Studies On Asymmetric Synthesis Of Anticancer Drug Irinotecan And Related Reactions

Irinotecan,one of three commercial(20S)-Camptothecin family anticancer drugs, was approved by US FDA for treatment of refractory colorectal cancer.Since the first asymmetric total synthesis of(20S)-CPT was accomplished by Corey et al in 1975,numerous synthetic routes to this alkaloid family have been developed.Advances on the synthetic studies for irinotecan and its analogues were reviewed in chapterⅠ,and we point out the Friedl(a|¨)der approach,utilizing C-5 substituted 2-aminobenzaldehyde(ketone) and the(5’S)-tricyclic hydroxylactone 8 as key building blocks seems to be most attractive.In this thesis,A ring building block of 7-ethyl-10-hydroxycamptothecin 2-amino-5-hydroxypropiophenone(7) has been prepared in five steps with an overall yield of 67%starting from the known 5-hydroxy-2-nitrobenzaldehyde(10) via methylation,condension/dehydration,etc.Elaboration of the propionyl group of 7 by Grignard addition of nitril 13 with ethylmagnesium bromide as key step is described in this process.Three attempted approaches to synthsis pyridoneα-keto ester 17 are explored by employing pyridinone ester 15 and 6-cyanoindolizine 26 as starting materials,but all were unsuccessful.An alternative synthetic route to the key chiral building block(5’S)-pyridone hydroxy lactone was designed via diastereoselective nucleophilic ethylation of chiralα-keto este as key step,providing new approach to total synthesis of irinotecan and its analogues.All involved compounds are identified by IR,NMR,MS spectrum.