Cascade Coupling of Ene-Reductases and ω-Transaminases for the Stereoselective Synthesis of Diastereomerically Enriched Amines

Article abstract of DOI:10.1002/cctc.201500424

One-pot sequential and cascade processes performed by employing ene-reductases (ERs) together with ω-transaminases (ω-TAs) for the obtainment of diastereomerically enriched (R)- and (S)-amine derivatives containing an additional stereocenter were investigated. By using either α- or β-substituted unsaturated ketones as substrates and by coupling purified ERs belonging to the Old Yellow Enzyme (OYE) family with a panel of commercially available ω-TAs, the desired products were obtained in up to >99% conversion and >99%de. The sequential reactions were performed in a one-pot fashion with no need to adapt the reaction conditions to the reductive amination step or to purify the reaction intermediate. Moreover, high chemoselectivity of the tested ω-TAs for the saturated ketones was shown in the cascade reactions.

Full text of DOI:10.1002/cctc.201500424

DOI: 10.1002/cctc.201500424
Communications
Cascade Coupling of Ene-Reductases and w-Transaminases
for the Stereoselective Synthesis of Diastereomerically
Enriched Amines
Daniela Monti,[a] Maria Chiara Forchin,[a] Michele Crotti,[b] Fabio Parmeggiani,[b]
Francesco G. Gatti,[b] Elisabetta Brenna,[b] and Sergio Riva*[a]
This manuscript is dedicated to Wolf-Dieter “Woody” Fessner on the occasion of his 60th birthday.
One-pot sequential and cascade processes performed by em-
ploying ene-reductases (ERs) together with w-transaminases
(w-TAs) for the obtainment of diastereomerically enriched (R)-
and (S)-amine derivatives containing an additional stereocenter
were investigated. By using either a- or b-substituted unsatu-
rated ketones as substrates and by coupling purified ERs be-
longing to the Old Yellow Enzyme (OYE) family with a panel of
commercially available w-TAs, the desired products were ob-
tained in up to >99% conversion and >99%de. The sequen-
tial reactions were performed in a one-pot fashion with no
need to adapt the reaction conditions to the reductive amina-
tion step or to purify the reaction intermediate. Moreover, high
chemoselectivity of the tested w-TAs for the saturated ketones
was shown in the cascade reactions.
volve the use of two or more enzymes in a defined reaction
pathway, have also been intensively investigated.[3] In fact, the
possibility to perform the enzymatic reactions of a multistep
process in a “one-pot” fashion, that is, without the isolation of
the intermediates, avoids time-consuming and yield-reducing
isolation and purification steps and minimizes the amounts of
chemicals/solvents required. Therefore, it might be effective in
reducing operation times, costs, and environmental impact.
As far as w-TAs are concerned, cascade reactions have been
widely applied to shift the equilibrium toward product forma-
tion.[4] Moreover, to achieve the in situ formation of ketone
substrates, w-TAs have been coupled to other enzymatic activi-
ties such as alcohol dehydrogenases (ADHs),[5] oxidases,[6] trans-
ferases,[7] and lyases.[8] In a few cases, the cascade process also
allowed the obtainment of products containing multiple ste-
reocenters, in particular chiral vicinal amino alcohols.[7,8]
Over the last years, other enzymes that have been thorough-
ly investigated for their application in asymmetric synthesis are
the ene-reductases (ERs) belonging to the Old Yellow Enzyme
(OYE) family.[9] They catalyze the stereospecific anti hydrogena-
tion of different activated olefins, including a,b-unsaturated
open-chain and cyclic ketones.
Chiral amines are valuable building blocks for the preparation
of pharmaceutical agents that span a range of therapeutic
areas including antihypertensives, antibiotics, antidepressants,
antihistamines, and antidiabetics.[1] In the last two decades,
biocatalysis has emerged as an interesting alternative to con-
ventional chemical methods for generating chiral amine com-
pounds. In particular, great efforts have been recently devoted
to the exploitation of the so-called w-transaminases (w-TAs) for
the preparation of optically pure primary amines.[2] These bio-
catalysts are pyridoxal-5’-phosphate (PLP)-dependent enzymes
capable of performing reductive amination reactions by using
either an a-amino acid or a simple aliphatic amine as the
amine donor. Therefore, they find several applications in the
asymmetric synthesis of a-chiral primary amines, and enzymes
with different substrate specificity are already available from
commercial sources.
Recently, we investigated the ER-catalyzed enantioselective
reduction of different open-chain a-alkyl-b-arylenones such as
1a,[10] as well as its coupling with the ADH-catalyzed synthesis
of the corresponding alcohols to give the most odorous ste-
reoisomers of the chiral commercial fragrance Muguesia
(Scheme 1a).[11]
Specifically, in the presence of the S. cerevisiae ER OYE3 and
a suitable d-glucose/glucose dehydrogenase (GDH) cofactor re-
To make the enzymatic processes more attractive for their
exploitation at an industrial level, multistep cascades, which in-
[a] Dr. D. Monti, M. C. Forchin, Dr. S. Riva
Istituto di Chimica del Riconoscimento Molecolare, CNR
Via Mario Bianco 9, 20131, Milano (Italy)
E-mail: sergio.riva@icrm.cnr.it
[b] M. Crotti, Dr. F. Parmeggiani, Prof. F. G. Gatti, Prof. E. Brenna
Politecnico di Milano, Department of Chemistry
Materials and Chemical Engineering “Giulio Natta”
Via Mancinelli 7, 20131, Milano (Italy)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500424.
Scheme 1. a) ER/ADH and b) ER/w-TA cascades starting from 1a.
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generation system, 1a was stereoselectively reduced to give
product (S)-2a with an enantiomeric excess (ee) value of 98%
in quantitative yield.[10] Subsequently, cascade coupling with
stereoselective ketone reduction was made possible by screen-
ing a set of commercially available (S)- and (R)-selective ADHs.
By optimization of the biotransformation conditions, the corre-
sponding syn and anti alcohols shown in Scheme 1a were ob-
tained in quantitative yields with 99% diastereomeric excess
(de) by adding all of the enzymes at the beginning of the reac-
tion to the mixture and without isolation of intermediate satu-
rated ketone (S)-2a.[11]
In the present work, we envisaged that, owing to the fact
that the structure of 2a resembles that of other common w-
TAs substrates,[2] corresponding syn and anti amine derivatives
3a could be obtained in a similar way by coupling the OYE3-
mediated alkene reduction of 1a with reductive amination re-
actions catalyzed by w-TAs (Scheme 1b).
lyzed by the respective w-TAs in the presence of an excess
amount of isopropylamine as the amine donor (Table 1). As ex-
pected, most w-TAs showed good to excellent activity towards
rac-2a, with conversion values up to 95% after 18 h. Only four
of the enzymes tested (i.e., ATA-007, ATA-200, ATA-254, and
ATA-301) were unable to catalyze the amine synthesis on
either enantiomer of 2a under these conditions.
The synthesis of both diastereoisomers of 3a by coupling
the ER-catalyzed alkene reduction and the w-TA-catalyzed re-
ductive amination was then investigated in one-pot sequential
processes. After performing the enantioselective reduction of
1a to (S)-2a by OYE3-catalyzed bioreduction (>99% conver-
sion, 98%ee), the w-TAs selected from the previous screening
were simply added to the reaction mixture together with the
PLP cofactor and the amine donor isopropylamine.
As shown in Table 1, all the tested w-TAs were capable of
catalyzing the formation of the amine derivative in these one-
pot reactions without the need to change the reaction condi-
tions or to purify the saturated reaction intermediate. As ex-
pected, in many cases the overall conversion values were
somehow lower than those observed during the previous w-
TAs screening on rac-2a, and this fact is consistent with the
lower amount of transaminase preparations employed in the
one-pot reactions (2 mgmLÀ1). However, in a few cases (i.e.,
ATA-025, ATA-113, ATA-237, ATA-251, and ATA-256), even quan-
titative conversions (>99%) were observed, which suggests an
appreciable enantiopreference of these enzymes towards (S)-
2a with respect to the other enantiomer.
To test this hypothesis, we decided to screen a commercially
available library of w-TAs (Codex ATA Screening Kit, obtained
from Codexis), including 24 enzymatic preparations showing
diverse substrate specificity and stereoselectivity. Notably, the
coupling of ERs and w-TAs in cascade reactions has not been
deeply studied to date, and no reports were available when
we started the present investigation. Only very recently, the
first example of an ER/w-TA cascade was reported by Born-
scheuer et al.,[12] finalized to the stereoselective synthesis of 1-
amino-3-methylcyclohexane diastereoisomers.
Racemic 2a (prepared by chemical reduction of 1a) was
tested as a substrate in reductive amination reactions cata-
Table 1. Screening of a panel of commercial w-TAs for the transamination of rac-2a and their combined application with OYE3 on substrate 1a (one-pot
sequential or cascade).
w-TA[a]
Typical selectivity[b] w-TA screening (substrate rac-2a) One-pot sequential OYE3/w-TA (substrate 1a) Cascade OYE3/w-TA (substrate 1a)
Conversion [%][c]
Conversion [%][c]
de [%][c]
Conversion [%][c] de [%][c]
ATA-007
ATA-013
ATA-025
ATA-113
ATA-117
ATA-200
ATA-217
ATA-234
ATA-237
ATA-238
ATA-251
ATA-254
ATA-256
ATA-260
ATA-301
ATA-303
ATA-412
ATA-415
(R)
(R)
(R)
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
0
84
93
93
84
0
76
89
92
88
92
0
–
55
>99
>99
18
–
35
42
>99
55
>99
–
>99
34
–
9
67
57
–
–
20
80
52
16
–
27
19
70
13
83
–
–
96 (2R,3S)-3a
96 (2R,3S)-3a
96 (2R,3S)-3a
>99 (2S,3S)-3a
>99 (2R,3S)-3a
–
>99 (2S,3S)-3a
>99 (2S,3S)-3a
95 (2S,3S)-3a
>99 (2S,3S)-3a
96 (2S,3S)-3a
–
96 (2R,3S)-3a
>99 (2S,3S)-3a
>99 (2R,3S)-3a
–
>99 (2S,3S)-3a
>99 (2S,3S)-3a
95 (2S,3S)-3a
>99 (2S,3S)-3a
96 (2S,3S)-3a
–
92
95
0
98 (2S,3S)-3a
94 (2S,3S)-3a
–
90
52
–
98 (2S,3S)-3a
94 (2S,3S)-3a
–
49
83
89
93
76
89
92
90
94
>99 (2R,3S)-3a
>99 (2R,3S)-3a
95 (2R,3S)-3a
97 (2S,3S)-3a
>99 (2S,3S)-3a
>99 (2S,3S)-3a
93 (2R,3S)-3a
96 (2R,3S)-3a
93 (2R,3S)-3a
5
>99 (2R,3S)-3a
>99 (2R,3S)-3a
95 (2R,3S)-3a
97 (2S,3S)-3a
>99 (2S,3S)-3a
>99 (2S,3S)-3a
93 (2R,3S)-3a
96 (2R,3S)-3a
93 (2R,3S)-3a
28
30
82
15
26
28
48
66
ATA-P1-B04 (S)
ATA-P1-F03 (S)
ATA-P1-G05 (S)
ATA-P2-A01 (R)
ATA-P2-A07 (R)
ATA-P2-B01 (R)
87
35
52
27
80
90
[a] Numbering according to the Codex ATA Screening Kit. [b] According to the manufacturer. [c] Determined by GC. The formation of byproducts was not
observed.
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Concerning the stereoselectivity, excellent results were ob-
tained with all the tested w-TAs, and the de values were be-
tween 93 and >99%. The previously described stereoprefer-
ence with prochiral aromatic ketones[2] was perfectly conserved
in all cases, and (S)-selective w-TAs formed (2S,3S)-3a, whereas
(2R,3S)-3a was obtained upon applying (R)-selective w-TAs.
Although saturated a-chiral ketone (S)-2a is a very stable
compound not posing any of the racemization issues observed
with other ERs products, for example, a-substituted aldehy-
des,[9f,13] the performance of OYE3/w-TAs cascade reactions,
that is, with all the enzymes and reagents present from the be-
ginning of the reaction, were investigated to further evaluate
the compatibility between these enzymes and the respective
reactions.
Although the conversion values obtained in the cascade re-
actions were in general slightly lower than those obtained in
the one-pot sequential processes, GC analyses showed good
compatibility of the two reactions. Remarkably, the formation
of the unsaturated amine derivative was never observed,
which thus shows the strict chemoselectivity of the tested w-
TAs for saturated ketone (S)-2a. Moreover, the stereoselectivity
was perfectly conserved, in terms of both the de and the abso-
lute configuration of the formed diastereoisomers.
Scheme 2. ER/w-TA cascades starting from 1b and 1c.
the synthesis of diastereomerically enriched derivatives 3b and
3c starting from 1b and 1c, respectively.
As shown in Table 2, the desired products, specifically,
amines (1S,3S)-3b and (1R,3S)-3b and amines (1S,3’S)-3c and
(1R,3’S)-3c, were obtained in both types of coupled processes
with similar conversions with up to 99% de, which thus dem-
onstrates the general applicability of ER/w-TA one-pot sequen-
tial and cascade reactions. As in the case of 1a, the typical ste-
reoselectivity shown by w-TAs was again well conserved, and
no formation of the unsaturated amines was observed in the
cascade reactions with these substrates, which thus confirms
the high chemoselectivity of the w-TAs toward the saturated
ketones.
To demonstrate the broad substrate scope of the ER/w-TA
coupled systems on structurally different substrates, two addi-
tional ketones were considered (Scheme 2). b-Substituted
cyclic enone 1b is a very well-known substrate for OYEs,[9,14]
and it has also been recently used to investigate the coupling
of ERs with other enzymatic activities such as ADHs and
Baeyer–Villiger monooxygenases,[15] and even w-TAs, as men-
tioned above.[12] Chromanyl derivative 1c was previously used
by our group as a building block to prepare amine (1R,3’S)-3c,
a precursor of analogues of NK-1 tachykinin receptor antago-
nists,[16] by an ER/ADH cascade and subsequent chemical modi-
fication.[13c] The choice of these two additional substrates also
required us to use different ERs in the alkene reduction step,
and OYE1 from S. pastorianus and OYE2 from S. cerevisiae
were reported to be the most stereoselective enzymes for the
preparation of (S)-2b (>99%ee)[15] and (S)-2c (98%ee),[13c] re-
spectively.
Selected ER/w-TA coupled reactions were scaled up (50 mg)
to isolate and characterize amine products 3a-c (see the Sup-
porting Information for details).
Although in the present work only two of the four possible
stereoisomers of chiral amines 3a–c were prepared, it might
be foreseen that the opposite enantiomer of intermediate sa-
turated ketone 2a–c could be obtained by using ER variants
with opposite stereoselectivity[9c,17] or by employing suitable
regioisomers of the starting material in a substrate-engineering
Preliminary screening of the w-TA library on racemic mix-
tures of saturated intermediates 2b and 2c showed that both
compounds are very good sub-
strates for the library of transa-
minases: rac-2b was accepted
Table 2. One-pot synthesis of optically pure diastereoisomers of amines 3b and 3c.
by all but three w-TAs (i.e., ATA-
007, ATA-117, and ATA-217),
whereas rac-2c was transformed
into the corresponding amines
by all the tested enzymes and in
most cases with quantitative
conversions (see the Supporting
Information for further details).
Subsequently, selected (R)-
and (S)-selective w-TAs were
evaluated in one-pot sequential
and cascade reactions aimed at
Substrate
Enzymes
One-pot sequential OYE/w-TA
Cascade OYE/w-TA
Conversion [%][a] de [%][a]
Conversion [%][a]
de [%][a]
1b
1b
1b
1b
1c
1c
1c
1c
OYE1/ATA-113
OYE1/ATA-237
OYE1/ATA-025
OYE1/ATA-415
OYE2/ATA-256
OYE2/ATA-113
OYE2/ATA-013
OYE2/ATA-025
63
78
70
64
63
87
65
96
>99 (1S,3S)-3b
>99 (1S,3S)-3b
90 (1R,3S)-3b
58 (1R,3S)-3b
79 (1S,3’S)-3c
80 (1S,3’S)-3c
80 (1R,3’S)-3c
75 (1R,3’S)-3c
78
62
99
62
95
90
68
93
98 (1S,3S)-3b
>99 (1S,3S)-3b
90 (1R,3S)-3b
72 (1R,3S)-3b
88 (1S,3’S)-3c
90 (1S,3’S)-3c
84 (1R,3’S)-3c
86 (1R,3’S)-3c
[a] Determined by GC. The formation of byproducts was not observed.
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approach, as it was, for example, already demonstrated for the
ER/ADH cascades.[18]
In summary, our investigation showed that the coupled use
of ene-reductases and w-transaminases could be exploited for
the obtainment of diastereomerically enriched (R)- and (S)-
amines with different structural features. The desired products
were obtained in one-pot sequential processes and even in
cascade processes, with up to >99% conversion and
>99%de.
Experimental Section
ERs (OYE1 from Saccharomyces pastorianus and OYE2 and OYE3
from S. cerevisiae) and Bacillus megaterium GDH were overex-
pressed in Escherichia coli BL21(DE3). Detailed methods are report-
ed in the Supporting Information. w-TA preparations were ob-
tained from Codexis (Codex ATA Screening Kit).
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The screening of w-TAs on racemic 2a–c was performed by adding
each substrate (10 mmol) dissolved in DMSO (20 mL) to a KPi buffer
solution (1.0 mL, 50 mm, pH 7.0) containing PLP (1 mm), iPrNH2
(1m), and the respective ATA preparation (10 mgmLÀ1). The mix-
ture was incubated for 18 h in an orbital shaker (160 rpm, 308C).
The solution was extracted with EtOAc (2”250 mL), centrifuging
after each extraction (15000 g, 1.5 min), and the combined organic
solutions were dried with anhydrous Na2SO4 and analyzed by GC.
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One-pot sequential ER/w-TA reactions were performed by adding
substrates 1a–c (10 mmol) dissolved in DMSO (20 mL) to a KPi
buffer solution (1.0 mL, 50 mm, pH 7.0) containing glucose
(20 mm), NADP+ (0.1 mm), GDH (4 UmLÀ1), and the required OYE
(60 mgmLÀ1). After 18 h of incubation in an orbital shaker (160 rpm,
308C), PLP (1 mm), iPrNH2 (1m), and the respective ATA preparation
(2 mgmLÀ1) were added, and the mixture was incubated for an ad-
ditional 18 h under the same conditions. Sample preparation and
analysis were performed as described for the screening of w-TAs
on racemic substrates.
Cascade ER/w-TA reactions on substrates 1a–c were performed by
mixing all of the reagents and enzymes described in the one-pot
sequential reaction at the beginning of the reaction. Samples were
recovered after 36 h and were analyzed as described for the
screening of w-TAs on racemic substrates.
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Acknowledgements
This work was supported by the “SusChemLombardia: prodotti
e processi sostenibili per l’industria lombarda” project, Accordo
Quadro Regione Lombardia-CNR, 16/07/2012 (protocol no.
18096/RCC).
Keywords: amines
·
biocatalysis
·
ene-reductases
·
stereoselectivity · transaminases
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Received: April 17, 2015
Revised: May 6, 2015
Published online on August 10, 2015
ChemCatChem 2015, 7, 3106 – 3109
www.chemcatchem.org
3109
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim