RESUMEN
Described herein is a novel Lewis acid catalyzed rearrangement-coupling of oxygen heterocycles and bis(diethylamino)chlorophosphine that provides direct formation of the phosphonomethyl ether functionality found in several important antiretroviral agents. A wide range of dioxolanes and 1,3-dioxanes may be employed, furnishing the desired products in good yield. The utility of this method is demonstrated in a novel synthesis of tenofovir, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B.
Asunto(s)
Adenina/análogos & derivados , Dioxanos/química , Dioxolanos/química , Éteres/química , Etilaminas/química , Ácidos de Lewis/química , Organofosfonatos/síntesis química , Fosfinas/química , Adenina/síntesis química , Adenina/química , Catálisis , Estructura Molecular , Organofosfonatos/química , TenofovirRESUMEN
Novel, efficient and mild preparation of 7- and 8-membered cyclic di- and 10-membered cyclic tripeptides containing α-, ß- or γ-amino acid residues is effected by a Staudinger-mediated ring closure. Medium-sized cyclic di- and tripeptides--recognized as difficult targets--were obtained in moderate to good yields according to a straightforward sequence. Empirical force-field calculations were undertaken to determine their conformational behaviors and showed high levels of similarity with X-ray results. A computational study at the B3LYP/6-31+G** level of theory afforded information regarding the impact of the sequence, ring-size and substitution on the activation barriers for the cyclization of azido peptide thioesters.
Asunto(s)
Péptidos Cíclicos/síntesis química , Aminoácidos/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Péptidos Cíclicos/química , Teoría CuánticaRESUMEN
The intramolecular long-range S â N acyl migration via 13-, 15-, and 16-membered cyclic transition states to form native tetra- and pentapeptide analogues was studied on S-acylcysteine peptides containing ß- or γ-amino acids. The pH-dependency study of the acyl migration via a 15-membered cyclic transition state indicated that the reaction is favored at a pH range from 7.0 to 7.6. Experimental observations are supported by structural and computational investigations.