Synthesis of Carbon E,E-Diene Chain-Linked Dinucleotide Analogues

Abstract

The synthesis of a dinucleotide thymidine-thymidine linked by a carbon E,E-diene chain is described. This dimer is synthesized by a coupling reaction between an (E)-vinylstannane and an (E)-iodovinyl partner prepared from acetylenic parents, which are both available from thymidine in six and five steps, respectively. In addition, a new efficient access to 3′-C-formyl thymidine is presented.

Key words

antisense agents - nucleobases - Stille reactions - alkynes - isomerizations

References and Notes

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13

De Mesmaeker, A., Lebreton, J. 1992, unpublished results.

19

Selected Physicochemical Data for Compound 7
^¹H NMR (400 MHz, CDCl₃): δ = 1.99 (s, 9 H, t-Bu), 1.82-1.92 (m, 1 H, H_{2 ′′}), 1.89 (s, 3 H, CH₃), 2.39 (ddd, 1 H, J = 10.0, 6.5, 3.0 Hz, H_{2 ′}), 4.20 (ddd, 1 H, J = 10.0, 3.0 Hz, H_{3 ′}), 4.24 (m, 1 H, H_{4 ′}), 6.23 (br s, 2 H, H_{5 ′} and H_{6 ′}), 6.34 (dd, 1 H, J = 6.5 Hz, H_{1 ′}), 6.93 (d, 1 H, J = 1.0 Hz, H₆), 7.38-7.50 (m, 6 H, H_ar), 7.59-7.67 (m, 4 H, H_ar), 9.28 (br s, 1 H, NH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 12.6 (CH₃, CH₃), 18.9 (C, t-Bu), 26.8 (CH₃, t-Bu), 39.6 (CH, C_{2 ′}), 75.4 (CH, C_{3 ′}), 80.7 (CH, C_{6 ′}), 84.8 (CH, C_{1 ′}), 88.2 (CH, C_{4 ′}), 111.3 (C, C₅), 127.9, 128.0 (CH, C_ar), 130.2 (CH, C_ar), 132.7 (C, C_ar), 134.9 (CH, C₆), 135.6, 135.8 (CH, C_ar), 142.1 (CH, C_{5 ′}), 150.2 (C, C=O), 163.6 (C, C=O) ppm. MS (CI/NH₃): m/z (C₂₇H₃₁I N₂O₄Si) = 620 [M + NH₄ ⁺], 603 [M + H⁺].

25

Selected Physicochemical Data for Compound 6
^¹H NMR (400 MHz, CDCl₃): δ = 0.70-0.80 (15 H, 3 CH₃ and 3 CH₂, CH₃ and CH₂ n-Bu), 1.02 (s, 9 H, 3 CH₃, t-Bu), 1.10-1.27 (m, 6 H, 3 CH₂, n-Bu), 1.38 (m, 6 H, 3 CH₂, n-Bu), 2.26 (m, 1 H, H_{2 ′}), 2.40 (m, 1 H, H_{2 ′}), 2.40 (s, 3 H, CH₃), 3.14 (m, 1 H, H_{3 ′}), 3.75-3.86 (m, 2 H, H_{4 ′} and H_{5 ′}), 4.11 (m, 1 H, H_{5 ′}), 5.76 (dd, 1 H, J = 7.0, 19.0 Hz, H_{3 ′′}), 6.15 (d, 1 H, J = 19.0 Hz, H_{3 ′′′}), 6.16 (dd, 1 H, J = 3.0, 7.0 Hz, H_{1 ′}), 7.22-7.49 (m, 6 H, H_ar), 7.66 (s, 1 H, H₆), 7.62-7.84 (m, 4 H, H_ar), 9.50 (s, 1 H, NH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 9.4 (CH₂, n-Bu), 11.9 (CH₃, CH₃), 13.6 (CH₃, n-Bu), 19.4 (C, t-Bu), 27.1 (CH₃, t-Bu), 27.4 (CH₂, n-Bu), 29.0 (CH₂, n-Bu), 39.3 (CH₂, C_{2 ′}), 45.0 (CH, C_{3 ′}), 62.5 (CH₂, C_{5 ′}), 84.7 (CH, C_{1 ′}), 85.6 (CH, C_{4 ′}), 110.5 (C, C₅), 127.8 (CH, C_ar), 129.8 (CH, C_ar), 132.5 (CH, C_{3 ′′′}), 132.8, 133.3 (C, C_ar), 135.2, 135.4 (CH, C_ar), 135.6 (CH, C₆), 145.5 (CH, C_{3 ′′}), 150.5 (C=O), 164.2 (C=O) ppm. ESI-HRMS: m/z [M + H⁺] calcd for C₄₀H₆₁N₂O₄SiSn [M(^¹¹9Sn) + H]⁺: 780.3433; found: 780.3431.

27

Selected Physicochemical Data for Compound 8
^¹H NMR (400 MHz, CDCl₃): δ = 1.09 (s, 9 H, t-Bu), 1.10 (s, 9 H, t-Bu), 1.58 (s, 3 H, CH_3A), 1.86 (s, 3 H, CH_3B), 2.44-2.19 (m, 4 H, H_{2 ′ A} and H_{2 ′ B}), 3.18-3.02 (tdd, 1 H, J = 8.0, 8.0, 8.0 Hz, H_{3 ′ A}), 3.79 (m, 1 H, H_{4 ′ A}), 3.75 (dd, part A of an AB system, 1 H, J = 12.0, 3.0 Hz, H_{5 ′ A}), 4.13-4.03 (dd, part B of an AB system, 1 H, J = 12.0, 3.0 Hz, H_{5 ′ A}), 4.22-4.14 (1 H, dt, J = 6.0, 3.0 Hz, H_{4 ′ B}), 4.42-4.33 (dd, 1 H, J = 7.0, 4.0 Hz, H_{3 ′ B}), 5.34-5.21 (m, 1 H, H_d), 5.52-5.38 (m, 1 H, H_a), 6.05-5.90 (2 dd, 2 H, J = 8.0 Hz, H_b and H_c), 6.19-6.09 (dd, 1 H, J = 4.0, 7.0 Hz, H_{1 ′ A}), 6.40-6.30 (dd, 1 H, J = 7.0 Hz, H_{1 ′ B}), 7.00 (s, 1 H, H_6B), 7.49-7.27 (m, 12 H, H_ar), 7.51 (s, 1 H, H_6A), 7.75-7.56 (m, 8 H, H_ar), 8.87-8.80 (2 br s, 2 H, 2 NH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 12.1 (CH₃, CH_3A), 12.3 (CH₃, CH_3B), 19.0 (C, t-Bu), 19.4 (C, t-Bu), 26.8 (CH₃, t-Bu), 27.0 (CH₃, t-Bu), 39.4 (CH₂, C_{2 ′ A}), 40.0 (CH₂, C_{2 ′ B}), 40.7 (CH, C_{3 ′ A}), 62. 8 (CH₂, C_{5 ′ A}), 76.5 (CH, C_{4 ′ B}), 84.8 (CH, C_{1 ′ A}), 85.1 (CH, C_{1 ′ B}), 85.6 (CH, C_{3 ′ B}), 86.8 (CH, C_{4 ′ A}), 110.7 (C, C_5A or C_5B), 111.1 (C, C_5A or C_5B), 128.0 (CH, CH_ar), 129.2 (CH, C_d), 130.1 (CH, CH_ar), 131.5 (CH, C_b and C_c), 132.3 (C, C_ar), 132.6 (CH, C_a), 133.2 (C, C_ar), 135.4, 135.5, 135.8, 135.9 (CH, CH_ar, C_6A and C_6B), 150.3 (C, C=O), 163.6 (C, C=O) ppm. The letter A refers to the upper moiety of the dimer 8. ESI-HRMS: m/z [M + Na⁺] calcd for C₅₅H₆₄N₄O₈Si₂Na: 987.4160; found: 987.4162.

31

To confirm the structure, this diyne was hydrogenated in MeOH in the presence of Pd/C to afford the corresponding known dimer with an alkane linkage (see ref. 11a).

32

Selected Physicochemical Data for Compound 20
^¹H NMR (400 MHz, CDCl₃): δ = 1.10 (s, 9 H, t-Bu), 1.11 (s, 9 H, t-Bu), 1.62 (s, 3 H, CH_3A), 1.84 (s, 3 H, CH_3B), 1.87-2.08 (ddd, 1 H, J = 5.0, 9.0, 14.0 Hz, H_{2 ′ B}), 2.32-2.66 (m,
3 H, H_{2 ′ A} and H_{2 ′ B}), 3.42 (ddd, 1 H, J = 8.0, 8.0, 8.0 Hz, H_{3 ′ A}), 3.83 (dd, part A of an AB system, 1 H, J = 2.0, 12.0 Hz, H_{5 ′ A}), 4.00 (ddd, 1 H, J = 2.0, 7.0, 12.0 Hz, H_{4 ′ A}), 4.08 (dd, part B of an AB system, 1 H, J = 2.0, 12.0 Hz, H_{5 ′ A}), 4.53 (d, 1 H, J = 4.0 Hz, H_{3 ′ B}), 4.67 (s, 1 H, H_{4 ′ B}), 6.20 (dd, 1 H, J = 13.0, 6.0 Hz, H_{1 ′ A}), 6.57 (dd, 1 H, J = 6.0, 8.0 Hz, H_{1 ′ B}), 7.34-7.51 (m, 14 H, H_ar, H_6A and H_6B), 7.62-7.68 (m, 8 H, H_ar), 9.16 (br s, 1 H, NH), 9.30 (br s, 1 H, NH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 12.1 (CH₃, CH_3A), 12.7 (CH₃, CH_3B, 19.0 (C, t-Bu), 19.4 (C, t-Bu), 26.8 (CH₃, t-Bu), 26.9 (CH₃, t-Bu), 29.6 (CH, C_{3 ′ A}), 38.9 (CH₂, C_{2 ′ A}), 40.5 (CH₂, C_{2 ′ B}), 62.5 (CH₂, C_{5 ′ A}), 66.4, 72.9, 73.5, 80.0 (C, C_a, C_b, C_c and C_d), 71.9 (CH, C_{4 ′ B}), 73.2 (CH, C_{3 ′ B}), 84.6 (CH, C_{1 ′ A}), 84.9 (CH, C_{4 ′ A}), 86.7 (CH, C_{1 ′ B}), 111.3 (C_5A and C_5B), 127.9, 128.0 (CH, CH_ar), 130.1 (CH, C_6A or C_6B), 130.2 (CH, C_6A or C_6B), 132.5, 132.6 (C, C_ar,), 134.9 (CH, CH_ar), 135.3, 135.5, 135.6 (CH, CH_ar), 150.4 (C, C=O), 163.7 (C, C=O) ppm. The letter A refers to the upper moiety of the dimer 20. ESI-HRMS: m/z [M + Na⁺] calcd for C₅₅H₆₀N₄O₈Si₂Na: 983.3847; found: 983.3837.