Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation
Abstrakt
A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+/-)-codonopsinol B and its N-nor-methyl analogue, starting from achiral materials, is presented. The strategy relies on the trans-stereoselective epoxidation of 2,3-dihydroisoxazole with in situ-generated DMDO, the syn-selective alpha-chelation-controlled addition of vinyl-MgBr/CeCl3 to the isoxazolidine-4,5-diol intermediate, and the substrate-directed epoxidation of the terminal double bond of the corresponding gamma-amino-alpha,beta-diol with aqueous hydrogen peroxide catalyzed by phosphotungstic heteropoly acid.
Each of the key reactions proceeded with an excellent diastereoselectivity (dr > 95:5). (+/-)-Codonopsinol B was prepared in 10 steps with overall 8.4% yield. The antiproliferative effect of (+/-)-codonopsinol B and its N-nor-methyl analogue was evaluated using several cell line models.