were reduced to afford the ꢀ,γ-alkenyl R-amino ester. It
should be noted that only a trans-alkene-substituted product
was observed during the reduction. This reaction provides
congested phosphoric acids emerged as catalysts with good to
excellent levels of enantioselectivity (entries 3, 6, and 8-10,
Table 1). The best result was obtained with 5 mol % of 1h
Table 1. Optimization of the Reaction Conditions for the
Asymmetric Transfer Hydrogenation of 3ba
eeb (%)
Figure 1. Chiral phosphoric acids and Hantzsch esters.
entry
1, R
x (mol %)
solvent
1
2
3
4
5
6
7
8
1a, H
1b, phenyl
1c, SiPh3
5
5
5
5
5
5
5
5
5
5
5
5
1
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
toluene
toluene
-22
57
-85
21
54
82
<1
90
72
87
26
straightforward access to optically pure ꢀ,γ-alkenyl R-amino
acid derivatives. The presence of a CdC bond in the product
offers a unique and highly valuable opportunity for further
transformation on the ꢀ,γ-position of R-amino acids.
Herein, we report the enantioselective synthesis of trans-
alkenyl R-amino esters by chiral phosphoric acid catalyzed
transfer hydrogenation of ꢀ,γ-alkynyl R-imino esters with
Hantzsch ester as the hydrogen donor. Excellent enantiose-
lectivities (up to 96% ee) have been obtained, and prelimi-
nary mechanistic studies have also been carried out.
1d, 3,5-(CF3)2-C6H3
1e, 4-NO2-C6H4
1f, 1-naphthyl
1g, 2-naphthyl
1h, 9-anthryl
1i, 9-phenanthryl
1j, 2,4,6-(iPr)3C6H2
1k, 4-biphenyl
1h, 9-anthryl
1h, 9-anthryl
9
10
11
12
13
92
92
a Reaction conditions: x mol % of 1, 220 mol % of 2b, 0.05 mol/L of
3b at room temperature for 24 h. b Determined by chiral HPLC analysis
(Chiralcel AD-H). PMP ) p-methoxyphenyl.
We first examined the hydrogenation of the phenylacetylenyl-
substituted R-imino ester 3b with 2.2 equiv of Hantzsch ester
2b in Et2O. With 5 mol % of 1, all reactions proceeded smoothly
at room temperature. From this survey, the sterically more
providing the trans-alkene-substituted R-amino ester 4b in 90%
ee (entry 8, Table 1). Interestingly, chiral phosphoric acids 1a
and 1c, derived from (S)-BINOL, led to 4b with reversed optical
rotation (entries 1 and 3, Table 1).
(4) For catalytic asymmetric synthesis of ꢀ,γ-alkynyl R-amino esters,
see: (a) Lin, W. Q.; He, Z.; Jing, Y.; Cui, X.; Liu, H.; Mi, A.-Q.
Tetrahedron: Asymmetry 2001, 12, 1583–1587. (b) Ji, J.-X.; Wu, J. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 11196–11200. (c) Shao, Z.; Wang, J.;
Ding, K.; Chan, A. S. C. AdV. Synth. Catal. 2007, 349, 2375–2379. (d)
Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed.
2007, 46, 6903–6906.
With 5 mol % of 1h at room temperature, the reactions
could be carried out smoothly in several common solvents
such as toluene (92% ee), CH2Cl2 (85% ee), THF (87% ee),
and tBuOMe (85% ee).10 Toluene was chosen as the optimal
solvent since the reaction in toluene led to the highest
enantioselectivity (92% ee, entry 12, Table 1). Further study
on the catalyst loadings disclosed that even with 1 mol %
of 1h, the reaction could afford the desired product with the
same enantioselectivity (92% ee, entry 13, Table 1). Several
Hantzsch esters have been tested, and 2b was chosen as the
optimal hydrogen source [85% ee (2a), 93% ee (2c), 86%
ee (2d)].10
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J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487. (n)
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different ester groups were tested for the reaction. As shown
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(10) See the Supporting Information for details.
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Org. Lett., Vol. 10, No. 10, 2008