Studies Directed Towards Total Syntheses of the Tropoloisoquinoline Alkaloids Grandirubrine and Imerubrine. I. Preparation of Two 4,5,6-Trimethoxycyclopent[ij]isoquinolin-7-ones and Their Response to Robinson Annulation Conditions

Abstract

In connection with efforts to develop total syntheses of the tropoloisoquinoline alkaloids grandirubrine (1) and imerubrine (2), preparations of tricyclic ketone (8) and the related ethoxycarbonyl system (47) are described. Of the various approaches to (8) which were investigated, that proceeding from the known 8-bromo-5,6,7-trimethoxyisoquinoline (27) proved most efficient. Thus, conversion of (27), over three steps, into the Reissert anion (37), followed by alkylation of the latter with methyl iodide or ethyl bromoacetate, afforded (38) and (46), respectively. Treatment of compound (38) with sodium ethoxide resulted in regeneration of the isoquinoline nucleus and provided the C1-substituted compound (40). Upon reaction with lithium diisopropylamide, isoquinoline (40) underwent Dieckmann-type cyclization to give compound (8). A similar reaction sequence involving diester (46) afforded enamine (47), the X-ray crystal structure of which is reported. Efforts to effect Robinson annulation of (8) or (47) with methyl vinyl ketone (or a synthetic equivalent), and thereby produce the tetracyclic compound (10), have been unsuccessful.