Ring Expansions to Access Structurally-Diverse Diketopiperazine Alkaloids

Baylor University, Waco TX

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Abstract

The goal of the proposed research is to provide direct and efficient synthetic access to biologically relevant structural motifs that are frequently found within complex natural products. Many naturally-occurring scaffolds exhibit inherent bioactivity against an assortment of bacteria, fungi, viruses and cancers and can serve as starting points for scientists to access more structurally complex and diverse libraries of compounds. Upon this derivation, they can be further screened against biological targets of interest in a quest to identify compounds with favorable pharmacological properties, and more importantly, efficacy against the target of interest. More specifically, the proposed research aims to develop a general, mild, and sustainable synthetic route to a series of difficult-to-access 2,5-diketopiperazines (2,5-DKPs) through an innovative ring expansion approach. The utility of the developed methodology will be realized by its application to complex molecule synthesis, specifically, to a total synthesis a family of natural products that have been shown to exhibit single-digit µM cytotoxic activity against human cervical and leukemia cancer cell lines. The successful synthesis of these molecules would provide authentic synthetic material that can be used in further biological studies. Furthermore, by employing readily available and inexpensive commodity chemicals in the ring expansion protocol to access DKPs, the proposed research seeks to facilitate the discovery of novel antibiotics, antiviral agents, and cancer therapeutics that contain the DKP scaffold.