Br?nsted acid catalyzed dynamic kinetic resolution of azlactones for the synthesis of aryl glycine derivatives

Article abstract of DOI:10.1055/s-0030-1259711

The dynamic kinetic resolution of C4-aryl azlactones with alcohols was investigated by employing Br?nsted acid catalysis. The reaction provided an efficient complementary approach to access chiral aryl glycine derivatives with excellent yields (up to 99%)

Full text of DOI:10.1055/s-0030-1259711

992
LETTER
Brønsted Acid Catalyzed Dynamic Kinetic Resolution of Azlactones for the
Synthesis of Aryl Glycine Derivatives
Dynamic
Kinetic
h
R
esolution o
a
f
A
zlacton
o
es for the Synthesis
W
of
A
ryl
G
lycine Deriva
a
tives ng, Hong-Wen Luo, Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of
China, Hefei 230026, P. R. of China
Fax +86(551)3606266; E-mail: gonglz@ustc.edu.cn
Received 30 January 2011
Dedicated to Professors Lin-Xin Dai and Xi-Yan Lu
ent on C4-aryl group of azlactones. Therefore, the devel-
Abstract: The dynamic kinetic resolution of C4-aryl azlactones
opment of new catalytic system for DKR of azlactones is
highly desirable and valuable for the enantioselective syn-
thesis of nonquaternary amino acid derivatives.
with alcohols was investigated by employing Brønsted acid cataly-
sis. The reaction provided an efficient complementary approach to
access chiral aryl glycine derivatives with excellent yields (up to
99%) and enantioselectivities (up to 96% ee).
OH
R1
O
O
Key words: dynamic kinetic resolution, azlactone, aryl glycine,
Brønsted acid, amino acid
O
O
O
R1
Ar
R1
Ar
Ar
N
N
N
II
ent-II
I
Optically enriched a-amino acids and their derivatives are
of great importance in pharmaceutical and biological
chemistry and serve as chiral pool in asymmetric organic
synthesis.1 The increasing demands for these compounds
have prompted organic chemists to develop new synthetic
methodologies.2 The most notable approach to access
these compounds is the transition-metal-catalyzed enantio-
selective hydrogenation of dehydroamino acid deriva-
tives,3 which, however, is principally unable to afford aryl
B*H
fast
B*H
slow
fast
HN
R2OH
R2OH
O
O
O
O
Ar
O
HN
R1
Ar
O
Ar
R1
N
R1
R2
R2
O
O
Scheme 1 Dynamic kinetic resolution of azlactones by asymmetric
glycine derivatives, another important type of amino acids alcoholysis
with widespread applications in organic synthesis as
building blocks.4 As a consequence, the development of
enantioselective catalytic synthesis5 of the aryl glycine
derivatives is of great importance.
Recently, our group11 has established an asymmetric
Brønsted acid catalyzed [4+2] cycloaddition of azlac-
tones, cinnamaldehydes, and primary amines to give dihy-
dropyridinones with high enantioselectivity, but
accompanying the generation of amides as byproducts. In
fact, the Brønsted acid is able to accelerate the amidation
reaction between the azlactones and primary amine. These
observation prompted us to hypothesize that Brønsted ac-
ids would be able to enantioselectively catalyze the DKR
of C4-substituted azlactones with suitable nucleophiles
(Scheme 1). Previous studies revealed that alcohols are
suitable nucleophiles in chiral Brønsted acid catalyzed nu-
cleophilic addition reactions.12 Therefore, we decided to
apply Brønsted acid catalysis13 to the DKR14 of azlactones
by using alcohols as nucleophiles.
The azlactones6 easily tautomerize into enol species of
type I to make the optically pure azlactones undergo race-
mization in the presence of either acid or base catalysts
and thereby rendering the dynamic kinetic resolution
(DKR) possible. Indeed, dynamic kinetic resolution7 of
azlactones proved to be an efficient approach to stereose-
lectively generate nonquaternary amino acid derivatives.
For instance, the enantioselective alcoholysis of azlac-
tones has been fulfilled by enzyme catalysis,8 metal catal-
ysis,9 and organocatalysis as well.10 However, the DKR of
C4-aryl azlactones, which furnishes aryl glycine deriva-
tives, has much less been explored. In 2010, Birman10e re-
ported an elegant work on DKR of azlactones using
enantioselective acyl-transfer reaction and demonstrated
that the benzotetramisole exhibited high catalytic effi-
ciency for the reaction involving C4-aryl azlactones to of-
fer good yields and excellent enantioselectivities.
However, the reaction was sensitive toward the substitu-
The catalytic competence of Brønsted acid in alcoholysis
of azlactones was confirmed by a reaction of 2,5-diphenyl
azlactone with ethanol as a nucleophile, which proceeded
smoothly to yield the ring-opening product. Systematic
studies to find out the suitable azlactones revealed that
both azlactones 1a and 1b with an electronically rich C2-
aryl group were stable and provided relatively higher
enantioselectivities (see Table S1 in Supporting Informa-
tion). Furthermore, both the reactivity and selectivity
were highly sensitive to the alcohol nucleophiles. In par-
ticular, the enantioselectivity actually benefited from ster-
SYNLETT 2011, No. 7, pp 0992–0994
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Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259711; Art ID: W05011ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Dynamic Kinetic Resolution of Azlactones for the Synthesis of Aryl Glycine Derivatives
993
Ar
Table 1 Optimization of Reaction Conditions of DKR of Azlac-
tonesa
O
O
O
Ph
N
O
P
OH
Ar
O
1a Ar = 4-MeOC6H4
Ar
O
catalyst 3 (10 mol%)
3 Å MS (100 mg)
1b Ar = 4-t-BuC6H4
H
Ph
R
3
Ar
N
Ph
+
O
PhMe
Ph
O
Ph
iPr
Ph
Cl
HO
4a Ar = 4-MeOC6H4, R = H
4b Ar = 4-t-BuC6H4, R = H
4c Ar = 4-t-BuC6H4, R = Et
Ph
Si
R
Ph
Ph
2a R = H
2b R = Et
Ar =
i-Pr
i-Pr
Entry
1
Cat.
3a
3b
3c
Product
4a
Temp (°C) Yield (%)b ee (%)c
3a
3d
3e
3b
3c
0
0
99
99
96
95
57
99
99
70
99
99
99
99
99
58
40
38
29
50
75
87
73
91
92
94
95
93
Figure 1 Phosphoric acids evaluated in this study
2
4a
ically bulky alcohols. However, the use of secondary
alcohol led to a significantly slow reaction. Consequently,
a series of b-substituted primary alcohols, which proved
to show high reactivity, were screened as nucleophiles. To
our delight, with diphenylethanol (2a) as the reaction
component, the DKR of azlactone 1a afforded the ring-
opening product 4a in 99% yield and with 58% ee in the
presence of 10 mol% of phosphoric acid 3a (Table 1, en-
try 1). Then, a number of chiral phosphoric acids derived
from BINOL (Figure 1) were evaluated for this model re-
action, but resulting in no improvement in the stereoselec-
tivity (Table 1, entries 2–5). Encouragingly, azlactones
1b reacted with 2a in the presence of 10 mol% 3a to fur-
nish 4b in 99% yield and 75% ee (Table 1, entry 6). Thus,
we turned our attention to tune the structure of alcohol and
found that the use of alcohol 2b was able to afford 4c in
87% ee (Table 1, entry 7).
3
4a
0
4
3d
3e
4a
0
5
4a
0
6
3a
3a
3a
3a
3a
3a
3a
3a
4b
4c
0
7
0
8d
9
4c
0
4c
–20
–30
–30
–40
–30
10
11e
12e
13e,f
4c
4c
4c
4c
a The reaction of azlactones 1 (0.1 mmol) and alcohol 2 (0.12 mmol)
was conducted in the presence of 3 Å MS (100 mg) and catalyst 3 (10
mol%) in PhMe (1 mL).
Subsequently, a survey of reaction parameters, including
solvents, temperature, and catalyst loading, was conduct-
ed to further optimize the reaction conditions. Surprising-
ly, the reaction performed in dichloromethane proceeded
sluggishly to furnish 4c in 70% yield and 73% ee (Table 1,
entry 8). Lowering the temperature led to the enhance-
ment in the enantioselectivity without the erosion of
yields (Table 1, entries 9–12). Significantly, when the re-
action was performed at –30 °C, a high enantioselectivity
of 92% ee was obtained for 4c (Table 1, entry 10). More
interestingly, even higher ee was observed at a lower con-
centration. Thus, the reaction performed at a concentra-
tion of 0.05 M in toluene at –30 °C afforded 4c with 94%
ee (Table 1, entry 11). Notably, the reaction proceeded
smoothly at –40 °C with complete conversion within 48
hours, giving 4c in 99% yield with 95% ee (Table 1, entry
12). Remarkably, the reaction still underwent smoothly in
the presence of 5 mol% 3a to afford high yields and stereo-
selectivity (Table 1, entry 13).
b Isolated yield.
c Determined by HPLC.
d In CH2Cl2.
e Conditions: 2 mL of solvent.
f Conditions: 5 mol% of 3a.
electronic properties of C4-aryl substituent had little ef-
fect on the reaction rate, but the azlactones with electron-
ically rich C4-aryl group provided relatively higher
enantioselectivities (Table 2, entries 1 and 2 vs. entries 3–
5). Although the azlactones with meta- and para-substi-
tuted C4-aryl group gave a slightly slower reaction, they
still provided excellent yields in prolonged reaction time
(Table 2, entries 7 and 8).
In summary, we have disclosed an asymmetric DKR of
azlatones through chiral Brønsted acid catalyzed alcohol-
ysis. The structure of alcohols played an important role in
the stereocontrol. This reaction provides an efficient
asymmetric catalytic method to access aryl glycine deriv-
atives in high optical purity of up 96% ee and thus can be
considered an efficient alternative to known procedures.
A number of C4-aryl-substituted azlactones were investi-
gated to react with 2b under the optimized conditions.
Generally, the reaction proceeded smoothly to generate
aryl glycine derivatives in excellent yields and with high
levels of enantioselectivity (Table 2). The variation of
Synlett 2011, No. 7, 992–994 © Thieme Stuttgart · New York

994
C. Wang et al.
LETTER
Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994, Chap. 2. (c) Tang, W.; Zhang, X. Chem. Rev.
2003, 103, 3029.
Table 2 Scope of Azlactones of the DKR Reactiona
R
N
Ar
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A. S. Chem. Rev. 1995, 95, 2135. (b) Meyer, E. M.;
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105, 913. (d) Spencer, J. L.; Flynn, E. H.; Roeske, R. W.;
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Hendrix, J. A. Chem. Rev. 1992, 92, 889.
O
O
O
5 Ar = 4-t-BuC6H4 catalyst 3a (10 mol%)
H
3 Å MS (100 mg)
Ar
N
+
O
PhMe (2 mL), –30 °C
Ph Ph
O
R
HO
6 Ar = 4-t-BuC6H4
Ph Ph
2b
Entry
R
6
Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
4-MeOC6H4
4-MeC6H4
4-FC6H4
6a
6b
6c
6d
6e
6f
24
24
24
24
24
24
36
48
24
99
95
99
99
97
99
95
95
99
93
95
93
90
92
96
91
93
95
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-ClC6H4
2-ClC6H4
6g
6h
(6) For a review of azlactone chemistry, see: Fisk, J. S.; Mosey,
R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432.
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a The reaction of azlactones 5 (0.1 mmol) and alcohol 2b (0.12 mmol)
was conducted in the presence of 3 Å MS (100 mg) and catalyst 3a
(10 mol%) in PhMe (2 mL) at –30 °C.
b Isolated yield.
c Determined by HPLC.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful for financial support from NSFC (20732006), CAS,
MOST (973 program 2010CB833300) and the Ministry of Educati-
on.
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