Iron-Catalyzed Reductive Cyclization by Hydromagnesiation: A Modular Strategy Towards N-Heterocycles.

A reductive cyclization to prepare a variety of N-heterocycles, through the use of ortho-vinylanilides, is reported. The reaction is catalyzed by an inexpensive and bench-stable iron complex and generally occurs at ambient temperature. The transformation likely proceeds through hydromagnesiation of the vinyl group, and trapping of the in situ generated benzylic anion by an intramolecular electrophile to form the heterocycle. This iron-catalyzed strategy was shown to be broadly applicable and was utilized in the synthesis of substituted indoles, oxindoles and tetrahydrobenzoazepinoindolone derivatives. Mechanistic studies indicated that the reversibility of the hydride transfer step depends on the reactivity of the tethered electrophile. The synthetic utility of our approach was further demonstrated by the formal synthesis of a reported bioactive compound and a family of natural products.

One-Pot, Three-Step Synthesis of Benzoxazinones via Use of the Bpin Group as a Masked Nucleophile.

The utilization of the Bpin group as a pronucleophile to facilitate the assembly of cyclic carbamates has been achieved. This one-pot process involves an initial copper-catalyzed borylation, a subsequent C-B bond oxidation to generate the reactive alcohol intermediate, and a cyclization. We report the use of this efficient, scalable, and simple method toward the synthesis of a wide range of benzoxazinone scaffolds, including enantioselective results. Subsequent transformations into useful scaffolds showcase the utility of this strategy.

Enantio- and diastereoselective conjugate borylation/Mannich cyclization.

Strategies to capitalize on enolate intermediates generated from stereoselective conjugate borylation to α,ß-unsaturated carbonyl systems are surprisingly rare despite the ubiquity of Michael acceptors, and the potential to generate valuable scaffolds bearing multiple stereocenters. Herein, we report a mild and stereoselective copper-catalyzed conjugate borylation/Mannich cyclization reaction. This strategy is feasible with a broad range of Michael acceptors, and can be leveraged to generate versatile borylated tetrahydroquinoline scaffolds bearing three contiguous stereocenters. The synthetic potential of these complex heterocycles has been explored through a series of derivatization studies.

Enantioselective C-H Activation with Earth-Abundant 3d Transition Metals.

Molecular syntheses largely rely on time- and labour-intensive prefunctionalization strategies. In contrast, C-H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C-H bonds has emerged as a transformative tool for the step- and atom-economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C-H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C-H activation by 3d base metals up to April 2019.

Mössbauer and mass spectrometry support for iron(ii) catalysts in enantioselective C-H activation.

A combination of electrospray-ionization mass spectrometry and Mössbauer spectroscopy was used to investigate the species generated in situ in highly enantioselective Fe/NHC-catalyzed C-H alkylations. The findings indicate an organometallic iron(ii)-NHC species to be of key relevance in the asymmetric catalysis.

Enantioselective Aluminum-Free Alkene Hydroarylations through C-H Activation by a Chiral Nickel/JoSPOphos Manifold.

Highly enantioselective nickel-catalyzed alkene endo-hydroarylations were accomplished with full selectivity by organometallic C-H activation. The asymmetric assembly of chiral six-membered scaffolds proved viable in the absence of pyrophoric organoaluminum reagents within an unprecedented nickel/JoSPOphos manifold.

Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors.

The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity.

Asymmetric Iron-Catalyzed C-H Alkylation Enabled by Remote Ligand meta-Substitution.

Highly enantioselective iron-catalyzed C-H alkylations by inner-sphere C-H activation were accomplished with ample scope. High levels of enantiocontrol proved viable through a novel ligand design that exploits a remote meta-substitution on N-heterocyclic carbenes within a facile ligand-to-ligand H-transfer C-H cleavage.

Catalytic Friedel-Crafts reaction of aminocyclopropanes.

A Lewis acid catalyzed Friedel-Crafts reaction between donor-acceptor aminocyclopropanes and indoles and other electron-rich aromatic compounds is reported. Indole alkylation at the C3 position was generally obtained for a broad range of functional groups and substitution patterns. In the case of C3-substituted indoles, C2 alkylation was observed. The reaction gives a rapid access to gamma amino acid derivatives present in numerous bioactive molecules.