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Synlett 2002(10): 1657-1660
DOI: 10.1055/s-2002-34218
LETTER
© Georg Thieme Verlag Stuttgart · New York

N-Glycosylation of 2,3-Dideoxyfuranose Derivatives Having Difluoro-methylene-phosphonate and -phosphonothioate Functionality at the 3α-Position

Tetsuo Murano, Soichiro Muroyama, Tsutomu Yokomatsu*, Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
e-Mail: yokomatu@ps.toyaku.ac.jp;
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Publication History

Received 3 August 2002
Publication Date:
23 September 2002 (online)

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Abstract

TiCl4-Mediated N-glycosylation of 2,3-dideoxyribofunanosides having a difluoromethylene-phosphonate or -phosphonothioate functional group at the 3α-position with silylated pyrimidines was examined. The phosphonate functional was a good directing group to induce α-N-glycosylation for α-N 3-pyrimidine-nucleotide analogue 13 in high diastereoselectivity. The phosphonothioate was an effective functional group to give β-N 1-pyrimidine-nucleotide analogues 18a-c with good diastereoselectivity. The nucleotide analogue 18a was transformed to the difluoromethylenephosphonate analogue 20 of thymidine-3¢-phosphate by oxidation with MCPBA, followed by aqueous work-up.

Key words

nucleotide analogues - N-glycosylations - neighbouring-group effects - phosphorus - fluorine

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Spectroscopic data for selected new compounds:
Compound 9: [α]D 20 +13.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.90-4.83 (1 H, m), 4.38-4.23 (4 H, m), 4.00 (1 H, dd, J = 2.6, 12.5 Hz), 3.72 (1 H, dd, J = 2.9, 12.5 Hz), 3.40-3.22 (1 H, m), 2.85 (2 H, d, J = 8.4 Hz), 2.56 (1 H, br s), 1.40 (6 H, t, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3): δ = 175.1, 119.1 (dt, J CP = 215.4 Hz, J CF = 263.0 Hz), 78.6 (d, J CP = 4.0 Hz), 65.2 (d, J CP = 7.1 Hz), 65.0 (d, J CP = 7.1 Hz), 63.0, 40.1 (dt, J CP = 15.8 Hz, J CF = 21.0 Hz), 20.3, 16.0 (d, J CP = 5.2 Hz). 19F NMR (376 MHz, CDCl3, benzo-trifluoride): δ = -54.49 (1 F, dd, J HF = 4.9 Hz, J PF = 105.2 Hz), -54.54 (1 F, J HF = 5.8 Hz, J PF = 105.2 Hz). 31P NMR (162 MHz, CDCl3): δ = 5.76 (t, J PF = 105.2 Hz). MS (EI):
m/z = 303 [M+ + 1], 285 [M+ - OH], 271 [M+ - CH2OH]. IR(film): 3247, 2988, 1789, 1645 cm-1. Anal. Calcd for C10H17O6F2P: C, 39.74; H, 5.67. Found: C, 39.43; H, 5.66.
Compound 13: [α]D 20 +60.4 (c 1.3, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 9.56 (1 H, d, J = 5.6 Hz), 7.74-7.62 (4 H, m), 7.48-7.31 (6 H, m), 6.91 (1 H, dd, J = 1.1, 5.6 Hz), 6.83 (1 H, t, J = 7.7 Hz), 4.90-4.83 (1 H, m), 4.34-4.19 (4 H, m), 4.02-3.94 (1 H, m), 3.82-3.74 (1 H, m), 3.64-3.45 (1 H, m), 3.02 (1 H, ddd, J = 8.4, 12.4, 12.4 Hz), 2.59-2.48 (1 H, m), 1.89 (3 H, d, J = 1.1 Hz), 1.37 (3 H, t, J = 7.1 Hz), 1.36 (3 H, t, J = 7.1 Hz), 1.07 (9 H, s). 13C NMR (100 MHz, CDCl3):
δ = 163.9, 152.6, 135.6, 135.5, 135.0, 133.4, 133.1, 129.6, 127.6, 120.1 (dt, J CP = 216.2 Hz, J CF = 263.7 Hz), 110.3, 83.1, 79.8, 64.7 (d, J CP = 6.7 Hz), 64.5 (J CP = 6.9 Hz), 64.1, 42.3 (dt, J CP = 14.4 Hz, J CF = 20.7 Hz), 29.9, 26.8, 19.3, 16.4 (d, J CP = 5.2 Hz), 12.9. 19F NMR (376 MHz, CDCl3, benzotrifluoride): δ = -47.1 (1 F, dd, J FF = 300.9 Hz, J FP = 105.7 Hz), -58.5 (1 F, ddd, J FF = 300.9 Hz, JFP = 111.5 Hz, J FH = 26.1 Hz). 31P NMR (162 MHz, CDCl3): δ = 6.77 (dd, J PF = 105.7, 111.5 Hz). MS (EI): m/z = 593 [M+ - t-Bu]. HRMS (EI): m/z calcd for C27H32N2O7F2PSi [M+ - t-Bu]: 593.1697. Found: 593.1697. Anal. Calcd for C31H41N2O7F2PSi: C, 57.22; H, 6.35; N, 4.30. Found: C, 56.61; H, 6.35; N, 4.22.
Compound 18a: [α]D 20 +30.2 (c 1.3, CHCl3) for a sample of 78% de. 1H NMR (400 MHz, CDCl3): δ = 8.07 (1 H, br s), 7.71-7.62 (4 H, m), 7.49-7.34 (7 H, m), 6.19 (1 H, t, J = 6.8 Hz), 4.46-4.40 (1 H, m), 4.31-4.17 (4 H, m), 4.16-4.08 (1 H, m), 3.84 (1 H, dd, J = 2.4, 11.6 Hz), 3.68-3.50 (1 H, m), 2.82-2.72 (1 H, m), 2.21-2.11 (1 H, m), 1.56-1.53 (3 H, m), 1.36 (32 H, t, J = 7.0 Hz), 1.34 (3 H, t, J = 7.0 Hz), 1.11 (9 H, s). 13C NMR (100 MHz, CDCl3): δ = 163.9, 150.3, 135.5, 135.2, 135.0, 133.1, 132.3, 130.0 (2 carbons), 127.9 (2 carbons), 120.9 (dt, J CP = 176.5 Hz, J CF = 268.4 Hz), 111.3, 84.5, 78.9, 64.9 (d, J CP = 6.7 Hz), 64.5, 41.5 (dt, J CP = 16.6 Hz, J CF = 20.4 Hz), 33.1, 26.9, 19.4, 16.1 (d, J CP = 5.7 Hz), 11.9. 19F NMR (376 MHz, CDCl3, benzotrifluoride): δ =
-50.3 (1 F, ddd, J HF = 13.1 Hz, J FF = 289.5 Hz, J FP = 110.6 Hz), -54.7 (1 F, ddd, J HF = 21.9 Hz, J FF = 289.5 Hz, J FP = 107.7 Hz). 31P NMR (162 MHz, CDCl3): δ = 74.9 (dd, J PF = 107.7 Hz, 110.6 Hz). MS (EI): m/z = 609 [M+ - t-Bu], 541 [M+ - thymine]. Anal. Calcd for C31H41N2O6F2PSSi: C, 55.84; H, 6.20; N, 4.20. Found: C, 55.65; H, 6.14; N, 4.01.
Compound 20: [α]D 20 +34.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.24 (1 H, br s), 7.71-7.61 (4 H, m), 7.48-7.33 (6 H, m), 6.19 (1 H, t, J = 6.9 Hz), 4.48-4.42 (1 H, m), 4.35-4.21 (4 H, m), 4.16-4.08 (1 H, m), 3.84 (1 H, dd, J = 2.5, 11.6 Hz), 3.46-3.25 (1 H, m), 2.85-2.73 (1 H, m), 2.24-2.12 (1 H, m), 1.54 (3 H, s), 1.38 (6 H, t, J = 7.1 Hz), 1.10 (9 H, s). 13C NMR (100 MHz, CDCl3): δ = 163.9, 150.3, 135.5, 135.4, 135.2, 133.1, 132.3, 130.0 (2 carbons), 127.9 (2 carbons), 119.9 (dt, J CP = 214.3 Hz, J CF = 263.3 Hz), 111.3, 84.5, 78.5, 64.9 (d, J CP = 6.8 Hz), 64.8 (d, J CP = 7.0 Hz), 64.6, 42.3 (dt, J CP = 15.0 Hz, J CF = 20.2 Hz), 32.7, 26.9, 19.4, 16.3 (d, J CP = 5.2 Hz), 11.9. 19F NMR (376 MHz, CDCl3, benzotrifluoride): δ = -51.1 (1 F, ddd, J HF = 14.5 Hz, J FF = 302.9 Hz, J PF = 106.8 Hz), -54.0 (1 F, ddd, J HF = 21.5 Hz, J FF = 302.9 Hz, J PF = 106.8 Hz).
31P NMR (162 MHz, CDCl3): δ = 6.31 (t, J PF = 106.8 Hz). MS (EI): m/z = 593 [M+ - t-Bu]. HRMS (EI): m/z calcd for C27H32N2O7F2PSi [M+ - t-Bu]: 593.1697. Found: 593.1672.

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Percy et al. reported that the diol i, in situ prepared stereoselectively from the corresponding olefin by OsO4-catalyzed dihydroxylation, was not readily cyclized to the cis-lactone ii under the conditions. [7b] They were never able to isolate more than 11% of ii. The results are consistent with our findings (Scheme [7] ).

Scheme 7

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The 1-ethoxy derivative 16 did not react with T(TMS)2 in the presence of TiCl4 at -40 °C and the lactol 15 was recovered in 80% yield.