A new, convenient synthesis of the chiral auxiliary (+)-8-phenylisomenthol

Article abstract of DOI:10.1016/S0040-4039(01)01000-0

A new, straitghtforward and efficient method for preparing (+)-8-phenylisomenthol 1 from its diastereomer (+)-8-phenylisoneomenthol 2 is described. Conversion of 2 to (+)-8-phenyl-2-menthene 5, followed by oxidation to the corresponding (+)-trans-epoxide 6 and reduction of 6 with LiBEt₃H afforded 1 in 78% overall yield.

Full text of DOI:10.1016/S0040-4039(01)01000-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5239–5240
A new, convenient synthesis of the chiral auxiliary
(+)-8-phenylisomenthol
Franco Ferna´ndez,a Xerardo Garc´ıa-Mera,a,* Jose´ Enrique Rodr´ıguez-Borgesb and
Jose´ Manuel Blancoa
aDepartamento de Qu´ımica Orga´nica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
bDepartamento de Qu´ımica, Faculdade de Cieˆncias do Porto, Rua do Campo Alegre, 687-4169007 Porto, Portugal
Received 15 May 2001; accepted 11 June 2001
Abstract—A new, straitghtforward and efficient method for preparing (+)-8-phenylisomenthol 1 from its diastereomer (+)-8-
phenylisoneomenthol 2 is described. Conversion of 2 to (+)-8-phenyl-2-menthene 5, followed by oxidation to the corresponding
(+)-trans-epoxide 6 and reduction of 6 with LiBEt3H afforded 1 in 78% overall yield. © 2001 Elsevier Science Ltd. All rights
reserved.
(−)-8-Phenylmenthol (3) is one of the most widely
employed recoverable chiral auxiliaries, being used to
achieve enantioselectivity in numerous syntheses.1 Its
popularity is due both to the good enantiomeric
excesses it affords (especially in face differentiation
processes, in which its capacity for faceselective stack-
ing via p interactions is decisive) and to its ready
availability (it can be prepared in good yields from the
inexpensive reagent (R)-(+)-pulegone).2 By contrast, the
high cost of its enantiomer (+)-8-phenylmenthol, ent-3,
which in principle is just as attractive as 3 as a chiral
auxiliary, has resulted in its only rarely having been
used as such.
recently, however, 1 has only been obtained as a side-
product in the standard preparation of 3 from (R)-(+)-
pulegone, and hence, in very low yield (6%) and only
after tiresome separation of diastereomers.
OH
OH
OH
OH
Ph
Ph
Ph
Ph
2
1
3
ent-3
Our interest in the preparation of 3-substituted 2-azabi-
cyclo[2.2.1]hept-5-enes, which are important intermedi-
ates in the syntheses of compounds of pharmaceutical
and/or biological relevance,4 has led us to investigate
the efficiencies of all the various stereomers of 8-phenyl-
menthol as chiral auxiliaries in aza-Diels–Alder reac-
tions. To this end we recently developed efficient
syntheses affording (−)-8-phenylisoneomenthol (2) and
Whitesell noted in 1986 that since the configuration of
ent-3 in the region responsible for chiral induction (C1
and C2) is the same as that of its diastereomer (+)-8-
phenylisomenthol 1, 1 ought to have the same effects as
ent-3 when used as a chiral auxiliary; and he verified
this prediction for Diels–Alder and ene reactions.3 Until
iv
S
ii
iii
93%
i
O
98%
95%
90%
SMe
OH
OH
O
Ph
Ph
Ph
Ph
Ph
5
6
2
1
4
Scheme 1. Reagents and conditions: (i) CS2, Me2SO4, nBuLi, THF; (ii) 200°C; (iii) m-CPBA 70%, Cl2CH2; (iv) LiBEt3H 1 M,
THF.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01000-0

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