3-Amino-5-hydroxybenzoic acid synthesis

Dankwardt SM, Phan TM, Krstenansky JL, Combinatorial synthesis of small-molecule libraries using 3-amino-5-hydroxybenzoic acid, Mol. Diversity, 1 113-20, 1996. 

Zlatoidsky (50) recently described the synthesis of N-protected a-amino aldehydes via reduction of the corresponding phenyl esters by lithium tri(tert-butoxy)aluminium hydride. Since 4-hydroxybenzoic acid is commercially available, we decided to explore this reaction in the soUd phase strategy. 

A regulator factor able to induce the synthesis of rifamycin B in a nonproducing mutant of A. mediienanei was isolated from yeast extracts (20). It was named B factor and identified as 3 -(l-bucylphosphoryl) adenosine. B factor appears to regulate the production of the rifamycin precursor 3-amino-5 hydroxybenzoic acid, since addition of the lat-... 

The evidence that (- )-shikimic acid plays a central role in aromatic biosynthesis was obtained by Davis with a variety of nutritionally deficient mutants of Escherichia coli. In one group of mutants with a multiple requirement for L-tyrosine, L-phenylalanine, L-tryptophan and p-aminobenzoic acid and a partial requirement for p-hydroxybenzoic acid, (—)-shikimic acid substituted for all the aromatic compounds. The quintuple requirement for aromatic compounds which these mutants displayed arises from the fact that, besides furnishing a metabolic route to the three aromatic a-amino acids, the shikimate pathway also provides in micro-organisms a means of synthesis of other essential metabolites, and in particular, the various isoprenoid quinones involved in electron transport and the folic acid group of co-enzymes. The biosynthesis of both of these groups of compounds is discussed below. In addition the biosynthesis of a range of structurally diverse metabolites, which are derived from intermediates and occasionally end-products of the pathway, is outlined. These metabolites are restricted to certain types of organism and their function, if any, is in the majority of cases obscure. 

The structure of PHBH is shown in Figure 8.12. It is an enzyme of 394 amino acids, with a three domain structure composed of an N-terminal "Rossman fold" domain that binds the ADP of the FAD coenzyme, a second domain that binds the para-hydroxybenzoate substrate and, a third, largely helical domain that is involved in dimerization wdth another subunit. The tricyclic isoalloxa-zine ring of the flavin is bound at the interface between the first two major domains, and there is known to be movement of flavin associated with the accommodation of substrate [46]. The structure of PHBH in the presence of NADPH has not been determined, but it is thought that there is only a transient association of the two cofactors to effect flavin reduction after which the NADP+ dissociates to permit substrate binding [46]. Although PHBH itself has not been the focus of studies in applications in synthesis, other Class A FPMO aromatic hydroxylases, such as hydroxybiphenyl monooxygenase from Pseudomonas azelaica have been used for the preparation of hydroxylated compounds. 

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