ORGANIC
LETTERS
2000
Vol. 2, No. 2
175-177
Enantioselective Synthesis of
(S)-(+)-Pantolactone
Sunil V. Pansare* and Rajendra P. Jain
DiVision of Organic Chemistry (Synthesis), National Chemical Laboratory,
Pune 411 008, Maharashtra, India
Received November 23, 1999
ABSTRACT
The Prins reaction of a chiral alkylidene morpholinone derived from (1R,2S)-ephedrine and 3-methyl-2-oxobutanoic acid proceeds with good
diastereoselectivity to generate a spiro bis-acetal. Lewis acid mediated diastereoselective reductive cleavage of the spiro acetal and subsequent
removal of the ephedrine portion generates a r-hydroxy-γ-methoxy carboxamide which is readily converted to (S)-(+)-pantolactone with high
enantiomeric excess.
The asymmetric synthesis of pantolactone continues to be
an area of active interest due to its utility as a building block
in the synthesis of natural products and their analogues1,2
and the biological activity of pantothenic acid and (R)-
panthenol.3 In addition, pantolactone has found application
as a chiral auxiliary in asymmetric synthesis.4 Enantiomeri-
cally enriched pantolactone has been obtained by several
procedures. These include chemical1a,5 or enzymatic6 resolu-
tion of the racemate, microbial or catalytic asymmetric
reduction of 3,3-dimethyl-2-oxobutyrolactone7 and asym-
metric functionalization of linear or cyclic precursors.8
We chose to examine a synthesis of pantolactone that
focused on the precursor hydroxy acid rather than function-
alization of the butyrolactone skeleton. The advantage of such
an approach would be the ready access to pantolactone
analogues. Herein, we describe a new approach to the
enantioselective construction of the R,γ-dihydroxy butyric
acid moiety, the precursor to pantolactone. The procedure
involves a stereoselective Prins reaction9 of an R-alkoxy
acrylamide as the key step.
(1) (a) Kagan, F.; Heinzelman, R. V.; Weisblat, D. T.; Greiner, W. J.
Am. Chem. Soc. 1957, 79, 3545. (b) Neidlein, R.; Greulich, P. HelV. Chim.
Acta 1992, 75, 2545. (c) Fischer, G. C.; Turakhia, R. H.; Morrow, C. J. J.
Org. Chem. 1985, 50, 2011.
(2) (a) Sone, H.; Suenaga, K.; Bessho Y.; Kondo, T.; Kigoshi, H.;
Yamada, K. Chem. Lett. 1998, 85. (b) Dolle, R. E.; Nicolou, K. C. J. Am.
Chem. Soc. 1985, 107, 1691. (c) Lavallee, P.; Ruel, R.; Grenier, L.;
Bissonnette, M. Tetrahedron Lett. 1986, 27, 679.
Acylation of (1R,2S)-ephedrine hydrochloride with 3-methyl-
2-oxobutanoyl chloride generates the hemiacetal 1 which is
(3) (a) Lipmann, F. Science 1954, 120, 855. (b) Shimizu, S,; Tani, Y.;
Ogata, K. Agric. Biol. Chem. 1974, 38, 1989.
(7) (a) Lanzillota, R. P. Bradley, D. G.; McDonald, K. M. Appl. Microb.
1974, 27, 130. (b) Roucoux, A.; Suisse, I.; Devocelle, M.; Carpentier, J.
F.; Agbossou, F.; Mortreaux, A. Tetrahedron: Asymm. 1996, 7, 379. (c)
Pasquier, C.; Eilers, J.; Reiners, I.; Martens, J.; Mortreux A.; Agbossou, F.
Synlett 1998, 1162.
(8) (a) Rao, A. V. R.; Rao, S. M.; Sharma. G. V. M. Tetrahedron Lett.
1994, 35, 5735. (b) Upadhya, T. T.; Gurunath, S.; Sudalai, A. Tetrahe-
dron: Asymmetry 1999, 10, 2899. (c) Effenberger, F.; Eichhorn, J.; Roos,
J. Tetrahedron: Assymetry 1995, 6, 271.
(4) (a) O’Meara, J. A.; Gardee, N.; Jung, M.; Ben, R. N.; Durst, T. J. J.
Org. Chem. 1998, 63, 3117. (b) Davies, H. M. L.; Ahmed, G.; Calvo, R.
L.; Churchill, M. R.; Churchill, D. G. J. Org. Chem. 1998, 63, 2641 and
references therein. (c) Hansen, M. M.; Bertsch, C. F.; Harkness, A. R.;
Huff, B. E.; Hutchison, D. R.; Khau, V. V.; LeTourneau, M. E.; Martinelli.,
M. J.; Misner, J. W.; Peterson, B. C.; Rieck, J. A.; Sullivan, K. A.; Wright,
I. G. J. Org. Chem. 1998, 63, 775.
(5) Paust, J.; Pfohl, S.; Reif, W.; Schmidt, W. Ann. Chem. 1978, 1024.
(6) (a) Fuelling, G.; Schudok, M. Ger. Offen. DE 4,005,150, 1990. (b)
Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989,
54, 2453.
(9) For reviews on the Prins reaction, see: (a) Adams, D. R.; Bhatnagar,
S. P. Synthesis 1977, 661. (b) Snyder, B. B. Compr. Org. Synth. 1991, 2,
527.
10.1021/ol990372g CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999