Palladium Catalyzed Polyene Cyclizations: An Approach to the Pentacyclic Carbon Framework of Halenaquinone and Xestoquinone

Abstract

A seven step synthesis of the pentacyclic framework of xestquinone and halenaquinone is described beginning with 3- (hydroxyrnethy1)furan and 3-bromo-2-naphthoyl chloride utilizing, as the key step, a palladium catalyzed polyene cyclization. The pentacyclic polyketides halenaquinone (1) and xestoquinone (2) have been isolated from a variety of sea sponges1s2 and shown to possess antibioticla and cardiotoniclc activity, and to inhibit protein tyrosine kinases.3 To date, only one synthesis of halenaquinone4a and xestquinone4b have been reported; both ktarting from the optically pure Wieland-Miescher ketone. In addition, a formal total synthesis of xestoquinone using a furan ring transfer reaction as the key step,4c and an approach to both halenaquinone and xestoquinone requiring the synthesis of a 5a-methyl-2H-naphtho1(1,8-bclfuran have been reported.4d As part of our efforts to develop new strategies for the use of furan rings in synthesis,5 we describe herein a new approach towards the preparation of the pentacyclic framework of halenaquinone and xestquinone, which involves only seven steps from the readily available 3-(hydroxymethyl)furan. Since the palladium catalyzed polyene cyclization has been shown to be a useful synthetic reaction for the construction of two or more rings in one step,6 we examined the possibility of employing this reaction to build the pentacyclic carbon skeleton of halenaquinone and westquinone. Our retrosynthetic analysis using this reaction is illustrated in Scheme 1. Thus, functional group interconversions and concomitant cleavage of the C4-CS and C6-C19 bonds lead to the ketofuran 3, which, when cleaved at the C8-C9 bond, provided 3- bromo-2-naphthoyl chloride (4) and furan (5). Furan 5 could be prepared from 3-(hydroxymethy1)furan by employing our recently reported variation of the Susuki reaction in which a furyl-boronic acid is generated and used in siru.7