Stereocontrolled total synthesis of Neuroprotectin D1/Protectin D1 and its aspirin-triggered stereoisomer

Abstract

Neuroprotectin D1/Protectin D1, a potent anti-inflammatory, proresolving, and neuroprotective lipid mediator derived biosynthetically from docosahexaenoic acid, was prepared in an enantiomerically pure form via total organic synthesis. The synthetic strategy is highly stereocontrolled and convergent, featuring epoxide opening of glycidol starting materials for the introduction of the 10(R) and 17(S) hydroxyl groups. The desired alkene Z geometry was secured via the cis-reduction of alkyne precursors, while the conjugated E,E,Z triene was introduced at the end, in order to minimize Z/E isomerization. The same strategy, was also employed for the total synthesis of aspirin-triggered neuroprotectin D1/protectin D1 having the 17(R)-stereochemistry. Synthetic compounds obtained with the reported method were matched with endogenously derived materials, and helped establish their complete stereochemistry.