Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines

Abstract

There are more than 400-reported bisbenzylisoquinoline alkaloids, many with interesting biological activity, but the reported syntheses are long and low yielding. As a result, there have been no systematic attempts at exploitation of the potential therapeutic applications. The concept of a sulfur 'stitch', restricting the conformational freedom of intermediates in the synthesis, will potentially allow analogues of the natural products to be prepared using relatively efficient routes. The synthesis of intermediate sulfur heterocycles is reported, based on 2,8-dimethylphenoxathiin, leading via 2,8-bis(bromomethyl) phenoxathiin-10,10-dioxide to a synthesis of 3,4,8,9-tetrahydro-13-oxa-6-thia-2, 10-diazapentacene, a key potential intermediate on the route to a variety of macrocyclic bisbenzylisoquinolines.