STRUCTURE AND CONFORMATION OF PYRIMIDINE LYXOFURANOSIDES - 1-BETA-D-LYXOFURANOSYLURACIL, 1-BETA-D-LYXOFURANOSYLCYTOSINE, AND SOME O'-METHYL DERIVATIVES

1H NMR spectroscopy was applied to a study of the conformation, in aqueous medium, of 1-.beta.-D-lyxofuranosyluracil (lyxo-U), 1-.beta.-D-lyxofuranosylcytosine (lyxo-C), and some O''-methyl derivatives [potential anticancer chemotherapeutics] of the latter. For the neutral molecules, and the protonated forms in the case of the lyxo-C derivatives, the pentose rings exhibit an N .dblarw. S type equilibrium; the gauche-gauche rotamer populations of the exocyclic 5''-CH2OH are relatively low (10-20%), as previously found for the corresponding xylofuranosyl nucleosides. For all the compounds, the 3 coupling constants for the pentose ring protons were interrelated, the resulting correlation being that expected for a 2-state equilibrium and implying a linear dependence of each of the 3 coupling constants on the conformer populations. In the solid state conformation of lyxo-U, established by X-ray diffraction, the pentose ring is in the rarely encountered twist form 3T2, the exocyclic carbinol group is gauche-trans with no intramolecular hydrogen bonding, and the position of the aglycone about the glycosidic bond is anti (.chi.CN = 27.degree.). In aqueous strongly alkaline medium (pD .apprx. 14) where the 2''-OH and/or 3''-OH are ionized, the conformation of 3''-O-methyl-lyxo-C becomes predominantly C(2'')endo and gauche-gauche, stabilized in this form by strong intramolecular hydrogen bonding, i.e., O(5'').sbd.H.cntdot..cntdot..cntdot.O(2'')-. Similar alkali-induced modifications occur with lyxo-C and lyxo-U but to a lesser extent, probably because of simultaneous ionization of the 3''-OH. The conformational changes in 2''-O-methyl-lyxo-C in strongly alkaline medium argue against formation of an intramolecular hydrogen bond of the form O(5'').sbd.H.cntdot..cntdot..cntdot.O(3'')-.