Iron-Catalyzed Intermolecular Oxyamination of Terminal Alkenes Promoted by HFIP Using Hydroxylamine Derivatives.

An atom-economical intermolecular iron-catalyzed oxyamination of alkenes is described herein. The insertion of oxygenated and nitrogenated moieties from the hydroxylamine substrate was observed with full regio- and chemo-selectivity for terminal alkenes in good yields. HFIP as a solvent appeared to have a synergistic effect with the iron catalyst to promote the formation of the oxyaminated products.

New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.

C407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein.

Modulators of CFTR. Updates on clinical development and future directions.

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival.

Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1-pyrazole-5-carboxylate as an HIV-1 replication inhibitor.

Inspired by the antiviral activity of known pyrazole-based HIV inhibitors, we screened our in-house library of pyrazole-based compounds to evaluate their activity against HIV-1 replication. Two hits with very similar structures appeared from single and multiple-round infection assays to be non-toxic and active in a dose-dependent manner. Chemical expansion of their series allowed an in-depth and consistent structure-activity-relationship study (SAR) to be built.

Access to Functionalized Imidazolidin-2-one Derivatives by Iron-Catalyzed Oxyamination of Alkenes.

Functionalized imidazolidin-2-one were prepared by using an iron-catalyzed alkene oxyamination reaction. Hydroxylamine derivatives were used in this atom-economical process, and the addition of an external oxidant was not required. The conditions developed were shown to be efficient for mono-, di-, and trisubstituted double bonds, and a large scope of diamino alcohol precursors were delivered in good yields with good diastereoselectivities.

Reductive Cleavage of Aromatic and Heteroaromatic Ester Functions via Copper-Catalyzed Proto-Decarbomethoxylation.

An unprecedented catalytic reductive cleavage of aromatic and heteroaromatic methyl ester functions was successfully achieved with a cheap, nontoxic, and air-stable Cu(OAc) catalyst. This reaction is fast, features good functional group tolerance, does not require inert atmosphere or anhydrous solvent, and can be scaled up to 1 g. Moreover, carboxylic acids and t-butyl esters also reacted smoothly under these conditions.

Development of a One-Pot Four C-C Bond-Forming Sequence Based on Palladium/Ruthenium Tandem Catalysis.

A one-pot four C-C bond-forming sequence has been developed using two distinct transition metal complexes. The sequence entails a double Pd-catalyzed allylic alkylation followed by a Ru-catalyzed ring-closing metathesis and a Pd-catalyzed Heck coupling. The use of various active methylene nucleophiles was examined with yields up to 76% (93% per C-C bond).

Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3).

Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II.

Synthesis of γ-lactams and γ-lactones via intramolecular Pd-catalyzed allylic alkylations.

CONSPECTUS: Lactones and lactams are a well-known class of natural products and can be used as building blocks in organic synthesis. In addition, they can be found in many natural sources and synthetic drugs and have a broad range of biological or odorant properties. Chemists can create these useful compounds through palladium catalysis, which is a highly efficient tool for organic synthesis and is conveniently functional group tolerant.

Microwave-assisted preparation of 4-amino-3-cyano-5-methoxycarbonyl-N-arylpyrazoles as building blocks for the diversity-oriented synthesis of pyrazole-based polycyclic scaffolds.

The synthesis of 4-amino-3-cyano-N-arylpyrazoles A based on a Thorpe-Ziegler cyclization as the key step has been achieved using microwave activation. Via a new diversity-oriented synthetic pathway, these highly functionalized building blocks allowed the access to various heteroaromatic scaffolds such as pyrazolo-pyridines B, pyrazolo-pyrimidines C and pyrazolo-oxadiazoles D. Interestingly, these platforms contain three to four reactive sites that could be used for post-functionalization in order to further increase the molecular diversity.

Dormant versus evolving aminopalladated intermediates: toward a unified mechanistic scenario in Pd(II)-catalyzed aminations.

Pd(II)-catalyzed alkene aminopalladation and allylic C-H activation are two competing reaction sequences sharing the same reaction conditions. This study aimed at understanding the factors that bias one or the other path in the intramolecular oxidative cyclization of two types of N-tosyl amidoalkenes. The results obtained are in accord with the initial generation of a high-energy cyclic (5- or 6-membered) aminopalladated intermediate.

Pd-catalyzed domino carbonylative-decarboxylative allylation: an easy and selective monoallylation of ketones.

In the presence of an allyl alcohol, α-chloroacetophenones undergo an allyloxycarbonylation reaction followed by in situ decarboxylative allylation to selectively afford the corresponding monoallylated ketones via a Pd-catalyzed domino sequence. The scope of the reaction was extended to substituted α-chloroacetophenones as well as various allyl alcohols.

Functionalized 2,3-dihydrofurans via palladium-catalyzed oxyarylation of α-allyl-β-ketoesters.

The palladium-catalyzed reaction of (hetero)aryl bromides, chlorides, and nonaflates with α-allyl-β-ketoesters provides ready efficient access to functionalized 2,3-dihydrofurans. The reaction tolerates several useful substituents including chloro, fluoro, ether, ketone, ester, cyano, and nitro groups.

Cavitand supported tetraphosphine: cyclodextrin offers a useful platform for Suzuki-Miyaura cross-coupling.

The cyclodextrin-tetraphosphine hybrid coined α-Cytep allows turnover numbers up to 340,000,000,000 and turnover frequencies up to 1,000,000,000 h(-1) to be reached in Suzuki-Miyaura reactions. These exceptional figures are clearly linked to the outstanding longevity of the reactive species induced by the ligand α-Cytep and illustrates the rising potential of cyclodextrins in catalytic applications.

γ- and δ-lactams through palladium-catalyzed intramolecular allylic alkylation: enantioselective synthesis, NMR Investigation, and DFT rationalization.

The Pd-catalyzed intramolecular allylic alkylation of unsaturated amides to give γ- and δ-lactams has been studied in the presence of chiral ligands. Ligand (R)-3,5-tBu-MeOBIPHEP (MeOBIPHEP = 6,6'-dimethoxybiphenyl-2,2-diyl)bis(diphenylphosphine)) afforded the best results and allowed the cyclization reactions to take place in up to 94:6 enantiomeric ratio. A model Pd-allyl complex has been prepared and studied through NMR spectroscopic analysis, which provided insight into the processes responsible for the observed enantiomeric ratios.

Aryl sulfoxides from allyl sulfoxides via [2,3]-sigmatropic rearrangement and domino Pd-catalyzed generation/arylation of sulfenate anions.

Allylic sulfoxides, via [2,3]-sigmatropic rearrangement and oxidative addition of the resulting allylic sulfenate esters to Pd(0), are found to be excellent precursors of sulfenate anions. This hitherto unknown reactivity is applied in a new Pd(0)-catalyzed domino sequence involving sulfenate anion generation followed by arylation to afford aryl sulfoxides.

A new cross-coupling-based synthesis of carpanone.

Carpanone has been stereoselectively synthesized in 55% yield and six steps from sesamol. The key step of the synthetic sequence is the direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II)-catalyzed oxidative coupling yields carpanone as a single diastereoisomer independently of the geometric configuration of the starting precursor.

Phosphine-free palladium-catalyzed allene carbopalladation/allylic alkylation domino sequence: a new route to 4-(alpha-styryl) gamma-lactams.

Free to decide: Various 4-(alpha-styryl) gamma-lactams are synthesized in 61-88% yield by a phosphine-free palladium-catalyzed carbopalladation/allylic alkylation domino sequence (see scheme). The cyclization is totally regio- and diastereoselective in favor of the 3,4-trans-disubstituted gamma-lactam. The process is successfully applied to the synthesis of a new aza analogue of the naturally occurring lignan (+)-oxo-parabenzlactone.

New picropodophyllin analogs via palladium-catalyzed allylic alkylation-Hiyama cross-coupling sequences.

Unsaturated malonyl esters underwent Pd-catalyzed intramolecular allylic alkylation to give 4-vinyl-substituted gamma-lactones. In contrast to the formerly studied cyclization of malonamides, this reaction could be achieved only with a substrate incorporating a suitably positioned silicon moiety, which directs the ionization toward the desired eta(3)-allylpalladium complex. The resulting 4-[dimethyl-(2-thienyl)silylvinyl]lactone could be subsequently engaged into Hiyama couplings with various iodoarenes, to give the corresponding 4-(alpha-styryl)-gamma-lactones.