There is no abstract available for this thesis. / Department of Chemistry

The synthesis of 7-N-formyllavendamycin methyl ester (59), 7-N-formyldemethyl lavendamycin n-octyl ester (60), 7-N-formyldemethyllavendamycin ethyl ester (61), 7-Nformyldemethyllavendamycin amide (62), are described.The Pictet-Spengler condensation of 7-N-formamido-2-formylquinoline-5,8-dione (52) with (3-methyltryptophan methyl ester (4),L-tryptophan ethyl ester (54), DL-tryptophan n-octyl ester (56), DL-tryptophan amide (58) in dry distilled xylene or anisole directly afforded the four lavendamycin analogs 59 - 62.Aldehyde 52 was prepared according to the following general procedure: Nitration of 8-hydroxy-2-methylquinoline (43) with a 70 % mixture of HNO3 / H2SO4 yielded 8-hydroxy2-methyl-5,7-dinitroquinoline (44). Compound 44 was then reduced in the presence of 5 palladium on charcoal in a hydrochloric acid solution to yield 5,7-diamino-8-hydroxy-2 methylquinoline dihydrochloride salt (45). Treatment of the resulting 45 with trimethylacetic formic anhydride (49) at 25° C under an argon atmosphere afforded _5,7-diformamido-8hydroxy-2-methylquinoline (50). Compound 50 was oxidized by potassium dichromate to give the 7-formamido-2-methylqunoline-5,8-dione (51). Oxidation of 51 by selenium dioxide in refluxing dry and distilled 1,4-dioxane afforded 7-formamido-2-formylquinoline5,8-dione (52).Trimethylacetic formic anhydride (49) was prepared according to Fife's method29 by the treatment of sodium formate (47) with trimethylacetic chloride (46) in the presence of poly 4-vinylpyridine-N-oxide (48) as a catalyst in dry acetonitrile at room temperature under argon. Tryptophans 54, 56, and 58 were prepared through the neutralization of L-tryptophan ethyl ester hydrochloride, DL-tryptophan octyl ester hydrochloride and DL-tryptophan amide hydrochloride with a 14 % ammonium hydroxide solution followed by extraction.A sample of P-methyltryptophan methyl ester (4) was given to me by Wen Cai. Ester 4 has been prepared by the method reported by Behforouz et.al.23The structures of the novel compounds 52, 59, 60, 61, 62 were confirmed by iH NMR, IR, EIMS and HRMS.The structures of 44, 45, 49, 50, 51, 54, 56, 58, were also confirmed by 1H NMR and IR spectroscopy. / Department of Chemistry

The synthesis of several 6-Chlorodemethyllavendamycin analogs and their chemistry are described. In this investigation the following compounds were prepared:6-Chlorodemethyllavendamycin methyl ester, 6-Chlorodemethyllavendamycin ethylester, 6-Chlorodemethyllavendamycin butyl ester, 6-Chlorodemethyllavendamycin isoamyl ester, 6-Chlorodemethyllavendamycin octyl ester, and 6-Chlorodemethyllavendamycin amide. Pictet Spengler condensation of 7-amino-6-chloro-2-formylquinoline-5,8-dione with tryptophan methyl ester, tryptophan ethyl ester, tryptophan butyl ester, tryptophan isoamyl ester, tryptophan octyl ester, and tryptophan amide in anisole afforded the compounds. 7-amino-6-chloro-2-formylquinoline-5,8-dione was prepared according to the following general procedures.The first step is the nitration of 8-Hydroxy-2-methylquinoline. 8-Hydroxy-2methylquinoline is reacted with 70% mixture of HNO3/H2SO4 to produce 5,7-dinitro-8hydroxy-2-methylquinoline. The next step requires hydrogenation and acylation. 5,7Dinitro-8-hydroxy-2-methylquinoline was reduced by H2/Pd-C in the presence of HCl and H20 filtered and then treated with sodium sulfite, sodium acetate and acetic anhydride to yield 5,7-diacetamido-8-acetoxy-2-methylquinoline. 5,7-Diacetamido-8-acetoxy-2methylquinoline was oxidized by potassium dichromate to produce 7-acetamido-2methylquinoline-5,8-dione. 7-Acetamido-2-methylquinoline-5,8-dione was chlorinated using hydrogen chloride gas in dry methanol producing 7-amino-6-chloro-2methylquinoline-5,8-dione. Treatment of 7-amino-6-chloro-2-methylquinoline-5,8-dione with selenium dioxide, under reflux in 1,4-dioxane produced 7-amino-6-chloro-2formylquinoline-5, 8-dione.All structures were confirmed by 'H NMR, IR, EIMS, and HRMS. / Department of Chemistry

The synthesis of 7-N-acetyl-3'-demethyllavendamycin propyl ester (61 ), 7-N-butr-3'-demethyllavendamycin amide of N,N-dimethylethylenediamine (62), 7-N-acetyllavendamycin butyl amide (64), 7-N- acetyllavendamycin amide of ethanolamine (63) are described. Incorporation of the Pictet-Spengler condensation of 7acetamido-2-formylquinoline-5, 8-dione (32) or 7-butyramido-2-formylquinoline-5, 8dione (7) with tryptophan propyl ester (65), L-tryptophan amide of N, N dimethylethylenediamine (66), f3-methyltryptophan butyl amide (68), or methyltryptophan amide of ethanolamine (67) in xylene afforded four lavendamycin analogs.Aldehydes 32, 74 and 86 were prepared according to the following general procedure. Nitration of 8-hydroxy-2-methylquinoline (69) yielded 8-hydroxy-2-methyl - 5,7-dinitroquinoline (29). Compound 29 was then hydrogenated and acylated with acetic anhydride or butyric anhydride or 2-furoyl chloride followed by hydrolysis to yield 5,7diacetamido-8-hydroxy-2-methylquinoline (75) or 5,7- dibutyramido-8- hydroxy-2methylquinoline (73) or 5,7-difuroylamino-8-hydroxy-2- methylquinoline (84). Compounds 75 and 73 and 84 were oxidized by potassium dichromate to give the corresponding 5,8-diones 31 or 72 or 85. Treatment of 31 or 72 or 85 with selenium dioxide in refluxing 1,4-dioxane afforded compounds 32 and 74 and 86, respectively.Tryptophan propyl ester (65) was synthesized via a Fischer esterification of Ltryptophan with propyl alcohol saturated with hydrogen chloride. Compounds 66, 67, 68, 76, 77, 78, 79, and 80 were synthesized via the conversion of esters to amides with dimethylaluminum amides. Tryptophan methyl ester (23) and (3-methyltryptophan methylester (11) were treated with premixed trimethylaluminum and primary amines and refluxed to afford the desired tryptophan and (3-methyltryptophan amides.The structures of the novel compounds 61, 62, 63, 64, 66, 67, 68, 76, 77, 78, 79, 80, were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of Compounds 66, 68, 76, 77, 78 and 80 were also included. 1H NMR and IR for known compounds 29, 30, 31, 32, 71, 73, 74, 75, 84, 85, 86 were provided also. / Department of Chemistry

The synthesis of 6-methoxylavendamycin methyl ester (39) and 6-methoxy detnethyllavendamycin methyl ester (40) is reported. Also the synthesis of 7-propionamido-2-methylquinoline-5,8-dione (33) and 7propionamido-3-methylquinoline-5,8-dione (34) via the Diels-Alder reaction is described.The Pictet-Spengler condensation of 7-amino-6-methoxy-2-formylquinoline-5,8-dione (37) with 8-methyltryptophan methyl ester (4) and tryptophan methyl ester (38), produced respectively the lavendamycin analogs 39 and 40.Aldehyde 37 was prepared by the oxidation of 7-amino-6-methoxy-2methylauinoline-5,8-dione (47) with selenium dioxide under reflux in dry 1,4-dioxane.Our original plan for the synthesis of aldehyde 37 via 7-bromo-6methoxy-2-methylquinoline-5,8-dione (36) was not successful. The DielsAlder reaction of 3-methoxy-2,6-dibromobenzoquinone (35) and N-(O-(t-butyldimethylsilyloxy)]-2-methyl-1-aza-1,3-butadiene (11) gave a very low yield of 36 and consequently this route was abandoned.An alternate known multistep route was chosen to produce the bromoquinolinedione 36. Reaction of 4-methoxy-2-nitroaniline (41) with crotonaldehyde (42) gave 6-methoxy-2-methyl-8-nitroquinoline-5,8-dione (43). Subsequent nitration, reduction, oxidation, and bromination of mononitroquinoline 43 yielded the desired bromoquinolinedione 36 with success. A change to Boger's procedure in the next reaction involving the azido intermediate 46 was done due to its effectiveness in producing a greater yield and purer product than that of Liao's procedure. The final preparation of 7-amino-6-methoxy-2-methylquinoline-5,8-dione (47) was accomplished by the hydrogenation of azidoquinolinedione 46 in the presence of platinum oxide in anhydrous methanol.Two other quinolinediones, 33 and 34, were earlier synthesized using the Diels-Alder reaction. Quinolinediones 33 and 34 were prepared by reacting 2-propionamido-6-bromobenzoquinone (32) with azadienes 11 and 19 to respectively yield 7-propionamido-2-methylquinoline-5,8-dione (33) and 7propionamido-3-methylquinoline-5,8-dione (34).Bromobenzoquinone 32 was prepared according to Kelly's method of preparation. 2,4-Dibromophenol (48) was nitrated, reduced, propionylated, hydrolyzed, and finally oxidized to produce 2-propionamido-6bromobenzoquinone (32). / Department of Chemistry