Stereoselective bioreduction of β-carboline imines through cell-free extracts from earthworms (Eisenia foetida)

Article abstract of DOI:10.1016/j.tetasy.2013.03.003

Although remarkable advances have been made over the last decade in organic synthesis, catalysis, and biotechnology, there is still a need to introduce and develop new processes for chemical production to achieve sustainable and cleaner approaches to support the increasing global pharmaceutical/chemical industry. There is a growing need to produce optically active compounds in high yields to maintain and support areas such as pharmaceutical and natural product synthesis. Thus, chemists today are looking for alternative reactions carried out under green conditions. In this context, we describe β-carboline imine reductions employing cell-free extracts from red Californian earthworms (Eisenia foetida) in high yields and enantiomeric excesses. The enantiomeric excess values of the bioreduction showed no dependence on the imine 1a-g substituents to afford amines with an (R)-configuration. Based on these data, a model for the cell-free extract from the earthworm is proposed.

Full text of DOI:10.1016/j.tetasy.2013.03.003

Tetrahedron: Asymmetry 24 (2013) 440–443
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective bioreduction of b-carboline imines through cell-free extracts
from earthworms (Eisenia foetida)
⇑
Yaneris Mirabal-Gallardo, Maria del Pilar C. Soriano, Leonardo S. Santos
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca PO Box 747, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 January 2013
Accepted 6 March 2013
Although remarkable advances have been made over the last decade in organic synthesis, catalysis, and
biotechnology, there is still a need to introduce and develop new processes for chemical production to
achieve sustainable and cleaner approaches to support the increasing global pharmaceutical/chemical
industry. There is a growing need to produce optically active compounds in high yields to maintain
and support areas such as pharmaceutical and natural product synthesis. Thus, chemists today are look-
ing for alternative reactions carried out under green conditions. In this context, we describe b-carboline
imine reductions employing cell-free extracts from red Californian earthworms (Eisenia foetida) in high
yields and enantiomeric excesses. The enantiomeric excess values of the bioreduction showed no depen-
dence on the imine 1a–g substituents to afford amines with an (R)-configuration. Based on these data, a
model for the cell-free extract from the earthworm is proposed.
Ó 2013 Elsevier Ltd. All rights reserved.
1
. Introduction
cell-free extract
from earthworms
1
Biocatalysis has attracted a growing interest in several fields
N
(E. foetida)
NH
2
3
4
N
H
N
H
such as genetics, molecular biology, fermentation technology,
NADPH, KPB
H
bioinformatics, nanotechnology,6 material sciences, advanced
5
7
R
R
3
7 °C, 2.5 h
8
9
10
spectroscopy, asymmetric organic synthesis, and others. Today,
biocatalysis is becoming one of the most powerful green tools in
chemistry and biotechnology. Several examples using multi-
enzymatic systems have been demonstrated for the large scale pro-
duction of pharmaceuticals and fine chemicals.11 Currently, bioca-
talysis has started to provide an important tool in synthetic
organic chemistry because there is an ever growing need to produce
optically active intermediate compounds under green conditions.
The availability of a certain microorganism is often the determin-
ing issue for an organic chemist when studying biotransformations
in synthetic reactions. For example, Baker’s yeast (BY, Saccharomy-
ces cerevisiae, and S. cerevisiae) is a readily available and often used
microorganism.
nes, we recently reported the bioreduction of b-carboline imines
mediated by Saccharomyces bayanus, which gave amine products
in good yields and enantiomeric excesses.9e Invertebrates, for exam-
ple, earthworms that are a widespread reptile living in the loose and
moist soils, which have been recognized as the main ecosystem
1
2
85-99% ee
Scheme 1. Bioreduction of b-carboline imines by cell-free extract from E. foetida.
to attract more interest in the area of waste biorecycling/biodegra-
19–25
dation.
Ishihara et al. reported the stereoselective reduction of
carbonyl compounds using the cell-free extract from earthworms
Lumbricus rubellus) in the presence of NADH or NADPH as a coen-
1
2
(
24
zyme. There are a few reports that employ cell-free extracts as bio-
catalysts to conduct asymmetric reduction of ketones, however
there are no reports based on prochiral imines.
Since a current challenge in synthetic organic chemistry is chi-
ral induction, we pursued the development of an efficient and
green methodology for the stereoselective synthesis of optically
active amines 2, via key intermediate 1 through bioreduction of
b-carboline imines employing the cell-free extract from earth-
worms (Eisenia foetida) in the presence of NADPH, as depicted in
Scheme 1.
1
3
1
4,15
For the production of chiral amines from imi-
1
7,18
engineers,
have not been used as alternative biocatalysts to
1
6
date. There are many reports available on anthelmintic activity
studies. However, it was only until a few years ago when they started
2
. Results and discussion
⇑
Corresponding author. Tel.: +56 71 201575; fax: +56 71 200448.
E-mail address: lssantos@utalca.cl (L.S. Santos).
Imine 1 was obtained in 75–83% overall yield from different
carboxylic acids and tryptamine by coupling with EDC/HOBt in
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.003

Y. Mirabal-Gallardo et al. / Tetrahedron: Asymmetry 24 (2013) 440–443
441
CH
2
Cl
2
at room temperature, which gave the corresponding
Si-face reduction
cell-free reductions)
(
amides. The amides were reacted by using Bischler–Napieralsky
N
R
Large
cyclization conditions to afford imines 1.28a After the production
(
whole-cell behaviour)
of several imines 1a–g, we next set out to explore the asymmetric
reduction. In nature, oxidoreductases catalyze selective transfer
hydrogenations of carbonyl compounds to alcohols using co-fac-
tors such as NAD(P)H. Therefore, NADPH might reduce imines in
a similar manner. Thus, the scope of the reduction of these imines
employing cell-free extracts from earthworms (E. foetida) as a bio-
catalyst was first investigated according to the reaction times
R
NH
Re-face reduction
RSmall
(whole-cell behaviour)
Figure 1. Proposed model for the bioreduction of b-carboline imines by the cell-
free extract from E. foetida (Si-face reductions) and RL/S group dependence found in
(Scheme 1, Table 1).
9e
whole-cell reductions mediated by Saccharomyces.
Table 1
Reduction of imines 1a–g by cell-free extract from E. foetida
Entry
R
ee%a,b Absolute configuration Yieldb (%)
3
. Conclusion
1
2
3
4
5
6
Me 1a
Et 1b
iso-Pr 1c
iso-Bu 1d
Ph 1e
>99
96
96
97
92
95
(R)
(R)
(R)
(R)
(R)
(R)
80
77
75
83
74
63
In conclusion, we have demonstrated the feasibility of this no-
vel protocol for the asymmetric biocatalytic reduction of b-carbo-
line imines to chiral amines through a cell-free extract from red
Californian earthworms with yields and %ee comparable to those
obtained by Noyori ruthenium methodology. Moreover, comparing
our approach with whole-cell systems, the cell-free extract has the
advantages of affording higher yields and selectivities, whereas in
the whole-cell method, we have observed that the cellular mem-
brane may retard the entry of the substrate into the cellular sys-
tems as well as inhibit the product from being released from the
system thus giving lower yields. This methodology is an attractive
alternative to the catalytic asymmetric methods employing Noyori
catalysts as well as whole-cell yeasts.
2 3
À(CH )10CH 1f
7
1g
95
(R)
68
O
a
Absolute configurations were determined by HPLC employing a ChiralPack-OD
column.
No changes were observed in the ee% or yields according to reaction times
between 2.5 and 24 h.
b
The reduction of 1a was carried out using an aqueous solution of
the cell-free extract, NADPH in a potassium phosphate buffer (pH
), and the mixture was stirred until completion of the reaction,
as monitored by TLC at 37 °C. After completion of the reaction,
the crude was basified with NaOH (1.0 M) to pH 10, after which
2
brine was added and extracted with Et O. Amine 2a was obtained
in 80% yield and >99% ee after 2.5 h. Then, in order to test whether
the reaction times might influence the ee% and yields, we per-
formed another experiment of 1a under the same conditions de-
scribed above with long reaction times. After 24 h of reaction, the
ee% values were similar to those previously as obtained, and no
improvement in the yields was observed (Table 1, entry 1). Next,
we tested other imines for the reduction with cell-free extracts
and NADPH, as depicted in Table 1. Enantiomeric excesses ranging
from 92% to 97% ee were observed with moderate to good yields
63–83%) of the amines 2b–g, as depicted in Table 1 (entries 2–7).
Finally, the absolute configuration of all the amine products was
determined to be (R); this was corroborated according to those
authentic amines obtained previously by the Noyori asymmetric
7
24
4
4
. Experimental
.1. General
4
-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride, tryp-
sin inhibitor from Glycine max (soybean), and b-nicotinamide ade-
nine dinucleotide reduced dipotassium salt (b-NADPH) were
obtained from Sigma–Aldrich. Imine compounds were synthesized
according to previously described protocols. Hexane, 2-propanol,
and diethylamine were of HPLC grade and used without further
treatment. Benzene, tryptamine, POCl , NaBH , as well as the
3 4
organic acids for imine preparation were purchased from Merck,
and used without previous purification. The enantiomeric excess
2
6
(
(
ee) values of the amine products were determined by HPLC anal-
ysis (Agilent 1260) equipped with an optically active capillary col-
umn (ChiralPack OD) by using hexane/2-propanol/diethylamine
2
6,28
reduction of imines.
For 1, the enzyme has to distinguish between the Si- and the Re-
face of the -system in order to yield chiral 2. The asymmetric
(
80:20:0.1) as the mobile phase at k 254.
p
reduction of imine-containing compounds by free-cell extract/
NADPH is not a widespread reaction. According to the results ob-
tained in Table 1, the imine reduction suggested a hydrogen trans-
fer to the Si-face of prochiral imine 1 with no influence of the R
groups. A noteworthy difference was observed when compared
with b-carboline imine reductions mediated by S. bayanus. In this
case, hydrogen transfers to the Re-face of prochiral imine 1 when R
S L
is R and hydrogen transfers to the Si-face when R is R or an aro-
4.2. Microorganisms
Red Californian earthworms (E. foetida) were collected from an
earthworm farm provider from Talca city, Maule, Chile. The sam-
ples of earthworm (approximately 25 g, equivalent to 60 earth-
worms) were mixed with 50 mL of potassium phosphate buffer
(KPB, 50 mM, pH 7). This suspension was cooled below 4 °C, and
subsequently homogenized in a blender for 1 minute at room tem-
perature. Then, the crude was placed in a refrigerated centrifuge
(Velocity 14R, Dynamica) at 10,000 rpm for 30 min at 4 °C, thus
eliminating cell debris. 4-(2-Aminoethyl) benzenesulfonyl fluoride
hydrochloride (final concentration, 10 mM) and trypsin inhibitor
(final concentration, 0.1 mM) were added as protease inhibitors.
The mixture was stirred gently for 30 min at 4 °C, and upon com-
pletion was again centrifuged at 10,000 rpm for 40 min at 4 °C.
The resulting supernatant (24.1 mL) was the crude cell-free
9
e
matic substituent adjacent to the imine group to yield amine 2, as
depicted in Figure 1. However, we noticed that when free-cell ex-
tract/NADPH was used, considerably higher ee% and yields were ob-
9
e
tained when compared with the whole-cell approaches. It is
known that in whole-cell biocatalysis, the cellular membrane often
retards the entry of the substrate into the cellular systems and
prevents the product from being released from the cellular system
for easy recovery, which explains the better yields observed in the
enzyme free-cell extracts.27
24
extract.

4
42
Y. Mirabal-Gallardo et al. / Tetrahedron: Asymmetry 24 (2013) 440–443
4
.3. Bioreduction
4.3.5. (R)-1-Phenyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
2
e
In a test tube of 10 mL were placed 1.0 mL of cell-free extract
[
a
3
]
D
= À4.2 (c 1.0, CHCl
3
), {lit. (R)-isomer, [
a
]
D
= À3.9 (c 1.03 in
2
8c
from E. foetida, NADPH (11
.1 M KPB (pH 7.0). The mixture was placed in an incubator shaker
ZHWY-100B, ZHICHENG) to 200 rpm at 37 °C with constant gentle
lmol), imines a–g (10
lmol), and
CHCl )}, 92% ee by HPLC analysis (ChiralPack OD, hexane/2-pro-
panol/diethylamine = 80:20:0.1, 1.0 mL/min, 254 nm, minor iso-
mer 15.8 min, major isomer 19.9 min). H NMR (400 MHz,
0
(
1
agitation for 2.5 and 24 h, respectively. After completion of the
reaction as determined by TLC monitoring, the mixture was basi-
fied with aqueous NaOH solution (1.0 M), extracted with diethyl
ether, dried with anhydrous sodium sulfate, and concentrated un-
der reduced pressure to furnish the crude products, which were
purified by silica-gel column chromatography, and finally analyzed
by HPLC to determine the ee%.
CDCl
1H), 5.17 (s, 1H), 7.10–7.19 (m, 3H), 7.30–7.37 (m, 5H), 7.56–7.60
(m, 1H), 7.66 (br s, 1H). HRMS (EI): m/z calcd for C17
248.1314, found 248.1309. The spectroscopic data are in accor-
3
): d 2.83–2.95 (m, 2H), 3.07–3.16 (m, 1H), 3.33–3.39 (m,
16 2
H N
2
8c
dance with previously reported data.
4.3.6. (R)-1-Undecyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
2
f
Compound 2f has not previously been described: [
.0, MeOH), 95% ee by HPLC analysis (ChiralPack OD, hexane/
D
a] = +52.4 (c
4
2
.3.1. (R)-1-Methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
1
a
= +52 (c 1.0, MeOH), {lit.28c (R)-isomer, [
D D
[a] a] = +53.5 (c 2.08,
2-propanol/diethylamine = 80:20:0.1, 0.8 mL/min, 254 nm, major
1
isomer 7.35 min, minor isomer 9.9 min). H NMR (400 MHz,
EtOH)}, >99% ee by HPLC analysis (Chiralcel OD, hexane/2-propa-
nol/diethylamine = 80:20:0.1, 1.0 mL/min, 254 nm, minor isomer
3
CDCl ): d 0.80 (t, 3H, J = 7.0 Hz), 1.10–1.89 (m, 16H), 1.30–1.45
1
(m, 2H), 1.59–1.69 (m, 1H), 1.72–1.82 (m, 1H), 2.62–2.73 (m,
H), 2.90–3.00 (m, 1H), 3.20–3.30 (m, 1H), 4.00 (br s, 1H), 7.03 (t,
8
.7 min, major isomer 5.6 min). H NMR (400 MHz, CDCl
3
): d 1.46
2
1
(
(
d, 3H, J = 6.7 Hz), 1.80 (br s, 1H), 2.88–2.83 (m, 2H), 3.05 (ddd,
H, J = 13.1, 9.2, 5.2 Hz), 3.37 (ddd, 1H, J = 13.1, 5.2, 3.7 Hz), 4.19
tq, 1H, J = 6.7, 2.0 Hz), 7.09 (dt, 1H, J = 7.3, 0.9 Hz), 7.15 (dt, 1H,
J = 7.3, 0.9 Hz), 7.31 (d, 1H, J = 7.3 Hz), 7,48 (d, 1H, J = 7.3 Hz),
H, J = 7.0 Hz), 7.09 (t, 1H, J = 7.0 Hz), 7.24 (d, 1H, J = 7.9 Hz), 7.39
1
(
1
3
d, 1H, J = 7.9 Hz), 8.00 (br s, 1H, NH). C NMR (100 MHz, CDCl
d 14.1, 22.7, 25.9, 29.4, 29.7, 29.73, 29.75, 29.79, 29.9, 32.0, 34.6,
6.0, 41.7, 52.4, 108.4, 110.9, 118.1, 119.4, 121.7, 127.3, 135.0,
3
):
3
7
.78 (br s, 1H). HRMS (ESI): m/z calcd for C12
H
14
N
2
187.1235, found
+
135.8. HRMS (ESI): m/z calcd for C22H34N2 327.2802, found
1
87.1234 [M+H] . The spectroscopic data are in accordance with
+
28a
327.2809 [C22H34N +H] .
previously reported data.
2
4
1
.3.7. (R)-1-(2,3-Dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-
H-b-carboline 2g
D 3
[a] ): d
.60–3.02 (m, 2H), 3.07 (t, 2H, J = 8.2 Hz), 3.05–3.20 (m, 1H), 3.26–
.45 (m, 2H), 4.50 (t, 2H, J = 8.2 Hz), 5.16 (s, 1H), 6.74 (d, 1H,
4
.3.2. (R)-1-Ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole 2b
= +61.0 (c 1.0, MeOH), {lit.29 (S)-isomer, [
= À62.6
COCH )}, 96% ee by HPLC analysis (ChiralPack OD, hexane/
-propanol/diethylamine = 80:20:0.1, 1.0 mL/min, 254 nm, major
[
a
]
D
a]
D
= +22.3 (c 1.0, MeOH). 1H NMR (300 MHz, CDCl
(
CH
3
3
2
3
2
1
isomer 8.8 min, minor isomer 11.2 min). H NMR (400 MHz,
CDCl ): d 1.10 (t, 3H, J = 7.1 Hz), 1.67–1.75 (m, 1H), 1.85–2.07 (m,
1
4
7
C
J = 7.8 Hz), 6.97–7.29 (m, 5H), 7.54 (d, 1H, J = 7.8 Hz), 10.4 (s, 1H).
The spectroscopic data are in accordance with previously reported
data.
3
H), 2.72–2.78 (m, 2H), 3.00–3.06 (m, 1H), 3.34–3.40 (m, 1H),
.00–4.04 (m, 1H), 7.06–7.19 (m, 2H), 7.32 (d, 1H, J = 7.2 Hz),
26b
.49 (d, 1H, J = 7.6 Hz), 7.77 (br s, 1H). HRMS (ESI): m/z calcd for
Acknowledgments
+
13
H
16
N
2
201.1392, found 201.1395 [M+H] . The spectroscopic
29b–d
data are in accordance with previously reported data.
The authors are thankful to the agronomist Camilo A. Rosales
Godoy for providing red Californian earthworms (E. foetida). This
work has been granted by FONDECYT (1110022). L.S.S. thanks
Proyecto Anillo (Integración de la Biología Estructural al desarrollo
de la Bionanotecnología, ACT 1107) for the support of research
activities.
4
2
.3.3. (R)-1-Isopropyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
c
[a]
D
= +57.2 (c 1.0, MeOH),30 96% ee by HPLC analysis (ChiralPack
OD, hexane/2-propanol/diethylamine = 80:20:0.1, 0.8 mL/min,
2
54 nm, major isomer 6.0 min, minor isomer 8.0 min). FT-IR: (KBr
À1
1
film, cm ) 1466, 3471. H NMR (400 MHz, CDCl
J = 7.2 Hz), 1.14 (d, 3H, J = 7.2 Hz), 2.16–2.28 (m, 1H), 2.72–2.77
m, 2H), 2.93–3.03 (m, 1H), 3.42–3.45 (m, 1H), 4.00–4.04 (m, 1H),
.10–7.15 (m, 2H), 7.31 (dd, 1H, J = 1.4, 7.3 Hz,), 7.50 (dd, 1H,
J = 1.4, 7.3 Hz,), 7.85 (br s, 1H). HRMS (EI): m/z calcd for C14
3
): d 0.91 (d, 3H,
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