3-Hydroxymollugin 2 and 3-methoxymollugin 3 are cytotoxic compounds isolated as minor compounds from Pentas longiflora and Rubia cordifolia. Syntheses of 3-hydroxymollugin 2 and 3-methoxymollugin 3 were developed starting from easily available 3-bromomollugin 6. Surprisingly, it was found that the reaction of 3-bromomollugin 6 with sodium methoxide in methanol resulted in the formation of 3-methoxymollugin 3 and the ring-contracted methyl isopropenylfuromollugin 7. A mechanism for this ring contraction is proposed on the basis of a pericyclic retro oxa-6pi ring-opening reaction. A second synthesis of 3-hydroxymollugin 2 was based on epoxidation of methyl 3-(3-methylbut-2-enyl)-1,4-naphthoquinone-2-carboxylate 17 and subsequent reduction of the quinone moiety, ring transformation, and DDQ oxidation. The latter oxidation process results in 3-hydroxymollugin 2 along with the rearranged furomollugin 4, which is a ring-contracted analogue of the natural product mollugin 1.
A new diastereoselective synthetic approach towards 1,2,3-trisubstituted pyrrolidines and 2,3-disubstituted tetrahydrofurans is described. The synthesis of the pyrrolidines involves reductive cyclization of g-chloroketimines, which were generated in situ from the reaction of 3-substituted 5-chloro-2-pentanones and a primary amine. Various reduction conditions were explored to induce a diastereoselective reductive cyclization. 2,3-Disubstituted tetrahydrofurans were obtained by the direct reduction of 3-substituted 5-chloro-2-pentanones with sodium borohydride.
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