Synthetic studies on bioactive natural products including α,α-disubstituted α-amino acid structure.

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Recently, compounds containing highly functionalized a-substituted a-amino acid moieties have been reported to possess intriguing biological activity. Lactacystin is an a-substituted a-amino acid derivative isolated from the culture broth of Streptomyces sp. The compound exhibits significant neurotropic activity due to its ability to inhibit the 20S proteasome. (R)-2-(Hydroxymethyl)glutamic acid is a selective agonist of metabolic glutamate receptor. Dysibetaine is an a-substituted a-amino acid derivative isolated from the marine sponge. As this compound is able to induce convulsive behavior in mice, it was suspected of acting on glutamate receptors in the central nervous system. These biological features have prompted many groups to pursue synthetic studies of compounds containing highly functionalized a-substituted a-amino acid moieties.Prochiral diol prepared from 2-amino-2-hydroxymethylpropane-1,3-diol and benzoic acid, was treated with vinyl acetate in THF in the presence of Lipase PS and gave mono acetate ( >99% ee). For the assessment of optically active acetate as a potential chiral building block of α-substituted α-amino acid derivatives. The chiral building block was easily converted to (R)-2-(hydroxymethyl)glutamic acid and a synthetic intermediate of (-)-deoxydysibetaine by Wittig reaction, hydrogenation and hydrolysis of oxazoline. The chiral building block was easily converted to a synthetic intermediate of lactacystin by Wittig reaction, asymmetric epoxidation, regioselective methylation, hydrolysis of oxazoline and protection of 1,2-diol.