Isoxazolinyl Spironucleosides: Stereoselectivity of 1,3-Dipolar Cycloadditions of 7-Methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones

Abstract

Novel 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-ones 11a-c were synthesized from commercially available orotic acid (6). 1,3-Dipolar cycloadditions of mesitonitrile oxide to the exocyclic double bond of the dipolarophiles 11 proceed with complete regioselectivity and lead to the spiroisoxazolinyl nucleosides 13 and 14 in good yields. Attack of the dipole from the less sterically hindered side of the dipolarophile affords C-5/C-7 trans isoxazolines as major isomers predominantly. The protection of the free hydroxyl group by the bulky substituent (TBDPS) leads to formation C-5/C-7 trans isomer 14c exclusively.

pyrrolo[1,2-c]pyrimidin-1(5H)-ones - dipolar cycloadditions - nitrile oxides - isoxazolines - modified spironucleosides

References

1 Haruyama H. Takayama T. Kinoshita T. Kondo M. Nakajima M. Haneishi T. J. Chem. Soc., Perkin Trans. 1  1991,  1637 

2a Kittaka A. Tanaka H. Odanaka Y. Ohnuki K. Yamaguchi K. Miyasaka T. J. Org. Chem.  1994,  59:  3636 

2b Kittaka A. Asakura T. Kuze T. Tanaka H. Yamada N. Nakamura KT. Miyasaka T. J. Org. Chem.  1999,  64:  7081 

2c Chatgilialoglu C. Gimisis T. Spada GP. Chem.-Eur. J.  1999,  5:  2866 

3 Yoshimura Y. Otter BA. Ueda T. Matsuda A. Chem. Pharm. Bull.  1992,  40:  1761 

4a Merino P. Curr. Med. Chem. -Anti-Infective Agents  2002,  1:  389 

4b Pan S. Amankulor NM. Zhao K. Tetrahedron  1998,  54:  6587 

5a Merino P. Franco S. Merchan FL. Tejero T. J. Org. Chem.  2000,  65:  5575 

5b Chiacchio U. Rescifina A. Corsaro A. Pistara V. Romeo G. Romeo R. Tetrahedron: Asymmetry  2000,  11:  2045 

5c Merino P. Del Alamo EM. Franco S. Merchan FL. Simon A. Tejero T. Tetrahedron: Asymmetry  2000,  11:  1543 

5d Colacino E. Coverso A. Liguori A. Napoli A. Siciliano C. Sindona G. Tetrahedron  2001,  57:  8551 ; and references cited therein

6a Dalpozzo R. De Nino A. Maiuolo L. Procopio A. De Munno G. Sindona G. Tetrahedron  2001,  57:  4035 

6b Iannazzo D. Piperno A. Pistara V. Rescifina A. Romeo R. Tetrahedron  2002,  58:  581 

6c Chiacchio U. Corsaro A. Iannazzo D. Piperno A. Pistara A. Procopio A. Rescifina A. Romeo G. Romeo R. Siciliano MCR. Valveri E. Arkivoc  2002,  159 

7a Chiacchio U. Corsaro A. Iannazzo D. Piperno A. Rescifina A. Romeo R. Romeo G. Tetrahedron Lett.  2001,  42:  1777 

7b Iannazzo D. Piperno A. Pistara V. Rescifina A. Romeo R. Tetrahedron  2002,  58:  581 

8a Fischer R. Drucková A. Fiera L. Rybár A. Hametner C. Cyránski MK. Synlett  2002,  1113 

8b Fischer R. Drucková A. Fiera L. Hametner C. Arkivoc  2002,  80 

9 Gershon H. J. Org. Chem.  1962,  27:  3507 

10 Aldehyde 8 was prepared from 7 by a two-steps process via selective oxidation of the corresponding alcohol in 84% yield: Snider BB. Chaoyu X. Tetrahedron Lett.  1998,  39:  7021 

11 Danel K. Pedersen EB. Nielsen C. Synthesis  1997,  1021 

12

Procedure for 2,4-Dimethoxy-6-(1-hydroxybut-3-en-1-yl)pyrimidine ( 9a): To a stirred suspension of Zn dust (1.98 g, 7.33 mmol) in anhyd THF (50 mL), allyl bromide (1.62 mL, 18.07 mmol) was added, followed by 2,4-dimethoxy-6-pyrimidinecarbaldehyde (8, 0.60 g, 3.57 mmol) and the mixture was stirred vigorously under reflux for 3 h. The reaction mixture was cooled to r.t., quenched with sat. aq NH₄Cl and vigorously stirred with CH₂Cl₂ (30 mL) for 15 min. The solid was removed by filtration through the Celite^® and the organic layer was separated. The aq phase was extracted with CH₂Cl₂ (20 mL) and the combined organic layers were dried with Na₂SO₄, filtered and the solvent removed. The final product was purified by the column chromatography on silica gel (hexane-EtOAc, 3:1) giving homoallyl alcohol 9a (0.63 g) as a colourless solid; yield 85%; mp 131-133 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.46 (ddddd, J _7,8a = 7.3 Hz, J _8a,8b = 14.3 Hz, J _8a,9 = 7.3 Hz,
J _8a,10a = 1.2 Hz, J _8a,10b = 1.2 Hz, 1 H, H-8a), 2.63 (ddddd,
J _7,8b = 4.7 Hz, J _8a,8b = 14.0 Hz, J _8b,9 = 7.0 Hz, J _8b,10a = 1.5 Hz, J _8b,10b = 1.2 Hz, 1 H, H-8b), 3.37 (d, J _7,OH = 5.0 Hz, 1 H, OH), 3.97, 4.00 (2 × s, 2 × 3 H, OCH₃), 4.62 (ddd, J _7,OH = 4.7 Hz, J _7,8a = 7.6 Hz, J _7,8b = 4.7 Hz, 1 H, H-7), 5.13 (dddd, J _8a,10b = 1.2 Hz, J _8b,10b = 1.2 Hz, J _9,10b = 10.2 Hz, J _10a,10b = 1.8 Hz, 1 H, H-10b), 5.14 (dddd, J _8a,10a = 1.5 Hz, J _8b,10a = 1.5 Hz, J _9,10a = 17.0 Hz, J _10a,10b = 2.0 Hz, 1 H, H-10a), 5.81 (dddd, J _8a,9 = 7.0 Hz, J _8b,9 = 7.0 Hz, J _9,10a = 17.0 Hz, J _9,10b = 10.2 Hz, 1 H, H-9), 6.39 (d, J _5,7 = 0.6 Hz, 1 H, H-5). ¹³C NMR (125 MHz, CDCl₃): δ = 42.2 (C-8), 54.4, 55.2 (OCH₃), 72.2
(C-7), 97.9 (C-5), 119.0 (C-10), 133.9 (C-9), 165.4 (C-6), 172.5, 173.0 (C-2, C-4).

13

Procedure for 10a: The stirred solution of the homoallyl alcohol 9b (0.20 g, 0.64 mmol) in CHCl₃ (20 mL) was warmed to 60 °C and a solution of Br₂ (0.10 g, 0.03 mL, 0.64 mmol) in CHCl₃ (10 mL) was slowly added dropwise over 4 h. The solvent was removed in vacuo and the reaction products were isolated by column chromatography on silica gel (hexane-EtOAc, 1:1) giving pyrimidinone 10b as a mixture of cis/trans isomers (0.20 g, 82%) as colorless foam.

14

Selected data: 6,7-Dihydro-5-hydroxy-3-methoxy-7-methylenepyrrolo[1,2- c ]pyrimidin-1(5 H )-one ( 11a): Yield 44%; colorless solid; mp 192-193 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.60 (dddd, J _5,6a = 6.1 Hz, J _6a,6b = 16.1 Hz, J _6a,10a = 2.1 Hz, J _6a,10b = 2.4 Hz, 1 H, H-6a), 3.07 (dddd, J _5,6b = 8.2 Hz, J _6a,6b = 16.1 Hz, J _6b,10a = 1.5 Hz, J _6b,10b = 1.8 Hz, 1 H, H-6b), 3.86 (s, 3 H, OCH₃), 4.89 (dd, J _6a,10a = 2.1 Hz, J _6b,10a = 1.5 Hz, J _10a,10b = 0 Hz, 1 H, H-10a), 4.98 (dddd, J _5,OH = 6.1 Hz, J _4,5 = 1.2 Hz, J _5,6a = 6.1 Hz, J _5,6b = 8.2 Hz, 1 H, H-5), 6.08 (d, J _4,5 = 1.2 Hz, 1 H, H-4), 6.10 (d, J _5,OH = 6.1 Hz, 1 H, OH), 6.14 (dd, J _6a,10b = 2.3 Hz, J _6b,10b = 1.8 Hz, 1 H, H-10b). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 38.2 (C-6), 55.1 (OCH₃), 68.0 (C-5), 91.5 (C-4), 99.1 (C-10), 143.1 (C-7), 154.2 (C-1), 164.7 (C-8), 171.6 (C-3). 6,7-Dihydro-5- tert -butyldiphenylsilyloxy-3-methoxy-7-methylenepyrrolo[1,2- c ]pyrimidin-1(5 H )-one ( 11b): Yield 66%; colorless syrup. ¹H NMR (400 MHz, CDCl₃):
δ = 1.10 [s, 9 H, OSiC(CH₃)₃], 2.68 (dddd, J _5,6a = 7.9 Hz, J _6a,6b = 15.2 Hz, J _6a,10a = J _6a,10b = 1.2 Hz, 1 H, H-6a), 2.76 (dddd, J _5,6b = 7.3 Hz, J _6a,6b = 15.2 Hz, J _6b,10a = J _6b,10b = 2.3 Hz, 1 H, H-6b), 3.95 (s, 3 H, OCH₃), 4.82 (ddd, J _6a,10a = J _10a,10b = 1.2 Hz, J _6b,10a = 2.1 Hz, 1 H, H-10a), 4.98 (ddd, J _4,5 = 1.2 Hz, J _5,6a = 7.9 Hz, J _5,6b = 7.3 Hz, 1 H, H-5), 5.77 (d, J _4,5 = 1.2 Hz, 1 H, H-4), 6.28 (ddd, J _6a,10b = J _10a,10b = 1.2 Hz, J _6b,10b = 2.3 Hz, 1 H, H-10b), 7.40-7.68 (m, 10 H, OSiPh₂). ¹³C NMR (125 MHz, CDCl₃): δ = 19.6 [OSiC(CH₃)₃], 27.2 [OSiC(CH₃)₃], 39.3 (C-6), 55.2 (OCH₃), 70.4 (C-5), 92.0
(C-4), 100.6 (C-10), 128.4, 128.5, 130.8, 132.7, 133.0, 136.1 (OSiPh₂), 141.3 (C-7), 154.8 (C-1), 161.9 (C-8), 171.6
(C-3). 6,7-Dihydro-5-benzoyloxy-3-methoxy-7-methylene-pyrrolo[1,2- c ]pyrimidin-1(5 H )-one ( 11c): Yield 80%; colorless syrup. ¹H NMR (400 MHz, CDCl₃): δ = 2.96 (dddd, J _5,6a = 4.6 Hz, J _6a,6b = 16.9 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-6a), 3.33 (dddd, J _5,6b = 8.2 Hz, J _6a,6b = 16.9 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-6b), 3.98 (s, 3 H, OCH₃), 5.01 (ddd, J _10a,10b = 1.2 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-10a), 6.13 (d, J _4,5 = 0.9 Hz, 1 H, H-4), 6.19 (ddd, J _4,5 = 0.9 Hz,
J _5,6a = 4.6 Hz, J _5,6b = 8.2 Hz, 1 H, H-5), 6.46 (ddd, J _10a,10b = 1.2 Hz, J = 1.8 Hz, J = 2.1 Hz, 1 H, H-10b), 7.44-8.04 (m,
5 H, COPh). ¹³C NMR (125 MHz, CDCl₃): δ = 35.4 (C-6), 55.4 (OCH₃), 69.8 (C-5), 94.0 (C-4), 101.1 (C-10), 129.1, 130.3, 134.3 (COPh), 141.0 (C-7), 154.8 (C-1), 157.5 (COPh), 166.0 (C-8), 171.5 (C-3).

15

General Procedure: Mesitonitrile oxide 12 and 7-methylenepyrrolo[1,2-c]pyrimidin-1(5H)-one 11 were dissolved in 1,4-dioxane and stirred under reflux. When no starting material remained (TLC), the solvent was removed in vacuo and the products of the cycloaddition were isolated by column chromatography (hexane-ethyl acetate). Selected data: (5,7- trans )-4′,5′,6,7-Tetrahydro-3′-(2,4,6-trimethylphenyl)-3-methoxy-5-hydroxyspiro[pyr-rolo[1,2- c ]pyrimidine-7(5 H ),5′-izoxazol]-1-one ( 14a): Yield 42%; colorless solid; mp 241-243 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.26 (s, 3 H, 4-CH₃Ph), 2.31 (s, 6 H, 2,6-CH₃Ph), 2.41 (dd, J _5,6a = 8.8 Hz, J _6a,6b = 13.7 Hz, 1 H, H-6a), 2.87 (dd, J _5,6b = 7.6 Hz, J _6a,6b = 13.7 Hz, 1 H, H-6b), 3.44 (d, J _{4a ′ ,4b ′} = 18.7 Hz, 1 H, H-4a′), 3.85 (s, 3 H, OCH₃), 4.22 (d, J _{4a ′ ,4b ′} = 18.7 Hz, 1 H, H-4b′), 5.13 (dddd, J _4,5 = 1.5 Hz, J _5,OH = 5.8 Hz, J _5,6a = 8.8 Hz, J _5,6b = 7.3 Hz, 1 H, H-5), 6.05 (d, J _4,5 = 1.2 Hz, 1 H, H-4), 6.29 (d, J _5,OH = 5.8 Hz, 1 H, OH), 6.93 (s, 2 H, Ph). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 20.4 (2,6-CH₃Ph), 21.5 (4-CH₃Ph), 46.3, 46.4 (C-6, C-4′), 55.1 (OCH₃), 68.4 (C-5), 90.7 (C-4), 102.6 (C-5′/C-7), 126.4 (C-4-Ph), 129.2 (CH-Ph), 137.7 (C-2,6-Ph), 139.1 (C-1-Ph), 153.8 (C-1), 158.4 (C-3′), 164.9 (C-4a), 173.1 (C-3).
(5,7- trans )-4′,5′,6,7-Tetrahydro-3′-(2,4,6-trimethyl-phenyl)-3-methoxy-5- tert -butyldiphenylsilyloxy-spiro[pyrrolo[1,2- c ]pyrimidine-7(5 H ),5′-izoxazol]-1-one ( 14c): Yield 79%; colorless solid; mp 214-215 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.12 [s, 9 H, OSiC(CH₃)₃], 2.28 (s, 3 H, 4-CH₃Ph), 2.37 (s, 6 H, 2,6-CH₃Ph), 2.32 (dd, J _5,6a = 8.8 Hz, J _6a,6b = 13.2 Hz, 1 H, H-6a), 2.67 (dd, J _5,6b = 7.3 Hz, J _6a,6b = 13.2 Hz, 1 H, H-6b), 3.09 (d, J _{4a ′ ,4b ′} = 18.4 Hz, 1 H, H-4a′), 3.94 (s, 3 H, OCH₃), 4.52 (d, J _{4a ′ ,4b ′} = 18.4 Hz, 1 H, H-4b′), 5.25 (ddd, J _4,5 = 1.2 Hz, J _5,6a = 8.8 Hz, J _5,6b = 7.3 Hz, 1 H, H-5), 5.77 (d, J _4,5 = 1.2 Hz 1 H, H-4), 6.89 (s, 2 H, H-Ph), 7.41-7.70 (m, 10 H, OSiPh₂). ¹³C NMR (125 MHz, CDCl₃): δ = 19.6 [OSiC(CH₃)₃], 20.4 (2,6-CH₃Ph), 21.5
(4-CH₃Ph), 27.3 [OSiC(CH₃)₃], 46.5, 47.6 (C-6, C-4′), 55.3 (OCH₃), 70.4 (C-5), 91.7 (C-4), 101.6 (C-5′/C-7), 125.5 (C-4-Ph), 128.5, 128.6, 129.0, 130.9, 131.0, 132.4, 132.8, 136.1 (CHPh, OSiPh₂), 137.8 (C-2,6-Ph), 139.4 (C-1-Ph), 154.3 (C-1), 158.2 (C-3′), 162.2 (C-4a), 173.2 (C-3).
(5,7- cis )-4′,5′,6,7-Tetrahydro-3′-(2,4,6-trimethylphenyl)-3-methoxy-5-benzoyloxyspiro[pyrrolo[1,2- c ]pyrimidine-7(5 H ),5′-izoxazol]-1-one ( 13b): Yield 14%; colorless solid; mp 164-165 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.30 (s, 3 H, 4-CH₃Ph), 2.43 (s, 6 H, 2,6-CH₃Ph), 2.85 (dd, J _5,6a = 7.0 Hz, J _6a,6b = 15.1 Hz, 1 H, H-6a), 2.99 (dd, J _5,6b = 2.3 Hz, J _6a,6b = 15.1 Hz, 1 H, H-6b), 3.23 (d, J _{4a ′ ,4b ′} = 18.4 Hz, 1 H, H-4a′), 3.97 (s, 3 H, OCH₃), 4,50 (d, J _{4a ′ ,4b ′} = 18.4 Hz, 1 H, H-4b′), 6.14 (d, J _4,5 = 0.9 Hz, 1 H, H-4), 6.22 (ddd, J _4,5 = 0.9 Hz, J _5,6a = 7.0 Hz, J _5,6b = 2.3 Hz, 1 H, H-5), 6.92 (s, 2 H, Ph), 7.45-8.11 (m, 5 H, COPh). ¹³C NMR (125 MHz, CDCl₃),
δ = 20.4 (2,6-CH₃Ph), 21.5 (4-CH₃Ph), 44.5, 46.9 (C-6, C-4′), 55.5 (OCH₃), 69.8 (C-5), 94.4 (C-4), 102.9 (C-5′/C-7), 125.4 (C-4-Ph), 129.0, 130.5, 134.3 (CHPh, COPh), 137.9 (C-2,6-Ph), 139.5 (C-1-Ph), 154.2 (C-1), 156.9 (COPh), 158.0 (C-3′), 166.2 (C-4a), 173.3 (C-3).
(5,7- trans )-4′,5′,6,7-Tetrahydro-3′-(2,4,6-trimethyl-phenyl)-3-methoxy-5-benzoyloxyspiro[pyrrolo[1,2- c ]pyrimidine-7(5 H ),5′-izoxazol]-1-one ( 14b): Yield 69%; colorless solid; mp 210-212 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.30 (s, 3 H, 4-CH₃Ph), 2.42 (s, 6 H, 2,6-CH₃Ph), 2.57 (dd, J _5,6a = 7.3 Hz, J _6a,6b = 14.0 Hz, 1 H, H-6a), 3.25 (d, J _{4a ′ ,4b ′} = 18.4 Hz, 1 H, H-4a′), 3.34 (dd, J _5,6b = 7.6 Hz, J _6a,6b = 14.0 Hz, 1 H, H-6b), 3.98 (s, 3 H, OCH₃), 4.58 (d, J _{4a ′ ,4b ′} = 18.1 Hz, 1 H, H-4b′), 6.06 (d, J _4,5 = 1.2 Hz, 1 H, H-4), 6.37 (ddd, J _4,5 = 1.2 Hz, J _5,6a = 7.3 Hz, J _5,6b = 7.6 Hz, 1 H, H-5), 6.92 (s, 2 H, H-Ph), 7.46-7.65 (m, 5 H, COPh). ¹³C NMR (125 MHz, CDCl₃): δ = 20.3 (2,6-CH₃Ph), 21.5 (4-CH₃Ph), 44.9, 47.0 (C-6, C-4′), 55.5 (OCH₃), 70.4 (C-5), 93.1 (C-4), 102.3 (C-5′/C-7), 125.4 (C-4-Ph), 129.0, 129.1, 130.3, 134.5 (CHPh, COPh), 137.9 (C-2,6-Ph), 139.6 (C-1-Ph), 154.2 (C-1), 157.7 (COPh), 158.2 (C-3′), 165.8 (C-4a), 173.2 (C-3).

16a Pereira SM. Savage GP. Simpson GW. Greenwood RJ. Mackay MF. Aust. J. Chem.  1993,  46:  1401 

16b Fiera L. Jaroková L. Matejková I. Heimgartner H. Heterocycles  1995,  1:  271 

16c Micúch P. Fiera L. Ondru V. Ertl P. Molecules  1997,  2:  57 

16d Cheng W.-C. Liu Y. Wong M. Olmstead MM. Lam KS. Kurth MJ. J. Org. Chem.  2002,  67:  5673 

16e Melsa P. Mazal C. Collect. Czech. Chem. Commun.  2002,  67:  353 

17

Crystallographic data for the structure 15 and 16 have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data can be obtained on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email: [e-mail]).