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. / Department of Chemistry

published_or_final_version / Chemistry / Master / Master of Philosophy

The synthesis of several 7-substituted analogs of 2-methylquinoline-5,8-dione and their chemistry are described. In this investigation the following compounds were prepared.5,7-Diformamido-8-hydroxy-2-methylquinoline (207), 7-formamido-2methylquinoline-5,8-dione (199), 7-acetamido-2-methylquinoline-5,8-dione (6), 7-isobutyramido-2-methylquinoline-5,8-dione (200), 7-amino-2-methylquinoline-5,8-dione (210), 7-amino-6-chloro-2-methylquinoline-5,8-dione (213), 7-methoxy-2-methylquinoline5,8-dione (214), 7-ethoxy-2-methylquinoline-5,8-dione (215), 7-isopropyloxy-2methylquinoline-5,8-dione (216), 7-amino-5-ethyl-5-hydroxy-2-methylquinoline-8-one (218), 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220), and 7-chloro-2methylquinoline-5,8-dione (222).Trimetylacetic formic anhydride (206) was prepared according to McGarvy,s 68 method from treatment of sodium formate (204) and trimethylacetyl chloride (203) in the presence of poly (4-vinylpyridine-N-oxide) (205) as catalyst. 7-Formamido-2methylquinoline-5,8-dione (199) was prepared according to the following general procedure. 8-Hydroxy-2-mehylquinoline (5) was reacted with a 70% mixture of HNO3/H2SO4 to produce 5,7-dinitro-8-hydroxy-2-methylquinoline (18). Compound 18 was reduced by H2/Pd-C in the presence of HCl and then the resulting 5,7-diamino-8-hydroxy-2 methylquinolin-5,8-dione hydrochloride salt (198) reacted with trimethylacetic formic anhydride to produce 5,7-diformamido-8-hydroxy-2-methylquinoline-5,8-dione (207). Compound 207 was treated with a solution of potassium dichromate in acetic acid-water mixture to give product 199.7-Acetamido-2-methylquinoline-5,8-dione (6) was prepared from reaction of a solution of 198 with acetic anhydride in the presence of sodium acetate and sodium sulfite followed by oxidation with potassium dichromate in acetic acid-water solution. 7-Isobutyramido-2methylquinoline-5,8-dione (200) was prepared according to following procedure. Treatment of a solution of 198 with isobutyric anhydride in the presence of sodium acetate and sodium sulfite afforded 5,7-diisobutyramido-8-isobutyroxy-2-methylquinoline (212). Partial hydrolysis of 212 in boiling methanol-water mixture gave 5,7-diisobutyramido-8-hydroxy-2methylquinoline (211). Oxidation of 211 by a solution of potassium dichromate in acetic acid-water mixture afforded product 200.7-amino-2-methylquinoline-5,8-dione (210) was prepared from alcoholysis of 7-acylamino-2-methylquinoline-5,8-diones 6, 199,and 200 with methanol and sulfuric acid. 7-Alkoxy-2-methylquinoline-5,8-diones 214, 215, and 216 were prepared from reaction of 7-acetamido compound 6 with alcohols in the presence of sulfuric acid. Reaction of 7-acylamino compounds 6, 199, and 200 with methanol in the presence of hydrogen chloride gas at 60°C afforded 7-amino-6-chloro-2-methylquinoline-5,8-dione (213).Reaction of compound 210 with diethylaluminum cyanide gave 7-amino-5-ethyl-5hydroxy-2-methylquinoline-8-one (218). The same reaction was carried out on compound 6 to give 7-acetamido-5-ethyl-5-hydroxy-2-methylquinoline-8-one (220).1-[(tert-Butyldimethylsilyl)oxy]-2-methyl-l-aza-1,3-butadiene (4) was prepared from treatment of methyl vinyl ketone (210) and t-butylmethylsilylhydroxylamine (202) in dichloromethane in the presence of molecular sieves. Cycloaddition reaction of a solution of 4 in dichloromethane with 2,6-dichloro-1,4-benzoquinone (221) in sealed tube afforded 7-chloro-2-methylquinoline-5,8-dione (222). / Department of Chemistry

The synthesis of 7-N -furoyllavendamycin methyl ester (35), 7-N -furoyl demethyllavendamycin methyl ester (36), 7-N -furoyldemethyllavendamycin ethyl ester (37), 7-N -furoyldemethyllavendamycin propyl ester (38), 7-N -furoyl demethyl lavendamycin butyl ester (39), 7-N -furoyldemethyllavendamycin isoamyl ester (40),7-N -furoyldemethyllavendamycin cyclohexyl ester (41), 7-N -furoyldemethyl lavendamycin octyl ester (42), 7-N -furoyldecarboxydemethyllavendamycin (43), and demethyl lavendamycin isoamyl ester (44) are described. Pictet-Spengler condensation of 7-furoylamino-2-formylquinoline-5, 8-dione (55) with (3-methyltryptophan methyl ester (4), Ltryptophan methyl ester (56), L-tryptophan ethyl ester (57), L-tryptophan propyl ester (58), L-tryptophan butyl ester (59), L-tryptophan isoamyl ester (60), L-tryptophan cyclohexyl ester (61), L-tryptophan octyl ester (62), L-tryptamine (63), in xylene, or anisole afforded ten lavendamycin analogs.Aldehyde 55 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) gave 8-hydroxy-2-methyl-5,7dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with 2-furoyl chloride (or acetic anhydride ) to yield 5,7-difuroylamino-8-hydroxy-2-methylquinoline (53) or 5,7-diacetamino-8-acetoxy-2-methyl- quinoline (33). Compounds 53 and 33 were oxidized by potassium dichromate to give the corresponding 5,8-diones 54, and 27. Treatment of 53, and 27 with selenium dioxide in refluxing wet dioxane afforded compounds 55 and 28.Compound 4 was previously prepared by other members of our group, compounds 56, 57, 59, and 62 were obtained through the neutralization of the corresponding Ltryptophan ester hydrochlorides with a 14% ammonium hydroxide solution followed by extraction. Compounds 58, 60, 61 were synthesized via a Fischer esterification of Ltryptophan with : propyl alcohol, isoamyl alcohol, and cyclohexyl alcohol saturated with hydrogen chloride.The structures of compounds 53, 54, 55, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 53, 54, and 55 are also included.The structures of esters 56, 57, 58, 59, 60, 61, 62, and 63 were confirmed by 1H NMR. / Department of Chemistry