Tetrahydro-β-carbolines (THBC) and 1,4-diazocycles are important structural motifs in various alkaloid natural products. For example, a potential THBC drug candidates includes etodolac, a nonsteroidal anti-inflammatory drug and in 1,4-diazacycle includes homofenazine, an anti-psychotic drug. We have developed synthetic methods to produce these compounds from abundant resources via hydrogen-borrowing N-alkylation cascade reactions, which are green, atom economical, and cost effective. Developing a tandem amination/Pictet-Spengler (PSR) reaction in which we combine a PSR with a hydrogen-borrowing amination strategy is conceptually similar to the route through nature uses to assemble the indole alkaloids. Such a strategy has an intrinsic problem: PSR cyclization necessitates an acid catalyst; whereas hydrogen borrowing catalysts rely on strong base to activate alcohols for β-hydride elimination. Resolving this dilemma, our group introduced a base free (pyridyl)phosphine-ligated ruthenium (II) catalyst ([(η6-cymene)RuCl(PyCH2PBu2t)]OTf) that enables the tandem amination-PSR by combining base-free amination with a Lewis acid-promoted PSR. This way we successfully synthesized a tetracyclic alkaloid harmicine. We have also employed this catalyst for diol-diamine coupling to produce small molecule drugs like cyclizine and homochlorcyclizine via two hydrogen- borrwing amine alkylation.

Synthesis of bioactive N-heterocycles by hydrogen-borrowing catalysis

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.