An efficient asymmetric biomimetic transamination of α-keto esters to chiral α-amino esters

Article abstract of DOI:10.1021/ol302427d

An efficient asymmetric biomimetic transamination of α-keto esters with quinine derivatives as chiral bases was described. A wide variety of α-amino esters containing various functional groups can be synthesized in high yield and enantioselectivity.

Full text of DOI:10.1021/ol302427d

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5270–5273
An Efficient Asymmetric Biomimetic
Transamination of r‑Keto Esters to Chiral
r‑Amino Esters
Xiao Xiao,† Mao Liu,† Chao Rong,† Fazhen Xue,† Songlei Li,† Ying Xie,† and
Yian Shi*,†,‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China, and Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523, United States
yian@lamar.colostate.edu
Received September 1, 2012
ABSTRACT
An efficient asymmetric biomimetic transamination of R-keto esters with quinine derivatives as chiral bases was described. A wide variety of
R-amino esters containing various functional groups can be synthesized in high yield and enantioselectivity.
Optically active R-amino acids and their derivatives
play crucial roles in biological systems and are important
for drug and food development as well as organic
Scheme 1. Biological Transamination
synthesis.1ꢀ5 In biological systems, transamination of
R-keto acids (1) with pyridoxamine (2)6,7 as an amine
donor catalyzed by transaminase is an important process
to generate R-amino acids (Scheme 1).8 An analogous
† Beijing National Laboratory for Molecular Sciences.
‡ Colorado State University.
(1) For a recent book, see: Amino Acids, Peptides and Proteins in
Organic Chemistry; Hughes, A. B., Ed.; Wiley-VCH: Weinheim, Germany,
2009.
biomimetic transamination with simple chiral catalysts
provides an attractive approach to synthesize optically
active R-amino acids and their derivatives, which has been
challenging and underdeveloped. Earlier, Berg et al.9
reported chiral guanidine catalyzed transamination of
isolated R-ketimine esters with up to 45% ee. Chiral Lewis
acid catalyzed transamination with in situ formation of
(2) For leading reviews on enzymatic synthesis of R-amino acids, see:
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r
10.1021/ol302427d
Published on Web 10/01/2012
2012 American Chemical Society

R-ketimine esters was described by Jørgensen et al.,10 and
up to 46% ee was obtained.11ꢀ13 Recently, we reported
a highly enantioselective biomimetic transamination of
R-keto esters 5 with readily available quinine-derived
compound C1 as the catalyst and o-ClPhCH2NH2 (6) as
the amine donor, giving a wide variety of R-amino esters 7in
47ꢀ71% yield and 88ꢀ92% ee (Scheme 2).14 Studies show
that the 60-OH group and the ether group at the 9 position of
catalyst C1 are very important for the reactivity and
enantioselectivity of the transamination process (Figure 1).
It is likely that the OH group forms a H-bond with the imine
to activate the substrate and influence the stereodifferentia-
tion (Figure 2).14 In efforts to further understand the effect
of the catalyst structure on the transamination and develop
more effective processes, we examined a series of quinine
derivatives15 with different H-bond donors at the 60-position
for the transamination (Figure 3). Herein we wish to report
our preliminary results on this subject.
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Scheme 2. Chiral Base-Catalyzed Biomimetic Transamination
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Figure 1. Quinine derivatives with different H-bond donors.
ꢁ
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Figure 2. Possible transition states for transamination.
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To evaluate the effect of the H-bond donor of the
catalyst on the transamination, several quinine derivatives
containing various nitrogen groups at the 60-position were
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2011, 133, 12914.
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Org. Lett., Vol. 14, No. 20, 2012
5271

Table 1. Studies on Catalysts and Solventsa
entry
cat.
solvent
time (h)
conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
benzene
36
36
36
36
36
36
36
36
36
36
36
36
36
36
60
60
60
60
60
60
60
60
60
60
19
45
12
76
40
43
23
47
25
8
30
32
40
85
81
86
52
59
51
57
68
80
83
68
54
66
59
85
88
85
82
91
86
92
91
93
94
92
85
84
41
70
8
9
C9
10
11
12
13
14
15d
16d
17d
18d
19d
20d
21d
22d
23d
C10
C11
C12
C13
C14
C14
C14
C14
C14
C14
C14
C14
C14
C15
toluene
n-hexane
CHCl3
THF
EtOAc
MeOH
CH3CN
benzene
54
ꢀ91
Figure 3. Selected examples of catalyst examined.
a All reactions were carried out with R-keto ester 5a (0.20 mmol),
o-ClPhCH2NH2 (6) (0.20 mmol), catalyst (0.020 mmol), and 5 Amolecular
sieves (0.020 g) in solvent (4.0 mL) at 50 °C unless otherwise noted. b The
conversion was determined by 1H NMR of the crude reaction mixture
based on R-keto ester and corresponding R-keto imine. c The ee’s were
determined by chiral HPLC (Chiralcel OD-H column) after the amino
esters were converted into their N-benzoyl derivatives. d o-ClPhCH2NH2
(6) (0.60 mmol) and 5 A molecular sieves (0.10 g) were used.
initially synthesized (Figure 3) and tested for the transa-
mination with R-keto ester 5a as the substrate and
o-ClPhCH2NH2 (6) as the amine donor (Table 1). As
shown in Table 1, catalysts with amine (C2), acetylamine
(C3), phosphorylamine (C4), and thiourea (C5)16 gave
lower ee’s than the catalyst with the OH group (C1)14,17
(entries 1ꢀ5). However, comparable enantioselectivity
was obtainedwithcatalystcontaining benzenesulfonamide
(C6) (Table 1, entry 6). Further studies showed that sub-
stituents on the phenyl group of benzenesulfonamide have
a significant effect on the enantioselectivity (Table 1, en-
tries 7ꢀ13), and up to 92% ee was obtained with 2,4,6-
triethylbenzenesulfonamide substituted quinine derivative
C12 (Table 1, entry 12). A slightly higher ee was obtained
by increasing the size of the ether group (Table 1, entries 14
and 15). The reaction conversion increased to 85% by
increasing the amount of o-ClPhCH2NH2 (6) and molec-
ular sieves with a longer reaction time (Table 1, entry 15).
Among various solvents examined, benzene and toluene
gave the highest ee (Table 1, entries 15 and 16). The
quinidine-derived catalyst (C15) gave amino ester product
7a in 80% conversion and 91% ee with the opposite
configuration (Table 1, entry 23).
The generality of the transamination was subsequently
examined with catalyst C14. Substituted 2-oxo-4-phenyl-
butanoates were found to be highly effective substrates,
giving various homophenylalanine derivatives in 84ꢀ91%
yield and 93ꢀ96% ee (Table 2, entries 1ꢀ6). High yields
and ee’s were also obtained for substrates containing other
aromatics such as naphthalene and thiophene (Table 2,
entries 7ꢀ9). When 2-oxo-3-phenylpropanoate was used
as substrate, phenylalanine ester was formed in 81% yield
and 90% ee (Table 2, entry 10). The transamination can be
extended to nonaromatic keto esters, giving amino esters
in 61ꢀ82% yield and 90ꢀ95% ee (Table 2, entries 11ꢀ18).
The side chains of amino esters can be saturated (Table 2,
entries 11ꢀ13) or unsaturated aliphatic groups (Table 2,
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Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra,
H. Angew. Chem., Int. Ed. 2006, 45, 929. (b) Biddle, M. M.; Lin, M.;
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830. (c) Liu, Y.; Sun, B.;
Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418.
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derivatives, see: (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906. (b) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc.
2006, 128, 732. (c) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem.
Commun. 2008, 4360. (d) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.;
Zheng, C.-W.; Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2009, 15, 13299.
(e) Bui, T.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2010,
132, 5574.
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Org. Lett., Vol. 14, No. 20, 2012

Table 2. Catalytic Asymmetric Transamination of R-Keto
Scheme 3
Estersa
entries 14 and 15). Other functional groups such as ester
(Table 2, entry 16) and ethers (Table 2, entries 17 and 18)
are also tolerated under the transamination conditions.
Overall the substrate scope for this transamination is quite
broad. It is worth mentioning that high ee’s can be obtained
for t-Bu keto esters under the current conditions while the
previously reported transamination with compound C1 as
the catalyst requires a sterically larger CEt3 group to obtain
a high ee.14 The t-Bu group has some practical advantages
over the CEt3 group. The transamination was also carried
out on gram scale. Both (R)- and (S)-7a were synthesized in
84% and 80% yield with 94% and 91% ee, respectively, using
catalysts C14 and C15 (Scheme 3). (R)-7a was further con-
verted into N-Fmoc derivative 8a and amino acid hydro-
chloride 9a quantitatively without loss of ee’s (Scheme 3).
In summary, we have found that the H-bond donors
at the 60-position of quinine have a large effect on the
reactivity and enantioselectivity of transamination and
discovered that certain substituted benzenesulfonamide
quinine derivatives are highly effective catalysts for trans-
amination of R-keto esters. A wide variety of R-amino
estershavebeenobtainedin61ꢀ93% yield and 90ꢀ96% ee
with 2,4,6-triethylbenzenesulfonamide substituted quinine
derivative C14 as the catalyst and o-ClPhCH2NH2 (6) as
the amine donor. Optically active R-amino acid derivatives
can also be obtained in gram scale via this transamination.
These studies provide a better understanding of the struc-
tural effect of the catalyst on transamination and new
insights for the development of more effective catalytic
systems for R-keto esters and other carbonyl compounds.
Acknowledgment. We gratefully acknowledge the Na-
tional Basic Research Program of China (973 program,
2010CB833300) and the Chinese Academy of Sciences for
financial support.
a The reactions were carried out with R-keto esters 5 (0.50 mmol),
o-ClPhCH2NH2 (6) (1.50 mmol), catalyst C14 (0.050 mmol), and 5 A
molecular sieves (0.25 g) in dry benzene (10.0 mL for entries 1ꢀ7 and 16,
5.0 mL for entries 8ꢀ15 and 17ꢀ18) at 50 °C for 60 h. b For entries 1 and
2, the absolute configurations (R) were determined by comparing the
optical rotations with reported ones of R-aminio acids after hydrolysis
(ref 18). The absolute configurations of remaining amino esters were
tentativelyproposedbyanalogy. c IsolatedyieldbasedonR-ketoesters5.
d The ee’s were determined by chiral HPLC (Chiralcel OD-H column)
after the amino esters were converted into their N-benzoyl derivatives.
e The reaction time was 72 h.
Supporting Information Available. Experimental proce-
dures, characterization data, data for determination of en-
antiomeric excess, and NMR spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
5273