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M. Blair et al.
PAPER
(1R,2R,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexane-1,2-diol
This work highlights a facile method for accessing four
diastereomerically pure products from the commercially
available limonene oxide mixture.
Chemical shifts are expressed in parts per million (d). H and 13C
NMR spectra were recorded on a Bruker AM 300 spectrometer at
300 and 75 MHz, respectively. Melting points were recorded on a
Kofler hot stage apparatus and are uncorrected. Mass spectrometry
(ESI) was performed on a Micromass Platform QMS spectrometer.
IR spectra were recorded on a Bruker Equinox 55 ATR spectrome-
ter. GC analyses were performed on a Varian 3700 with a SGE 30
QC5 BPX5 (1.0 mm column of internal diameter, 0.53 mm × 30m)
(He carrier gas, 85 °C for 3 min, then ramped to 280 °C at 8 °C/
min). Optical rotations were obtained using a PolAAR 2001 auto-
matic polarimeter, using a 1 dm cell with CHCl3 as solvent, at a
wavelength of 589 nm (sodium D line). (+)-Limonene oxide (cis/
trans mixture, 53:47, Aldrich) was used as received.
(4)
To a solution of HgCl2 (250 mL, 67 mM in 330 mM tris buffer, pH
7) was added (+)-limonene oxide (cis/trans epoxides 1 and 2, 4.0 g,
26.3 mmol) dropwise. The mixture was stirred at r.t. and the
progress of the reaction was followed by GC. Aliquots (1 mL) were
diluted with aq sat. NaHCO3 (1 mL) followed by extraction with
EtOAc (2 mL). The samples were then analysed by GC analysis.
After 40 min, the trans-epoxide 2 was completely consumed. The
mixture was extracted with hexane (3 × 70 mL), to remove unreact-
ed cis-(+)-limonene oxide (1; 1.64 g, maximum theoretical yield
96%, >98% de) and NaBH4 (3.20 g, 84.6 mmol) was subsequently
added to the aqueous phase. After stirring at r.t. for 3 h, the mixture
was extracted with EtOAc (3 × 100 mL), dried (Na2SO4), and con-
centrated in vacuo to afford a white crystalline solid [2.52 g, 99%
based on starting trans-(+)-limonene oxide, yields of cis- or trans-
limonene oxide via kinetic separation are calculated from the initial
percent composition (i.e., 53:47)]. A mixture of the diequatorial and
1
1
(1S,2S,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexane-1,2-diol(3)
(+)-Limonene oxide (cis/trans isomers 1 and 2, 1.0 g, 6.57 mmol)
was added to a solution of NaOAc (200 mL, 100 mM, pH 4). Stir-
ring was continued until total consumption of the cis-epoxide oc-
curred (ca. 3.5 h) as detected by GC analysis. The mixture was
neutralised with aq sat. NaHCO3, extracted with hexane (3 × 100
mL), dried (Na2SO4), and concentrated in vacuo to afford the unre-
acted trans-epoxide 2 [373 mg, 87% recovery yield based on initial
(+)-trans-limonene oxide, de >98%, yields of cis- or trans-
limonene oxide via kinetic separation are calculated from the initial
percent composition (i.e., 53:47)]. The residual aqueous phase was
extracted EtOAc (3 × 100 mL), dried (Na2SO4) and concentrated
under reduced pressure to afford the diaxial diol 3 [487 mg, 76%
based on initial (+)-cis-limonene oxide, >98% de].
diaxial diols (20:1) was observed by H NMR spectroscopy. Re-
crystallisation from water afforded the diastereomerically pure
diequatorial diol 4 (68%, >98% de).
Mp 74–76 °C; [a]D20 –5.5 (c 0.01, CHCl3); tR = 11.03 min (SGE 30
QC5 BPX5).
IR (solid sample): 3330, 3251, 3075, 2981, 2864, 1697, 1644, 1434,
1374 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.20 (s, 3 H), 1.21–1.26 (m, 2 H),
1.29–145 (m, 2 H), 1.67 (s, 3 H), 1.72 (dt, J = 2.4, 9.6 Hz, 1 H)
1.85–1.95 (m, 2 H), 2.05 (tt, J = 2.9, 9.3 Hz, 1 H), 2.91 (s, 1 H), 3.20
(s, 1 H), 3.56 (dd, J = 3.3, 9.0 Hz, 1 H), 4.71 (s, 2 H).
13C NMR (CDCl3, 75 MHz): d = 18.9, 20.8, 28.7, 36.1, 38.5, 43.6,
74.0, 77.2, 109.1, 148.5.
Mp 68–70 °C; [a]D20 +18.1 (c 0.01, CHCl3); tR = 10.81 min (SGE
30 QC5 BPX5).
X-ray Data
For X-ray crystal data of 4, please see ref. 18.
IR (solid sample): 3354, 3081, 2931, 2235, 1644, 1448, 1371, 1240
cm–1.
(+)-cis-Limonene Oxide (1)
1H NMR (CDCl3, 300 MHz): d = 1.26 (s, 3 H), 1.54–1.61 (m, 4 H),
1.62–1.68 (m, 1 H), 1.71–1.74 (m, 3 H), 1.87–98 (m, 1 H), 2.22–
2.28 (m, 1 H), 3.61–3.64 (m, 1 H), 4.72–4.73 (m, 2 H).
13C NMR (CDCl3, 75 MHz): d = 21.3, 26.45, 26.9, 33.9, 34.3, 37.7,
71.5, 74.2, 109.2, 149.6.
[a]D20 +48.1 (c 0.01, CHCl3) {Lit.10 [a]D +44 (neat)}; tR = 7.40 min
(SGE 30 QC5 BPX5).
1H NMR (CDCl3, 300 MHz): d = 1.30 (s, 3 H), 1.45–1.68 (m, 3 H),
1.69–1.72 (m, 3 H), 1.80–1.96 (m, 2 H), 1.85–1.95 (m, 2 H), 2.10–
2.20 (m, 1 H), 3.04–3.06 (m, 1 H), 4.65–4.67 (m, 1 H), 4.67–4.73
(m, 1 H).
Spectral data was consistent to that previously reported.10
(+)-trans-Limonene Oxide (2)
[a]D20 +78 (neat) {Lit.4 [a]D +77 (neat)}; tR = 7.46 min (SGE 30 Acknowledgment
QC5 BPX5).
The authors acknowledge the support of Monash University, the
School of Chemistry, Monash University, VICS, and the Australian
Research Council for a LIEF grant.
1H NMR (CDCl3, 300 MHz): d = 1.34 (s, 3 H), 1.35–1.40 (m, 2 H),
1.66–1.67 (m, 3 H), 1.69–1.70 (m, 2 H), 1.84–1.87 (m, 2 H), 2.98
(d, J = 4.0 Hz, 1 H), 4.65–4.67 (m, 2 H).
Complete Conversion of cis/trans-Limonene Oxide Mixture to
(1S,2S,4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexane-1,2-diol (3)
(+)-Limonene oxide (cis/trans isomers 1 and 2, 5.0 g, 32.9 mmol)
in potassium phosphate buffer (200 mL, 200 mM, pH 3) was stirred
at r.t. for 12 h. During this time the product, the diaxial diol, precip-
itated. The diaxial diol 3 was removed by filtration and the aqueous
solution was concentrated to a quarter of its original volume. The
solution was allowed to stand overnight at 5 °C to afford a second
crop of diaxial diol 3 [3.93 g, 70% based on initial (+)-limonene
oxide, >98% de]. The spectroscopic data of the title compound 3
was identical to that obtained when NaOAc was the buffer.
References
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Synthesis 2007, No. 10, 1523–1527 © Thieme Stuttgart · New York