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Synthesis of Some Valine Derivatives As Potential Antibacterial Agents Frederick Nelson Minard Iowa State College

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Synthesis of Some Valine Derivatives As Potential Antibacterial Agents Frederick Nelson Minard Iowa State College Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1949 Synthesis of some valine derivatives as potential antibacterial agents Frederick Nelson Minard Iowa State College Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Biochemistry Commons, Microbiology Commons, and the Organic Chemistry Commons Recommended Citation Minard, Frederick Nelson, "Synthesis of some valine derivatives as potential antibacterial agents " (1949). Retrospective Theses and Dissertations. 13722. https://lib.dr.iastate.edu/rtd/13722 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. NOTE TO USERS This reproduction is the best copy available. UMI SYNTHESIS OF SOME VALINE DERIVATIVES AS POTENTIAL ANTIBACTERIAL AGENTS by Frederick N* Minard A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of The Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Subjects Oheiaist Approved! Signature was redacted for privacy. In CSiarge of/Major Work Signature was redacted for privacy. Head of Maj(^ Dei^rtment Signature was redacted for privacy. fill ti Fi(l Miir' r,! r^r . m Dean of Graduate CollegeCo] Iowa State College 19»fr9 UMI Number: DP12856 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. UMI UMI Microform DP12856 Copyright 2005 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 -11- o.x>ssi /vt <3 <3 1 s TiiBLi^ OF CaWTiSiN'TS IMTaQDUGTIOS . • . • INITIOS OF TiSKMS HISTORICAL The Structure of Peptlde-llke Antibiotics iLKPMIMJNfAL ••••••••••• Preparations Helated to the Problem • . Phthaloyl-D^valine .••••• Phthaloyl-cJ-valine monohydrate • • Phthaloyl-^ and valine • • • • cis-l.2-GyclQbutanedloarbonvl- valine ola-1. 2-Cyclobutanedlcarbony 1-^ valir» monohydrate •••••••• Ola-1,2-Gy c lobu taned icar boHQr ^ Bionohydrate •• .«•••• olB-l. 2-Cyolobutanedlcarbony 1-^vallne monohydrate *••••••• Procedure for hydrolysis of the imldes o-Carboxybenzoyl-Mf-vallne ... £-Carb03Qrbenzoyl-i5-vallm • • • . £-Garboxybenzoy 1-5-valine . « . ^ ^la-2-Qar bo xycycl^utaneoar bo nyl-QL-valine 33 cla-g-Garboxycyclobutaneoarbonyl-^valine 33 ci8-2-Gar bo xycyolobutanecarbonyl-^ valine Maleyl-D|j-vallne • • • • Maleyl-S- and L-valine . • Fumaryl*dl-I^vallne . Itaconlo anl^drlde . • • Gltraconlc anhydride • • j&thyl Itaconyl-DL-vallnate Itaconyl-D^valme • • • % endo-cls-^?6-iilndomethylene- tetrahydro- phthalovi-DL-valine ••••••• 39 endo-cla-3,6^ndomethylene- tetrahydro- phtCToyl-|i-valine . 39 N-Phenvl-endo-oiB-5,6-endoine thy lene- tetrahydrophthalimlde 40 endo-clB-3.6-andoffiethylene- A^-tetrahydro- phthalanilic acid. • . • •• • 41 4-Hy droxy-clj|-3»6-endometi:Qrlenehexahydro- phthalic aold V-lactone . • • • 42 -lli- 2-Carboxy-4-hydro3qr-ol8-3»6-endomethyl0n©- hexahydrobenzanlXlde '^-Xaotone . • • 42 Methyl ester of 2-carboxy-4-hydro3qr-,2i£- 3,6-®ndoma thylenehexalj^drobenzoyl-gf^ valine V-lactone .43 2»0arboxy-4-hydroxy"ClB-3,6-endoBie thy lene- hexahydrobenzoyl-D]^valine 'I'-lactone . 44 Methyl ester of 2-oa!^oxy"4-hydroxy~clg- 3 > o-endome thylenehe xahydrobenzoic acid ^-lactone ..........45 2-Gsurboxy-4-hydrQxy-trang-3,S -endoae thy 1- enehexahydrobenaolc acid '/-lactone , . 46 2-Garboxy-4-hydroxy-trang-3,6-endoiaQthy 1- enehexahydrobenzoyl-£j^valIne -lactone 46 Miscellaneous Preparations .•••.••47 ^-Valine methyl ester hydrochloride . 4? ^^Vallne n-butyl ester sulfate • • • • 48 ASatyl-DL-vallne 48 Benzoyl^^vallne methyl ester . • . 49 W-{n-3utyT)-phthalamic acid ..... 50 cls-1.2-Qyolobutanedicarboxlatide ... 51 ois-l. 2-Oyolobutanedicarboxainic acid • . 51 Resolution of D^vallne by the brucine salt method ••••••.... 52 Purification of recovered brucine ... 55 Attempted enzymio resolution of J^valine 55 M-Phenylphthallmide precipitations ... 57 DISCUSSION 59 SUMMAHSt 63 AaKWOWLfiy}GM£iiTS 65 INTRODUGTIOH Among tha features of many peptide-like antibiotics are specific structures and the occurrence of certain amino acids in the atypical fom. Because the field of anti­ biotics is recent in development, there has been vei^ little report of research which is directed toward the correlation of antibacterial activity with structure and optical iso- marisja. Undoubtedly there will be a trend away from the isolation of antibiotics and toward the preparation of materials similar to them, but only after their structural characteristics have become more known and evaluated, fhe present thesis involves the synthesis of acyl derivatives of valine which may possibly have antibacterial action. The acyl groups have been chosen because they offer a wide range of structures, and many of them can occur as geometrical isomers. The three optical forms of valine have been in­ corporated into some of the derivatives. Valine was selected since it is fairly common in antibiotics, sometimes occurring as the SL form, and sometimes as the ••D form. There are no clearly defined principles enabling one to predict structures which can give antibacterial activity to amino acid derivatives. In other investigations of sub­ stances exhibiting a biological effect, success has often been obtained by the screening of many types of structures. -2- A bacteriological invastigation of the compounds prepared for this thesis may offer a guide to such principles* DiiFIillTlON OF TSRMS A uasful dafinltion of an antibiotic ia that given by VVaksman (1): An antibiotic ie **a chemical substance pro-> duced by mlcroorganisias which has the capacity to inhibit the growth of bacteria and other microorganisms and even to destroy them," Inhibition may be considered as a retardation or ces­ sation of enzymic processes within a microorganism caused by an influence usually foreign to that organism and evidenced by a lack of growth or multiplication. Waksman (1) has defined antagonism as the phenomenon of a living organism inhib­ iting or interfering with the activities of another living organism as a result of the creation of unfavorable conditions in the medium or the production of a specific anti­ microbial substance. Tha atypical configuration of an amino acid is the anti- pode of that isomer which usually occurs in nature. Since this antipode sometimes does occur naturally, the often-used term "unnatural configuration" is not properly descriptive. (1) Waksman,"microbial Antagonism and Antibiotic Sub­ stances," p. 331. The Goamonwealth Fund. New York, 1947. -4- HISTORIGAL The Structure of Peptlde-llke Antibiotics It la believed that Paateur and Joubert (2) were the first to call attention to bacterial antagonism and to sug­ gest its use against infections. Since then, but only after a long lapse of time, there has been developed a large back- grouiKi of chemical and microbiological information concerning antagonism and the metabolic products which cause it. These products have been termed "antibiotics" by waksman (3). In 1899 Smmerlch and Leow (4) reported the antibacterial acti­ vity of the culture medium from Paeudomonas pyocyaneus (Pseu- domonas aeruginosa) as being due to a substance "pyocyanase." This was the first antibiotic discovered. Subsequent reports of antibiotic materials were the following: penloillic acid in 1913 (5)» actinomycetln in 1924 (6), penicillin in 1929 {?)» citrinin in 1931 (8)# and gliotoxln in 1936 (9)« A surge of Interest in the antibacterial effects of these metabolic products began in 1939 when Dubos and (2) Pasteur and Joubert, Gompt. rend.. §5, 101 (1877). (3) vvaksman. Horning, Vvelsch, and Woodruff, Soil Scl.. 261 (1942). (4) .Sffiaerlch and Leow, 2. Hy«. Infekt. K«. 1 (1899). (5) Alsberg and Black, U. Dept. Aizxlc. Bur. Plant Ii^.. Bull. Mo. 270 (19137. (6) Gratia and Dath, Goaot. rend, soc. biol.. 91. 1442 (1924). (7) Fleming, Brit, g, 2^{1929j. (8) Hetherlngton and Raistrlck, Trans. Roy. Soc. (London). 220. 269 (1931)• Original not seen. Abstracted in C. A., 2486 (1932). (9) Weindling and iSmerson, fhy to pathology. 26. 1068 (1936). -5 Qattanao (10) reported the strong activity of tyrothricin, a protein fraction isolated from cultures of Bacillus brevis. Since then numerous other antibiotics have been isolated and investigated both chemically and bacteriologically. This review will consider only those antibiotics which have been shown to contain or can poseibly be derived from amino acids, and whose structure may contribute something to the problem. *»ith several possible exceptions the complete structures of these antibiotics are unknown. This lack of Information is perhaps due to a variety of reasons, of which the following are Importants the molecules are often very complex in char­ acter, protein
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