Catalytic Asymmetric Carbene Transfer Reactions of Diazo Oxime Ethers with Olefins and Their Synthetic Applications

Article abstract of DOI:10.1021/acs.orglett.9b02771

The first catalytic asymmetric cyclopropanation of diazo oxime ethers with olefins was developed. In the presence of a Ru(II)-Pheox catalyst, various optically active cyclopropyl oxime derivatives were obtained in high yields (up to 99%) with high enantioselectivities (up to 98% ee). Furthermore, optically active cyclopropyl oxime ethers could be successfully converted into the corresponding cyclopropyl methylamine derivatives via metal hydride and Grignard reagent mediated Beckmann rearrangement, which are potential candidates for the assessment of biological and pharmaceutical activities.

Full text of DOI:10.1021/acs.orglett.9b02771

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Asymmetric Carbene Transfer Reactions of Diazo Oxime
Ethers with Olefins and Their Synthetic Applications
Linh Da Ho, Nansalmaa Otog, Ikuhide Fujisawa, and Seiji Iwasa*
Department of Applied Chemistry and Life Science, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8580, Japan
S
* Supporting Information
ABSTRACT: The first catalytic asymmetric cyclopropanation of diazo oxime ethers with olefins was developed. In the
presence of a Ru(II)-Pheox catalyst, various optically active cyclopropyl oxime derivatives were obtained in high yields (up to
99%) with high enantioselectivities (up to 98% ee). Furthermore, optically active cyclopropyl oxime ethers could be successfully
converted into the corresponding cyclopropyl methylamine derivatives via metal hydride and Grignard reagent mediated
Beckmann rearrangement, which are potential candidates for the assessment of biological and pharmaceutical activities.
Scheme 1. Synthetic Applications of α-Diazo Oxime Ethers
rganic compounds containing an oxime ether group are
widespread in antifungal,1 antibacterial,2 and anticancer3
O
agents as well as other medicinal compounds.4 Oxime ethers
also play an important and versatile role in organic synthesis.
In particular, synthetic transformations of oxime ethers into
various nitrogen- and oxygen-containing compounds, including
amines, 1,2-amino alcohols, nitriles, α- and β-amino acids, and
lactams via Beckmann rearrangement have been reported,5
leading to the rapid and continuous development of oxime
group chemistry in the past decades.
On the other hand, the first carbene transfer reaction for the
synthesis of cyclopropanes was reported by Buchner in 1903.6
Since then, organic synthesis involving diazo compounds has
attracted the attention of organic chemists. Decomposition of
diazo compounds by a transition-metal catalyst has been
widely used as an effective tool to develop a novel synthetic
pathway via a carbene intermediate.7 α-Diazo carbonyl
compounds have known extensive development because of
their stability and ease of preparation.8 However, there are
limited reports on the application of α-diazo oxime ethers
because of the harsh reaction conditions required for their
preparation and the rapid isomerization of α-diazo imines to
triazoles.9 By overcoming the aforementioned drawbacks,
various α-diazo oxime ethers have recently been prepared in
good to excellent yields.10 α-Diazo oxime ethers have been
widely applied in heterocycle synthesis. For instance, the
cycloaddition of α-diazo oxime ethers with enamines, enol
ethers, and nitriles in the presence of [Au]10a or [Cu]10e,g
catalysts gave the corresponding pyrroles and oxazoles in high
yields (Scheme 1a). On the other hand, N−O moieties in
heterocycles such as isoxazoles could be obtained by the C−H
activation of the α-hydrogen adjacent to the oxygen in α-diazo
oxime ethers10f,h (Scheme 1b). Furthermore, another hetero-
cyclic synthesis based on 2H-azirine derivatives from α-diazo
oxime ethers has been reported.10b,d
Received: August 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Despite the widespread research into the synthesis of
heterocycles from diazo oxime ethers, cyclopropanation via a
carbene transfer reaction has not been reported until now.11
Since the oxime group can be transformed into various useful
organic molecules via Beckmann rearrangement and other
reactions, we examined diazo oxime ethers as carbene
precursors having an oxime functional group for catalytic
asymmetric cyclopropanation. Based on the results of our
previous studies on the cyclopropanation of various diazo
resources12 (Scheme 1c), the Ru(II)-Pheox catalyst was
examined for the metal-catalyzed decomposition of diazo
compounds while controlling the enantioselectivity of the
cyclopropyl oxime ether derivatives.
Pheox catalyst (Cat. 3) was found to be the best choice for the
reaction. In our study, the desired cyclopropyl oxime products
were only (E)-isomers.
Next, the reaction conditions were optimized in various
solvents and temperatures using Ru(II)-Pheox (Cat. 3) as the
catalyst. The results are summarized in Table S1 (see
Supporting Information Table S1). No improvement was
observed using Et2O, THF, toluene, acetone, and acetonitrile
as the solvent (Table S1, entries 2−6). When the reaction
temperature was decreased, the enantioselectivity increased
slightly to 95% ee, whereas the stereoselectivity and yield
remained unchanged (Table S1, entries 1, 7, and 8). The effect
of the catalyst amount was also investigated, as shown in Table
2. When decreasing catalyst loading to 0.1 mol %, the catalytic
We first evaluated well-known carbene transfer catalysts and
a series of Ru(II)-Pheox complexes in the asymmetric catalytic
cyclopropanation of α-diazo oxime ether 2a with p-
methoxystyrene 1a. The results are summarized in Table 1.
Table 2. Catalyst Loading
Table 1. Initial Catalyst Screening
yield
a
trans/
b
c
d
e
entry x [mol %]
[%]
cis
ee [%] TON TOF [h−1
]
1
2
3
4
3
1
0.1
0.01
99
96
91
55
80/20
80/20
80/20
73/27
94/86
94/86
94/86
57/16
33
96
910
17
48
455
f
5500
115
a
b
c
Isolated yield. Determined by crude 1H NMR. Determined by
d
chiral HPLC. TON (turnover number) = Product [mol]/cat. [mol].
e
f
TOF (turnover frequency) = TON/time [h]. Reaction did not
proceed to completion even after 48 h of stirring.
asymmetric cyclopropanation proceeded smoothly to give the
optically active cyclopropyl oxime 3a in good yield (91%) with
the same level of enantioselectivity and diastereoselectivity
(Table 2, entry 3). However, the catalyst activity was
drastically reduced when the catalyst amount was less than
0.1 mol %, and lower enantioselectivity and stereoselectivity
were observed (Table 2, entry 4). The high TON (up to 5500)
and TOF (up to 455) values were also remarked.
b
c
d
entry
1
2
3
4
5
6
7
cat.
3a [%]
trans/cis
ee [%]
41/7
Cat. 1
Cat. 2
Cat. 3
Cat. 4
Cat. 5
Cat. 6
Cat. 7
65
24
99
92
90
92
89
43:57
76:24
80:20
76:24
79:21
78:22
80:20
e
4/-20
94/86
93/72
82/69
93/95
93/88
With the optimized reaction conditions in hand, we next
examined the substrate scope of the cyclopropanation of diazo
oxime ether 2a with various olefins 1a−l. The results are
summarized in Scheme 2. Various para-substituted styrene
derivatives were compared for the electronic effect in the
cyclopropanation reactions (Scheme 2, 3a−f). Electron-
donating groups and electron-withdrawing groups affected
the reactivity of the styrene derivatives with 2a. When a more
electron-rich substituent was installed at the para-position,
better yield of the product was obtained (Scheme 2, 3a−f).
This phenomenon could be explained by the general
mechanism of the cyclopropanation catalyzed by a transition-
metal system. Electron-rich olefins reacted more smoothly with
the metal−carbene complex intermediate having an oxime
ether functional group as an electron-withdrawing group. In
contrast, higher enantioselectivity was achieved for both
styrenes containing electron-withdrawing groups, such as
para-Cl and para-NO2 substituents (96% ee and 95% ee,
respectively). The highest enantioselectivity was observed in
compound 3e: 96% ee for the trans product and 99% for the cis
product. On the other hand, both electron-withdrawing and
electron-donating substituents at the ortho-position of styrene
resulted in slightly lower dr and ee (Scheme 2, 3g−h). The
a
Reaction conditions: A solution of diazo oxime ether 2a (0.2 mmol,
1 equiv) in CH2Cl2 (2.0 mL) was added slowly over 2 h to a solution
of the corresponding catalyst (3 mol %) and 1a (1.0 mmol, 5 equiv)
in CH2Cl2 (2.0 mL) at room temperature, under argon atmosphere.
b
c
d
Isolated yield. Determined by crude 1H NMR. Determined by
e
chiral HPLC. Reaction did not proceed to completion even in 48 h.
The reaction of 1a with diazo oxime 2a in the presence of the
Box-Cu or Pybox-Ru complex gave cyclopropyl oxime product
3a in low yield and with low enantioselectivity (Table 1,
entries 1 and 2). In contrast, 2a reacted smoothly with 1a in
the presence of Ru(II)-Pheox catalyst Cat. 3, without
dimerization, to give 3a in quantitive yield (99%) with high
ee (up to 94% ee) (Table 1, entry 3). A series of Ru(II)-Pheox
complexes (Cat. 4−7) were also evaluated for their catalytic
efficiency. Catalysts (Cat. 4 and 5) with electron-donating or
electron-withdrawing substituents as well as those with steric
effects caused by the substituent on the oxazoline ring (Cat. 6
and 7) gave almost the same results in terms of the yield and
stereoselectivity for the carbene transfer reactions (Table 1,
entries 4−7). Among of Ru(II)-Pheox complexes, Ru(II)-
B
DOI: 10.1021/acs.orglett.9b02771
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Organic Letters
Letter
Scheme 2. Asymmetric Cyclopropanation of Various Olefins
Scheme 3. Ru(II)-Pheox-Catalyzed Asymmetric
Cyclopropanation of Various α-Diazo Oxime Ethers
a
b
c
Isolated yield. Determined by crude 1H NMR. Determined by
chiral HPLC.
Moreover, the reaction between 1-naphthyl diazo oxime 2p
and 1b gave cyclopropyl oxime 3p in high yield with excellent
enantioselectivity (98% ee) and dr (Scheme 3, 3p).
The structure and absolute configuration of cyclopropyl
oximes (major trans product) were determined in an efficient
manner by comparison of cyclopropyl oximes with the
synthetic transformation of a cyclopropyl ketone into a
cyclopropyl oxime product. As shown in Scheme 4, diphenyl
a
b
c
Three mol % Ru(II)-Pheox was used. Isolated yield. Determined
d
e
1
by crude H NMR. Determined by chiral HPLC. 0.22 g of 3b was
synthesized in 1 mmol scale in 86% yield, 81:19 trans/cis, and 92%/
76% ee.
Scheme 4. Determination of the Structure and Absolute
Configuration of the Cyclopropyl Oxime Product
same result was observed in the case of styrene with a
substituent at the meta-position, and the dr value could be well
maintained; however, the enantioselectivity was 90% ee for
product 3i and 94% ee for 3c. When 3 mol % of Cat. 3 was
used, excellent yields of 3a and 3b were observed, with high
stereoselectivity and enantioselectivity. α-Methylstyrene gave
3j in high yield with high ee for both trans and cis isomers
(92% ee for trans and 93% for cis). Unfortunately, tetra-
substituted and inner olefins gave only the dimer of the diazo
oxime ether. We then turned our attention to other olefins
such as n-butyl vinyl ether and vinyl acetate. The reaction
between 2a and n-butyl vinyl ether furnished compound 3k in
83% yield, with moderate enantioselectivity for the trans
isomer (74% ee) but low ee for the cis isomer (57% ee). The
electron-deficient olefin 1l resulted in a slow reaction and gave
a low yield of 3l with moderate dr and ee. The 1 mmol scale
reaction gave 3b (0.22 g) in 86% yield and 92% ee (Scheme
2).
To expand the generality of cyclopropanation using α-diazo
oxime ethers, a series of α-diazo oxime ethers were employed
with styrene 1b in the presence of Ru(II)-Pheox catalyst (Cat.
3). The results are listed in Scheme 3. The electronic effect on
the benzene ring of the α-diazo oxime ether gave the same
result of products 3b and 3m−n in yield, dr, and ee. However,
steric hindrance strongly affected the stereoselectivity and
enantioselectivity. When 2-naphthyl diazo oxime 2o was used
as the carbene source in the cyclopropanation with styrene,
compound 3o was obtained in high yield (84%), with high
enantioselectivity (93% ee) and very high dr ratio (95:5 d.r.).
cyclopropane ketone 513 having only the trans isomer was
successfully transformed into a mixture of anti and syn isomers
3b′ bearing an oxime functional group. Besides, trans and cis
cyclopropyl oxime products 3b were produced by the reaction
of α-diazo oxime ether 2a with styrene 1b, as mentioned
before. The absence of the NMR peak attributed to the syn
isomer in the 3b mixture as well as the absence of the peak due
to the cis product in the 3b′ mixture helped identify the
structure of the trans and cis cyclopropyl oximes in 3b (see
Supporting Information). Furthermore, the consistency
between the measured [α]D (Scheme 4) and the reported
value14 was used for determining the absolute configuration of
the (R,R)-3b product. Moreover, the minor product cis-3f was
successfully isolated by crystallization, and its absolute
configuration was confirmed by single-crystal X-ray diffraction
analysis.15
Further synthetic applications of cyclopropyl oxime ethers
via metal hydride and Grignard reagent mediated Beckmann
C
DOI: 10.1021/acs.orglett.9b02771
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Organic Letters
Letter
rearrangement were explored, as described in Scheme 5. To
demonstrate the utility of our direct enantioselective cyclo-
excellent yields (up to 99%) with high diastereoselectivities
(up to 95:5) and enantioselectivities (up to 98% ee). In
addition, the catalytic efficiency of Ru(II)-Pheox resulted in a
high TON (5500) and TOF (455). We also successfully
developed a synthetic pathway for optically active cyclopropyl
methyl amine derivatives as useful bioactive intermediates
starting from the cyclopropyl oxime ethers.
Scheme 5. Synthetic Transformation of Cyclopropyl Oxime
Ethers
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02771.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1944711 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: iwasa@ens.tut.ac.jp.
ORCID
Linh Da Ho: 0000-0003-1730-0600
Seiji Iwasa: 0000-0002-5012-1420
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.I. thanks Ikeda Bussan Co. Ltd. for the financial support and
thanks Associate Professor Keiichi Noguchi (Tokyo University
of Agriculture and Technology) for his help concerning the X-
ray equipment.
a
b
c
Isolated yield. Determined by crude 1H NMR. Determined by
d
chiral HPLC. Reaction was carried out at RT.
REFERENCES
■
(1) (a) Babazadeh-Qazijahani, M.; Badali, H.; Irannejad, H.;
Afsarian, M. H.; Emami, S. Eur. J. Med. Chem. 2014, 76, 264−273.
(b) Parthiban, P.; Kabilan, S.; Ramkumar, V.; Jeong, Y. T. Bioorg.
Med. Chem. Lett. 2010, 20, 6452−6458. (c) Emami, S.; Falahati, M.;
Banifatemi, A.; Shafiee, A. Bioorg. Med. Chem. 2004, 12, 5881−5889.
(2) (a) Liang, J. H.; Dong, L. J.; Wang, H.; An, K.; Li, X. L.; Yang,
L.; Yao, G. W.; Xu, Y. C. Eur. J. Med. Chem. 2010, 45, 3627−3635.
(b) Parthiban, P.; Rathika, P.; Ramkumar, V.; Son, S. M.; Jeong, Y. T.
Bioorg. Med. Chem. Lett. 2010, 20, 1642−1647. (c) Bhandari, K.;
Srinivas, N.; Keshava, G. S.; Shukla, P. K. Eur. J. Med. Chem. 2009, 44,
437−447.
propyl oxime ethers in synthetic transformations, we herein
report the first DIBALH-mediated and Grignard reagent
mediated Beckmann rearrangement16,17 of 3 to obtain
cyclopropyl methylamine derivatives 6a−6o and 6o′, which
are candidates for Serotonin 2C receptor agonists.18
All of these cases proceeded in high yield with retained
enantioselectivity. The reaction of DIBALH and 3o was
initially carried out at room temperature. A high yield was
observed, whereas the enantioselectivity was slightly decreased
(Scheme 5). To maintain the chiral environment in 6, a low
temperature is essential. At lower temperatures (−10 °C), the
cyclopropyl oxime ethers were completely transformed into
cyclopropyl methylamines in high yields (>80% yield) with the
same ee and dr ratio. An excellent result was obtained in the
reductive Beckmann rearrangement of 3m, with 95% yield
(Scheme 5).
(3) Chakravarti, B.; Akhtar, T.; Rai, B.; Yadav, M.; Akhtar-Siddiqui,
J.; Dhar-Dwivedi, S. K.; Thakur, R.; Singh, A. K.; Singh, A. K.; Kumar,
H.; et al. J. Med. Chem. 2014, 57, 8010−8025.
(4) (a) Gannarapu, M. R.; Vasamsetti, S. B.; Punna, N.; Royya, N.
K.; Pamulaparthy, S. R.; Nanubolu, J. B.; Kotamraju, S.; Banda, N.
Eur. J. Med. Chem. 2014, 75, 143−150. (b) Emami, S.; Kebriaeezadeh,
A.; Ahangar, N.; Khorasani, R. Bioorg. Med. Chem. Lett. 2011, 21,
655−659. (c) Park, H. J.; Lee, K.; Park, S. J.; Ahn, B.; Lee, J. C.; Cho,
H.; Lee, K. I. Bioorg. Med. Chem. Lett. 2005, 15, 3307−3312.
(d) Chern, J. H.; Lee, C. C.; Chang, C. S.; Lee, Y. C.; Tai, C. L.; Lin,
Y. T.; Shia, K. S.; Lee, C. Y.; Shih, S. R. Bioorg. Med. Chem. Lett. 2004,
14, 5051−5056. (e) Delmas, F.; Gasquet, M.; Timon-David, P.;
In conclusion, we have developed the first catalytic
asymmetric cyclopropanation of α-diazo oxime ethers with
olefins in the presence of a Ru(II)-Pheox catalyst to obtain a
variety of optically active cyclopropyl oxime derivatives in
D
DOI: 10.1021/acs.orglett.9b02771
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Letter
Madadi, N.; Vanelle, P.; Vaille, A.; Maldonado, J. Eur. J. Med. Chem.
1993, 28, 23−27.
(5) (a) Mirjafary, Z.; Abdoli, M.; Saeidian, H.; Boroon, S.;
Kakanejadifard, A. RSC Adv. 2015, 5, 79361−79383. (b) Moody,
C. J. Chem. Commun. 2004, 1341−1351.
(6) Buchner, E.; Feldmann, L. Ber. Dtsch. Chem. Ges. 1903, 36,
3509−3517.
(7) (a) Kang, Z.; Wang, Y.; Zhang, D.; Wu, R.; Xu, X.; Hu, W. J. Am.
Chem. Soc. 2019, 141, 1473−1478. (b) Lin, X.; Tang, Y.; Yang, W.;
Tan, F.; Lin, L.; Liu, X.; Feng, X. J. Am. Chem. Soc. 2018, 140, 3299−
3305. (c) Haubenreisser, S.; Woste, T. H.; Martinez, C.; Ishihara, K.;
Muniz, K. Angew. Chem., Int. Ed. 2016, 55, 1−6. (d) Guzman, P. E.;
Lian, Y.; Davies, H. M. L. Angew. Chem., Int. Ed. 2014, 53, 13083−
13087. (e) Xu, X.; Zavalij, P. Y.; Hu, W.; Doyle, M. P. Chem.
Commun. 2012, 48, 11522−11524. (f) Lourdusamy, E.; Yao, L.; Park,
C. M. Angew. Chem., Int. Ed. 2010, 49, 7963−7967.
(8) (a) Kidonakis, M.; Stratakis, M. Org. Lett. 2018, 20, 4086−4089.
́
(b) Wang, D.; Szabo, K. J. Org. Lett. 2017, 19, 1622−1625. (c) Liu,
L.; Zhang, J. Chem. Soc. Rev. 2016, 45, 506−516. (d) Ford, A.; Miel,
H.; Ring, A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Chem.
Rev. 2015, 115, 9981−10080.
(9) (a) Shatzmiller, S.; Bercovici, S. Liebigs Ann. Chem. 1992, 1992,
877−878. (b) Romeiro, G. A.; Pereira, L. O. R.; Souza, M. C. B. V.;
Ferreira, V. F.; Cunha, A. C. Tetrahedron Lett. 1997, 38, 5103−5106.
(10) (a) Loy, N. S. Y.; Choi, S.; Kim, S.; Park, C. M. Chem. Commun.
2016, 52, 7336−7339. (b) Loy, N. S. Y.; Kim, S.; Park, C. M. Org.
Lett. 2015, 17, 395−397. (c) Kuruba, B. K.; Shariff, N.;
Vasanthkumar, S.; Emmanuvel, L. Synth. Commun. 2015, 45, 2454−
2461. (d) Qi, X.; Xu, X.; Park, C. M. Chem. Commun. 2012, 48,
3996−3998. (e) Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.
M. Chem. Commun. 2012, 48, 3133−3135. (f) Qi, X.; Jiang, Y.; Park,
C. M. Chem. Commun. 2011, 47, 7848−7850. (g) Lourdusamy, E.;
Yao, L.; Park, C. M. Angew. Chem., Int. Ed. 2010, 49, 7963−7967.
(h) Wang, J.; Stefane, B.; Jaber, D.; Smith, J. A. I.; Vickery, C.; Diop,
M.; Sintim, H. O. Angew. Chem., Int. Ed. 2010, 49, 3964−3968.
(11) Choi, S.; Ha, S.; Park, C. M. Chem. Commun. 2017, 53, 6054−
6064.
(12) Chanthamath, S.; Iwasa, S. Acc. Chem. Res. 2016, 49, 2080−
2090.
(13) (a) Diphenyl cyclopropane ketone 5 was synthesized according
to Nicolas’s procedure13b using p-nitro-Ru(II)-diphenyl-Pheox
catalyst.13c (b) Nicolas, I.; Maux, P. L.; Simonneaux, G. Tetrahedron
Lett. 2008, 49, 2111−2113. (c) Chi, L. T. L.; Suharto, A.; Da, H. L.;
Chanthamath, S.; Shibatomi, K.; Iwasa, S. Adv. Synth. Catal. 2019,
361, 951−955.
(14) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 13410−13411.
(15) The X-ray measurement was performed with the X-ray
equipment at the institution of instrumental analysis in Tokyo
University of Agriculture and Technology.
(16) Imaizumi, T.; Okano, K.; Tokuyama, H. In Organic Syntheses;
Xu, L. T., Ma, D., Ed.; Wiley-VCH, 2016; Vol. 93, pp 1−13.
(17) Mukhopadhyay, P. P.; Miyata, O.; Naito, T. Synlett 2007, 9,
1403−1406.
(18) Zhang, G.; Cheng, J.; McCorvy, J. D.; Lorello, P. J.; Caldarone,
B. J.; Roth, B. L.; Kozikowski, A. P. J. Med. Chem. 2017, 60, 6273−
6288.
E
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