the amino catalyst and 1-2 cycles of the NHC-catalyst.5
Nowadays, as atom economy has emerged as a guiding
principle for the development of time-cost-effective reac-
tions,6 we aimed to develop a more efficient and practical
protocol to ꢀ-hydroxy and ꢀ-amino esters by using combined
amino-4 and NHC-catalysis.7 In the present work, we
demonstrate that catalyst loadings of 2.5 mol % of the amino
catalyst and 1-2.5 mol % of the NHC catalyst are generally
sufficient to achieve high yields and excellent enantioselec-
tivities in this transformation. It is notable that all catalysts
applied may be purchased from commercial sources, and the
reaction sequence does not require inert conditions, which
greatly improves the practical aspects of the developed
protocol.
epoxidation/aziridination of enals with an intramolecular
redox reaction,3 thereby facilitating the reductive ring-
opening and the formation of an activated carboxylate (B).
Final acyl-transfer in the presence of another nucleophilic
species (R1OH) furnishes the overall transformation from
simple enals to ꢀ-hydroxy and ꢀ-amino esters (C) in one
pot.
We initiated our screening using trans-2-nonenal 3a as
model substrate (Table 1). Full conversion into the 2,3-epoxy
The design of the reaction sequence is outlined in Scheme
1. The key intermediates, 2,3-epoxy and 2,3-aziridine alde-
Figure 1. Catalysts used in this study.
Scheme 1
. Synthesis of ꢀ-Hydroxy/ꢀ-Amino Esters Using
Combined Amino- and NHC-Catalysis
Table 1. Optimization of the Reaction Conditions for the
Synthesis of ꢀ-Hydroxy Ester 4aa
entry 2 (mol %) DIPEA (mol %) t (h)b convn (%)c ee (%)d
1e f
2a (10)
2b (10)
2b (10)
2b (10)
2b (5)
8
20
20
20
10
5
15
24
2
2
2
<10
>95
,
2e g
,
92
94
94
94
94
94
3e
4
5
>95 (52)
>95 (70)
>95 (73)
>95 (75)
>95 (84)
hydes (A), are easily generated in an enantioselective manner
by using a commercially available amino catalyst and R,ꢀ-
unsaturated aldehydes by an improved protocol recently
developed by our group.8 Subsequent in situ generation of
the NHC catalyst efficiently couples the amino-catalyzed
6
2b (2.5)
2b (1)
4
16
7h
2
a Reactions performed at 0.1 mmol scale of 3a in 0.2 mL of CH2Cl2
(see the Supporting Information). b Reaction time for the second step.
c
1
Conversion of 2,3-epoxy aldehyde as judged by H NMR spectroscopy,
isolated yield in parentheses. d Determined by chiral stationary phase GC.
e Reaction performed in the absence of 4 Å MS. f Reaction performed at
30 °C. g Reaction performed with 10 mol % imidazole as additive at 40
°C. h Reaction performed at 0.5 mmol scale.
(4) For recent reviews on amino-catalysis see e.g.: (a) Acc. Chem. Res.
2004, 37 (8), special issue on organocatalysis. (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Berkessel, A.; Gro¨ger, H., Eds.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2004. (d)
Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (e) List, B.; Yang,
J.-W. Science 2006, 313, 1584. (f) List, B. Chem. Commun. 2006, 819. (g)
Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (h) Guillena,
G.; Ramo´n, D. J. Tetrahedron: Asymmetry 2006, 17, 1465. (i) Sulzer-Mosse´,
S.; Alexakis, A. Chem. Commun. 2007, 3123. (j) Chem. ReV. 2007, 107
(12), special issue on organocatalysis. (k) Gaunt, M. J.; Johansson, C. C. C.;
McNally, A.; Vo, N. C. Drug DiscoVery Today 2007, 2, 8. (l) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701. (m) Vicario, J. L.; Bad´ıa, D.; Carrillo,
L. Synthesis 2007, 2065. (n) Almasi, D.; Alonso, D.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (o) Dalko, P. I., Ed. EnantioselectiVe Organo-
catalysis; Wiley-VCH: Weinheim, Germany, 2007. (p) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638. (q) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (r) Bertelsen,
S.; Jørgensen, K. A. Chem. Soc. ReV. 2009, 38, 2178. (s) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167.
aldehyde was achieved after 24 h at rt with 2.5 mol % of
the prolinol-derived catalyst 1 (Figure 1).9 Following the
(8) For an improved protocol of enal epoxidation/aziridination, see: (a)
Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen, S. G.;
Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 9188. For the first report
on amino-catalyzed enal epoxidations, see: (b) Marigo, M.; Franze´n, J.;
Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 6964. For other reports, see: (c) Sunde´n, H.; Ibrahem, I.; Co´rdova, A.
Tetrahedron Lett. 2006, 47, 99. (d) Lee, S.; MacMillan, D. W. C.
Tetrahedron 2006, 62, 11413. For previous reports on enal aziridination,
see: (e) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Co´rdova, A. Angew.
Chem., Int. Ed. 2007, 46, 778. (f) Arai, H.; Sugaya, N.; Sasaki, N.; Makino,
K.; Lectard, S.; Hamada, Y. Tetrahedron Lett. 2009, 50, 3329.
(5) (a) Zhao, G.-L.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 5976. For
related work, see: (b) Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunde´n,
H.; Dziedzic, P.; Co´rdova, A. Chem.sEur. J. 2008, 14, 7867.
(9) For the first application of silyldiarylprolinol ethers as catalysts see:
(a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed 2005, 44, 794. See also: (b) Marigo, M.; Fielenbach, D.;
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silyldiarylprolinol ethers as catalysts see: (d) Mielgo, A.; Palomo, C. Chem.
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(6) Trost, B. M. Science 1991, 254, 1471.
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Org. Lett., Vol. 12, No. 21, 2010
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