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Molecules 2003, 8(7), 599-606; doi:10.3390/80700599

Preparation Crystal Structure of (1S, 5S, 7S, 8R)-8-Hydroxy-7-phenyl-2,6-dioxabicyclo[3.3.0]octan-3-one
Vratislav Langer 1,*, Dalma Gyepesová 2, Marian Koman 3, Peter Kapitán 4, Matej Babjak 4, Tibor Gracza 4 and Miroslav Koóš 5
Department of Environmental Inorganic Chemistry, Chalmers University of Technology, SE-41296 Göteborg, Sweden
Institute of Inorganic Chemistry, Slovak Academy of Sciences, SK-84536 Bratislava, Slovakia
Department of  Inorganic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovakia
Department of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovakia
Institute of Chemistry, Slovak Academy of Sciences, SK-84538 Bratislava, Slovakia
Author to whom correspondence should be addressed; Fax: (+46)-31-7722846; Tel.: (+46)-31-7722877
Received: 4 September 2002; in revised form: 25 June 2003 / Accepted: 28 June 2003 / Published: 15 July 2003


The absolute configuration at two newly formed stereogenic centres (5S, 7S) during the key steps of the total synthesis of naturally occuring goniothalesdiol was established by single-crystal X-ray diffraction analysis relative to stereocentres (1S, 8R) of the title compound (alternatively named 3,6-anhydro-2-deoxy-6-phenyl-l-ido-1,4-hexonolactone, C12H12O4). The conformation of both 5-membered lactone and furanose fused rings is also discussed.
Lactones; palladium(II)-catalysis; oxycarbonylation; X-ray diffraction analysis; conformation


As a part of our long-term programme on palladium(II)-catalyzed oxycarbonylation of unsaturated polyols [1], we are interested in the preparation of naturally occuring biologically active lactones [2,3,4,5] structurally related to precursors of goniothalesdiol (1) (Figure 1). Recently, this compound was isolated from the bark of the Malaysian tree Goniothalamus borneensis (Annonaceae) and was shown to have a significant cytotoxicity against P388 mouse leukemia cells and insecticidal activities [6].
Figure 1.
Figure 1.
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Results and Discussion

The title compound 3,6-anhydro-2-deoxy-6-phenyl-l-ido-1,4-hexonolactone (2), representing the key intermediate in the first total synthesis of goniothalesdiol [5], was prepared by palladium(II)-catalyzed oxycarbonylation of diastereomeric mixture of (1S, 2S, 3R) and (1R, 2S, 3R)-1-phenylpent-4-ene-1,2,3-triol (3) (Scheme 1). The products were separated by column chromatography.
Scheme 1.
Scheme 1.
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From the point of view of the synthetic project, it is very important to know its correct configuration at the C-1, C-5, C-7, and C-8 atoms. Because of the obvious difficulties in unambiguously establishing the configuration at two newly formed stereogenic centres C-5 and C-7 (R versus S) by NMR methods, suitable crystals of compound 2 were subjected to X-ray analysis. This confirmed 5-S and 7-S (relatively to the known 1-S and 8-R) configuration of 2 thus indicating a cis-fusion of the five-membered lactone and tetrahydrofuran rings. The relevant 1H-NMR coupling constants J7,8 = 2.6 Hz and J1,5 = 4.3 Hz are also confirmative of the established structural arrangement. A perspective view and the numbering scheme adopted for molecule of 2 is depicted in Figure 2. The relevant crystallographic and structure refinement data for lactone 2 are given in Table 1. The selected bond lengths and bond angles are listed in Table 2. A list of selected torsion angles is given in Table 3. The hydrogen bond geometry is shown in Table 4. Atomic coordinates and equivalent anisotropic displacement parameters have been deposited with CCDC as supplementary information [7].
Figure 2. Thermal ellipsoids plot at 50% probability level and atomic numbering of lactone 2.
Figure 2. Thermal ellipsoids plot at 50% probability level and atomic numbering of lactone 2.
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The presence of a five-membered lactone ring fused to a furanose ring at the 2,3-position (C-5 and C-1 in Figure 2 or C-3 and C-4 according to carbohydrate nomenclature of 2) imposes some conformational rigidity on this compound. The values of relevant torsion angles O-2–C-1–C-5–C-4 = 15.69(14)°, C-1–C-5–C-4–C-3 = – 12.53(15)°, C-5–C-4–C-3–O-2 = 5.14(16)°, C-4–C-3–O-2–C-1 = 5.32(16)°, C-3–O-2–C-1–C-5= – 13.49(14)° and puckering parameters [8] Q = 0.152(2) Å, ϕ = 55.7(6)° indicate that O-2–C-1–C-5–C-4–C-3 five-membered lactone ring adopts the 2E conformation which is significantly deformed (twisted on C-1–C-5 bond) adopting the shape which is very close to the C-5TC-1 conformation with the C-5 atom oriented endo and C-1 exo to the reference plane defined by the atoms O-2, C-3, and C-4. Analogously, the puckering parameters Q = 0.378(2) Å, ϕ = 124.8(2)° and the relevant dihedral angles O-6–C-5–C-1–C-8 = 12.40(15)°, C-5–C-1–C-8–C-7 = – 30.83(13)°, C-1–C-8–C-7–O-6 = 39.33(13)°, C-8–C-7–O-6–C-5 = – 33.23(15)°, and C-7–O-6–C-5–C-1 = 13.00(15)° are indicative of E3 conformation distorted (twisted on C-7–C-8 bond) almost completely to the C-7TC-8 direction for tetrahydrofuran ring (O-6–C-5–C-1–C-8–C-7) with the C-7 atom lying in the endo and C-8 exo direction with respect to the plane defined by the atoms C-1, C-5, and O-6.
Table 1. Crystal and experimental data for compound 2a
Table 1. Crystal and experimental data for compound 2a
Empirical formulaC12H12O4
Formula weight220.22
Temperature, T (K)183(2)
Wavelength, λ (Å)0.71073
Crystal systemorthorhombic
Space groupP212121
Unit cell dimensions (Å)a = 5.7069(1)
b = 8.4010(1)
c = 21.2427(4)
Unit cell volume, V3)1018.45(3)
Formula units per unit cell Z4
Dcalcd (g/cm3)1.436
Absorption coefficient, μ (mm-1)0.108
Crystal size (mm)0.70 × 0.54 × 0.44
DiffractometerSiemens SMART CCD
θ Range (°)2.61–28.25
Range of h–7→7
Range of k–11→11
Range of l–27→27
Independent reflections2371 (Rint = 0.0328)
Completeness to θ = 28.25 (%)95.7
Absorption correctionmulti-scan
Max. and min. transmission0.9539 and 0.9281
Refinement methodFull-matrix least-squares on F2
Data / restraints / parameters2371 / 0 / 158
Goodness-of-fit on F21.002
Final R indices [I>2σ(I)]R1 = 0.0336, wR2 = 0.0798
R indices (all data)R1 = 0.0400, wR2 = 0.0846
Largest difference peak and hole (e/Å3)0.195 and –0.209
a Standard deviations in parentheses.
Table 2. Selected bond lengths [Å] and bond angles [º] for compound 2a
Table 2. Selected bond lengths [Å] and bond angles [º] for compound 2a
O(1)-C(3)1.2065(17) C(5)-C(1)-C(8)104.37(11)
O(2)-C(3)1.3533(18) O(1)-C(3)-O(2)120.39(15)
O(2)-C(1)1.4474(16) O(1)-C(3)-C(4)128.97(14)
O(3)-C(8)1.4211(15) O(2)-C(3)-C(4)110.63(12)
O(6)-C(7)1.4379(17) C(3)-C(4)-C(5)105.48(12)
O(6)-C(5)1.4382(17) O(6)-C(5)-C(1)106.39(11)
C(1)-C(5)1.540(2) O(6)-C(5)-C(4)112.97(13)
C(1)-C(8)1.5206(18) C(1)-C(5)-C(4)103.71(12)
C(3)-C(4)1.499(2) O(6)-C(7)-C(9)112.15(12)
C(4)-C(5)1.524(2) O(6)-C(7)-C(8)104.29(11)
C(7)-C(9)1.5076(19) C(9)-C(7)-C(8)114.36(11)
C(7)-C(8)1.5315(19) O(3)-C(8)-C(1)105.62(11)
C(3)-O(2)-C(1)111.22(11) O(3)-C(8)-C(7)112.58(12)
C(7)-O(6)-C(5)108.55(11) C(1)-C(8)-C(7)101.00(11)
O(2)-C(1)-C(5)106.51(11) C(10)-C(9)-C(7)123.04(13)
O(2)-C(1)-C(8)109.74(11) C(14)-C(9)-C(7)117.78(13)
a Standard deviations in parentheses.
Table 3. Selected torsion angles [º] for compound 2a
Table 3. Selected torsion angles [º] for compound 2a
O(2)-C(1)-C(5)-C(4)15.69(14) O(2)-C(1)-C(5)-O(6)–103.68(12)
C(1)-C(5)-C(4)-C(3)–12.53(15) C(8)-C(1)-C(5)-C(4)131.77(11)
C(5)-C(4)-C(3)-O(2)5.14(16) C(3)-C(4)-C(5)-O(6)102.24(14)
C(4)-C(3)-O(2)-C(1)5.32(16) C(5)-O(6)-C(7)-C(9)–157.52(11)
C(3)-O(2)-C(1)-C(5)–13.49(14) O(2)-C(1)-C(8)-O(3)–159.61(11)
O(6)-C(5)-C(1)-C(8)12.40(15) C(5)-C(1)-C(8)-O(3)86.59(13)
C(5)-C(1)-C(8)-C(7)–30.83(13) O(2)-C(1)-C(8)-C(7)82.97(13)
C(1)-C(8)-C(7)-O(6)39.33(13) O(6)-C(7)-C(8)-O(3)–72.88(14)
C(8)-C(7)-O(6)-C(5)–33.23(15) C(9)-C(7)-C(8)-O(3)49.98(16)
C(7)-O(6)-C(5)-C(1)13.00(15) C(9)-C(7)-C(8)-C(1)162.18(12)
C(3)-O(2)-C(1)-C(8)–125.91(12) C(8)-C(7)-C(9)-C(10)–106.15(16)
C(7)-O(6)-C(5)-C(4)–100.14(14) O(6)-C(7)-C(9)-C(14)–168.01(12)
a Standard deviations in parentheses.
Analysis of the molecular packing in the unit cell revealed two hydrogen bonds (Table 4). Atom O(1) acts as a bifurcated acceptor of both hydrogen bonds. The first-level descriptors based on the graph-set theory [9] give chain C1,1(7) for O...O hydrogen bond while C...O hydrogen bond forms chain C1,1(5). On the second-level, C2,2(12) and C1,2(6) chains are formed by both types of hydrogen bonds. For convenience, the notation Xa,d(n) has also been adopted in this paper, in which (X) is the pattern descriptor, (a) is number of acceptors, (d) is number of donors and (n) is the number of atoms comprising the pattern.
Figure 3. Packing scheme along a-axis for lactone 2. Hydrogen bonds are shown as broken lines.
Figure 3. Packing scheme along a-axis for lactone 2. Hydrogen bonds are shown as broken lines.
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Table 4. Hydrogen bond geometry in compound 2a
Table 4. Hydrogen bond geometry in compound 2a
X–H…YSymmetry codeX–H(Å)H…Y(Å)X…Y(Å)X–H…Y(°)
O(3)–H(3)…O(1)x, y+1, z0.842.122.8885(14)151.2
C(1)–H(1)…O(1)x, y+0.5, –z+
a Standard deviations in parentheses.



1H- and 13C-NMR spectra (in CDCl3 with Me4Si as an internal standard) were recorded on a Bruker Avance DPX 300 instrument operating at working frequencies of 300.13 and 75.46 MHz, respectively. For the assignments of signals, 1D NOESY and C–H heterocorrelated experiments were used. The EI mass spectrum (70 eV) was obtained on a Finnigan MAT SSQ 710 instrument. Specific rotation was determined on a Perkin–Elmer 241 polarimeter (10 cm cell). Microanalyses were performed on a Fisons EA 1108 analyser. Melting point was determined with a Boetius PHMK 05 microscope. Column chromatography was performed as flash chromatography on Silica Gel 60 (E. Merck, 0.063–0.200 mm).

X-ray techniques

Crystal and experimental data for lactone 2 are summarized in Table 1. Preliminary orientation matrix was obtained from the first frames using Siemens SMART software [10]. Final cell parameters were obtained by refinement of 7739 reflections using Siemens SAINT software [10]. The data were empirically corrected for absorption and other effects using SADABS program [11] based on the method of Blessing [12]. The structure was solved by direct methods and refined by full-matrix least-squares on all F2 data using Bruker SHELXTL [13]. The non-H atoms were refined anisotropically. Hydrogen atoms were constrained to the ideal geometry using an appropriate riding model. Molecular graphics were obtained using the program DIAMOND [14].

(1S, 5S, 7S, 8R)-8-Hydroxy-7-phenyl-2,6-dioxabicyclo[3.3.0]octan-3-one (2).

A 25-mL flask, purged with CO and connected to a balloon with CO gas, was charged with PdCl2 (10 mg, 0.05 mol), anhydrous CuCl2 (200 mg, 1.56 mmol), NaOAc (130 mg, 1.56 mmol), a mixture of (1S, 2S, 3R) and (1R, 2S, 3R)-1-phenylpent-4-en-1,2,3-triol (3) (100 mg, 0.52 mmol), and AcOH (10 mL). The mixture was stirred for 20 h at room temperature, then filtered through a short tube filled with cellulose (2 g). The solvent was evaporated under diminished pressure and the residue was purified by chromatography on a column of silica gel using hexane–ethyl acetate (5 : 2, v/v) as an eluent. The fractions with Rf = 0.4 (1:1 hexane–ethyl acetate) were collected, evaporated and the product recrystallized from 1:1 EtOAc–hexane affording the title compound 2 (37 mg, 32 %, colourless crystals). M.p. 177–180 °C; [α]D + 38° (c 0.31, MeOH); 1H-NMR (300 MHz, CDCl3): δ 7.46–7.35 (m, 5H, Ph), 5.23 (d, 1 H, J7,8 = 2.6 Hz, H-7), 5.20 (ddd, 1 H, J1,5 = 4.3 Hz, J4a,5 = 5.6 Hz, J4b,5 = 1.4 Hz, H‑5), 5.07 (d, 1 H, J1,5 = 4.3 Hz, H-1), 4.47 (d, 1 H, J7,8 = 2.6 Hz, H-8), 2.88 (dd, 1 H, J4a,4b = 18.8 Hz, J4a,5 = 5.6 Hz, H-4a), 2.79 (dd, 1 H, J4a,4b = 18.8 Hz, J4b,5 = 1.4 Hz, H-4b); 13C-NMR (75 MHz, CDCl3): δ 175.4 (C-3), 134.2 (C-1 in Ph), 128.9 (C-3 and C-5 in Ph), 128.6 (C-4 in Ph), 126.6 (C-2 and C-6 in Ph), 87.2 (C-1), 82.9 (C-7), 77.1 (C-5), 75.8 (C-8), 36.0 (C-4); EIMS (70 eV): m/z 220 [M]+, 202, 192, 176, 143, 114, 106, 85, 84. Anal. Calcd for C12H12O4 (220.22): C, 65.40; H, 5.49. Found: C, 65.29; H, 5.52.


Financial support of this work by the Scientific Grant Agency (VEGA, Slovak Academy of Sciences and Ministry of Education, Bratislava, projects Nos. 2/7204/20, 1/9251/02 and 1/7314/20) is gratefully appreciated.

References and Notes

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  7. CCDC 194248 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336030; e-mail: or www:
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  • Samples Availability: Compound 2 reported in this paper is available from MDPI.
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