5240
F. Ferna´ndez et al. / Tetrahedron Letters 42 (2001) 5239–5240
(+)-8-phenylneomenthol in 40% yields from (R)-(+)-
pulegone, and we obtained 1 in 20% yield from 2 by
isolation from the mixture of four diastereomeric 8-
phenylmenthols produced by Sarett oxidation of 2 and
reduction of the resulting (+)-8-phenylisomenthone
(C-2%+C-6%), 128.50 (C-3%+C-5%), 149.63 (C-1%), 214.47
(C(S)).
7. (3R,6S)-3-Methyl-6-(1-methyl-1-phenylethyl)-1-cyclohex-
ene, 5: Compound 4 (1.1 g, 3.79 mmol) was heated for 1 h
at 200°C (without any solvent). The residue was purified
by flash chromatography [silica gel 60; hexane] affording 5
as an oil (0.73 g; 90%). [h]2D3 +71.5 (c 1.0, CHCl3). IR (film)
wmax: 3019, 2958, 2867, 1559, 1495, 1457, 1365, 1311, 1240,
i
with Na in PrOH.5 We have now developed the follow-
ing new, very efficient stereospecific route from 2 to 1.
1
1098, 1030, 961, 765 cm−1. H NMR (300 MHz, CDCl3):
8-Phenylmenthol 2 was easily converted to the S-
methyl xanthate 4,6 which was then transformed into
8-phenyl-2-menthene 5 by pyrolytic syn elimination.7
trans-Epoxide 6 was obtained in good yield by oxida-
tion of 5 with m-CPBA,8 which took place with high
facial stereoselectivity because of the great difference in
steric hindrance between the two faces of the CꢀC
bond. Finally, clean reduction of 6 with LiBEt3H
(Super-Hydride®), which occurs at the less-hindered
position, gave (+)-8-phenylisomenthol 1 (Scheme 1).9
0.95 (d, 3H, J=7.1 Hz, 3-CH3), 1.29 and 1.31 (2s, 6H,
C-(CH3)2), 1.33–1.42 (m, 3H), 1.61–1.66 (m, 1H), 2.14–
2.15 (m, 1H), 2.38–2.40 (m, 1H), 5.47 (d×t, 1H, Jd=10.3
Hz, Jt=1.7 Hz, 2-H), 5.66 (d×t, 1H, Jd=10.3 Hz, Jt=3.2
Hz, 1-H), 7.17–7.22 (m, 1H, ArH), 7.26–7.39 (m, 4H,
ArH). 13C NMR (75 MHz, CDCl3): 20.65 (CH3), 21.36
(CH2), 25.60 (CH3), 25.77 (CH3), 29.13 (CH), 29.65 (CH2),
40.64 (C-8), 46.70 (CH), 125.83 (C-4%), 126.54 and 126.61
(C-2%+C-6%), 128.30 and 128.35 (C-3%+C-5%), 134.75 (C-1+C-
2), 150.17 (C-1%).
8. (1R,2S,3R,6R)-1,2-Epoxy-3-methyl-6-(1-methyl-1-phenyl-
ethyl)cyclohexane, 6: A solution of 5 (0.59 g, 2.75 mmol) in
dry Cl2CH2 (4 mL) was added dropwise under argon to a
solution of 70% m-CPBA (0.85 g, 3.40 mmol) in dry
Cl2CH2 (10 mL) at 0°C. After stirring for 3 h at room
temperature the mixture was treated with a saturated
aqueous solution of NaSO3H (80 mL) and extracted with
Cl2CH2 (3×80 mL). The combined organic phases were
washed with saturated K2CO3 (3×90 mL) and brine (80
mL), and after drying (Na2SO4) the solvents were removed
in vacuo, affording 6 as a colourless oil (0.59 g; 93%). [h]D23
+30.2 (c 1.0, CHCl3). IR (film) wmax: 3057, 2962, 1598,
1496, 1444, 1369, 1128, 1032, 930, 800, 765 cm−1. 1H NMR
(300 MHz, CDCl3): 1.00 (d, 3H, J=7.2 Hz, 3-CH3),
1.03–1.27 (m, 3H), 1.33 and 1.41 (2s, 6H, C-(CH3)2),
1.54–1.63 (m, 1H), 2.14–2.27 (m, 2H, 3-H and 6-H),
2.79–2.87 (m, 2H, 1-H and 2-H), 7.16–7.22 (m, 1H, ArH),
7.29–7.41 (m, 4H, ArH). 13C NMR (75 MHz, CDCl3):
15.80 (CH3), 17.31 (CH2), 24.74 (CH2), 25.53 (CH3), 26.27
(CH3), 27.23 (CH), 40.60 (C-8), 44.71 (CH), 54.36 (CH),
58.19 (CH), 126.19 (C-4%), 126.49 (C-2%+C-6%), 128.60 (C-
3%+C-5%), 149.16 (C-1%).
Acknowledgements
This work was supported by the Xunta de Galicia
under project XUGA20309B98.
References
1. Jones, G. B.; Chapman, B. J. Synthesis 1995, 475–497.
2. Ort, O. Org. Synth. 1987, 65, 203–214.
3. Whitesell, J. K.; Lin, C.-L.; Buchanan, C. M.; Chen,
H.-H.; Minton, M. A. J. Org. Chem. 1986, 51, 551–553.
4. (a) Rodr´ıguez-Borges, J. E. Ph.D. Dissertation, Universi-
dade de Santiago de Compostela, 1995; (b) Blanco, J. M.;
Caaman˜o, O.; Ferna´ndez, F.; Garc´ıa-Mera, X.; Lo´pez, C.;
Rodr´ıguez, G.; Rodr´ıguez-Borges, J. E.; Rodr´ıguez-
Hergueta, A. Tetrahedron Lett. 1998, 39, 5663–5666.
5. Ferna´ndez, F.; Garc´ıa-Mera, X.; Lo´pez, C.; Rodr´ıguez,
G.; Rodr´ıguez-Borges, J. E. Tetrahedron: Asymmetry 2000,
11, 4805–4815.
9. (1S,2R,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohex-
anol, 1: A 1.0 M solution of lithium triethylborohydride in
dry THF (4.3 mL, 10 equiv.) was added under argon, at
room temperature and in one dose, to a solution of 6 (100
mg, 0.43 mmol) in 5 mL of the same solvent. The mixture
was cooled to 0°C, treated with 50 mL of 5% NaOH
solution followed by 25 mL of 3% H2O2, and extracted
with Et2O (3×50 mL). The combined organic phases were
washed with brine (80 mL), and after drying (Na2SO4) the
solvents were removed in vacuo, leaving an oil that upon
purification by flash chromatography [silica gel 60; 9:1
hexane/Et2O] afforded 1 as a colourless oil (98 mg; 98%).
[h]2D3 +11.5 (c 1.0, CHCl3). IR (film) wmax: 3566, 3402, 3087,
3057, 2921, 1601, 1495, 1444, 1380, 1343, 1155, 1061, 1031,
6. (1R,2R,5R)-S-Methyl-O-[5-methyl-2-(1-methyl-1-phenyl-
ethyl)cyclohexyl]dithiocarbonate, 4: To a solution of 2 (1 g,
4.3 mmol) in THF (10 mL) at −60°C under argon was
added a 2.5 M solution of butyllithium in hexanes (1.89
mL, 1.1 equiv.) followed by CS2 (2.15 mL) and Me2SO4
(0.45 mL, 1.1 equiv.). The mixture was allowed to warm to
room temperature and after a further 4 h was washed with
Et2O (80 mL) and H2O (80 mL). The combined organic
phases were washed again with water (100 mL) and brine
(80 mL), and after drying (Na2SO4) the solvents were
removed in vacuo, leaving a solid that upon purification
by flash chromatography [silica gel 60; 9:1 hexane/Et2O]
afforded 4 as a white solid (1.20 g; 95%). Mp 71–73°C.
[h]2D3 +41.0 (c 1.0, CHCl3). IR (KBr) wmax: 2921, 1495,
1
1014, 972, 763, 700 cm−1. H NMR (CDCl3): 0.93 (d, 3H,
1455, 1383, 1292, 1220, 1146, 1111, 1050, 768, 698 cm−1
.
J=7.2 Hz, 5-CH3), 1.31 and 1.43 (2s, 6H, C-(CH3)2),
1.20–1.55 (m, 5H), 1.61–1.77 (m, 2H), 1.97–2.05 (m, 1H),
3.76 (d×t, Jt=9.7 Hz, Jd=4.3 Hz, 1ax-H), 7.15–7.21 (m,
1H, 4%-H), 7.29–7.34 (m, 2H, 3%-H+5%-H), 7.38–7.41 (m,
2H, 2%-H+6%-H). 13C NMR (CDCl3): 19.08 (CH3), 21.65
(CH2), 24.91 (CH3), 28.06 (CH), 28.83 (CH3), 31.88 (CH2),
40.30 (C-8), 42.24 (CH2), 55.39 (CH), 69.18 (C-1), 126.18
(C-4%+C-2%+C-6%), 128.80 (C-3%+C-5%), 150.70 (C-1%).
1H NMR (300 MHz, CDCl3): 0.98 (d, 3H, J=7.4 Hz,
5-CH3), 1.33 and 1.35 (2s, 6H, C-(CH3)2), 1.39–2.08 (m,
8H), 2.52 (s, 3H, SCH3), 5.68 (s, 1H, 1-H), 7.15–7.20 (m,
1H, ArH), 7.28–7.32 (m, 4H, ArH). 13C NMR (75 MHz,
CDCl3): 18.06 (CH2), 19.25 (SCH3), 20.74 (CH3), 26.35
(CH3), 26.45 (CH3), 26.92 (CH), 32.38 (CH2), 35.61 (CH2),
40.61 (C-8), 52.54 (C-2), 82.29 (C-1), 126.02 (C-4%), 126.51