Ugi 4-CR/Pictet-Spengler reaction as a short route to tryptophan-derived peptidomimetics.
We report here a two step efficient route for the synthesis of 1,2,3,4-tetrahydro-β-carboline (THBC)-based tetracyclic peptidomimetics from a Ugi 4-CR/Pictet-Spengler reaction sequence. Suitably N-protected 2-aminoacetaldehyde was for the first time applied as the carbonyl component in a Ugi four-component reaction, opening the way to the employment of N-protected α-amino acid-derived aldehydes in the same role. The potential of the obtained scaffolds is related to the possibility of further derivatization with the desired pharmacophoric groups, on both the terminal acid and amine functional groups, for the development of conformationally constrained tryptophan-containing peptide ligands. Extensive molecular modeling and (1)H NMR studies highlighted a robust, folded, β-turn-like conformation for one of these peptidomimetic compounds.
Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy. giordano.lesma@unimi.it
Giordano
G
Lesma
Roberto
R
Cecchi
Sergio
S
Crippa
Paola
P
Giovanelli
Fiorella
F
Meneghetti
Manuele
M
Musolino
Alessandro
A
Sacchetti
Alessandra
A
Silvani
D060326:Chemistry Techniques, Synthetic; D008958:Models, Molecular; D008968:Molecular Conformation; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry*
D057786:Peptidomimetics; D014364:Tryptophan