ORGANIC
LETTERS
2013
Vol. 15, No. 4
860–863
A Simple Protocol for NMR Analysis
of the Enantiomeric Purity of Chiral
Hydroxylamines
David A. Tickell,† Mary F. Mahon,‡ Steven D. Bull,*,† and Tony D. James*,†
Department of Chemistry, University of Bath, Claverton Down, Bath, BA27AY, U.K.
s.d.bull@bath.ac.uk; t.d.james@bath.ac.uk
Received December 30, 2012
ABSTRACT
1
A practically simple three-component chiral derivatization protocol for determining the enantiopurity of chiral hydroxylamines by H NMR
spectroscopic analysis is described, involving their treatment with 2-formylphenylboronic acid and enantiopure BINOL to afford a mixture of
diastereomeric nitrono-boronate esters whose ratio is an accurate reflection of the enantiopurity of the parent hydroxylamine.
Chiral hydroxylamines and their derivatives exhibit a
wide range of biological properties1 and have been used as
substrates for a wide range of synthetic methodology. This
includes reaction with R-keto-acids to afford amide bonds,2
their use as reagents for the asymmetric R-oxyacylation of
cyclic ketones,3 as substrates for the preparation of chiral
Weinreb amide derivatives,4 and their condensation
with aldehydes to afford chiral nitrones as substrates for
asymmetric reactions.5 Hydroxylamines have also been
employed as versatile chiral building blocks for the pre-
paration of chiral hydroxamic acids,6 β-amino acids,7
peptides,8 and a number of natural products.9 They are
normally prepared via oxidation of the parent chiral
amine,10 stereoselective reduction of the corresponding
oxime,11 or amination of chiral enolates.12 Therefore, the
† Department of Chemistry.
‡ Bath X-ray Crystallographic Suite.
(1) (a) Vigh, L.; Literati, P. N.; Horvath, I.; Torok, A.; Balogh, G.;
Glatz, A.; Kovacs, E.; Boros, I.; Ferdinandy, P.; Farkas, B.; Jaszlits, L.;
Jednakovits, A.; Kornayi, L.; Maresca, B. Nat. Med. 1997, 3, 1150–1154.
(b) Igarashi, N.; Moriyama, H.; Fujiwara, T.; Fukumori, Y.; Tanaka, N.
Nat. Struct. Biol. 1997, 4, 276–284. (c) Hanna, P. E. Curr. Med. Chem.
1996, 3, 195–210. (d) Hogg, J. H.; Ollmann, I. R.; Haeggstrom, J. Z.;
Wetterholm, A.; Samuelsson, B.; Wong, C. H. Bioorg. Med. Chem. 1995,
3, 1405–1415.
(6) (a) Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122,
10452–10453. (b) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007,
129, 286–287.
(7) (a) Hanselmann, R.; Zhou, J. C.; Ma, P.; Confalone, P. N. J. Org.
Chem. 2003, 68, 8739–8741. (b) Bentley, S. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron
2010, 66, 4604–4620.
(2) (a) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int.
Ed. 2006, 45, 1248–1252. (b) Pusterla, I.; Bode, J. W. Angew. Chem., Int.
Ed. 2012, 51, 513–516.
(3) Smithen, D. A.; Mathews, C. J.; Tomkinson, N. C. O. Org.
Biomol. Chem. 2012, 10, 3756–3762.
(4) Chernega, A. N.; Davies, S. G.; Goodwin, C. J.; Hepworth, D.;
Kurosawa, W.; Roberts, P. M.; Thompson, J. E. Org. Lett. 2009, 11,
3254–3257.
(5) (a) Chang, Z. Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3464–
3474. (b) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41,
3455–3462. (c) Jost, S.; Gimbert, Y.; Greene, A. E.; Fotiadu, F. J. Org.
Chem. 1997, 62, 6672–6677. (d) Goti, A.; Cicchi, S.; Mannucci, V.;
Cardona, F.; Guarna, F.; Merino, P.; Tejero, T. Org. Lett. 2003, 5, 4235–
4238. (e) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett.
2008, 10, 4493–4496. (f) Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira,
E. M Angew. Chem., Int. Ed. 2002, 41, 3054–3056.
(8) Wang, L.; Phanstiel, O. J. Org. Chem. 2000, 65, 1442–1447.
(9) (a) Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.;
Adams, J. P. J. Am. Chem. Soc. 1999, 121, 4900–4901. (b) Snider, B. B.;
Lin, H. J. Am. Chem. Soc. 1999, 121, 7778–7786. (c) White, J. D.;
Hansen, J. D. J. Org. Chem. 2005, 70, 1963–1977. (d) Patel, S. K.; Murat,
K.; Py, S.; Vallee, Y. Org. Lett. 2003, 5, 4081–4084.
(10) (a) Tokuyama, H.; Kuboyama, T.; Amano, A.; Yamashita, T.;
Fukuyama, T. Synthesis 2000, 1299–1304. (b) Heydari, A.; Aslanzadeh,
S. Adv. Synth. Catal. 2005, 347, 1223–1225. (c) Patel, I.; Smith, N. A.;
Tyler, S. N. G. Org. Process Res. Dev. 2009, 13, 49–53. (d) Wittman,
M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 1981–
1983. (e) Wang, Q. X.; King, J.; Phanstiel, O. J. Org. Chem. 1997, 62,
8104–8108.
r
10.1021/ol303566k
Published on Web 02/04/2013
2013 American Chemical Society