Chiral Thiols: The Assignment of Their Absolute Configuration by 1 H NMR Silvia Porto, ² Jose ´ Manuel Seco, ² Aurelio Ortiz, ‡ Emilio Quin ˜ oa ´, ² and Ricardo Riguera* ,² Departamento de Quı ´mica Orga ´ nica, Facultad de Quı ´mica y Unidad de RMN de Biomole ´ culas Asociada al CSIC, UniVersidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain, and Centro de InVestigacio ´ n, Facultad de Ciencias Quı ´micas, Beneme ´ rita UniVersidad Auto ´ noma de Puebla, 72570 Puebla, Mexico ricardo@usc.es Received September 12, 2007 ABSTRACT A general NMR spectroscopy protocol for determination of absolute configuration of thiols, that includes the introduction of new aryl-tert- butoxyacetic acids as chiral derivatizing agents (CDAs), is described. 1 H NMR has become a very convenient tool for the assignment of absolute configuration of a variety of organic compounds. Derivatization of the substrate with selected chiral derivatizing agents (CDAs) and interpretation of the Δδ parameters (Δδ RS , Δδ T1T2 , Δδ Ba ...) obtained by compari- son of two NMR spectra (either from two diastereomeric derivatives or from a single derivative at different temper- atures or before/after formation of a metal complex) allow one to infer the configuration. Chiral substrates that are amenable to treatment with these methods include primary and secondary alcohols, primary amines, carboxylic acids, cyanohydrins, diols, triols, and amino alcohols. 1 Thiols, the simplest organic compounds of sulfur, are relevant not only for their presence as natural products and their roles in biochemistry but also for their applications in the preparation of other organosulfur compounds 2 and for their uses as catalysts in asymmetric synthesis. 3 Hence, easy and cheap procedures for the reliable assignment of the absolute configuration of thiols should be very useful. In this communication, we describe a procedure for chiral secondary thiols that requires derivatization of the thiol with the two enantiomers of 2-methoxy-2-phenylacetic acid (MPA) and comparison of the 1 H NMR spectra of the corresponding diastereomeric thioesters. 4 In addition, the new and more efficient reagent 2-tert-butoxy-2-(2-naphthyl)acetic acid (2-NTBA) is presented. To establish a general and validated methodology for the assignment of configuration of thiols and to know which one yielded the largest Δδ RS values, 5 we derivatized the R enantiomers of 2-methoxy-2-phenylacetic acid (MPA, 1), 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (MTPA, 2), Boc-phenylglycine (BPG, 3), and 2-(9-anthryl)-2-meth- * To whom correspondence should be addressed. Fax: +34 981591091. Tel: +34 981591091 (R.R.). ² Universidad de Santiago de Compostela. ‡ Beneme ´rita Universidad Auto ´noma de Puebla. (1) For review, see: (a) Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Chem. ReV. 2004, 104, 17. For polyfunctional compounds, see: (b) Lallana, E.; Freire, F.; Seco, J. M.; Quin ˜oa ´, E.; Riguera, R. Org. Lett. 2006, 8, 4449 and references therein. (2) (a) Patai, S. The Chemistry of the Thiol Group: Parts Iⅈ John Wiley & Sons: New York, 1974; Vol. 2. (b) Barret, G. C. Thiols. In ComprehensiVe Organic Chemistry; Jones, D. N. Ed.; Pergamon Press: Oxford, 1979: Vol. 3, Chapter 11.1. (3) (a) Tseng, S. L.; Yang, T. K. Tetrahedron: Asymmetry 2005, 16, 773. (b) Haque, M. B.; Roberts, B. P. Tetrahedron Lett. 1996, 37, 9123. (4) Two previous reports dealing with the use of NMR for this purpose consisted of empirical methods using acetic acid derivatives tested with a small number of thiols (three and two, respectively). See: (a) Helmchen, G.; Schmierer, R. Angew. Chem., Int. Ed. Engl. 1976, 15, 703. (b) Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1981, 46, 3239. ORGANIC LETTERS 2007 Vol. 9, No. 24 5015-5018 10.1021/ol7022196 CCC: $37.00 © 2007 American Chemical Society Published on Web 10/31/2007