One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald–Hartwig N-Arylation

Article abstract of DOI:10.1002/anie.202006246

The combination of biocatalysis and chemo-catalysis increasingly offers chemists access to more diverse chemical architectures. Here, we describe the combination of a toolbox of chiral-amine-producing biocatalysts with a Buchwald–Hartwig cross-coupling reaction, affording a variety of α-chiral aniline derivatives. The use of a surfactant allowed reactions to be performed sequentially in the same flask, preventing the palladium catalyst from being inhibited by the high concentrations of ammonia, salts, or buffers present in the aqueous media in most cases. The methodology was further extended by combining with a dual-enzyme biocatalytic hydrogen-borrowing cascade in one pot to allow for the conversion of a racemic alcohol to a chiral aniline.

Full text of DOI:10.1002/anie.202006246

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Accepted Article
Title: One-pot synthesis of chiral N-arylamines by combining
biocatalytic aminations with Buchwald-Hartwig N-arylation
Authors: Sebastian Cosgrove, Matthew Thompson, Syed Ahmed,
Fabio Parmeggiani, and Nicholas John Turner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202006246
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Angewandte Chemie International Edition
10.1002/anie.202006246
One-pot synthesis of chiral N-arylamines by combining
biocatalytic aminations with Buchwald-Hartwig N-arylation
Sebastian C. Cosgrove,[a],[b],# Matthew P. Thompson,[a],#,± Syed T. Ahmed,[a], Fabio Parmeggiani,*,[a],[c]
and Nicholas J. Turner*,[a],[b]
[
a]
Dr S. C. Cosgrove, Dr. M. P. Thompson, Dr S. T. Ahmed, Dr F. Parmeggiani and Prof N. J. Turner
Department of Chemistry, University of Manchester,
Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, UK
E-mail: fabio.parmeggiani@polimi.it, nicholas.turner@manchester.ac.uk
Dr S. C. Cosgrove and Prof N. J. Turner
Future Biomanufacturing Research Hub, University of Manchester,
Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, UK
Dr F. Parmeggiani
[
[
b]
c]
Department of Chemistry, Materials and Chemical Engineering “G. Natta”, Politecnico di Milano
Via Mancinelli 7, 20131, Milano, Italy
#
These authors contributed equally to this work. ±Current address: EnginZyme AB, Tomtebodavägen 6, House A1, Floor 4, 171 65, Solna, Sweden.
Supporting information for this article is given via a link at the end of the document.
Abstract: The combination of biocatalysis and chemo-catalysis
increasingly offers chemists access to more diverse chemical
architectures. Here, we describe the combination of a toolbox of chiral
amine producing biocatalysts with a Buchwald-Hartwig cross-coupling
reaction, affording a variety of -chiral aniline derivatives. The use of
a surfactant allowed reactions to be performed sequentially in the
same flask, preventing the palladium catalyst being inhibited by the
high concentrations of ammonia, salts or buffers present in the
aqueous media in most cases. The methodology was further
extended by combining with a dual-enzyme biocatalytic borrowing
hydrogen cascade in one-pot, to allow for the conversion of a racemic
alcohol to a chiral aniline.
Biocatalysis represents a powerful tool for the synthesis of
enantiomerically pure chiral amines.[9] Several different enzyme
classes have been reported including amine dehydrogenases
(AmDH),[10,11] imine reductases (IRED) and reductive aminases
(RedAm),[12–14] amine oxidases (MAO),[15,16] ω-transaminases (ω-
TA), [17,18] and engineered cytochrome P411s.[19,20] Despite the
broad application of these biocatalysts for the synthesis of both
cyclic and acyclic 1°, 2° and 3° amines, there have been few
reports describing the application of these systems for the
synthesis of N-aryl amines.[15,21,22] Interestingly, two recent papers
reported homologues of AspRedAm that accepted aniline as
amine donor with conversions up to 99%, however the substrate
scope was limited.[23,24]
N-arylamines are an important structural motif present in an array
of bioactive molecules including APIs and agrochemicals (Figure
1
). Methods for the synthesis of these compounds in
enantiomerically enriched form, that are typically based on
asymmetric reductive aminations of ketones using anilines as the
amine donor, are well known.[1] Transition metal catalysed
reductive amination often requires elevated temperatures and
pressures in addition to complex chiral ligands to achieve
Scheme 1. Retrosynthetic strategies for the chemoenzymatic formation of chiral
N-arylamines.
The combination of biocatalysts and chemo-catalysts allows
chemists to effect overall transformations with high efficiency, not
achievable using the individual catalysts alone.[25–28] Several
strategies for merging precious-metal catalysis and biocatalysis
have been reported.[29–34] In particular, palladium catalysed
methods have featured in several reported chemoenzymatic
reactions, with biocatalytic processes coupled to Suzuki-
Miyaura[35] and Heck[36] cross-coupling or Wacker[37] oxidation.
One frequently used Pd-catalysed transformation yet to be
combined with biocatalysis is the Buchwald-Hartwig cross-
coupling (BHA), which couples nucleophilic amines and aryl
halides to afford anilines.[38–41]
Figure 1. High-value chiral N-arylamine derivatives.
satisfactory yields and enantiomeric excess (ee).[2–5] On the other
hand, organocatalytic approaches require anhydrous conditions
in order to proceed however excellent yield and ee can be
obtained under relatively mild conditions.[6–8]
1
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Angewandte Chemie International Edition
10.1002/anie.202006246
Herein we present a chemoenzymatic approach to chiral N-
arylamines, combining a variety of enantioselective biocatalytic
transformations with
a
surfactant-enabled BHA (Scheme
1).[11,40,42]
We initially envisaged a one-pot process involving conversion of
the substrate (ketone/imine/alcohol) followed by in situ BHA in an
aqueous environment without any intermediate workup. In line
with the principles of green chemistry there is significant interest
in performing transition metal catalysed reactions in water.[43] For
example, the use of water-soluble palladium sources in the Suzuki
cross-coupling combined with an alcohol dehydrogenase (ADH)
reported by Borchert et al., gave excellent yields and ee but is
limited to water soluble starting materials.[33] Other approaches
using heterogeneous, immobilised or compartmentalised
catalysts have also been described.[29,34]
One plausible reason for the limited number of one-pot chemo-
enzymatic processes reported is the low solubility of many organic
reagents in water,[44] leading to slow reaction rates and low yields.
The Lipshutz group have reported a designer surfactant DL-α-
tocopherol methoxypolyethylene glycol succinate (TPGS-750-M,
Figure 2) that enables a variety of important cross-coupling
reactions to proceed in water.[45–47] Owing to the relatively low
concentration of the surfactant, reactants are highly concentrated
Figure 2. Structural components of TPGS-750-M.
within the lipophilic core. Rate acceleration, even at room
temperature, is commonly observed as a result. The Lipshutz
group demonstrated recently that TPGS-750-M could be used in
one-pot, chemo-enzymatic transformations using several
precious-metal catalysts and ADH enzymes.[48] They showed Pd
could be used in conjunction with ADH as well, however the
biotransformation mixture was added after the metal-catalysed
step was complete.
From the outset, it was unknown if either the enzyme or any
component of the biotransformation mixture would be detrimental
to the performance of the cross-coupling step. Initially we chose
to use engineered amine dehydrogenases (AmDHs), which use
ammonia as the sole amine source.[10,42] AmDHs have also been
applied in an elegant redox-neutral cascade alongside ADHs for
the asymmetric amination of alcohols.[49–52]
Table 1. Optimisation of Buchwald-Hartwig amination under biocatalyst conditions.
Entry
Temp.
Solvent
Pd-cat
Ligand
CyJohnPhos
CyJohnPhos
cBRIDP
Additive
n.a.
Conv. (%)[a]
1
2
3
4
5
6
7
8
9
100
water
[PdCl(cinnamyl)]
[PdCl(cinnamyl)]
2
2
6
0
100
1 M NH4Cl
n.a.
room temp.
water
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
[PdCl(allyl)]
2
2
2
2
2
2
2
2
2
2
2
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
TPGS-750-M
57 (24 h)
26
room temp.
1 M NH4Cl
cBRIDP
40
1 M NH4Cl
cBRIDP
>99
9
40
1 M NH4Cl +CFE
cBRIDP
40
1 M NH
4Cl +filtered CFE
cBRIDP
23
room temp.
water
tBuXPhos
tBuXPhos
tBuXPhos
tBuXPhos
tBuXPhos
tBuXPhos
0
50
50
50
50
50
water
>99
>99
80
1
1
1
1
0
1
2
3
1 M NH
1 M NH Cl +CFE
1 M NH Cl + filtered CFE
1 M NH Cl + purified enzyme
4Cl
4
4
95
4
90
[
a] Conversion determined by GC-FID analysis.
2
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Angewandte Chemie International Edition
10.1002/anie.202006246
Hence, there is also an opportunity to generate optically enriched
N-arylamines from racemic alcohols.
presumably due to the presence of the competing nucleophilic
amine alanine. Instead, the reaction mixture from the
biotransformation containing (R)-1 was extracted into toluene and
then coupling of (R)-1 with 2a–c and 2f–g could be performed
Initially we screened a number of palladium pre-catalysts, ligands
and conditions to promote the coupling of model substrate rac-1
with bromobenzene 2a (Table 1).[45,53,54] To investigate any
potential inhibitory effects, the cross-coupling conditions were
screened in the presence of reagents required for the biocatalytic
step. The impact of different biocatalyst preparations (cell free
extract (CFE) or purified proteins), and the presence of high
concentrations of ammonium salts were thus investigated.
The ligand tBuXPhos, has been reported to be a general ligand
suited to the coupling of primary amines,[54] and in combination
Table 2. Conversions for N-arylation of amines (R)-1 and (R)-5 with aryl
bromides 2a-g.
with the [PdCl(allyl)]
2
pre-catalyst reliably gave the best
conversions in the absence of the biocatalyst. Importantly, the
addition of concentrated ammonium chloride (necessary for the
AmDH step) did not affect the outcome of the cross-coupling
Product
3a
Conv. (%)[a][b]
90 (81)
Product
6a
Conv. (%)[a][b]
90 (81)
(entry 10). Finally, it was noted that in the presence of the CFE
containing the biocatalyst (entry 11) the conversions were lower
than with filtered CFE (entry 12). However, in the presence of the
purified enzymes the conversions were good to excellent (90 %)
3
b
71 (64)
6b
65 (59)
3c
93 (83)
6c
82 (74)
(
entry 13).Encouraged that the chemoenzymatic process could
3
d
e
91 (82)
6d
81 (73)
be combined efficiently in a one-pot, two-step process, the
reductive amination of ketones 4 and 7 (50 mM) to afford amines
3
62 (56)
6e
59[c] (53)
54 (49)
(R)-1 and (R)-5 (90% conversion, 90% and >99% ee respectively)
was performed using previously optimised conditions for AmDH
biotransformations.[55] The crude reaction mixture was diluted 1:1
with a solution of TPGS-750-M (5 wt% in H O) followed by
3f
70 (63)
6f
3
g
76 (68)
6g
90 (81)
2
addition of the reagents for the cross-coupling step (Scheme 2).
[
a] Conversion determined by GC-FID analysis. [b] Conversion for Buchwald-
Hartwig step indicated out of brackets, with overall conversion from ketone to
aniline indicated in brackets. [c] Oxidation to the corresponding aromatic
aldehyde was observed.
under reported conditions to give 3a–c and 3f–g (63–99%
conversion and >99% ee) (see Supporting Information).
To further exemplify the scope of our combined chemo-enzymatic
approach, we envisaged extending the process to the N-arylation
of cyclic chiral amines to furnish tertiary N-arylamines. Imine
reductases (IREDs) have been reported for the reduction of cyclic
imines,[22] amongst which the (S)-imine reductase (S-IRED) from
Streptomyces sp. GF3546 is reported to catalyse the asymmetric
reduction of cyclic five-, six-, and seven-membered imines.[12,56]
The S-IRED catalysed asymmetric reduction of pyrroline 8 was
performed under previously reported conditions to afford (S)-2-
methylpyrrolidine 9 (80% conv. >92% ee). The reaction mixture
was then diluted with a solution of TPGS-750-M as described
above. Using the Takasago ligand cBRIDP in lieu of tBuXPhos[57]
gave efficient coupling with aryl bromides 2a–g to the
corresponding N-arylamines 10a–g with good to excellent
conversions (Table 3). To demonstrate the synthetic utility of this
method, 10a was prepared on a preparative scale with the
addition of a toluene layer for the BHA, affording >100 mg in a
Scheme 2. Combined AmDH amination with BHA of ketones 4 and 7
The coupling of amines (R)-1 and (R)-5 with a panel of aryl
bromides 2a–g was accomplished using the optimised conditions
for the cross-coupling step to yield N-arylamines 3a–g and 6a–g
with good to excellent conversions (Table 2). Importantly, the
chirality generated during the biocatalytic step was preserved
during the cross-coupling step (see Supporting Information).
We next considered a one-pot N-arylation reaction in which the
chiral amine was generated by an ω‐transaminase (ω-TA).[17] ω‐
TAs are attractive options for the first step since they possess
broad substrate scope and give excellent ees.[17,18] The
transamination of ketone 4 (50 mM) with ATA-117 (Codexis, USA)
gave (R)-1 (>99% conversion, >99% ee) using an excess of
alanine as the amine donor. However, when the one-pot N-
arylation of 1 with 2a was attempted, no coupling was observed,
65% isolated yield and >99% ee (see Supporting Information).
Lastly, the same methodology was shown to be compatible with
the recently developed biocatalytic hydrogen-borrowing
amination of alcohols.[52] The system employs
a
non-
enantioselective variant (W110A-G198D) of an alcohol
dehydrogenase from Thermoanaerobacter ethanolicus coupled
with ChiAmDH (Scheme 3). On a preparative scale the chiral N-
arylamine 6c was obtained directly from the racemic alcohol 11
3
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Angewandte Chemie International Edition
10.1002/anie.202006246
In summary, we have demonstrated a new approach to the
synthesis of chiral N-arylamines by combining biocatalytic
reductive amination or imine reduction with surfactant-enabled
Table 3. Conversions for N-arylation of amine (S)-9 with aryl bromides 2a–g.
Buchwald-Hartwig
corresponding N-arylated amines are good to excellent (up to
0%). Importantly, the asymmetric centre established in the
cross-coupling. Conversions to
the
9
biocatalytic step is unaffected by the subsequent cross-coupling
reaction.
We envisage that this biocompatible, surfactant-enabled cross-
coupling approach will broaden the application of chemo-
enzymatic processes for the synthesis of high-value compounds.
Acknowledgements
S.C.C. acknowledges the EPSRC, BBSRC and UKRI for funding
through the Future Biomanufacturing Research Hub (grant
number EP/S01778X/1). M.P.T. is grateful to the Industrial
Affiliates of CoEBio3 for a studentship. S.T.A. and F.P. were
supported by the BBSRC and GSK (sLoLa grant number
BB/K00199X/1). N.J.T. is grateful to the ERC for the award of an
Advanced Grant (grant number 742987).
Product
Conv. (%)[a][b]
93 (74)
1
1
1
1
1
0a
0b
0c
0d
0e
84 (67)
94 (75)
95 (76)
Keywords: Amines • Biocatalysis • Chemo-enzymatic synthesis
67 (54)
•
Enzymes • Palladium catalysis
1
0f
61 (49)
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Angewandte Chemie International Edition
10.1002/anie.202006246
Entry for the Table of Contents
A two-step, one-pot chemoenzymatic synthesis of chiral anilines is reported. Chiral amine producing biocatalysts have been
combined in the same pot as a Pd catalyst to allow the direct conversion of prochiral and racemic starting materials to enantiopure
anilines. The use of a surfactant to enable this one-pot process is a first for biocatalysis.
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This article is protected by copyright. All rights reserved.