Bio-inspired enantioselective full transamination using readily available cyclodextrin

Article abstract of DOI:10.1039/c6ra27525g

The mimics of vitamin B₆-dependent enzymes that catalyzed an enantioselective full transamination in the pure aqueous phase have been realized for the first time through the establishment of a new “pyridoxal 5′-phosphate (PLP) catalyzed non-covalent cyclodextrin (CD)-keto acid inclusion complexes” system, and various optically active amino acids have been obtained.

Full text of DOI:10.1039/c6ra27525g

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Bio-inspired enantioselective full transamination
using readily available cyclodextrin†‡
Cite this: RSC Adv., 2017, 7, 4203
a
b
b
a
a
a
*
Shiqi Zhang, Guangxun Li, Hongxin Liu, Yingwei Wang, Yuan Cao, Gang Zhao
b
*
and Zhuo Tang
Received 29th November 2016
Accepted 20th December 2016
The mimics of vitamin B6-dependent enzymes that catalyzed an enantioselective full transamination in the
pure aqueous phase have been realized for the first time through the establishment of a new “pyridoxal 50-
phosphate (PLP) catalyzed non-covalent cyclodextrin (CD)-keto acid inclusion complexes” system, and
various optically active amino acids have been obtained.
DOI: 10.1039/c6ra27525g
www.rsc.org/advances
Amino acids play important roles in almost all biological enantioselectivity was obtained in half-transamination, attrib-
processes, and most of them are synthesized through trans- uted to the binding of the phenyl group in the b-CD cavity.18,19
amination in the cell, which is promoted by transaminase (also Well-designed bifunctionalized cyclodextrins5,20,21 consisting of
known as amino acid aminotransferase).1 Transaminase is two cooperating units, a modied B6 coenzyme grouping, and
a
pyridoxal-50-phosphate-dependent enzyme that catalyzes an amino apoenzyme grouping (Fig. 2A, 5d), showed remark-
aminotransferation from an amino acid (1) to a prochiral a-keto able enantioselectivity in half-transamination, generating
acid (3) with the assistance of its unique structure generating phenylalanine (Phe) with up to 96% ee's in MeOH. Employing
the corresponding new chiral amino acid (4), as shown in disubstituted glycine as a sacricial amine source instead of
Fig. 1.2,3 Moreover, the original amino acid (1) is converted into a monosubstituted a-amino acid, record turnover numbers (up
the corresponding a-keto acid (2).
to 100 turnovers) were obtained for the oxidative decarboxyl-
Inspired by biological transamination, extensive studies ation process with polyethylenimine (PEI) derivatives as enzyme
have been conducted to mimic this process for the purpose mimics. Breslow and coworkers22 for the rst time realized the
of obtaining optically active amino acids in an environmen- non-enzymatic biomimic of the full transamination (Fig. 2B).
tally friendly method since the 1970s.4–8 Various strategies Taking advantage of the abovementioned ndings, the rst
have been designed, which mainly focused on the enantiose- chiral-pyridoxal-catalyzed asymmetric biomimetic trans-
lective half-transamination,8–14 whereas rarely on the full amination was achieved by the Zhao's group23 last year, where
transamination.
the chiral pyridoxal-diarylprolinol derivatives (Fig. 2B, 5f) were
In prior research studies, addition of different Lewis acids applied as catalysts in a mixed system of THF and H2O (7 : 3)
(including copper, iron, aluminum, silver, indium, and zinc
salts)8–14 to form chiral metal complexes with chiral ligands
(L*)11–14 (Fig. 2A, M–L*) or chiral pyridoxamine (PM) deriva-
tives5,8,15,16 (Fig. 2A, 5b), and application of various chiral pyri-
doxamine analogues through bounding with chiral basic
side chains (Fig. 2A, 5c) or b-cyclodextrin (b-CD) (Fig. 2A, 5d)
without metal ions were two most common strategies in
the half-transamination reaction. Since the 1980s, various
cyclodextrin-pyridoxamine articial enzymes have been
designed by covalently linking pyridoxamine with b-cyclodex-
trin at primary17 or secondary7 edges, and moderate
aSchool of Chemical Engineering, Sichuan University, Sichuan 610065, China. E-mail:
gzhao@scu.edu.cn
bNatural Products Research Center, Chengdu Institution of Biology, Chinese Academy
of Science, Chengdu, Sichuan 610041, China. E-mail: tangzhuo@cib.ac.cn
† This paper is dedicated to Prof. Thomas C. W. Mak on the occasion of his 80th
birthday.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra27525g
Fig. 1 Biological transamination of a-keto acids.
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(Fig. 2B). However, to date, enantioselective full transamination hours, a new spot with a strong uorescence intensity could be
in the pure aqueous phase has not been realized. detected by TLC, which had been identied by NMR to be
Based on previous research, the bottlenecks of mimicking benzophenone (as the oxidative decarboxylation byproduct)
the enantioselective full transamination in the pure aqueous (Fig. S1‡), and phenylalanine was obtained in 7% yields with
phase could be summarized as follows: (1) the creation of a local 12% ee's (Table S1‡). When EDTA was added to the model
hydrophobic region to mimic the hydrophobic interaction system to further block the effect of any possible metal
between transaminase and substrates. Moreover, the whole ion contaminants, the enantioselectivity was dramatically
process of transamination should take place in a less than enhanced with a slower reaction rate (Table 1, entry 1), which
a fully aqueous environment,24,25 (2) the selection of a suitable could be explained by the addition of EDTA that eliminated the
amine source to improve the relatively low turnovers of the possible acceleration of the transamination by trace metals in
entire cycle, which is composed of two reversible half- the buffer.12–14 Thus, EDTA was added to the system as an
transamination processes, and (3) the introduction of an additive in the following reactions. To obtain a higher yield,
appropriate chiral source to realize the enantioselectivity of the prolonging the reaction time was considered; however, aer 36
products, and the crux of this is how to ensure the matching hours, no signicant increase in yield was found with a slight
degree of a chiral source and the substrates. As shown, there are decrease of ee probably due to the partial racemization of the
still plenty of unsolved problems. As a result, mimicking the product, for details see the ESI (Table S1).‡ Then, we studied the
enantioselective full transamination in the pure aqueous phase inuence of temperature by varying the reaction temperature in
is extremely challenging and meaningful; therefore, we con- controlled trials. The results showed that temperatures that
ducted a series of studies.
were too high or too low disfavored the reaction (Table S2‡), so
ꢀ
Inspired by Breslow's studies about employing a modied 50 C was chosen as the nal temperature.
vitamin B6-b-CD (5d) as the articial pyridoxamine enzyme for
Next, we studied the effects of the buffer on this trans-
the asymmetry half-transamination20 (Fig. 2A) and designing amination reaction (Table 1, entries 1–6 and Table S3‡).
a non-covalent PEI/PM system22 (Fig. 2B), we considered using Examination of various buffers (Table 1, entries 1–3 and Table
well-dened commercially available b-CD instead of PEIs, S3‡) indicated that the transamination worked better in
whose structures are poorly dened to develop a non-bond nitrogen-based buffers, such as Tris, MOPS, HEPES, and EDTA,
system for a better transaminase mimic, due to the chirality than others and Tris provided the best yield and enantiose-
and inclusion property of CD. Furthermore, 2,2-disubstituted lectivity, which could be possibly explained by general acid-base
glycines22,26 were applied as a sacricial amine source instead of catalysis mimicking of the transaminase's lysine amino group
monosubstituted a-amino acids to improve the turnovers of the (Fig. 1).8,13,30 Tris buffer is also well-known for the ability of
process by oxidative decarboxylation (Table 1). To realize the absorbing CO2, as the byproduct of oxidative decarboxylation;
mimic of vitamin B6-dependent enzymes to catalyze the enan- so, a higher concentration resulted in better promotion of the
tioselective full transamination in the pure aqueous phase, we full-transamination (Table 1, entries 1, 4 and Table S3‡). The
developed a new non-bond system, which is easy to obtain with behavior of the system at different pH-values was also evalu-
inexpensive raw materials.
ated, which showed an obvious pH-dependence. When the pH
Our initial studies started with phenylpyruvic acid (3a) as value exceeded 8, the enantioselectivity was improved at the
a substrate, diphenylglycine (7a) as an amine donor, 1.2 equiv. expense of yield (Table 1, entries 1, 5–6 and Table S3‡). Inte-
of b-CD for chiral induction, and PLP as a catalyst at a concen- grating both ee and yield, 300 mM pH 8.0 Tris buffer was
tration of 2.5 mM in 300 mM various weak basic buffer solu- selected as the optimum condition.
tions. When the reaction mixture was stirred at 50 ꢀC for 24
Subsequently, we studied the relationship between the
reaction results and the dosage of PLP. The ee and yield showed
the opposite changes. Upon the addition of increasing amounts
of the catalyst, the yield increased, whereas the ee decreased
(Table S4‡). Aer this, the impact of the types of CD's on the
transamination was also investigated by varying the chiral
pocket size of the CD from six D-glucopyranose units to eight or
enhancement of its water solubility (Table 1, entries 1, 7–8 and
Table S5‡). a-CD consisting of six glucose units yielded chiral
phenylalanine with 20% ee's, smaller a-CD with only 5% ee's
and extremely low yield (Table 1, entry 7), bigger g-CD and
better water solubility HP-b-CD yielded a racemic product that is
same as in the reaction without chiral induction (b-CD) (Table 1,
entry 8 and Table S5‡), which indirectly proved that a b-CD
inclusion complex might be formed, leading to the enantiose-
lectivity results. When we studied the different dosage of b-CD,
0.06 mmol (1.2 equiv.) was still chosen as the appropriate
amount of b-CD considering both the enantioselectivity and
Fig. 2 Vitamin B6-based biomimetic asymmetric transamination.
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Table 1 Optimization for PLP-catalyzed asymmetric transamination of phenylpyruvic acid with the assistance of CDa
Entry
7
Buffer
CD
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
7a (R2: Ph, M: H)
7a
7a
7a
7a
7a
7a
7a
Tris buffer
b-CD
b-CD
b-CD
b-CD
b-CD
b-CD
a-CD
g-CD
b-CD
b-CD
9
4
5
6
1
3
2
2
20
16
9
17
8
24
5
0
Carbonic acid buffer
Phosphate buffer
Tris bufferd
Tris buffere
Tris bufferf
Tris buffer
Tris buffer
Tris buffer
7b (R2: Me, M: H)
11
27
19
20
7c (R2: Ph, M: Na+)
Tris buffer
a
All reactions were carried out with phenylpyruvic acid (3a) (0.05 mmol), diphenylglycine (7) (0.05 mmol), CD (0.06 mmol), EDTA (0.01 mmol), and
PLP (0.01 mmol) in 300 mM Tris buffer (4.0 mL), pH 8.0, at 50 ꢀC for 36 h. b The yield was determined by chiral HPLC through the standard addition
c
method27,28 (Table S1). The ee's were determined by chiral HPLC (Chiralpak AD-H column) aer the amines were converted into their N-Bz
d
derivatives.29 The absolute conguration of 4a was assigned as S by comparison with the standard product. 150 mM Tris buffer, pH 8.0.
e
f
300 mM Tris buffer, pH 7.0. 300 mM Tris buffer, pH 9.0.
yield. A lower yield was obtained despite a slight increase in ee transamination. In general, 4-phenylpyruvic acid with electron-
when the dosage exceeded 0.06 mmol (Table S5‡). donating groups (methoxy (4b) and methyl (4e)) was more
Based on the status of the low yield, the poor solubility of the effective than those with electron-withdrawing groups (4f). para-
sacricial amine source was considered as one of the possible
reasons; thus, various amine sources with different amounts
Table 2 Substrate screening for the asymmetric transamination of
a-keto acidsa
were examined in this system (Table 1, entries 1, 9–10 and Table
S6‡). The result of (ꢁ) methylphenylglycine (Table 1, entry 9)
was almost the same as diphenylglycine, both of which under-
went oxidative decarboxylation in the transamination. When
diphenylglycine was made into its alkali metal salts including
lithium (Table S6‡), sodium (Table 1, entry 10), and potassium
(Table S6‡), higher yields without loss of ee were obtained.
However, the reaction was not affected by the amount of sodium
diphenylglycine, and the same results were achieved when
4 equiv. or 1 equiv. of amine source were used (Table S6‡),
which indicated that the second half-transamination was the
rate-determining step. Therefore, the optimal reaction condi-
tions were phenylpyruvic acid (1) (0.05 mmol), sodium diphe-
nylglycine (7c) (0.05 mmol), b-CD (0.06 mmol), EDTA (0.01
mmol), and PLP (0.01 mmol) in 300 mM Tris buffer (4.0 mL), pH
ꢀ
8.0, at 50 C stirred for 36 h. Phenylpyruvic acid was obtained
with 20% ee's and in 27% yield.
Under the optimal conditions, the substrate scope was then
examined with a series of pyruvic acid derivatives, and the
results are shown in Table 2. A series of analogs of pyruvic acids
were synthesized following a modied method reported in
literature,31 in which the corresponding aldehydes were
condensed with hydantoin with ethanolamine as catalyst, and
were then hydrolyzed under alkaline conditions (Fig. S1‡).
Results showed that the electronic and steric effects of the
phenyl substituent of phenylpyruvic acids had signicant
impacts on the reactivity and enantioselectivity of the
a
All reactions were carried out with a-keto acid (3) (0.05 mmol), sodium
diphenylglycine (7c) (0.05 mmol), b-CD (0.06 mmol), EDTA (0.01 mmol),
and PLP (0.01 mmol) in 300 mM Tris buffer (4.0 mL), pH 8.0, at 50 ꢀC for
36 h or 72 h. The ee's were determined by chiral HPLC analysis aer the
a-amino acids were converted into the corresponding N-benzoyl
derivatives29 for 4a, 4d, 4e, 4g, 4i, 4k, 4l, and 4o or N-Fmoc
derivatives32 for the rest of them. The absolute congurations of 4b–
4o were tentatively proposed by the analogue. The yield was
determined by chiral HPLC through the standard addition method.27,28
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Substituted substrates including methoxy (4b) and methyl (4e)
all exhibited better enantioselectivity than that of the phenyl-
pyruvic acid, yet the highly electron-decient system (4f) was
ineffective with less than 3% product obtained even in an
increased temperature and with a prolonged reaction time.
Halogens (4i, 4j, 4k) also exhibited good enantioselectivity and
activity as a special case for the common effect of both the
negative inductive effect and the electron donating conjugative
effect. We attributed the three different results to the combined
effects of the inductive effect, conjugation, and the size of the
three halogens, which could affect the matching degree of the
guest (the a-keto acid) host (the b-CD cavity) molecules, which
further inuenced the yield and ee. When the substituted group
was replaced by a hydroxyl group (4h), tyrosine was obtained
with 16% ee's. This relatively poor result could be explained by
the hydrogen bonding between the keto acid and hydroxyl
group of b-CD. In addition, it was easy to nd that the position
of the substituent had a major impact on the reaction, where
the para-substitution showed the highest selectivity, meta
second, and ortho gave the racemic product (4b–4d). The
disubstituted substrate (4g) gave the corresponding a-amino
acid with no ee probably because it was too sterically bulky for
this system. When the phenyl ring was replaced by thiophene
(4l), 14% ee's were obtained. However, with the shortening of
carbon chain (4m), almost no enantioselectivity was observed,
which is the same as that for pyruvic acid (4n), but a low ee
could be achieved with the increase of the aliphatic chain (4o),
likely due to the matching between the substrates and the
cyclodextrin cavity during chirality induction.
It appeared that the enantioselectivity was primarily inu-
enced by the a-keto acid moiety, very little by the amine sources,
and the type of CD also greatly inuenced the results. To further
understand the mechanism of transamination and how b-CD
works as the only chiral source in the whole process, several
control experiments were designed, and 4-uorophenylpyruvic
acid (4i) was chosen as the substrate for the studies because of
its good performance in the reaction process. The binding
experiments were designed as follows: 4-uorophenylpyruric
acid (4i) and sodium diphenylglycine (7c) were respectively
added to the b-CD Tris buffer solution (D2O was applied to
replacꢀe H2O) and the resulting mixtures were stirred overnight
at 50 C. Nuclear magnetic resonance (NMR) analysis showed
that only 4-uorophenylpyruvic acid could form the b-CD
inclusion complexes, resulting in an upeld shi of H3 and
downeld shi of H5 on the 1H NMR spectrum33 (Fig. 3B), since
the magnetic screening environment of aromatic molecule34. To
gain more information about the conformational geometry in
the complex, a NOESY experiment was employed to study the
inclusion complex.35 The contour map expansion for a 1 : 1
molar ratio of 4-uorophenylpyruric acid/b-CD is presented in
Fig. 3C. As shown in Fig. 3C (top), cross peak correlation
between the aromatic hydrogen atoms of 4-uorophenylpyruric
acid (K-Aro H) and the internal (H3 and H5) protons of the b-CD
molecule was observed, which is in agreement with the 1H NMR
results. In Fig. 3C (bottom), cross-peak correlation between the
benzyl hydrogen in 4-uorophenylpyruric acid (K–H30) and
protons of b-CD showed that the benzyl hydrogens were
Fig. 3 NMR study of the inclusion of 4-fluorophenylpyruric acid in b-
CD. (A) Possible conformational geometry of 4-fluorophenylpyruric
acid-b-CD inclusion complex. (B) 1H NMR solution spectra of b-CD
solution (top), complex of 4-fluorophenylpyruric acid with b-CD
solution (bottom), (0.02 M) in Tris buffer (pH ¼ 8.0, D2O). (C) Partial
contour plot of the 400 MHz NOESY spectrum for the binding of 4-
fluorophenylpyruric acid (50 mM) to b-CD (50 mM) in Tris buffer (pH ¼
8.0, D2O).
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correlated with H5 and not with H3, suggesting that the chain of hydrogen transfer in the presence of b-CD. Hydrolysis of 12 gave
4-uorophenylpyruric acid was in close proximity to the the chiral amino acid 4i and regenerated PLP, nishing a whole
secondary rim of the cyclodextrin (the wider side, Fig. 3A).
catalytic cycle of the transamination. The key step for the whole
The same conclusion was drawn from the control experi- process is regarded as the stereoselective protonation of keti-
ments (Table S7‡) when the catalyst and the amine source were mine 11 at the a-C of the carboxyl group affording the optically
added to the reaction system containing the well prepared active aldimine 12. Therefore, the formation of the inclusion
4-uorophenylpyruric acid-b-CD inclusion complex. About a 9% complexes is particularly important.
higher ee could been obtained than the one-pot method
To summarize, mimicking the enantioselective biological
obtaining 4-uorophenylalanine with 44% ee's, which indirectly full transamination in the pure aqueous phase has been real-
indicated that the self-assembly of phenylpyruvic acid deriva- ized for the rst time by establishing a new “PLP catalyzed CD-
tives and b-CD resulted in the enantioselectivity of the trans- keto acid inclusion complexes” system. Readily available b-CD
amination. As for the at enantioselectivity of the reaction, was added to the system as a well-dened macromolecular
which could be explained as the strong competition between transaminase model, successfully self-assembly with the a-keto
the enclosed keto acid and the free one with the amine source, acid forming the inclusion complex, which closely mimicked
the latter one reacted out of the cavity, leading to the racemic the real transaminase as a non-covalent complex formed from
products. Under the improved conditions, increasing the the pyridoxamine cofactor and the enzyme protein. Through
amount of b-CD could obtain up to 50% ee's due to the a series of optimization experiments, various optically active
improvement of the inclusive rate (Table S7‡).
a-amino acids were obtained up to 42% yields with up to 50%
All of the abovementioned evidence pointed to the conclu- ee's under mild conditions. The 1H NMR study showed that the
sion that the enantioselectivity of the product was induced by possible mechanism of this enantioselective transamination
the chirality of b-CD, and the inclusion complex was formed by could be explained by the a-keto acid reversibly binding into the
the self-assembly of keto acid and b-CD. This was in good chiral b-cyclodextrin. While a precise understanding of the
agreement with the phenomenon, as shown in Table 2, that the origin of the enantioselectivity still awaited further study, the ee
different enantioselectivity and activity of the keto acid was and yield of the product remained to be improved probably by
positively correlated with the difficulty and stability of the application of different modied cyclodextrins. However, note
formation of the inclusion complexes.36 Also, the previous that the successful mimicking of this enantioselective trans-
assumptions about the substituent position (4b–4d) and the amination process using b-CD encourage us to make more
substrate size (4a, 4g, 4l, 4n, and 4o) were veried.
attempts to utilize various chiral cavity macromolecules for
Therefore, a plausible catalytic cycle of this enantioselective enantioselective biological processes.
full transamination could be considered as the composition
of two half-transaminations, and b-CD only played a role in the
second part for chiral induction. The rst half-transamination
started with the condensation of PLP with 7a to form aldi-
Notes and references
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afforded PMP and the byproduct benzophenone 8. Then, PMP
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as shown in Fig. 4, to form ketimine 11. The product 11 iso-
merized to optically active aldimine 12 via an asymmetric 1,3
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