Directing Group-Free Formal Suzuki-Miyaura Coupling of Simple Ketones Enabled by Activation of Unstrained C-C Bonds.

The use of ketones as electrophiles to couple with arylboronic acid derivatives via C-C bond activation has become a significant progress in the area of Suzuki-Miyaura coupling (SMC) reaction, in which a permanent or temporary directing group is often required to promote the activation of the unstrained C-C bond via oxidative addition. Herein, we disclosed the first example of directing group free formal SMC reaction of simple ketones with arylboronates via Rh-catalyzed unstrained C-C bond activation. A wide range of simple ketones, including aryl alkyl ketones, diaryl ketones and aryl perfluoroalkyl ketones, can serve as electrophiles to participate in the SMC reaction with aryl or perfluoroalkyl as the leaving group. The key to the success of this reaction is by means of nucleophilic addition/ß-carbon elimination sequence that can activate the unstrained ketone carbonyl C-C bond without the assistance of directing group.

Copper-assisted synthesis of dihydropyrano[2.3-b]indole-4-ones by domino cascade reaction.

A novel copper-catalyzed cascade intermolecular and intramolecular oxidation/cyclization domino one-pot reaction process for the regioselective synthesis of dihydropyrano[2.3-b]indol-4(9H)-ones has been successfully developed. In this methodology, it is proposed for the first time that the 4-benzyloxy group of indole substrates can be used as a guiding group to promote cyclization under mild conditions. Meanwhile, reaction mechanism studies indicate that carbonyl oxygen in pyranoindole-4-ones came from water and the guiding group is critical to the progress of the reaction.

Rhodium Catalyzed Regioselective C-H Allylation of Simple Arenes via C-C Bond Activation of Gem-difluorinated Cyclopropanes.

Herein, we report a rhodium catalyzed directing-group free regioselective C-H allylation of simple arenes. Readily available gem-difluorinated cyclopropanes can be employed as highly reactive allyl surrogates via a sequence of C-C and C-F bond activation, providing allyl arene derivatives in good yields with high regioselectivity under mild conditions. The robust methodology enables facile late-stage functionalization of complex bioactive molecules. The high efficiency of this reaction is also demonstrated by the high turnover number (TON, up to 1700) of the rhodium catalyst on gram-scale experiments. Preliminary success on kinetic resolution of this transformation is achieved, providing a promising access to enantio-enriched gem-difluorinated cyclopropanes.

Novel one-pot synthesis of imidazolinones from esters: a concise synthesis of GSK2137305.

A new copper-catalyzed one-pot reaction resulted in the practical synthesis of imidazolinones in moderate yields from esters. The use of inexpensive copper iodide as the catalyst, (NH4)2CO3 as the nitrogen source and readily available starting materials makes this process economically viable. Applying this protocol to the synthesis of GSK2137305, a concise approach was developed to obtain GSK2137305 from the ester in only three steps with an overall yield of 26.9%.

Intramolecular One-Carbon Homologation of Unstrained Ketones via C-C Activation-Enabled 1,1-Insertion of Alkenes.

Here, we describe the development of a Rh-catalyzed intramolecular one-carbon homologation of unstrained aryl ketones through a formal 1,1-insertion process of olefins, enabled by temporary directing group (TDG)-aided C-C activation. The reaction provides a distinct approach to access various substituted 1-indanones. Computational mechanistic studies reveal that the formal 1,1-insertion is realized by a selective C(sp2)-C(sp3) activation and turnover limiting 2,1-insertion into the alkene, followed by a facile ß-H elimination and reinsertion process.

Novel synthesis of divergent aryl imidazoles from ketones involving copper-catalyzed α-amination and oxidative C-C bond cleavage.

A one-pot synthesis, initiated by a copper salt with inorganic (NH4)2CO3 as the nitrogen source, forms divergent aryl imidazole derivatives from ketones via α-amination and oxidative C-C bond cleavage reactions. The approach provides a simple and rapid synthesis of imidazole derivatives and has certain versatility.

Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism.

Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the structure of targeted proteins, HAT inhibitors are designed and modified for higher affinity and better bioactivity. However, there are still some challenges, such as cell permeability, selectivity, toxicity and synthetic availability, which limit the improvement of HAT inhibitors. So far, only few HAT inhibitors have been approved for commercialization, indicating the urgent need for more successful and effective structure-based drug design and synthetic strategies. Here, we summarized three classes of HAT inhibitors based on their sources and structural scaffolds, emphasizing on their synthetic methods and structure-activity relationships and molecular mechanisms, hoping to facilitate the development and further application of HAT inhibitors.

Deciphering the regulatory and catalytic mechanisms of an unusual SAM-dependent enzyme.

S-adenosyl-1-methionine (SAM)-dependent enzymes regulate various disease-related behaviors in all organisms. Recently, the leporin biosynthesis enzyme LepI, a SAM-dependent enzyme, was reported to catalyze pericyclic reactions in leporin biosynthesis; however, the mechanisms underlying LepI activation and catalysis remain unclear. This study aimed to investigate the molecular mechanisms of LepI. Here, we reported crystal structures of LepI bound to SAM/5'-deoxy-5'-(methylthio) adenosine (MTA), S-adenosyl-homocysteine (SAH), and SAM/substrate states. Structural and biochemical analysis revealed that MTA or SAH inhibited the enzyme activities, whereas SAM activated the enzyme. The analysis of the substrate-bound structure of LepI demonstrated that this enzymatic retro-Claisen rearrangement was primarily driven by three critical polar residues His133, Arg197, Arg295 around the active site and assisted by SAM with unclear mechanism. The present studies indicate that the unique mechanisms underlying regulatory and catalysis of the unusual SAM-dependent enzyme LepI, not only strengthening current understanding of the fundamentally biochemical catalysis, but also providing novel insights into the design of SAM-dependent enzyme-specific small molecules.