Total synthesis of lavendamycin esters and analogs

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Mohammadi, Farahnaz
Behforouz, Mohammad
Issue Date
Thesis (M.S.)
Department of Chemistry
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The purpose of this research was to synthesize 7-bromodeaminolavendamycin methyl ester (11), deaminolavendamycin methyl ester (19), 7-N-isobutyryldemethyllavendamycin methyl ester (54), 7-N-acetyldemethyllavendamycin ethyl ester (64), 7-Nisobutyryldemethyllavendamycin butyl ester (76), 7-N-isobutyryldemethyllavendamycin tbutyl ester (78), 7-N-cetyldemethyllavendamycin phenyl ester(79), and 7-Nisobutyryldemethyllavendamycin isopropyl ester (80).Lavendamycins 54, 64, 76, 80 were synthesized via the Pictet-Spengler condensation of the corresponding tryptophan esters with 7-N-acetamido-2-formylquinolinedione (91) or 7-N-isobutyramido-2-formylquinolinedione (92). 3-Carbomethoxy-l-( 8-hydroxyquinoline2-yl )-4-methyl-(3-carboline (18), and 3-carbomethoxy-l-(5-acetamido-8-acetoxy-7bromo-2-yl)-4-methyl-(3-carboline (109) were also prepared through the Pictet-Spengler condensation of p-methyl tryptophan methyl ester with 2-formyl-8-hydroxyquinoline (103) and 5-acetamido-8-acetoxy-7-bromo-2-formylquinoline (108), respectively.Compounds 18 and 109 were oxidized by potassium dichromate or Fremy's salt to give deaminolavendamycin methyl ester (19) and 7-bromodeaminolavendamycin methyl ester (11) respectively.7-Isobutyramido-2-formylquinoline-5,8-dione (92) was prepared according to the following general procedure. 8-Hydroxy-2-methylquinoline (26) was reacted with a 70% mixture of HNO3 / H2SO4 to produce 8-hydroxy-2-methyl-5,7-dinitroquinoline (39). Compound 39 was reduced by H2 / Pd-C and then reacted with isobutyric anhydride in the presence of sodium sulfite and sodium acetate to produce 88. Recrystallization of 88 with methanol gave 5,7-diisobutyramido-8-hydroxy-2-methylquinoline (98). Compound 98 was suspended in acetic acid and oxidized by a solution of potassium dichromate to give 7isobutyramido-2-methylquinoline-5,8-dione (90). The dione derivative 90 was oxidized by selenium dioxide in 1,4-dioxane to yield the target aldehyde 92. 2-Formyl-8hydroxyquinoline (103) was synthesized through a selenium dioxide oxidation of 8hydroxy-2-methylquinoline (26).Ester 96 was prepared by the Fischer esterification of L-tryptophan with an excess amount of isopropyl alcohol in the presence of dry HCI. L-Tryptophan phenyl ester (97) was prepared through a two-step reaction. NCBZ-L-tryptophan (101) was treated with phenol and BOP reagent in the presence of triethylamine in acetonitrile to yield NCBZ-L tryptophan phenyl ester (102). The N-protected ester was reduced to L-tryptophan phenyl ester (97) by ammonium formate in the presence of palladium on charcoal in N,Ndimethylformamide. Esters 93-95 were obtained by the treatment of their commercially available hydrochloride salts with 14% NH4OH and then extraction with ethyl acetate.The structures of the compounds 11, 18, 19, 54, 64, 76, 80, 88, 90, 92, 96, 97, 98, 102, 103, 106, 108 and 109 were comfirmed through tH NMR, IR, and MS. Elemental analyses of 90, 92, 96, 98, 103 and 106 and HRMS of 98, 19, 54, 76, 95, 109 are also included. 1H NMR are also provided for compounds 39, 94,95.