Elsevier

Tetrahedron

Volume 49, Issue 11, 12 March 1993, Pages 2287-2298
Tetrahedron

Conformational studies of thymidine dimers containing sulfonate and sulfonamide linkages by NMR spectroscopy

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Abstract

The conformations of 3′-azido-terminated-sulfonate-dimer 1 and 3′-amino-terminated-sulfonamide-dimer 2 are characterized by the following features: (1) The 5′-terminal nucleoside moiety of 1 has a S-type sugar (87% S), a staggered γ+ (rotamer across the C4′C5′ bond (65%) and an anti orientation of the base about the glycosidic bond. The 5′-terminal nucleoside moiety of 2 has an almost equal population of S and N conformations, a staggered γ+ rotamer (69 %) and an anti orientation of the base. (2) The 3′-terminal nucleoside moieties of 1 and 2 are in ∼50% N ⇄ S equilibrium and the γt conformer is the most populated. A comparison of the conformational properties of 1 and 2 with the natural thymidyl(3′ → 5′)thymidine [d(TpT)] 3, thymidylyl-(3′ → 5′)-5′-thio-5′-deoxythymide d(TpST)5 4 and thymidinylacetamido-[3′(O)→5′(C)]-5′-deoxythymidine NH2d(TcmT)5 5, show the following characteristics: (i) The conformational preference of the sugar ring is partially determined by the gauche effect. This means that the more polar the C3′X bond due to the electronegative character of the 3′-α-X substituent, the more than N ⇌ S equilibrium is biased toward the S-type conformation: 3′-O-S > 3′-O-H > 3′-N3 > 3′-NH2. (ii) The conformation about the C4′C5′ bond (γ) is also influenced by the gauche effect based on the nature of the 5′-substituent and by the ability of the 5′-substituent to form hydrogen bonding with the H6 of thymine. Thus, the population of the γ+ conformer follows the order: 5′-O > 5′-N > 5′-S > 5′-C. (iii) The C5′C6′ bond has a slight preference for the βt conformation (56 % βt in 1 and 58 % βt in 2), while in natural d(TpT) 3, the C5′O5′ bond accounts for 83% of βt conformation. Upon substitution of the 5′-oxygen by 5′-sulfur, as in d(TpST) 4, the population of βt conformer was found to decrease to 57 %. This decrease in the βt population in 1, 2 and 4 is a result of the reduced polarity of the 5′CX [X = CH2 in 1 and 2 and X  S in 4] in comparaison to the 5′CO bond in 3, which weaken the gauche effect.

500 MHz NMR spectroscopic study on the solution conformations of 1 and 2 is reported

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