Unusual hemiacetal structure derived from Salvinorin A

Carvalho, P.; Bikbulatov, R.; Zjawiony, J.K.; Avery, M.A.

doi:10.1107/S160053680800144X

organic compounds

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ISSN: 2056-9890

Volume 64| Part 7| July 2008| Pages o1370-o1371

doi:10.1107/S160053680800144X

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Unusual hemiacetal structure derived from Salvinorin A

Paulo Carvalho,^a Ruslan Bikbulatov,^b Jordan K. Zjawiony ^b,^c and Mitchell A. Avery ^a,^c,^d ^*

^aDepartment of Medicinal Chemistry, University of Mississippi, 417 Faser Hall, University, MS 38677, USA, ^bDepartment of Pharmacognosy, University of Mississippi, PO Box 1848, 443 Faser Hall, University, MS, 38677-1848, USA, ^cNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA, and ^dDepartment of Chemistry and Biochemistry, University of Mississippi, University, MS 38677, USA
^*Correspondence e-mail: mavery@olemiss.edu

(Received 11 December 2007; accepted 14 January 2008; online 28 June 2008)

The salvinorin A analog dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9bS)-2-(3-furyl)-9,9a-dihydroxy-3a,6a-dimethyldodecahydrobenzo[de]chromene-4,7-dicarboxylate, C₂₂H₃₀O₈, has a relatively simple spatial arrangement in which molecules are linked into layers by two pairs of O—H⋯O hydrogen bonds. Each molecule has as the central feature a dodecahydro-1H-phenalene ring system. Its three six-membered rings are in the chair conformation, with two axial methyl groups, one axial OH, and one equatorial OH, these OH groups being directly responsible for linking of the molecules in the crystal structure.

Related literature

For the synthesis of analogs of salvinorin A, see: Bikbulatov et al. (2007 ); Lee et al. (2006 ); Beguin et al. (2006 ); Stewart et al. (2006 ) and references cited therein. For modifications of salvinorin A with changed pharmacological profile, see: Rothman et al. (2007 ); Groer et al. (2007 ); Tidgewell et al. (2006 ); Harding et al. (2005 , 2006 ).

Experimental

Crystal data

C₂₂H₃₀O₈
M_r = 422.46
Monoclinic, P 2₁
a = 11.6801 (5) Å
b = 6.0522 (3) Å
c = 15.3739 (6) Å
β = 107.678 (2)°
V = 1035.47 (8) Å³
Z = 2
Cu Kα radiation
μ = 0.86 mm⁻¹
T = 296 (2) K
0.32 × 0.15 × 0.13 mm

Data collection

Bruker SMART CCD area-detector diffractometer
Absorption correction: none
18724 measured reflections
3726 independent reflections
3615 reflections with I > 2σ(I)
R_int = 0.037

Refinement

R[F² > 2σ(F²)] = 0.037
wR(F²) = 0.096
S = 1.05
3726 reflections
277 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.41 e Å⁻³
Δρ_min = −0.21 e Å⁻³
Absolute structure: Flack (1983 ), 1587 Friedel pairs
Flack parameter: 0.14 (18)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O2ⁱ	0.82	1.99	2.757 (2)	155
O2—H2A⋯O1ⁱ	0.82	2.07	2.787 (2)	146
Symmetry code: (i) $[-x+1, y-{\script{1\over 2}}, -z+2]$ .

Data collection: SMART (Bruker, 2003 ); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053680800144X/gw2037sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S160053680800144X/gw2037Isup2.hkl

checkCIF report

Comment top

The structure was solved using Direct methods and difference Fourier techniques SHELXTL, V6.12 (Sheldrick, 2008). Hydrogen atoms were placed in their expected chemical positions using the HFIX command and were included in the final cycles of least squares with isotropic U^ij related to the atoms ridden upon. All non-hydrogen atoms were refined anisotropically.Structure solution, refinement, graphics and generation of publication materials were performed by using SHELXTL, V6.12 software. Additional details of data collection and structure refinement are given in Table 1.

Related literature top

For the synthesis of analogs of salvinorin A, see: Bikbulatov et al. (2007); Lee et al. (2006); Beguin et al. (2006); Stewart et al. (2006) and other references cited therein. For modifications of salvinorin A with changed pharmacological profile, see: Rothman et al. (2007); Groer et al. (2007); Tidgewell et al. (2006); Harding et al. (2005, 2006).

Experimental top

Synthesis of hemiacetal (2): Salvinorin A (10 mg, 23 mmol) was placed in aqueous 5% KOH (5 ml) and refluxed for two hours producing a yellow solution. Upon reaching room temperature, the solution was cooled in an ice bath and neutralized with cold aqueous 0.5M HCl. The resulting precipitate was collected by vacuum filtration. The product was purified by passing through a short silica column eluting with ethyl acetate to yield 6.2 mg of 1a (69%).

1 ml of TMSCHN₂ (0.13 mmol) in benzene was added at room temperature to a solution of 1a (20 mg, 0.05 mmol) in methanol (5 ml). The mixture was stirred at room temperature for 30 min and concentrated to give the corresponding dimethyl ester 2. The product was purified by column chromatography using hexanes: ethyl acetate (2:1) for elution. Yield 18.3 mg (87%).

Crystals of dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9 bS)-2-(3-furyl)-9,9a-dihydroxy-3a,6a-dimethyldodecahydrobenzo[de]chromene-4,7-dicarboxylate (2) were obtained from slow evaporation of a solution in ethyl acetate/hexanes 1:9. A suitable crystal was coated with Paratone N oil, suspended in a CryoLoop (Hampton Research) and placed in a cooled nitrogen gas stream at 100 K on a Bruker D8 APEX II CCD sealed tube diffractometer with graphite monochromated Cu K_a(1.54178 Å) radiation. Data were measured using a series of combinations of phi and omega scans with 10 s frame exposures and 0.5^oframe widths. Data collection, indexing and initial cell refinements were all carried out using APEX II software (Bruker, 2003).Frame integration and final cell refinements were done using SAINT (Bruker, 2003) software. The final cell parameters were determined from least-squares refinement on 3446 reflections

Considering that the Flack parameter (Flack, 1983) does not confirm unambiguously the absolute configuration of the molecule, The chiral centers were assigned based in the original known configuration of the starting material, Salvinorin A.

Computing details top

Data collection: SMART (Bruker, 2003); cell refinement: SMART (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

	Fig. 1. Molecular projection, showing the atom-labeling scheme. H atoms were ommited to allow better visualization.
	Fig. 2. The packing in the crystal structure, showing the O—H···O hydrogen bonds as dashed blue lines.
	Fig. 3. Synthesis of the title compound

dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9bS)-2-(3-furyl)-9,9a-dihydroxy-3a,6a-dimethyldodecahydrobenzo[de]chromene-4,7-dicarboxylate top

Crystal data top

C₂₂H₃₀O₈	F(000) = 452
M_r = 422.46	D_x = 1.355 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2yb	Cell parameters from 8551 reflections
a = 11.6801 (5) Å	θ = 3.0–69.4°
b = 6.0522 (3) Å	µ = 0.86 mm⁻¹
c = 15.3739 (6) Å	T = 296 K
β = 107.678 (2)°	Blocks, colourless
V = 1035.47 (8) Å³	0.32 × 0.15 × 0.13 mm
Z = 2

Data collection top

Bruker SMART CCD area-detector diffractometer	3615 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube, Siemens KFF Cu 2 K90	R_int = 0.037
Graphite monochromator	θ_max = 69.4°, θ_min = 3.0°
phi and ω scans	h = −13→13
18724 measured reflections	k = −7→7
3726 independent reflections	l = −18→18

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.037	H-atom parameters constrained
wR(F²) = 0.096	w = 1/[σ²(F_o²) + (0.0458P)² + 0.4492P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max < 0.001
3726 reflections	Δρ_max = 0.42 e Å⁻³
277 parameters	Δρ_min = −0.21 e Å⁻³
1 restraint	Absolute structure: Flack (1983), 1587 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.14 (18)

Crystal data top

C₂₂H₃₀O₈	V = 1035.47 (8) Å³
M_r = 422.46	Z = 2
Monoclinic, P2₁	Cu Kα radiation
a = 11.6801 (5) Å	µ = 0.86 mm⁻¹
b = 6.0522 (3) Å	T = 296 K
c = 15.3739 (6) Å	0.32 × 0.15 × 0.13 mm
β = 107.678 (2)°

Data collection top

Bruker SMART CCD area-detector diffractometer	3615 reflections with I > 2σ(I)
18724 measured reflections	R_int = 0.037
3726 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.037	H-atom parameters constrained
wR(F²) = 0.096	Δρ_max = 0.42 e Å⁻³
S = 1.05	Δρ_min = −0.21 e Å⁻³
3726 reflections	Absolute structure: Flack (1983), 1587 Friedel pairs
277 parameters	Absolute structure parameter: 0.14 (18)
1 restraint

Special details top

Experimental. The structure was solved using Direct methods and difference Fourier techniques SHELXTL, V6.12 (Bruker, 2003). Hydrogen atoms were placed in their expected chemical positions using the HFIX command and were included in the final cycles of least squares with isotropic U^ij related to the atoms ridden upon. All non-hydrogen atoms were refined anisotropically.Structure solution, refinement, graphics and generation of publication materials were performed by using SHELXTL, V6.12 software. Additional details of data collection and structure refinement are given in Table 1.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)

are estimated using the full covariance matrix. The cell e.s.d.'s are taken

into account individually in the estimation of e.s.d.'s in distances, angles

and torsion angles; correlations between e.s.d.'s in cell parameters are only

used when they are defined by crystal symmetry. An approximate (isotropic)

treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and

goodness of fit S are based on F², conventional R-factors R are based

on F, with F set to zero for negative F². The threshold expression of

F² > σ(F²) is used only for calculating R-factors(gt) etc. and is

not relevant to the choice of reflections for refinement. R-factors based

on F² are statistically about twice as large as those based on F, and R-

factors based on ALL data will be even larger.

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

	x	y	z	U_iso*/U_eq
C2	0.18522 (17)	0.9011 (4)	0.91971 (13)	0.0308 (5)
H2	0.1571	0.7482	0.9184	0.037*
C5	0.15034 (17)	0.9159 (3)	0.58226 (12)	0.0226 (4)
H5A	0.1171	0.7690	0.5668	0.027*
H5B	0.1226	1.0076	0.5282	0.027*
C3	0.12566 (17)	1.0070 (4)	0.82782 (12)	0.0261 (4)
H3A	0.1552	1.1568	0.8281	0.031*
H3B	0.0396	1.0144	0.8176	0.031*
C6	0.28737 (16)	0.9033 (3)	0.61198 (12)	0.0217 (4)
H6A	0.3195	1.0521	0.6224	0.026*
H6B	0.3122	0.8401	0.5626	0.026*
C4	0.10549 (16)	1.0123 (3)	0.65832 (12)	0.0209 (4)
H4	0.1380	1.1622	0.6711	0.025*
C8	0.54094 (17)	0.7152 (4)	0.82950 (13)	0.0283 (4)
H8A	0.5286	0.5568	0.8302	0.034*
H8B	0.6268	0.7428	0.8472	0.034*
C9	0.48763 (17)	0.8258 (3)	0.89657 (12)	0.0256 (4)
H9	0.4971	0.9857	0.8914	0.031*
C7	0.48158 (17)	0.8048 (3)	0.73302 (12)	0.0230 (4)
H7	0.4950	0.9648	0.7349	0.028*
C3A	0.15070 (16)	0.8761 (3)	0.74901 (11)	0.0202 (4)
C6A	0.34211 (16)	0.7655 (3)	0.69886 (12)	0.0197 (4)
C9A	0.35251 (18)	0.7770 (3)	0.87112 (13)	0.0239 (4)
C9B	0.29098 (16)	0.8644 (3)	0.77341 (11)	0.0191 (4)
H9B	0.3154	1.0198	0.7767	0.023*
C10	0.16237 (19)	1.0186 (5)	0.99865 (14)	0.0448 (7)
C12	0.1441 (3)	1.0759 (8)	1.13703 (17)	0.0705 (12)
H12	0.1433	1.0539	1.1967	0.085*
C11	0.1675 (3)	0.9226 (8)	1.0830 (2)	0.0778 (12)
H11	0.1846	0.7751	1.0985	0.093*
C13	0.1359 (3)	1.2334 (7)	1.00599 (18)	0.0751 (12)
H13	0.1281	1.3414	0.9615	0.090*
C16	−0.03024 (17)	1.0299 (3)	0.62641 (12)	0.0252 (4)
C18	0.54524 (17)	0.7069 (4)	0.66942 (13)	0.0261 (4)
C14	0.08432 (17)	0.6535 (3)	0.73785 (13)	0.0257 (4)
H14A	0.1270	0.5548	0.7856	0.039*
H14B	0.0801	0.5906	0.6796	0.039*
H14C	0.0045	0.6763	0.7414	0.039*
C15	0.31545 (17)	0.5190 (3)	0.67784 (13)	0.0259 (4)
H15A	0.2316	0.5000	0.6460	0.039*
H15B	0.3359	0.4370	0.7339	0.039*
H15C	0.3623	0.4661	0.6405	0.039*
C19	0.6056 (3)	0.7648 (5)	0.53744 (18)	0.0490 (7)
H19A	0.6898	0.7427	0.5672	0.073*
H19B	0.5951	0.8701	0.4890	0.073*
H19C	0.5692	0.6270	0.5128	0.073*
C17	−0.1957 (2)	1.2172 (6)	0.65095 (18)	0.0505 (7)
H17A	−0.2322	1.2419	0.5868	0.076*
H17B	−0.2122	1.3404	0.6846	0.076*
H17C	−0.2279	1.0848	0.6688	0.076*
O1	0.31411 (11)	0.9003 (3)	0.93685 (8)	0.0273 (3)
O3	0.32773 (13)	0.5526 (2)	0.87711 (9)	0.0286 (3)
H3	0.3709	0.5030	0.9256	0.043*
O5	−0.09773 (12)	0.9134 (3)	0.57030 (10)	0.0352 (4)
O6	−0.06776 (13)	1.1939 (3)	0.66985 (10)	0.0349 (4)
O2	0.54549 (13)	0.7663 (3)	0.98856 (9)	0.0311 (3)
H2A	0.5935	0.6663	0.9902	0.047*
O7	0.58818 (15)	0.5249 (3)	0.67619 (11)	0.0429 (4)
O8	0.54884 (15)	0.8474 (3)	0.60324 (11)	0.0383 (4)
O4	0.1223 (2)	1.2643 (7)	1.09199 (17)	0.1192 (16)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C2	0.0193 (9)	0.0538 (13)	0.0210 (9)	−0.0075 (10)	0.0087 (7)	−0.0039 (9)
C5	0.0235 (9)	0.0264 (9)	0.0172 (8)	−0.0001 (8)	0.0053 (7)	0.0016 (7)
C3	0.0159 (9)	0.0401 (11)	0.0237 (9)	−0.0026 (8)	0.0078 (7)	−0.0048 (9)
C6	0.0233 (9)	0.0242 (9)	0.0195 (8)	−0.0030 (8)	0.0093 (7)	−0.0008 (7)
C4	0.0202 (9)	0.0206 (9)	0.0226 (9)	−0.0014 (7)	0.0074 (7)	−0.0020 (7)
C8	0.0190 (9)	0.0402 (12)	0.0239 (9)	0.0031 (8)	0.0037 (8)	−0.0023 (8)
C9	0.0222 (10)	0.0362 (11)	0.0178 (8)	−0.0017 (8)	0.0051 (7)	−0.0020 (8)
C7	0.0198 (9)	0.0281 (10)	0.0215 (9)	−0.0020 (8)	0.0067 (7)	−0.0046 (7)
C3A	0.0161 (9)	0.0257 (9)	0.0185 (8)	−0.0028 (7)	0.0050 (7)	−0.0016 (7)
C6A	0.0174 (9)	0.0236 (9)	0.0180 (8)	−0.0013 (7)	0.0054 (7)	−0.0011 (7)
C9A	0.0222 (10)	0.0311 (10)	0.0199 (8)	−0.0026 (8)	0.0084 (7)	0.0001 (8)
C9B	0.0174 (9)	0.0207 (9)	0.0190 (8)	−0.0034 (7)	0.0053 (7)	−0.0003 (7)
C10	0.0168 (10)	0.098 (2)	0.0218 (10)	−0.0058 (12)	0.0089 (8)	−0.0109 (12)
C12	0.0373 (15)	0.160 (4)	0.0190 (11)	0.0052 (19)	0.0150 (10)	−0.0089 (18)
C11	0.082 (2)	0.126 (3)	0.0380 (15)	−0.036 (2)	0.0370 (15)	−0.0145 (18)
C13	0.072 (2)	0.120 (3)	0.0285 (13)	0.050 (2)	0.0076 (13)	−0.0206 (16)
C16	0.0219 (9)	0.0290 (10)	0.0249 (9)	0.0025 (8)	0.0075 (8)	0.0039 (8)
C18	0.0175 (9)	0.0341 (11)	0.0254 (9)	0.0010 (8)	0.0048 (7)	−0.0053 (8)
C14	0.0209 (9)	0.0306 (10)	0.0243 (9)	−0.0062 (8)	0.0048 (7)	0.0024 (8)
C15	0.0252 (10)	0.0257 (10)	0.0254 (9)	0.0003 (8)	0.0060 (8)	−0.0028 (8)
C19	0.0518 (16)	0.0625 (17)	0.0461 (13)	0.0102 (13)	0.0350 (12)	0.0024 (13)
C17	0.0283 (11)	0.0711 (18)	0.0494 (14)	0.0197 (12)	0.0077 (11)	−0.0069 (13)
O1	0.0180 (7)	0.0454 (8)	0.0191 (6)	−0.0045 (6)	0.0066 (5)	−0.0041 (6)
O3	0.0278 (7)	0.0308 (7)	0.0235 (6)	−0.0033 (6)	0.0022 (5)	0.0080 (6)
O5	0.0237 (7)	0.0461 (9)	0.0313 (7)	−0.0011 (7)	0.0015 (6)	−0.0102 (7)
O6	0.0259 (7)	0.0379 (8)	0.0393 (8)	0.0089 (7)	0.0074 (6)	−0.0058 (7)
O2	0.0292 (8)	0.0361 (8)	0.0244 (7)	0.0024 (6)	0.0027 (6)	−0.0009 (6)
O7	0.0443 (9)	0.0492 (10)	0.0389 (8)	0.0204 (8)	0.0181 (7)	0.0006 (8)
O8	0.0409 (9)	0.0458 (10)	0.0395 (8)	0.0042 (7)	0.0290 (7)	0.0025 (7)
O4	0.0566 (14)	0.244 (5)	0.0456 (13)	0.063 (2)	−0.0011 (11)	−0.063 (2)

Geometric parameters (Å, º) top

C2—O1	1.447 (2)	C9A—O1	1.433 (2)
C2—C10	1.499 (3)	C9A—C9B	1.548 (2)
C2—C3	1.515 (3)	C9B—H9B	0.9800
C2—H2	0.9800	C10—C13	1.349 (5)
C5—C6	1.527 (3)	C10—C11	1.405 (4)
C5—C4	1.535 (2)	C12—O4	1.318 (6)
C5—H5A	0.9700	C12—C11	1.328 (5)
C5—H5B	0.9700	C12—H12	0.9300
C3—C3A	1.548 (3)	C11—H11	0.9300
C3—H3A	0.9700	C13—O4	1.391 (3)
C3—H3B	0.9700	C13—H13	0.9300
C6—C6A	1.540 (2)	C16—O5	1.204 (2)
C6—H6A	0.9700	C16—O6	1.342 (3)
C6—H6B	0.9700	C18—O7	1.202 (3)
C4—C16	1.514 (2)	C18—O8	1.336 (3)
C4—C3A	1.567 (2)	C14—H14A	0.9600
C4—H4	0.9800	C14—H14B	0.9600
C8—C9	1.513 (3)	C14—H14C	0.9600
C8—C7	1.533 (3)	C15—H15A	0.9600
C8—H8A	0.9700	C15—H15B	0.9600
C8—H8B	0.9700	C15—H15C	0.9600
C9—O2	1.416 (2)	C19—O8	1.456 (3)
C9—C9A	1.535 (3)	C19—H19A	0.9600
C9—H9	0.9800	C19—H19B	0.9600
C7—C18	1.517 (3)	C19—H19C	0.9600
C7—C6A	1.571 (2)	C17—O6	1.440 (3)
C7—H7	0.9800	C17—H17A	0.9600
C3A—C14	1.538 (3)	C17—H17B	0.9600
C3A—C9B	1.568 (2)	C17—H17C	0.9600
C6A—C15	1.538 (3)	O3—H3	0.8200
C6A—C9B	1.563 (2)	O2—H2A	0.8200
C9A—O3	1.398 (2)

O1—C2—C10	106.57 (15)	O3—C9A—O1	110.13 (15)
O1—C2—C3	109.20 (15)	O3—C9A—C9	112.80 (17)
C10—C2—C3	114.2 (2)	O1—C9A—C9	103.77 (15)
O1—C2—H2	108.9	O3—C9A—C9B	110.57 (15)
C10—C2—H2	108.9	O1—C9A—C9B	110.73 (15)
C3—C2—H2	108.9	C9—C9A—C9B	108.67 (15)
C6—C5—C4	111.12 (14)	C9A—C9B—C6A	114.36 (15)
C6—C5—H5A	109.4	C9A—C9B—C3A	113.02 (14)
C4—C5—H5A	109.4	C6A—C9B—C3A	116.49 (14)
C6—C5—H5B	109.4	C9A—C9B—H9B	103.6
C4—C5—H5B	109.4	C6A—C9B—H9B	103.6
H5A—C5—H5B	108.0	C3A—C9B—H9B	103.6
C2—C3—C3A	111.77 (17)	C13—C10—C11	105.5 (3)
C2—C3—H3A	109.3	C13—C10—C2	128.8 (3)
C3A—C3—H3A	109.3	C11—C10—C2	125.6 (3)
C2—C3—H3B	109.3	O4—C12—C11	108.6 (3)
C3A—C3—H3B	109.3	O4—C12—H12	125.7
H3A—C3—H3B	107.9	C11—C12—H12	125.7
C5—C6—C6A	114.07 (15)	C12—C11—C10	109.2 (4)
C5—C6—H6A	108.7	C12—C11—H11	125.4
C6A—C6—H6A	108.7	C10—C11—H11	125.4
C5—C6—H6B	108.7	C10—C13—O4	107.7 (3)
C6A—C6—H6B	108.7	C10—C13—H13	126.1
H6A—C6—H6B	107.6	O4—C13—H13	126.1
C16—C4—C5	110.25 (14)	O5—C16—O6	123.23 (18)
C16—C4—C3A	111.23 (15)	O5—C16—C4	125.74 (18)
C5—C4—C3A	112.15 (15)	O6—C16—C4	111.03 (16)
C16—C4—H4	107.7	O7—C18—O8	122.7 (2)
C5—C4—H4	107.7	O7—C18—C7	125.1 (2)
C3A—C4—H4	107.7	O8—C18—C7	112.15 (17)
C9—C8—C7	110.12 (16)	C3A—C14—H14A	109.5
C9—C8—H8A	109.6	C3A—C14—H14B	109.5
C7—C8—H8A	109.6	H14A—C14—H14B	109.5
C9—C8—H8B	109.6	C3A—C14—H14C	109.5
C7—C8—H8B	109.6	H14A—C14—H14C	109.5
H8A—C8—H8B	108.2	H14B—C14—H14C	109.5
O2—C9—C8	113.43 (16)	C6A—C15—H15A	109.5
O2—C9—C9A	110.34 (15)	C6A—C15—H15B	109.5
C8—C9—C9A	110.20 (15)	H15A—C15—H15B	109.5
O2—C9—H9	107.5	C6A—C15—H15C	109.5
C8—C9—H9	107.5	H15A—C15—H15C	109.5
C9A—C9—H9	107.5	H15B—C15—H15C	109.5
C18—C7—C8	108.61 (16)	O8—C19—H19A	109.5
C18—C7—C6A	112.77 (14)	O8—C19—H19B	109.5
C8—C7—C6A	112.85 (15)	H19A—C19—H19B	109.5
C18—C7—H7	107.4	O8—C19—H19C	109.5
C8—C7—H7	107.4	H19A—C19—H19C	109.5
C6A—C7—H7	107.4	H19B—C19—H19C	109.5
C14—C3A—C3	109.09 (16)	O6—C17—H17A	109.5
C14—C3A—C4	109.84 (14)	O6—C17—H17B	109.5
C3—C3A—C4	109.53 (15)	H17A—C17—H17B	109.5
C14—C3A—C9B	116.24 (16)	O6—C17—H17C	109.5
C3—C3A—C9B	105.55 (14)	H17A—C17—H17C	109.5
C4—C3A—C9B	106.38 (14)	H17B—C17—H17C	109.5
C15—C6A—C6	109.81 (15)	C9A—O1—C2	113.84 (14)
C15—C6A—C9B	115.31 (16)	C9A—O3—H3	109.5
C6—C6A—C9B	106.15 (14)	C16—O6—C17	116.61 (17)
C15—C6A—C7	109.91 (15)	C9—O2—H2A	109.5
C6—C6A—C7	108.86 (15)	C18—O8—C19	115.88 (19)
C9B—C6A—C7	106.57 (13)	C12—O4—C13	108.9 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2ⁱ	0.82	1.99	2.757 (2)	155
O2—H2A···O1ⁱ	0.82	2.07	2.787 (2)	146

Symmetry code: (i) −x+1, y−1/2, −z+2.

Experimental details

Crystal data
Chemical formula	C₂₂H₃₀O₈
M_r	422.46
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	296
a, b, c (Å)	11.6801 (5), 6.0522 (3), 15.3739 (6)
β (°)	107.678 (2)
V (Å³)	1035.47 (8)
Z	2
Radiation type	Cu Kα
µ (mm⁻¹)	0.86
Crystal size (mm)	0.32 × 0.15 × 0.13

Data collection
Diffractometer	Bruker SMART CCD area-detector diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	18724, 3726, 3615
R_int	0.037
(sin θ/λ)_max (Å⁻¹)	0.607

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.037, 0.096, 1.05
No. of reflections	3726
No. of parameters	277
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.42, −0.21
Absolute structure	Flack (1983), 1587 Friedel pairs
Absolute structure parameter	0.14 (18)

Computer programs: SMART (Bruker, 2003), SAINT (Bruker, 2003), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2ⁱ	0.82	1.99	2.757 (2)	155.3
O2—H2A···O1ⁱ	0.82	2.07	2.787 (2)	146.2

Symmetry code: (i) −x+1, y−1/2, −z+2.

Acknowledgements

The authors thank Dr K. Hardcastle for his helpful advice. We also thank the Center for Disease Control and Prevention, USA, for providing financial assistance (CDC cooperative agreements 1UO1 CI000211–03 and1UO1 CI000362–01). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program grant No. C06 Rr-14503–01 from the National Center for Research Resources, National Institutes of Health.

References

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