Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Published in: Beilstein journal of organic chemistry Vol. 17; no. 1; pp. 2781 - 2786
• Main Authors: Ďurina, Lukáš, Ďurinová, Anna, Trejtnar, František, Janotka, Ľuboš, Messingerová, Lucia, Doháňošová, Jana, Moncol, Ján, Fischer, Róbert
• Format: Journal Article
• Language: English
• Published: Germany Beilstein-Institut 24.11.2021
• Subjects: alkaloids; antiproliferative effect; Chemistry; codonopsinol b; diastereoselectivity; Full Research Paper; pyrrolidines; antiproliferative effect; codonopsinol B; diastereoselectivity; pyrrolidines; alkaloids
• ISSN: 1860-5397; 1860-5397
• DOI: 10.3762/bjoc.17.188

A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (±)-codonopsinol B and its -nor-methyl analogue, starting from achiral materials, is presented. The strategy relies on the -stereoselective epoxidation of 2,3-dihydroisoxazole with in situ-generated DMDO, the -selective α-chelation-controlled addition of vinyl-MgBr/CeCl to the isoxazolidine-4,5-diol intermediate, and the substrate-directed epoxidation of the terminal double bond of the corresponding γ-amino-α,β-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 -nor-methyl analogue was evaluated using several cell line models.