Twofold Radical-Based Synthesis of N, C-Difunctionalized Bicyclo[1.1.1]pentanes

Article abstract of DOI:10.1021/jacs.1c04180

Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]propellane to afford iodo-BCPAs; the newly formed C-I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.

Full text of DOI:10.1021/jacs.1c04180

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Twofold Radical-Based Synthesis of N,C‑Difunctionalized
Bicyclo[1.1.1]pentanes
Helena D. Pickford, Jeremy Nugent, Benjamin Owen, James. J. Mousseau, Russell C. Smith,
and Edward A. Anderson*
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ABSTRACT: Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich
bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical
functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to
[1.1.1]propellane to afford iodo-BCPAs; the newly formed C−I bond in these products is then functionalized via a silyl-mediated
Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-
BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.
icyclo[1.1.1]pentanes (BCPs) are of significant interest to
the pharmaceutical, agrochemical, and materials industries
B
as sp3-rich surrogates for 1,4-disubstituted arenes, tert-butyl
groups, and alkynes.1−9 Bicyclo[1.1.1]pentylamines (BCPAs)
are similarly attractive due to their potential use as nontoxic
bioisosteres for aniline and N-tert-butyl motifs in drug
candidates. BCPAs have been shown to improve properties
such as metabolic tolerance and bioactivity (Figure 1a),10,11
and they are featured as desirable derivatives in numerous
patents.12−16
Early approaches to BCPAs involved multistep routes using
preformed BCP building blocks (derived from [1.1.1]-
propellane 1, Figure 1b), such as acyl nitrene rearrange-
ments17−20 or reduction of BCP azides or hydrazines.21,22
More recently, methods have been developed that prepare
BCPAs directly from 1 by reaction with amide anions,23−25
which can also provide access to N,C-disubstituted BCPAs
(Figure 1b, path a). However, these processes can require
elevated temperatures, restricting functional group tolerance.
The amination of BCP radicals formed by addition of C-
centered radicals to 1 (generated under Fe(II)26 or metal-
laphotoredox27 catalysis) offers alternative solutions (paths b,
c). In marked contrast to the addition of C-centered radicals to
1, reactions with N-centered radicals are underexplored as an
entry to BCPAs. Following the seminal work of Wiberg on the
reaction of 1 with nitric oxide,28 this area lay dormant until the
elegant demonstration by Leonori et al. of a three component
construction of 1,3-disubstituted BCPAs via photoredox
decarboxylative generation of amidyl radicals (path d).29
However, even this chemistry is restricted to the installation
of halogen or sulfur substituents at the 3-position of the BCPA.
Very recently, an amidopyridylation of [1.1.1]propellane has
been described by Hong and co-workers.30
Figure 1. (a) Bicyclopentyl[1.1.1]amines (BCPAs) in pharmaceut-
icals. (b) Methods to access BCPAs. (c) Fragmentation/N-centered
radical ATRA and photocatalyzed functionalization of iodo-BCPAs.
Received: April 21, 2021
Published: June 23, 2021
In previous work we described the efficient synthesis of
iodo-BCPs by atom transfer radical addition (ATRA) of alkyl
and (hetero)aryl iodides to the C1−C3 bond of 131,32 and
questioned whether this approach could be applied to the
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synthesis of BCPAs. We recognized that N-centered radicals
can be conveniently accessed by fragmentation of α-
iodoaziridines (2, Figure 1c)33,34 and hypothesized that 1
could serve as a suitable radical acceptor, with the resulting
BCP radical then abstracting an iodine atom from the α-
iodoaziridine starting material. The C−I bond resident in the
iodo-BCPA product 3 would then provide a handle for further
functionalization, potentially via reformation of a BCP radical.
Here we report the realization of this α-iodoaziridine
fragmentation/ATRA to form iodo-BCPAs and the application
of these products in photoredox-catalyzed Giese-type
processes35,36 to access C-substituted BCPAs 4.37
limiting reagent proved equally effective (entry 6). Pleasingly,
the reaction could also be performed on multigram scale with
near-equivalent efficiency using just 1.1 equiv of 1 (entry 7,
6.50 mmol (2.19 g) of 2a, 67%). Comparable yields were
achieved under photoredox catalysis,38 with fac-Ir(ppy)3
performing the best;39 however, a higher loading of 1 was
required (entries 8−9).
Under the optimized conditions, iodo-BCPA synthesis was
found to be applicable to a wide range of α-iodoaziridines
(Figure 2). Aryl sulfonamide aziridines bearing electron-
donating (3a−c, 61%−75%), electron-neutral (3d, 75%), and
electron-withdrawing (3e−i, 55−73%) substituents all gave
high yields of the desired products, although aryl nitro-
sulfonamides were less successful (3j and 3k,10−36%).
Notably, an aryl ketone (3f) was also tolerated, which would
likely not be possible under anionic conditions for amide
additions to 1. Aziridines featuring heterocyclic sulfonamides
including thiophenes (3l−m), oxazole (3n), pyrazole (3o),
benzothiophene (3p), and imidazothiazole (3q) all reacted
smoothly, affording the corresponding BCPA products in good
to excellent yields (52−81%).
α-Iodoaziridine 2a was selected for reaction optimization
(Table 1). Based on the studies of Taguchi33,34 and our
Table 1. Optimization of α-Iodoaziridine Fragmentation/N-
Centered Radical Addition to 1
Alkyl sulfonamide (3r−t, 37−66%) and sulfamide sub-
stituted aziridines (3u−3v, 21−61%) were also accommo-
dated.40
We next investigated substitution of the α-iodoaziridine
backbone. Pleasingly, aziridines featuring substituents at the 1-,
2-, and 3-positions were tolerated, including fused cyclo-
pentane and cyclohexane aziridines (3w−aa, 30−73%),
although reaction of a trisubstituted aziridine was low yielding
(3ab, 4%). Finally, the potential of this chemistry to operate in
settings relevant to medicinal chemistry research was
demonstrated via iodobicyclopentylation of the nonsteroidal
anti-inflammatory drug celecoxib (3ac, 70%).
The C−I bond in the iodo-BCPA product is an attractive
handle for C−C bond formation. However, attempted
lithiation/electrophilic trapping of iodo-BCPA 3a was
unsuccessful due to ejection of the sulfonamide anion,
presumably accompanied by reformation of 1.39 Precedent
for radical-based BCP bridgehead C−C bond formation in
N,C-BCPs is limited: to date only a handful of azide or triazole
N-substituents have been studied, with reliance on organotin
reagents22 or the radical acceptor as reaction solvent.41 We
questioned whether photoredox catalysis could offer a solution
to this challenge, where the bridgehead C−I bond could be
functionalized through Giese-type reactions.35,36 Previous
studies have demonstrated the use of silane and silanol
mediators42 to generate radicals from simple alkyl43−47 and
aryl48 halides under photoredox catalysis; however, use on the
BCP scaffold is unprecedented.
Iodo-BCPA 3a was selected for reaction optimization (Table
2), with allyl sulfone 6a as an acceptor (Table 2). Initial
attempts using Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 with
(Me3Si)3SiH(TTMSS) as a radical mediator delivered addition
product 4a in 16% yield, along with a significant amount of the
deiodination product 3a-H (entry 1).49 This competing H-
atom abstraction by the presumed BCPA radical intermediate
could be avoided by using (Me3Si)3SiOH, which acts as a silyl
radical source via silanolate oxidation/radical-Brook rearrange-
ment.48,50 This led to a significant improvement in yield (38%,
entry 2), which was further enhanced to 60% using CH2Cl2 as
solvent, likely due to improved solubility of 6a (entry 3).
Variation of the photocatalyst led to decreased yields of 4a,
although the organocatalyst 4-CzIPN was also well-suited to
b
1
Temp
Yield
d
3a:3a-
a
c
e
Entry Conditions (equiv) Cosolvent
(°C)
(%)
S
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
A
B
B
2.0
2.0
1.3
1.3
1.3
20
0
67
63
71
6:1
11:1
17:1
>20:1
>20:1
>20:1
>20:1
20:1
20
20
20
20
20
30
30
f
CH2Cl2
72 (75)
g
CH2Cl2
CH2Cl2
CH2Cl2
t-BuCN
t-BuCN
64
65
67
31
57
h
1.0
1.1
1.3
2.0
14:1
a
Conditions A: Et3B (10 mol %), air, 5 h. Conditions B: fac-Ir(ppy)3
(2.5 mol %), blue LEDs (18 W), N2, 18 h. 1 was used as a 0.6−0.8
M solution in Et2O unless indicated otherwise. 2a was prepared as a
b
c
d
1.0 M solution in the cosolvent, where used. NMR yield, determined
e
using mesitylene as internal standard. Determined by 1H NMR
f
spectroscopic analysis of the crude reaction mixture. Yield in
parentheses is the isolated yield, including <5% 3a-S and 3a-H
impurities. 1 was prepared as a 1.06 M solution in CH2Cl2. 1.5
equiv of 2a.
g
h
experience with the addition of C-centered radicals to 1,31,32
triethylborane was first tested as an initiator. Pleasingly, the
desired C−N σ bond fragmentation/ATRA proceeded
efficiently using 2.0 equiv of 1, giving iodo-BCP sulfonamide
3a in 67% yield (entry 1); small amounts of staffane 3a-S, H-
atom abstraction product 3a-H, and N-allylsulfonamide 5a
were also observed. The proportion of staffane (6:1) could be
significantly reduced by lowering the reaction temperature
(11:1, entry 2) or the equivalents of 1 (17:1, entry 3).
Suspecting that 3a-H and 5a might arise from H-atom
abstraction from the solvent, use of CH2Cl2 as cosolvent was
tested and indeed reduced the levels of these byproducts
(entry 4), giving a 75% yield of 3a with <5% of 3a-S and 3a-H.
A solution of 1 in CH2Cl2 was prepared; however, no further
benefit in yield was observed (entry 5). Employing 1 as the
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Figure 2. Scope of α-iodoaziridine fragmentation/ATRA with 1. Reactions conducted on 0.15 mmol scale, yields are isolated yields. aIsolated as an
b
c
inseparable 7:1 mixture with the corresponding staffane 3q−S; yield of 3q. 1.6 equiv of 1. 0.09 mmol scale.
Table 2. Giese Reaction Optimization
a
Entry
Catalyst
6 (equiv)
Mediator
Solvent
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Yield (%)
1
2
3
4
5
6
7
8
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
6a (3)
6a (3)
6a (3)
6a (3)
6a (3)
6a (3)
6b (3)
6b (6)
6b (6)
6b (6)
(Me3Si)3SiH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiOH
(Me3Si)3SiH
(Me3Si)3SiH
(Me3Si)3SiH
16
38
60
b
c
4-CzIPN
56
6
41
3
Ru(bpz)3(PF6)2
Ir[(dF(F)ppy)2(dCF3bpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6
9
9
10
11
CH2Cl2
MeOH/H2O
MeOH/H2O
48
60
d
d
b
6b (3)
44
a
b
c
d
NMR yield, determined using mesitylene as internal standard. Isolated yield. 5 mol % catalyst. MeOH/H2O (9:1).
this chemistry (entries 4−6). To our surprise, use of methyl
acrylate (6b) as a radical acceptor under these conditions
resulted in poor yields of product 4b, even with increased
acceptor loading (3−9%, entry 7−8). Use of TTMSS restored
productive reactivity (48%, entry 9), and changing the reaction
solvent to MeOH/H2O (9:1) (entry 10) delivered an
optimum yield of 6b of 60%.
With two sets of reaction conditions in hand (Conditions
Table 2, entry 3; Conditions BTable 2, entry 10), the Giese
methodology was applied to a wide range of radical acceptors
(Figure 3). Under Conditions A, various 2-substituted allylic
sulfones delivered the corresponding allyl-BCPA products 4a,
4c, and 4d (29−60%). Reaction of a benzothiazole sulfone
delivered the heteroarylated BCPA 4e in modest yield, while
sulfurization with N-(phenylthio)phthalimide also proved
possible (4f, 32%). Variation of the sulfonamide group was
also well tolerated (4g and 4h, 50−53%), the former of which
demonstrates functionalization of the anti-inflammatory agent
Celecoxib. Encouraged by these results, we further tested the
methodology on C-substituted iodo-BCPs; to our delight,
these readily accessible substrates,31,32 featuring ester, piper-
idine, and pyridine functionalities, reacted well with allyl
sulfone 6a to give 4i−k in 40−59% yield.
Conditions B proved suitable for acrylonitrile, acrylate, and
acrylamide type acceptors (4b, 4l−4o, 42−60%); reaction on a
1.0 mmol scale proceeded with similar efficiency, giving a yield
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Figure 3. Scope of iodo-BCPA functionalization; reactions conducted on 0.15 mmol scale with Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 (2.5 mol %). Red
a
b
yields indicate Conditions A; blue yields indicate Conditions B. 1.00 mmol scale. 0.13 mmol scale. 4l was determined by single crystal X-ray
diffraction.51 cThe crude boronic ester was directly oxidized with H2O2/NaOH (aq); the yield refers to the isolation of the corresponding alcohol.
of 50% of 4b. Somewhat surprisingly, the use of 2-benzylidene
malononitrile proceeded poorly under these conditions but
delivered 4p in 57% yield using Conditions A. Variation of the
electron-withdrawing group to a vinyl sulfone (4q) and even a
vinylpyridine (4r) or vinylboronic esters (4s−4t) was also
successful. In the latter cases, the boronic esters proved
challenging to purify, and for 4t an oxidative workup instead
directly provided the corresponding alcohol.
the silane to the N-centered radical outcompeted addition to
[1.1.1]propellane 1 (Scheme 1). However, by delaying
Scheme 1. One-Pot Synthesis of C,N-Difunctionalized BCP
4b
The photocatalytic iodo-BCPA functionalization also offers a
powerful strategy for the mild generation of previously
unobtainable, pharmaceutically relevant BCPA α-amino acid
derivatives. This was demonstrated through the reaction of
dehydroalanine with a range of iodo-BCPAs (under Con-
ditions B) to give BCPA analogues of 4-amino phenylalanine
(4u−4y, 38−69%). Once again, we were pleased to find that
this chemistry translated well to C-substituted iodo-BCPs. This
two-step approach thus provided access to diverse BCP
phenylalanine derivatives 4z−4ad (44−58%), including
nicotinic acid derivative 4ac (45%) and BCP-Brequinar
analogue 4ad (53%). Collectively, these examples illustrate
the excellent functional group tolerance of this Giese
chemistry, which should render it of significant utility in
drug discovery programs.
With both the iodoaziridine fragmentation/ATRA and Giese
addition established, we questioned whether the two processes
might take place in a single reaction, such that the intermediate
BCPA radical is captured directly by the radical acceptor or
that the intermediate iodo-BCPA undergoes an in situ Giese
reaction. Attempts to realize a one-pot cascade resulted only in
formation of N-allyl sulfonamide 4a, where direct HAT from
addition of the silane until complete consumption of the
iodoaziridine 2a (16 h, [Ir] catalysis), the entire ATRA/Giese
process could be performed without isolation of the
intermediate iodo-BCPA. The overall yield for this trans-
formation (31%, 55% per step) is consistent with that for the
isolated steps (57%, 60%).
The distinct nature of the two silanes used in these Giese
functionalizations may suggest that different mechanisms
operate in the two cases. Previous studies42−44,48 have
suggested that reaction with either mediator requires initial
formation of a silyl radical. In the case of (Me3Si)3SiOH
(Figure 4a, Conditions A), this can be achieved by oxidation of
the silanolate ion (generated on deprotonation of the silanol
under basic conditions) by the redox-active excited triplet state
of the iridium catalyst (Ered Ir(III)*/Ir(II) = +1.21 V vs SCE in
MeCN),52,53 followed by radical Brook rearrangement.54 The
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explore this possibility, a Stern−Volmer quenching study was
carried out (Figure 4b). To our surprise, this revealed that
(Me3Si)3SiH is a poor quencher of the excited state
photocatalyst (blue line), but iodo-BCPA 3a is an efficient
quencher (purple line). In contrast, (Me3Si)3SiOH (in the
presence of Na2CO3 to mimic basic reaction conditions) is able
to quench the catalyst excited state (red line), which offers
support that Conditions A can proceed according to the
proposed mechanism.
Voltammetry experiments39 revealed that the first (irrever-
sible) reduction of 3a occurs at −2.29 V, which is in excess of
the reducing power of most common photocatalysts and
renders an oxidative quenching pathway unlikely. We further
considered that visible light might effect homolysis of the C−I
bond; however, UV/visible spectroscopy (Figure 4c) revealed
no absorption at 455 nm (blue LEDs). Control experiments
(see the SI) further demonstrated that all reaction components
were essential for the success of the reaction and that no
addition occurred in the absence of the silane. We therefore
suggest that the efficient quenching of the photocatalyst
excited state by iodo-BCPA may be due to Dexter energy
transfer.57,58 The energy of the T1 triplet state of Ir[(dF-
(CF3)ppy)2(dtbbpy)]PF6 is 258 kJ mol−1;52 given the bond
dissociation energy of C−I bonds is in the region of ∼213 kJ
mol−1, homolysis of the C−I bond by this mechanism appears
feasible. The resulting BCP radical A can then undergo
addition to the acceptor to give the EWG-stabilized radical D
(or competing HAT to generate C). Radical D then undergoes
H atom transfer with (Me3Si)3SiH to generate the Giese
product, along with (Me3Si)3Si•, which propagates the
reaction by I atom abstraction from the iodo-BCPA.
Deuteration studies were carried out to gain support for this
reaction pathway or whether a possible reduction by Ir(II)
operates (Ered •CH(CH3)CO2Et/−CH(CH3)CO2Et = +0.66 V
vs SCE in MeCN) as in Conditions A (Figure 4d).59 In
contrast to findings by ElMarrouni et al.,45 no product
deuteration was observed on conducting the reaction in
CD3OD/D2O, suggesting SET from Ir(II) is not operative.
However, use of (Me3Si)3SiD led to complete deuteration at
the α-position (>95%), which strongly supports the proposed
propagation pathway. The observation of the silane adduct of
methyl acrylate (6b-Si) further supports the intermediacy of
the silyl radical.
With methods to access diverse 1,3-disubstituted BCPAs
established, we briefly investigated a selection of further
transformations (Figure 5). Principal among these was the
ability to cleave either the allyl or sulfonyl substituent from the
nitrogen atom. The former was achieved on BCPA 3a under
Figure 4. (a) Possible mechanisms of Giese reaction of iodo-BCPAs.
(b) Stern−Volmer quenching study using 3a, (Me3Si)3SiH,
(Me3Si)3SiOH, and methyl acrylate. (c) UV/visible spectra of 3a,
(Me3Si)3SiH, and (Me3Si)3SiH + 3a. (d) Deuterium labeling study.
resulting silyl radical then abstracts an iodine atom from the
iodo-BCP(A) to give the BCP(A) radical A, which then
undergoes addition to the radical acceptor. For acceptors such
as allyl sulfones (Conditions A, radical B), this addition is
presumably sufficiently slow that H atom transfer to A can
compete when using (Me3Si)3SiH as mediator (to give C),
rationalizing the need for (Me3Si)3SiOH. Catalyst turnover is
then achieved via reduction of the sulfinyl radical to the
sulfinate ion (Ered PhSO2 / PhSO2 = +0.37 V vs SCE;55 Eox
•
−
Ir(II)/Ir(III) = +1.37 V vs SCE in MeCN).52
For Conditions B ((Me3Si)3SiH mediator), it has been
proposed that (Me3Si)3Si• can be generated by direct
oxidation of the silane ([Eox (Me3Si)3SiH/(Me3Si)3SiH•+
=
+0.73 V vs SCE in MeCN),56 followed by deprotonation. To
Figure 5. Further transformations.
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mild conditions using Pd(PPh3)4 and 1,3-dimethylbarbituric
acid (7, 72%),60 while smooth detosylation was effected on 4b
via sonication with Mg/MeOH, which gave amine 8 in 64%
yield. Simple deiodination of 3a was carried out under
photoredox conditions (9, 54%), while the N-allyl group
could be oxidized to epoxide 10 (oxone/KBr, 71%),61
aldehyde 11 (O3, 71%), or BCP glycine analogue 12
(RuCl3/NaIO4, 34%). Finally, cross metathesis with methyl
acrylate gave 13 (Grubbs II, 72%).
In summary, this twofold radical functionalization of
[1.1.1]propellane offers a versatile and convenient route to
prepare 1,3-N,C-disubstituted BCPs, opening up a new route
to valuable aniline isosteres. The chemistry displays high
functional group tolerance, affording products that are
unobtainable by previous methods. The application of this
chemistry to amino acid and drug analogues highlights the
potential utility of this methodology for the pharmaceutical
industry.
ACKNOWLEDGMENTS
■
H.D.P. thanks the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine for a studentship (EP/
L015838/1) generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Jannsen, Novartis, Pfizer, Syngenta,
Takeda, UCB, and Vertex. J.N. thanks the Marie Skłodowska-
Curie actions for an Individual Fellowship (GA No 786683).
E.A.A. thanks the EPSRC for support (EP/S013172/1). We
thank the reviewers for useful insight concerning the
mechanisms of the Giese reactions.
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■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04180.
■
sı
Experimental details and copies of both H and 13C
NMR spectra (PDF)
1
Accession Codes
CCDC 2078089 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
Edward A. Anderson − Chemistry Research Laboratory,
University of Oxford, Oxford OX1 3TA, United Kingdom;
orcid.org/0000-0002-4149-0494;
■
Email: edward.anderson@chem.ox.ac.uk
Authors
Helena D. Pickford − Chemistry Research Laboratory,
University of Oxford, Oxford OX1 3TA, United Kingdom
Jeremy Nugent − Chemistry Research Laboratory, University
of Oxford, Oxford OX1 3TA, United Kingdom
Benjamin Owen − Chemistry Research Laboratory, University
of Oxford, Oxford OX1 3TA, United Kingdom
James. J. Mousseau − Pfizer Worldwide Research and
Development, Groton, Connecticut 06340, United States
Russell C. Smith − Janssen PRD, San Diego, California
92121, United States; Present Address: (R.C.S.) Abbvie,
Drug Discovery Science & Technology (DDST) Dept.
R467, AP10-208, 1 North Waukegan Road, North
Chicago, IL 60064.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04180
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
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