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Synlett 2002(11): 1779-1782
DOI: 10.1055/s-2002-34890
LETTER
© Georg Thieme Verlag Stuttgart · New York

DBU Catalyzed Cyclative Amidation Reaction: A Convenient Synthesis of C-Nucleoside Analogs [1]

Neetu Tewari, Ram C. Mishra, Vinod K. Tiwari, Rama P. Tripathi*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow-226001, India
Fax: +91(522)223938 ; e-Mail: rpt_56@yahoo.com;
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Publication History

Received 21 August 2002
Publication Date:
21 October 2002 (online)

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Abstract

Dihydropyrimidinone C-nucleosides have been synthesized stereoselectively through ureidyl tetrahydroheptofuranoates by cyclative amidation with a combination of DBU-tetrabutyl ammonium bromide-4 Å MS in good yields.

Key words

dihydropyrimidinone - tetrabutylammonium bromide - DBU - C-nucleosides

1

CDRI communication No. 6299.

    References

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1

CDRI communication No. 6299.

12

Mishra, R. C.; Tewari, N.; Arora, K.; Tripathi, R. P.; Tiwari, V. K.; Walter R. D.; Srivastava A. K. Comb. Chem. High Throughput Screening 2002, in press.

15

General procedure for the synthesis of compounds 2a-k, 4a and 4b: β-Amino ester 1a (1.15 g, 3.12 mmol) and p-n-butyl phenyl isocyanate (0.546 mL, 3.12 mmol) in anhydrous dichloromethane (15.0 mL) were magnetically stirred at ambient temperature for 2 h. Solvent was evaporated and the reaction mixture was chromatographed over a SiO2 column using a gradient of hexane-ethyl acetate (3:2) as eluent to give compound 2a (1.56 g, 95%). Similarly compounds 2b-k were synthesized in quantitative yield by reaction with the corresponding isocyanates. For the synthesis of compounds 4a,b, 2 mmoles of glycosylated β-amino esters 1 were treated with 1 mmole of diisocyanate under similar experimental conditions.

16

General procedure for the synthesis of compounds 3a-k, 5a and 5b:A mixture of compound 2a (0.3 g, 0.622 mmol), 4 Å MS (0.03 g), TBAB (0.03 g, 0.093 mmol) and DBU (0.093 mL, 0.622 mmol) in anhydrous toluene (15 mL) was refluxed for 2 h. Solvent was evaporated and the residue was chromatographed over a SiO2 column using a gradient of hexane-ethyl acetate (3:1) as eluent to give compound 3a. Similarly, compounds 3b-k and 5a,b were synthesized from the corresponding ureidyl derivatives 2b-k and 4a,b, respectively. The yields and reaction time are given in Table [1] .

17

Physical Data of the precursor of C-nucleosides. 2a:
[α]D = -37.94 (c, 0.437, CHCl3); FAB MS: m/z = 541
(M + H)+; IR (Neat): cm-1 3346, 2933, 1725, 1667, 1603, 1524, 1080, 1022. 1H NMR (200 MHz, CDCl3): δ 0.90 (t,
J = 7.2 Hz, 3 H, CH2CH2CH2CH3), 1.25 (t, J = 7.0 Hz, 3 H, -OCH2CH3), 1.32 and 1.51 [s each, 3 H each, >C (CH3)2], 1.55 (m, 4 H, CH2CH2CH2CH3), 2.40 (dd, J = 16.4 Hz and 3.8 Hz, 1 H, H-6a), 2.53 (t, J = 7.7 Hz, 3 H, CH2CH2CH2CH3), 2.80 (dd, J = 16.4 Hz and 8.4 Hz, 1 H,
H-6b), 3.37 (s, 3 H, -OCH3), 3.61 (d, J = 2.4 Hz, 1 H, H-3), 4.11 (q, J = 7.0 Hz, 2 H, -OCH2CH3), 4.51 (m, 3 H, H-4, H-5, -NCHa), 4.60 (d, J = 3.8 Hz, 1 H, H-2), 4.69 (d, J = 16.7 Hz, 1 H, NCHb), 5.89 (d, J = 3.8 Hz, 1 H, H-1), 6.31 (m, 2 H, furyl proton), 7.05 (d, J = 8.4 Hz, 2 H, ArH), 7.24 (d, J = 8.4 Hz, 2 H, ArH), 7.33 (s, 1 H, furyl proton), 7.58 (bs, 1 H, -NHAr). 4a: [α]D = -16.3 (c, 0.33, CHCl3); FAB MS: m/z = 891 (M + H)+; IR (Neat): cm-1 3365, 1729, 1572. 1H NMR (200 MHz, CDCl3): δ 1.22 (t, J = 7.1 Hz, 3 H, -OCH2CH3), 1.45 and 1.26 [s each, 3 H each, >C(CH3)2], 1.54 (s, 1 H,
-NHCH), 2.71 (m, 2 H, H-6), 3.90 (m, 1 H, H-3), 4.09 (m,
3 H,-OCH2CH3 and H-5), 4.68-4.38 (m, 4 H, -OCH2Ph,
H-2, H-4), 5.95 (d, J = 3.6 Hz, 1 H, H-1), 6.98 (m,1 H, NHAr), 7.17 (m, 7 H, ArH).

18

Physical data of C-nucleosides. 3a: [α]D = -2.40 (c, 0.250, CHCl3); FAB MS: m/z = 521 (M + Na)+; IR (Neat): cm-1 2932, 1680, 1452, 1376, 1210, 1080, 1017. 1H NMR (300 MHz, CDCl3): δ 0.92 (t, J = 7.2 Hz, 3 H, CH2CH2CH2CH3), 1.21 and 1.26 [s, 6 H, >C(CH3)2], 1.39 (m, 2 H, CH2CH2-CH2CH3), 1.58 (m, 2 H, CH2CH2CH2CH3), 2.58 (d, J = 9.0 Hz, 1 H, H-5a), 2.62 (t, J = 7.8 Hz, 3 H, CH2CH2CH2CH3), 2.98 (dd, J = 16.8 Hz and 6.6 Hz, 1 H, H-5b), 3.41 (s, 3 H,
-OCH3), 3.72 (d, J = 2.4 Hz, 1 H, H-3′), 4.00 (dd, J = 7.5 Hz and 8.1 Hz, 1 H, H-6), 4.34 (d, J = 15.6 Hz, 1 H, N-CHA), 4.46 (dd, J = 6.9 Hz and 2.7 Hz, 1 H, H-4′); 4.62 (d, J = 3.6 Hz, 1 H, H-2′), 5.28 (d, J = 15.9 Hz, 1 H, -NCHBPh), 5.97 (d, J = 3.6 Hz, 1 H, H-1′), 6.32 (m, 2 H, furyl proton), 7.04 (d,
J = 7.8 Hz, 2 H, ArH), 7.24 (d, J = 7.8 Hz, 2 H, ArH), 7.39 (s, 1 H, furyl proton). 13C NMR: δ 14.41, 22.86, 26.69, 27.37, 30.20, 33.82, 35.05, 35.82, 44.99, 50.84, 58.01, 81.15, 81.49, 84.25, 105.71, 109.40, 110.93, 112.53, 128.77, 129.67, 133.35, 142.97, 143.62, 151.32, 153.14, 168.97. 3b: [α]D = -27.05 (c, 0.425, CHCl3); FAB MS: m/z = 483 (M + H)+; IR (Neat): cm-1 3361,2932, 1652, 1462, 1369, 1201, 1080. 1H NMR (300 MHz, CDCl3):δ 1.27 [s, 6 H, >C(CH3)2], 2.45 (d, J = 16.6 Hz, 1 H, H-5a), 3.37 (s, 3 H, OCH3), 3.65 (d, J = 3.0 Hz, 1 H, H-3′), 3.98 (two d, J = 6.5 Hz, 1 H, H-6), 4.11 (dd, J = 6.5 Hz and 3.0 Hz, 1 H, H-4′), 4.27 (d, J = 15.7 Hz, 1 H, CHBPh), 4.57 (d, J = 3.7 Hz, 1 H, H-2′), 4.97(d, J = 4.4 Hz, 2 H, -NCH2Ph), 5.14 (d, J = 15.7 Hz, 1 H, CHAPh), 5.92 (d, J = 3.72 Hz, 1 H, H-1′), 6.91 and 7.36 (2 m, 9 H, Ar-H), 8.57 (br s, 1 H, Ph-OH). 13C NMR:
δ 26.56, 27.11, 30.07, 34.21, 44.35, 49.33, 50.97, 53.80, 57.84, 80.92, 81.10, 84.03, 105.58, 112.52, 118.12, 120.29, 123.12, 127.89, 128.87, 128.98, 130.68, 131.60, 137.64, 155.10, 156.20, 168.16. 3c: [α]D = -9.60 (c, 0.250, CHCl3); FAB MS: m/z = 483 (M + H)+; IR (Neat): cm-1 3371, 2928, 1652, 1461, 1377, 1208, 1080, 1026. 1H NMR (300 MHz, CDCl3): δ 1.23 and 1.26 [s, 6 H, >C(CH3)2], 2.62 (dd, J = 16.5 Hz and 6.4 Hz, 1 H, H-5a), 3.03 (d, J = 16.5 Hz, 1 H, H-5b), 3.43 (s, 3 H, OCH3), 3.61 (d, J = 3.0 Hz, 1 H, H-3′), 3.97 (dd, J = 6.3 Hz and 3.01 Hz, 1 H, H-4′), 4.05 (m, 1 H, H-6), 4.55 (d, J = 3.68 Hz, 1 H, H-2′), 4.89 and 4.80 (two d, each J = 14.8 Hz, 1 H each, NCHAPh and NCHBPh), 4.96 and 4.30 (two d, each J = 15.6 Hz, 1 H each, NCHAPhOH and NCHBPhOH), 5.80 (d, J = 3.68 Hz, 1 H, H-1′), 6.89 and 7.27 (two m, 9 H, Ar-H), 8.61 (br s, 1 H, Ph-OH).13C NMR:
δ 26.71, 27.13, 33.92, 48.09, 50.50, 57.41, 79.80, 80.88, 84.24, 105.14, 112.48, 118.30, 120.39, 122.78, 127.69, 127.74, 128.76, 128.83, 129.04, 130.98, 137.78, 155.72, 156.13, 168.65. 3g: [α]D = -12.0 (c, 0.200, CHCl3); FAB MS: m/z = 453 (M + H)+; IR (Neat): cm-1 3019, 2928, 1685, 1548, 1447, 1413, 1381, 1216. 1H NMR (200 MHz, CDCl3): δ 1.34 and 1.49 [s each, 3 H each, >C(CH3)2], 2.64 (m, 2 H, H-5), 3.94 (m, 2 H, H-3′ and H-6), 4.10 (dd, J = 3.0 Hz and 2.7 Hz, 1 H, H-4′), 4.66 (d, J = 3.0 Hz, 1 H, H-2′), 4.74 (d,
J = 11.7 Hz, 1 H, -OCHAPh), 5.98 (d, J = 3.0 Hz, 1 H, H-1′), 7.04 (d, J = 8.0 Hz, 2 H, Ar-H), 7.24 (m, 2 H, Ar-H), 7.38 (m, 5 H, Ar-H). 13C NMR: δ 21.20, 26.27, 26.87, 34.21, 46.35, 72.06, 81.39, 81.49, 82.02, 105.14, 112.31, 128.13, 128.38, 128.62, 28.88, 129.53, 129.84, 132.28, 136.34, 138.35, 153.98, 168.46. 3h: [α]D = -26.10 (c,0.475, CHCl3); FAB MS: m/z = 453 (M + H)+; 1H NMR (200 MHz, CDCl3): δ 1.30 nd 1.43 [s each, 3 H each, >C(CH3)2], 2.50 (m, 2 H, H-5), 3.82 (m, 1,H, H-6), 3.94 (m, 2 H, H-3′ and H-4′), 4.42 (d, J = 11.8 Hz, 1 H, -OCHAPh), 4.62 (d, J = 3.3 Hz, 1 H, H-2′), 4.68 (d, J = 11.8 Hz, 1 H, -OCHBPh), 4.92 (br s, 2 H, NCH2), 5.88 (br s, NH and H-1′), 7.29(m, 10 H, ArH). 13C NMR: δ 26.16, 26.74, 29.62, 31.38, 31.85, 33.59, 43.35, 45.98, 71.89, 81.14, 81.86, 104.95, 112.16, 127.23, 128.04, 128.28, 128.50, 128.77, 136.26, 137.50, 153.79, 168.09. 5a: [α]D = -24.20 (c, 0.14, CH3OH); FAB MS: m/z = 805 (M + Li)+; 1H NMR (200 MHz, CDCl3): δ 1.46 and 1.28 [s each,
3 H each, >C(CH3)2], 2.50 (m, 2 H, H-5), 3.66 (m, 1 H,
H-6), 3.90 (d, J = 3.0 Hz, 1 H, H-3′), 4.42 (d, J = 11.8 Hz,
1 H, -OCHAPh), 4.67 (d, J = 3.3 Hz, 1 H, H-2′), 4.68 (d, J = 11.8 Hz, 1 H, -OCHBPh), 5.95 (d, J = 3.6 Hz, 1 H, H-1′), 6.98 (s,1 H, NHCO), 7.30 (m, 7 H, ArH). 13C NMR: 137, 134, 128,121, 112, 105, 80, 81,82,72, 53, 52, 26, 25. 5b:
[α]D = -23.20 (c, 0.13, CH3OH); FAB MS: m/z = 799
(M + H)+; IR (Neat): cm-1 3361 (NH), 1614 (CO). 1H NMR (200 MHz, CDCl3): δ 1.46 and 1.28 [s each, 3 H each, >C(CH3)2], 2.62 and 2.97 (m each, 2 H each, H-5), 3.39 and 3.60 (m, each 1 H, diastereomeric H-6), 4.26 (m, 2 H, dia-stereomeric H-3′ and H-4′), 4.55 (m, 3 H, H-2′, -OCHAPh and -OCHBPh), 5.95 and 5.90 (d, J = 4.2 Hz, 1 H, diastereo-meric H-1′), 7.29 (m, 7 H, ArH). 13C NMR: 176, 172, 167,140, 137, 128, 124, 114, 112, 111, 105, 82.6, 82.07, 81.8, 72.29, 52.6, 50.06, 46, 26, 25.