(7R,8R,8aS)-8-Hydr­oxy-7-phenyl­per­hydro­indolizin-3-one

Ľubomír Švorc; Viktor Vrábel; Jozefína Žúžiová; Mária Bobošíková; Jozef Kožíšek

doi:10.1107/S160053680901085X

. 2009 Mar 28;65(Pt 4):o895–o896. doi: 10.1107/S160053680901085X

(7R,8R,8aS)-8-Hydroxy-7-phenylperhydroindolizin-3-one

Ľubomír Švorc ^a, Viktor Vrábel ^a,^*, Jozefína Žúžiová ^b, Mária Bobošíková ^b, Jozef Kožíšek ^c

PMCID: PMC2968891 PMID: 21582602

Abstract

The absolute configuration of the title compound, C₁₄H₁₇NO₂, was assigned from the synthesis. There are two molecules in the asymmetric unit. Their geometries are very similar and corresponding bond lengths are almost identical [mean deviation for all non-H atoms = 0.015 (2) Å]. The six-membered ring of the indolizine system adopts a chair conformation. In the crystal structure, molecules form chains parallel to the a axis via intermolecular O—H⋯O hydrogen bonds, which help to stabilize the crystal structure.

Related literature

Polyhydroxylated indolizidine alkaloids are excellent inhibitors of biologically important pathways, see: Melo et al. (2006 ▶); Michael (2003 ▶); Lillelund et al. (2002 ▶); Gerber-Lemaire & Juillerat-Jeanneret (2006 ▶); Butters (2002 ▶); Compain & Martin (2001 ▶); Shi et al. (2008 ▶); Fujita et al. (2004 ▶). For indolizines as antimycobacterial agents against mycobacterial tuberculosis, see: Gundersen et al. (2003 ▶). For the biological activity of indolizine derivatives, see: Teklu et al. (2005 ▶); Foster et al. (1995 ▶). For their pharmacological applications, see: Couture et al. (2000 ▶); Jorgensen et al. (2000 ▶). For puckering parameters, see: Cremer & Pople (1975 ▶). For conjugation of the lone-pair electrons in simple amides, see: Brown & Corbridge (1954 ▶); Pedersen (1967 ▶). For bond lengths and angles in related structures, see: Vrábel et al. (2004 ▶); Švorc et al. (2008 ▶). For the synthesis, see: Šafář et al. (2009 ▶).

Experimental

Crystal data

C₁₄H₁₇NO₂
M _r = 231.29
Orthorhombic,
a = 25.3592 (4) Å
b = 16.1467 (2) Å
c = 6.0086 (1) Å
V = 2460.33 (6) Å³
Z = 8
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 298 K
0.33 × 0.26 × 0.15 mm

Data collection

Oxford Diffraction Gemini R CCD diffractometer
Absorption correction: analytical (Clark & Reid, 1995 ▶) T _min = 0.965, T _max = 0.988
60218 measured reflections
3791 independent reflections
1856 reflections with I > 2σ(I)
R _int = 0.035

Refinement

R[F ² > 2σ(F ²)] = 0.033
wR(F ²) = 0.097
S = 0.98
3791 reflections
311 parameters
H-atom parameters constrained
Δρ_max = 0.12 e Å⁻³
Δρ_min = −0.11 e Å⁻³

Data collection: CrysAlis CCD (Oxford Diffraction, 2006 ▶); cell refinement: CrysAlis RED (Oxford Diffraction, 2006 ▶); data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: DIAMOND (Brandenburg, 2001 ▶); software used to prepare material for publication: enCIFer (Allen et al., 2004 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053680901085X/fj2203sup1.cif

e-65-0o895-sup1.cif^{(26.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680901085X/fj2203Isup2.hkl

e-65-0o895-Isup2.hkl^{(185.9KB, 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
O4—H4⋯O1ⁱ	0.82	1.92	2.7366 (19)	175
O2—H2⋯O3ⁱⁱ	0.82	1.88	2.6963 (18)	179

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

Acknowledgments

The authors thank the Grant Agency of the Slovak Republic (grant Nos. 1/0161/08 and 1/0817/08) and the Structural Funds, Interreg IIIA for financial support in purchasing the diffractometer and the Development Agency under contract No. APVV-0210–07.

supplementary crystallographic information

Comment

The synthesis of biologically active indolizine derivatives continues to attract the attention of organic chemists, because of their wide spectrum of biological activity. Indolizines are natural structures, which are remarkable in its diversity and efficacy. For example, polyhydroxylated indolizidine alkaloids represented by the so popular castanospermine and swainsonine are well known for their ability to function as excellent inhibitors of biologically important pathways. These include the binding and processing of glycoproteins, potent glycosidase inhibitory activities (Melo et al., 2006; Michael, 2003; Lillelund et al., 2002), activity against AIDS virus HIV and some carcinogenic cells as well as against other important pathologies (Gerber-Lemaire & Juillerat-Jeanneret, 2006; Butters, 2002; Compain & Martin, 2001). More importantly, some hybrids of these structures have shown in numerous cases an increase of glycosidase activities as demonstrated by the Pearson's group and others (Shi et al., 2008; Fujita et al., 2004). Indolizines have also been tested as antimycobacterial agents against mycobacterial tuberculosis (Gundersen, et al., 2003). Many studies demonstrated that indolizine derivatives show biological activity such as antioxidative (Teklu et al., 2005) and antiherpes (Foster et al., 1995). The other well known pharmacological applications associated with this ring compounds are well documented in the literature (Couture et al., 2000; Jorgensen et al., 2000).

Due to the diverse properties of indolizine derivatives, the structure of the title compound, (I), has been determined as part of our study of the conformational changes caused by different substituents at various positions on the indolizine ring system. We report here the synthesis, molecular and crystal structure. The absolute configuration was established by synthesis and is depicted in the scheme and figure. The asymmetric unit of title compound contains two crystallographic independent molecules as shown in Fig. 1. The expected stereochemistry of atoms C5, C6 and C7 (C19, C20 and C21 for molecule B) was confirmed as S, R and R, respectively. The corresponding bond lengths and angles in the independent molecules agree with each other and are almost identical (mean deviation for all non-H atoms 0.015 (2) Å). The central six-membered N-heterocyclic ring is not planar and adopts a chair conformation (Cremer & Pople, 1975). A calculation of least-squares planes shows that this ring is puckered in such a manner that the four atoms C5, C6, C8 and C9 (C19, C20, C22 and C23 for molecule B) are coplanar to within 0.012 (2)Å [0.014 (1) Å], while atoms N1 (N2) and C7 (C21) are displaced from this plane on opposite sides, with out-of-plane displacements of -0.573 (2) and 0.639 (2)Å [-0.573 (1) and 0.664 (2)Å for molecule B], respectively. The phenyl ring attached to the indolizine ring system is planar (mean deviation is 0.009 (2)Å for molecule A and 0.011 (2)Å for molecule B). As shown in Table of geometric parameters, the N1—C5 (N2—C19) and N1—C9 (N2—C23) bonds are approximately equivalent and both are much longer than the N1—C2 (N2—C16) bond. Moreover, the N1 (N2) atom is sp² hybridized, as evidenced by the sum of the valence angles around it [359.8 (2)° for molecule A and 358.4 (2)° for molecule B]. These data are consistent with conjugation of the lone-pair electrons on N1 (N2) with the adjacent carbonyl and agree with literature values for simple amides (Brown & Corbridge, 1954; Pedersen, 1967). The bond length of the carbonyl group C2=O1 (C16=O3) is 1.228 (2)Å [1.229 (2) Å], respectively, is somewhat longer than typical carbonyl bonds. This may be due to the fact that atoms O1 and O3 participate as acceptors in intermolecular hydrogen bonds with atoms O4 and O2 as donators. These intermolecular O—H···O hydrogen bonds link the molecules of (I) into extended chains, which run parallel to the a axis (Fig. 2) and help to stabilize the crystal structure of the compound. The bond lengths and angles in the indolizine ring system are in good agreement with values from the literature (Vrábel et al., 2004, Švorc et al., 2008).

Experimental

The title compound (7R,8R,8aS)-8-hydroxy-7-phenylhexahydroindolizin-3(5H)-one was prepared according literature procedures of Šafář et al. (2009).