(-)-(1'S,4aS,7R,8aR)-4a-Ethyl-7-hydroxy-1-(1'-phenylethyl)perhydroquinolinium bromide

In the structure of the title compound, C₁₉H₃₀NO⁺·Br^-, the rings of the perhydro­quinolinium moiety are cis fused. The successful reduction of the ketone functionality of the quinolinone used as starting material is confirmed by the hydroxy C-O bond length of 1.428 (3) Å.

S1. Comment

In the course of the total synthesis of a natural product, is it essential to check carefully the configuration of the generated stereogenic centres, in order to obtain the expected final product with the correct configuration. In spite of sophisticated tools available in the form of modern NMR techniques, dubious or even incorrect configurations can be deduced from these spectroscopic data. The best way to determine the absolute configuration of a chiral molecule is still to use anomalous X-ray methods, providing that at least one heavy atom (Z ≥ 14 for Mo radiation) is present and that a large fraction of Friedel pairs have been measured.

It has long been known that the treatment of non-chiral endocyclic enamines with methyl vinyl ketone affords a racemic mixture of cis-fused octahydroquinolin-7-ones. However, the separation of this mixture into the corresponding enantiomers is a very laborious process. We recently reported a diastereoselective synthesis of 4a-ethyl-1-(1'-phenylethyl)octahydroquinolin-7-ones (Vázquez et al., 2001). Both diastereoisomers were easily separated by chromatography, and their relative absolute configurations were assigned by NMR experiments. These chiral non-racemic compounds are versatile starting materials for the synthesis of aspidosperma alkaloids if the bicycle is cis-fused (Meyers & Berney, 1989; Schultz & Pettus, 1997; Iyengar et al., 2000; Toczko & Heathcock, 2000).

In order to confirm unambiguously the absolute configuration of the two chiral centres belonging to the octahydroquinoline moiety, we used the following procedure. The ketone group of chiral non-racemic (-)-(1'S,4aS,8aR)-4a-ethyl-1-(1'-phenylethyl)octahydroquinolin-7-one was reduced, giving a diastereoisomeric mixture of octahydroquinolin-7-ols (see Experimental). The main diastereoisomer was easily separated by chromatography, and its bromide salt, (I), was crystallized and characterized by X-ray diffraction methods. \sch

The structure of (I) (Fig. 1 and Table 1) clearly shows that the two six-membered cycles of the octahydroquinoline moiety adopt chair conformations. The puckering angles θ (Cremer & Pople, 1975) are 175.2 and 2.64° for the N1/C2/C3/C4/C4a/C8a and C4a/C5/C6/C7/C8/C8a rings, respectively (Spek, 1998). These rings are cis fused, with the ethyl group on C4a and the H atom on C8a oriented toward the same face of the bicycle.

The hydroxyl group generated during the reduction step is characterized by an C7—O15 bond length of 1.428 (3) Å, with the hydroxy group placed equatorially. The crystallization of (I) as a bromide salt allowed the determination of the absolute configuration for the five chiral centres. The final value of the Flack (1983) parameter, 0.002 (8), determines the configurations unambiguously as N1S, C1'S, C4aS, C8aR and C7R. This assignation is in agreement with the configuration of the chiral inductor, (-)-(S)-1-phenylethylamine, which is retained as 1'S.

Finally, as expected, the structure of (I) is stabilized in the solid state through moderate hydrogen bonds involving Br1 as the acceptor and N1—H1 and O15—H15 as donor groups, with approximately linear X—H···Br angles (Table 2). These interactions link alternating cations and anions into chains running parallel to the b axis. Is this text, added by the coeditor, OK?

S2. Experimental

(-)-(1'S,4aS,8aR)-4a-ethyl-1-(1'-phenylethyl)octahydroquinolin-7-one (0.91 g, 0.32 mmol) was dissolved in tetrahydrofuran (30 ml) and NaBH₄ (0.024 g, 0.63 mmol) was added. A solution of NaOH (5%, 3.5 ml) and H₂O (3.5 ml) was added to the mixture, which was refluxed for 8 h. After cooling, the mixture was extracted (5 ×) with Et₂O, and the organic phases were combined, dried over Na₂SO₄ and evaporated to dryness, yielding 0.091 g (98%) of a diastereoisomeric mixture of alcohols. This crude product was easily separated by chromatography (Al₂O₃, n-hexane/AcOEt), giving pure diastereoisomers in a 7:3 ratio. The main diastereoisomer was treated with HBr, yielding (I), which was crystallized from AcOEt/MeOH.

S3. Refinement

In order to refine the Flack parameter accurately, 2088 Friedel pairs were collected, corresponding to 88% of the accessible pairs. Atoms H1 (bonded to N1) and H15 (bonded to O15) were localized in difference maps and their positions refined freely. The remaining H atoms, bonded to sp²– and sp³-hybridized C atoms, were placed on idealized positions. In the final cycles, the hydroxyl H atom was allowed to refine as part of a rigid rotating group, while the other H atoms were constrained to ride on their parent atoms, with U_iso(H) = xU_eq(parent), where x = 1.5 for methyl and hydroxyl H atoms and 1.2 for all others. Constrained distances were O—H 0.74, N—H 0.91, aryl C—H 0.93, methine C—H 0.98, methylene C—H 0.97 and methyl C—H 0.96 Å.

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXTL-Plus (Sheldrick, 1998); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-Plus; software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. A view of the structure of (I) showing atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii.

(-)-(1'S,4aS,7R,8aR)-4a-ethyl-1-(1'-phenylethyl)octahydroquinolinium-7-ol bromide

Crystal data

C19H30NO^+·Br^−	F(000) = 388
Mr = 368.35	Dx = 1.330 Mg m^−3
Monoclinic, P21	Melting point: 403 K
Hall symbol: P 2yb	Mo Kα radiation, λ = 0.71073 Å
a = 9.6977 (8) Å	Cell parameters from 61 reflections
b = 9.2191 (7) Å	θ = 4.5–12.5°
c = 10.3008 (8) Å	µ = 2.24 mm^−1
β = 92.624 (7)°	T = 300 K
V = 919.97 (13) Å^3	Block, colourless
Z = 2	0.62 × 0.60 × 0.40 mm

Data collection

Bruker P4 diffractometer	3804 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.028
Graphite monochromator	θmax = 28.0°, θmin = 2.0°
2θ/ω scans	h = −12→12
Absorption correction: ψ scan (30 ψ scans with XSCANS; Siemens, 1996)	k = −12→12
Tmin = 0.292, Tmax = 0.409	l = −13→13
6148 measured reflections	3 standard reflections every 97 reflections
4443 independent reflections	intensity decay: 2.5%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: see text
R[F^2 > 2σ(F^2)] = 0.033	H-atom parameters constrained
wR(F^2) = 0.079	w = 1/[σ^2(Fo^2) + (0.0358P)^2 + 0.1874P] where P = (Fo^2 + 2Fc^2)/3
S = 1.02	(Δ/σ)max = 0.001
4443 reflections	Δρmax = 0.28 e Å^−3
199 parameters	Δρmin = −0.29 e Å^−3
1 restraint	Absolute structure: Flack (1983); 2088 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.002 (8)

Special details

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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. Atoms H1 and H15 were found on difference maps and refined as riding to O15 and N1 respectively.

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

	x	y	z	Uiso*/Ueq
Br1	0.41070 (2)	−0.06005 (3)	0.71041 (3)	0.05686 (9)
N1	0.2932 (2)	0.2967 (2)	0.67736 (19)	0.0362 (4)
H1	0.3168	0.2065	0.7068	0.043*
C1'	0.1942 (3)	0.2839 (3)	0.5576 (2)	0.0404 (5)
H1'A	0.1799	0.3817	0.5221	0.048*
C2	0.4335 (3)	0.3514 (3)	0.6439 (3)	0.0483 (6)
H2A	0.4246	0.4477	0.6066	0.058*
H2B	0.4716	0.2881	0.5793	0.058*
C2'	0.2535 (3)	0.1907 (4)	0.4514 (3)	0.0548 (7)
H2'A	0.1888	0.1863	0.3781	0.082*
H2'B	0.2705	0.0945	0.4841	0.082*
H2'C	0.3385	0.2324	0.4251	0.082*
C3	0.5308 (3)	0.3566 (3)	0.7630 (3)	0.0522 (6)
H3A	0.6169	0.4011	0.7397	0.063*
H3B	0.5510	0.2583	0.7915	0.063*
C4	0.4722 (2)	0.4412 (4)	0.8752 (2)	0.0459 (5)
H4A	0.4667	0.5431	0.8521	0.055*
H4B	0.5344	0.4321	0.9512	0.055*
C4a	0.3282 (2)	0.3873 (3)	0.9088 (2)	0.0377 (5)
C5	0.2667 (3)	0.4886 (3)	1.0097 (3)	0.0457 (6)
H5A	0.1826	0.4449	1.0389	0.055*
H5B	0.3312	0.4950	1.0842	0.055*
C6	0.2334 (3)	0.6418 (3)	0.9622 (3)	0.0527 (7)
H6A	0.1903	0.6961	1.0302	0.063*
H6B	0.3179	0.6914	0.9415	0.063*
C7	0.1376 (3)	0.6347 (3)	0.8435 (3)	0.0477 (6)
H7A	0.0519	0.5881	0.8687	0.057*
C8	0.1976 (3)	0.5428 (3)	0.7367 (3)	0.0434 (6)
H8A	0.2808	0.5886	0.7076	0.052*
H8B	0.1316	0.5375	0.6632	0.052*
C8a	0.2319 (2)	0.3891 (2)	0.7848 (2)	0.0331 (5)
H8AA	0.1448	0.3435	0.8071	0.040*
C9	0.3428 (3)	0.2344 (3)	0.9701 (3)	0.0460 (6)
H9A	0.3858	0.1717	0.9080	0.055*
H9B	0.4058	0.2415	1.0457	0.055*
C10	0.2122 (3)	0.1606 (4)	1.0115 (3)	0.0635 (8)
H10A	0.2345	0.0663	1.0461	0.095*
H10B	0.1487	0.1507	0.9377	0.095*
H10C	0.1706	0.2180	1.0769	0.095*
C11	0.0548 (3)	0.2270 (3)	0.5962 (2)	0.0381 (5)
C12	−0.0640 (3)	0.2955 (3)	0.5487 (3)	0.0481 (6)
H12A	−0.0571	0.3797	0.4996	0.058*
C12'	0.0431 (3)	0.1028 (3)	0.6703 (2)	0.0405 (5)
H12B	0.1222	0.0552	0.7022	0.049*
C13	−0.1929 (3)	0.2402 (4)	0.5732 (3)	0.0532 (7)
H13A	−0.2720	0.2861	0.5394	0.064*
C13'	−0.0859 (3)	0.0487 (3)	0.6974 (3)	0.0459 (6)
H13B	−0.0929	−0.0336	0.7489	0.055*
C14	−0.2040 (3)	0.1165 (3)	0.6482 (3)	0.0487 (6)
H14A	−0.2904	0.0793	0.6653	0.058*
O15	0.1029 (2)	0.7752 (2)	0.7937 (2)	0.0677 (6)
H15	0.1687	0.8096	0.7759	0.102*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.05259 (13)	0.04875 (13)	0.06874 (17)	−0.00308 (17)	−0.00264 (10)	0.00670 (17)
N1	0.0352 (9)	0.0334 (9)	0.0404 (10)	−0.0005 (8)	0.0055 (8)	−0.0021 (8)
C1'	0.0470 (13)	0.0404 (12)	0.0338 (11)	−0.0018 (11)	0.0009 (10)	0.0027 (10)
C2	0.0410 (13)	0.0516 (15)	0.0538 (15)	−0.0054 (11)	0.0173 (11)	−0.0055 (12)
C2'	0.0604 (18)	0.0638 (18)	0.0409 (14)	−0.0062 (15)	0.0103 (13)	−0.0106 (13)
C3	0.0350 (12)	0.0540 (15)	0.0682 (17)	−0.0020 (12)	0.0072 (12)	−0.0117 (14)
C4	0.0394 (10)	0.0423 (10)	0.0556 (12)	−0.0057 (17)	−0.0005 (9)	−0.0038 (18)
C4a	0.0374 (11)	0.0344 (10)	0.0413 (12)	0.0031 (9)	0.0015 (9)	−0.0022 (9)
C5	0.0524 (14)	0.0443 (13)	0.0405 (13)	0.0078 (10)	0.0019 (11)	−0.0055 (10)
C6	0.0609 (18)	0.0414 (14)	0.0561 (16)	0.0115 (13)	0.0072 (13)	−0.0101 (12)
C7	0.0505 (14)	0.0346 (12)	0.0584 (16)	0.0131 (11)	0.0054 (13)	0.0022 (11)
C8	0.0474 (14)	0.0362 (12)	0.0465 (14)	0.0078 (11)	−0.0002 (11)	0.0030 (11)
C8a	0.0337 (11)	0.0306 (10)	0.0355 (11)	0.0022 (8)	0.0063 (9)	−0.0006 (8)
C9	0.0520 (15)	0.0411 (13)	0.0448 (14)	0.0070 (11)	−0.0004 (11)	0.0054 (11)
C10	0.0680 (19)	0.0523 (16)	0.070 (2)	−0.0029 (15)	0.0039 (16)	0.0171 (15)
C11	0.0435 (12)	0.0361 (11)	0.0345 (11)	−0.0009 (10)	−0.0005 (9)	−0.0002 (9)
C12	0.0537 (15)	0.0461 (14)	0.0445 (14)	0.0085 (12)	0.0006 (11)	0.0107 (11)
C12'	0.0426 (12)	0.0360 (11)	0.0426 (13)	0.0027 (10)	−0.0017 (10)	0.0003 (10)
C13	0.0452 (15)	0.0674 (19)	0.0468 (15)	0.0132 (13)	−0.0003 (12)	0.0020 (14)
C13'	0.0499 (14)	0.0407 (12)	0.0477 (14)	−0.0013 (11)	0.0095 (11)	−0.0013 (11)
C14	0.0417 (13)	0.0555 (15)	0.0494 (15)	−0.0003 (12)	0.0063 (11)	−0.0116 (12)
O15	0.0782 (15)	0.0380 (10)	0.0868 (16)	0.0238 (10)	0.0010 (13)	0.0044 (10)

Geometric parameters (Å, º)

N1—C2	1.506 (3)	C2'—H2'A	0.9600
N1—C1'	1.533 (3)	C2'—H2'B	0.9600
N1—C8a	1.538 (3)	C2'—H2'C	0.9600
C1'—C11	1.520 (3)	C3—H3A	0.9700
C1'—C2'	1.524 (4)	C3—H3B	0.9700
C2—C3	1.514 (4)	C4—H4A	0.9700
C3—C4	1.525 (4)	C4—H4B	0.9700
C4—C4a	1.536 (3)	C5—H5A	0.9700
C4a—C5	1.538 (3)	C5—H5B	0.9700
C4a—C8a	1.548 (3)	C6—H6A	0.9700
C4a—C9	1.548 (3)	C6—H6B	0.9700
C5—C6	1.525 (4)	C7—H7A	0.9800
C6—C7	1.503 (4)	C8—H8A	0.9700
C7—O15	1.428 (3)	C8—H8B	0.9700
C7—C8	1.525 (4)	C8a—H8AA	0.9800
C8—C8a	1.532 (3)	C9—H9A	0.9700
C9—C10	1.516 (4)	C9—H9B	0.9700
C11—C12	1.384 (3)	C10—H10A	0.9600
C11—C12'	1.384 (3)	C10—H10B	0.9600
C12—C13	1.385 (4)	C10—H10C	0.9600
C12'—C13'	1.386 (4)	C12—H12A	0.9300
C13—C14	1.384 (4)	C12'—H12B	0.9300
C13'—C14	1.381 (4)	C13—H13A	0.9300
N1—H1	0.9103	C13'—H13B	0.9300
C1'—H1'A	0.9800	C14—H14A	0.9300
C2—H2A	0.9700	O15—H15	0.7429
C2—H2B	0.9700
C2—N1—C1'	112.36 (18)	C2—C3—H3B	109.0
C2—N1—C8a	111.25 (18)	C4—C3—H3B	109.0
C1'—N1—C8a	111.93 (17)	H3A—C3—H3B	107.8
C11—C1'—C2'	111.3 (2)	C3—C4—H4A	109.1
C11—C1'—N1	110.33 (18)	C4a—C4—H4A	109.1
C2'—C1'—N1	112.2 (2)	C3—C4—H4B	109.1
N1—C2—C3	111.2 (2)	C4a—C4—H4B	109.1
C2—C3—C4	113.0 (2)	H4A—C4—H4B	107.9
C3—C4—C4a	112.3 (2)	C6—C5—H5A	108.4
C4—C4a—C5	109.9 (2)	C4a—C5—H5A	108.4
C4—C4a—C8a	109.32 (19)	C6—C5—H5B	108.4
C5—C4a—C8a	108.21 (19)	C4a—C5—H5B	108.4
C4—C4a—C9	108.6 (2)	H5A—C5—H5B	107.5
C5—C4a—C9	108.0 (2)	C7—C6—H6A	109.8
C8a—C4a—C9	112.7 (2)	C5—C6—H6A	109.8
C6—C5—C4a	115.4 (2)	C7—C6—H6B	109.8
C7—C6—C5	109.5 (2)	C5—C6—H6B	109.8
O15—C7—C6	112.3 (2)	H6A—C6—H6B	108.2
O15—C7—C8	109.6 (2)	O15—C7—H7A	107.7
C6—C7—C8	111.7 (2)	C6—C7—H7A	107.7
C7—C8—C8a	111.4 (2)	C8—C7—H7A	107.7
C8—C8a—N1	111.40 (19)	C7—C8—H8A	109.4
C8—C8a—C4a	113.00 (19)	C8a—C8—H8A	109.4
N1—C8a—C4a	110.45 (17)	C7—C8—H8B	109.4
C10—C9—C4a	117.5 (2)	C8a—C8—H8B	109.4
C12—C11—C12'	119.0 (2)	H8A—C8—H8B	108.0
C12—C11—C1'	119.1 (2)	C8—C8a—H8AA	107.2
C12'—C11—C1'	121.8 (2)	N1—C8a—H8AA	107.2
C11—C12—C13	120.8 (2)	C4a—C8a—H8AA	107.2
C11—C12'—C13'	120.4 (2)	C10—C9—H9A	107.9
C14—C13—C12	119.9 (3)	C4a—C9—H9A	107.9
C14—C13'—C12'	120.3 (3)	C10—C9—H9B	107.9
C13'—C14—C13	119.6 (3)	C4a—C9—H9B	107.9
C2—N1—H1	99.6	H9A—C9—H9B	107.2
C1'—N1—H1	109.7	C9—C10—H10A	109.5
C8a—N1—H1	111.4	C9—C10—H10B	109.5
C11—C1'—H1'A	107.6	H10A—C10—H10B	109.5
C2'—C1'—H1'A	107.6	C9—C10—H10C	109.5
N1—C1'—H1'A	107.6	H10A—C10—H10C	109.5
N1—C2—H2A	109.4	H10B—C10—H10C	109.5
C3—C2—H2A	109.4	C11—C12—H12A	119.6
N1—C2—H2B	109.4	C13—C12—H12A	119.6
C3—C2—H2B	109.4	C11—C12'—H12B	119.8
H2A—C2—H2B	108.0	C13'—C12'—H12B	119.8
C1'—C2'—H2'A	109.5	C12—C13—H13A	120.0
C1'—C2'—H2'B	109.5	C14—C13—H13A	120.0
H2'A—C2'—H2'B	109.5	C14—C13'—H13B	119.9
C1'—C2'—H2'C	109.5	C12'—C13'—H13B	119.9
H2'A—C2'—H2'C	109.5	C13'—C14—H14A	120.2
H2'B—C2'—H2'C	109.5	C13—C14—H14A	120.2
C2—C3—H3A	109.0	C7—O15—H15	106.6
C4—C3—H3A	109.0
C2—N1—C1'—C11	179.4 (2)	C2—N1—C8a—C4a	−58.9 (2)
C8a—N1—C1'—C11	−54.5 (2)	C1'—N1—C8a—C4a	174.51 (18)
C2—N1—C1'—C2'	54.8 (3)	C4—C4a—C8a—C8	−68.7 (3)
C8a—N1—C1'—C2'	−179.2 (2)	C5—C4a—C8a—C8	51.0 (3)
C1'—N1—C2—C3	−177.5 (2)	C9—C4a—C8a—C8	170.3 (2)
C8a—N1—C2—C3	56.1 (3)	C4—C4a—C8a—N1	56.8 (3)
N1—C2—C3—C4	−53.1 (3)	C5—C4a—C8a—N1	176.54 (18)
C2—C3—C4—C4a	52.8 (3)	C9—C4a—C8a—N1	−64.1 (2)
C3—C4—C4a—C5	−172.6 (2)	C4—C4a—C9—C10	179.7 (2)
C3—C4—C4a—C8a	−54.0 (3)	C5—C4a—C9—C10	60.5 (3)
C3—C4—C4a—C9	69.4 (3)	C8a—C4a—C9—C10	−59.0 (3)
C4—C4a—C5—C6	66.6 (3)	C2'—C1'—C11—C12	−101.5 (3)
C8a—C4a—C5—C6	−52.7 (3)	N1—C1'—C11—C12	133.3 (2)
C9—C4a—C5—C6	−175.0 (2)	C2'—C1'—C11—C12'	74.0 (3)
C4a—C5—C6—C7	56.1 (3)	N1—C1'—C11—C12'	−51.2 (3)
C5—C6—C7—O15	−179.7 (2)	C12'—C11—C12—C13	−0.7 (4)
C5—C6—C7—C8	−56.1 (3)	C1'—C11—C12—C13	174.9 (3)
O15—C7—C8—C8a	−178.1 (2)	C12—C11—C12'—C13'	−0.6 (4)
C6—C7—C8—C8a	56.8 (3)	C1'—C11—C12'—C13'	−176.1 (2)
C7—C8—C8a—N1	−179.7 (2)	C11—C12—C13—C14	1.2 (4)
C7—C8—C8a—C4a	−54.6 (3)	C11—C12'—C13'—C14	1.5 (4)
C2—N1—C8a—C8	67.6 (2)	C12'—C13'—C14—C13	−1.0 (4)
C1'—N1—C8a—C8	−59.0 (2)	C12—C13—C14—C13'	−0.3 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Br1	0.91	2.62	3.492 (2)	161
O15—H15···Br1^i	0.74	2.75	3.491 (3)	179

Symmetry code: (i) x, y+1, z.