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

Lukáš Ďurina,Ján Moncol,Anna Ďurinová,Róbert Fischer,Jana Doháňošová,Lucia Messingerová,František Trejtnar,Ľuboš Janotka

doi:10.3762/bjoc.17.188

Abstract

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 α-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 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 N-nor-methyl analogue was evaluated using several cell line models.

Highlights

Codonopsinol B (1) is a polyhydroxylated pyrrolidine alkaloid isolated from the roots of the plant Codonopsis pilosula (Figure 1) [1]
Each of the key reactions proceeded with an excellent diastereoselectivity. (±)-Codonopsinol B was prepared in 10 steps with overall 8.4% yield
We have developed an efficient highly diastereoselective synthesis of racemic codonopsinol B (1) and its N-normethyl analogue 2 starting from achiral materials

Summary

Introduction

Codonopsinol B (1) is a polyhydroxylated pyrrolidine alkaloid isolated from the roots of the plant Codonopsis pilosula (Figure 1) [1]. A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (±)-codonopsinol B and its N-nor-methyl analogue, starting from achiral materials, is presented.

Results

Conclusion