Enantioselective Synthesis of a Highly Preorganised 2′-Deoxy-spiro-nucleoside

Abstract

The synthesis of a novel spiro-nucleotide, in which the C(4′) and the C(5′) of a nucleotide are connected by an additional ethylene bridge, is reported. The γ-torsional angle of the resulting novel nucleotides is in the region of the one observed in natural double stranded DNA.

Keywords

DNA - asymmetric synthesis - dihydroxylations - nucleosides - spiro compounds

References

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9

This ee is not sufficient for incorporation of the prepared nucleosides into oligonucleotides.

11

Ee’s were determined by chiral HPLC (Chiralcel OD-H); for analytical purpose, the enantiomer of 4 was prepared with β-AD-mix.

12

Ee of 9 was not determined.

16

1α: ¹H NMR (500 MHz, CDCl₃): δ = 7.95 (b, 1 H, NH), 7.74 (q, J = 1.0 Hz, 1 H, H-6), 6.38 (dd, J = 8.3 and 1.8 Hz, 1 H, H-1′), 4.09 (d, J = 5.3 Hz, 1 H, H-3′), 3.78 (dd, J = 9.4 and 7.3 Hz, 1 H, H-5′), 2.85 (ddd, J = 14.4, 8.3 and 5.3 Hz, 1 H, H-2′β), 1.92 [d, J = 1.0 Hz, 3 H, CH₃-C(5)], 1.83 (dd, J = 14.4 and 1.8 Hz, 1 H, H-2’α), 1.5-2.1 (m, 6 H, H-6′, H-7′,
H-8′), 0.97 (m, 18 H, CH ₃ CH₂Si), 0.62 (m, 12 H, CH₃ CH ₂ Si). The configuration of C-1′ was established by NOE: Both H-1′ and H-3′ show a strong NOE with H-2′β. No NOE was observed between H-3′ and H-6. Furthermore, a strong NOE was observed between H-3′ and H-5′ proving the configuration of C-3′ and C-5′ given in Scheme [4] . ¹³C NMR (125 MHz, CDCl₃, as obtained from the HSQC and HMBC spectra): δ = 163.7 (C-4), 150.3 (C-2), 137.6 (C-6), 109.7 (C-5), 97.8 (C-4′), 85.5 (C-1′), 78.3 (C-5′), 75.6 (C-3′), 42.9 (C-2′), 31.9 and 29.4 (C-8′ and C-6′), 17.9 (C-7′), 12.4 (CH₃-C-5), 6.7 (CH ₃ CH₂Si), 4.9 (CH₃ CH ₂ Si). ESI-MS: 511 (M + H⁺); 509 (M - H⁺).
1β: ¹H NMR (500 MHz, CDCl₃): δ = 8.01 (b, 1 H, NH), 8.00 (q, J = 1.0 Hz, 1 H, H-6), 6.28 (dd, J = 7.8 and 5.5 Hz, 1 H, H-1′), 4.23 (dd, J = 5.6 and 3.0 Hz, 1 H, H-3′), 3.91 (dd, J = 9.5 and 8.3 Hz, 1 H, H-5′), 2.25 (ddd, J = 12.9, 5.5 and 3.0 Hz, 1 H, H-2′α), 2.11 (ddd, J = 12.9, 7.8 and 5.6 Hz, 1 H,
H-2′β), 1.94 [d, J = 1.0 Hz, 3 H, CH₃-C(5)], 1.5-2.1 (m, 6 H, H-6′, H-7′, H-8′), 0.97 (m, 18 H, CH ₃ CH₂Si), 0.62 (m, 12 H, CH₃ CH ₂ Si). The configuration of C-1′ was established by NOE: H-1′ shows a strong NOE with H-2′α, and H-3′ a strong NOE with H-2′β. A weak NOE was observed between H-3′ and H-6. Furthermore, a strong NOE was observed between H-3′ and H-5′ proving the configuration of C-3′ and C-5′ given in Scheme [4] . ¹³C NMR (125 MHz, CDCl₃, as obtained from the HSQC and HMBC spectra):
δ = 163.7 (C-4), 150.3 (C-2), 136.6 (C-6), 109.7 (C-5), 95.7 (C-4′), 84.4 (C-1′), 76.9 (C-5′), 74.4 (C-3′), 41.8 (C-2′), 31.4 and 29.2 (C-8′ and C-6′), 17.8 (C-7′), 12.4 (CH ₃ -C-5), 6.7 (CH ₃ CH₂Si), 4.9 (CH₃ CH ₂ Si). ESI-MS: 511(M + H⁺); 509 (M - H⁺).