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DOI: 10.1055/s-2002-34218
N-Glycosylation of 2,3-Dideoxyfuranose Derivatives Having Difluoro-methylene-phosphonate and -phosphonothioate Functionality at the 3α-Position
Publication History
Publication Date:
23 September 2002 (online)

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
-
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
References
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.
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
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.