ORGANIC LETTERS
A General Method for the Enantioselective Synthesis of Pantolactone Derivatives
2002 Vol. 4, No. 20 3379-3382
David A. Evans,* Jimmy Wu, Craig E. Masse, and David W. C. MacMillan Department of Chemistry & Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
[email protected] Received July 9, 2002
ABSTRACT
An efficient enantioselective synthesis of β,β-dialkyl-γ-substituted pantolactones has been achieved utilizing the cationic [Sc((S,S)-R-pybox)](Cl)2+, R ) Ph (9), t-Bu (10), complex in a catalyzed aldol reaction as the key step. The pantolactone derivatives are isolated in high enantiomeric excesses.
The asymmetric synthesis of pantolactone (1a), pantothenic acid (2a), and their derivatives (Figure 1) continue to be of
Figure 1. Biologically active pantolactone and pantothenic acid derivatives.
interest to organic chemists as a consequence of their biological activity and utility as a secondary alcohol derived chiral auxiliary. The taurine derivative of panthothenic acid (pantoyltaurine, 2b) has been shown to inhibit the growth of streptococci, pneumococci, plasmodium relictum,1 and certain strains of diphtheria bacilli.2 γ-Methylpantolactone and its open-chain derivative, as well as a variety of related γ-substituted pantolactone analogues (1a-c), all possess (1) Winterbottom, R.; Clapp, J. W.; Miller, W. H.; English, J. P.; Roblin, R. O., Jr. J. Am. Chem. Soc. 1947, 69, 1393-1401. (2) Roblin, R. O., Jr. Chem. Rev. 1946, 38, 255-367. 10.1021/ol026489d CCC: $22.00 Published on Web 09/07/2002
© 2002 American Chemical Society
inhibitory properties toward lactic acid bacteria and malaria.3 The purpose of this Letter is to describe a catalytic enantioselective approach to the synthesis of this family of lactone targets and their γ-substituted analogues. Since racemic, unsubstituted pantolactone (1a) is readily prepared in a “one-pot” reaction from hydroxypivalaldehyde, sodium cyanide, hydrochloric acid, and calcium chloride,4 various methods for its chemical5 and enzymatic6 resolution have been developed. Direct access to enantiopure pantolactone may also be achieved by enantioselective hydrogenation of 3,3-dimethyl2-oxobutyrolactone with a variety of different metal catalyst systems.7 Recently, Upadhya has also reported that Sharpless’s asymmetric dihydroxylation of the corresponding cyclic silylketene acetal pantolactone precursor affords the desired pantolactone in high enantiomeric excess.8 (3) (a) Drell, W.; Dunn, M. S. J. Am. Chem. Soc. 1948, 70, 2057-2063. Drell, W.; Dunn, M. S. J. Am. Chem. Soc. 1954, 76, 2804-2808. (4) Ford, J. H. J. Am. Chem. Soc. 1944, 66, 20-21. (5) (a) Stiller, E. T.; Harris, S. A.; Finkelstein, J.; Keresztesy, J. C.; Folkers, K. J. Am. Chem. Soc. 1940, 62, 1785-1790. (b) Fuji, K.; Node, M.; Murata, M. Tetrahedron Lett. 1986, 27, 5381-5382. (c) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem. 1989, 54, 24532455. (d) Kagan, F.; Heinzelman, R. V.; Weisblat, D. I.; Greiner, W. J. Am. Chem. Soc. 1957, 79, 3545-3549. (6) (a) Baumann, M.; Hauer, B. H.; Bornscheuer, U. T. Tetrahedron: Asymmetry 2000, 11, 4781-4790.
Table 1. Catalyst Survey for Silylketene Acetals and Ketone Enolsilane Additions to Ethyl Glyoxylate (eqs 2, 3)a
catalyst
% eeb
configc
conv%
catalyst
% eeb
configc
conv %
[Cu((S,S)-t-Bu-box)](OTf)2 (6) [Sn((S,S)-Bn-box)](OTf)2 (7) [Sc((S,S)-Ph-pybox)](OTf)3 (8) [Sc((S,S)-Ph-pybox)](Cl2)(SbF6) (9) [Sc((S,S)-t-Bu-pybox)](Cl2)(SbF6) (10)
98 95 6 95 62
(S) (S) (R) (R) (S)
61 89 87 90 45
[Cu((S,S)-t-Bu-box)](OTf)2 (6) [Sn((S,S)-Bn-box)](OTf)2 (7) [Sc((S,S)-Ph-pybox)](OTf)3 (8) [Sc((S,S)-Ph-pybox)](Cl2)(SbF6) (9) [Sc((S,S)-t-Bu-pybox)](Cl2)SbF6) (10)
95 76 4 32 95
(S) (S) (R) (R) (S)
