Biocatalytic Routes to Enantiomerically Enriched Dibenz[c,e]azepines

Article abstract of DOI:10.1002/anie.201708453

Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified

Full text of DOI:10.1002/anie.201708453

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Accepted Article
Title: Biocatalytic Routes to Enantiomerically Enriched
Dibenz[c,e]azepines
Authors: Scott P France, Godwin A Aleku, Mahima Sharma, Juan
Mangas-Sanchez, Roger M Howard, Jeremy Steflik, Rajesh
Kumar, Ralph W Adams, Iustina Slabu, Robert Crook, Gideon
Grogan, Timothy W Wallace, and Nicholas John Turner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708453
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http://dx.doi.org/10.1002/ange.201708453

Angewandte Chemie International Edition
10.1002/anie.201708453
COMMUNICATION
Biocatalytic Routes to Enantiomerically Enriched
Dibenz[c,e]azepines
[
a]
[a]
[b]
[a]
Scott P. France, Godwin A. Aleku, Mahima Sharma, Juan Mangas-Sanchez, Roger M.
[
c,d]
[c]
[c]
[e]
[a]
[d]
Howard, Jeremy Steflik, Rajesh Kumar, Ralph W. Adams, Iustina Slabu, Robert Crook,
[
b]
[e]
[a]
Gideon Grogan, Timothy W. Wallace, and Nicholas J. Turner*
Abstract: Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines
employing synthetic routes identified by traditional disconnection
strategies. In order to identify new and potentially more efficient
routes to these compounds, we sought to apply the principles
has highlighted the use of imine reductase (IRED) and

transaminase (-TA) biocatalysts to establish the key
stereocentres of these molecules. Several enantiocomplementary
IREDs were identified for the synthesis of (R)- and (S)-5-methyl-6,7-
dihydro-5H-dibenz[c,e]azepine with excellent enantioselectivity by
reduction of the parent imines. Crystallographic evidence suggests
that IREDs may be able to bind one conformer of the imine substrate
such that, upon reduction, the major product conformer is generated
directly. ω-TA biocatalysts were also successfully employed for the
production of enantiopure 1-(2-bromophenyl)ethan-1-amine enabling
an orthogonal route for the installation of chirality into
dibenz[c,e]azepine frameworks.
and
retrosynthesis.
continually
expanding
scope
of
biocatalytic
[
11–14]
Dibenz[c,e]azepines belong to a class of privileged bridged
biaryl frameworks that possess unique conformational features.
These architectures feature in several bioactive compounds,
[1]
such as anti-obesity drugs and analogues of the alkaloid
[
2]
colchicine, as well as providing key structural elements in chiral
[3,4]
[5]
organocatalysts
and
chiral
bases
(Figure
1a).
Dibenz[c,e]azepines can also act as molecular switches, owing
to the conformational influence of C-centred chirality on the
azepine ring with the axial chirality of the system. In their lowest
energy conformation, substituents at the C(5) or C(7) position of
the azepine ring are found to occupy a pseudo-equatorial
position, imposing a particular conformation on the biaryl axis.
Therefore, setting the C-centred chirality during the synthesis of
these compounds also establishes the preferred biaryl
conformation. If the C(5) or C(7) substituent is perturbed from a
pseudo-equatorial to a pseudo-axial position, for example after
N-derivatisation, a resulting switch in axial conformation occurs
Figure 1. Dibenz[c,e]azepine architectures. a) Dibenz[c,e]azepine frameworks
found in active pharmaceutical ingredients, natural product analogues,
organocatalysts and reagents in organic synthesis. b) Dibenz[c,e]azepine
acting as a molecular switch with the axial conformation inverting upon N-Boc
derivatisation.
The suite of biocatalysts available for the asymmetric synthesis
[15–
of chiral amines currently includes ω-transaminases (ω-TAs),
18]
[19–22]
imine reductases (IREDs),
reductive aminases
[
6]
via this centre-axis relay effect (Figure 1b).
Enantiomerically pure dibenz[c,e]azepines have previously been
[23]
[24,25]
(
RedAms),
ammonia lyases
amine dehydrogenases (AmDHs)
and
[26]
[27,28]
as well as hydrolases
and monoamine
for (dynamic) kinetic resolution or
[
5,7]
synthesised by employing chiral pool starting materials,
auxiliary methodology
chiral
[29–31]
oxidases (MAOs)
[
6,8,9]
[10]
or chiral transition metal catalysis
deracemisation procedures respectively.
With this toolbox of enzymes in mind, we initially envisaged
setting the C(5) stereogenic centre of the dibenz[c,e]azepine
framework by employing an IRED in the final step (Figure 2).
IREDs catalyse the NADPH-dependent asymmetric reduction of
prochiral imines to afford chiral amines and have been applied to
[
a]
S. P. France, Dr. G. A. Aleku, Dr. J. Mangas-Sanchez, I. Slabu,
Prof. N. J. Turner
School of Chemistry, University of Manchester, Manchester Institute
of Biotechnology, 131 Princess Street, Manchester M1ꢀ7DN, UK.
E-mail: nicholas.turner@manchester.ac.uk
[
32–
the synthesis of a range of chiral pyrrolidines and piperidines.
[
[
[
[
b]
c]
d]
e]
Dr. M. Sharma, Prof. G. Grogan
3
6]
York Structural Biology Laboratory, Department of Chemistry,
University of York, Heslington, York, YO10 5DD UK.
Dr. R. M. Howard, J. Steflik, Dr. R. Kumar
Recently, a sub-group of the IRED family, known as
[
23]
RedAms,
has been identified and shown to catalyse imine
formation as well as imine reduction in reductive amination
reactions of carbonyl compounds, although RedAms can also
catalyse the reduction of preformed cyclic imines. The imine
substrate 1 for the IRED mediated reduction could be derived
from the corresponding Boc-protected amino ketone 3 which
could itself be made via a Suzuki-Miyaura cross-coupling of aryl
boronic acid 4 and aryl bromide 5. Furthermore, we envisaged
preparing the chiral amine 5 using an ω-TA biocatalyst. ω-TAs
are pyridoxal-5’-phosphate (PLP)-dependent enzymes that
Groton Laboratories, Pfizer Worldwide Research and Development,
445 Eastern Point Road, Groton, Connecticut, 06340, US.
Dr. R. M. Howard, R. Crook
Sandwich Laboratories, Pfizer Worldwide Research and
Development, Discovery Park, Sandwich, Kent, CT13 9NJ, UK.
Dr. R. W. Adams, Dr. T. W. Wallace
School of Chemistry, University of Manchester, Manchester M13
9PL, UK.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
10.1002/anie.201708453
COMMUNICATION
transfer an amino group from an amine donor, such as
isopropylamine (IPA) or alanine, to a carbonyl compound.
The panel of imine substrates 1a-d was then screened with a
[
15]
[37,38]
library of 49 IREDs
including three from the recently
[
23]
described fungal RedAm sub-group
;
AspRedAm from
Aspergillus oryzae, AdRedAm from Ajellomyces dermatitidis and
AtRedAm from Aspergillus terreus. Biotransformation results
showed that imine substrates 1a and 1b, when reduced by an
IRED, typically gave high conversions (Table 2). Interestingly, in
the reduction of 1a, the fungal RedAms and the IRED from
[
38]
Amycolatopsis orientalis (AoIRED)
gave the (R)-configured
product while the other bacterial IREDs screened displayed
opposite enantioselectivity with excellent ee. For substrate (±)-
1c, the ability of the IREDs to perform a kinetic resolution by
reducing a single enantiomer of this compound was assessed,
however, this substrate proved to be generally more challenging
with typically lower conversions, modest product ees and E
values <5 observed in each case. Unfortunately, substrate (±)-
1d showed little to no conversion across all the wild-type
enzymes screened.
Table 2. Highlighted best performing enzymes from IRED
screen with substrates 7a-d.
Figure 2.
A biocatalytic retrosynthetic approach to the synthesis of 2
incorporating IRED and ω-TA biocatalysts.
The planned forward synthesis was carried out by preparing four
1
2
model imine substrates 1a-d that varied at R and R by H or Me.
Suzuki-Miyaura coupling of boronic acids 4i-ii and N-Boc aryl
bromides 5i-ii catalysed by Pd(amphos)Cl
biaryls 3a-d. Subsequent Boc deprotection by trifluoroacetic acid
TFA) and spontaneous intramolecular condensation furnished
imines 1a-d which were isolated as their hydrochloride salts
Table 1). 1D selective EXSY experiments of 1a in D O revealed
a half-life to axis inversion of 1.7 ± 0.4 seconds at 298 K with an
2
successfully afforded
(
Conversion of substrate/%, ee/% (R or S)
(
2
Enzyme
1a
1b
1c
1d
AspRedAm
AdRedAm
AtRedAm
AoIRED
IR52
>99, >99 (R)
>99, >99 (R)
6, 52 (R)
98
>99
25
5
>99
76
5
0
1
0
0
0
0
1
0
0
0
1
0
0
-1
energy barrier of 75.2
± 0.5 kJ mol (see Supporting
41, 16 (R)
27, 57 (R)
<1
26, 29 (R)
32, 6 (S)
38, 6 (S)
5
82, 11 (R)
80, 27 (R)
>99, 0
8
Information). Therefore, at room temperature there is fast
interconversion between conformers.
51, >99 (R)
94, >99 (S)
>99, >99 (S)
45, >99 (S)
99, >99 (S)
99, >99 (S)
>99, >99 (S)
>99, >99 (S)
97, >99 (S)
64, >99 (S)
IR55
IR62
IR67
IR86
IR89
IR91
IR92
IR93
>99
94
Table 1. Synthesis of imines 1a-d
>99
>99
>99
>99
59
4
Reaction conditions: 5 mM 1, 20% v/v cell lysate (equivalent to 50 mg/mL wet
cell weight final concentration), 0.3 mg/mL glucose dehydrogenase CDX-901
+
(
GDH), 50 mM glucose, NADP (0.4 mM), 100 mM NaP
i
buffer, pH 7.5, 25°C,
250 rpm, 24 h. Conversion and ee determined by HPLC or GC-FID analysis
on a chiral phase.
Preparative-scale reactions with 1a were successfully performed
with AspRedAm and IR91 to isolate opposite enantiomers of 2a
in high conversion, yield and enantioselectivity, demonstrating
the synthetic utility of this biocatalytic approach (Scheme 1).
Product NMR spectra were identical to those previously
1
2
Entry
R
R
H
Yield of 3
%]
3a, 95
Yield of 1
[%]
[
[
6,7]
1
2
3
4
Me
Me
H
1a, 87
reported,
confirming the predominant conformers as (R,aS)-
[
a]
[b]
Me
Me
H
3b, -[
1b, 52
a]
[b]
2a and (S,aR)-2a respectively. The conformers obtained are the
3c, -
1c, 63
[
a]
[b]
result of thermodynamic equilibration (86:14 major:minor at
H
3d, -
1d, 69
[
6]
2
98K). As the conformers of imine 1a can interconvert rapidly,
[
a] Impure after several rounds of column chromatography therefore isolated
it is possible the enzymes can carry out a dynamic process in
which a single conformer of the imine is converted to the major
product conformer (Scheme 1, Path A). However, we cannot
yield given after the next step. [b] Yield over two steps from 5 as limiting
reagent.
[
39]
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Angewandte Chemie International Edition
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COMMUNICATION
rule out whether the enzymes can reduce the imine conformer
that would lead to the minor conformer (Scheme 1, Path B).
Figure 3: Active site of AtRedAm in complex with substrate 1a and the
inactive cofactor NADPH
between monomers A (light blue) and B (gold). Electron densities correspond
to the F -F and 2F -F maps at levels of 2.5 σ and 1 σ respectively. The
4
. The active site is formed at the dimer interface
o
c
o
c
structure suggests that the enzyme can selectively bind conformer (aS)-1a
and subsequent hydride attack would lead directly to the lowest energy
product conformer (R,aS)-2a.
Scheme 1. Preparative-scale biotransformations to afford opposite
enantiomers of 2a employing AspRedAm and IR91. A dynamic process could
occur in which a single imine conformer is reduced to the major product
Table 3. Biotransformations with improved AspRedAm and
AoIRED variants.
conformer (A) although path
B may also occur. The same process is
envisaged to occur for the reaction with IR91 which is not shown in full for
brevity.
A crystal structure of AtRedAm, which has a closely related
active-site to AspRedAm, in complex with the imine substrate 1a
was successfully obtained through co-crystallisation with the
redox inactive cofactor analogue NADPH
4
.
Interestingly,
although the ligand is not bound in a mode that positions the
electrophilic imine carbon atom close to the C4 atom of the
cofactor analogue, the structure suggests that these enzymes
may be able to selectively bind a single conformer of the biaryl
imine 1a from a rapidly equilibrating mixture. Furthermore, this
conformer, (aS)-1a, would lead directly to the lowest energy
conformation of the product (R,aS)-2a upon reduction (Figure 3).
Wild-type AspRedAm and AoIRED gave poor conversions of (±)-
Conversion of substrate/%, ee/% (R or S)
IRED
1a
1b
1c
1d
AspRedAm WT
AspRedAm Q240A
AspRedAm M214A
AspRedAm W210A
AoIRED WT
>99, >99 (R)
>99, >99 (R)
92, >99 (R)
95, >99 (R)
51, >99 (R)
22, 92 (R)
5
98
>99
>99
>99
5
5
0
8
0
0
0
0
0
67, 7 (S)
17, 30 (R)
7, 9 (R)
<1
23, 40 (R)
16, 7 (R)
AoIRED N241A
AoIRED N241C
23
>99
1c and (±)-1d, therefore mutagenesis was explored in attempts
Reaction conditions: 5 mM 7, 0.5 mg/mL purified IRED, 0.4 mg/mL glucose
to improve activity towards these substrates. Analysis of the
ligand binding site as revealed by the ternary structure of
AtRedAm (Figure 3) and a sequence alignment with AspRedAm
and AdRedAm highlighted the following conserved residues;
+
dehydrogenase CDX-901(GDH), 20 mM glucose, NADP (0.3 mM), 100 mM
i
NaP buffer, pH 7.0, 30°C, 250 rpm, 24 h. WT = wild-type. † Conversion and
ee determined by HPLC or GC-FID analysis on a chiral phase.
(
(
A)D175, (B)W215, (B)M219 and (B)Q245 [(A)D169, (B)W210,
B)M214 and (B)Q240 in AspRedAm respectively] that may play
Mutagenesis of another enzyme, AoIRED, was also investigated
by performing alanine-scanning site-directed mutagenesis of
amino acid residues within 8 Å of the ligand binding site. The
single-point mutants generated (N171A, L175A, M178A, Y179A,
N241A, T244A, Y282A and Y283A) were screened for activity
towards (±)-1c in whole-cell biotransformations. The M178A and
N241A variants displayed good activity towards (±)-1c with
N241A showing higher conversion (23%). Attempts to further
expand the binding pocket did not improve the efficiency of
these variants as the double mutants M178A/N241A and
Y179A/N241A afforded lower conversion when compared to
N241A. Interestingly, residue Q240 in AspRedAm and N241 in
AoIRED are in analogous positions within their respective active
important roles in substrate binding and recognition. We
therefore generated and screened AspRedAm site-directed
mutants D169A, D169N, W210A, W210S, M214A and Q240A, in
an attempt to open up the active site to allow these bulkier
substrates to bind. Of these mutants, only the Q240A variant
afforded significantly improved conversion of (±)-1c (67%),
although with low enantioselectivity (7%, S). Furthermore, this
variant was able to convert substrate (±)-1d in contrast to the
wild-type (8% vs 0%).
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Angewandte Chemie International Edition
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COMMUNICATION
sites and mutagenesis studies showed that alanine variants at
these positions were the most successful for improving activity
towards (±)-1c and (±)-1d. Therefore, this position is potentially
an important target for expanding the substrate scope of
IREDs/RedAms towards bulkier substrates.
award from BBSRC and Dr Reddy’s (Grant code BB/K013076/1).
N.J.T. acknowledges the ERC for the award of an Advanced
Grant. Thanks also go to Oliver J. Dunks for assistance with
chemical synthesis and to Dr. Nicholas J. Weise for insightful
discussions.
The preparation of chiral imine (S)-1c in single enantiomer form
was achieved with the aid of TA biocatalysts ATA-113 and Pc-
Experimental Section
See supporting information.
[
40]
SpuC from P. chlororaphis subsp. aureofaciens
for the
synthesis of the intermediate (S)-7 from ketone 6 in high yield
and enantioselectivity (Scheme 2). Imine (S)-1c is a versatile
intermediate for the synthesis of various dibenz[c,e]azepine
Keywords: dibenz[c,e]azepines
retrosynthesis • imine reductase • transaminase
• biocatalysis • biocatalytic
[
41]
frameworks such as 8 via nucleophilic attack onto the imine.
This route could also provide access to compound 2d which was
not possible in high conversion with IRED catalysis. (S)-1c was
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Angewandte Chemie International Edition
10.1002/anie.201708453
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Scott P. France, Godwin A. Aleku,
IRED
ω-TA
Mahima Sharma, Juan Mangas-
Sanchez, Roger M. Howard, Jeremy
Steflik, Rajesh Kumar, Ralph W. Adams,
Iustina Slabu, Robert Crook, Gideon
Grogan, Timothy W. Wallace, and
Nicholas J. Turner*
>99% ee
Up to >99% ee
Up to 95% isolated
Up to 86% isolated yield
Biocatalytic Retrosynthesis
1
2
R
= H, Me; R = H, Me
Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines highlighted the use of
imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish key
stereocentres of these molecules. Several enantiocomplementary IREDs were
identified for the synthesis of enantiopure dibenz[c,e]azepines. Crystallographic
evidence suggests that IREDs may be able to bind one conformer of the imine
substrate. ω-TA biocatalysts also enabled an orthogonal route for the installation of
chirality.
Page No. – Page No.
Biocatalytic Routes to
Enantiomerically Enriched
Dibenz[c,e]azepines
This article is protected by copyright. All rights reserved.