A tetra­hydro­penta­leno[1,6a-a]naphthalen-4(2H)-one of defined relative stereochemistry for use towards Agariblazeispirol C

Towards the synthesis of the novel natural product Agariblazeispirol C, (5aR*,11bR*)-9-meth­oxy-3,8,11b-trimethyl-5,6,7,11b-tetra­hydro-1H-penta­leno[1,6a-a]naphthalen-4(2H)-one, C₂₀H₂₄O₂, has been prepared at a key stage of the preparative programme. The structure shows the desired stereochemical outcome of the central cyclization protocol, viz. a syn-relationship between the aliphatic methyl group on the 11b-position and the methyl­ene group on the 5a-position [C-C-C-C = -34.57 (18)°].

S1. Comment

Over recent years, studies within our laboratory have focused on the development of a series of metal-mediated methods and their application in organic synthesis. In this regard, a selection of these techniques have found direct application within the arena of natural product synthesis (Crawford et al., 2006; Caldwell et al., 2005; Kerr et al., 2001). More recently, these studies have targeted the total synthesis of Agariblazeispirol C, (I), which was isolated from the cultured mycelia of Agaricus blazei (Hirotani et al., 2005). Our specific approach towards the synthesis of this target includes the development of an intramolecular Pauson–Khand cyclization to expediently construct the tetracyclic core of the natural product.

The cyclization precursor, (II), an advanced intermediate within our synthetic programme, was employed in the key Pauson–Khand cyclization, under sulfide-promoted conditions (Brown et al., 2005) to yield the cyclopentenone product in an excellent 86% yield. A crucial feature of the desired angularly fused ring skeleton of Agariblazeispirol C is the relative stereochemical arrangement across carbons 5a and 11b, as shown. Despite NMR spectroscopic studies only showing one diastereoisomer of product, the required syn arrangement at the two adjacent stereogenic centres could not be established with certainty. In an attempt to confirm the desired relative configuration, colourless crystals were grown by slow diffusion of light petroleum ether into a near-saturated diethyl ether solution of (III) at room temperature. The resulting structure (Fig. 1) allowed the elucidation of the syn relationship between the aliphatic methyl group on C11b and the methylene on C5a [C5—C5a—C11b—C15 = -34.57 (18) °] confirming that the key Pauson–Khand annulation provides the stereochemistry required in the final natural product.

In order to assess the relative frequency of syn and anti arrangements in similar systems, a search of the Cambridge Structural Database (CSD; Allen, 2002) was undertaken. However, suprisingly few relevant structures were found. Only two structures with a similar system of three fused aliphatic rings were found (Prakash & Mohanakrishnan, 2008; Sha et al. 1999). Similarly, only two structures with fused five-membered rings with similar substitution to (III) were found (Simonen & Kivekäs, 1984; Inoue et al., 2006). The bond lengths and angles found for (III) closely match the comparable parameters in these literature structures. In the absense of any strong hydrogen-bond donors, the structure adopted is essentially discrete with the shortest intermolecular contact taking place between the carbonyl O atom and a methylene group (O1···H2b* = 2.47 Å where * = 1 - x, -1/2 + y, 0.5 - z).

Related literature

For related literature, see: Brown et al. (2005); Caldwell et al. (2005); Crawford et al. (2006); Hirotani et al. (2005); Inoue et al. (2006); Kerr et al. (2001); Prakash & Mohanakrishnan (2008); Sha et al. (1999); Simonen & Kivekäs (1984).

S2. Experimental

A round-bottom flask was flame dried under vacuum prior to cooling under a blanket of nitrogen. The vessel was charged with alkyne, (II) (0.175 g, 0.316 mmol), as a solution in 1,2-dichloroethane (15 ml). To this was added dicobaltoctacarbonyl (0.151 g, 0.442 mmol) and the resulting mixture was stirred at room temperature for 1 h. After this time, dodecylmethyl sulfide (0.29 ml, 1.106 mmol) was added and the resulting mixture was refluxed for 5 h before filtering through a plug of celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0–20% diethyl ether in petroleum ether) to afford (III) (0.08 g, 86% yield) as a white solid. Infra-red (CH₂Cl₂) major peaks (cm^-1): 1664, 1701; ¹H NMR δ(400 MHz, CDCl₃): 1.15 (s, 3H, alkyl CH₃), 1.46 (ddd, ²J = 13.3 Hz, J = 5.1 Hz, J = 2.0 Hz, 1H, alkyl CH₂), 1.75 (s, 3H, vinylic CH₃), 1.98–2.08 (m, 2H, alkyl CH₂), 2.14 (s, 3H, ArCH₃), 2.26–2.42 (m, 3H, alkyl protons), 2.54–2.71 (m, 3H, alkyl protons), 2.84 (ddd, ²J = 14.0 Hz, J = 5.1 Hz, J = 2.0 Hz, 1H, alkyl CH₂), 3.82 (s, 3H, OCH₃), 6.77 (d, J = 8.6 Hz, 1H, ArH), 7.17 p.p.m. (d, J = 8.6 Hz, 1H, ArH); ¹³C NMR δ(100 MHz, CDCl₃): 8.4, 11.3, 23.6, 23.6, 25.4, 31.2, 42.8, 43.1, 43.4, 53.7, 55.6, 108.6, 124.1, 124.6, 132.1, 134.0, 135.7, 155.4, 186.8, 210.9 p.p.m.; HRMS m/z (ESI) calculated for C₂₀H₂₅O₂ (M⁺+H⁺): 297.1851. Found: 297.1849. Melting point: 421–423 K.

S3. Refinement

H atoms were positioned geometrically and refined in riding modes with C—H distances set at 0.95, 0.98 and 0.99 Å for aromatic, CH₂ and CH₃ groups, respectively. U_iso(H) = 1.5U_eq(C) for methyl groups and 1.2U_eq(C) for all other groups.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2009); cell refinement: CrysAlis CCD (Oxford Diffraction, 2009); data reduction: CrysAlis RED (Oxford Diffraction, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

Fig. 1. The molecular structure of (III), showing the atom-labelling scheme and 50% probability displacement ellipsoids.

(5aR*,11bR*)-9-methoxy-3,8,11b-trimethyl- 5,6,7,11b-tetrahydro-1H-pentaleno[1,6a-a]naphthalen- 4(2H)-one

Crystal data

C20H24O2	F(000) = 640
Mr = 296.39	Dx = 1.256 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P2ybc	Cell parameters from 3575 reflections
a = 10.4995 (4) Å	θ = 2.5–29.7°
b = 15.4913 (5) Å	µ = 0.08 mm^−1
c = 9.8227 (3) Å	T = 123 K
β = 101.117 (3)°	Prism, colourless
V = 1567.69 (9) Å^3	0.25 × 0.22 × 0.22 mm
Z = 4

Data collection

Oxford Diffraction Gemini S diffractometer	2387 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.037
Graphite monochromator	θmax = 27.5°, θmin = 2.5°
ω scans	h = −13→13
10529 measured reflections	k = −20→17
3593 independent reflections	l = −12→12

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)] = 0.047	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.100	H-atom parameters constrained
S = 0.96	w = 1/[σ^2(Fo^2) + (0.0488P)^2] where P = (Fo^2 + 2Fc^2)/3
3593 reflections	(Δ/σ)max < 0.001
203 parameters	Δρmax = 0.29 e Å^−3
0 restraints	Δρmin = −0.24 e Å^−3

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.

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

	x	y	z	Uiso*/Ueq
O1	0.50657 (12)	−0.11712 (6)	0.28287 (11)	0.0265 (3)
O2	1.19249 (10)	0.17397 (7)	−0.04017 (11)	0.0205 (3)
C1	0.73083 (15)	0.21509 (10)	0.30167 (16)	0.0208 (4)
H1A	0.7819	0.2488	0.3790	0.025*
H1B	0.7206	0.2500	0.2158	0.025*
C2	0.59672 (16)	0.19172 (10)	0.33355 (17)	0.0215 (4)
H2A	0.5968	0.1965	0.4341	0.026*
H2B	0.5281	0.2297	0.2820	0.026*
C2A	0.57688 (15)	0.10005 (10)	0.28552 (15)	0.0165 (3)
C3	0.49558 (16)	0.03708 (10)	0.30614 (15)	0.0183 (3)
C4	0.55223 (16)	−0.04545 (10)	0.27301 (15)	0.0195 (4)
C5	0.68397 (15)	−0.02758 (9)	0.23675 (16)	0.0194 (4)
H5A	0.6935	−0.0584	0.1510	0.023*
H5B	0.7549	−0.0455	0.3132	0.023*
C5A	0.68512 (15)	0.07072 (9)	0.21534 (15)	0.0159 (3)
C6	0.64988 (15)	0.09144 (10)	0.05950 (15)	0.0171 (3)
H6A	0.5723	0.0577	0.0169	0.021*
H6B	0.6281	0.1535	0.0471	0.021*
C7	0.76107 (15)	0.07027 (10)	−0.01358 (15)	0.0176 (3)
H7A	0.7735	0.0069	−0.0138	0.021*
H7B	0.7383	0.0897	−0.1113	0.021*
C7A	0.88617 (15)	0.11251 (9)	0.05505 (15)	0.0159 (3)
C8	0.98528 (15)	0.12315 (9)	−0.02143 (15)	0.0160 (3)
C9	1.09876 (15)	0.16510 (9)	0.04071 (15)	0.0167 (3)
C10	1.11464 (15)	0.19655 (10)	0.17470 (15)	0.0199 (4)
H10	1.1914	0.2268	0.2149	0.024*
C11	1.01747 (15)	0.18339 (10)	0.24921 (16)	0.0196 (4)
H11	1.0294	0.2042	0.3418	0.023*
C11A	0.90316 (15)	0.14093 (9)	0.19352 (15)	0.0153 (3)
C11B	0.80061 (15)	0.12821 (9)	0.28317 (15)	0.0167 (3)
C12	0.37378 (16)	0.04216 (11)	0.36289 (16)	0.0238 (4)
H12A	0.3796	0.0907	0.4279	0.036*
H12B	0.3621	−0.0117	0.4114	0.036*
H12C	0.2996	0.0508	0.2866	0.036*
C13	0.96885 (15)	0.09056 (10)	−0.16847 (15)	0.0194 (4)
H13A	1.0511	0.0964	−0.2007	0.029*
H13B	0.9017	0.1245	−0.2285	0.029*
H13C	0.9430	0.0297	−0.1717	0.029*
C14	1.31065 (16)	0.21471 (12)	0.02047 (18)	0.0294 (4)
H14A	1.2931	0.2740	0.0462	0.044*
H14B	1.3689	0.2155	−0.0464	0.044*
H14C	1.3517	0.1827	0.1035	0.044*
C15	0.86308 (16)	0.09359 (11)	0.42714 (15)	0.0241 (4)
H15A	0.9122	0.0410	0.4167	0.036*
H15B	0.7951	0.0804	0.4798	0.036*
H15C	0.9218	0.1373	0.4768	0.036*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0318 (7)	0.0170 (6)	0.0305 (6)	−0.0067 (6)	0.0058 (5)	0.0006 (5)
O2	0.0142 (6)	0.0244 (6)	0.0233 (6)	−0.0012 (5)	0.0045 (5)	0.0011 (5)
C1	0.0216 (9)	0.0165 (8)	0.0244 (8)	−0.0033 (7)	0.0052 (7)	−0.0057 (7)
C2	0.0228 (10)	0.0165 (8)	0.0257 (8)	0.0003 (7)	0.0062 (7)	−0.0024 (7)
C2A	0.0177 (9)	0.0170 (8)	0.0136 (7)	0.0035 (7)	−0.0001 (6)	0.0011 (6)
C3	0.0193 (9)	0.0201 (8)	0.0146 (8)	−0.0001 (7)	0.0012 (6)	0.0009 (6)
C4	0.0236 (9)	0.0196 (8)	0.0137 (7)	−0.0042 (7)	−0.0004 (7)	0.0014 (6)
C5	0.0224 (9)	0.0144 (8)	0.0217 (8)	0.0019 (7)	0.0051 (7)	−0.0001 (6)
C5A	0.0168 (9)	0.0134 (7)	0.0176 (8)	−0.0012 (7)	0.0036 (7)	0.0007 (6)
C6	0.0163 (9)	0.0161 (8)	0.0179 (8)	−0.0032 (7)	0.0006 (7)	−0.0006 (6)
C7	0.0195 (9)	0.0181 (8)	0.0144 (7)	−0.0028 (7)	0.0009 (7)	−0.0006 (6)
C7A	0.0171 (9)	0.0120 (7)	0.0173 (7)	0.0008 (7)	0.0003 (6)	0.0015 (6)
C8	0.0175 (9)	0.0129 (7)	0.0171 (8)	0.0031 (7)	0.0023 (7)	0.0017 (6)
C9	0.0155 (9)	0.0147 (8)	0.0201 (8)	0.0038 (7)	0.0044 (7)	0.0037 (6)
C10	0.0154 (9)	0.0205 (8)	0.0222 (8)	−0.0021 (7)	0.0000 (7)	−0.0015 (7)
C11	0.0205 (9)	0.0201 (8)	0.0171 (8)	−0.0005 (7)	0.0013 (7)	−0.0033 (6)
C11A	0.0157 (9)	0.0123 (7)	0.0173 (8)	0.0015 (7)	0.0020 (7)	0.0013 (6)
C11B	0.0154 (9)	0.0178 (8)	0.0163 (8)	−0.0010 (7)	0.0017 (6)	−0.0013 (6)
C12	0.0232 (10)	0.0272 (9)	0.0217 (8)	−0.0032 (8)	0.0058 (7)	0.0014 (7)
C13	0.0176 (9)	0.0213 (8)	0.0193 (8)	−0.0005 (7)	0.0036 (7)	−0.0008 (6)
C14	0.0189 (10)	0.0391 (11)	0.0307 (9)	−0.0091 (8)	0.0059 (8)	−0.0015 (8)
C15	0.0215 (9)	0.0329 (9)	0.0176 (8)	−0.0032 (8)	0.0027 (7)	0.0015 (7)

Geometric parameters (Å, º)

O1—C4	1.2206 (17)	C7—H7B	0.9900
O2—C9	1.3856 (16)	C7A—C8	1.406 (2)
O2—C14	1.4168 (19)	C7A—C11A	1.408 (2)
C1—C2	1.543 (2)	C8—C9	1.391 (2)
C1—C11B	1.560 (2)	C8—C13	1.508 (2)
C1—H1A	0.9900	C9—C10	1.383 (2)
C1—H1B	0.9900	C10—C11	1.381 (2)
C2—C2A	1.498 (2)	C10—H10	0.9500
C2—H2A	0.9900	C11—C11A	1.385 (2)
C2—H2B	0.9900	C11—H11	0.9500
C2A—C3	1.337 (2)	C11A—C11B	1.5295 (19)
C2A—C5A	1.508 (2)	C11B—C15	1.536 (2)
C3—C4	1.473 (2)	C12—H12A	0.9800
C3—C12	1.492 (2)	C12—H12B	0.9800
C4—C5	1.519 (2)	C12—H12C	0.9800
C5—C5A	1.538 (2)	C13—H13A	0.9800
C5—H5A	0.9900	C13—H13B	0.9800
C5—H5B	0.9900	C13—H13C	0.9800
C5A—C6	1.538 (2)	C14—H14A	0.9800
C5A—C11B	1.548 (2)	C14—H14B	0.9800
C6—C7	1.519 (2)	C14—H14C	0.9800
C6—H6A	0.9900	C15—H15A	0.9800
C6—H6B	0.9900	C15—H15B	0.9800
C7—C7A	1.505 (2)	C15—H15C	0.9800
C7—H7A	0.9900
C9—O2—C14	117.66 (12)	C8—C7A—C7	118.91 (13)
C2—C1—C11B	106.78 (12)	C11A—C7A—C7	120.37 (13)
C2—C1—H1A	110.4	C9—C8—C7A	118.69 (13)
C11B—C1—H1A	110.4	C9—C8—C13	120.46 (13)
C2—C1—H1B	110.4	C7A—C8—C13	120.85 (14)
C11B—C1—H1B	110.4	C10—C9—O2	122.83 (14)
H1A—C1—H1B	108.6	C10—C9—C8	121.21 (13)
C2A—C2—C1	103.61 (12)	O2—C9—C8	115.96 (13)
C2A—C2—H2A	111.0	C11—C10—C9	119.13 (15)
C1—C2—H2A	111.0	C11—C10—H10	120.4
C2A—C2—H2B	111.0	C9—C10—H10	120.4
C1—C2—H2B	111.0	C10—C11—C11A	122.22 (14)
H2A—C2—H2B	109.0	C10—C11—H11	118.9
C3—C2A—C2	134.25 (14)	C11A—C11—H11	118.9
C3—C2A—C5A	114.12 (13)	C11—C11A—C7A	117.95 (13)
C2—C2A—C5A	110.99 (13)	C11—C11A—C11B	119.10 (13)
C2A—C3—C4	107.64 (13)	C7A—C11A—C11B	122.94 (14)
C2A—C3—C12	129.51 (14)	C11A—C11B—C15	110.61 (13)
C4—C3—C12	122.68 (13)	C11A—C11B—C5A	113.98 (12)
O1—C4—C3	126.20 (14)	C15—C11B—C5A	110.82 (12)
O1—C4—C5	125.01 (14)	C11A—C11B—C1	110.76 (12)
C3—C4—C5	108.57 (13)	C15—C11B—C1	108.71 (12)
C4—C5—C5A	104.12 (12)	C5A—C11B—C1	101.54 (12)
C4—C5—H5A	110.9	C3—C12—H12A	109.5
C5A—C5—H5A	110.9	C3—C12—H12B	109.5
C4—C5—H5B	110.9	H12A—C12—H12B	109.5
C5A—C5—H5B	110.9	C3—C12—H12C	109.5
H5A—C5—H5B	109.0	H12A—C12—H12C	109.5
C2A—C5A—C5	102.09 (11)	H12B—C12—H12C	109.5
C2A—C5A—C6	109.52 (12)	C8—C13—H13A	109.5
C5—C5A—C6	109.64 (12)	C8—C13—H13B	109.5
C2A—C5A—C11B	103.10 (11)	H13A—C13—H13B	109.5
C5—C5A—C11B	122.49 (13)	C8—C13—H13C	109.5
C6—C5A—C11B	109.06 (11)	H13A—C13—H13C	109.5
C7—C6—C5A	111.46 (12)	H13B—C13—H13C	109.5
C7—C6—H6A	109.3	O2—C14—H14A	109.5
C5A—C6—H6A	109.3	O2—C14—H14B	109.5
C7—C6—H6B	109.3	H14A—C14—H14B	109.5
C5A—C6—H6B	109.3	O2—C14—H14C	109.5
H6A—C6—H6B	108.0	H14A—C14—H14C	109.5
C7A—C7—C6	112.21 (12)	H14B—C14—H14C	109.5
C7A—C7—H7A	109.2	C11B—C15—H15A	109.5
C6—C7—H7A	109.2	C11B—C15—H15B	109.5
C7A—C7—H7B	109.2	H15A—C15—H15B	109.5
C6—C7—H7B	109.2	C11B—C15—H15C	109.5
H7A—C7—H7B	107.9	H15A—C15—H15C	109.5
C8—C7A—C11A	120.71 (14)	H15B—C15—H15C	109.5
C11B—C1—C2—C2A	−18.47 (16)	C14—O2—C9—C8	−178.66 (13)
C1—C2—C2A—C3	164.77 (18)	C7A—C8—C9—C10	−0.4 (2)
C1—C2—C2A—C5A	−5.25 (16)	C13—C8—C9—C10	179.01 (14)
C2—C2A—C3—C4	−160.49 (17)	C7A—C8—C9—O2	−179.68 (12)
C5A—C2A—C3—C4	9.30 (18)	C13—C8—C9—O2	−0.24 (19)
C2—C2A—C3—C12	14.8 (3)	O2—C9—C10—C11	−178.68 (13)
C5A—C2A—C3—C12	−175.45 (15)	C8—C9—C10—C11	2.1 (2)
C2A—C3—C4—O1	178.17 (16)	C9—C10—C11—C11A	−1.1 (2)
C12—C3—C4—O1	2.5 (2)	C10—C11—C11A—C7A	−1.5 (2)
C2A—C3—C4—C5	3.30 (16)	C10—C11—C11A—C11B	179.47 (14)
C12—C3—C4—C5	−172.35 (14)	C8—C7A—C11A—C11	3.2 (2)
O1—C4—C5—C5A	171.36 (15)	C7—C7A—C11A—C11	−176.70 (14)
C3—C4—C5—C5A	−13.69 (15)	C8—C7A—C11A—C11B	−177.80 (13)
C3—C2A—C5A—C5	−17.56 (17)	C7—C7A—C11A—C11B	2.3 (2)
C2—C2A—C5A—C5	154.63 (13)	C11—C11A—C11B—C15	−47.50 (18)
C3—C2A—C5A—C6	98.59 (15)	C7A—C11A—C11B—C15	133.51 (15)
C2—C2A—C5A—C6	−89.23 (15)	C11—C11A—C11B—C5A	−173.15 (13)
C3—C2A—C5A—C11B	−145.42 (13)	C7A—C11A—C11B—C5A	7.9 (2)
C2—C2A—C5A—C11B	26.77 (16)	C11—C11A—C11B—C1	73.11 (18)
C4—C5—C5A—C2A	17.60 (15)	C7A—C11A—C11B—C1	−105.89 (16)
C4—C5—C5A—C6	−98.45 (13)	C2A—C5A—C11B—C11A	−155.26 (12)
C4—C5—C5A—C11B	131.89 (13)	C5—C5A—C11B—C11A	90.97 (16)
C2A—C5A—C6—C7	175.00 (12)	C6—C5A—C11B—C11A	−38.93 (16)
C5—C5A—C6—C7	−73.75 (15)	C2A—C5A—C11B—C15	79.20 (14)
C11B—C5A—C6—C7	62.85 (15)	C5—C5A—C11B—C15	−34.57 (18)
C5A—C6—C7—C7A	−53.29 (16)	C6—C5A—C11B—C15	−164.48 (12)
C6—C7—C7A—C8	−159.64 (13)	C2A—C5A—C11B—C1	−36.13 (14)
C6—C7—C7A—C11A	20.26 (19)	C5—C5A—C11B—C1	−149.90 (13)
C11A—C7A—C8—C9	−2.3 (2)	C6—C5A—C11B—C1	80.19 (13)
C7—C7A—C8—C9	177.62 (13)	C2—C1—C11B—C11A	155.68 (13)
C11A—C7A—C8—C13	178.29 (14)	C2—C1—C11B—C15	−82.59 (15)
C7—C7A—C8—C13	−1.8 (2)	C2—C1—C11B—C5A	34.29 (14)
C14—O2—C9—C10	2.1 (2)