Guanine hydrolysis under basic conditions to substituted imidazoles

Tetrahedron Letters

Volumn 41, Issue 26, 2000, Pages 5025-5029

  Gala, Dinesh ^a   Puar, Mohindar S ^a   Czarniecki, Michael ^a   Das, Pradip R ^a   Kugelman, Max ^a   Kaminski, James J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GUANINE DERIVATIVE; IMIDAZOLE DERIVATIVE;

ARTICLE; HYDROGEN BOND; HYDROLYSIS; MOLECULAR STABILITY; PROTON NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

EID: 0034709562     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(00)00770-X     Document Type: Article

References (13)

1. Ahn, H.-S.; Czarniecki, M., et al. J. Med. Chem. 1997, 40, 2196.
2. Vemulapalli, S.; Watkins, R. W.; Chintala, M.; Davis, H.; Ahn, H.-S.; Fawi, A.; Tulshian, D.; Chiu, P.; Chatterjee, M.; Lin, C.-C.; Sybertz, E. J. J. Cardiovasc. Pharmacol. 1996, 28, 862.
3. (a) Fischer, E. Ber. 1910, 43, 805;
4. (b) Bang, I.; Bichim, Z. 1910, 26, 293.
5. (a) Yamakazi, A.; Kumashiro, I.; Takenishi, T. J. Org. Chem. 1967, 32, 1825.
6. (b) Shewach, D. S.; Daddona, P. E.; Townsend, L. B. J. Med. Chem. 1993, 36, 1024.
7. (a) Elliott, R. D.; Montgomery, J. A.; Riordan, J. M. J. Org. Chem. 1987, 52, 2892.
8. (b) Minamoto, K.; Tanaka, T.; Azuma, K.; Suzuki, N.; Eguchi, S. J. Org. Chem. 1986, 51, 4417.
9. Taylor, E. C.; Otiv, S. R.; Durucasu, I. Heterocycles 1993, 36, 1883.
10. 2×3), δ 55.9, 62.0 (CHN, CHNH), δ 120.3, 131.1, 142.5 (all quaternary carbons), 158.9 (C=O), 159.7 (C=O)
11. 3, measured 351.1429, calculated 351.1433.
12. 2 to separate the products. In the case of compound 2a, the reaction mixture was carefully concentrated under vacuum (to minimize sublimation of the product) and then extracted with i-PrOH to isolate the product. Spirocyclic imidazoles 9a-b were isolated by mere filtration of the cooled reaction mixture
13. The aqueous base catalyzed hydrolysis of SCH 47687, 1a, were investigated using the molecular mechanics and semiempirical quantum mechanics methods. The objective was to understand the mechanism of hydrolysis and provide support for the proposed pathway to the final hydrolysis product. Molecules were built using the molecular construction tools in Sybyl or Spartan. The structures then underwent a preliminary minimization using the Sybyl MAXIMIN force field. These intermediate structures were then subjected to a full geometry optimization using the AM1 (aq.) method in the Spartan program. The parameter set modifies the basic AM1 method to simulate energies in an aqueous medium. The energies reported reflect the result of these calculations. The calculations were repeated using the generic AM1 parameters (in vacuo) and the conclusions are qualitatively similar. In molecules with significant conformational flexibility the lowest energy conformations were determined in a two step procedure. Available conformations were generated using the Random Search (Saunders procedure; 1000 Monte Carlo steps) within Sybyl. The conformers generated were then minimized using the Sybyl MAXIMIN force field. The lowest energy conformation resulting from each conformational search was then subjected to a second geometry optimization using the modified AM1 (aq.) method) and these represent the reported energies of the lowest energy conformer identified. The relative energies of the imidazole tautomers of all reactants and potential products were compared. Although small energy differences between tautomers were observed in no case did this affect conclusions regarding reaction pathway or product distribution.