Kosuke Yamamoto

ConspectusStereodefined aliphatic heterocycles are one of the fundamental structural motifs observed in natural products and biologically active compounds. Various strategies for the synthesis of these building blocks based on transition metal catalysis, organocatalysis, and noncatalytic conditions have been developed. Although electrosynthesis has also been utilized for the functionalization of aliphatic heterocycles, stereoselective transformations under electrochemical conditions are still a challenging field in electroorganic chemistry.This Account consists of four main topics related to our recent efforts on the diastereo- and/or enantioselective synthesis of aliphatic heterocycles, especially N-heterocycles, using anodic oxidations as key steps. The first topic is the development of stereoselective synthetic methods for multisubstituted piperidines and pyrrolidines from anodically prepared α-methoxy cyclic amines. Our strategies were based primarily on N-acyliminium ion chemistry, and the key electrochemical transformations were diastereoselective anodic methoxylation, diastereoselective arylation, and anodic deallylative methoxylation. Furthermore, we found a unique property of the N-cyano protecting group that enabled the electrochemical α-methoxylation of α-substituted cyclic amines. The second topic of investigation is memory of chirality in electrochemical decarboxylative methoxylation. We observed that the electrochemical decarboxylative methoxylation of oxazolidine and thiazolidine derivatives with the appropriate N-protecting group occurred in a stereospecific manner even though the reaction proceeded through an sp2 planar carbon center. Our findings demonstrated the first example of memory of chirality in N-acyliminium ion chemistry. The third topic is the synthesis of chiral azabicyclo-N-oxyls and their application to chiral organocatalysis in the electrochemical oxidative kinetic resolution of secondary alcohols. The final topic is stereoselective transformations utilizing anodically generated halogen cations. We investigated the oxidative kinetic resolution of amino alcohol derivatives using anodically generated bromo cations. We also developed an intramolecular C–C bond formation of keto amides, a diastereoselective bromoiminolactonization of α-allyl malonamides, and an oxidative ring expansion reaction of allyl alcohols. It is noteworthy that most of the electrochemical reactions were performed in undivided cells under constant-current conditions, which avoided a complicated reaction setup and was beneficial for a large-scale reaction. In addition, we developed some enantioselective electrochemical transformations that are still challenges in electroorganic chemistry. We hope that our research will contribute to the further development of diastereo- and/or enantioselective transformations and the construction of valuable heterocyclic compounds using an electrochemical approach.

Ruthenium-catalyzed C-H functionalization was successfully combined with palladium-catalyzed asymmetric allylic alkylation in one pot. The novel dual-metal-catalyzed reaction provides a variety of 3-allyl-3-aryl oxindoles from the corresponding α-diazoamides in up to 99% yield with up to 85% ee. The appropriate ligand choice is important to promote the sequential reaction, avoiding undesired metal interaction or ligand exchange.

[5]Helicenes with a substituent exclusively oriented toward the interior curvature of the helix are synthesized by metal-catalyzed cycloisomerization. In addition, novel azulene-fused helicenes have been found through cycloisomerization studies. These [5]helicenes shows a high enough configurationally stability to allow resolution by HPLC on a chiral stationary phase.

A multicomponent multicatalyst reaction (MC)(2)R for constructing fully substituted 1,2,3-triazoles is reported. An application of chemoselectivity and latent catalysis in a sequence of multicatalytic reactions confers control over a number of undesired processes, where all of the reagents coexist in the same reaction vessel. The sequence of a chemoselective copper-catalyzed azide alkyne cycloaddition followed by a palladium/copper-catalyzed Sonogashira cross-coupling afforded 1,2,3-triazoles regioselectively with good to high yields and a broad scope.

A series of novel optically active [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure- and L2, with a fully aromatic [5]helicene core structure) were synthesized. Despite their structural similarities, L1 and L2 exhibit particularly different characteristics in their use as chiral ligands. L1 was highly effective in the asymmetric allylation of indoles with 1,3-diphenylallyl acetate (up to 99% ee), and in the etherification of alcohols (up to 96% ee). In contrast, L2 was highly effective in the stereocontrol of helical chirality in Suzuki-Miyaura coupling (SMC) reaction (up to 99% ee). Density functional theory analysis was employed to propose a model that accounts for the origin of the enantioselectivity in these reactions.