Are Both the (R)- and the (S)-MPA Esters Really Needed for the Assignment of the Absolute Configuration of Secondary Alcohols by NMR? The Use of a Single Derivative Shamil K. Latypov, ² Jose ´ M. Seco, Emilio Quin ˜ oa ´ , and Ricardo Riguera* Contribution from the Departamento de Quı ´mica Orga ´ nica, Facultad de Quı ´mica and Instituto de Acuicultura, UniVersidad de Santiago, E-15706, Santiago de Compostela, Spain ReceiVed January 2, 1997. ReVised Manuscript ReceiVed October 24, 1997 Abstract: The absolute configuration of a secondary alcohol can be deduced from the 1 H NMR spectra of a single methoxyphenylacetic ester derivative [MPA, either the (R) or the (S)] recorded at two different temperatures. This new approach simplifies the current NMR-based methodologies, requiring just one derivatizing reaction, instead of two, and, correspondingly, half of the usual amount of sample. At low temperature, the relative population of the most stable sp conformer is increased and the resonances of the substituents of the alcohol (L 1 /L 2 ), located under the shielding cone of the phenyl ring, are shifted upfield. At the same time, those protons under the shielding cone in the less populated ap conformer are shifted downfield. In this way, the spatial location of L 1 /L 2 around the asymmetric center of the alcohol can be established comparing the 1 H NMR spectra both at room and low temperatures. Application of this finding to alcohols of known absolute configuration, including complex structures such as cis-androsterone, is presented. Introduction With increasing frequency, chemists worldwide face the need to work with very small amounts of compounds. Microscale methodologies are strongly welcomed in many research fields, particularly those where the amount of sample available is very limited. So, the search for new accurate elucidation techniques to be applied to minute amounts of a substrate is a continuous need in chemistry. One of the most popular procedures to establish the absolute configuration of a chiral secondary alcohol or a primary R-substituted amine is the NMR approach, introduced by Raban and Mislow 1 and further developed by Mosher, 2a Trost, 2b and other researchers. 2c-f In this method, the substrate (i.e., alcohol or amine) of unknown absolute stereochemistry, (?)-A, is separately coupled with the (R) and (S) enantiomers of an auxiliary reagent B. Comparison of the 1 H NMR spectra of the two resulting diastereomers (?)-A-(R)-B and (?)-A-(S)-B, allows the establish- ment of the spatial location of the A substituents with regard to those of reagent B, that is to say, the absolute configuration at the asymmetric center of the substrate A is deduced. 2 Typical auxiliary reagents for the determination of the absolute configuration of secondary alcohols and amines are chiral arylmethoxyacetic acids such as methoxyphenylacetic acid (MPA), where their aromatic rings are able to produce selective shielding on the protons of the substrate moiety. In this paper we disclose evidence demonstrating that derivatization of the alcohol with both (R)- and (S)-MPA is not necessary. A simpler NMR procedure that requires the use of only one enantiomer of the auxiliary reagent (either the (R)- or * Fax: 34 81 59109. ² Present address: The Institute of Organic & Physical Chemistry of Russian Academy of Sciences, Kazan, 420083, Tatarstan, the Russian Federation. (1) (a) Raban, M.; Mislow, K. Tetrahedron Lett. 1965, 48, 4249-4253. (b) Raban, M.; Mislow, K. Top. Stereochem. 1967, 2, 199-230. (c) Lewis, R. A.; Korpiun, O.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4847-4853.- (d) For a review, see: Uray, G. In Houben-Weyl Methods in Organic Chemistry; Helchen G., Hoffmann R. W., Mulzer J., Schaumann E., Eds.; Thieme: Stuttgart, 1996; Vol. 1, p. 253. (2) (a) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143-2147. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370-2374. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4029-4096. (d) Trost, B. M.; Bunt, R. C.; Pulley, Sh. R. J. Org. Chem. 1994, 59, 4202-4205. (e) Latypov, Sh. K.; Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. J. Org. Chem. 1995, 60, 1538-1545. (f) Latypov, Sh. K.; Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569-8577. Figure 1. (a) Structure of the sp and ap conformers of a (R)-MPA ester; (b) chemical shifts of L1 and L2 in the sp and ap conformers; (c) average chemical shifts of L1 and L2 at room temperature (T1); and (d) average chemical shifts of L1 and L2 at low temperature (T2). 877 J. Am. Chem. Soc. 1998, 120, 877-882 S0002-7863(97)00005-X CCC: $15.00 © 1998 American Chemical Society Published on Web 01/23/1998