Computationally-Guided Development of a Chelated NHC-P Iridium(I) Complex for the Directed Hydrogen Isotope Exchange of Aryl Sulfones

Article abstract of DOI:10.1021/acscatal.0c03031

Herein, we report the rational, computationally-guided design of an iridium(I) catalyst system capable of enabling directed hydrogen isotope exchange (HIE) with the challenging sulfone directing group. Substrate binding energy was used as a parameter to g

Full text of DOI:10.1021/acscatal.0c03031

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Article
Computationally-Guided Development of a Chelated NHC-P Iridi-um(I)
Complex for the Directed Hydrogen Isotope Exchange of Aryl Sulfones
William J. Kerr, Gary J. Knox, Marc Reid, Tell Tuttle, Jonas Bergare, and Ryan A. Bragg
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c03031 • Publication Date (Web): 01 Sep 2020
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ACS Catalysis
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Computationally-Guided Development of a Chelated NHC-P
Iridium(I) Complex for the Directed Hydrogen Isotope Exchange of
Aryl Sulfones
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†
†
†
William J. Kerr, *,† Gary J. Knox, Marc Reid, Tell Tuttle, Jonas Bergare, and Ryan A. Bragg
‡
§
†Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, Scotland, U.K.
‡Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden
§Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, U.K.
ABSTRACT: Herein we report the rational, computationally-guided design of an iridium(I) catalyst system capable of enabling
directed hydrogen isotope exchange (HIE) with the challenging sulfone directing group. Substrate binding energy was used as a
parameter to guide rational ligand design via an in-silico catalyst screen, resulting in a lead series of chelated iridium(I) NHC-
phosphine complexes. Subsequent preparative studies show that the optimal catalyst system displays high levels of activity in HIE,
and we demonstrate the labeling of a broad scope of substituted aryl sulfones. We also show that the activity of the catalyst is
maintained at low pressures of deuterium gas, and apply these conditions to tritium radiolabeling, including the expedient
synthesis of a tritium-labeled drug molecule.
KEYWORDS: rational catalyst design, hydrogen isotope exchange, iridium catalysis, C–H activation, sulfone
X
The incorporation of heavy isotopes into potential drug
PR3
Cl
molecules has, over time, become an indispensable tool within
the pharmaceutical industry.1 One of the most utilized
methods in this area is directed hydrogen isotope exchange
(HIE, Scheme 1), wherein hydrogen atoms ortho to a Lewis
basic directing group (DG) are replaced with deuterium or
tritium.2
Ir
Ir
IMes
NHC
X = PF6 X = BArF
NHC
IMes
IMesMe
IPr
1a
1b
1c
2a
2b
2c
3a
PPh3
PBn3
3b
3c
PMe2Ph
primary aryl sulfonamides and aryl aldehydes.6
Scheme 1. General Reaction Scheme for Directed HIE
Despite these advances, however, certain high-value
functionalities, common throughout pharmaceutical motifs
and natural products, still present significant challenges for
directed HIE. One such example is the aryl sulfone unit, which
is prevalent throughout drug discovery.7 For example,
sulfones are present in antibiotics, such as Dapsone and
Dextrosulphenidol,8a,b and are also components within a
range of other medicines, including the non-steroidal anti-
inflammatory, Rofecoxib, and the retinoid, Sumarotene
(Figure 2).8c,d However, the capacity to exploit the sulfone as a
directing group in C–H activation processes,9 including HIE,10
is currently vastly undermet. With specific regard to HIE,
Muri and Pfaltz have reported a N,P-chelated Ir(I) catalyst
which mediates deuterium labeling of a series of substrates,
including one example of a simple aryl (phenyl methyl)
sulfone. This catalyst system does, however, require activation
with elevated pressures (2.2 bar) of deuterium.10a Nonetheless,
the abundance of the sulfone moiety in pharmaceutically
active agents makes
D/T
DG
DG
D/T
[Ir] Cat.
D2 or T2
Homogeneous iridium catalysts have proven highly active in
ortho-directed HIE.3 These species have enabled the use of a
broad range of directing groups in the labeling of small
molecules and potential drug candidates.4 Related to this,
studies within our own laboratory have led to the
development of a series of catalytically active iridium(I)
NHC/phosphine complexes 1-2 (Figure 1), which deliver heavy
isotopes of hydrogen (deuterium, D, and tritium, T) to aryl
and alkenyl substrates via a directed C–H activation process
with a broad range of directing groups.3d,5 Additionally,
iridium(I) NHC chloride complexes of type 3 have shown
utility in the labeling of
Figure 1. Ir(I) Precatalysts for directed HIE
Figure 2. Examples of Sulfone-containing Drug
Molecules
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1a and 3a.6a We hypothesized that the use of a tethered N-
heterocyclic carbene-phosphine ligand (NHC-P, Figure 3b)
would result in a less hindered catalyst environment, more
able to accommodate the sulfone unit.
O O
S
O O
S
1
2
3
4
5
6
7
8
OH
O
Cl
H2N
NH2
O
N
H
OH
Dextrosulphenidol
Cl
The paradigm of rational ligand design is emerging as an
appreciably powerful tool through which the knowledge and
understanding gained from mechanistic insights allows an
effective catalyst to be accessed rapidly.11,12 We selected this
approach to address the challenge of developing a broadly
effective chelated catalyst system with the ability to label
sulfone-bearing substrates to high levels of isotope
incorporation under mild reaction conditions. Specifically, a
system derived from rational, computational design would not
only provide a solution to the challenge of sulfone labeling,
but would also potentially facilitate the application of the
designed system to a more diverse array of substrate classes.
Dapsone
O
S
O O
S
O
O
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Rofecoxib
Sumarotene
the ability to exploit these functional units as handles for
ortho-directed HIE a particularly attractive goal. Additionally,
applying a mechanistic approach to such a challenge has the
potential to deliver an enhanced, and potentially predictive,
understanding of such directed functionalization endeavors,
enabling the use of sulfones in a broader range of C–H
activation processes.
To initiate our studies, and guided by our postulate that
substrate binding was limiting in the sulfone case (Figure 3),
computational modeling was used to calculate the binding
energy (EBind) of model substrate methyl phenyl sulfone 4a to
catalytically relevant5c iridium(III) hydride complexes of
varying designs (Figure 4). The binding energy was calculated
using the counterpoise method, as described by Boys and
Bernardi.13 We observed that, while methyl phenyl sulfone 4a
could coordinate to the monodentate NHC/phosphine
iridium(III) hydride derived from 1a (Figure 4a), a modest
binding energy of only -15.3 kcal mol-1 was calculated, with a
similarly poor binding energy of -15.9 kcal mol-1 for precatalyst
3a (Figure 4b). To place these binding energies in context,
when the same method was applied to the binding of
acetophenone 5 (which has been shown to label to high levels
using precatalyst 1a5c), a significantly more negative, and
therefore more favorable, binding energy of -23.1 kcal mol-1
was found (Figure 4c).
Current iridium-catalyzed HIE processes directed by
sulfones have a range of limitations. For example, previous
studies within our laboratory towards sulfone-directed HIE
have employed monodentate iridium(I) catalysts; specifically,
NHC/phosphine 1a and NHC/Cl analogue 3a. When these
catalyst systems were applied to the labeling of phenyl methyl
sulfone 4a, low levels of incorporation were observed (Figure
3a).6a We hypothesized that, in this case, substrate binding
was, unusually, the turnover-limiting step, in contrast to less
hindered directing groups where C–H activation is turnover
limiting.5c
Figure 3. Sulfone Labeling: Challenges with Monodentate
Catalysts and a Potential Chelated Catalyst Solution
a:
Previous work
D
O
O
Figure 4. Calculation of Binding Energy with
Monodentate Ligand Systems
O
O
S
Ir(I) catalyst (5 mol%)
D2, DCM, 25 °C, 16 h
S
4a
d-4a
Ph
P
Ph
P
D
O
S
O
a:
PF6
%D
9
Ph
Ph
Ph
Ph
PPh3
Ir
IMes
O
4a
1a
O
O
H
H
H
H
S
Ir
Ir
H
EBind = -15.3 kcal mol-1
leading to 9% D6a
Cl
Ir
IMes
3a
17
Mes
Mes
Mes
Mes
N
N
N
N
b: This work - solution to challenges in sulfone labelling
O
S
O
b:
Cl
Ir
Cl
Ir
O
S
Cl
H
Ir
O
S
P
4a
O
O
H
H
H
H
O
H
O
O
H
H
H
H
S
S
Ir
Ir
EBind = -15.9 kcal mol-1
H
P
H
H
H
leading to 17% D6a
Mes
c:
Mes
Mes
Mes
N
N
N
N
N
N
N
N
N
N
Monodentate
NHC/Phosphine
Monodentate
NHC/Chloride
NHC-Phosphine
Tethered Catalyst
Ph
Ph
P
O
Ph
Ph
Ph
Ph
P
Ir
Bearing in mind that catalysts 1-3 possess very large NHC
and (for 1 & 2) phosphine ligands, coordinated in a trans
relationship (Figure 3b), the tetrahedral nature of the sulfone
directing group results in significant steric repulsion between
the substrate and ligand when compared to more planar
directing groups, such as acetyl. This may inhibit substrate
binding which, in turn, would severely limit the isotope
incorporation in sulfone-derived substrates, as observed with
5
O
H
H
H
H
Ir
EBind = -23.1 kcal mol-1
leading to 97% D5c
H
Mes
Mes
Mes
Mes
N
N
N
N
In terms of selecting a chelating ligand system to overcome
these binding issues, a number of tethered NHC-P ligand
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motifs have been reported.14 Due to the range of tethers and
reduced
binding
energy
with
respect
to
the
1
2
3
4
5
6
7
8
combinations of NHC and phosphine substituents already
established, an in silico screening was carried out to determine
which characteristics of the chelating ligand would lead to an
increased sulfone binding energy, and thus a potentially
effective catalyst system. Accordingly, we proposed a virtual
library of eighteen structurally diverse NHC-P ligands,
covering a number of chelate sizes (from four to seven
membered rings), and a range of steric and electronic
parameters, as dictated by the substituents on the NHC and
phosphine moieties. In each case, the binding energy of
methyl phenyl sulfone to the relevant chelated iridium(III)
hydride was calculated (Scheme 2).
diphenylphosphinyl analogue 15, and, as such, no further
dialkylphosphines were considered. The effect of the chelate
ring size and rigidity was next examined, with the ortho-
phenylene, 19, methylene
Figure 5. Calculated Binding Energies with Sulfone 4a
9
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11
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13
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Firstly, it was noted that only those ligands with N-aryl
substituents gave significantly higher sulfone binding energies
Scheme 2. In Silico Screen of Bidentate Ligands, and
the Calculated Binding Energy for Methyl Phenyl
Sulfone
Figure 6. Summary of the Targeted Iridium(I)
Precatalysts
O
O
H
O
H
BArF
S
BArF
BArF
O
S
Ph2P
Ir
Ph2P
Ir
H
H
P
Ph2P
Ir
Ir
Ir
4a
R
R
R
R
N
N
P
H
Calculate
N
N
N
Mes
24
25
26
DiPP
R1
R1
N
N
Mes
Binding Energy
(Ebind, kcal mol-1
N
N
N
)
R2 R2
R2 R2
BArF
BArF
BArF
Ph2P
Ph2P
Ir
Ph2P
Ir
Ir
PPh2
PPh2
-24.9 kcal mol-1
PPh2
-17.1 kcal mol-1
N
N
N
N
N
N
N
N
Ph
Bn
Bn
N
N
N
N
Mes
Mes
DiPP
-1
27
28
29
6
7
8
-17.4 kcal mol
bridged, 20, and directly N-P bound ligand, 21, all displaying
favorable binding energies. Interestingly, phosphite, 22,
returned the highest binding energy of all ligand variations
examined. Finally, the benzimidazole-derived NHC, 23, was
also found to be favorable, resulting in a binding energy of -
30.8 kcal mol-1. The calculated binding energies for each of the
18 bidentate complexes, as well as monodentate complexes 1a
and 3a, are shown graphically in Figure 5.
PtBu2
-27.5 kcal mol-1
PCy2
-29.5 kcal mol-1
PPh2
N
N
N
N
N
N
Ph
Mes
Ph
-1
9
10
11
-27.0 kcal mol
N
N
PPh2
PPh2
N
N
N
N
Ph
14
Mes
DiPP
PPh2
-27.8 kcal mol-1
-23.7 kcal mol-1
-24.1 kcal mol-1
12
13
From this in silico screen, a total of six ligands (11, 13, 15, 17,
18, and 23) were selected for progression based on their
binding energy of methyl phenyl sulfone 4a, coupled with
their synthetic tractability in each case. The structures of the
targeted iridium(I) precatalysts 24-29 are shown in Figure 6,
with the selected ligands predicted to give complexes with a
range of substrate binding energies, from -23.7 to -30.8 kcal
mol-1. The ligands for the iridium(I) precatalysts shown were
then synthesized via modification of existing literature
procedures.14d-g,15
N
N
N
N
N
N
Mes
Mes
Mes
PPh2
-27.4 kcal mol-1
PCy2
PPh2
-28.6 kcal mol-1
-22.8 kcal mol-1
15
16
17
N
N
Mes
PPh2
-27.9 kcal mol-1
N
N
N
N
DiPP
Mes
Ph2P
PPh2
-27.8 kcal mol-1
-27.4 kcal mol-1
18
19
20
OPPh2
N
N
N
N
Mes
Mes
21
PPh2
N
N
Mes
With the iridium(I) precatalysts 24-29 in hand, their labeling
of methyl phenyl sulfone 4a was investigated. This initial
catalyst screen was performed at 25 °C in dichloromethane,
with a standard catalyst loading of 5 mol% and a reaction time
of 16 h. In the majority of cases (i.e. with the exception of 25
PPh2
-30.8 kcal mol-1
-27.1 kcal mol-1
-31.6 kcal mol-1
22
23
than the monodentate systems (cf. 6 vs 7). In general, ethylene
tethered systems (6, 9-13) showed a favorable range of binding
energies, from -23.7 kcal mol-1 for 13, to -29.5 kcal mol-1 for 10.
Also, aryl and alkyl phosphines both gave enhanced binding
energies when compared to the aforementioned monodentate
catalysts. Furthermore, substitution on the backbone of the
NHC appeared to deliver a moderately more favorable binding
energy in some cases (cf. 12 vs 11). The larger, benzyl-tethered
ligands, 14-18, also showed favorable sulfone binding energies,
with a similar pattern to the corresponding ethylene-bridged
systems being observed in terms of the NHC substituent.
Dicyclohexyl phosphinyl variant 16, however, displayed a
Table 1. Catalyst Screen
D
O O
S
O O
S
[Ir] Cat (5 mol%)
D2, DCM, 25 °C, 16 h
D
4a
d-4a
Entry
Catalyst
%D incorporationa
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1
1a
3a
24
25
26
27
28
29
96a
176a
35
manifold from nitrogen to deuterium, thus simplifying the
1
2
3
4
5
6
7
8
practical procedure. Notably, maintaining catalyst loadings at
5 mol%, the reaction time could be reduced to 1 h, with no
drop in the observed isotope incorporation.15 These conditions
were then applied to a broad range of aryl sulfones to establish
the scope of our developed process (Scheme 3). A total of
eighteen additional substrates were examined, encompassing
2
3
4
5
6
7
8
12
a
diverse range of sulfones, with, generally, excellent
23
13
deuterium incorporation effectiveness observed throughout
the series. Both electron-donating and electron-withdrawing
substituents in the ortho (4b-4d) and meta (4e-4h) positions
of the aryl ring were well tolerated, leading to high levels of
incorporation. Notably, meta-trifluoromethyl substrate 4g
exhibits almost no incorporation at the considerably hindered
position between both aryl substituents, but displays excellent
levels of deuterium labeling at the less hindered position ortho
to the sulfone. With less sterically encumbered meta
substituents (4f and 4h) both positions ortho to the sulfone
are labeled to a high degree. A range of electronically distinct
para-substituents are
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aReactions performed in triplicate.
Figure 7. Solvent Applicability in Sulfone Labeling15
BArF
D
O
S
O
O
S
O
29
Ph2P
Ir
(5 mol%)
Scheme 3. Scope of Aryl Sulfone Labeling
D2, Solvent
25 °C, 16 h
D
N
BArF
29
DiPP
N
4a
d-4a
D
Ph2P
Ir
O
S
O
O
S
O
29
(5 mol%)
R
R
N
D2, PhCl, 25 °C, 1 h
29
[93]
d-4f
4
d-4
DiPP
N
D
F
Cl
O
O
O
S
O
O
O
O
S
O
S
O
O O
S
[80]
S
O
[83]
[73]
[92]
[80]a
[90]
d-4b
d-4c
d-4d
d-4i
d-4e
O
O
S
O
S
O
O
O
S
O
O
O O
[4]
[85]
CF3
Cl
S
S
[94]
[92]
[87]
[89]
[89]
[57]
F
Cl
d-4g
d-4l
d-4h
d-4j
d-4k
O
O
S
O
O
O
O
S
O
O
O O
S
[91]
S
S
[70]
[88]
[48]
[82]
O
O2N
CF3
O
d-4o
d-4m
d-4n
d-4p
O
S
O
O O
[80]
[66]
[23]
S
tBu
S
O
O
d-4q
d-4r
d-4s
and 27), a marked increase in the isotope incorporation was
observed, compared to the monodentate systems 1a and 3a
(Table 1).
a Incorporation averaged across both positions.
also well tolerated (4i-4l, 4n). In the case of para-nitro
substrate 4m, this alternative directing group is shown to
mildly outcompete the sulfone, but does not prevent an
acceptable level of isotope incorporation through sulfone-
directed HIE. Furthermore, restricting the orientation of the
sulfone, as in cyclic substrate 4o, did not result in a decrease
in the excellent levels of incorporation generally observed. We
next turned our attention to the effects of increasing the steric
bulk around the sulfone group, with substrates 4p-4r. While a
slight decrease in the levels of incorporated deuterium were
observed in diphenyl sulfone 4p and iso-propyl phenyl sulfone
4q (57% and 66%, respectively), an excellent incorporation of
80% was observed with the bulky tert-butyl phenyl sulfone 4r.
We also investigated labeling of benzyl methyl sulfone 4s,
where the sulfone would direct labeling via a 6-membered
metallacyclic intermediate (6-mmi), which is considerably
less favored than the more common 5-mmi.5c Nonetheless,
moderate levels of incorporation were still observed in this
more challenging substrate under these mild standard
conditions with a low catalyst loading of 5 mol%.
Based on the labeling results shown in Table 1, the most
promising catalyst, 29, was selected for further optimization,
beginning with a solvent screen, and exploiting the versatility
of the catalyst’s BArF counterion in this regard.5d As shown in
Figure 7, the observed incorporation reached significantly
higher levels in a broad range of solvents compared to the
initial labeling result in DCM. In particular, chlorobenzene
and fluorobenzene delivered the highest levels of labeling,
affording excellent 93% and 91% incorporations, respectively.
Additionally, use of non-halogenated solvents such as di-iso-
propyl ether, MTBE, diethyl ether, and toluene also provided
high levels (>70%) of deuterium incorporation.
Accordingly, chlorobenzene was chosen as the optimal
solvent for this sulfone labeling process with catalyst 29. Not
only did this medium allow for the best incorporation from
the eleven solvents examined but additional technical
advantages were delivered, in that the higher boiling nature of
chlorobenzene meant that cooling to -78 °C could be avoided
when exchanging the atmosphere within the reaction
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In order to further expand the utility of our newly developed
range of solvents, and an extensive substrate scope has been
established, with high levels of deuterium incorporation being
exhibited across the series. Furthermore, the catalyst system
has been shown to retain its activity when applied to the low-
pressure labeling systems currently used extensively in the
pharmaceutical industry. Finally, the emerging iridium(I)
NHC-P catalyst has been applied to tritium labeling,
furnishing a selectively tritiated sample of GPR119 agonist t-30
with high levels of specific activity. Our current studies are
focused on extending our understanding of these catalytic
systems in order to further refine our design process to
encompass even more challenging substrates.
1
2
3
4
5
6
7
8
catalyst system, we investigated the effects of employing a
reduced pressure of deuterium gas using a TRITEC manifold
system, with these conditions more closely emulating those
deployed for radiolabeling with tritium gas within
a
pharmaceutical industry setting. Following only minimal
optimization of our standard conditions,15 we obtained high
levels of labeling under these low-pressure conditions
(Scheme 4). Employing phenyl methyl sulfone 4a, it was found
that with a deuterium pressure of only ~400 mbar, a mildly
elevated catalyst loading of 7.5 mol% allowed for similar levels
of deuterium incorporation to the standard (non-TRITEC)
laboratory set-up. Notably, when employing the most active
catalyst reported by Pfaltz and Muri,10a very low levels of
labeling of this same substrate, 4a, were observed when
employing 1 atm of D2 for catalyst activation,15 as is routinely
employed with our suite of Ir(I) catalysts, including 29.
Indeed, the requirement for supra-atmospheric catalyst
activation with this previously reported system may present
practical challenges when applying the methodology to low-
pressure tritiations (vide infra).
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AUTHOR INFORMATION
Corresponding Author
*Email: w.kerr@strath.ac.uk
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
With a successful reduced atmosphere protocol in hand
using catalyst 29, the conditions were then applied to the
tritium
BArF, tetrakis(3,5-bis(trifluoromethyl)phenyl)borate; Bn,
benzyl; CPME, cyclopentyl methyl ether; DCE, 1,2-
dichloroethane; DCM, dichloromethane; DiPP, 2,6-di-iso-
propylphenyl; Mes, 2,4,6-trimethylphenyl; MTBE, methyl tert-
butyl ether; NHC, N-heterocyclic carbene.
Scheme 4. Reduced Pressure Deuterium and Tritium
Labeling of Methyl Phenyl Sulfone 4a
T
D
O
O
O
O
O O
ASSOCIATED CONTENT
S
S
S
29
29
(7.5 mol%)
(7.5 mol%)
Details of experimental procedures and computational
methods can be found in the Electronic Supporting
Information (ESI). This material is available free of charge via
the Internet at http://pubs.acs.org.
D2 (405 mbar)
PhCl, 25 °C, 1 h
6.40 M Scale
T2 (405 mbar)
PhCl, 25 °C, 1 h
6.40 M Scale
T
D
d-4a [90]
4a
t-4a
51.3 Ci/mmol
labeling of the same sulfone 4a. Exposure of 4a to 7.5 mol% of
precatalyst 29 under 405 mbar of tritium gas afforded t-4a
with a high activity of 51.3 Ci/mmol, corresponding to a
tritium incorporation of 88% across both ortho positions.
Additionally, the major mass ion of [M+4] confirmed that the
sample had indeed been labeled with two units of tritium
(Scheme 4).
ACKNOWLEDGMENT
An EPSRC Industrial CASE PhD Studentship (G.J.K.) with
additional support from AstraZeneca, and a Carnegie Trust
Studentship (M.R.) are gratefully acknowledged. Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
Finally, in order to further demonstrate the power of our
developed catalyst as applied to radiolabeling, as shown in
Scheme 5 we targeted a tritium-labeled sample of the highly
potent GPR119 agonist 30.16 Accordingly, benzylic bromide-
containing sulfone 4t could be readily tritiated and alkylated
in one pot to afford t-30 with excellent levels of radiolabel
incorporation.
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Scheme 5. Tritium Labeling of GRP119 Agonist 30
T
O
S
O
O
S
O
29
(7.5 mol%)
T2 (411 mbar)
PhCl, 25 °C, 1 h
4.01 M Scale
Br
N
Br
T
4t
t-4t
N
N
T
N
O
K2CO3 (2 eq.)
DMF, rt, 16 h
O
S
N
N
O
O
CF3
N
N
N
N
N
N
OH
T
t-30
36.8 Ci/mmol
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BArF
T
O
O
S
T
Ph2P
Ir
Tritiated GPR119
Agonist
D
N
O
O
O
O
5 mol%
D2, PhCl, 25 °C, 1 h
• Computational Ligand Design
DiPP
N
O
R
S
D
R
S
N
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N
N
N
• 20 Examples Isotopically Labelled
• Flexible Solvent Scope
O
Specific Activity:
36.8 Ci/mmol
CF3
• Short Reaction Times
8
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