The quinoline ring system is a common structural component of a wide variety of natural products with highly desirable biological activity, including antimalarial agents such as quinine, chloroquine and mefloquine, as well as antitumor agents such as dynemicin A, luotonin A, and camptothecin. The synthesis of the highly effective, yet prohibitively toxic, antitumor antibiotic streptonigrin is targeted in this research. A concise, convergent synthesis of this antitumor agent will pave the way for an expeditous survey of streptonigrin analogues that have similar pharmaceutical value with diminished toxicity. Our retrosynthetic plan required the development of new methodology to form the heterocyclic ring of quinoline, in a manner that would allow the utilization of palladium-catalyzed coupling of complex aryl triflates to form the tetracyclic structure of this highly functionalized natural product.

A method has been developed to synthesize complex, substituted quinolines in a facile manner through the utilization of o-nitrophenyl propargyl alcohols. Through either direct lithium acetylide addition of available alkynes, or Sonogashira coupling to terminal propargyl alcohols, the assembly of complex internal propargyl alcohols has directly lead to 2-aryl-, 2-alkenyl and 2-alkylquinolines via reductive cyclization under mildly acid conditions. This reductive cyclization takes advantage of the facile Meyer-Schuster rearrangement of resonance-stabilized o-anilinopropargyl alcohols to o-aminochalcones, which cyclize to quinoline in a one-pot procedure.

This work has also examined the use of this reductive cyclization to form 2-pyridylquinolines, however such cyclization has repeatedly led to the 4-quinolone. The mechanism of such an anomalous cyclization has been studied. Although the mechanism has not been definitively identified, several potential pathways have been examined, with evidence favoring an acid-catalyzed, non-Meyer-Schuster rearrangement of the propargyl alcohol leading to cyclization and oxidative rearomatization to form the observed quinolone.

Lastly, reductive cyclization has been applied to model systems for the ABC-ring system of the natural product streptonigrin. The synthesis of an appropriate A-ring precursor o-mononitrobenzaldehyde has been achieved, and elaborated to the final 6,8-dimethoxy-2-(2’-pyridyl)quinolone through reductive cyclization. A more intriguing A-ring precursor dinitrobenzaldehyde, with built-in functionality to produce streptonigrin’s 7-amino group, was also targeted. Efforts toward its regioselective synthesis are also described.