Proposal of 14- Step Total Synthesis Route of Dihydrolucilactaene, a Potent Antimalarial Compound

Abstract

Malarial disease has been under heated discussion. The Osada group has extracted and purified pot antimalarial compounds, including dihydrolucilactaene and its derivatives. In this work, a 14-step total synthetic route of Dihydrolucilactaene, the compound with the highest pharmaceutical value among its derivatives, is designed and presented after considering and combining four partially feasible but hindered approaches. The complex molecule is first split into lactam-containing and long unsaturated fragments. The long unsaturated carbon chain can be effectively synthesized by two subsequent aldol condensations and the enabling Wittig reaction. Dicarbonyl synthesis and a basemediated intramolecular nucleophilic attack can synthesize the lactam fragment. The final connection between two fragments are conducted through an enolate attack of electrophilic nitrile followed by hydrolysis. Three protection groups, named trimethyl silyl, acetal, and N-Boc, facilitate the synthesis in the last step. This research successfully developed a 14-step efficient total synthetic route of dihydrolucilactaene with commercially available building blocks and catalysts. The proposed total synthesis route consists of developed and straightforward synthetic methodologies and therefore is expected to be efficient and have a high overall yield.