Experimental and theoretical approaches into the C- and D-ring problems of sterol biosynthesis. Hydride shift versus C-C bond migration due to cation conformational changes controlled by the counteranion

Article abstract of DOI:10.1016/j.tet.2004.07.064

The C- and D-ring problems of sterol biosynthesis, how an enzyme overcomes the Markovnikov wall, were investigated by using a model compound from an experimental as well as theoretical standpoint. When model diol 20 was treated with BF₃·Et

Full text of DOI:10.1016/j.tet.2004.07.064

Tetrahedron 60 (2004) 9223–9234
Experimental and theoretical approaches into the C- and D-ring
problems of sterol biosynthesis. Hydride shift versus C–C bond
migration due to cation conformational changes controlled
by the counteranion
†
Mugio Nishizawa, Arpita Yadav, Yoshihiro Iwamoto and Hiroshi Imagawa
*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 26 June 2004; revised 21 July 2004; accepted 22 July 2004
Abstract—The C- and D-ring problems of sterol biosynthesis, how an enzyme overcomes the Markovnikov wall, were investigated by using
a model compound from an experimental as well as theoretical standpoint. When model diol 20 was treated with BF3$Et2O, SnCl4, TiF4,
Sc(OTf)3, FeCl3, or TfOH, spirocyclic ether 21 was formed as the sole product via a tert-cationic intermediate 16 through 1,2-hydride shift.
However, the treatment with TiCl4 afforded six-membered ring products 22, 23, 24, 25, 26, and 27 via the ring expansion into the unstable
six-membered ring secondary cation 17. Occurrence of both a and b chloride 23 and 24 is distinctive evidence of the existence of secondary
cation 17, ruling out the idea of the concerted mechanism. Molecular mechanics calculations of the naked cation 15 elucidated two possible
conformers, parallel 15-I (five membered ring and cationic plane) that is favorable for the hydride shift generating 16 and perpendicular 15-II
leading to C–C bond migration to 17. The first ab initio calculation of the cation conformation in the presence of counteranions such as
[TiCl4OH]K, [TiF4OH]K, [BF3OH]K, and [OTf]K entirely supported our experimental results. Although the counteranion [TiCl4OH]K
stabilizes perpendicular cation 15-II, it destabilizes the parallel conformer 15-I significantly, and thus, the C–C bond migration to 17
becomes the only possible pass. On the other hand, [TiF4OH]K, [BF3OH]K, and [OTf]K stabilize parallel conformer 15-I and the hydride
shift to 16 becomes the only possible pass. The relative location or distance of the counteranion from the cation should be the biggest factor to
control the stability and, thus, the conformation of the cation. Our results indicate that the carboxylate anions in the enzyme cavity enable to
control the conformation of pre-C-ring cationic intermediate 3 to be perpendicular leading to six-membered C-ring secondary cation 4. The
parallel conformation of the cation 5 could lead to hydride shift to give tirucallanoids or lanostanoids. Therefore, this result is the first
example that overcame the big Markovnikov wall experimentally and theoretically at least to our knowledge.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
competing processes leading to tirucallanoids and tetra-
hymanoids, respectively. In the animal kingdom, steroids
are also constructed through the corresponding boat-form
B-ring intermediates (Scheme 1).1b,5,6
Remarkable enzymatic cyclization of squalene and oxido-
squalene has been achieved by a wide range of micro-
organisms and higher eukaryotes to yield polycyclic
triterpenoides.1,2 Today, the biosynthesis of phytosterols
such as dammaranoid, lupanoid, oleananoid, and tirucalla-
noid are explained by the stepwise cyclization of oxido-
squalene via the monocyclic cation 1, the bicyclic cation 2,
the tricyclic 6/6/5-cation (pre-C ring cation) 3, the
secondary 6/6/6-cation 4, and the 6/6/6/5-cation 5.3,4
Hydride shift (a) and C–C bond migration (b) from 5 are
In 1985, we achieved the cyclization of geranylgeranyl
acetate 6 with our original cyclization agent, Hg(OTf)2–
dimethylaniline complex,5 in the presence of water when
the mono-, bi-, and tricyclic cationic intermediates were
trapped to give tert-alcohols 7–9.6 This is the first
experimental evidence that the biomimetic olefin cycliza-
tion takes place via conformationally flexible cationic
intermediates. In 1984, we also achieved the cyclization
of 6 without water and found that the chair/chair cyclization
competed with the chair/boat cyclization in 5:1 ratio to give
10, 11, and 12 after bromination.7 This result served as the
first example to show that the boat-form B-ring product was
formed by means of biomimetic olefin cyclization.8
Recently, we have shown that the 6/5-trans-selective
Keywords: Steroid biosynthesis; C-ring problem; TiCl4; anti-Markovnikov
rearrangement; Cation conformation with counteranion.
* Corresponding author. Tel.: C81886229611; fax: C81886553051;
e-mail: mugi@ph.bunri-u.ac.jp
† On leave from Institute of Engineering and Technology, C.S.J.M.
University, Kanpur, India.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.064

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M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
investigate its chemical behaviour. The hydride shift to
the tert-cation 16 corresponds to the hydride shift a in the
dammaranoid cation 5. Likewise, ring enlargement to the
anti-Markovnikov cation 17 corresponds to the carbon–
carbon bond migration b in the cation 5 leading to the
formation of the six-membered D-rings and C-ring
formation from 3. Olah has pointed out that the equilibrium
between the cyclopentylmethyl cation 18 and the cyclo-
hexyl cation 19 favors overwhelmingly 18 based on NMR
experiments.12 Harding has also reported a similar tendency
through the synthesis of 1-acetyl-2-methylcyclopentene
from cyclohexane and CH3COCl in the presence of
AlCl3.13 Theoretical calculations of model cations have
also pointed out the energetical disadvantage of the latter
process.11a Therefore, we investigated the reactions of the
diol 20 with a variety of Lewis acids. Although most of the
Lewis acids afforded only the spiro-product 21 via a hydride
shift by generating the cation 16, TiCl4 surprisingly
generated the anti-Markovnikov cation 17 selectively and
affordedthesix-memberedringcompound22alongwithother
related products.14 The remarkable selectivity achieved
with TiCl4 was explained by the counteranion-controlled
conformational changes in the cation.15 These were, in fact,
the first theoretical calculations on cation conformations in
the presence of counteranions (Scheme 3).
Scheme 1.
cyclization of 2 into 3 does not depend upon any special
enzyme power by achieving a similar 6/5-trans-selective
cyclization of 13 into 14 by a chemical process promoted by
a Lewis acid.9 The next mystery to be solved was the
enzymatic rearrangement of the stable tert-cation 3 to the
unstable six-membered ring secondary-cation 4, how the
enzyme overcomes the formidable Markovnikov wall
(Scheme 2).1a,3b,3e,10,11
Although the diol 20 was inert to BF3$Et2O (3 equiv) in
CH2Cl2 at 0 8C, a rapid reaction took place at 25 8C to afford
the spirocyclic species 21 as the sole product in 82% yield
(Table 1, entry 1). The reactions of 20 with 3 equiv each of
SnCl4, Sc(OTf)3, FeCl3, TiF4, and CF3SO3H in CH2Cl2 at
25 8C for 30 min also provided only the spiro-ether 21.
However, the reaction of 20 with 3 equiv of TiCl4 in CH2Cl2
at 25 8C afforded an entirely different result. Intensive
purification of the complicated reaction mixture provided
the 6/5 cis-fused ether 22 (16%), the cis-chloro alcohol 23
(13%) and its trans-isomer 24 (26%), the 6/5 cis-fused ether
25 (9%), the cis-chloro alcohol 26 (16%), and the trans-
chloro alcohol 27 (7%) along with 1% of 21 (Table 1, entry
8). The 6/5 trans-fused ether 28 was not detected from any
of these reactions. When the corresponding acetate 20a was
treated with TiCl4, a very clean reaction took place to afford
a 3:2 mixture of the chlorinated products 23a and 24a in
86% yield. On the other hand, the reaction of 20a with
BF3$Et2O afforded a 2:3 mixture of the olefins 29 and 30.
Thus, the latter reaction induced only a hydride shift
corresponding to the transformation of 15 into 16. The
reaction of 20 with AlCl3 and ZrCl4 under identical
conditions provided an alternative result. Only the 5/6 cis-
product 25 was obtained in 87% and 84% yields,
respectively (entries 12 and 13). The products 25–27 should
be generated via the cation 31 through 1,2-migration of the
side chain from 17. Treatment of 20 with FeCl2, TiCl2(O-i-
Pr)2, ZnCl2 and Zn(OTf)2 provided no product and the
starting material was recovered almost quantitatively.
2. Results and discussion
The transformation of 3 into 4 involves ring expansion of a
tert-cation into an unstable sec-cation.3b To achieve a
similar transformation through organic synthesis, we
planned to generate a model cation such as 15 and
The diol 20 was prepared from 3-tert-butyldimethylsilyloxy-
propanal (32).16 Grignard reaction of 32 with cyclopentyl-
magnesium bromide afforded the alcohol 33 which,
following oxidation and methylation, provided the tert-
alcohol 35. Cleavage of the TBS group by TBAF provided
the diol 20, and acetylation afforded the acetate 20a.
Structural studies of the cationic reaction products were
Scheme 2.

M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
9225
Scheme 3.
carried out carefully by preparing authentic materials. The
spirocyclic ether 21 was derived from the known 1-(3-
hydroxy-1-methylpropyl)cyclopentanol on reaction with
p-TsCl in pyridine in 95% yield.17 Regioselective allylation
of the enol acetate 36 according to Tsuji’s protocol afforded
the ketone 37 in 90% yield.18 NaBH4 reduction of 37
followed by treatments with OsO4-NMO and NaIO4, in that
order, afforded the cis-fused hemiacetal 38 and the trans-
hydroxy aldehyde 39 in 38 and 25% yields, respectively.
The reaction of the hemiacetal 38 with triethylsilane in the
presence of CF3COOH provided the 6/5 cis-fused ether 22
in 83% yield.19 The alcohol obtained from NaBH4 reduction
of 38 was acetylated and then chlorinated with (Ph3P–
CCl4)20 to give 24a (13%), 44 (40%), and 45 (13%). NaBH4
reduction of 39 afforded the trans-diol 40. Part of 40 was
converted into the 6/5-trans-fused ether 28 on treatment
Table 1. Reaction of diol 20 with acid and Lewis acids in CH2Cl2
Entry
Acid
Product (% yield)
21
22
23
24
25
26
27
1
2
3
4
5
6
7
8
BF3Et2O
SnCl4
Sc(OTf)3
FeCl3
FeCl2
CF3SO3H
TiF4
TiCl4
TiCl4(O-i-Pr)2
ZnCl2
82
90
51
76
—
88
76
1
—
—
—
—
—
—
—
—
—
—
—
—
16
—
—
—
—
—
—
—
—
—
—
—
—
13
—
—
—
—
—
—
—
—
—
—
—
—
26
—
—
—
—
—
—
—
—
—
—
—
—
9
—
—
—
87
84
—
—
—
—
—
—
—
16
—
—
—
—
—
—
—
—
—
—
—
—
7
—
—
—
—
—
9
10
11
12
13
Zn(OTf)2
AICl3
ZrCl4

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M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
with p-TsCl in 33% yield. Alternatively, the acetylation of
40 followed by its chlorination afforded 23a (13%), 44
(26%), and 46 (18%). Hydrolyses of 23a and 24a using
NaOMe in MeOH afforded 23 and 24, respectively, in
quantitative yields. The stereochemical assignments of 23
and 24 were achieved by NOE experiments. Clear NOE
cross-peaks between the axial methyl and the axial protons
of 1,3-relationship were detected for 24; 23 did not show
any distinctive NOE cross-peaks. 2-Allylcyclohexanone 41,
prepared from 1-acetoxycyclohexene using Tsuji’s proto-
col,18 was treated with MeMgCl to give the cis-carbinol 42
in 73% yield. Cleavage of the double bond of 42 using
OsO4-NMO followed by oxidation with NaIO4 gave the
hemiacetal 43 in 62% yield. Treatment of 43 with Et3SiH in
the presence of CF3COOH provided the cis-fused ether 25
in 76% yield.19 NaBH4 reduction of 43 and further treatment
with concd HCl in ether afforded the cis-chloroalcohol 26 in
30% yield. Although the formation of the trans-isomer 27
was not detected from this chlorination, the stereochemical
assignments of 26 and 27 were confirmed by NOE
experiments as well (Scheme 4).
Scheme 5.
membered ring and the cationic plane, is geometrically
suited to hydride shift to generate the cation 16. The
conformer 15-II, that assumes a perpendicular relationship
of the cationic plane and the five-membered ring, should
instead result in a marked carbon–carbon bond migration
and afford the anti-Markovnikov cation 17. Detection of the
actual conformational changes reflecting the nature of the
counteranion is the next target of our research (Scheme 5).
Not only our MM2 calculations but also almost all other
publications dealing with the calculations of carbocations11,22
have been carried out without any counteranion; only the
stabilities of the naked cations were discussed. Recently,
Farcasiu and co-workers23 have studied carbocations in ion
pairs using ab initio MO methods to understand the
behaviour of carbocations in media of low to moderate
dielectric constants and where the reaction pathway was
determined by transformation of carbocations forming tight
ion pair conditions. As indicated by these studies and our
own recent calculations,15 the major stabilization of a cation
is likely to come from a counteranion through electrostatic
effects. The location of the counteranion in respect of the
cation should, therefore, constitute the most important
factor for the conformational control of the latter. Thus, we
undertook the first calculations of the conformers 15-I
and 15-II in the presence of counteranions [TiCl4OH]K,
[TiF4OH]K, [BF3OH]K, and [OTf]K. As expected, the
counteranion indeed contributed significantly to the stabil-
ization of the carbocation that led us to conclude that the
rearrangement of the cation 3 to 4 was a reasonable
pathway.15
It is exciting to consider how the above clear selectivity
comes about.16 MM2 calculations of the cation 15 using the
CAChe-CONFLEX-MOPAC programs elucidated the
existence of two conformers 15-I and 15-II.21 The
conformer 15-I, that takes parallel alignment of the five-
Recently, the conversion of pre-C-ring cation 3 to C-ring
cation 4 has also been explained by a concerted mechan-
ism.11b–e Our non-selective chlorination to give 23 and 24
from 20 (as well as 23a and 24a from 20a) are the distinctive
evidence of the existence of the six-membered ring
secondary cation 17. Although the cyclization to form 22
took place stereoselectively, it is quite natural by consider-
ing the stability of 6/5 cis-fused system over trans based
system upon the ring strain. Therefore, the present result
definitively denied the idea of concerted mechanism from 3
to 4.
We performed ab initio Hartree Fock molecular orbital
calculations with the 6-31G* basis set.24 The cations 15-I,
15-II, 16, and 17 and the anions [TiCl4OH]K, [TiF4OH]K,
[BF3OH]K, and [OTf]K were completely optimized
separately using the Berny optimization algorithm25,26 of
the Gaussian 98 package.27 The anions were slowly brought
in from a distance to the cation and, at each point, the
interaction energy of the two was calculated using super-
molecule approach. These interaction energies are without
the incorporation of the basis set superposition error (BSSE)
correction. Since we are interested only in the relative
Scheme 4.

M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
9227
stabilities of various supermolecules, the BSSE will almost
cancel out. In this manner, the optimal cation–anion
distance was estimated as the one at which the attractive
interaction energy was the maximum. The counteranion was
then placed at this optimal distance and the cation was
completely optimized in its presence to locate the stationary
point for the supermolecule. Although the anion was kept
frozen in a particular orientation and the stationary point
was found using only partial optimization, all gradients
were found to be within the convergence criterion.28 The
anion was then rotated to a different orientation and the
resultant supermolecule was optimized for yet another
stationary point. The stationary points corresponding to
several possible orientations of the counteranion were
located. The energetically most favoured orientations of
cation and counteranion are reported here.
changes in the cation do take place to allow for any possible
H-bonds or to maximize interactions with the counteranion.
The relative energies of the optimized product cations in the
presence of counteranion [TiCl4OH]K (16a and 17a)
indicate that 15-Ia, once formed, will quickly rotate to 15-
IIa and initiate a carbon–carbon bond migration to 17a even
though it is an endothermic reaction. The conversion of 15-
IIa back to 15-Ia and then to 16a is unlikely as was indeed
observed from our model study (Scheme 6).
From the above discussion, the shape and size of the
counteranion appear to be important in determining its
electrostatically most favored disposition in respect of the
cation that, in turn, may determine the fate of the cation
itself. To further understand this, we considered calculations
with [TiF4OH]K that carries the same Ti metal but has a
smaller ligand (F vs Cl). It can be seen clearly that the
counteranion can now penetrate much closer to the cation
The fully optimized conformations and the relative energies
of the naked cations 15-I, 15-II, 16, and 17 are collected in
Figure 1. The perpendicular cation 15-II, that is suitable for
carbon–carbon bond migration, is energetically more
favored than the parallel cation 15-I that is suitable for
hydride transfer. As expected, the conversion of 15-II into
the anti-Markovnikov cation 17 is an unfavorable process
with an energy requirement of 9.8 kcal/mol that is
comparable to 12 kcal/mol reported by Jorgensen.11a In
contrast, the transition of the cation 15-I to 16 is favored by
4.5 kcal/mol. The cations 15-I and 15-II, being in
equilibrium due to a small energy difference (2.6 kcal/
mol), are therefore expected to rearrange to 16 in preference
to 17. This, however, contrasts with our experimental
findings.
C
C
˚
(C /TiZ4.00 A in 15-IIb as compared to C /TiZ
˚
4.82 A in 15-IIa) to benefit from greater electrostatic
stabilization. The relative energies indicate that the
energetics are now controlled largely by the electrostatic
interactions and that the conformational effects are reduced
to marginal, if not negligible, due to the smaller size of the
counteranion. From rotationally isomeric 15-Ib and 15-IIb,
15-Ib is transformed to 16b via hydride shift in a process
that is predicted to be exothermic by 5.2 kcal/mol (8.9 kcal/
mol from 15-IIb). On the contrary, the transformation of 15-
IIb to 17b via carbon–carbon migration is predicted to be
endothermic with an energy requirement as high as
17.2 kcal/mol. This is supported from our experimental
results as we observed only the product of hydride
migration.
In this study we demonstrate the stabilization of a cation by
a counteranion and its effect on the energetics of the reaction
and, thus, the fate of the cation. The relative stabilities of the
energetically most favored conformations of cations in the
presence of [TiCl4OH]K indicate that it stabilizes prefer-
entially the cation 15-II that is suitable for carbon–carbon
bond migration. A close examination reveals that the
Further, we have performed calculations on the cations in
the presence of [BF3OH]K and [OTf]K as the counter-
anions. The shape and size of these counteranions is such
that they can penetrate close to both the rotationally
isomeric cations, i.e. (15-Ic and 15-IIc), and (15-Id and
counteranion approached closer (C /TiZ4.82 A) to the
15-IId) and stabilize them to almost equal extent (CC/BZ
C
˚
C
C
˚
˚
˚
cation 15-IIa than to the cation 15-Ia (C /TiZ5.5 A)
3.5 A for 15-Ic and 15-IIc both); (C /SZ3.5 A for 15-Id
and 15-IId both). The relative energies of 15-Ic and 15-IIc
indicate that they will exist in equilibrium with a small
energy difference of 1.39 kcal/mol. This difference is further
reduced in the case of [OTf]K counteranion; 15-Id and 15-
IId will exist in equilibrium with an energy difference of
only 0.91 kcal/mol. This difference is due to the minor
differences in electrostatic interactions with the counter-
anion and almost negligible contribution from the
(Fig. 1). This allows for better electrostatic interactions in
15-IIa than in 15-Ia. An estimate of the electrostatic
interaction energy helps us to understand its contribution to
preferential stabilization of one cation over the other. We
note that 14.8 kcal/mol out of a total difference of 17.4 kcal/
mol is due solely to the difference in electrostatic
interactions; the remaining difference is of conformational
origin. However, minor anion-induced conformational
Scheme 6.

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M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
Figure 1. Conformation of cation. (a) Relative energy, (b) Interaction energy.

M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
9229
conformational aspects due to the small size of the ligand
and the compact size of the counteranion in both the cases.
The equilibrium will be driven to the exothermic hydride
transfer process (1.6 kcal/mol from 15-IIc; 1.65 kcal/mol
from 15-IId) as compared to carbon–carbon bond migration
that is highly endothermic. These calculations support our
experimentally observed major hydride transfer product
with BF3$Et2O (82% yield) and TfOH (88% yield; c.f.
Table 1).
44; HR-MS (EI) m/z calcd for C9H16O (MC) 140.1187;
Found 140.1207. Reactions of 20 with SnCl4, Sc(OTf)3,
FeCl3, CF3COOH, and TiF4 were carried out essentially in
the same manner.
3.1.2. Reaction of 20 with TiCl4. To a stirred solution of 20
(530 mg, 3.35 mmol) in dichloromethane (10 mL) was
added TiCl4 (1.14 mL, 10.38 mmol) at 0 8C, and the mixture
was stirred at room temperature for 30 min. After addition
of saturated aqueous sodium hydrogen carbonate, the
organic phase was dried and concentrated. Column
chromatography using hexane and ethyl acetate afforded
Fractions I and II. Fraction I was further purified by HPLC
using YMC-Pack R and D SIL-5 (20!250 mm) column and
hexane–ethyl acetate (90:1, 20 mL/min) to give 22 (74 mg,
16%): FT-IR (film): 2935, 2868, 1462, 1381, 1159, 1090,
1053, 1032 cmK1; 1H NMR (300 MHz, CDCl3) d 1.05 (3H,
s), 1.86–1.11 (10H, m), 3.43 (1H, dd, JZ3.3, 2.7 Hz),
3.97–3.80 (2H, m); 13C NMR (75 MHz in CDCl3) d 20.57
(t), 21.95 (t), 22.26 (q), 26.37 (t), 32.94 (t), 39.31 (t), 40.74
(s), 64.90 (t), 82.09 (d); MS (CI) m/z 140 (MC), 139, 122
(base), 107, 96, 84, 67, 55, 49, 41; HR-MS (EI) m/z calcd for
C9H16O (MC) 140.1201; Found 140.1171, 25 (42 mg, 9%):
FT-IR (film) 2937, 2873, 1448, 1373, 1271, 1180, 1122,
We have, therefore, succeeded in overcoming the formid-
able Markovnikov wall by changing the counteranion and,
in turn, by changing the conformation of the cation. We
know the significance of solvent effects. However, the
solvent effects cannot outweigh the electrostatic aspects.
According to Jorgensen, solvent effect on the similar
transformation of his model compound did not exceed
2 kcal/mol.11a The relative location or distance of the
counteranion from the cation should be the biggest factor to
control the stability and, thus, the conformation of the
cation. In the enzymatic sterol biosynthesis, the possible
counteranion should be limited to the carboxylates of
aspartic acid and glutamic acid residues. The relative
location of these carboxylates and the cationic center in an
enzymatic cavity enable to control the conformation of the
pre-C-ring cation 3 or D-ring cation 5 to take the
perpendicular conformation leading to carbon–carbon
bond migration to give the six-membered ring sec-cation
or the parallel conformation leading to hydride shift to give
tirucallanoids or lanostanoids.1a,1b,3d,e,4,29
1
1086, 1049, 954 cmK1; H NMR (300 MHz in CDCl3) d
1.19 (3H, s), 1.74–1.25 (8H, m), 1.88–1.77 (2H, m), 2.11–
1.98 (1H, m), 3.97–3.82 (2H, m); 13C NMR (75 MHz in
CDCl3) d 22.40 (t), 22.82 (t), 25.58 (q), 27.11 (t), 30.58 (t),
34.12 (t), 42.63 (d), 64.34 (t), 80.30 (s); HR-MS (EI) m/z
calcd for C9H16O (MC) 140.1201; Found 140.11, along
with 21 (7 mg, 1%). Fraction II was further purified by
HPLC using three straight connections of YMC-Pack R and
D SIL-5 (20!250 mm) column and hexane–ethyl acetate
(7.5:1, 12 mL/min) to give 23 (75.3 mg, 13%): FT-IR (film)
3336, 2938, 2866, 1452, 1051 cmK1; 1H NMR (600 MHz in
CDCl3) d 1.08 (3H, s), 1.14 (1H, ddd, JZ14.0, 9.1,
4.9 Hz),1.29 (1H, br s), 1.41–1.34 (1H, m), 1.51–1.42 (2H,
m), 1.89–1.70 (5H, m), 2.00–1.95 (1H, m), 3.74 (2H, ddd,
JZ10.2, 9.1, 6.1 Hz), 3.88 (1H, dd, JZ9.3, 3.8 Hz); 13C
NMR (150 MHz in CDCl3) d 20.96 (t), 24.42 (t), 25.45 (q),
31.78 (t), 35.45 (t), 36.57 (t), 37.78 (t), 59.15 (s), 71.04 (d);
MS (CI) m/z 177 (MCC1), 159, 141 (base), 124, 95, 81;
HR-MS (EI) m/z calcd for C9H18OCl (MCC1) 177.1046;
Found 177.1033, 24 (148.4 mg, 26%): FT-IR (film) 3346,
3. Experimental
3.1. General
All commercially available chemicals were used without
further purification. All reactions were carried out with dry
glassware under argon atmosphere. Analytical TLC was
carried out on Merck 60 F254 silica gel plate and column
chromatography was performed on Merck 60 silica gel
(230–400 mesh). IR spectra were recorded on a JASCO
1
FT/IR-410 spectrometer. H and 13C NMR spectra were
recorded on a Varian Unity-600, Varian Mercury-300,
Varian Unity-200, Varian Gemini-200, and JEOL JMNGX-
400 apparatus. Mass spectra were taken on JEOL AX-500.
2939, 2862, 1446, 1381, 1053, 972 cmK1 1H NMR
;
(600 MHz in CDCl3) d 1.03 (3H, s), 1.33 (2H, m), 1.46
(3H, m), 1.63 (1H, dddd, JZ9.3, 5.8, 3.6, 2.2 Hz), 1.69 (1H,
ddd, JZ14.0, 8.2, 6.8 Hz), 1.80 (3H, m), 1.99 (1H, dddd,
JZ13.5, 5.3, 4.2, 1.1 Hz), 3.75 (2H, ddd, JZ10.4, 7.9,
6.6 Hz), 3.91 (1H, dd, JZ11.0, 4.1 Hz); 13C NMR
(150 MHz in CDCl3) d 18.6 (q), 21.0 (t), 25.9 (t), 32.6 (t),
36.6 (t), 38.4 (s), 44.1 (t), 58.9 (t), 69.5 (d); HR-MS (EI) m/z
calcd for C9H18OCl (MCC1) 177.1046; Found 177.1041,
26 (92.1 mg, 16%): FT-IR (film) 3338, 2935, 2812, 1446,
3.1.1. Reaction of 3-cyclopentylbutane-1,3-diol (20) with
BF3$OEt2. To a stirred solution of 20 (91 mg, 0.58 mmol)
in dichloromethane (16 mL) was added BF3$Et2O (220 mL,
1.80 mmol) at 0 8C and the mixture was stirred at 25 8C for
30 min. After addition of saturated aqueous NaHCO3, the
organic phase was dried and concentrated. Column
chromatography using hexane and ether afforded
4-methyl-1-oxa-spiro[4.4]nonane (21) (67 mg, 82%) as a
colorless oil. FT-IR (film) 2958, 2873, 1454, 1376, 1332,
1184, 1049 cmK1; 1H NMR (600 MHz, CDCl3) d 0.97 (3H,
d, JZ6.6 Hz), 1.61–1.48 (6H, m), 1.77–1.68 (3H, m), 2.04
(1H, dddd, JZ14.2, 7.4, 7.2, 6.8 Hz), 2.17–2.07 (1H, m),
3.74 (1H, dd, JZ15.1, 7.7 Hz), 3.80 (1H, ddd, JZ8.5, 4.7,
3.8 Hz); 13C NMR (50 MHz in CDCl3) d 15.39 (q), 23.73
(t), 24.25 (t), 31.76 (t), 34.13 (t), 36.95 (t), 39.65 (d), 64.40
(t), 93.42 (s); MS (CI) m/z 140 (MC), 111, 98 (base), 85, 55,
1
1055, 1014 cmK1; H NMR (600 MHz in CDCl3) d 1.23
(1H, m), 1.35 (1H, ddd, JZ13.2, 11.3, 3.6 Hz), 1.44 (3H,
m), 1.56 (2H, m), 1.59 (3H, s), 1.67 (1H, dddd, JZ11.0, 4.7,
3.3, 1.4 Hz), 1.74 (2H, m), 1.98 (2H, m), 3.65 (1H, ddd, JZ
10.5, 8.8, 5.8 Hz), 3.75 (1H, ddd, JZ10.8, 7.5, 4.7 Hz); 13C
NMR (150 MHz in CDCl3) d 22.2 (t), 25.6 (t), 27.6 (t), 31.7
(q), 34.1 (t), 42.9 (t), 44.2 (d), 60.8 (t), 76.0 (s); HR-MS (CI)
m/z calcd for C9H18OCl (MCC1) 176.6864; Found
177.1019, and 27 (39.2 mg, 7%): FT-IR (film) 3340, 2935,

9230
M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
1
2862 cmK1; H NMR (600 MHz in CDCl3) d 1.13 (1H,
dddd, JZ12.0, 8.7, 6.0, 3.5 Hz), 1.36 (4H, m), 1.50 (3H, s),
1.66 (2H, m), 1.83 (1H, dddd, JZ13.2, 5.7, 3.8, 1.9 Hz),
1.89 (1H, dddd, JZ13.8, 6.3, 3.9, 2.5 Hz), 1.97 (1H, ddd,
JZ12.9, 9.1, 3.8 Hz), 2.14 (2H, m), 3.66 (1H, ddd, JZ10.4,
8.2, 6.3 Hz), 3.76 (1H, ddd, JZ10.6, 7.6, 4.9 Hz); 13C NMR
(150 MHz in CDCl3) d 23.5 (q), 24.2 (t), 25.2 (t), 29.5 (t),
34.1 (t), 44.4 (t), 45.8 (d), 61.4 (t), 76.3 (s); HR-MS (CI) m/z
calcd for C9H18OCl (MCC1) 177.1046; Found 177.1039.
HCl, NH4Cl, and NaHCO3. The dried and concentrated
extract was subjected to column chromatography to give 21
(167 mg, 95%) as a colorless oil. Spectral data were
identical with that of the acid reaction product.
3.1.6. 3-(tert-Butyldimethylsilyloxy)-1-cyclopentylpro-
pan-1-ol (33). To a stirred solution of Grignard reagent
prepared from magnesium (3.62 g, 150 mmol) and bromo-
cyclopentane (4.45 g, 30 mmol) in THF (100 mL) was
added a solution of 3-(tert-butyldimethylsilyloxy)-propanal
(32) (5.74 g, 30 mmol) in THF (60 mL) dropwise at K40 8C
and the resultant mixture was stirred for 2 h at this
temperature. After addition of aqueous NH4Cl, the organic
material was extracted into ether. The dried and concen-
trated extract was subjected to column chromatography
using hexane and ethyl acetate to give alcohol 33 in 65%
yield as a colorless oil. FT-IR (film) 3458, 2962, 2861, 2738,
3.1.3. Reaction of 3-cyclopentyl-3-hydroxybutyl acetate
(20a) with TiCl4. TiCl4 (1.33 g, 7.0 mmol) was added to a
stirred solution of 20a (530 mg, 2.65 mmol) in CH2Cl2
(10 mL) at 0 8C and the mixture was stirred at 25 8C for 1 h.
After cooling to 0 8C, aqueous NaHCO3 solution was added
and extracted with CH2Cl2. The dried and concentrated
extract was subjected to column chromatography using
hexane and ethyl acetate to give a 3:2 mixture of 23a and
24a (498 mg, 86%). The mixture was purified by HPLC
using YMS-Pack R and D SIL D-SIL-5 20!250 mm
column and hexane–ethyl acetate (50:1, 20 mL/min) to give
23a and 24a as colorless oils. 23a: FT-IR (film) 2943, 2846,
1
1471, 1389, 1362, 1257, 1103 cmK1, H NMR (300 MHz,
CDCl3) d 0.08 (6H, s), 0.90 (9H, s), 1.95–1.13 (11H, m),
3.66–3.55 (1H, m), 3.97–3.76 (2H, m); 13C NMR (50 MHz,
CDCl3) d K5.68 (2o), 17.97 (e), 25.55 (e), 25.75 (3o), 28.63
(e), 28.86 (e), 37.29 (o), 46.24 (e), 62.84 (e), 76.04 (o); MS
(CI) m/z 259 (MCC1), 189, 109, 67 (base); HR-MS (CI) m/z
calcd for C14H31O2Si (MCC1) 259.2093; Found 259.2098.
1747, 1456, 1367, 1252, 1142, 1034 cmK1 1H NMR
;
(200 MHz in CDCl3) d 1.08 (3H, s), 1.19 (1H, m), 1.42
(3H, m), 1.85 (6H, m), 2.05 (3H, s), 3.85 (1H, dd, JZ5.0,
4.0 Hz), 4.14 (2H, dddd, JZ7.0, 3.6, 2.6, 1.6 Hz); 13C NMR
(50 MHz in CDCl3) d 20.8 (t), 20.9 (q), 24.5 (t), 25.3 (q),
31.8 (2C, t), 35.3 (t), 37.7 (s), 61.0 (t), 70.7 (d), 171.0 (s);
HR-MS (CI) m/z calcd for C11H20O2Cl (MCC1) 219.1152;
Found 219.1147. 24a: FT-IR (film) 2941, 2866, 1747, 1448,
3.1.7. 3-(tert-Butyldimethylsilyloxy)-1-cyclopentylpro-
pan-1-one (34). To a stirred solution of alcohol 33 (1.1 g,
4.26 mmol) in dichloromethane (15 mL) was added pyri-
dinium dichromate (3.2 g, 8.5 mmol) at 0 8C and the
mixture was stirred for 46 h at 25 8C. After addition of
ether (200 mL) and then Celite (20 g), the mixture was
stirred for another 10 min. This was filtered through a celite
pad and concentrated. The residue was subjected to column
chromatography using hexane and ethyl acetate to give the
ketone 34 (11.7 g, 59%) as a colorless oil. FT-IR (film) 2954,
1367, 1250, 1034, 973 cmK1 1H NMR (200 MHz in
;
CDCl3) d 1.04 (3H, s), 1.64 (10H, m), 2.05 (3H, s), 3.85
(1H, dd, JZ6.2, 4.4 Hz), 4.16 (2H, dddd, JZ7.4, 0.8, Hz);
13C NMR (50 MHz in CDCl3) d 18.0 (q), 20.7 (2C, t), 25.6
(t), 32.3 (q), 36.0 (t), 38.0 (t), 39.3 (s), 60.4 (t), 68.7 (d),
170.6 (s); HRMS (CI) m/z calcd for C11H20O2Cl (MCC1)
219.1152; Found 219.1147.
1
2858, 1711, 1471, 1389, 1362, 1255, 1095 cmK1, H NMR
(300 MHz, CDCl3) d 0.05(6H, s), 0.87 (9H, s), 1.67–1.55 (4H,
m), 1.87–1.68 (4H, m), 2.56 (2H, t, JZ6.3 Hz), 2.89 (1H,
dddd, JZ8.0, 7.7 Hz), 3.94 (2H, t, JZ6.3 Hz); 13C NMR
(75 MHz, CDCl3) d K5.86 (2q), 17.80 (t), 25.53 (3q), 25.69
(2t), 27.99 (2t), 44.16 (t), 51.68 (d), 58.56 (t), 210.97 (s).
3.1.4. Reaction of 20a with BF3$Et2O. BF3$Et2O
(78.5 mg, 0.55 mmol) was added to a stirred solution of
acetate 20a (52 mg, 0.26 mmol) in CH2Cl2 (5 mL) at 0 8C
and the mixture was stirred at 25 8C for 30 min. After
cooling to 0 8C, aqueous NaHCO3 was added, and extracted
with CH2Cl2. The dried and concentrated extract was
subjected to column chromatography using hexane and
ethyl acetate to give a 2:3 mixture of 29 and 30 (41 mg,
87%). 29: 1H NMR (200 MHz in CDCl3) d 1.05 (3H, d, JZ
6.8 Hz), 1.80 (4H, m), 2.04 (3H, s), 2.30 (5H, m), 4.09 (2H,
m), 5.36 (1H, m); 13C NMR (50 MHz in CDCl3) d 19.5 (q),
21.0 (q), 26.7 (d), 27.0 (t), 30.4 (t), 32.2 (t), 33.8 (t), 62.9 (t),
3.1.8. 4-(tert-Butyldimethylsilyloxy)-2-cyclopentylbutan-
2-ol (35). To a stirred solution of MeMgCl (3.0 M in THF,
1.80 mL, 3.95 mmol) was added a solution of the ketone 34
(0.95 g, 3.71 mmol) in THF (5 mL) at 0 8C and the mixture
was stirred for 2 h at the same temperature and another 2 h
at 25 8C. After addition of aqueous NH4Cl, the organic
material was extracted with ether. The dried and concen-
trated extract was subjected to column chromatography
using hexane and ethyl acetate to give the alcohol 35
(1.00 g, 99%) as a colorless oil. FT-IR (film) 3512, 2954,
2860, 1471, 1389, 1255, 1088 cmK1, 1H NMR (200 MHz,
CDCl3) d 0.09 (6H, s), 0.90 (9H, s), 1.18 (3H, s), 1.68–1.43
(10H, m), 1.99–1.76 (1H, m), 4.01–3.81 (2H, m); 13C NMR
(50 MHz, CDCl3) d K5.99 (q), K5.96 (9), 17.71 (t), 23.57
(q), 25.54 (3q), 25.64 (t), 25.66 (t), 26.33 (t), 26.90 (t), 40.71
(t), 50.08 (d), 60.43 (t), 73.60 (t).
1
123.4 (d), 139.7 (s), 171.2 (s). 30: H NMR (200 MHz in
CDCl3) d 1.64 (3H, m), 1.80 (4H, m), 2.04 (3H, s), 2.30 (6H,
m), 4.09 (2H, m); 13C NMR (50 MHz in CDCl3) d 19.1 (q),
21.0 (q), 23.3 (t), 30.8 (t), 32.0 (t), 32.2 (t), 34.8 (t), 63.2 (t),
120.6 (s), 148.2 (s), 171.2 (s).
3.1.5. 4-Methyl-1-oxaspiro[4.4]nonane (21). p-TsCl
(482 mg, 2.52 mmol) was added to a solution of 1-(3-
hydroxy-1-methylpropyl)cyclopentanol
(200 mg,
1.26 mmol) in pyridine (10 mL) at 0 8C and the mixture
was stirred for 43 h at 25 8C. After addition of aqueous
NaHCO3, the organic material was extracted into ether. The
ether extract was successively washed with aqueous 2 M
3.1.9. 3-Cyclopentylbutane-1,3-diol (20). To a solution of
the alcohol 35 (3.15 g, 11.56 mmol) in THF (20 mL) was
added n-Bu4NCl (1.0 M THF solution, 17.3 mL,
17.3 mmol) at 0 8C and the mixture was stirred for 3 h at

M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
9231
25 8C. After addition of water, the organic material was
extracted into ethyl acetate and the dried and concentrated
extract was subjected to column chromatography using
hexane and ethyl acetate to give the diol 20 (1.74 g, 95%) as
a colorless oil. FT-IR (film) 3361, 2958, 2868, 1454, 1052,
(1H, br s), 3.43 (1H, m), 9.90 (1H, dd, JZ3.3, 2.7 Hz); 13C
NMR (75 MHz, CDCl3) d 17.9 (q), 20.8 (t), 24.5 (t), 35.3 (t),
37.6 (t), 39.6 (s), 56.0 (t), 76.1 (d), 203.9 (s).
3.1.12. cis-Octahydro-3a-methylbenzofuran (22). To a
solution of triethylsilane (64 mg, 0.55 mmol) and trifluor-
oacetic acid (62 mg, 0.55 mmol) in dichloromethane (5 mL)
was added a solution of the hemiacetal 38 (29 mg,
0.18 mmol) in dichloromethane (3 mL) at K78 8C. The
mixture was stirred for 2 h at 0 8C. After aqueous workup,
the dried and concentrated ether extract was chromato-
graphed using pentane and ether to give the cis-ether 22
(21 mg, 83%) as a colorless oil. Spectral data were identical
with that of the product formed from the reaction of 20 with
TiCl4.
1
1016 cmK1, H NMR (600 MHz, CDCl3) d 1.22 (3H, s),
1.33–1.26 (1H, m), 1.46–1.40 (1H, m), 1.64–1.51 (5H, m),
1.72–1.64 (2H, m), 1.88 (1H, ddd, JZ14.3, 9.1, 4.7 Hz),
2.02 (1H, ddd, JZ17.5, 9.6, 8.2 Hz), 2.22 (1H, br s), 2.88
(1H, br s), 3.85–3.82 (1H, m), 3.95 (1H, ddd, JZ8.2, 3.3,
3.0 Hz); 13C NMR (150 MHz, CDCl3) d 23.92 (q), 25.90
(q), 25.91 (t), 26.60 (t), 27.25 (t), 40.81 (t), 50.45 (d), 59.87
(t), 75.57 (t); MS (CI) m/z 159 (MCC1), 141, 123, 113, 95
(base), 89, 81, 43; HR-MS (CI) m/z calcd for C9H18O2
(MCC1) 159.1385; Found 159.1370.
3.1.10. 2-Allyl-2-methylcyclohexanone (37). To a solution
of the enol acetate 36 (2.0 g, 13.0 mmol) in dioxane (50 mL)
was successively added allyl methyl carbonate (3.0 g,
25.9 mmol), 1,2-bis(diphenylphosphino)ethane (520 mg,
1.3 mmol), and tris(dibenzylidene-acetone)dipalladium(0)-
chloroform adduct (670 mg, 0.65 mmol), and the mixture
was stirred for 10 min at 25 8C. After addition of tributyltin
methoxide (840 mg, 2.62 mmol), the mixture was heated to
reflux for 10 h and then cooled to 25 8C. Saturated aqueous
NaCl and ice were added and the organic material was
extracted into ether. The organic phase was washed with
aqueous NaHCO3. The dried and concentrated extract was
chromatographed using hexane and ethyl acetate to give 37
(1.78 g, 90%) as a colorless oil. FT-IR (film) 3076, 2935,
2868, 1712, 1639, 1452, 1377, 1313, 1215, 1124, 995,
914 cmK1; 1H NMR (200 MHz, CDCl3) d 1.07 (3H, s), 1.72
(6H, m), 2.30 (4H, m), 5.31 (2H, m), 5.70 (1H, m); 13C
NMR (50 MHz, CDCl3) d 20.8 (t), 22.3 (q), 27.1 (t), 38.3 (t),
38.4 (t), 41.7 (t), 48.1 (s), 117.4 (t), 133.5 (d).
3.1.13. trans-2-(2-Chloro-1-methylcyclohexyl)ethyl ace-
tate (24a). NaBH4 (57 mg, 1.5 mmol) was added to a
solution of 37 (193 mg, 1.2 mmol) in 2-propanol (3 mL) at
0 8C and the mixture was stirred at room temperature for
7 h. After cooling to 0 8C, aqueous 2 M HCl was added and
the organic material was extracted into ether to give the
crude diol. This was dissolved in dichloromethane (2 mL)
and mixed with pyridine (0.2 mL) and CH3COCl (95 mg,
1.2 mmol). The mixture was stirred for 30 min at 0 8C. After
aqueous workup, the dried and concentrated organic extract
was subjected to column chromatography using hexane and
ethyl acetate to give the mono acetate 171 mg (69% in two
steps). FT-IR (film) 3467, 2933, 2862, 1738, 1722, 1454,
1392, 1367, 1247, 1136, 1053, 1032 cmK1 1H NMR
;
(200 MHz, CDCl3) d 0.97 (3H, s), 1.43 (10H, m), 2.04
(3H, s), 3.40 (1H, dd, JZ4.6, 3.0 Hz), 4.16 (2H, m); 13C
NMR (75 MHz, CDCl3) d 20.9 (t), 21.0 (q), 23.1 (t), 24.0
(q), 29.7 (t), 31.9 (t), 34.9 (t), 36.9 (s), 61.6 (t), 76.3 (d),
171.3 (s); HR-MS (EI) m/z calcd for C11H20O3 (MC)
200.1412; Found 200.1395. The cis-monoacetate (150 mg,
0.75 mmol) was dissolved in CCl4 (10 mL) and triphenyl-
phosphine (294 mg, 1.1 mmol) was added. The mixture was
heated to reflux for 58 h. After addition of hexane, the
mixture was filtered through a celite pad. The concentrated
filtrate was subjected to column chromatography using
hexane and ethyl acetate to give the crude mixture.
Purification by HPLC using YMC-Pack R and D SIL D-
Sil-5 10!250 mm column and hexane–ethyl acetate 40:1,
15 mL/min) gave 24a (21 mg, 13%), 43 (54 mg, 40%), and
44 (21 mg, 13%). The material 24a was identical with the
reaction product of 20a and TiCl4. 43: FT-IR (film) 3012,
2931, 2866, 2837, 1741, 1458, 1389, 1365, 1234, 1034,
3.1.11. cis-Octahydro-3a-methylbenzofuran-2-ol (38)
and trans-(2-hydroxy-1-methylcyclohexyl)-acetaldehyde
(39). NaBH4 (57 mg, 1.5 mmol) was added to a solution of
37 (152 mg, 1.0 mmol) in 2-propanol (5 mL) at 0 8C and the
mixture was stirred at 25 8C for 4 h. After cooling to 0 8C,
2 M aqueous HCl was added and the organic material was
extracted into ether. The dried and concentrated extract was
dissolved in aqueous CH3CN (2:1, 6 mL) and mixed with
4-methylmorpholine N-oxide (194 mg, 1.66 mmol) and 2%
aqueous OsO4 (4.0 mL, 0.08 mmol). The resulting mixture
was stirred at 25 8C for 10 h. After addition of aqueous
sodium thiosulfate at 0 8C, the organic material was
extracted into ethyl acetate, and the extract was washed
with aqueous 1M HCl and saturated NaHCO3. The dried and
concentrated extract was subjected to column chromato-
graphy using hexane and ethyl acetate to give a mixture of
triols. The crude product was dissolved in aqueous THF
(3:1, 8 mL), and mixed with NaIO4 (195 mg, 0.91 mmol) at
0 8C. The mixture was stirred at 0 8C for 3.5 h and then
water was added. The dried and concentrated ether extract
was subjected to column chromatography using hexane and
ether to give the crude material. HPLC using YMC-Pack R
and D Sil D-SIL-5 10!250 column and hexane–ether 3:1,
15 mL/min) afforded hemiacetal 38 (60 mg, 38%) and
hydroxy aldehyde 39 (39 mg, 25%) as colorless oils.
1
731 cmK1; H NMR (300 MHz, CDCl3) d 1.00 (3H, s),
1.68–1.34 (6H, m), 1.98–1.89 (2H, m), 2.03 (3H, s), 4.116–
4.08 (2H, m), 5.44–5.37 (1H, m), 5.62 (1H, dt, JZ6.0,
1.8 Hz); 13C NMR (50 MHz, CDCl3) d 19.19 (t), 21.18 (q),
25.08 (t), 27.73 (q), 33.53 (t), 35.03 (t), 40.75 (t), 61.87 (s),
126.21 (d), 135.59 (d), 171.24 (s). 44: FT-IR (film) 2939,
2864, 1739, 1454, 1373, 1250, 1036 cmK1 1H NMR
;
(300 MHz, CDCl3) d 0.95 (3H, s), 1.74–1.16 (8H, m),
2.00–1.82 (2H, m), 2.06 (3H, s), 3.62–3.47 (2H, m), 4.60
(1H, dd, JZ3.5, 3.3 Hz); 13C NMR (75 MHz, CDCl3) d
20.91 (t), 21.33 (q), 23.19 (t), 23.81 (q), 26.64 (t), 35.31 (t),
37.18 (t), 37.95 (t), 40.97 (t), 78.44 (d), 170.57 (s); MS (CI)
m/z 219 (MCC1), 159, 123 (base), 95, 43; HR-MS (CI) m/z
calcd for C11H20O2Cl (MCC1) 219.1152; Found 219.1154.
1
Hydroxy aldehyde 39: H NMR (300 MHz, CDCl3) d 0.92
(3H, s), 1.53 (8H, m),2.09 (2H, dd, JZ12.6, 5.5 Hz), 3.33

9232
M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
3.1.14. trans-2-(2-Chloro-1-methylcyclohexyl)-ethanol
(24). Sodium methoxide (28% solution in MeOH, 0.6 mL,
0.003 mmol) was added to a solution of 24a (7 mg,
0.32 mmol) in methanol (2 mL) and the mixture was stirred
at 25 8C for 3 h. Amberlite IR-120B was added to neutralize
the reaction mixture which was then filtered through a celite
pad and concentrated. The residue was subjected to column
chromatography using hexane and ethyl acetate to give 24
(5.7 mg, 99%). The spectral data were identical with that of
the reaction product of 20 and TiCl4.
chromatography using hexane and ethyl acetate to give a
crude mixture. Purification by HPLC using YMC-Pack R
and D SIL D-Sil-5 10!250 mm column and hexane–ethyl
acetate 40:1, 15 mL/min) afforded 23a (6 mg, 13%), 44
(10 mg, 26%), and 46 (8 mg, 18%). This 23a was identical
with the reaction product of 20a and TiCl4. 46: FT-IR (film)
1
2937, 2866, 1743, 1450, 1373, 1251, 1032, 985 cmK1; H
NMR (300 MHz, CDCl3) d 0.98 (3H, s), 1.90–1.24 (10H,
m), 2.05 (3H, s), 3.60–3.46 (2H, m), 4.60 (1H, dd, JZ3.9,
3.8 Hz); 13C NMR (75 MHz, CDCl3) d 18.12 (q), 20.91 (t),
21.37 (q), 23.79 (t), 26.94 (t), 35.64 (t), 37.45 (t), 40.57 (t),
43.88 (s), 77.52 (d), 170.66 (s); MS (CI) m/z 219 (MCC1),
159, 123 (base), 95; HR-MS (CI) m/z calcd for C11H20O2Cl
(MCC1) 219.1152; Found 219.1153.
3.1.15. trans-2-(2-Chloro-1-methylcyclohexyl)ethanol
(40). NaBH4 (19 mg, 1.0 mmol) was added to a solution
of 39 (156 mg, 1.0 mmol) in 2-propanol (3 mL) at 0 8C and
the mixture was stirred at 25 8C for 4 h. After cooling to
0 8C, aqueous 2 M HCl was added and the organic material
was extracted into ether. The dried and concentrated extract
was subjected to column chromatography using hexane and
ethyl acetate to give the trans-diol (129 mg, 82%) as a
colorless oil. FT-IR (film) 3320, 2937, 2867, 2360, 1450,
1147, 1076, 979 cmK1; 1H NMR (200 MHz, CDCl3) d 0.91
(3H, s), 1.47 (10H, m), 3.28 (2H, br s), 3.39 (1H, dd, JZ7.0,
4.0 Hz), 3.74 (2H, m); 13C NMR (75 MHz, CDCl3) d 14.7
(q), 21.2 (t), 25.0 (t), 30.0 (t), 38.0 (t), 39.2 (t), 46.7 (t), 57.8
(t), 76.0 (d); MS (EI) m/z(MCKH2O) 140.
3.1.18. cis-2-(2-Chloro-1-methylcyclohexyl)-ethanol (23).
Sodium methoxide (28% in methanol, 0.6 mL, 0.003 mmol)
was added to a solution of 23a (7 mg, 0.32 mmol) in
methanol (2 mL), and the mixture was stirred at 25 8C for
3 h. Amberlite IR-120B was added to neutralize the reaction
mixture which was filtered through a celite pad and
concentrated. The residue was subjected to column
chromatography using hexane and ethyl acetate to give 23
(4.6 mg, 81%). The spectral data were identical with that of
the reaction product of 20 and TiCl4.
3.1.19. cis-2-Allyl-1-methyl-cyclohexanol (42). MeMgCl
(3 M THF solution, 0.45 mL, 1.24 mmol) was added to a
solution of 41 (700 mg, 5.1 mmol) in THF (5 mL) at 0 8C,
and the mixture was stirred for 30 min at the same
temperature. Aqueous workup following chromatography
of the concentrated ether extract using hexane and ethyl
acetate gave 42 (585 mg, 73%). FT-IR (film) 3365, 2937,
2862, 1651, 1446, 1377, 1265, 1159, 1056, 1018 cmK1; 1H
NMR (200 MHz, CDCl3) d 1.26 (3H, s), 1.52 (10H, m), 3.70
(2H, m); 13C NMR (50 MHz, CDCl3) d 22.0 (t), 25.7 (t),
26.9 (t), 28.7 (q), 32.5 (t), 40.0 (t), 43.4 (t), 59.6 (t), 70.9 (s);
HR-MS (EI) m/z calcd for C9H18O2 (MC) 158.2407; Found
158.2404.
3.1.16. trans-Octahydro-3a-methylbenzofuran (28). p-
TsCl (197 mg, 1.0 mmol) was added to a solution of the
diol 40 (78 mg, 0.49 mmol) in pyridine (5 mL), and the
mixture was stirred for 5 h at 25 8C. After aqueous workup,
extraction of the product into ether, and concentration of the
dried extract furnished the crude product that was subjected
to column chromatography using hexane and ethyl acetate
to give 28 (23 mg, 33%) as a colorless oil. FT-IR (film)
2935, 2873, 2360, 1456, 1377, 1279, 1147, 1070, 1031 cmK1
;
1H NMR (200 MHz, CDCl3) d 0.85 (3H, s), 1.53 (10H, m),
3.06 (1H, dd, JZ3.8, 3.2Hz), 3.87 (2H, ddd, JZ8.4, 6.6,
3.2 Hz); 13C NMR (50 MHz in CDCl3) d 16.8 (q), 21.1 (t),
24.6 (t), 25.4 (t), 35.8 (t), 40.1 (t), 40.3 (s), 65.0 (t), 84.6 (d);
HR-MS (CI) m/z calcd for C9H16O (MCK1) 139.1123;
Found 139.1133.
3.1.20. cis-Octahydro-7a-methylbenzofuran-2-ol (43). To
a solution of 42 (305 mg, 2.0 mmol) in aqueous acetonitrile
(2:1, 15 mL) was added 4-methylmorpholine N-oxide
(469 mg, 4.0 mmol) and 2% aqueous solution of OsO4
(1.0 mL, 0.02 mmol). The resulting mixture was stirred at
25 8C for 3 h. After addition of sodium thiosulfate at 0 8C,
the organic material was extracted into ethyl acetate, and the
extract was washed with aqueous 1M HCl and saturated
NaHCO3. The dried and concentrated extract was subjected
to column chromatography using hexane and ethyl acetate
to give the desired triols. The crude product was dissolved in
aqueous THF (3:1, 16 mL) and mixed with NaIO4 (381 mg,
1.78 mmol) at 0 8C. The mixture was stirred at 0 8C for 4 h,
and then water was added. The dried and concentrated ether
extract was subjected to column chromatography using
hexane and ether to give 43 as a colorless oil.
3.1.17. cis-2-(2-Chloro-1-methylcyclohexyl)ethyl acetate
(23a). CH3COCl (25 mg, 0.32 mmol) was added to a
solution of the diol 40 (43 mg, 0.27 mmol) in dichloro-
methane (2 mL) and pyridine (44 mL), and the mixture was
stirred at 0 8C for 30 min. Aqueous workup and column
chromatography of the crude material using hexane and
ethyl acetate furnished the monoacetate (43 mg, 80%) as a
colorless oil. FT-IR (film) 3458, 2929, 2862, 1738, 1714,
1
1365, 1236, 1030 cmK1; H NMR (200 MHz, CDCl3) d
0.93 (3H, s), 1.55(10H, m), 2.05 (3H, s), 3.39 (1H, dd, JZ
6.4, 3.8 Hz), 4.19 (2H, t, JZ7.8 Hz); 13C NMR (75 MHz,
CDCl3) d 16.6(q), 20.9 (q), 20.9(t), 24.2 (q), 30.3 (t), 35.8
(t), 37.4 (s), 39.3 (t), 61.4 (t), 75.4 (d), 171.2 (s); HR-MS
(EI) m/z calcd for C9H18O2 (MC) 158.2407; Found
158.2411.
3.1.21. cis-Octahydro-7a-methylbenzofuran (25). To a
solution of triethylsilane (110 mg, 0.95 mmol) and trifluoro-
acetic acid (108 mg, 0.95 mmol) in dichloromethane (5 mL)
was added a solution of hemiacetal 43 (50 mg, 0.32 mmol)
in dichloromethane (3 mL) at K78 8C. The mixture was
stirred for 2 h at 0 8C. Aqueous workup and chromatography
The above acetate (43 mg, 21.5 mmol) was dissolved in
CCl4 (5 mL) and triphenylphosphine (84 mg, 0.32 mmol)
was added. The mixture was heated to reflux for 68 h. After
addition of pentane, the mixture was filtered through a celite
pad. The concentrated filtrate was subjected to column

M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
9233
88, 4750–4751. (f) van Tamelen, E. E.; Willett, J. D.; Clayton,
R. B.; Load, K. E. J. Am. Chem. Soc. 1966, 88, 4752–4754.
3. (a) Corey, E. J.; Matsuda, S. P. T.; Bartel, B. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 2211–2215. (b) Corey, E. J.; Virgil,
S. C.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Singh, V.;
Sarshar, S. J. Am. Chem. Soc. 1995, 117, 11819–11820.
(c) Corey, E. J.; Cheng, H. Tetrahedron Lett. 1996, 37,
2709–2712. (d) Corey, E. J.; Cheng, H.; Baker, C. H.;
Matsuda, S. P. T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997,
119, 1277–1288. (e) Corey, E. J.; Cheng, H.; Baker,
C. H.; Matsuda, S. P. T.; Li, D.; Song, X. J. Am. Chem. Soc.
1997, 119, 1289–1296. (f) Dodd, D. S.; Oehlschlager, A. C.
J. Org. Chem. 1992, 57, 2794–2803. (g) Zheng, Y. F.;
Oehlschlager, A. C.; Georgopapadakou, N. H.; Hartman,
P. G.; Scheliga, P. J. Am. Chem. Soc. 1995, 117, 670–680.
4. (a) Sato, T.; Abe, T.; Hoshino, T. Chem. Commun. 1998,
2617–2618. (b) Zheng, Y. F.; Abe, I.; Prestwich, G. D. J. Org.
Chem. 1998, 63, 4872–4873. (c) Kushiro, T.; Shibuya, M.;
Ebizuka, Y. J. Am. Chem. Soc. 1999, 121, 1208–1216.
5. (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y.
Tetrahedron Lett. 1983, 24, 2581–2584. (b) Nishizawa, M.;
Morikuni, E.; Asoh, K.; Kan, Y.; Uenoyama, K.; Imagawa, H.
Synlett 1995, 169–170.
of the concentrated ether extract using pentane and ether
gave 25 (35 mg, 76%) as a colorless oil. The spectral data
were identical with that of the reaction product of 20 and
TiCl4.
3.1.22. cis-2-(2-Chloro-2-methylcyclohexyl)-ethanol (26).
NaBH4 (14 mg, 0.37 mmol) was added to a solution of 43
(115 mg, 0.74 mmol) in 2-propanol (5 mL) at 0 8C, and the
mixture was stirred at 25 8C for 4 h. After cooling the
reaction mixture to 0 8C, aqueous 2M HCl was added and
the organic material was extracted into ether to give the
crude diol that was purified by column chromatography
using hexane and ethyl acetate; 100 mg (85%). FT-IR (film)
3365, 2937, 2862, 1651, 1446, 1377, 1265, 1159, 1056,
1
1018 cmK1; H NMR (200 MHz, CDCl3) d 1.26 (3H, s),
1.52 (10H, m), 3.70 (2H, m); 13C NMR (50 MHz, CDCl3) d
22.0 (t), 25.7 (t), 26.9 (t), 28.7 (q), 32.5 (t), 40.0 (t), 43.4 (t),
59.6 (t), 70.9 (s); HR-MS (EI) m/z calcd for C9H18O2 (MC)
158.2407; Found 158.2411.
The above diol (75 mg, 0.47 mmol) was dissolved in ether
(5 mL), and water (10 mL) and concd HCl (35%, 30 mL)
were added at 25 8C. The mixture was stirred for 15 min at
this temperature. After aqueous workup, the concentrated
ether extract was chromatographed using hexane and ether
to give 26 (25 mg, 30%) as a colorless oil. The spectral data
were identical with that of the reaction product of 20 and
TiCl4.
6. (a) Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Am. Chem.
Soc. 1985, 107, 522–523. (b) Nishizawa, M.; Takenaka, H.;
Hayashi, Y. J. Org. Chem. 1986, 51, 806–813.
7. Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Am. Chem., Soc.
1984, 106, 4290–4291. The structure of compound 14 of this
reference paper is wrong due to simple mistake, and the correct
structure is 12 of the present paper.
8. Corey, E. J.; Wood, H. B., Jr J. Am. Chem. Soc. 1996, 118,
11982–11983.
Acknowledgements
9. (a) Nishizawa, M.; Takao, H.; Iwamoto, Y.; Yamada, H.;
Imagawa, H. Synlett 1998, 76–78. (b) Nishizawa, M.; Takao,
H.; Iwamoto, Y.; Yamada, H.; Imagawa, H. Synlett 1998,
79–80.
This study was financially supported by a Grant-in-Aid from
Yamada Science Foundation and by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science, and
Technology of Japanese Government.
10. (a) van Tamelen, E. E.; Willet, J.; Schwartz, M.; Nadeau, A.
J. Am. Chem. Soc. 1966, 88, 5937–5938. (b) Sharpless, K. B.;
van Tamelene, E. E. J. Am. Chem. Soc. 1969, 91, 1848–1849.
(c) Berckmoes, K.; De Clercq, P. J. J. Am. Chem. Soc. 1995,
117, 5857–5858.
Supplementary data
11. (a) Jenson, C.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119,
10846–10854. (b) Hess, B. A. J. Am. Chem. Soc. 2002, 124,
10286–10287. (c) Hess, B. A., Jr Org. Lett. 2003, 5, 165–167.
(d) Gao, D.; Pan, Y.-K. J. Am. Chem. Soc. 1998, 120,
4045–4046.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2004.07.064
12. Olah, G. A.; Bollinger, J. M.; Cupas, C. A.; Lukas, J. J. Am.
Chem. Soc. 1967, 89, 2692–2694.
References and notes
13. Harding, K. H.; Clement, K. S. J. Org. Chem. 1984, 49,
2049–2050.
14. Nishizawa, M.; Iwamoto, Y.; Takao, H.; Imagawa, H.;
Sugihara, T. Org. Lett. 2000, 2, 1685–1687.
1. (a) Hoshino, T.; Sato, T. Chem. Comm. 2002, 291–301.
(b) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R.
Angew. Chem. Int., Ed. Engl. 2000, 39, 2812–2833. (c) Abe, I.;
Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93,
2189–2206.
15. Nishizawa, M.; Yadav, A.; Imagawa, H.; Sugihara, T.
Tetrahedron Lett. 2003, 44, 3867–3870.
16. Dhokte, U. P.; Khau, V. V.; Hutchison, D. R.; Martinelli,
M. J. Tetrahedron Lett. 1998, 39, 8771–8774.
2. (a) Woodward, R. B.; Bloch, K. J. Am. Chem. Soc. 1953, 75,
2023–2024. (b) Eschenmoser, A.; Ruzicka, L.; Jeger, O.;
Arigoni, D. Helv. Chim. Acta 1955, 38, 1890–1904. (c) Stork,
G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77,
5068–5077. (d) Cornforth, J. W.; Cornforth, R. H.; Donninger,
C.; Popjak, G.; Shimizu, Y.; Ichii, S.; Forchielli, E.; Caspi, E.
J. Am. Chem. Soc. 1965, 87, 3224–3228. (e) Corey, E. J.;
Russey, W. E.; Ortiz de Montellano, J. J. Am. Chem. Soc. 1966,
17. (a) Rautenstrauch, V. Helv. Chim. Acta 1974, 57, 496–508.
(b) Yadav, J. S.; Mysorekar, S. V. Syn. Commun. 1989, 19,
1057–1060.
18. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
4713–4714.
19. Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc.,
Chem. Commun. 1986, 1568–1569.

9234
M. Nishizawa et al. / Tetrahedron 60 (2004) 9223–9234
20. Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86–87.
21. Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2 1993,
187–198.
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski,
J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J.
B.; Cioslowski, J.; Ortiz, J. V.; Stefanov; Liu, G.; Liashenko,
A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98
(Revision A.1), Gaussian Inc., Pittsburgh, PA, 1998.
22. Dewar, M. J. S.; Reynolds, C. H. J. Am. Chem. Soc. 1984, 106,
1744–1750.
23. (a) Farcasiu, D.; Lukinskas, P. J. Phys. Chem. A 1998, 102,
10436–10441. (b) Farcasiu, D.; Hancu, D. J. Am. Chem. Soc.
1999, 121, 7173–7181. (c) Farcasiu, D.; Norton, S. H.; Hancu,
D. J. Am. Chem. Soc. 2000, 122, 668–676.
24. Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984,
80, 3265–3269.
28. The largest gradients for the frozen internal coordinates of
anion were of the order of 10K2
25. Peng, C.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comp.
Chem. 1996, 17, 49–56.
.
29. (a) Wendt, K.; Poralla, K.; Schltz, G. E. Science 1977, 277,
1811–1815. (b) Feil, C.; Sussmath, G.; Jung, K. Poralla. Eur.
J. Biochem. 1996, 242, 51–55. (c) Sato, T.; Hoshino, T.;
Biosci, R. Biotechnol. Biochem. 1999, 63, 2189–2198.
(d) Morita, M.; Shibuya, M.; Kushiro, T.; Masuda, K.;
Ebizuka, Y. Eur. J. Biochem. 2000, 267, 3453–3460.
26. Schlegel, H. B. Theo. Chim. Acta 1984, 66, 33–36.
27. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich,
S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;