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The structure of an iridolactone isolated from Valeriana laxiflora was established as (4R,4aR,6S,7S,7aS)-6-hydroxy-7-hydroxy­methyl-4-methyl­per­hydro­cyclo­penta­[c]­pyran-1-one chloro­form solvate, C10H16O4·CHCl3. The two rings are cis-fused. The [delta]-lactone ring adopts a slightly twisted half-chair conformation with approximate planarity of the lactone group and the cyclo­pentane ring adopts an envelope conformation. The hydroxy group, the hydroxymethyl group and the methyl group all have [beta] orientations. The absolute configuration was determined using anomalous dispersion data enhanced by the adventitious inclusion of a chloro­form solvent mol­ecule. Hydro­gen bonding, crystal packing and ring conformations are discussed in detail.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270104021511/sx1145sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270104021511/sx1145Isup2.hkl
Contains datablock I

CCDC reference: 257000

Comment top

The alarming increase in the number of deaths due to tuberculosis (TB) and growing resistance to existing drugs has created an urgent need for the identification of leads for new antimycobacterial drugs. There were 8.3 million new cases of tuberculosis in the year 2000 alone, and this number is on the rise. Approximately one death every 15 s is due to TB, for a total of about two million TB deaths annually (Corbett et al., 2003). Strains of TB resistant to existing drugs are found in nearly every country (Cohn et al., 1997), and a percentage of these strains are resistant to multiple drugs, making effective treatment extremely expensive and in many cases impossible. Most patients in developing countries, where TB is an even bigger problem than elsewhere in the world, cannot afford expensive drug treatments. There have been no new drugs developed for TB in over 30 years. Current TB therapy relies on drugs that are 50 years old and take six to nine months to complete, making patient compliance very difficult (World Health Organization, 2003). As a part of the International Cooperative Biodiversity Group, our program focuses on the search for novel antitubercular principles of plant or microbial origins from the dryland biodiversity of Latin America. It is in this regard that the bioassay guided chemical investigation of the Chilean plant Valeriana laxiflora DC (Valerianaceae) was initiated. The methanolic extract of V. laxiflora was found to be active against the H37Rv strain (ATCC 27294) of Mycobacterium tuberculosis, and the bioassay directed fractionation led to the isolation of the title compound (I), an iridolactone, as previously described (Gu et al., 2004). X-ray crystallographic analysis of (I) was initiated to establish unequivocally its chemical structure and to determine absolute and relative stereochemistry of all the functional groups and the ring junction at atoms C5 and C9.

The two rings are cis-fused, with both atom H5 and atom H9 β oriented, as shown in Fig. 1. The δ-lactone ring adopts a slightly twisted half-chair conformation and the cyclopentane ring adopts an envelope conformation. The hydroxy group at atom C7 and the methyl hydroxy group at atom C8 both have β orientations, as does the C4 methyl group. The unusually long bond distance of 1.572 (7) Å between the bridge atoms C5 and C9 suggests strain in the fused system. This observation has been made previously for a closely related iridolactone (Eisenbraun et al., 1981). As expected in the case of δ-lactones, differences in the two C—O1 bond distances are observed, the C3—O1 bond being longer [1.45 (7)3 Å] than the C1—O1 bond [1.336 (7) Å] (Cheung et al., 1965). The C9—C1(O2)—O1—C3 lactone group is almost planar, with a root mean deviation of 0.0208 Å and a maximum deviation of 0.352 (0.0038) Å observed for atom O1. The C3—O1—C1—O2 torsion angle is +177.3 (5)°, showing only a slight deviation from planarity. This configuration concurs with that reported for (+)-nepetalic acid (Eisenbraun et al., 1981) and an iridane-derived lactone, boonein (Marini-Bettolo et al., 1983). The packing is dominated by hydrogen bonding, which creates an infinite tape of molecules coincident with the 21 axis (Table 1 and Fig. 2). The C7 hydroxy group of each molecule is hydrogen bonded through the O3/H3 group to the b-translated neighbouring methylhydroxy atom O4 to form a chain. Each chain faces another chain of molecules related by a 21 axis, so that the cyclopentane rings of the first chain are facing the cyclopentane rings of the next. Each C7 hydroxy group is then also hydrogen bonded through atom O3 to the H4/O4 methyl hydroxy group of the molecule facing it, forming a molecular tape. A solvent-accessible channel along each side of the tape allows for hydrogen bonding to the chloroform solvent (Fig. 1). Each molecule of chloroform is hydrogen bonded through atom H20 to atom O4 of the methylhydroxy group. In addition, each carbonyl O2 atom is hydrogen bonded to atom H5 of an adjacent molecule in the same tape, as well as to atom H9 of a molecule in an adjoining tape. The inclusion of a chloroform solvent molecule in the crystal lattice allowed the the anomalous dispersion data to be used to arrive at the absolute configuration of (I) as 4R,5R,7S,8S,9S. The same absolute configuration has been determined by the Mosher ester procedure, which also unequivocally proves enantiomeric purity (Gu et al., 2004). Although, we are on the edge of full confidence in our refinement of the Flack parameter (Flack & Bernardinelli, 2000), our results are fully consistent with supporting NMR data from the synthesis of R– and S-MTPA (α-methoxy-α-trifluoromethylphenylacetic acid) esters. The crystals were isolated as very thin plates, and crystal decomposition due to evaporation of solvent at room temperature posed considerable problems in the selection and mounting of a suitable crystal. Nevertheless, we were able to obtain important information on the structure, conformation and absolute configuration of (I) from this study. This information can now be used to predict the three-dimensional structure of closely-related iridolactones isolated as natural products but which do not crsytallize. To our knowledge, this is the first report of the absolute configuration of 1-iridolactones based on X-ray data.

Experimental top

Dried and powdered aerial parts as well as roots of V. laxiflora (770 g) were extracted repeatedly with MeOH. This MeOH extract was filtered, the solvent was evaporated under vaccuum and the resultant extract was partitioned between 90% aqueous MeOH and n-hexane. The 90% aqueous MeOH soluble portion was dried under vacuum and subsequently partitioned between CH2Cl2 and H2O (1:1). The CH2Cl2 soluble extract was further fractionated by column chromatography on a silica gel column using a step gradient of CHCl3/MeOH. The fraction eluting with CHCl3/MeOH (20:1, 2.2 g) was chromatographed on a silica gel column using an n-hexane/iPrOH/MeOH step gradient. The fraction eluting with n-hexane/iPrOH/MeOH (18:1:1, 370 mg) was applied to a Sephadex LH-20 column, using MeOH as the mobile phase. The fraction containing (I) (60 mg) was purified by reversed-phase high-perfomance liquid chromatography (RP-HPLC) using CH3CN/H2O (1:1). Compound (I) (14 mg) was isolated at Rf = 0.62 (Gu et al., 2004). Crystals were obtained as very thin colorless rectangular plates using CHCl3. Crystals were removed in a drop of the mother liquor using a pipette and transfered to a drop of paratone oil to seal in the solvent and prevent evaporation. A suitable crystal was selected and transfered to a glass fiber, covered by a thin protective film of paratone and quickly mounted to prevent solvent loss by evaporation. The paratone oil was graciously provided by Professor Marilyn Olmstead of the University of California, Davis.

Refinement top

The best available crystal, which was larger than the beam in one dimension, was used in order to enhance diffraction (Gorbitz, 1999). Nevertheless, the observed diffraction pattern was weak. The structure was solved using direct methods. H atoms were easily visible in difference Fourier maps, but all H atoms were placed at ideal positions and constrained to ride on the atoms to which they were bonded (C—H = 0.98–1.00 Å), except the hydroxy H atoms, which were constrained to an O—H distance of 0.84 Å and a C—O—H angle of 109.5°. As a result of the fortuitous inclusion of a heavy-atom solvent molecule (CHCl3) in the crystal structure, we were able to use the anomalous dispersion data to arrive at the absolute configuration of (I).

Computing details top

Data collection: SMART (Bruker, 1997); cell refinement: SMART; data reduction: SAINT (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. A view of (I), with 50% probability displacement ellipsoids.
[Figure 2] Fig. 2. Packing geometry of (I), looking at the face of the hydrogen-bonded tape. Atoms labelled with the suffixes A and B are at symmetry positions (-x, y + 1/2, −z + 2) and (x, y − 1, z), respectively.
(4R,5R,7S,8S,9S)-7-hydroxy-8-hydroxymethyl-4-methyl-perhydrocyclopenta[c]pyran- 1-one chloroform solvate top
Crystal data top
C10H16O4·CHCl3F(000) = 332
Mr = 319.60Dx = 1.491 Mg m3
Monoclinic, P21Melting point = 91–93 K
Hall symbol: P 2ybMo Kα radiation, λ = 0.71073 Å
a = 10.523 (3) ÅCell parameters from 794 reflections
b = 6.0404 (15) Åθ = 2.6–18.8°
c = 11.231 (3) ŵ = 0.65 mm1
β = 94.478 (5)°T = 173 K
V = 711.7 (3) Å3Parallelepiped, colourless
Z = 20.78 × 0.09 × 0.02 mm
Data collection top
Bruker SMART CCD area-detector
diffractometer
2420 independent reflections
Radiation source: fine-focus sealed tube1504 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.088
ϕ and ω scansθmax = 25.0°, θmin = 1.8°
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
h = 1212
Tmin = 0.268, Tmax = 0.987k = 77
6446 measured reflectionsl = 1313
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.062H-atom parameters constrained
wR(F2) = 0.104 w = 1/[σ2(Fo2) + (0.0327P)2]
where P = (Fo2 + 2Fc2)/3
S = 0.98(Δ/σ)max < 0.001
2420 reflectionsΔρmax = 0.30 e Å3
161 parametersΔρmin = 0.26 e Å3
128 restraintsAbsolute structure: Flack (1983), 1032 Friedel pairs
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.11 (12)
Crystal data top
C10H16O4·CHCl3V = 711.7 (3) Å3
Mr = 319.60Z = 2
Monoclinic, P21Mo Kα radiation
a = 10.523 (3) ŵ = 0.65 mm1
b = 6.0404 (15) ÅT = 173 K
c = 11.231 (3) Å0.78 × 0.09 × 0.02 mm
β = 94.478 (5)°
Data collection top
Bruker SMART CCD area-detector
diffractometer
2420 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 2003)
1504 reflections with I > 2σ(I)
Tmin = 0.268, Tmax = 0.987Rint = 0.088
6446 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.062H-atom parameters constrained
wR(F2) = 0.104Δρmax = 0.30 e Å3
S = 0.98Δρmin = 0.26 e Å3
2420 reflectionsAbsolute structure: Flack (1983), 1032 Friedel pairs
161 parametersAbsolute structure parameter: 0.11 (12)
128 restraints
Special details top

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.

A previous data collection on a smaller crystal was inferior and gave an even more unsatisfactory refinement of the Flack (1983) parameter than that reported here. A refinement allowing a variable occupancy for the chloroform molecule, starting at 0.95, was attempted, but after the final refinement, the value returned to full occupancy. The Flack parameter after this refinement was 0.119 (120). When compared with the original values of 0.112 (120), the s.u. value did not change and the Flack value appeared to get worse.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.1912 (4)0.3611 (6)0.4568 (3)0.0362 (11)
C10.1348 (5)0.4481 (10)0.5484 (5)0.0246 (13)
O20.0906 (3)0.6346 (8)0.5344 (3)0.0378 (10)
O30.0647 (3)0.1578 (7)0.8928 (3)0.0342 (10)
H30.08360.02270.89180.051*
C30.2504 (5)0.1447 (11)0.4704 (5)0.0385 (14)
H3B0.31260.12630.40940.046*
H3A0.18440.02880.45680.046*
O40.0414 (4)0.7213 (6)0.9032 (3)0.0326 (11)
H40.00300.67120.95600.049*
C40.3168 (4)0.1160 (10)0.5917 (4)0.0274 (13)
H4A0.37440.24600.60780.033*
C50.2182 (4)0.1193 (10)0.6822 (4)0.0238 (12)
H50.16920.02260.67590.029*
C60.2713 (5)0.1495 (11)0.8112 (4)0.0306 (13)
H6B0.28370.00430.85130.037*
H6A0.35420.22790.81470.037*
C70.1730 (5)0.2858 (9)0.8705 (5)0.0266 (13)
H70.21100.35730.94530.032*
C80.1348 (5)0.4596 (9)0.7743 (4)0.0207 (13)
H80.20800.56370.76890.025*
C90.1223 (5)0.3170 (9)0.6584 (4)0.0212 (13)
H90.03460.25230.65210.025*
C100.0183 (5)0.5939 (9)0.7956 (4)0.0292 (14)
H10B0.00220.69420.72710.035*
H10A0.05530.49420.80290.035*
C110.3991 (4)0.0941 (7)0.5994 (4)0.0475 (19)
H11C0.46200.08680.53960.071*
H11B0.34460.22420.58400.071*
H11A0.44310.10540.67930.071*
C200.2904 (4)0.7714 (7)1.1136 (4)0.0318 (15)
H200.20900.77441.06130.038*
Cl10.40796 (13)0.6408 (3)1.03652 (13)0.0442 (4)
Cl20.26433 (15)0.6295 (3)1.24554 (13)0.0485 (5)
Cl30.33798 (17)1.0475 (2)1.14733 (14)0.0483 (5)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.051 (3)0.035 (3)0.024 (2)0.000 (2)0.014 (2)0.0045 (19)
C10.023 (4)0.027 (3)0.024 (3)0.009 (3)0.000 (3)0.002 (3)
O20.056 (3)0.026 (2)0.031 (2)0.009 (3)0.0012 (18)0.011 (2)
O30.057 (3)0.008 (2)0.040 (2)0.004 (2)0.0143 (18)0.005 (2)
C30.052 (4)0.033 (3)0.034 (3)0.006 (4)0.023 (3)0.008 (4)
O40.055 (3)0.021 (2)0.025 (2)0.0035 (19)0.0227 (19)0.0015 (18)
C40.028 (3)0.017 (3)0.038 (3)0.007 (3)0.009 (2)0.000 (3)
C50.032 (3)0.013 (3)0.027 (3)0.001 (3)0.004 (2)0.003 (3)
C60.033 (3)0.026 (3)0.031 (3)0.013 (3)0.004 (2)0.005 (3)
C70.037 (4)0.016 (3)0.027 (3)0.004 (3)0.007 (3)0.001 (3)
C80.023 (3)0.015 (3)0.024 (3)0.001 (3)0.004 (3)0.004 (2)
C90.024 (3)0.020 (3)0.019 (3)0.006 (3)0.001 (2)0.002 (2)
C100.030 (3)0.023 (4)0.035 (3)0.001 (3)0.005 (2)0.001 (3)
C110.049 (5)0.030 (4)0.065 (5)0.010 (3)0.016 (4)0.006 (4)
C200.035 (4)0.027 (4)0.035 (4)0.002 (3)0.012 (3)0.002 (3)
Cl10.0329 (9)0.0441 (10)0.0563 (10)0.0009 (10)0.0086 (7)0.0141 (10)
Cl20.0601 (11)0.0372 (10)0.0499 (10)0.0045 (11)0.0148 (8)0.0154 (10)
Cl30.0715 (12)0.0295 (9)0.0463 (10)0.0066 (10)0.0204 (8)0.0000 (9)
Geometric parameters (Å, º) top
O1—C11.335 (6)C6—H6B0.9900
O1—C31.451 (7)C6—H6A0.9900
C1—O21.224 (6)C7—C81.537 (7)
C1—C91.482 (7)C7—H71.0000
O3—C71.416 (6)C8—C101.505 (7)
O3—H30.8400C8—C91.558 (7)
C3—C41.492 (7)C8—H81.0000
C3—H3B0.9900C9—H91.0000
C3—H3A0.9900C10—H10B0.9900
O4—C101.438 (6)C10—H10A0.9900
O4—H40.8400C11—H11C0.9800
C4—C51.508 (6)C11—H11B0.9800
C4—C111.535 (7)C11—H11A0.9800
C4—H4A1.0000C20—Cl21.752 (4)
C5—C61.523 (6)C20—Cl11.752 (4)
C5—C91.572 (7)C20—Cl31.774 (5)
C5—H51.0000C20—H201.0000
C6—C71.516 (7)
C1—O1—C3119.1 (4)O3—C7—H7111.2
O2—C1—O1116.8 (5)C6—C7—H7111.2
O2—C1—C9122.7 (5)C8—C7—H7111.2
O1—C1—C9120.4 (5)C10—C8—C7115.4 (4)
C7—O3—H3109.5C10—C8—C9114.5 (4)
O1—C3—C4111.6 (5)C7—C8—C9102.1 (4)
O1—C3—H3B109.3C10—C8—H8108.2
C4—C3—H3B109.3C7—C8—H8108.2
O1—C3—H3A109.3C9—C8—H8108.2
C4—C3—H3A109.3C1—C9—C8113.2 (5)
H3B—C3—H3A108.0C1—C9—C5116.7 (4)
C10—O4—H4109.5C8—C9—C5105.5 (4)
C3—C4—C5108.4 (4)C1—C9—H9107.0
C3—C4—C11111.7 (4)C8—C9—H9107.0
C5—C4—C11112.8 (4)C5—C9—H9107.0
C3—C4—H4A107.9O4—C10—C8109.6 (4)
C5—C4—H4A107.9O4—C10—H10B109.8
C11—C4—H4A107.9C8—C10—H10B109.8
C4—C5—C6115.0 (4)O4—C10—H10A109.8
C4—C5—C9111.2 (4)C8—C10—H10A109.8
C6—C5—C9104.7 (4)H10B—C10—H10A108.2
C4—C5—H5108.6C4—C11—H11C109.5
C6—C5—H5108.6C4—C11—H11B109.5
C9—C5—H5108.6H11C—C11—H11B109.5
C7—C6—C5105.7 (4)C4—C11—H11A109.5
C7—C6—H6B110.6H11C—C11—H11A109.5
C5—C6—H6B110.6H11B—C11—H11A109.5
C7—C6—H6A110.6Cl2—C20—Cl1111.2 (2)
C5—C6—H6A110.6Cl2—C20—Cl3109.9 (2)
H6B—C6—H6A108.7Cl1—C20—Cl3109.3 (2)
O3—C7—C6111.5 (4)Cl2—C20—H20108.8
O3—C7—C8109.1 (4)Cl1—C20—H20108.8
C6—C7—C8102.3 (4)Cl3—C20—H20108.8
C3—O1—C1—O2177.2 (5)C6—C7—C8—C943.2 (5)
C3—O1—C1—C95.6 (8)O2—C1—C9—C838.1 (8)
C1—O1—C3—C438.9 (6)O1—C1—C9—C8144.9 (5)
O1—C3—C4—C565.2 (6)O2—C1—C9—C5160.8 (5)
O1—C3—C4—C11169.8 (4)O1—C1—C9—C522.2 (8)
C3—C4—C5—C6165.5 (5)C10—C8—C9—C176.7 (6)
C11—C4—C5—C670.3 (6)C7—C8—C9—C1157.9 (5)
C3—C4—C5—C946.7 (6)C10—C8—C9—C5154.5 (4)
C11—C4—C5—C9171.0 (4)C7—C8—C9—C529.1 (5)
C4—C5—C6—C7145.3 (5)C4—C5—C9—C16.1 (7)
C9—C5—C6—C723.0 (5)C6—C5—C9—C1130.9 (5)
C5—C6—C7—O374.6 (5)C4—C5—C9—C8120.6 (5)
C5—C6—C7—C841.8 (6)C6—C5—C9—C84.2 (5)
O3—C7—C8—C1049.8 (6)C7—C8—C10—O463.0 (6)
C6—C7—C8—C10168.1 (4)C9—C8—C10—O4178.9 (4)
O3—C7—C8—C975.0 (5)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O4i0.841.882.651 (5)152
O4—H4···O3ii0.841.872.654 (4)156
C20—H20···O41.002.423.402 (6)166
C5—H5···O2i1.002.703.575 (7)146
C9—H9···O2iii1.002.493.188 (6)127
Symmetry codes: (i) x, y1, z; (ii) x, y+1/2, z+2; (iii) x, y1/2, z+1.

Experimental details

Crystal data
Chemical formulaC10H16O4·CHCl3
Mr319.60
Crystal system, space groupMonoclinic, P21
Temperature (K)173
a, b, c (Å)10.523 (3), 6.0404 (15), 11.231 (3)
β (°) 94.478 (5)
V3)711.7 (3)
Z2
Radiation typeMo Kα
µ (mm1)0.65
Crystal size (mm)0.78 × 0.09 × 0.02
Data collection
DiffractometerBruker SMART CCD area-detector
diffractometer
Absorption correctionMulti-scan
(SADABS; Sheldrick, 2003)
Tmin, Tmax0.268, 0.987
No. of measured, independent and
observed [I > 2σ(I)] reflections
6446, 2420, 1504
Rint0.088
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.062, 0.104, 0.98
No. of reflections2420
No. of parameters161
No. of restraints128
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.30, 0.26
Absolute structureFlack (1983), 1032 Friedel pairs
Absolute structure parameter0.11 (12)

Computer programs: SMART (Bruker, 1997), SMART, SAINT (Bruker, 1997), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O4i0.841.882.651 (5)152
O4—H4···O3ii0.841.872.654 (4)156
C20—H20···O41.002.423.402 (6)166
C5—H5···O2i1.002.703.575 (7)146
C9—H9···O2iii1.002.493.188 (6)127
Symmetry codes: (i) x, y1, z; (ii) x, y+1/2, z+2; (iii) x, y1/2, z+1.
 

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