Asymmetric Transamination of α-Keto Acids Catalyzed by Chiral Pyridoxamines

Article abstract of DOI:10.1021/acs.orglett.6b01714

A new type of novel chiral pyridoxamines 3a-g containing a side chain has been developed. The pyridoxamines displayed catalytic activity and promising enantioselectivity in biomimetic asymmetric transamination of α-keto acids, to give various α-amino acids in 47-90% yields with up to 87% ee's under very mild conditions. An interesting effect of the side chain on enantioselectivity was observed in the reaction.

Full text of DOI:10.1021/acs.orglett.6b01714

Letter
pubs.acs.org/OrgLett
Asymmetric Transamination of α‑Keto Acids Catalyzed by Chiral
Pyridoxamines
Xiaoyu Lan, Chuangan Tao, Xuliang Liu, Aina Zhang, and Baoguo Zhao*
The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai
Normal University, Shanghai 200234, P. R. China
S
* Supporting Information
ABSTRACT: A new type of novel chiral pyridoxamines 3a−g
containing a side chain has been developed. The pyridoxamines
displayed catalytic activity and promising enantioselectivity in
biomimetic asymmetric transamination of α-keto acids, to give various
α-amino acids in 47−90% yields with up to 87% ee’s under very mild
conditions. An interesting effect of the side chain on enantioselectivity
was observed in the reaction.
pyridoxal/pyridoxamine catalysts. In 1984, Breslow and his co-
ransamination of α-keto acids is one of the most
Timportant transformations in biological systems and workers developed a novel chiral pyridoxamine analogue 2
tethered with a side amine arm.6h,i By using stoichiometric
provides various chiral amino acids to sustain the metabolism
of lives.1 Besides the biological significance, enzymatic trans-
chiral pyridoxamine 2 as the amino source, asymmetric
transamination of α-keto acids was realized with excellent
enantioselectivity (up to 92% ee) in the presence of zinc
acetate. Encouraged by this work, we designed and synthesized
a new class of chiral pyridoxamines 3 with a rigid fused five-
membered ring and a chiral side arm for catalytic asymmetric
transamination. Herein, we report our results on the subject.
The studies commenced with the synthesis of chiral
pyridoxamines 3 (Scheme 2). By following a similar method
to Breslow’s,6h the pyridine skeleton was constructed via Diels−
Alder reaction between diethyl maleate 4 and ethoxyoxazole 5.
The pyridine derivative 6 then underwent protection of the
hydroxyl group with benzyl bromide, intramolecular Claisen
condensation, and subsequent decarboxylation to give
cyclopenta[b]pyridine-5-one 7 in good yield. Condensation of
the cyclic ketone 7 with (S)-tert-butylsulfinamide, followed by
reduction with NaBH4, gave a pair of chromatographically
separable diasteroisomers (S,R)-8 and (S,S)-8. The structure
and absolute configuration of compound (S,R)-8 were
confirmed by X-ray analysis (Figure 1). Enantiopure (S,R)-8
was converted to hydroxyl amine 9 by reduction of the ester
group with LiAlH4 and subsequent deprotection with HCl (6
M). Condensation of 9 with a carboxylic acid gave compound
10 with a side amide arm, which was further converted into the
desired chiral pyridoxamines 3 via reaction with diphenyl-
phosphoryl azide (DPPA) and Pd/C-catalyzed hydrogenation.
For compounds 3d−f containing a NH side chain, N-Boc
protected carboxylic acids were used in the condensation with
primary amine 9; thus, an additional step for the deprotection
of the Boc group with an acid was employed in the synthesis of
3 from intermediates 10.
amination also has been broadly applied in industrial synthesis
of pharmaceuticals and fine chemicals.2,3 Imitation of the
biological process, i.e. biomimetic asymmetric transamination,
represents an intriguing method for the synthesis of optically
active amino acids.4,5 Great efforts have been contributed to
this area including pyridoxal/pyridoxamine-based enantioselec-
tive transamination6−11 and chiral bases or acids promoted/
catalyzed asymmetric 1,3-proton transfer of imines.12 Pyridox-
al/pyridoxamine and their phosphates are the coenzymes of
transaminases, serving as the catalytic center in enzymatic
transamination.1 In the absence of enzymes, pyridoxal/
pyridoxamine and their analogues can promote or catalyze
transamination of α-keto acids.5,6 And the structure of the
pyridoxal/pyridoxamine derivatives is remarkably influential
regarding enantioselectivity and activity in the transamination.
Therefore, searching for new chiral pyridoxal/pyridoxamine
catalysts is significant and highly desirable for the development
of the chemistry.13,14
Very recently, we reported a catalytic asymmetric trans-
amination of α-keto acids with pyridoxal 1 bearing an (S)-α,α-
diarylprolinol moiety as the catalyst (Scheme 1), to provide a
series of α-amino acids in 29−85% yields with 53−80% ee’s.11
As a part of further studies on biomimetic asymmetric
transamination, we have been focusing on developing new
Scheme 1. Chiral Pyridoxals 1 and Pyridoxamines 2−3
Received: June 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Chiral Pyridoxamines 3
Table 1. Optimization of Reaction Conditions for the
a
Asymmetric Transamination of α-Keto Acids
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
3a
3b
3c
3d
3e
3f
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH−H2O (9:1)
MeOH
81
39
57
31
48
44
39
27
23
22
19
16
28
40
trace
37
39
38
35
76
12
31
17
22
50
76
74
57
64
53
76
78
76
39
64
54
2
3
4
5
6
7
3g
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
3e
8
9
MeOH−H2O (8:2)
MeOH−H2O (7:3)
MeOH−H2O (6:4)
THF−H2O (7:3)
EtOH/H2O (7:3)
DMF/H2O (7:3)
CHCl3/H2O (7:3)
10
11
12
13
14
15
16
17
d
buffer (pH = 5.0)
16
66
66
80
70
46
36
e
buffer (pH = 7.4)
f
18
MeOH−H2O (7:3)
MeOH−H2O (7:3)
MeOH−H2O (7:3)
MeOH−H2O (7:3)
MeOH−H2O (7:3)
g
19
20
h
21
i
22
a
All the reactions were carried out with α-amino acid 11a (0.10
mmol), 2,2-diphenylglycine 12 (0.10 mmol), catalyst 3 (0.010 mmol
for entries 8−18 and 21−22, 0.020 mmol for entries 1−7 and 19−20)
in solvent (1.0 mL) at room temperature for 3 d unless otherwise
stated. The reaction time was 6 d for entries 19−20 and 2 d for entries
b
c
1−7. Isolated yield based on 11a. Determined by chiral HPLC
analysis of the corresponding methyl ester of the amino acid 13a.
Na2HPO4 0.103 M, citric acid 0.0485 M. Na2HPO4 0.182 M, citric
acid 0.00915 M. The reaction was carried out at 30 °C. The reaction
was carried out at 5 °C. NH4Al(SO4)2 (0.050 mmol) was added.
d
e
f
g
h
i
Zn(OAc)2 (0.0010 mmol) was added.
Figure 1. X-ray structure of compound (S,R)-8.
Moderate enantioselectivity (70% ee) and a good yield (76%)
could be obtained when the transamination was carried out
with 20 mol % of 3e as the catalyst at room temperature for 6
days (Table 1, entry 20). The reaction is heterogeneous at the
outset owing to the low solubility of 2,2-diphenylglycine (12)
in MeOH−H2O (8:2). Compound 12 was gradually consumed
as the reaction proceeded, and most of the white solid
disappeared at the end of the reaction.
Under the established optimal conditions, the substrate
scope was then examined for the catalytic asymmetric
transamination (Scheme 3). Various aliphatic linear (Scheme
3, for 13b−f), aromatic linear (Scheme 3, for 13a and 13g−k),
and γ-substituted (Scheme 3, for 13l−n) α-keto acids could be
smoothly asymmetrically transaminated with 2,2-diphenylgly-
cine (12) in the presence of 20 mol % of the catalyst 3e, to give
the corresponding optically active α-amino acids in 47−90%
yields with 63−87% ee’s. α-Keto acids with a bigger chain
displayed a relatively higher enantioselectivity in the reaction
(Scheme 3, 13d−e vs 13b and 13n vs 13l). 2-Oxopentanedioic
acid (Scheme 3, for 13o) was also transaminated in an 82%
yield under the conditions. The additional carboxylic group
The chiral pyridoxamines 3a−g were then examined in the
asymmetric transamination of α-keto acid 11a with 2,2-
diphenylglycine (12) as the sacrificial amine source (Table
1).15−17 All of the pyridoxamines exhibited catalytic activity for
the transamination (Table 1, entries 1−7). Chiral pyridox-
amines bearing an amine side chain such as 3d−g are more
enantioselective catalysts (Table 1, entries 4−7 vs 1−3). And
pyridoxamine 3e displayed the best performance in terms of
enantioselectivity and activity in the transamination (Table 1,
entry 5). Water has an obvious impact on the transamination
(Table 1, entries 8−11). A mixed MeOH−H2O (7:3) was
chosen as the solvent (Table 1, entries 10 and 12−15). A buffer
system such as Na2HPO4−citric acid buffer did not help to
improve the activity and enantioselectivity for the trans-
amination (Table 1, entries 16 and 17). A high temperature
(30 °C) led to a decrease of enantioselectivity (Table 1, entry
18), while a low temperature (5 °C) resulted in a remarkable
loss of activity (Table 1, entry 19). Lewis acid additives such as
NH4Al(SO4)2 and Zn(OAc)2 led to an obvious negative effect
on enantioselectivity and activity (Table 1, entries 21 and 22).
B
DOI: 10.1021/acs.orglett.6b01714
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Organic Letters
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Scheme 3. Substrate Screening for the Asymmetric
Transamination of α-Keto Acids
Scheme 4. Proposed Mechanistic Pathway for the
Pyridoxamine-Catalyzed Transamination
a
pyridoxamine 3e as the catalyst, various α-keto acids were
asymmetrically transaminated with 2,2-diphenylglycine (12) as
the amine source under very mild conditions to give
biologically and chemically important α-amino acids in 47−
90% yields with 63−87% ee’s. An interesting effect of the chiral
side chain on enantioselectivity was observed in the asymmetric
transamination. Further studies on detailed mechanisms and
developing a more efficient catalytic process are underway.
a
All reactions were carried out with α-keto acids 11 (0.10 mmol), 2,2-
diphenylglycine 12 (0.10 mmol), catalyst 3e (0.020 mmol) in
MeOH−H2O (7:3, 1.0 mL) at room temperature for 6 d unless
otherwise stated. For 13b−c, 13j, 13l−m, and 13o, the reactions were
carried out in a double scale. For 13b and 13k, the reactions were
carried out for 5 d. The isolated yields were based on α-keto acids 11.
The ee’s were determined by chiral HPLC analysis after the amino
acids were converted into the corresponding methyl ester for 13a and
N-benzoyl-protected methyl esters for 13b−o. The absolute
configurations of 13b, 13j, and 13o were assigned as R by comparison
of their optical rotations with the reported ones (ref 18). The absolute
configurations of other amino acids were tentatively proposed by
analog.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01714.
Procedures for synthesis of compounds 3 and trans-
amination of α-keto acids, characterization data, and X-
ray data and NMR spectra along with HPLC chromato-
grams (PDF)
seems to have little influence on the reactivity, but caused a
dramatic decrease of the enantioselectivity.
Crystallographic data for (S,R)-8 (CIF)
A plausible mechanistic pathway has been proposed for the
transamination (Scheme 4).5b,11 The pyridoxamine 3 con-
denses with α-keto acid 11 to form a Schiff base 15. The
ketimine 15 undergoes an asymmetric 1,3-proton transfer via a
delocalized azaallylanion 16 to give an aldimine 17, which is
further hydrolyzed to the amino acid product 13 and the
corresponding chiral pyridoxal 18. The pyridoxal 18 is then
reconverted to the pyridoxamine 3 by condensation with the
amine source 12 to form Schiff base 19, decarboxylation of
compound 19 generates azaallylanion 20,19 and protonation of
the anion 20 occurs at the pyridine-4-ylmethenyl carbon,
followed by subsequent hydrolysis of the ketimine 21, finishing
a catalytic cycle for the transamination.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhaobg2006@hotmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21272158,
21472125) and the Program for New Century Excellent
Talents in University (NCET-12-1054). And we also thank
Professor Hongchao Guo for providing chiral starting materials
(synthesized in the National Key Technologies R&D Program
of China, 2015BAK45B01, CAU).
In summary, a class of new chiral pyridoxamines 3a−g
bearing a side chain has been developed from diethyl maleate 4
and ethoxyoxazole 5 via multiple steps. In the presence of the
C
DOI: 10.1021/acs.orglett.6b01714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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