An enantioselective artificial Suzukiase based on the biotin-streptavidin technology

Article abstract of DOI:10.1039/c5sc03116h

Introduction of a biotinylated monophosphine palladium complex within streptavidin affords an enantioselective artificial Suzukiase. Site-directed mutagenesis allowed the optimization of the activity and the enantioselectivity of this artificial metalloenzyme. A variety of atropisomeric biaryls were produced in good yields and up to 90% ee. The hybrid catalyst described herein shows comparable TOF to the previous aqueous-asymmetric Suzuki catalysts, and excellent stability under the reaction conditions to realize higher TON through longer reaction time.

Full text of DOI:10.1039/c5sc03116h

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An enantioselective artificial Suzukiase based on
the biotin–streptavidin technology†
Cite this: Chem. Sci., 2016, 7, 673
Anamitra Chatterjee,a Hendrik Mallin,a Juliane Klehr,a Jaicy Vallapurackal,a
b
b
b
a
*
Aaron D. Finke, Laura Vera, May Marsh and Thomas R. Ward
Introduction of
a biotinylated monophosphine palladium complex within streptavidin affords an
enantioselective artificial Suzukiase. Site-directed mutagenesis allowed the optimization of the activity
and the enantioselectivity of this artificial metalloenzyme. A variety of atropisomeric biaryls were
produced in good yields and up to 90% ee. The hybrid catalyst described herein shows comparable TOF
to the previous aqueous-asymmetric Suzuki catalysts, and excellent stability under the reaction
conditions to realize higher TON through longer reaction time.
Received 21st August 2015
Accepted 17th October 2015
DOI: 10.1039/c5sc03116h
www.rsc.org/chemicalscience
an articial Suzukiase. The resulting articial Suzukiase however
did not outperform the free cofactor (no enantioselectivity,
turnover frequency TOF: 3500 hꢁ1, no TON mentioned).13
Inspired by a seminal contribution by Whitesides in 1978,32 we
report herein our effort to engineer an asymmetric articial
Suzukiase based on the biotin–streptavidin technology.
Introduction
The palladium-catalyzed Suzuki–Miyaura cross-coupling reac-
tion (SMC hereaer) of organic halides with boronic acids is one
of the most versatile methods for the synthesis of biaryls.1–3
Such structural motifs are present in numerous agrochemicals,
natural products, pharmaceuticals, and polymers.4,5 For this
purpose, the SMC has been widely studied.6–11 More recently,
the SMC has found applications in the context of chemical
biology. Indeed, both reactants and products can be regarded as
bio-orthogonal.12–18 In this promising context however, high
catalyst loadings are routinely required with reactions per-
formed in a biological environment.12,13,15,17,19–27
In stark contrast to the SMC, Nature relies on very different
mechanisms to install (atropisomeric) Caryl–Caryl bonds.28 Despite
numerous reports on asymmetric SMC in organic media,6–8,29
only two reports describe enantioselective SMC in water.30,31
Uozumi reported on an heterogeneous SMC in water requiring
a high catalyst loading (TON < 10, 94% ee at 80 ꢀC).30 More
Results and discussion
With the aim of identifying suitable cross-coupling reaction
conditions, we evaluated ve different biotinylated catalyst
precursors 1–5 in the presence of either avidin or streptavidin
(Avi and Sav hereaer). For this purpose, the reaction of 1-
iodonaphthalene 6c with 2-methoxy-1-naphthaleneboronic acid
7c was selected as a model system (Scheme 1). Initial experi-
ments revealed that protonolysis of the boronic acid led to
modest cross-coupling yields. Systematic variation of the base,
pH, and organic co-solvent led to the identication of suitable
reaction conditions: sodium hydroxide in DMSO : water (1 : 9)
proved to be particularly effective in preventing protonolysis.
However, competing deboronation required the use of excess
boronic acid (1.5 equivalents vs. aryl halide) to achieve full
conversion. Gel electrophoresis of the reaction mixture revealed
that Sav remained largely tetrameric and active toward biotin
binding even aer an SMC performed at 50 ꢀC (see ESI Fig. S3†).
Having identied suitable reaction conditions, we screened
biotinylated phosphine- and NHC ligands 1–5 combined with
WT (strept)avidin (Table 1). This screening led to the identi-
cation of complexes 1, 2, and 3 as the most promising catalysts
in combination with WT Sav. Despite the structural similarity
between avidin and streptavidin, the result obtained with avidin
was inferior to those obtained with Sav. We thus focused on Sav
for further optimization studies. Past experience with other
ArMs based on the biotin–streptavidin technology suggest that
mutations at positions S112 and K121 (which lie closest to the
¨
recently, Kundig et al. reported an asymmetric SMC in an water–
organic solvent mixture (TON ¼ 17, up to 80% ee) at room
temperature.31 To complement these efforts, we speculated that,
thanks to their well-dened second coordination sphere, arti-
cial metalloenzymes (ArMs hereaer) may offer a propitious
environment to engineer an asymmetric “Suzukiase”-that is, an
enzyme that catalyzes the SMC. ArMs result from the incorpo-
ration of an abiotic cofactor within a macromolecule (protein or
oligonucleotide).13,14,32–35 In this context, Ueno and coworkers
anchored a palladium moiety within a ferritin container to yield
aDepartment of Chemistry, University of Basel, Spitalstrasse 51, 4056 Basel,
Switzerland. E-mail: thomas.ward@unibas.ch
bSwiss Light Source, Paul Scherrer Institute 5232 Villigen PSI, Switzerland
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5sc03116h
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Scheme 1 Biotinylated cofactors 1–5 tested in the presence of (strept)
avidin as artificial Suzukiase for the synthesis of enantioenriched 2-
methoxy-1,10-binaphthyl 8b.
Table 1 Identification of the most suitable ligand for the synthesis of
2-methoxy-1,10-binaphthyl 8ba
Entry
Complex
Protein
eeb [%]
TON
1
2
3
4
5
6
1
2
3
4
5
1
WT Sav
WT Sav
WT Sav
WT Sav
WT Sav
WT Avi
58 (R)
10 (S)
42 (R)
6 (R)
rac
78
73
45
8
<5
10
Fig. 1 Fingerprint display of the results of the chemogenetic optimi-
zation for the synthesis of 2-methoxy-1,10-binaphthyl 8b. The size of
the circles is proportional to the conversion, and the color codes the
enantiomeric excess. Numerical results are collected Table 2 and in
Table S1 (ESI†).
3 (R)
a
Reactions were carried out with 50 mM substrate in a total reaction
volume 0.2 mL using 1 mol% complex 1–5 (see ESI for experimental
details). ee value determined by HPLC on a chiral stationary phase;
b
absolute conguration assigned by comparison with literature data.
WT ¼ wild-type, Sav ¼ streptavidin, Avi ¼ avidin. All reactions were
performed in duplicate: Dee ¼ ꢂ1%, Dconv. ¼ ꢂ5%.
(c) The enantioenriched nature of the cross-coupled product
8b strongly supports the hypothesis that the SMC is indeed
catalysed by a homogeneous protein-embedded Pd-cofactor
rather than Pd-nanoparticles.12,25,26,37
biotinylated metal cofactor) offer a versatile means to rapidly
optimize the ArM's performance. Complexes 1–3 were thus
screened with a small library of Sav mutants. The results of the
chemogenetic optimization for the synthesis of 2-methoxy-1,10-
binaphthyl 8b are displayed as a ngerprint in Fig. 1, and
selected results are collected in Table 2.
(d) Varying the spacer between the biotin anchor and the P(t-
Bu)2 from ethyl to propyl affords opposite enantiomers of biaryl
8b for a given Sav mutant. The best ees in favour of (S)-8b were
obtained with 2$Sav K121A and 2$Sav S112M (Table 2, entries 8
and 9). These ndings illustrate the versatility of chemogenetic
optimization strategy: upon varying the length of the spacer the
Pd-moiety experiences a very different second coordination
sphere environment which is reected in the enantioselectivity.
Having identied 1$Sav K121E as a promising rst genera-
tion Suzukiase (Table 2, entry 3), we screened double mutants
bearing a glutamate at position 121 (Fig. 1 and Table 2, entries
14–21):
From these data, the following features emerge:
(a) Compared to the free cofactor, higher conversions are
observed with the articial Suzukiase. This demonstrates that
the Sav host protein exerts a benecial inuence on both the
activity (i.e. protein accelerated catalysis)36 and the selectivity.
(b) The electron-donating properties and bulkiness of the
phosphine play a key role in determining the activity of the
corresponding articial Suzukiase. Accordingly, the (t-Bu)2P-
bearing catalysts outperform the (Ph)2P-systems. Strikingly,
both ligands 1 and 3 (Table 2, entries 10–13) show similar
activity in case of S112M and S112A mutants.
(a) The double mutant 1$Sav S112A–K121E (Table 2, entry 20)
gives better ee and TON than the single mutant Sav S112A
(Table 2, entry 13). Likewise, 1$Sav S112Y–K121E gave the
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Table 2 Selected results for genetic optimization of the artificial
Suzukiase for the synthesis of 2-methoxy-1,10-binaphthyl 8b
Entry
Temp [ꢀC]
Complex
Protein
ee [%]
TON
1
2
3
4
5
6
7
8
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
16
1
1
1
1
1
1
1
2
2
3
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
—
WT
K121E
K121D
K121Q
K121M
K121F
K121A
S112M
S112M
S112A
S112M
rac
20
78
50
7
58 (R)
76 (R)
34 (R)
74 (R)
67 (R)
67 (R)
47 (S)
44 (S)
38 (R)
36 (R)
14 (S)
60 (R)
74 (R)
76 (R)
76 (R)
72 (R)
76 (R)
69 (R)
70 (R)
80 (R)
80 (R)
84 (R)
86 (R)
90 (R)
20
59
38
32
53
78
52
58
58
73
79
75
86
64
61
80
90
160a
50
50b
50c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
S112A
N118K–K121E
N118S–K121E
N118E–K121E
N118L–K121E
S112W–K121E
S112N–K121E
S112A–K121E
S112Y–K121E
S112Y–K121E
S112Y–K121E
S112Y–K121E
S112Y–K121E
4
4
a
b
0.50 mol% catalyst loading, 0.25 mol% Sav (tetramer) loading. 0.50
mol% catalyst loading, 0.25 mol% Sav (tetramer) loading, aer 7 days.
c
Preparative scale (100 mmol). All reactions were performed in
duplicate: Dee ¼ ꢂ1%, Dconv. ¼ ꢂ5%.
highest turnover with good ee (Table 2, entry 22). This nding
highlights the non-additive nature of multiple mutations.38,39
Decreasing the temperature to 4 ꢀC leads to an improvement in
enantioselectivity (86% ee, Table 2, entry 24) albeit at the cost of
a slower rate.
(b) Increasing the ratio of complex 1 vs. Sav tetramer (S112Y–
K121E mutant) from one to four leads to a gradual erosion of
enantioselectivity (from 80 to 69% ee, see Table S4, ESI†). This
suggests that an empty biotin binding site adjacent to a complex
1 within Sav is favorable for selectivity.
(c) On a preparative scale, up to 90% ee (R)-8b, were obtained
using 0.50 mꢀol% catalyst loading and 0.25 mol% Sav (tetramer)
loading at 4 C (Table 2, entry 25).
(d) Upon decreasing the catalyst loading, a TON ¼ 160 (TOF <
10 hꢁ1) is obtained with a constant ee (Table 2 entries 21–22).
This TON compares favourably with the other aqueous asym-
metric homogeneous SMC catalysts (TON ¼ 10,30 and 17
respectively31) compared to the achiral Suzukiase reported by
Ueno13 however, the TOF is signicantly lower (compare TOF
3500 hꢁ1 vs. <10 hꢁ1).
Fig. 2 Substrates tested for the asymmetric Suzuki–Miyaura cross-
coupling reaction catalysed by 1$S112Y–K121E.
(b) Substitution of the methoxy group by either a methyl and
ethoxy group on the arylboronic acid (compare 7c to 7b and 7d)
leads lower enantioselectivities (Table 3, entries 7, 10 and 12).
Depending on the nature of the ortho-substituent of the aryl
moiety, the CIP priorities are inverted, yielding the opposite
absolute conguration (e.g. compare 8b and 8d) for the same
spacial arrangement. With the exception of the biphenyl-
binaphthyl 8h, all SMC products afford the same spacial
arrangement using 1$S112Y–K121E Sav. We speculate that upon
binding to the palladium cofactor, the bulky biphenyl group 7h
forces the catalyst into a different second coordination sphere
environment, leading to the opposite enantiomer (and spacial
arrangement) of the coupled product.
(c) The system affords the highest enantioselectivity for
binaphthyls or naphthyl-o-biphenyl products (albeit with the
opposite chirality) in the presence of one smaller coupling
partner, (e.g. 6h), the enantioselectivity is signicantly lower.
The articial Suzukiase performed well on a range of
hydrophobic substrates, leading to the following observations
(Table 3, Fig. 2):
(a) The nature of the aryl halide does not inuence the
enantioselectivity but to lower conversions on going from
iodide to bromide to chloride 6a–c (Table 3, entries 6–8).
X-ray structure
To gain structural insight on the second coordination sphere
around the Pd moiety, crystals of Sav S112Y–K121E were grown
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Table 3 Selected results for the SMC with 1$S112Y–K121E Sav on
a variety of substratesa
Entry
ArX
Ar0B(OH)2
Product
Temp [ꢀC]
ee [%]
TON
1
2
3
4
5
6
7
8
6d
6g
6d
6g
6g
6a
6b
6c
6f
6b
6b
6c
6e
6h
7a
7e
7e
7f
8b
8d
8e
8f
RT
50
50
50
RT
RT
RT
RT
RT
50
4
80 (R)
80 (S)
74 (R)
64 (S)
65 (R)
80 (R)
80 (R)
80 (R)
69 (S)
76 (S)
87 (S)
68 (R)
77 (R)
35 (R)
32
20
61
50
29
7
63
80
64
81
8b
88
55
80
Fig. 3 Close-up view of the structure of the artificial Suzukiase
1$S112Y–K121E Sav (pdb code: 5CSE). The solvent-excluded surfaces
of two symmetry-related Sav monomers are highlighted in grey and
magenta respectively. The biotinylated Pd-cofactor 1 and the mutated
residues S112Y and K121E are displayed as stick. No electron density for
the cinnamyl-moiety (turquoise) could be detected and was thus
modelled, minimizing steric-clashes.
7h
7c
7c
7c
7a
7b
7b
7d
7a
7c
8h
8b
8b
8b
8a
8a
8a
8c
8b
8g
9
10
11
12
13
14
RT
RT
RT
that the origin of the enantioselectivity observed is from the
outer-sphere ligand effect of the protein. Inspection of the X-ray
structure of the active site of 1$S112Y–K121E shows that the Pd-
phosphine ligand is effectively “locked” into place by the steric
environment of the Sav protein, which is evidenced by the
discrete atomic position of the Pd and P and their relatively low
B-factors despite proximity to the solvent pocket. The restricted
conformational space around the Pd atom limits certain
conformations. The nearby mutated residues play an additional
role. In particular, mutation of S112 to the larger tyrosine
provides a signicant steric barrier on the lower face of the Pd
atom and is most likely responsible for the modest improve-
ment in enantioselectivity upon mutation. Furthermore, the
conformation of Y112 is effectively locked in place by an H-
bonding interaction of the sidechain oxygen with the backbone
a
All reactions were performed in duplicate: Dee ¼ ꢂ1%, Dconv. ¼ ꢂ5%.
The absolute conguration of the product were assigned according to
ref. 8. See ESI for experimental details. b Aer 7 days.
and soaked with a solution of 1 in DMSO (for details, see ESI†).
The resulting crystals were subjected to X-ray diffraction at the
beamline X06DA at the Swiss Light Source. In the resulting
structure of complex 1$S112Y–K121E Sav, there is strong
residual electron density in the 2Fo ꢁ Fc difference map in the
biotin-binding vestibule. The Pd atom was unambiguously
assigned as a strong peak in the difference map (12s) with
a corresponding peak in the anomalous difference map (8s).
The density map clearly highlights the presence of the phos-
phine ligand, the palladium, and the chloride (see ESI Fig. S5†).
However, the cinnamyl ligand could not be resolved, likely due
to disorder caused by ligand uxionality. The amide linker
exhibits two H-bonding interactions with the protein backbone:
the amide nitrogen exhibits an H-bonding interaction with the
side-chain of S88, and the carbonyl oxygen exhibits an H-
bonding interaction with the backbone nitrogen of N49. The
palladium atoms of two symmetry related-cofactors (face-to-
˚
carbonyl of E121 (distance 2.88 A), which would not be the case
with the similarly large S112W mutation (Table 2, entry 18).
Further X-ray studies of 1$Sav with various mutations are
currently underway.
It should be emphasized however that, while the X-ray
structure sheds light on the position of the biotinylated catalyst
precursor, we cannot exclude that the loaded catalyst, bearing
the two bulky aromatic coupling partners, adopts a different
position within the biotin-binding vestibule. As demonstrated
recently for an articial imine reductase, QM-MM studies may
shed light on the enantioselection mechanism and the precise
geometry of the transition state.41 In this context, reducing the
cofactor exibility by introducing stabilizing interactions with
the protein has proven useful.42
˚
face) are separated by 11.7 A. The palladium was found in the
vicinity of the O atoms of S112Y and K121E (Pd/O distance 6.4
˚
˚
A and 7.1 A respectively). The average B-factor of Pd is 36.10,
suggesting that the complex may be uxional or located in
a shallow energy minimum (Fig. 3).
In the synthesis of chiral biaryls by the SMC, enantiose-
lectivity is dictated by the conformation of the Pd intermediate
just prior to reductive elimination.40,43 In previous DFT studies
of enantioselective reductive eliminations in the SMC, it was
shown that weak interactions between substrates and
substrate–ligand interactions were largely responsible for
biasing certain conformations and thus leading to enantioin-
duction.6,40,44 By contrast, in the 1$Sav system, it is more likely
Conclusions
In summary, incorporation of an electron-rich phosphino–
palladium moiety within Sav affords an articial Suzukiase for
the synthesis of enantioenriched binaphthyls (up to 90% ee and
50 TONs for 2-methoxy-binaphthyl 8b). While it is straightfor-
ward to identify aminoacids close to the cofactor, it is remains
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extremely challenging to predict or rationalize why a given 20 C. D. Spicer and B. G. Davis, Chem. Commun., 2011, 47, 1698.
mutation leads to an improvement in catalytic performance. 21 S. V. Chankeshwara, E. Indrigo and M. Bradley, Curr. Opin.
The chemogenetic optimization strategy allows to address this
Chem. Biol., 2014, 21, 128.
challenge with a limited effort: combining a small library of m 22 A. Unciti-Broceta, E. M. V. Johansson, R. M. Yusop,
´
´
mutants with a small library of n biotinylated ligands affords an
m$n diversity matrix. Current efforts are aimed at performing
catalytic asymmetric SMC with articial Suzukiases in vivo.
R. M. Sanchez-Martın and M. Bradley, Nat. Protoc., 2012, 7,
1207.
23 H. L. Parker, E. L. Rylott, A. J. Hunt, J. R. Dodson, A. F. Taylor,
N. C. Bruce and J. H. Clark, PLoS One, 2014, 9, e87192.
24 X. Ma, H. Wang and W. Chen, J. Org. Chem., 2014, 79, 8652.
25 C. Yang, A. K. Manocchi, B. Lee and H. Yi, J. Mater. Chem.,
2011, 21, 187.
26 L. S. Søbjerg, D. Gauthier, A. T. Lindhardt, M. Bunge,
K. Finster, R. L. Meyer and T. Skrydstrup, Green Chem.,
2009, 11, 2041.
Acknowledgements
TRW thanks the Swiss National Science Foundation (grant
200020_162348 as well as the NNCR “Molecular Systems Engi-
neering”) for generous nancial support.
27 M. Yang, J. Li and P. R. Chen, Chem. Soc. Rev., 2014, 43, 6511.
28 H. Aldemir, R. Richarz and T. A. M. Gulder, Angew. Chem.,
Int. Ed., 2014, 53, 8286.
References
1 A. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 6722.
2 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
´
29 A. N. Cammidge and K. V. L. Crepy, Chem. Commun., 2000,
´
3 J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire,
1723.
Chem. Rev., 2002, 102, 1359.
4 A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41,
4176.
30 Y. Uozumi, Y. Matsuura, T. Arakawa and Y. M. A. Yamada,
Angew. Chem., Int. Ed., 2009, 48, 2708.
¨
31 L. Benhamou, C. Besnard and E. P. Kundig, Organometallics,
5 S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58,
9633.
6 X. Shen, G. O. Jones, D. A. Watson, B. Bhayana and
S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 11278.
7 D. Zhang and Q. Wang, Coord. Chem. Rev., 2015, 286, 1.
2014, 33, 260.
32 M. E. Wilson and G. M. Whitesides, J. Am. Chem. Soc., 1978,
100, 306.
33 J. Pierron, C. Malan, M. Creus, J. Gradinaru, I. Hafner,
A. Ivanova, A. Sardo and T. R. Ward, Angew. Chem., Int. Ed.,
2008, 120, 713.
´
8 A. Bermejo, A. Ros, R. Fernandez and J. M. Lassaletta, J. Am.
Chem. Soc., 2008, 130, 15798.
¨
34 T. K. Hyster, L. Knorr, T. R. Ward and T. Rovis, Science, 2012,
9 B. H. Lipshutz, T. B. Petersen and A. R. Abela, Org. Lett., 2008,
10, 1333.
338, 500.
¨
35 M. Durrenberger and T. R. Ward, Curr. Opin. Chem. Biol.,
10 B. H. Lipshutz and S. Ghorai, Aldrichimica Acta, 2008, 41, 59.
11 V. Polshettiwar, A. Decottignies, C. Len and A. Fihri,
ChemSusChem, 2010, 3, 502.
2014, 19, 99.
36 J. Collot, N. Humbert, M. Skander, G. Klein and T. R. Ward,
J. Organomet. Chem., 2004, 689, 4868.
12 R. M. Yusop, A. Unciti-Broceta, E. M. V. Johansson,
37 C. Deraedt and D. Astruc, Acc. Chem. Res., 2014, 47, 494.
38 M. T. Reetz and J. Sanchis, ChemBioChem, 2008, 9, 2260.
39 D. M. Weinreich, N. F. Delaney, M. A. Depristo and
D. L. Hartl, Science, 2006, 312, 111.
40 W. Tang, N. D. Patel, G. Xu, X. Xu, J. Savoie, S. Ma,
M.-H. Hao, S. Keshipeddy, A. G. Capacci, X. Wei, Y. Zhang,
J. J. Gao, W. Li, S. Rodriguez, B. Z. Lu, N. K. Yee and
C. H. Senanayake, Org. Lett., 2012, 14, 2258.
´
´
R. M. Sanchez-Martın and M. Bradley, Nat. Chem., 2011, 3,
239.
13 S. Abe, J. Niemeyer, M. Abe, Y. Takezawa, T. Ueno, T. Hikage,
G. Erker and Y. Watanabe, J. Am. Chem. Soc., 2008, 130,
10512.
14 J. Li and P. R. Chen, ChemBioChem, 2012, 13, 1728.
15 J. M. Chalker, C. S. C. Wood and B. G. Davis, J. Am. Chem.
Soc., 2009, 131, 16346.
˜
´
41 V. Munoz Robles, P. Vidossich, A. Lledos, T. R. Ward and
16 Z. Gao, V. Gouverneur and B. G. Davis, J. Am. Chem. Soc.,
2013, 135, 13612.
´
J.-D. Marechal, ACS Catal., 2014, 4, 833.
¨
42 T. Heinisch, M. Pellizzoni, M. Durrenberger, C. E. Tinberg,
17 C. D. Spicer, T. Triemer and B. G. Davis, J. Am. Chem. Soc.,
2012, 134, 800.
18 N. Li, R. K. V. Lim, S. Edwardraja and Q. Lin, J. Am. Chem.
Soc., 2011, 133, 15316.
19 Z. Gao, V. Gouverneur and B. G. Davis, J. Am. Chem. Soc.,
2013, 135, 13612.
¨
¨
V. Kohler, J. Klehr, D. Haussinger, D. Baker and
T. R. Ward, J. Am. Chem. Soc., 2015, 137, 10414.
43 B. H. Ridgway and K. A. Woerpel, J. Org. Chem., 1998, 63, 458.
44 A. H. Cherney, N. T. Kadunce and S. E. Reisman, Chem. Rev.,
2015, 115, 9587.
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