First Stereoselective Total Synthesis of Marliolide-(4R,5R,3E)-4-hydroxy-5-methyl-3-tetradecylidenedihydrofuran-2(3H)-one and Vittarilide-B: A Unified Strategy Utilizing a Chiral Pool Approach

High Resolution Image Download MS PowerPoint Slide The first stereoselective total synthesis of the natural products Marliolide-(4 R,5 R,3 E )-4-hydroxy-5-methyl-3-tetradecylidenedihydrofuran-2(3 H )-one ( 1 ) and Vittarilide-B ( 1b ) has been accomplished using a carbohydrate-based approach starting from d -glucose. The synthesis of Marliolide-(4 R,5 R,3 E )-4-hydroxy-5-methyl-3-tetradecylidenedihydrofuran-2(3 H )-one ( 1 ) was achieved in 13 steps with an overall yield of 6.5%, featuring key transformations such as reduction, Wittig olefination, TEMPO-mediated oxidation, isomerization, and debenzylation. Vittarilide-B ( 1b ) was synthesized in 18 steps with an overall yield of 8.8%, involving crucial steps like inversion, radical-mediated lactonization, Steglich esterification, and deprotection. The synthesis of Marliolide (1) led to the discovery of a notable isomerization phenomenon, where the Z -isomer was converted to the E -isomer during the oxidation step using BAIB and TEMPO. Various reaction conditions were investigated for this isomerization process, with the TEMPO-mediated reaction consistently providing the best results. The synthesis of Vittarilide-B ( 1b ) required the inversion of stereochemistry at the C-2 position of the common intermediate 6b, followed by a sequence of steps to obtain the final product. The analytical data for both synthetic Marliolide-(4 R,5 R,3 E )-4-hydroxy-5-methyl-3-tetradecylidenedihydrofuran-2(3 H )-one ( 1 ) and Vittarilide-B ( 1b ) were consistent with the data reported for the natural compounds. This work demonstrates the efficiency of using readily available chiral pool materials like d -glucose in the stereoselective synthesis of complex natural products and provides a foundation for further exploration of their biological activities and potential therapeutic applications.