Diastereoselective Synthesis of (±)-Deethyleburnamonine Using a Catalytic Cyclopropane Ring-Opening / Friedel-Crafts Alkylation Strategy

Abstract

A short, diastereoselective synthesis of (±)-deethyleburnamonine is reported with an overall yield of ~18% over six steps.The key synthetic step involves an indium(III)-catalyzed tandem ring-opening/Friedel-Crafts alkylation of a donor-acceptor-acceptor amino cyclopropane to generate the ABDE portion of the target.The eburnan 1 alkaloids and the structurally-related tacaman 2 alkaloids represent a large group of biologically-active, naturally-occurring indole alkaloids that are isolated from several plants of the Apocyanaceae and Tabernaemontana genera (Figure 1).Each member of the eburnan and tacaman families is characterized by a common pentacyclic framework (1) that contains either a cis-or trans-fused D/E ring system. 3While the vast majority of compounds have a cis-fused D/E ring system, several important biologically-active derivatives, such as vindeburnol (2), possess a trans-fused junction.The eburnan skeleton has an ethyl group at C(20), while the tacaman skeleton has the ethyl group at C( 14) instead. 4Many of these compounds exhibit a variety of pharmacological activities, ranging from antitumor activity to muscle-stimulating activity. 5Over the past 10 years, numerous efforts to fully understand the compounds' modulatory effects on brain circulation and neuronal homeostasis have been reported. 6For example, vincamine (3) has been shown to have neuroprotective effects resulting from the blockage of voltage-gated sodium ion channels.Similarly, vinpocetine (5), the most extensively studied cogener of the eburnan class, is currently prescribed in Europe (tradename: Cavinton) for the treatment of disorders arising from cerebrovascular and cerebral neurodegenerative diseases. 7This therapeutic potential has led to intense pharmacological and synthetic studies over the past several decades. 8