Dynamic kinetic resolution of 2-phenylpropanal derivatives to yield β-chiral primary amines via bioamination

Article abstract of DOI:10.1002/adsc.201400217

The amination of racemic α-chiral aldehydes, 2-phenylpropanal derivatives, was investigated employing ω-transaminases. By medium and substrate engineering the optical purity of the resulting β-chiral chiral amine could be enhanced to reach optical purities up to 99% ee. Using enantiocomplementary ω-transaminases allowed us to access the (R)- as well as the (S)-enantiomer in most cases. It is important to note that the stereopreference of the ω-transaminases found for α-chiral aldehydes did not correlate with the stereopreference previously observed for the amination of methyl ketones. In one case the stereopreference switched even upon exchanging a methyl substituent to a methoxy group.

Full text of DOI:10.1002/adsc.201400217

FULL PAPERS
DOI: 10.1002/adsc.201400217
Dynamic Kinetic Resolution of 2-Phenylpropanal Derivatives to
Yield b-Chiral Primary Amines via Bioamination
Christine S. Fuchs,a Manuel Hollauf,b Maximilian Meissner,b Robert C. Simon,a,b
Tatiana Besset,c,d Joost N. H. Reek,c Waander Riethorst,e Ferdinand Zepeck,e
and Wolfgang Kroutilb,*
a
Austrian Centre of Industrial Biotechnology ACIB GmbH, c/o Heinrichstrasse 28, 8010 Graz, Austria
Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
b
Fax : (+43)-316-380-9840, phone: (+43)-316-380-5350; e-mail: wolfgang.kroutil@uni-graz.at
University of Amsterdam, Science Park 904, Amsterdam, The Netherlands
Current address: UMR 6041-CNRS COBRA, Universitꢀ de Rouen, 76821 Mont Saint Aignan, Cedex, France
Sandoz GmbH, Biocatalysis Lab, Biochemiestraße 10, 6250 Kundl, Austria
c
d
e
Received: February 27, 2014; Published online: June 4, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400217.
Abstract: The amination of racemic a-chiral alde- transaminases found for a-chiral aldehydes did not
hydes, 2-phenylpropanal derivatives, was investigated correlate with the stereopreference previously ob-
employing w-transaminases. By medium and sub- served for the amination of methyl ketones. In one
strate engineering the optical purity of the resulting case the stereopreference switched even upon ex-
b-chiral chiral amine could be enhanced to reach op- changing a methyl substituent to a methoxy group.
tical purities up to 99% ee. Using enantiocomple-
mentary w-transaminases allowed us to access the
(R)- as well as the (S)-enantiomer in most cases. It is Keywords: amines; asymmetric catalysis; biotransfor-
important to note that the stereopreference of the w- mations; transaminases; b-chiral amines
Introduction
ported not exceeding in general 60% ee;[2a] for only
one designated substrate a de of 98% was reported
w-Transaminases (w-TAs)[1] have been shown to be using commercial enzymes.
versatile catalysts for the preparation of optically
Using w-TAs with reported amino acid sequences,
pure a-chiral amines[2] from the corresponding ke- we investigated the influence of the substitution pat-
tones via asymmetric reductive amination. The poten- tern of 2-phenylpropanal derivatives on the chiral rec-
tial of these biocatalysts has also been appreciated by ognition in the stereoselective amination. The envis-
the pharmaceutical industry.[3,4] The enzymes are aged 2-phenyl-1-propylamine derivatives are de-
mainly employed for the asymmetric amination of ke- scribed as bioactive compounds or/and are building
tones[1,2,4] and to a lesser extent for the transformation blocks for pharmaceuticals.[8]
of non-chiral aldehydes to prepare terminal amines.[5]
To the best of our knowledge there are only two re-
ports focusing on the amination of a-chiral aldehydes Results and Discussion
to access b-chiral terminal amines in enantioenriched
form via dynamic kinetic resolution (DKR) using Racemic 2-phenylpropanal derivatives rac-2a–g were
commercial enzymes. The first example concerns prepared by hydroformylation of readily available sty-
a GABA analogue which was obtained with moderate rene derivatives 1a–g using
a rhodium catalyst
stereoselectivity [max. 45% ee (S)- and 68% ee (R)-4- (Scheme 1).[9] The desired a-chiral aldehydes rac-2a–g
phenylpyrrolidin-2-one],[6] and the second deals with were obtained in 43 to 72% yield.
the synthesis of the potential anti-tumour agent nira-
Since substrates 2 are racemates, the stereoselective
amination reaction would lead to a kinetic resolution,
parib, reaching >99% ee.[7]
For the amination of a-chiral ketones only very low which is limited by 50% yield. However, the a-chiral
chiral recognition of the a-chiral centre has been re- aldehydes rac-2a–g racemise spontaneously in buffer
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Christine S. Fuchs et al.
Table 1. Bioamination of racemic 2-phenylpropanal 2a.[a]
w-TA
Conv.[b] [%] 4a[b] [%] 3a[b] [%] ee 3a[c] [%]
PP1-w-TA 73
PP2-w-TA 75
ArS-w-TA 59
ArR-w-TA 65
6
3
67
72
58
64
46
54
83 (R)
78 (R)
10 (R)
20 (R)
50 (R)
92 (S)
1[d]
1[e]
3[e]
19
AT-w-TA
49
HN-w-TA 73
Scheme 1. Synthesis of rac-2-phenylpropanal derivatives rac-
2a–g via Rh-catalysed hydroformylation.
[a]
Reaction conditions: substrate 2a (50 mM), w-TA
(lyophilised cells, 20 mgmLÀ1) in phosphate buffer
(100 mM, pH 7, 1 mM PLP) at 308C, 120 rpm, 24 h, l- or
d-alanine (250 mM), AlaDH (12 U), FDH (11 U), NAD+
(1 mM) and ammonium formate (150 mM).
Determined from area by GC-FID measurement on an
achiral stationary phase. The value for 3/4 represents the
percentage in the mixture of 2a/3a/4a.
[b]
[c]
Optical purity was measured for the corresponding tri-
fluoroacetamide derivative by GC-FID on a chiral phase.
Contained 10% 1-phenylethylamine.
[d]
[e]
Contained 20% 1-phenylethylamine.
Scheme 2. Dynamic kinetic resolution of 2-phenylpropanal
derivatives rac-2a–g to yield optically enriched b-chiral 2-
phenylpropylamines 3a–g via stereoselective biocatalytic
amination.
ence giving access to (R)-3a. In contrast, the w-TA
from H. neptunium catalysed the formation of (S)-3a;
HN-w-TA displayed previously the same stereoprefer-
ence for the amination of methyl ketones as ArR-w-
TA and AT-w-TA. These results clearly show that
already at pH 7, due to the labile chiral centres in the there is no correlation between the stereopreference
benzylic position as well as in the a-position to the for the amination of ketones and a-chiral aldehydes
carbaldehyde moiety. Consequently, the racemisation for the w-TAs.
enables
a
dynamic kinetic resolution (DKR)
Beside the desired product 3a also the formation of
acetophenone 4a as a side product was found. Inter-
(Scheme 2).[10,11]
Starting with the unsubstituted aldehyde 2a as estingly the amount of decarbonylation depended on
a model substrate, various w-TAs were evaluated for the enzyme employed and was also partly present
their biocatalytic reductive amination. w-TAs with re- when testing only E. coli in the absence of overex-
ported amino acid sequences originating from Pseu- pressed w-TAs or solely alanine in blank reactions.
domonas pudita (PP1-w-TA and PP2-w-TA),[12] Ar- This formation of acetophenone as minor side prod-
throbacter sp. (ArS-w-TA[13] and ArR-w-TA[14]), As- uct has been reported as a background reaction in the
pergillus terreus (AT-w-TA) and Hyphomonas neptu- biocatalytic as well as metal-catalysed transformation
nium (HN-w-TA)[15] were over-expressed heterolo- of aldehyde 2a and derivatives.[19]
gously in E. coli BL21
G
To identify the most suitable pH for the dynamic
were used as catalyst. Alanine was used as amine kinetic resolution, the amination was tested with se-
donor and the thermodynamic equilibrium was shifted lected transaminases at pH values between pH 6 and
to the product side using an l-alanine dehydrogenase pH 10 (Figure 1).
(AlaDH) from Bacillus subtilis[16] to remove pyru-
The conversion showed in general a maximum at
pH 7 with all transaminases tested. The ee values ob-
vate.[17]
DKR of substrate rac-2a was successfully per- served were independent of pH and conversion for
formed leading to the corresponding (R)- and (S)- HN-w-TA. The ee of (R)-3a formed by PP2-w-TA
amines with up to 83% ee and 92% ee, respectively varied from 85 to 95% ee between pH 6 and pH 9. In
(Table 1). It is noteworthy that in previous stud- the case of ArR-w-TA a decrease of ee with increas-
ies[2,12,14,15,18] the w-TAs PP1, PP2 and ArS showed op- ing pH was observed which can be attributed to
posite stereopreference for the amination of ketones a lower stereoselectivity of this enzyme with increas-
compared to the transaminases ArR and AT. Thus, w- ing pH value.
TA-PP1/PP2/ArS were described to be (S)-selective
In order to test the influence of a cosolvent on the
for the amination of methyl ketones while ArR and stereoselectivity and conversion of the bioamination,
AT were (R)-selective. However, for the amination of the water miscible solvents DME (1,2-dimethoxy-
2a all five enzymes displayed the same stereoprefer- ethane), DMF (N,N-dimethylformamide) and DMSO
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Dynamic Kinetic Resolution of 2-Phenylpropanal Derivatives
Table 3. Amination of para-substituted aldehydes rac-2b and
rac-2c.[a]
w-TA
Substrate Conv.[b] [%]
3
[b] [%] ee 3[c] [%]
PP1-w-TA rac-2b
PP2-w-TA rac-2b
ArR-w-TA rac-2b
97
97
96
91
59
80
67
59
<1
86
95
99
94
<1
86 (R)
76 (R)
10 (R)
44 (R)
n.d.[d]
92 (R)
94 (R)
32 (S)
28 (R)
n.d.[d]
AT-w-TA
rac-2b
HN-w-TA
rac-2b
38
PP1-w-TA rac-2c
PP2-w-TA rac-2c
ArR-w-TA rac-2c
>99
>99
>99
>99
50
AT-w-TA
HN-w-TA
rac-2c
rac-2c
Figure 1. Amount and optical purity (ee) of amine 3a de-
pending on the pH employed for the amination reaction.
Solid lines represent the percentage of 3a, dashed lines: ee
[a]
Reaction conditions: see Table 1.
[b]
Determined from the area by GC-FID measurement on
an achiral stationary phase. The value for 3 represents
the percentage of 3 in the mixture of 2, 3 and 4.
Optical purity was determined for the corresponding tri-
fluoroacetamide derivative by GC-FID on a chiral phase.
Not determined due to low conversion.
&
*
value [( ) PP2-w-TA, giving (R)-3a; ( ) ArR-w-TA, giving
~
(R)-3a; ( ) HN-w-TA, giving (S)-3a].
[c]
[d]
(dimethyl sulfoxide) were selected at concentrations
of 10, 20 and 30 vol% (Table 2).
Upon adding DME, the optical purity of 3a in-
creased from an ee of 10% in the absence of cosol-
Substrate engineering[20] may allow improving the
vent to an ee of 50% at 30 vol% DME employing stereochemical outcome of a transformation and gives
ArS-w-TA. In a similar fashion the ee of amine 3a a first preliminary indication whether high stereo rec-
produced by ArR-w-TA rose from 34% (R) (w/o co- ognition is achievable at all. Consequently, substrates
solvent) to 52% (R) (20% DMF). On the other hand, bearing one methyl- or methoxy-substituent in para-,
HN-w-TA did not tolerate cosolvents leading only to meta- and ortho-positions of the phenyl ring (2b–g)
very low conversion (4%). In general, for the three were investigated.
enzymes investigated in detail (PP2, ArR and ArS), it
The methyl substituent in the para-position (sub-
was observed that an increase of cosolvent led in strate 2b) being most far away from the reaction
most cases also to improved ee values. Enhanced con- centre led to comparable ee values as obtained for
versions were observed with increasing amounts of substrate 2a with hydrogen in the para-position
solvent for the two enzymes originating from Arthro- (Table 3). Interestingly, HN-w-TA did not convert 2b
bacter, while PP2 was less efficient.
or 2c into the amines but produced significant
Table 2. Influence of a cosolvent on the stereoselectivity of the amination of 2-phenylpropanal rac-2a.[a]
PP2-w-TA
3a[b]
[%]
ArR-w-TA
3a[b]
[%]
ArS-w-TA
3a[b]
[%]
Cosolvent Amount
[vol%]
Conv.[b]
[%]
ee 3a[c]
[%]
Conv.[b]
[%]
ee 3a[c]
[%]
Conv.[b]
[%]
ee 3a[c]
[%]
none
DME
–
75
41
50
28
44
25
18
40
67
61
72
33
8
<1
42
<1
<1
40
45
34
78 (R)
94 (R)
95 (R)
n.d.[d]
65
54
59
55
51
50
63
51
56
56
64
54
44
27
51
49
45
50
53
47
20 (R)
26 (R)
48 (R)
48 (R)
23 (R)
52 (R)
50 (R)
18 (R)
36 (R)
42 (R)
59
51
58
59
47
60
65
54
62
63
58
50
35
26
47
50
50
47
53
40
10 (R)
30 (R)
42 (R)
50 (R)
8 (R)
20 (R)
26 (R)
12 (R)
20 (R)
28 (R)
10
20
30
10
20
30
10
20
30
DMF
80 (R)
n.d.[d]
n.d.[d]
DMSO
82 (R)
91 (R)
92 (R)
[a]
Reaction conditions: substrate 2a (50 mM), w-TA (lyophilised cells, 20 mgmLÀ1) in phosphate buffer (100 mM, pH 7,
1 mM PLP) at 308C, 120 rpm, 24 h; l- or d-alanine (250 mM), AlaDH (12 U), FDH (11 U), NAD+ (1 mM) and ammoni-
um formate (150 mM) in the presence of the indicated amount of cosolvent.
Determined from the area by GC-FID measurement on an achiral stationary phase. The value for 3 represents the per-
centage in the mixture of 2a/3a/4a.
[b]
[c]
[d]
Optical purity was measured for the corresponding trifluoroacetamide derivative by GC-FID on a chiral phase.
Not determined due to low conversion.
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Christine S. Fuchs et al.
Table 4. Amination of meta-substituted aldehydes rac-2d
and rac-2e.[a]
Table 5. Amination of ortho-substituted aldehydes rac-2f
and rac-2g.[a]
w-TA
Substrate Conv.[b] [%]
3
[b] [%] ee 3[c] [%]
wTA
Substrate Conv.[b] [%]
3
[b] [%] ee 3[c] [%]
PP1-w-TA rac-2d
PP2-w-TA rac-2d
ArR-w-TA rac-2d
ArS-w-TA rac-2d
>99
>99
>99
>99
>99
90
>99
>99
>99
>99
>99
60
79
89
87
84
91
8
97
98
99
>99
99
<1
94 (R)
91 (R)
40 (R)
rac
52 (R)
80 (S)
76 (R)
66 (R)
10 (S)
rac
PP1-w-TA rac-2f
PP2-w-TA rac-2f
ArR-w-TA rac-2f
ArS-w-TA rac-2f
99
99
99
>99
99
87
96
84
90
89
31
99
99
98 (R)
96 (R)
92 (R)
62 (S)
56 (R)
96 (S)
90 (R)
90 (R)
62 (S)
32 (R)
96 (S)
AT-w-TA
HN-w-TA
rac-2d
rac-2d
AT-w-TA
HN-w-TA
rac-2f
rac-2f
60
PP1-w-TA rac-2e
PP2-w-TA rac-2e
ArR-w-TA rac-2e
ArS-w-TA rac-2e
PP1-w-TA rac-2g
PP2-w-TA rac-2g
ArR-w-TA rac-2g
>99
>99
>99
>99
>99
>99
>99
95
AT-w-TA
HN-w-TA
rac-2g
rac-2g
AT-w-TA
HN-w-TA
rac-2e
rac-2e
64 (R)
n.d.[d]
[a]
Reaction conditions: see Table 1.
[a]
[b]
Reaction conditions: see Table 1.
Determined from the area by GC-FID measurement on
an achiral stationary phase. The value for 3 represents
the percentage of 3 in the mixture of 2, 3 and 4.
[b]
Determined from the area by GC-FID measurement on
an achiral stationary phase. The value for 3 represents
the percentage of 3 in the mixture of 2, 3 and 4.
Optical purity was determined for the corresponding tri-
fluoroacetamide derivative by GC-FID on a chiral phase.
Not determined due to low conversion.
[c]
Optical purity was determined for the corresponding tri-
[c]
[d]
fluoroacetamide derivative by GC-FID on a chiral phase.
highest conversions and highest ee values in most
cases (Table 5).
amounts of the side product 4b and 4c. On the other
Thus (S)-3f and (S)-3g were obtained with 96% ee
hand, ArR-w-TA switched the stereopreference from and (R)-3f and (R)-3g were formed with 98% ee and
para-methyl as substituent (2b) to para-methoxy (2c), 90% ee, respectively. For substrates 2f and 2g, the
thus 2b led to the (R)-enantiomer, while 2c gave the switch of stereopreference with ArR-w-TA regarding
(S)-enantiomer. The para-methoxy-substituent (2c) the methyl- and methoxy-substituted substrates was
led to higher conversions within 24 h compared to the most significant, since on the one hand this enzyme
methyl moiety and allowed us to reach increased ee formed (R)-3f with 90% ee and on the other hand
values (92–94%) employing the w-TAs from Pseudo- (S)-3g was formed with 62% ee. In general the o-me-
monas pudita (PP1, PP2).
thoxy-substituted aldehyde 2g was transformed to the
Switching to substrates possessing substituents in corresponding amines with excellent conversion (>
the meta-position, aldehydes 2d and 2e with a meta- 95% after 24 h) and side product formation was mini-
methyl- and meta-methoxy moiety, respectively, were mised.
investigated (Table 4). Amine 3d was formed with in-
Since the enantiomerically pure compounds (R)-
creased stereoselectivity [94% ee (R)] employing PP1- and (S)-3b–g were not commercially available and
w-TA. Aldehyde 2d was also accepted by HN-w-TA, also not characterised in the literature, the absolute
yielding the (S)-enantiomer of amine 3d. The ee configuration of these products was determined by (i)
values for 3d (max. 94%) were in general higher than circular dichroism, supported by (ii) optical rotation,
for 3e [max. 76% ee (R)]. AT-w-TA gave also higher and (iii) elution order on a chiral GC phase.
conversions and elevated ee values for both meta-sub-
The amination of compounds 2b–g was finally per-
stituted amines 3d and 3e compared to the para-sub- formed on a preparative scale (~100 mg) leading to
stituted products 3b and 3c. The amount of amine isolated yields between 50–86% of the corresponding
formed was again higher for the methoxy derivative amine 3b–g (Table 6), The optical purity was in some
than for the methyl derivative.
cases lower than on a small scale but also higher as
Also in case of the meta-substituted aldehydes for 3g (99% ee).
a switch of stereopreference was observed for ArR-w-
TA from methyl- to the methoxy-substituted sub-
strates, thus it produced (R)-3d and (S)-3e.
Conclusions
We expected that the ortho-substituted substrates
2f and 2g would be moderate substrates, since the Optically enriched b-chiral amines, 2-phenyl-1-propyl-
substituent is closest to the centre of the reaction and amine derivatives, were prepared within two steps
might therefore cause steric hindrance as previously starting from the corresponding styrene derivatives.
described for a hydroxynitrile lyase.[21] However, The stereo-recognition of w-TAs for the a-centre of
these substrates were transformed best and led to aldehydes remains still a challenging task. Employing
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Dynamic Kinetic Resolution of 2-Phenylpropanal Derivatives
Table 6. Preparative amination of a-chiral aldehydes 2b–g.[a]
Aldehyde Preparation
Reactions were carried out under an atmosphere of argon
using standard Schlenk techniques. In all cases, the indicated
temperature referred to the inner temperature in the auto-
clave. Catalytic experiments were generally performed in
a stainless steel 150-mL autoclave charged with a glass
insert. Before each run, the autoclaves were tested for leaks
at ca. 20 bar of H2, evacuated, flushed with 3ꢂ10 bar syngas
(CO/H2, 1/1) and then pressurised.
Amine
w-TA
Amine
donor
Isol. yield
of 3 [%]
ee 3[b]
[%]
3b
3c
3d
3e
3f
3g
PP1-w-TA
PP1-w-TA
PP1-w-TA
PP1-w-TA
PP1-w-TA
HN-w-TA
l-Ala
l-Ala
l-Ala
l-Ala
l-Ala
d-Ala
62
86
56
82
75
50
75 (R)
92 (R)
80 (R)
50 (R)
89 (R)
99 (S)
Flash chromatography was performed on Screening Devi-
ces b.v. silica gel (60–200 mm, 60 ꢃ) by a standard technique.
[a]
Reaction conditions: substrate 2b–g (50 mM), w-TA
(lyophilised cells, 300 mg) in phosphate buffer (15 mL,
100 mM, pH 7, 1 mM PLP), l- or d-alanine (250 mM),
AlaDH (180 U), FDH (165 U), NAD+ (1 mM) and am-
monium formate (150 mM) at 308C, 120 rpm, 24 h.
General Procedure for the Preparation of Racemic
Aldehydes
A typical experiment was carried out in a stainless steel au-
toclave (150 mL) charged with a glass insert or in a 4-mini-
autoclave equipped with a glass inner beaker. A solution of
[Rh4CO12] in toluene were added in the glass insert followed
by the addition of the styrene derivative (see details for
each experiment). Before starting the catalysis, the charged
autoclave was purged three times with 10 bar of syngas
(CO/H2 =1/1) and then pressurised to 40 bar and heated
96 h at 408C. Then, the autoclave was cooled down to 08C,
the pressure was reduced to 1.0 bar. Each of the crude reac-
tion mixtures were analyzed by NMR and then purified by
SiO2 gel column chromatography.
[b]
Optical purity was determined for the corresponding tri-
fluoroacetamide derivative by GC-FID on a chiral phase.
(R)- or (S)-selective enzymes, both enantiomers of
most of the desired amines were prepared with high
ee compared to commercial TAs aminating similar al-
dehydes.[6,7] Due to the racemisation of the a-chiral
phenyl aldehydes in the reaction medium, the reac-
tion proceeded via dynamic kinetic resolution and re-
2-(para-Tolyl)propanal (rac-2b): From Rh4CO12 (0.0176 g,
sulted in excellent conversions to the desired product. 0.0236 mmol) in 1.9 mL of toluene and 4-methylstyrene
(2.1 mL, 15.9 mmol, 673 equiv.), 4-mini-autoclaves. Product
purified by SiO2 gel column chromatography (height
170 mm, width 35 mm) in pentane/EtOAc (98:2); yellow oil;
Substrate engineering showed that maximum conver-
sions and highest optical purity can be obtained for
the applied enzyme when transforming ortho-substi-
tuted amines 3f and 3g.
1
isolated yield: 56%. H NMR (400.1 MHz, CD2Cl2): d=1.40
3
3
(d, J3,2 =7.2 Hz, 3H, 3-H), 2.34 (s, 3H, 1’-H), 3.59 (q, J2,3
=
3
7.2 Hz, 1H, 2-H), 7.10 (d, J=8.0 Hz, 2H, Harom), 7.20 (d,
3J=8.0 Hz, 2H, Harom), 9.65 (s, 1H, 1-H); 13C NMR
(100.6 MHz, CD2Cl2): d=14.8 (3-C), 21.1 (1’-C), 52.9 (2-C),
128.6 (arom. C), 130.0 (arom. C), 135.3 (arom. Cipso), 137.6
(arom. Cipso), 201.5 (1-C).
Experimental Section
General Information
2-(4-Methoxyphenyl)propanal (rac-2c): From Rh4CO12
(0.071 g, 0.094 mmol) in 11 mL of toluene and 4-vinylanisole
(9 mL, 67.7 mmol, 717 equiv.), stainless steel autoclave.
Product purified by SiO2 gel column chromatography
(height 130 mm, width 50 mm) in pentane/EtOAc (97:3);
All chemicals/reagents were purchased from commercial
suppliers and used without further purification except for all
styrene derivatives which were purified by filtration over
a plug of basic alumina and degassed by bubbling argon
prior to use. Aldehyde 2a was commercially available from
Sigma Aldrich. The toluene was distilled from sodium prior
to use. NMR spectra of aldehydes 2b–g were recorded on
a Bruker Avance 400 MHz (400.1 MHz and 100.6 MHz for
1H and 13C respectively) at 298 K. NMR spectra of amines
3b–g were recorded on a 300 MHz Bruker NMR unit at
293 K. Chemical shifts (d) are quoted in ppm downfield of
tetramethylsilane or relative to the resonance of the solvent.
Coupling constants (J) are quoted in Hz. High-resolution
fast atom bombardment mass spectrometric (HR-MS-FAB)
measurements were carried out on a JEOL JMS SX/SX
102A spectrometer. Samples were loaded in a 3-nitrobenzyl
alcohol matrix and bombarded with xenon atoms. Plasmids
for overexpression of w-transaminases were obtained from
GeneArt AG (Regensburg, Germany), cloned and trans-
formed into E. coli BL21 (DE3) as previously reported.[22]
Purified recombinant l-alanine dehydrogenase was prepared
as described recently.[18]
1
fair yellow oil; yield: 43%. H NMR (400.1 MHz, CD2Cl2):
d=1.43 (d, 3J3,2 =7.2 Hz, 3H, 3-H), 3.62 (q, 3J2,3 =7.2 Hz,
1H, 2-H), 3.83 (s, 3H, -OCH3), 6.92–6.98 (m, 2H, Harom),
7.13–7.20 (m, 2H, Harom), 9.67 (d, 3J1,2 =1.2 Hz, 1H, 1-H);
13C NMR (100.6 MHz, CD2Cl2): dC =14.9 (3-C), 52.4 (2-C),
55.6 (-OCH3), 114.7 (arom. C), 129.7 (arom. C), 130.2
(arom. Cipso), 159.4 (arom. Cipso), 201.4 (1-C); HR-MS
(FAB+): m/z=165.0911, calcd. for [(C10H12O2)H]+: 165.0916.
2-(meta-Tolyl)propanal (rac-2d): From Rh4CO12 (0.0707 g,
0.0945 mmol) in 11 mL of toluene and 3-methylstyrene
(9 mL, 67.8 mmol, 717 equiv.), stainless steel autoclave.
Product purified by SiO2 gel column chromatography
(height 130 mm, width 50 mm) in pentane/EtOAc (97:3);
1
yellow oil; yield: 69%. H NMR (400.1 MHz, CDCl3): dH =
3
1.46 (d, J3,2 =7.2 Hz, 3H, 3-H), 2.39 (s, 3H, 1’-H), 3.62 (qd,
3J2,3 =7.2 and 3J2,1 =1.2 Hz, 1H, 2-H), 7.01–7.07 (m, 2H,
3
Harom), 7.15 (d, J=7.2 Hz, Harom), 7.26–7.34 (m, Harom), 9.70
3
(d, J1,2 =1.2 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CD2Cl2):
Adv. Synth. Catal. 2014, 356, 2257 – 2265
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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FULL PAPERS
Christine S. Fuchs et al.
d=14.8 (3-C), 21.5 (1’-C), 53.3 (2-C), 125.7 (arom. C), 128.5
(arom. C), 129.2 (arom. C), 129.4 (arom. C), 138.3 (arom.
Cipso), 139.2 (arom. Cipso), 201.5 (1-C); HR-MS (FAB+):
m/z=149.0966, calcd. for [(C10H12O)H]+: 149.0966.
Hydrochloric acid 2M in diethyl ether was added and the
solvent was evaporated.
2-para-Tolylpropan-1-amine hydrochloride (3b·HCl):
From 2-(para-tolyl)propanal 2b (260 mg, 1.7 mmol), benzyl-
2-(3-Methoxyphenyl)propanal (rac-2e): From Rh4CO12
(0.0676 g, 0.090 mmol) in 11 mL of toluene and 3-vinylani-
sole (9 mL, 64.86 mmol, 717 equiv.), stainless steel autoclave.
Product purified by SiO2 gel column chromatography
(height 130 mm, width 50 mm) in pentane/EtOAc (97:3);
amine (215 mL, 2 mmol) and NaBHACTHNUTRGENUN(G OAc)3 (540 mg,
2.6 mmol). The pure product was isolated as hydrochloride
salt without further purification; yield: 140 mg (0.8 mmol,
3
45%). 1H NMR (300 MHz, MeOD): d=1.32 (d, J3,2
=
7.96 Hz, 3H, 3-H), 2.32 (s, 3H, 1’-H), 3.00–3.13 (m, 1H, 2-
1
3
yellow oil; yield: 61%. H NMR (400.1 MHz, CD2Cl2): d=
H), 3.19–3.26 (q, J1,2 =7.25 Hz, 2H, 1-H), 7.14–7.28 (m, 4H,
3
3
Harom); 13C NMR (75 MHz, MeOD) : d=18.6 (3-C), 19.7 (1’-
C), 37.8 (2-C), 45.4 (1-C), 126.7 (arom. C), 129.4 (arom. C),
136.9 (arom. Cipso), 138.7 (arom. Cipso).
1.41 (d, J3,2 =6.8 Hz, 3H, 3-H), 3.60 (q, J2,3 =6.8 Hz, 1H, 2-
H), 3.80 (-OCH3), 6.72–6.88 (m, 3H, Harom), 7.29 (t, 3J=
8.0 Hz, 1H, Harom), 9.66 (d, 3J1,2 =1.2 Hz, 3H, 1-H);
13C NMR (100.6 MHz, CD2Cl2): d=14.7 (3-C), 53.3 (2-C),
55.6 (-OCH3), 113.0 (arom. C), 114.5 (arom. C), 120.9
(arom. C), 130.3 (arom. C), 140.0 (arom. Cipso), 160.6 (arom.
Cipso), 201.2 (1-C); HR-MS (FAB+): m/z=165.0910, calcd.
for [(C10H12O2)H]+: 165.0916.
2-(para-Methoxyphenyl)propan-1-amine
hydrochloride
(3c·HCl): From 2-(4-methoxyphenyl)propanal 2c (51 mg,
0.3 mmol), benzylamine (45 mL, 0.42 mmol) and NaBH-
AHCTUNGRTEG(NNUN OAc)3 (143 mg, 0.68 mmol). The pure product was isolated
as hydrochloride salt without further purification; yield:
1
2-(ortho-Tolyl)propanal (rac-2f): Rh4CO12 (0.0176 g,
0.024 mmol) in 1.8 mL toluene and 2-methylstyrene (2.2 mL,
16.9 mmol, 717 equiv.), 4-mini-autoclaves. Product purified
by SiO2 gel column chromatography (height 170 mm, width
35 mm) in pentane/EtOAc (98:2); yellow oil; yield: 72%.
1H NMR (400.1 MHz, CD2Cl2): dH =1.39 (d, 3J3,2 =6.8 Hz,
35 mg (0.17 mmol, 58%). H NMR (300 MHz, MeOD): d=
1.34 (d, 3J1,2 =6.58 Hz, 3H, 3-H), 3.10–319 (m, 2H, 1-H),
3.32 (mc, 1H, 2-H), 3.81 (s, 3H, OCH3), 6.71–7.39 (m, 4H,
H
arom); 13C NMR (75 MHz, MeOD): d=18.5 (3-C), 38.3 (2-
C), 45.4 (1-C), 54.3 (-OCH3), 112.4 (arom. C), 112.7 (arom.
C), 118.9 (arom. C), 129.9 (arom. C), 143.4 (arom. C), 160.3
(arom. Cipso).
2-(meta-Tolylpropan-1-amine hydrochloride (3d·HCl):
From 2-(para-tolyl)propanal 2d (73 mg, 0.49 mmol), benzyl-
3
3H, 3-H), 2.36 (s, 3H, 1’-H), 3.85 (q, J2,3 =6.8 Hz, 1H, 2-H),
7.02–7.07 (m, 1H, Harom), 7.16–7.27 (m, 3H, Harom), 9.65 (d,
3J1,2 =0.8 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CD2Cl2): d=
14.5 (3-C), 19.8 (1’C), 49.6 (2-C), 126.9 (arom. C), 127.7
(arom. C), 127.9 (arom. C), 131.2 (arom. C), 137.1 (arom.
amine (65 mL, 0.6 mmol) and NaBHACTHNUTRGENUN(G OAc)3 (204 mg,
0.96 mmol). The pure product was isolated as hydrochloride
Cipso), 137.2 (arom. Cipso), 201.4 (1-C): HR-MS
(FAB+): m/z=
ACHTUNGTRENNUNG
salt without further purification; yield: 52 mg (0.28 mmol,
149.0966, calcd. for [(C10H12O)H]+: 149.0966.
3
57%). 1H NMR (300 MHz, MeOD) d=1.32 (d, J3,2
=
2-(2-Methoxyphenyl)propanal (rac-2g): From Rh4CO12
(0.0165 g, 0.022 mmol) in 2 mL of toluene and 2-vinylanisole
(2 mL, 14.92 mmol, 673 equiv.), 4-mini-autoclaves. Product
purified by SiO2 gel column chromatography (height
170 mm, width 35 mm) in pentane/EtOAc (80:20); fair
yellow oil; yield. 49%. 1H NMR (400.1 MHz, CD2Cl2) d=
6.69 Hz, 3H, 3-H), 2.35 (s, 3H, 1’-H) 3.10–3.20 (m, 2H, 1-
H), 3.33 (mc, 1H, 2-H), 7.05–7.32 (m, 4H, Harom). 13C NMR
(75 MHz, MeOD): d=18.6 (3-C), 20.1 (1’-C), 38.2 (2-C),
45.4 (1-C), 123.9 (arom. C), 127.5 (arom. C), 127.9 (arom.
C), 128.7 (arom. C), 138.6 (arom. C), 141.7 (arom. Cipso).
2-(meta-Methoxyphenyl)propan-1-amine
(3e·HCl): From 2-(meta-methoxyphenyl)propanal
(81.6 mg, 0.5 mmol), benzylamine (70 mL, 0.66 mmol) and
NaBH(OAc)3 (160 mg, 0.76 mmol). The pure product was
hydrochloride
3
1.37 (d, J3,2 =7.2 Hz, 3H, 3-H), 3.82 (s, 3H, -OCH3), 3.84 (q,
2e
3J2,3 =7.2 Hz, 1H, 2-H), 6.92–6.96 (m, 1H, Harom), 6.98 (dd,
4
3
3J=7.6 Hz and J=1.2 Hz, 1H, Harom), 7.12 (dd, J=7.6 Hz
AHCTUNGTRENNUNG
4
and J=1.6 Hz, 1H, Harom), 7.25–7.32 (m, 1H, Harom), 9.65
isolated as hydrochloride salt without further purification;
(d, J1,2 =0.8 Hz, 1H, 1-H); 13C NMR (100.6 MHz, CD2Cl2):
3
yield: 49 mg (0.24 mmol, 49%). 1H NMR (300 MHz,
d=13.6 (3-C), 47.7 (2-C), 55.8 (-OCH3), 111.2 (arom. C),
121.2 (arom. C), 127.7 (arom. Cipso), 129.0 (arom. C), 129.5
(arom. C), 157.6 (arom. Cipso), 202.1 (1-C).
3
MeOD) d=1.31 (d, J3,2 =6.40 Hz, 3H, 3-H), 2.97–3.15 (m,
2H, 1-H), 3.33 (mc, 1H, 2-H), 3.80 (s, 3H, -OCH3) 6.86–7.30
(m, 4H, Harom). 13C NMR (75 MHz, MeOD): dC =18.6 (3-C),
37.4 (2-C), 45.6 (1-C), 54.3 (-OCH3), 114.1 (arom. C), 127.9
(arom. C), 133.6 (arom. C), 159.1 (arom. Cipso).
2-(ortho-Tolyl)propan-1-amine hydrochloride (3f·HCl):
From 2-ortho-tolylpropanal 2f (143.86 mg, 0.97 mmol), ben-
General Procedure for the Preparation of Amines
Aldehyde 2b–g and benzylamine (1.2 equiv.) were dissolved
in dry THF and stirred for 25 min under a nitrogen atmos-
phere. NaBHACHTUNGTRENNUNG(OAc)3 (1.5 equiv.) was added and the suspen-
zylamine (130 mL, 1.2 mmol) and NaBHACTHNUTRGENUG(N OAc)3 (359 mg,
1.7 mmol). The pure product was isolated as hydrochloride
sion was stirred for 3 h at room temperature.[23] The reaction
was quenched with saturated NaHCO3 solution and after ex-
traction with ethyl acetate the combined organic phases
were dried over Na2SO4 and the solvent was evaporated.
The product was purified by column chromatography. The
N-benzyl-2-phenyl-1-propylamine intermediate was dis-
solved in tert-butyl methyl ether and 10% palladium on
charcoal was added. Hydrogenation was performed under
a hydrogen atmosphere at ambient pressure at room tem-
perature overnight.[24] The mixture was filtered over Celiteꢄ
and the filter cake was washed with tert-butyl methyl ether.
without further purification; yield: 91 mg (0.49 mmol,
3
981%). 1H NMR (300 MHz, MeOD) d=1.32 (d, J3,2
=
6.77 Hz, 3H, 3-H), 2.40 (s, 3H, 1’-H), 3.08–3.48 (m, 3H, 3-
H, 2-H), 7.12–7.32 (m, 4H, Harom); 13C NMR (75 MHz,
MeOD): d=18.2 (3-C, 1’-C), 33.0 (2-C), 44.7 (1-C), 124.8
(arom. C), 126.5 (arom. C), 126.8 (arom. C), 130.5 (arom.
C), 135.7 (arom. C), 140.0 (arom. Cipso).
2-(ortho-Methoxyphenyl)propan-1-amine (3g): From 2-
(ortho-methoxyphenyl)propanal 2g (240 mg, 1.4 mmol), ben-
zylamine (215 mL, 2 mmol) and NaBH
ACHTUNGRTENUN(NG OAc)3 (540 mg,
2.6 mmol). The pure product was isolated without further
2262
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Adv. Synth. Catal. 2014, 356, 2257 – 2265

FULL PAPERS
Dynamic Kinetic Resolution of 2-Phenylpropanal Derivatives
purification; yield: 60 mg (0.36 mmol, 25%). 1H NMR References
3
(300 MHz, CDCl3) d=1.20 (d, J3,2 =3.18 Hz, 3H, 3-H), 2.35
3
(s, 2H, NH2), 2.84 (mc, 1H, 2-H), 3.23–3.30 (q, J1,2
=
[1] For reviews see: a) R. C. Simon, N. Richter, E. Busto,
W. Kroutil, ACS Catal. 2014, 4, 129–143; b) W. Kroutil,
E.-M. Fischereder, C. S. Fuchs, H. Lechner, F. G. Mutti,
D. Pressnitz, A. Rajagopalan, J. H. Sattler, R. C.
Simon, E. Siiriola, Org. Process Res. Dev. 2013, 17,
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993–1001; d) M. S. Malik, E.-S. Park, J.-S. Shin, Appl.
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Hua, Biotechnol. J. 2009, 4, 1420–1431; i) M. Hçhne,
U. T. Bornscheuer, ChemCatChem 2009, 1, 42–51.
6.92 Hz, 2H, 1-H), 3.82 (s, 3H, -OCH3), 6.86–6.97 (m, 2H,
Harom), 7.15–7.26 (m, 2H, Harom); 13C NMR (75 MHz,
CDCl3): d=18.0 (3-C), 35.8 (2-C), 49.8 (1-C), 55.4 (-OCH3),
110.5 (arom. C), 120.5 (arom. C), 126.9 (arom. C), 133.0
(arom. Cipso), 157.4 (arom. Cipso).
General Procedure for Biotransformations
All experiments were carried out on a one millilitre scale
using 2 mL Eppendorf tubes as reaction vessels. d-Alanine
was used as amine donor with ArR-w-TA, AT-w-TA and
HN-w-TA because these transaminases show (R)-selectivity
for the amination of ketones. When using other TAs, l-ala-
nine was applied as donor. All experiments were done in
duplicate.
[2] Selected recent examples employing w-TAs (only
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CatChem 2013, 5, 1734–1738; g) M. Schrewe, N.
Ladkau, B. Bꢅhler, A. Schmid, Adv. Synth. Catal. 2013,
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Munsberg, C. Vickers, A. Thontowi, S. Schꢆtzle, T.
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555–559; o) E. Siirola, F. G. Mutti, B. Grischek, S. F.
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Lyophilised cells of E. coli containing overexpressed w-
transaminase (20 mg) were rehydrated in phosphate buffer
(1 mL, pH 7, 100 mM) containing PLP (1 mM) and NADH
free acid (1 mM) at 308C and 120 rpm for 30 min. AlaDH
(15 mL, 12 U), FDH (5 mg, 11 U), ammonium formate
(9.5 mg, 150 mM) and alanine (22.3 mg, 250 mM) as well as
the substrate (50 mM) were added. Reductive amination
was carried out at 308C in a thermo shaker (750 rpm) for
24 h. Reaction was quenched by addition of NaOH 10N so-
lution (200 mL). After extraction with EtOAc (2ꢂ500 mL)
the combined organic phases were dried over Na2SO4 and
analysed via gas chromatography.
For medium engineering the respective parameters were
changed.
Biotransformations on a Preparative Scale
Lyophilised cells of E. coli containing overexpressed w-
transaminase (300 mg) and FDH (75 mg, 165 U) were rehy-
drated in phosphate buffer (15 mL, pH 7, 100 mM) contain-
ing PLP (1 mM) and NADH free acid (1 mM) at 308C and
120 rpm for 30 min. AlaDH (225 mL, 180 U), ammonium
formate (143 mg, 150 mM) and alanine (335 mg, 250 mM) as
well as the substrate (105 mL, 50 mM) were added. Reduc-
tive amination was carried out at 308C in an orbital shaker
(120 rpm) for 24 h. The reaction was extracted with tert-
butyl methyl ether (2ꢂ10 mL) and after addition of aqueous
NaOH (3 mL, 10N) the solution was extracted again (3ꢂ
10 mL). The combined organic phases of the basic extrac-
tion were dried over Na2SO4 and the solvent was evaporat-
ed. Products were obtained as yellow oils or solids in 50–
86% isolated yield.
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Acknowledgements
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This work has been supported by the Austrian BMWFJ,
BMVIT, SFG, Standortagentur Tirol and ZIT through the
Austrian FFG-COMET-Funding Program. Sandoz GmbH is
thanked for its financial contribution. Support by NAWI
Graz is acknowledged.
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