Chiral Silylation Reagents: Determining Configuration via NMR-Spectroscopic Coanalysis Frank C. Schroeder, Douglas B. Weibel, and Jerrold Meinwald* Department of Chemistry and Chemical Biology, Cornell UniVersity, Ithaca, New York 14853-1301 circe@cornell.edu Received April 27, 2004 (Revised Manuscript Received June 30, 2004) ABSTRACT Derivatization with (+)- and (-)-chloromenthoxydiphenylsilane was used to determine the absolute configuration of the insect defensive agent pinoresinol (1). Although the 1 H NMR chemical shift differences of the resulting two diastereomers are small, 1 H NMR spectroscopy provided for the unambiguous assignment of the natural product’s configuration. For this purpose, a new approach involving NMR spectra of mixtures of diastereomers was used. Our method resembles coinjecting mixtures of samples of known and unknown configuration in GC and HPLC. One of the most widely used techniques for determining the absolute stereochemistry of natural products involves the incorporation of a chiral derivatizing agent (CDA) and subsequent analysis via NMR spectroscopy. 1 These methods frequently involve the introduction of a chiral substituent directly at or in close proximity to the chiral center of interest to achieve complete separation of corresponding NMR signals in the two complementary diastereomers. While complete separation is desirable, it is often not possible to introduce a chiral substituent sufficiently close to the chiral center to achieve such a high degree of chemical shift separation, especially if the chiral center is not at or next to a hydroxy or amino group. Using the comparatively much smaller chemical shift differences induced by derivatizing a chiral, conformationally flexible molecule at a location far away from the chiral centers of interest seems less obvious. 2 In this situation, corresponding signals in the 1 H NMR spectra of the resulting complementary diastereomers would usually not be well separated, although the respective chemical shift values might be somewhat different. 3 We here report the determination of the absolute configuration of a natural product, pinoresinol (1), via derivatization with a chiral silylating agent at the periphery of the molecule, using the resulting minute 1 H NMR chemical shift differences for unambiguous stereochemical assignment. We recently identified pinoresinol (1) as a minor com- ponent in the defensive secretion obtained from larvae of the European cabbage butterfly, Pieris rapae. 4 This finding was somewhat surprising because pinoresinol, though widely (1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512- 519. (b) Seco, J. M.; Quin ˜oa ´, E.; Riguera, R, J. Org. Chem. 1999, 64, 4669- 4675. (c) Kato, N. J. Am. Chem. Soc. 1990, 112, 254-257. (d) Anderson, R. C.; Shapiro, M. J. J. Org. Chem. 1984, 49, 1304-1305. (e) Doolittle, R. E.; Heath, R. R. J. Org. Chem. 1984, 49, 5041-5050. (f) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 1092-4096. For a recent review, see: Seco, J. M.; Quinoa, E.; Riguera, R. Chem. ReV. 2004, 104, 17-117. (2) Seco, J. M.; Latypov, Sh.; Quin ˜oa ´, E.; Riguera, R. Tetrahedron 1997, 53, 8541-8564. (3) For an example for the use of small chemical shift differences to establish remote stereochemical relationships, see: Boyle, C. D.; Kishi, Y. Tetrahedron Lett. 1995, 36, 5695-5698. (4) Schroeder, F. C.; Grant, J. B.; Weibel, D. B.; Smedley, S. R.; Bolton, K. L.; Meinwald, J.; Eisner, T. Proc. Natl. Acad. Sci. U.S.A., submitted. ORGANIC LETTERS 2004 Vol. 6, No. 18 3019-3022 10.1021/ol049233b CCC: $27.50 © 2004 American Chemical Society Published on Web 08/13/2004