Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin.
Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of alpha-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl alpha-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (+/-)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).
Bennasar
M-Lluïsa
ML
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain. bennasar@farmacia.far.ub.es
Zulaica
Ester
E
Juan
Cecília
C
Alonso
Yolanda
Y
Bosch
Joan
J
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry*; D004952:Esters; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D011726:Pyridinium Compounds; D013237:Stereoisomerism
D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D007202:Indicators and Reagents; D011726:Pyridinium Compounds; D002166:Camptothecin