lactams. The reaction is successful with a wide range of secondary amines and can be used as a late-stage functionalization tactic to deliver advanced, highly functionalized amine products of utility for pharmaceutical research and other areas.