Acetoacetate from aromatic amino acids

The pathways involved in the catabolism of the individual amino acids range from one-step reactions, such as with aspartate, glutamate, and alanine, which use the appropriate amino transferases, to multistep pathways of the aromatic amino acids and lysine (e.g., tyrosine is degraded in four steps to acetoacetate and fumarate). 

Homogcntisate oxidase plays a part in the metabolic sequence which forms fumarate and acetoacetate from phenylalanine (123, 204,223,239.433,577,656,825, and especially the comprehensive review of aromatic amino acid metabolism by Dalgliesh (182)),... 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

T. a. for therapeutic purposes are derived almost entirely from plant sources. The tropane ring is derived biosynthetically from compounds of the glutamic acid/proline/ornithine group, via an iV-methylpyrro-line cation which condenses with acetoacetic acid to form ketones (of the tropinone type). Following reduction of the ketone function, the resulting amino alcohol becomes esterified with an appropriate aromatic acid (ecgonine is esterified with benzoic acid, with additional methylation of the 2-carboxyl function to form cocaine tropine is esterified with tropic acid to form hyoscyamine, which can be further epox-idized to scopolamine). See Fig. 2. 

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