Asymmetric total synthesis of (-)-octahydro-1H-benzofuro[3,2-e] isoquinoline, a partial structure of morphine
Journal
Journal of the Chinese Chemical Society
Journal Volume
52
Journal Issue
2
Pages
339-346
Date Issued
2005
Author(s)
Abstract
Octahydro-1H-benzofuro[3,2-e]isoquinolines, which possess the ACNO partial structure of morphine, displayed potent oral analgesic and narcotic-antagonism activity. However, due to inefficiency in their synthesis the ACNO derivatives have not been developed for clinical use. Here, we report in detail the first asymmetric total synthesis of (-)-octahydro-1H-benzofuro[3,2-e]isoquinoline as exemplified by the preparation of (-)-1 and (-)-2. The key intermediate (+)-5-hydroxy-3,4,5,6,7,8-hexahydro-1H-isoquinoline-2-carboxylic acid ethyl ester ((+)-5) was prepared in 81% yield and with 100% ee by asymmetric reduction of 5-oxo-3,4,5,6,7,8-hexahydro-1H-isoquinoline-2-carboxylic acid ethyl ester (6) using RuCl[(R,R)-Tsdpen](p-cymene) as catalyst with a S/C of 200. The three chiral centers of ACNO skeleton were constructed via a reaction sequence of asymmetric transfer hydrogenation, Heck reaction, and catalytical hydrogenation, and all of these stereoselective reactions were metal-catalyzed (i.e. Ru, Pd, and Pt, respectively).
Type
journal article