Stereoselective hydroboration of (-)-isopulegol and subsequent fractional crystallization furnishes the title compound, C10H20O2. The relative configuration of the stereogenic centres has been assigned by means of X-ray diffraction analysis since the monoterpenediol is employed as a versatile chiral building block in stereospecific natural product synthesis.
Supporting information
CCDC reference: 140953
The preparation of (-)-(I) from (II) is described by Kreiser & Körner (2000). For the X-ray diffraction analysis, pure (I) (1.00 g, 5.80 mmol) was dissolved completely in the required amount of dry Et2O at reflux temperature. Thereafter, further Et2O (10 ml) was added and crystals [m.p. 377.5–378 K, [α]D295 = −19.6° (c = 2.67, CHCl3)] were grown slowly at 273 K.
The weighting scheme proposed by the refinement resulted in the low goodness-of-fit value.
Data collection: KappaCCD Software (Nonius, 1997); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-Plus (Sheldrick, 1991); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997) and PARST95 (Nardelli, 1995).
Crystal data top
| C10H20O2 | F(000) = 192 |
| Mr = 172.26 | Dx = 1.094 Mg m−3 |
| Monoclinic, P21 | Mo Kα radiation, λ = 0.71069 Å |
| a = 8.5710 (7) Å | Cell parameters from 6694 reflections |
| b = 6.4665 (3) Å | θ = 3.7–25.8° |
| c = 9.8502 (8) Å | µ = 0.07 mm−1 |
| β = 106.783 (3)° | T = 291 K |
| V = 522.69 (7) Å3 | Needle, colourless |
| Z = 2 | 0.30 × 0.08 × 0.05 mm |
Data collection top
Nonius KappaCCD
diffractometer | 1299 reflections with I > 2σ(I) |
| Radiation source: fine-focus sealed tube | Rint = 0.027 |
| Graphite monochromator | θmax = 25.8°, θmin = 3.7° |
| Detector resolution: 19 vertical, 18 horizontal pixels mm-1 | h = −10→10 |
| 360 frames via ω rotation (Δω = 1°) and 2 × 60 s per frame scans | k = −7→7 |
| 6694 measured reflections | l = −11→11 |
| 1935 independent reflections | |
Refinement top
| Refinement on F2 | Primary atom site location: structure-invariant direct methods |
| Least-squares matrix: full | Secondary atom site location: difference Fourier map |
| R[F2 > 2σ(F2)] = 0.050 | Hydrogen site location: inferred from neighbouring sites |
| wR(F2) = 0.187 | H-atom parameters constrained |
| S = 0.72 | Calculated w = 1/[σ2(Fo2) + (0.1903P)2]
where P = (Fo2 + 2Fc2)/3 |
| 1935 reflections | (Δ/σ)max < 0.001 |
| 112 parameters | Δρmax = 0.21 e Å−3 |
| 1 restraint | Δρmin = −0.28 e Å−3 |
Crystal data top
| C10H20O2 | V = 522.69 (7) Å3 |
| Mr = 172.26 | Z = 2 |
| Monoclinic, P21 | Mo Kα radiation |
| a = 8.5710 (7) Å | µ = 0.07 mm−1 |
| b = 6.4665 (3) Å | T = 291 K |
| c = 9.8502 (8) Å | 0.30 × 0.08 × 0.05 mm |
| β = 106.783 (3)° | |
Data collection top
Nonius KappaCCD
diffractometer | 1299 reflections with I > 2σ(I) |
| 6694 measured reflections | Rint = 0.027 |
| 1935 independent reflections | |
Refinement top
| R[F2 > 2σ(F2)] = 0.050 | 1 restraint |
| wR(F2) = 0.187 | H-atom parameters constrained |
| S = 0.72 | Δρmax = 0.21 e Å−3 |
| 1935 reflections | Δρmin = −0.28 e Å−3 |
| 112 parameters | |
Special details top
Experimental. The data collection covered the whole sphere of reciprocal space. The crystal to detector distance was 2.8 cm. Crystal decay was monitored by repeating the initial frames at the end of data collection. Analysing the duplicate reflections there were no indications for any decay. The structure was solved by direct methods (Sheldrick, 1990) and successive difference Fourier syntheses. |
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. Refinement applied full-matrix least-squares methods (Sheldrick, 1997). Hydrogen atoms were placed in calculated position and refined with a riding model (including free rotation about C—C and O—C for one O—H–group and HFIX 83 for the other), and with Uiso constrained to be 1.5 times Ueq of the carrier atom. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top| | x | y | z | Uiso*/Ueq | |
| O1 | 0.4074 (3) | 0.3324 (3) | 0.3519 (2) | 0.0543 (6) | |
| H1 | 0.4705 | 0.2855 | 0.3109 | 0.081* | |
| O1' | 0.4684 (3) | −0.2647 (3) | 0.3710 (2) | 0.0656 (7) | |
| H1' | 0.5005 | −0.2225 | 0.4529 | 0.098* | |
| C1 | 0.2435 (3) | 0.2921 (4) | 0.2697 (3) | 0.0454 (7) | |
| H1A | 0.2243 | 0.3616 | 0.1779 | 0.068* | |
| C1' | 0.4996 (4) | −0.1111 (5) | 0.2767 (4) | 0.0597 (9) | |
| H1'1 | 0.5703 | −0.1684 | 0.2252 | 0.090* | |
| H1'2 | 0.5546 | 0.0064 | 0.3312 | 0.090* | |
| C2 | 0.2228 (4) | 0.0607 (4) | 0.2436 (3) | 0.0446 (7) | |
| H2 | 0.2413 | −0.0048 | 0.3366 | 0.067* | |
| C2' | 0.3418 (4) | −0.0407 (5) | 0.1731 (3) | 0.0500 (8) | |
| H2' | 0.2876 | −0.1654 | 0.1255 | 0.075* | |
| C3 | 0.0450 (4) | 0.0174 (6) | 0.1605 (3) | 0.0617 (9) | |
| H3A | 0.0236 | 0.0764 | 0.0664 | 0.093* | |
| H3B | 0.0293 | −0.1309 | 0.1500 | 0.093* | |
| C3' | 0.3798 (5) | 0.0934 (6) | 0.0582 (4) | 0.0664 (10) | |
| H3'1 | 0.4429 | 0.2112 | 0.1014 | 0.100* | |
| H3'2 | 0.2798 | 0.1392 | −0.0075 | 0.100* | |
| H3'3 | 0.4406 | 0.0136 | 0.0087 | 0.100* | |
| C4 | −0.0773 (4) | 0.1048 (6) | 0.2308 (4) | 0.0667 (10) | |
| H4A | −0.0659 | 0.0332 | 0.3197 | 0.100* | |
| H4B | −0.1869 | 0.0804 | 0.1699 | 0.100* | |
| C5 | −0.0532 (4) | 0.3351 (6) | 0.2591 (4) | 0.0596 (9) | |
| H5 | −0.0749 | 0.4054 | 0.1674 | 0.089* | |
| C5A | −0.1721 (5) | 0.4205 (9) | 0.3350 (5) | 0.0889 (14) | |
| H5A1 | −0.1553 | 0.3510 | 0.4242 | 0.133* | |
| H5A2 | −0.2819 | 0.3980 | 0.2772 | 0.133* | |
| H5A3 | −0.1536 | 0.5660 | 0.3511 | 0.133* | |
| C6 | 0.1249 (4) | 0.3767 (5) | 0.3423 (3) | 0.0541 (8) | |
| H6A | 0.1413 | 0.5247 | 0.3548 | 0.081* | |
| H6B | 0.1471 | 0.3147 | 0.4356 | 0.081* | |
Atomic displacement parameters (Å2) top| | U11 | U22 | U33 | U12 | U13 | U23 |
| O1 | 0.0465 (12) | 0.0449 (12) | 0.0684 (14) | −0.0030 (9) | 0.0116 (10) | −0.0059 (10) |
| O1' | 0.0796 (17) | 0.0377 (11) | 0.0688 (15) | −0.0050 (10) | 0.0044 (13) | 0.0012 (10) |
| C1 | 0.0427 (16) | 0.0411 (15) | 0.0492 (16) | −0.0009 (13) | 0.0085 (14) | 0.0008 (12) |
| C1' | 0.059 (2) | 0.0380 (16) | 0.080 (2) | −0.0011 (14) | 0.0175 (17) | −0.0044 (15) |
| C2 | 0.0456 (17) | 0.0377 (16) | 0.0484 (16) | −0.0061 (13) | 0.0105 (14) | 0.0017 (13) |
| C2' | 0.0527 (18) | 0.0388 (15) | 0.0571 (18) | −0.0041 (12) | 0.0138 (15) | −0.0077 (13) |
| C3 | 0.057 (2) | 0.059 (2) | 0.066 (2) | −0.0104 (16) | 0.0123 (17) | −0.0158 (17) |
| C3' | 0.075 (2) | 0.065 (2) | 0.064 (2) | −0.0004 (17) | 0.0262 (19) | −0.0015 (16) |
| C4 | 0.045 (2) | 0.074 (2) | 0.079 (2) | −0.0092 (16) | 0.0149 (18) | −0.0065 (19) |
| C5 | 0.0513 (19) | 0.068 (2) | 0.0591 (19) | 0.0098 (17) | 0.0146 (15) | 0.0016 (16) |
| C5A | 0.064 (3) | 0.113 (4) | 0.096 (3) | 0.017 (2) | 0.033 (2) | −0.014 (3) |
| C6 | 0.0576 (19) | 0.0455 (16) | 0.0579 (18) | 0.0031 (14) | 0.0145 (15) | −0.0043 (14) |
Geometric parameters (Å, º) top
| O1—C1 | 1.429 (4) | C3—H3A | 0.9700 |
| O1—H1 | 0.8200 | C3—H3B | 0.9700 |
| O1'—C1' | 1.437 (4) | C3'—H3'1 | 0.9600 |
| O1'—H1' | 0.8200 | C3'—H3'2 | 0.9600 |
| C1—C6 | 1.505 (4) | C3'—H3'3 | 0.9600 |
| C1—C2 | 1.520 (4) | C4—C5 | 1.518 (6) |
| C1—H1A | 0.9800 | C4—H4A | 0.9700 |
| C1'—C2' | 1.510 (5) | C4—H4B | 0.9700 |
| C1'—H1'1 | 0.9700 | C5—C5A | 1.530 (5) |
| C1'—H1'2 | 0.9700 | C5—C6 | 1.534 (4) |
| C2—C2' | 1.536 (4) | C5—H5 | 0.9800 |
| C2—C3 | 1.533 (4) | C5A—H5A1 | 0.9600 |
| C2—H2 | 0.9800 | C5A—H5A2 | 0.9600 |
| C2'—C3' | 1.534 (4) | C5A—H5A3 | 0.9600 |
| C2'—H2' | 0.9800 | C6—H6A | 0.9700 |
| C3—C4 | 1.522 (5) | C6—H6B | 0.9700 |
| | | |
| C1—O1—H1 | 109.5 | H3A—C3—H3B | 107.7 |
| C1'—O1'—H1' | 109.5 | C2'—C3'—H3'1 | 109.5 |
| O1—C1—C6 | 110.7 (2) | C2'—C3'—H3'2 | 109.5 |
| O1—C1—C2 | 108.8 (2) | H3'1—C3'—H3'2 | 109.5 |
| C6—C1—C2 | 112.1 (3) | C2'—C3'—H3'3 | 109.5 |
| O1—C1—H1A | 108.4 | H3'1—C3'—H3'3 | 109.5 |
| C6—C1—H1A | 108.4 | H3'2—C3'—H3'3 | 109.5 |
| C2—C1—H1A | 108.4 | C3—C4—C5 | 111.9 (3) |
| O1'—C1'—C2' | 110.4 (3) | C3—C4—H4A | 109.2 |
| O1'—C1'—H1'1 | 109.6 | C5—C4—H4A | 109.2 |
| C2'—C1'—H1'1 | 109.6 | C3—C4—H4B | 109.2 |
| O1'—C1'—H1'2 | 109.6 | C5—C4—H4B | 109.2 |
| C2'—C1'—H1'2 | 109.6 | H4A—C4—H4B | 107.9 |
| H1'1—C1'—H1'2 | 108.1 | C5A—C5—C6 | 112.1 (3) |
| C1—C2—C2' | 115.9 (3) | C5A—C5—C4 | 111.7 (4) |
| C1—C2—C3 | 108.7 (3) | C6—C5—C4 | 109.4 (3) |
| C2'—C2—C3 | 111.6 (2) | C5A—C5—H5 | 107.8 |
| C1—C2—H2 | 106.7 | C6—C5—H5 | 107.8 |
| C2'—C2—H2 | 106.7 | C4—C5—H5 | 107.8 |
| C3—C2—H2 | 106.7 | C5—C5A—H5A1 | 109.5 |
| C1'—C2'—C3' | 109.2 (3) | C5—C5A—H5A2 | 109.5 |
| C1'—C2'—C2 | 113.9 (2) | H5A1—C5A—H5A2 | 109.5 |
| C3'—C2'—C2 | 113.7 (3) | C5—C5A—H5A3 | 109.5 |
| C1'—C2'—H2' | 106.5 | H5A1—C5A—H5A3 | 109.5 |
| C3'—C2'—H2' | 106.5 | H5A2—C5A—H5A3 | 109.5 |
| C2—C2'—H2' | 106.5 | C1—C6—C5 | 112.8 (2) |
| C4—C3—C2 | 113.5 (3) | C1—C6—H6A | 109.0 |
| C4—C3—H3A | 108.9 | C5—C6—H6A | 109.0 |
| C2—C3—H3A | 108.9 | C1—C6—H6B | 109.0 |
| C4—C3—H3B | 108.9 | C5—C6—H6B | 109.0 |
| C2—C3—H3B | 108.9 | H6A—C6—H6B | 107.8 |
| | | |
| O1—C1—C2—C2' | −55.7 (3) | C1—C2—C3—C4 | −54.3 (4) |
| C6—C1—C2—C2' | −178.5 (2) | C2'—C2—C3—C4 | 176.8 (3) |
| O1—C1—C2—C3 | 177.7 (2) | C2—C3—C4—C5 | 55.1 (4) |
| C6—C1—C2—C3 | 55.0 (3) | C3—C4—C5—C5A | −177.8 (3) |
| O1'—C1'—C2'—C3' | −170.2 (2) | C3—C4—C5—C6 | −53.1 (4) |
| O1'—C1'—C2'—C2 | 61.5 (3) | O1—C1—C6—C5 | −179.3 (3) |
| C1—C2—C2'—C1' | 87.7 (3) | C2—C1—C6—C5 | −57.6 (3) |
| C3—C2—C2'—C1' | −147.2 (3) | C5A—C5—C6—C1 | 179.5 (3) |
| C1—C2—C2'—C3' | −38.3 (3) | C4—C5—C6—C1 | 55.1 (4) |
| C3—C2—C2'—C3' | 86.7 (3) | | |
Hydrogen-bond geometry (Å, º) top
| D—H···A | D—H | H···A | D···A | D—H···A |
| O1′—H1′···O1i | 0.82 | 1.89 | 2.702 (3) | 170 |
| Symmetry code: (i) −x+1, y−1/2, −z+1. |
Experimental details
| Crystal data |
| Chemical formula | C10H20O2 |
| Mr | 172.26 |
| Crystal system, space group | Monoclinic, P21 |
| Temperature (K) | 291 |
| a, b, c (Å) | 8.5710 (7), 6.4665 (3), 9.8502 (8) |
| β (°) | 106.783 (3) |
| V (Å3) | 522.69 (7) |
| Z | 2 |
| Radiation type | Mo Kα |
| µ (mm−1) | 0.07 |
| Crystal size (mm) | 0.30 × 0.08 × 0.05 |
| |
| Data collection |
| Diffractometer | Nonius KappaCCD
diffractometer |
| Absorption correction | – |
No. of measured, independent and
observed [I > 2σ(I)] reflections | 6694, 1935, 1299 |
| Rint | 0.027 |
| (sin θ/λ)max (Å−1) | 0.612 |
| |
| Refinement |
| R[F2 > 2σ(F2)], wR(F2), S | 0.050, 0.187, 0.72 |
| No. of reflections | 1935 |
| No. of parameters | 112 |
| No. of restraints | 1 |
| H-atom treatment | H-atom parameters constrained |
| Δρmax, Δρmin (e Å−3) | 0.21, −0.28 |
Selected torsion angles (º) top| C6—C1—C2—C2' | −178.5 (2) | C3—C4—C5—C5A | −177.8 (3) |
| O1—C1—C2—C3 | 177.7 (2) | O1—C1—C6—C5 | −179.3 (3) |
| C2'—C2—C3—C4 | 176.8 (3) | C5A—C5—C6—C1 | 179.5 (3) |
Hydrogen-bond geometry (Å, º) top
| D—H···A | D—H | H···A | D···A | D—H···A |
| O1'—H1'···O1i | 0.82 | 1.89 | 2.702 (3) | 170 |
| Symmetry code: (i) −x+1, y−1/2, −z+1. |
The preparation of the title compound, (-)-(I), by hydroboration of (-)-isopulegol, (II), was first reported by Schulte-Elte & Ohloff (1967). In the meantime, (-)-(I) has found broad application as an optically active starting material in the synthesis of natural products, especially of the antimalarial drug artemisinin and a number of its analogues (Imakura et al., 1988; Constantino et al., 1996; Avery et al., 1990, 1994; Hui et al., 1997). Although the stereochemistryof (-)-(I) appears to be well established in the literature by NMR data and by the configuration of derivatives sythesized from it, the crystal structure of the important relay compound itself is still lacking. During our 18-step stereospecific preparation of the bis-abolane sesquiterpenes β-turmerone, (III), and β-sequiphellandrene, (IV) (Kreiser & Körner, 2000), we succeeded in determining the relative configuration of the vicinal asymmetric C atoms by X-ray diffraction analysis of their synthetic intermediate (-)-(I), since during further transformation, C2 and C2' of (-)-(I) become C1' and C6 in the corresponding sesquiterpenes. (-)-(I) was prepared from technical grade (-)-isopulegol, (II), of moderate enantiomeric and diastereomeric purity, but after repeated crystallization from Et2O, the material was identical in melting point and optical rotation with the data reported for (-)-(I) derived from highly pure (II). Therefore, the configuration given in Fig. 1 is most likely to be the absolute one. In the crystalline state, the cyclohexane part of (-)-(I) displays an almost perfect undistorted chair conformation since all the six torsion angles involving the three substituents (O1—C1—C2—C3, O1—C1—C6—C5, C2'—C2—C3—C4, C6—C1—C2—C2', C3—C4—C5—C5a and C5a—C5—C6—C1) are in the range 176.8 (3)–179.5 (3)°. Accordingly, the hydroxy, isopropyl and methyl substituents (O1, C2' and C5a, respectively) are found in ideal all-equatorial positions. Consequently, the relative arrangement of the hydroxy and isopropyl groups is anti, and of the hydroxy and the methyl groups is syn, in accordance with the predicted 1R,2S,5R stereochemistry. Considering that the stereogenic centres at C1 and C5 are going to be extinguished during the course of further synthetic manipulation, the most important aspect is the relative stereochemistry between C2 and C2', which can be deduced from Fig. 1. Provided that the configuration at C2 is S, that at C2' has to be R.