Electrochemistry represents one of the most intimate ways of interacting with molecules. This review discusses advances in synthetic organic electrochemistry since 2000. Enabling methods and synthetic applications are analyzed alongside innate advantages as well as future challenges of electroorganic chemistry.

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates

The preparation of urea by Wöhler constituted a landmark achievement in organic chemistry, and it laid the ground for the early days of target-oriented organic synthesis.1 Since then, significant progress has been achieved in this discipline; many powerful single bond forming reactions and asymmetric variants have been developed. These discoveries have paved the way for the stereoselective assembly of complex organic molecules, a task deemed inconceivable by early practitioners. A great many strategies were invented by chemists in order to facilitate the synthesis of complex natural products.2 One avenue in emulating nature’s efficiency would * To whom correspondence should be addressed. E-mail: dennis.hall@ ualberta.ca. † Novartis Institute for Biomedical Research. ‡ Department of Chemistry, University of Alberta. Chem. Rev. 2009, 109, 4439–4486 4439

Natural product synthesis using multicomponent reaction strategies.

The nature and characteristics of the CH/π interaction are discussed by comparison with other weak molecular forces such as the CH/O and OH/π interaction. The CH/π interaction is a kind of hydrogen bond operating between a soft acid CH and a soft base π-system (double and triple bonds, C6 and C5 aromatic rings, heteroaromatics, convex surfaces of fullerenes and nanotubes). The consequences of CH/π hydrogen bonds in supramolecular chemistry are reviewed on grounds of recent crystallographic findings and database analyses. The topics include intramolecular interactions, crystal packing (organic and organometallic compounds), host/guest complexes (cavity-type inclusion compounds of cyclodextrins and synthetic macrocyclic hosts such as calixarenes, catenanes, rotaxanes and pseudorotaxanes), lattice-inclusion type clathrates (including liquid crystals, porphyrin derivatives, cyclopentadienyl compounds and C60 fullerenes), enantioselective clathrate formation, catalytic enantioface discriminating reactions and solid-state photoreaction. The implications of the CH/π concept for crystal engineering and drug design are evident.

CH/π hydrogen bonds in crystals

Domino reactions have received great attention as efficient synthetic methodologies for the construction of structurally complex molecules from simple materials in a single operation. Catalysts in domino reactions have also been well studied. In these reactions, a catalyst activates the substrate(s) only once, and the structure of the product is delineated at that time. Recently, the new concept of "tandem catalysis" in domino reactions, in which catalyst(s) sequentially activate more than two mechanistically distinct reactions, has been proposed. Tandem catalysis is categorized into three subclasses: orthogonal-, auto-, and assisted-tandem catalyses. Auto-tandem catalysis is defined as a process in which one catalyst promotes more than two fundamentally different reactions in a single reactor. An overview of recent and significant achievements in auto-tandem catalysis is presented in this paper.

Auto-tandem catalysis: a single catalyst activating mechanistically distinct reactions in a single reactor.

Nonenzymatic Kinetic Resolution of Racemic Alcohols through an “Induced Fit” Process

Tf2NH, an organic acid, efficiently catalyzes (2 + 2) cycloaddition reactions of silyl enol ethers with acrylates or propiolate. The process affords highly substituted cyclobutanes in high yield with high stereoselectivity under practical and environmentally benign conditions. Application for the formation of terpene skeletons and multigram synthesis of four-membered carbocycles were demonstrated.

A practical catalytic method for preparing highly substituted cyclobutanes and cyclobutenes.

The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.

Enhanced rate and selectivity by carboxylate salt as a basic cocatalyst in chiral N-heterocyclic carbene-catalyzed asymmetric acylation of secondary alcohols.

We demonstrated a catalytic cascade inverse electron demand hetero-Diels−Alder reaction (Povarov reaction) and hydrogen-transfer process. The reaction of electron-rich olefins and excess amount of imines in the presence of acid catalysts under appropriate conditions affords substituted quinolines in a single operation. In the cascade process, the catalysts, such as Tf2NH, TfOH, and Lewis acids, catalyze two mechanistically distinct reactions (auto-tandem catalysis). We also describe the synthetic utility of the prepared quinolines.

Kiyosei Takasu

Papers

Auto-tandem catalysis: a single catalyst activating mechanistically distinct reactions in a single reactor.

Nonenzymatic Kinetic Resolution of Racemic Alcohols through an “Induced Fit” Process

A practical catalytic method for preparing highly substituted cyclobutanes and cyclobutenes.

Enhanced rate and selectivity by carboxylate salt as a basic cocatalyst in chiral N-heterocyclic carbene-catalyzed asymmetric acylation of secondary alcohols.

Auto-Tandem Catalysis in the Synthesis of Substituted Quinolines from Aldimines and Electron-Rich Olefins : Cascade Povarov-Hydrogen-Transfer Reaction