ORGANIC
LETTERS
1999
Vol. 1, No. 13
2061-2063
Enantioselective Synthesis of r-Hydroxy
Acids Employing
(1S)-(+)-N,N-Diisopropyl-10-camphorsulfonamide
as Chiral Auxiliary
,†
Jia-Wen Chang,† Der-Pin Jang,† Biing-Jiun Uang,* Fen-Ling Liao,‡ and
Sue-Lein Wang†,‡
Department of Chemistry and Instrumentation Center, National Tsing Hua UniVersity,
Hsinchu, Taiwan 300, Republic of China
Received September 20, 1999
ABSTRACT
Lewis acid (BF3‚OEt2) catalyzed condensation of dimethoxy acetal 2 with r-hydroxy acids produces chiral 1,3-dioxolanones I. The enolates
derived from these compounds undergo reactions with alkyl halides with a high level of diastereoselectivity. Subsequent hydrolysis of these
alkylated products II gives mono- and disubstituted r-hydroxy acids III with high enantiomeric excesses.
Optically active R-hydroxy acids are structural subunits of
many natural products, such as motuporin,1a integerrimine,1b
monocrotaline,1c and eremantholide A.1d In addition, R-hy-
droxy acid derivatives are important intermediates for
asymmetric synthesis.2 A number of useful synthetic methods
for the preparation of enantiomertically pure R-branched
R-hydroxy acids have been developed.3 However, the need
for development of a more efficient method still exists.
Herein we report an enantioselective synthetic method for
mono- and disubstituted R-hydroxy acids from glycolic acid,
lactic acid, and mandelic acid, employing (1S)-(+)-N,N-
diisopropyl-10-camphorsulfonamide 1 as a chiral auxiliary.4
1,3-dioxolanone or gave it in low yield. However, Lewis
acid (BF3‚OEt2) catalyzed condensation of dimethoxy acetal
(2) (a) Scott, J. W. In Asymmetric Synthesis; Morrison, J. D., Scott, J.
W., Eds.; Academic Press: New York, 1984; Vol. 4. (b) Seeback, D. In
Modern Synthetic Methods; Scheffold, R., Ed.; Otto Salle Verlag: Frankfurt,
1980. (c) Coppola, G. M.; Schuster, H. F. In R-Hydroxy Acids In
EnantioselectiVe Synthesis; Academic Press: Weinheim, 1997. (d) Shibasaki,
M.; Nishikimi, Y.; Iimori, T.; Sodeoka, M. J. Org. Chem. 1989, 54, 3354.
(e) Suzuki, K.; Tomooak, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi,
G. J. Am. Chem. Soc. 1986, 108, 5221. (f) Seebach, D.; Naef, R. Liebigs
Ann. Chem. 1983, 1930. (g) Davies, S. G.; Coote, S. J.; Middlemiss, D.;
Naylor, A. Tetrahedron Lett. 1989, 30, 3581. (h) Tsuchihashi, G.; Suzuki,
K.; Ohkuma, T. Tetrahedron Lett. 1985, 26, 861. (i) Heimgartner, H.;
Obrecht, D. HelV. Chim. Acta 1990, 73, 221. (j) Sugiyama, T.; Murayama,
T.; Yamashita, K. Tetrahedron Lett. 1990, 31, 7343.
(3) (a) Pearson, W. H.; Cheng, M.-C.; J. Org. Chem. 1986, 51, 3746.
(b) Seeback, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313. (c)
Ley, S. V.; Boons, G.-J.; Downham, R. Kim, K. S.; Woods, M. Tetrahedron
1994, 50, 7157. (d) Xiang, Y.-B.; Snow, K.; Belley, M. J. Org. Chem.
1993, 58, 993. (e) Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron:
Asymmetry 1997, 8, 1877. (f) Wang, Z.; La, B.; Fortunak, J. M.; Meng,
X.-J.; Kabalka, G. W. Tetrahedron Lett. 1998, 39, 5501. (g) Verducci, J.;
Cavelier, F.; Gomez, S.; Jacquier, R. Tetrahedron Lett. 1994, 35, 2891. (h)
Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-Mo¨ller, C. R. J. Am. Chem.
Soc. 1998, 120, 708. (i) Yamamoto, Y.; Kin, H.; Suzuki, I.; Asao, N.
Tetrahedron Lett. 1996, 37, 1863. (j) Kirschning, A.; Dra¨ger, G.; Jung, A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 253.
Under the conditions of Farines5 or Pearson,6 condensation
of 1 with glycolic acid either did not give the expected chiral
† Department of Chemistry.
‡ Instrumentation Center.
(1) (a) Schreiber, S. L.; Valentekovich, R. J. J. Am. Chem. Soc. 1995,
117, 9069. (b) Yamada, K.; Niwa, H.; Miyachi, Y.; Okamoto, O.; Uosaki,
Y.; Kuroda, A.; Ishiwata, H. Tetrahedron 1992, 48, 393. (c) Yamada, K.;
Niwa, H.; Ogawa, T.; Okamoto, O. Tetrahedron 1992, 48, 10531. (d)
Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem. Soc.
1991, 113, 9682.
10.1021/ol9910666 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999