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

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.

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

References

1a Norbeck DW. Ann. Rep. Med. Chem.  1990,  25:  149 

1b Nucleoside and Nucleotides as Antitumor and Antiviral Agents   Chu CK. Baker DC. Plenum Press; New York: 1993. 

2 Engel R. Chem. Rev.  1977,  77:  349 

3a Albrecht HP. Jones GH. Moffatt JG. J. Am. Chem. Soc.  1970,  92:  5510 

3b Morr M. Ernst L. Grotjahn L. Z. Naturforsch., B: Chem. Sci.  1983,  38:  1665 

3c Albrecht HP. Jones G. Moffatt JG. Tetrahedron  1984,  40:  79 

3d Morr M. Ernst L. Schomburg D. Liebigs Ann. Chem.  1991,  615 

3e Morr M. Ernst L. Liebigs Ann. Chem.  1993,  1205 

4a Blackburn GM. Chem. Ind.  1981,  134 

4b Chamber RD. O’Hagan D. Lamount RB. Jain SC. J. Chem. Soc., Chem. Commun.  1990,  1053 

4c O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 ; and the references cited therein

For recent leading references, see

5a Burke TR. Ye B. Yan X. Wang S. Jia Z. Chen L. Zhang Z.-Y. Barford D. Biochemistry  1996,  35:  15989 

5b Jia Z. Ye Q. Dinaut AN. Wang Q. Waddleton D. Payette P. Ramachandran C. Kennedy B. Hum G. Taylor SD. J. Med. Chem.  2001,  44:  4584 

5c Yokomatsu T. Murano T. Umesue I. Soeda S. Shimeno H. Shibuya S. Bioorg. Med. Chem. Lett.  1999,  9:  529 

5d Halazy S. Ehrhard A. Eggenspiller A. Berges-Gross V. Danzin C. Tetrahedron  1996,  52:  177 

5e Yokomatsu T. Hayakawa Y. Kihara T. Koyanagi S. Soeda S. Shimeno H. Shibuya S. Bioorg. Med. Chem.  2000,  8:  2571 

5f Yokomatsu T. Takechi H. Akiyama T. Shibuya S. Kominato T. Soeda S. Shimeno H. Bioorg. Med. Chem. Lett.  2001,  11:  1277 

6a Blackburn GM. Guo M.-J. Tetrahedron Lett.  1993,  34:  149 

6b Matulic-Adamic J. Usman N. Tetrahedron Lett.  1994,  35:  7193 

6c Matulic-Adamic J. Haeberli P. Usman N. J. Org. Chem.  1995,  60:  2563 

7a Lequeux TP. Percy JM. Synlett  1995,  361 

7b Butt AH. Percy JM. Spencer NS. Chem. Commun.  2000,  1691 

8a Yokomatsu T. Sada T. Shimizu T. Shibuya S. Tetrahedron Lett.  1998,  39:  6299 

8b Yokomatsu T. Sada T. Shimizu T. Shibuya S. Heterocycles  2000,  52:  515 

Reviews for N-glycosylation in the synthesis of nucleosides and nucleotides:

9a Vorbüggen H. Acc. Chem. Res.  1995,  28:  509 

9b Wilson LJ. Hager MW. El-Kattan YA. Liotta DC. Synthesis  1995,  1465 

9c Vorbrüggen H. Ruh-Pohlenz C. Org. React.  2000,  55:  1 

10a Martin SF. Dean DW. Wagman AS. Tetrahedron Lett.  1992,  33:  1839 

10b Berkowitz DB. Eggen M. Shen Q. Shoemarker R. J. Org. Chem.  1996,  61:  4666 

11

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, J_FP = 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.

12

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

13

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.