2-Amino-α-carboline is a heterocyclic aromatic amine implicated in human cancers, whereby its metabolites form adducts with DNA at the C8 position of guanine. Extensive biophysical studies are needed to elucidate the mutagenic mechanisms of 2-amino-α-carboline, but efficient routes to generate this molecule and its analogs are lacking. The work described herein highlights independent efforts by two different academic laboratories in Rhode Island to solve this problem. At the University of Rhode Island (URI), a strategy has been developed to synthesize 2-amino-α-carboline, 2-nitro-α-carboline, and their fluorinated analogs (for 19F NMR with DNA) via coupling reactions. Coupling of 2-amino-6-bromopyridine and benzotriazole followed by an acid-catalyzed intramolecular cyclization led to formation of 2-amino-α-carboline in low yield. Similar methodology was used to prepare 2-nitro-α-carboline, but suffered from poor regioselectivity. To address this, a palladium-catalyzed coupling of 2-nitro-6-bromopyridine with anilines followed by intramolecular arylation is now being explored. This route is expected to show selectivity in the synthesis of the fluorinated carboline. At the same time, at Providence College (PC), a scheme towards α-carbolines via intermolecular rhodium-catalyzed [2+2+2] cyclizations is in its infancy. This strategy builds upon an intramolecular variant that successfully led to 3,4-annulated α-carbolines in good yield. The key to this sequence is the construction of a protected cyanamide as the source of the α-carboline nitrogen. Preliminary studies indicate that intermolecular cyclizations with exogenous alkynes require more forcing reaction conditions. Extension of this methodology to the intermolecular fluoro-analog will be described. With these two different approaches from URI and PC, a unexpected synergy has evolved between our academic institutions, which has been fruitful in deepening collaboration.

Synthesis of 2-substituted α-carbolines via synergistic methods

254th National Meeting (2017)

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