N-(9,11-Dimeth­oxy-4-oxo-2,3,4,6,7,11b-hexa­hydro-1H-pyrido[2,1-a]isoquinolin-3-yl)benzamide

Hoong-Kun Fun; Punlop Kuntiyong; Pittaya Tuntiwachwuttikul; Suchada Chantrapromma

doi:10.1107/S1600536810050737

. 2010 Dec 11;67(Pt 1):o113–o114. doi: 10.1107/S1600536810050737

N-(9,11-Dimethoxy-4-oxo-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-3-yl)benzamide

Hoong-Kun Fun ^a,^*,^‡, Punlop Kuntiyong ^b, Pittaya Tuntiwachwuttikul ^b, Suchada Chantrapromma ^c,^§

PMCID: PMC3050218 PMID: 21522625

Abstract

The title schulzeine derivative, C₂₂H₂₄N₂O₄, crystallizes with two crystallographically independent molecules of almost identical conformation in the asymmetric unit. The tricyclic core of schulzeine has a fused-three-ring system comprising the tetrahydroisoquinoline and δ-lactam moieties. In both molecules, the pyridine ring adopts a twisted-boat conformation, whereas the lactam ring is in a boat conformation. The two methoxy groups are slightly twisted from the attached benzene ring [C—O—C—C torsion angles = −21.3 (2) and −20.5 (2)° in molecule A, and −6.3 (2) and −16.2 (2)° in molecule B] and the benzamide moiety is in a (−)-synclinal conformation with respect to the lactam ring. In the crystal, molecules are linked into V-shaped dimers by intermolecular N—H⋯O hydrogen bonds and weak C—H⋯O interactions. These dimers are stacked into V-shaped columns along the a axis. Adjacent columns are further linked in an antiparallel manner. C—H⋯π interactions are also observed.

Related literature

For hydrogen-bond motifs, see: Bernstein et al. (1995 ▶). For bond-length data, see: Allen et al. (1987 ▶). For ring conformations, see: Cremer & Pople (1975 ▶). For background to schulzeines, see, for example: Kuntiyong et al. (2006 ▶); Melo et al. (2006 ▶); Takada et al. (2004) ▶. For the stability of the temperature controller used in the data collection, see: Cosier & Glazer (1986) ▶.

Experimental

Crystal data

C₂₂H₂₄N₂O₄
M _r = 380.43
Orthorhombic,
a = 12.6530 (3) Å
b = 15.5256 (4) Å
c = 19.7819 (5) Å
V = 3886.06 (17) Å³
Z = 8
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.56 × 0.44 × 0.41 mm

Data collection

Bruker SMART APEX2 CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2005 ▶) T _min = 0.952, T _max = 0.964
110999 measured reflections
6224 independent reflections
5979 reflections with I > 2σ(I)
R _int = 0.044

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.098
S = 1.04
6224 reflections
509 parameters
H-atom parameters constrained
Δρ_max = 0.60 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 2005 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810050737/rz2531sup1.cif

e-67-0o113-sup1.cif^{(36.3KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810050737/rz2531Isup2.hkl

e-67-0o113-Isup2.hkl^{(304.7KB, hkl)}

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

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

Cg1 and Cg2 are the centroids of the C1A–C6A and C15A–C20A benzene rings, respectively.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2A—H2AA⋯O1Bⁱ	0.86	2.08	2.8994 (18)	158
N2B—H2BA⋯O1Aⁱⁱ	0.86	2.24	2.9807 (18)	145
C1A—H1AA⋯O4Bⁱⁱⁱ	0.93	2.52	3.405 (2)	160
C10A—H10B⋯O3A	0.97	2.58	3.127 (2)	115
C3B—H3BA⋯O4A^iv	0.93	2.49	3.348 (2)	153
C7B—H7BB⋯O4A^v	0.97	2.47	3.407 (2)	163
C16A—H16A⋯O1Bⁱ	0.93	2.32	3.228 (2)	165
C20B—H20B⋯O1Aⁱⁱ	0.93	2.51	3.281 (2)	141
C22A—H22A⋯O2A^iv	0.96	2.52	3.266 (2)	135
C22A—H22B⋯O4B^vi	0.96	2.47	3.393 (2)	160
C22B—H22D⋯O4A^iv	0.96	2.58	3.414 (2)	146
C11A—H11B⋯Cg2ⁱⁱ	0.97	2.78	3.686 (2)	156
C8B—H8BA⋯Cg1^iv	0.97	2.60	3.4864 (17)	152
C18B—H18B⋯Cg1ⁱ	0.93	2.81	3.607 (2)	144

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

Acknowledgments

PK thanks the Thailand Research Fund (TRF) for financial support. SC thanks the Prince of Songkla University for generous support through the Crystal Materials Research Unit. The authors also thank Universiti Sains Malaysia for the Research University grant No. 1001/PFIZIK/811160.

supplementary crystallographic information

Comment

Schulzeine alkaloids were isolated from the marine sponge Penares schulzei (Takada et al., 2004). Schulzenine A—C inhibits α-glucosidase with IC₅₀ values of 48–170 nM (Melo et al., 2006). The potent α-glucosidase inhibitory activity makes them attractive leads for drug candidate for diseases such as cancer, diabetes and viral infections. During the course of our research on natural product synthesis of schulzeines, the title schulzeine benzamide derivative was synthesized (Kuntiyong et al., 2006). The single-crystal x-ray structural study of the title compound (I) was undertaken in order to gain detailed conformations of the molecular structure.

The title compound crystallized with two crystallographically independent molecues A and B in the asymmetric unit (Fig. 1). These two molecules are almost conformationally identical with slightly different bond lengths and angles. The bond lengths in (I) are within normal ranges (Allen et al., 1987). The tricyclic core of schulzeine (C1–C13/N1/O1) has a fused-three-ring system comprising of the tetrahydro isoquinoline and δ-lactam moieties. In both molecules, the pyridine ring (C5–C9/N1) adopts a twisted boat conformation with puckering parameters Q = 0.6943 (17) Å, θ = 92.19 (14)° and φ = 245.21 (14)° in molecule A [Q = 0.5265 (16) Å, θ = 112.63 (17)° and φ = 263.90 (19)° in molecule B] and the lactam ring (C9–C13/N1/O1) has a standard boat conformation (Cremer & Pople 1975). The two methoxy groups are slightly twisted from the attached benzene ring with the torsion angles C21–O2–C2–C3 = -21.3 (2)° and C22–O3–C4–C3 = -20.5 (2)° in molecule A [the corresponding values are -6.3 (2) and -16.2 (2)° in molecule B]. The benzamide moiety is not planar with the dihedral angle between the mean plane through C14–C15/N2/O4 and C15–C20 benzene ring being 8.97 (9)° in molecule A [8.10 (11)° in molecule B]. The orientation of the benzamide moiety can be described by the torsion angle C14–N2–C12–C13 = -92.77 (17)° in molecule A [-82.56 (18)° in molecule B] which shows the (-)-syn-clinal conformation with respect to the lactam ring. There are two stereogenic centers at atoms C12 and C9 (Fig. 1) or postions 3 and 11b of the tricyclic core of schulzeine. Fig. 1 show that H atoms at C12 and C9 are in cis-relationship. An intramolecular C10A—H10B···O3A weak interaction (Table 1; Fig. 1) generates a S(6) ring motif (Bernstein et al., 1995).

In the crystal packing (Fig. 2), molecules are linked into V-shaped dimers by N—H···O hydrogen bonds and C—H···O weak interactions (Table 1) which generate two S(7) ring motifs (Bernstein et al., 1995). These dimers are stacked into V-shaped columns along the a axis. Adjacent columns are further linked by C—H···O weak interactions in an antiparallel manner. C—H···π interactions were also observed (Table 1); Cg₁ and Cg₂ are the centroid of C1A–C6A and C15A–C20A benzene rings, respectively.

Experimental

The title schulzeine benzamide derivative was synthesized according to the previous reported method (Kuntiyong et al., 2006). Colourless block-shaped single crystals of the title compound suitable for x-ray structure determination were crystallized from hexane:ethylacetate (2:1 v/v) by slow evaporation at room temperature after a few days.