Stereoselective synthesis of cis-p-menth-8-ene-1,7-diol, cis-p-menthane-1,7-diol, and cis-p-menthane-1,7,8-triol

Article abstract of DOI:10.1002/chem.200401147

The natural products cis-p-mentharie-1,7-diol (cis-IV), cis-p-menth-8-ene-1,7-diol (cis-I) and cis-p-menthane-1,7,8-triol (cis-II) are obtained starting from the corresponding cis-cyanohydrins, cis-2 and cis-7, respectively, by chemical transformation of

Full text of DOI:10.1002/chem.200401147

FULL PAPER
Stereoselective Synthesis of cis-p-Menth-8-ene-1,7-diol, cis-p-Menthane-1,7-
diol, and cis-p-Menthane-1,7,8-triol**
Christoph Kobler and Franz Effenberger*[a]
Abstract: The natural products cis-p-
menthane-1,7-diol (cis-IV), cis-p-
the very high cis-selectivity (ꢀ 96%)
of the MeHNL-catalyzed HCN addi-
tion to 4-alkylcyclohexanones. From 4-
isopropylcyclohexanone (1) the cyano-
hydrin cis-2 and from 4-(1-methylvi-
nyl)cyclohexanone (6) the cyanohydrin
cis-7 result almost quantitatively. Re-
gioselective hydroxylation of cis-I af-
fords the triol cis-II. X-ray crystal
structure determinations of the final
products confirm their cis-configura-
tion.
menth-8-ene-1,7-diol (cis-I) and cis-p-
menthane-1,7,8-triol (cis-II) are ob-
tained starting from the corresponding
cis-cyanohydrins, cis-2 and cis-7, re-
spectively, by chemical transformation
of the cyano into the hydroxymethyl
group. The key step of the synthesis is
Keywords: cyanohydrins · hydroxy-
nitrile lyase · natural products ·
total synthesis
Introduction
The acetonide of cis-I, the farnesyl protein transferase in-
hibitor XR3054 (cis-III), is a promising antitumor candidate
and, therefore, stereoselective chemical syntheses have been
developed.[4] Carman and Garner[4a] obtained II as a side
product in 10–20% yield after oxymercuration and reduc-
tion of (S)-(À)-perillylalcohol. A straightforward synthesis
of both I and III was achieved by Donaldson et al.[4b] start-
ing from (S)-(À)-perillylalcohol; Sharpless epoxidation and
subsequent hydrogenation with LiAlH4 gave I, which easily
can be treated with acetone to give III. The only known syn-
thesis of a cis/trans-mixture of triol II was published in 1993,
starting from d-terpineol.[5] The direct oxidation of d-terpi-
neol with alkaline KMnO4 gives only trans-p-menthane-1,8-
diol.
The monoterpene cis-p-menthane-1,7,8-triol (cis-II) was first
isolated, but not completely characterized, in 1992 by
Konda et al., from the roots of Cynanchum hancockianum
in addition to the antitumor active Antofin.[1] In 1998 the
isolation and characterization of both the cis- and the trans-
isomer of p-menthane-1,7,8-triol (II) from the methanolic
extract of Foeniculum vulgare was achieved by Ishikawa
et al.[2] The dehydration product of cis-II, cis-p-menth-8-ene-
1,7-diol (cis-I) was isolated from urine of rats after treat-
ment with b-Myrcen.[3]
A structural analogue of the monoterpenes I–III is the
monoterpenediol IV, which was obtained as a byproduct in
the stereoselective hydroxylation of cis/trans-p-menthane by
Pseudomonas mandocina-SF.[6]
The natural products discussed so far (I, II, and IV) are 4-
alkyl-1-hydroxymethyl cyclohexanols, all of which can be
retro-synthetically derived from cyanohydrins of the corre-
sponding 4-alkylcyclohexanones. Recently, we have publish-
ed hydroxynitrile lyase (HNL)-catalyzed additions of HCN
to 4-substituated cyclohexanones.[7] In nonenzymatic-cata-
lyzed chemical additions the cis/trans-ratio of the HCN addi-
tion to 4-alkylcyclohexanones is roughly 13:87.[7b] Therefore,
chemical syntheses of compounds I–IV via the correspond-
ing cyanohydrins, all with cis-configuration, would be very
unfavourable, because of the very high trans-ratio. In our
methodically oriented investigations of applications of hy-
[a] Dr. C. Kobler, Prof. Dr. F. Effenberger
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax : (+49)711-685-4269
E-mail: franz.effenberger@po.uni-stuttgart.de
[**] Enzyme-catalyzed Reactions, Part 51. For Part 50 see: C. Kobler, F.
Effenberger, Tetrahedron: Asymmetry 2004, 15, 3731–3742.
Chem. Eur. J. 2005, 11, 2783 – 2787
DOI: 10.1002/chem.200401147
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2783

droxynitrile lyases (HNL) we observed very high cis/trans-
selectivity in the HNL-catalyzed cyanohydrin formations of
4-alkylcyclohexanones.[7] We obtained trans-selectivity with
(R)-PaHNL from almonds and cis-selectivity with (S)-
MeHNL from cassava as catalysts.[7]
Since the transformation of a cyano function into a hy-
droxymethyl group is well known, the stereoselective syn-
thesis of the natural products I, II, and IV starting from cis-
4-alkylcyclohexanone cyanohydrins should be possible.
Figure 1. ORTEP view of cis-(1-hydroxy-4-isopropylcyclohexyl)-methyl-
4-nitrobenzoate (cis-5).
tion not only for cis-5, but also for cis-IV, cis-3, and cis-2
Results and Discussion
(Scheme 1).[9]
Synthesis of cis-p-methane-1,7-diol (cis-IV): In Scheme 1
the synthesis of cis-IV, starting from 4-isopropylcyclohexa-
none (1) is illustrated.
Syntheses of cis-p-menth-8-ene-1,7-diol (cis-I) and cis-p-
menthane-1,7,8-triol (cis-II): In Scheme 2 the synthesis of
cis-I and cis-II is summarized.
Scheme 1. Synthesis of cis-p-menthane-1,7-diol (cis-IV) from 4-isopropyl-
cyclohexanone (1).
Scheme 2. Synthesis of cis-p-menth-8-ene-1,7-diol (cis-I) and cis-p-men-
thane-1,7,8-triol (cis-II) from 4-isopropenylcyclohexanone (6).
The MeHNL-catalyzed addition of HCN to 1 was per-
formed under the optimized conditions described earlier.[7b]
The cyanohydrin 2 was obtained almost quantitatively in a
cis/trans-ratio of 96:4. After recrystallization from diisoprop-
yl ether (iPr2O) pure cis-2 results as colorless needles. By
dissolving cis-2 in a saturated solution of HCl in absolute
ethanol and heating for 16 h in a glass autoclave at 958C,
the corresponding imidate hydrochloride separates as amor-
phous solid, which was not isolated. Workup in ice water re-
sulted in the ester cis-3, which was isolated and purified by
extraction with diethyl ether and vacuum distillation. The
hydrogenation of cis-3 with LiAlH4 was performed in THF
at room temperature. The final product, cis-IV, was obtained
as a colorless powder and after recrystallization from iPr2O
gave colorless, rhombic crystals with a melting point of
898C.
4-(1-Methylvinyl)cyclohexanone (4-isopropenylcyclohexa-
none) (6) was prepared as described in the literature.[8] The
MeHNL-catalyzed addition of HCN to 6 was carried out as
described earlier.[7b] The cyanohydrin 7 was obtained in
99% yield with a cis/trans-ratio of 96:4. After recrystalliza-
tion from n-hexane/methylenechloride pure cis-7 was ob-
tained as colorless, cuboid crystals.[7a,9] Before the reduction
of the nitrile function with DIBAL-H, the hydroxyl group of
cis-7 was protected with a trimethylsilyl group to give cis-
8.[10] The reduction of cis-8 with DIBAL-H was performed
in n-hexane at À458C. The resulting “aminoalane” as an in-
termediate was transformed to the aldehyde cis-9 in a two-
phase system (CH2Cl2/H2O) by careful treatment with dilut-
ed sulfuric acid. The hydrogenation of the O-protected alde-
hyde cis-9 to the corresponding hydroxymethyl derivative
cis-10 was performed in absolute ethanol at 08C.[11] Depro-
tection of cis-10 with TBAF in THF yielded cis-I, the pre-
cursor of the farnesylprotein transferase inhibitor XR3054.[4]
Compound cis-I was recrystallized from iPr2O to give color-
less crystals suitable for X-ray structure analysis.[9]
Since the crystals of cis-IV were not suitable for an X-ray
structure determination, it was transformed to the p-nitro-
benzoyl derivative cis-5 by reaction with p-nitrobenzoyl
chloride in pyridine (Scheme 1). The X-ray structure of cis-5
in Figure 1 demonstrates unambiguously the cis-configura-
2784
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www.chemeurj.org
Chem. Eur. J. 2005, 11, 2783 – 2787

Natural Products
FULL PAPER
The X-ray structure of the synthesized compound I in
Figure 2 clearly demonstrates the cis-configuration of the
diol I, which is also evidence for the cis-configurations of
compounds 7, 8, 9, and 10.
none (6) the MeHNL-catalyzed HCN addition results in the
almost quantitative formation of the cis-cyanohydrin, cis-7.
The stereoselective transformation of the cyano group of
cis-7 to the hydroxymethyl group in the final product cis-p-
menth-8-ene-1,7-diol (cis-I) can be performed easily by
known chemical procedures. Cis-p-menthane-1,7,8-triol (cis-
II) is obtained by regioselective hydroxylation of cis-I. The
cis-configuration of all synthesized natural products, that is
cis-I, cis-II, and cis-IV, was assured by X-ray crystal struc-
ture analysis. The farnesyl transferase inhibitor XR3054 (cis-
III) is now conveniently available through the novel synthe-
sis of cis-I.
Experimental Section
General: Melting points were determined on a Bꢀchi SMP-20 and are
uncorrected. Unless otherwise stated, 1H and 13C NMR spectra were re-
corded on a Bruker AC 250 F (250 MHz) and ARX 500 (500 MHz) in
CDCl3 with TMS as internal standard. 13C NMR multiplicities were deter-
mined with DEPT experiments. Chromatography was performed using
silica gel, grain size 0.040–0.063 mm (Fluka). Cis/trans-ratios: GC separa-
tions were conducted by using: 1) capillary glass columns (20 m) with OV
1701, carrier gas 0.4–0.6 bar hydrogen; 2) a Chiraldex B-TA and G-TA
column (30 mꢃ0.32 mm), carrier gas hydrogen. Details of the X-ray crys-
tallographic measurements are given in Table 1. 4-Isopropylcyclohexa-
none (1) is commercially available. 4-(1-Methylvinyl)cyclohexanone (4-
isopropenylcyclohexanone; 6) was prepared according to known litera-
ture procedures.[8] All solvents were dried and distilled. All yields are not
optimized.
Figure 2. ORTEP view of cis-p-menth-8-ene-1,7-diol (cis-I).
The regioselective hydroxylation of the olefinic double
bond of cis-I was performed with mercury(ii) acetate and
subsequent demercuration with an alkaline sodium borohy-
dride solution.[12] The natural product cis-II was recrystal-
lized from a mixture of CHCl3/iPr2O/EtOH as colorless,
crystalline needles. The X-ray structure analysis of these
crystals proves the cis-configuration of II unambiguously, as
shown in Figure 3.
cis-1-Hydroxy-4-isopropylcyclohexanecarbonitrile (cis-2):[7b]
A solution
of (S)-MeHNL (7990 U, 2.88 mL, Pw =40.8 mgmLÀ1) was added to nitro-
cellulose (2.20 g) [Pro-Celloidin (Fluka): 1 g (dry), soaked in a 0.02m
sodium citrate buffer (50 mL), pH 3.3, for 0.5 h; the buffer was decanted
and nitrocellulose centrifuged (5700ꢃg for 30 min) and dried under high
vacuum for 5 h], followed after 15 min by addition of diisopropyl ether
(75 mL), compound
1
(2.31 g, 16.47 mmol) and anhydrous HCN[13]
(2.5 mL, 63.6 mmol). After stirring at room temperature for 5 h, the sup-
port was removed by filtration and was washed twice with diethyl ether;
the combined filtrates were concentrated under vacuum. The white resi-
due (2.68 g, 97%, cis/trans-ratio=96:4) was recrystallized from iPr2O to
give colorless crystals of pure cis-2. M.p. 528C; 1H NMR (250 MHz,
3
CDCl3): d=0.87 (d, J=6.8 Hz, 6H; CH(CH3)2), 1.04–1.18 (m, 1H; C4H),
1.33–1.51 (m, 3H; C3Hax, C5Hax, CH(CH3)2), 1.56–1.64 (m, 2H; C3Heq
,
C5Heq),
1.81
(ddd,
3J(C2Hax,C3Heq)=4.2 Hz,
2J(C2Hax,C2Heq)ꢁ
3J(C2Hax,C3Hax)=13.2 Hz, 2H; C2Hax, C6Hax), 2.07–2.14 (m, 2H; C2Heq
,
C6Heq), 3.57 ppm (brs, 1H; OH); 13C NMR (62.9 MHz, CDCl3): d=19.73
(CH(CH3)2), 23.24 (C3H2, C5H2), 32.03 (CH(CH3)2), 36.50 (C2H2, C6H2),
42.27 (C4H), 66.87 (C1), 123.04 ppm (CN).
Figure 3. ORTEP view of cis-p-menthane-1,7,8-triol (cis-II).
cis-Ethyl-1-hydroxy-4-isopropylcyclohexanecarboxylate (cis-3):[7b] A so-
lution of cis-2 (2.47 g, 14.77 mmol) in ethanolic HCl (30 mL) was stirred
at 958C for 18 h in a pressure vessel. To open the vessel, it was cooled
with ice water. The reaction mixture was diluted with diethyl ether
(50 mL), and ice water was added until the white precipitate dissolved.
The layers were separated, and the aqueous layer was extracted three
times with diethyl ether. The combined organic layers were washed with
saturated NaHCO3 solution, dried (Na2SO4), and concentrated. The resi-
due was distilled under vacuum to give cis-3 (2.09 g, 66%) as a colorless
oil. B.p. 718C, 0.01 Torr; IR (neat): n˜max =2954, 2937, 1724, 1367, 1255,
Conclusion
The very high cis-selectivity (ꢀ96%) of MeHNL-catalyzed
HCN additions to 4-alkylcyclohexanones, resulting in the
corresponding cis-cyanohydrins, is an excellent starting basis
for the stereoselective synthesis of cis-4-alkly-hydroxyme-
thylcyclohexanols, which are interesting monoterpenes in
natural products. Starting from 4-isopropylcyclohexanone
(1) the corresponding cis-cyanohydrin (cis-2) is obtained
almost quantitatively. The chemical transformations of cis-2
to the final product, cis-p-methane-1,7-diol (cis-IV) is
straightforward and can be performed without problems in
only two steps. Starting from 4-(1-methylvinyl)cyclohexa-
1223, 1152, 1094, 1052, 1022, 987 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=
3
3
0.89 (d, J=6.9 Hz, 6H; CH(CH3)2), 1.07–1.17 (m, 1H; C4H), 1.29 (t, J=
7.1 Hz, 3H; CH2CH3), 1.38–1.49 (m, 3H; C3Hax, C5Hax, CH(CH3)2), 1.58–
1.61 (m, 2H; C3Heq, C5Heq), 1.69–1.81 (m, 4H; C2Hax, C6Hax, C2Heq
,
C6Heq), 2.89 (brs, 1H; OH), 4.22 ppm (q, 3J=7.1 Hz, 2H; CH2CH3);
13C NMR (62.9 MHz, CDCl3): d=14.24 (CH2CH3), 19.84 (CH(CH3)2),
Chem. Eur. J. 2005, 11, 2783 – 2787
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2785

F. Effenberger and C. Kobler
Table 1. X-ray crystal data collection and refinement for cis-5, cis-I, and cis-II.
(CH3)2), 0.99–1.16 (m, 1H; C4H),
1.31–1.55 (m, 5H; C2Hax, C6Hax,
C3Hax, C5Hax, CH(CH3)2), 1.60–1.64
(m, 2H; C3Heq, C5Heq), 1.72 (brs, 1H;
cis-5
cis-I
cis-II
formula
Mr
crystal system
space group
a [ꢄ]
b [ꢄ]
c [ꢄ]
a [8]
C17H23NO5
321.37
monoclinic
P21/n
14.9154(8)
5.6903(4)
20.9257(17)
90
C10H18O2
170.25
monoclinic
P21/c
16.201(4)
17.239(5)
11.766(5)
90
C10H20O3
188.27
monoclinic
P21/n
6.3415(3)
13.8270(7)
12.1563(4)
90
99.665(4)
90
1050.78(8)
4
1.190
416
0.694
OH), 1.80–1.84 (m, 2H; C2Heq
,
C6Heq), 4.42 (s, 2H; CH2O), 8.21–
8.32 ppm (m, 4H; HPh); 13C NMR
(62.9 MHz, CDCl3): d=19.84 (CH-
(CH3)2), 24.08 (C3H2, C5H2), 32.64
(CH(CH3)2), 34.13 (C2H2, C6H2),
43.67 (C4H), 70.44 (C1), 73.88
(CH2O), 123.61, 130.78, 135.46, 150.62
(CPh), 164.72 ppm (OCO); elemental
analysis calcd (%) for C17H23NO5
b [8]
107.691(5)
90
1692.0(2)
4
1.262
688
107.67(2)
90
3132.8(18)
12
1.083
1128
g [8]
V [ꢄ3]
Z
(321.37):
C 63.54, H 7.21, N 4.36;
1calcd [mgmÀ3
F(000)
]
found: C 63.46, H 7.06, N 4.37.
cis-1-Hydroxy-4-isopropenylcyclohex-
anecarbonitrile (cis-7):[7b] Reaction
conditions and workup as for cis-2.
(S)-MeHNL (10000 U, 3.61 mL, Pw =
40.8 mgmLÀ1), nitrocellulose (2.70 g),
diisopropyl ether (125 mL), com-
pound 6 (4.11 g, 29.73 mmol), and an-
m [mmÀ1
]
0.765
0.073
q range [8]
3.22–64.99
1.77–22.49
4.88–67.95
data collection[a]
reflections collected/unique
data/restraints/parameters
goodness-of-fit on F2
final R indices [I>2s(I)]
R1
3818/2788
2788/0/213
1.068
4263/4096
4096/0/332
1.047
2607/1857
1857/0/131
1.070
hydrous
HCN[13]
(4.5 mL,
0.0801
0.2089
0.1225
0.2157
0.0539
0.1501
114.4 mmol), reaction time 5 h. The
white residue (4.71 g, 96%, cis/trans-
ratio=96:4) was recrystallized from
n-hexane/CH2Cl2 to afford cis-7 as
colorless crystals.[9] M.p. 658C; IR
(neat): n˜max =3420, 2939, 1645, 1434,
1399, 1373, 1230, 1140, 1060, 972, 932,
wR2
R indices (all data)
R1
0.1027
0.2379
0.0639
0.1642
0.192/À0.217
wR2
0.2630
0.416/À0.357
0.2545
0.220/À0.172
largest diff. peak/hole [eꢄÀ3
]
[a] T=293 K, Nicolet P3 diffractometer, MoKa (l=0.71073 ꢄ) or Siemens P4 diffractometer, CuKa (l=
1.54178 ꢄ) radiation.
893 cmÀ1
;
1H NMR
(500 MHz,
CDCl3): d=1.60–1.68 (m, 4H; C3Hax,
C5Hax, C3Heq, C5Heq), 1.72 (s, 3H;
24.31 (C3H2, C5H2), 32.82 (CH(CH3)2), 34.90 (C2H2, C6H2), 43.17 (C4H),
61.71 (CH2CH3), 73.36 (C1), 177.84 ppm (COO); elemental analysis calcd
(%) for C12H22O3 (214.30): C 67.26, H 10.35; found: C 67.18, H 10.13.
CH3), 1.85–1.99 (m, 3H; C2Hax, C6Hax, C4H), 2.15–2.18 (m, 2H; C2Heq
,
C6Heq), 2.86 (brs, 1H; OH), 4.71–4.74 ppm (m, 2H;=CH2); 13C NMR
(125.8 MHz, CDCl3): d=20.89 (CH3), 25.00 (C3H2, C5H2), 36.49 (C2H2,
C6H2), 43.26 (C4H), 66.59 (C1), 109.44 (=CH2), 122.89 (CN), 148.76 ppm
(C=); elemental analysis calcd (%) for C10H15NO (165.24): C 72.69, H
9.15, N 8.48; found: C 72.65, H 9.05, N 8.55.
cis-1-(Hydroxymethyl)-4-isopropylcyclohexane-1-ol (cis-IV): A solution
of cis-3 (1.0 g, 4.67 mmol) in THF (10 mL) at 08C was added dropwise to
a stirred suspension of LiAlH4 (231.0 mg, 6.07 mmol) in THF (5 mL).
After stirring for 15 min, the reaction mixture was allowed to warm
slowly to room temperature and stirred for a further 1 h. After cooling
down to 08C, the mixture was hydrolyzed with brine (5 mL) and extract-
ed with CH2Cl2 (3ꢃ10 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The pure white resi-
due recrystallized from iPr2O to afford cis-IV (0.71 g, 88%) as colorless,
rhombic crystals. M.p. 898C; IR (neat): n˜max =3276, 2936, 2865, 1228,
cis-4-Isopropenyl-1-trimethylsilyloxycyclohexanecarbonitrile
(cis-8):[10]
Chlorotrimethylsilane was added (3.11 g, 28.63 mmol) to a stirred so-
lution of imidazole (3.43 g, 49.62 mmol) in DMF (65 mL) at 08C under
an atmosphere of nitrogen. After stirring for 15 min, a solution of cis-7
(4.10 g, 24.81 mmol) in DMF (15 mL) was added dropwise and allowed
to warm slowly to room temperature and stirred for a further 1 h. Then
water (125 mL) was added, and the resulting mixture was extracted with
diethyl ether (3ꢃ25 mL). The combined extracts were dried (Na2SO4)
and concentrated under reduced pressure. The crude product was puri-
fied by chromatography on SiO2 using a short column eluting with petro-
leum ether/EtOAc (7:1) (Rf =0.60) to afford cis-8 (5.14 g, 87%) as color-
less oil. IR (neat): n˜max =1645 (w), 1252, 1079, 1054, 1030, 889, 840,
1175, 1074, 1050, 1025, 992, 976, 900, 739, 671, 643 cmÀ1
;
1H NMR
3
(500 MHz, CDCl3): d=0.88 (d, J=6.8 Hz, 6H; CH(CH3)2), 0.99–1.06 (m,
1H; C4H), 1.21–1.37 (m, 4H; C2Hax, C6Hax, C3Hax, C5Hax), 1.43–1.50 (m,
1H; CH(CH3)2), 1.56–1.59 (m, 2H; C3Heq, C5Heq), 1.72–1.75 (m, 2H;
C2Heq, C6Heq), 2.28 (brs, 1H; OH), 2.75 (t, 3J=5.9 Hz, 1H; CH2OH),
3.39 ppm (d, 3J=5.6 Hz, 2H; CH2OH); 13C NMR (125.8 MHz, CDCl3):
d=20.01 (CH(CH3)2), 24.47 (C3H2, C5H2), 32.03 (CH(CH3)2), 33.84
(C2H2, C6H2), 44.09 (C4H), 71.57 (C1), 71.86 ppm (CH2OH); elemental
analysis calcd (%) for C10H20O2 (172.27): C 69.72, H 11.70; found: C
69.87, H 11.71.
754 cmÀ1 1H NMR (250 MHz, CDCl3): d=0.26 (Si(CH3)3), 1.56–1.64 (m,
;
4H; C3Hax, C5Hax, C3Heq, C5Heq), 1.71 (s, 3H; CH3), 1.72–1.99 (m, 3H;
C2Hax, C6Hax, C4H), 2.06–2.15 (m, 2H; C2Heq, C6Heq), 4.70–4.73 ppm (m,
2H; =CH2); 13C NMR (62.9 MHz, CDCl3): d=1.18 (Si(CH3)3), 20.80
(CH3), 25.16 (C3H2, C5H2), 37.96 (C2H2, C6H2), 43.19 (C4H), 67.39 (C1),
109.17 (=CH2), 122.86 (CN), 149.00 ppm (C=); elemental analysis calcd
(%) for C13H23NOSi (237.42): C 65.77, H 9.76, N 5.90; found: C 65.76, H
9.74, N 5.70.
cis-(1-Hydroxy-4-isopropylcyclohexyl)methyl-4-nitrobenzoate (cis-5):[7b]
DMAP (15 mg) and p-nitrobenzoyl chloride (0.23 g, 1.24 mmol) were
added to a vigorously stirred solution of cis-IV (0.18 g, 1.04 mmol) in pyr-
idine (4 mL), and the reaction mixture was stirred for 14 d at room tem-
perature. Then water (5 mL) was added, the layers were separated, and
the aqueous layer was extracted with diethyl ether (3ꢃ20 mL). The com-
bined extracts were washed with diluted HCl until neutral, dried
(Na2SO4), and concentrated. The residue was subjected to chromatogra-
phy on SiO2 with petroleum ether/EtOAc (7:1) and recrystallized from
iPr2O to afford pure cis-5 (0.31 g, 92%) as colorless crystals.[9] M.p.
1038C; 1H NMR (250 MHz, CDCl3): d=0.90 (d, 3J=6.8 Hz, 6H; CH-
cis-4-Isopropenyl-1-trimethylsilyloxycyclohexanecarbaldehyde (cis-9): A
DIBAL-H solution (1m in n-hexane, 25 mL) at À458C was added drop-
wise to a vigorously stirred solution of cis-8 (3.57 g, 15.0 mmol) in n-
hexane (25 mL) under an inert atmosphere. The reaction mixture then
was allowed to warm up slowly to 158C and stirred at this temperature
for 15 h. The mixture was diluted with CH2Cl2 (50 mL) and quenched
with 0.5m aqueous H2SO4 (75 mL). After vigorous stirring for 0.5 h at
room temperature, the organic layer was separated and the aqueous
2786
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 2783 – 2787

Natural Products
FULL PAPER
layer was extracted with CH2Cl2 (3ꢃ20 mL). The combined organic layer
was dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by chromatography on SiO2 using a short column
eluting with petroleum ether/EtOAc (10:1) (Rf =0.54) to afford cis-9
(2.53 g, 70%) as a colorless oil. IR (neat): n˜max =1713, 1645 (w), 1164,
high vacuum. The white residue (mp 131–1338C) was recrystallized from
a mixture of CHCl3/iPr2O/EtOH to yield cis-II (290.6 mg, 72%) as color-
less, crystalline needles.[9] M.p. 133–1358C; IR (neat): n˜max =3269, 2934,
1367, 1173, 1130, 1043, 1026, 1006, 952, 927, 913, 900, 736, 641 cmÀ1
;
1H NMR (500 MHz, [D4]methanol):[2] d=1.15 (s, 6H; CH3), 1.22–1.27
(m, 1H; C4H), 1.34–1.49 (m, 4H; C3Hax, C5Hax, C2Hax, C6Hax,), 1.64–1.66
(m, 4H; C3Heq, C5Heq, C2Heq, C6Heq), 3.30 ppm (brs, 2H; CH2OH);
13C NMR (125.8 MHz, [D4]methanol): d=23.21 (C3H2, C5H2), 26.88
(CH3), 34.44 (C2H2, C6H2), 50.24 (C4H), 72.05 (C), 72.23 (CH2OH),
73.42 ppm (C); 1H NMR (500 MHz, [D5]pyridine): d=1.40 (s, 6H; CH3),
1
888, 813 cmÀ1; H NMR (500 MHz, CDCl3): d=0.16 (Si(CH3)3), 1.51–1.77
(m, 8H; 8 CH), 1.73 (s, 3H; CH3), 1.86–1.93 (m, 1H; C4H), 4.72 (s, 2H;
=CH2), 9.56 ppm (s, 1H; CHO); 13C NMR (62.9 MHz, CDCl3): d=2.26
(Si(CH3)3), 20.70 (CH3), 25.50 (C3H2, C5H2), 32.13 (C2H2, C6H2), 44.24
(C4H), 80.10 (C1), 108.73 (=CH2), 149.96 (C=), 204.25 ppm (CHO); ele-
mental analysis calcd (%) for C17H24O2Si (240.42): C 64.95, H 10.06;
found: C 64.86, H 10.05.
1.58–1.76 (m, 3H; 2 CHax, C4H), 2.00–2.16 (m, 6H; 2 CHax, C3Heq, C5Heq
,
C2Heq, C6Heq), 3.84 ppm (brs, 2H; CH2OH); 13C NMR (125.8 MHz,
[D5]pyridine): d=23.08 (C3H2, C5H2), 27.77 (CH3), 34.92 (C2H2, C6H2),
50.17 (C4H), 71.08 (C), 71.61 (C), 72.39 ppm (CH2OH); elemental analy-
sis calcd (%) for C10H20O3 (188.27): C 63.80, H 10.71; found: C 63.79, H
10.69.
cis-(4-Isopropenyl-1-trimethylsilyloxycyclohexyl)methanol
(cis-10):[11]
NaBH4 (60.0 mg, 1.58 mmol) was added slowly to a stirred solution of
cis-9 (250.0 mg, 1.04 mmol) in absolute EtOH (2.5 mL) at 08C under an
atmosphere of nitrogen. After stirring for 30 min, concentrated
CH3COOH (35 mL) was added. The mixture was concentrated under re-
duced pressure, and the residue was extracted with CH2Cl2. The com-
bined organic layer was washed with brine, dried (Na2SO4), and concen-
trated under reduced pressure. The crude product was purified by chro-
matography on SiO2 with a short column eluting with petroleum ether/
EtOAc (7:1) (Rf =0.47) to afford cis-10 (229.5 mg, 91%) as a colorless
oil, which after some time began to crystallize. M.p. 818C; IR (neat):
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie and the
Degussa AG. The authors thank Dr. Wolfgang Frey for X-ray crystallo-
graphic analyses.
n˜max =1643 (w), 1250, 1067, 869, 837, 747 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=0.12 (s, 9H; Si(CH3)3), 1.25 (ddd, 3J(C2Hax,C3Heq)=4.7 Hz,
3
2J(C2Hax,C2Heq)ꢁ J(C2Hax,C3Hax)=13.1 Hz, 2H; C2Hax, C6Hax), 1.58–1.74
(m, 6H; C3Hax, C5Hax, C2Heq, C6Heq, C3Heq, C5Heq), 1.74 (s, 3H; CH3),
1.85 (tt, 3J(C4Hax,C3Heq)=4.0 Hz, 3J(C4Hax,C3Hax)=11.3 Hz, 1H; C4H),
2.12 (s, 1H; OH), 3.34 (s, 2H; CH2OH), 4.69–4.72 ppm (m, 2H; =CH2);
13C NMR (125.8 MHz, CDCl3): d=À0.56 (Si(CH3)3), 20.88 (CH3), 26.47
(C3H2, C5H2), 33.94 (C2H2, C6H2), 45.47 (C4H), 70.26 (C1), 71.37
(CH2OH), 108.35 (=CH2), 150.58 ppm (C=); HRMS (70 eV, EI) calcd for
C13H26O2Si+: 242.1702; found 242.1702.
[1] Y. Konda, Y. Toda, H. Takaynagi, H. Ogura, Y. Harigaya, H. X.
Lou, X. Li, M. Onda, J. Nat. Prod. 1992, 55, 1118–1123.
[2] T. Ishikawa, J. Kitajima, Y. Tanaka, Chem. Pharm. Bull. 1998, 46,
1603–1606.
[3] K. M. Madyastha, V. Srivatsan, Xenobiotica 1987, 17, 539–549.
[4] a) R. M. Carman, A. C. Garner, Aust. J. Chem. 1996, 49, 741–749;
b) M. J. Donaldson, V. Skoumas, M. Watson, P. A. Ashworth, H.
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[7] a) F. Effenberger, J. Roos, C. Kobler, Angew. Chem. 2002, 114,
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679.
[8] a) M. E. Jung, C. A. McCombs, Y. Takeda, Y.-G. Pan, J. Am. Chem.
Soc. 1981, 103, 6677–6685; b) R. V. Stevens, K. F. Albizati, J. Org.
Chem. 1985, 50, 632–640; c) M. E. Jung, C. A. McCombs, Tetrahe-
dron Lett. 1976, 17, 2935–2938.
[9] CCDC-250608–CCDC-250610 and CCDC-174989 contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
cis-1-(Hydroxymethyl)-4-isopropenylcyclohexane-1-ol (cis-I): A solution
of nBu4NF (359.7 mg, 1.14 mmol) in THF (1.2 mL) was added slowly to a
stirred solution of cis-10 (229.5 mg, 0.95 mmol) in THF (5 mL) at 08C.
The reaction was stirred for 0.5 h. Then H2O (6.0 mL) and CH2Cl2
(8.0 mL) were added, and the organic layer was separated, reextracting
with CH2Cl2 (3ꢃ8 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The residue was pu-
rified by chromatography on SiO2 with petroleum ether/EtOAc (1:1)
(Rf =0.21) to give cis-I (120.0 mg, 74%) as a white solid. Recrystalliza-
tion from iPr2O afforded colorless crystals.[9] M.p. 768C; IR (neat): n˜max
3290, 2926, 2856, 1644 (w), 1434, 1222, 1158, 1051, 992, 959, 883, 736,
642 cmÀ1 1H NMR (500 MHz, CDCl3): d=1.25–1.34 (m, 2H; C2Hax,
=
;
C6Hax), 1.53–1.65 (m, 4H; C3Hax, C5Hax, C3Heq, C5Heq), 1.71–1.79 (m, 2H;
C2Heq, C6Heq), 1.74 (s, 3H; CH3), 1.87 (tt, 3J(C4Hax,C3Heq)=3.4 Hz, 3J
(C4Hax, C3Hax)=11.7 Hz, 1H; C4Hax), 2.45 (brs, 1H; OH), 2.72 (brs, 1H;
OH), 3.42 (s, CH2OH), 4.70–4.71 ppm (m, 2H; =CH2); 13C NMR
(125.8 MHz, CDCl3): d=20.93 (CH3), 26.29 (C3H2, C5H2), 33.66 (C2H2,
C6H2), 45.18 (C4H), 71.12 (C1), 71.70 (CH2OH), 108.50 (=CH2),
150.22 ppm (C=); elemental analysis calcd (%) for C10H18O2 (170.25): C
70.55, H 10.66; found: C 70.38, H 10.71.
[10] J. Brussee, W. T. Loos, C. G. Kruse, A. van der Gen, Tetrahedron
1990, 46, 976–986.
cis-1-Hydroxymethyl-4-(1-hydroxy-1-methylethyl)cyclohexane-1-ol) (cis-
II):[12] A solution of cis-I (364.6 mg, 2.14 mmol) in THF (0.8 mL) was
added to a stirred suspension of mercuric acetate (732.0 mg, 2.27 mmol)
in a 1:1 mixture of THF/H2O (4.6 mL). The yellow color disappeared
after 2 min. The reaction mixture was stirred for 40 min at room temper-
ature and then an aqueous solution of NaOH (3.0m, 2.3 mL) and a so-
lution of NaBH4 (0.5m) in NaOH (3m, 2.3 mL) were added. The gray
mixture was stirred until it clarified and mercury settled out. The reaction
mixture was neutralized with citrus acid monohydrate and extracted with
Et2O in a perforator. After the extraction the organic solution was con-
centrated under reduced pressure. Traces of AcOH were removed under
[11] J. L. G. Ruano, C. G. Paredes, C. Hamdouchi, Tetrahedron: Asym-
metry 1999, 10, 2935–2944.
[12] a) H. C. Brown, P. J. Geoghegan, Jr., J. Org. Chem. 1970, 35, 1842–
1850; b) C. H. Heathcock, R. Ratcliffe, J. Am. Chem. Soc. 1971, 93,
1746–1757; c) G. Blay, V. Bargues, L. Cardona, B. Garcia, J. R.
Pedro, Tetrahedron 2001, 57, 9719–9725.
[13] P. Kurtz in Houben-Weyl, Methoden der Organischen Chemie, Vol. 8,
4th Ed. (Ed.: E. Mꢀller), Thieme, Stuttgart 1952, pp. 255–256.
Received: November 15, 2004
Published online: February 28, 2005
Chem. Eur. J. 2005, 11, 2783 – 2787
www.chemeurj.org
ꢂ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2787