The synthesis of lignans and related structures using quinodimethanes and isobenzofurans: approaches to the podophyllins

Abstract

Novel routes to 1 -aryl-5,6-dialkoxy-l,3-dihydrobenzo[cJthiophene 2'2-dioxides (1 3) and to the corresponding benzo[c]furan (8) have been developed; these species yield quinodimethanes (1 2) via thermal extrusion of SO, and isobenzofurans (5c) in an acid-catalysed process, respectively, which then react with various dienophiles to provide structural analogues of the aryltetralin and arylnaphthalene lignans. OMe

E,E- and E,Z-α-phenyl-α′-acetoxyorthoquinodimethane: steric and electronic control of cycloaddition reactions

“…Recently there has been an interest in the use of orthoquinodimethanes as intermediates in lignan synthesis (1)(2)(3)(4)(5). This work has been stimulated by a growing interest in podophyllotoxin 1 and its derivatives, which show promise as cancer chemotherapeutic agents (6) .…”

“…Previous work on the addition of oxy and phenyl substituted orthoquinodirnethanes (0-QDMs) to alkenes (1,2,4,(7)(8)(9) indicated that the regio-and stereochemical course of the addition followed that expected for the Diels-Alder reaction of substituted dienes with alkenes. A cis-1.2 substituted Dattern seemed to predominate, as shown by the following two I examples (1,9). '~u t h o r to whom correspondence may be addressed.…”

A practical synthesis of the anti-tumour agent 2-methyl-4-deoxyisopicropodophyllotoxin and related podophyllin analogues

“…In 1985 we described a route to 2-substituted-4-deoxyanalogues of podophyllotoxin 5 which proceeded uia cycloaddition reactions between the orthoquinodimethane 6 and dienophiles 7 (Scheme l). 3 We went on to show that several of these analogues, most notably 5a, exhibited marked in uiuo antitumour activity despite possessing a cis-lactone ring rather than the trans-ring of podophyllotoxin. Computer modelling of the various X-ray structures for analogues 5 demonstrated that they all possessed very similar three-dimensional structures to podophyllotoxin.…”