Concurrent Biocatalytic Oxidation and C-C Bond Formation via Gold Catalysis: One-Pot Alkynylation of N-Alkyl Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acscatal.8b03169

A cross-dehydrogenative coupling process has been developed involving the enzymatic oxidation of tetrahydroisoquinolines (THIQ) together with gold-catalyzed C-C bond-formation. The transformation demonstrates the compatibility of gold-mediated chemocatalysis and monoamine oxidase biocatalysis which act co-operatively in one vessel. A range of N-alkyl THIQs were functionalized in this manner at C-(1) position in high yields.

Full text of DOI:10.1021/acscatal.8b03169

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Letter
Concurrent Biocatalytic Oxidation and C–C Bond Formation via Gold
Catalysis: One-Pot Alkynylation of N-Alkyl Tetrahydroisoquinolines
Marcin Odachowski, Michael F Greaney, and Nicholas J Turner
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03169 • Publication Date (Web): 21 Sep 2018
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ACS Catalysis
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Concurrent Biocatalytic Oxidation and C–C Bond Formation via Gold
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Catalysis: One-Pot Alkynylation of N-Alkyl Tetrahydroisoquinolines
Marcin Odachowski†,‡, Michael F. Greaney*,† & Nicholas J. Turner*,‡
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†
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom.
‡
School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manches-
ter, M1 7DN, United Kingdom.
ABSTRACT: A cross-dehydrogenative coupling process has been developed involving the enzymatic oxidation of tetrahy-
droisoquinolines (THIQ) together with gold-catalyzed C–C bond-formation. The transformation demonstrates the com-
patibility of gold mediated chemocatalysis and monoamine oxidase biocatalysis which act co-operatively in one vessel. A
range of N-alkyl THIQs were functionalized in this manner at C-(1) position in high yields.
KEYWORDS biocatalysis, gold catalysis, concurrent catalysis, chemobiocatalytic, one-pot process, cross-dehydrogenative cou-
pling, green chemistry, process intensification
The development of one-pot chemoenzymatic processes
is a very active area of research, creating new vistas to
safer, shorter and more efficient routes1–3. The combina-
tion of chemo- and biocatalysis has great potential for
advances in process intensification under Green Chemis-
try principles, taking inspiration from Nature4 where
chemical components can fulfil their tasks sequentially
with enzymes as in a natural biosynthetic cascade.5 In this
way, not only reduction of production costs, waste gener-
ation and improvement of overall efficiency is achieved
but also implementation of new technologies relying on
clean reactions and fewer purification steps becomes fea-
sible (e.g. flow chemistry).6,7 Biocatalysts have proven ex-
tremely valuable in chemical production due to the ex-
quisite efficiency and selectivity with which they catalyze
reactions. The tolerance of biocatalysts to organic sol-
vents and high substrate concentrations has been signifi-
cantly improved through protein engineering,8 setting the
stage for new co-operative syntheses using concurrent
chemobiocatalytic processes.
used membrane compartmentalization to effect an effi-
cient halogenation-coupling cascade of heteroarenes un-
der aqueous conditions. Interestingly, Grubbs catalyst
could be engaged in the alkene metathesis reaction lead-
ing to an intermediate pyrroline in a biphasic system
where MAO-N oxidative activity allowed for the synthesis
of N-phenyl pyrroles [Scheme 1., c)].11,12 We were interest-
ed in expanding the scope of transition metals (TMs) that
could be harnessed in chemobiocatalytic synthesis to cat-
alyze the formation of carbon–carbon bonds under bio-
logical conditions (i.e. buffered aqueous system, aerobic
atmosphere). Gold catalysis has witnessed extensive
growth in recent years, particularly in respect to alkyne
functionalization under mild conditions, creating new
transformations for base chemical building blocks.13,14 One
of the main features of gold catalysis is that the oxidation
state of the metal during the catalytic cycle often remains
unchanged.15 We reasoned that such redox neutrality of
gold catalysts could be harnessed to address the issue of
incompatibility of a metal catalyst and the enzymatic co-
factor (e.g. FAD) which impacts on the design of concur-
rent chemobiocatalytic processes.
One of the strengths of chemocatalysis that is particularly
attractive to combine with biocatalysis is the ability of
chemocatalysts to catalyze carbon–carbon bond for-
mation. For example, Suzuki cross-coupling of an aryl
halide has been used by Gröger and-co-workers in a one-
pot, two-step process in conjunction with ketoreductase.
[Scheme 1., a)].9 The Suzuki reaction has also been cou-
pled with regioselective, enzymatic halogenation as
shown by Micklefield and Greaney [Scheme 1., b)],10 who
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Scheme 1. Current State-of-the-Art Methods for One-
Pot, Chemoenzymatic Processes Involving C-C Bond
Formation.
Page 2 of 7
to oxygen in aqueous medium in contrast to organic sol-
vents.27 We discovered that gold acetylide addition to
iminium ions occurred with quantitative yield at room
temperature in potassium phosphate buffered solution
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a) Gröger, 2008. Two-step, telescopic process: Suzuki coupling and enzymatic reduction.
(0.2
M substrate concentration (see SI, Section 5, for dis-
Pd(PPh3)2Cl2
(2 mol%)
PhB(OH)2 (1.0 equiv.)
Na2CO3 (40 equiv.)
cussion and optimization). With a view to achieving con-
current catalysis with a biocatalyst, it is critical to consid-
er that enzymes often operate at lower substrate concen-
tration. Therefore, we carefully optimized conditions for
two separate processes: i) enzymatic oxidation of 1 and ii)
O
O
OH
(S)-ADH
NADH
i-PrOH:buffer
48 h, rt, pH 7
Br
Ph
Ph
H2O, 17 h, 70 °C
91 %
>99 % ee
b) Micklefield & Greaney, 2016. Compartmentalized enzymatic halogenation & Suzuki coupling.
organometallic addition to 2 and identified 0.1
M as opti-
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mum substrate concentration (see SI, Table S1.). Pleasing-
ly, we were able to integrate these two transformations
into a one-pot process where both catalysts operate in
aqueous phase without mutual deactivation delivering
product 3a in excellent 79 % yield (Table 1.). To the best
of our knowledge, this is the first example where gold
catalysis is working simultaneously with an operational
biocatalyst.
Pd(OAc)2 (10 mol %)
PhB(OH)2 (5.0 equiv.)
CsF (10 equiv.)
HO2C
HO2C
HO2C
Halogenase CLEA
FAD, GDH2, NaBr
N
N
N
Br
buffer, 16 h, rt
buffer, 24 h, 80 °C
H
H
H
75 % yield
membrane
c) Turner & Castagnolo, 2016. Biphasic process: alkene metathesis & enzymatic oxidation.
Grubbs II (5 mol%)
MAO-N D5
N
Ph
N
Ph
N
iso-octane:buffer
24 h, 37 °C
Ph
78 % yield
d) This work:
Having developed a simple procedure for the chemobio-
catalytic, one-pot assembly of α-disubstituted N-Me-
THIQ we next explored the substrate scope of this trans-
formation. As illustrated in Table 1, substitution around
the phenyl ring of arylacetylenes was well tolerated. In
this fashion, electron-rich alkoxy- and alkylethynylben-
zenes were coupled with excellent yields giving products
3a-g. Similarly, arylacetylenes decorated with an amino
substituent (3h and 3i) coupled with good yields, includ-
ing the unprotected ortho-aniline (3i) which coupled with
50 % yield without any formation of indole in the pres-
ence of gold catalyst. 1-Naphthyl- (3j) as well as heteroar-
omatic thiophenylacetylene (3m) coupled with good
yields too. Typically, para- substitution with electron-
withdrawing group was not well tolerated resulting in a
low yield for para-chloroethynylbenzene (3l) and para-
bromoethynylbenzene (not shown). At this point, we de-
cided to develop two complementary methods A & B (see
annotation under Table 1). Although most products were
obtained under Method A, some exceptions, such as 3l
was only achieved by performing the reaction in a se-
quential process whereby enzymatic oxidation occurred
at 37 °C with the organogold addition step at 60 °C
(Method B). In such case, formation of 2 was confirmed
by NMR and TLC, suggesting the attenuated nucleophilic-
ity of gold acetylides with para-EWGs on the aryl moiety.
Interestingly, some electron-deficient ethynylbenzenes
reacted with good yields. 2-fluoroethynylbenzene partici-
pated in a one-step reaction giving product 3k in 80 %
yield. Simultaneously, 3-pyridylethynylbenzene afforded
3n in 74 % yield, whereas 2-pyridylethynyl-benzene re-
sulted in traces of product (not shown). 1,4-
Diethynylbenzene added effectively to the THIQ nucleus
with 48 % obtained from addition at either end of di-
acetylene and 14 % of mono addition with facile separa-
tion of two products through flash chromatography. Al-
kylacetylenes led to 3p and 3q in moderate yields. Having
established that a range of acetylenes can participate in
MAO-N D5
HAuCl4•H2O (5 mol %)
H
N
N
N
phosphate buffer
R
R
R
16 h, 37 °C, air
Ar
3
2
1, R = alkyl
Ar
• orthogonal tandem catalysis • mild conditions for oxidation/C-C formation
• formal cross-dehydrogenative coupling • broad range of acetylenes
a)-c) Chronological state-of-the-art examples combining chemo-
and biocatalysis in one pot. d) Integrated chemobiocatalytic
process without compartmentalization.
Pioneering work from the Toste and Raymond groups
demonstrated combined gold catalysis for C–O bond for-
mation triggered by an enzymatic hydrolysis step,16 and
the groups of González-Sabín and Mihovilovic have re-
cently demonstrated gold-catalyzed alkyne hydration in
conjugation with subsequent enzymatic reduction of a
carbonyl group.17,18 Sieber and co-workers have described
a compartmentalized system for heterogeneous gold-
catalyzed oxidation followed by enzymatic dehydration.19
The combination of Au-catalyzed C–C bond formation,
however, has yet to be explored in chemobiocatalytic
transformations.20
Our proposed reaction system is shown in Scheme 1., d),
and is inspired by the A3 reaction from Li and co-workers
who demonstrated gold-catalyzed addition of alkynes to
iminium species in water at reflux.21, 22 Oxidation of the
isoquinoline 1 using the MAO-N class of oxygen-
dependent enzymes23-25 would form an iminium ion 2 that
could potentially undergo electrophilic addition with a
gold acetylide. While merging TM catalysis with biocatal-
ysis in water is frequently challenging, some features of
the proposed chemistry provided grounds for optimism,
namely: i) the hydration of unfunctionalized alkynes does
not occur where water is a dominant solvent,26 ii) C-C
bond formation through the A3 reaction manifold is
known to take place at room temperature22 and iii) late
stage TMs are reported to have diminished susceptibility
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the reaction we progressed to probing the scope of the
yields of 6b and 6c. Acyl- and benzyl-protected THIQs
did not undergo biocatalytic oxidation due to electronic
(6d) and steric effects (6e) affecting the oxidation. Fur-
thermore, unprotected THIQ did not yield any addition
product, even after the adjustment of pH with hydrochlo-
ric acid (adjusted to pH = 5) for the protonation of imine.
However, this remains in accordance with literature prec-
edence which suggests that only iminium ions arising
from oxidation α- to tertiary amines are electrophilic
enough for gold acetylide addition in the A3 reaction.22
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enzymatic oxidation of various N-substituted THIQs.
Table 1. Chemoenzymatic alkynylation of N-Methyl
Tetrahydroisoquinolines.
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Table 2. Exploration of Nitrogen Substitution in
Chemoenzymatic alkynylation of N-Substituted Tet-
rahydroisoquinolines.
aMethod A: MAO-N (0.2 g, w/w), 1a (1 equiv., 0.2 mmol), acety-
lene (2 equiv., 0.4 mmol), H[AuCl]4•H2O (0.05 equiv, 0.01 mmol),
KPi, 16 h, 37 °C, air. bMethod B: MAO-N (0.2 g, w/w), 1a (1 equiv.,
0.2 mmol), KPi, 16 h, 37 °C, air, then: acetylene (2 equiv., 0.4
mmol), H[AuCl]4•H2O (0.05 equiv, 0.01 mmol), KPi, 16 h, 60 °C,
air. crecovered starting material in 83 %. drecovered starting ma-
terial in 64 % epH adjusted to 5 after enzymatic oxidation.
In conclusion, we have developed a chemobiocatalytic
cross-dehydrogenative coupling process which combines
benign biocatalytic oxidation of N-substituted THIQs and
a gold-catalyzed alkynylation. This process exemplifies
the complementarity of TM-catalysis for C–C bond for-
mation integrated with biological catalysts for functional
group manipulation. The process proceeds under mild
conditions in aqueous media, and has been exemplified
across a range of acetylene and THIQ coupling partners.
Further investigations into Au / biocatalysis cascade
chemistry are ongoing in our laboratories.
aMethod A: MAO-N (0.2 g, w/w), 1a (1 equiv., 0.2 mmol), acety-
lene (2 equiv., 0.4 mmol), H[AuCl]4•H2O (0.05 equiv, 0.01 mmol),
KPi, 16 h, 37 °C, air. bMethod B: MAO-N (0.2 g, w/w), 1a (1 equiv.,
0.2 mmol), KPi, 16 h, 37 °C, air, then: acetylene (2 equiv., 0.4
mmol), H[AuCl]4•H2O (0.05 equiv, 0.01 mmol), KPi, 16 h, 60 °C,
air. cmono- and diaddition products isolated separately.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and methods, substrate synthesis
and isolated product characterization, and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Although MAO-N has been subjected to extensive protein
engineering and the chemical space of its active site has
been largely explored,28 the current project served as a
useful tool to identify new substrates for the D5 variant. A
panel of THIQs was prepared with varied substitution on
nitrogen (Table 2.). We were encouraged to see that N-Et-
THIQ could be functionalized by the addition of phenyla-
cetylene to furnish 6a in excellent 88 % yield. Neverthe-
less, allyl and homoallyl substituents resulted in moderate
AUTHOR INFORMATION
Corresponding Author
*E-mail for N.J.T.: Nicholas.Turner@manchester.ac.uk
*E-mail for M.F.G.: Michael.Greaney@manchester.ac.uk
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Alkynes for the Construction of Molecular Complexity.
Chem. Rev. 2015, 115, 9028–9072.
ABBREVIATIONS
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2
3
4
5
6
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TM, transition metal; MAO-N, monoamine oxidase type N;
THIQ, tetrahydroisoquinoline; TLC, thin layer chromatog-
raphy.
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cells for in situ formation of fluorescent probes: (a) Do, J.
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ACKNOWLEDGMENT
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This work was supported by the Engineering and Physical
Sciences Research Council (EPSRC) through grant
EP/M013219/1.
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