The synthesis of C2 symmetry diesters of (3R,4R)-TTFOL through a green and stereoselective (2R,3R)-TADDOL rearrangement

Toward the cholinesterase inhibition potential of TADDOL derivatives: Seminal biological and computational studies

“…The synthesis of C 2 ‐symmetric 2,2,5,5‐tetraphenyltetrahydrofuran‐3,4‐diol ((3 R ,4 R )‐TTFOL or ( R , R )‐TTFOL) diester derivatives were realized through an ( R , R )‐TADDOL dioxolane cleavage and rearrangement by its reaction with a carboxylic acid in the presence of trifluoroacetic acid anhydride (TFAA)/H 3 PO 4 under mild conditions in generally high yields within a few minutes. [ 68,69 ]…”

“…[67] The synthesis of C 2 -symmetric 2,2,5,5-tetraphenyltetrahydrofuran-3,4-diol ((3R,4R)-TTFOL or (R,R)-TTFOL) diester derivatives were realized through an (R,R)-TADDOL dioxolane cleavage and rearrangement by its reaction with a carboxylic acid in the presence of trifluoroacetic acid anhydride (TFAA)/H 3 PO 4 under mild conditions in generally high yields within a few minutes. [68,69] We also decided to test the aza-Michael reaction of phthalimide (4) and saccharin (5) with enantiomerically pure α,β-unsaturated diesters of (R,R)-TADDOL (2a) and (R,R)-TTFOL (3a) using microwave (MW) irradiation. Commonly, the aza-Michael reaction is used to synthesize β-amino carbonyl compounds, valuable building blocks for the synthesis of biologically and pharmaceutically important molecules (Scheme 2).…”

“…(b) Unsaturated acids, air, TFAA, H 3 PO 4 , 50°C, 52%-93% yield. [68,69] F I G U R E 1 Chemical structure of the chiral TADDOL backbone.…”

“…The 1 H and 13 The syntheses of compounds 2-3 were carried out according to the literature procedures. [67,68] The esters of TADDOL and TTFOL (0.25 mmol), imides (phthalimide and saccharine) (0.76 mmol), TBAB (0.25 mmol), and ZnO (55%, 0.14 mmol) in 8 ml of dry DMF were placed in a closed MW vessel and stirred carefully. The mixture was then irradiated in the MW oven at 130°C for the times reported in Table 1.…”

“…aq. 4.1.3 | General procedure for the synthesis of TTFOL-diester derivatives (3a-3f) [68] TFAA (4.1 g, 2.76 ml, 0.020 mol) was added at room temperature to a stirred mixture of 0.5 g (1.07 mmol) of TADDOL, the required carboxylic acid (2.36 mmol) and 0.046 g (0.027 ml, 0.47 mmol) of H 3 PO 4 in a two mouth round bottom flask equipped with a reflux condenser and magnetic stirrer, under a normal open atmosphere.…”