We present a new methodology for the straightforward preparation of peptides containing 2-oxo-1,3-oxazolidine-4-carboxylate (in short: Oxd) peptides and/or dehydro-amino acids, by treatment of arylsulfonyl peptides containing L or D-configured beta-hydroxy amino acids with DSC and a base. To expand the scope of the methodology, we introduced in a single step two Oxd rings, consecutive or separated by other amino acids, from peptides containing Ser/Thr/PhSer. The synthesis of the linear precursors and the cyclization reaction was performed either in solution or in the solid phase, making the entire process a convenient method for the preparation of constrained peptidomimetics. Further, the elaboration of the dehydro-amino acids allows preparing different unnatural aminoacids. Interestigly, the procedure gave in a single step the dehydro-amino acids equipped with a effective oxazolidinone chiral auxiliary for asymmetric syntheses. The cyclization mechanism has been investigated by varying the reaction conditions, and the results were rationalized with the aid of theoretical computations. The Oxd residues can be regarded to as suitable constrained pseudo-Pro. The peptides containing the Oxd show an all-trans conformation instead of mixtures of cis and trans conformers. Homochiral sequences tend to adopt extended conformations, while the presence of a D-Oxd ring induces folded conformations, giving rise to different types of γ- or beta-turn or inverse turns. Oxd-peptides have been the subject of much interest as self-assembling scaffolds forming nanostructures, and in the preparation of foldamers,(2) short synthetic oligomers which have a tendency to form well-defined secondary structures, stabilized by noncovalent interactions.(3)(4) Among the potential applications in medicinal chemistry, we utilized these peptidomimetics for the design of constrained analogues of the opioid peptides endomorphins, for the preparation of anti-inflammatory integrin inhibitors, or of analogues of the antibiotic Linezolid
R. De Marco, A. Tolomelli, M. Campitiello, P. Rubini, S. Rupiani, A. Greco, et al. (2012). One-step synthesis of constrained peptidomimetics including oxazolidinones and/or dehydro-amino acids, and application to the design of bioactive compounds. Pavia : SCI.
One-step synthesis of constrained peptidomimetics including oxazolidinones and/or dehydro-amino acids, and application to the design of bioactive compounds
DE MARCO, ROSSELLA;TOLOMELLI, ALESSANDRA;RUPIANI, SEBASTIANO;GRECO, ARIANNA;GENTILUCCI, LUCA
2012
Abstract
We present a new methodology for the straightforward preparation of peptides containing 2-oxo-1,3-oxazolidine-4-carboxylate (in short: Oxd) peptides and/or dehydro-amino acids, by treatment of arylsulfonyl peptides containing L or D-configured beta-hydroxy amino acids with DSC and a base. To expand the scope of the methodology, we introduced in a single step two Oxd rings, consecutive or separated by other amino acids, from peptides containing Ser/Thr/PhSer. The synthesis of the linear precursors and the cyclization reaction was performed either in solution or in the solid phase, making the entire process a convenient method for the preparation of constrained peptidomimetics. Further, the elaboration of the dehydro-amino acids allows preparing different unnatural aminoacids. Interestigly, the procedure gave in a single step the dehydro-amino acids equipped with a effective oxazolidinone chiral auxiliary for asymmetric syntheses. The cyclization mechanism has been investigated by varying the reaction conditions, and the results were rationalized with the aid of theoretical computations. The Oxd residues can be regarded to as suitable constrained pseudo-Pro. The peptides containing the Oxd show an all-trans conformation instead of mixtures of cis and trans conformers. Homochiral sequences tend to adopt extended conformations, while the presence of a D-Oxd ring induces folded conformations, giving rise to different types of γ- or beta-turn or inverse turns. Oxd-peptides have been the subject of much interest as self-assembling scaffolds forming nanostructures, and in the preparation of foldamers,(2) short synthetic oligomers which have a tendency to form well-defined secondary structures, stabilized by noncovalent interactions.(3)(4) Among the potential applications in medicinal chemistry, we utilized these peptidomimetics for the design of constrained analogues of the opioid peptides endomorphins, for the preparation of anti-inflammatory integrin inhibitors, or of analogues of the antibiotic LinezolidI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
