The Cephalotaxus alkaloids have been extensively studied as synthetic targets, due to the antileukemic activity of certain ester derivatives and the synthetically challenging core structure. Homoharringtonine, also known as omacetaxin mepesuccinate, has recently been approved as a treatment for chronic myeloid leukemia. However, despite these studies, only minimal modifications of the active natural product have been studied for activity, and synthetic variation has only been performed on the ester side chain. This proposal describes a detailed strategy for the synthesis of the core cephalotaxine scaffold in 7-9 steps, a sizable reduction over known syntheses. Through the modification of one step in the synthesis, the route can be made enantioselective to synthesize the natural product. The use of flow chemistry allows for the rapid synthesis of the core scaffold, and enables the safe use of reactive and toxic reagents. In-line preparation of reactive intermediates allows for the rapid introduction of complexity that would be infeasible on large scale. The strategy is designed to enable a modular approach to the synthesis of structural analogs for the purposes of structure-activity relationship studies and the development of improved therapeutics.
Cephalotaxine-based drugs, such as omacetaxin mepesuccinate, have not been thoroughly studied with respect to their structure-activity relationships, despite longtime interest in their mode of action as antileukemic inhibitors of protein translation. This proposal describes the concise and modular synthesis of this class of compounds using continuous flow technology to rapidly access structural analogs of the drug for biological evaluation.
