Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes

Article abstract of DOI:10.1016/j.chempr.2018.11.007

Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)₂. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)₂. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.

Full text of DOI:10.1016/j.chempr.2018.11.007

Article
Site-Selective C–H Functionalization of
(Hetero)Arenes via Transient, Non-symmetric
Iodanes
Stacy C. Fosu, Chido M.
Hambira, Andrew D. Chen,
James R. Fuchs, David A. Nagib
fuchs.42@osu.edu (J.R.F.)
nagib.1@osu.edu (D.A.N.)
HIGHLIGHTS
C–H functionalization of arenes or
heteroarenes with Cl, Br, OMs,
OTs, and OTf anions
Transient generation of reactive,
non-symmetric iodanes from
anions and PhI(OAc)2
Site-selective C–H chlorination of
medicinally relevant arenes or
heteroarenes
Computational methods for
predicting sites of reactivity with
complex molecules
Fosu, Hambira, and colleagues describe the direct C–H functionalization of
medicinally relevant arenes or heteroarenes. This strategy is enabled by transient
generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The
site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules,
including within medicines and natural products, can be conducted by the
operationally simple procedure included herein. A computational model for
predicting site selectivity is also included.
Fosu et al., Chem 5, 1–12
February 14, 2019 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.11.007

Please cite this article in press as: Fosu et al., Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes, Chem
(2018), https://doi.org/10.1016/j.chempr.2018.11.007
Article
Site-Selective C–H Functionalization
of (Hetero)Arenes via Transient,
Non-symmetric Iodanes
1,4,
Stacy C. Fosu,1,3 Chido M. Hambira,2,3 Andrew D. Chen,1 James R. Fuchs,2, and David A. Nagib
*
*
SUMMARY
The Bigger Picture
The discovery of new medicines is
a time- and labor-intensive
process that frequently requires
over a decade to complete. A
major bottleneck is the synthesis
of drug candidates, wherein each
complex molecule must be
prepared individually via a multi-
step synthesis, frequently
A strategy for C–H functionalization of arenes and heteroarenes has been devel-
oped to allow site-selective incorporation of various anions, including Cl, Br,
OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive,
non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The
utility of this mechanism is demonstrated via para-selective chlorination of
medicinally relevant arenes, as well as site-selective C–H chlorination of hetero-
arenes. Spectroscopic, computational, and competition experiments describe
the unique nature, reactivity, and selectivity of these transient, unsymmetrical
iodanes.
requiring a week of effort per
molecule for thousands of
INTRODUCTION
candidates. As an alternate
strategy, direct, post-synthetic
functionalization of a lead
In the realm of medicinal chemistry, synthetic methods for the replacement of C–H
bonds within complex molecules are of significant value.1–3 Among various ap-
proaches that enable aryl C–H functionalization,4–13 we are most interested in the
suitability of hypervalent iodine-mediated chemistry14–20 to enable post-synthetic
modification of medicinal agents. Since the pioneering contributions of Kita et al.,
l3-iodanes have been known to substitute electron-rich arenes with certain nucleo-
philes (e.g., N3, CN, OAc).21–26 With the goal of expanding the scope of arenes and
nucleophiles that may be coupled by this mechanism, we sought to develop a new,
in situ iodane activation strategy (Figure 1).
candidate could enable this
diversification in a single
operation. In this article, we
describe a new method for direct
manipulation of drug-like
molecules by incorporation of
motifs with either known
pharmaceutical value (halides) or
that permit subsequent
Although it is generally understood that bench-stable iodanes, like PhI(OAc)2, may
be activated with Lewis (e.g., BF3, Me3Si+)21–26 or Brønsted acids (e.g., TsOH,
TfOH, Ts2NH),27–30 the precise nature of this acid activation remains unclear. Recent
investigations by Shafir and co-workers revealed that it entails transient formation of
a non-symmetric iodane (e.g., BF3 coordination to one of the ligands of PhI(OAc)2).31
This model for increased reactivity via iodane desymmetrization may also explain the
novel reactivity of Koser’s reagent, PhI(OH)OTs,27 and other hybrid iodanes.19,32–46
With this hypothesis in mind, we proposed that although unsymmetrical iodanes
typically require preformation, their in situ generation may provide the dual benefits
of (1) using bench-stable precursors and (2) harnessing greater reactivity, including
toward heteroarenes. Furthermore, we anticipated that in situ generation of non-
symmetric iodanes with anions may enable the use of a wide range of nucleophiles
for aryl C–H functionalization.
conversion (pseudo-halides) to
medicinally relevant analogs. This
user-friendly strategy is enabled
by combining commercial iodine
reagents with salts and acids. We
expect this simple method for
selective, post-synthetic
incorporation of molecular
diversity will streamline the
discovery of new medicines.
In designing a unified strategy for site-selective, aryl C–H functionalization via
non-symmetric iodanes, we expected these reactive intermediates could be
readily accessed through ligand exchange47 of bench-stable iodanes by anions
Chem 5, 1–12, February 14, 2019 ª 2018 Elsevier Inc.
1

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(2018), https://doi.org/10.1016/j.chempr.2018.11.007
Figure 1. Selective C–H Functionalization of Arenes and Heteroarenes with Anions, Enabled by
In Situ Activation of an Iodane
(A) Ligand exchange promoted by HX.
(B) Mechanisms enabled by iodane association.
(Figure 1A). As a simple and versatile source of anions, we proposed addition
of acids, HX, to PhI(OAc)2 may promote ligand substitution to form PhIX2, in
analogy to acid-mediated formation of PhI(OH)OTs and Ph2IOTf.48 Moreover, we
anticipated any acids stronger than AcOH should drive this acid/base equilibrium
toward PhIX2, an unstable reagent class associated with non-selective, homolytic
reactivity.14–20 Essentially, however, we noted this process must proceed via an un-
symmetrical iodane intermediate (I). We postulated this highly reactive species—
having an elongated I–X bond and low-lying lowest unoccupied molecular
orbital31—could react selectively with arenes through either of two transient iodo-
nium-based mechanisms (Figure 1B).49 First, anionic dissociation of X– affords
1Department of Chemistry and Biochemistry,
The Ohio State University, Columbus,
OH 43210, USA
cationic PhI(OAc)+, which may participate in single-electron transfer (SET) to
oxidize an arene.21 The resulting radical cation is then prone to nucleophilic attack
by the dissociated anion (X–). After net loss of Hd, this mechanism can enable para-
2Division of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, The Ohio
State University, Columbus, OH 43210, USA
selective reactivity through the site-specific electrophilicity of an aryl radical
cation.8,50,51 Alternatively, AcO– dissociation from non-symmetric iodane I affords
3These authors contributed equally
a net polarity-reversal of X– via an electrophilic PhI(X)+ iodonium species. Attack by
4Lead Contact
the (hetero)arene nucleophile at its most nucleophilic position and subsequent
*Correspondence: fuchs.42@osu.edu (J.R.F.),
nagib.1@osu.edu (D.A.N.)
deprotonation would afford the X-substituted product. Thus, site-selective C–H
https://doi.org/10.1016/j.chempr.2018.11.007
functionalization may also be accessed by a closed-shell mechanism.
2
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Figure 2. Site-Selective C–H Functionalization Incorporates the Anions of Acids, Salts, and Acyl Halides
(A) Aryl C–H functionalization with acids, HX.
(B) Aryl C–H chlorination with chlorides, MCl or RCl.
(C) Heteroarene C–H chlorination with acyl chlorides, RCl.
RESULTS AND DISCUSSION
To test our hypothesis of the generalizability of this in situ iodane activation strategy,
a series of acids was combined with N-Piv-o-toluidine and PhI(OAc)2 in dichloroethy-
lene (DCE) at 50ꢀC (Figure 2A). Surprisingly, several acids (spanning a range of
>10 pKa units) afforded para-selective C–H functionalization by incorporation of
their conjugate bases into the arene. Notably, TfOH alone facilitates iodane-medi-
ated C–H oxytriflation to afford aryl triflate 1, without the need for stoichiometric
AgOTf.52 Similarly, C–H oxy-sulfonylations are observed with TsOH and MsOH,
which afford tosylate 2 and mesylate 3, also without additional promoters (e.g.,
BF3).53 Importantly, aqueous mineral acids, HBr and HCl, afford halogenated arenes,
4 and 5, with high efficiency (up to 88% yield) and para-selectivity (>20:1).
With a highly, para-selective C–H functionalization observed for each of these ha-
lides and pseudo-halides, we chose to focus further studies on the most valuable
of these reactions: chlorination. The post-synthetic halogenation of a medicinal
candidate has 2-fold utility: (1) improving biological properties by enhancing bind-
ing affinity, cellular membrane permeability, or metabolic stability,4 and (2) enabling
further synthetic manipulation. As a prototypical halide, the chloride is ubiquitous in
medicines, with Cl ranking as the sixth most common element found in approved
pharmaceuticals (after H, C, N, O, S),54 especially as a para-aryl substituent.55 Yet,
although direct, post-synthetic modification by aryl C–H functionalization offers
streamlined access to libraries of chlorinated medicinal candidates, such analogs
are typically prepared by iterative synthesis with pre-halogenated arenes. In the
case of chloride, the challenge arises from the traditional reliance on harsh reagents
and non-selective methods for aryl chlorination, which are often not applicable to
complex, drug-like molecules. An explanation is that aryl chlorination reagents
t
either require (1) overly reactive reagents (e.g., Cl2, SO2Cl2, BuOCl), or (2) milder,
more practically handled reagents that are sometimes not sufficiently reactive
(e.g., N-chlorosuccinimide). This challenge has been addressed in recent years by
the development of novel chlorination methods with reagents, such as Palau’chlor
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and iodosobenzoic acid (IBA)-Cl.56,57 Nonetheless, we noted that the ‘‘mild reagent
versus sufficient reactivity’’ paradox remains unsolved in the realm of aryl C–H
chlorination.58,59
Encouraged by the simple use of dilute, mineral acids (e.g., 1 M HCl in water) to
enable this C–H functionalization, we questioned whether other chloride reagents
might also promote this ligand exchange to access this unique iodane reactivity
from PhI(OAc)2 (Figure 2B). Indeed, we observed that several chlorides afford aryl
chlorination, including Lewis acids (e.g., MgCl2), salts (e.g., LiCl), and acyl halides
(e.g., AcCl).
Finally, cognizant of the privileged role of N-containing heterocycles in medicine,60
we focused our attention on the C–H chlorination of heteroarenes (Figure 2C).
Notably, there are few ways to prepare chloro-(iso)quinolines—each analog
requiring its own multi-step synthesis.61–63 With this in mind, we subjected isoquino-
line to the HCl-mediated conditions. Although this acidic protocol did not afford
chlorination, we observed complete protonation by 1H NMR, which likely renders
the heteroarene significantly less nucleophilic. We therefore investigated other chlo-
ride reagents for aryl chlorination. Although many of these chloride reagents were
also ineffective (e.g., MgCl2), we found that acyl chlorides promote this reaction effi-
ciently (up to 92% yield). We suspect these anhydrous sources of chloride anion,
which may also function as desiccants, lack the acidity to deactivate the isoquinoline
nucleophile. Interestingly, the observed selectivity in this case (for nucleophilic C4) is
orthogonal to most heteroarene functionalizations (for electrophilic C1 or C3) via
polar64–66 or radical mechanisms.67,68
With robust conditions in hand for the selective C–H chlorination of either arenes or
heteroarenes, we sought to investigate the generality and utility of this transformation
(Figure 3). In the case of HCl-mediated aryl chlorination, various drug-like scaffolds
are amenable to this reaction, including those containing halides, amides, esters, ke-
tones, and imides (7–18). Notably, exclusive para-regioselectivity is observed in all
cases. In addition, this iodane-mediated reaction is chemo-selective, affording only
sp2 C–H chlorination—with neither benzylic nor a-carbonyl oxidation (positions high-
lighted in gray), as typically observed via homolysis of PhICl2.26,69–71 In the case of
heteroarenes, aryl chlorination of both five-membered heterocycles (e.g., indoles,
pyrazoles, 19–21) and six-membered heterocycles (e.g., isoquinoline, quinoline, py-
rimidine, pyridine, 6, 23–30, via acyl chlorides) are also possible (up to 92%).
With our ultimate goal of medicinal application in mind, we then subjected a series of
pharmaceuticals and natural products to this post-synthetic C–H chlorination strat-
egy. Remarkably, a wide range of functionality is tolerated, including esters, amides,
amines, imides, enamides, pyrroles, and dimethoxyarenes. As shown in Figure 3, the
chlorinated analogs of naproxen, lidocaine, uracil, caffeine, and papaverine (31–38)
were each accessed in a single step using this protocol. Notably, the tertiary amine
of lidocaine 33 remains intact, despite its oxidant sensitivity, likely due to protection
by protonation under these acidic conditions. As expected, bromination is also
possible for both arenes (4) and heteroarenes (22), including within more complex
drug-like scaffolds (32, 35, 38).
Finally, we sought to test this iodane-based strategy within the context of an
active medicinal chemistry program. In particular, we have shown that analogs of
phyllanthusmin D exhibit potent, anti-cancer activity against HT-29 human colon
cancer cells.72 Although this natural product is structurally related to the DNA
4
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(2018), https://doi.org/10.1016/j.chempr.2018.11.007
Figure 3. C–H Chlorination of Arenes and Heteroarenes via an In Situ Generated, Non-symmetric Iodane Strategy
Site-selective (hetero)aryl C–H chlorination: arene (0.4 mmol), chloride reagent (5 equiv), PhI(OAc)2 (1.5 equiv), DCE (0.2 M), 50ꢀC, 45 min to 24 hr.
Isolated yields. No regioisomeric chlorination observed (susceptible positions highlighted with gray circles). Chloride reagents: a1 M HCl, bBu4NCl,
f
i
j
cPhI(OAc)2 (0.9 equiv), d1 M HCl (10 equiv), PhI(OAc)2 (2.5 equiv), eEtO2CCl, KBr, gC6F5COCl, hAcCl, 3:1 para:ortho, 48% HBr, k2 M HCl in Et2O.
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(2018), https://doi.org/10.1016/j.chempr.2018.11.007
Figure 4. Computational Experiments Predict Regioselectivity
topoisomerase IIa inhibitor, etoposide, it appears to exhibit biological activity via a
distinct mechanism of action. Notably, when non-natural sugars are affixed to the
aglycone core of phyllanthusmin, especially potent analogs have been identified
(half maximal inhibitory concentration <10 nM).73,74 In order to streamline our explo-
ration of the structure-activity relationship for substitution of the aryl core, we pur-
sued a C–H functionalization strategy to rapidly generate a library of medicinal
analogs. To this end, we subjected Ac-phyllanthusmin D to our HCl-mediated pro-
tocol. Unfortunately, the critical sugar was rapidly hydrolyzed off under these acidic
conditions, affording the biologically inactive agylcone. On the other hand, using
Bu4NCl as the chloride reagent yields the C–H chlorinated derivative (39) in a single
step. Similarly, LiBr affords direct C–H bromination (40). Interestingly, divergent
regioselectivity is observed for these two reactions, with the smaller Cl atom
substituting the more electron-rich naphthalene and the larger Br atom adding to
the less-hindered, axially rotatable benzene. Importantly, in both cases, the sugar
substituent is unperturbed, allowing us to access a family of potent derivatives
from a single advanced intermediate.
In order to better understand the excellent regioselectivity observed in the C–H
halogenations of various arenes in Figure 3, we conducted density functional theory
(DFT) experiments according to Ritter’s procedure.10 Specifically, we determined
Fukui index values for several (hetero)arenes by computing a population analysis
for each arene and its corresponding N-1 ionization state, and then subtracting
the charge densities of the latter from the former in each case (see Supplemental
Information for details). As shown in Figure 4, this Fukui analysis correctly predicts
the most reactive positions of several complex molecules from Figure 3.
In particular, this analysis predicts and explains the results obtained for anilide 5, as
well as the medicinally relevant natural products, papaverine and phyllanthusmin.
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Figure 5. Computationally Supported Divergent Mechanisms Explain Predicted and Observed Regioselectivities for Arenes versus Heteroarenes
Each example contains polyaromatic rings with multiple possible sites of reactivity.
Yet, Fukui analysis predicts the most reactive atom in the case of papaverine (37) and
the two most reactive positions for phyllanthusmin (i.e., sites of chlorination 39 and
bromination 40).
On the other hand, we noted that a simple electron-density map of partial charges
provides a more accurate predictor of the site selectivity observed for heteroarene
C–H functionalization. For example, the most negative position by natural popula-
tion analysis correlates to the most reactive position for quinoline (25), isoquinoline
(6), indole (19), and quinoxaline (26). Interestingly, for three of these four classes of
heteroarene, Fukui analysis predicts alternate regioselectivity, suggesting divergent
mechanisms between the arene and heteroarene reactions.
Thus, given the correct prediction of site selectivity by these DFT calculations, we
propose that the mechanisms proposed in Figure 1 are both viable. As shown in Fig-
ure 5, given the strong correlation of the Fukui analysis, which is dependent on
radical cation character, to predict regioselectivity for the arenes, we suggest that
the ‘‘radical cation’’ mechanism is likely more relevant for the electron-rich arenes.
In this case, the transient, non-symmetric iodane intermediate likely promotes
single-electron oxidation to afford a radical cation with electrophilicity (and nucleo-
philic attack) localized at the predicted para position. Alternatively, for less electron-
rich heteroarenes, the iodane likely combines directly with the heteroarene via the
‘‘iodonium’’ mechanism. This pathway is supported by the C3 regioselectivity of
the products, which are correctly (and exclusively) predicted via partial charge anal-
ysis as correlating to the most negative, or electron-dense, sites.
The chemoselectivity observed among the various arenes in Figure 3 also led us to
question the possibility of developing methods to enable reagent-based control
over selectivity. To this end, we subjected a 1:1 mixture of heteroarene and arene
to a series of competition experiments (Figure 6). Indeed, when heteroaryl condi-
tions are used (e.g., EtO2CCl), isoquinoline chlorination (6) is exclusively observed,
even in the presence of electron-rich anisoles. Yet, under acidic, aryl conditions (e.g.,
HCl), isoquinoline is presumably protonated, affording exclusive anisole chlorina-
tion (41).
We were also interested in further probing the unique C–H chlorination of heteroar-
enes, especially given the importance of these motifs in medicine. To the best of
our knowledge, this in situ iodane activation strategy comprises the mildest and
most efficient protocol for C–H chlorination of (iso)quinolines,75–77 affording regio-
selective substitution of the most nucleophilic carbon (e.g., 4-Cl-isoquinoline or
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Figure 6. Competition Experiments Demonstrate Chemoselectivity
3-Cl-quinoline). To test this hypothesis, we investigated the chlorination of both iso-
quinoline and quinoline by common aryl chlorination methods, as shown in Figure 7.
Surprisingly, no chlorinated products were detected for either class of heteroarene
(6 or 25), even in the presence of state-of-the-art chlorinating reagents, Palau’chlor
and IBA-Cl. Similarly, several other arenes in Figure 3 are not efficiently halogenated
using alternate literature methods, such as PhICl2 (e.g., 10, 15, 33, 39; see Supple-
mental Information).
Noting a distinct difference in reactivity between our postulated, transient non-
symmetric iodane and cyclic IBA-Cl in particular, we sought to investigate the pre-
cise nature of the in situ generated iodane. We first probed if a diaryliodonium
pathway could promote this unprecedented heteroaryl chlorination (Figure 8A).
To examine the viability of such a mechanism, we prepared 3-pyridyl-diaryliodo-
nium and heated it in the presence of acyl chloride, both with and without
PhI(OAc)2. In both cases, we did not observe any chlorination (aryl or heteroaryl)
thereby precluding this type of mechanism. Similarly, Ph2I+ClÀ does not afford
PhCl, when heated with or without HCl. In addition, bis-N-substituted di(hetero)
aryl iodonium was prepared and subjected to various acyl chlorides (Figure 8B).
In this mechanistic probe, no chloroarene was obtained, either with or without
PhI(OAc)2, further suggesting such iodoniums are not likely intermediates in this
mechanism.
Figure 7. Reactivity Comparison with Other Chlorinating Reagents
8
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Figure 8. Mechanistic Probes Suggest that Alternate Iodonium Pathways Are Not Viable
(A) Diaryliodonium pathway.
(B) Bis-N-substituted di(hetero)aryliodinium pathway.
To obtain further support for our proposed mechanism (cf. Figure 1), we sought to
spectroscopically observe the transient, non-symmetric iodane intermediate.
Several representative NMR experiments from this investigation are shown in Fig-
ure 9. After identifying diagnostic, aromatic 1H NMR signals for the homo-di-
substituted iodanes, PhI(OAc)2 and PhICl2, we subjected PhI(OAc)2 to varying
stoichiometries of HCl and observed a new signal, which we ascribe to the non-sym-
metric iodane, PhI(OAc)Cl. Notably, this signal is also observed when AcCl is used as
the chloride reagent. And interestingly, the same signal is observed upon combina-
tion of PhICl2 with Ac2O, which serves as an anhydrous source of acetate.
In order to examine the role of this observed species as a possible intermediate, we
then subjected isoquinoline to chlorination under various conditions (Figure 10). As
expected, Willgerodt’s reagent, PhICl2, does not afford appreciable quantities of
Figure 9. 1H NMR Experiments Indicate the Intermediacy of a Non-symmetric Iodane
Intermediate
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Figure 10. Heteroarene Chlorination by Orthogonal Reagents; Recapitulation of Reactivity
Supports Mono-chloro-iodane Hypothesis
chlorination (6). However, a combination of PhICl2 and Ac2O, which also generates
the unsymmetrical iodane in situ, recapitulates the reactivity of PhI(OAc)Cl that is not
observed for PhICl2 alone. In addition, a mixture of AcCl and PhI(OAc)2, which more
selectively forms PhI(OAc)Cl over PhICl2, affords the desired heteroaryl chloride in
high yield (86%; similar to EtO2CCl, 92%).
In summary, a site-selective hetero(aryl) C–H functionalization strategy has been
developed. This practical method is enabled by in situ generation of non-symmetric
iodanes from PhI(OAc)2 and the anions of acids, salts, and acyl halides. These mild
conditions afford access to new types of reactivity and selectivity, as illustrated in
the chemo- and regio-selective C–H halogenation of a range of medicinally relevant
(hetero)arenes. Importantly, spectroscopic, computational, and experimental sup-
port for in situ generation of unsymmetrical iodanes under such conditions provides
mechanistic validation to enable further development of new iodane reactivity.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 157
figures, 4 schemes, and 33 tables and can be found with this article online at
https://doi.org/10.1016/j.chempr.2018.11.007.
ACKNOWLEDGMENTS
We thank The Ohio State University, National Institutes of Health (NIH R35
GM119812 and P01 CA125066), National Science Foundation (NSF CAREER
1654656), and American Chemical Society Petroleum Research Fund for financial
support. S.C.F. is supported by an HHMI Gilliam Fellowship. C.M.H. is supported
by the Jane Chen Fellowship in Medicinal Chemistry. High performance computing
resources were provided by The Ohio Supercomputer Center.
AUTHOR CONTRIBUTIONS
S.C.F. and D.A.N. designed the strategy. S.C.F. and C.M.H. designed, performed,
and analyzed all chemical experiments. A.D.C. performed computational experi-
ments. All authors contributed to writing this manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
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Received: July 11, 2018
Revised: September 26, 2018
Accepted: November 8, 2018
Published: December 13, 2018
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