Revisiting the absolute chirality and polymorphism of (–)-Istanbulin A

The terpenoid (−)-Istanbulin A is a natural product isolated from Senecio filaginoides DC, one of the 270 species of Senecio (Asteraceae) which occurs in Argentina. The structure and absolute configuration of this com­pound [9a-hy­droxy-3,4a,5-trimethyl-4a,6,7,8a,9,9a-hexa­hydro-4H,5H-naphtho­[2,3-b]-furan-2,8-dione or (4S,5R,8R,10S)-1-oxo-8β-hy­droxy-10βH-eremophil-7(11)-en-12,8β-olide, C₁₅H₂₀O₄] were determined by single-crystal X-ray diffraction studies. It proved to be a sesquiterpene lactone showing an eremophilanolide skeleton whose chirality is described as 4S,5R,8R,10S. Structural results were also in agreement with the one- and two-dimensional (1D and 2D) NMR and HR–ESI–MS data, and other com­plementary spectroscopic information. In addition, (−)-Istanbulin A is a polymorph of the previously reported form of (−)-Istan­bulin A, form I; thus, the title com­pound is denoted form II or polymorph II. Structural data and a literature search allowed the chirality of Istanbulin A to be revisited. The anti­microbial and anti­fungal activities of (−)-Istanbulin A, form II, were evaluated in order to establish a reference for future com­parisons and applications related to specific crystal forms of Istanbulins.

Computing details

Data collection: CrysAlis PRO (Rigaku OD, 2015); cell refinement: CrysAlis PRO (Rigaku OD, 2015); data reduction: CrysAlis PRO (Rigaku OD, 2015); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(4aS,5R,8aR,9aS)-9a-Hydroxy-3,4a,5-trimethyl-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-b]furan-2,8-dione

Crystal data

C15H20O4	Dx = 1.235 Mg m^−3
Mr = 264.31	Cu Kα radiation, λ = 1.54184 Å
Orthorhombic, P212121	Cell parameters from 3879 reflections
a = 7.3660 (4) Å	θ = 4.5–72.8°
b = 12.8932 (6) Å	µ = 0.73 mm^−1
c = 14.9661 (7) Å	T = 298 K
V = 1421.35 (11) Å^3	Needle, colourless
Z = 4	0.5 × 0.2 × 0.1 mm
F(000) = 568

Data collection

Rigaku OD Xcalibur Eos Gemini diffractometer	2871 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Cu) X-ray Source	2155 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.085
Detector resolution: 16.1158 pixels mm^-1	θmax = 74.4°, θmin = 4.5°
ω scans	h = −9→8
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2015)	k = −16→15
Tmin = 0.729, Tmax = 1.000	l = −18→18
14329 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.052	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.151	w = 1/[σ^2(Fo^2) + (0.0682P)^2 + 0.065P] where P = (Fo^2 + 2Fc^2)/3
S = 1.08	(Δ/σ)max < 0.001
2871 reflections	Δρmax = 0.14 e Å^−3
179 parameters	Δρmin = −0.23 e Å^−3
0 restraints	Absolute structure: Flack x determined using 709 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.2 (2)

Special details

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

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

	x	y	z	Uiso*/Ueq
O1	0.6911 (4)	0.4941 (2)	0.6809 (2)	0.0762 (9)
O2	−0.0672 (6)	0.2921 (3)	0.4683 (2)	0.0892 (11)
O3	0.0801 (4)	0.4206 (2)	0.53747 (16)	0.0609 (7)
O4	0.0533 (4)	0.5349 (2)	0.65638 (19)	0.0572 (7)
H4	−0.067 (8)	0.523 (4)	0.657 (3)	0.093 (17)*
C1	0.5925 (5)	0.4803 (3)	0.7454 (3)	0.0562 (9)
C2	0.6567 (6)	0.4879 (3)	0.8394 (3)	0.0689 (12)
H2A	0.6160	0.5532	0.8646	0.083*
H2B	0.7883	0.4879	0.8400	0.083*
C3	0.5881 (6)	0.3991 (3)	0.8979 (3)	0.0652 (11)
H3A	0.6546	0.3365	0.8833	0.078*
H3B	0.6120	0.4155	0.9601	0.078*
C4	0.3857 (5)	0.3792 (3)	0.8860 (2)	0.0559 (9)
H4A	0.3225	0.4429	0.9036	0.067*
C5	0.3387 (5)	0.3593 (3)	0.7870 (2)	0.0477 (8)
C6	0.1317 (5)	0.3437 (3)	0.7760 (2)	0.0524 (9)
H6A	0.0977	0.2768	0.8004	0.063*
H6B	0.0680	0.3968	0.8094	0.063*
C7	0.0761 (5)	0.3488 (3)	0.6807 (2)	0.0480 (8)
C8	0.1355 (5)	0.4427 (3)	0.6286 (2)	0.0494 (8)
C9	0.3376 (5)	0.4562 (3)	0.6347 (3)	0.0543 (9)
H9A	0.3732	0.5205	0.6058	0.065*
H9B	0.3981	0.3994	0.6044	0.065*
C10	0.3935 (5)	0.4585 (3)	0.7327 (2)	0.0495 (8)
H10	0.3282	0.5167	0.7599	0.059*
C11	−0.0059 (5)	0.2823 (3)	0.6267 (3)	0.0536 (9)
C12	−0.0066 (6)	0.3273 (3)	0.5368 (3)	0.0623 (10)
C13	−0.0868 (7)	0.1778 (3)	0.6428 (3)	0.0720 (12)
H13A	−0.0237	0.1270	0.6076	0.108*
H13B	−0.2127	0.1787	0.6262	0.108*
H13C	−0.0760	0.1605	0.7050	0.108*
C14	0.4369 (7)	0.2640 (3)	0.7501 (3)	0.0623 (10)
H14A	0.4067	0.2044	0.7855	0.093*
H14B	0.5657	0.2753	0.7521	0.093*
H14C	0.4000	0.2524	0.6894	0.093*
C15	0.3228 (8)	0.2937 (4)	0.9496 (3)	0.0795 (14)
H15A	0.1936	0.2856	0.9449	0.119*
H15B	0.3539	0.3122	1.0098	0.119*
H15C	0.3813	0.2297	0.9341	0.119*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0512 (16)	0.082 (2)	0.095 (2)	−0.0066 (15)	0.0129 (16)	0.0022 (17)
O2	0.127 (3)	0.085 (2)	0.0556 (17)	−0.015 (2)	−0.0252 (19)	−0.0076 (16)
O3	0.0758 (19)	0.0650 (16)	0.0420 (13)	−0.0089 (14)	−0.0039 (13)	0.0084 (11)
O4	0.0489 (15)	0.0543 (14)	0.0683 (17)	0.0010 (12)	0.0001 (13)	−0.0023 (12)
C1	0.043 (2)	0.0462 (17)	0.079 (3)	0.0012 (16)	0.003 (2)	−0.0051 (17)
C2	0.049 (2)	0.067 (2)	0.091 (3)	−0.0044 (19)	−0.013 (2)	−0.012 (2)
C3	0.064 (3)	0.063 (2)	0.069 (3)	0.004 (2)	−0.014 (2)	−0.0065 (19)
C4	0.057 (2)	0.060 (2)	0.050 (2)	0.0016 (17)	−0.0053 (17)	−0.0044 (16)
C5	0.049 (2)	0.0466 (17)	0.0472 (18)	−0.0009 (15)	0.0015 (15)	−0.0016 (14)
C6	0.054 (2)	0.061 (2)	0.0421 (17)	−0.0076 (16)	0.0011 (16)	0.0016 (16)
C7	0.0443 (18)	0.0542 (18)	0.0455 (18)	−0.0048 (16)	0.0016 (15)	0.0028 (14)
C8	0.053 (2)	0.0516 (18)	0.0439 (17)	−0.0027 (15)	0.0028 (15)	0.0018 (15)
C9	0.051 (2)	0.056 (2)	0.056 (2)	0.0005 (17)	0.0093 (16)	0.0072 (17)
C10	0.044 (2)	0.0479 (17)	0.0562 (19)	0.0021 (14)	0.0048 (16)	−0.0030 (15)
C11	0.056 (2)	0.052 (2)	0.052 (2)	−0.0047 (16)	−0.0034 (17)	0.0025 (16)
C12	0.077 (3)	0.059 (2)	0.051 (2)	−0.002 (2)	−0.009 (2)	−0.0027 (17)
C13	0.080 (3)	0.057 (2)	0.080 (3)	−0.015 (2)	−0.013 (3)	0.0046 (19)
C14	0.076 (3)	0.051 (2)	0.060 (2)	0.0055 (19)	0.000 (2)	−0.0045 (17)
C15	0.090 (4)	0.095 (3)	0.054 (2)	−0.011 (3)	−0.007 (2)	0.009 (2)

Geometric parameters (Å, º)

O1—C1	1.221 (5)	C6—H6B	0.9700
O2—C12	1.207 (5)	C6—C7	1.485 (5)
O3—C8	1.452 (4)	C7—C8	1.505 (5)
O3—C12	1.362 (5)	C7—C11	1.324 (5)
O4—H4	0.90 (6)	C8—C9	1.502 (5)
O4—C8	1.397 (4)	C9—H9A	0.9700
C1—C2	1.488 (6)	C9—H9B	0.9700
C1—C10	1.505 (5)	C9—C10	1.524 (5)
C2—H2A	0.9700	C10—H10	0.9800
C2—H2B	0.9700	C11—C12	1.465 (5)
C2—C3	1.527 (6)	C11—C13	1.493 (5)
C3—H3A	0.9700	C13—H13A	0.9600
C3—H3B	0.9700	C13—H13B	0.9600
C3—C4	1.523 (6)	C13—H13C	0.9600
C4—H4A	0.9800	C14—H14A	0.9600
C4—C5	1.542 (5)	C14—H14B	0.9600
C4—C15	1.529 (6)	C14—H14C	0.9600
C5—C6	1.547 (5)	C15—H15A	0.9600
C5—C10	1.568 (5)	C15—H15B	0.9600
C5—C14	1.530 (5)	C15—H15C	0.9600
C6—H6A	0.9700
C12—O3—C8	108.2 (3)	O4—C8—O3	108.9 (3)
C8—O4—H4	107 (3)	O4—C8—C7	113.8 (3)
O1—C1—C2	123.3 (4)	O4—C8—C9	108.3 (3)
O1—C1—C10	120.5 (4)	C9—C8—C7	110.5 (3)
C2—C1—C10	116.2 (3)	C8—C9—H9A	109.8
C1—C2—H2A	109.0	C8—C9—H9B	109.8
C1—C2—H2B	109.0	C8—C9—C10	109.2 (3)
C1—C2—C3	112.9 (3)	H9A—C9—H9B	108.3
H2A—C2—H2B	107.8	C10—C9—H9A	109.8
C3—C2—H2A	109.0	C10—C9—H9B	109.8
C3—C2—H2B	109.0	C1—C10—C5	109.8 (3)
C2—C3—H3A	109.1	C1—C10—C9	112.8 (3)
C2—C3—H3B	109.1	C1—C10—H10	106.4
H3A—C3—H3B	107.8	C5—C10—H10	106.4
C4—C3—C2	112.5 (4)	C9—C10—C5	114.5 (3)
C4—C3—H3A	109.1	C9—C10—H10	106.4
C4—C3—H3B	109.1	C7—C11—C12	107.8 (3)
C3—C4—H4A	107.0	C7—C11—C13	131.9 (4)
C3—C4—C5	111.1 (3)	C12—C11—C13	120.3 (4)
C3—C4—C15	110.2 (4)	O2—C12—O3	120.8 (4)
C5—C4—H4A	107.0	O2—C12—C11	129.3 (4)
C15—C4—H4A	107.0	O3—C12—C11	109.9 (3)
C15—C4—C5	114.2 (3)	C11—C13—H13A	109.5
C4—C5—C6	110.2 (3)	C11—C13—H13B	109.5
C4—C5—C10	107.7 (3)	C11—C13—H13C	109.5
C6—C5—C10	107.7 (3)	H13A—C13—H13B	109.5
C14—C5—C4	112.0 (3)	H13A—C13—H13C	109.5
C14—C5—C6	108.8 (3)	H13B—C13—H13C	109.5
C14—C5—C10	110.2 (3)	C5—C14—H14A	109.5
C5—C6—H6A	109.3	C5—C14—H14B	109.5
C5—C6—H6B	109.3	C5—C14—H14C	109.5
H6A—C6—H6B	108.0	H14A—C14—H14B	109.5
C7—C6—C5	111.6 (3)	H14A—C14—H14C	109.5
C7—C6—H6A	109.3	H14B—C14—H14C	109.5
C7—C6—H6B	109.3	C4—C15—H15A	109.5
C6—C7—C8	116.9 (3)	C4—C15—H15B	109.5
C11—C7—C6	133.1 (3)	C4—C15—H15C	109.5
C11—C7—C8	109.7 (3)	H15A—C15—H15B	109.5
O3—C8—C7	104.3 (3)	H15A—C15—H15C	109.5
O3—C8—C9	111.0 (3)	H15B—C15—H15C	109.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O1^i	0.90 (6)	1.85 (6)	2.744 (4)	169 (5)
C2—H2A···O2^ii	0.97	2.55	3.493 (5)	163
C10—H10···O4	0.98	2.56	2.925 (5)	102
C13—H13C···O4^iii	0.96	2.63	3.534 (5)	156
C14—H14C···O2^iv	0.96	2.44	3.344 (5)	157

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