The Synthesis of (S)-Camptothecin and Clinically Useful Analogs

irinotecan;camptothecin;haloquinolines;karenitecin

Nolan, Jason Michael ; Daniel L. Comins, Committee Chair,Nolan, Jason Michael ; Daniel L. Comins ; Committee Chair

University:North Carolina State University

关键词: irinotecan;    camptothecin;    haloquinolines;    karenitecin;   

Others  :  https://repository.lib.ncsu.edu/bitstream/handle/1840.16/3716/etd.pdf?sequence=1&isAllowed=y

美国|英语

来源: null

【 摘 要 】

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 CPT-analog 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 tri-substituted 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 ortho-metallation (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.