The lack of C2 molecular symmetry in (1R,2R,3S,6S)-3,6-di­benzyl­oxycyclo­hex-4-ene-1,2-diol

The results of a single-crystal X-ray experiment and density functional theory calculations performed for the title compound, C₂₀H₂₂O₄, demonstrate that the lowest energy conformation of this mol­ecule does not contain C2 molecular symmetry.

S1. Comment

We have synthesized the chiral title molecule, (I), during the course of our work on the synthesis of natural products related to marine sponge extracts. Herein we report the structure of (I), discuss its molecular symmetry, and present results of density functional theory (DFT) (Schrödinger Inc., 1998) calculations. \sch

The absolute stereochemistry of the chiral centers is assigned 3S, 4R, 5R, and 6S from knowledge of the synthesis. The benzyloxy groups occupy pseudoequatorial positions while the hydroxyl substituents are located in axial positions. Unfavorable steric interactions are minimized when the bulky substituents occupy pseudoequatorial positions and this feature is similarly observed in the related compounds 3,5-dicyano-6-(2-methoxy-1,1,2-trimethylpropyl)cyclohexene, (II), cis-1,3-dicyano-4-(2-methoxy-1,1,2-trimethylpropyl)cyclohexene, and cis-1,5-dicyano-4-(2-methoxy-1,1,2-trimethylpropyl)cyclohexene (Borg et al., 1984).

The conformation of the cyclohexene ring in (I) is a half-chair. Atoms C1, C2, C3, and C6 are planar within 0.02 Å. Atoms C4 and C5 are located 0.372 (4) and 0.388 (4) Å above and below this plane, respectively. The C2—C1—C6—C5 and C1—C2—C3—C4 torsion angles are 18.7 (3) and 18.1 (3)°, correspondingly. Relevant torsion angles in the related structures, (II), 5-n-butyl-3-hydroxymethyl-6-methylcyclohexen-4-ol (Batey et al., 1999), (+)-(1S,2S,3S,6R,1'S)-methyl-2-(1-hydroxyethyl)- 3-hydroxymethyl-6-methyl-4-cyclohexene-1-carboxylate, and (+)-(1S, 2S, 3S, 6R,1'S,1''R)-methyl-2,3-bis(1-hydroxyethyl)-6-methyl-4-cyclohexene- 1-carboxylate (Ainsworth et al., 1995) range from 5.9 to 25.4°. Notably, the DFT calculated torsion angles C2—C1—C6—C5 (13.9°) and C1—C2—C3—C4 (13.9°) of cyclohexene (III) fall in the middle of this range.

Several statistically significant differences are observed in the chemically equivalent bond lengths and torsion angles of (I). The O2—C4 distance [1.428 (2) Å] is 0.010 Å longer than the related O3—C5 distance [1.418 (2) Å]. In 4574 relevant compounds containing 8321 Csp³—OH bonds reported to the Cambridge Structural Database (CSD) (Allen & Kennard, 1993), the corresponding values averaged 1.424 (15) Å. Additionally, the O4—C14 distance [1.430 (2) Å] is 0.016 Å longer than O1—C7 [1.414 (2) Å], and the torsion angles O1—C7—C8—C13 [-31.6 (3)°] and O4—C14—C15—C16 [-56.5 (3)°] are substantially different. To account for these discrepancies, several DFT geometry optimizations were performed on molecules of (I) and (III). Results of calculations for one molecule of (III) verify its optimal geometry to be C2 symmetric. However, this is not observed in the case of (I). The DFT calculated molecular parameters of (I) are in close agreement with the experimentally observed values. One exception to this is that the calculated O1—C7—C8—C13 and O4—C14—C15—C16 torsion angles are 41.0 and 69.4°, respectively. Although π-stacking interactions are not observed, other crystal packing forces likely contribute to this difference. To test the hypothesis that the C2 symmetric geometry of (I) is not the lowest in energy, DFT calculations were carried out for (I) by starting from the symmetrical conformation and consecutively lifting all of the symmetry constraints. In the progress of optimization the molecule departed from the symmetrical conformation. Additionally, DFT calculations were performed on (I) with two additional water molecules fixed at the observed O3.·O2[1 - x, y - 1/2, 1/2 - z] and O2.·O3[1 - x, y + 1/2, 1/2 - z] distances to simulate possible hydrogen bonding in the structure. This structure optimization did not fully converge. [The maximum displacement (2.13×10^-2) and r.m.s. displacement (7.88×10^-3) values were above the standard threshold values of 1.8×10^-3 and 1.2×10^-3 respectively, which in turn, is indicative of a flat minimum on the potential energy surface.] Consequently, it is concluded that hydrogen bonding probably does not contribute significantly to this symmetry lowering.

Weak hydrogen-bonding interactions between the hydroxyl substituents of symmetry-related molecules in the lattice of (I) are likely. An intermolecular hydrogen-bonding interaction is observed between donor atom O3 and acceptor atom O2[1 - x, y - 1/2, 1/2 - z], Table 2. The corresponding values for 2222 compounds with 3998 similar hydrogen bonds in structures reported to the CSD comprised 2.79 (9) Å and 166 (7)°. The longer O···O separation in (I) is indicative of a weaker hydrogen bond. Interestingly, the chemically equivalent intermolecular O2.·H—O3 hydrogen-bonding interaction is not observed and also confirms the lack of C2 molecular symmetry. Results of this study demonstrate that the C1 molecular symmetry of (I) is determined by its conformational stability rather than by packing forces alone.

S2. Experimental

Compound (I) was synthesized from L-diethyl tartrate (IV) in seven steps. Conversion of (IV) to its acetonide followed by reduction with diisobutylaluminum hydride and addition of vinylmagnesium bromide gave a bis(allylic alcohol) (V) as a 71:23:6 mixture of diastereomers in a 72% yield. Benzylation of (V) was followed by hydrolysis of the isopropylidene ketal to give the diol in a 92% yield, which was then acetylated with acetic anhydride to provide the bis(acetate), (VI). Separation of the three stereoisomers was possible at this stage by chromatography on silica gel, providing the desired isomer in 55% yield along with 35% of the two undesired isomers. Subjection of diene (VI) to ring-closing metathesis with 3 mol% of a 1,3-dimesityl-4,5-dyhydroimidazol-2-ylidene substituted second generation Grubbs' catalyst (Scholl et al., 1999) in refluxing benzene gave the (+)-conduritol E derivative in a 93% yield along with 3% of unreacted starting material. Cleavage of the acetate esters in basic methanol then provided the title compound (I) in a 96% yield. The overall yield of the seven-step synthesis was 36%.

Computing details

Data collection: SMART (Siemens, 1996); cell refinement: SMART; data reduction: SHELXTL (Sheldrick, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

Fig. 1. Molecular structure of (I). The displacement ellipsoids are shown at the 50% probability level.

(I)

Crystal data

C20H22O4	Dx = 1.314 Mg m^−3
Mr = 326.38	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 1921 reflections
a = 8.5979 (9) Å	θ = 2.0–50.0°
b = 10.109 (1) Å	µ = 0.09 mm^−1
c = 18.9828 (18) Å	T = 173 K
V = 1649.9 (3) Å^3	Block, colourless
Z = 4	0.62 × 0.62 × 0.40 mm
F(000) = 696

Data collection

Bruker CCD-1000 area detector diffractometer	1869 independent reflections
Radiation source: fine-focus sealed tube	1625 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.018
ϕ and ω scans	θmax = 26.4°, θmin = 2.3°
Absorption correction: empirical (using intensity measurements) (SADABS; Blessing, 1995)	h = −10→10
Tmin = 0.946, Tmax = 0.965	k = 0→12
3184 measured reflections	l = 0→22

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)] = 0.033	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.079	H-atom parameters constrained
S = 1.00	w = 1/[σ^2(Fo^2) + (0.0473P)^2] where P = (Fo^2 + 2Fc^2)/3
1869 reflections	(Δ/σ)max < 0.001
219 parameters	Δρmax = 0.16 e Å^−3
0 restraints	Δρmin = −0.14 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	0.49733 (18)	0.89156 (12)	0.06757 (7)	0.0317 (4)
O2	0.50548 (19)	1.08578 (13)	0.16656 (8)	0.0369 (4)
H2	0.4920	1.1075	0.1243	0.055*
O3	0.34986 (16)	0.82285 (14)	0.27480 (8)	0.0331 (4)
H3	0.4086	0.7678	0.2946	0.050*
O4	0.61733 (17)	0.87617 (13)	0.35123 (6)	0.0294 (3)
C1	0.6922 (2)	0.8380 (2)	0.23195 (10)	0.0298 (5)
H1	0.7884	0.8020	0.2474	0.036*
C2	0.6417 (2)	0.8068 (2)	0.16817 (11)	0.0300 (5)
H2A	0.7064	0.7538	0.1390	0.036*
C3	0.4883 (2)	0.8506 (2)	0.13992 (10)	0.0274 (4)
H3A	0.4137	0.7750	0.1433	0.033*
C4	0.4217 (2)	0.96691 (18)	0.18099 (10)	0.0274 (5)
H4	0.3099	0.9793	0.1681	0.033*
C5	0.4347 (2)	0.9397 (2)	0.25963 (10)	0.0267 (4)
H5	0.3872	1.0152	0.2860	0.032*
C6	0.6051 (2)	0.92721 (19)	0.28076 (10)	0.0269 (5)
H6	0.6539	1.0170	0.2793	0.032*
C7	0.4894 (3)	0.7851 (2)	0.01935 (10)	0.0340 (5)
H7A	0.3921	0.7348	0.0270	0.041*
H7B	0.5782	0.7245	0.0272	0.041*
C8	0.4936 (2)	0.8369 (2)	−0.05522 (10)	0.0282 (4)
C9	0.5592 (2)	0.7603 (2)	−0.10810 (11)	0.0333 (5)
H9	0.6035	0.6767	−0.0972	0.040*
C10	0.5599 (2)	0.8061 (2)	−0.17714 (11)	0.0382 (6)
H10	0.6045	0.7536	−0.2134	0.046*
C11	0.4966 (3)	0.9269 (2)	−0.19314 (12)	0.0394 (5)
H11	0.4982	0.9581	−0.2403	0.047*
C12	0.4305 (3)	1.0033 (2)	−0.14100 (11)	0.0397 (6)
H12	0.3851	1.0863	−0.1523	0.048*
C13	0.4307 (3)	0.9583 (2)	−0.07210 (11)	0.0340 (5)
H13	0.3870	1.0117	−0.0360	0.041*
C14	0.6098 (3)	0.9794 (2)	0.40260 (10)	0.0362 (5)
H14A	0.5345	1.0475	0.3870	0.043*
H14B	0.7131	1.0219	0.4070	0.043*
C15	0.5607 (2)	0.92596 (19)	0.47313 (10)	0.0263 (4)
C16	0.4230 (3)	0.8572 (2)	0.48053 (12)	0.0367 (5)
H16	0.3620	0.8381	0.4401	0.044*
C17	0.3728 (3)	0.8157 (2)	0.54590 (12)	0.0459 (6)
H17	0.2769	0.7698	0.5504	0.055*
C18	0.4624 (3)	0.8410 (2)	0.60502 (12)	0.0448 (6)
H18	0.4285	0.8119	0.6501	0.054*
C19	0.6004 (3)	0.9084 (2)	0.59835 (11)	0.0405 (6)
H19	0.6619	0.9264	0.6388	0.049*
C20	0.6496 (2)	0.9500 (2)	0.53252 (10)	0.0326 (5)
H20	0.7456	0.9958	0.5281	0.039*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0476 (8)	0.0297 (7)	0.0179 (8)	−0.0041 (7)	0.0001 (7)	−0.0007 (6)
O2	0.0558 (9)	0.0268 (7)	0.0282 (8)	−0.0035 (7)	−0.0034 (8)	0.0038 (6)
O3	0.0331 (8)	0.0341 (8)	0.0320 (9)	−0.0018 (6)	0.0014 (7)	0.0028 (7)
O4	0.0408 (8)	0.0296 (7)	0.0178 (7)	0.0016 (7)	−0.0019 (6)	−0.0013 (6)
C1	0.0274 (10)	0.0371 (11)	0.0250 (12)	0.0058 (9)	0.0010 (9)	0.0030 (9)
C2	0.0334 (11)	0.0308 (11)	0.0258 (12)	0.0051 (9)	0.0074 (9)	−0.0011 (9)
C3	0.0369 (11)	0.0280 (10)	0.0174 (10)	−0.0027 (10)	0.0002 (9)	0.0019 (9)
C4	0.0304 (10)	0.0260 (10)	0.0260 (12)	0.0025 (9)	−0.0024 (9)	−0.0004 (8)
C5	0.0310 (10)	0.0249 (10)	0.0242 (11)	0.0018 (9)	0.0028 (9)	−0.0028 (8)
C6	0.0338 (11)	0.0277 (10)	0.0193 (10)	−0.0008 (9)	−0.0023 (9)	0.0007 (8)
C7	0.0462 (12)	0.0287 (10)	0.0271 (12)	−0.0017 (10)	0.0007 (11)	−0.0019 (9)
C8	0.0283 (10)	0.0327 (10)	0.0235 (11)	−0.0067 (9)	−0.0027 (9)	−0.0006 (9)
C9	0.0320 (11)	0.0355 (11)	0.0324 (13)	−0.0012 (9)	−0.0020 (10)	−0.0044 (10)
C10	0.0330 (11)	0.0560 (15)	0.0255 (13)	−0.0069 (11)	0.0031 (10)	−0.0137 (11)
C11	0.0425 (12)	0.0561 (14)	0.0195 (11)	−0.0125 (13)	−0.0036 (10)	0.0037 (11)
C12	0.0474 (13)	0.0387 (12)	0.0330 (13)	−0.0008 (11)	−0.0122 (11)	0.0027 (11)
C13	0.0387 (11)	0.0388 (12)	0.0246 (12)	0.0029 (10)	−0.0021 (10)	−0.0043 (9)
C14	0.0563 (14)	0.0303 (11)	0.0220 (12)	−0.0063 (10)	0.0015 (11)	−0.0041 (9)
C15	0.0324 (10)	0.0240 (9)	0.0224 (11)	0.0028 (9)	0.0012 (9)	−0.0022 (8)
C16	0.0377 (12)	0.0396 (12)	0.0327 (13)	−0.0035 (10)	−0.0025 (11)	−0.0064 (10)
C17	0.0459 (13)	0.0458 (13)	0.0459 (15)	−0.0173 (12)	0.0133 (12)	−0.0040 (12)
C18	0.0667 (17)	0.0371 (12)	0.0306 (13)	−0.0039 (12)	0.0125 (12)	0.0022 (11)
C19	0.0565 (15)	0.0417 (13)	0.0232 (12)	0.0005 (11)	−0.0056 (11)	−0.0015 (10)
C20	0.0333 (11)	0.0369 (11)	0.0275 (13)	−0.0039 (10)	−0.0004 (10)	−0.0039 (9)

Geometric parameters (Å, º)

O1—C7	1.414 (2)	C8—C9	1.387 (3)
O1—C3	1.437 (2)	C9—C10	1.390 (3)
O2—C4	1.428 (2)	C9—H9	0.9500
O2—H2	0.8400	C10—C11	1.371 (3)
O3—C5	1.418 (2)	C10—H10	0.9500
O3—H3	0.8400	C11—C12	1.377 (3)
O4—C14	1.430 (2)	C11—H11	0.9500
O4—C6	1.437 (2)	C12—C13	1.385 (3)
C1—C2	1.324 (3)	C12—H12	0.9500
C1—C6	1.494 (3)	C13—H13	0.9500
C1—H1	0.9500	C14—C15	1.504 (3)
C2—C3	1.492 (3)	C14—H14A	0.9900
C2—H2A	0.9500	C14—H14B	0.9900
C3—C4	1.522 (3)	C15—C16	1.380 (3)
C3—H3A	1.0000	C15—C20	1.384 (3)
C4—C5	1.522 (3)	C16—C17	1.379 (3)
C4—H4	1.0000	C16—H16	0.9500
C5—C6	1.524 (3)	C17—C18	1.385 (3)
C5—H5	1.0000	C17—H17	0.9500
C6—H6	1.0000	C18—C19	1.374 (3)
C7—C8	1.510 (3)	C18—H18	0.9500
C7—H7A	0.9900	C19—C20	1.385 (3)
C7—H7B	0.9900	C19—H19	0.9500
C8—C13	1.379 (3)	C20—H20	0.9500
C7—O1—C3	113.38 (14)	C13—C8—C7	121.13 (19)
C4—O2—H2	109.5	C9—C8—C7	119.65 (18)
C5—O3—H3	109.5	C8—C9—C10	119.9 (2)
C14—O4—C6	111.67 (14)	C8—C9—H9	120.1
C2—C1—C6	123.14 (18)	C10—C9—H9	120.1
C2—C1—H1	118.4	C11—C10—C9	120.3 (2)
C6—C1—H1	118.4	C11—C10—H10	119.9
C1—C2—C3	123.20 (19)	C9—C10—H10	119.9
C1—C2—H2A	118.4	C10—C11—C12	120.2 (2)
C3—C2—H2A	118.4	C10—C11—H11	119.9
O1—C3—C2	112.43 (16)	C12—C11—H11	119.9
O1—C3—C4	106.71 (15)	C11—C12—C13	119.6 (2)
C2—C3—C4	112.22 (16)	C11—C12—H12	120.2
O1—C3—H3A	108.4	C13—C12—H12	120.2
C2—C3—H3A	108.4	C8—C13—C12	120.8 (2)
C4—C3—H3A	108.4	C8—C13—H13	119.6
O2—C4—C5	107.64 (16)	C12—C13—H13	119.6
O2—C4—C3	111.21 (16)	O4—C14—C15	110.96 (16)
C5—C4—C3	109.59 (15)	O4—C14—H14A	109.4
O2—C4—H4	109.5	C15—C14—H14A	109.4
C5—C4—H4	109.5	O4—C14—H14B	109.4
C3—C4—H4	109.5	C15—C14—H14B	109.4
O3—C5—C4	108.17 (16)	H14A—C14—H14B	108.0
O3—C5—C6	111.82 (17)	C16—C15—C20	118.66 (19)
C4—C5—C6	110.11 (16)	C16—C15—C14	120.80 (19)
O3—C5—H5	108.9	C20—C15—C14	120.48 (18)
C4—C5—H5	108.9	C17—C16—C15	120.9 (2)
C6—C5—H5	108.9	C17—C16—H16	119.6
O4—C6—C1	108.89 (15)	C15—C16—H16	119.6
O4—C6—C5	110.19 (16)	C16—C17—C18	119.9 (2)
C1—C6—C5	111.64 (17)	C16—C17—H17	120.0
O4—C6—H6	108.7	C18—C17—H17	120.0
C1—C6—H6	108.7	C19—C18—C17	119.8 (2)
C5—C6—H6	108.7	C19—C18—H18	120.1
O1—C7—C8	110.00 (16)	C17—C18—H18	120.1
O1—C7—H7A	109.7	C18—C19—C20	119.8 (2)
C8—C7—H7A	109.7	C18—C19—H19	120.1
O1—C7—H7B	109.7	C20—C19—H19	120.1
C8—C7—H7B	109.7	C15—C20—C19	120.9 (2)
H7A—C7—H7B	108.2	C15—C20—H20	119.6
C13—C8—C9	119.21 (19)	C19—C20—H20	119.6
C6—C1—C2—C3	−3.8 (3)	O1—C7—C8—C13	−31.6 (3)
C7—O1—C3—C2	83.1 (2)	O1—C7—C8—C9	149.55 (19)
C7—O1—C3—C4	−153.49 (18)	C13—C8—C9—C10	−0.4 (3)
C1—C2—C3—O1	138.4 (2)	C7—C8—C9—C10	178.5 (2)
C1—C2—C3—C4	18.1 (3)	C8—C9—C10—C11	0.2 (3)
O1—C3—C4—O2	−51.4 (2)	C9—C10—C11—C12	−0.5 (3)
C2—C3—C4—O2	72.2 (2)	C10—C11—C12—C13	1.0 (3)
O1—C3—C4—C5	−170.27 (15)	C9—C8—C13—C12	0.9 (3)
C2—C3—C4—C5	−46.7 (2)	C7—C8—C13—C12	−177.9 (2)
O2—C4—C5—O3	179.13 (15)	C11—C12—C13—C8	−1.2 (3)
C3—C4—C5—O3	−59.8 (2)	C6—O4—C14—C15	157.99 (17)
O2—C4—C5—C6	−58.4 (2)	O4—C14—C15—C16	−56.5 (3)
C3—C4—C5—C6	62.7 (2)	O4—C14—C15—C20	126.4 (2)
C14—O4—C6—C1	150.68 (17)	C20—C15—C16—C17	1.4 (3)
C14—O4—C6—C5	−86.6 (2)	C14—C15—C16—C17	−175.7 (2)
C2—C1—C6—O4	140.6 (2)	C15—C16—C17—C18	−1.1 (4)
C2—C1—C6—C5	18.7 (3)	C16—C17—C18—C19	0.6 (4)
O3—C5—C6—O4	−48.4 (2)	C17—C18—C19—C20	−0.3 (3)
C4—C5—C6—O4	−168.66 (15)	C16—C15—C20—C19	−1.2 (3)
O3—C5—C6—C1	72.7 (2)	C14—C15—C20—C19	175.9 (2)
C4—C5—C6—C1	−47.5 (2)	C18—C19—C20—C15	0.7 (3)
C3—O1—C7—C8	177.88 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2^i	0.84	2.12	2.920 (2)	160

Symmetry code: (i) −x+1, y−1/2, −z+1/2.