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Thesis (M. Diploma in Technology (Chemistry))--Cape Technikon, 1994 / Some naturally occurring compounds containing the naphtho [2,3 - c] pyran ring system have been found to be useful antibiotic agents and thus the laboratory synthesis ofthese compounds and their derivatives are of importance in the medical field. Their antibiotic and even antineoplastic activities are attributed to their potential to act as alkylating agents, via a bioreductive process. This thesis deals with studies directed towards the synthesis of some benzo [c] pyrans as these compounds also possess the correct structural configuration to undergo the bioreductive process, and act as alkylating agents to cellular nucleic acids. Chapter Two describes the synthesis 00,4 dihydro - 1,3 - dimethyl- IH - benzo - [cl pyran - 5,8 - quinone (13) by employing a base induced cyclization with potassium tertiary butoxide. This compound was proven to be biologically active against both Gram positive and Gram negative organisms. (±) (1R, 3R, 4R) - 3,4 - Dihydro - 4 - hyroxy -1,3 - dimethyl- 1H - benzo [e] pyran - 5,8quinone (17) and its 4 S diastereomer (18) were synthesized with cerium (IV) ammonium nitrate as the cyclizing reagent. Antimicrobial evaluation ofcompound (17) displayed inhibitory activity against both Gram positive and Gram negative organism growth. This is discussed in Chapter Three. In Chapter Four, the synthesis ofthe benzo analogue ofthe naturally occurring naphthopyran antibiotic, hongconin, is discussed. The synthetic route used for this synthesis could well be applied to synthesise hongconin.

Graduation date: 1999

This thesis is divided into two parts: Part 1 (i) The Synthesis of a Biologically Active Analogue of Antibiotic A-32390A Methodology for the preparation of vinyl formamides from thiooximes has been developed for use with α-carboxy systems and successfully applied to the synthesis of (2S, 3S)-2,3-di-[hydroxybutane]-1,4-di-[2-isocyano-3-methyl-but-2-enoate], a vinyl isonitrile that is a biologically active analogue of the natural product, antibiotic A-32390A. In addition trifluoromethane sulfonic anhydride has been shown to be an effective reagent for the dehydration of vinyl formamides to vinyl isonitriles in these systems. (ii) The Synthesis of (±)-Isonitrin C (Trichoviridin) Further application of the methodology for the synthesis of vinyl formamides from thiooximes allowed for the effective preparation of 1α-(1'-^t-butyldimethylsilyloxyethyl)-2β, 3β-epoxy-4-en-4-isocyano-cyclopentan-1β-ol, a key intermediate in the syntheses of the naturally occurring vinyl isonitriles, (±)-isonitrin A and (±)-isonitrin B. New methodology was developed for the synthesis of the epoxy-isonitrile functionality of (±)-isonitrin C (trichoviridin). Masking of the isonitrile functionality of 1α-(1'-^t-butyldimethylsilyloxyethyl)- 2β, 3βp-epoxy-4-en-4-isocyano-cyclopentan-1β-ol by formation of the corresponding dibromoimine was followed by epoxidation of the C-C double bond with methyl (trifluoromethyl)dioxirane and removal of the bromine groups to regenerate the isonitrile moiety. Deprotection afforded (±)-isonitrin C (trichoviridin). (iii) Mechanism of the Thiooxime Rearrangement Some insight into the mechanism of the thiooxime rearrangement was obtained by ¹³C n.m.r. experiments and elucidation of the reaction by-products. Part 2 A flexible route to optically pure γ-keto-α-amino acids using carbon based nucleophilic ring opening of activated monocyclic β-lactams has been established. Nucleophiles examined include lithiated sulfones, Lipshutz higher order organocuprates and lithiated phosphonates. This methodology has been applied to a high yielding synthesis of the naturally occurring potent ACE inhibitor WF-10129. The stereochemistry of WF-10129 was established, by synthesis of all possible diastereomers, to be S at all stereocentres.

The synthesis of 7-acetyl-11'-benzyloxylavendamycin methyl ester (47), 7acetyl-11'-hydroxylavendamycin methyl ester (48), 11'-hydroxylavendamycin methyl ester (49), 11'-benzyloxylavendamycin methyl ester (50), are described. Pictet-Spengler condensation of 7-N-acetyl-2-formylquinoline-5,8-dione (26) with 5-benzyloxytrytophan methyl ester (45) or 5-hydroxytryptophan methyl ester (46) in dry xylene or anisole directly afforded lavendamycin analogs 47 or 48. Compound 49 was obtained by hydrolysis of 48 with 70% H2SO4 - H2Osolution. Compound 50 was obtained by hydrolysis of 47 with sodium carbonate solution.Aldehyde 26 was prepared according to the following general procedure. Nitration of 8-hydroxy-2-methylquinoline (28) yielded 8-hydroxy-2-methyl5,7-dinitroquinoline (29). Compound 29 was then hydrogenated and acylated with acetic anhydride to yield 5,7-bis(diacetamido)-8-hydroxy-2methylquinoline (31). Compound 31 was oxidized to give 5,8- dione 25 by using potassium dichromate. Treatment of compound 25 with selenium dioxide in refluxing 1,4-dioxane yielded compound 26.3 (Isopropylaminoethylidene)-6,7-dimethoxyindole (39) was prepared via the following procedure. Acylation of vanillin (32) with acetic anhydride yielded acetylvanillin (33). Compound 33 was nitrated and hydrolyzed to give 2nitrovanillin (35). Compound 35 was then methylated using dimethyl sulfate to produce 2-nitroveratric aldehyde (36). Condensation of compound 36 with nitromethane yielded 3,4-dimethoxy-2-f3-nitrostyrene (37). Ammonium formate reductive cyclization of compound 37 in refluxing methanol in the presence of a catalytic amount of 10% palladium on charcoal yielded 6,7dimethoxyindole (38). Electrophilic substitution reaction of compound 38 with ethylideneisopropylamine (41) in dry toluene yielded compound 39.Methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)]butanoate (45) and methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)]butanoate (46) were obtained following the procedure described below. Electrophilic substitutionreaction of 5-bezyloxyindole (40) with ethylideneisopropylamine (41) in dry toluene yielded 3-(isopropylaminoethylidene)-5-benzyloxyindole (42). Condensation of compound 42 with methyl nitroacetate (43) in dry toluene gave methyl 3-[3-(5-benzyloxyindolyl)]3-nitrobutanoate (44). Hydrogenation of compound 44 in the presence of Raney nickel and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)] butanoate (45). Hydrogenation of compound 44 in the presence of 10% palladium on charcoal and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)] butanoate (46).The structures of the novel compounds were confirmed by 1H NMR, IR, and HRMS or elemental analysis. / Department of Chemistry

The chemistry of quinonline-5,8-dione as a functional group is a developing field because of its various biological aspects. Lavendamycin and streptonigrin are known antibiotic, antitumor agents containing the quinolone-5,8-dione functional group believed to provide their antitumor properties. Most cancer cells show an elevated level of NQO1 enzyme which activates lavendamycin to act as an antitumor agent. The research goal is to explore different synthetic methods and reactions to produce novel quinolone-5,8-dione analogues with unique structural features while keeping the selective cytotoxicity. Lavendamycin contains a β-carboline and streptonigrin has a substituted pyridine connected to the 2-position of the quinolone-5,8-dione. The overall goal of this project will develop synthetic methods to create 1,2,3-triazoles and 1,2-diazoles attached to the quinoline moiety from azides and diazonium salts, respectively. In order to accomplish this, 8-hydroxyquinoline undergoes through a four step synthesis to install an azide at the two position of the quinoline ring. 8-Hydroxyquinoline was oxidized to produce 8-hydroxyquinoline-N-oxide, converted into 8-acetoxy-2-hydroxyquinoline with acetic anhydride, reacted with POCl3 to produce 2-chloro-8-hydroxyquinoline, and treated with sodium azide to form 2-azido-8-hydroxyquinoline. However it was found that the product cyclized to yield 8-hydroxy-tetrazole[1,5-a]quinoline. In the quinoline-5,8-dione synthesis, 7-amidoquinoline-5,8-dione is prepared through a three step synthesis. 8-Hydroxquinoline was nitrated to form 8-hydroxy-5,7-dinitroquinoline, hydrogenated/acylated to give 5,7-diacetamido-8-acetoxyquinoline, and oxidized to yield 7-acetamidoquinoline-5,8-dione. In order to reach the end of this project, the four step tetrazole and the three step quinoline-5,8-dione syntheses required merging. Further research will focus on the optimization of these syntheses. / Synthesis of 8-hydroxy-tetrazole [1,5-a] quinoline -- Synthesis of 7-amino-quinoline-5,8-dione -- Novel synthesis of quinoline-5,8-dione analogues. / Department of Chemistry

This thesis is divided into two parts: Part One describes synthetic approaches to the naturally occurring antibiotic Lactivicin (1) and its acylamino derivatives, involving the condensation of protected L-cycloserine with 2-oxoglutaric acid. The phenoxyacetyl-amino derivative (2) exhibited antibacterial activity. A method was developed for the selective deprotonation of the endocyclic amide of the protected cycloserine; the resulting anion was then quenched with various electrophiles. In this manner, the Lactivicin analogues (3) and (4) were prepared. Whilst (3) was biologically inactive, (4) showed appreciable antibacterial activity. [See pdf file for chemical structures (1)-(4)]. Part Two details the use of N-benzoylamino-2-bromoglycine methyl ester, a glycidyl radical precursor, as a novel a-amino acid synthon. Its synthetic utility in free radical reactions was demonstrated with 2-functionalised allylstannanes as allyl transfer reagents, to produce a range of substituted a-allylglycines. Using this procedure, the naturally occuring amino acid, 4-methyleneglutamic acid, was prepared in its racemic form. Studies on the extension of this methodology to the asymmetric synthesis of a-amino acids are also described. A synthesis of (alpha)-allenylglycine, a previously undocumented amino acid, was developed. The synthetic route involves the Lewis acid mediated reaction of propargyltriphenylstannane with N-benzoylyamino-2-bromoglycine methyl ester, followed by aqueous acidic deprotection.

This thesis reports the work done on two research projects which were carried out independently of each other but converge on the central theme of β-lactam biosynthesis. Chapter 1 provides an overview of biosynthesis in secondary metabolism, with special emphasis on current knowledge about the β-lactams. The first project, covered from Chapters 2 to 5, was part of our group's continuing effort to understand the structure and mechanism of Ring Expandase-Hydroxylase (REXH), an enzyme involved in the biosynthesis of cephalosporin C in Cephalosporium acremonium. REXH is a bifunctional enzyme, converting penicillin N to DAOC and thence to DAC. [diagram omitted from transcription] Chapter 3 discusses the investigation of purification protocols for native REXH and soluble recombinant REXH, as well as an improved refolding method for recombinant REXH expressed as inclusion bodies. Chapter 4 describes two new alternative substrates for REXH, viz. carba-DAOC and DAC, whilst the y-lactam analogue of penicillin N was not found to be a substrate for REXH. Chapter 5 summarises some structural investigations of REXH employing methods such as electrospray mass spectrometry, selective proteolysis and inhibition kinetics. [diagram omitted from transcription] The second project, covered from Chapters 6 to 9, represents the first biosynthetic studies on valclavam, an antifungal produced by Streptomyces antibioticus. Valclavam belongs to the family of clavams which includes clavulanic acid as its most well studied member. [diagram omitted from transcription] Chapter 7 details the development of methods for the bioassay, fermentation and isolation of valclavam. It also describes the isolation of a stable degradation fragment of valclavam which led to the revision of the structures of valclavam and Tü 1718B (another metabolite from the same organism). Chapter 8 gives an account of the whole-cell feeding experiments which strongly suggest that the primary metabolic precursors for valclavam are L-valine, L-arginine, L-methionine and glycerol. Chapter 9 reports the discovery of two enzymic activities, belonging to those of clavaminic acid synthase and proclavaminic acid amidino hydrolase, which are likely to be involved in the biosynthesis of valclavam. Together, the results of Chapters 8 and 9 point to an extensive overlap between the clavulanic acid pathway in Streptomyces clavuligerus and the valclavam pathway in Streptomyces antibioticus.