Development of an alkaloid-pyrone annulation: synthesis of pleiomaltinine.

g-Pyrone natural products are an important class of compounds that exhibit a wide range of biological activity. Similarly, indole-containing compounds are found throughout nature as well as in pharmaceuticals and agrochemicals. Recently, Kam and co-workers isolated pleiomaltinine 1 (Scheme 1), an unusual alkaloid-pyrone natural product that is able to reverse multidrug resistance in vincristineresistant KB (VJ300) cells (IC50= 12 mgmL 1 in the presence of vincristine [0.1 mgmL ]). They proposed that pleiomaltinine may be derived biosynthetically from the indole-alkaloid pleiocarpamine 2, co-isolated from the same plant species (Alstonia angustofolia) and 2-methylene-3,4-diketone 3 derived from dehydrogenation of naturally occurring maltol (4). We were intrigued by intermediate 3 and its potential reactivity in cycloaddition chemistry, which was expected to be analogous to that of o-quinone methides. Herein, we report the development of a method for the synthesis of alkaloid-pyrones using a novel pyrone annulation, and the application of this method to the synthesis of pleiomaltinine 1 from pleiocarpamine 2. After initial unsuccessful attempts to generate reactive intermediate 3 by dehydrogenation of 4 with 2,3-dichloro-5,6dicyanobenzoquinone (DDQ), we considered that 3 could alternatively be derived from a precursor such as 3-siloxy-4pyrone 5 by fluoride-induced desilylation. In the event, treatment of 5 and N-methyl carbazole 6 with tetra-nbutylammonium fluoride (TBAF) led to the formation of cycloadduct 7 in low yield (Scheme 2). Further optimization through a solvent screen revealed that benzene afforded 7 in 43% yield (Table 1, entry 1). Cycloadduct 7 was also produced in protic solvents such as methanol without the inclusion of additives (entry 2). With these results in hand, we hypothesized that HBr could be produced as a byproduct and