The synthesis of (S)-camptothecin and clinically useful analogs

by Nolan, Jason Michael

NOLAN, JASON MICHAEL. The Synthesis of (S)-Camptothecin and Clinically Useful Analogs. (Under the direction of Daniel L. Comins.) A six-step synthesis of (S)-camptothecin (CPT) was completed relinquishing a fast, efficient route to this natural product. The key steps included the formation of the 4-iodo-2,3-pyridylacetal intermediate 56 required to obtain the DE ring moiety of CPT, and an intramolecular Heck reaction for the closure of ring C. The convergence of this synthesis provided a straightforward method for CPTanalog development. Application is displayed in the syntheses of the clinically useful CPT-derivatives Karenitecin BNP1350 and the Irinotecan precursor 66. These syntheses are highlighted by short, high-yielding routes to the tetra- and trisubstituted quinoline rings, respectively. The DE ring portion of homocamptothecin (hCPT) was completed utilizing the same key intermediate 56 of the CPT synthesis. Although racemic, this seminal synthesis is very concise, being significantly shorter than known protocols. An investigation for the use of 2-haloquinolines as synthetic building blocks in CPT-analog development was completed. Attempts to use directed orthometallation (DoM) chemistry on 2-chloro-3-quinolinecarboxaldehyde and derivatives proved to be inapplicable. However, regioselective lithium-halogen exchange and palladium-catalyzed coupling reactions were discovered for 2,4-dihaloquinolines. This success provides a versatile method for synthesizing highly substituted quinolines.