Structural Analogues of the Hydroxy‐Substituted Spiro‐Oxepin Isoxazoline Moiety Found in Psammaplysins

A synthetic approach to new 4‐hydroxy‐substituted spiro‐isoxazolines, structural analogues of the spiro‐oxepin isoxazoline moiety found in psammaplysins, has been described. The synthetic strategy for the spiro scaffold involves the trans ‐stereoselective epoxidation of 5‐substituted 2,3‐dihydroisoxazoles using in situ generated 3,3‐dimethyldioxirane, followed by the acid‐catalyzed cyclization of 5‐substituted isoxazolidine‐4,5‐diols with an unprotected hydroxy group on the side chain to produce the corresponding spiro‐isoxazolidines. The RuCl ₃ ‐catalyzed oxidation of the aryl substituent and oxidation of the C─N to C═N bond with CuCl ₂ are key steps in the synthesis of the desired isoxazoline‐carboxylic acid derivatives. The antiproliferative activity of these derivatives was evaluated using one human liver cancer cell line (HepG2) and two human colon cancer cell lines (Caco‐2 and HT‐29).