Selective construction of alkaloid scaffolds by alcohol-based direct and mild aerobic oxidative Pictet–Spengler reactions

Abstract

Employing TBN/TEMPO as the catalysts and oxygen as the oxidant, the biologically and pharmaceutically significant tetrahydro-β-carboline and β-carboline alkaloid scaffolds that used to be obtained by multi-step processes can now be selectively obtained in only one-step via direct aerobic oxidative Pictet–Spengler reactions of tryptamines with alcohols under mild conditions, with water generated as the byproduct. In this reaction, TBN/TEMPO was interestingly found to be able to facilitate the cyclization step of the whole reaction. This method tolerates a variety of C- and N-substituted tryptamines, and both the more reactive benzylic and allylic alcohols and the less reactive aliphatic alcohols. This method can also be extended to dihydro-β-carboline synthesis and applied to the more available and more economical tryptophan for β-carboline synthesis, revealing its broad substrate scope and potential in synthetic applications.