On the existence of the chair conformation in six-membered ring phosphates bearing an aryl group axially oriented at the C4 position: cyclic nucleotides as model compounds for cyclic phosph(on)ate and phosphoramide prodrugs.
A series of cyclic nucleotide analogues to HepDirect prodrugs were prepared by a three-component reaction of protected thymine, phosphoryl chloride, and 5-aryl-alpha-D-xylofuranoses derivatives. One of the cyclic nucleotides showed NMR data that suggest a predominant twisted conformation; however, in spite of having an aryl group at the C4 position within the crystal lattice, the cyclic nucleotide had a chair conformation with the aryl group axially oriented. By analyzing the unprecedented X-ray structure, it was observed that the oxygen atom from the phoshoryl group (P=O) is found in close proximity to the o-hydrogen atom of the aryl group (2.51 A), suggesting thus an attractive nonbonding electrostatic interaction, which might be the driving force that overcomes the steric diaxial interactions imposed by the aryl group. Theoretical studies (NBO) for two model compounds showed that there are indeed interactions between filled (donor) Lewis-type NBOs and empty (acceptor) non-Lewis NBOs corresponding to the nO-->sigma*(C-H) interaction. Additionally, conversion of a diastereomeric mixture of cyclic nucleotides into the more stable diastereomeric cyclic nucleotide was observed and explained by spontaneous isomerization in the phosphorinane ring. This finding supports the recently established hypothesis for the mode of action of prodrug cleavage, for which the anomeric effect plays an important role.
Quintero
Leticia
L
Centro de Investigación de la Facultad de Ciencias Químicas, BUAP. 14 Sur Esq. San Claudio, San Manuel. 72570, Puebla, México.
Sánchez-Vazquez
Mario
M
Cruz-Gregorio
Silvano
S
Sartillo-Piscil
Fernando
F
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D009712:Nucleotides, Cyclic / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013941:Thymine / Q000737:chemistry*
D000577:Amides; D009712:Nucleotides, Cyclic; D009943:Organophosphorus Compounds; D011355:Prodrugs; D013941:Thymine