Synthesis of Chiral Tetramic Acids: Preparation of (S)-5-Benzylpyrrolidine-2,4-dione from L-Phenylalanine Methyl Ester Hydrochlorides and Synthetic Efforts Towards Dracocephalone A




Medley, Austin

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The pyrrolidine-2,4-dione moiety, colloquially known as tetramic acid, is a highly versatile molecular scaffold underpinning many biologically active natural products. That is to say, natural products containing these scaffolds are known to possess an array of bioactive properties including the following: antibiotic, antiviral, antifungal, cytotoxic, and antiproliferative. Implicit in how versatile the tetramic acid containing products are in acting against biopharmaceutical interested disease classes is the necessity for a concerted, enantiospecific synthesis of these targets, and continued synthesis of their moiety containing natural products. Moreover, as part of a larger effort to develop chiral tetramic acid precursors for N-hydroxy-2,5-diketopiperazine containing natural products, hereafter referred to as DKPs, a highly enantiospecific synthesis of these tetramic acids was developed. Herein is described the synthesis of (S)-5-Benzylpyrrolidine-2,4-dione from L-Phenylalanine Methyl Ester Hydrochloride. Dracocephalone A is a 20-norabietane diterpene which was isolated from the Dracocephalone Komarovi semi-shrub by Uchiyama and coworkers in 2002. When studied in conjunction with other D. Komvarovi isolates, Dracocephalone A was found to possess moderate trypanocidal against epimastigotes of Trypanosoma cruzi, the pathogen underlying Chagras’ disease with a minimal lethal concentration, or MLC, of 200 micromoles. Although the biological activity is moderate at best, the unique molecular scaffold of Dracocephalone A, along with no previous recorded syntheses, provides an exciting opportunity for a total synthetic pursuit of this molecule. Furthermore, unlike syntheses of Dracocephalone’s conjuners reported by Thommen and coworkers, our work sought to access the novel 5,5,5,6 fused ring system through an intramolecular diels-alder reaction with a subsequent photochemical tertiary methyl functionalization in order to form the requisite methyl-ether bridge.



Synthetic Efforts Towards Dracocephalone A