rac-(2R*,3S*,5S*,6R*,7S*,8S*)-7,8-Dichloro­bicyclo­[2.2.2]octane-2,3,5,6-tetrayl tetra­acetate

Ertan Şahin; Arif Baran; Metin Balcı

doi:10.1107/S160053680900484X

. 2009 Feb 13;65(Pt 3):o526–o527. doi: 10.1107/S160053680900484X

rac-(2R,3S,5S,6R,7S,8S)-7,8-Dichlorobicyclo[2.2.2]octane-2,3,5,6-tetrayl tetraacetate

Ertan Şahin ^a,^*, Arif Baran ^b, Metin Balcı ^c

PMCID: PMC2968458 PMID: 21582188

Abstract

The title compound, C₁₆H₂₀Cl₂O₈, contains a central bicyclo[2.2.2]octane skeleton with slightly twisted conformation. In this structure, the C—C bond lengths are in the range 1.525 (2)–1.552 (2) Å. Two sides of this skeleton have cis,cis acetoxy substituents and the Cl atoms have a trans arrangement. An extensive network of weak C—H⋯O interactions stabilizes the crystal structure.

Related literature

For background information on inositol and its derivatives, see: Michell (2008 ▶); Reitz (1991 ▶); Dwek (1996 ▶); Billington et al. (1994 ▶); Varki (1993 ▶); Heightman & Vasella (1991 ▶). For background on the carba-analogues of oligosaccharides, see: Ogawa et al. (2000 ▶, 1988 ▶); Saumi (1990 ▶); Saumi & Ogawa (1990 ▶). For related structures, see: Baran et al. (2008 ▶); Mehta et al. (2007 ▶); Shih et al. (2007 ▶); Gültekin et al. (2004 ▶); Mehta & Ramesh (2001 ▶); Balcı (1997 ▶); Balcı et al. (1990 ▶);Ülkü et al. (1995 ▶); Buser & Vasella (2006 ▶). graphic file with name e-65-0o526-scheme1.jpg

Experimental

Crystal data

C₁₆H₂₀Cl₂O₈
M _r = 411.22
Monoclinic,
a = 10.1061 (3) Å
b = 13.3383 (4) Å
c = 14.2229 (3) Å
β = 90.189 (2)°
V = 1917.21 (9) Å³
Z = 4
Mo Kα radiation
μ = 0.38 mm⁻¹
T = 294 K
0.5 × 0.3 × 0.2 mm

Data collection

Rigaku R-AXIS RAPID-S diffractometer
Absorption correction: multi-scan (Blessing, 1995 ▶) T _min = 0.873, T _max = 0.927
54750 measured reflections
5628 independent reflections
5575 reflections with I > 2σ(I)
R _int = 0.024

Refinement

R[F ² > 2σ(F ²)] = 0.065
wR(F ²) = 0.157
S = 1.32
5628 reflections
239 parameters
H-atom parameters constrained
Δρ_max = 0.38 e Å⁻³
Δρ_min = −0.38 e Å⁻³

Data collection: CrystalClear (Rigaku/MSC, 2005 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680900484X/kp2205sup1.cif

e-65-0o526-sup1.cif^{(20.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680900484X/kp2205Isup2.hkl

e-65-0o526-Isup2.hkl^{(270KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C7—H7⋯O6ⁱ	0.98	2.46	3.425 (3)	169
C8—H8⋯O8ⁱⁱ	0.98	2.42	3.377 (3)	166
C16—H16A⋯O7ⁱⁱ	0.96	2.53	3.416 (4)	154
C12—H12B⋯O5ⁱⁱⁱ	0.96	2.52	3.297 (4)	137
C6—H6⋯O7^iv	0.98	2.60	3.240 (3)	123

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

The authors are indebted to TUBITAK (Scientific and Technological Research Council of Turkey) and TUBA (Turkish Academy of Sciences) for their financial support of this work. Furthermore, we are grateful to the Department of Chemistry (Atatürk University) for the use of the X-ray diffractometer purchased under grant No. 2003/219 of the University Research Fund.

supplementary crystallographic information

Comment

Glycosidases and their inhibitors have been the subject of much research in the last decade. Inositols (cyclohexanehexols) are sugar-like molecules. There are nine stereoisomers, all of which may be referred to as inositol (Michell, 2008; Reitz, 1991). The most prominent naturally occurring form is myo-inositol, cis-1,2,3,5-trans-4,6-cyclohexanehexol and it is actively involved in cellular events and processes. Inositol and their derivatives can inhibit the glycosidases and affect many biological processes (Dwek, 1996; Billington et al. 1994; Varki, 1993; Heightman & Vasella 1991). Carba-analogues of oligosaccharides (carbasugar) generated by replacing the endocyclic oxygen atom in monosaccharides (Ogawa et al. 2000 and 1988; Saumi, 1990; Saumi & Ogawa, 1990) are thought to be more potent drug candidates than natural sugars, since they are hydrolytically stable.

New synthetic methodologies for various inositols and their derivatives have been developed. After this discovery, an enormous increase in the synthesis of cyclitol derivatives (Mehta et al. 2007; Shih et al. 2007; Gültekin et al. 2004; Mehta & Ramesh, 2001; Balcı, 1997; Balcı et al.1990) was observed since these show glycosidase inhibitory properties. More recently, a bridged and bicyclic system, the racemic gluco-configured norbornane has been synthesised and tested as inhibitor of β-glycosidases (Buser & Vasella, 2006). They noticed that the configuration of the hydroxy group play an important role in inhibitor activity. Motivated by the medical value of certain cyclitol derivatives, we were interested in designing a new generation of possible glycosidase inhibitors with the bicyclic structures having bicyclo[2.2.2]octane skeleton.

For the construction of the bicyclo[2.2.2]octane skeleton we started from 2,2-dimethyl-3a,7a-dihydro-1,3-benzo-dioxole and vinylene carbonate and synthesized the tetraacetate 1 in 3 steps (Baran et al., 2008).

For the synthesis of isomeric hexols with bicyclo[2.2.2]octane skeleton, the tetracetate 1 was reacted with m-CPBA. The reaction was completed after 21 days by refluxing in chloroform. Recently, we isolated a side product I in 8% yields beside the major product 2 (86%). The structure of the side product was confirmed by NMR-spectroscopic studies. The incorporation of the chlorine atoms into the molecule and their configuration were determined by X-ray diffraction analysis. The title compound (I) C₁₆H₂₀O₈Cl₂ contains a central bicyclo[2.2.2]octane skeleton with slightly twisted conformation. In this structure C—C bond lengths are in the range of 1.525 (2)- 1.552 (2) Å. Two sides of this skeleton have cis, cis –OAc substituents. In addition to this, Cl atoms have trans stereochemistry at the other side (C7—Cl1=1.796 (2), C8—Cl2=1.798 (2) Å). Intermolecular C—H···O hydrogen bonds are effective in determining the molecular conformation and the crystal structure of the title compound (Table 1).

Experimental

Oxidation of 2S,3R,5R,6S-rel-Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetraacetate with m-CPBA in chloroform was performed as followed. (1.0 g, 2.94 mmol) tetraacetate 1 in 100 ml of chloroform was reacted with (1.50 g, 6 mmol, 70%) m-CPBA as described in the literature (Baran et al., 2008). Evaporation of solvent under reduced pressure and recrystallization of product from ethyl acetate gave epoxide 2. After separation of epoxide 2, the solvent was removed and the residue was dissolved in ether and crystallization at 273 K gave colourless crystals of the dichloro compound I (97 mg, 8%) m.p. 469–472 K. ¹H NMR (400 MHz, CDCl₃) δ 5.41 (dd, J = 8.0 and 4.4 Hz, 1H), 5.33–5.28 (m, 3H), 4.59 (dd, J = 7.6 and 2. 0 Hz, 1H), 3.97 (br d, J = 7.6 Hz, 1H), 2.92 (dt, J= 4.4 and 1.2 and Hz, 1H), 2.43 (q, J = 2.0 Hz, 1H), 2.14 (s, –CH₃), 2.11 (s,-CH₃), 2.074 (s, –CH₃), 2.07 (s, –CH₃). ¹³C NMR (100 MHz, CDCl₃) δ 168.1, 167.8, 167.6, 167.4, 64.7, 63.6, 62.3, 61.9, 57.8, 56.5, 43.9, 40.2, 19.2, 18.8, 18.7, 18.6. IR (KBr, cm^-1) 2984, 2968, 1758, 1431, 1370, 1201, 982, 900. Anal. Calcd for C₁₆H₂₀C_l2O₈: C, 46.73; H, 4.90. Found: C, 46.80; H, 5.16.

Chlorination of 2S*,3R*,5R*,6S*--Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetraacetate was according the described procedure. (0.3 g, 0.88 mmol) tetraacetate 1 was dissolved in 100 ml of dichloromethane. Chlorine gas (generated from the reaction of KMnO₄ with HCl) was passed through the solution. After 20 m the gas flow was stopped and the flask was closed with a stopper. The mixture was stirred at room temperature for 3 h, and then the solvent was evaporated. The crude product was dissolved in ether and crystallized at 273 K to give (0.29 g, 80%) colourless crystals of I (m.p.469–472 K). The interesting feature of this reaction is the unusual formations of chlorine adduct I during epoxidation reaction. A similar reaction was also observed during the epoxidation reaction of a benzobarrelene derivative (Ülkü et al., 1995) which was also completed in three weeks. We assume that solvent, chloroform undergoes a slow oxidation reaction with the m-chloroperbenzoic acid and generates chlorine which adds to the double bond.

To test whether the adduct I has been generated by addition of free chlorine to the double bond or by other mechanism, we treated the tetraacetate 1 with chlorine gas for 3 h. The chlorine added to the double bond in 1 in a yield of 80% and gave I, which was identical with the adduct isolated from the epoxidation reaction of 1 as the side product.

To the best of our knowledge, chlorine addition to a double bond during an epoxidation reaction has been not presented in the literature. This reaction can be probably encountered only during those reactions which are completed in 2–3 weeks because of the very slow oxidation of chloroform.