Deoxygenative radical cross-coupling of C(sp3)-O/C(sp3)-H bonds promoted by hydrogen-bond interaction.

Building C(sp3)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp3)-H and C(sp3)-O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form C(sp3)-C(sp3) bonds is rarely explored in existing literature. Conventional methods for forming C(sp3)-C(sp3) bonds via radical-radical coupling pathways often suffer from poor selectivity, severely limiting their practicality in synthetic applications. In this study, we present a single electron transfer (SET) strategy that enables the cleavage of amine α-C - H bonds and heterobenzylic C - O bonds to form C(sp3)-C(sp3) bonds. Preliminary mechanistic studies reveal a hydrogen bond interaction between substrates and phosphoric acid facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

Convergent Synthesis of (R)-Silodosin via Decarboxylative Cross-Coupling.

A new approach to Silodosin capitalizing on a radical retrosynthetic strategy to dissect the molecule into two halves is reported. Using a reductive decarboxylative cross-coupling, a simple indoline can be coupled to a chiral pool-derived fragment to arrive at the target in only seven steps (LLS). This route avoids the use of resolution strategies or asymmetric hydrogenation that requires a subsequent Curtius rearrangement to install a key amino functionality.

Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents.

This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.

Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Redox-Active Esters in Fe-Catalyzed C-C Coupling.

Cross-couplings of alkyl halides and organometallic species based on single electron transfer using Ni and Fe catalyst systems have been studied extensively, and separately, for decades. Here we demonstrate the first couplings of redox-active esters (both isolated and derived in situ from carboxylic acids) with organozinc and organomagnesium species using an Fe-based catalyst system originally developed for alkyl halides. This work is placed in context by showing a direct comparison with a Ni catalyst for >40 examples spanning a range of primary, secondary, and tertiary substrates. This new C-C coupling is scalable and sustainable, and it exhibits a number of clear advantages in several cases over its Ni-based counterpart.

Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids.

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross-coupling between alkyl-carboxylic acids and boronic acids is described. This Ni-catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox-active ester derivatives, specifically N-hydroxy-tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl2 ⋅6 H2 O-$9.5 mol(-1) , Et3 N) coupled to the virtually unlimited commercial catalog of available starting materials bodes well for its rapid adoption.

Pd-catalyzed highly regio-, diastereo-, and enantioselective allylic alkylation of α-fluorophosphonates.

Highly efficient Pd-catalyzed asymmetric allylic alkylation reaction of ethyl-2-fluoro-2-(diethoxyphosphoryl)acetate with monosubstituted allylic substrates has been developed, affording corresponding α-fluorophosphonates with two chiral centers in high regio-, diastereo- and enantio-selectivities. The usefulness of the products in organic synthesis has been demonstrated.