Dendocarbin A: a sesquiterpene lactone from Drimys winteri

The natural compound dendocarbin A, C₁₅H₂₂O₃, is a sesqui­terpene lactone isolated for the first time from Drimys winteri for var chilensis. The compound crystallizes in the ortho­rhom­bic space group P2₁2₁2₁ and its X-ray crystal structure confirmed the S/R character of the chiral centres at C-5/C-10 and C-9/C-11, respectively. The α-OH group at C-11 was found to be involved in inter­molecular hydrogen bonding, defining chains along the <100> 2₁ screw axis.

S1. Introduction

Drimys winteri (Winter­aceae) is a native tree of Chile, sacred for the native people (Araucanian) due to its medicinal properties, such us bactericidal, anti­fungal and insecticidal (Kubo et al., 2005; Jansen & de Groot, 2004). The main secondary metabolites in its barks are drimane sesquiterpenoids which have been described by Appel et al. (1963). On the other hand, the main scope of the present report, the natural compound dendocarbin A, (I), even if not novel, has been treated only tangentially in the literature. It had originally been obtained from ethanol extracts of the Japanese udibranch Dendrodoris carbunculosa by Sakio et al. (2001), who found cytotoxic activity in its extracts and molecules. A few years later, Gaspar et al. (2005), reported the first chemical study of the porostome nudibranch Doriopsilla pelseneeri collected off the Portuguese coast, finding in his case the secondary metabolite. Finally, Xu et al. (2009) reported compound (I) as being isolated from the ethyl acetate extract of Warburgia ugandensis (Canellaceae) barks.

The present work is part of a series of structural characterizations of naturally occurring molecules isolated from southern Andean flora (a seemingly inextinguishable source for extractive chemists). We describe herein the crystal structure of (I), isolated for the first time from Drimys winteri var chilensis (Winter­aceae), in order to ascertain unambiguously the relative stereochemistry of the OH group at C-11 and the methyl group at C-15, as well as to confirm the relative configurations of the remaining asymmetric centres.

S2. Experimental

S2.1. Synthesis and crystallization

Compound (I) was isolated from the stem bark of Drimys winteri (Canelo) collected in Concepcion, VIII Region of Chile, in February 2012. The bark (1 kg) was powdered and extracted by maceration with ethanol for 3 d, giving a crude product (20 g) which was further purified by column chromatography. Compound (I) afforded as a white solid from hexane/ethyl acetate (1:1 v/v) and this was recrystallized from methanol producing colourless crystals suitable for X-ray diffraction analysis.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. All H atoms were identified in an inter­mediate difference map, and treated differently in the refinement. H atoms on C atoms were idealized and allowed to ride both in coordinates as in displacement factors, the latter taken as U_iso(H) = xU_eq(C), with C—H = 0.93 Å and x = 1.2 for aromatic, C—H = 0.97 Å and x = 1.2 for methyl­ene and C—H = 0.96 Å and x = 1.5 for methyl groups. The hy­droxy H atom was refined freely. The combined effect of weak diffractors and a medium quality data set precluded a trustable determination of the configuration of the chiral centers, even if a weak suggestion for the one herein presented was obatined from refinement [Flack parameters = 0.3 (8) and -0.7 (8) for the reported and inverted configurations, respectively]. The present `handness', however, defined by C5(S), C9(R), C10(S), C11(R), was found to coincide with that reported in (IV), in turn assigned by similarity with related compounds.

S3. Results and discussion

The molecule of (I) (Fig. 1) is characterized by a rigid backbone made out of three fused rings (see Scheme for labelling), where lateral ring A (atoms C1–C5/C10) has a chair conformation [θ = 6.1 (4)°; cf. θ = 0.00° for an ideal chair (Boeyens, 1978)], central ring B (atoms C5–C10) has a half-chair conformation [θ = 52.8 (3)° and ϕ = 321.5 (5)° = 5 × 60 + 21.5°; cf. θ = 50.8 and ϕ = k × 60 + 30° for an ideal half-chair (Boeyens, 1978)] and five-membered lactone ring C (atoms C8/C9/C11/C12/O3) has an envelope conformation [ϕ = 63.7 (6)° = 2 × 36 - 8.3°; cf. ϕ = k × 36 + 0° for anideal envelope (Cremer & Pople, 1975)], with the carbonyl group at atom C12 conjugated with the C7═C8 double bond. It is worth mentioning that this envelope geometry for the lactone ring is favoured by the `outer' position of the double bond; when the location is instead `inner' (C8═C9), the group is strictly planar, with mean deviations from planarity smaller than 0.02 Å (see, for example, Nicotra et al., 2006; Qian & Zhao, 2012; von Nussbaum et al., 2012)

A search in the Cambridge Structural Database (CSD, Version 5.34; Allen, 2002) disclosed that the structure is closely related to three analogues, viz. the disteromer lactone drimenin, (II) (CSD refcode DIWSEI; Brito, López-Rodríguez et al., 2008), cinnamolide, (III) (CSD refcode UTONUN; Brito, Cardenas et al. 2008) and 3-hy­droxy-7-drimen-12,11-olide hemihydrate, (IV) (CSD refcode UCOKUT; Zhang et al., 2006) (see Scheme). All four structures are, as expected, quite similar and and Table 2 provides a comparison of corresponding parameters highlighting the most noticeable differences, while Fig. 2 presents, in turn, a superposition of all four molecules, where the almost identical rings A, unaffected by the differing locations of the carbonyl group, have been used for the least-squares fitting.

The most relevant differences regarding bond distances or angles are to be found around the lactone O3 atom, and have to do precisely with the position of the carbonyl group [C12═O2 in (I), (III) and (IV), and C11═O1 in (II)]. In all cases, the C═O presents a clear resonance with the neighbouring C12—O3 (C11—O3) group, which is sensibly shorter than its C11—O3 (C12—O3) neighbour (see Table 2). On the other hand, the identical lactone rings in (III) and (IV) appear rather parallel to each other, even if slightly offset. The inclusion of an O atom at C11, either single bonded as in (I) or double bonded as in (II), tends to twist the group, as shown in Fig. 2 and can be assessed by the difference in the torsion angles presented in Table 2.

Regarding the supra­molecular structure, there are two significant inter­molecular inter­actions in (I) (entries 1 and 2 in Table 3). These hydrogen bonds generate R₂²(7) loops (for graph-set nomenclature, see Bernstein et al., 1995) connecting neighbouring molecules along the rather short a direction, riding on a twofold screw. This generates a one-dimensional substructure threaded by the symmetry axis (Fig. 3). In these chains, molecules are not stacked alongside, but laterally, for what both inter­actions have extremely short repetition codes, viz. C(6) for the O—H···O and C(3) for the C—H···O hydrogen bonds.

On the other side, these <100> chains are poorly inter­acting, the only mentionable link being an extremely weak C—H···O contact (presented as entry 3 in Table 3 and drawn as dotted lines in Fig. 4), by way of which the parallel chains end up forming a weakly bound three-dimensional structure. By comparison, structures (II) and (III), which do not have any active hydro­hen-bond donor, present absolutely non-inter­acting molecules just sustained by van der Waals forces. Compound (IV), instead, presents a comparable display of inter­molecular inter­actions, through the OH groups in the two independent moieties, as well as an active water solvate, giving rise to tightly bound two-dimensional substructures of justaposed chains. In spite of the obvious differences due to the different OH position and the presence of the water solvate in (IV), the way in which chains are formed is similar, threaded along a 2₁ axis.

Related literature

For related literature, see: Allen (2002); Appel et al. (1963); Bernstein et al. (1995); Boeyens (1978); Brito, Cardenas, Zarraga, Paz, Perez & Lopez-Rodrıguez (2008); Brito, López-Rodríguez, Zárraga, Paz & Pérez (2008); Cremer & Pople (1975); Gaspar et al. (2005); Jansen & de Groot (2004); Kubo et al. (2005); Nicotra et al. (2006); Nussbaum et al. (2012); Qian & Zhao (2012); Sakio et al. (2001); Xu et al. (2009); Zhang et al. (2006).

Computing details

Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell refinement: CrysAlis PRO (Oxford Diffraction, 2009); data reduction: CrysAlis PRO (Oxford Diffraction, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL2013 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures

	Fig. 1. Ellipsoid plot of (I), with displacement ellipsoids drawn at the 30% probability level.
	Fig. 2. Superposition of the structures of (I), (II), (III) and (IV).
	Fig. 3. A view of the hydrogen-bonded chain in (I), with the hydrogen bonds drawn as broken lines. Hashes (#) indicate hydrogen bonds included in Table 3. [Symmetry code: (i) x+1/2, -y+3/2, -z+1.]
	Fig. 4. Packing view of (I) along a, the chain direction, showing the latter in projection and in broken/dotted lines the intra/inter chain hydrogen bonds. Hashes (#) indicate hydrogen bonds included in Table 3.

(1R,5aS,9aS,9bR)-5,5a,6,7,8,9,9a,9b-Octahydro-1-hydroxy-6,6,9a-trimethylnaphtho[1,2-c]furan-3(1H)-one

Crystal data

C15H22O3	Dx = 1.179 Mg m^−3
Mr = 250.32	Mo Kα radiation, λ = 0.71069 Å
Orthorhombic, P212121	Cell parameters from 2073 reflections
a = 6.335 (4) Å	θ = 3.9–21.5°
b = 13.399 (5) Å	µ = 0.08 mm^−1
c = 16.613 (5) Å	T = 295 K
V = 1410.2 (11) Å^3	Block, colourless
Z = 4	0.35 × 0.25 × 0.20 mm
F(000) = 544

Data collection

Oxford Diffraction Gemini CCD S Ultra diffractometer	2059 reflections with I > 2σ(I)
ω scans, thick slices	Rint = 0.044
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009)	θmax = 29.2°, θmin = 3.8°
Tmin = 0.91, Tmax = 0.94	h = −8→8
12609 measured reflections	k = −18→17
3411 independent reflections	l = −22→18

Refinement

Refinement on F^2	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.055	w = 1/[σ^2(Fo^2) + (0.0532P)^2 + 0.1546P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.133	(Δ/σ)max < 0.001
S = 0.99	Δρmax = 0.13 e Å^−3
3411 reflections	Δρmin = −0.16 e Å^−3
170 parameters	Absolute structure: Flack x determined using 627 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons & Flack, 2004)
0 restraints	Absolute structure parameter: 0.3 (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.

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

	x	y	z	Uiso*/Ueq
O1	0.0934 (4)	0.64026 (17)	0.40375 (15)	0.0712 (7)
H1O	0.158 (7)	0.616 (3)	0.451 (3)	0.110 (15)*
O2	−0.1961 (4)	0.93607 (18)	0.45904 (13)	0.0734 (7)
O3	−0.0232 (4)	0.79121 (17)	0.45638 (11)	0.0655 (6)
C1	0.3357 (7)	0.6921 (3)	0.2291 (2)	0.0815 (11)
H1A	0.2005	0.6637	0.2141	0.098*
H1B	0.3970	0.6496	0.2701	0.098*
C2	0.4797 (8)	0.6918 (3)	0.1556 (2)	0.1016 (15)
H2A	0.6198	0.7141	0.1708	0.122*
H2B	0.4911	0.6245	0.1344	0.122*
C3	0.3901 (7)	0.7605 (3)	0.0918 (2)	0.0838 (12)
H3A	0.2540	0.7348	0.0749	0.101*
H3B	0.4829	0.7592	0.0453	0.101*
C4	0.3626 (5)	0.8683 (3)	0.11857 (18)	0.0576 (8)
C5	0.2292 (4)	0.8690 (2)	0.19758 (16)	0.0466 (7)
H5	0.0893	0.8454	0.1811	0.056*
C6	0.1905 (6)	0.9740 (2)	0.23063 (19)	0.0666 (9)
H6A	0.3254	1.0064	0.2397	0.080*
H6B	0.1142	1.0127	0.1908	0.080*
C7	0.0686 (6)	0.9739 (3)	0.3072 (2)	0.0656 (9)
H7	0.0195	1.0340	0.3280	0.079*
C8	0.0286 (4)	0.8903 (2)	0.34624 (17)	0.0487 (7)
C9	0.1088 (4)	0.7899 (2)	0.32286 (16)	0.0443 (7)
H9	−0.0056	0.7551	0.2947	0.053*
C10	0.2986 (4)	0.7955 (2)	0.26493 (17)	0.0467 (7)
C11	0.1352 (5)	0.7406 (2)	0.40490 (17)	0.0531 (8)
H11	0.2777	0.7526	0.4257	0.064*
C12	−0.0772 (5)	0.8798 (3)	0.42476 (18)	0.0557 (8)
C13	0.5800 (6)	0.9193 (4)	0.1250 (3)	0.0924 (14)
H13A	0.6452	0.9213	0.0729	0.139*
H13B	0.6679	0.8823	0.1615	0.139*
H13C	0.5624	0.9861	0.1448	0.139*
C14	0.2401 (7)	0.9234 (3)	0.0522 (2)	0.0823 (12)
H14A	0.3099	0.9140	0.0015	0.124*
H14B	0.2347	0.9934	0.0645	0.124*
H14C	0.0991	0.8974	0.0491	0.124*
C15	0.4940 (5)	0.8312 (3)	0.3109 (2)	0.0809 (12)
H15A	0.5342	0.7817	0.3497	0.121*
H15B	0.4624	0.8927	0.3379	0.121*
H15C	0.6080	0.8417	0.2737	0.121*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0958 (18)	0.0539 (15)	0.0640 (15)	−0.0100 (13)	−0.0033 (13)	0.0134 (11)
O2	0.0826 (16)	0.0779 (17)	0.0596 (14)	0.0063 (14)	0.0100 (13)	−0.0122 (12)
O3	0.0768 (15)	0.0693 (15)	0.0505 (11)	0.0004 (13)	0.0082 (12)	0.0064 (11)
C1	0.109 (3)	0.057 (2)	0.078 (2)	0.025 (2)	0.027 (2)	0.0098 (19)
C2	0.138 (4)	0.076 (3)	0.090 (3)	0.042 (3)	0.043 (3)	0.011 (2)
C3	0.109 (3)	0.079 (3)	0.063 (2)	0.014 (2)	0.026 (2)	−0.001 (2)
C4	0.0609 (19)	0.062 (2)	0.0501 (18)	−0.0001 (17)	0.0052 (15)	0.0069 (15)
C5	0.0444 (15)	0.0480 (17)	0.0474 (15)	−0.0025 (13)	−0.0077 (13)	0.0048 (13)
C6	0.092 (2)	0.0468 (19)	0.0613 (19)	0.0037 (18)	0.006 (2)	0.0084 (16)
C7	0.085 (2)	0.0519 (19)	0.0599 (19)	0.0117 (18)	0.0048 (19)	−0.0014 (16)
C8	0.0470 (15)	0.0538 (19)	0.0454 (16)	−0.0022 (14)	−0.0067 (13)	−0.0007 (13)
C9	0.0423 (14)	0.0458 (17)	0.0447 (15)	−0.0053 (13)	−0.0080 (13)	0.0007 (12)
C10	0.0395 (14)	0.0495 (17)	0.0509 (15)	0.0020 (14)	−0.0041 (13)	0.0084 (13)
C11	0.0567 (18)	0.0507 (19)	0.0520 (17)	−0.0047 (15)	−0.0037 (14)	0.0071 (14)
C12	0.0528 (18)	0.063 (2)	0.0508 (18)	−0.0056 (16)	−0.0020 (15)	−0.0073 (16)
C13	0.072 (2)	0.120 (4)	0.086 (3)	−0.017 (2)	0.015 (2)	0.026 (2)
C14	0.097 (3)	0.096 (3)	0.053 (2)	0.008 (2)	0.003 (2)	0.0171 (19)
C15	0.0415 (17)	0.126 (3)	0.075 (2)	−0.010 (2)	−0.0164 (17)	0.026 (2)

Geometric parameters (Å, º)

O1—C11	1.370 (4)	C6—C7	1.489 (5)
O1—H1O	0.94 (4)	C6—H6A	0.9700
O2—C12	1.208 (4)	C6—H6B	0.9700
O3—C12	1.343 (4)	C7—C8	1.319 (4)
O3—C11	1.483 (4)	C7—H7	0.9300
C1—C10	1.526 (4)	C8—C12	1.473 (4)
C1—C2	1.524 (5)	C8—C9	1.489 (4)
C1—H1A	0.9700	C9—C11	1.524 (4)
C1—H1B	0.9700	C9—C10	1.542 (4)
C2—C3	1.515 (5)	C9—H9	0.9800
C2—H2A	0.9700	C10—C15	1.531 (4)
C2—H2B	0.9700	C11—H11	0.9800
C3—C4	1.521 (5)	C13—H13A	0.9600
C3—H3A	0.9700	C13—H13B	0.9600
C3—H3B	0.9700	C13—H13C	0.9600
C4—C14	1.538 (5)	C14—H14A	0.9600
C4—C13	1.542 (5)	C14—H14B	0.9600
C4—C5	1.561 (4)	C14—H14C	0.9600
C5—C6	1.530 (4)	C15—H15A	0.9600
C5—C10	1.554 (4)	C15—H15B	0.9600
C5—H5	0.9800	C15—H15C	0.9600
C11—O1—H1O	104 (3)	C7—C8—C9	125.0 (3)
C12—O3—C11	110.6 (2)	C12—C8—C9	107.5 (3)
C10—C1—C2	114.1 (3)	C8—C9—C11	101.3 (2)
C10—C1—H1A	108.7	C8—C9—C10	112.6 (2)
C2—C1—H1A	108.7	C11—C9—C10	119.6 (2)
C10—C1—H1B	108.7	C8—C9—H9	107.6
C2—C1—H1B	108.7	C11—C9—H9	107.6
H1A—C1—H1B	107.6	C10—C9—H9	107.6
C3—C2—C1	109.6 (3)	C1—C10—C15	110.7 (3)
C3—C2—H2A	109.8	C1—C10—C9	108.6 (2)
C1—C2—H2A	109.8	C15—C10—C9	109.6 (2)
C3—C2—H2B	109.8	C1—C10—C5	109.8 (2)
C1—C2—H2B	109.8	C15—C10—C5	112.9 (3)
H2A—C2—H2B	108.2	C9—C10—C5	105.0 (2)
C2—C3—C4	114.5 (3)	O1—C11—O3	109.1 (2)
C2—C3—H3A	108.6	O1—C11—C9	113.1 (3)
C4—C3—H3A	108.6	O3—C11—C9	104.1 (2)
C2—C3—H3B	108.6	O1—C11—H11	110.2
C4—C3—H3B	108.6	O3—C11—H11	110.2
H3A—C3—H3B	107.6	C9—C11—H11	110.2
C3—C4—C14	107.7 (3)	O2—C12—O3	121.7 (3)
C3—C4—C13	109.8 (3)	O2—C12—C8	129.9 (3)
C14—C4—C13	106.7 (3)	O3—C12—C8	108.3 (3)
C3—C4—C5	108.3 (3)	C4—C13—H13A	109.5
C14—C4—C5	109.1 (3)	C4—C13—H13B	109.5
C13—C4—C5	115.0 (3)	H13A—C13—H13B	109.5
C6—C5—C10	111.7 (2)	C4—C13—H13C	109.5
C6—C5—C4	113.2 (2)	H13A—C13—H13C	109.5
C10—C5—C4	116.6 (2)	H13B—C13—H13C	109.5
C6—C5—H5	104.6	C4—C14—H14A	109.5
C10—C5—H5	104.6	C4—C14—H14B	109.5
C4—C5—H5	104.6	H14A—C14—H14B	109.5
C7—C6—C5	112.9 (3)	C4—C14—H14C	109.5
C7—C6—H6A	109.0	H14A—C14—H14C	109.5
C5—C6—H6A	109.0	H14B—C14—H14C	109.5
C7—C6—H6B	109.0	C10—C15—H15A	109.5
C5—C6—H6B	109.0	C10—C15—H15B	109.5
H6A—C6—H6B	107.8	H15A—C15—H15B	109.5
C8—C7—C6	121.4 (3)	C10—C15—H15C	109.5
C8—C7—H7	119.3	H15A—C15—H15C	109.5
C6—C7—H7	119.3	H15B—C15—H15C	109.5
C7—C8—C12	127.1 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O2^i	0.94 (4)	1.89 (5)	2.832 (4)	176 (4)
C11—H11···O3^i	0.98	2.40	3.190 (4)	137
C6—H6B···O1^ii	0.97	2.67	3.630 (4)	172

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