Development of C2-Symmetric Chiral Bifunctional Triamines: Synthesis and Application in Asymmetric Organocatalysis

Article abstract of DOI:10.1021/acs.orglett.8b01957

The synthesis and application of a newly designed C₂-symmetric chiral bifunctional triamine family (C₂-CBT) is reported. These enantiopure chiral triamine scaffolds can be accessed in multigram amounts from simple amino acids while avoiding chromatographic purification. As a proof of principle, C₂-CBT has been studied in the aldol reaction of cyclic ketones with isatins, with the target tertiary alcohols being formed in a highly efficient manner. Catalyst recovery by simple extraction techniques and subsequent reuse has been performed.

Full text of DOI:10.1021/acs.orglett.8b01957

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development of C2‑Symmetric Chiral Bifunctional Triamines:
Synthesis and Application in Asymmetric Organocatalysis
†,§
†
,†,‡
̀
̀
Pedro Alonso, and Miquel A. Pericas*
̃
Santiago Canellas,
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Avda. Països Catalans 16,
E-43007 Tarragona, Spain
‡
̀
̀
̀
Departament de Química Inorganica i Organica, Universitat de Barcelona, Martí i Franques 1-11, 08028 Barcelona, Spain
§
̀
Departament de Química Analítica i Química Organica, Universitat Rovira i Virgili, Marcel lí Domingo, 1, 43007 Tarragona, Spain
S
* Supporting Information
ABSTRACT: The synthesis and application of a newly
designed C2-symmetric chiral bifunctional triamine family
(C2-CBT) is reported. These enantiopure chiral triamine
scaffolds can be accessed in multigram amounts from simple
amino acids while avoiding chromatographic purification. As a
proof of principle, C2-CBT has been studied in the aldol
reaction of cyclic ketones with isatins, with the target tertiary
alcohols being formed in a highly efficient manner. Catalyst
recovery by simple extraction techniques and subsequent
reuse has been performed.
symmetric organocatalysis has attracted a great deal of
A
attention over the past two decades,1 especially due to the
environmentally benign and nontoxic nature, low cost,
robustness, operational simplicity, and easy structural mod-
ification of the organocatalytic scaffolds.2 In particular,
aminocatalysts are a class of organocatalysts based on primary
or secondary amines that are able to activate carbonyls, one of
the most ubiquitous functional groups in organic chemistry.3,4
This field exploded in 2000, when Barbas, Lerner, List, and
MacMillan independently set the concepts of enamine and
iminium catalysis.4 With time, organocatalytic species have
gained complexity, approaching enzymes by design and
behavior. For instance, the simultaneous activation of at least
two functional groups or coupling partners has led to new
synthetic transformations that were otherwise impossible or
inefficient. To allow further development in this direction, the
design of new bi- or multifunctional catalysts has become a
main trend.5,6
Figure 1. C2-symmetric organocatalysts for aldol reactions.
The aldol condensation of ketones and isatins has emerged
as a benchmark reaction within the field of organocatalysis
since its first report in 2006 by the group of Tomasini.8 It is
noteworthy that this transformation provides access to
enantioenriched compounds possessing a 3-hydroxy-2-oxin-
dole skeleton, a structural motif that is present in a plethora of
natural products and drug candidates with relevant pharmaco-
logical properties.9
From a synthetic point of view, one of the main challenges
associated with the preparation of this family of compounds is
the incorporation of an alkyl chain at the C3-position, since
controlling the configuration of this quaternary center has
proven not to be trivial.10 Nevertheless, great improvements
have been achieved in this task through catalyst design, as
remarkable degrees of stereocontrol have been reported by the
groups of Zhao, Xu, Cheng, and Ishimaru.11 While the groups
of Xu and Cheng have already reported the use of C2-
symmetric catalysts for the aldol reaction of isatins and ketones
(Figure 1), further improvements are yet to be expected. For
In this respect, the presence of a 2-fold symmetry axis in
chiral catalytic species usually provides substantial advantages
over its nonsymmetric counterpart. Chemically identical active
centers of C2-symmetric organocatalysts offer more chances for
substrate activation, thus increasing reaction rates and
improving selectivities.7 This issue might be especially relevant
in amino-catalyzed reactions due to the typically long reaction
times.
Taking this into account, and inspired by the performance of
chiral vicinal diamines,6a,c−e we envisioned that usually
inefficient aminocatalyzed reactions could be ameliorated by
the use of a newly designed C2-symmetric chiral bifunctional
organocatalyst type (Figure 1c).
Received: June 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01957
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Letter
instance, the group of Xu (Figure 1, a) only reported one
example of this transformation, and the conditions described
by the group of Cheng (Figure 1, b) required the use of the
cyclic ketone as a solvent of the reaction.
Table 1. Catalyst Screening
Herein, we report the synthesis of a new C2-symmetric chiral
aminocatalyst type (Figure 1, c) that shows enhanced activity
and improved performance in the selected benchmark
transformation when compared to typically used amino-
catalysts.
For the synthesis of the target chiral triamines, we focused
our efforts on the use of cheap and widely available building
blocks, the feasibility on multigram scale and the avoidance of
column-chromatography separations. The key synthetic step to
this end was the double ring-opening of a chiral, N-protected
aziridine by a primary amine. The N-protected aziridine, in
turn, would be prepared from abundant, enantiopure α-amino
acids (Scheme 1).
Scheme 1. Synthesis of Organocatalysts I−III
entry
catalyst
5a, yield (%)
dr (syn/anti)
ee (%)
1
2
3
4
5
6
7
8
I
II
80
72
13
80
27
<5
<5
<5
99
<5
99
82
13:1
5:1
3.5:1
3:1
7:1
nd
nd
nd
22:1
nd
28:1
13:1
90
71
40
78
92
nd
nd
nd
−48
nd
58
III
IV
V
VI
VII
VIII
IX
X
The use of a Boc protecting/activating group of the aziridine
moiety in combination with aprotic solvents for the key ring-
opening step was initially tested but led to product mixtures
due to a very slow second aziridine ring opening. Alternatively,
the use of a more efficient activator, such as the nosyl group,
and methanol as the solvent allowed the two consecutive
aziridine ring opening steps to be performed in a highly
efficient manner. The synthetic approach summarized in
Scheme 1 allows the facile structure modification of both the
central tertiary amine (R2, arising from the primary amine
nucleophile) and the bulky R1 group (from the chiral α-amino
acid) designed to be responsible for enantiodiscrimination. All
synthetic steps in the optimized route are simple and high-
yielding. As we will discuss later, we have developed a
chromatography-free, multigram synthesis of the triamines
based on this route.
We next explored the catalytic activity of these C2-symmetric
triamines using the benchmark aldol reaction of cyclo-
hexanones and isatins. For this purpose, we compared the
results obtained with catalysts I−III with those obtained with
other aminocatalysts typically employed in the same process.
Thus, under the conditions summarized in Table 1, the aldol
condensation between 1-methylisatin 3a and cyclohexanone 4a
was studied.
Among the new class of C2-symmetric triamine catalysts
synthesized, I performed substantially better than II and III
(Table 1, entries 1−3). With I, the reaction smoothly
proceeded to afford 5a in 80% yield as a 13.0:1 mixture of
diastereoisomers, the major one with excellent ee (90%). On
the other hand, catalysts II and III performed less efficiently
(Table 1, entries 2 and 3). We then compared our best result
(Table 1, entry 1) with those obtained with other well-known
primary and secondary aminocatalysts. Interestingly, when a
nonsymmetric analogue (Luo’s catalyst IV6c−e) was employed
under the same reaction conditions, the same yield was
9
10
11
XI
I
a
12
93
a
Reaction run for 15 h with 5 equiv of 4a, 10 mol % of I, and TfOH at
25 °C at 0.66 M concentration in THF.
observed for product 3a, while the diastereoselectivity and
enantioselectivity of the transformation were significantly lower
(Table 1, entry 4). Polystyrene-supported derivative V6a was
able to afford a higher enantiomeric excess (92%) while
achieving an acceptable diastereomeric ratio (7:1). However, a
much lower catalytic activity was observed (Table 1, entry 5).
Very high activities were recorded when diamines IX and XI
were used as catalysts. In these cases, aldol adduct 5a was
isolated in high yield and excellent diastereoselectivity, but
only moderate enantioselectivities were achieved (Table 1,
entries 9 and 11).
The use of proline, the Jørgensen−Hayashi catalyst, or a
similar diamine VI, VII, or VIII resulted in almost complete
recovery of the starting material, an outcome that highlights
the importance of primary amines for the activation of ketones
in the aldol reaction (Table 1, entries 6−8). Finally, after
further experimentation, we identified the best conditions to
carry out this transformation as those summarized in entry 12
of Table 1, where 5a could be isolated in 82% yield as a 13.0:1
mixture of diastereoisomers (syn/anti) and 93% enantiomeric
excess for the major diastereoisomer using the C2-CBT catalyst
I.12
Among several reaction parameters, we studied the influence
of the ratio I/TfOH to the catalytic performance. The best
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balance between the yield and the enantiomeric excess was
found with equimolar ratio of the catalyst I and TfOH. This
fact suggests that both primary amines are involved in the
generation of reactive enamine intermediates. On the other
hand, the in situ generated ammonium triflate salt from the
central tertiary amine plays a crucial role on the activation of
the isatin. Nonetheless, we cannot rule out the possibility of an
additional role of the second primary amine as a hydrogen-
bond donor.12
Having identified the optimized conditions to carry out the
aldol reaction between 1-methylisatin and cyclohexanone, the
applicability of the method was tested by studying the scope of
the reaction. Therefore, a set of isatins with different
substitution patterns 3 was reacted with a series of cyclic
ketones 4, leading to the formation of aldols 5a−r. The results
of this study are shown in Scheme 2. Remarkably, the
efficiency of the C2-CBT aminocatalyst I was demonstrated
since complete conversion of the starting materials was
generally observed after 15 h of reaction at 25 °C while
using a 5-fold excess of the corresponding ketone. As the
results gathered in Scheme 2 show, substitution in the nitrogen
atom does not affect the diastereo- and enantioselectivity of
the process, since up to seven different N-substituted adducts
were synthesized with excellent results (5a−g). The relative
configuration of the adducts was unambiguously assigned by
X-ray single-crystal analysis of 5b with the assumption of a
similar stereochemical course, as is present in the other studied
cases.13
The induction of chirality proved to be more challenging
when isatins bearing functionality in the aromatic ring were
used, regardless of the electronic properties of the substituent.
Thus, compounds 5h−l were obtained with slightly lower
enantioselectivities (ee = 61−83%), while yields and
diastereoisomeric ratios were generally very high. These results
are in good agreement with other studies reported in the
literature and place I among the best catalysts for this
reaction.10b,f,g Finally, other cyclic ketones were tested in order
to further enlarge the scope of the transformation. In this case,
when tetrahydro-4H-thiopyran-4-one was used for the
reaction, excellent results were obtained since compounds
5m,n were isolated in high yields and excellent diastereo- and
enantioselectivities. Nevertheless, when other ketone deriva-
tives were employed such as tetrahydro-4H-pyran-4-one and
4,4-dimethylcyclohexanone, adducts 5o and 5p were synthe-
sized in excellent yields, albeit with moderate to good
enantiomeric excesses. In addition, cyclopentanone and
cycloheptanone gave their corresponding aldol products 3q
and 3r with poor diasteroselectivity under these reaction
conditions, a result that is in good agreement with other
reported catalysts for this transformation.10f,g Finally, the
desymmetrization of 4-substituted cyclohexanones was per-
formed, exerting remarkable levels of stereocontrol. Thus,
adducts 5s and 5t were isolated with good diastereoselectivities
(dr = 6:1:1 for 5s and 10:1:1 for 5t) and enantioselectivities
(ee = 82−84%).
a
Scheme 2. Scope and Limitations of the Reaction
As already mentioned, given the straightforward nature of
the preparation of I and its optimal catalytic performance,
effort was devoted to the development of a practical synthesis
for this C2-symmetric chiral triamine. Taking into account the
clean nature of the reactions involved in the preparation of I,
we concentrated on the use of simple purification procedures
(extraction, precipitation, or crystallization) on a multigram
scale (Scheme 3).12 In this manner, an overall 60% yield could
be recorded in the six-step sequence from tert-leucine, and
catalyst I could be characterized by single-crystal X-ray
analysis.
Inspired by the last step of the catalyst synthesis (where the
catalyst is extracted to the aqueous phase under acidic
conditions and extracted back to the organic phase under
basic conditions), we envisioned that the catalyst could be
easily recovered at the end of the enantioselective trans-
formation by using simple extraction techniques. This would
make possible overcoming one of the most important
limitations associated with the use of homogeneous catalysts,
that is, the possibility of efficient recovery and reuse.
To test this possibility, isatin 3b was reacted with
cyclohexanone 4a on a 5 mmol scale under the optimized
reaction conditions (Scheme 4). Once the starting material was
consumed, aqueous HCl was added, and the aldol product 5b
was extracted in CH2Cl2 with excellent results (85% yield, ee =
93.7% and dr = 12.4:1). Then the aqueous phase was treated
with aqueous NaOH and the catalyst was extracted in CH2Cl2
(75% recovery, analytically pure). This recovered catalyst was
a
General reaction conditions: 3 (0.181 mmol), 4 (5 equiv), I (10 mol
b
%), TfOH (10 mol %), THF (0.66 M), 25 °C, 15 h. Reaction time
was extended to 36 h.
C
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derivatives as a ligand in metal-catalyzed asymmetric trans-
formations.
Scheme 3. Multigram Scale and Column Chromatography
Free Synthesis of C2-Symmetric Chiral Bifunctional
Triamine I
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01957.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 1851132−1851133 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mapericas@iciq.es.
ORCID
Scheme 4. Scale-up Reaction, Recovery, and Reuse of C2-
Symmetric Chiral Bifunctional Triamine I
Santiago Canellas: 0000-0002-8700-4615
̃
̀
̀
Miquel A. Pericas: 0000-0003-0195-8846
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the MINECO (Grant No. CTQ2015-
69136-R (AEI/MINECO/FEDER, UE)) and CERCA Pro-
gramme/Generalitat de Catalunya and DEC Generalitat de
Catalunya (Grant No. 2014SGR827) is gratefully acknowl-
edged. We also thank the MINECO for support through the
Severo Ochoa Excellence Accreditation 2014-2018 (SEV-
2013-0319). S.C. thanks the AEI/MINECO for a Severo
Ochoa FPI fellowship (BES-2015-072152). We are grateful to
the ICIQ X-ray diffraction unit for the single-crystal X-ray
analyses of I and 5b and Dr. Ayats (Institute of Chemical
Research of Catalonia) for his contribution in the preliminary
stages.
REFERENCES
■
(1) (a) List, B. Chem. Rev. 2007, 107, 5413−5415. (b) MacMillan,
D. W. C. Nature 2008, 455, 304−308.
(2) Anebouselvy, K.; Ramachary, D. B.; Kumar, I. Dienamine
Catalysis for Organic Synthesis; The Royal Society of Chemistry, 2018.
(3) (a) Dalko, P. I. Enantioselective Organocatalysis; Wiley-VCH:
Weinheim, 2007. (b) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015,
48, 986−997.
reused in a new catalytic cycle (3.75 mmol of 3b) showing the
same catalytic activity as the fresh batch (86% yield, ee =
97.7% and dr = 10:1).
(4) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395−2396. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan,
In summary, we have synthesized a new class of C2-
symmetric chiral bifunctional triamines (C2-CBT) from cheap
and widely available chiral α-amino acids and primary amines.
These organocatalysts showed an excellent performance in the
enantioselective aldol addition of cyclic ketones to isatins (up
to 98% yield, ee = 96%, dr = 13:1). The catalyst of choice was
synthesized on a multigram scale with high overall yield and
using operationally simple techniques (avoiding column
chromatography purifications). Moreover, the chiral catalyst
was recovered after the enantioselective reaction by extraction
techniques and was reused in a new catalytic cycle. We are
currently focused on the use of this C2-CBT scaffold and its
̈
D. W. C. J. Am. Chem. Soc. 2000, 122, 4243−4244. (c) Erkkila, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416−5470.
(d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471−5569.
(5) For selected early examples on bifunctional catalysts, see:
(a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 2641−2642. (b) Takamura, M.; Funabashi, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801−6808.
(c) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187−
2210. (d) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906−9907. (e) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2005, 127, 8964−8965. (f) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.;
D
DOI: 10.1021/acs.orglett.8b01957
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105−108. (g) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 15872−15883.
(6) For recent examples on bifunctional organocatalysis, see:
̀
(a) Canellas, S.; Ayats, C.; Henseler, A. H.; Pericas, M. ACS Catal.
̃
́
́
2017, 7, 1383−1391. (b) Jimenez, E. I.; Vallejo Narvaez, W. E.;
́
Rocha-Rinza, T.; Hernandez-Rodríguez, M. Catal. Sci. Technol. 2017,
7, 4470−4477. (c) You, Y.; Zhang, L.; Cui, L.; Mi, X.; Luo, S. Angew.
Chem., Int. Ed. 2017, 56, 13814−13818. (d) Zhu, L.; Zhang, L.; Luo,
S. Angew. Chem., Int. Ed. 2018, 57, 2253−2258. (e) Cui, L.; You, Y.;
Mi, X.; Luo, S. J. Org. Chem. 2018, 83, 4250−4256. (f) Matador, E.;
́
Retamosa, M.; Monge, D.; Iglesias-Siguenza, J.; Fernandez, R.;
̈
Lassaletta, J. M. Chem. - Eur. J. 2018, 24, 6854−6860.
(7) For a review on C2-symmetric diamines as asymmetric
organocatalysts, see: Zlotin, S. G.; Kochetkov, S. V. Russ. Chem.
Rev. 2015, 84, 1077−1099 and references cited therein.
(8) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q.
B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418−7421.
(9) (a) Popp, F. D.; Parson, R.; Donigan, B. E. J. Heterocycl. Chem.
1980, 17, 1329−1330. (b) Monde, K.; Sasaki, K.; Shirata, A.;
Takasugi, M. Phytochemistry 1991, 30, 2915−2917. (c) Rasmussen, H.
B.; MacLeod, J. K. J. Nat. Prod. 1997, 60, 1152−1154. (d) Kohno, J.;
Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki,
T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990−995. (e) Tokunaga,
T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.;
Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R.
́
J. Med. Chem. 2001, 44, 4641−4649. (f) Suchy, M.; Kutschy, P.;
Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.;
́
Balentova, E. J. Org. Chem. 2001, 66, 3940−3947. (g) Hibino, S.;
́
Choshi, T. Nat. Prod. Rep. 2001, 18, 66−87. (h) Frechard, A.; Fabre,
́
́
N.; Pean, C.; Montaut, S.; Fauvel, M.-T.; Rollin, P.; Fouraste, I.
Tetrahedron Lett. 2001, 42, 9015−9017. (i) Lin, S.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2002, 41, 512−515. (j) Hewawasam, P.; Erway,
M.; Moon, S. L.; Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson,
D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med.
Chem. 2002, 45, 1487−1499. (k) Kawasaki, T.; Nagaoka, M.; Satoh,
T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron 2004, 60, 3493−
3503.
(10) (a) Shen, C.; Shen, F.; Xia, H.; Zhang, P.; Chen, X.
Tetrahedron: Asymmetry 2011, 22, 708−712. (b) Liu, Y.; Gao, P.;
Wang, J.; Sun, Q.; Ge, Z.; Li, R. Synlett 2012, 23, 1031−1034.
́
́
(c) Hernandez, J. G.; García-Lopez, V.; Juaristi, E. Tetrahedron 2012,
68, 92−97. (d) Guo, Q.; Zhao, J. C.-G. Tetrahedron Lett. 2012, 53,
1768−1771. (e) Zhang, F.; Li, C.; Qi, C. Tetrahedron: Asymmetry
2013, 24, 380−388. (f) Wang, J.; Liu, Q.; Hao, Q.; Sun, Y.; Luo, Y.;
Yang, H. Chirality 2015, 27, 314−319. (g) Ogasawara, A.; Reddy, U.
V. S.; Seki, C.; Okuyama, Y.; Uwai, K.; Tokiwa, M.; Takeshita, M.;
Nakano, H. Tetrahedron: Asymmetry 2016, 27, 1062−1068. (h) Cao,
Z.-Y.; Zhou, F.; Zhou, J. Acc. Chem. Res. 2018, 51, 1443−1454.
(11) (a) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int. Ed.
2010, 49, 9460−9464. (b) Deng, Y.; Liu, L.; Sarkisian, R. G.;
Wheeler, K.; Wang, H.; Xu, Z. Angew. Chem., Int. Ed. 2013, 52, 3663−
3667. (c) Mao, Z.; Zhu, X.; Lin, A.; Li, W.; Shi, Y.; Mao, H.; Zhu, C.;
Cheng, Y. Adv. Synth. Catal. 2013, 355, 2029−2036. (d) Tanimura,
Y.; Yasunaga, K.; Ishimaru, K. Eur. J. Org. Chem. 2013, 2013, 6535−
6539.
(12) See the Supporting Information for further details
(13) The absolute configuration was assigned by comparing the
HPLC traces with reported data.
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