Propargylaminyl 3α-hy­droxy-11-oxo-18β-olean-12-en-29-oate

Laszlo Czollner; Ulrich Jordis; Kurt Mereiter

doi:10.1107/S1600536811043534

. 2011 Oct 29;67(Pt 11):o3052–o3053. doi: 10.1107/S1600536811043534

Propargylaminyl 3α-hydroxy-11-oxo-18β-olean-12-en-29-oate

Laszlo Czollner ^a, Ulrich Jordis ^a, Kurt Mereiter ^b,^*

PMCID: PMC3247445 PMID: 22220063

Abstract

The title compound, C₃₃H₄₉NO₃, is the propargylamide of 18β-glycyrrhetinic acid, a pentacyclic triterpenoid of interest as a therapeutic agent. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring C in a half-chair conformation. In the crystal, the terminal N-propargylcarboxamide group has remarkable structural effects on weak hydrogen-bond-like interactions. Particularly noteworthy are an intermolecular O—H⋯π interaction accepted side-on by the terminal alkyne group [O⋯C = 3.097 (2) and 3.356 (2) Å] and a short intermolecular C—H⋯O interaction [C⋯O = 3.115 (2) Å] donated by the alkyne C—H group. An N—H⋯O [N⋯O = 3.251 (2) Å] and a C_alkyl—H⋯O [C⋯O = 3.254 (2) Å] interaction complement the crystal structure.

Related literature

For general information on the therapeutic aspects of the parent compounds glycyrrhizin and 18β-glycyrrhetinic acid, see: Baran et al. (1974 ▶); Kitagawa (2002 ▶); Asl & Hosseinzadeh (2008 ▶). For the synthesis of derivatives of 18β-glycyrrhetinic acid with a therapeutic background, see: Su et al. (2004 ▶); Beseda et al. (2010 ▶). For the crystal structures of 18β-glycyrrhetinic acid and derivatives, see: Campsteyn et al. (1977 ▶); Alvarez-Larena et al. (2007 ▶); Beseda et al. (2010 ▶); Amer et al. (2010 ▶). For the crystal structure data of several N-propargylcarboxamides, see: Hashmi et al. (2004 ▶); Frey et al. (2008 ▶). For weak hydrogen bonds involving C C—H moieties, see: Desiraju & Steiner (1999 ▶).

Experimental

Crystal data

C₃₃H₄₉NO₃
M _r = 507.73
Orthorhombic,
a = 6.7534 (8) Å
b = 13.4879 (16) Å
c = 31.132 (4) Å
V = 2835.8 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.07 mm⁻¹
T = 100 K
0.56 × 0.43 × 0.38 mm

Data collection

Bruker Kappa APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.87, T _max = 0.97
41876 measured reflections
4658 independent reflections
4531 reflections with I > 2σ(I)
R _int = 0.026

Refinement

R[F ² > 2σ(F ²)] = 0.033
wR(F ²) = 0.089
S = 1.08
4658 reflections
349 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.36 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT, SADABS and XPREP (Bruker, 2008 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811043534/jj2102sup1.cif

e-67-o3052-sup1.cif^{(29.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811043534/jj2102Isup2.hkl

e-67-o3052-Isup2.hkl^{(228.2KB, hkl)}

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

Table 1. Hydrogen-bond and O—H⋯π geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1O⋯C32ⁱ	0.81 (2)	2.57 (2)	3.3559 (17)	164 (2)
O1—H1O⋯C33ⁱ	0.81 (2)	2.40 (2)	3.0973 (17)	145 (2)
N1—H1N⋯O2ⁱⁱ	0.80 (2)	2.57 (2)	3.2511 (15)	144 (2)
C31—H31B⋯O1ⁱⁱⁱ	0.99	2.56	3.2541 (17)	127
C33—H33⋯O2^iv	0.95	2.27	3.1154 (17)	148

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

Acknowledgments

The work was supported by the ZIT Zentrum für Innovation und Technologie GmbH (Vienna Spot of Excellence, 182081).

supplementary crystallographic information

Comment

18β-glycyrrhetinic acid (GA) is a pentacyclic triterpene and the aglycone of glycyrrhizin, the main sweet tasting compound from liquorice root in use as flavoring and sweetener (Kitagawa, 2002). GA is a therapeutic agent with a broad range of activity by modulating the steroid hormone cortisol (Baran et al., 1974; Asl & Hosseinzadeh, 2008). One strategy to improve or modify its therapeutic profile is to leave the triterpene core of GA unaltered and to attach suitable functional groups to its 3-hydroxy group (Su et al., 2004). An example for this strategy is the hydrogen succinate of GA, the licenced anti-ulcer drug Carbenoxolone. An analogous approach was used for the title compound (I), here however with the COOH group at the opposite side of GA functionalized by a propargylamide group. The synthesis of this compound and a series of relatives was recently described (Beseda et al., 2010). Here we report the crystal structure of this compound. The molecular structure of (I) is shown in Fig. 1. The GA core of the molecule consists of four six-membered rings A, B, D, and E in chair conformation and the unsaturated ring C in half-chair conformation (Fig. 1). The GA core agrees well in bond lengths, bond angles, and conformation with related compounds (Campsteyn et al., 1977; Alvarez-Larena et al., 2007; Beseda et al., 2010) and needs no further discussion. The carboxamide group O3═C29—N1 is exo-oriented with respect to N, C18—C20—C29—N1 = 162.3 (1)°. In case of endo-orientation (rare) this angle is about -30° (for examples, see: Amer et al., 2010). The propargyl group has a C32≡C33 bond length of 1.197 (2) Å and an orientation defined by the torsion angle C29—N1—C31—C32 = 106.5 (1)°. In N-propargylcarboxamides this torsion angle varies widely (Hashmi et al., 2004; Frey et al., 2008). In the unit cell the molecules of (I) are aligned with their longest direction slightly inclined to the c-axis and adopt in this direction an undular head-to-tail-like arrangement (Fig. 2). Along the short a-axis (6.75 Å) the molecules are stacked directly upon each other by translation. Coherence of the structure is provided by a combination of van der Waals and weak hydrogen bond interactions listed in Table 1. Most interesting in this respect are the interactions of the N-propargylcarboxamide group outlined in Fig. 3. The terminal alkyne group C32≡C33—H33 has a distinctly acidic hydrogen atom and forms the by far shortest weak hydrogen bond-like interaction of the structure with distances of H33···O2^iv = 2.27 Å and C33···O2^iv = 3.115 (2) Å to the 11-keto-oxygen of the compound. After normalization (C—H = 1.083 Å; Desiraju & Steiner, 1999), the distance H33···O2^iv is 2.16 Å, distinctly shorter than the mean distance d(H···O) = 2.29 (3) Å reported by Desiraju & Steiner (1999; Table 2.3 of this reference) for C≡C—H···O═C< entities. The second remarkable association in Fig. 3 is the intermolecular O—H···π interaction from the hydroxy group O1^v—H1o^v side-on to the two alkyne carbon atoms C32 and C33. The normalized H1o^v···C distances (O1—H1o normalized to 0.983 Å), are 2.26 Å to C33 and 2.41 Å to C32, and correspond to the shortest O—H···π interactions reported by Desiraju & Steiner (1999; Table 3.12 of this reference). Comparable C—H···O and X—H···π interactions with mostly longer respective interatomic distances can be found in a small group of N-propargylcarboxamide containing crystal structures reported by Hashmi and coworkers in context with oxazole ring forming reactions (Hashmi et al., 2004; Frey et al., 2008).

Experimental

The synthesis and properties of the title compound were described by Beseda et al. (2010). Platy colourless crystals for X-ray diffraction were obtained from CH₂Cl₂ by diethyl ether vapour diffusion at ambient temperature.