Deracemisation of α-chiral primary amines by a one-pot, two-step cascade reaction catalysed by ω-transaminases

Article abstract of DOI:10.1002/ejoc.200801265

Racemic a-chiral primary amines were deracemised to optically pure amines in up to >99 % conversion and >99 % ee within 48 h. The deracemisation was a result of a stereoinver- sion of one amine enantiomer; the formal stereoinversion was achieved by a one-pot, two-step procedure: in the first step, kinetic resolution of the chiral racemic amine was performed by employing a -transaminase to yield an intermediate ketone and the remaining optically pure amine; in the second step, the ketone intermediate was stereoselectively transformed into the amine by employing alanine as the amine donor and a -transaminase displaying opposite stereopref- erence than the -transaminase in the first step. In the second step, lactate dehydrogenase was used to remove the side product pyruvate to shift the unfavourable reaction equilibrium to the product side. Depending on the order of the en- antiocomplementary enzymes employed in the cascade, the (R), as well as the (S), enantiomer was accessible.

Full text of DOI:10.1002/ejoc.200801265

FULL PAPER
DOI: 10.1002/ejoc.200801265
Deracemisation of α-Chiral Primary Amines by a One-Pot, Two-Step Cascade
Reaction Catalysed by ω-Transaminases
Dominik Koszelewski,[a] Dorina Clay,[a] David Rozzell,[b] and Wolfgang Kroutil*[a]
Dedicated to Kalle Hult on the occasion of his 65th birthday
Keywords: Amines / Deracemisation / Asymmetric catalysis / Biotransformations / Enzymes
Racemic α-chiral primary amines were deracemised to op-
tically pure amines in up to Ͼ99% conversion and Ͼ99%ee
within 48 h. The deracemisation was a result of a stereoinver-
sion of one amine enantiomer; the formal stereoinversion was
achieved by a one-pot, two-step procedure: in the first step,
kinetic resolution of the chiral racemic amine was performed
by employing a ω-transaminase to yield an intermediate
ketone and the remaining optically pure amine; in the second
step, the ketone intermediate was stereoselectively trans-
formed into the amine by employing alanine as the amine
donor and a ω-transaminase displaying opposite stereopref-
erence than the ω-transaminase in the first step. In the sec-
ond step, lactate dehydrogenase was used to remove the side
product pyruvate to shift the unfavourable reaction equilib-
rium to the product side. Depending on the order of the en-
antiocomplementary enzymes employed in the cascade, the
(R), as well as the (S), enantiomer was accessible.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
binding of the (R)-mexiletine to a cardiac sodium channel
and the higher antiarrhythmic activity of this enantio-
mer.[12,13] Consequently, there is a need for efficient meth-
ods to obtain the desired (R) or (S) enantiomer in optically
pure form starting from easily accessible substrates. Resolu-
tion of some of these amines has been carried out by frac-
tional crystallisation or distillation of the diastereomeric
salts,[14,15] chromatographic separation of diastereomeric
amides,[16] microbial hydrolysis of an N-acyl derivative[17–19]
or by enantioselective acylation of racemic amines catalysed
by lipase B from Candida antarctica.[20–22] Furthermore, ω-
transaminases received recently increased attention for (i)
the kinetic resolution of racemic amines and (ii) the asym-
metric amination of the corresponding ketones.[23–34]
Introduction
Optically active amines are required for the preparation
of a broad range of biologically active compounds showing
various pharmacological properties.[1,2] Subsequently, chiral
amines have been used as resolving agents, chiral auxiliaries
and building blocks in the synthesis of neurological, cardio-
vascular, immunological, antihypertensive, anti-infective
and antiemetic drugs.[3] In most cases, the pharmacological
activities of these amines are related to the configuration of
the stereogenic centre.[4,5] For example, (R)-4-phenylbutan-
2-amine (1g) is a precursor of the antihypertensive dileva-
lol,[6] and (S)-sec-butylamine (1b), (S)-1-methoxy-2-propan-
amine (1c) and (S)-1-cyclohexylethylamine (1d) are precur-
sors of inhibitors of tumour necrosis factor-α(TNF-α).[7]
Furthermore, 1-phenyl-1-propylamine (1f) is a precursor of
corticotropin releasing factor type-1 receptor antagonist, a
potent antidepressant agent.[8] Finally, mexiletine (1h) is an
orally effective antiarrhythmic,[9] antimyotonic[10] and anal-
gesic[11] agent in its racemic form and is available for clinical
use as the racemate (Figure 1). Mexiletine undergoes stereo-
selective disposition in vivo associated with the selective
[a] Research Centre Applied Biocatalysis c/o Department of Chem-
istry, Organic and Bioorganic Chemistry, University of Graz
Heinrichstrasse 28, 8010 Graz, Austria
Figure 1. Racemic amines 1a–h chosen for the biocatalytic one-pot,
two-step deracemisation protocol employing two ω-transaminases.
Fax: +43-316-380-9840
E-mail: wolfgang.kroutil@uni-graz.at
[b] Codexis, Inc.,
Additionally, protocols like dynamic kinetic resolution of
amines[35–37] and cyclic deracemisation[38] for the deracemi-
sation of racemic amines to yield optically pure products in
Redwood City, California, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2009, 2289–2292
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Koszelewski, D. Clay, D. Rozzell, W. Kroutil
FULL PAPER
100% yield and Ͼ99%ee have been developed. Because in Table 1. Kinetic resolution of amines 1 catalysed by commercially
available ω-transaminases.
various cases the racemic amine is more readily available
than the corresponding ketone, deracemisation will gain in-
creased attention; for example, the corresponding ketones
of 1d and 1h are not commercially available. Therefore, we
envisaged a two-step, one-pot process as outlined in
Scheme 1 that consists of (i) a kinetic resolution and (ii) a
stereoselective amination. The advantage of this concept is
to avoid the limitation of kinetic resolution (50% conver-
sion) giving quantitative yield of optically pure amine start-
ing with racemic amines.
Entry
Substrate
ATA[a]
c [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
117
117
113
113
114
117
113
114
117
117
113
114
117
113
114
117
113
114
117
113
114
117
113
114
117
113
114
57
50[d]
88
51[d]
86
52
62
58
76
65[e]
79
96
51
50
49
50
51
53
50
48
49
50
93
61
61
60
43
Ͼ99 (S)
94 (S)
Ͼ99 (R)
87 (R)
Ͼ99 (R)
Ͼ99 (S)
Ͼ99 (R)
Ͼ99 (R)
99 (S)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
97 (S)
87 (R)
96 (R)
Results and Discussion
Ͼ99 (S)
Ͼ99 (R)
98 (R)
Ͼ99 (S)
Ͼ99 (R)
Ͼ99 (R)
Ͼ99 (S)
98 (R)
99 (R)
Ͼ99 (S)
35 (R)
Ͼ99 (R)
Ͼ99 (S)
Ͼ99 (R)
29 (R)
For the deracemisation of amines by a two-step process
as outlined in Scheme 1 a kinetic resolution step is required
first, followed by a reductive amination step.
1f
1f
1g
1g
1g
1h
1h
1h
[a] Reaction conditions: amine
1 (50 m), sodium pyruvate
(50 m), ω-transaminase (6 mg), phosphate buffer (100 m, pH
7.0, 1 m PLP), shaking at 30 °C for 24 h. [b] Determined by GC.
[c] Determined by GC analysis on a chiral phase. [d] A 25 m solu-
tion of sodium pyruvate was employed. [e] 30 m.
Scheme 1. One-pot, two-step synthesis procedure towards enantio-
enriched amines employing two ω-transaminases (ω-ATAs) with
opposite stereopreference. Removal of pyruvate was performed by
its reduction employing lactate dehydrogenase (LDH) to shift the
equilibrium to the product side.
quence without separation of intermediate mixtures
(Scheme 1). Shifting the ketone–amine equilibrium to the
Testing first the kinetic resolution for various amines, amine side is a challenge with ω-transaminases, especially
three commercial ω-transaminases (ATA-113, ATA-114 when using an amino acid like alanine as an amino donor,
and ATA-117) were chosen as catalysts (Table 1). The ω- as in this case the equilibrium is on the side of the sub-
transaminases catalysed this reaction efficiently, giving the strates (ketone, alanine) and not on the side of the products
amines with up to Ͼ99%ee (Table 1).
(amine, pyruvate).[23] To shift the equilibrium[29,31] the pyr-
For a number of substrate/enzyme combinations, the for- uvate formed was removed by reduction by using lactate
mal ideal 50% conversion barrier was surpassed, indicating dehydrogenase (LDH) in a coupled reaction system. The
that the ω-transaminases possess for these amines a nonper- stereoselectivity for the reductive amination of the commer-
fect enantioselectivity. For instance, in the case for which a cial ketones was already previously reported.[24]
limiting amount of pyruvate was used, the enantiomeric ex-
The reaction sequence was performed in a way that after
cess at 50% conversion was not perfect (Table 1, Entries 2 the kinetic resolution the second ω-transaminase with op-
and 4). However, because the ketone will be transformed posite stereopreference was added together with the corre-
back to the remaining amine enantiomer in the second step sponding alanine enantiomer. Because the two ω-transami-
of the one-pot transformation, the goal of the first step is nases should also have different stereopreference for the ala-
complete removal of the “wrong” enantiomer. The most im- nine enantiomers, we speculated that this approach should
portant point, however, was that transaminases ATA-113 work. However, as can be seen from the results (Table 2),
and ATA-114 showed (S) preference, whereas ATA-117 dis- the optical purity of the final product was moderate, al-
played (R) preference; thus, enantiocomplementary en- though exclusively amine could be detected in almost all
zymes were available. This is actually the basis for the com- cases. The reason for this was that the ω-transaminases also
plete deracemisation sequence.
accept, to a certain extent, the opposite alanine enantiomer,
Having identified the suitable conditions for the kinetic meaning that the ω-transaminase of the first step also cata-
resolution of the desired amines we turned our attention to lysed the amination reaction although at a reduced rate.
couple the first step (i.e., kinetic resolution) with the stereo- Overall, this led to a diminished ee value. The same was
selective amination to achieve a deracemisation reaction se- observed when DMSO was added in the second step, al-
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Eur. J. Org. Chem. 2009, 2289–2292

Deracemisation of α-Chiral Primary Amines
though DMSO partially inhibited ω-transaminase ATA-
Depending on the order of addition of the ω-transami-
113, whereas the activity of ATA-117 stayed untouched nases, either the (R) or the (S) enantiomer was accessible.
(Table 2, Entries 1 and 3 vs. 2 and 4).
Thus, just by switching the order, the other enantiomer was
obtained.
Table 2. Two-step procedure catalysed by various commercially
available ω-transaminases.
Employing the optimised conditions, a preparative trans-
formation of 50 mg of rac-1d at 20 m substrate concentra-
tion yielded (S)-1d at Ͼ99% conversion after 48 h with
Ͼ99%ee and 92% isolated yield. Transformation of 50 mg
of racemic 1-(2,6-dimethylphenoxy)-2-propanamine (1h) led
to optically pure amine (S)-1h with complete conversion,
Ͼ99%ee and 95% isolated yield.
Entry
Sub-
strate
ATA1/
DMSO
[%vv–1]
c [%][b] ee [%][c]
ATA2[a]
1
2
3
4
5
6
1a
1a
1a
1a
1b
1b
117/113
117/113
113/117
113/117
117/113
117/113
–
10
–
10
–
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
96
77 (S)
75 (S)
29 (R)
56 (R)
88 (S)
86 (S)
10
Conclusions
[a] Order of addition of ω-transaminase; in the case of ATA-117,
-Ala was used in the amination reaction and -Ala was used with
ATA-113 and ATA-114. [b] Determined by GC. [c] Determined by
GC analysis on a chiral phase.
In summary, a one-pot, two-step deracemisation cascade
leading to optically pure pharmacologically relevant amines
through kinetic resolution and subsequent stereoselective
amination catalysed by two enantiocomplementary ω-trans-
aminases was described. The resulting amines were ob-
tained with up to quantitative conversion and excellent
enantioselectivities (up to Ͼ99%ee).
To solve this problem, heat treatment was introduced be-
tween the two steps. Thus, after the kinetic resolution, the
sample was kept at 75 °C for 30 min before the enzyme re-
quired for the second step was added. Although destruction
of the enzyme may lead to an expensive process, this trick
enabled efficient one-pot, two-step deracemisation leading
to optically enriched and even optically pure (R)- or (S)-
amines with very high conversion (Table 3). From all eight
substrates 1a–h only the (S) enantiomer of 1g was obtained
with a low ee value. For all other cases, the ee value was at
least 96% [(R)-1c], otherwise the value was Ͼ99% for both
enantiomers.
Experimental Section
Amines 1a–h and ketones, as well as solvents (DMSO), were pur-
chased from Sigma–Aldrich (Vienna, Austria) or BASF (Ludwigsh-
afen, Germany) and used as received unless otherwise stated. All
chemicals used were of analytical grade. ω-Transaminases ATA-
113, 114 and 117 (transaminase ATA-113, 102907WW,
0.46 Umg–1; transaminase ATA-117, 102907WW, 1.9 Umg–1;
transaminase ATA-114, 1091108MW, 2.7 Umg–1) and lactate dehy-
drogenase mix (LDH, PRM-102, 101807KVP, mixture of lactate
dehydrogenase, glucose dehydrogenase, glucose, NAD+) were ob-
tained from Codexis Inc. One unit of ω-transaminase was defined
as the amount of enzyme that catalyses the formation of 1 µmol
acetophenone from α-methylbenzylamine at pH 9.0 at 22 °C.
Table 3. Two-step procedure with the addition of heat to 75 °C after
the first step catalysed by various commercially available ω-trans-
aminases.
Entry
Substrate
ATA1/ATA2[a]
c [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1f
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
114/117
117/113
113/117
99
82
87
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
62
86
88
60
80
84
82
75
72
Ͼ99
96
Ͼ99
Ͼ99
81
Ͼ99 (S)
Ͼ99 (R)
Ͼ99 (R)
Ͼ99 (S)
98 (R)
Ͼ99 (R)
Ͼ99 (S)
86 (R)
Kinetic Resolution: All biocatalytic reactions were performed at
30 °C for 24 h in sodium phosphate buffer (100 m, pH 7) contain-
ing pyridoxal-5Ј-phosphate monohydrate (1 m) in a 2-mL eppen-
dorf tube. The reaction buffer (1 mL) was mixed with ω-transami-
nase (6 mg) and sodium pyruvate (50 m). The reaction mixture
contained 50 m of corresponding amine 1. The conversion to
ketone 2 was measured by GC chromatography. The reaction was
stopped by adding NaOH (200 µL, 10 ), followed by extraction
with ethyl acetate (600 µL, 2ϫ). Organic phase was dried with an-
hydrous Na2SO4.
9
96 (R)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ͼ99 (S)
Ͼ99 (R)
Ͼ99 (R)
Ͼ99 (S)
Ͼ99 (R)
Ͼ99 (R)
Ͼ99 (S)
97 (R)
Ͼ99 (R)
5 (S)
97 (R)
Ͼ99 (R)
Ͼ99 (S)
Ͼ99 (R)
Analysis of Optical Purity of Products: The enantiomeric excess of
amines 2a–g was analysed by gas chromatography on a chiral phase
after derivatisation to the acetoamides, which was performed by
adding a DMAP and a 20-fold excess of acetic acid anhydride.
Amine 2h was analysed after derivatisation to trifluoroacetamide,
which was performed by adding a 20-fold excess of trifluoroacetic
acid anhydride. After washing with water and drying with anhy-
drous Na2SO4 the ee value of the derivatised compound was mea-
sured.[24,25]
1f
1f
1g
1g
1g
1h
1h
Representative Example for Amination with Heating at 75 °C: After
the kinetic resolution step (24 h), the mixture was kept at 75 °C for
30 min, cooled to room temperature and LDH-mix (40 mg, 1 m
NAD+, glucose, lactate dehydrogenase, glucose dehydrogenase) was
[a] Order of addition of ω-transaminase; in the case of ATA-117,
-Ala was used in the amination reaction and -Ala was used with
ATA-113 and ATA-114. [b] Determined by GC. [c] Determined by
GC analysis on a chiral phase.
Eur. J. Org. Chem. 2009, 2289–2292
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D. Koszelewski, D. Clay, D. Rozzell, W. Kroutil
FULL PAPER
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Received: December 19, 2008
Published Online: April 1, 2009
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