P. Herdewijn

Phosphonates Derivatives of 2′,3′-Dideoxy-2′,3′-didehydro-pentopyranosyl Nucleosides

Abstract Adenine and thymine derivatives of 2′,3′-dideoxy-2′,3′-didehydropento-pyranosyl nucleosides carrying a phosphonomethyl moiety at their 4′-O-position and in a cis relationship with the heterocyclic base have been synthesized.

1-(2,3-Dideoxy-erythro-β-d-hexopyranosyl)cytosine: an example of the conformational and stacking properties of pyranosyl pyrimidine nucleosides. A crystallographic and computational approach

C10H15N3O4, Mr = 241.25, orthorhombic, P2(1)2(1)2(1), a = 7.4013 (4), b = 8.7563 (5), c = 17.392 (1) A, V = 1127.1 (1) A3, Z = 4, Dm = 1.42, Dx = 1.422 Mg m-3, Ni-filtered Cu K alpha radiation, lambda = 1.54178 A, mu = 0.895 mm-1, F(000) = 512, T = 293 K, final R = 0.044 for 1024 unique observed [F greater than or equal to 6 sigma (F)] reflections. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. In order to assess the possible use of pyranosyl-modified pyrimidine nucleosides in the design of new synthetic oligonucleotides, the conformational and packing properties of 13 structures were examined. From this study, it becomes clear that the pyrimidine-base geometry is independent of the sugar ring type (furanosyl- or pyranosyl-like). The bases are always positioned in an equatorial orientation on the pyranoside sugar, which means that the sugar adopts a 4C1 conformation in alpha- and 4C1 in beta-enantiomers. As a result of the anomeric effect the O5-C1 bond length is 0.020 (4) A shorter than the C5-O5 distance (C1 is the anomeric C atom). The O5-C1-N1-C2 torsion angle chi in the 13 nucleosides is centered around 244 (8) degrees and varies from 196.4 (3) to 287.0 (2) degrees. Molecular-mechanics calculations on uncharged pyranosyl nucleosides are found to be less accurate compared with semi-empirical quantum-chemical methods or molecular-mechanics calculations on charged molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure of 1-(2-deoxy-β-D-ribopyranosyl)-5-iodouracil

C 9 H 11 IN 2 O 5 cristalline dans P2 1 avec a=5,458, b=8,237, c=12,812 A, β=98,42°, Z=2; affinement jusqua R=0,039. Le cycle du sucre adopte une conformation chaise legerement aplatie. La base heterocyclique est placee dans une orientation -ap (antiperiplane) par rapport au sucre (χ=196,4°). Lempilement du cristal est determinee par trois liaisons hydrogene intermoleculaires, impliquant O(33), O(2) et O(44)

Structure of 1-(2-deoxy-2-fluoro-α-d-arabinopyranosyl)-5-iodouracil

C2oHI4N4, Mr=3104 . a -Form: monoclinic, P21/c, a = 9 . 4 3 4 ( 8 ) , b = 6 . 1 1 0 ( 4 ) , c = 13.322 (10) A,/3 = 105.02 (6) °, V = 741.7 (9) A 3, Z = 2, Dx = 1-39 Mg m -3, a(Mo Ka) = 0-71069 A, /.t = 0-08 mm-~, F(000) = 324, T = 160 K, R = 0.052 for 976 independent observed reflections. /3-Form: monoclinic, P2~/n, a = 7.224 (5), b = 11.530 (6), c = 8.978 (6) A, /3 = 91.21 (5) °, V = 747.7 (8) A 3, Z = 2, Dx = 1.38 Mg m -3, A(Mo Ka) = 0.71069/~, ~ = * Author to whom correspondence should be addressed. 0108-2701/91 / 102247-03

Structure of the modified nucleoside 2',3'-dideoxy-3'-fluorocytidine

03.00 0.08 m m l , F(000) = 324, T = 160 K, R = 0.047 for 617 independent observed reflections. In both forms the molecules exist in a centrosymmetric planar conformation with transom 2,2(and 2,2 -) linkages and pack with a common herringbone pattern but with different molecular stackings. Experimental. Recrystallization of the title compound (I) from ethanol gave a mixture of two macroscopically distinguishable modifications, crystals of which were separated manually. The a-form

Structures of 1-(2,3-dideoxy-erythro-α-D-hexopyranosyl)thymine and the 1-(2,3-dideoxy-erythro-β-D-hexopyranosyl)thymine.Dioxane complex

C 9 H 12 FN 3 O 3 cristallise dans P1 avec a=6,997, b=7,396, c=10,639 A, α=94,48, β=107,74, γ=104,40°, Z=2; affinement jusqua R=0,033. La maille asymetrique contient deux molecules A et B. Il apparait un appariement des bases entre A et B, et il se forme ainsi un centre de pseudoinversion entre les deux bases. Dans A, χ=−143,5°, le plissement est 2 T 1 PE avec P=154 et ψ m =40°; γ=63,4°. Dans B χ=−153,0, γ=71,4° le plissement est 2 E avec P=164 et ψ m =36°

Structure of a nucleoside analogue, 3'-deoxy-2'-fluorothymidine

C 11 H 16 N 2 O 5 (I) cristallise dans P2 1 2 1 2 1 avec a=4,871, b=13,182, c=18,678 A, Z=4; affinement jusqua R=0,032. C 11 H 16 N 2 O 5 •C 4 H 8 O 2 (II) cristallise dans C2 avec a=17,23, b=7,651, c=13,401 A, β=101,14°, Z=4; affinement jusqua R=0,048. Dans les deux cas, le cycle pyranose adopte une conformation chaise aplatie en C(4) et en C(1) pour (I) et pour (II) respectivement. Lempilement est determine par des liaisons hydrogene intermoleculaires

Structures of the 1-(2-deoxy-2-fluoro-β-d-arabinopyranosyl)thymine–water complex and 1-(2-deoxy-2-fluoro-β-d-arabinopyranosyl)-5-ethyluracil

C 10 H 13 FN 2 O 4 cristallise dans P2, avec a=10,6001, b=6,1847, c=16,9227 A, β=98,040 o , Z=4; affinement jusqua R=0,033. Lunite asymetrique contient deux molecules (A et B). Pour la molecule A: langle de torsion N-glycosidique, χ est de −155,2 o dans le domaine anti; le plissement du sucre est 3/2 avec P=12 o et ψ m =35 o et la conformation du C4−C5 est +x avec γ=55,1 o . Pour la molecule B: langle de torsion N-glycosidique χ est de −16,80 o dans le domaine anti; le plissement du sucre est 3/2 avec P=8 o et ψ m =35 o et la conformation du C4−C5 est +x avec γ=49,7 o

Structure of a nucleoside analogue, 2',3'-dideoxy-3'-fluoro-5-iodouridine

I) 1-(2-Deoxy-2-fluoro-/3-o-arabinopyra- nosyl)thymine-water complex, C~oH13FN205.H20, Mr=278.24, monoclinic, P21, a=8669(4), b = 6.395 (3), c = 10.713 (7)/~, /3 = 103.73 (5) °, V= 576.9 (6) A, 3, Z = 2, Dm = 160, Dx = 1.602 Mg m-3, graphite-monochromated MoKa radiation, A= 0.71069 A,, ~ = 0-134 mm- 1, F(000) = 292, room temperature, final R=0.030 for 1307 unique observed (F> 4o-(F)) reflections. (II) 1-(2-Deoxy-2- fluoro-/3-o-arabinopyranosyl)-5-ethyluracil, C t IH15- FN2Os, Mr = 274.25, hexagonal, P65, a = 10.108 (7), c -- 19.48 (1) .~, V = 1724 (2) A, 3, Z = 6, Dm= 154, Dx = 1585 Mg m-3, graphite-monochromated Mo Ka radiation, ,t = 0.71069 A~, IZ = 0.127 mm- t F(000) = 864, room temperature, final R = 0.026 for 694 unique observed (F _> 4cr(F)) reflections. The geo- metries of molecules (I) and (II) show a close simi- larity. In both structures the sugar ring adopts a

trans- and cis-S-C-C-S conformations in 5-(2,2'-dithien-5-yl)-2'-deoxyuridine

C 9 H 10 FIN 2 O 4 cristallise dans B22 1 2 avec a=7,917, b=16,962, c=17,692 A, Z=8; affinement jusqua R=0,022. Langle de torsion Y, N-glycosidique est de −107,0 o dans le domaine anti; le plissement du sucre est 2/3 T avec p=184 o et ψ m =29 o et la conformation C4−C5 est +x avec γ=43,8 o . La formation de la paire de base se produit entre les molecules reliees par leur symetrie