Crystal structure and absolute configuration of (4S,5R,6S)-4,5,6-trihy­droxy-3-methyl­cyclo­hex-2-enone (gabosine H)

Tibhe, G.D.; Macías, M.A.; Pandolfi, E.; Schapiro, V.; Suescun, L.

doi:10.1107/S2056989017004509

research communications

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Volume 73| Part 4| April 2017| Pages 606-609

https://doi.org/10.1107/S2056989017004509

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Crystal structure and absolute configuration of (4S,5R,6S)-4,5,6-trihydroxy-3-methylcyclohex-2-enone (gabosine H)

Gaurao D. Tibhe,^a Mario A. Macías,^b ‡ Enrique Pandolfi,^a Valeria Schapiro ^a and Leopoldo Suescun ^c ^*

^aDepartamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo 11800, Uruguay, ^bDepartment of Chemistry, Universidad de los Andes, Cra 1 N° 18A-12, 111711 Bogotá, Colombia, and ^cCryssmat-Lab./DETEMA, Facultad de Química - Universidad de la República, Av. Gral. Flores 2124, Montevideo 11800, Uruguay
^*Correspondence e-mail: leopoldo@fq.edu.uy

Edited by C. Rizzoli, Universita degli Studi di Parma, Italy (Received 10 March 2017; accepted 21 March 2017; online 28 March 2017)

The molecule of the title keto carbasugar, C₇H₁₀O₄, is formed by a cyclohexene skeleton with an envelope conformation, substituted by carbonyl, methyl and hydroxyl groups. The crystal structure is controlled mainly by a combination of strong O—H⋯O and weak C—H⋯O hydrogen bonds, forming nearly perpendicular chains running parallel to the [110] and [-110] directions. This perpendicularity is caused by a tetragonal pseudosymmetry influenced by the similarity between the a and b axes, the value of 90.9770 (10)° of the β angle and the action of a 2₁ screw axis, which transform each chain into its corresponding nearly orthogonal one.

Keywords: crystal structure; absolute configuration; Mitsunobu inversion reaction; natural product.

CCDC reference: 1539327

1. Chemical context

Gabosines are regarded as secondary metabolites and were first isolated in 1974 from Streptomyces strains (Tsushiya et al., 1974 ). These compounds are closely related to carbasugars and exhibit DNA binding properties (Tang et al., 2000 ). To date, 15 gabosines have been isolated, of which 14 have been synthesized. Gabosine H is one of such kind, whose total synthesis has recently been achieved by our research group (Tibhe et al., 2017 ), starting from a biotransformation of toluene that introduces chirality. A further sequence of reactions, including Mitsunobu and final removal of the acetyl protective group, led to the title compound.

2. Structural commentary

Fig. 1 shows the molecule of the title compound. The absolute configuration of gabosine H with the carbonyl, methyl and hydroxyl groups in equatorial positions, determined as 4S,5R,6S on the basis of synthetic pathway, was confirmed by X-ray diffraction on the basis of anomalous dispersion of light atoms only. The six-membered ring (C1–C6) in the molecule adopts an envelope conformation with atom C5 as the flap [deviating from the plane through the other ring atoms by 0.639 (2) Å] and puckering parameters Q = 0.4653 (19) Å, θ = 129.5 (2)° and φ = 66.7 (3)°.

Figure 1
The molecular structure of the title compound, showing the anisotropic displacement ellipsoids drawn at the 50% probability level.

3. Supramolecular features

In the crystal structure, hydrogen bonds O4—H41⋯O1ⁱ [symmetry code: (i) x − 1, y − 1, z] link the molecules into chains that run along the [110] direction (Table 1). These chains are further connected by weaker C6—H6⋯O4ⁱⁱ and C4—H4⋯O6ⁱⁱⁱ [symmetry codes: (ii) x + 1, y, z; (iii) x, y − 1, z] hydrogen bonds along the [ $[\overline{1}]$ 10] direction, forming (001) sheets (Fig. 2). Considering that the chains run along the diagonal of the ab plane and the fact that a≃b, it is possible to observe that the 2₁ screw axis parallel to b transforms each chain into a nearly orthogonal one along [ $[\overline{1}]$ 10] (Fig. 3). The orthogonal chains are connected by single C6—H6⋯O6^iv, O6—H61⋯O5^v and bifurcated O5—H51⋯O4^vi and O5—H51⋯O5^vi hydrogen bonds [symmetry codes: (iv) −x + 1, y − $[{1\over 2}]$ , −z + 1; (v) −x + 1, y + $[{1\over 2}]$ ; (vi) −x, y + $[{1\over 2}]$ , −z + 1] to define a three-dimensional array along the [001] direction. These hydrogen bonds connect the orthogonal chains by pairs along [001]. Between these neighboring [001] sheets, weak dipolar or van der Waals forces stabilize the assembly along the c-axis direction.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O4—H41⋯O1ⁱ	0.94 (4)	1.96 (4)	2.873 (2)	163 (3)
C6—H6⋯O4ⁱⁱ	0.98	2.46	3.195 (2)	131
C4—H4⋯O6ⁱⁱⁱ	0.98	2.36	3.345 (3)	179
C6—H6⋯O6^iv	0.98	2.62	3.306 (2)	127
O6—H61⋯O5^v	0.87 (4)	1.99 (4)	2.811 (2)	155 (3)
O5—H51⋯O4^vi	0.85 (4)	2.45 (3)	3.050 (2)	128 (3)
O5—H51⋯O5^vi	0.85 (4)	2.26 (4)	3.0402 (12)	152 (3)
Symmetry codes: (i) x-1, y-1, z; (ii) x+1, y, z; (iii) x, y-1, z; (iv) $[-x+1, y-{\script{1\over 2}}, -z+1]$ ; (v) $[-x+1, y+{\script{1\over 2}}, -z+1]$ ; (vi) $[-x, y+{\script{1\over 2}}, -z+1]$ .

Figure 2
Partial crystal packing of the title compound showing the C—H⋯O and O—H⋯O hydrogen bonds (dotted lines) along [110] and [ $[\overline{1}]$ 10], forming sheets parallel to the (001) plane.

Figure 3
Partial crystal packing of the title compound connected into a nearly orthogonal assembly along [001] through C—H⋯O and O—H⋯O hydrogen bonds (dotted lines).

4. Database survey

A search of the Cambridge Structural Database (CSD Version 5.36 with one update; Groom et al., 2016 ) was carried out considering molecular structures similar to gabosine and its derivatives. Among the natural compounds, only the structure of gabosine N, (4R,5R,6R)-4,5,6-trihydroxy-2-methylcyclohex-2-enone (Tang et al. 2000), has been reported. The remaining hits were mainly derivatives of other gabosines different from H or derivatives such as 5-hydroxy-4-methyl-7-oxabicyclo[4.1.0]hept-3-en-2-one (White et al., 2010 ), which is an epoxide with different configuration of the asymmetric carbons compared with gabosine H.

5. Synthesis and crystallization

The synthesis of gabosine H was achieved by inversion of the allylic –OH group using Mitsunobu conditions followed by deprotection. (4R,5R,6S)-5-Acetoxy-4,5-dihydroxy-3-methylcyclohex-2-enone (2, Fig. 4; 0.149 mmol, 0.030 g) was dissolved in 1 ml of benzene and TPP (0.283 mmol, 0.078 g) was added along with p-nitrobenzoic acid (0.299 mmol, 0.050 g) and diisopropyl azodicarboxylate (DIAD; 0.297 mmol, 0.060 g). The reaction mixture was stirred at room temperature for 6 h. The solvent was evaporated and the crude mass was used for the next reaction without further purification. The crude product was dissolved in MeOH (3.4 mL), a catalytic quantity of K₂CO₃ was added and the reaction mixture was stirred at room temperature for 5 min and filtered. Evaporation of the solvent from the filtrate afforded crude gabosine H, which was purified by column chromatography (CH₂Cl₂/MeOH, 9:1 v/v) to afford pure gabosine H as a white crystalline powder (yield: 7.2 mg, 30%; m.p. 390.6 K. Suitable crystals for X-ray analysis were obtained by dissolving the solid in a minimum amount of methanol and allowing it to evaporate at room temperature. IR (KBr): 3400, 2875, 1660 cm^{−1. 1}H NMR (400 MHz, CD₃OD): δ = 2.07 (s, 3 H), 3.56 (dd, J = 10.8, 2.4 Hz, 1 H), 4.01 (d, J = 10.8 Hz, 1 H), 4.23 (d, J = 8.4 Hz, 1 H), 5.92 (s, 1 H).

Figure 4
Reaction scheme.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms bonded to C were placed in calculated positions (C—H = 0.93–0.98 Å) and included as riding contributions with isotropic displacement parameters set to 1.2–1.5 times the U_eq of the parent atom. Hydroxy H atoms were located in difference density maps and were refined with U_iso(H) = 1.5 U_eq(O). The absolute structure parameter y was calculated using PLATON (Spek, 2009 ). The resulting value of 0.07 (7) indicates that the absolute structure was determined correctly (Hooft et al., 2008 ).

Table 2
Experimental details

Crystal data
Chemical formula	C₇H₁₀O₄
M_r	158.15
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	298
a, b, c (Å)	5.4143 (2), 5.4176 (2), 11.9200 (5)
β (°)	90.977 (1)
V (Å³)	349.59 (2)
Z	2
Radiation type	Cu Kα
μ (mm⁻¹)	1.06
Crystal size (mm)	0.37 × 0.34 × 0.10

Data collection
Diffractometer	Bruker D8 Venture/Photon 100 CMOS
Absorption correction	Multi-scan (SADABS; Bruker, 2013 )
T_min, T_max	0.588, 0.754
No. of measured, independent and observed [I > 2σ(I)] reflections	12187, 1492, 1472
R_int	0.046
(sin θ/λ)_max (Å⁻¹)	0.637

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.033, 0.088, 1.08
No. of reflections	1492
No. of parameters	111
No. of restraints	1
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.25, −0.18
Absolute structure	Flack x determined using 639 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.09 (11)
Computer programs: SAINT (Bruker, 2013), SHELXS2014 (Sheldrick, 2008 ), SHELXL2014 (Sheldrick, 2015 ), Mercury (Macrae et al., 2008 ).

Supporting information

CCDC reference: 1539327

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989017004509/rz5209sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017004509/rz5209Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989017004509/rz5209Isup3.cml

checkCIF report

Computing details top

Data collection: SAINT (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXS2014 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015).

(4S,5R,6S)-4,5,6-Trihydroxy-3-methylcyclohex-2-enone top

Crystal data top

C₇H₁₀O₄	F(000) = 168
M_r = 158.15	D_x = 1.502 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
a = 5.4143 (2) Å	Cell parameters from 9784 reflections
b = 5.4176 (2) Å	θ = 3.7–78.8°
c = 11.9200 (5) Å	µ = 1.06 mm⁻¹
β = 90.977 (1)°	T = 298 K
V = 349.59 (2) Å³	Parallelepiped, colorless
Z = 2	0.37 × 0.34 × 0.10 mm

Data collection top

Bruker D8 Venture/Photon 100 CMOS diffractometer	1492 independent reflections
Radiation source: Cu Incoatec microsource	1472 reflections with I > 2σ(I)
Detector resolution: 10.4167 pixels mm^-1	R_int = 0.046
\j and ω scans	θ_max = 79.1°, θ_min = 3.7°
Absorption correction: multi-scan (SADABS; Bruker, 2013)	h = −6→6
T_min = 0.588, T_max = 0.754	k = −6→6
12187 measured reflections	l = −15→14

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.033	w = 1/[σ²(F_o²) + (0.0546P)² + 0.0518P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.088	(Δ/σ)_max < 0.001
S = 1.08	Δρ_max = 0.25 e Å⁻³
1492 reflections	Δρ_min = −0.18 e Å⁻³
111 parameters	Extinction correction: SHELXL2014 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
1 restraint	Extinction coefficient: 0.161 (15)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack x determined using 639 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.09 (11)

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.4992 (3)	0.2954 (4)	0.22586 (16)	0.0293 (4)
C2	0.3815 (4)	0.1293 (4)	0.14457 (16)	0.0313 (5)
H2	0.4304	0.1373	0.0702	0.038*
C3	0.2068 (3)	−0.0338 (3)	0.17173 (15)	0.0262 (4)
C31	0.0921 (4)	−0.2029 (5)	0.08715 (17)	0.0374 (5)
H31A	0.1711	−0.1813	0.0163	0.056*
H31B	−0.0807	−0.1656	0.0790	0.056*
H31C	0.1119	−0.3706	0.1116	0.056*
C4	0.1234 (3)	−0.0631 (3)	0.29155 (15)	0.0249 (4)
H4	0.2190	−0.1965	0.3269	0.030*
C5	0.1658 (3)	0.1719 (4)	0.35829 (15)	0.0237 (4)
H5	0.0534	0.3005	0.3302	0.028*
C6	0.4314 (3)	0.2607 (3)	0.34819 (14)	0.0258 (4)
H6	0.5418	0.1368	0.3818	0.031*
O1	0.6472 (3)	0.4524 (3)	0.19769 (14)	0.0453 (5)
O4	−0.1316 (3)	−0.1192 (3)	0.29994 (14)	0.0398 (4)
H41	−0.172 (6)	−0.273 (8)	0.269 (3)	0.060*
O5	0.1120 (3)	0.1206 (3)	0.47319 (11)	0.0336 (4)
H51	0.096 (5)	0.263 (7)	0.502 (3)	0.050*
O6	0.4549 (3)	0.4821 (3)	0.40965 (13)	0.0374 (4)
H61	0.606 (7)	0.485 (7)	0.437 (3)	0.056*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0252 (8)	0.0305 (10)	0.0322 (9)	−0.0046 (8)	0.0038 (7)	0.0021 (8)
C2	0.0322 (9)	0.0360 (11)	0.0257 (8)	−0.0051 (8)	0.0055 (7)	−0.0002 (8)
C3	0.0251 (8)	0.0263 (9)	0.0274 (8)	0.0013 (7)	0.0018 (6)	−0.0011 (7)
C31	0.0429 (11)	0.0358 (11)	0.0335 (10)	−0.0084 (10)	0.0007 (8)	−0.0050 (9)
C4	0.0241 (8)	0.0219 (9)	0.0289 (9)	0.0001 (7)	0.0061 (6)	0.0011 (7)
C5	0.0227 (8)	0.0242 (9)	0.0243 (8)	0.0024 (6)	0.0037 (6)	0.0007 (6)
C6	0.0240 (8)	0.0267 (10)	0.0267 (8)	0.0011 (7)	0.0004 (6)	−0.0019 (7)
O1	0.0464 (9)	0.0459 (10)	0.0440 (8)	−0.0236 (8)	0.0080 (7)	−0.0002 (7)
O4	0.0287 (8)	0.0363 (9)	0.0548 (9)	−0.0099 (6)	0.0152 (6)	−0.0124 (7)
O5	0.0363 (7)	0.0388 (8)	0.0260 (7)	−0.0005 (6)	0.0091 (5)	−0.0016 (6)
O6	0.0329 (7)	0.0364 (9)	0.0429 (8)	−0.0016 (6)	−0.0044 (6)	−0.0125 (7)

Geometric parameters (Å, º) top

C1—O1	1.220 (3)	C4—C5	1.517 (2)
C1—C2	1.461 (3)	C4—H4	0.9800
C1—C6	1.521 (2)	C5—O5	1.432 (2)
C2—C3	1.338 (3)	C5—C6	1.523 (2)
C2—H2	0.9300	C5—H5	0.9800
C3—C31	1.490 (3)	C6—O6	1.410 (2)
C3—C4	1.514 (2)	C6—H6	0.9800
C31—H31A	0.9600	O4—H41	0.94 (4)
C31—H31B	0.9600	O5—H51	0.85 (4)
C31—H31C	0.9600	O6—H61	0.87 (4)
C4—O4	1.419 (2)

O1—C1—C2	121.89 (18)	O4—C4—H4	108.6
O1—C1—C6	121.36 (18)	C3—C4—H4	108.6
C2—C1—C6	116.75 (16)	C5—C4—H4	108.6
C3—C2—C1	123.26 (17)	O5—C5—C4	107.89 (15)
C3—C2—H2	118.4	O5—C5—C6	110.15 (14)
C1—C2—H2	118.4	C4—C5—C6	110.99 (14)
C2—C3—C31	122.04 (17)	O5—C5—H5	109.3
C2—C3—C4	121.40 (16)	C4—C5—H5	109.3
C31—C3—C4	116.52 (16)	C6—C5—H5	109.3
C3—C31—H31A	109.5	O6—C6—C1	111.83 (16)
C3—C31—H31B	109.5	O6—C6—C5	107.72 (14)
H31A—C31—H31B	109.5	C1—C6—C5	110.99 (14)
C3—C31—H31C	109.5	O6—C6—H6	108.7
H31A—C31—H31C	109.5	C1—C6—H6	108.7
H31B—C31—H31C	109.5	C5—C6—H6	108.7
O4—C4—C3	113.27 (15)	C4—O4—H41	113 (2)
O4—C4—C5	106.33 (14)	C5—O5—H51	103 (2)
C3—C4—C5	111.22 (14)	C6—O6—H61	106 (2)

O1—C1—C2—C3	−175.5 (2)	O4—C4—C5—C6	−175.86 (15)
C6—C1—C2—C3	5.4 (3)	C3—C4—C5—C6	−52.12 (19)
C1—C2—C3—C31	−179.29 (19)	O1—C1—C6—O6	28.4 (3)
C1—C2—C3—C4	−1.9 (3)	C2—C1—C6—O6	−152.56 (18)
C2—C3—C4—O4	145.37 (18)	O1—C1—C6—C5	148.7 (2)
C31—C3—C4—O4	−37.2 (2)	C2—C1—C6—C5	−32.2 (2)
C2—C3—C4—C5	25.7 (2)	O5—C5—C6—O6	−62.1 (2)
C31—C3—C4—C5	−156.85 (17)	C4—C5—C6—O6	178.49 (14)
O4—C4—C5—O5	63.37 (19)	O5—C5—C6—C1	175.17 (16)
C3—C4—C5—O5	−172.89 (14)	C4—C5—C6—C1	55.8 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O4—H41···O1ⁱ	0.94 (4)	1.96 (4)	2.873 (2)	163 (3)
C6—H6···O4ⁱⁱ	0.98	2.46	3.195 (2)	131
C4—H4···O6ⁱⁱⁱ	0.98	2.36	3.345 (3)	179
C6—H6···O6^iv	0.98	2.62	3.306 (2)	127
O6—H61···O5^v	0.87 (4)	1.99 (4)	2.811 (2)	155 (3)
O5—H51···O4^vi	0.85 (4)	2.45 (3)	3.050 (2)	128 (3)
O5—H51···O5^vi	0.85 (4)	2.26 (4)	3.0402 (12)	152 (3)

Symmetry codes: (i) x−1, y−1, z; (ii) x+1, y, z; (iii) x, y−1, z; (iv) −x+1, y−1/2, −z+1; (v) −x+1, y+1/2, −z+1; (vi) −x, y+1/2, −z+1.

Footnotes

‡Joint first author.

Acknowledgements

The authors would like to thank ANII (EQC_2012_07), CSIC and the Facultad de Química for funds to purchase the diffractometer and the financial support of OPCW and PEDECIBA. GT and MM also thank ANII for their respective postdoctoral fellowships (PD_NAC_2014_1_102498 and PD_NAC_2014_1_102409).

Funding information

Funding for this research was provided by: Organisation for the Prohibition of Chemical Weapons; Agencia Nacional de Investigación e Innovación (award Nos. PD_NAC_2014_1_102498, PD_NAC_2014_1_102409, EQC_2012_07).

References

Bruker (2013). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CSD CrossRef IUCr Journals Google Scholar
Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96–103. Web of Science CrossRef CAS IUCr Journals Google Scholar
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466–470. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Tang, Y. Q., Maul, C., Höfs, R., Sattler, I., Grabley, S., Feng, X. Z., Zeeck, A. & Thiericke, R. (2000). Eur. J. Org. Chem. 2000, 149–153. CrossRef Google Scholar
Tsushiya, T., Mikami, N., Umezawa, S., Umezawa, H. & Naganawa, H. (1974). J. Antibiot. 27, 579–586. PubMed Google Scholar
Tibhe, G. D., Macías, M. A., Pandolfi, E., Suescun, L. & Schapiro, V. (2017). Synthesis, 49, 565–570. CAS Google Scholar
White, L. V., Dietinger, C. E., Pinkerton, D. M., Willis, A. C. & Banwell, M. G. (2010). Eur. J. Org. Chem., pp. 4365–4367. Google Scholar

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