Concise approach to 1,4-dioxygenated xanthones via novel application of the Moore rearrangement

Abstract

The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore rearrangement as a key transformation has been developed. The approach features an acetylide stitching step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone. Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized xanthones. The utility of the approach was demonstrated by its application to a concise and efficient synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named dulcisxanthone C was also corrected to that of the xanthone 1.

Total synthesis of the aglycone of IB-00208

“…When the cyclobutenol 23 was heated, a simple Moore rearrangement occurred to give 24 . 10,11 The putative acetylenic vinyl ketene intermediate did not undergo the desired cyclization as expected from the work of Fuganti 15 under any of the conditions examined.…”

“…The regiochemical outcome of the cyclization to form the spirocyclic ring system in 26 rather than the desired 1,4-dioxygenated xanthone ring in 27 was consistent with previous observations from our laboratory in which we found that the substitution pattern on the F-ring of 25 governs the regioselectivity of cylization. 11 Microwave heating of 25 resulted in rearrangement of the spirocycle to the thermodynamically favored xanthone, and an aqueous base work-up resulted in oxidation of the hydroquinone intermediate and isolation of quinone 27 in quantitative yield. Although our initially proposed reaction sequence for forming xanthones directly from cyclobutenones was unsuccessful, we devised an alternative approach that allowed us to effectively convert cyclobutenedione 22 into xanthone 27 in only five steps.…”

“…Scheme 5) and earlier work. 11 Gratifyingly, heating 40 in nitrobenzene led to the rearrangement of the spirocycle to furnish 41 in 58% yield. This critical sequence of reactions established the underlying viability of our novel approach to the pentacyclic core of IB-00208.…”

“…A key structural subunit embedded in many of these natural products is a 1,4-dioxygenated xanthone, which itself presents some significant challenges to synthesis. 9 In the context of our interest in these and other polycyclic xanthone natural products, we developed a concise and general route to 1,4-dioxygenated xanthones that features a novel extension of the Moore cyclization, 10,11 and we recently reported the application of this approach to xanthones to the first total synthesis of the aglycone of IB-00208 ( 1 ). 12 Herein, we report a detailed account of these efforts.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…Such compounds range in structural complexity from the tricyclic tetramethoxyxanthone 43 to the polycyclic representatives IB-00208, 44 citreamicin η, 45 and kibdelone C (Figure 5, xanthone rings highlighted in blue). Many compounds of this class exhibit potent antibacterial and anticancer activity.…”