Synthesis and characterization of all stereoisomers of 8-phenylmenthol

Article abstract of DOI:10.1016/S0957-4166(00)00454-7

New, improved and/or specific syntheses of the diastereoisomers of (-)-8-phenylmenthol are described. The configurations of these products, usable as chiral auxiliaries, were confirmed by X-ray diffractometry of their 3,5-dinitrobenzoates.

Full text of DOI:10.1016/S0957-4166(00)00454-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4805–4815
Synthesis and characterization of all stereoisomers of
8-phenylmenthol
Franco Ferna´ndez,a Xerardo Garc´ıa-Mera,a,* Carmen Lo´pez,a Gonzalo Rodr´ıguezb and
Jose´ Enrique Rodr´ıguez-Borgesa,†
aDepartamento de Qu´ımica Orga´nica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15706 Santiago de Compostela, Spain
bDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad Auto´noma de Madrid,
E-28048 Madrid, Spain
Received 7 November 2000; accepted 15 November 2000
Abstract
New, improved and/or specific syntheses of the diastereoisomers of (−)-8-phenylmenthol are described.
The configurations of these products, usable as chiral auxiliaries, were confirmed by X-ray diffractometry
of their 3,5-dinitrobenzoates. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since 1975, when Corey1 used (+)-8-phenylmenthol 1 for the enantioselective synthesis of
prostaglandins, this compound and its enantiomer, 2, have ranked among the most versatile
chiral auxiliaries in the armamentarium of asymmetric organic synthesis, being especially useful
for face-differentiation.
* Corresponding author. Fax: +00 34 981 59 49 12; e-mail: qoxgmera@usc.es
†
Present address: Departamento de Qu´ımica da Faculdade de Cieˆncias do Porto, Rua do Campo Alegre, 687-
4169007 Porto, Portugal.
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00454-7

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For example, in view of the excellent stereoselectivity of [4+2] cycloaddition reactions of
8-phenylmenthyl enoates, 2 was used to direct intramolecular ene reactions;2 and this use was
later extended by other authors to intermolecular ene reactions between 8-phenylmenthyl
glyoxylates and simple alkenes3 and related cycloadditions.4
Oppolzer5 was the first to describe BF3-mediated Michael addition of organocopper reagents
to enoates of 2. Likewise in the 1980s, conjugated addition of amines to 8-phenylmenthyl
crotonates was achieved with high yield and diastereoselectivity,6 and excellent stereoselectivity
was reported for the addition of Grignard reagents to 8-phenylmenthyl glyoxylates7a and their
imino derivatives.7b
In the 1990s, the use of 2 as a chiral auxiliary was further extended to stereoselective addition
of hydride to glyoxylates,8 addition of organomagnesium reagents to salts of 1-(8-phenylmenthyl-
oxycarbonyl)pyridinium en route to chiral 2-alkyl-2,3-dihydro-4-pyridones,9 aza-Darzens con-
densation reactions,10 asymmetric Horner–Wadsworth–Emmons reactions,11 [3+2] photocy-
cloaddition of esters to alkenes,12 stereoselective Birch reduction of pyrroles,13 and
enantioselective aza-Diels–Alder reactions of imines of glyoxylates.14
Corey’s1 original syntheses of 1 and 2 involved copper(I)-mediated conjugated addition of
phenylmagnesium bromide to the pulegone with the appropriate configuration (e.g. 3 for 2),
treatment of the resulting trans/cis mixture of ketones with alkaline medium to shift the
equilibrium towards the trans form (obtaining, for example, 85:15 4/5), and final reduction with
Na/PriOH to obtain, as the major product, the equatorial alcohol 2, which was then purified by
chromatography on silica gel,1 by preparative HPLC,15 or by fractionated crystallization of its
chloroacetate followed by saponification.16
Because of the ease of preparation and low cost of (R)-(+)-pulegone 3, use of 2 rapidly
became widespread; for example, 2 was the 8-phenylmenthol used in almost all the studies
mentioned above. By contrast, use of 1 was hindered by the almost prohibitively high cost of

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4807
(S)-(−)-pulegone. Seeking to redress the imbalance, Corey17 also synthesized 1 enantiodiver-
gently from 3, but this involves seven steps and affords only a 42% overall yield.
It was pointed out by Whitesell15 in 1986 that the configuration of 1 in the region responsible
for chiral induction (C1 and C2) is the same as that of its diastereomer (+)-8-phenylisomenthol
6, and that 6 therefore ought to exhibit the same effects as 1 when used as a chiral auxiliary, a
prediction he verified for Diels–Alder and ene reactions. Similarly, Quinkert18 hypothesized that
(+)-8-phenylneomenthol 7 ought to behave like 1 in certain ScN% cyclopropanation reactions, and
successfully used it to prepare a vinylcyclopropane with the configuration opposite to that
afforded by the use of 2, and hence to obtain enantiomerically pure (−)-jasmonate methyl ester.
Surprisingly, in spite of 6 and 7 both being considerably less expensive than 1, as far as we know
there have been no further reports on the use of diastereomers of 2 as chiral auxiliaries.19 This
apparent lack of interest is doubtless due to the preparation methods published hitherto having
involved the separation of mixtures of isomers by single- or double-stage HPLC (usually
followed by Kugelrohr distillation), and to overall yields from commercially available starting
materials being only moderate (47%18 or 66%19 for 7; cf. 42% for Corey’s17 synthesis of 1 from
3) or very low (6% for 6,15 10% for (−)-8-phenylisoneomenthol, 819).
In view of this situation, we embarked on the development of procedures affording better
yields of 6, 7, and 8. At the same time, we decided to use X-ray diffraction analysis of crystalline
derivatives to confirm the configurations of these compounds, which appear to have been
inferred hitherto only on the most plausible but fallible basis of the identities of the starting
ketone and the reducing system.
2. Results and discussion
(−)-8-Phenylmenthol 2,20 which we initially intended to use only for purposes of comparison,
was easily prepared from (R)-(+)-pulegone by Ort’s16 modified version of Corey’s1 procedure.
Since reduction of 2-alkylcyclohexanones with L-Selectride affords the corresponding axial
alcohols with almost no contaminating equatorial epimer,19,21 we aimed to obtain 7 and 8 by
L-Selectride reduction of (−)-8-phenylmenthone 4 and (+)-8-phenylisomenthone 5, respectively.
All known syntheses of these intermediates start by conjugate addition of phenylmagnesium
bromide to pulegone 3, and give mixtures of 4 and 5 in proportions that depend on the method
used to quench the resulting enolate.15,16,22 The method reported22 to afford the highest yield of
the thermodynamically disfavored epimer, 5, consists in quenching with trimethylsilyl chloride,
isolation of the trimethylsilylenolether 9a, and treatment of 9a with 40% HF/MeCN. In our
hands, however, this method did not give the reported22 50:50 mixture of 4 and 5, but a 70:30
mixture. An even worse result was achieved when we tried using acetyl chloride instead of
trimethylsilyl chloride and subjecting the resulting enol intermediate 9b to alkaline saponifica-
tion; this afforded 4 and 5 in 85:15 ratio, the same as is obtained when mixtures of 4 and 5 are
equilibrated by treatment with KOH/EtOH. In view of these results, following Ort,16 we finally
quenched the enolate with 2N HCl, obtaining 4 and 5 in 55:45 ratio. Reduction of this mixture
with L-Selectride afforded a mixture of the desired axial alcohols 7 and 8 which was cleanly
resolved by column chromatography (SiO2), both compounds being obtained in 40% yield with
respect to the starting pulegone. For the low-melting solid 8 this is a considerable improvement
over the 10% achieved by the only other published synthesis.19

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With 2, 7, and 8 in hand we found that their oxidation with CrO3–pyridine afforded good
yields of the corresponding ketones 4 and 5 with no contaminating epimer. As reported
previously in a preliminary communication,23 this allowed 7 to be obtained in 87% yield from
pulegone 3 via 2 and 4 (Scheme 1), which is to date the most efficient known route to this
product.
i
Scheme 1. Reagents: (i) L-Selectride. (ii) KOH/EtOH; Na, PrOH. (iii) PhMgBr, CuCl; AcCl. (iv) CrO3, py. (v) Na,
iPrOH. (vi) 3,5-Dinitrobenzoyl chloride
As described above, the axial alcohol 8 is obtained without contaminating epimer by
L-Selectride reduction of 5. By contrast, all available methods for reducing 5 to the equatorial
alcohol 6 without contamination by 8 involve conditions that induce the prior or competitive
isomerization of 5 to the thermodynamically favored epimer 4, which naturally results in yields
of 6 being very poor. We have nevertheless somewhat improved the yield of 6 with respect to
starting pulegone 3 from 6%15 to 21% (calculated for pure 6 following chromatographic
separation of a mixture of four 8-phenylmenthols) by reducing pure 5 with Na/PriOH in boiling
toluene.
The preparation of pure 4 and 5 allowed them to be characterized for the first time as pure
1
compounds; in Section 3 we present their optical activities and IR and H and 13C NMR
spectra. The 8-phenylmenthols 2, 6, 7, and 8 were characterized not only in terms of their optical
activities and IR and 1H and 13C NMR spectra, but also by studies of the respective
3,5-dinitrobenzoates 10–13, including X-ray diffraction studies of 11–13 that confirmed the

F. Ferna´ndez et al. / Tetrahedron: Asymmetry 11 (2000) 4805–4815
4809
iconfigurations of 6–8 (Figs. 1–3). In 11–13 the cyclohexane ring is a more or less distorted chair
with the bulky C(Me)2Ph group equatorial, which makes the O equatorial and the C5 Me axial
in 11 and 6, the O axial and the C5 Me equatorial in 12 and 7, and the O and C5 Me both axial
n 13 and 8. It is of interest that the ester and phenyl groups of 11 and 12 are close together,
Figure 1. (+)-8-Phenylisomenthol 3,5-dinitrobenzoate 11
Figure 2. (+)-8-Phenylneomenthol 3,5-dinitrobenzoate 12

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Figure 3. (−)-8-Phenylisoneomenthol 3,5-dinitrobenzoate 13
since if the same holds in the analogues used in chiral synthesis (e.g. the acrylate or glyoxylate
derivatives of 6 and 7) it would allow the p-stacking interactions that have often been invoked
as responsible for the stereoselectivity of the reactions of 8-arylmenthols. By contrast, the phenyl
and ester groups of 13 point in opposite directions, which would prevent p-stacking.
Although NMR data for the 8-phenylmenthols have already been published in the papers
reporting their various syntheses, we present here data for 2, 6, 7, and 8 that, having been
obtained under identical conditions, allow more rigorous comparisons to be made. The salient
1
features of the H NMR spectra are the methyl and C1 proton signals. In those of 2 and 6, in
both of which the OH group is equatorial, the geminal methyls appear 0.12 ppm apart, a much
greater difference than the 0.02 ppm found in the cases of 7 and 8, in which OH is axial. Also,
the C1 proton signal of 2 appears 0.21 ppm from that of 6, whereas those of 7 and 8 appear at
practically the same position. As expected, the C1 proton signals of 2 and 6 are triplets (J]10
Hz) of doublets (J:4 Hz) due to two trans-diaxial anti vicinal couplings and an axial–equatorial
gauche vicinal coupling, whereas those of 7 and 8 appear as the envelope of an unresolved
multiplet due to three gauche vicinal couplings (two equatorial–axial and one equatorial–equato-
rial). The C5 methyl protons are more shielded in 2, in which this group is equatorial, than in
6, in which it is axial; and are similarly more shielded in 7 than in 8, although the strong
deshielding in 8 is largely attributable to the 1,3-diaxial steric interaction between the methyl and
the OH group.

F. Ferna´ndez et al. / Tetrahedron: Asymmetry 11 (2000) 4805–4815
4811
3. Experimental
Melting points are uncorrected and were determined in a Reichert Kofler Thermopan or in
capillary tubes in a Bu¨chi 510 apparatus. Observed rotations at the Na-D line were determined
at 23°C in a Perkin–Elmer 241 polarimeter. Infrared spectra were recorded in a Perkin–Elmer
1
681 spectrophotometer. H NMR spectra (300 MHz) and 13C NMR spectra (75.47 MHz) were
recorded in a Bruker WM spectrometer, using TMS as the internal reference (chemical shifts in
l values, J in Hz). Mass spectra were recorded on a Kratos MS-59 spectrometer. Microanalyses
were performed in a Perkin–Elmer 240B element analyzer by the Microanalysis Service of the
University of Santiago. Flash chromatography was performed on silica gel (Merck 60, 230–240
mesh) and analytical TLC data on pre-coated silica gel plates (Merck 60 F254, 0.25 mm).
Crystallographic data were obtained with a Seifert XRD 3000S diffractometer.
3.1. (1S,2S,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 7 and
(1R,2R,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexanol 8
A 55:45 mixture of diastereomers 4 and 5 of the crude product (8.00 g), obtained by
copper(I)-catalyzed addition of PhMgBr to (R)-(+)-pulegone (5.13 g; 33.7 mmol),16 was dis-
solved in dry THF and added dropwise with a syringe to an L-Selectride solution (52 mL, 1.0
M in THF; 52 mmol) at 0°C. The reaction mixture was stirred at 0°C for 4 h, at which point
aqueous 3 M NaOH (18 mL; 54 mmol) was added dropwise followed by slow addition of 30%
H2O2 (18 mL, 180 mmol). The solution was stirred for 30 min at room temperature and
extracted with Et2O (4×30 mL). The combined organic phases were washed with water (2×20
mL) and dried (Na2SO4). The solvent was removed, giving a mixture of 7 and 8 (7.68 g) as an
oil that was resolved by flash chromatography (220 g SiO2; 9:1 hexane:AcOEt). Compound 8
(3.13 g; 40%) was the first to elute, followed by 7 (3.11 g; 40%); both were colorless oils with no
1
alien signals in their H and 13C NMR spectra. Compound 8 crystallized spontaneously upon
standing for a few days at room temperature.
3.1.1. (1S,2S,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 7
[h]2D3 +34.0 (c 1.0, CHCl3). IR (film) wmax: 3464, 3087, 3056, 2946, 1600, 1495, 1446, 1386, 1148,
1
1093, 1031, 1003, 964, 771, 700 cm−1. H NMR (CDCl3): 0.84 (d, 3H, J=6.18 Hz, 5-CH3),
0.88–1.11 (m, 2H), 1.38 and 1.40 (2s, 6H, 8-(CH3)2), 1.43–1.76 (m, 6H), 3.86 (a.s., 1H, 1eq-H),
7.16–7.21 (q, 1H, J=7.13, 5.92, 1.21 Hz, 4%-H), 7.26–7.33 (m, 2H, 3%-H+5%-H), 7.37–7.40 (m, 2H,
2%-H+6%-H). 13C NMR (CDCl3): 21.75 (C-3), 22.63 (C-7), 26.26 (C-9), 26.53 (C-5), 28.05 (C-10),
36.06 (C-4), 40.60 (C-8), 44.26 (C-6), 52.71 (C-2), 68.62 (C-1), 125.92 (C-4%), 126.59 (C-2%+C-6%),
128.42 (C-3%+C-5%), 150.31 (C-1%). Anal. calcd for C16H24O: C, 82.70; H, 10.41; found: C, 82.47;
H, 10.69.
3.1.2. (1R,2R,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 8
Mp 28–30°C. [h]2D3 −4.2 (c 0.5, CHCl3). IR (film) wmax: 3586, 3489, 2945, 2908, 1601, 1497,
1381, 1186, 1120, 1032, 959, 768, 700 cm−1. 1H NMR (CDCl3): 0.91 (a.s., 1H, ꢀ1/2=7.7 Hz), 1.13
(d, 3H, J=7.41 Hz, 5-CH3), 1.40 and 1.42 (2s, 6H, 8-(CH3)2), 1.35–1.64 (m, 6H), 1.72–1.81 (t×d,
1H, Jt=12.49 Hz, Jd=3.53 Hz), 1.86–1.90 (m, 1H), 3.85 (a.s., 1H, ꢀ1/2=8.8 Hz, 1eq-H),
7.17–7.22 (m, 1H, 4%-H), 7.29–7.34 (m, 2H, 3%-H+5%-H), 7.39–7.41 (m, 2H, 2%-H+6%-H). 13C NMR
(CDCl3): 16.85 (C-3), 21.69 (C-7), 26.01 (C-9), 26.86 (C-5), 28.14 (C-10), 33.18 (C-4), 40.81

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(C-8), 40.85 (C-6), 53.04 (C-2), 69.54 (C-1), 125.90 (C-4%), 126.62 (C-2%+C-6%), 128.40 (C-3%+C-5%),
150.27 (C-1%). Anal. calcd for C16H24O: C, 82.70; H, 10.41; found: C, 82.98; H, 10.71.
3.2. Preparation of 8-phenylmenthones by Sarett oxidation
3.2.1. (2S,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanone 4
To a solution of pyridine (24.9 g; 311 mmol) in CH2Cl2 (260 mL) at 0°C was added CrO3
(15.48 g; 155 mmol; portionwise addition) followed by a solution of 2 (6.00 g; 25.8 mmol) in
CH2Cl2 (25 mL). The mixture was stirred at 0°C for 45 min, filtered through Celite, and washed
with Et2O (4×90 mL). The pooled organic phases were concentrated to half volume, washed
with water (100 mL) and brine (100 mL), and dried (Na2SO4). Evaporation of the remaining
solvent left an oil (6.4 g) that was purified by column chromatography (210 g SiO2; 9:1
1
hexane:AcOEt), giving 4 (5.47 g; yield 93%) as a colorless oil with no alien signals in its H and
13C NMR spectra. Application of the same procedure to 7 instead of 2 afforded a 91% yield of
4. [h]2D3 −49.1 (c 1.0, CHCl3). IR (film) wmax: 2953, 2870, 1709, 1600, 1446, 1364, 1205, 770 cm−1.
1H NMR (CDCl3): 0.97 (d, 3H, J=6.22 Hz, 5-CH3), 1.41 and 1.47 (2s, 6H, 8-(CH3)2), 1.50–1.89
(m, 5H), 1.91–2.06 (m, 1H, 6-H), 2.22–2.27 (m, 1H, 6-H), 2.61–2.70 (m, 1H, 2-H), 7.13–7.37 (m,
5Harom). 13C NMR (CDCl3): 22.73, 24.43, 26.91, 29.45, 35.09, 36.69, 39.43 (C-8), 52.76, 59.94,
125.91 (C-4%), 126.16 (C-2%+C-6%), 128.38 (C-3%+C-5%), 150.31 (C-1%), 211.92 (C-1). Anal. calcd for
C16H22O: C, 83.43; H, 9.63; found: C, 83.80; H, 9.33.
3.2.2. (2R,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanone 5
Application of the above procedure to 8 (6.00 g; 25.8 mmol) afforded 5 (5.71 g; 96%) as a
1
colorless oil with no alien signals in its H and 13C NMR spectra. [h]D23 +86.6 (c 1.0, CHCl3). IR
1
(film) wmax: 2953, 2870, 1709, 1600, 1446, 1364, 1205, 770 cm−1. H NMR (CDCl3): 0.91 (d, 3H,
J=7.08 Hz, 5-CH3), 1.43 and 1.48 (2s, 6H, 8-(CH3)2), 1.50–2.25 (m, 7H), 2.44–2.52 (m, 1H,
2-H), 7.10–7.40 (m, 5Harom). 13C NMR (CDCl3): 19.70, 24.28, 25.29, 27.61, 31.64, 32.63, 38.89
(C-8), 50.68, 60.08, 126.02 (C-4%), 126.31 (C-2%+C-6%), 128.41 (C-3%+C-5%), 149.78 (C-1%), 212.96
(C-1). Anal. calcd for C16H22O: C, 83.43; H, 9.63; found: C, 83.57; H, 9.42.
3.3. Preparation of 8-phenylmenthols by reduction of pure 8-phenylmenthones with L-Selectride
3.3.1. (1S,2S,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 7
Reduction of 4 (3.50 g; 15.2 mmol) with L-Selectride following the procedure described above
in Section 3.1 afforded 7 (3.14 g; yield 89%), with the same spectral data as reported in Section
3.1.
3.3.2. (1R,2R,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 8
Reduction of 5 with L-Selectride following the procedure described above in Section 3.1
afforded 8 (yield 92%) as a colorless oil that crystallized spontaneously upon standing. Spectral
data as reported in Section 3.1.
3.4. Preparation of 8-phenylmenthols by reduction of pure 8-phenylmenthone 5 with Na/PriOH
A solution of 5 (3.62 g; 15.7 mmol) in 2-propanol (3.6 mL, 2.83 g; 47 mmol) was added
dropwise to a stirred suspension of Na (1.08 g; 47 mmol) in boiling toluene (140 mL). The

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4813
resulting mixture was stirred and refluxed until the Na dissolved (ca. 3 h), cooled to 0°C, and
carefully treated with 2 M HCl (18 mL). The organic layer was separated and the aqueous phase
extracted with Et2O (2×100 mL). The combined organic layers were washed with brine (2×100
mL) and dried (Na2SO4), and the solvent was removed leaving an oil (3.66 g), that upon column
chromatography (130 g SiO2; 9:1 hexane:Et2O) successively afforded 8 (0.37 g; 10%), 7 (0.18 g;
5%), 2 (2.06 g; 56%) and 6 (0.76 g; 21%).
3.4.1. (1R,2S,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 2
[h]2D3 −25.3 (c 0.5, CHCl3). IR (film) wmax: 3561, 3412, 2951, 2918, 1599, 1494, 1456, 1387, 1370,
1
1095, 1055, 1030, 1001, 763, 700 cm−1. H NMR (CDCl3): 0.81–1.12 (m, 4H), 0.91 (d, 3H,
J=6.50 Hz, 5-CH3), 1.32 and 1.45 (2s, 6H, 8-(CH3)2), 1.34–1.50 (m, 1H), 1.62–1.77 (m, 3H),
1.87 (d×t, 1H, Jd=12.4 Hz, Jt=3.74 Hz, Jd=2.35 Hz), 3.55 (t×d, Jt=11.94 Hz, Jd=3.61 Hz,
1ax-H), 7.18–7.23 (m, 1H, 4%-H), 7.31–7.44 (m, 4H, 2%-H+3%-H+5%-H+6%-H). 13C NMR (CDCl3):
22.46 (C-7), 25.01 (C-3), 26.97 (C-9), 28.94 (C-5), 31.96 (C-10), 35.34 (C-4), 40.26 (C-8), 45.58
(C-6), 54.59 (C-2), 73.35 (C-1), 126.19 (C-4%), 126.23 (C-2%+C-6%), 128.84 (C-3%+C-5%), 151.75
(C-1%). Anal. calcd for C16H24O: C, 82.70; H, 10.41; found: C, 82.35; H, 10.71.
3.4.2. (1S,2R,5R)-2-(1-Methyl-1-phenylethyl)-5-methylcyclohexanol 6
[h]2D3 +11.5 (c 1.0, CHCl3). IR (film) wmax: 3566, 3402, 3087, 3057, 2921, 1601, 1495, 1444, 1380,
1
1343, 1155, 1061, 1031, 1014, 972, 763, 700 cm−1. H NMR (CDCl3): 0.93 (d, 3H, J=7.22 Hz,
5-CH3), 1.31 and 1.43 (2s, 6H, 8-(CH3)2), 1.20–1.55 (m, 5H), 1.61–1.77 (m, 2H), 1.97–2.05 (m,
1H), 3.72–3.80 (d×t, Jt=9.70 Hz, Jd=4.32 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 (C-7), 21.65 (C-3),
24.91 (C-9), 28.06 (C-5), 28.83 (C-10), 31.88 (C-4), 40.30 (C-8), 42.24 (C-6), 55.39 (C-2), 69.18
(C-1), 126.18 (C-4%+C-2%+C-6%), 128.80 (C-3%+C-5%), 150.70 (C-1%). Anal. calcd for C16H24O: C,
82.70; H, 10.41; found: C, 83.03; H, 10.53.
3.5. Preparation of 8-phenylmenthyl 3,5-dinitrobenzoates: general procedure
A mixture of the appropriate 8-phenylmenthol (300 mg; 1.29 mmol), 3,5-dinitrobenzoyl
chloride (320 mg; 1.39 mmol; freshly crystallized from CCl4), dry Et3N (0.20 mL, 145 mg; 1.43
mmol), DMAP (10 mg), and dry THF (20 mL) was refluxed for 5 h under argon, with stirring,
cooled, and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (80 mL).
The organic layer was drawn off and dried (Na2SO4), and removal of the solvent left an oil that
was purified by column chromatography (SiO2; 9:1 hexane:AcOEt).
3.5.1. (1%R,2%S,5%R)-2%-(1-Methyl-1-phenylethyl)-5%-methylcyclohexyl 3,5-dinitrobenzoate 10
Yield 86%. Mp 116–119°C (cyclohexane–ether). [h]2D3 −175.2 (c 1.0, CHCl3). IR (KBr) wmax
:
3111, 2958, 1725, 1654, 1627, 1544, 1495, 1458, 1342, 1276, 1173, 1074, 730, 720, 700 cm−1. H
NMR (CDCl3): 0.93–0.95 (d, 3H, J=6.47 Hz, 5%-CH3), 1.03–1.11 (m, 2H), 1.17 and 1.32 (2s, 6H,
8%-(CH3)2), 1.55–1.61 (m, 2H), 1.79–1.91 (m, 2H), 2.07–2.12 (m, 2H), 2.30–2.38 (m, 1H),
1
5.16–5.23 (d×t, 1H, Jt=10.72 Hz, Jd=5.38 Hz, 1% -H), 6.55–6.60 (m, 1H, 4¦-H), 6.89–6.95 (m,
ax
2H, 3¦-H+5%-H), 7.19–7.22 (d, 2H, Jd=8.03 Hz, 2¦-H+6¦-H), 8.41–8.42 (d, 2H, J=2.20 Hz,
2-H+6-H), 9.05–9.07 (t, 1H, Jt=4.28 Hz, Jd=2.20 Hz, 4-H). 13C NMR (CDCl3): 21.43 (C-7%),
22.16 (C-5%), 26.44 (C-3%), 31.62 (C-9%), 31.79 (C-10%), 34.80 (C-4%), 39.70 (C-8%), 42.06 (C-6%),
50.69 (C-2%), 76.82 (C-1%), 122.15 (C-4), 124.68 (C-4¦), 125.36 (C-2¦+C-6¦), 128.40 (C-3¦+C-5¦),

4814
F. Ferna´ndez et al. / Tetrahedron: Asymmetry 11 (2000) 4805–4815
129.44 (C-2+C-6), 134.10 (C-1), 148.41 (C-1¦), 152.65 (C-3+C-5), 161.65 (C(O)). Anal. calcd for
C23H26N2O6: C, 64.78; H, 6.15; N, 6.57; found: C, 64.56; H, 6.01; N, 6.39.
3.5.2. (1%S,2%R,5%R)-2%-(1-Methyl-1-phenylethyl)-5%-methylcyclohexyl 3,5-dinitrobenzoate 11
Yield 87%. Mp 126–128°C (cyclohexane–ether). [h]2D3 +164.0 (c 1.0, CHCl3). IR (KBr wmax
:
1
3090, 2970, 1717, 1654, 1627, 1549, 1458, 1343, 1280, 1168, 1076, 730, 718, 705 cm−1. H NMR
(CDCl3): 1.06–1.08 (d, 3H, J=7.28 Hz, 5%-CH3), 1.19 and 1.35 (2s, 6H, 8%-(CH3)2), 1.52–1.69 (m,
5H), 1.87–1.93 (m, 1H), 2.10–2.20 (m, 1H), 2.30–2.38 (m, 1H), 5.38–5.46 (d×t, 1H, Jt=10.31 Hz,
Jd=5.08 Hz, 1% -H), 6.57–6.62 (m, 1H, 4¦-H), 6.91–6.96 (m, 2H, 3¦-H+5¦-H), 7.21–7.25 (m, 2H,
ax
2¦-H+6¦-H), 8.44–8.45 (d, 2H, J=2.21 Hz, 2-H+6-H), 9.18–9.19 (t, 1H, Jt=4.25 Hz, Jd=2.18
Hz, 4-H). 13C NMR (CDCl3): 18.54 (C-7%), 21.35 (C-3%), 21.77 (C-5%), 28.21 (C-9%), 31.24 (C-10%),
31.51 (C-4%), 39.01 (C-6%), 39.92 (C-8%), 51.47 (C-2%), 73.98 (C-1%), 122.14 (C-4), 124.77 (C-4¦),
125.47 (C-2¦+C-6¦), 128.40 (C-3¦+C-5¦), 129.45 (C-2+C-6), 134.17 (C-1), 148.42 (C-1¦), 152.39
(C-3+C-5), 161.61 (C(O)). Anal. calcd for C23H26N2O6: C, 64.78; H, 6.15; N, 6.57; found: C,
64.98; H, 6.34; N, 6.70.
3.5.3. (1%S,2%S,5%R)-2%-(1-Methyl-1-phenylethyl)-5%-methylcyclohexyl 3,5-dinitrobenzoate 12
Yield 77%. Mp 139–140°C (cyclohexane–ether). [h]2D3 +116.8 (c 1.0, CHCl3). IR (KBr wmax
:
3112, 2954, 1719, 1654, 1629, 1548, 1497, 1457, 1342, 1276, 1170, 1119, 1072, 730, 718, 705 cm−1.
1H NMR (CDCl3): 0.83–0.86 (d, 3H, J=7.56 Hz, 5%-CH3), 1.02–1.25 (m, 2H), 1.36 and 1.41 (2s,
6H, 8%-(CH3)2), 1.58–1.99 (m, 6H), 5.45 (a.s., 1H, 1% -H), 6.88–6.93 (t, 1H, 4¦-H), 7.08–7.13 (t,
eq
2H, 3¦-H+5%-H), 7.23–7.25 (d, 2H, J=7.48 Hz, 2¦-H+6¦-H), 8.82–8.83 (d, 2H, J=2.12 Hz,
2-H+6-H), 9.17–9.18 (t, 1H, Jt=4.23 Hz, Jd=2.11 Hz, 4-H). 13C NMR (CDCl3): 22.29 (C-3%),
23.26 (C-7%), 26.30 (C-5%), 27.51 (C-9%), 27.88 (C-10%), 35.65 (C-4%), 40.19 (C-6%), 40.34 (C-8%),
52.19 (C-2%), 74.27 (C-1%), 122.47 (C-4), 125.76 (C-4¦), 126.63 (C-2¦+C-6¦), 128.40 (C-3¦+C-5¦),
129.52 (C-2+C-6), 134.80 (C-1), 148.40 (C-1¦), 148.87 (C-3+C-5), 161.71 (C(O)). Anal. calcd for
C23H26N2O6: C, 64.78; H, 6.15; N, 6.57; found: C, 64.93; H, 6.19; N, 6.36.
3.5.4. (1%R,2%R,5%R)-2%-(1-Methyl-1-phenylethyl)-5%-methylcyclohexyl 3,5-dinitrobenzoate 13
Yield 74%. Mp 160–161°C (cyclohexane–ether). [h]2D3 −102.4 (c 1.0, CHCl3). IR (KBr wmax
:
3093, 2981, 2953, 2905, 1721, 1631, 1598, 1542, 1497, 1458, 1382, 1343, 1274, 1172, 1115, 1072,
923, 730, 719, 703 cm−1. 1H NMR (CDCl3): 0.92–0.94 (d, 3H, J=7.38 Hz, 5%-CH3), 1.37 and 1.42
(2s, 6H, 8%-(CH3)2), 1.58–2.07 (m, 8H), 5.40 (a.s., 1H, 1% -H), 6.90–6.95 (t, 1H, 4¦-H), 7.08–7.13
eq
(t, 2H, 3¦-H+5%-H), 7.22–7.25 (d, 2H, 2¦-H+6¦-H), 8.83–8.84 (d, 2H, J=2.18 Hz, 2-H+6-H),
9.18–9.19 (t, 1H, Jt=4.15 Hz, Jd=2.19 Hz, 4-H). 13C NMR (CDCl3): 18.17 (C-3%), 21.16 (C-7%),
26.29 (C-5%), 27.72 (C-9%), 27.91 (C-10%), 32.40 (C-4%), 36.97 (C-6%), 40.34 (C-8%), 52.35 (C-2%),
74.75 (C-1%), 122.47 (C-4), 125.78 (C-4¦), 126.63 (C-2¦+C-6¦), 128.39 (C-3¦+C-5¦), 129.52
(C-2+C-6), 134.73 (C-1), 148.39 (C-1¦), 148.92 (C-3+C-5), 161.74 (C(O)). Anal. calcd for
C23H26N2O6: C, 64.78; H, 6.15; N, 6.57; found: C, 64.95; H, 6.41; N, 6.38.
Acknowledgements
The authors would like to thank the Spanish Ministry of Education and Science (MEC-
DGICYT, PB94-0617) and the Xunta de Galicia (XUGA 20307B94) for financially supporting
this work.

F. Ferna´ndez et al. / Tetrahedron: Asymmetry 11 (2000) 4805–4815
4815
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