Total Synthesis of Dragocins A-C through Electrochemical Cyclization.

The first total synthesis of dragocins A-C, remarkable natural products containing an unusual C4' oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C-H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful.

Scalable Electrochemical Decarboxylative Olefination Driven by Alternating Polarity.

A mild, scalable (kg) metal-free electrochemical decarboxylation of alkyl carboxylic acids to olefins is disclosed. Numerous applications are presented wherein this transformation can simplify alkene synthesis and provide alternative synthetic access to valuable olefins from simple carboxylic acid feedstocks. This robust method relies on alternating polarity to maintain the quality of the electrode surface and local pH, providing a deeper understanding of the Hofer-Moest process with unprecedented chemoselectivity.

General electrochemical Minisci alkylation of N-heteroarenes with alkyl halides.

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of N-heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors. Primary, secondary and tertiary alkyl radicals have been shown to be efficiently generated and coupled with a large variety of N-heteroarenes. The method presents a very high functional group tolerance, including various heterocyclic-based natural products, which highlights the robustness of the methodology. This applicability has been further proved in the synthesis of various interesting biologically valuable building blocks. In addition, we have proposed a mechanism based on different proofs and pieces of electrochemical evidence.

Unlocking the direct photocatalytic difluoromethylation of C[double bond, length as m-dash]N bonds.

The current study presents a direct CF2H radical addition to C[double bond, length as m-dash]N bonds predicated on the photocatalytic activation of commercially available zinc difluoromethanesulfinate. The mild conditions in place lead to impressive structural diversity, as quinoxalinones and dibenzazepines, among others, are successfully functionalized.

Intramolecular Homolytic Substitution Enabled by Photoredox Catalysis: Sulfur, Phosphorus, and Silicon Heterocycle Synthesis from Aryl Halides.

Aryl radical generation and manipulation constitutes a long-standing challenge in organic synthesis. Photocatalytic single-electron reduction of aryl halides has been established as a premier activation pathway to reach these intermediates. The current study integrates the conceptual simplicity of the classical intramolecular homolytic substitution with the practicality of the modern photocatalytic approach. Predicated on an efficient metal-free dehalogenation of aryl halides under mild organo-photoredox conditions, sulfur, phosphorus, and silicon heteroatoms capture the C(sp2)-centered radical in an intramolecular fashion.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

A General Amino Acid Synthesis Enabled by Innate Radical Cross-Coupling.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

Development and Application of Asymmetric Organocatalytic Mukaiyama and Vinylogous Mukaiyama-Type Reactions.

Organocatalysis is a growing area that is benefiting from advances in many fields. Its implementation has begun in areas such as supramolecular chemistry, organic chemistry and natural product synthesis. While a considerable number of important publications in the field of organocatalytic Mukaiyama-type additions have been reported, they are yet to be fully covered in a review. Therefore, we would like to highlight the applications of various kinds of organocatalysts in Mukaiyama-type reactions, while also including the vinylogous Mukaiyama variation. Herein we describe and discuss the development and current state of the art of the organocatalytic Mukaiyama reaction, vinylogous Mukaiyama and related reactions.

Intramolecular hydrogen-bond activation for the addition of nucleophilic imines: 2-hydroxybenzophenone as a chemical auxiliary.

The addition of nucleophilic imines, using 2-hydroxybenzophenone as a chemical auxiliary, is presented. An intramolecular six-membered ring via hydrogen bonding that enhances the reactivity and selectivity is the key of this strategy, which is supported by DFT calculations and experimental trials.

Asymmetric radical alkylation of N-sulfinimines under visible light photocatalytic conditions.

In this communication, a new photocatalytic strategy for the addition of alkyl-radical derivatives to N-sulfinimines with complete diastereoselectivity and moderate to good yields is presented. This is the first asymmetric photocatalytic addition to N-sulfinimines under visible light irradiation with smooth conditions and functional group tolerance.