Rhodium(III)-catalyzed indazole synthesis by C-H bond functionalization and cyclative capture

Article abstract of DOI:10.1021/ja402761p

An efficient, one-step, and highly functional group-compatible synthesis of substituted N-aryl-2H-indazoles is reported via the rhodium(III)-catalyzed C-H bond addition of azobenzenes to aldehydes. The regioselective coupling of unsymmetrical azobenzenes

Full text of DOI:10.1021/ja402761p

Communication
pubs.acs.org/JACS
Rhodium(III)-Catalyzed Indazole Synthesis by C−H Bond
Functionalization and Cyclative Capture
Yajing Lian,† Robert G. Bergman,‡ Luke D. Lavis,*,§ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
§Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States
S
* Supporting Information
nucleophile to afford pharmaceutically important N-aryl-2H-
indazoles by formal [4+1] annulation (Figure 1).9,10 Substituents
ABSTRACT: An efficient, one-step, and highly functional
group-compatible synthesis of substituted N-aryl-2H-
on unsymmetrical azobenzenes that effect a high level of
indazoles is reported via the rhodium(III)-catalyzed C−
regiocontrol have been established to significantly enhance the
H bond addition of azobenzenes to aldehydes. The
scope of the method. Moreover, by capitalizing on substituent
regioselective coupling of unsymmetrical azobenzenes
control of regioselectivity, a readily cleavable 2-aryl substituent
was further demonstrated and led to the development of
has been developed that provides straightforward access to
a new removable aryl group that allows for the preparation
indazoles lacking N-substitution. Finally, we have determined
of indazoles without N-substitution. The 2-aryl-2H-
that appropriately substituted 2-aryl-2H-indazoles represent a
indazole products also represent a new class of readily
prepared fluorophores for which initial spectroscopic
new class of fluorophores that may find utility as fluorescent
probes for biological study or as specialized materials. Initial
characterization has been performed.
spectroscopic characterization of representative derivatives has
therefore been performed.
hodium(III)-catalyzed addition of sp2-hybridized C−H
Indazole is recognized as a privileged structure in the
pharmaceutical industry with multiple drugs and drug candidates
Rbonds to polarized π-bonds, including those present in
in clinical trials incorporating this pharmacophore.11 The more
difficult to prepare 2-substituted 2H-indazole class has in
particular begun to attract the increased attention of the
synthetic community due to the promise of drug candidates
that contain this motif.12,13 We envisioned that convergent entry
to 2-substituted 2H-indazoles 3 should be possible by Rh(III)-
catalyzed addition of azobenzenes 1 to aldehydes 2 (Scheme 1).
We rationalized that the azo functional group would direct ortho
C−H bond activation, followed by the reversible addition to
aldehyde 2 to provide alcohol 5. Cyclative capture by an
intramolecular nucleophilic substitution to give 6 followed by
rapid aromatization should provide the desired 2H-indazole 3.
aldehydes,1 imines,2 isocyanates,3 aziridines,4 carbon monoxide,5
and isonitriles,6 has proven to be a versatile and highly functional
group-compatible synthetic approach.7 Aldehydes are partic-
ularly attractive inputs because a vast number of derivatives are
commercially available. However, the addition of C−H bonds to
aldehydes is often reversible with the alcohol addition products
typically favored when highly electron-deficient aldehydes are
used.1c,d,h We have previously demonstrated that this inherent
challenge can be overcome by cyclative capture of the hydroxyl
group to obtain valuable heterocycle products (Figure 1).1a,b,8
Herein, we introduce a new cyclative capture approach where the
initially generated hydroxyl serves as a leaving group rather than a
Scheme 1. Proposed Reaction Pathway for 2H-Indazole
Synthesis
Received: March 18, 2013
Figure 1. Two distinct approaches for cyclative capture.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja402761p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
An enormous number of azobenzenes have been prepared due
to their many applications in the chemical industry,14 and it is
therefore not surprising that the cyclometalation of azobenzene
was one of first examples of this type of transformation.15 Despite
this, there have been few reports on the catalytic C−H
functionalization of azobenzenes,16 and none have relied on
Rh(III) catalysis. Moreover, except for one substrate example,16c
the regioselective functionalization of unsymmetrical azoben-
zenes is unexplored.
Table 2. Electronic and Steric Effects on 2H-Indazole
Regioselectivity
ab c
, ,
We first chose to evaluate azobenzene 1a and benzaldehyde 2a
as model substrates and surveyed conditions that had previously
been determined to be optimal for Rh(III) catalyzed additions to
aldehydes (Table 1).1a The use of 5 mol% of [Cp*RhCl2]2 and
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
Ag salt
yield (external)
46
1
2
3
4
5
6
7
8
9
10
DCE
AgSbF6
none
c
DCE
trace
THF
AgSbF6
AgSbF6
AgSbF6
AgBF4
AgPF6
46
64
81
52
15
40
0
HOAc
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
a
Conditions: azobenzene (0.20 mmol), benzaldehyde (0.40 mmol) in
b
c
1.0 mL of dioxane for 24 h. Isolated yield. Ratio was determined by
d
crude 1H NMR. Reaction was conducted in 0.4 mL of dioxane.
e
Reaction was conducted in 1.0 mL of THF with 100 mg of MgSO4.
AgBC24F20
none
d
methoxy group is meta to the site of reaction and therefore
contributes an inductive effect but does not provide resonance
stabilization. The inductive effect could either slow the rate of
C−H functionalization or affect the rate of cyclative capture of
the reversibly formed alcohol addition product. To test this
assumption, the 3-methoxy substitution pattern in 1d with the
methoxy group capable of providing resonance stabilization was
evaluated. As expected, the reaction favored 3d′ with a 9:1
regioselectivity for C−H functionalization occurring on the more
electron-rich aromatic ring. The exclusive functionalization of
azobenzene 1d para rather than ortho to the methoxy group
suggests that steric effects are important. For this reason,
azobenzenes 1e and 1f, which are 3,5-disubstituted with electron-
rich methyl or electron-deficient CF3 groups, respectively, were
evaluated, and each exclusively reacted at the less hindered ring
to give indazoles 3e and 3f as single regioisomers.
The overriding importance of steric effects upon regioselec-
tivity led to the design of azobenzene derivative 1g. This
approach provides 2-aryl-2H-indazoles with an electron-rich aryl
substituent that can readily be cleaved by straightforward
oxidative methods to provide indazole products lacking
substitution on nitrogen. Specifically, coupling azobenzene 1g
with benzaldehyde smoothly afforded indazole 3g as a single
regioisomer in good yield. For this hydroxy-substituted
azobenzene, addition of MgSO4 as a drying agent was found to
modestly improve the reaction yield. Moreover, THF provided a
higher yield than dioxane, 68% vs 48%, respectively.
AgSbF6
0
a
Conditions: 1 (0.10 mmol), 2 (0.20 mmol) in 0.5 mL of solvent for
b
1
24 h. Determined by H NMR relative to 2,6-dimethoxytoluene as
external standard. In place of (Cp*RhCl2)2, Cp*Rh-
(CH3CN)3(SbF6)2 was used. No (Cp*RhCl2)2 was added.
c
d
20 mol% of AgSbF6 in DCE afforded the desired product 3a in
46% yield (entry 1). The preformed cationic rhodium catalyst
[Cp*Rh(CH3CN)3(SbF6)2] is often effective for aldehyde
additions,1c,g but for this substrate combination this catalyst
completely shut down the reaction (entry 2). Because solvent
can play a key role in the reaction outcome,1b a variety of solvents
were screened. THF maintained the same yield as DCE (entry
3), HOAc improved the yield to 64% (entry 4), and dioxane
proved to be the most effective, affording the product in 81%
yield (entry 5). Replacing AgSbF6 with other silver salts reduced
the yield of product (entries 6−8). Rationalizing the change in
reaction yield upon variation of the counterion and solvent is
complicated by the potential for differential effects upon C−H
bond-functionalization and cyclization. No reaction was
observed when either [Cp*RhCl2]2 or AgSbF6 alone was used
(entries 9 and 10), which suggests that a cationic Rh(III) species
is required for this C−H bond functionalization process.
Having defined an effective catalyst and reaction conditions for
the synthesis of 2H-indazole 3a, we next explored substrate scope
for unsymmetrical azobenzenes. The 4-nitro-substituted azo-
benzene 1b led to the indazole products in 62% combined yield
with 9:1 regioselectivity favoring 3b with C−H functionalization
of the more electron-rich phenyl ring (Table 2). In contrast, the
4-methoxy-substituted azobenzene 1c generated the regioiso-
meric products 3c and 3c′ with low selectivity. The major
product 3c was obtained by C−H functionalization on the less
electron-rich phenyl ring of the azobenzene, which is opposite to
the selectivity observed with the 4-nitro derivative 1b. For 3c′ the
With an understanding of how electronic and steric effects
control regioselectivity, we next explored substrate scope with a
diverse set of azobenzenes 1 and aldehydes 2 (Table 3). We
primarily focused on reactions of 4-hydroxy-3,5-dimethylphenyl
derivatives of 1 because this group can be oxidatively removed
from the 2H-indazole products 3 to provide the corresponding
indazoles lacking N-substitution (vide infra). Both electron-poor
and electron-rich aldehydes afforded the indazole products
B
dx.doi.org/10.1021/ja402761p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
a b
,
Table 3. Substrate Scope
Table 4. Oxidative Cleavage of Phenol by CAN
a
Conditions: azobenzene (0.10 mmol), CAN (0.20 mmol) in 4.0 mL
b
of methanol at 0 °C for 10 min. Isolated yield.
a
Table 5. Spectral Properties of Fluorophores
compd
λmax (nm)
λem (nm)
ε (M−1 cm−1
)
Φ
3a
3b
3c
314
398
nd
11700
15600
14700
9800
0.08
<0.01
0.10
344
308
419
420
412
418
nd
3c′
3d′
3f
331
0.26
303
16800
13400
15300
12600
7700
0.06
303
0.17
3g
3h
3w
3v
309
<0.01
0.11
317
408
434
438
a
Conditions: azobenzene (0.20 mmol), aldehyde (0.40 mmol), 100
301
0.14
b
c
mg of MgSO4 in 1.0 mL of THF for 24 h. Isolated yield. Reaction
was conducted in 0.4 mL of dioxane.
309, 351
14300, 8900
0.08
a
Fluorescence measurements taken in 10 mM HEPES pH 7.3. Full
spectra are given in the Supporting Information.
(3h−3n) in comparable yields, and ortho-substituents (3l) were
also well tolerated. However, extension of the reaction to an
aliphatic aldehyde (3o) resulted in a lower yield.
of a wide range of N-aryl 2H-indazoles with varied substitution
patterns for facile optimization of fluorophore properties. The
indazole fluorophores exhibited high extinction coefficients
(∼104 M−1 cm−1) comparable to the widely used coumarin
fluorophores.17 These novel dyes also showed large Stokes shifts
(∼100 nm; Figure 2), which is an attractive property for
The reaction is sensitive to electronic effects introduced by
substitution on azobenzenes 1. Electron rich and neutral
substituents led to indazole products in good yields (3p, 3q
and 3s to 3u), while the electron-deficient CF3 group decreased
the yield to 46% (3r). Consistent with the regiochemistry
observed for m-methoxy substitution in 1d, m-methyl sub-
stitution exclusively afforded the 2H-indazole functionalized at
the less hindered C−H site (3t). It is also significant that even for
an ortho-substituted azobenzene, the indazole product was
obtained in high yield (3u). Azobenzenes 3v and 3w were
prepared to evaluate substituent effects on fluorescence (vide
infra), and were obtained in somewhat lower yield due to the
electron-deficient 3,5-bis-trifluoromethyl groups (see 3v vs 3s).
Excellent functional group compatibility was observed with
bromo (3p), chloro (3k), fluoro (3l), ester (3i), nitro (3j),
methyl (3m), methoxy (3n), acetamido (3w), trifluoromethyl
(3h), and phenol groups (3i−3u) all tolerated for this one step
2H-indazole synthesis.
Figure 2. Absorbance (abs), fluorescence excitation (ex), and
fluorescence emission (em) spectra for (A) 3a and (B) 3c′.
We hypothesized that indazoles lacking N-substitution should
be accessible from those 2H-indazoles substituted with the N-4-
hydroxy-3,5-dimethylphenyl group. Although oxidative cleavage
of N-hydroxyphenyl groups from 2H-indazoles had not
previously been reported, oxidation with ceric ammonium
nitrate (CAN) in methanol provided the indazoles 7 in excellent
yield (Table 4). Good functional group compatibility for the
oxidation step was observed, with chloro, methyl, nitro, and
methoxy groups all being well tolerated.
A number of the synthesized N-aryl-2H-indazoles were
fluorescent. We therefore chose to characterize the fluorescence
properties of representative derivatives (Table 5), in particular
because our single-step synthesis strategy enables the preparation
biological probes. Electron-donating substituents on the 5-
position of the indazole ring (3c′ and 3w, Figure 2B) and 3,5-bis-
trifluoromethyl groups on the N-phenyl ring (3f) resulted in
bathochromic shifts in emission wavelength and increases in
quantum yield. However, with either the 4-hydroxy-3,5-dimethyl
(3g) or 4-nitro (3b) substitution patterns on the N-phenyl
group, minimal fluorescence was observed. Replacement of the
3-phenyl group with a 3-(4-trifluoromethylphenyl) group on the
indazole had only a modest effect on the fluorescent properties
(see 3a vs 3h). Substitution on both the indazole and the N-
phenyl group (3v) did not prove cumulative but instead resulted
in a compound exhibiting complex optical properties and modest
quantum yield.
C
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Journal of the American Chemical Society
Communication
(4) Li, X.-W.; Yu, S.-J.; Wan, F.; Wan, B.-S.; Yu, X.-Z. Angew. Chem., Int.
Ed. 2013, 52, 2577.
In summary, a formal [4+1] annulation for the preparation of
N-aryl-2H-indazoles from azobenzenes and aldehydes has been
developed. The reaction is initiated by Rh(III)-catalyzed direct
addition of an azobenzene C−H bond to an aldehyde with
subsequent cyclization and aromatization. In addition to
enabling the Rh(III)-catalyzed activation of ortho-C−H bonds,
the azo moiety serves as a nucleophile to trap the initial aldehyde
addition product. A broad range of aldehydes and azobenzenes
participate in the reaction to provide access to a large variety of
differently substituted indazoles. Regioselective functionalization
of unsymmetrical azobenzenes can be controlled by either
electronic or steric effects. The N-4-hydroxy-3,5-dimethylphenyl
substituent can readily be oxidatively cleaved from 2H-indazoles
to provide indazoles lacking N-substitution. Moreover, N-aryl-
2H-indazoles represent a new class of fluorophores with high
extinction coefficients and large Stokes shifts. The preparation
and evaluation of 2H-indazoles with extended chromophores for
near-infrared applications18 and with appropriate substitution for
use as fluorogenic substrates19 are under active investigation.
(5) Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 12074.
(6) Zhu, C.; Xie, W.; Falck, J, R. Chem.Eur. J. 2011, 17, 12591.
(7) For recent reviews on Rh(III)-catalyzed C−H functionalization,
see: (a) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212.
(b) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41,
3651.
(8) Other groups have also trapped the alcohol products generated
from Rh(III)-catalyzed direct addition of C−H bonds to aldehydes by
adding excess of an external oxidant to give ketones, see refs 1e, f, and g.
(9) For recent examples of Rh(III)-catalyzed nitrogen heterocycle
synthesis via coupling to carbon−carbon π-bonds, see: (a) Neely, J. M.;
Rovis, T. J. Am. Chem. Soc. 2013, 135, 66. (b) Zhen, W.; Wang, F.; Zhao,
M.; Du, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 51, 11819. (c) Hyster, T.
K.; Knorr, L.; Ward, T. R.; Rovis, T. Science 2012, 338, 500. (d) Ye, B.;
̈
Cramer, N. Science 2012, 338, 504. (e) Neely, J. M.; Rovis, T. J. Am.
Chem. Soc. 2013, 135, 66. (f) Wang, H.; Grohmann, C.; Nimphius, C.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 19595. (g) Wang, H.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 7318.
(10) For selected reviews on heterocycle synthesis through C−H
functionalization, see: (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K.
Angew. Chem,. Int. Ed. 2012, 51, 8960. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (d) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Typing the names of the following drug and drug candidates into
PubChem (http://pubchem.ncbi.nlm.nih.gov/) provides the com-
pound structure, bioactivity, published studies, and information
regarding ongoing clinical trials, applications, and usage: niraparib,
granisetron, pazopanib, linifanib, axitinib, and GDC-0941.
(12) (a) Information on 2-substituted 2H-indazole clinical candidates
niraparib and pazopanib can be accessed according to the instructions
provided in reference 11. (b) De Angelis, M.; Stossi, F.; Carlson, K. A.;
Katzenellenbogen, B. S.; Katzenellenbogen, K. A. J. Med. Chem. 2005,
48, 1132.
(13) For reviews on 2H-indazole synthesis, see: (a) Haddadin, M. J.;
Conrad, W. E.; Kurth, M. J. Mini-Rev. Med. Chem. 2012, 12, 1293.
(b) Sapeta, K.; Kerr, M. A. Sci. Synth., Knowledge Updates 2011, 1, 15.
For some recent selected syntheses of 2H-indazoles, see: (c) Hu, J.-T.;
Cheng, Y.-F.; Yang, Y.-Q.; Rao, Y. Chem. Commun. 2011, 47, 10133.
(d) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542.
(e) Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879. (f) Stokes, B.
J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12,
2884. (g) See also ref 16d.
(14) For selected reviews, see: (a) Beharry, A. A.; Woolley, G. A. Chem.
Soc. Rev. 2011, 40, 4422. (b) Natansohn, A.; Rochon, P. Chem. Rev.
2002, 102, 4139. (c) Ichimura, K. Chem. Rev. 2000, 100, 1847.
(15) (a) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(b) Murahashi, S.; Horiie, S. J. Am. Chem. Soc. 1956, 78, 4816.
(16) (a) Kakiuchi, F.; Matsumoto, M.; Tsuchiya, K.; Igi, K.; Hayamizu,
T.; Chatani, N.; Murai, S. J. Organomet. Chem. 2003, 686, 134. (b) Dick,
A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.
(c) Ma, X.-T.; Tian, S.-K. Adv. Synth. Catal. 2013, 355, 337. (d) Li, H.-J.;
Li, P.-H.; Wang, L. Org. Lett. 2013, 15, 620. In this publication, a Pd-
catalyzed coupling of only symmetrical azobenzenes with aldehydes was
performed in the presence of excess TBHP as an oxidant to provide
ketone products. In a second step, reductive cyclization with Zn, NH4Cl
was performed to provide 2-aryl-2H-indazoles.
AUTHOR INFORMATION
■
Corresponding Author
jonathan.ellman@yale.edu; lavisl@janelia.hhmi.org
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grant GM069559 (to J.A.E.).
R.G.B. acknowledges funding from The Director, Office of
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under Contract
DE-AC02-05CH11231. L.D.L. is supported by the Howard
Hughes Medical Institute.
REFERENCES
■
(1) For Rh(III)-catalyzed direct C−H bonds addition to aldehydes,
see: (a) Lian, Y.; Bergman, R. B.; Ellman, J. A. Chem. Sci. 2012, 3, 3088.
(b) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2013, 52, 629. (c) Yang, L.; Correia, C. A.; Li, C.-J.
Adv. Synth. Catal. 2011, 353, 1269. (d) Li, Y.; Zhang, X.-S.; Chen, K.; He,
K.-H.; Pan, F.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2012, 14, 636. (e) Park, J.;
Park, E.; Kim, A.; Lee, Y.; Chi, K. W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S.
Org. Lett. 2011, 13, 4390. (f) Sharma, S.; Park, E.; Park, J.; Kim, I. S. Org.
Lett. 2012, 14, 906. (g) Zhou, B.; Yang, Y.; Li, Y. Chem. Commun. 2012,
48, 5163. (h) Shi, X.-Y.; Li, C.-J. Adv. Synth. Catal. 2012, 354, 2933.
(2) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2011, 133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang,
W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50,
2115. (c) Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482. (d) Hesp, K. D.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2012, 14, 2304. (e) Li, Y.; Zhang,
X.-S.; Li, H.; Wang, W.-H.; Chen, K.; Li, B.-J.; Shi, Z.-J. Chem. Sci. 2012,
3, 1634. (f) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2012, 14,
4498. (g) Zhou, B.; Yang, Y.-X.; Lin, S.; Li, Y.-C. Adv. Synth. Catal. 2013,
355, 360.
(17) Lavis, L. D.; Raines, R. T. ACS Chem. Biol. 2008, 3, 142−155.
(18) Kiyose, K.; Kojima, H.; Nagano, T. Chem. Asian J. 2008, 3, 506−
515.
(19) (a) Grimm, J. B.; Heckman, L. M.; Lavis, L. D. Prog. Mol. Biol.
Transl. Sci. 2013, 113, 1−34. (b) Harris, J. L.; Backes, B. J.; Leonetti, F.;
Mahrus, S.; Ellman, J. A.; Craik, C. S. Proc. Natl. Acad. Sci. U.S.A. 2000,
97, 7754.
(3) (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 11430. (b) Zhou, B.; Hou, W.; Yang, Y.-X.; Li, Y.-C. Chem.
Eur. J. 2013, 19, 4701.
D
dx.doi.org/10.1021/ja402761p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX