Fluorinated enamines of nucleobases as precursors of nucleoside analogues. Synthesis, spectroscopic and structural studies

Abstract

The 1 H and 19 F NMR spectra of N-a-fluoro-b-trifluoromethylenamines and isostructural N-b-fluoro-b-trifluoromethylenamines of nucleobases dissolved in CDCl 3 and DMSO-d 6 have shown distinct differences associated with the conformational conversion between the Z and E stereoisomers. In the E stereoisomer the tetrafluoropropenyl group is rotated relative to the heteroring plane, whereas the Z stereoisomer assumes the most planar structure. The flat conformation of the Z stereoisomer is stabilised by internal hydrogen bonding between C a -H and the carbonyl oxygen (pyrimidinic bases) or the endocyclic nitrogen (purinic bases). Large variations in the magnitudes of the chemical shifts of C b -H, C a -F, C 6 -H and C 8 -H were observed, i.e. the chemical shift increased with increasing polarity and ability of DMSO-d 6 to establish intermolecular hydrogen bonds in competition with intramolecular hydrogen bonds. The (Z)-N 4 -benzoyl-N 1 -(1,3,3,3-tetrafluoroprop-1-enyl)cytosine crystals undergo a phase transition at 230 K induced by the tetrafluoropropenyl substituent reorientations. Between 300 and 230 K the molecules are present in two conformations, and below 230 K the molecules gradually assume five conformations, remaining in a stable equilibrium with intermolecular forces, evidenced by single-crystal X-ray diffraction.

Synthesis and spectral properties of α,α-difluorinated β-iminophosphonates

“…Thus in 14a, the through space interactions of benzylic -CH 2 -protons (t, 5 J HF 2 Hz at d: 4.61 in 1 H NMR) and both fluorine atoms (br d, at d: À107.7, split up after apodization at doublet of triplets 2 J FP 101 Hz, 5 J FH 2 Hz in 19 F NMR) have suggested the Z-configuration. Similar longrange coupling constants have been observed for N 1 -(2,3,3,3-tetrafluoroprop-1-enyl)uracil/thymine derivatives [21]. Thus, the stereoisomers Z, in contrast to their E analogues, prefer to adopt the planar conformation stabilized by stereospecific intramolecular nonbonding interactions, confirmed by coupling of fluorine atom in the (Z)-tetrafluoropropenyl moiety with H(6) hydrogen of uracil/thymine rings with 5 J HF 1-2 Hz.…”

Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies

“…On the other hand, for α,α -difluorinated β -iminophosphonate analogs, the through-space interactions of PG (benzylic) protons and one of the fluorine atoms indicated the major formation of the Z -stereoisomer [ 54 ]. Long-range F-H intramolecular nonbonding interactions have also been observed in the case of ( Z )- N -tetrafluoropropenyl-uracil/thymine derivatives and α -fluorinated imines [ 35 , 58 ]. Moreover, it is worth noting that less than 10% of difluoro, dibromo, or dichloro derivatives were also formed during the reaction.…”

Synthesis and applications of fluorinated nucleoside analogues

“…The spectroscopic and chemical experimental results demonstrated, that both, (Z)-N-a-fluoro-b-trifluoromethyl enamines and obtained recently, in the reaction with 1,2,3,3,3-pentafluoropropene, isostructural (Z)-N-b-fluoro-b-trifluoromethyl enamines of nucleobases 347c-351c, in contrast to their E analogues, are involved in stereospecific intramolecular interactions [142]. The formation of C b -HÁ Á ÁO5 5C 2 and C b -HÁ Á ÁN 3 hydrogen bonds helps anchor the planar orientation in stereoisomers Z.…”