Absolute configuration of N-[(-)-2-(7-methoxy-1,2,3,4-tetra­hydro­-1-naphthyl)­ethyl]­cyclo­propyl­carbox­amide, a highly potent and selective melatonin analogue

The title compound, C₁₇H₂₃NO₂, a tetra­hydro­naphthalenic analogue of melatonin, crystallizes in the monoclinic space group P2₁ with one mol­ecule in the asymmetric unit. The crystal structure has been determined by X-ray analysis at room temperature. The absolute configuration of this compound was determined unambiguously as R at the chiral naphthalene C-1 position.

S1. Comment

Melatonin (N-acetyl-5-methoxytryptamine), (I), is a hormone synthesized and secreted primarily by the pineal gland during darkness, by all mammalian species (Reiter, 1991). The hormone has been the focus of considerable clinical interest in recent years. It is now well recognized that it regulates circadian rhythms in humans and in different animal species (Arendt & Deacon, 1997). Melatonin's effects seem to be mediated through membrane receptors, recently classified as MT₁, MT₂ and MT₃. \sch

This interest prompted us to develop new melatonin receptor ligands and led us to the synthesis (Yous et al., 1992) and crystallographic studies of naphthalenic bioisosteres (II) and (III) (Tinant et al., 1993, 1994). Recently we have synthesized a tetrahydronaphtalenic analog, (IV) (Fourmaitraux et al., 1998). The presence of a chiral centre in this compound together with the pharmacological studies which showed enantiomers of many drugs differ in activity, metabolism, toxicity, trigger the investigation of the racemic mixture (IV). Chiral direct HPLC has been recognized as a useful methodology for the resolution of racemates (Francotte & Junker-Buchheit, 1992). We obtain the two enantiomers of (4) (Belloli et al., 2000), by preparative chiral HPLc to investigate their biochemical stereoselective affinity. Preliminary results show that the (-) form is the most affin enantiomer. Therefore, our pronounced interest was focused on the elucidation of the absolute configuration of the tetrahydronaphthalenic analogues of melatonin. A view of the molecule (4) with the atomic numbering is given in Fig. 1. The chiral center is found to have the R configuration. The nonaromatic nucleus shows a half-chair conformation. Methylene atoms C7 and C8 are located at -0.475 (5) and 0.278 (5) Å, respectively, from the mean molecular plane (C5,C6,C9,C10). The amide and the naphthalene moieties are practically perpendicular: the dihedral angle between the two mean planes was 87.6 (1)°. This conformation is different from that of one of the two independant molecules of N-cyclopropylcarbonyl-2-(7-methoxy-1-naphthyl)ethylamine (Tinant et al., 1993) in which the amide and the naphthalene planes are approximately parallel. The methoxy group is close to the plane of the aromatic ring and the conformation about C2—O1 bond is staggered (sp) with a torsion angle C11—C2—O1—C1 of 3.3 (3)°. The distance between the methoxy O atom O1 and the amide H atom H1, i.e. the two presumed polar anchoring points on the receptor (Lesieur, 1992), is 7.36 Å. By comparison, this distance is 7.34 Å in melatonin (Mostad & Romming, 1974) and 6.98 Å in molecule (A) of N-cyclopropylcarbonyl-2-(7-methoxy-1-naphthyl)ethylamine (Tinant et al., 1993).

S2. Refinement

The absolute configuration was determined by refinement of the Flack (1983) parameter, based on 1143 Friedel pairs. The reported configuration yielded x = 0.01 (14) while the inverse configuration yielded x = 1.01 (14). The NH and CH H atoms were included in the observed positions and refined. Other H atoms were placed in calculated positions with C—H distances of 0.93 (Csp²), 0.97 (CH₂) and 0.96 Å (CH₃). All hydrogen atoms were assigned an isotropic displacement parameter corresponding to 1.2U_eq of the attached parent atom.

Computing details

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures

Fig. 1. View of C17H23NO2 showing the labelling of the non-H atoms. Displacement ellipsoids are shown at the 30% probability level; H atoms are drawn as small circles of arbitrary radius.

(IV)

Crystal data

C17H23NO2	F(000) = 296
Mr = 273.36	Dx = 1.191 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 6.6653 (6) Å	Cell parameters from 5338 reflections
b = 5.0767 (4) Å	θ = 4.4–25.3°
c = 22.615 (2) Å	µ = 0.08 mm^−1
β = 95.262 (2)°	T = 293 K
V = 762.0 (2) Å^3	Needle, colourless
Z = 2	0.20 × 0.18 × 0.08 mm

Data collection

Bruker SMART-CCD diffractometer	2422 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.023
Graphite monochromator	θmax = 25.3°, θmin = 2.7°
ω scans	h = −7→7
9999 measured reflections	k = −6→6
2673 independent reflections	l = −27→27

Refinement

Refinement on F^2	H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.0703P)^2 + 0.0399P] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.036	(Δ/σ)max = 0.001
wR(F^2) = 0.107	Δρmax = 0.18 e Å^−3
S = 1.06	Δρmin = −0.16 e Å^−3
2673 reflections	Absolute structure: Flack (1983)
191 parameters	Absolute structure parameter: 0.01 (14)
1 restraint

Special details

Experimental. The crystal was positioned at a distance of 45 mm from the CCD area- detector entry. 3600 frames were recorded as an ω scan of 0.3 degees. The integration (Lorentz and polarization correction, data reduction and processing) was carried out using the SAINT program of the SMART CCD software package (Bruker, 1998). The structure was solved by direct methods (SIR92, (Altomare et al., 1993)) and refined by a full-matrix least-squares procedure (SHELXL97 (Sheldrick, 1997)).

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.0510 (3)	0.0142 (5)	0.43540 (9)	0.0689 (5)
H1A	0.1216	−0.1472	0.4296	0.083*
H1B	−0.0268	0.0622	0.3992	0.083*
H1C	−0.0372	−0.0094	0.4663	0.082*
O1	0.1917 (2)	0.2164 (3)	0.45189 (5)	0.0686 (4)
C2	0.3333 (2)	0.2774 (4)	0.41389 (7)	0.0524 (4)
C3	0.4720 (3)	0.4662 (4)	0.43405 (8)	0.0628 (5)
H3	0.4653	0.5432	0.4711	0.075*
C4	0.6200 (3)	0.5396 (4)	0.39895 (9)	0.0659 (5)
H4	0.7133	0.6663	0.413	0.079*
C5	0.6351 (2)	0.4312 (4)	0.34327 (8)	0.0525 (4)
C6	0.8037 (3)	0.5158 (4)	0.30655 (10)	0.0666 (5)
H6A	0.9275	0.4282	0.3215	0.08*
H6B	0.8246	0.7041	0.311	0.08*
C7	0.7580 (3)	0.4509 (5)	0.24100 (10)	0.0698 (6)
H7A	0.6507	0.5639	0.2238	0.084*
H7B	0.8767	0.4826	0.2202	0.084*
C8	0.6952 (3)	0.1655 (4)	0.23386 (10)	0.0671 (5)
H8A	0.8014	0.0538	0.2522	0.08*
H8B	0.6767	0.1222	0.1919	0.08*
C9	0.4988 (3)	0.1104 (4)	0.26230 (8)	0.0510 (4)
H9	0.490 (3)	−0.069 (5)	0.2689 (9)	0.061*
C10	0.4954 (2)	0.2413 (3)	0.32264 (7)	0.0456 (4)
C11	0.3448 (2)	0.1651 (3)	0.35862 (7)	0.0480 (4)
H11	0.2516	0.0373	0.3451	0.057*
C12	0.3096 (3)	0.1760 (3)	0.22112 (7)	0.0546 (4)
H12A	0.1951	0.1878	0.2445	0.065*
H12B	0.3271	0.3467	0.203	0.065*
C13	0.2662 (4)	−0.0230 (6)	0.17362 (11)	0.0880 (8)
H13A	0.382	−0.0356	0.1507	0.105*
H13B	0.2488	−0.1931	0.192	0.105*
N1	0.0893 (3)	0.0323 (3)	0.13336 (6)	0.0584 (4)
H1	0.067 (3)	0.190 (6)	0.1252 (10)	0.07*
C14	−0.0154 (3)	−0.1599 (4)	0.10576 (7)	0.0538 (4)
O2	0.0279 (2)	−0.3937 (3)	0.11287 (7)	0.0752 (5)
C15	−0.1913 (3)	−0.0772 (4)	0.06503 (9)	0.0638 (5)
H15	−0.217 (3)	0.104 (6)	0.0602 (10)	0.076*
C16	−0.3728 (3)	−0.2522 (6)	0.05985 (11)	0.0849 (7)
H16A	−0.3687	−0.4099	0.0841	0.102*
H16B	−0.504	−0.1691	0.0536	0.102*
C17	−0.2417 (4)	−0.2429 (6)	0.01076 (9)	0.0804 (7)
H17A	−0.2927	−0.1539	−0.0255	0.096*
H17B	−0.1573	−0.3948	0.0051	0.096*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0669 (12)	0.0803 (14)	0.0622 (10)	−0.0126 (11)	0.0201 (9)	0.0040 (11)
O1	0.0665 (8)	0.0902 (10)	0.0509 (6)	−0.0134 (8)	0.0149 (6)	−0.0109 (7)
C2	0.0509 (9)	0.0614 (11)	0.0447 (8)	−0.0007 (8)	0.0022 (7)	0.0024 (8)
C3	0.0686 (11)	0.0688 (13)	0.0493 (9)	−0.0085 (10)	−0.0043 (8)	−0.0078 (9)
C4	0.0636 (11)	0.0653 (12)	0.0660 (11)	−0.0164 (10)	−0.0094 (9)	−0.0008 (10)
C5	0.0463 (9)	0.0508 (9)	0.0590 (9)	−0.0028 (8)	−0.0028 (7)	0.0132 (8)
C6	0.0498 (10)	0.0658 (11)	0.0839 (13)	−0.0084 (9)	0.0037 (9)	0.0212 (11)
C7	0.0655 (11)	0.0676 (13)	0.0805 (13)	0.0043 (10)	0.0291 (10)	0.0174 (10)
C8	0.0648 (11)	0.0610 (13)	0.0795 (13)	0.0114 (9)	0.0282 (9)	0.0094 (10)
C9	0.0502 (9)	0.0492 (9)	0.0547 (9)	0.0063 (8)	0.0117 (7)	0.0034 (8)
C10	0.0403 (8)	0.0470 (9)	0.0490 (8)	0.0053 (7)	0.0018 (6)	0.0068 (7)
C11	0.0442 (8)	0.0518 (10)	0.0474 (8)	−0.0043 (7)	0.0018 (6)	−0.0020 (7)
C12	0.0632 (10)	0.0527 (11)	0.0481 (9)	0.0123 (8)	0.0062 (7)	−0.0010 (7)
C13	0.0869 (15)	0.0886 (16)	0.0836 (15)	0.0345 (13)	−0.0181 (12)	−0.0322 (13)
N1	0.0742 (10)	0.0482 (8)	0.0516 (8)	0.0114 (7)	−0.0001 (7)	−0.0032 (7)
C14	0.0743 (11)	0.0468 (10)	0.0415 (8)	0.0092 (8)	0.0121 (8)	0.0002 (7)
O2	0.1026 (11)	0.0475 (8)	0.0731 (9)	0.0135 (7)	−0.0046 (8)	−0.0004 (6)
C15	0.0804 (13)	0.0538 (10)	0.0562 (10)	0.0132 (10)	0.0000 (9)	−0.0037 (8)
C16	0.0696 (13)	0.0979 (18)	0.0870 (15)	0.0044 (13)	0.0060 (11)	−0.0184 (14)
C17	0.0901 (14)	0.0907 (17)	0.0584 (11)	0.0111 (13)	−0.0048 (10)	−0.0155 (12)

Geometric parameters (Å, º)

C1—O1	1.417 (3)	C9—C10	1.520 (3)
O1—C2	1.369 (2)	C9—C12	1.534 (3)
C2—C3	1.380 (3)	C10—C11	1.403 (2)
C2—C11	1.383 (2)	C12—C13	1.484 (3)
C3—C4	1.373 (3)	C13—N1	1.450 (3)
C4—C5	1.386 (3)	N1—C14	1.322 (3)
C5—C10	1.391 (2)	C14—O2	1.228 (2)
C5—C6	1.519 (3)	C14—C15	1.484 (3)
C6—C7	1.522 (3)	C15—C16	1.496 (4)
C7—C8	1.513 (3)	C15—C17	1.500 (3)
C8—C9	1.537 (3)	C16—C17	1.475 (3)
C2—O1—C1	118.43 (14)	C5—C10—C11	119.28 (15)
O1—C2—C3	115.41 (15)	C5—C10—C9	122.68 (15)
O1—C2—C11	125.00 (16)	C11—C10—C9	118.04 (15)
C3—C2—C11	119.59 (15)	C2—C11—C10	120.85 (15)
C4—C3—C2	119.51 (16)	C13—C12—C9	112.75 (15)
C3—C4—C5	122.23 (17)	N1—C13—C12	114.60 (18)
C4—C5—C10	118.53 (16)	C14—N1—C13	121.12 (19)
C4—C5—C6	120.22 (17)	O2—C14—N1	122.95 (19)
C10—C5—C6	121.23 (17)	O2—C14—C15	121.15 (18)
C5—C6—C7	112.28 (16)	N1—C14—C15	115.91 (18)
C8—C7—C6	109.87 (18)	C14—C15—C16	117.9 (2)
C7—C8—C9	111.58 (15)	C14—C15—C17	117.01 (18)
C10—C9—C12	111.79 (14)	C16—C15—C17	58.97 (16)
C10—C9—C8	112.29 (16)	C17—C16—C15	60.65 (16)
C12—C9—C8	113.01 (15)	C16—C17—C15	60.38 (16)
C1—O1—C2—C3	−176.73 (17)	C12—C9—C10—C11	64.4 (2)
C1—O1—C2—C11	3.3 (3)	C8—C9—C10—C11	−167.39 (15)
O1—C2—C3—C4	179.87 (18)	O1—C2—C11—C10	179.74 (16)
C11—C2—C3—C4	−0.1 (3)	C3—C2—C11—C10	−0.2 (3)
C2—C3—C4—C5	0.4 (3)	C5—C10—C11—C2	0.4 (2)
C3—C4—C5—C10	−0.2 (3)	C9—C10—C11—C2	−179.79 (16)
C3—C4—C5—C6	−179.00 (18)	C10—C9—C12—C13	−156.68 (19)
C4—C5—C6—C7	−160.80 (17)	C8—C9—C12—C13	75.5 (2)
C10—C5—C6—C7	20.4 (2)	C9—C12—C13—N1	−179.57 (19)
C5—C6—C7—C8	−50.6 (2)	C12—C13—N1—C14	−152.2 (2)
C6—C7—C8—C9	63.4 (2)	C13—N1—C14—O2	1.0 (3)
C7—C8—C9—C10	−43.2 (2)	C13—N1—C14—C15	−179.08 (19)
C7—C8—C9—C12	84.4 (2)	O2—C14—C15—C16	34.0 (3)
C4—C5—C10—C11	−0.2 (2)	N1—C14—C15—C16	−145.88 (19)
C6—C5—C10—C11	178.60 (15)	O2—C14—C15—C17	−33.3 (3)
C4—C5—C10—C9	−179.98 (17)	N1—C14—C15—C17	146.8 (2)
C6—C5—C10—C9	−1.2 (2)	C14—C15—C16—C17	−106.3 (2)
C12—C9—C10—C5	−115.82 (17)	C14—C15—C17—C16	107.8 (2)
C8—C9—C10—C5	12.4 (2)