Enantioselective Total Synthesis of 10-Desoxy Analogue of a Previously Reported Natural Peroxyguaidiol

Described herein is an enantioselective synthesis of an analogue of a previously reported guaiane endoperoxide isolated from aerial parts of Croton arboreous. The polycyclic framework of the target structure was constructed with the C-7 stereogenic center derived from L-(-)-carvone and other stereogenic centers installed via substrate chirality-induced asymmetric reactions, starting with the synthesis of the seven-membered ring through regioselective enolization of carvone, ring-expansion, and installation of a conjugated C═C bond. Further functionalization was then achieved through regioselective enolization, triflation, and installation of an isopropenyl group. During the synthesis, some exceptions to the well-known rules of "thermodynamic control" and "kinetic control" in enolization of asymmetric cyclic ketones were observed. In construction of the bridged five-membered and endoperoxy rings, a peroxycarbenium [3 + 2] cycloaddition reaction with alkenes was carried out with several alkenes-silyl-gem-dihydroperoxides of different relative configurations. However, no expected [3 + 2] products were observed. Finally, the five-membered ring was smoothly installed through an intramolecular Darzens reaction, and the peroxy functionality was introduced via a carbon-centered radical-mediated reaction with triplet oxygen, followed by an intramolecular etherification under acidic conditions. Comparison of the ¹H and ¹³C NMR spectra of the synthetic analogue and the natural product revealed that the latter was definitely not an endoperoxide.