Synthesis of bis-γ-butyrolactones containing conformationally constrained (S)- and (R)-diacylglycerol structures Original Research Article

The synthesis of two sets of rigid diacylglycerol (DAG) analogues with either the (S)-DAG or (R)-DAG enantiomer embedded into a bis-γ-butyrolactone template was accomplished stereoselectively from di-O-isopropylidene-α-d-apiose. The key step in both syntheses was the assemblage of the bicyclic perhydrofuro[3,4-b]furan ring system via a radical exo-dig intramolecular cyclization. A lipophilic undecanyl alkyl chain attached at C-3 of the fully assembled perhydrofuro[3,4-b]furan-2,4-dione (bis-γ-butyrolactone) template can adopt two orientations with the one directed away from the concave face of the bicyclic system favored by a 4 to 1 ratio in each case. Evaluation of the final target pairs of enantiomers as PK-Cα ligands revealed that the template containing an embedded (R)-DAG structure was more effective. The difference in binding affinity was also modulated by the direction of the alkyl chain.