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Fig. 3. X-Ray diffraction structure of Bz-(R)-FlAib-(S)-Phe-NHChx.Results and DiscussionThe 3,4-dimethyl-fluorenone structure required for the synthesis of FlAib was obtained bydiazotization of the corresponding dimethyl-aminobenzophenone (prepared from theknown 2-amino-3,4-dimethylbenzoic acid). Bromination of the side chains of thisdimethyl-fluorenone gave 3,4-(bis)bromomethyl-fluorenone, which was used in thebis(alkylation) of ethyl-isocyanoacetate under phase-transfer conditions to give the cyclic,racemic amino acid H-FlAib-OEt (OEt, ethoxy) after acid hydrolysis. N α -Benzoyl (Bz)protection, saponification of the ester function, and coupling with H-(S)-Phe-NHChx (Chx,cyclohexyl) gave two dipeptide diastereomers (Figure 2) which could be resolved bycrystallization and chromatography.A crystal of one of these diastereomers, Bz-(R)-FlAib-(S)-Phe-NHChx, subjected toX-ray diffraction analysis, allowed the assignment of the absolute configuration of theFlAib residue (Figure 3). The (R)-FlAib residue is able to induce a (type-I) β-turn in themolecule, thus behaving as an (S)-protein amino acid.References1. Kauer, J.C., Erickson-Viitanen, S., Wolfe, H.R., Jr., DeGrado, W.F. J. Biol. Chem. 261, 10695-10700 (1986).2. Saviano, M., Improta, R., Benedetti, E., Carrozzini, B., Cascarano, G.L., Didierjean, C., Toniolo, C.,Crisma, M. ChemBioChem 5, 541-544 (2004).3. Toniolo, C., Crisma, M., Formaggio, F., Peggion, C. Biopolymers (Pept. Sci.) 60, 396-419 (2001).4. Wright, K., Moretto, A., Crisma, M., Wakselman, M., Mazaleyrat, J.-P., Formaggio, F., Toniolo, C.Org. Biomol. Chem. 8, 3281-3286 (2010).47