Short, enantioselective total syntheses of (-)-8-demethoxyrunanine and (-)-cepharatines A, C, and D.

The hasubanan akaloids are a large collection of natural products isolated from several medicinal herbs that are used in traditional Chinese medicine.[i] Members of this family share a common aza-[4.4.3]-propellane core, but vary substantially in the oxidation patterns of their peripheral structure. The least oxidized hasubanans are 8-demethoxyrunanine (1)[ii] and cepharamine (3);[iii] runanine (2),[iv] aknadinine (4),[v] and hasubanonine (5)[vi] are the result of further oxidation at C8 (Figure 1). These compounds are closely related to an isomeric family of natural products, the cepharatines (7–10), which were isolated in 2011 from S. cepharantha, the same plant from which cepharamine (3) was isolated.[vii] The structural similarities between the hasubanans and the cepharatines have led to the hypothesis that both arise biosynthetically from common precursors. For example, 3, 7, and 8 are proposed to derive from sinoacutine (11),[vii, viii] a compound related, though antipodal, to morphine. Indeed, due to the topographical similarities between compounds 1– 5 and morphine, there is speculation that the unnatural enantiomers of the hasubanans may exhibit analgesic properties.[ix]