Catharanthinol and di­hydro­catha­ranth­inol: two Iboga-class alkaloids

The title compounds are indole alkaloids of the Iboga class. In both compounds, viz. catharanthinol methanol solvate, C₂₀H₂₄N₂O·CH₄O, (I), and di­hydro­catharanthinol mono­hydrate, C₂₀H₂₆N₂O·H₂O, (II), a nitrogen-containing seven-membered ring is fused to the indole system and shares two sides with a tricyclic isoquinuclidine group. The main difference between (I) and (II) is the presence of a C=C bond in the isoquinuclidine ring in (I). The presence of amine and hydroxy groups in these mol­ecules and of methanol [in (I)] or water [in (II)] solvent mol­ecules results in intra- and/or intermolecular hydrogen bonding.

S1. Comment

Compounds (I) and (II) pertain to the Iboga class of alkaloids, characterized by their indoloazepine-isoquinuclidine skeleton. Several members of this family have been characterized crystallographically, such as ibogaine, extracted from West African Tabernanthe iboga (Arai et al., 1960; Soriano-García, 1992), coronaridine (Kutney et al., 1973), bonafousine (Damak et al., 1976), epiheyneanine (Vencato et al., 1987), ibogamine (Soriano-García et al., 1988) and hydroxyibogamine (Massiot et al., 1983). Alkaloids of the closely related voacanga class have also been described (Soriano-García et al., 1989, 1991). \sch

Compounds (I) and (II) have been synthesized from catharanthine, which is a naturally occurring alkaloid isolated from the leaves of the Madagascar periwinkle Catharanthus roseus, and whose crystal structure has not yet been elucidated. Compound (I) differs from catharanthine by replacement of the methylester substituent of the latter with a hydroxymethyl group. Hydrogenation of catharanthine, under heterogeneous conditions, is known to afford dihydrocatharanthine as a single diastereomer. The selectivity of this process can be rationalized by assuming that addition of hydrogen takes place from the less hindered side of the Iboga skeleton. During our studies of the selective reduction of the C15═C20 bond, we envisioned that the stereochemical course of hydrogenation could be influenced by the presence of a neighbouring hydroxymethyl group. Indeed, association of the hydroxymethyl heteroatom with the catalyst surface can lead to delivery of hydrogen from the hindered `bottom' side. For the purpose of this study, we synthesized the starting substrate, (I), and also compound (II), which results from classical hydrogenation.

Both (I) and (II) crystallize as solvates. The asymmetric unit contains one alkaloid molecule and one methanol or one water molecule in (I) and (II), respectively (Figs. 1 and 2). The two compounds possess a hydroxymethyl substituent on atom C16, common to the seven-membered ring and the isoquinuclidine system, and an ethyl substituent on the latter. The isoquinuclidine ring includes a C15═C20 bond in (I) [bond length 1.329 (4) Å] whereas this bond is hydrogenated in (II) [bond length 1.537 (3) Å], with the ethyl substituent trans with respect to the isoquinuclidine atom N4. This same substituent is in a cis position in ibogaine. To the best of our knowledge, this is the first crystallographic characterization in this family of compounds of a molecule including a double bond in the quinuclidine system. A search of the Cambridge Structural Database (CSD, Version 5.25; Allen, 2002) gives 13 instances of substituted quinuclidine rings including such a bond, with a mean bond length of 1.329 (4) Å, which perfectly matches that in (I). The other bond lengths in both compounds are in agreement with those reported for other high-quality structure determinations of indole (Nigović et al., 2000) and alkaloid (Soriano-García et al., 1988, 1989) systems.

The indole ring system is planar, with r.m.s. deviations of 0.007 and 0.009 Å in (I) and (II), respectively. The seven-membered ring is in a chair conformation in (I) and in a distorted boat conformation in (II). Both conformations have previously been encountered in compounds of the same family, with no obvious rationale. This conformation change is mainly due to the different position of atoms N4 and C5 in (I) and (II); the distances to the indole plane of atoms N4, C5, C6, C16 and C21 of the seven-membered ring are −0.031 (4), 0.429 (5), −0.127 (4), −0.086 (4) and 0.577 (4) Å, respectively, in (I), and 0.997 (3), 1.428 (3), 0.293 (3), 0.037 (3) and −0.185 (3) Å, respectively, in (II). The mean plane defined by the seven-membered ring has r.m.s. deviations of 0.216 and 0.373 Å in (I) and (II), respectively, and has dihedral angles with the indole plane of 7.07 (12) in (I) or 23.69 (8)° in (II). The dihedral angle between the C21—N4—C3—C14 plane defined by the isoquinuclidine moiety [r.m.s. deviation 0.053 in (I) and 0.067 Å in (II)] and the indole system is 78.57 (10) in (I) and 73.53 (7)° in (II); values in the range 69.1 (1)–114.0 (2)° have been reported for other members of this family of compounds (Soriano-García, 1992). The dihedral angle between the same plane and the mean seven-membered ring plane is 85.62 (11) for (I) and 60.85 (8)° for (II). The two triangular isoquinuclidine planes, N4—C16—C20 and C3—C15—C17, define a dihedral angle of 5.6 (2) in (I) and 1.88 (3)° in (II) and are thus tilted slightly with respect to their parallel position in the ideal conformation.

Apart from van der Waals interactions, the alkaloid molecules are held in the crystal packing by hydrogen bonds involving the solvent molecules in both (I) and (II). In (I), an intramolecular hydrogen bond links the N1—H group and the hydroxy atom O1 in the same molecule. The O1—H group itself acts as a donor towards the methanol atom O2, the latter being finally hydrogen bonded to the isoquinuclidine atom N4 of a neighbouring molecule related to the first by the binary screw axis parallel to the a axis (Table 1). This hydrogen-bonding network gives rise to zigzag chains directed along the a axis.

No intramolecular hydrogen bond is present in (II). Atom O1 acts as a donor towards atom N4 of a neighbouring molecule related by the binary screw axis parallel to the b axis, and as an acceptor from the water molecule. Finally, atom N1 is bound to another water molecule related to the first by the screw axis parallel to the a axis (Table 2). The resulting arrangement is three-dimensional.

Some significant C—H···π interactions are present in both compounds. In (I), an interaction involves the H atom of the isoquinuclidine bridgehead atom, C14, and the six-membered aromatic ring of a second molecule related to the first by the screw axis parallel to the c axis [H14···centroid distance 2.74 Å and C14—H14···centroid angle 164°] and thus links adjacent hydrogen-bonded chains. In (II), such an interaction is found between the water H atom which is not involved in hydrogen bonding and the indole five-membered ring in the same unit [H4···centroid distance 2.52 Å and O2—H4···centroid angle 129°], and two others between H atoms bound to atoms C14 and C15 and the indole six- and five-membered rings, respectively, of the molecule related by the screw axis parallel to the c axis [H14···centroid distance 2.81 Å and C14—H14···centroid angle 138°, and H15A···centroid distance 2.59 Å and C15—H15A···centroid angle 159°].

S2. Experimental

Reduction of the ester group of (+)-catharanthine with lithium aluminium hydride gave compound (I), which was recrystallized from methanol. Compound (II) was obtained in two steps from catharanthine, the catalytic hydrogenation of the C15═C20 bond being followed by reduction of the ester group by LiAlH₄, as reported in the literature method of Gorman et al. (1965). Crystals of (II) were obtained by recrystallization from diethyl ether.

S3. Refinement

The amino, hydroxy and water H atoms were found in a difference Fourier map and were introduced as riding atoms, with U_iso(H) = 1.2U_eq(O,N). All other H atoms were introduced in calculated positions as riding atoms, with C—H bond lengths of 0.93 (aromatic CH), 0.98 (aliphatic CH), 0.97 (CH₂) and 0.96 Å (CH₃), and with U_iso(H) = 1.2U_eq(C) for CH and CH₂ and 1.5U_eq(C) for CH₃. In the absence of suitable anomalous scatterers, Friedel equivalents could not be used to determine the absolute configuration. Refinement of the Flack parameter (Flack, 1983) led to inconclusive values (Flack & Bernardinelli, 2000) of −1.4 (16) for (I) and −0.1 (14) for (II). Therefore, the 1439 and 1322 Friedel equivalents for (I) and (II), respectively, were merged before the final refinements. The configuration adopted is that of the precursor of both compounds, natural (+)-catharanthine.

Computing details

For both compounds, data collection: KappaCCD Server Software (Nonius, 1997); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1999); software used to prepare material for publication: SHELXTL and PLATON (Spek, 2003).

Figures

	Fig. 1. A view of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. Hydrogen bonds are shown as dashed lines. The primed atom is in the molecule at symmetry position (x + 1/2, 3/2 − y, −z).
	Fig. 2. A view of (II), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. Hydrogen bonds are shown as dashed lines. The primed atom is in the molecule at symmetry position (x − 1/2, 3/2 − y, 2 − z) and the doubly primed atom is in the molecule at symmetry position (2 − x, y − 1/2, 1/2 − z).

(I) catharanthinol methanol solvate

Crystal data

C20H24N2O·CH4O	F(000) = 736
Mr = 340.45	Dx = 1.269 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 13656 reflections
a = 10.7136 (5) Å	θ = 2.9–25.7°
b = 12.6846 (8) Å	µ = 0.08 mm^−1
c = 13.1078 (9) Å	T = 100 K
V = 1781.32 (19) Å^3	Platelet, colourless
Z = 4	0.24 × 0.20 × 0.08 mm

Data collection

Nonius KappaCCD area-detector diffractometer	1707 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.063
Graphite monochromator	θmax = 25.7°, θmin = 2.9°
ϕ scans	h = 0→13
13656 measured reflections	k = 0→15
1927 independent reflections	l = 0→15

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.041	H-atom parameters constrained
wR(F^2) = 0.090	w = 1/[σ^2(Fo^2) + (0.0305P)^2 + 0.7559P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
1927 reflections	Δρmax = 0.19 e Å^−3
229 parameters	Δρmin = −0.19 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.022 (3)

Special details

Experimental. The unit-cell parameters have been determined from 10 frames, then refined on all data. The crystal-to-detector distance was fixed to 28 mm. One-half of the diffraction sphere was scanned (90 frames, ϕ scans, 2° by frame).

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. Structure solved by direct methods and subsequent Fourier-difference synthesis. All non-hydrogen atoms were refined with anisotropic displacement parameters. The H atoms bound to O and N were found on the Fourier-difference map and introduced as riding atoms with an isotropic displacement parameter equal to 1.2 times that of the parent atom. All other atoms were introduced at calculated positions as riding atoms with an isotropic displacement parameter equal to 1.2 (CH, CH2) or 1.5 (CH3) times that of the parent atom. 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.

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

	x	y	z	Uiso*/Ueq
N1	0.6342 (2)	0.72220 (18)	0.32211 (16)	0.0238 (5)
H1	0.7035	0.7625	0.3124	0.029*
O1	0.80485 (18)	0.81010 (16)	0.20168 (14)	0.0282 (5)
H2	0.8384	0.8748	0.1760	0.034*
C2	0.5922 (3)	0.6624 (2)	0.23949 (19)	0.0221 (6)
C3	0.6237 (3)	0.4613 (2)	0.0557 (2)	0.0276 (6)
H3A	0.6140	0.4062	0.0051	0.033*
H3B	0.6172	0.4297	0.1229	0.033*
N4	0.5246 (2)	0.54254 (17)	0.04233 (18)	0.0228 (5)
C5	0.4109 (3)	0.5270 (2)	0.1028 (2)	0.0262 (6)
H5A	0.3690	0.4647	0.0769	0.031*
H5B	0.3562	0.5865	0.0901	0.031*
C6	0.4240 (3)	0.5146 (2)	0.2179 (2)	0.0278 (7)
H6A	0.3410	0.5113	0.2472	0.033*
H6B	0.4644	0.4476	0.2315	0.033*
C7	0.4954 (3)	0.5988 (2)	0.2722 (2)	0.0234 (6)
C8	0.4772 (2)	0.6213 (2)	0.3793 (2)	0.0226 (6)
C9	0.3931 (3)	0.5832 (2)	0.4522 (2)	0.0278 (6)
H9	0.3334	0.5332	0.4347	0.033*
C10	0.4006 (3)	0.6217 (2)	0.5512 (2)	0.0270 (6)
H10	0.3453	0.5969	0.6003	0.032*
C11	0.4904 (3)	0.6974 (2)	0.5783 (2)	0.0252 (6)
H11	0.4935	0.7217	0.6452	0.030*
C12	0.5744 (3)	0.7364 (2)	0.5076 (2)	0.0247 (6)
H12	0.6340	0.7863	0.5256	0.030*
C13	0.5661 (3)	0.6979 (2)	0.4079 (2)	0.0235 (6)
C14	0.7520 (3)	0.5148 (2)	0.0434 (2)	0.0257 (6)
H14	0.8189	0.4622	0.0400	0.031*
C15	0.7497 (3)	0.5819 (2)	−0.0516 (2)	0.0256 (6)
H15	0.8053	0.5726	−0.1054	0.031*
C16	0.6625 (2)	0.6724 (2)	0.1392 (2)	0.0219 (6)
C17	0.7703 (2)	0.5892 (2)	0.1354 (2)	0.0255 (6)
H17A	0.8500	0.6250	0.1295	0.031*
H17B	0.7708	0.5484	0.1980	0.031*
C18	0.7254 (3)	0.7341 (3)	−0.2228 (2)	0.0322 (7)
H18A	0.8094	0.7419	−0.1985	0.048*
H18B	0.7061	0.7907	−0.2689	0.048*
H18C	0.7174	0.6680	−0.2579	0.048*
C19	0.6355 (3)	0.7368 (2)	−0.1328 (2)	0.0253 (6)
H19A	0.6390	0.8062	−0.1019	0.030*
H19B	0.5513	0.7264	−0.1581	0.030*
C20	0.6615 (2)	0.6555 (2)	−0.0518 (2)	0.0225 (6)
C21	0.5793 (2)	0.6501 (2)	0.0434 (2)	0.0216 (6)
H21	0.5127	0.7028	0.0389	0.026*
C22	0.7129 (2)	0.7854 (2)	0.1261 (2)	0.0239 (6)
H22A	0.7495	0.7926	0.0588	0.029*
H22B	0.6443	0.8350	0.1313	0.029*
O2	0.90688 (17)	0.99099 (15)	0.13719 (14)	0.0261 (5)
H3	0.9525	0.9795	0.0735	0.031*
C23	0.9903 (3)	1.0280 (2)	0.2140 (2)	0.0293 (7)
H23A	1.0413	1.0834	0.1866	0.044*
H23B	1.0426	0.9710	0.2363	0.044*
H23C	0.9432	1.0544	0.2708	0.044*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0262 (11)	0.0247 (12)	0.0205 (12)	−0.0059 (10)	0.0004 (10)	−0.0017 (10)
O1	0.0288 (10)	0.0328 (11)	0.0229 (10)	−0.0096 (9)	−0.0037 (9)	−0.0004 (9)
C2	0.0248 (14)	0.0220 (14)	0.0196 (13)	0.0026 (11)	−0.0017 (12)	−0.0003 (11)
C3	0.0309 (15)	0.0205 (14)	0.0313 (15)	0.0011 (12)	−0.0014 (13)	−0.0004 (12)
N4	0.0211 (11)	0.0233 (12)	0.0241 (11)	−0.0023 (9)	0.0016 (10)	0.0006 (10)
C5	0.0253 (14)	0.0288 (15)	0.0244 (14)	−0.0057 (12)	0.0004 (12)	−0.0013 (12)
C6	0.0279 (15)	0.0313 (16)	0.0241 (15)	−0.0064 (13)	0.0004 (13)	0.0008 (12)
C7	0.0236 (13)	0.0255 (14)	0.0211 (14)	−0.0003 (11)	−0.0004 (12)	0.0007 (11)
C8	0.0203 (13)	0.0253 (14)	0.0223 (14)	0.0016 (11)	−0.0012 (11)	0.0035 (11)
C9	0.0273 (15)	0.0291 (15)	0.0270 (15)	0.0006 (12)	−0.0001 (13)	0.0011 (13)
C10	0.0272 (14)	0.0316 (15)	0.0221 (14)	0.0031 (12)	0.0027 (13)	0.0024 (12)
C11	0.0282 (14)	0.0266 (14)	0.0208 (14)	0.0041 (12)	−0.0002 (12)	−0.0037 (11)
C12	0.0279 (14)	0.0222 (14)	0.0239 (14)	−0.0011 (12)	−0.0023 (12)	−0.0012 (11)
C13	0.0255 (14)	0.0214 (13)	0.0235 (14)	0.0014 (11)	0.0010 (12)	0.0021 (11)
C14	0.0244 (13)	0.0242 (14)	0.0285 (14)	0.0040 (11)	0.0005 (13)	0.0004 (13)
C15	0.0259 (14)	0.0295 (15)	0.0214 (13)	0.0014 (12)	0.0020 (13)	−0.0044 (12)
C16	0.0237 (13)	0.0227 (14)	0.0192 (13)	−0.0021 (11)	−0.0013 (12)	−0.0006 (11)
C17	0.0226 (13)	0.0292 (15)	0.0248 (14)	0.0012 (12)	−0.0027 (12)	0.0004 (12)
C18	0.0325 (16)	0.0393 (18)	0.0248 (15)	−0.0045 (14)	0.0006 (13)	0.0036 (13)
C19	0.0274 (14)	0.0284 (15)	0.0201 (14)	−0.0014 (12)	−0.0011 (12)	−0.0005 (12)
C20	0.0246 (14)	0.0235 (14)	0.0192 (13)	−0.0034 (11)	−0.0014 (12)	−0.0028 (11)
C21	0.0210 (12)	0.0231 (14)	0.0207 (13)	0.0023 (11)	−0.0009 (12)	0.0010 (11)
C22	0.0244 (14)	0.0260 (15)	0.0214 (14)	−0.0035 (12)	−0.0028 (12)	−0.0003 (11)
O2	0.0251 (10)	0.0340 (11)	0.0193 (9)	−0.0042 (8)	−0.0008 (8)	−0.0028 (8)
C23	0.0338 (15)	0.0296 (16)	0.0244 (14)	−0.0040 (13)	−0.0059 (13)	−0.0032 (12)

Geometric parameters (Å, º)

N1—C13	1.376 (3)	C12—C13	1.397 (4)
N1—C2	1.397 (3)	C12—H12	0.9300
N1—H1	0.9106	C14—C15	1.508 (4)
O1—C22	1.432 (3)	C14—C17	1.544 (4)
O1—H2	0.9579	C14—H14	0.9800
C2—C7	1.382 (4)	C15—C20	1.329 (4)
C2—C16	1.520 (4)	C15—H15	0.9300
C3—N4	1.490 (3)	C16—C22	1.541 (4)
C3—C14	1.540 (4)	C16—C21	1.565 (4)
C3—H3A	0.9700	C16—C17	1.566 (4)
C3—H3B	0.9700	C17—H17A	0.9700
N4—C5	1.466 (3)	C17—H17B	0.9700
N4—C21	1.485 (3)	C18—C19	1.524 (4)
C5—C6	1.524 (4)	C18—H18A	0.9600
C5—H5A	0.9700	C18—H18B	0.9600
C5—H5B	0.9700	C18—H18C	0.9600
C6—C7	1.493 (4)	C19—C20	1.506 (4)
C6—H6A	0.9700	C19—H19A	0.9700
C6—H6B	0.9700	C19—H19B	0.9700
C7—C8	1.445 (4)	C20—C21	1.529 (4)
C8—C9	1.400 (4)	C21—H21	0.9800
C8—C13	1.411 (4)	C22—H22A	0.9700
C9—C10	1.388 (4)	C22—H22B	0.9700
C9—H9	0.9300	O2—C23	1.426 (3)
C10—C11	1.405 (4)	O2—H3	0.9786
C10—H10	0.9300	C23—H23A	0.9600
C11—C12	1.384 (4)	C23—H23B	0.9600
C11—H11	0.9300	C23—H23C	0.9600
C13—N1—C2	110.0 (2)	C3—C14—H14	111.0
C13—N1—H1	132.2	C17—C14—H14	111.0
C2—N1—H1	117.4	C20—C15—C14	114.2 (2)
C22—O1—H2	101.7	C20—C15—H15	122.9
C7—C2—N1	108.6 (2)	C14—C15—H15	122.9
C7—C2—C16	133.5 (2)	C2—C16—C22	110.3 (2)
N1—C2—C16	117.7 (2)	C2—C16—C21	113.3 (2)
N4—C3—C14	108.6 (2)	C22—C16—C21	106.2 (2)
N4—C3—H3A	110.0	C2—C16—C17	109.7 (2)
C14—C3—H3A	110.0	C22—C16—C17	111.4 (2)
N4—C3—H3B	110.0	C21—C16—C17	105.8 (2)
C14—C3—H3B	110.0	C14—C17—C16	110.1 (2)
H3A—C3—H3B	108.3	C14—C17—H17A	109.6
C5—N4—C21	116.5 (2)	C16—C17—H17A	109.6
C5—N4—C3	115.8 (2)	C14—C17—H17B	109.6
C21—N4—C3	110.6 (2)	C16—C17—H17B	109.6
N4—C5—C6	118.2 (2)	H17A—C17—H17B	108.2
N4—C5—H5A	107.8	C19—C18—H18A	109.5
C6—C5—H5A	107.8	C19—C18—H18B	109.5
N4—C5—H5B	107.8	H18A—C18—H18B	109.5
C6—C5—H5B	107.8	C19—C18—H18C	109.5
H5A—C5—H5B	107.1	H18A—C18—H18C	109.5
C7—C6—C5	116.4 (2)	H18B—C18—H18C	109.5
C7—C6—H6A	108.2	C20—C19—C18	114.5 (2)
C5—C6—H6A	108.2	C20—C19—H19A	108.6
C7—C6—H6B	108.2	C18—C19—H19A	108.6
C5—C6—H6B	108.2	C20—C19—H19B	108.6
H6A—C6—H6B	107.3	C18—C19—H19B	108.6
C2—C7—C8	106.7 (2)	H19A—C19—H19B	107.6
C2—C7—C6	130.8 (2)	C15—C20—C19	127.9 (3)
C8—C7—C6	122.3 (2)	C15—C20—C21	112.1 (2)
C9—C8—C13	119.4 (2)	C19—C20—C21	120.0 (2)
C9—C8—C7	132.9 (3)	N4—C21—C20	105.1 (2)
C13—C8—C7	107.7 (2)	N4—C21—C16	113.5 (2)
C10—C9—C8	118.6 (3)	C20—C21—C16	108.6 (2)
C10—C9—H9	120.7	N4—C21—H21	109.8
C8—C9—H9	120.7	C20—C21—H21	109.8
C9—C10—C11	121.1 (3)	C16—C21—H21	109.8
C9—C10—H10	119.4	O1—C22—C16	111.6 (2)
C11—C10—H10	119.4	O1—C22—H22A	109.3
C12—C11—C10	121.3 (2)	C16—C22—H22A	109.3
C12—C11—H11	119.4	O1—C22—H22B	109.3
C10—C11—H11	119.4	C16—C22—H22B	109.3
C11—C12—C13	117.4 (3)	C19—C22—H22B	90.2
C11—C12—H12	121.3	H22A—C22—H22B	108.0
C13—C12—H12	121.3	C23—O2—H3	109.8
N1—C13—C12	130.7 (3)	O2—C23—H23A	109.5
N1—C13—C8	107.1 (2)	O2—C23—H23B	109.5
C12—C13—C8	122.2 (3)	H23A—C23—H23B	109.5
C15—C14—C3	108.7 (2)	O2—C23—H23C	109.5
C15—C14—C17	107.6 (2)	H23A—C23—H23C	109.5
C3—C14—C17	107.5 (2)	H23B—C23—H23C	109.5
C15—C14—H14	111.0

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1	0.91	1.91	2.660 (3)	138
O1—H2···O2	0.96	1.72	2.679 (3)	176
O2—H3···N4^i	0.98	1.73	2.703 (3)	177

Symmetry code: (i) x+1/2, −y+3/2, −z.

(II) dihydrocatharanthinol monohydrate

Crystal data

C20H26N2O·H2O	F(000) = 712
Mr = 328.44	Dx = 1.328 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 12617 reflections
a = 10.6728 (4) Å	θ = 3.0–25.7°
b = 12.0168 (6) Å	µ = 0.09 mm^−1
c = 12.8132 (7) Å	T = 100 K
V = 1643.33 (14) Å^3	Parallelepiped, colourless
Z = 4	0.25 × 0.25 × 0.20 mm

Data collection

Nonius KappaCCD area-detector diffractometer	1621 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.066
Graphite monochromator	θmax = 25.7°, θmin = 3.0°
ϕ scans	h = 0→12
12617 measured reflections	k = 0→14
1788 independent reflections	l = 0→15

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.035	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.088	H-atom parameters constrained
S = 1.07	w = 1/[σ^2(Fo^2) + (0.0441P)^2 + 0.4399P] where P = (Fo^2 + 2Fc^2)/3
1788 reflections	(Δ/σ)max < 0.001
218 parameters	Δρmax = 0.16 e Å^−3
0 restraints	Δρmin = −0.20 e Å^−3

Special details

Experimental. The unit-cell parameters have been determined from 10 frames, then refined on all data. The crystal-to-detector distance was fixed to 28 mm. One-half of the diffraction sphere was scanned (90 frames, ϕ scans, 2° by frame).

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. Structure solved by direct methods and subsequent Fourier-difference synthesis. All non-hydrogen atoms were refined with anisotropic displacement parameters. The H atoms bound to O and N were found on the Fourier-difference map and introduced as riding atoms with an isotropic displacement parameter equal to 1.2 times that of the parent atom. All other atoms were introduced at calculated positions as riding atoms with an isotropic displacement parameter equal to 1.2 (CH, CH2) or 1.5 (CH3) times that of the parent atom. 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.

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

	x	y	z	Uiso*/Ueq
N1	0.96599 (18)	0.84084 (16)	1.04012 (14)	0.0192 (4)
H1	0.9063	0.7850	1.0403	0.023*
O1	1.06105 (15)	0.79923 (14)	0.80113 (13)	0.0220 (4)
H2	1.0825	0.7359	0.7552	0.026*
C2	0.9680 (2)	0.92951 (19)	0.97081 (17)	0.0180 (5)
C3	0.7357 (2)	1.1242 (2)	0.8246 (2)	0.0218 (5)
H3A	0.7095	1.1708	0.7668	0.026*
H3B	0.6977	1.1530	0.8878	0.026*
N4	0.87548 (18)	1.12787 (16)	0.83443 (15)	0.0186 (4)
C5	0.9132 (2)	1.16724 (19)	0.93929 (19)	0.0210 (5)
H5A	0.8538	1.1391	0.9902	0.025*
H5B	0.9085	1.2478	0.9406	0.025*
C6	1.0448 (2)	1.13179 (19)	0.97164 (19)	0.0224 (5)
H6A	1.1010	1.1364	0.9123	0.027*
H6B	1.0760	1.1810	1.0258	0.027*
C7	1.0404 (2)	1.0141 (2)	1.01160 (17)	0.0197 (5)
C8	1.0850 (2)	0.9763 (2)	1.11184 (18)	0.0198 (5)
C9	1.1589 (2)	1.0240 (2)	1.1911 (2)	0.0237 (5)
H9	1.1916	1.0953	1.1833	0.028*
C10	1.1820 (2)	0.9631 (2)	1.2807 (2)	0.0257 (6)
H10	1.2311	0.9938	1.3333	0.031*
C11	1.1324 (2)	0.8554 (2)	1.2936 (2)	0.0245 (5)
H11	1.1497	0.8163	1.3546	0.029*
C12	1.0589 (2)	0.8063 (2)	1.21782 (18)	0.0224 (5)
H12	1.0257	0.7354	1.2269	0.027*
C13	1.0364 (2)	0.86766 (19)	1.12683 (17)	0.0192 (5)
C14	0.6915 (2)	1.00436 (19)	0.80605 (19)	0.0210 (5)
H14	0.5999	1.0003	0.8108	0.025*
C15	0.7347 (2)	0.9703 (2)	0.69627 (19)	0.0215 (5)
H15A	0.6826	1.0056	0.6438	0.026*
H15B	0.7287	0.8903	0.6878	0.026*
C16	0.8969 (2)	0.9215 (2)	0.86882 (18)	0.0181 (5)
C17	0.7516 (2)	0.9269 (2)	0.88732 (19)	0.0197 (5)
H17A	0.7159	0.8529	0.8814	0.024*
H17B	0.7345	0.9545	0.9570	0.024*
C18	1.0500 (2)	1.0113 (2)	0.5533 (2)	0.0278 (6)
H18A	1.1031	1.0435	0.6057	0.042*
H18B	1.0115	1.0695	0.5133	0.042*
H18C	1.0991	0.9650	0.5081	0.042*
C19	0.9489 (2)	0.9414 (2)	0.60560 (19)	0.0221 (5)
H19A	0.9880	0.8791	0.6411	0.027*
H19B	0.8935	0.9117	0.5525	0.027*
C20	0.8715 (2)	1.00833 (19)	0.68450 (17)	0.0185 (5)
H20	0.8672	1.0840	0.6561	0.022*
C21	0.9293 (2)	1.02089 (18)	0.79529 (18)	0.0178 (5)
H21	1.0205	1.0280	0.7894	0.021*
C22	0.9291 (2)	0.80721 (19)	0.82055 (18)	0.0189 (5)
H22A	0.9036	0.7484	0.8679	0.023*
H22B	0.8836	0.7979	0.7556	0.023*
O2	1.25670 (15)	0.80843 (14)	0.94605 (14)	0.0281 (4)
H3	1.1850	0.8056	0.8994	0.034*
H4	1.2333	0.8541	1.0028	0.034*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0209 (9)	0.0194 (10)	0.0174 (10)	−0.0005 (8)	−0.0007 (8)	0.0002 (8)
O1	0.0196 (8)	0.0211 (8)	0.0253 (9)	0.0026 (7)	−0.0004 (7)	−0.0045 (7)
C2	0.0200 (11)	0.0176 (11)	0.0164 (12)	0.0026 (10)	−0.0003 (9)	0.0009 (9)
C3	0.0202 (12)	0.0213 (12)	0.0238 (13)	0.0033 (10)	0.0027 (9)	0.0014 (10)
N4	0.0192 (9)	0.0175 (9)	0.0190 (10)	0.0019 (8)	−0.0002 (8)	−0.0015 (8)
C5	0.0265 (12)	0.0159 (11)	0.0204 (12)	−0.0006 (9)	0.0007 (9)	0.0002 (10)
C6	0.0244 (12)	0.0204 (12)	0.0225 (12)	−0.0026 (10)	0.0002 (10)	−0.0016 (10)
C7	0.0191 (11)	0.0215 (12)	0.0185 (11)	0.0006 (10)	0.0006 (9)	−0.0009 (9)
C8	0.0174 (11)	0.0216 (12)	0.0202 (12)	0.0016 (9)	0.0006 (9)	−0.0015 (10)
C9	0.0212 (11)	0.0229 (12)	0.0270 (13)	0.0001 (10)	0.0008 (10)	−0.0046 (11)
C10	0.0246 (12)	0.0315 (13)	0.0210 (13)	0.0017 (11)	−0.0031 (10)	−0.0067 (11)
C11	0.0266 (12)	0.0267 (13)	0.0202 (12)	0.0088 (11)	−0.0005 (10)	0.0009 (11)
C12	0.0218 (11)	0.0208 (11)	0.0244 (12)	0.0055 (10)	0.0018 (10)	0.0019 (10)
C13	0.0185 (11)	0.0219 (12)	0.0171 (11)	0.0033 (10)	0.0009 (9)	−0.0033 (9)
C14	0.0174 (11)	0.0220 (12)	0.0236 (12)	0.0001 (10)	0.0008 (9)	0.0000 (10)
C15	0.0213 (12)	0.0217 (12)	0.0214 (12)	0.0023 (10)	−0.0024 (9)	−0.0004 (10)
C16	0.0168 (11)	0.0187 (11)	0.0189 (12)	0.0004 (9)	0.0010 (9)	−0.0003 (10)
C17	0.0195 (11)	0.0190 (11)	0.0207 (12)	−0.0007 (10)	0.0004 (9)	−0.0014 (10)
C18	0.0283 (13)	0.0281 (13)	0.0269 (13)	−0.0021 (11)	0.0063 (11)	−0.0024 (11)
C19	0.0244 (12)	0.0235 (13)	0.0184 (12)	0.0016 (10)	−0.0002 (9)	−0.0007 (10)
C20	0.0200 (11)	0.0171 (11)	0.0182 (11)	0.0005 (9)	−0.0015 (9)	0.0006 (10)
C21	0.0185 (11)	0.0166 (11)	0.0184 (11)	0.0007 (9)	−0.0007 (9)	−0.0012 (10)
C22	0.0191 (11)	0.0186 (11)	0.0190 (11)	0.0012 (9)	−0.0013 (9)	0.0008 (9)
O2	0.0245 (9)	0.0312 (9)	0.0285 (9)	0.0035 (8)	−0.0030 (7)	−0.0037 (8)

Geometric parameters (Å, º)

N1—C13	1.379 (3)	C12—C13	1.400 (3)
N1—C2	1.387 (3)	C12—H12	0.9300
N1—H1	0.9249	C14—C15	1.536 (3)
O1—C22	1.434 (3)	C14—C17	1.537 (3)
O1—H2	0.9882	C14—H14	0.9800
C2—C7	1.379 (3)	C15—C20	1.537 (3)
C2—C16	1.514 (3)	C15—H15A	0.9700
C3—N4	1.498 (3)	C15—H15B	0.9700
C3—C14	1.534 (3)	C16—C22	1.545 (3)
C3—H3A	0.9700	C16—C21	1.560 (3)
C3—H3B	0.9700	C16—C17	1.571 (3)
N4—C5	1.480 (3)	C17—H17A	0.9700
N4—C21	1.495 (3)	C17—H17B	0.9700
C5—C6	1.526 (3)	C18—C19	1.522 (3)
C5—H5A	0.9700	C18—H18A	0.9600
C5—H5B	0.9700	C18—H18B	0.9600
C6—C7	1.505 (3)	C18—H18C	0.9600
C6—H6A	0.9700	C19—C20	1.533 (3)
C6—H6B	0.9700	C19—H19A	0.9700
C7—C8	1.443 (3)	C19—H19B	0.9700
C8—C9	1.407 (3)	C20—C21	1.555 (3)
C8—C13	1.418 (3)	C20—H20	0.9800
C9—C10	1.384 (4)	C21—H21	0.9800
C9—H9	0.9300	C22—H22A	0.9700
C10—C11	1.408 (4)	C22—H22B	0.9700
C10—H10	0.9300	O2—H3	0.9713
C11—C12	1.380 (3)	O2—H4	0.9452
C11—H11	0.9300
C13—N1—C2	109.12 (19)	C3—C14—H14	110.1
C13—N1—H1	122.9	C15—C14—H14	110.1
C2—N1—H1	124.7	C17—C14—H14	110.1
C22—O1—H2	112.5	C14—C15—C20	107.22 (19)
C7—C2—N1	109.4 (2)	C14—C15—H15A	110.3
C7—C2—C16	130.9 (2)	C20—C15—H15A	110.3
N1—C2—C16	119.7 (2)	C14—C15—H15B	110.3
N4—C3—C14	110.33 (18)	C20—C15—H15B	110.3
N4—C3—H3A	109.6	H15A—C15—H15B	108.5
C14—C3—H3A	109.6	C2—C16—C22	106.90 (18)
N4—C3—H3B	109.6	C2—C16—C21	111.20 (19)
C14—C3—H3B	109.6	C22—C16—C21	112.93 (18)
H3A—C3—H3B	108.1	C2—C16—C17	111.23 (19)
C5—N4—C21	118.35 (18)	C22—C16—C17	108.43 (18)
C5—N4—C3	110.91 (19)	C21—C16—C17	106.18 (18)
C21—N4—C3	109.22 (18)	C14—C17—C16	109.56 (19)
N4—C5—C6	114.1 (2)	C14—C17—H17A	109.8
N4—C5—H5A	108.7	C16—C17—H17A	109.8
C6—C5—H5A	108.7	C14—C17—H17B	109.8
N4—C5—H5B	108.7	C16—C17—H17B	109.8
C6—C5—H5B	108.7	H17A—C17—H17B	108.2
H5A—C5—H5B	107.6	C19—C18—H18A	109.5
C7—C6—C5	109.01 (19)	C19—C18—H18B	109.5
C7—C6—H6A	109.9	H18A—C18—H18B	109.5
C5—C6—H6A	109.9	C19—C18—H18C	109.5
C7—C6—H6B	109.9	H18A—C18—H18C	109.5
C5—C6—H6B	109.9	H18B—C18—H18C	109.5
H6A—C6—H6B	108.3	C18—C19—C20	112.5 (2)
C2—C7—C8	106.9 (2)	C18—C19—H19A	109.1
C2—C7—C6	125.5 (2)	C20—C19—H19A	109.1
C8—C7—C6	126.0 (2)	C18—C19—H19B	109.1
C9—C8—C13	118.8 (2)	C20—C19—H19B	109.1
C9—C8—C7	134.4 (2)	H19A—C19—H19B	107.8
C13—C8—C7	106.8 (2)	C19—C20—C15	114.9 (2)
C10—C9—C8	118.9 (2)	C19—C20—C21	116.03 (19)
C10—C9—H9	120.5	C15—C20—C21	108.44 (18)
C8—C9—H9	120.5	C19—C20—H20	105.5
C9—C10—C11	121.0 (2)	C15—C20—H20	105.5
C9—C10—H10	119.5	C21—C20—H20	105.5
C11—C10—H10	119.5	N4—C21—C20	103.71 (17)
C12—C11—C10	121.6 (2)	N4—C21—C16	111.75 (18)
C12—C11—H11	119.2	C20—C21—C16	112.90 (18)
C10—C11—H11	119.2	N4—C21—H21	109.4
C11—C12—C13	117.3 (2)	C20—C21—H21	109.4
C11—C12—H12	121.4	C16—C21—H21	109.4
C13—C12—H12	121.4	O1—C22—C16	110.31 (18)
N1—C13—C12	129.9 (2)	O1—C22—H22A	109.6
N1—C13—C8	107.78 (19)	C16—C22—H22A	109.6
C12—C13—C8	122.3 (2)	O1—C22—H22B	109.6
C3—C14—C15	107.40 (19)	C16—C22—H22B	109.6
C3—C14—C17	109.60 (19)	H22A—C22—H22B	108.1
C15—C14—C17	109.51 (18)	H3—O2—H4	106.6

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2^i	0.92	1.96	2.870 (3)	168
O1—H2···N4^ii	0.99	1.79	2.778 (3)	176
O2—H3···O1	0.97	1.83	2.797 (2)	174

Symmetry codes: (i) x−1/2, −y+3/2, −z+2; (ii) −x+2, y−1/2, −z+3/2.