Communications

Angewandte

Chemie

International Edition: DOI: 10.1002/anie.201706763
German Edition:
DOI: 10.1002/ange.201706763

Organocatalysis

Forging Fluorine-Containing Quaternary Stereocenters by a LightDriven Organocatalytic Aldol Desymmetrization Process
Sara Cuadros, Luca Dell’Amico, and Paolo Melchiorre*
Abstract: Reported herein is a light-triggered organocatalytic
strategy for the desymmetrization of achiral 2-fluoro-substituted cyclopentane-1,3-diketones. The chemistry is based on an
intermolecular aldol reaction of photochemically generated
hydroxy-o-quinodimethanes and simultaneously forges two
adjacent fully substituted carbon stereocenters, with one
bearing a stereogenic carbon–fluorine unit. The method uses
readily available substrates, a simple chiral organocatalyst, and
mild reaction conditions to afford an array of highly functionalized chiral 2-fluoro-3-hydroxycyclopentanones.

The unique properties of the carbon–fluorine (CÀF) bond

explain why organofluorine compounds play a central role in
agrochemicals, pharmaceuticals, and materials science.[1] For
example, the selective incorporation of fluorine atoms into
drug candidates has produced some best-selling pharmaceuticals.[2] Unsurprisingly, the synthetic community has worked
hard to develop catalytic methods for the enantioselective
synthesis of stereodefined fluorinated organic molecules.[3]
There has been great progress in the last decade, mainly by
using either electrophilic[4] or nucleophilic[5] fluorinating
agents in combination with chiral metal-based or organic
catalysts. An alternative approach uses racemic molecules,
bearing a labile CÀF stereogenic unit, which undergo
a stereocontrolled carbon–carbon bond-forming process
while setting a configurationally stable fluorine-containing
stereocenter.[6]
We report herein a different catalytic strategy for the
stereoselective construction of valuable fluorine-containing
quaternary stereocenters, which is based on the desymmetrization of achiral 2-substituted-2-fluorocyclopentane-1,3[*] Prof. Dr. P. Melchiorre
ICREA—Catalan Institution for Research and Advanced Studies
Passeig Lluís Companys 23, 08010 Barcelona (Spain)
S. Cuadros, Dr. L. Dell’Amico, Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia the Barcelona
Institute of Science and Technology
Avenida Països Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research group/profpaolo-melchiorre/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201706763.
 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial, and no
modifications or adaptations are made.
Angew. Chem. Int. Ed. 2017, 56, 11875 –11879

Figure 1. a) The proposed strategy for forging fluorine-containing quaternary stereocenters by a desymmetrizing aldol reaction of achiral 2fluoro-substituted cyclopentane-1,3-diketones (1). b) The photoenolization mechanism of 2-methylbenzophenones (2) leading to the hydroxyo-quinodimethanes A, which can serve as nucleophiles in the intermolecular aldol desymmetrization process. Nu = nucleophile.

diketones (1), where a prochiral fluorine-containing carbon
center is preinstalled (Figure 1 a). The chemistry exploits the
ability of a chiral organic catalyst to choose between
enantiotopic carbonyl groups within 1 while facilitating
a desymmetric intermolecular aldol process with a suitable
nucleophile. The resulting symmetry-breaking process generates two stereocenters simultaneously, and forges a CÀF
stereogenic unit far from the reaction site. The desymmetrization of centrosymmetric or meso compounds by chiral
catalysts is a powerful method for making chiral molecules,[7]
and has been used extensively to synthesize natural compounds and biologically relevant molecules.[7a] However, this
strategy has never yet been used to install quaternary
fluorine-containing stereocenters.[8]
The idea for selecting a nucleophilic partner suitable for
the proposed aldol desymmetrization strategy came from our
recent studies[9] on the reactivity of hydroxy-o-quinodimethanes (A; Figure 1 b). These highly reactive intermediates
are easily generated upon light irradiation of 2-alkylbenzophenones (2).[10] Our studies demonstrated that they can
participate in a stereoselective processes promoted by chiral
organic catalysts.[11] Notably, the reactivity of A is not
restricted to traditional cycloaddition mechanisms.[9a] They
can also engage in intermolecular addition pathways.[9b,c]
Building on these precedents, we wondered whether the
photoenolization strategy, combined with the action of
a chiral organocatalyst, could be applied to the desymmetrization of 2-fluoro-2-alkylsubstituted cyclopentane-1,3-diones
(1). The resulting desymmetrizing aldol process affords chiral
2-fluoro-3-hydroxycyclopentanones (3) with two adjacent
fully substituted carbon stereocenters, with one bearing

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a stereogenic CÀF unit (Figure 1 b).[12] To the best of our
knowledge, the chemistry provides the first example of an
intermolecular-aldol-based desymmetrization of achiral cyclic
1,3-diketones. Since the pioneering work of Hajos and
Parrish,[13] symmetric 1,3-diketones of type 1 have been
used extensively to design new desymmetric aldol processes.
However, these have proceeded through intramolecular
manifolds exclusively.[7a, 13]
Our exploratory studies focused on the intermolecular
aldol reaction between the commercially available 2-methylbenzophenone (2 a) and 2-benzyl-2-fluorocyclopentane-1,3dione (1 a; see Table 1). The aldol acceptor is easily prepared
from cyclopentane-1,3-dione following a Knoevenagel condensation/reduction/electrophilic fluorination (using Selectfluor) sequence. The catalytic experiments were conducted in
toluene over 16 hours and under irradiation by a single blacklight-emitting diode (black LED, lmax = 365 nm). We initially
evaluated a large set of different chiral organic catalysts with
a known propensity to activate substrates by hydrogenbonding or ion-pairing interactions.[14] Specifically, we used
a screening platform to automate the parallel execution of
small-scale reactions to determine the efficiency of a library
of 60 novel and known organocatalysts in this desymmetric
aldol reaction (see Figure S1 in the Supporting Information
for selected results). This evaluation quickly identified the
commercially available amido-thiourea 4 a[15] as the most
promising catalyst.
The optimization studies were then continued on a meaningful experimental scale (0.1 mmol). We first confirmed that
the catalyst 4 a (20 mol %) afforded the product 3 a with good
chemical yield and stereoselectivity (Table 1, entry 1; single
diastereoisomer). Modification of the benzyl amide moiety in
4 revealed that incorporating an additional stereogenic center
imparted a slightly higher stereoinduction, but with a minimal
matched/mismatched effect (entries 2 and 3). These results
suggested that the steric profile of the tertiary benzyl amide
component could play a more prominent role than the
presence of a second stereocontrol element in dictating the
reactions stereoselectivity. In consonance with this reasoning,
the best results were achieved with the catalysts 4 d and 4 e,
both containing a more encumbered amide moiety but
a single stereogenic center (entries 4 and 5).
The N-benzhydryl-substituted amido-thiourea catalyst
4 e[15b] was selected for further optimization studies. A solvent
screening identified o-dichlorobenzene as the best reaction
medium (Table 1, entry 6). Since our illumination system
consisted of a black LED connected to an external power
supply, we could finely tune and control the intensity of light
emission (see Figure S2 for details of the illumination set-up).
Increasing the irradiance from 10 Æ 1 (used in the initial
experiments) to 15 Æ 1 mW cmÀ2, while extending the reaction
time to 30 hours provided 3 a in 89 % yield, as a single
diastereoisomer, and with 90 % ee (entry 7). Then, control
experiments were conducted to glean insights into the
mechanism of the photochemical organocatalytic desymmetrization aldol process. The absence of light irradiation
completely suppressed the reaction (entry 8), while the
racemic adduct 3 a was isolated in 15 % yield in the absence
of 4 (entry 9). The last result, along with the high stereocon-

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Table 1: Optimization of the model reaction.[a]

Entry

Catalyst

Solvent

Yield [%][b]

ee [%][c]

1
2
3
4
5
6
7[d]
8[e]
9

4a
4b
4c
4d
4e
4e
4e
4e
none

toluene
toluene
toluene
toluene
toluene
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4

50
31
41
45
40
69
89
0
15

76
83
87
89
90
91
90
–
0

[a] Reactions performed over 16 h on a 0.1 mmol scale using 3 equiv of
2 a under illumination by black LED (lmax = 365 nm) with an irradiance of
10 Æ 1 mWcmÀ2. [b] Yield of the isolated 3 a. [c] Enantiomeric excess of
3 a determined by UPC2 analysis on a chiral stationary phase. In all cases
a single diastereoisomer was observed by 19F NMR analysis of the crude
reaction mixture. [d] Irradiance of 15 Æ 1 mWcmÀ2 and 30 hours of
reaction time. [e] In the dark.

trol achieved with the chiral amido-thiourea 4 e, implies that
the rate acceleration facilitated by 4 e is large enough to
overcome a racemic background process.
We then evaluated the generality of the light-driven
organocatalytic aldol desymmetrization process using the
optimized reaction conditions described in Table 1, entry 7.
We studied the reactivity of a variety of achiral 2-substituted2-fluorocyclopentane-1,3-diketones (1). As displayed in
Figure 2, different substituents at the aromatic ring of the
benzyl moiety in 1 could be used, regardless of either their
electronic and steric properties or position on the phenyl ring
(3 a–h). To probe the synthetic utility of the method, we
demonstrated that good efficiency was maintained when
running the reaction on a 1 mmol scale (3 a). A product
bearing a heteroaryl framework could be synthesized, as
shown for the furyl-substituted adduct 3 i. The desymmetric
aldol reaction is also effective for 2-alkyl-2-fluoro cyclopentane-1,3-diones, thus affording the corresponding adducts
3 j,k with high enantioselectivities. For this substrate class, we
observed a correlation between the steric profile of the 2-alkyl
substituent and the relative stereocontrol of the desymmetrization process, since the diastereoselectivity increases with
the length of the alkyl chain (d.r. from 5.5:1 to 19:1 when
moving from a methyl to a butyl substituent; 3 j and 3 k). Xray crystallographic analysis[16] performed on crystals from
the adduct 3 h allowed the assignment of the absolute
configuration for the newly formed fluorine-containing qua-

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Communications

Figure 2. Survey of the 2-fluoro-substituted 1,3-diketones 1 which can
participate in the photochemical organocatalytic desymmetrization
aldol process. Reactions performed on a 0.1 mmol scale using 3 equiv
of 2 a. The d.r. value is inferred by 19F NMR analysis of the crude
reaction mixture. Yields and enantiomeric excesses of the isolated
products 3 are indicated below each entry (average of two runs).
*Performed on a 1 mmol scale.

ternary stereogenic center while establishing the stereochemical outcome of the aldol-based desymmetrization. The
photochemical organocatalytic system also shows some
limitations. The presence of a 2-phenyl substituent in 1 greatly
affected the reactivity of the process, although the stereoselectivity was preserved (3 l). The six-membered-ring product
3 m could be obtained only in poor yield and enantiomeric
excess.
We then probed the scope with respect to the 2alkylbenzophenones 2, which can participate in the reaction
by acting as donors upon photochemical generation of the
reactive photoenol intermediates. As detailed in Figure 3,
a wide range of substituents at both the non-enolizable (3 n–q)
and the enolizable (3 r–u) aromatic ring of 2 are well
tolerated, thus granting access to chiral 2-fluoro-3-hydroxycyclopentanones 3 n–u.
We then applied the photochemical organocatalytic
desymmetrization strategy to the straightforward one-pot
synthesis of the highly functionalized Hajos–Parrish-type
ketone 5 (Scheme 1). This type of scaffold belongs to a class of
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Figure 3. Survey of the 2-alkylbenzophenones 2 which can participate
in the photochemical organocatalytic desymmetrization aldol process.
Reactions performed on a 0.1 mmol scale using 3 equiv of 2. The
d.r. value is inferred by 19F NMR analysis of the crude reaction mixture.
Yields and enantiomeric excesses of the isolated products 3 are
indicated below each entry (average of two runs).

Scheme 1. One-pot organocatalytic enantioselective synthesis of the
fluorinated Hajos–Parrish-type ketone 5 proceeding through an intermolecular desymmetrizing aldol reaction of 1 v with subsequent
enamine-mediated intramolecular aldolization.

valuable chiral intermediates which are useful for synthesizing biologically relevant compounds and natural products.[7a, 13, 17] The organocatalytic desymmetrization of 2fluoro-2-(3-oxobutyl) cyclopentane 1,3-dione (1 v), which
transiently affords the enantioenriched fluorinated 3-hydroxyketone 3 v, was followed by an enamine-mediated cyclization
upon addition of pyrrolidine (50 mol %) to the same reaction
flask.
In summary, we have documented a novel catalytic
strategy to stereoselectively construct valuable fluorine-containing quaternary stereocenters, thus demonstrating that the
desymmetrization of centrosymmetric compounds can be

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used for this purpose. Specifically, we used the ability of
a readily available amido-thiourea catalyst to selectively
activate one of the enantiotopic carbonyl groups within
achiral 2-substituted-2-fluorocyclopentane-1,3-diketones (1).
The resulting desymmetric intermolecular aldol process with
photochemically generated, highly reactive hydroxy-o-quinodimethanes generates two stereocenters simultaneously, and
forges a stereogenic CÀF unit far from the reaction site. This
methodology could be used to develop other asymmetric
catalytic entries into useful stereogenic carbon-fluorine
synthons.

[5]

Acknowledgements
Financial support was provided by the Generalitat de
Catalunya (CERCA Program), MINECO (CTQ2016-75520P and Severo Ochoa Excellence Accreditation 2014–2018,
SEV-2013-0319), and the European Research Council (ERC
681840—CATA-LUX). S.C. is grateful to the MECD for
a FPU fellowship (ref. FPU14/06541). L.D. thanks the Marie
Curie COFUND action (2014-1-ICIQ-IPMP) for a postdoctoral fellowship. We also thank the CELLEX Foundation
through the CELLEX-ICIQ high throughput experimentation platform

[6]

[7]

Conflict of interest
The authors declare no conflict of interest.
Keywords: desymmetrization · fluorine · organocatalysis ·
photochemistry · synthetic methods

[8]

How to cite: Angew. Chem. Int. Ed. 2017, 56, 11875 – 11879
Angew. Chem. 2017, 129, 12037 – 12041
[1] a) Organofluorine compounds. Chemistry and applications (Ed.:
T. Hiyama), Springer, New York, 2000; b) P. Jeschke, ChemBioChem 2004, 5, 570 – 589; c) S. M. Ametamey, M. Honer, P. A.
Schubiger, Chem. Rev. 2008, 108, 1501 – 1516.
[2] a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
1886; b) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; c) D. OHagan, J. Fluorine
Chem. 2010, 131, 1071 – 1081.
[3] For reviews, see: a) G. K. S. Prakash, P. Beier, Angew. Chem. Int.
Ed. 2006, 45, 2172 – 2174; Angew. Chem. 2006, 118, 2228 – 2230;
b) V. A. Brunet, D. OHagan, Angew. Chem. Int. Ed. 2008, 47,
1179 – 1182; Angew. Chem. 2008, 120, 1198 – 1201; c) J.-A. Ma,
D. Cahard, Chem. Rev. 2008, 108, PR1 – PR43; d) X. Yang, T.
Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015, 115, 826 – 870.
[4] For pioneering work, see: a) L. Hintermann, A. Togni, Angew.
Chem. Int. Ed. 2000, 39, 4359 – 4362; Angew. Chem. 2000, 112,
4530 – 4533; For selected examples: b) Y. Hamashima, K. Yagi,
H. Takano, L. Tamµs, M. Sodeoka, J. Am. Chem. Soc. 2002, 124,
14530 – 14531; c) T. D. Beeson, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 8826 – 8828; d) M. Marigo, D. Fielenbach,
A. Braunton, A. Kjærsgaard, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2005, 44, 3703 – 3706; Angew. Chem. 2005, 117, 3769 –
3772; e) D. D. Steiner, N. Mase, C. F. Barbas III, Angew. Chem.
Int. Ed. 2005, 44, 3706 – 3710; Angew. Chem. 2005, 117, 3772 –
3776; f) T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S.

11878

www.angewandte.org

[9]

[10]

[11]

[12]

Angewandte

Chemie

Nakamura, T. Toru, M. Shiro, Angew. Chem. Int. Ed. 2008, 47,
4157 – 4161; Angew. Chem. 2008, 120, 4225 – 4229; g) O. Lozano,
G. Blessley, T. Martinez del Campo, A. L. Thompson, G. T.
Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouverneur,
Angew. Chem. Int. Ed. 2011, 50, 8105 – 8109; Angew. Chem.
2011, 123, 8255 – 8259; h) P. Kwiatkowski, T. D. Beeson, J. C.
Conrad, D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133, 1738 –
1741; i) J. Erb, D. H. Paull, T. Dudding, L. Belding, T. Lectka, J.
Am. Chem. Soc. 2011, 133, 7536 – 7546; j) V. Rauniyar, A. D.
Lackner, G. L. Hamilton, F. D. Toste, Science 2011, 334, 1681 –
1684; k) X. Yang, R. J. Phipps, F. D. Toste, J. Am. Chem. Soc.
2014, 136, 5225 – 5228.
For selected examples, see: a) J. A. Kalow, A. G. Doyle, J. Am.
Chem. Soc. 2010, 132, 3268 – 3269; b) M. H. Katcher, A. G.
Doyle, J. Am. Chem. Soc. 2010, 132, 17402 – 17404; c) M. H.
Katcher, A. Sha, A. G. Doyle, J. Am. Chem. Soc. 2011, 133,
15902 – 15905; d) E. M. Woerly, S. M. Banik, E. N. Jacobsen, J.
Am. Chem. Soc. 2016, 138, 13858 – 13861; e) S. M. Banik, J. W.
Medley, E. N. Jacobsen, Science 2016, 353, 51 – 54.
For selected examples, see: a) M. Nakamura, A. Hajra, K. Endo,
E. Nakamura, Angew. Chem. Int. Ed. 2005, 44, 7248 – 7251;
Angew. Chem. 2005, 117, 7414 – 7417; b) X. Jiang, M. Gandelman, J. Am. Chem. Soc. 2015, 137, 2542 – 2547; c) J. Saadi, H.
Wennemers, Nat. Chem. 2016, 8, 276 – 280; d) K. Balaraman, C.
Wolf, Angew. Chem. Int. Ed. 2017, 56, 1390 – 1395; Angew.
Chem. 2017, 129, 1411 – 1416.
For recent reviews, see: a) K.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F.
Zhou, J. Zhou, Chem. Rev. 2016, 116, 7330 – 7396; b) A. Borissov,
T. Q. Davies, S. R. Ellis, T. A. Fleming, M. S. W. Richardson,
D. J. Dixon, Chem. Soc. Rev. 2016, 45, 5474 – 5540; For recent
examples of catalytic desymmetrization processes of 2,2-dialkyl
substituted cyclopentane-1,3-diones, see: c) B. M. Partridge, M.
Callingham, W. Lewis, H. W. Lam, Angew. Chem. Int. Ed. 2017,
56, 7227 – 7232; Angew. Chem. 2017, 129, 7333 – 7338; d) S.
PrØvost, N. DuprØ, M. Leutzsch, Q. Wang, V. Wakchaure, B. List,
Angew. Chem. Int. Ed. 2014, 53, 8770 – 8773; Angew. Chem.
2014, 126, 8915 – 8918.
Recently, the asymmetric ring opening of meso epoxides with
fluoride anions has been reported. This desymmetrization
process is based on a CÀF bond-forming step and can only
forge fluorine-containing tertiary (and not quaternary) stereocenters. See Ref. [5a] and: a) J. A. Kalow, A. G. Doyle, J. Am.
Chem. Soc. 2011, 133, 16001 – 16002; b) J. Zhu, G. C. Ysui, M.
Lautens, Angew. Chem. Int. Ed. 2012, 51, 12353 – 12356; Angew.
Chem. 2012, 124, 12519 – 12522.
Diels–Alder reaction: a) L. DellAmico, A. Vega-PeÇaloza, S.
Cuadros, P. Melchiorre, Angew. Chem. Int. Ed. 2016, 55, 3313 –
3317; Angew. Chem. 2016, 128, 3374 – 3378; Mannich-type
reaction: b) H. B. Hepburn, G. Magagnano, P. Melchiorre,
Synthesis 2017, 76 – 86; Conjugate addition: c) L. DellAmico,
V. M. Fernµndez-Alvµrez, F. Maseras, P. Melchiorre, Angew.
Chem. Int. Ed. 2017, 56, 3304 – 3308; Angew. Chem. 2017, 129,
3352 – 3356.
a) N. C. Yang, C. Rivas, J. Am. Chem. Soc. 1961, 83, 2213 – 2213;
b) P. G. Sammes, Tetrahedron 1976, 32, 405 – 422; c) “Photoenolization and its applications”: P. Klµn, J. Wirz, A. Gudmundsdottir in CRC Handbook of Organic Photochemistry and
Photobiology, 3rd ed. (Ed.: A. Griesbeck), CRC, Boca Raton,
2012, chap. 26, pp. 627 – 651.
For a review on enantioselective catalytic photochemical
processes, see: R. Brimioulle, D. Lenhart, M. M. Maturi, T.
Bach, Angew. Chem. Int. Ed. 2015, 54, 3872 – 3890; Angew.
Chem. 2015, 127, 3944 – 3963.
Similar fluorine-containing chiral cyclic scaffolds, prepared in
racemic fashion, have been used as intermediates in the synthesis
of pyrrolopyridazine JAK3 inhibitors. See: Bristol-Meyers
Squibb Company; T. W. Stephen, G. D. Brown, L. M. Doweyko,

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Angew. Chem. Int. Ed. 2017, 56, 11875 –11879

Communications
J. Duan, J. Guo, J. Hynes, B. Jian, J. Kempson, S. Lin, Z. Lu, S. H.
Spergel, J. S. Tokarski, H. Wu, B. V. Yang, Patent WO2012/
125886A1, 2012.
[13] a) “Asymmetric Synthesis of Optically Active Polycyclic
Organic Compounds”: Z. G. Hajos, D. R. Parrish, German.
Patent, DE 2102623, 1971; b) Z. G. Hajos, D. R. Parrish, J. Org.
Chem. 1974, 39, 1612 – 1615; c) U. Eder, G. Sauer, R. Wiechert,
Angew. Chem. Int. Ed. Engl. 1971, 10, 496 – 497; Angew. Chem.
1971, 83, 492 – 493.
[14] a) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45,
1520 – 1543; Angew. Chem. 2006, 118, 1550 – 1573; b) K. Brak,
E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534 – 561;
Angew. Chem. 2013, 125, 558 – 588.
[15] a) S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
2008, 130, 7198 – 7199; b) S. J. Zuend, M. P. Coughlin, M. P.

Angew. Chem. Int. Ed. 2017, 56, 11875 –11879

Angewandte

Chemie

Lalonde, E. N. Jacobsen, Nature 2009, 461, 968 – 971; c) D. D.
Ford, D. Lehnherr, C. R. Kennedy, E. N. Jacobsen, J. Am. Chem.
Soc. 2016, 138, 7860 – 7863.
[16] CCDC 1552622 (3 h) contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[17] J. M. Eagan, M. Hori, J. Wu, K. S. Kanyiva, S. A. Snyder, Angew.
Chem. Int. Ed. 2015, 54, 7842 – 7846; Angew. Chem. 2015, 127,
7953 – 7957.
Manuscript received: July 3, 2017
Revised manuscript received: July 25, 2017
Accepted manuscript online: July 25, 2017
Version of record online: August 18, 2017

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