Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds

Article abstract of DOI:10.1038/nature14615

Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.

Full text of DOI:10.1038/nature14615

LETTER
doi:10.1038/nature14615
Conversion of amides to esters by the
nickel-catalysed activation of amide C–N bonds
Liana Hie1, Noah F. Fine Nathel1, Tejas K. Shah1, Emma L. Baker1, Xin Hong1, Yun-Fang Yang1, Peng Liu1,
K. N. Houk1 & Neil K. Garg1
Amides are common functional groups that have been studied for activation of acid chlorides9, anhydrides9, and 2-pyridyl esters10, to
more than a century1. They are the key building blocks of proteins
our knowledge, the direct metal-catalysed activation of C–N bonds
and are present in a broad range of other natural and synthetic
compounds. Amides are known to be poor electrophiles, which is
typically attributed to the resonance stability of the amide bond1,2.
Although amides can readily be cleaved by enzymes such as prote-
ases3, it is difficult to selectively break the carbon–nitrogen bond of
an amide using synthetic chemistry. Here we demonstrate that
amide carbon–nitrogen bonds can be activated and cleaved using
nickel catalysts. We use this methodology to convert amides to
esters, which is a challenging and underdeveloped transformation.
The reaction methodology proceeds under exceptionally mild reac-
tion conditions, and avoids the use of a large excess of an alcohol
nucleophile. Density functional theory calculations provide insight
into the thermodynamics and catalytic cycle of the amide-to-ester
transformation. Our results provide a way to harness amide func-
tional groups as synthetic building blocks and are expected to lead
to the further use of amides in the construction of carbon–hetero-
atom or carbon–carbon bonds using non-precious-metal catalysis.
The ability to interconvert functional groups is important in syn-
thetic chemistry and many biological processes. Methodologies4,5 have
been developed that enable chemists to strategically harness the react-
ivity of most functional groups. Likewise, breakthroughs in biochem-
istry have led to an understanding of how changes in functional groups
regulate physiological processes6.
of amides is unknown. This is notable given the widespread use of
O
O–
a
+
R′
R′
N
N
R″
R″
Resonance stabilization of amides
Methods for amide bond cleavage
In nature
Using chemical synthesis
Enzymatic hydrolysis
(for example, proteases)
Low reactivity of
amides
Benefits to human health
Minimal use of amides in
(for example, energy, natural functions)
C–N bond cleavage processes
b
O
O
R′
Nucleophile
R′
HN
+
N
Nuc
Transition-metal
R″
R″
catalysis
1
3
4
One particularly interesting dichotomy exists in considering the
amide functional group1, which is the key component of all proteins
(Fig. 1a). Since Schwann’s initial discovery of pepsin—the first enzyme
to be discovered—in 1836, scientists have been intrigued by the ability
of enzymes to break amide linkages3,6. Such amide cleavage processes
govern many cellular regulatory functions and are responsible for the
degradation of proteins to amino acids1,3. In contrast, the synthetic
chemistry of amide-bond cleavage has remained underdeveloped,
even though amides are well suited for use in multistep synthesis
because of their stability under a variety of reaction conditions.
Commonly used methods to break amide carbon–nitrogen (C–N)
bonds include the reductive conversion of amides to aldehydes using
Schwartz’s reagent7 and the displacement of Weinreb’s N-OMe-N-Me
amides with organometallic reagents en route to ketones8. Following
Pauling’s seminal postulate regarding amide planarity2, the poor react-
ivity of amides is now well understood as being a result of the strength
of the resonance-stabilized amide C–N bond1.
To circumvent the long-standing problem involving the low react-
ivity of amides and their modest synthetic use in C–N bond cleavage
processes, we designed the general approach shown in Fig. 1b. The
C–N bond of amide 1 undergoes activation by a transition-metal
catalyst. Following oxidative addition, the resultant acyl metal species
2 is trapped by an appropriate nucleophile to furnish product 3, with
the release of amine 4. This approach allows for the breakdown of
amides, and renders amides useful synthetic building blocks.
Although examples exist for the metal-catalysed C–heteroatom bond
O
• Deconstruction
of amides
R′
Catalytic
amide C–N
bond activation
M
N
Ln
• Amides as synthetic
building blocks
R″
2
Amide
Ester
c
O
O
R′
R′
Ni catalysis
+
+
HN
HO R′′′
N
OR′′′
R″
R″
1
5
6
4
• Readily available and stable substrates
• Non-precious-metal catalysis
• Mild reaction conditions
• Amide activation via Ni catalysis
• Amides as synthetic tools
Figure 1
|
Amide-bond cleavage using transition-metal catalysis. a, An
illustration of the stability of amides and the contrast between how amides are
used in nature and in chemical synthesis. b, Design of amide C–N bond
activation to deconstruct amides and exploit them as synthetic building blocks
(nuc, nucleophile; Ln, ligands coordinated to transition metal; blue spheres,
R9, R0, R-, any carbon-based functional groups). c, Strategy for the conversion
of amides to esters.
1Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA.
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RESEARCH LETTER
O
O
Figure 2
|
Experimental and computational
Ni(cod)2 (10 mol%)
SIPr (10 mol%)
R′
R′
study of amide-bond activation during the
conversion of benzamides 7 to methyl benzoate
8a. The DG values for the overall reactions were
obtained using DFT calculations (assuming a
temperature of 298K). DFT methods were used to
calculate oxidative addition barriers using Ni/SIPr
as the metal/ligand combination. Reactions were
carried out with bis(1,5-cyclooctadiene)nickel(0)
(Ni(cod)2, 10 mol%), SIPr (10 mol%), substrate
(50.0 mg, 1.0equiv.), methanol (1.2 or 2.0equiv.),
and toluene (1.0M), for 12 h at the specified
temperatures. Yields were determined by 1H
nuclear magnetic resonance (NMR) analysis using
hexamethylbenzene as an internal standard. Me,
methyl; OMe, methoxy; Ph, phenyl.
+
+
HO Me
HN
N
OMe
Toluene, temperature
R″
R″
7
8a
4
Calculated oxidative
addition barrier with
R′
Calculated ΔG
(kcal mol–1
Temperature Equivalents of
N
Entry
Yield of ester
)
(°C)
MeOH
Ni/SIPr (kcal mol–1
)
R″
N
1
2
7a
7b
+2.4
36.8
2.0
0%
0%
110
Me
N
0.0
36.2
34.0
2.0
2.0
110
110
Me
N
3
7c
–1.1
23%
O
OMe
Me
N
4
5
7d
7e
–6.1
+3.1
31.9
39.0
2.0
2.0
22%
0%
110
110
Me
N
H
H
N
6
7f
–4.3
–6.8
30.6
26.0
2.0
55%
110
Ph
>99%
>99%
7
8
2.0
1.2
110
80
Me
N
7g
Ph
a
Ni(cod)2 (10 mol%)
SIPr (10 mol%)
O
Ni(cod)2 (10 mol%)
SIPr (10 mol%)
O
b
O
O
Me
R′
+
+
HO
R
HO Me
N
OR
N
OMe
Toluene, 80 °C
Toluene, 80 °C
7g Ph
R″
8
Amide
Yield of
methyl ester
Amide
Yield of
methyl ester
Ester
product
Yield of
ester
Ester
product
Yield of
ester
Entry
Entry
10
Entry
Entry
substrate
substrate
O
Me
Ph
O
O
O
N
Boc
N
88%
(R = H)
Me
1
2
91%
19
20
82%
64%
25
26
67%
N
O
O
R
Ph
O
80%
(R = p-CF3)
O
N
O
Me
11
12
84%
56%
N
O
Ph
92%
(R = p-F)
65%
3
4
Ot-Bu
O
Me
N
O
Ph
90%
(R = p-OMe)
O
N
21
22
23
67%
90%
49%
O
N
90%
(R = p-Me)
H
5
6
7
O
Bu
13
14
15
92%
78%
58%
N
O
Ph
83%
(R = m-Me)
O
O
Me
O
Me
O
O
Me
27
O
O
91%
N
Me
O
89%
(R = o-Me)
Ph
O
O
Me
Me
O
O
O
N
O
Me
8
9
94%
94%
N
Ph
O
Me
R
16
49%
N
Me
O
Me
Me
N
O
74%
Ts
28
O
O
H
Ph
24
88%
O
84%
(R = Me)
17
18
O
H
H
N
TBSO
Me
Me
89%
(R = Bn)
Boc
Figure 3
|
Scope of our methodology. a, b, The scope of the amide-to-ester
12 h. Yields shown reflect the average of two isolated experiments, except for
entry 10; the yield for entry 10 was determined by 1H NMR analysis using
hexamethylbenzene as an internal standard, owing to the volatility of the ester
transformation was evaluated with respect to the amide substrate (a), and
with respect to the alcohol nucleophile, using 7g as the amide substrate (b).
Reactions were carried out with Ni(cod)2 (10 mol%), SIPr (10 mol%), substrate product. t-Bu, tert-butyl; p, para; m, meta; o, ortho.
(100.0 mg, 1.00 equiv.), alcohol (1.2equiv.), and toluene (1.0 M) at 80 uC for
2
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LETTER RESEARCH
transition-metal catalysis in organic synthesis, where there exist many amides are known for their stability, we assessed whether the amide-
examples of catalytic transformations occurring smoothly in the pres- to-ester conversion could be rendered thermodynamically favourable
ence of amide linkages.
by the judicious choice of amide N-substituents. Using DFT methods,
we calculated the change in Gibbs free energy DG for the reaction of
amides 7 with methanol to give esters 8a and amines 4. Whether this
transformation is favourable or not depends on the nature of the
N-substituents (entries 1–8). Methanolysis of Weinreb amide 7d
(entry 4) and N-arylated substrates 7f and 7g (entries 6–8) were found
to be the most energetically favourable. In contrast, esterifications of
N-alkyl amides 7a, 7b, and 7e were deemed thermodynamically un-
favourable. This is in line with the experimentally measured equilib-
rium constant for the reaction of N,N-dimethylbenzamide 7b and
methanol (entry 2), in which the reverse reaction is thermodynamically
favoured (see Supplementary Information for further discussion)16.
Encouraged by the unique ability of nickel to catalyse the activation
We validate the strategy outlined in Fig. 1b through the conversion
of amides to esters (Fig. 1c). Amide to ester conversion, much like
transamidation11,12, remains a challenging and underdeveloped syn-
thetic transformation. Amides are often stable enough that esterifica-
tion is difficult and requires the use of harsh acidic or basic conditions,
while employing a large excess of nucleophile (for example, using the
alcohol nucleophile as a solvent)1. Perhaps the most promising pro-
tocol to achieve amide-to-ester conversions is Keck’s methylation/
hydrolysis sequence13, although this methodology is limited to the
synthesis of methyl esters. Esterifications using acyl aziridines14 and
N-methylamides (albeit with activation by nitrosation)15 have also
been reported. Here we demonstrate the nickel-catalysed conversion
of amides to esters, which proceeds under exceptionally mild reaction of strong aryl–heteroatom bonds17–19, particularly those in phenol19,
conditions. In addition to establishing the scope of this methodology, aniline20–22, and phthalimide23 derivatives, we also calculated the
we use density functional theory (DFT) calculations to predict whether activation free energies for acyl C–N bond oxidative addition of each
the amide-to-ester conversion, or the reverse, is thermodynamically amide substrate using nickel catalysis. The barriers calculated for com-
favoured. DFT calculations are also used to predict a plausible catalytic mercially available N-heterocyclic carbene ligand SIPr (entries 1–8)
cycle. These experimental and computational studies not only sub- reveal that the oxidative addition barriers are reasonable in some cases.
stantiate the notion of using non-precious-metal catalysis for the We studied these reactions experimentally using 10 mol% Ni(cod)2,
activation of amide C–N bonds, but also lay the foundation for further 10 mol% SIPr, 2.0 equivalents of methanol, and toluene as solvent at
studies aimed at the strategic manipulation of amides as synthetic 110 uC for 12 h. There was good agreement between our observations
building blocks using catalysis.
and computational predictions. No reaction or low yields were seen for
substrates 7a–7e (entries 1–5). However, when the calculated DG and
the oxidative addition barrier were favourable, substantial formation
of product 8a was observed (entries 6 and 7). Coupling of substrate 7g
We examined the conversion of benzamides 7 to methyl benzoate 8a
both computationally (using the ‘Gaussian 09’ software; see
Supplementary Information) and experimentally (Fig. 2). Because
Oxidative
addition
Reductive
elimination
Product
extrusion
Ligand exchange
N
N
N
N
N
Dipp
Dipp
N
N
Dipp
Dipp
Ph
Dipp
O
Dipp
Ni
Ni
N
Me
O
Ni
O
O
Ph
H
MeO
Me
Me
Ph
Ph
Ph
11
26.0
14
24.8
17
23.2
22.2
N
PhNHMe
15.7
MeOH
19.6
O
15.6
N
Dipp
MeO
Dipp
O
Me
N
N
N
12.0
Dipp
Dipp
Me
Dipp
O
Ni
N
Dipp
N
N
Ph
Dipp
Ph
Dipp
O
N
N
N
Ph
Me
Dipp
Dipp
O
O
Ni
N
N
N
Dipp
7g
H
Ph
Ni
H
Ni
N
O
Ph
15
Me
N
Ni
MeO
N
Me
Dipp
Dipp
Ph
13
Ph
Me
12
0.0
Ph
1.6
N
Ph
N
16
9
10
N
N
N
N
N
O
Dipp
Dipp
Dipp
Dipp
Dipp
MeO
Dipp
Dipp
–6.8
O
Ni
Ni
N
OMe
18
9
8a
1.90 Å
1.87 Å
1.91 Å
1.90 Å
1.20 Å
1.28 Å
1.90 Å
1.84 Å
11 (oxidative addition transition state)
14 (ligand exchange transition state)
17 (reductive elimination transition state)
Figure 4
|
Computational study of catalytic cycle. DFT methods were used to addition, ligand exchange, and reductive elimination. Key transition
calculate the full catalytic cycle for the amide-to-ester conversion (assuming a state structures (11, 14, and 17) are shown at the bottom. Dipp,
temperature of 298K). We propose that the reaction occurs by oxidative
2,6-diisopropylphenyl.
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RESEARCH LETTER
gave a quantitative yield of product (entry 7), and further optimization strates for esterification, following a straightforward activation step
showed that even with only 1.2 equivalents of methanol and a tem- (Boc-protection).
perature of 80 uC, product formation occurred smoothly (entry 8) to
give complete conversion to 8a. Importantly, no reaction takes place if
either the precatalyst or the ligand are omitted, whereas the use of
alternative N-heterocyclic carbene or phosphine ligands typically leads
to lower yields or no reaction. We conclude that nickel catalysis is
indeed operative in the amide activation/esterification process.
Using amide 7g as the substrate, we evaluated the scope of the
methodology with respect to the alcohol nucleophile (Fig. 3b). As
shown, synthetically useful yields of product were obtained using only
1.2 equivalents of the alcohol, even when complex and hindered alco-
hols were used. Cyclohexanol, t-butanol, and 1-adamantol coupled
smoothly to give the corresponding esters (entries 19–21, respectively);
Having determined the optimal reaction conditions, we examined tert-butyl esters can readily be hydrolysed to carboxylic acids under
the scope of the transformation with regard to the amide substrate acidic conditions. Similarly, we found that cyclopropyl carbinol and an
(Fig. 3a). In addition to the parent benzamide (entry 1), substrates oxetane-derived alcohol could be used in the esterification reaction
containing the electron-withdrawing trifluoromethyl or fluoride sub- (entries 22 and 23, respectively). The use of the hindered secondary
stituents (entries 2 and 3) or the electron-donating methoxy or methyl alcohol (–)-menthol was also tested and the desired ester was obtained
substituents (entries 4 and 5) were well tolerated. The transformation in 88% yield (entry 24). Furthermore, we found that Boc-L-prolinol
also proceeded smoothly using meta- and ortho-methyl-substituted was tolerated in the methodology (entry 25), in addition to an indole-
substrates to give the desired esters in excellent yields (entries 6 containing alcohol (entry 26), which further demonstrates the promise
and 7). Beyond the use of phenyl derivatives, we examined naphthyl our methodology holds for reactions of heterocyclic substrates. As
and heterocyclic substrates. Naphthyl compounds readily coupled shown in entries 27 and 28, a complex sugar-containing alcohol bear-
(entries 8 and 9), as did furan, quinoline, and isoquinoline substrates ing two acetals and an estrone-derived steroidal alcohol, respectively,
(entries 10–12, respectively). However, amides derived from alkyl also underwent the desired esterification reaction.
carboxylic acids did not undergo the nickel-catalysed esterification
under our reaction conditions. This attribute provides opportunities
to realize selective amide C–N bond cleavages in more complex sub-
strates (see below).
Although nickel-catalysed aryl and acyl C–O bond activation pro-
cesses have been previously studied computationally24–28, no analogous
studies involving C–N bond activation have been reported. Thus, to shed
light on the mechanism of the facile amide-to-ester conversion, the
A variety of N-substituents were also surveyed, as shown in Fig. 3a. catalytic cycle was computed using DFT calculations. Figure 4 provides
In addition to the longer N-butyl (Bu) and the branched N-iso-propyl the free energy profile using amide substrate 7g. The [Ni(SIPr)2] com-
alkyl chains (entries 13 and 14, respectively), we found that a cyclic plex, 9, is believed to be the resting state of the catalytic cycle. Dissociation
amide derived from indoline was tolerated by the methodology (entry of one carbene ligand from complex 9 provides a coordination site for
15). Lastly, protected N-alkyl benzamides were tested. Although use of amide 7g. Following coordination to give intermediate 10, oxidative
the N-p-toluenesulfonyl (Ts) derivative gave the corresponding ester addition occurs via transition state 11. This key event cleaves the amide
in modest yield (entry 16), the corresponding N-tert-butyloxycarbonyl C–N bond and produces acyl nickel species 12. The next step of the
(Boc) substrate more efficiently underwent conversion to ester 8a catalytic cycle is ligand exchange, which proceeds by coordination of
(entry 17). The analogous N-benzyl, N-tert-butyloxycarbonyl methanol to give intermediate 13. Subsequent ligand exchange via trans-
(N-Bn,Boc) substrate was also evaluated and gave the desired ester ition state 14 facilitates the deprotonation of methanol, giving nickel
in 89% yield (entry 18). These results show that the methodology is complex 15. Dissociation of N-Me-aniline produces acyl nickel species
not restricted to anilide substrates, as long as the overall reaction 16, which in turn, undergoes reductive elimination via transition state 17
energetics are thermodynamically favourable (see Supplementary to deliver the ester-coordinated complex 18. Finally, the ester product 8a
Information for energetics involving the N-Boc,Me substrate). is released to regenerate catalyst 9. The rate-determining step in the
Moreover, secondary benzamides can be used strategically as sub- catalytic cycle is the oxidative addition (transition state 11) with an
a
Me
Figure 5
|
Selective amide-bond
Me
N-Me,Ar
benzamide
H
cleavage processes. a, Cleavage of
tertiary over secondary amide using
menthol (1.2 equiv.). b, Cleavage of
benzamide over an alkyl proline-
derived amide using menthol
(1.2 equiv.). c, Cleavage of valine-
derived amide in the presence of an
ester using menthol (1.2 equiv.).
e.e., enantiomeric excess.
N
Ph
O
H
Ni(cod)2 (15 mol%)
SIPr (30 mol%)
N
Ph
O
+
H
O
+
Ph
O
HO
N
O
Toluene, 80 °C
Ph
N
Me
Me
Me
Me
Me
Me
N-H,Ar
benzamide
19
20
21
82% yield
22
80% yield
b
Me
Me
N-Me,Ar
Me
N
Me
benzamide
*
O
Ni(cod)2 (10 mol%)
SIPr (10 mol%)
N
*
N
Boc
O
+
N
H
O
+
Ph
O
Boc
HO
N
O
Toluene, 80 °C
Ph
N
Me
Me
Me
Me
Me
Me
N-Me,Ar
alkylamide
23
92% e.e.
20
21
78% yield
24
83% yield
92% e.e.
c
Valine-derived
arylamide
Me
Me
Me
Me
Ester
Me
Me
O
Ni(cod)2 (10 mol%)
SIPr (10 mol%)
O
O
*
Ot-Bu
+
H
Ot-Bu
+
HO
Ph
N
Ph
O
N
*
Toluene, 80 °C
Ph
O
Ph
Me
Me
Me
Me
25
99% e.e.
20
21
70% yield
26
79% yield
96% e.e.
4
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LETTER RESEARCH
overall barrier of 26.0 kcal mol21 relative to the resting state 9. Theoverall
reaction is thermodynamically favoured by 26.8 kcal mol21. Because
decarbonylation of acyl nickel species have been observed29,30, we also
calculated the kinetic barrier for decarbonylation events (see
Supplementary Information). Consistent with experiments, decarbony-
lation pathways from acyl nickel species 12 or 16 were found to be less
favourable than the product formation pathways.
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As highlighted by the experiments shown in Fig. 5, the nickel-
catalysed conversion of amides to esters can be used to achieve
selective and mild amide-bond cleavages. First, we performed the
esterification of bis(amide) substrate 19 using (–)-menthol (Fig. 5a).
Although both amides are N-arylated benzamides, only the tertiary
amide wascleaved to give ester21, while alsoreleasing aminoamide22.
Second, bis(amide) 23, which possesses two tertiary amides, was
studied in the nickel-catalysed esterification reaction (Fig. 5b). In this
case, the tertiary L-proline-derived alkyl amide was not disturbed,
while the tertiary benzamide underwent cleavage to give ester 21
and aminoamide 24 in good yields. Lastly, we prepared L-valine deriv-
ative 25, which also bears an ester (Fig. 5c). Upon exposure of 25 to 1.2
equivalents of (–)-menthol and the nickel-catalysed conditions, ester
21 and aminoester 26 were obtained in 70% and 79% yields, respect-
ively. We believe that the ester functionality withstands the reaction
conditions because it is not attached to an arene, analogous to the lack
of reactivity seen in our attempts to esterify amides derived from alkyl
carboxylic acids (for example, 23). Compounds 24 and 26 were
obtained in high enantiomeric excess, highlighting the mild nature
of the reaction conditions, which avoid any substantial epimerization
of the a stereocentres.
We have presented an efficient way to convert amides to esters. The
methodology circumvents the classic problem of amides being poorly
reactive functional groups by using nickel catalysis to achieve the
previously unknown catalytic activation of amide C–N bonds. DFT
calculations support a catalytic cycle that involves a rate-determining
oxidative addition step, followed by ligand exchange and reductive
elimination. The methodology is broad in scope, particularly with
respect to the alcohol nucleophiles, and proceeds under exceptionally
mild reaction conditions using just 1.2 equivalents of the alcohol
nucleophile. Moreover, selective amide-bond cleavage is achieved in
the presence of other functional groups, including less reactive amides
and esters, without the epimerization of a stereocentres. We envision
that this methodology will lead to advances such as the catalytic
esterification of primary amides, additional N,N-disubstituted amides,
amides derived from alkyl or vinyl carboxylic acids, and perhaps
even polyamide substrates bearing multiple stereocentres. This
study should enable the further use of amides as valuable building
blocks for the construction of C–heteroatom or C–C bonds using
non-precious-metal catalysis.
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Supplementary Information is available in the online version of the paper.
Acknowledgements We are grateful to Boehringer Ingelheim, DuPont, Bristol-Myers
Squibb, the Camille and Henry Dreyfus Foundation, the A. P. Sloan Foundation, the
S. T. Li Foundation, the University of California, Los Angeles (UCLA), and the
NIH-NIGMS (grant number GM036700 to K.N.H.) for financial support. We are grateful
to the NIH (grant number F31 GM101951-02 to N.F.F.N.), the NSF (grant number
DGE-1144087 to E.L.B.), the Foote Family (L.H., T.K.S. and X.H.), and the ACS Division
of Organic Chemistry (L.H.) for fellowship support. Computations were performed with
resources made available by the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by the NSF (grant number OCI-1053575),
as well as the UCLA Institute of Digital Research and Education (IDRE). This work was
also supported by shared instrumentation grants from the NSF (grant number
CHE-1048804) and the National Center for Research Resources (grant number
S10RR025631).
Received 20 December 2014; accepted 20 May 2015.
Published online 22 July 2015.
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Author Contributions L.H., N.F.F.N., T.K.S., and E.L.B. designed and performed the
experiments and analysed the experimental data; X.H., Y.-F.Y., and P.L. designed the
computational studies and performed the analysis; K.N.H. and N.K.G. conceived and
directed the investigations, and prepared the manuscript with contributions from all
authors; all authors contributed to discussions.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to K.N.H. (houk@chem.ucla.edu) and
N.K.G. (neilgarg@chem.ucla.edu).
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