A convenient, NMR-based method for the analysis of diastereomeric mixtures of pseudoephedrine amides

Organic Letters

Volumn 9, Issue 2, 2007, Pages 355-357

  Chain, William J ^a   Myers, Andrew G ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; DRUG DERIVATIVE; EPHEDRINE; OXAZOLE DERIVATIVE;

ARTICLE; CHEMISTRY; CONFORMATION; CYCLIZATION; METHODOLOGY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; SENSITIVITY AND SPECIFICITY; STANDARD; STEREOISOMERISM; SYNTHESIS;

AMIDES; CYCLIZATION; EPHEDRINE; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR CONFORMATION; OXAZOLES; REFERENCE STANDARDS; SENSITIVITY AND SPECIFICITY; STEREOISOMERISM;

EID: 33846566302     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol0628762     Document Type: Article

References (15)

1. 6-DMSO); see: Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
2. The transformation has also been successfully conducted with as little as 1.2 equiv of triflic anhydride (3.0 equiv of pyridine).
3. The ephedrine amide substrate of transformation III was prepared by coupling (1R,2S)-ephedrine and (2R)-2-methyl-3- phenylpropionic acid (97% ee) in the presence of PyBOP. The ephedrine amide substrate of transformation IV was prepared by coupling (1R,2S)- ephedrine and (2S)-2-methyl-3-phenylpropionic acid (94% ee) in the presence of PyBOP.
4. (a) Charette, A. B.; Chua, P. Synlett 1998, 163-165.
5. (b) Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Rosangela, M. Tetrahedron Lett. 1998, 39, 711-714.
6. (c) Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908-909.
7. (d) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677-1680.
8. The observed cyclization pathway is reminiscent of the cyclization of serine and threonine amides in the presence of Burgess reagent to form dihydrooxazoles: (a) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910.
9. See also: (b) Ikuma, S. J. Pharm. Soc. Jpn. 1955, 75, 52-53.
10. (c) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Tetrahedron Lett. 1987, 28, 6331-6334.
11. (d) Poelert, M. A.; Hulshof, L. A.; Kellogg, R. M. Recl. Trav. Chim. Pays-Bas 1994, 113, 355-364.
12. (e) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.
13. In the particular case of the substrates of Figure 1 a detailed analysis of chemical shift information provides not only internal consistency, but a means to correlate the stereochemistry of the α-position with the stereochemistry of the pseudoephedrine or ephedrine residues. In this analysis the products of Scheme 1 are assumed to adopt a conformation in which the α-C-H bond is co-planar with the N-methyl group (as indicated in the structural drawings of Figure 1); the α-benzyl group is found to shield the methyl protons C by ∼0.3 ppm when these groups are cofacial. The analysis is found to extend to α-aryl pseudoephedrine amides (see the Supporting Information). These and other correlations from the compiled examples in the Supporting Information may provide a basis for the determination of the absolute configuration of many carboxylic acids.
14. Reference samples of mixtures of α-diastereomeric pseudoephedrine amides can be obtained by epimerization of the α-center, where this is possible, under acidic or basic conditions, as previously described; see ref 1.
15. Pseudoephedrine amides with an α-quaternary center cyclize with ≥99% stereospecificity, presumably reflecting an increased rate of cyclization of the triflate intermediates relative to ionization.