Enantioselective Total Syntheses of Manzamine A and Related Alkaloids

As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series
of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2]
cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These
experiments clearly demonstrated that the geometry of the internal double bond and the presence of an
electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation
of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75),
ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured
a novel domino Stille/Diels−Alder reaction to construct the tricyclic ABC ring core embodied in these
alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical
operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to
form the 13- and 8-membered rings leading to Z-72 and 74, the latter of which was quickly elaborated into
ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following
literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially
available starting materials with the longest linear sequence being 21 steps.