Ultrasound-Promoted Enantioselective Decarboxylative Protonation of α-Aminomalonate Hemiesters by Chiral Squaramides: A Practical Approach to Both Enantiomers of α-Amino Esters

Article abstract of DOI:10.1002/ejoc.201700786

Herein, we report an ultrasound-promoted enantioselective decarboxylative protonation reaction of α-aminomalonate hemiesters 1 in the presence of chiral cinchona-derived squaramide Br?nsted bases under mild conditions, which afforded both the (S)- and (R)-enantiomers of α-amino acid derivatives 2 in excellent yields (> 90 %) and excellent enantioselectivities (up to 98 % ee).

Full text of DOI:10.1002/ejoc.201700786

A Journal of
Accepted Article
Title: Ultrasound Promoted Enatioselective Decarboxylative
Protonation of α-Aminomalonate Hemiesters by Chiral
Squaramides: A Practical Approach to Both Enantiomers of α-
Amino Esters
Authors: Surajit Some, Han Yong Bae, Mun jong Kim, Yong Jian
Zhang, and Choong Eui Song
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700786
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European Journal of Organic Chemistry
10.1002/ejoc.201700786
FULL PAPER
Ultrasound Promoted Enatioselective Decarboxylative
Protonation of α-Aminomalonate Hemiesters by Chiral
Squaramides: A Practical Approach to Both Enantiomers of α-
Amino Esters
[a]†
[a]§
[a]
[b]
[a]
Surajit Some, Han Yong Bae, Mun Jong Kim, Yong Jian Zhang,* and Choong Eui Song*
Dedication ((optional))
Abstract Ultrasound promoted enantioselelctive decarboxylative
protonation reaction of α-aminomalonate hemiesters in the
enantioselectivities (85–93% ee). The slow reaction rate might
be attributed to the formation of the stable ionic complex I by the
interaction of chiral Brønsted base (B*) with acidic α-
1
presence of chiral cinchona-derived squaramide Brønsted bases
under mild conditions afforded both the (S) and (R) enantiomers of
α-amino acid derivatives 2 in excellent yields (>90%) and excellent
enantioselectivities (up to 98% ee).
aminomalonate
hemiester
1.
Thus,
the
sequential
decarboxylation followed by enantioselective protonation of II,
affording the product 2, can be retarded (Scheme 1).
B*H
B*H
R1
R1
R1
R1
CO2H
CO2Et
B*
CO2
CO2Et
R2
R2
R2
O
R2
H
Introduction
N
N
N
N
CO2Et
PG
rac-1
PG
CO2
PG OEt
B*
PG
I
II
2
Optically active natural or unnatural α-amino acids have
numerous applications in the preparation of natural products,
peptides, chiral drugs, ligands, and catalysts. However, the
development of practical methods for their synthesis is still a
Scheme 1. Chiral Brønsted base (B*) promoted asymmetric decarboxylative
protonation of racemic α-aminomalonate hemiesters 1. PG = protecting group.
[
1]
challenging task.
The enantioselective decarboxylative
protonation (EDP) reaction of α-aminomalonate hemiesters is a
remarkable practical route for the synthesis of optically active α-
[7]
Our group recently reported that cinchona-based squaramides
are remarkably efficient chiral hydrogen bonding organocatalysts
[
2]
amino acids. Although EDP reaction was first reported in 1904,
satisfactory enantioselectivity for this reaction has not yet been
for diverse asymmetric catalytic transformations, namely,
[8a]
dynamic kinetic resolution of racemic azlactones,
Michael
[
3]
accomplished to date. The first approach to the chiral amino
acids by the EDP reaction of α-aminomalonate hemiesters was
reported based on chiral cobalt complexes; however, only poor
addition reactions of various enolate precursors such as 1,3-
[8b]
[8c]
diketones,
malonates, and malonic acid half thioesters
MAHTs), direct Mannich reaction of dithiomalonates to N-Boc
[8d]
(
[
4]
to moderate enantioselectivities were observed. Brunner et
[8e]
imines,
and Michael addition reactions of unreactive β,β-
[
5a]
[5b,5c]
[5d]
al., Lasne et al.,
and Kim et al. independently reported
[8f]
disubstituted nitroalkenes. In particular, in the case of the
catalytic asymmetric decarboxylative Michael addition reaction
of MAHTs to β-nitro-olefins, increasing the reaction temperature
from 20 °C to 45 °C efficiently accelerated the decarboxylative
that chiral organic promoters can also promote the EDP of α-
aminomalonate hemiesters; however, the enantioselectivities
obtained were still unsatisfactory. Recently, Rouden and
coworkers discovered that chiral Brønsted bases (B*) such as
[8d]
addition rate. Likewise, commitment of some external energy
[
6a]
[6b]
cinchona-based thioureas
or squaramides can be used as
might address the slow reaction rate of the decarboxylative
protonation reaction.
highly enantioselective promoters for the EDP of α-
aminomalonate hemiesters, affording enantio-enriched chiral α-
amino esters 2. However, very long reaction time (3–7 days) is
required to obtain higher yields (>90%) and good to excellent
As a green and powerful technique to promote some organic
reaction, ultrasound irradiation has been widely employed in last
[9]
decades. In some cases, this high-energy input enhances the
mechanical effects in heterogeneous processes, or expedites
the formation of unexpected chemical species. The EDP
reaction proceeds heterogeneously in nonpolar organic solvents,
because of the formation of ionic complex I, and precipitation
occurs during the progress of the reaction. In this regard, we
presumed that ultrasound irradiation might accelerate the rate of
current EDP reaction.
[
a]
b]
Department of Chemistry, Sungkyunkwan University, 2066, Suwon,
Korea.
E-mail: s1673@skku.edu, Homepage: http://cesong.skku.edu
School of Chemistry and Chemical Engineering, Shanghai Jiao
Tong University, Shanghai 200240, P. R. China.
E-mail: yjian@sjtu.edu.
[
[†]
Present address: Institute of Chemical Technology, Department of
Herein, we report the ultrasound promoted highly
enatioselective decarboxylative protonation of α-aminomalonate
hemiesters (1) using chiral squaramide Brønsted bases. This
methodology provides a facile and practical protocol, allowing
rapid access to both optically active enantiomers of α-amino
esters (2), with simple catalyst recovery.
Dyestuff Technology, Mumbai, Maharashtra, India
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
§
[
]
45470 Mülheim an der Ruhr, Germany.
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European Journal of Organic Chemistry
10.1002/ejoc.201700786
FULL PAPER
Results and Discussion
[a]
Table 1. Optimization of the EDP reaction of α-aminomalonate hemiester 1a
We commenced our study by carrying out the EDP reaction of
racemic cyclic α-aminomalonate hemiester 1a in the presence of
several different chiral Brønsted bases (1 equiv) as a model
reaction to afford chiral α-amino ester 2a in toluene (Entries 1–6).
As
base
promotors,
quinine-
and
quinidine-derived
[
10]
[11]
[7,8]
sulfonamides,
thioureas,
and squaramides
were
examined (Figure 1). As listed in Table 1, the EDP reactions
were dramatically accelerated under ultrasound irradiation
conditions without any erosion of enantioselectivity, and all the
reactions with different chiral Brønsted bases afforded good to
moderate isolated yields in 24 h (Entries 1–4). In particular,
chiral squaramides promoted the EDP reaction more efficiently
than the corresponding chiral thioureas or sulfonamides, in
terms of chemical yields and enantioselectivities (Entries 1 and 2
vs. Entries 3 and 4). The best results were obtained, when the
reaction was performed using HQN-SQA bearing an ethyl group
[
b]
c]
Entry
Chiral base
QN-SA
Solvent
Yield (%)
ee (%)[
1
2
3
4
PhMe
PhMe
PhMe
PhMe
40
47
57
92
84 (R)
89 (R)
93 (R)
95 (R)
QN-TU
QN-SQA
HQN-SQA
[
d]
e]
5
6
7
8
9
1
1
HQN-SQA
HQN-SQA
HQD-SQA
HQN-SQA
HQN-SQA
HQN-SQA
HQN-SQA
HQN-SQA
HQN-SQA
HQN-SQA
PhMe
55
17
92
90
65
71
75
87
82
85
92 (R)
97 (R)
94 (S)
94 (R)
90 (R)
91 (R)
88 (R)
92 (R)
90 (R)
91 (R)
[
PhMe
PhMe
[
12]
at the C-3 carbon.
The reaction was completed within 24 h,
DCE
affording chiral pipecolate 2a in 92% yield and 95% ee (Entry 4).
Notably, the opposite configuration of the product 2a was also
obtained using C-3 hydrogenated quinidine squaramide HQD-
SQA with the same efficacy (Entry 6). However, without
ultrasound irradiation, the same reaction proceeded much
slower (Entry 4 vs Entry 5). Moreover, under the catalytic
condition (20 mol% of HQN-SQA), the reaction proceeded very
slowly and ended up at 17% yield (97% ee after 48 h) (Entry
acetone
MeCN
THF
0
1
12
MTBE
1
3
4
benzene
cyclohexane
1
[
13,14]
6).
Next, the solvent effect on the EDP reaction was
[a] Unless otherwise indicated, the reaction was performed with the substrate
a (0.10 mmol) and chiral Brønsted base (0.10 mmol) in solvent (1.0 mL)
1
investigated. The reaction proceeded well in diverse solvents
with different polarities, affording high enantioselectivities (88–
under ultrasound irradiation (100 W, 40 kHz) at 25 °C. [b] The yield was
determined after the chromatographic purification. [c] The ee of the product
was determined by HPLC on a chiral stationary phase. [d] The reaction was
performed without ultrasound irradiation. [e] The reaction was performed with
the substrate 1b (0.10 mmol) and HQN-SQA (0.02 mmol) in PhMe (1.0 mL)
under ultrasound irradiation at 25 °C for 48 h
95% ee, Entries 8–14), although the reactivity slightly decreased
in the polar solvents such as acetone (65%, Entry 9), acetonitrile
(
71%, Entry 10), and THF (75%, Entry 11).
OMe
OMe
N
N
As shown in Scheme 2, elevation of temperature without
ultrasound irradiation also efficiently accelerated the reaction
rate. However, enantioselectivity significantly decreased (77%
ee at 50 °C). Notably, very slow reaction rate at ambient
temperature without ultrasound irradiation can be attributed by
the extraordinary robustness of the ionic complex 3 between
N
O
O
H
N
S
N
H
N
H
N
S
CF3
F3C
F3C
CF3
QN-SA
QN-TU
(a)
(b)
R
OMe
N
N
COPh
3
HQN-SQA
(1.0 equiv)
N
CO2Et
O
OMe
N
OMe
N
2
CO2H
CO2Et
H
H
H
N
O
H
1
N
N
N
CO2Et
N
PhMe
temp.
CF3
R
Me
O
Me
O
O
N
H
H
N
rac-1a
(R)-2a: using HQN-SQA
N
O
2
5 °C: 24 h, 55%, 92% ee
50 °C: 12 h, 90%, 77% ee
F C
H
3
CF3
H
CF3
3
[
HQN-SQA · 1b complex]
N
O
O
N
+
observed [M+Na] : m/z 974.3537
+
calcd. [M+Na] : m/z 974.3534
O
O
F C
CF3
3
Scheme 2. (a) EDP reaction of rac-1a without ultrasound irradiation. (b)
Detection of the complex 3 by ESI-HRMS.
QN-SQA (R = -CH=CH2)
HQN-SQA (R = -CH CH )
QD-SQA (R = -CH=CH2)
HQD-SQA (R = -CH CH )
2
3
2
3
Figure 1. Chiral Brønsted bases screened in this study
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European Journal of Organic Chemistry
10.1002/ejoc.201700786
FULL PAPER
HQN-SQA and 1b. The ionic intermediate 3 was detected even Conclusions
by the thin-layer chromatography analysis and electrospray
ionization high-resolution mass spectroscopy (ESI-HRMS) (at
m/z 974.3537) (see Supporting Information).
In summary, we developed ultrasound promoted EDP reaction
of racemic α-aminomalonate hemiesters using cinchona-based
chiral squaramide Brønsted bases, providing α-amino esters in
almost quantitative yields with up to 98% ee. Remarkably, this
process readily afforded both the (S) and (R) enantiomers of α-
amino esters with high ee. Furthermore, the chiral squaramide
Brønsted bases were easily recovered by a simple precipitation
method, allowing their repeated recycling, albeit with somewhat
decreased enantioselectivity. The detailed mechanism of the
EDP reaction, the basis of enantioselectivity, and further
Under the optimized reaction conditions, diverse α-
aminomalonate hemiesters 1 were subjected to this protocol in
the presence of HQN-SQA or HQD-SQA under the ultrasound
irradiation condition. As shown in Scheme 3, a variety of N-acyl,
N-substituted benzoyl, or N-Cbz protected starting material 1b–
1
f smoothly converted to the corresponding chiral pipecolates
b–2f with excellent enantiomeric excess (88–98% ee), in PhMe
2
or 1,2-dichloroethane (DCE). Even in the cases of acyclic
substrates 1g and 1h, still good to high ee was obtained (82–88% catalytic protocol are currently under investigation and will be
ee).
reported in due course.
R1
R1
R1
chiral base (1.0 equiv)
CO2H
CO2Et
R2
R2
H
R2
H
Experimental
N
N
CO2Et
N
CO2Et
PhMe or DCE
PG
rac-1
PG
(R)-2
using HQN-SQA
PG
(S)-2
using HQD-SQA
25 °C, 24 h
))))
General procedure for enantioselective decarboxylative protonation
of hemimalonic esters using a chiral base
H
H
H
2
H
2
N
CO Et
N
CO Et
N
CO Et
N
CO Et
2
2
A solution of racemic hemimalonic ester 1 (0.1 mmol) and chiral base
2
-OMe(C6H4)
O
4-OMe(C6H4)
(S)-2d
O
4-F(C6H4)
O
Ph
O
(0.1 mmol) in 1 mL of toluene or dichloroethane was sonicated for 24 h at
(
R)-2b
(S)-2c
(S)-2e
PhMe: 91%, 92% ee
DCE: 89%, 95% ee
25 °C. After the completion of the reaction, the solvent was removed
PhMe: 91%, 98% ee
DCE: 92%, 96% ee
PhMe: 91%, 98% ee
DCE: 92%, 96% ee
PhMe: 88%, 88% ee
DCE: 90%, 90% ee
under reduced pressure. The reaction mixture was acidified (HCl 1 N)
and extracted with CH Cl . The combined organic extract was dried with
Me
Me
2
2
Bn
H
H
2
H
2
anhydrous MgSO4 and concentrated to give the crude product 2, which
was purified by flash chromatography (silica gel, CH Cl /AcOEt: 1/1).
N
CO Et
HN
CO Et
HN
CO Et
2
2
2
BnO
O
Me
O
Me
O
(
S)-2f
(R)-2g
PhMe: 82%, 82% ee
DCE: 85%, 85% ee
(R)-2h
PhMe: 79%, 84% ee
DCE: 83%, 87% ee
[
5a,5c,6a ]
PhMe: 92%, 93% ee
DCE: 91%, 95% ee
Products 2a–2h are known compounds in the literature,
and their
spectroscopic data were consistent with literature values (see,
Supporting Information). The absolute configuration of 2 was determined
Scheme 3. EDP reaction of various substrates (1b–1h) with HQN-SQA or
HQD-SQA. Conditions: substrate 1 (0.10 mmol) and chiral Brønsted base
[5c,6a]
by comparison of the retention time of HPLC with the literature data.
(0.10 mmol) in solvent (1.0 mL) under ultrasound irradiation at 25 °C. The yield
was determined after the chromatographic purification, and the ee of product 2
was determined by HPLC on a chiral stationary phase.
Acknowledgements ((optional))
This study was supported by the Ministry of Science, ICT, and
Finally, the recyclability of the cinchona base was also examined.
Because of their poor solubility in organic solvents, the chiral
squaramide bases were readily recovered as a pale yellow solid
by simple precipitation. Upon the completion of the reaction, the
concentration of the reaction mixture followed by the addition of
methylcyclohexane induced the nearly complete precipitation of
HQN-SQA, allowing their easy recovery. The recovered chiral
base could be reused for the next runs, albeit with somewhat
decreased enantioselectivity (Scheme 4) (for the experimental
details, see the ESI).
Future
Planning
in
Korea
(Grant
No:
NRF-
2014R1A2A1A01005794 and NRF-2016R1A4A1011451).
Keywords: Ultrasound irradiation • Brønsted base catalysis •
enantioselective decarboxylative protonation • α-amino acids •
chiral cinchona-based squaramides
[1]
For selected recent reviews, see (a) Amino Acids, Peptides and
Proteins in Organic Chemistry, (Ed.: A. B. Hughes), Wiley-VCH,
Weinheim, 2009; (b) C. Nájera, J. M. Sansano, Chem. Rev. 2007, 107,
4584; (c) L. Aurelio, R. T. C. Brownlee, A. B. Hughes, Chem. Rev. 2004,
1
04, 5823; (d) K. Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013; (e) H.
CO2H
2
HQN-SQA (1.0 equiv)
H
Gröger, Chem. Rev. 2003, 103, 2795; (f) J. S. Ma, Chim. Oggi. 2003,
1, 65.
N
CO Et
N
CO Et
2
PhMe
25 °C, 24 h
))))
2
Ph
O
Ph
O
rac-1b
(R)-2b
[2]
[3]
(a) W. Marckwald, Ber. Dtsch. Chem. Ges. 1904, 37, 349; (b) W.
Marckwald, Ber. Dtsch. Chem. Ges. 1904, 37, 1368.
Before reaction
substrate, chiral base dissolved
1st 91%yield, 96% ee
2nd 91%yield, 92% ee
Chiral base recovery by
simple precipitation method
For reviews on EDP reactions, see (a) Rouden, J. in Cinchona
Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and
Organocatalysis, (Ed.: C. E. Song), Wiley-VCH, Weinheim, 2009, pp.
171; (b) For a recent review of enantioselective protonation, see: J. T.
Mohr, A. Y. Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359.
Scheme 4. Chiral base recycling experiments
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European Journal of Organic Chemistry
10.1002/ejoc.201700786
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[4]
(a) R. G. Asperger, C. F. Liu, Inorg. Chem. 1967, 6, 796; (b) R. C. Job,
T. Bruice, J. Am. Chem. Soc. 1974, 96, 809; (c) M. Ajioka, S. Yano, K.
Matsuda, S. Yoshikawa, J. Am. Chem. Soc. 1981, 103, 2459; (d) M.
Yashiro, S. Miura, T. Matsuyama, S. Yoshikawa, M. Komiyama, S.
Yano, Inorg. Chem. 1994, 33, 1003.
[5]
(a) H. Brunner, M. A. Baur, Eur. J. Org. Chem. 2003, 2854; (b) L. M.-A.
Rogers, J. Rouden, L. Lecomte, M.-C. Lasne, Tetrahedron Lett. 2003,
44, 3047; (c) T. Seitz, J. Baudoux, H. Bekolo, D. Cahard, J.-C.
Plaquevent, M.-C. Lasne, J. Rouden, Tetrahedron 2006, 62, 6155; (d)
H. Park, R. Nandhakumer, S. Lee, Y. Ahn, K. M. Kim, Bull. Korean
Chem. Soc. 2010, 31, 2449.
[
6]
7]
(a) M. Amere, M.-C. Lasne, J. Rouden, Org. Lett. 2007, 9, 2621; (b) M.
Pigeaux, R. Laporte, D. C. Harrowven, J. Baudoux, J. Rouden,
Tetrahedron Lett. 2016, 57, 4599.
[
(a) J. P. Malerich, K. Hagihara, V. H. Rawal. J. Am. Chem. Soc. 2008,
130, 14416. For selected recent reviews, see: (b) J. Alemán, A. Parra,
H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890; (c) X. Han,
H.-B. Zhou, C. Dong, Chem. Rec. 2016, 16, 897.
[8]
(a) J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang, C. E. Song,
Chem. Commun. 2009, 7224; (b) H. Y. Bae, S. Some, J. S. Oh, Y. S.
Lee, C. E. Song, Chem. Commun. 2011, 47, 9621; (c) H. Y. Bae, C. E.
Song, ACS Catal. 2015, 5, 3613; (d) H. Y. Bae, S. Some, J. H. Lee, J.
Y. Kim, M. J. Song, S. Lee, Y. J. Zhang, C. E. Song, Adv. Synth. Catal.
2011, 353, 3196; (e) H. Y. Bae, M. J. Kim, J. H. Sim, C. E. Song,
Angew. Chem. Int. Ed. 2016, 55, 10825; (f) J. H. Sim, C. E. Song,
Angew. Chem. Int. Ed. 2017, 56, 1835.
[9]
For recent reviews, see (a) G. Cravotto, P. Cintas, Chem. Soc. Rev.
2
006, 35, 180; (b) A. Bruckmann, A. Krebs, C. Bolm, Green Chem.
008, 10, 1131.
2
[
10] (a) S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin, C. E.
Song, Angew. Chem. Int. Ed. 2008, 47, 7872; (b) H. Y. Bae, J. H. Sim,
J.-W. Lee, B. List, C. E. Song, Angew. Chem. Int. Ed. 2013, 52, 12143;
(
c) For a review, see: C. E. Song, H. Y. Bae, Bull. Korean Chem. Soc.
014, 35, 1590.
11] (a) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett
2
[
2005, 603; (b) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett.
2005, 7, 1967; (c) For a review, see: S. J. Connon, Chem. Commun.
2008, 2499.
[
12] One of the possible reasons for the superior reactivities of chiral bases
in reduced form (e.g., HQN-SQA) compared with the non-hydrogenated
bases (e.g., QN-SQA) might be their higher solubility in the early stage
of the reaction progress. However, the exact reason for this result is
unclear yet.
[
13] Although low efficiency of chiral base HQN-SQA was observed under
catalytic conditions, this chiral base could be considered to act as a
catalyst. Indeed, almost no reaction occurred without HQN-SQA and
this chiral base was recovered unchanged after reaction by a simple
precipitation method, allowing its repeated recycling.
[14]
Regardless of the conversion, almost same ee values of the products
were observed, indicating that kinetic resolution does not occur. Similar
observation was already reported by Brunner at. al (see, ref. [5a]). All
these results suggest that the reaction proceeds via
decarboxylation /enantioselective protonation mechanism.
a two step
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European Journal of Organic Chemistry
10.1002/ejoc.201700786
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Ultrasound irradiation • Brønsted
base catalysis • enantioselective
decarboxylative protonation • α-
amino acids • chiral cinchona-based
squaramides
[
a]
[a]
Surajit Some, Han Yong Bae, Mun
[
a]
[b]
Jong Kim, Yong Jian Zhang,* and
Ultrasound promoted enantioselelctive decarboxylative protonation reaction of α-
[
a]
Choong Eui Song*
aminomalonate hemiesters
1 in the presence of chiral cinchona-derived
squaramide Brønsted bases under mild conditions afforded both the (S) and (R)
enantiomers of α-amino acid derivatives 2 in excellent yields (>90%) and excellent
enantioselectivities (up to 98% ee).
Page No. – Page No.
Ultrasound Promoted Enatioselective
Decarboxylative Protonation of α-
Aminomalonate Hemiesters by Chiral
Squaramides: A Practical Approach
to Both Enantiomers of α-Amino
Esters
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