Camtobell hydrochloride synthesis

The total synthesis route is depicted in the Scheme. The known pyridinone 7 was converted to the bicyclic pyridinone 8 by treatment with methyl acrylate and K2CO3 in DMF. Hydrolysis and decarboxylation of 8 to ketone 9 was effected by refluxing in a mixture of HOAc and conc. HCl under nitrogen. Ketalization was performed in a two phase system of toluene and ethylene glycol to provide ketal 10 in 90% yield. Functionalization of the methyl group in 10 using diethyl carbonate in the presence of KH furnished the ester 11 in 76% yield. Ethylation of 11 was accomplished by use of KOBut and EtI in DME. Catalytic hydrogenation of 12 using Raney Ni in a mixture of Ac2O and HOAc gave the amide 13. Removal of the catalyst by filtration followed by addition of NaNO2 to the filtrate gave the N-nitroso amide. Decomposition of the nitroso amide by heating in an inert solvent (CCl4) gave the acetate 14. The diester 14 was lactonized by LiOH in MeOH/H2O to give lactone 15 in 92% yield. The carbonyl group in 15 was then reduced with DIBAL-H in THF to give lactol, which was dehydrated via its mesylate to afford 16. The asymmetric dihydroxylation of 16 gave diasteromeric mixtures in favor of the desired isomer 17 (81% d.e.). Compound 16 was then oxidized directly with iodine in the presence of CaCO3 to give a-hydroxy lactone 18. The deketalization was accomplished by HCl in THF/H2O to provide the ketone 19. Condensation of ketone 19 and the amine 20 in the presence of p-TSA followed by hydrolytic removal of Cbz group provided the free base Which was convert to its corresponding HCl salt as belotecan hydrochloride (II).