Hantzsch esters as the hydrogen source. Successfully used
substrates contain either CdC or CdN bonds.8 Here we
extend these studies to the reduction of compounds with a
CdO bond. We found that C2-symmetric chiral Cu(II)-
bisoxazoline complexes catalyze the enantioselective reduc-
tion of tert-butyl-R-ketoesters to the corresponding alcohols
in high enantioselectivities (Scheme 1).
ing substrates such as glyoxalates. We reasoned that Cu(II)-
bisoxazoline complexes may also be suitable for the reduction
of R-ketoesters if combined with the established hydride
delivery potency of Hantzsch esters.22 In this sense, such a
system could be described as an alcohol dehydrogenase
mimic,23 the Cu(II)-bisoxazoline complex functioning as the
zinc-metalloenzyme equivalent and the Hantzsch ester
mimicking the NADH cofactor. Previously, such Lewis acid
mediated reductions have been described only using a
stoichiometric amount of chiral Hantzsch esters.6e-i
Scheme 1. Asymmetric Transfer Hydrogenation of CdC,
CdN, and CdO with a Hantzsch Ester
Preliminary studies led us to determine that Cu(OTf)2, in
combination with certain chiral bisoxazoline ligands and
Hantzsch ester 4a, gave appreciable reactivity and enantio-
selectivity in the reduction of ketone 1a (Table 1). As
Table 1. Catalyst Development
C2-symmetric chiral Lewis acidic Cu(II)-bisoxazoline
complexes are versatile catalysts for asymmetric carbon-
carbon and carbon-heteroatom bond formations such as
Diels-Alder,9 aldol,10 cycloaddition,11 ene,12 Michael,13
amination,14 Friedel-Crafts,15 Henry,16 Mannich,17 benzoyl-
ation,18 Claisen rearrangement,19 and allylic oxidation reac-
tions.20,21 These catalysts work particularly well with chelat-
entry
ligand
R
R1
solvent
yield (%)a
erb
nd
nd
nd
(8) (a) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006,
128, 13074. (b) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128,
13368. (c) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (d)
Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 108. (e) Hoffmann, S.; Seayad, A. M.; List, B.
Angew. Chem., Int. Ed. 2005, 44, 7424. (f) Yang, J. W.; Hechavarria
Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (g) Yang, J.
W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004, 43,
6660. For the use of the Hantzsch ester as the reductant in asymmetric
catalysis by other groups, see: (h) Tuttle, J. B.; Ouellet, S. G.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 12662. (i) Rueping, M.; Antonchick,
A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (j) Ouellet,
S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
(k) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051. (l) Rueping, M.; Sugiono, E.; Azap, C.;
Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
tBu
Ph
Bn
tBu
Ph
Bn
Bn
Bn
H
H
H
Me
Me
Me
Me
Me
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
<5
<5
<5
<5
20
80
80
90
nd
91:9
90:10
92:8
91:9
3f
3f
CHCl3
a Isolated yield. b Determined by chiral HPLC analysis on a Chiralcel
OD-H column.
(9) (a) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
Soc. 1999, 121, 7559. (b) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc.
1998, 120, 4895. (c) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.;
Jørgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599.
(10) (a) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 1997, 119, 7893. (b) Evans, D. A.; Murry, J. A.;
Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814.
(11) (a) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50. (b)
Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125.
(12) (a) Yang, D.; Yang, M.; Zhu, N.-Y. Org. Lett. 2003, 5, 3749. (b)
Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J.
Am. Chem. Soc. 1998, 120, 5824.
(13) (a) Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem. 2003,
68, 5067. (b) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999,
1, 865. (c) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994.
(14) (a) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 2420.
(b) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.
(15) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Gathergood, N.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 12517.
(16) (a) Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2002, 67, 4875. (b) Knudsen, K. R.; Risgaard, T.; Nishiwaki,
N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
(17) (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.-Eur. J. 2003, 9, 2359. (b) Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 2995.
revealed in Table 1, exposure of ethyl benzoylformate to
commercially available Hantzsch ester 4a in the presence
of a catalytic amount of Cu(OTf)2 and box ligands 3a-e
resulted in an inefficient (e20%) reduction (Table 1, entries
1-5). In contrast, a dramatic increase in reaction efficiency
and enantioselectivity was achieved using the [(S,S)-benzyl-
box 3f]-Cu(OTf)2 complex (entry 8, 91:9 er). A survey of
reaction media for this reduction revealed that CHCl3
(21) For a catalytic asymmetric addition reaction to R-ketoester and a
similar substrate with alternative metal complexes, see: (a) Kong, J.-R.;
Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718. (b) Akullian,
L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 6532.
(c) Blay, G.; Ferna´ndez, I.; Marco-Aleixandre, A.; Pedro, J. R. Org. Lett.
2006, 8, 1287. (d) Wieland, L. C.; Deng, H.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2005, 127, 15453. (e) Harb, W.; Ruiz-Lo´pez, M. F.;
Coutrot, F.; Grison, C.; Coutrot, P. J. Am. Chem. Soc. 2004, 126, 6996. (f)
Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 5489. (g) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem.
Soc. 2002, 124, 12668.
(22) For a single example of a chiral Sn-(pybox) complex-catalyzed
reduction of an R-ketoester with polymethyl-hydrosiloxane (PMHS), see:
Lawrence, N. J.; Bushell, S. M. Tetrahedron Lett. 2000, 41, 4507.
(23) (a) Filho, M. V.; Stillger, T.; Mu¨ller, M.; Liese, A.; Wandrey, C.
Angew. Chem., Int. Ed. 2003, 42, 2993. (b) Lo, H. C.; Fish, R. H. Angew.
Chem., Int. Ed. 2002, 41, 478.
(18) Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325.
(19) (a) Ko¨rner, M.; Hiersemann, M. Synlett 2006, 121. (b) For a review,
see: Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002, 1461.
(20) Andrus, M. B.; Zhou, Z. J. Am. Chem. Soc. 2002, 124, 8806.
5654
Org. Lett., Vol. 8, No. 24, 2006