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Synlett 2002(7): 1113-1117
DOI: 10.1055/s-2002-32579
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Chiral Nitrones in the Synthesis of Modified Nucleosides

Róbert Fischera, Alexandra Druckováa, Lubor Fiera*a, Alfonz Rybárb, Christian Hametnerc, MichaŠ K. CyraŇskid
a Department of Organic Chemistry, Slovak University of Technology, 812 37 Bratislava, Slovak Republic
e-Mail: fisera@cvt.stuba.sk;
b Institute of Chemistry, Slovak Academy of Sciences, 842 38 Bratislava, Slovak Republic
c Institute of Applied Synthetic Chemistry, University of Technology, 1060 Vienna, Austria
d Department of Chemistry, University Warsaw, 02 093 Warsaw, Poland
Further Information

Publication History

Received 18 April 2002
Publication Date:
07 February 2007 (online)

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Abstract

New chiral nitrones 7 and 12, easily prepared from d-xylose by multistep synthetic routes, undergo regioselective 1,3-dipolar cycloadditions with N-vinylated bases (uracil, adenine) giving isoxazolidinyl nucleosides in good yields. Attack of the dipolarophile on the Z-configuration of the nitrone through exo and endo transition states from the si face of nitrone (C-1′/C-3 erythro) affords C-3/C-5 cis (exo) and C-3/C-5 trans (endo) isoxazolidines as two major isomers.

Key words

chiral - dipolar cycloadditions - nitrones - isoxazolidines - modified nucleosides

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Selected Data: ( Z )- N -(1-Deoxy-2,3:4,5-di- O - iso propylidene- d - xylo -1-ylidene)-benzylamine- N -oxide(7): Colorless solid, mp 95-97 °C (crystalized from hexanes); total yield 20%; [α]D = +41.3 (CHCl3, c 0.22); 1H NMR (400 MHz, CDCl3): δ = 1.36, 1.38, 1.43, 1.48 [4 × s, 4 × 3 H, C(CH3)2], 3.73 (dd, 1 H, J 4,5a = 6.8 Hz, J 5a,5b = 8.6 Hz, H-5a), 3.95 (dd, 1 H, J 2,3 = 5.9 Hz, J 3,4 = 6.7 Hz, H-3), 4.09 (dd, 1 H, J 4,5b = 6.7 Hz, J 5a,5b = 8.8 Hz, H-5b), 4.40 (q, 1 H, J 3,4 = 6.7 Hz, J 4,5a = J 4,5b = 6.7 Hz, H-4), 4.89 (s, 2 H, NCH2Ph), 5.07 (dd, 1 H, J 1,2 = J 2,3 = 6.2 Hz, H-2), 6.81 (d, 1 H, J 1,2 = 6.0 Hz, H-1), 7.41-4.42 (br s, 5 H, NCH2Ph); 13C NMR (125 MHz, CDCl3): δ = 25.8, 26.8, 27.0, 27.4 [C(CH3)2], 66.1 (C-5), 70.1 (NCH2Ph), 73.6 (C-2), 76.8 (C-4), 81.1 (C-3), 110.1, 111.3 [C(CH3)2], 129.4, 129.5, 129.7, 129.8, 130.0, 132.5 (NCH2Ph), 137.4 (C-1). ( Z )- N -(1-Deoxy-2,3- O - iso propylidene-4- O -benzoyl-5- O - tert -butyldiphenylsilyl-d- xylo -1-ylidene)-benzylamine- N -oxide(12): Colorless oil, total yield 15%; [α]D = +9.5 (CHCl3, c 0.22); 1H NMR (400 MHz, CDCl3): δ = 1.04 [s, 9 H, OSiC(CH3)3], 1.39, 1.50 [2 × s, 2 × 3 H, C(CH3)2], 3.99 (dd, 1 H, J 4,5a = 5.7 Hz, J 5a,5b = 10.4 Hz, H-5a), 4.10 (dd, 1 H, H-5b, J 4,5b = 6.1 Hz, J 5a,5b = 10.2 Hz, H-5b), 4.50 (dd, 1 H, J 2,3 = 6.7 Hz, J 3,4 = 3.8 Hz, H-3), 4.86 (s, 2 H, NCH2Ph), 5.23 (dd, 1 H, J 1,2 = J 2,3 = 6.3 Hz, H-2), 5.68 (dt, 1 H, J 3,4 = 3.8 Hz, J 4,5a = J 4,5b = 5.8 Hz, H-4), 6.79 (d, 1 H, J 1,2 = 5.6 Hz, H-1), 7.28-8.11 (m, 20 H, NCH2Ph, OSiPh2); 13C NMR (125 MHz, CDCl3): δ = 19.6 [OSiC(CH3)3], 27.0 [C(CH3)2], 27.2 [OSiC(CH3)3], 27.3 [C(CH3)2], 62.9 (C-5), 69.9 (NCH2Ph), 72.9 (C-2), 74.0 (C-4), 78.6 (C-3), 111.0 [C(CH3)2], 128.0-136.1 (NCH2Ph, OSiPh2), 136.9 (C-1), 166.0 (COPh).

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Typical Experimental Procedure: A mixture of nitrone and N-vinylated base was stirred in toluene for 12-24 h under reflux. When starting nitrone had been consumed (TLC), the toluene was evaporated under vacuum and the mixture of isomers was separated by flash column chromatography (silica gel, CHCl3:MeOH = 95: 5).

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Yields of cycloadditions depended on the numbers of equivalents of the dipolarophiles employed, presumably due to the nitrone’s instability. Nitrone 7 in the absence of dipolarophile was completely decomposed after 24 h in toluene at 110 °C.

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Selected Data: 1-{(3 S ,5 R )-2-Benzyl-3-[1,2:3,4-di- O - iso propylidene-d- xylo ]isoxazolidine-5-yl}uracil(13a): Colorless solid, mp 187-189 °C (from toluene); yield 33%; [α]D = -52.7 (MeOH, c 0.12); 1H NMR (400 MHz, CDCl3): δ = 1.38, 1.40, 1.41, 1.44 [4 × s, 4 × 3 H, C(CH3)2], 2.60 (ddd, 1 H, J 3,4b = 7.3 Hz, J 4a,4b = 13.7 Hz, J 4b,5 = 3.2 Hz, H-4b), 2.91 (dt, 1 H, J 3,4a = 8.5 Hz, J 4a,4b = 14.3 Hz, J 4a,5 = 8.5 Hz, H-4a), 3.19 (ddd, 1 H, J 1 ′ ,3 = 2.9 Hz, J 3,4a = 6.9 Hz, J 3,4b = 8.9 Hz, H-3), 3.64 (dd, 1 H, J 1 ′ ,2 ′ and J 2 ′ ,3 ′ = 3.4 Hz and 8.6 Hz, H-2′), 3.87 (t, 1 H, J 3 ′ ,4 ′ a = J 4 ′ a,4 ′ b = 7.9 Hz, H-4′a), 4.00 (dd; 1 H, J 3 ′ ,4 ′ b = 6.7 Hz, J 4 ′ a,4 ′ b = 8.2 Hz, H-4′b), 4.04 (d, 1 H, NCH2Ph, J = 14.3 Hz), 4.08-4.13 (m, 2 H, H-1′, H-3′), 4.24 (d, 1 H; NCH2Ph, J = 14.0 Hz), 5.70 (dd, 1 H, J 5 ′′ ,6 ′′ = 8.2 Hz, J 5 ′′ ,NH = 2.1 Hz, H-5′′), 6.28 (dd, 1 H, J 4a,5 = 7.9 Hz, J 4b,5 = 2.9 Hz, H-5), 7.30-7.40 (m, 5 H, NCH2Ph), 7.96 (d, 1 H, J 5 ′′ ,6 ′′ = 8.2 Hz, H-6′′), 8.81 (s, 1 H, NH); 13C NMR (125 MHz, CDCl3): δ = 25.9, 26.5, 27.3, 27.4 [C(CH3)2], 37.3 (C-4), 61.6 (NCH2Ph), 65.3 (C-3), 66.0 (C-4′), 74.7, 75.1 (C-1′, C-3′), 78.6 (C-2′), 83.3 (C-5), 102.1 (C-5′′), 110.2, 110.5 [C(CH3)2], 128.4, 128.9, 129.1, 129.6, 135.9 (NCH2Ph), 141.7 (C-6′′), 151.0, 163.8 (CO). 1-{(3 S ,5 R )-2-Benzyl-3-[1,2- O - iso propylidene-3- O -benzoyl-4- O - tert -butyldiphenylsilyl-d- xylo ]isoxazolidine-5-yl}uracil(14a): Colorless solid, mp 57-60 °C (purified by column chromatography); yield 40%; [α]D = -30.9 (CHCl3, c 0.13); 1H NMR (400 MHz, CDCl3): δ = 1.04 [s, 9 H, OSiC(CH3)3], 1.32, 1.37 [2 × s, 2 × 3 H, C(CH3)2], 2.61 (ddd, 1 H, J 3,4b = 7.0 Hz, J 4a,4b = 14.0 Hz, J 4b,5 = 3.0 Hz, H-4b), 2.91 (ddd, 1 H, J 3,4a = 9.2 Hz, J 4a,4b = 14.0 Hz, J 4a,5 = 8.0 Hz, H-4a), 3.27 (ddd, 1 H, J 1 ′ ,3 = 2.4 Hz, J 3,4a = 9.4 Hz, J 3,4b = 7.0 Hz, H-3), 3.84 (dd, 1 H, J 1 ′ ,2 ′ = 8.6 Hz, J 1 ′ ,3 = 2.6 Hz, H-1′), 3.94 (dd, 1 H, J 3 ′ ,4 ′ a = 6.0 Hz, J 4 ′ a,4 ′ b = 2.4 Hz, H-4′a), 3.99-4.02 (m; 2 H, H-2′, H-4′b), 4.01 (d, 1 H, NCH2Ph, J = 14.8 Hz), 4.10 (d, 1 H, NCH2Ph, J = 14.0 Hz), 5.35 (dt, 1 H, J 3 ′ ,4 ′ a = 6.0 Hz, J 3 ′ ,4 ′ b = 2.7 Hz, H-3′)5.62 (dd, 1 H, J 5 ′′ ,6 ′′ = 8.4 Hz, J 5 ′′ ,NH = 2.4 Hz, H-5′′), 6.28 (dd, 1 H, J 4a,5 = 7.8 Hz, J 4b,5 = 3.0 Hz, H-5), 7.20-7.70 and 8.07-8.09 (m, 20 H, NCH2Ph, COPh, OSiPh2), 7.99 (d, 1 H, J 5 ′′ ,6 ′′ = 8.4 Hz, H-6′′), 9.03 (d, 1 H, J 5 ′′ ,NH = 1.6 Hz, NH); 13C NMR (125 MHz, CDCl3): δ = 19.5 [OSiC(CH3)3], 27.1, 27.3 [C(CH3)2, OSiC(CH3)3], 37.5 (C-4), 61.7 (NCH2Ph), 63.3 (C-4′), 65.7 (C-3), 72.1 (C-3′), 74.5 (C-1′), 77.8 (C-2′), 83.3 (C-5), 102.0 (C-5′′), 110.3 [C(CH3)2], 128.2-141.9 (NCH2Ph, COPh, OSiPh2), 151.0 (C-6′′), 163.8, 166.5 (CO). 9-{(3 S ,5 R )-2-Benzyl-3-[1,2:3,4-di- O - iso propylidene-d- xylo ]isoxazolidine-5-yl}adenine(15a): Colorless solid, mp 59-62 °C (purified by column chromatography); yield 59%; [α]D = -69.4 (CHCl3, c 0.16); 1H NMR (400 MHz, CDCl3): δ = 1.31, 1.39, 1.42, 1.46 [4 × s, 4 × 3 H, C(CH3)2], 2.95 (ddd, 1 H, J 3,4b = 6.8 Hz, J 4a,4b = 13.6 Hz, J 4b,5 = 2.4 Hz, H-4b), 3.04 (ddd, 1 H, J 3,4a = 9.2 Hz, J 4a,4b = 13.6 Hz, J 4a,5 = 8.0 Hz, H-4a), 3.25 (ddd, 1 H, J 1 ′ ,3 = 2.4 Hz, J 3,4a = 9.2 Hz, J 3,4b = 6.8 Hz, H-3), 3.64 (dd, 1 H, J 1 ′ ,2 ′ = 8.8 Hz and J 2 ′ ,3 ′ = 3.2 Hz, H-2′), 3.87 (dd, 1 H, J 3 ′ ,4 ′ a = 7.2 Hz, J 4 ′ a,4 ′ b = 8.0 Hz, H-4′a), 3.89 [s, 6 H, N(SO2CH3)2], 4.01 (dd; 1 H, J 3 ′ ,4 ′ b = 6.8 Hz, J 4 ′ a,4 ′ b = 8.0 Hz, H-4′b), 4.08 (dt, 1 H, J 2 ′ ,3 ′ = 3.6 Hz, J 3 ′ ,4 ′ a and J 3 ′ ,4 ′ b = 6.8 Hz, H-3′) 4.16 (d, 1 H, NCH2Ph, J = 14.0 Hz), 4.17 (dd, 1 H, J 1 ′ ,3 = 2.4 Hz, J 1 ′ ,2 ′ = 8.4 Hz, H-1′), 4.30 (d, 1 H, NCH2Ph, J = 14.0 Hz), 6.61 (dd, 1 H, J 4a,5 = 8.0 Hz, J 4b,5 = 2.4 Hz, H-5), 7.35-7.36 (m, 5 H, NCH2Ph), 8.88, 8.91 (2 × s, 2 × 1 H, H-adenine); 13C NMR (125 MHz, CDCl3): δ = 25.9, 26.5, 27.2, 27.4 [C(CH3)2], 36.9 (C-4), 45.4 [N(SO2CH3)2], 60.7 (NCH2Ph), 64.9 (C-3), 66.0 (C-4′), 74.5 (C-1′, C-3′), 78.6 (C-2′), 81.0 (C-5), 110.2, 110.6 [C(CH3)2], 128.4, 128.9, 130.0, 130.9, 135.6, 146.5, 154.2 (NCH2Ph, C-adenine), 146.3, 152.3 (CH-adenine). 9-{(3 S ,5 S )-2-Benzyl-3-[1,2:3,4-di- O - iso propylidene-d- xylo ]isoxazolidine-5-yl}adenine(15b): Colorless solid, mp 67-70 °C (purified by column chromatography); yield 10%; [α]D = +13.8 (CHCl3, c 0.05); 1H NMR (400 MHz, CDCl3): δ = 1.42, 1.43, 1.45, 1.47 [4 × s, 4 × 3 H, C(CH3)2], 3.23 (ddd, 1 H, J 3,4a = 4.0 Hz, J 4a,4b = 13.6 Hz, J 4a,5 = 7.6 Hz, H-4a), 3.48 (m, 1 H, H-4b), 3.60 (dd, 1 H, J = 4.2 Hz, J = 7.4 Hz, H-2′), 3.68 (m, 1 H, H-3), 3.90 [s, 6 H, N(SO2CH3)2], 3.86-3.93 (m, 1 H, H-4a′), 4.00 (dd, 1 H, J 3 ′ ,4 ′ b = 6.6 Hz, J 4 ′ a,4 ′ b = 8.2 Hz, H-4′b) 4.18-4.23 (m, 2 H, H-1′, H-3′), 4.19 (d, 1 H, NCH2Ph, J = 12.4 Hz), 4.26 (d, 1 H; NCH2Ph, J = 12.8 Hz), 6.40 (dd, 1 H, J 4a,5 = 7.6 Hz, J 4b,5 = 5.2 Hz, H-5), 7.27-7.31 (m, 5 H, NCH2Ph), 8.27, 8.92 (2 × s, 2 × 1 H, H-adenine); 13C NMR (75 MHz, CDCl3): δ = 25.7, 26.3, 27.0, 27.4 [C(CH3)2], 35.1 (C-4), 45.0 [N(SO2CH3)2], 61.9 (NCH2Ph), 65.4 (C-3), 65.7 (C-4′), 75.6 (C-1′, C-3′), 79.6 (C-2′), 86.0 (C-5), 109.8, 110.3 [C(CH3)2], 128.2-131.5 (NCH2Ph, C-adenine), 146.8, 153.1 (CH-adenine).

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Crystallographic data for the structure 13a have been deposited with the Cambridge Crystallographic Data Centre; reference number CCDC 178867(13a). Copies of the data can be obtained on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email: deposit@ccdc.cam.ac.uk).