Anodic Oxidation for the Stereoselective Synthesis of Heterocycles

Abstract

Stereodefined 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 sp 2 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.

Making electrochemistry easily accessible to the synthetic chemist

“…The advantages of the setup employed will be discussed for each type of reaction. See the following reviews for specific transformations: cross coupling, [24][25][26] CH activation, [27][28][29][30][31][32][33][34][35][36] asymmetric synthesis, 14 heterocycle formation, [37][38][39] arylation, 40 fluorination, 41 organometallic catalysis, 42,43 cation pool method. 44 The different types of reactions can be summarised as: (1) direct electrochemical reaction with solvent degradation as counter reaction, (2) direct electrochemical reaction with nonsolvent degradation as counter reaction, (3) mediated or catalysed electrochemical reaction, (4) redox combined electrochemical reaction (Fig.…”

“…This tutorial review provides an introduction to electrochemistry and is not designed to be an extensive review of all synthetic electrochemical examples. For further information recent reviews and the references therein are recommended: certain transformations including cross coupling, [24][25][26] CH activation, [27][28][29][30][31][32][33][34][35][36] asymmetric synthesis, 14 heterocycle formation, [37][38][39] arylation, 40 fluorination, 41 organometallic catalysis, 42,43 cation pool method, 44 continuous reactor types, [45][46][47][48][49][50][51][52][53][54][55] analytical tools 56,57 and general reviews and perspectives. [1][2][3][4][5][6][7][8][9][10][11][12][13]…”

Dialling‐In New Reactivity into the Shono‐Type Anodic Oxidation Reaction

“…Building upon early results for low diastereoselectivity in the α‐alkoxylation reaction, [58–59] enantioselective Shono‐type cross‐coupling [60] and stereoselective synthesis of heterocycles [61] is rapidly gaining momentum and could be a game‐changing application of electrosynthesis in stereocontrolled synthesis.…”

Recent Advances in Paired Electrosynthesis

“…Gaseous hydrogen is not easily oxidised for example on carbon anodes (preventing shunt processes) and therefore acceptable as an easily separable and potentially valuable side product. In work for example by Onomura and coworkers, a wide range of heterocycle synthesis protocols have been developed based on this strategy [23] including “chiral memory effects” and for multi‐functional target molecules.…”