Total synthesis of kaitocephalin

Abstract

For the synthesis of kaitocephalin, we have developed novel synthetic pathway emphasizing on high stereoselectivity, efficiency and convergence. The approach would rely on epoxidation followed by regioselective azidolysis for the C2 and C3 stereochemistry, desymmetrization for the C4 stereocenter, and mercuriocyclization for the C7 asymmetric carbon. The key intermediate pyrrolidine 222 would be derived by a sequence of mercuriocylization of the carbamate 223, reduction of the ester, epoxidation of the allylic alcohol and epoxide opening with azide anion to install the stereocenter C2, C3 and C7. Desymmetrization of the N-Cbz protected diol 131 using diisopropyl-bisoxazoline (118)-CuCl2 complex would generate the C4 stereogenic center, which would be prepared through alkylating the aminomalonate 93 with the iodide 79 prepared from (R)-Garner aldehyde 7. After the installation of the amide moiety, the resulting triol 281 derived from 273 was successively subjected to AZADO-catalyzed oxidation, desilylation and hydrogenolysis. The resulting kaitocephalin was purified through Dowex 50WX4 and then through COSMOSIL 75C18-OPN to give 286 as an ammonium salt of kaitocephalin 1.