The Assignment of the Absolute Configuration of Diethyl Hydroxy- and Aminophosphonates by 1 H and 31 P NMR Using Naproxen as a Reliable Chiral Derivatizing Agent Katarzyna Blaz ˘ ewska, † Piotr Paneth, ‡ and Tadeusz Gajda* ,† The Faculty of Chemistry, Technical UniVersity of Lodz (Politechnika), Z ˙ eromskiego St. 116, 90-924 Lodz, Poland tmgajda@p.lodz.pl ReceiVed October 10, 2006 The assignment of the absolute configuration of hydroxy- and aminophosphonates by their double derivatization with commercially available naproxen is presented. The correlation between the spatial arrangement around the stereogenic carbon center and the signs of the Δδ RS allows determination of the absolute configuration of hydroxy- and aminophosphonates by simple comparison of the 1 H and 31 P NMR spectra of the (R)- and (S)-naproxen ester or amide derivatives. Extensive conformational analysis (theoretical calculations, low-temperature experiments) supported by the NMR studies of structurally diverse naproxen esters and amides of hydroxy- and aminophosphonates proved that a simplified model can be successfully used. Introduction NMR spectroscopy is one of the most widely used techniques for the assignment of enantiomeric purity and absolute config- uration of different classes of compounds. 1-4 Since enantiomers cannot be distinguished in the achiral environment, to make every enantiomer visible in the NMR spectra, there is a need for the introduction of a chiral auxiliary. Besides chiral solvating agents (CSAs) 5-7 and chiral lanthanide shift reagents (CLSRs), 2,8-10 chiral derivatizing agents (CDAs) 1 seem to be the most popular reagents for this purpose. The credible CDA needs to have such structural features as the anisotropic substituent and the functional group providing linkage to the substrate. Moreover, the existence of the conformational preference must be main- tained in the two diastereomeric derivatives, irrespective of the configuration and structure of the derivatized compound. According to the methodology set by Mosher et al., 3 Trost et al., 4 and Riguera et al., 1 application of CDA requires derivatization of the substrate of unknown configuration with two, (R) and (S), enantiomers of the derivatizing agent (double derivatization). 11 Subsequently, spectra of both diastereomeric derivatives must be recorded separately. Then, the configuration (of the investigated compound) is assigned 1 by subtraction of their chemical shifts δ, expressed by the Δδ RS ) δ R - δ S (the † Institute of Organic Chemistry. ‡ Institute of Applied Radiation Chemistry. (1) (a) Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Chem. ReV. 2004, 104, 17. (b) Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915. (c) Lallana, E.; Freire, F.; Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Org. Lett. 2006, 8, 4449. (2) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis; John Wiley: Chichester, U.K. 2001; p 16. (3) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (4) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370. (5) Weisman, G. R. W. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1983; Vol. 1, p 153. (6) Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13, 263. (7) Pazos, Y.; Leiro, V.; Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Tetrahe- dron: Asymmetry 2004, 15, 1825. (8) Sullivan, G. R. Top. Stereochem. 1979, 10, 287. (9) Parker, D. Chem. ReV. 1991, 91, 1441. (10) Omata, K.; Aoyagi, S.; Kabuto, K. Tetrahedron: Asymmetry 2004, 15, 2351. (11) In the case of single derivatization, which is not the subject of this paper, the substrate needs to be derivatized with one enantiomer of CDA. 878 J. Org. Chem. 2007, 72, 878-887 10.1021/jo062097z CCC: $37.00 © 2007 American Chemical Society Published on Web 01/10/2007