RESUMO
BACKGROUND: Thalidomide is one of the promising multidimensional drugs that possess high activity against serious diseases such as rheumatoid arthritis, Crohn's disease, leprosy, AIDS and various cancers. However, its medicinal applications are plagued by its configurational instability, as it easily undergoes racemization under the physiological conditions (t(1/2) = 8 h at pH 7.1, 37°C in water). Consequently, the design and synthesis of configurationally stable analogs of thalidomide continue to be an important area of research in bioorganic and medicinal chemistry. DISCUSSION: 4-trifuoromethyl thalidomide-3c was identified as an important synthetic target, which was expected to be a configurationally stable analog of thalidomide. Synthetic challenges in preparation of compound 3c were truly multipronged, considering the unique steric, electronic as well as electrostatic characteristics of trifluoromethyl group, significantly affecting properties of parent amino acids. After numerous experiments and unsuccessful attempts, both (3S,4R) and (3R, 4S) enantiomers of 4-trifluoromethyl-substituted thalidomide were effectively synthesized in six steps starting from enantio- and diastereomerically pure 3-(trifluoromethyl)pyroglutamates, prepared by highly diastereoselective Michael addition reactions between achiral glycine equivalents and chiral 3-(trifluoromethyl)acrylate. CONCLUSION: We have developed a reliable asymmetric approach for preparation of hitherto unknown 4-trifluoromethyl-substituted thalidomide in (3S,4R) and (3R,4S) enantiomerically pure forms. These thalidomide derivatives were shown to be configurationally stable and therefore may serve as useful lead compounds for the development of a new generation of thalidomide-based pharmaceuticals.