Ag(I)-Catalyzed Synthesis of Azabicyclic Alkaloid Frameworks from Ketimine-Tethered Ynones: Total Synthesis of Indolizidine 209D

Article abstract of DOI:10.1021/acs.orglett.8b00225

An efficient Ag(I)-catalyzed π-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the method is demonstrated by a formal synthesis of (±)-lasubine II and in a short total synthesis of (±)-indolizidine 209D.

Full text of DOI:10.1021/acs.orglett.8b00225

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ag(I)-Catalyzed Synthesis of Azabicyclic Alkaloid Frameworks from
Ketimine-Tethered Ynones: Total Synthesis of Indolizidine 209D
Hon Eong Ho, Michael J. James, Peter O’Brien, Richard J. K. Taylor,* and William P. Unsworth*
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
S
* Supporting Information
ABSTRACT: An efficient Ag(I)-catalyzed π-acid activation
method for the cyclization of cyclic ketimine-tethered ynones
is reported. Various nitrogen-containing scaffolds commonly
found in bioactive alkaloids can be prepared in high yields, and
the utility of the method is demonstrated by a formal synthesis
of ( )-lasubine II and in a short total synthesis of
( )-indolizidine 209D.
zabicycles are ubiquitous in bioactive alkaloids,1 with
Scheme 1. Aza-ynone Cyclization Reactions
A
exemplar compounds 1−6 representing a small fraction of
the diverse structural classes found in Nature (Figure 1).2
Figure 1. Alkaloid natural products containing fused azacycles.
Fused bicyclic indolizidines (e.g., 1 and 2) and quinolizidines
are particularly common motifs, although alkaloids based on
other ring sizes (e.g., 6,7-bicylic systems such as 3) and more
complex polycyclic systems (e.g., 4−6) are also known. The
challenge of constructing such azacycles, allied to the fact that
many exhibit broad biological activity, has propagated much
research effort to develop efficient methods for their synthesis.1
We recently reported a new method for the preparation of
6,6-fused azacycles, exemplified in a five-step total synthesis of
the quinolizidine alkaloid lasubine II (9) (Scheme 1A).3 A key
step in this dearomative synthesis4 was the cyclization of pyridyl
ynone 7 into quinolizinone 8 via π-acid activation5 of the
alkyne with catalytic Ag(I).6 Following hydrogenation7 and two
further steps to epimerize the alcohol, a short, gram-scale
synthesis of lasubine II (9) was completed in 36% overall yield.8
This method was also shown to work well with other pyridyl
ynones and represents an efficient method for the preparation
of quinolizinones while also allowing entry into the
quinolizidine framework following hydrogenation. In this
paper, we describe the application of a similar strategy to
cyclic ketimines (Scheme 1B). While the cyclization of
protected saturated amine nucleophiles onto tethered alkynes
is reasonably well-established (via aza-Michael-type reactions or
metal-catalyzed hydroamination),9 to the best of our knowl-
edge, there are no published examples of similar processes that
proceed via cyclization through the sp2-hybridized nitrogen of a
cyclic ketimine precursor.10
There are several benefits of the approach outlined in
Scheme 1B compared to our previous work on pyridyl systems:
(1) a much wider array of azabicycles should be accessible, as
we will not be limited to pyridyl starting materials; (2) the
requisite starting materials can be easily prepared by exploiting
the enamine character of ketimine precursors, without the need
Received: January 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to use protecting groups;11 (3) the use of nonaromatic starting
materials reduces the number of bonds requiring hydrogenation
to prepare saturated alkaloid analogues. The realization of this
Ag(I)-catalyzed cyclization approach is described herein,
enabling a range of alkaloid frameworks to be prepared in
high yields under operationally simple reaction conditions. The
utility of the method in natural product synthesis is also
demonstrated during a formal synthesis of ( )-lasubine II and
in a short total synthesis of ( )-indolizidine 209D.
With optimized conditions in hand, we next examined the
scope of this reaction with other pyrroline-tethered ynones
(Scheme 2). Pyrroline−ynones 11b−h were prepared from
Scheme 2. Substrate Scope for Ag(I)-Catalyzed Cyclization
of Pyrroline-Tethered Ynones
We started by examining the cyclization of pyrroline-tethered
ynone 11a, which is readily prepared from 2-methyl-1-pyrroline
10 and methyl phenylpropiolate (Table 1).12 Thus, ynone 11a
a
Table 1. Optimization of the Cyclization of 11a
b
entry
catalyst (mol %)
solvent
time (h)
12a (%)
1
Cu(MeCN)4PF6 (10)
Cu(OTf)2 (10)
Ph3PAuNTf2 (10)
AgOTf (10)
AgNTf2(10)
AgNO3 (10)
AgTFA(10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
18
18
18
18
18
18
18
21
21
11
11
1
0
0
2
3
0
4
36
5
64
6
100
100
>95
100
57
7
8
AgNO3 (5)
commercially available sources in good to excellent yield using
methods similar to that used to prepare 11a (see the
Supporting Information); as before, these substrates exist
largely in their enamine form in solution in CDCl3. First,
pyrrolines tethered to aliphatic ynone subunits were well
tolerated under the standard conditions, affording products 12b
and 12c in near-quantitative yields. The preparation of 12b was
also achieved on a 1.67 g scale with no appreciable drop in
yield. Ynone substrates bearing functionalized phenyl groups
were also well tolerated (12d and 12e) as was a thiophene-
substituted ynone (to form 12f). Additional substituents on the
ynone tether were also compatible with the standard method
(12g and 12h), with all of the examples proceeding in excellent
to quantitative yield (92−100%). These results are especially
pleasing given the abundance of the 5,6-framework in
indolizidine alkaloids.13
The scope of the reaction with respect to the cyclic ketimine
was then examined (Scheme 3). The methylated cyclic
ketimines were prepared from the corresponding lactam
precursors using a reported procedure14 and then converted
into the tethered ynones using the same method used to make
11a (see the SI).15 First, two dihydropiperidine ketimine
derivatives of the form 13 were prepared and converted into
cyclized products 14a and 14b using 2 and 10 mol % of AgTFA
respectively; notably, compound 14a, which is a key
intermediate in our previous synthesis of lasubine II, was
obtained in particularly high yield (90%).3 Next, two partially
unsaturated isoquinoline-tethered ynones of the form 15 were
prepared, and each was converted into the corresponding 4-
pyridone adducts in high yield, following treatment with 5 mol
9
AgTFA (5)
10
11
AgTFA (5)
AgTFA (5)
100
100
100 (100)
<5
c
12
AgTFA (5)
PhMe
c
13
AgTFA (2)
PhMe
1
c
14
PhMe
1
a
Reactions were performed using 0.2 mmol of 11a, with the listed
catalyst/loading and solvent, at 0.1 M at 40 °C, unless otherwise
b
stated. Yields determined using 1H NMR spectroscopy of the
unpurified reaction mixtures using 3,5-bis(trifluoromethyl)-
bromobenzene as an internal standard. Isolated yield is shown in
parentheses. Reaction performed at 110 °C.
c
(which exists predominantly as its enamine tautomer 11a′ in
solution in CDCl3) was reacted with common Cu(I)-, Cu(II)-,
Au(I)-, and Ag(I)-based catalysts (10 mol %) in DCM at 40 °C
for 18 h (entries 1−7), with AgNO3 and AgTFA (entries 6 and
7) being particularly effective at promoting the desired
transformation into 4-pyridone 12a (structure confirmed by
X-ray crystallography). Further optimization showed that
AgTFA was slightly more effective than AgNO3, solvent
screens revealed that the rate of reaction could be increased
by performing the reaction in toluene, and the catalyst loading
could be reduced to 2 mol % by raising reaction temperature to
110 °C, which also led to a reduced reaction time of 1 h (entry
12). Control experiments showed that only trace amounts of
pyridone 12a were formed under thermal conditions without a
catalyst (entry 12).
B
DOI: 10.1021/acs.orglett.8b00225
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Organic Letters
Letter
Scheme 3. Substrate Scope for Ag(I)-Catalyzed Cyclization
of Ketimine-Tethered Ynones
Scheme 4. Proposed Mechanism
believe that this pathway is less likely in view of the expected
low nucleophilicity of the nitrogen (a vinylogous amide) in this
form.
Finally, the utility of the Ag(I)-catalyzed cyclization was
demonstrated in a short total synthesis of indolizidine 209D, an
alkaloid isolated from the skin secretions of the Dendrobates
family of neotropical frogs, that is part of a family of alkaloids
known to be effective noncompetitive inhibitors of the
neuromuscular transmission receptor and nicotinic acetylcho-
line receptors.17,18 Our synthesis began the with the acylation
of 2-methyl-1-pyrroline 10 with ester 21 to provide 11b in 70%
yield. Then, AgTFA-catalyzed cyclization afforded the desired
bicyclic product 12b in quantitative yield as described above.
This was followed by dearomative hydrogenation, using
catalytic platinum(IV) oxide and hydrogen at 8 bar, which
afforded a 1:2 mixture of hydroxylated product 22 and the fully
saturated target molecule ( )-indolizidine 209D (1). The
products were separable and isolated separately (with isolated
yields of 21% for 22 and 39% for 1), and each was formed as a
single diastereoisomer, with the spectroscopic properties of the
natural product 1 identical to those previously reported.18
Furthermore, the yield of the natural product could be
increased by subjecting partially reduced side product 22 to
standard Barton−McCombie deoxygenation conditions,18c
which furnished an additional quantity of ( )-indolizidine
209D 1 (when added to the original sample of 1, an overall
49% yield for the conversion of 12b into 1 was obtained). In
total, 0.78 g of ( )-indolizidine 209D was prepared in four
steps in 34% overall yield from ketimine 10 (Scheme 5).
In summary, we have developed an efficient and operation-
ally simple Ag(I)-catalyzed cyclization of cyclic ketimine-
% of AgTFA under the usual conditions. Simple 7-membered
cyclic ketimine precursors (of the form 17) were also well
tolerated, furnishing products 18a,b under similar conditions.
We were also keen to demonstrate that the procedure is
applicable to more complex systems with additional function-
ality that might improve the medicinal properties of the
products. Thus, starting materials 19a and 19b, which were
prepared from benzodiazepine precursors, were converted into
the products 20a and 20b, respectively, and in the case of the
latter, via a high-yielding double cyclization, from starting
material 19b. Many benzodiazepines are psychoactive and act
as minor sedatives, and they have been used for the treatment
of various neurological conditions including anxiety, insomnia,
seizures, muscle spasms, and alcohol withdrawal.16
Scheme 5. Synthesis of ( )-Indolizidine 209D
A proposed mechanism is outlined in Scheme 4. In all cases,
the starting materials exist predominantly as enamine
tautomers, which are likely stabilized by an intramolecular H-
bond and present in the conformation depicted (A).
Tautomerization (A → A′) followed by bond rotation (A′ →
A″) is proposed to generate an intermediate capable of
undergoing cyclization via nucleophilic attack of the ketimine
nitrogen lone-pair, induced by Ag(I)-mediated π-acid activation
of the alkyne (A″ → B). Subsequent deprotonation and
protodemetalation would then generate the indolizinone
product and release Ag(I) back into the catalytic cycle.
Alternatively, intermediate A″ might tautomerize back to the
analogous E-enamine prior to cyclization to give C, although we
C
DOI: 10.1021/acs.orglett.8b00225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
G.; Schenk, K.; Renaud, P. Org. Lett. 2011, 13, 4774. (d) Weinreb, S.
M. Chem. Rev. 2006, 106, 2531. (e) Pilli, R. A.; Ferreira de Olivera, M.
C. Nat. Prod. Rep. 2000, 17, 117−127. (f) Pilli, R. A.; Rosso, G. B.;
Ferreira de Olivera, M. C. Nat. Prod. Rep. 2010, 27, 1908. (g) Ronson,
T. O.; Kitsiou, C.; Unsworth, W. P.; Taylor, R. J. K. Tetrahedron 2016,
72, 6099.
tethered ynones to form partially saturated azabicycles
containing 4-pyridones. The method is compatible with a
range of cyclic ketimines, enabling the facile synthesis of several
classes of azabicyclics. The prevalence of azabicycles in
bioactive alkaloids augurs well for the use of this method in
natural product synthesis and medicinal chemistry,19 demon-
strated in this work by a four-step total synthesis of
( )-indolizidne 209D. The method is also likely to be
applicable to other more complex nitrogen-containing natural
products; applications in target synthesis are ongoing in our
laboratories, and these results will be reported in due course.
(3) James, M. J.; Grant, N. D.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Org. Lett. 2016, 18, 6256.
(4) For reviews on dearomatization reactions, see: (a) Zhuo, C.-X.;
Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662.
(b) Roche, S. P.; Youte Tendoung, J.-J.; Treguier, B. Tetrahedron 2015,
71, 3549. (c) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W.
P. Chem. - Eur. J. 2016, 22, 2856. (d) Liang, X.-W.; Zheng, C.; You, S.-
L. Chem. - Eur. J. 2016, 22, 11918. (e) Wu, W.-T.; Zhang, L.; You, S.-L.
Chem. Soc. Rev. 2016, 45, 1570.
ASSOCIATED CONTENT
■
S
* Supporting Information
(5) For the π-acid activation of alkynes, including pyridyl systems,
see: (a) Johnson, D. G.; Lynam, J. M.; Mistry, N. S.; Slattery, J. M.;
Thatcher, R. J.; Whitwood, A. C. J. Am. Chem. Soc. 2013, 135, 2222.
(b) Halliday, C. J. V.; Lynam, J. M. Dalton Trans. 2016, 45, 12611.
(6) For previous work from our laboratories on dearomatizing
spirocyclization reactions of aromatic ynones, see: (a) Unsworth, W.
P.; Cuthbertson, J. D.; Taylor, R. J. K. Org. Lett. 2013, 15, 3306.
(b) James, M. J.; Cuthbertson, J. D.; O’Brien, P.; Taylor, R. J. K.;
Unsworth, W. P. Angew. Chem., Int. Ed. 2015, 54, 7640. (c) James, M.
J.; Clubley, R. E.; Palate, K. Y.; Procter, T. J.; Wyton, A. C.; O’Brien,
P.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2015, 17, 4372.
(d) Liddon, J. T. R.; James, M. J.; Clarke, A. K.; O’Brien, P.; Taylor, R.
J. K.; Unsworth, W. P. Chem. - Eur. J. 2016, 22, 8777. (e) Clarke, A. K.;
James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Angew.
Chem., Int. Ed. 2016, 55, 13798. (f) Liddon, J. T. R.; Clarke, A. K.;
Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2016, 18, 6328. (g) Clarke,
A. K.; Liddon, J. T. R.; Cuthbertson, J. D.; Taylor, R. J. K.; Unsworth,
W. P. Org. Biomol. Chem. 2017, 15, 233.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00225.
Experimental procedures and compound characterization
data (PDF)
Accession Codes
CCDC 1532716 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
(7) For related dearomative hydrogenation approaches, see: Yu, H.;
Zhang, G.; Huang, H. Angew. Chem., Int. Ed. 2015, 54, 10912 and
references cited therein.
*E-mail: richard.taylor@york.ac.uk.
*E-mail: william.unsworth@york.ac.uk.
(8) For selected previous syntheses of lasubine II, see: (a) Yu, R. T.;
Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (b) Verkade, J. M. M.;
van der Pijl, F.; Willems, M. M. J. H. P.; Quaedflieg, P. J. L. M.; van
Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2009, 74, 3207.
(c) Chandrasekhar, S.; Murali, R. V. N. S.; Reddy, C. R. Tetrahedron
Lett. 2009, 50, 5686. (d) Saha, N.; Biswas, T.; Chattopadhyay, S. K.
Org. Lett. 2011, 13, 5128.
ORCID
Peter O’Brien: 0000-0002-9966-1962
William P. Unsworth: 0000-0002-9169-5156
Notes
The authors declare no competing financial interest.
(9) For selected examples, see: (a) Turunen, B. J.; Georg, G. I. J. Am.
Chem. Soc. 2006, 128, 8702. (b) Niphakis, M. J.; Turunen, B. J.; Georg,
G. I. J. Org. Chem. 2010, 75, 6793. (c) Pepe, A.; Pamment, M.; Georg,
G. I.; Malhotra, S. V. J. Org. Chem. 2011, 76, 3527. (d) Gouault, N.; Le
Roch, M.; Cheignon, A.; Uriac, P.; David, M. Org. Lett. 2011, 13, 4371.
(e) Stevens, K.; Tyrrell, A. J.; Skerratt, S.; Robertson, J. Org. Lett. 2011,
13, 5964.
(10) For a discussion of the nucleophilicity of cyclic ketimines, see:
(a) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013, 15,
258. (b) Unsworth, W. P.; Taylor, R. J. K. Synlett 2016, 27, 2051.
(11) This contrasts to the majority of published amine cyclization
methods (see refs 1 and 9) in which protecting groups are needed to
attenuate the nucleophilicity of the amine.
ACKNOWLEDGMENTS
■
We thank the Engineering and Physical Sciences Research
Council (EP/N035119/1, H.E.H.), the Leverhulme Trust (for
an Early Career Fellowship, ECF-2015-13, W.P.U.) and the
University of York (H.E.H., M.J.J., and W.P.U.) for financial
support. We are also grateful to Dr. A. C. Whitwood and R. R.
Bean for X-ray crystallography and to Dr. P. J. Rayner for
assistance with the hydrogenation reactions (all University of
York).
REFERENCES
■
(12) A modified protocol based on a literature method was used; see
the SI and: Podoll, J. D.; Liu, L.; Chang, L.; Walls, S.; Wang, W.;
Wang, X. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 15573.
(1) For the synthesis and biological activity of fused alkaloids, see the
following books and reviews and the references cited therein:
(a) Michael, J. P. In The Alkaloids: Chemistry and Biology; Academic
Press: New York, 2001; Vol. 55, pp 91−258. (b) Michael, J. P. Nat.
Prod. Rep. 2008, 25, 139. (c) Daly, J. W.; Spande, T. F.; Garraffo, H.
M. J. Nat. Prod. 2005, 68, 1556. (d) Michael, J. P. Nat. Prod. Rep. 2007,
24, 191. (e) Bhat, C.; Tilve, S. G. RSC Adv. 2014, 4, 5405.
(f) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2017, 34, 62. (g) The
(13) (a) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10,
1409. (b) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett.
2005, 46, 2101. (c) Kim, G.; Jung, S.-D.; Kim, W.-J Org. Lett. 2001, 3,
2985. (d) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55,
4688. (e) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991,
113, 3513. (f) Peroche, S.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-
C. Tetrahedron Lett. 2001, 42, 4617. (g) Kim, G.; Lee, E. Tetrahedron:
Asymmetry 2001, 12, 2073. (h) Corvo, M. C.; Pereira, M. M. C.
Tetrahedron Lett. 2002, 43, 455. (i) Amat, M.; Llor, N.; Hidalgo, J.;
Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919. (j) Sun, Z.; Yu, S.;
Alkaloids; Knolker, H.-J., Ed.; Elsevier: Cambridge, MA, 2018; Vol. 79.
̈
(2) For background and the synthesis of compounds 1−6, see:
(a) Dau, X. D.; Willis, A. C.; Pyne, S. G. Eur. J. Org. Chem. 2015, 2015,
7282. (b) Brambilla, M.; Davies, S. G.; Fletcher, A. I.; Roberts, P. M.;
Thomson, J. E.; Zimmer, D. Tetrahedron 2016, 72, 7417. (c) Lapointe,
D
DOI: 10.1021/acs.orglett.8b00225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300. (k) Cuthbertson,
J. D.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2013, 52, 1490.
(14) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A.
A. J. Org. Chem. 1990, 55, 3682.
(15) As for the pyrroline series, starting materials 13, 15, 17, and 19
exist largely as their enamine tautomeric form in solution in CDCl3.
For simplicity, all substrates are drawn in their imine forms.
(16) For background on benzodiazepines, see: Rudolph, U.;
Knoflach, F. Nat. Rev. Drug Discovery 2011, 10, 685 and references
cited therein.
(17) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1987;
Vol. 5, Chapter 1. (b) Aronstam, R. S.; Daly, J. W.; Spande, T. F.;
Narayanan, T. K.; Albuquerque, E. X. Neurochem. Res. 1986, 11, 1127.
(18) For additional background and selected previous syntheses of
indolizidine 209D, see ref 13d and: (a) Kim, G.; Jung, S.-D.; Kim, W.-J.
Org. Lett. 2001, 3, 2985. (b) Alegret, G.; Riera, A. J. Org. Chem. 2008,
73, 8661. (c) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem.,
Int. Ed. 2009, 48, 2379. (d) Chiou, H.-W.; Chen, H.-Y. RSC Adv. 2017,
7, 684 and references cited therein.
(19) For selected examples in which similar strategies have been
used, see: (a) Katritzky, A. R.; Rogers, J. W.; Witek, R. M.; Nair, S. K.
ARKIVOC 2004, 8, 52. (b) Natarajan, S. R.; Chen, M.-H.; Heller, S.
T.; Tynebor, R. M.; Crawford, E. M.; Minxiang, C.; Kaizheng, H.;
Dong, J.; Hu, B.; Hao, W.; Chen, S.-H. Tetrahedron Lett. 2006, 47,
5063. (c) Tynebor, R. M.; Chen, M. H.; Natarajan, S. R.; O’Neill, E.
A.; Thompson, J. E.; Fitzgerald, C. E.; O’Keefe, S. J.; Doherty, J. B.
Bioorg. Med. Chem. Lett. 2011, 21, 411.
E
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