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Synlett 2009(20): 3341-3345  
DOI: 10.1055/s-0029-1218357
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Valérie Fargeasa, Adjou Anéb, Didier Dubreuila, Jacques Lebreton*a
a Laboratoire CEISAM-UMR 6230, Faculté des Sciences et des Techniques, CNRS, Université de Nantes, 2 Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax: +33(2)51125562; e-Mail: jacques.lebreton@univ-nantes.fr;
b Laboratoire de Chimie Organique, UFR SSMT, Université de Cocody 22, BP 582, Abidjan 22, Côte d’Ivoire
Further Information

Publication History

Received 3 September 2009
Publication Date:
11 November 2009 (online)

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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

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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De Mesmaeker, A., Lebreton, J. 1992, unpublished results.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, H2 ′′), 1.89 (s, 3 H, CH3), 2.39 (ddd, 1 H, J = 10.0, 6.5, 3.0 Hz, H2 ′), 4.20 (ddd, 1 H, J = 10.0, 3.0 Hz, H3 ′), 4.24 (m, 1 H, H4 ′), 6.23 (br s, 2 H, H5 ′ and H6 ′), 6.34 (dd, 1 H, J = 6.5 Hz, H1 ′), 6.93 (d, 1 H, J = 1.0 Hz, H6), 7.38-7.50 (m, 6 H, Har), 7.59-7.67 (m, 4 H, Har), 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, C2 ′), 75.4 (CH, C3 ′), 80.7 (CH, C6 ′), 84.8 (CH, C1 ′), 88.2 (CH, C4 ′), 111.3 (C, C5), 127.9, 128.0 (CH, Car), 130.2 (CH, Car), 132.7 (C, Car), 134.9 (CH, C6), 135.6, 135.8 (CH, Car), 142.1 (CH, C5 ′), 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, H2 ′), 2.40 (m, 1 H, H2 ′), 2.40 (s, 3 H, CH3), 3.14 (m, 1 H, H3 ′), 3.75-3.86 (m, 2 H, H4 ′ and H5 ′), 4.11 (m, 1 H, H5 ′), 5.76 (dd, 1 H, J = 7.0, 19.0 Hz, H3 ′′), 6.15 (d, 1 H, J = 19.0 Hz, H3 ′′′), 6.16 (dd, 1 H, J = 3.0, 7.0 Hz, H1 ′), 7.22-7.49 (m, 6 H, Har), 7.66 (s, 1 H, H6), 7.62-7.84 (m, 4 H, Har), 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, C2 ′), 45.0 (CH, C3 ′), 62.5 (CH2, C5 ′), 84.7 (CH, C1 ′), 85.6 (CH, C4 ′), 110.5 (C, C5), 127.8 (CH, Car), 129.8 (CH, Car), 132.5 (CH, C3 ′′′), 132.8, 133.3 (C, Car), 135.2, 135.4 (CH, Car), 135.6 (CH, C6), 145.5 (CH, C3 ′′), 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, CH3A), 1.86 (s, 3 H, CH3B), 2.44-2.19 (m, 4 H, H2 ′ A and H2 ′ B), 3.18-3.02 (tdd, 1 H, J = 8.0, 8.0, 8.0 Hz, H3 ′ A), 3.79 (m, 1 H, H4 ′ A), 3.75 (dd, part A of an AB system, 1 H, J = 12.0, 3.0 Hz, H5 ′ A), 4.13-4.03 (dd, part B of an AB system, 1 H, J = 12.0, 3.0 Hz, H5 ′ A), 4.22-4.14 (1 H, dt, J = 6.0, 3.0 Hz, H4 ′ B), 4.42-4.33 (dd, 1 H, J = 7.0, 4.0 Hz, H3 ′ B), 5.34-5.21 (m, 1 H, Hd), 5.52-5.38 (m, 1 H, Ha), 6.05-5.90 (2 dd, 2 H, J = 8.0 Hz, Hb and Hc), 6.19-6.09 (dd, 1 H, J = 4.0, 7.0 Hz, H1 ′ A), 6.40-6.30 (dd, 1 H, J = 7.0 Hz, H1 ′ B), 7.00 (s, 1 H, H6B), 7.49-7.27 (m, 12 H, Har), 7.51 (s, 1 H, H6A), 7.75-7.56 (m, 8 H, Har), 8.87-8.80 (2 br s, 2 H, 2 NH) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 12.1 (CH3, CH3A), 12.3 (CH3, CH3B), 19.0 (C, t-Bu), 19.4 (C, t-Bu), 26.8 (CH3, t-Bu), 27.0 (CH3, t-Bu), 39.4 (CH2, C2 ′ A), 40.0 (CH2, C2 ′ B), 40.7 (CH, C3 ′ A), 62. 8 (CH2, C5 ′ A), 76.5 (CH, C4 ′ B), 84.8 (CH, C1 ′ A), 85.1 (CH, C1 ′ B), 85.6 (CH, C3 ′ B), 86.8 (CH, C4 ′ A), 110.7 (C, C5A or C5B), 111.1 (C, C5A or C5B), 128.0 (CH, CHar), 129.2 (CH, Cd), 130.1 (CH, CHar), 131.5 (CH, Cb and Cc), 132.3 (C, Car), 132.6 (CH, Ca), 133.2 (C, Car), 135.4, 135.5, 135.8, 135.9 (CH, CHar, C6A and C6B), 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, CH3A), 1.84 (s, 3 H, CH3B), 1.87-2.08 (ddd, 1 H, J = 5.0, 9.0, 14.0 Hz, H2 ′ B), 2.32-2.66 (m,
3 H, H2 ′ A and H2 ′ B), 3.42 (ddd, 1 H, J = 8.0, 8.0, 8.0 Hz, H3 ′ A), 3.83 (dd, part A of an AB system, 1 H, J = 2.0, 12.0 Hz, H5 ′ A), 4.00 (ddd, 1 H, J = 2.0, 7.0, 12.0 Hz, H4 ′ A), 4.08 (dd, part B of an AB system, 1 H, J = 2.0, 12.0 Hz, H5 ′ A), 4.53 (d, 1 H, J = 4.0 Hz, H3 ′ B), 4.67 (s, 1 H, H4 ′ B), 6.20 (dd, 1 H, J = 13.0, 6.0 Hz, H1 ′ A), 6.57 (dd, 1 H, J = 6.0, 8.0 Hz, H1 ′ B), 7.34-7.51 (m, 14 H, Har, H6A and H6B), 7.62-7.68 (m, 8 H, Har), 9.16 (br s, 1 H, NH), 9.30 (br s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 12.1 (CH3, CH3A), 12.7 (CH3, CH3B, 19.0 (C, t-Bu), 19.4 (C, t-Bu), 26.8 (CH3, t-Bu), 26.9 (CH3, t-Bu), 29.6 (CH, C3 ′ A), 38.9 (CH2, C2 ′ A), 40.5 (CH2, C2 ′ B), 62.5 (CH2, C5 ′ A), 66.4, 72.9, 73.5, 80.0 (C, Ca, Cb, Cc and Cd), 71.9 (CH, C4 ′ B), 73.2 (CH, C3 ′ B), 84.6 (CH, C1 ′ A), 84.9 (CH, C4 ′ A), 86.7 (CH, C1 ′ B), 111.3 (C5A and C5B), 127.9, 128.0 (CH, CHar), 130.1 (CH, C6A or C6B), 130.2 (CH, C6A or C6B), 132.5, 132.6 (C, Car,), 134.9 (CH, CHar), 135.3, 135.5, 135.6 (CH, CHar), 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.