Synthesis and absolute configuration at C(8) of 'p-menthane-3,8,9-triol' derived from (-)-isopulegol

Article abstract of DOI:10.1002/hlca.200490233

Two diastereoisomers of the new, potentially insecticidal 'p-menthane-3,8,9-triol' (=(25)- and (2R)- 2-[(1R,2R,4R)-2-hydroxy-4- methylcyclohexyl]propane-1,2-diol; (8S)- and (8R)-1), have been synthesized from (-)-isopulegol by both conventional dihydroxyl

Full text of DOI:10.1002/hlca.200490233

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Helvetica Chimica Acta Vol. 87 (2004)
Synthesis and Absolute Configuration at C(8) of −p-Menthane-3,8,9-triol×
Derived from( )-Isopulegol
by Yoshifumi Yuasa*a) and Yoko Yuasab)
a) Takasago International Corporation, 1-5-1 Nishiyawata, Hiratsuka, Kanagawa, 254-0073, Japan
(phone: 81-(0)463-21-7516; fax: 81-(0)463-21-7413; e-mail: yoshifumi_yuasa@takasago.com)
b) School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, 192-0392,
Tokyo, Japan (e-mail: yuasay@ps.toyaku.ac.jp)
Two diastereoisomers of the new, potentially insecticidal −p-menthane-3,8,9-triol× (ˆ(2S)- and (2R)- 2-
[(1R,2R,4R)-2-hydroxy-4-methylcyclohexyl]propane-1,2-diol; (8S)- and (8R)-1), have been synthesized from
(
)-isopulegol by both conventional dihydroxylation and catalytic Sharpless dihydroxylation (Scheme). The
absolute configuration at C(8) of the corresponding orthoformate adduct (8S)-3a was determined by 1H-NMR
and X-ray crystallographic analysis (Figure).
Introduction. Dihydroxylated monoterpenes are known to exert a repellent effect
on insect pests such as mosquitoes and fleas [1 12]. In particular, −p-menthane-3,8-
diol×, obtained from ( )-citronellal, is being used in this context1). In view of this, we
report the synthesis and absolute configuration of the unknown p-menthane-derived
triol 1 (ˆ2-[(1R,2R,4R)-2-hydroxy-4-methylcyclohexyl]propane-1,2-diol), which was
prepared by classical dihydroxylation or catalytic Sharpless dihydroxylation [13] of
(
)-isopulegol (ˆ(1R,2S,5R)-5-methyl-2-(1-methylethenyl)cyclohexanol).
Results and Discussion. The dihydroxylation of ( )-isopulegol was performed
with formic acid (HCOOH) and 30% aqueous hydrogen peroxide (H2O2), followed by
alkaline hydrolysis [14][15]. H2O2 was slowly added to a solution of ( )-isopulegol and
HCOOH at 508, and the reaction was monitored by gas chromatography (GC). Upon
completion of the reaction, the mixture was hydrolyzed with aqueous 15% NaOH soln.
at 508 to afford a diastereoisomeric mixture of (8S)-1/(8R)-1 in a ratio of 53 :47
(Scheme), as determined by 1H-NMR spectroscopy. The epimeric mixture was purified
by column chromatography (SiO2) to afford (8S)-1 in pure, crystalline form, together
with an enriched, oily mixture of predominantly (8R)-1.
1
By means of 2D-NMR techniques, all H- and 13C-NMR chemical shifts could be
assigned for both epimers (Table 1). To determine the configuration at the C(8)-
atom2), crystalline (8S)-1 was converted to the corresponding acetonide (8S)-2 and
orthoformate (8S)-3, respectively, in 66% and 95% yield (Scheme). Whereas the
absolute configuration could not be derived from NOE studies with (8S)-1 and -2, this
was possible with (8S)-3. From the observed NOEs between HÀC(3) and one of the
HÀC(9) H-atoms (see Scheme), the (8S)-configuration was assigned.
1
)
−p-Menthane-3,8-diol× (systematic name: 2-(1-hydroxy-1-methylethyl)-5-methylcyclohexanol) is a regis-
tered pesticide: U.S. EPA pesticide chemical code 011550 (issued: 5/2000).
Arbitrary atom numbering (see the Scheme).
2
)
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 87 (2004)
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Scheme. Synthesis of the New Menthane-Derived Epimeric Triols 1, and Conversion of (8S)-1 to the
Corresponding Orthoformate 2 and Acetonide 3, Respectively. The structure of (8S)-1 was secured by NOE
measurements (box) and X-ray analysis (see the Figure). Arbitrary atom numbering.
The absolute configuration of (8S)-3 was confirmed by X-ray crystal-structure
analysis (see Figure, and Table 2 in the Exper. Part). In contrast to its precursor (8S)-1,
whose crystal shape was not suited for X-ray analysis, (8S)-3 afforded nice crystals from
MeOH. Attempts to prepare other crystalline derivatives of (8S)-1, e.g., the 4-
nitrobenzoate or the 3-nitrophthalate, were unsuccessful.
Table 1. 1H- and 13C-NMR Chemical Shifts of the Epimers (8R)- and (8S)-1. Recorded at 500/125 MHz in
CDCl3; d in ppm. Arbitrary atom numbering (see the Scheme).
(8R)-1
d(C)
(8S)-1
d(C)
d(H)
d(H)
CH(1)
CH2(2)
CH(3)
CH(4)
CH2(5)
CH2(6)
Me(7)
C(8)
31.23
44.70
72.25
1.4497.715.550
26.23
34.18
21.94
76.53
68.67
19.37
1.39 1.47
1.03 1.11, 1.89 1.97
3.8072.65
1.62 1.7052.0
0.85 0.98, 1.89 1.97
1.62 1.70
31.38
45.12
1.38 1.48
0.96 1.05, 1.89 1,95
3.81
26.33
34.55
21.88
76.32
66.83
24.29
0.96 1.05, 1.75 1.79
0.86 0.94, 1.66 1.72
0.92
0.93
CH2(9)
Me(10)
3.37, 3.53
1.14
3.45, 3.75
1.18

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Helvetica Chimica Acta Vol. 87 (2004)
Although the enriched epimer (8R)-1 had been obtained as a viscous oil, the
corresponding pure orthoformate (8R)-3 could be readily crystallized from the
diastereoisomeric mixture. However, its crystal shape was inconvenient for X-ray
crystallographic analysis. Its configuration, however, was in accord with a significant
NOE between the H-atoms HÀC(4) and HÀC(9) (not shown).
Figure. X-Ray crystal structure (ORTEP plot) of the orthoformate (8S)-3. Arbitrary atom numbering.
We also examined the application of the asymmetric Sharpless dihydroxylation
(AD) on ( )-isopulegol, using the commercial catalyst mixtures −AD-mix-a× and −AD-
mix-b× [16]. However, these reactions were not very successful, with diastereoisomeric
ratios of (8S)-1/(8R)-1 of 59 :41 and 43 :57, respectively.
Experimental Part
General. All reagents and solvents were obtained from commercial sources and used without further
purification. GC: HP-5890 with an FID detector; column: Silicon NB-1 (df ˆ 0.15 mm; 0.25 mm  25 m); carrier
gas: N2 (0.1 MPa); oven temp.: 70 2008 at 48/min, injection temp.: 2508, detector temp.: 2508. M.p.: Yanagimoto
micromelting apparatus; uncorrected. IR Spectra: Nicolet Avatar-360 FT-IR spectrometer; in cmÀ1 1H- and
.
13C-NMR Spectra: Bruker DRX-500 (500/125 MHz) apparatus, in CDCl3; chemical shifts d in ppm rel. to Me4Si
(ˆ0ppm) as internal standard, coupling constants J in Hz. EI-MS: Hitachi M-80A mass spectrometer, at 70eV;
in m/z.
(2R)- and (2S)-2-[(1R,2R,4R)-2-hydroxy-4-methylcyclohexyl]propane-1,2-diol ((8R)- and (8S)-1)2). To a
mixture of ( )-isopulegol (65.5 g, 424 mmol) and HCOOH (43.3 g, 943 mmol) was added 30% aq. H2O2 (65 g,
573 mmol) dropwise over 4 h at 508, and the mixture was stirred for another 4 h at this temp. A 15% aq. NaOH
soln. (260ml) was added dropwise at 50 8, and the mixture was stirred for 1 h at this temp. Then, AcOEt (200 ml)
was added, and the org. phase was washed successively with 10% aq. Na2SO3 soln. (100 ml) and brine (100 ml),
dried (MgSO4), and concentrated in vacuo to give a crude oil (66.63 g), which was distilled under reduced
pressure to afford a 53 :47 mixture of (8S)-1 and (8R)-1 (49.2 g), boiling at 140 145 8 (0.08 torr). The distillate

Helvetica Chimica Acta Vol. 87 (2004)
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was further purified by column chromatography (CC; SiO2, hexane/AcOEt 1:2) to afford pure (8S)-1 as a solid
(18.1 g, 23%), and impure (8R)-1 (25.2 g, 32%) as an oil containing the (8S)-epimer.
Data for (8S)-1. Crystalline solid. M.p. 65.0 65.5 8. [a]2D2 ˆ ‡16.21 (c ˆ 1.11, CHCl3). IR (CHCl3): 3402,
3020, 2955, 2925, 1521, 1452, 1423. 1H-NMR (CDCl3): 0.86 0.94 (m, 1 H); 0.92 (d, J ˆ 6.5, 3 H); 0.96 1.05 (m,
2 H); 1.18 (s, 3 H); 1.38 1.48 (m, 1 H); 1.49 1.55 (m, 1 H); 1.66 1.72 (m, 1 H); 1.75 1.79 (m, 1 H); 1.89 1.95
(m, 1 H); 3.45 (d, J ˆ 11.1, 1 H); 3.75 (d, J ˆ 11.1, 1 H); 3.81 (dt, J ˆ 4.3, 10.6, 1 H). 13C-NMR (CDCl3): 21.88,
24.29 (2 Me); 26.33 (CH2); 31.38 (CH); 34.55, 45.12 (2 CH2); 52.00 (CH); 66.83 (CH2); 72.65 (CH); 76.32 (Cq).
‡
EI-MS: 157 ([M À 31] ), 139, 123, 109, 108, 96, 95, 81, 75, 71, 54, 43. Anal. calc. for C10H20O3: C 63.80, H 10.71;
found: C 63.82, H 10.72.
Data for (8R)-1. Viscous oil. 1H-NMR (CDCl3): 0.85 0.98 (m, 1 H); 0.93 (d, J ˆ 6.5, 3 H); 1.03 1.11 (m,
1 H); 1.14 (s, 3 H); 1.39 1.47 (m, 1 H); 1.62 1.70( m, 2 H); 1.89 1.97 (m, 2 H); 3.37 (d, J ˆ 11.2, 1 H); 3.53 (d,
J ˆ 11.2, 1 H); 3.80( q, J ˆ 4.3, 10.8, 1 H). 13C-NMR (CDCl3): 19.37, 21.94 (2 Me); 26.23 (CH2); 31.23 (CH);
‡
34.18, 44.70(2 CH 2); 47.75 (CH); 68.67 (CH2); 72.25 (CH); 76.53 (Cq). EI-MS: 157 ([M À 31] ), 139, 123, 109,
108, 96, 95, 81, 75, 71, 54, 43.
(1R,2R,5R)-5-Methyl-2-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]cyclohexan-1-ol ((8S)-2). Compound (8S)-
1 (1.0g, 5.3 mmol), 4-methylbenzenesulfonic acid (TsOH, 20mg), and 2,2-dimethoxypropane (5 ml) in CH 2Cl2
(20ml) were stirred at r.t. for 1 h. The solvent was evaporated, and the residue was purified by CC (SiO 2
;
hexane/AcOEt 4 :1): 0.8 g (66%). Oil. [a]2D2 ˆ À10.89 (c ˆ 1.56, CHCl3). IR (neat): 3447, 2983, 2922, 1455, 1375.
1H-NMR (CDCl3): 0.84 0.98 (m, 2 H); 0.92 (d, J ˆ 6.5, 3 H); 0.99 (q, J ˆ 12.3, 23.1, 1 H); 1.30( s, 3 H); 1.38
1.47 (m, 1 H); 1.47 (s, 3 H); 1.54 1.58 (m, 1 H); 1.65 1.67 (m, 1 H); 1.80 1.83 ( m, 1 H); 1.94 (m, 1 H); 3.57 (m,
1 H); 3.67 (br. s, 1 H); 3.74 (d, J ˆ 8.7, 1 H); 3.94 (d, J ˆ 8.7, 1 H). 13C-NMR (CDCl3): 21.98, 23.81 (2 Me); 26.37
(CH2); 26.40, 28.13 (2 Me); 31.19 (CH); 34.22, 43.97 (2 CH2); 51.42, 70.84 (2 CH); 72.37 (CH2); 84.83, 108.61
‡
(2 Cq). EI-MS: 213 ([M À 15] ), 195, 170, 153, 135, 115, 95, 81, 72, 57, 43.
(1R,2R,5R)-5-Methyl-2-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]cyclohexan-1-ol ((8R)-2). Obtained in
analogy to (8S)-2 from an epimeric mixture of 1. Oil. [a]2D1 ˆ À13.88 (c ˆ 0.36, CHCl3). IR (neat): 3518,
2984, 2926, 2870, 1454, 1378. 1H-NMR (CDCl3): 0.87 1.07 (m, 3 H); 0.93 (d, J ˆ 6.5, 3 H); 0.99 (q, J ˆ 12.3, 23.1,
1 H); 1.27 (s, 3 H); 1.36 (s, 3 H); 1.45 (s, 3 H); 1.39 1.51 (m, 3 H); 1.61 1.67 (m, 1 H); 2.00 2.05 (m, 1 H); 3.71
(dt, J ˆ 4.5, 10.3, 1 H); 3.78 (d, J ˆ 8.6, 1 H); 3.82 (d, J ˆ 8.6, 1 H); 4.58 (s, 1 H). 13C-NMR (CDCl3): 20.00, 22.00,
26.56 (3 Me); 27.13 (CH2); 27.62 (Me); 30.86 (CH); 34.16, 43.50 (2 CH2); 51.90, 71.05 (2 CH); 74.85 (CH2);
‡
85.13, 109.97 (2 Cq). EI-MS: 213 ([M À 15] ), 195, 170, 153, 135, 115, 95, 81, 72, 57, 43.
(5S,5aR,8R,9aR)-4,5,5a,6,7,8,9,9a-Octahydro-5,8-dimethyl-2,5-epoxy-2H-[1,3-]benzodioxepine ((8S)-3).
Compound (8S)-1 (1.0g, 5.3 mmol), TsOH (20mg), and trimethyl orthoformate (1.12 g, 10.6 mmol) in CH 2Cl2
(30ml) were stirred at r.t. for 30min. The solvent was evaporated, and the residue was purified by CC (SiO
;
2
hexane/AcOEt 4 :1) to afford a solid (1.0g, 95%), which was recrystallized from MeOH. M.p. 75 76 8 (MeOH).
[a]2D1 ˆ À66.03 (c ˆ 1.06, CHCl3). IR (CHCl3): 3021, 2894, 1521, 14577, 1385. 1H-NMR (CDCl3): 0.88 (d, J ˆ 6.6, 3
H); 0.88 0.98 (m, 2 H); 1.0 4 (q, J ˆ 11.7, 23.5, 1 H); 1.27 (s, 3 H); 1.43 1.51 (m, 1 H); 1.52 1.58 (m, 1 H); 1.59
1.63 (m, 1 H); 1.68 1.70( m, 1 H); 1.78 1.81 (m, 1 H); 3.30( dd, J ˆ 1.3, 7.3, 1 H); 3.60( dt, J ˆ 3.8, 9.3, 1 H); 3.95
(d, J ˆ 7.4, 1 H); 5.95 (s, 1 H). 13C-NMR (CDCl3): 19.11, 22.10(2 Me); 24.81 (CH 2); 31.33 (CH); 39.47 (CH2);
‡
49.21 (CH); 69.70(CH 2); 71.83 (CH); 80.51 (Cq); 112.21 (CH). EI-MS: 197 ([M À 1] ), 168, 152, 137, 123, 109,
108, 96, 95, 93, 81, 67, 55, 43, 29. Anal. calc. for C11H18O3: C 66.64, H 9.15; found: C 66.63, H 9.15.
(5R,5aR,8R,9aR)-4,5,5a,6,7,8,9,9a-Octahydro-5,8-dimethyl-2,5-epoxy-2H-[1,3-]benzodioxepine ((8R)-3).
Obtained in analogy to (8S)-3 from an epimeric mixture of 1. Crystalline solid. M.p. 125 1268 (Et2O).
[a]2D1 ˆ ‡38.82 (c ˆ 1.05, CHCl3). IR (CHCl3): 3021, 2930, 2895, 1521, 1478, 1445, 1385. 1H-NMR (CDCl3): 0.87
(d, J ˆ 6.6, 3 H); 0.78 0.89 (m, 1 H); 0 .97 (q, J ˆ 11.8, 23.7, 1 H); 1.24 1.34 (m, 1 H); 1.30( s, 3 H); 1.41 1.51
(m, 1 H); 1.60 1.69 ( m, 3 H); 1.88 1.93 (m, 1 H); 3.26 (d, J ˆ 6.8, 1 H); 3.27 (dt, J ˆ 3.6, 10.1, 1 H); 3.64 (d, J ˆ
6.7, 1 H); 6.03 (s, 1 H). 13C-NMR (CDCl3): 16.03, 21.97 (2 Me); 26.38 (CH2); 31.21 (CH); 34.68, 39.90(2 CH 2),
‡
52.04, 68.94 (2 CH); 76.64 (CH2); 79.16 (Cq), 111.54 (CH). EI-MS: 197 ([M À 1] ); 168, 152, 137, 123, 109, 108,
103, 95, 93, 81 (100), 67, 55, 43, 29. Anal. calc. for C11H18O3: C 66.64, H 9.15; found: C 66.6, H 9.13.
X-Ray Crystal-Structure Analysis. The crystal data for (8S)-3 are collected in Table 2, and a representation
can be found in the Figure. All diagrams and calculations were performed with maXus on a Bruker Nonius
apparatus (Delft & MacScience, Japan).

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Helvetica Chimica Acta Vol. 87 (2004)
Table 2. Crystallographic Data of (8S)-3a)
Crystallized from
MeOH
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
C11H18O3
198.262
Colorless, prism
0.50 Â 0.25 Â 0.25
296
]
Crystal system
Space group
Monoclinic
P 21
Z
2
Reflections for cell determination
1070
2q-Range [8]
6.28 54.26
Unit-cell parameters:
a [ä]
b [ä]
c [ä]
a [8]
6.504(2)
7.056(4)
11.832(5)
90.00
b [8]
94.10(2)
90.00
541.6(4)
1.216
0.087
54.26
g [8]
V [ä3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
2qmax [8]
]
Total reflections
1070
measured
Independent reflections
Reflections used (I > 2s(I))
1070
931
Parameters refined
130
Final R
0.0452
wR
0.1134
Extinction coefficient
0.142(19)
0.000
Dmax/s
D/1 (max; min) [e äÀ3
Flack parameter
]
0.141; À 0.150
À 1 (2)
a) Crystallographic data, excluding structure factors, for the structure of (8S)-3 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-215546. Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
‡ 44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk).
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Received July 8, 2004