ORGANIC
LETTERS
2
000
Vol. 2, No. 1
7-60
Diastereoselective Formation of
Cyanohydrins from r-Alkoxy Aldehydes
5
Dale E. Ward,* Matthew J. Hrapchak, and Marcelo Sales
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon SK S7N 5C9, Canada.
dale.ward@usask.ca.
Received October 29, 1999
ABSTRACT
The reaction of r-alkoxy aldehydes with Et
cyanohydrins in good yield with high diastereoselectivity. Excess MgBr
Et NAg(CN) (but not Me SiCN) is sufficiently reactive to give cyanohydrins at −78 °C, and higher diastereoselectivity is obtained at this
temperature.
4
NAg(CN)
2
or Me
3
SiCN in the presence of MgBr
2
‚OEt
2 2 2
in CH Cl at 0 °C gives the corresponding syn
2
‚OEt (typically 5 equiv) is required for high diastereoselectivity.
2
4
2
3
Cyanohydrins are versatile synthetic intermediates for the
preparation of a variety of useful compounds. The enantio-
mixture of cyanohydrins in favor of the manno (i.e., 2,3-
anti) diastereomer. Subsequently, diastereoselectivities of
1
5
selective formation of cyanohydrins from achiral aldehydes
has been extensively investigated in recent years, and several
highly selective methods have been reported.2 By contrast,
cyanohydrins are often formed with poor diastereoselectivity
from chiral aldehydes. More than a century ago, Fischer
reported that addition of HCN to L-arabinose gave a 2:1
1.5-5:1 in favor of the syn isomer have been reported for
cyanohydrin formation from R-alkoxy aldehydes using
trimethylsilyl cyanide (TMSCN) in the presence of various
,3
6
Lewis acids. Our ongoing interest in the design and
4
development of enantiotopic group selective reactions
prompted an examination of cyanohydrin formation from
7
R-alkoxy aldehydes. However, the poor diastereoselectivity
(
1) Jackson, W. R.; Jacobs, H. A.; Jayatilake, G. S..; Mathews, B. R.;
Watson, K. G. Aust. J. Chem. 1990, 43, 2045. (b) Kruze, C. G. In Chirality
in Industry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley: New
York, 1992; pp 279-299. (c) Effenberger, F. Angew. Chem., Int. Ed. Engl.
1993, 115, 40. (k) Faller, J. W.; Gunderson, L. Tetrahedron Lett. 1993, 34,
2275. (l) Vogeleisen, N. A. F.; Uguen, D. Tetrahedron Lett. 1996, 37, 5893.
(m) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J.
Am. Chem. Soc. 1999, 121, 8401.
1
994, 33, 1555.
(
2) Review: North, M. Synlett 1993, 807. See also ref 1c.
(5) (a) Fischer, E. Ber. Dtsch. Chem. Ges. 1890, 23, 2611. For related
reactions of carbohydrates see: (b) Gy o¨ rgyde a´ k, Z.; Pelyv a´ s, I. F.
Monosaccharide Sugars; Academic: San Diego, 1998, Chapter 1, pp 18-
30.
(3) See inter alia: (a) Hwang, C.-D.; Hwang, D.-R.; Uang, B.-J. J. Org.
Chem. 1998, 63, 6762. (b) Hamashima, Y.; Sawada, D.; Kanai, M.;
Shibisaki, M. J. Am. Chem. Soc. 1999, 121, 2641. (c) Belokon′, Y. N.;
Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev,
V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo,
M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968.
(6) (a) Reetz, M. T.; Kesseler, K.; Jung, A. Angew. Chem., Int. Ed. Engl.
1985, 24, 989. (b) Dostert, P.; Melloni, P.; Torre, A. D.; Varasi, M.; Merlini,
L.; Bonsignori, A.; Ricciardi, S. Eur. J. Med. Chem. 1990, 25, 757. (c)
Nishimura, S.; Hayashi, N. Chem. Lett. 1991, 1815. (d) Effenberger, F.;
Hopf, M.; Ziegler, T.; Hudelmayer, J. Chem. Ber. 1991, 124, 1651. (e)
Nakai, T.; Gu, J. H.; Okamoto, M.; Terada, M.; Mikami, K. Chem. Lett.
1992, 1169. (f) Reetz, M. T.; Fox, D. N. A. Tetrahedron Lett. 1993, 34,
1119. (g) Ipaktschi, J.; Heydari, A Chem. Ber. 1993, 126, 1905. (h) Ipaktschi,
J.; Heydari, A.; Kalinowski, H.-O. Chem. Ber. 1994, 127, 905. (i) Cativiela,
C.; D ´ı az-de-Villegas, M. D.; G a´ lvez, J. A.; Garc ´ı a, J. I. Tetrahedron 1996,
52, 9563. (j) Yang, Y.; Wang, D. Synlett 1997, 1379.
(4) See inter alia: (a) Nishizawa, R.; Saino, T. J. Med. Chem. 1977, 20,
5
2
1
10. (b) Rich, D. H.; Moon, B. J.; Boparai, A. S. J. Org. Chem. 1980, 45,
288. (c) Luly, J. R.; Hsiao, C.; BaMaung, N.; Plattner, J. J. J. Org. Chem.
988, 53, 6109. (d) Reetz, M. T.; Drewes, M. W.; Harms, K.; Rief, W.
Tetrahedron Lett. 1988, 29, 3295. (e) Herranz, R.; Castro-Pichel, J.; Garcia-
Lopez, T Synthesis 1989, 703. (f) Rychnovsky, S. D.; Zeller, S.; Skalitzky,
D. J.; Griesgraber, G. J. Org. Chem. 1990, 55, 5550. (g) Herranz, R.; Castro-
Pichel, J.; Vinuesa, S.; Garcia-Lopez, M. T. J. Org. Chem. 1990, 55, 2232.
(
h) Herranz, R.; Vinuesa, S.; Perez, C.; Garcia-Lopez, M. T. J. Chem. Soc.,
(7) (a) Ward, D. E.; Liu, Y.; Rhee, C. K. Can. J. Chem. 1994, 72, 1429.
(b) Ward, D. E.; How, D.; Liu, Y. J. Am. Chem. Soc. 1997, 119, 1884. (c)
Ward, D. E.; Lu, W.-L. J. Am. Chem. Soc. 1998, 120, 1098
Perkin Trans. 1 1991, 2749. (i) Utimoto, K.; Takai, T.; Matsubara, S Chem.
Lett. 1991, 1447. (j) Molander, G. A.; Haar, J. P., Jr. J. Am. Chem. Soc.
1
0.1021/ol991198z CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999