Carlini, Rina2006-07-282006-07-2819981998http://hdl.handle.net/10012/224Viridin (1), a powerful antifungal agent first isolated over 50 years ago, is a member of a family of furanosteroir antibiotics (1-8) which all share the unique tricyclic naphtho[1,8-bc]furan structural subunit for rings A-B-E containing an angular methyl group at the A-B ring junction. In this study directed at a first synthesis of viridin, a plan was devised for annulating two rings of this tricyclic subunit by a novel one-pot intramolecular Diels-Alder (IMDA) reaction of an o-quinonoid monoketal generated in situ by oxidation of the benz[e]indanone thiol ester 81 (a substituted o-methoxynaphthol) in the presence of excess (E)-2,4-pentadienol. The dienophilic reactivity of the o-quinonoid ring in such monoketals was promoted by both the placement of an electron-withdrawing substituent (COSCH3) on the o-quinone ring, and by involving one of quinone double bonds in aromatic resonance. The thiol ester group was chosen as a synthetic precursor to the required angular methyl group in viridin as it was expected to provide a better handle for chemoselective reduction in the presence of other carbonyl groups. The pentacyclic advanced intermediate 80 was synthesized in 8 steps and 34% overall yield, which represents a first and efficient synthesis of the furanosteroid framework of viridin. The synthetic route began with a regiocontrolled intermolecular Diels-Alder reaction between methyl (E)-4,6-heptadienoate and the dienophilic o-quinone generated from commercially available 2,3-dihydroxybenzoic acid, and culminated with the installation of rings A and E by the novel one-pot IMDA reaction. A synthetic survey of regiocontrolled intermolecular Diels-Alder reactions of substituted o-quinones, along with some interesting rearrangements and further transformations of these adducts, was conducted in the course of this work. The selective desulfurization of the pentacyclicthiol ester 80 and model thiol esters 79, 130 by a variety of reduction methods met with limited success. Furthermore, it was found that due to a general anomeric effect, the ketal group of the exo IMDA adducts, including exo pentacycle 80b, could not be transformed to furanoid analogues by acid-catalyzed elimination of methanol in ring E. These complications propelled investigations toward a convergent synthesis of viridin which would utilize the tricyclic 5a-methylnaphtho[1,8-bc]furan system. The novel one-pot IMDA reaction was investigated with several o-benzoquinone monoketals, generated from oxidation of substituted guaiacols 64-66 and 172-176 in the presence of excess (E)-2,4-pentadienol. In these reactions, the o-quinonoid species behaved as both a diene and a dienophile forming the bridged adducts 67 and 177 as the major IMDA product, along with the minor naphthofuran endo-adducts 68 and 178, in good overall yield. The bridged IMDA adducts were subsequently converted to the naphthofuran compounds by way of Cope rearrangements, thereby allowing a rapid synthesis of the important tricyclic compound 68, the structural subunit of both viridin (1) and zestoquinone (12), in two steps and 56% overall yield from commercial 2-methoxy-4-methylphenol 64. Several analogues of 68 were also prepared for investigating the synthesis of viridin and analogues by various convergent routes, based on either a Diels-Alder strategy or tandem Michael additions. Although viridin was not synthesized in this endeavour, the dienophilic reactivity of o-benzoquinones and their monoketals was uncovered and efficiently manipulated for constructing advanced precursors of viridin and congeners.application/pdf10936651 bytesapplication/pdfenCopyright: 1998, Carlini, Rina. All rights reserved.Harvested from Collections CanadaDoctoral Thesis