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Synthesis of substrate analogues and inhibitors for phosphoribosyl anthranilate isomerase and indole-3-glycerolphosphate synthase : a thesis presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University, Turitea, Palmerston North, New Zealand
The general biosynthetic pathway for tryptophan is known. However, little information has been gathered on how substrates and enzymes interact when phosphoribosylanthranilate isomerase (PRAI) and indole-3-glycerolphosphate synthase (IPGS) convert a substituted phenyl ring, PRA, into an indole moiety, IGP, via 1-(O-carboxyphenylamino)-1-deoxyribulose-5-phosphate (CdRP). There has been no serious synthetic approach to develop methodology to produce a plethora of substrate and product analogues of CdRP. The studies described in this thesis cover methodology focusing on secondary aryl amine formation, using reductive amination, nucleophilic substitution and epoxide ring opening, leading to CdRP analogues. Reductive aminations with D-ribose failed to produce any aryl glycosylamine precursor, possibly due to the low nucleophilicity of aryl amines such as aniline. Removing the aromaticity and using cyclohexylamine produced secondary amines in moderate yield in the presence of benzylpentanal, and NaBH3CN, at a pH of 5.5. This led to a successful reductive amination using anthranilate methyl ester. Secondary aryl amine synthesis via epoxide ring opening proved consistently reproducible. Using LiNTf2 and high equivalents of cyclohexylamine or aniline in neat conditions opened protected epoxides. This has led to the formation of advanced secondary aryl amine synthons and the development of methodology leading to target compounds with functionality at the 1,2 and 5 positions. Nucleophilic substitution using caesium base, high equivalents aniline at room temperature, gave a moderate yield of secondary aryl amines from sulfonyl and bromide good leaving groups. Raising the reaction temperature improved yields using low equivalents of aniline, with the optimal temperature being 50 °C. Ultimately using both the high equivalents of aniline or anthranilate methyl ester and warming the reaction in DMF gave the highest yields of secondary aryl amines. No overalkylated tertiary amine was isolated when a caesium base was used. Boc N-protection of 1-phenylamino-4-pentene and asymmetric dihydroxylation gave the corresponding diol, which was phosphorylated giving the protected target 1,4,5 compound. The methodology leading to the protected target 1,4,5 compound synthesis provides a means to the synthesis additional of CdRP analogues.