Asymmetric Synthesis of 4,4-Disubstituted-2-Imidazoli-dinones: Potent NK1 Antagonists

Organic Letters

Volumn 5, Issue 23, 2003, Pages 4249-4251

  Reichard, Gregory A ^a,d   Stengone, Carmine ^a   Paliwal, Sunil ^a   Mergelsberg, Ingrid ^b   Majmundar, Sapna ^a   Wang, Cheng ^a   Tiberi, Robert ^a   McPhail, Andrew T ^c   Piwinski, John J ^a   Shih, Neng Yang ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Werthenstein Chemie AG   (Switzerland)

^c DUKE UNIVERSITY   (United States)

^d PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IMIDAZOLINE DERIVATIVE;

AQUEOUS SOLUTION; ARTICLE; CHIRALITY; CRYSTAL STRUCTURE; STEREOCHEMISTRY; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

EID: 10744221221     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol030104p     Document Type: Article

References (16)

1. Shih, N.-Y.; Shue, H.-J.; Reichard, G. A.; Paliwal, S.; Blythin, D. J.; Piwinski, J. J.; Xiao, D.; Chen, X. PCT Int. Appl. WO 0144200, 2001.
2. Seebach, D.; Imwinkelried, R.; Weber, T. Mod. Synth. Methods 1986, 129.
3. Swain, C. J.; Cascieri, M. A.; Owens, A.; Saari, W.; Sadowski, S.; Strader, C.; Teall, M.; Van Neal, M. B.; Williams, B. J. Bioorg. Med. Chem. Lett. 1994, 4, 2161.
4. Typically, the nitrogen of the imidazolidinone employed for Seebach's approach is functionalized as a carbamate or acyl derivative in order to control the cis/trans ratio of the temporary stereocenter or confer crystallinity for purification purposes.
5. Hydrolytic cleavage of bulky disubstituted imidazolidinones can be quite problematic, particularly for substituents larger than methyl on the phenylglycine system (ref 6a,b). The structural requirements for our compounds were not tolerant of these conditions.
6. (a) Studer, A.; Seebach, D. Liebigs Ann. 1995, 217.
7. (b) Obrecht, D.; Heimgartner, H. Helv. Chim. Acta 1981, 64, 482.
8. Although the diastereoselective ethylation of imidazolidinone 13 has been reported (see ref 8), we could find no characterization of imidazolidinone 13 or any further reference of its use.
9. See: Seebach, D.; Aebi, J. D.; Naef, R.; Weber, T. Helv. Chim. Acta 1985, 68, 144.
10. Standard amidation conditions utilizing a methanolic solution of methylamine require long reaction times (> 14 h) and epimerize the α-proton resulting in the isolation of 12 in 70% ee. An alternative solution to this racemization problem employs the coupling of N-Boc phenylglycine with methylamine using HOOBT to provide N-Boc amino amide in >98% ee. Standard deprotection conditions provide 12 in excellent yield.
11. Prepared from treatment of a melt of paraformaldehyde and 3,5-bis(trifluoromethyl)benzyl alcohol with gaseous hydrobromic acid.
12. Deoxygenation of the solvent and reagents is critical for clean and reproducible runs of the alkylation.
13. Isolated yields after column chromatography. Generally, for largescale reactions, the product was purified by crystallization, which provided 15 in 50% isolated yield (see Experimental Section).
14. Swain, C. J.; Williams, B. J.; Baker, R.; Cascieri, M. A.; Chicchi, G.; Forrest, M.; Herbert, R.; Keown, L.; Ladduwahetty, T.; Luell, S.; Macintyre, D. E.; Metzger, J.; Morton, S.; Owens, A. P.; Sadowski, S.; Watt, A. P. Bioorg. Med. Chem. Lett. 1997, 7, 2959.
15. For an excellent review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
16. The % ee of 18, checked by hydrolysis back to the chiral alcohol 17 by treatment on silica gel, was found to be unchanged (95% ee) as a result of the conditions required for bromomethyl ether formation.