Deracemization by simultaneous bio-oxidative kinetic resolution and stereoinversion

Article abstract of DOI:10.1002/anie.201400027

Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100-% conversion and 100-% ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure (S)-berbines. The racemic substrates were transformed to optically pure products (ee>97-%) with up to 98-% conversion and up to 88-% yield of isolated product. From two make one: Chemo-enzymatic stereoinversion and enzymatic kinetic resolution have been combined in a simultaneous cascade process to transform racemic substrates (A, ent-A) into optically pure product P. The concept was exemplified for benzylisoquinolines rac-1 yielding optically pure berbines (S)-2. The reaction system comprised a monoamine oxidase (MAO-N), morpholine-borane, and the berberine bridge enzyme (BBE).

Full text of DOI:10.1002/anie.201400027

Angewandte
Chemie
DOI: 10.1002/anie.201400027
Redox Deracemization
Deracemization By Simultaneous Bio-oxidative Kinetic Resolution and
Stereoinversion**
Joerg H. Schrittwieser, Bas Groenendaal, Verena Resch, Diego Ghislieri, Silvia Wallner, Eva-
Maria Fischereder, Elisabeth Fuchs, Barbara Grischek, Johann H. Sattler, Peter Macheroux,
Nicholas J. Turner,* and Wolfgang Kroutil*
Abstract: Deracemization, that is, the transformation of
a racemate into a single product enantiomer with theoretically
100% conversion and 100% ee, is an appealing but also
challenging option for asymmetric synthesis. Herein a novel
chemo-enzymatic deracemization concept by a cascade is
described: the pathway involves two enantioselective oxidation
steps and one non-stereoselective reduction step, enabling
stereoinversion and a simultaneous kinetic resolution. The
concept was exemplified for the transformation of rac-benzyl-
isoquinolines to optically pure (S)-berbines. The racemic
substrates were transformed to optically pure products (ee >
97%) with up to 98% conversion and up to 88% yield of
isolated product.
S
everal techniques have been developed to overcome the
limitation of a kinetic resolution (50% maximum yield), such
as dynamic kinetic resolution (DKR),[1] dynamic kinetic
asymmetric transformation (DYKAT),[2] stereoinversion,[3,4]
or enantioconvergent processes (Scheme 1).[5,6] These tech-
niques allow the process of deracemization to be achieved,
that is, conversion of a racemate into an optically pure
product with theoretically 100% yield and 100% ee.
Scheme 1. a) Kinetic resolution, b)–e) basic strategies for deracemiza-
tion, and f) the designed strategy to combine stereoinversion and
kinetic resolution.
[*] Dr. J. H. Schrittwieser, Dr. V. Resch, E.-M. Fischereder, E. Fuchs,
B. Grischek, Dr. J. H. Sattler, Prof. Dr. W. Kroutil
Institut fꢀr Chemie, Organische und Bioorganische Chemie
Karl-Franzens-Universitꢁt Graz
Heinrichstrasse 28, A-8010 Graz (Austria)
E-mail: wolfgang.kroutil@uni-graz.at
The berberine bridge enzyme (BBE) catalyzes the
enantioselective transformation of 1-benzyl-1,2,3,4-tetrahy-
Dr. B. Groenendaal, Dr. D. Ghislieri, Prof. Dr. N. J. Turner
School of Chemistry, University of Manchester
Manchester Institute of Biotechnology
131 Princess Street, Manchester, M1 7DN (UK)
E-mail: nicholas.turner@manchester.ac.uk
À
droisoquinolines to yield berbines by aerobic C H activation
À
at the N-methyl group, forming a new intramolecular C C
bond (Scheme 2). This reaction has been shown to be suitable
Dr. S. Wallner, Prof. Dr. P. Macheroux
Institut fꢀr Biochemie, Technische Universitꢁt Graz
Petersgasse 12, 8010 Graz (Austria)
[**] This study was financed by the Austrian Science Fund (FWF Project
P20903-N17 and P22115-N17). E.-M.F. received funding from the
European Union’s seventh framework program FP7/2007–2013
under grant agreement no. 289646 (KyroBio). B.G. and D.G. were
supported by a Marie Curie ITN (Biotrains FP7-ITN-238531), and we
also acknowledge a Royal Society Wolfson Merit Award to N.J.T.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400027.
ꢂ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
À
Scheme 2. Kinetic resolution by enantioselective oxidative C C bond
formation catalyzed by the berberine bridge enzyme (BBE).
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Communications
for the preparation of various novel optically pure berbines.[7]
As the enzyme transforms only one substrate enantiomer, this
reaction is a kinetic resolution.
To overcome the limitation of BBE-catalyzed kinetic
resolution, we first envisioned to introduce racemization of
the substrate enantiomers to set up a DKR. However, this
strategy proved problematic for the compounds of interest:
Among the published procedures for amine racemization,
which rely on homogeneous[8] or heterogeneous[9] metal
catalysis, or thiyl radical-mediated reversible H-abstrac-
tion,[10] no method was suitable to act exclusively on the
benzylisoquinoline substrates whilst leaving the berbine
products untouched. For example, Shvoꢀs diruthenium com-
plex[11] racemized benzylisoquinolines and berbines alike[7a]
when employed under previously described reaction condi-
tions.[8g] Raney nickel led to degradation of the complex
alkaloids, whereas palladium on charcoal did not show any
detectable racemization activity at all.
Figure 1. Results of substrate screening with MAO-N variant D11.
Activity (criterion: mean> 5 standard deviations) was found for
substrates 1a–d (light gray), as well as the positive controls rac-
phenylethylamine 3 and rac-crispine A 4 (both dark gray). Error ranges
represent standard deviations of triplicate experiments.
As a chemical racemization process could not be realized
and because no suitable enzyme for racemization of these
substrates is known,[12] an alternative was required. However,
neither a DYKAT nor an enantioconvergent process seemed
feasible. A stereoinversion is also unsuitable, as in this case
the product structure is identical to the substrate except for its
optical purity. Consequently, we designed a strategy wherein
the concept of stereoinversion is combined with kinetic
resolution (Scheme 1 f). Generally speaking, stereoinversion
of the enantiomer ent-A will give its mirror image A, which
will be transformed further in the kinetic resolution to yield
exclusively product P in theoretically 100% yield. In the
present case, this strategy should allow the conversion of both
substrate enantiomers of benzylisoquinolines rac-1 into opti-
cally pure berbines (S)-2.
Stereoinversion by cyclic deracemization of various
amines has been described employing a monoamine oxidase
(MAO) in combination with an achiral reducing agent.[3]
Unfortunately, all established MAOs[3] were unsuitable for
substrates 1a–d. However, a recently developed variant of the
MAO from Aspergillus niger (MAO-N variant D11) has been
reported to oxidize 1-phenyl-1,2,3,4-tetrahydroisoquinoline
with high (R)-selectivity.[13] The combination of this biocat-
alytic oxidation with non-stereoselective reduction of the
resulting imine by ammonia–borane afforded the (S)-enan-
tiomer (ee = 98%) from the racemate.
soluble boranes would be more compatible with BBE, as they
would be prevented from entering the active site of the
enzyme. Consequently, tBuNH2·BH3, Me3N·BH3, and mor-
pholine·BH3 were tested as alternative reductants and proved
more suitable for our system (Supporting Information, Fig-
ure S1).
Comparing the Me3N·BH3 and morpholine·BH3 complex
with NH3·BH3 in the stereoinversion (MAO), it turned out
that the former two actually performed better than the
commonly employed reducing agent NH3·BH3, whereby
morpholine·BH3 worked best (Supporting Information, Fig-
ure S2).
After these prerequisite investigations, a stepwise one-pot
procedure was tested first (Scheme 3); thus, the stereoinver-
sion of substrates rac-1a–c by the MAO-N/borane-system was
run to completion before BBE was added to the reaction
mixture. The BBE-catalyzed ring-closure was either carried
Testing the MAO-N D11 variant for the oxidation of
substrates 1a–d showed that they were indeed accepted
(Figure 1). Additionally and importantly, the desired products
including 2c and 2d were not oxidized, which is the
prerequisite for their stereochemical stability under the
conditions of a final simultaneous cascade process. Chiral
analysis of the MAO-N catalyzed oxidations revealed that
1a–c were converted with excellent enantioselectivity (E >
200), transforming essentially only the (R)-enantiomer, while
the enantioselectivity was low for 1d (E = 6.5). Consequently,
1d was not investigated further.
Previous studies have found that BBE is inhibited by
reducing agents,[14] as we confirmed for the ammonia–borane
complex, which is most commonly employed in combination
with MAO-N. We hypothesized that more bulky or less water-
Scheme 3. Deracemization of benzylisoquinolines rac-1 to berbines
(S)-2 by a MAO/BBE/borane redox cascade (performed either in
a stepwise or a concurrent fashion). MAO=monoamine oxidase
MAO-N (variant D11).
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Angew. Chem. Int. Ed. 2014, 53, 3731 –3734

Angewandte
Chemie
out after removal of the MAO-N biocatalyst by centrifuga-
tion, or BBE was directly added to the reaction mixture.
The overall transformation of rac-1 to (S)-2 proceeded
similarly well in both cases, resulting in high conversions
(Table 1). Additionally, all compounds were obtained in
In summary, a new concept to transform a racemic
substrate to an optically pure product was established,
whereby the substrate and product differ in structure. The
concept combines stereoinversion of one substrate enantio-
mer with a kinetic resolution. In the example presented
herein, the cascade comprises an enantioselective biocatalytic
amine oxidation, a chemical non-stereoselective iminium ion
Table 1: Deracemization of benzylisoquinolines rac-1 to berbines (S)-2 by
a stepwise transformation using MAO in the first step and BBE in the
second.
À
reduction, and an enantioselective aerobic C C bond for-
mation to transform benzylisoquinolines rac-1 to berbines
(S)-2. The three-step system led to conversions of up to 98%
with up to 88% yield of isolated optically pure product (S)-2
(ee > 97%, HPLC). Intriguingly, the two flavin-dependent
oxidases employed act on different parts of the benzylisoqui-
noline substrate whereby each enzyme (MAO-N, BBE)
preferentially transform the opposite enantiomer. The dera-
cemization cascade was successfully demonstrated on prep-
arative scale (150 mg), stimulating further developments for
cascade reactions involving chemical and biocatalytic steps to
avoid the disadvantages of kinetic resolution, thereby
increasing the yield and making synthetic routes more
economic and environmentally benign.
Substrate
Procedure[a]
Time[b] [h]
(S)-2[c] [%]
ee (2)[d] [%]
1a
1a
1b
1b
1c
1c
A
B
A
B
A
B
48+24
48+24
48+24
48+24
72+24
72+24
93
90
97
>97
>97
>97
>97
>97
>97
95
79[e]
79[e]
[a] Procedure A: direct addition of BBE to the reaction mixture after
completion of the first step. Procedure B: addition of BBE after removal
of MAO by centrifugation. [b] Reaction time for 1st+2nd step.
[c] Determined by HPLC on an achiral stationary phase. [d] Determined
by HPLC on a chiral stationary phase. [e] 4% of regioisomer formed.
enantiomerically pure form (ee > 97%, HPLC), which indi- Experimental Section
Representative MAO-N/BBE cascade transformation on preparative
cated that the enantioselectivity of BBE was not impaired by
the extended reaction system.
scale: In an Erlenmeyer flask (250 mL), lyophilized cells of E. coli
C43(DE3) expressing MAO-N D11 (5.0 g) were resuspended in
phosphate buffer (45 mL; 100 mm K-phosphate, pH 7.7). Morpholi-
Consequently, the two transformations were performed
simultaneously in one pot. Thus, the two enantioselective
oxidation reactions catalyzed by two different flavin-depen-
dent enzymes (MAO and BBE) and the non-stereoselective
morpholine–borane reduction were started concurrently for
this cascade. It is noteworthy that in contrast to our previous
studies on BBE,[7b] where catalase was required to protect the
enzyme from oxidative inactivation by hydrogen peroxide,
the cascade system did not profit from the addition of
catalase.[15]
As the initial experiments indicated that the simultaneous
reaction worked well for substrate rac-1a and rac-1b,[16] the
synthetic applicability of the simultaneous cascade system
was investigated in preparative-scale reactions (150–165 mg,
0.5 mmol). Excellent conversions were achieved for both
substrates; for example, the deracemization of rac-1b reached
near-completion within 24 h (Table 2). The reaction products
(S)-2a and (S)-2b were isolated in 88% and 80% yield,
respectively, in optically pure form (ee > 97%).
ne·BH3 (505 mg, 5 mmol), BBE solution (105 mL of
a 354 mm
preparation; final conc. 0.05 gLÀ1) and a solution of substrate 1e
(150 mg, 0.5 mmol; final conc. 10 mm) in DMSO (5 mL) were added,
and the mixture was shaken at 378C and 150 rpm. After 24 h,
additional morpholine·BH3 (250 mg, 2.5 mmol) and BBE solution
(105 mL) were added, and shaking was continued. After 48 h, a sample
(250 mL) was taken, extracted with EtOAc and analyzed for
conversion. HPLC analysis showed 92% product formation, and
the reaction mixture was centrifuged (4000 rpm, 1 h, 218C) to remove
the cell mass. The supernatant was extracted with EtOAc (3 ꢁ 20 mL),
whereby phase separation was accelerated by centrifugation; the cell
pellets were suspended in EtOAc, centrifuged again (4000 rpm,
10 min, 218C), and the EtOAc phase was combined with the extracts.
The combined organic phases were dried over Na2SO4 and the solvent
was evaporated under reduced pressure to give 0.60 g of a yellowish
liquid. Column chromatography (silica gel, CH2Cl2/MeOH/
NH3(aq) = 96:3:1) afforded 131 mg (88%) of (S)-2e as a white solid
(for product characterization, see the Supporting Information).
Received: January 2, 2014
Published online: February 24, 2014
À
Keywords: alkaloids · asymmetric synthesis · C C coupling ·
deracemization · enzyme catalysis · simultaneous cascades
Table 2: Deracemization of benzylisoquinolines rac-1 to berbines (S)-2
via a cascade transformation using MAO, BBE, and morpholine-borane
concurrently.[a]
.
Substrate
Time
[h]
Conv. (2)[b]
Yield (S)-2[c]
ee (2)[d]
[%]
[%]
[%]
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incomplete conversion to 2c.
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