Highly enantioselective transfer hydrogenation of α-imino esters by A phosphoric acid

Article abstract of DOI:10.1002/adsc.200700235

Chiral phosphoric acids have been identified as highly efficient organocatalysts for the asymmetric transfer hydrogenation of α-imino esters and amide. Utilizing Hantzsch esters as the hydrogen donor, versatile highly enantioenriched a-amino esters and th

Full text of DOI:10.1002/adsc.200700235

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DOI: 10.1002/adsc.200700235
Highly Enantioselective Transfer Hydrogenation of a-Imino
Esters by a Phosphoric Acid
Qiang Kang,a Zhuo-An Zhao,a and Shu-Li Youa,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5087; e-mail: slyou@mail.sioc.ac.cn
Received: April 14, 2007; Revised: May 9, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Chiral phosphoric acids have been identi-
fied as highly efficient organocatalysts for the asym-
metric transfer hydrogenation of a-imino esters and
amide. Utilizing Hantzsch esters as the hydrogen
donor, versatile highly enantioenriched a-amino
esters and their derivatives were obtained with up
to 98% ee.
are used as efficient catalysts for asymmetric transfer
hydrogenations of C=N double bonds with Hantzsch
esters as the hydrogen donors,[9–10] we envisaged that
chiral phosphoric acids would be efficient organocata-
lysts for the hydrogenation of a-imino esters and their
derivatives (Figure 1). In this communication, we
Keywords: amino esters; asymmetric catalysis;
asymmetric transfer hydrogenation; Hantzsch
esters; imino esters; organic catalysis
The synthesis of optically pure a-amino acids and
their derivatives constitutes an important task in or-
ganic synthesis because of their broad utility in all dis-
ciplines of biology, medicine and chemistry.[1] Among
Figure 1. Chiral phosphoric acids and Hantzsch esters.
the currently existing catalytic asymmetric ap- report a highly enantioselective synthesis of a-amino
proaches,[2] the transition metal-catalyzed enantiose- esters and their derivatives with a focus on a-arylimi-
lective hydrogenation of a-dehydroamino acids has no esters by chiral phosphoric acids-catalyzed transfer
been one of the most efficient methods to synthesize hydrogenation with Hantzsch esters as the hydrogen
a-amino acids and their derivatives.[3] However, aryl- donor (up to 98% ee).
glycines, an important class of a-amino acids that has
We first examined the hydrogenation of 3a with 1.4
found wide applications in the synthesis of biological- equivalents of Hantzsch ester 2a in toluene (Table 1).
ly active compounds,[4] have to be prepared via hydro- With 10 mol% of 1, all the phosphoric acids could
genation of the a-imino esters instead of the a-enam- catalyze the reduction at 608C, affording phenylgly-
ides. In spite of the fact that asymmetric hydrogena- cine ethyl ester 4a with variable degrees of enantiose-
tion of the corresponding a-imino acid and deriva- lectivity. Phosphoric acid 1h gave the product 4a with
tives is a direct way to deliver the glycine derivatives, 82% conversion in 48 h with the best enantioselectivi-
there has been very limited success in this transforma- ty (88% ee, entry 8, Table 1). Surprisingly, phosphoric
tion mainly due to the poor reactivity of these sub- acid 1c led to a low conversion and gave a nearly rac-
strates towards hydrogenation.[5] Recently, an excel- emic product in spite of its excellent performance for
lent report from Zhangꢀs group shows that an Rh- the reductive amination between aryl ketones and
tangphos catalyst could catalyze the asymmetric hy- anilines.[9c]
drogenation of a-arylimino esters affording a-aryl-
With 10 mol% of 1h as the catalyst at 608C or
amino esters with high ees up to 95%.[6] As part of under reflux (when the boiling point of the solvent is
our program is the search for applications of chiral below 608C), various solvents have been examined
phosphoric acids[7–8] and since the these compounds for this reaction, as summarized in Table 2. The asym-
Adv. Synth. Catal. 2007, 349, 1657 – 1660
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Qiang Kang et al.
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Table 1. Optimization of the reaction conditions for the
asymmetric transfer hydrogenation of 3a.[a]
(90% ee), THF (91% ee), AcOEt (92% ee), CHCl3
(91% ee), CH2Cl2 (92% ee), t-BuOMe (90% ee), n-
Bu2O (89% ee) and Et2O (92% ee). Et2O was chosen
as the optimal solvent since the reaction in Et2O led
to complete conversion in 16 h (entry 11, Table 2). In-
terestingly, running the reaction at room temperature
did not show any effect on either the conversion or
the enantioselectivity (entry 12, Table 2). Further
studies on the catalyst loadings disclosed that high re-
action conversion and enantioselectivity were ob-
tained even with 1 mol% of 1h (91% conversion,
92% ee, entry 15, Table 2).
Entry
Catalyst
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
82
69
20
3
85
84
56
82
61
3
45
<1
9
3
2
Several Hantzsch esters have been tested and the
results are summarized in Table 3. Hantzsch ester 2a
was found to be the optimal in terms of both reaction
conversion and ee of the product.
36
66
40
88
70
Table 3. Investigation of Hantzsch esters.
[a]
Reaction conditions: 10 mol% of 1, 140 mol% of 2a, 0.05
mol/L of 3a in toluene at 608C.
Determined by H NMR.
[b]
[c]
1
Determined by chiral HPLC analysis (Chiralcel AD-H).
PMP=para-methoxyphenyl.
Entry[a]
2
Time [h]
Conversion [%][b]
ee [%][c]
Table 2. Screening of solvents.
1
2
3
4
2a
2b
2c
2d
3
3
3
36
6
6
6
91
3
48
92
92
9
73
91
[a]
Reaction conditions: 1 mol% of 1h, 140 mol% of 2, 0.05
mol/L of 3a in Et2O at 258C.
Determined by H NMR.
Entry[a]
X
Solvent
Time Conversion ee
[h]
[mol%]
[%][b]
[%][c]
[b]
[c]
1
Determined by chiral HPLC analysis (Chiralcel AD-H).
1
2
310
4
5
6
7
8
9
10
11
12[d]
13[d]
14[d]
15[d]
10
10
Xylene
10
10
10
10
10
10
10
10
10
5
Toluene
Benzene
48
CHCl3
DCM
Dioxane
THF
AcOEt
t-BuOMe
Bu2O
48
48
82
48
48
48
48
48
3
16
16
20
20
3
82
76
88
89
89
79
61
78
94
91
>95
91
>95
>95
>95
6
91
92
90
91
92
90
89
92
92
93
In presence of 1 mol% of 1h and 1.4 equivs. of 2a,
a variety of a-imino esters have been reduced in Et2O
to examine the reaction scope. The results are sum-
marized in Table 4. The effect of different esters was
first examined. We found that the enantioselectivity
was highly dependent on the steric size of the ester
group. High ees were obtained for the substrates bear-
ing bulky ester groups such as Bn (95% ee), i-Pr
(97% ee) and t-Bu (97% ee), whereas only 33% ee
Et2O
Et2O
Et2O
Et2O
was given for the methyl ester substrate 3b (entries 1–
2
1
93
91
91
1
Et2O
3
6
92
5, Table 4). For the scope of R , several substituted
phenyl isopropyl esters containing either electron-do-
nating or electron-withdrawing groups all led to good
yields and excellent ees (97–98% ee, entries 6–11,
Table 4). In addition, enantiopure 4f was obtained by
one simple recrystallization, and a single crystal X-ray
analysis disclosed its absolute configuration as S.[11]
Asymmetric transfer hydrogenation of 2-naphthyl-
[a]
Reaction conditions: 10 mol% of 1h, 140 mol% of 2a,
0.05 mol/L of 3a in solvent at 608C or under reflux.
Determined by H NMR.
Determined by chiral HPLC analysis (Chiralcel AD-H).
Reaction was carried out at 258C.
[b]
[c]
[d]
1
metric transfer hydrogenation reactions could be car- bearing imino ester 3l afforded the corresponding
ried out smoothly in several conventional solvents amino ester in 93% yield with 98% ee (entry 12,
such as benzene (89% ee), xylene (89% ee), dioxane Table 4). A low reactivity towards the alkyl-substitut-
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Transfer Hydrogenation of a-Imino Esters by a Phosphoric Acid
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Table 4. Asymmetric transfer hydrogenation of a-imino esters and amide 3.[a]
Entry
R1
R2
Product
Yeld [%][b]
ee [%][c]
Configuration
1
2
3
4
5
6
7
8
C6H5 (3a)
C6H5 (3b)
C6H5 (3c)
C6H5 (3d)
OEt
OMe
OBn
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
88
85
86
87
78
92
95
82
90
94
89
9398
46
78
85
92
33
95
97
97
97
98
97
98
97
98
(+)
(+)
(+)
(+)
(+)
S (+)[e]
(+)
(+)
(+)
(+)
(+)
+)
O-i-Pr
O-t-Bu
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
O-i-Pr
NH-t-Bu
C6H5 (3e)
4-BrC6H4 (3f)
4-ClC6H4 (3g)
4-FC6H4 (3h)
4-CH3C6H4 (3i)
4-MeOC6H4 (3j)
3-CH3C6H4 (3k)
2-naphthyl (3l)
cyclohexyl (3m)
thienyl (3n)
C6H5(3o)
A
9
10
11
12
13[f]
14[g]
15
88
84
96
(À)
(+)
(+)
[a]
Reaction conditions: 1 mol% of 1h, 140 mol% of 2a, 0.05 mol/L of 3 in Et2O at room temperature unless noted other-
wise.
Isolated yields.
[b]
[c]
[d]
[e]
[f]
Determined by chiral HPLC.
After one recrystallization.
Determined by single crystal X-ray diffraction analysis.
With 5 mol% of 1h under reflux.
With 5 mol% of 1h.
[g]
ed imino ester was observed. For instance, only 46%
In summary, we have identified chiral phosphoric
yield was obtained for imino ester 3m having a cyclo- acids as highly efficient organocatalysts for the asym-
hexyl group with 88% ee (entry 13, Table 4). It should metric transfer hydrogenation of a-imino esters. The
be noted that thienyl-derived 3n also underwent the advantages include good yields, excellent ees, mild re-
reduction and afforded the desired product in 84% ee action conditions, as well as an operationally simple
(entry 14, Table 4). In addition, substrate 3o with a and environmentally benign procedure. All these fea-
carboxyl amide group is also well tolerated to afford tures together with tolerability of a-imino carboxyla-
the hydrogenated product 4o in 85% yield with 96% mides warrant the wide application of the current
ee (entry 15, Table 4).
methodology for the synthesis of highly enantioen-
To test the practicality of the current method for riched a-amino esters and their derivatives.
the synthesis of a-amino acid derivatives, the asym-
metric transfer hydrogenation of a-imino ester 3d in a
gram-scale was carried out using 0.1 mol% of 1h [Eq.
(1)]. With 140 mol% of Hantzsch ester 2a in Et2O at
Experimental Section
room temperature, a-amino ester 4d was obtained in
85% yield and 96% ee (1.19 g, 4 mmol of 3d).
General Procedure for the Asymmetric Transfer
Hydrogenation of a-Imino Esters
In a dry Schlenk tube, a-imino ester 3 (0.2 mmol) and phos-
phoric acid 1 (0.002 mmol) were dissolved in Et2O (4 mL)
under argon. The solution was stirred for 10 min at room
temperature. Subsequently, Hantzsch ester 2 (0.28 mmol)
was added in one portion. After the reaction was complete
(monitored by TLC), the solvent was removed under re-
duced pressure. The crude product was purified by silica gel
column chromatography (ethyl acetate/petroleum ether=1/
8 to 1/50) to afford the respective a-amino ester 4.
Adv. Synth. Catal. 2007, 349, 1657 – 1660
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Qiang Kang et al.
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Acknowledgements
eyama, Org. Lett. 2001, 3, 313–315; d) R. Kadyrov,
T. H. Riermeier, U. Dingerdissen, V. Tararov, A.
Bçrner, J. Org. Chem. 2003, 68, 4067–4070; for recent
examples for reduction of imines, see: e) C. Moessner,
C. Bolm, Angew. Chem. Int. Ed. 2005, 44, 7564–7567;
f) Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang,
Angew. Chem. Int. Ed. 2006, 45, 3832–3835; g) S.-F.
Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li, Q.-L. Zhou, J. Am.
Chem. Soc. 2006, 128, 12886–12891; h) Y.-Q. Wang, Y.-
G. Zhou, Synlett 2006, 1189–1192.
We gratefully acknowledge the Chinese Academy of Sciences
and the National Natural Science Foundation of China for
generous financial support.
References
[1] a) G. C. Barrett, Chemistry and Biochemistry of the
Amino Acids, Chapman and Hall, London, 1985;
b) R. M. Williams, J. A. Hendrix, Chem. Rev. 1992, 92,
889–917; c) J.-A. Ma, Angew. Chem. Int. Ed. 2003, 42,
4290–4299.
[6] G. Shang, Q. Yang, X. Zhang, Angew. Chem. Int. Ed.
2006, 45, 6360–6362.
[7] Q. Kang, Z.-A. Zhao, S.-L. You, J. Am. Chem. Soc.
2007, 129, 1484–1485.
[8] For reviews: a) S. J. Connon, Angew. Chem. Int. Ed.
2006, 45, 3909–3912; b) T. Akiyama, J. Itoh, K. Fu-
chibe, Adv. Synth. Catal. 2006, 348, 999–1010; for lead-
ing references, see: c) T. Akiyama, J. Itoh, K. Yokota,
K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566–
1568; d) D. Uraguchi, M. Terada, J. Am. Chem. Soc.
2004, 126, 5356–5357.
[9] a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M.
Bolte, Org. Lett. 2005, 7, 3781–3783; b) S. Hofmann,
A. M. Seayad, B. List, Angew. Chem. Int. Ed. 2005, 44,
7424–7426; c) R. I. Storer, D. E. Carrera, Y. Ni,
D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 84–
86; d) S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem.
Soc. 2006, 128, 13074–13075; e) M. Rueping, A. P. An-
tonchick, T. Theissmann, Angew. Chem. Int. Ed. 2006,
45, 3683–3686; f) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. Int. Ed. 2006, 45, 6751–
6755.
[2] Selected reviews: a) H. Grçger, Chem. Rev. 2003, 103,
2795–2827; b) K. Maruoka, T. Ooi, Chem. Rev. 2003,
103, 3013–3028; c) M. J. OꢀDonnell, Acc. Chem. Res.
2004, 37, 506–517; d) B. Lygo, B. I. Andrews, Acc.
Chem. Res. 2004, 37, 518–525.
[3] For reviews, see: a) P. A. Chaloner, M. A. Esteruelas, F.
Jok, L. A. Oro, Homogeneous Hydrogenation, Kluwer,
Dordrecht, 1994; b) J. M. Brown, in: Comprehensive
Asymmetric Catalysis, Vol. 1, (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin, 1999, chap. 5.1;
c) R. Noyori, Asymmetric Catalysis in Organic Synthe-
sis, Wiley, New York, 1994, chap. 2; d) W. Tang, X.
Zhang, Chem. Rev. 2003, 103, 3029–3069; e) H. U.
Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M.
Studer, Adv. Synth. Catal. 2003, 345, 103–151; f) X.
Cui, K. Burgess, Chem. Rev. 2005, 105, 3272–3297;
g) S. Gladiali, E. Alberico, Chem. Soc. Rev. 2006, 35,
226–236.
[10] During the preparation of our manuscript, Antilla and
[4] a) C. A. Townsend, A. M. Brown, J. Am. Chem. Soc.
1983, 105, 913–918; b) J. L. Spencer, E. H. Flynn, R. W.
Roeske, F. Y. Siu, R. R. Chauvette, J. Med. Chem. 1966,
9, 746–750; c) A. V. Rama Rao, M. K. Gurjar, K.
Laxma Reddy, A. S. Rao, Chem. Rev. 1995, 95, 2135–
2167.
[5] a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99,
1069–1094; b) M. J. Burk, J. E. Feaster, J. Am. Chem.
Soc. 1992, 114, 6266–6267; c) H. Abe, H. Amii, K. Un-
co-workers reported
a VAPOL-derived phosphoric
acid-catalyzed reduction of a-imino esters, please see:
G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc. 2007,
129, 5830–5831.
[11] CCDC 643978 contains the supplementary crystallo-
graphic data for 4f. These data can be obtained free of
charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data request/cif.
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Adv. Synth. Catal. 2007, 349, 1657 – 1660