Reconciling the stereochemical course of nucleopalladation with the development of enantioselective wacker-type cyclizations

Article abstract of DOI:10.1002/anie.201206702

A stereochemical substrate probe was used to assess the factors that affect the stereochemical course of nucleopalladation in the context of an enantioselective Wacker-type reaction. The enantioselectivity correlates directly with the nucleopalladation pathway, and both the neutral-donor and anionic ligands on palladium are capable of controlling selectivity for cis- or trans-nucleopalladation (see scheme; TFA=trifluoroacetate). Copyright

Full text of DOI:10.1002/anie.201206702

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DOI: 10.1002/anie.201206702
Asymmetric Catalysis
Reconciling the Stereochemical Course of Nucleopalladation with the
Development of Enantioselective Wacker-Type Cyclizations**
Adam B. Weinstein and Shannon S. Stahl*
Palladium(II)-catalyzed oxidative functionalization of
alkenes has been the focus of intense interest for decades,
and Wacker-type cyclizations,[1] which enable synthesis of
diverse heterocycles, are a prominent class of these reac-
tions.[2] Substantial effort has been directed toward enantio-
selective applications, but successful examples (e.g.,
ꢀ 90% ee) remain rare and often exhibit limited substrate
scope.[3,4] A key challenge associated with these reactions is
the possibility of cis- or trans-nucleopalladation (NP) of the
alkene, because the formation of diastereomeric intermedi-
ates from these pathways could have significant consequences
for the development of enantioselective transformations
(Scheme 1).[3] Examples of both cis- and trans-NP pathways
nistic investigation of the factors that affect the stereochem-
ical course of NP in the context of a recently discovered
catalyst system for the enantioselective cyclization of g-
alkenyl tosylamides. Implementation of a novel stereochem-
ical probe demonstrates that both the chiral neutral-donor
ligand and the anionic ligands on the palladium center are
capable of controlling the stereochemical pathway for ami-
dopalladation (AP), but only the trans-AP pathway exhibits
high enantioselectivity. These data provide the first direct
correlation between NP stereoselectivity and the enantio-
selectivity of the transformation in question. Such insights
highlight valuable considerations for the development of
enantioselective reactions that involve nucleopalladation of
an alkene.
Recently, we showed that a palladium(II) catalyst with
a chiral pyridine oxazoline (pyrox) ligand enables preparation
of pyrrolidines (e.g., 2 from 1) in excellent yield and
enantioselectivity (Scheme 2).[4p,7] Based on several closely
related precedents, we predicted that the PdII/pyrox catalyst
Scheme 1. Stereochemical pathways for alkene nucleopalladation.
Scheme 2. Enantioselective cyclization of g-alkenyl tosylamides.
M.S.=molecular sieves, TFA=trifluoroacetate, Ts=4-toluenesulfonyl.
in catalytic reactions have been documented,[5,6] but only
three enantioselective variants of these reactions have been
characterized with respect to the stereochemical course of NP.
All three examples exhibited a preference for cis-NP.[4f,k,n] The
possible impact of the stereochemical course of NP on the
enantioselectivity of a given asymmetric Wacker-type reac-
tion has not been established. Herein, we present a mecha-
system would favor a cis-AP mechanism.[8–11] For example, the
isotopically labeled substrate 3-d-4 has been used to assess the
mechanism of several different palladium(II)
catalyst systems for the aerobic, oxidative
amidation of alkenes,[5d] and Pd(OAc)2/pyridine
and Pd(TFA)2/(À)-sparteine were among the
[*] A. B. Weinstein, Prof. S. S. Stahl
catalyst systems shown to afford products
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: stahl@chem.wisc.edu
exclusively arising from cis-AP of the
alkene.[12] In the enantioselective cyclization of
Homepage: http://www.chem.wisc.edu/~stahl
g-alkenyl tosylamides, the identity of the
[**] We thank Dr. Richard I. McDonald and Chun Pong Tam for initiating
the synthesis of substrate probe 6-D-1, and Paul B. White and Dr.
Charlie G. Fry for assistance with NMR spectroscopic measure-
ments. We thank the NIH (R01 GM67163) and Organic Syntheses
(ACS Division of Organic Chemistry fellowship for A.B.W.) for
financial support of this work. Spectroscopic instrumentation was
partially funded by the NSF (CHE-0342998, CHE-9629688, CHE-
9208463) and NIH (1 S10 RR13866-01).
anionic ligand was found to have a significant impact on the
reaction outcome. Replacing [Pd(pyrox)(TFA)2] with [Pd-
(pyrox)(OAc)2] gave a significantly diminished yield and
enantioselectivity under otherwise identical reaction condi-
tions (Scheme 2). The disparity of these results raised the
possibility that the reactions with these catalysts might
involve different AP pathways.
Our initial attempt to probe the AP pathway for the
enantioselective reaction involved the use of the substrate 3-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206702.
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d-4 under the previously optimized reaction conditions.
However, a mixture of all four of the possible bicyclic
pyrrolidines was obtained in 61% yield, favoring the trans-AP
products in approximately a 3:1 ratio relative to cis-AP
products (Scheme 3). This result was unexpected for two
Scheme 3. Cyclization of the substrate 3-d-4 with chiral catalyst.
reasons: first, the cis-AP pathway was anticipated to be
dominant for these reaction conditions, and second, it seemed
unlikely that a highly enantioselective reaction would involve
simultaneous operation of both cis- and trans-AP pathways.
Analysis of the product mixture by HPLC using a chiral
stationary phase revealed poor kinetic resolution. The
products 3-d-5 and 5 were formed in 13% ee, and the
products 3-d-6 and 2-d-6 were formed in 56% ee. The
relevance of these results was not entirely clear, in part,
because the cyclic alkene in 3-d-4 could influence the
stereochemical course of the AP step and may not be
a good model for acyclic alkenes which undergo highly
enantioselective cyclization.[4p]
Scheme 4. a) Mechanistic pathways for the reaction of 6-d-1 and
b) mathematical relationships used to determine the yields of products
A–D.
To circumvent the complications associated with the use
of 3-d-4 as a mechanistic probe, we prepared a novel acyclic
deuterated substrate probe, 6-d-1, which is a chiral analogue
of substrate 1 (Scheme 4).[13] Analysis of the products formed
by oxidative cyclization of 6-d-1 is more involved than the
analysis of products derived from the substrate 3-d-4 because
both the absolute configuration of the product and the loss or
retention of the deuterium atom must be accounted for (the
four products A–D differ only in the absolute configuration of
the stereogenic center and/or the presence or absence of the
styrenyl deuterium atom at C6, Scheme 4a). Reliable results
with 6-d-1 are possible because trans-styrenyl products are
obtained with high selectivity over the cis isomers, and very
little deuterium scrambling (ꢁ 5%) occurs.[14]
a system of four equations and four unknowns to determine
the quantities a, b, c, and d, from which the trans-AP/cis-AP
selectivity was obtained from the ratio (a + b)/(c+d).[16]
The substrate 6-d-1 was subjected to the optimized
reaction condition using the chiral catalyst, and the reaction
proceeded in excellent yield and enantioselectivity (90%
yield and 96% ee), which is consistent with the reactivity of
1 reported previously (Scheme 2).[4p] 1H NMR spectroscopic
analysis of the initial product mixture revealed a 93:7
preference for the protio products (Scheme 5). Because we
had previously determined that the S configuration of the
pyrox ligand 3 favors formation of the R configuration of the
pyrrolidine, the initial 1H NMR and HPLC analyses were
enough to conclude that product A was the major species and
the trans-AP pathway was heavily favored over the cis
pathway. The product ratio was established more definitively
with 1H NMR analysis of the purified major enantiomer
species A and C. The three measurements show that these
reactions exhibit a very high selectivity for a trans-AP
pathway (trans-AP/cis-AP = 91:9). The correlation between
the high enantioselectivity and high trans/cis-AP selectivity
obtained from the substrate 6-d-1 may be contrasted to the
poor enantioselectivity and poor trans-AP/cis-AP selectivity
observed with the substrate 3-d-4 (see Scheme 3).[17,18]
Three independent analytical measurements were used to
establish the yield of the products A–D from the reaction of 6-
d-1 under various reaction conditions. First, the H/D ratio at
1
C6 in the four styrenyl products was obtained by H NMR
spectroscopy. This quantity established the relationship (a +
d) = x(b+c), where a, b, c, and d represent the percent
composition of the species A–D, and x = H/D at C6 (Sche-
me 4b). Second, the enantiomeric ratio of the products was
obtained by HPLC analysis. This quantity established the
relationship (a + c) = y(b+d), where y = [R products/S pro-
ducts]. Third, the two sets of enantiomeric products were
separated by HPLC using a chiral stationary phase, and the H/
D ratio of the enantiomerically pure products was obtained by
1H NMR spectroscopy.[15] This quantity established the a/c
and b/d ratios. With these data in hand and accounting for full
mass balance (a + b + c + d = 100), it was possible to solve
These results established the utility of the substrate probe
6-d-1 and the protocol for product analysis to correlate the
enantioselectivity with the AP pathway of the oxidative
cyclization reaction. We then turned our attention to the
[Pd(pyrox)(OAc)2]-catalyzed reaction, which proceeds with
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Scheme 6. Experimental data and trans-AP/cis-AP selectivity obtained
from oxidative cyclization of substrate 6-d-1 with a [Pd(pyrox)(OAc)2]
catalyst system (refer to Scheme 5 for depiction of the reaction).
Table 1: Summary of amidopalladation studies with pyrox-ligated and
ligand-free catalysts.
Entry PdII[a]
Ligand[b] Yield [%][c] ee [%][d] trans-AP/cis-AP[e]
1
2
3
4
Pd(TFA)2 (S)-3
90
48
55
15
96
20
0
>9:1
1:9
1:6
Pd(OAc)2 (S)-3
Pd(TFA)2 none
Pd(OAc)2 none
0
<1:9
[a] Used 5 mol%. [b] Used 7.5 mol%. [c] Determined by 1H NMR
analysis of the crude reaction mixture. [d] Determined by HPLC analysis
of the purified products. [e] See the Supporting Information for full
disclosure of the raw data.
Scheme 5. Experimental data and trans-AP/cis-AP selectivity obtained
from oxidative cyclization of substrate 6-d-1 with the optimized
reaction conditions with a chiral catalyst.
much lower enantioselectivity under reaction conditions
identical to the [Pd(pyrox)(TFA)2]-catalyzed reaction. The
reactivity of 6-d-1 with [Pd[(S)-3](OAc)2] as the catalyst was
tested and, consistent with our prior results, the reaction
ligand. The results show that both palladium(II) sources favor
cis-AP of the alkene (Table 1, entries 3 and 4; see also
Schemes S7 and S8 in the Supporting Information). The
selectivity is considerably higher with Pd(OAc)2; only trace
quantities of the trans-AP-derived product are detected by
NMR/HPLC analysis. With Pd(TFA)2, the trans-AP/cis-AP
selectivity is 1:6, thus suggesting that while the TFA ligand is
intrinsically more compatible with the trans-AP mechanism, it
still favors cis-AP. Taken together, the data in Table 1
demonstrate that the pyrox ligand plays an important role
in enforcing the trans-AP pathway with Pd(TFA)2 as the
palladium(II) source. Previous efforts to understand the
factors that influence trans- versus cis-AP selectivity have
implicated the carboxylate ligand as a Brønsted base to
mediate palladium—amidate bond formation in the cis-AP
pathway.[5d,19] The present findings reveal that only with the
combined presence of a trifluoroacetate anionic ligand and
the pyrox neutral-donor ligand is a trans-AP pathway,
initiated by substitution of TFA by the substrate alkene,
favored over the cis-AP pathway involving formation of a Pd-
amidate.
In summary, the design, synthesis and implementation of
a novel chiral substrate probe (6-d-1) has enabled key insights
into the relationship between the NP pathway and the
enantioselectivity of a catalytic transformation. The ability
of an ancillary neutral-donor ligand to alter the stereochem-
ical course of NP only when a suitable anionic ligand is
present highlights the challenges associated with the discov-
ery of efficient catalysts for the asymmetric Wacker-type
oxidation of alkenes. Ideally, the factors that affect the NP
1
proceeded in only 48% yield and 20% ee. H NMR analysis
of the initial product mixture revealed a 48:52 H/D ratio.
After separation of the two enantiomeric products by HPLC,
analysis of the R-configured products revealed a 14:86 H/D
ratio, while the purified S-configured products displayed
a 96:4 H/D ratio (Scheme 6). Incorporation of the data from
either of these two measurements into the system of four
equations led to similar product ratios for species A, B, C, and
D, and the results show that the reaction strongly favored
a cis-AP pathway (trans-AP/cis-AP = 10:90), with a 9:1:51:39
ratio for A/B/C/D. While the overall reaction exhibited low
enantioselectivity, consideration of the minor products A and
B, which arose from trans-AP of the alkene, revealed that the
trans-AP pathway was quite enantioselective (e.r. = 9:1).
Thus, with this substrate and pyrox/PdII catalyst system, the
trans-AP pathway proceeds with high enantioselectivity while
the cis-AP pathway exhibits low enantioselectivity. These
observations represent the first direct assessment of the
enantioselectivity of two different NP pathways for otherwise
identical reactions.
The results of the reactions with the chiral ligands are
summarized in entries 1 and 2 of Table 1. In an effort to
separate the influence of the neutral-donor and anionic
ligands on the stereochemical course of the AP step, we
investigated the oxidative cyclization of 6-d-1 with Pd(OAc)2
and Pd(TFA)2 in the absence of an ancillary neutral-donor
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[7] Quinox and pyrox ligands have emerged as a versatile class of
chiral ligands for palladium(II)-catalyzed reactions with alkenes.
For examples other than those described in Refs [4k,m,o,p] and
[11], see: a) N. S. Perch, R. A. Widenhoefer, J. Am. Chem. Soc.
1999, 121, 6960 – 6961; b) N. S. Perch, T. Pei, R. A. Widenhoefer,
J. Org. Chem. 2000, 65, 3836 – 3845; c) Y. Zhang, M. S. Sigman, J.
Am. Chem. Soc. 2007, 129, 3076 – 3077; d) T. P. Pathak, K. M.
Gligorich, B. E. Welm, M. S. Sigman, J. Am. Chem. Soc. 2010,
132, 7870 – 7871; e) R. Jana, T. P. Pathak, K. H. Jensen, M. S.
Sigman, Org. Lett. 2012, 14, 4074 – 4077.
stereochemistry should be considered in conjunction with the
exploration of chiral ancillary ligands in the future develop-
ment of enantioselective reactions.
Received: August 18, 2012
Published online: October 16, 2012
Keywords: asymmetric catalysis · enantioselectivity · oxidation ·
.
palladium · reaction mechanisms
[8] See Ref. [5d] and: X. Ye, G. Liu, B. V. Popp, S. S. Stahl, J. Org.
Chem. 2011, 76, 1031 – 1044.
[9] Investigation of a well-defined (bipyridine)PdII-tosylamidate
complex provided fundamental insights into alkene insertion
[1] P. M. Henry in Palladium Catalyzed Oxidation of Hydrocarbons,
Vol. 2, D. Reidel Publishing Co., Dordrecht, The Netherlands,
1980.
[2] a) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285 – 2309;
b) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Chem. Rev. 2007, 107, 5318 – 5365; c) A. Minatti, K. MuÇiz,
Chem. Soc. Rev. 2007, 36, 1142 – 1152; d) V. Kotov, C. C.
Scarborough, S. S. Stahl, Inorg. Chem. 2007, 46, 1910 – 1923;
e) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem. 2008, 6,
4083 – 4088.
À
into a Pd N(R)Ts bond (i.e., the cis-AP step). See a) P. B. White,
S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 18594 – 18597. For other
À
studies of alkene insertion into Pd N bonds, see the following
leading references: b) P. S. Hanley, J. F. Hartwig, J. Am. Chem.
Soc. 2011, 133, 15661 – 15673; c) J. D. Neukom, N. S. Perch, J. P.
Wolfe, Organometallics 2011, 30, 1269 – 1277.
[10] Yang and co-workers recently reported a PdII/quinoline-oxazo-
line (quinox)catalyst system for enantioselective oxidative
cyclization of anilides bearing tethered alkenes, and stereo-
chemical analysis of the products revealed that the reaction
involves cis-AP of the alkene (see Ref. [4k]).
[3] R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981 –
3019.
[11] Further circumstantial evidence supporting a cis-AP mechanism
comes from the use of quinox and pyrox ligands in other
palladium(II)-catalyzed reactions, such as oxidative Heck reac-
tions, which involve cis addition of palladium(II) and an aryl
[4] For leading primary references, see: a) T. Hosokawa, T. Uno, S.
Inui, S.-I. Murahashi, J. Am. Chem. Soc. 1981, 103, 2318 – 2323;
b) Y. Uozumi, K. Kato, T. Hayashi, J. Am. Chem. Soc. 1997, 119,
5063 – 5064; c) Y. Uozumi, K. Kato, T. Hayashi, J. Org. Chem.
1998, 63, 5071 – 5075; d) M. A. Arai, M. Kuraishi, T. Arai, H.
Sasai, J. Am. Chem. Soc. 2001, 123, 2907 – 2908; e) R. M. Trend,
Y. K. Ramtohul, E. M. Ferreira, B. M. Stoltz, Angew. Chem.
2003, 115, 2998 – 3001; Angew. Chem. Int. Ed. 2003, 42, 2892 –
2895; f) T. Hayashi, K. Yamasaki, M. Mimura, Y. Uozumi, J. Am.
Chem. Soc. 2004, 126, 3036 – 3037; g) R. M. Trend, Y. K.
Ramtohul, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778 –
17788; h) K.-T. Yip, M. Yang, K.-L. Law, N.-Y. Zhu, D. Yang, J.
Am. Chem. Soc. 2006, 128, 3130 – 3131; i) Y. J. Zhang, F. Wang,
W. Zhang, J. Org. Chem. 2007, 72, 9208 – 9213; j) T. Tsujihara, T.
Shinohara, K. Takenaka, S. Takizawa, K. Onitsuka, M. Hata-
naka, H. Sasai, J. Org. Chem. 2009, 74, 9274 – 9279; k) W. He, K.-
T. Yip, N.-Y. Zhu, D. Yang, Org. Lett. 2009, 11, 5626 – 5628;
l) C. C. Scarborough, A. Bergant, G. T. Sazama, I. A. Guzei,
L. C. Spencer, S. S. Stahl, Tetrahedron 2009, 65, 5084 – 5092;
m) F. Jiang, Z. Wu, W. Zhang, Tetrahedron Lett. 2010, 51, 5124 –
5126; n) D. N. Mai, J. P. Wolfe, J. Am. Chem. Soc. 2010, 132,
12157 – 12159; o) K. H. Jensen, J. D. Webb, M. S. Sigman, J. Am.
Chem. Soc. 2010, 132, 17471 – 17482; p) R. I. McDonald, P. B.
White, A. B. Weinstein, C. P. Tam, S. S. Stahl, Org. Lett. 2011, 13,
2830 – 2833; q) G. Yang, C. Shen, W. Zhang, Angew. Chem. 2012,
124, 9275 – 9279; Angew. Chem. Int. Ed. 2012, 51, 9141 – 9145.
[5] For examples of cis-nucleopalladation, see the following leading
references: [4f,g,k,n] and a) J. E. Ney, J. P. Wolfe, Angew. Chem.
2004, 116, 3689 – 3692; Angew. Chem. Int. Ed. 2004, 43, 3605 –
3608; b) M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005, 127,
16468 – 16476; c) J. S. Nakhla, J. W. Kampf, J. P. Wolfe, J. Am.
Chem. Soc. 2006, 128, 2893 – 2901; d) G. Liu, S. S. Stahl, J. Am.
Chem. Soc. 2007, 129, 6328 – 6335; e) K. MuÇiz, C. H. Hovel-
mann, J. Streuff, J. Am. Chem. Soc. 2008, 130, 763 – 773; f) B. W.
Michel, L. D. Steffens, M. S. Sigman, J. Am. Chem. Soc. 2011,
133, 8317 – 8325.
=
group across an alkene C C bond. For cis-NP reactions employ-
ing pyrox/quinox ligands, see Refs [4k, 5f], and: K. S. Yoo, C. P.
Park, C. H. Yoon, S. Sakaguchi, J. OꢀNeil, K. W. Jung, Org. Lett.
2007, 9, 3933 – 3935.
[12] See Ref. [5d]. (À)-Sparteine is a chiral diamine (bidentate)
ligand.
[13] The substrate 6-d-1 was synthesized from (S)-mandelic acid in
ten steps, with the first five steps having direct precedent in the
literature: M. N. Alberti, G. Vassilikogiannakis, M. Orfanopou-
los, Org. Lett. 2008, 10, 3997 – 4000. Derivatization and analysis
of an advanced intermediate established the stereochemical
purity of the substrate probe to be very high (> 20:1, see the
Supporting Information for details).
[14] A detailed consideration of how alkene isomerization and
deuterium scrambling could complicate our results is provided in
the Supporting Information (Scheme S1). However, under all
catalyst conditions tested in this study, the trans-styrenyl
products are obtained in > 20:1 selectivity, and it was possible
to remove trace quantities of the cis-styrenyl products by
chromatography prior to further analysis. The extent of deute-
2
rium scrambling was characterized by H NMR analysis of the
mixture of the four products A–D (Scheme S3–S8), and only
trace quantities (ꢁ 5%) of deuterium at the C5 position were
observed in our experiments.
[15] This quantity was corroborated by ESI/MS analysis of the
enantiomerically pure products (see Schemes S3–S8 in the
Supporting Information).
[16] The validity of this protocol was tested by subjecting 6-d-1 to the
previously reported Pd(OAc)2/pyridine oxidative cyclization
conditions. The data arising from this experiment show that
the reaction proceeds with very high selectivity for cis-AP of the
alkene (trans/cis = 8:92; see Scheme S3 in the Supporting
Information), thus supporting the previously reported conclu-
sions derived from the use of substrate 3-d-4 as the mechanistic
probe (see Ref. [5d]).
[6] For examples of trans-nucleopalladation, see the following
leading references: Refs. [4g,o, 5c,d] and a) M. P. Watson, L. E.
Overman, R. G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031 –
5044; b) B. M. Cochran, F. E. Michael, J. Am. Chem. Soc. 2008,
130, 2786 – 2792; c) P. A. Sibbald, C. F. Rosewall, R. D. Swartz,
F. E. Michael, J. Am. Chem. Soc. 2009, 131, 15945 – 15951.
[17] Cyclization of 6-d-1 with the opposite antipode of the ligand,
(R)-3, resulted in 93% yield, 96% ee, and a 96:4 trans/cis-AP
ratio (see Scheme S5 in the Supporting Information). The similar
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trans/cis-AP ratios obtained with ligands (S)-3 and (R)-3 in the
reactions of 6-d-1 show that any kinetic isotope effect associated
with b-hydride elimination from the C6 position has minimal
impact on the AP pathway.
exists that is lower in energy than the one presented in Ref. [4p].
DFT calculations to explore this issue and to analyze the trans-
AP mechanism are currently under investigation.
[19] For other discussion of factors contributing to cis- versus trans-
nucleopalladation, see Refs [3, 4g, 5c] and the following: J. A.
Keith, P. M. Henry, Angew. Chem. 2009, 121, 9200 – 9212;
Angew. Chem. Int. Ed. 2009, 48, 9038 – 9049.
[18] We previously reported DFT calculations that implicated high
enantioselectivity for a cis-AP pathway (see Ref. [4p]). The
present results suggest that at least one other cis-AP pathway
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