Synthesis and circular dichroism of steroids with 2,3-dihydro-1-benzofuran and 4H-benzopyran chromophores; revision of the absolute configuration of some norneolignans from Krameria cystisoides

Article abstract of DOI:10.1039/a905697a

Starting from cholesterol the 2,3-dihydrobenzo[b]furans 12a, 12b, and the 4H-benzopyran derivative 14 with known absolute conformation were synthesized by a stereocontrolled sequence. The same helicity rule was found to be valid for both chromophores; the P/M helicity of the heteroring leads to a negative/positive CD within the α-band. On the basis of this rule the absolute configuration of norneolignans 24-26 isolated from Krameria cystisoides was also revised. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a905697a

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Synthesis and circular dichroism of steroids with 2,3-dihydro-1-
benzofuran and 4H-benzopyran chromophores; revision of the
absolute configuration of some norneolignans from Krameria
cystisoides
1
Tibor Kurtán,a Eszter Baitz-Gács,b Zsuzsa Majerc and Sándor Antus*a
a Department of Organic Chemistry, Lajos Kossuth University, P.O.B. 20, H-4010 Debrecen,
Hungary
b Institute of Chemistry, C. R. C., Hungarian Academy of Sciences, P.O.B. 32,
H-1515 Budapest, Hungary
c Institute of Organic Chemistry, L. Eötvös University, H-1518 Budapest 112, P.O.B. 32,
Hungary
Received (in Cambridge, UK) 14th July 1999, Accepted 3rd November 1999
Starting from cholesterol the 2,3-dihydrobenzo[b]furans 12a, 12b, and the 4H-benzopyran derivative 14 with known
absolute conformation were synthesized by a stereocontrolled sequence. The same helicity rule was found to be valid
for both chromophores; the P/M helicity of the heteroring leads to a negative/positive CD within the α-band. On the
basis of this rule the absolute configuration of norneolignans 24–26 isolated from Krameria cystisoides was also
revised.
conformation other than the regular half chair. Snatzke and
Introduction
co-workers3,5 have found that the substitution pattern of the
The 2,3-dihydro-1-benzofuran and 4H-benzopyran chromo-
phores are found in many naturally occurring chiral O-hetero-
aromatic ring or the substituent at the benzylic positions cannot
1
always be neglected. Namely, the sign of the B2u CE can be
cycles possessing a wide range of remarkable biological
reversed by some patterns of substitution of the aromatic ring,
as well as by a pseudoaxial substituent at the benzylic carbon
atom.
Therefore, to unambiguously determine the absolute con-
figuration of this type of compound by chiroptical methods, it
activity.1 In many cases chiroptical methods (ORD or CD) have
been used to determine their absolute configuration.2 These
examinations were usually based on a simple comparison of
their chiroptical data with those of the analogous compounds
whose absolute configuration had been deduced by chemical
is necessary to examine thoroughly which form of Snatzke’s
correlation or X-ray analysis. Although this method is widely
helicity rule is valid for both the studied and the reference ring-
used in natural product chemistry, there is a possibility that the
systems or compounds. To continue our program on the chiro-
absolute configuration for the above-mentioned chromophore
ptical properties of naturally occurring O-heterocycles,6 we
systems is incorrectly assigned. In terms of chromophore sys-
investigated a possible extension of Snatzke’s helicity rule to the
tems, chiral 2,3-dihydrobenzo[b]furan and 4H-benzopyran in
2,3-dihydrobenzo[b]furan and 4H-benzopyran chromophore
fact belong to the benzene chromophores with a chiral second
systems. In order to study the relationship between the stereo-
sphere according to Snatzke’s terminology.3 For this type of
chemistry and the chiroptical properties of these chromophore
benzene chromophore a simple helicity rule was discovered by
systems, using our method,7 we synthesized a few derivatives, in
Snatzke and Ho4 as depicted in Fig. 1.
If pseudoaxial substituents are not present at the benzylic
which the 2,3-dihydro-1-benzofuran and the 4H-benzopyran
rings are connected to ring A of a steroid as a chiral perturber.
Below we discuss their synthesis and CD spectra.
carbon atoms, P-helicity of the non-aromatic ring leads to a
positive Cotton effect (CE) within the 1B2u transition (α-band),
and M-helicity leads to a negative Cotton effect. The terms
Results and discussion
P- and M-helicity, which describe the chirality, can be used even
in those cases when the chiral non-aromatic ring adopts a
2,3-Dihydro-1-benzofurocholestanes have not yet been
described in the literature. The synthesis of the desired model
compounds (12a,b and 13) containing a chiral second sphere
with M- and P-helicity, respectively, started from cholesterol
(1). Cholesterol (1) was converted to 5α-cholestan-3-one (2) in
two steps as described in the literature.8 Compound 2 was then
treated with 2-benzyloxyphenylmagnesium bromide prepared
from 2-benzyloxybromobenzene9 in THF in the presence of
magnesium turnings. This resulted in a 1:1 mixture of the C-3
epimeric alcohols 3a and 3b, which could be separated by
column chromatography on silica gel. The stereochemistry of
3a was established by NOE experiments. Crystallisation from
methanol of the alcohol 3a with the bulky 2-benzyloxy group in
an equatorial position furnished a pure crystalline compound
with mp 79–81 ЊC; the 3β-hydroxy isomer 3b suffered elimin-
Fig. 1 Sign of the second sphere contribution of tetralin (tetrahydro-
isoquinoline) derivatives to the B2u band CD. The arrow indicates the
direction of projection. P and M refer to the absolute conformation
(helicity) of the non-aromatic ring.
1
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453

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ation of water under similar conditions to give the cholest-∆2-
ene derivative 4. The olefin 4 was also prepared from 3a in the
presence of toluene-p-sulfonic acid in dry toluene at room tem-
perature in 48% yield (Scheme 1). The ∆2 position of the double
methane at 0 ЊC. It is reasonable to assume that by cleavage of
the C-3 carbon–oxygen bond of 5a, a stable carbocation was
formed first, which could be stabilized by the migration of the
hydrogen from C-2 (A→B) followed by the formation of a
carbonyl group at C-2 as depicted in Scheme 2. According to
Scheme 2 Reagents: i, BF3ؒOEt2, CH2Cl2, 0 ЊC.
this mechanism, the 2-benzyloxyphenyl group must be attached
to C-3 in the thermodynamically less favoured axial position in
6a. In accordance with this stereochemistry, a substantial NOE
effect could be detected in 6a between the H-1α proton and the
3Ј,6Ј-protons of the aryl group at C-3. This stereochemistry was
also supported by epimerization at C-3. Treatment of 6a with
sodium methoxide in a 1:1 mixture of methanol and dichloro-
methane resulted in 6b, carrying the bulky 2-benzyloxyphenyl
group in a pseudoequatorial position. This configuration of the
aryl group in 6b was unequivocally determined by NMR and
CD measurements. The diagnostic NMR spectral parameters
of H-3 (δ = 3.84 ppm, J = 12.8 and 6.3 Hz) are indicative of an
axially oriented hydrogen at C-3. According to the octant rule,11
the smaller positive n→π* band CE of the carbonyl group
compared to that of the 5α-cholestan-2-one (∆ε ϩ2.95) proved
the equatorial orientation of the aryl group at C-3. Reduction
of 6b with lithium aluminium hydride in THF took place with
high stereoselectivity to furnish a ca. 12:1 mixture of the
corresponding alcohols 7 and 8, which were separated by flash
chromatography. The configuration of the hydroxy group at
C-2 in 7 was determined unambiguously by means of the coup-
ling constants of H-2 and the absence of an NOE effect
between H-2 and the C-19 methyl protons.
Starting from 7, the main product of the reduction of 6b, we
intended to synthesize the trans-fused 2,3-dihydro-1-benzo-
[b]furan derivative 13 in three steps (7→9→10→13) following
Scheme 1 Reagents: i, ref. 8; ii, 2-BnO-C6H5Br, Mg, THF; iii, toluene,
PTSA, room temp.; iv, m-CPBA or DMD, CH2Cl2, room temp.; v,
BF3ؒOEt2, CH2Cl2, 0 ЊC; vi, NaOMe, MeOH–CH2Cl2.
bond in 4 was established by NMR (decoupling and HETCOR)
experiments. Epoxidation of 4 was performed with m-chloro-
perbenzoic acid in dichloromethane at room temperature as the
next step of the synthesis of the target molecules 12a,b and 13.
In agreement with our expectations, the attack of the reagent
took place at the less-hindered α-side of the steroid nucleus to
afford the thermodynamically more stable α-epoxide 5a as the
main product, in which the 2-benzyloxyphenyl group adopted a
quasiequatorial position. This stereochemistry was supported
by an NOE effect between the C-10 methyl group and the proton
at C-2. TLC monitoring of the epoxidation of 4 clearly showed
that a small amount of the β-epoxide 5b was also formed, but it
was transformed very quickly to the cholestan-2-one 6b under
the acidic conditions of the epoxidation. Although this process
could be stopped by using dimethyldioxirane (DMD) as a neu-
tral oxidizing agent,10 isolation of 5b failed because of its high
instability. Rearrangement of the epoxide 5a to the correspond-
ing ketone derivative 6a was carried out by treatment with a
catalytic amount of boron trifluoride–diethyl ether in dichloro-
our earlier methodology,12 but attempts to prepare the mesylate
9 under standard conditions were completely unsuccessful.
Therefore, after removal of the benzyl protecting group
(7→11) by catalytic hydrogenation over palladium on charcoal
in THF, ring closure was attempted by treating 11 with boron
trifluoride–diethyl ether in dry dichloromethane. As shown in
Scheme 3, we supposed that the carbocation A could be gener-
ated from 11 by a Lewis acid which would give 13 and 12a by
the attack of the phenolic hydroxy group from the α- and β-side
of the steroid nucleus, respectively.
TLC monitoring of the reaction showed that three products
were formed instead of the expected two, which were isolated
by means of preparative TLC. Their structures were elucidated
454
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Scheme 3 Reagents: i, BF3ؒOEt2, CH2Cl2, room temp.
by spectroscopic methods (MS, NMR) and chemical correl-
ations. Although the MS and elemental analysis of the main
product 14 (mp 124–125 ЊC) were in good agreement with the
molecular formula of the expected 2,3-dihydro-1-benzofuran
derivatives 12a, 13 (C35H50O), these structures were unambigu-
ously excluded since the 1H and 13C NMR spectra revealed that
the oxygen atom is bonded to a quaternary carbon. From an
HMBC experiment this carbon was identified as C-1.
This unexpected transformation of 11 to 14 can be explained
by a threefold hydride shift (A→B→C→D) starting from
the carbocation A as depicted in Scheme 3. The structure of
the second major compound (mp 130–132 ЊC), isolated in
17% yield, was also determined by NMR and MS to be the
1-benzofuran derivative 16, which means that the expected ring
closure of 11 via the carbocation A to 12a or 13 was apparently
followed by dehydrogenation to result in 16 in moderate yield.
In order to clarify the route of this transformation, the cholest-
∆2-ene 15 was synthesized in three steps from the alcohol 17,
prepared from the ketone 6a [6a→17, (18)→19→15, see the
Experimental section].
According to our assumption, both carbocations A and B
could lose a hydrogen to give 15, whose reaction with boron
trifluoride–diethyl ether could result in 16. To confirm these
speculations, 15 was transformed to 16, 12a and 14.† It is note-
worthy that the presence of the trans-fused 2,3-dihydro-
1-benzofuran derivative 13 could not be detected in the
transformation of either 11 or 15 with BF3ؒOEt2, which is in
good agreement with the observation of Rupprecht et al.13
Quantum chemical calculations and stereocontrolled synthetic
studies clearly showed that the cis-fused 2,3-dihydro-1-
benzofuran ring system is 3 kcal molϪ1 more stable than the
trans system. The synthesis of 16 was also achieved via a more
simple route starting from the ketone 6b. As shown in Scheme
4, on treating 6b with excess boron trifluoride–diethyl ether
in dichloromethane, the Lewis acid first cleaved the benzyl
protecting group to afford the hydroxyketone 20, which then
spontaneously cyclized to 16 via the hemiketal 21. Catalytic
hydrogenation of 16 resulted in 12a and the other cis-fused 2,3-
dihydro-1-benzofuran 12b in good yield (79%), which also
served as a suitable model compound for our CD studies.
According to the Dreiding model of 12a, it seemed obvious
to suppose that the ring A of the cholestane skeleton adopts the
thermodynamically more stable chair conformation, to which
the heteroring is fused at C-2 and C-3 in an envelope conform-
ation with an M-helicity defined by the torsional angle of
C-7Јa, O, C-2, C-3. In this stereochemistry the substituted
† The reaction was followed by TLC using hexane as the eluent and the
formerly assigned compounds as standards (for comparison).
J. Chem. Soc., Perkin Trans. 1, 2000, 453–461
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Fig. 2 Ring inversions of 12a.
1
Fig. 3 B2u (α) band CE of compound 12a in hexane (– – –) and in
acetonitrile (——).
ring A accompanied by P-helicity, however, can be excluded.
This conformation would lead to the trans-diaxial orientation
of the H-1β and H-2 protons, which is in contradiction with the
measured value of the J1β,2 coupling (1.5 Hz). Moreover, the
presence of a strong NOE connection of C-19 methyl protons
with H-1β and the absence of this connection with H-1α
corroborate that the participation of the boat conformer in the
conformational equilibrium is also negligible.
Inspection of the Dreiding model of 12b reveals that in the
real chair conformation of the steroid ring A, the H-5 proton is
in the shielding zone of the aryl ring. By contrast, both the
chemical shift of this proton (1.12 ppm) and the coupling con-
stants of H-3 with the H-4α and H-4β protons (1.0 and 7.0 Hz,
respectively) indicate that the preferred conformation of ring A
is a distorted chair, where the C-4Јa, C-3, C-4, C-5 torsional
angle is somewhat flattened. In this conformation the aryl
residue is in a pseudoequatorial position which causes the
P-helicity of the heteroring (Fig. 4). In addition to the coupling
constant information the measured NOE effects also exclude
the notable participation of the chair form in the conform-
ational equilibrium. In that conformation a significant NOE is
expected between the H-4β and C-19 methyl protons, which was
not observable. This is in agreement with the fact that 12b
shows a strong negative Cotton effect with pronounced fine
structure within the α band (∆ε for 0–0 line is Ϫ3.30 at 289 nm)
in n-hexane, which is somewhat smaller in acetonitrile (∆ε
Ϫ2.50 at 287 nm) (Fig. 5).
Scheme 4 Reagents: i, BF3ؒOEt2, CH2Cl2, room temp.; ii, H2, Pd(C),
THF.
phenyl group at C-3 would assume equatorial orientation while
the oxygen bridge at C-2 would be in the axial position.
1
Although the H NMR data of 12a in d12-cyclohexane solu-
tion were in complete agreement with this stereochemistry,
the coupling constants between the proton at C-2 and the
α- and β-protons at C-1 (J = 5.0 and 1.5 Hz, respectively) clearly
showed that the preferred conformation of ring A of the steroid
moiety differs from a real chair form. The coupling data are
consistent with a distorted chair conformation of ring A, where
the aryloxy group is shifted away from the axial orientation to
relieve the steric strain between the C-2–O bond and the C-10
methyl group (Fig. 2). However, this conformational change of
ring A did not invert the helicity of the heteroring. The CD
spectrum of 12a in n-hexane shows a positive Cotton effect
(∆ε 0.89 at 279 nm) within the α band, and a smaller positive
one in acetonitrile (∆ε 0.32 at 279 nm), whose first line
wavelengths (0–0 transition) are in good agreement with the
predicted values14 (286 nm) (Fig. 3).
The decrease of the ∆ε value with the increasing polarity of
the solvent indicated that C-1 moves upward by a greater extent
which causes the heteroring to shift from the envelope con-
formation toward the plane of the aromatic ring. The very
small ∆ε value of the α band CE in acetonitrile reflects the fact
that the heteroring approaches a conformation which is pseudo-
achiral (C-7a–O and C-3–C-4a bonds are differently polarized)
since the heteroring becomes almost planar while C-2 moves
into the plane of the benzene ring, and the second sphere
contribution becomes almost zero. The notable presence of the
twist boat conformation as an extreme case of the distortion of
It is to be noted that the absolute values of the α band CE of
12b both in n-hexane and acetonitrile are significantly larger
than those of 12a which compares favourably with the NMR
data. The J1β,2 and J2,3 coupling constants of 12b (6.9 and 7.9
Hz, respectively) reflect a more puckered heteroring than that
of 12a (the corresponding J1α,2 and J2,3 values in 12a are 5.0 and
6.5 Hz, respectively). The CD data can be explained by the
sector rule revealed by Dornhege and Snatzke.15 According to
1
this rule, shown in Fig. 6, the measured positive CE for B2u
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Fig. 4 Ring inversions of 12b.
Scheme 5 Conformations of heteroring of 12a (R1 = Hα, R2 = C-1,
R3 = C-4, R4 = Hα), 12b (R1 = C-1, R2 = Hβ, R3 = Hβ, R4 = C-4).
1
ring is fixed in a half-chair conformation with P-helicity (tor-
sion angle is defined by C-17, C-16, C-24, C-1), any conform-
ational change of the heteroring is totally impossible because
of the annulation with ring A of the steroid skeleton. The
negative sign of the α band CE can be predicted according to
our former rule,7b although a substituent at the benzylic
position (C-16) is present. In this case the heteroring cannot
adopt a sofa conformation unlike the 4-substituted flavanone
derivatives,5 and therefore the contribution of the chiral third
sphere must be smaller than the second as usually expected, and
this determines the sign of the α band CD.
Fig. 5 B2u (α) band CE of compound 14 in acetonitrile (– – –) and 12b
in acetonitrile (——) and in hexane (– – —— – –).
Fig. 6 Projections perpendicular to (a) and along (b) the long axis
of the benzene ring. P-helicity of the envelope conformation leads to
negative Cotton effects of the α band CE of 22 (X = NH3ϩ, R1 = OH,
R2 = H) and 23 (X = NH3ϩ, R1 = H, R2 = OH).
Conclusion
The synthesis and the study of the chiroptical properties of 2,3-
dihydro-1-benzofuran and 4H-benzopyran derivatives with
rigid and known conformation were performed. It was found
that the same helicity rule is valid for both chromophores: the
P/M helicity of the heteroring leads to a negative/positive CD
(α band) transition of 12a reflects the M-helicity of its
heteroring.
Since the plane of the benzene ring itself is not a nodal plane,
contributions have the same signs above and below this plane.
Therefore, epimerization at the benzylic carbon atom (Hα or
Hβ at C-3) or at both chiral centers does not change the sign
of the Cotton effect, as long as the chirality of the envelope
conformation does not change. If both 12a and 12b adopted
the chair conformation of ring A of the cholestane skeleton,
the helicity of both heterorings would be M and their Cotton
effect would have the same sign, but 12b turns over P-helicity
as C-4 moves upward flipping ring A into a distorted chair
(Scheme 5). This is in agreement with the coupling constants
measured between H-4α, H-4β and H-3 in d12-cyclohexane (J4α,3
1.0 Hz, J4β,3 7.0 Hz). In addition, J1α,2 was found to be 10.5 Hz
which unambiguously shows that H-2 is axially oriented. The
difference in the value of J2,3 of 12a and 12b (6.5 and 7.9 Hz,
respectively) is mostly due to the different degree of distortion
of ring A.
1
within the B2u (α) band. Considering this helicity rule, the
2R,3R configuration for norneolignans 24–26 isolated from
Krameria cystisoides2d must be revised (Chart 1).
Since the CD spectra of 24 and 25 published by Achenbach
and co-workers2d exhibit a negative Cotton effect at 281 nm,
which corresponds well with the predicted 1B2u (α band) transi-
tion of the dihydro-1-benzofuran chromophore, their hetero-
rings should adopt P-helicity according to the above-mentioned
helicity rule. Taking into account that the substituents attached
to the heteroring at C-2 and C-3 are equatorially oriented in
both cases (J2,3 8.9 and 9.3 Hz), their absolute configurations
are 2S,3S. As 26 was chemically correlated with 24, its absolute
configuration must also be the opposite from that assigned
previously.
In the CD spectrum of 14 four Cotton effects were observed
in acetonitrile, of which the band with negative sign at the
longest wavelength could be unequivocally assigned to the 1B2u
transition of the 4H-benzopyran chromophore. Since its hetero
Experimental
Melting points were determined with a Kofler hot-stage appar-
atus and are uncorrected. Microanalyses were performed in the
J. Chem. Soc., Perkin Trans. 1, 2000, 453–461
457

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monohydrate (5.2 g, 27.33 mmol) were stirred in dry toluene for
24 h at room temperature and then poured into water. After
extraction with toluene and evaporation of the solvent, the
crude product was crystallized from acetone to give white
crystals of 4 (5.6 g, 48%). Mp 110–112 ЊC, [α]D20 = ϩ56.4 (c 0.12
in chloroform) (Found: C, 86.8; H, 10.1; C40H56O requires C,
86.9; H, 10.2%); νmax (KBr)/cmϪ1 3026, 2930, 2866, 2850, 1598,
1578, 1498; δH(400 MHz, CDCl3) 0.65 (3H, s, H-18), 0.70 (1H,
m, H-9), 0.82 (3H, s, H-19), 0.86 (6H, d, J 6.8, H-26 and H-27),
0.88 (1H, m, H-7), 0.92 (3-H, d, J 6.3, H-21), 0.98 (1H, m,
H-17), 0.98 (1H, m, H-22), 1.00 (1H, m, H-15), 1.05 (1H, m,
H-14), 1.10 (1H, m, H-12), 1.10 (1H, m, H-23), 1.08–1.12 (2H,
m, H-24), 1.18 (1H, m, H-16), 1.20 (1H, m, H-6), 1.30 (1H,
m, H-20), 1.30 (1H, m, H-22), 1.30 (1H, m, H-23), 1.32 (1H, m,
H-11), 1.32 (1H, m, H-8), 1.40 (1H, m, H-6), 1.44 (1H, m, H-5),
1.44 (1H, m, H-11), 1.47 (1H, m, H-25), 1.57 (1H, m, H-15),
1.65 (1H, m, H-7), 1.78 (1H, m, H-16), 1.87 (1H, m, J 17, 2.5
and 2.5, 2.0, H-1), 1.99 (1H, m, J 12.5, 3.0 and 3.0, H-12), 2.10
(1H, m, J 17.0 and 5.5, H-1), 2.18 (2H, m, H-4), 5.10 (2H, s,
OCH2), 5.68 (1H, m, J 5.5 and 2.5, H-2), 6.90 (1H, m, J 7.8 and
1.1, H-3Ј), 6.91 (1H, m, J 7.2, 7.0 and 1.0, H-5Ј), 7.13 (1H, m,
J 7.2 and 1.9, H-6Ј), 7.17 (1H, m, J 7.8, 7.0 and 1.9, H-4Ј), 7.27–
7.43 (5H, m, aromatics); δC(100 MHz, CDCl3) 11.92 (C-18),
12.06 (C-19), 18.75 (C-21), 21.13 (C-11), 22.61 (C-26), 22.87
(C-27), 23.88 (C-23), 24.28 (C-15), 28.06 (C-25), 28.29 (C-16),
28.75 (C-6), 31.91 (C-7), 33.84 (C-4), 34.27 (C-10), 35.71
(C-8), 35.85 (C-20), 36.23 (C-22), 39.56 (H-24), 40.10
(C-12), 40.52 (C-1), 41.91 (C-5), 42.56 (C-13), 54.03 (C-9),
56.32 (C-14), 56.57 (C-17), 70.36 (OCH2), 112.62 (C-3Ј), 121.00
(C-5Ј), 125.19 (C-2), 127.15 (C-6Ј), 127.63 (C-4Ј), 127.66,
128.38 and 129.63 (aromatics), 134.10 (C-3), 135.87 (aro-
matics), 137.45 (C-1Ј), 155.93 (C-2Ј); m/z (EI) 461 (46%), 173
(16), 91 (100).
Chart 1 The revised absolute configuration of norneolignans based
on the helicity rule set up above.
Lajos Kossuth University microanalysis laboratory. Infrared
spectra were recorded on a Perkin-Elmer 16PC FT-IR spec-
trometer. Optical rotations were measured with a Carl Zeiss
(Jena) Polamat-A polarimeter, the CD and UV spectra with a
slightly modified Jobin-Yvon-Isa dichrograph-6. [α]D values
1
are given in 10Ϫ1 deg cm2 gϪ1. H- and 13C-NMR spectra were
recorded with a Varian Unity-Inova spectrometer with TMS as
the internal standard (δ = 0) for solutions in CDCl3. Integrals
were always in agreement with the assigned number of protons.
The coupling constants J are quoted in Hz. The notation
“aromatics” in the NMR assignment refers to the aryl protons
or carbons of the benzyl group. Flash chromatography was
carried out using Merck-Kieselgel 60 (0.040–0.063 mm). TLC
was visualized with UV light (254 nm) and with phospho-
molybdenic acid hydrate in methanol. Electron ionisation mass
spectra were obtained on a VG 7035 spectrometer at 70 eV. For
work-up the solutions were dried over MgSO4, and the solvents
were evaporated in vacuum. All the reagents were purchased
from Sigma or Aldrich.
3ꢀ-(2-Benzyloxyphenyl)-2,3-epoxy-5ꢁ-cholestane 5a
To a solution of 4 (2.56 g, 4.63 mmol) in dichloromethane
(50 ml, distilled from KMnO4) was added m-chloroperbenzoic
acid (1.60 g, 9.27 mmol) at room temperature. The precipitation
of m-chlorobenzoic acid showed the progress of the reaction.
After two hours stirring, the reaction mixture was washed with
NaHCO3 solution, and evaporation of the solvent gave a
yellow oil which crystallized slowly. Recrystallization from 2:1
acetone–methanol furnished 5a as white crystals (1.28 g, 48%).
Mp 156–157 ЊC, [α]D20 = ϩ49.5 (c 0.12 in chloroform) (Found: C,
84.4, H, 9.9; C40H56O2 requires C, 84.4; H; 9.9%); δH(400 MHz,
CDCl3) 0.61 (3H, s, H-18), 0.92 (3H, s, H-19), 0.8–2.0 (38H, m,
steroid skeleton), 3.11 (1H, d, J 5.4, H-2), 5.06 and 5.12 (2H,
2 × d, J 11.8, OCH2), 6.86 (1H, dd, J 7.7, 1.2, H-3Ј), 6.92 (1H,
m, J 7.6, 7.0, 1.2, H-5Ј), 7.18 (1H, m, J 7.7, 7.0, 1.3, H-4Ј), 7.6
(1H, overlapped multiplet, H-6Ј), 7.6–7.8 (5H, m, aromatics);
δC(100 MHz, CDCl3) 11.97 and 12.52 (C-18 and C-19), 18.67
(C-21), 20.93 (C-11), 22.57 and 22.83 (C-26 and C-27), 23.81
(C-23), 24.19 (C-15), 28.02, 28.18, 28.20 (C-25, C-16, C-6),
31.71 (C-7), 33.52 and 33.64 (C-10 and C-4), 35.61 (C-20), 35.80
(C-8), 36.15 (C-22), 37.62 (C-5), 39.03 (C-1), 39.52 (C-24),
39.92 (C-12), 42.42 (C-13), 53.96 (C-9), 56.18 (C-14), 56.33
(C-17), 58.85 (C-2), 60.28 (C-3), 70.21 (OCH2), 111.39 (C-3Ј),
120.74 (C-5Ј), 128.01 and 128.42 (C-4Ј and C-6Ј), 128.05–
128.52 (aromatics), 136.67 (C-1Ј), 155.62 (C-2Ј).
3ꢀ-(2-Benzyloxyphenyl)-5ꢁ-cholestan-3ꢁ-ol 3a
Mg (3.90 g, 0.16 mol) in dry THF was activated with 1,2-
dibromoethane (0.2 ml). After the cessation of evolution of
ethylene, 2-benzyloxybromobenzene (10.0 g, 38.00 mmol,
vacuum-distilled) in dry THF was added dropwise to the solu-
tion under an argon atmosphere. It was stirred for 30 minutes
and then 5α-cholestan-3-one (2) (10.0 g, 25.86 mmol) in THF
was added. After one hour the reaction mixture was poured
into a saturated NH4Cl solution and extracted with ether. The
combined organic extracts were dried, and evaporation of the
solvent resulted in a yellow oil which was purified by silica gel
column chromatography (1:2 hexane–toluene) to afford 3a
(4.40 g, 30%) and 3b (4.26 g, 29%). Compound 3a could be
crystallized from methanol–acetone, 3:1. Mp 79–81 ЊC, [α]D20
=
ϩ29.2 (c 0.13 in chloroform) (Found: C, 84.1; H, 10.2; C40H58O2
requires C, 84.2; H, 10.2%); δH(400 MHz, CDCl3) 0.64 (3H, s,
H-18), 0.71 (3H, s H-19), 0.8–1.9 (38H, m, steroid skeleton),
1.92 (1H, dd, J 13.1 and 12.5, H-4β), 2.03 (1H, m, J 13.5, 13.0
and 4.8, H-2β), 3.60 (1H, s, OH), 5.12 (2H, s, OCH2), 6.9–7.0
(2H, m, Ar-H), 7.1–7.2 (1H, m, Ar-H), 7.3–7.4 (6H, m, Ar-H);
δC(100 MHz, CDCl3) 11.07 and 11.84 (C-18 and C-19), 18.41
(C-21), 20.72 (C-11), 22.29 and 22.56 (C-26 and C-27), 23.56
(C-23), 23.94 (C-15), 27.75 (C-25), 27.99 (C-6), 28.33 (C-16),
31.80 (C-1), 32.25 (C-2), 33.73 (C-7), 35.28 (C-10), 35.29 (C-8),
35.54 (C-20), 35.91 (C-22), 38.78 (C-12), 39.26 (C-24), 39.82 (C-
4), 40.38 (C-5), 42.35 (C-13), 53.82 (C-9), 55.95 (C-14), 56.30
(C-17), 70.28 (OCH2), 75.30 (C-3), 112.16 (C-3Ј), 120.95 (C-5Ј),
125.56 (C-4Ј), 128.03 (C-6Ј), 127.51, 127.64, 128.53 and 136.01
(aromatics), 136.01 (C-1Ј), 156.07 (C-2Ј).
3ꢁ-(2-Benzyloxyphenyl)-5ꢁ-cholestan-2-one 6a
BF3ؒOEt2 (0.4 ml) was added at 0 ЊC to 5a (5.17 g, 9.08 mmol)
dissolved in dichloromethane (50 ml) and stirred for 50 minutes.
The mixture was poured into water and washed with NaHCO3
solution. The organic layer was dried and evaporated to afford
5.07 g crude product whose purification by flash chromato-
graphy (toluene) gave 6a as a yellow syrup (4.44 g, 86%); δH(400
MHz, CDCl3) 0.65 (3H, s, H-18), 0.86 (3H, s, H-19), 0.86–2.00
(36H, m, steroid skeleton), 2.07 (1H, d, J 15.3, H-1β), 2.42 (1H,
3-(2-Benzyloxyphenyl)cholest-ꢂ2-ene 4
Compound 3a (11.9 g, 20.84 mmol) and toluene-p-sulfonic acid
458
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d, J 15.3, H-1α), 3.88 (1H, dd, J 2.0 and 8.0, H-3), 5.02 (2H, s,
OCH2), 6.8–6.9 (2H, m, H-3Ј and H-5Ј), 7.3–7.45 (7H, m, H-4Ј,
H-6Ј and aromatics); δC(100 MHz, CDCl3) 11.96 and 13.18
(C-18 and C-19), 18.64 (C-21), 21.02 (C-11), 22.56 and 22.83
(C-26 and C-27), 23.86 (C-23), 24.19 (C-15), 28.00, 28.13,
28.22 (C-25, C-16, C-6), 31.52 (C-7), 34.27 (C-10), 34.85 and
35.79 (C-8 and C-20), 36.15 (C-22), 39.24–39.76 (C-4, C-12
and C-24), 41.16 (C-5), 42.46 (C-13), 49.17 (C-3), 53.65 (C-1),
53.82 (C-9), 56.25 (C-14), 56.27 (C-17), 70.23 (OCH2), 112.09
(C-3Ј), 120.73 (C-5Ј), 127.9 and 128.0 (C-4Ј and C-6Ј),
127.81–128.6 (aromatics), 136.68 (C-1Ј), 155.62 (C-2Ј), 213.21
(C-2).
69.41 (C-2), 69.81 (OCH2), 111.68 (C-3Ј), 120.84 (C-5Ј), 127.47
(C-4Ј), 127.80 (C-6Ј), 131.48 (C-1Ј), 156.12 (C-2Ј), 126.98,
128.54, 128.59 and 137.20 (aromatics).
3ꢀ-(2-Hydroxyphenyl)-5ꢁ-cholestan-2ꢀ-ol 11
Compound 7 (991 mg, 1.73 mmol) in dry THF was hydrogen-
ated over 10% Pd/C (690 mg) at room temperature. After 24
hours, the reaction mixture was diluted with dichloromethane
and the catalyst was filtered off. The solvent was evaporated
and the crude product was crystallized from acetone to give 11
as white crystals (281 mg, 81%). Mp 217–218 ЊC, [α]D20 = ϩ55.4
(c 0.14 in chloroform) (Found: C, 82.5; H, 10.9; C33H52O2
requires C, 82.4; H, 10.9%); δH(400 MHz, CDCl3) 0.63 (3H, s,
H-18), 0.88 (3H, s, H-19), 0.90–1.90 (36H, m, steroid skeleton
and OH), 1.37 (1H, dd, J 15.0 and 3.0, H-1α), 2.01 (1H, dd,
J 15.0 and 2.5, H-1β), 2.34 (1H, m, J 13.0, 13.5 and 11.0, H-4β),
2.82 (1H, m, J 13.0, 3.0 and 3.0, H-3), 4.38 (1H, m, J 3.0, 3.0
and 2.5, H-2), 6.83 (1H, m, J 7.8, 7.0 and 1.2, H-5Ј), 6.86 (1H,
dd, J 7.8 and 1.2, H-3Ј), 7.05 (1H, dd, J 7.7 and 1.3, H-6Ј), 7.13
(1H, m, J 7.8, 7.0 and 1.3, H-4Ј), 8.3 (1H, s, OH); δC(100 MHz,
CDCl3) 12.14 and 15.21 (C-18 and C-19), 18.67 (C-21), 21.15
(C-11), 22.57 and 22.82 (C-26 and C-27), 23.83 (C-32), 24.16
(C-15), 28.02 (C-25), 28.10 (C-16), 28.23 (C-4), 28.38 (C-6),
31.99 (C-7), 34.89 (C-8), 35.17 (C-22), 35.64 (C-10), 35.79
(C-20), 39.51 (C-24), 40.08 (C-12), 42.66 (C-13), 46.09 (C-1),
48.35 (C-5), 49.60 (C-3), 55.33 (C-9), 56.28 (C-14), 56.47
(C-17), 73.05 (C-2), 117.85 (C-3Ј), 120.36 (C-5Ј), 128.21 (C-4Ј),
130.06 (C-1Ј), 131.06 (C-6Ј), 155.23 (C-2Ј).
3ꢀ-(2-Benzyloxyphenyl)-5ꢁ-cholestan-2-one 6b
Compound 6a (4.44 g, 7.80 mmol) was dissolved in MeOH–
CH2Cl2 (1:1, 100 ml), the pH was adjusted to 9–10 with a
methanolic NaOMe solution, and the mixture was refluxed for
8 hours. The reaction mixture was acidified with 5% hydro-
chloric acid solution and extracted with dichloromethane. The
organic layer was washed with aqueous NaHCO3 and dried.
Evaporation of the solvent yielded 4.3 g of a white crystalline
solid whose recrystallization from 2:1 acetone–methanol gave
6b (3.24 g, 73%). Mp 143–144 ЊC, [α]D20 = ϩ20.0 (c 0.20 in chloro-
form) (Found: C, 84.5; H, 9.9; C40H56O2 requires C, 84.4; H,
9.9%); λmax (CH3CN)/nm 221.8sh (ε × 10Ϫ4/MϪ1 cmϪ1 0.63),
271.6 (0.17), 279.6 (0.12); CD in CH3CN nm (∆ε) 203.60
(ϩ1.89), 210.80 (ϩ1.66), 225.20 (ϩ2.64), 272.00 (ϩ0.71),
278.20 (ϩ0.66), 301.20 (ϩ0.71); νmax (KBr)/cmϪ1 2932, 2866,
1714, 1600, 1586, 1540; δH(400 MHz, CDCl3) 0.58 (3H, s,
H-18), 0.64 (3H, s, H-19), 0.70–2.00 (36H, m, steroid skeleton),
2.02 and 2.43 [(1H, d, J 3.5) and (1H, d, J 13.5) H-1α and
H-1β], 3.84 (1H, dd, J 12.8 and 6.3, H-3), 4.94 (2H, s, OCH2),
6.8–6.9 (2H, m, H-3Ј, H-5Ј), 7.0–7.6 (7H, m, H-4Ј, H-6Ј and
aromatics); δC(100 MHz, CDCl3) 12.00 and 12.49 (C-18 and
C-19), 18.64 (C-21), 21.05 (C-11), 22.55 and 22.81 (C-26
and C-27), 23.81 (C-23), 24.19 (C-15), 27.74, 28.21 and 27.99
(C-25, C-16 and C-6), 31.70 (C-7), 34.79 (C-8), 35.71 (C-10),
35.76 (C-20), 36.13 (C-22), 39.48, 39.77 and 41.10 (C-4, C-12
and C-24), 42.48 (C-13), 45.86 (C-5), 51.88 (C-3), 54.12 (C-1),
53.88 (C-9), 56.19 (C-14), 56.32 (C-17), 70.34 (OCH2), 112.03
(C-3Ј), 120.83 (C-5Ј), 127.79 and 127.99 (C-4Ј and C-6Ј), 127.6–
129.28 (aromatics), 137.10 (C-1Ј), 156.34 (C-2Ј), 209.55 (C-2);
m/z (EI) 568 (M, 11%), 553 (12), 550 (6), 477 (100), 460 (52).
8-[(1R)-1,5-Dimethylhexyl]-9,13-dimethyl-(1R,4S,5S,8R,9R,
12S,13R,16R)-23-oxahexacyclo[14.7.1.01,13.04,12.05,9.017,22]-
tetracosa-17(22),18,20-triene 14
BF3ؒOEt2 (2 ml) was added to a dichloromethane solution of 11
(104 mg, 0.21 mmol) and the mixture was stirred for two days.
After usual work-up, the crude product was purified by pre-
parative TLC with hexane to yield 14 (28 mg, 28%), 16 (17 mg,
17%) and 12a (8 mg, 8%).
14: mp 124–125 ЊC, [α]D20 = ϩ62.0 (c 0.22 in chloroform)
(Found: C, 85.6; H, 10.8; C33H50O requires C, 85.6; H, 10.9%);
λmax (CH3CN)/nm 200.80 (ε × 10Ϫ4/MϪ1 cmϪ1 3.04), 227.00
(0.52), 278.00 (1.17), 283.80 (0.16); CD in CH3CN nm (∆ε)
204.20 (ϩ8.58), 227.40 (Ϫ4.69), 277.20 (Ϫ1.01), 284.00
(Ϫ0.93); δH(400 MHz, CDCl3) 0.67 (3H, s, C(9) Me), 0.86 (3H,
d, J 6.8, H-6 acyclic), 0.87 (3H, d, J 6.8, C(5) Me), 0.91 (3H, d,
J 6.3, C(1) Me), 0.98 (1H, m, H-2 acyclic), 0.99 (3H, s, C(13)
Me), 1.03 (1H, m, H-8), 1.06 (1H, m, H-6), 1.08 (1H, m, H-5),
1.08 (1H, m, H-7), 1.09 (1H, m, J 15.5, 14.0 and 5.3, H-14α)
1.05–1.12 (2H, m, H-4 acyclic), 1.13 (1H, m, H-3 acyclic), 1.14
(1H, m, H-10), 1.24 (1H, m, H-11), 1.25 (1H, m, H-3), 1.32
(1H, m, H-3 acyclic), 1.34 (1H, m, H-2 acyclic), 1.36 (1H, m,
H-1 acyclic), 1.40 (1H, m, H-15), 1.41 (1H, m, H-24), 1.42 (1H,
m, H-4), 1.42 (1H, m, H-2), 1.43 (1H, m, H-14β), 1.43 (1H, m,
H-12), 1.46 (1H, m, H-11), 1.50 (1H, m, H-5 acyclic), 1.55 (1H,
m, H-6), 1.61 (1H, m, H-7), 1.78 (1H, m, J 13.3, 3.2 and 3.0,
H-15), 1.82 (1H, m, H-3), 2.01 (1H, m, J 12.3, 3.1 and 3.0,
H-10), 2.06 (1H, m, J 13.3, 13.1 and 5.6, H-2), 2.53 (1H, m,
J 13.6 and 3.2, H-24), 2.97 (1H, m, J 3.4, 3.2, 3.0 and 3.0, H-16),
6.78 (1H, m, J 7.2, 6.9 and 1.3, H-19), 6.79 (1H, m, J 8.1 and
1.3, H-21), 6.95 (1H, m, J 7.2 and 1.6, H-18), 7.07 (1H, m, J 8.1,
6.9 and 1.6, H-20); δC(400 MHz, CDCl3), 12.11 [C(9) Me], 17.65
[C(13) Me], 18.65 [C(1) Me], 21.35 (C-11), 22.58 (C-6 acyclic),
22.84 [C(5) Me], 23.83 (C-3 acyclic), 24.20 (C-6), 27.71 (C-14),
28.03 (C-5 acyclic), 28.23 (C-7), 28.32 (C-3), 28.88 (C-15), 30.47
(C-24), 32.61 (C-16), 34.58 (C-2), 34.93 (C-4), 35.78 (C-1
acyclic), 36.16 (C-2 acyclic), 39.52 (C-4 acyclic), 40.15 (C-10),
42.67 (C-9), 42.68 (C-13), 43.66 (C-12), 56.22 (C-5), 56.66
(C-8), 79.53 (C-1), 114.95 (C-21), 118.93 (C-19), 126.82 (C-17),
127.30 (C-20), 127.97 (C-18), 156.67 (C-22); m/z (EI) 462 (M,
8%), 256 (10), 43 (100).
3ꢀ-(2-Benzyloxyphenyl)-5ꢁ-cholestan-2ꢀ-ol 7
LAH (248 mg, 6.53 mmol) was added to a well-stirred solution
of 6b (805 mg, 1.41 mmol) in dry THF (30 ml). After 1.5 hours,
ethyl acetate was added to decompose the excess of LAH. The
mixture was then extracted with dichloromethane, the organic
layer was dried, and the solvent evaporated. The resulting
brownish oil was purified by flash chromatography (12:1
hexane–ethyl acetate) to furnish 7 (576 mg, 71%) and 8 (47 mg,
5%).
7: mp 124–125 ЊC, [α]D20 = ϩ70.3 (c 0.10 in chloroform)
(Found: C, 84.08; H, 10.1; C40H58O2 requires C, 84.1; H,
10.2%); δH(400 MHz, CDCl3) 0.59 (3H, s, H-18), 0.96 (3H, s,
H-19), 0.80–1.93 (37H, m, steroid skeleton and OH), 1.31 (1H,
dd, J 14.8 and 3.0, H-1α), 2.00 (1H, dd, J 14.8 and 2.5, H-1β),
3.33 (1H, m, J 13.0, 3.0 and 3.0, H-3), 4.22 (1H, m, J 3.0, 3.0
and 2.5, H-2), 4.98 and 5.03 (2H, 2 × d, J 11.7, OCH2), 6.82
(1H, dd, J 7.8 and 1.2, H-3Ј), 6.88 (1H, m, J 7.6, 7.0 and 1.2,
H-5Ј), 7.20 (1H, m, J 7.8, 7.0 and 1.3, H-4Ј), 7.39 (1H, dd, J 7.6
and 1.3, H-6Ј), 7.62 (5H, m, aromatics); δC(100 MHz, CDCl3)
12.13 and 14.65 (C-18 and C-19), 18.67 (C-21), 21.13 (C-11),
22.57 and 22.83 (C-26 and C-27), 23.85 (C-23), 24.20 (C-15),
27.95 (C-4), 28.02 (C-25), 28.26 (C-16), 28.67 (C-6), 32.13
(C-7), 34.96 (C-8), 35.81 (C-20), 36.19 (C-22), 35.81 (C-10),
39.52 (C-24), 40.13 (C-12), 42.47 (C-3), 42.67 (C-13), 44.48
(C-1), 47.91 (C-5), 55.40 (C-9), 56.31 (C-14), 56.61 (C-17),
J. Chem. Soc., Perkin Trans. 1, 2000, 453–461
459

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2ꢀ,3ꢀ-Dihydro-1-benzofuro[2Ј,3Ј:2,3]-5ꢁ-cholest-2-ene 12b, and
2ꢁ,3ꢁ-dihydro-1-benzofuro[2Ј,3Ј:2,3]-5ꢁ-cholest-2-ene 12a
for 8 hours. Usual work-up gave a brown oil, which was
purified by flash chromatography (hexane) to yield white
crystalline 16 (128 mg, 19.5%). Mp 130–132 ЊC, [α]D20 = ϩ60.08 (c
0.24 in chloroform) (Found: C, 86.0; H 10.4; C33H48O requires
C, 86.0; H, 10.5%); νmax (KBr)/cmϪ1 2928, 2868, 1644, 1452;
δH(400 MHz, CDCl3) 0.68 and 0.83 [(3H, s and 3H, s) H-18
and H-19], 0.86 (3H, d, J 6.8, H-26), 0.87 (3H, d, J 6.8, H-27),
0.91 (3H, d, J 6.3, H-21), 0.92 (1H, m, H-9), 0.95 (1H, m,
H-7), 1.00 (1H, m, H-22), 1.02 (1H, m, H-15), 1.03 (1H, m,
H-17), 1.05–1.15 (2H, m, H-24), 1.08 (1H, m, H-14), 1.08 (1H,
m, H-23), 1.18 (1H, m, H-12), 1.20 (1H, m, H-11), 1.20
(1H, m, H-16), 1.30 (1H, m, H-23), 1.35 (1H, m, H-22), 1.35
(1H, m, H-8), 1.40 (1H, m, H-20), 1.40 (1H, m, H-6), 1.50 (1H,
m, H-25), 1.50 (1H, m, H-11), 1.52 (1H, m, H-5), 1.58 (1H, m,
H-15), 1.6 (1H, m, H-6), 1.75 (1H, m, H-7), 1.80 (1H, m, H-16),
1.99 (1H, m, J 12.4, 3.0 and 3.0, H-12), 2.23 (1H, m, J 16.0,
10.0, 2.5 and 2.5, H-4β), 2.39 (1H, m, J 16.5, 2.5 and 1.5,
H-1α), 2.56 (1H, m, J 16.0, 5.0 and 1.5, H-4α), 2.69 (1H, m,
J 16.5 and 1.5, H-1β), 7.16 (1H, m, H-6Ј), 7.16 (1H, m, H-4Ј),
7.36 (1H, m, H-7Ј), 7.36 (1H, m, H-5Ј); δC(100 MHz, CDCl3)
12.02 and 12.16 (C-18 and C-19), 18.72 (C-21), 21.25 (C-11),
22.61 (C-26), 22.86 (C-27), 23.88 (C-23), 24.30 (C-15), 25.46
(C-4), 28.05 (C-25), 28.28 (C-16), 28.90 (C-6), 31.79 (C-7),
35.55 (C-8), 35.84 (C-20), 36.20 (C-22), 37.26 (C-10), 37.76
(C-1), 39.55 (C-24), 39.95 (C-12), 42.32 (C-5), 42.52 (C-13),
53.94 (C-9), 56.29 (C-14), 56.37 (C-17), 110.79 (C-7Ј), 111.20
(C-3), 118.40 (C-5Ј), 122.09 (C-6Ј), 122.73 (C-4Ј), 128.62
(C-4aЈ), 154.08 (C-2), 154.60 (C-7aЈ); m/z (EI) 460 (M, 70%),
144 (100).
Compound 16 (55 mg, 0.12 mmol) in dry THF was hydrogen-
ated over 10% Pd/C (220 mg) at 16 bar pressure and room
temperature. Usual work-up gave 12b (44 mg, 79%) and 12a
(6 mg, 11%).
12b: mp 115–116 ЊC, [α]D20 = ϩ85.44 (c 0.20, in chloroform)
(Found: C, 85.7; H, 10.8; C33H50O requires C, 85.6; H, 10.9%);
λmax (n-hexane)/nm 282.2 (ε × 10Ϫ3/MϪ1 cmϪ1 3.18), 288.8
(3.08); CD in n-hexane nm (∆ε) 282 (Ϫ3.1), 289 (Ϫ3.3), in
CH3CN 281 (Ϫ2.4), 287 (Ϫ2.5); δH(400 MHz, CDCl3) 0.63 (3H,
s, H-18), 0.81 (3H, s, H-19), 0.85–2.0 (33H, m, steroid skeleton),
1.12 (1H, m, H-5), 1.78 (1H, m, H-4β), 1.84 (1-H, m, H-1α),
1.98 (1H, m, J 14.5, 3.8 and 1.0, H-4α), 2.06 (1H, dd, J 13.0
and 6.5, H-1β), 3.56 (1H, m, J 8.0, 7.5 and 1.0, H-3), 4.92
(1H, m, J 10.5, 8.0 and 6.5, H-2), 6.78 (1H, dd, J 6.8 and 1.2,
H-7Ј), 6.90 (1H, m, J 6.8, 7.0 and 1.3, H-5Ј), 7.12 (1H, dd,
J 7.0 and 1.3, H-4Ј), 7.13 (1H, m, J 7.0, 7.0 and 1.2, H-6Ј);
δC(100 MHz, CDCl3) 11.61 and 11.97 (C-18 and C-19), 18.62
(C-21), 20.77 (C-11), 22.54 and 22.81 (C-26 and C-27), 23.80
(C-23), 24.18 (C-15), 27.99 (C-25), 28.20 (C-16), 28.29 (C-6),
28.45 (C-4), 31.56 (C-7), 34.86 (C-8), 35.55 (C-10), 35.77
(C-20), 36.11 (C-22), 39.49 (C-24), 39.84 (C-12), 39.99 (C-1),
40.12 (C-5), 40.29 (C-3), 40.39 (C-13), 53.29 (C-9), 56.12
(C-14), 56.36 (C-17), 81.83 (C-2), 110.28 (C-7Ј), 120.32
(C-5Ј), 123.05 (C-6Ј), 127.77 (C-4Ј), 130.61 (C-4Јa), 159.02
(C-7Јa).
Relevant 1H data in d12-cyclohexane: 0.62 (3H, s, H-18), 0.78
(3H, s, H-19), 3.39 (1H, m, J 7.9, 7.0 and1.0, H-3), 4.70 (1H, m,
J 10.5, 7.9 and 6.9, H-2); m/z (EI) 462 (M, 32%), 460 (43), 144
(95), 43 (100).
3ꢁ-(2-Benzyloxyphenyl)-5ꢁ-cholestan-2ꢁ-ol 17
12a: mp 144–145 ЊC, [α]D20 = Ϫ7.88 (c 0.16 in chloroform)
(Found: C, 85.7; H, 10.9; C33H50O requires C, 85.6; H, 10.9%);
λmax (n-hexane)/nm 279.4 (ε × 10Ϫ3/MϪ1 cmϪ1 2.36), 285.8
(2.13); CD in CH3CN nm (∆ε) 199.60 (Ϫ10.13), 214.20 (ϩ1.09),
226.80 (ϩ2.42), 279.60 (ϩ0.32) in n-hexane 279.5 (ϩ0.89);
δH(400 MHz, CDCl3) 0.66 (3H, s, H-18), 0.91 (3H, s, H-19),
1.0–2.04 (36H, m, steroid skeleton), 1.36 (1H, m, H-1α), 2.43
(1H, dd, J 15.2 and 1.5, H-1β), 3.04 (1H, m, J 10.7, 7.0 and 6.5,
H-3), 4.65 (1H, m, J 6.5, 5.5 and 1.5, H-2), 6.78–6.85 (2H, m,
H-7Ј and H-5Ј), 7.05–7.20 (2H, m, H-6Ј and H-4Ј); δC(100
MHz, CDCl3) 12.03 and 12.92 (C-18 and C-19), 18.67 (C-21),
20.86 (C-11), 22.57 and 22.82 (C-26 and C-27), 23.82 (C-23),
24.21 (C-15), 28.02, 28.20 and 28.61 (C-25, C-16 and C-6),
31.94 (C-7), 34.01 (C-4), 34.95 (C-10), 35.00 (C-8), 35.80
(C-20), 36.18 (C-22), 39.52, 40.01 and 40.03 (C-1, C-12 and
C-24), 40.77 (C-3), 42.50 (C-13), 43.39 (C-5), 54.93 (C-9), 56.27
(C-14), 56.54 (C-17), 83.39 (C-2), 109.89 (C-7Ј), 120.37 (C-5Ј),
123.75 and 127.67 (C-6Ј and C-4Ј), 134.96 (C-4Јa), 158.78
(C-7Јa).
LAH (500 mg, 13.17 mmol) was added to 6a (3.47 g, 6.09
mmol) in dry THF. After 20 minutes, ethyl acetate was added
to the mixture to decompose the excess of LAH. The mixture
was then extracted with dichloromethane, the extract was
dried and evaporated to dryness. Chromatography on silica
gel with 1:2 hexane–toluene gave a white crystalline product
which was recrystallized from methanol to give pure 17 (1.52
g, 52%). Mp 147–149 ЊC (Found: C, 84.0; H, 10.2; C40H58O2
requires C, 84.1; H, 10.2%); δH(400 MHz, CDCl3) 0.65 (3H, s,
H-18), 0.81 (3H, s, H-19), 0.7–2.0 (34H, m, steroid skeleton),
2.22 (1H, d, J 4.2, OH), 3.90 (1H, m, J 6.3, 6.0 and 1.4, H-3),
4.24 (1H, m, J 12.0, 6.3, 5.0 and 4.2, H-2), 5.09 and 5.13
(2H, 2 × d, J 11.6, OCH2), 6.90 (2H, m, H-3Ј and H-5Ј), 7.20
(1H, m, H-4Ј), 7.30–7.50 (5H, m, aromatics), 7.62 (1H, m,
H-6Ј).
3ꢁ-(2-Hydroxyphenyl)-5ꢁ-cholestan-2ꢁ-ol 19
Compound 17 (360 mg, 0.63 mmol) was hydrogenated in dry
THF over 10% Pd/C (300 mg) at room temperature. After
stirring for 24 h the mixture was filtered. The solvent was
evaporated and the crude product was purified by silica gel
chromatography with 8:1 hexane–ethyl acetate to yield 19
(296 mg, 97%). Mp 88–89 ЊC, [α]D20 = Ϫ12.76 (c 0.10 in chloro-
form) (Found: C, 82.4; H, 10.8; C33H52O2 requires C, 82.4; H,
10.9%); δH(400 MHz, CDCl3) 0.66 (3H, s, H-18), 0.90 (3H, s,
H-19), 0.85–1.95 (38H, m, steroid skeleton), 2.08 (1H, br s,
OH), 3.56 (1H, m, J 5.5, 4.0 and 3.5, H-3), 4.37 (1H, m,
J 11.9, 6.3 and 4.0, H-2), 6.92 (2H, m, H-3Ј and H-5Ј), 7.16
(1H, m, H-4Ј), 7.41 (1H, m, H-6Ј), 8.3 (1H, s, OH); δC(100
MHz, CDCl3) 12.16 and 13.32 (C-18 and C-19), 18.69
(C-21), 21.00 (C-11), 22.60 and 22.86 (C-26 and C-27),
23.90 (C-23), 24.18 (C-15), 27.96 (C-6), 28.05 (C-25), 28.28
(C-16), 31.70 (C-4), 31.91 (C-7), 34.87 (C-8), 35.84
(C-20), 36.17 (C-22), 37.50 (C-10), 38.58 (C-3), 39.53 (C-24),
39.91 (C-12), 42.68 (C-13), 42.87 (C-5), 43.39 (C-1), 54.69
(C-9), 56.29 (C-14), 56.37 (C-17), 72.03 (C-2), 117.98 (C-3Ј),
120.56 (C-5Ј), 127.92 (C-4Ј), 128.49 (C-1Ј), 129.27 (C-6Ј),
156.19 (C-2Ј).
Relevant 1H data in d12-cyclohexane: 0.62 (3H, s, H-18), 0.81
(3H, s, H-19), 2.36 (1H, dd, J 15.1 and 1.4, H-1β), 2.82 (1H, m,
J 10.7, 7.0 and 6.5, H-3), 4.44 (1H, m, J 6.5, 5.0 and 1.5, H-2).
3-(2-Hydroxyphenyl)cholest-ꢂ2-ene 15
BF3ؒOEt2 (2 ml) was added to a dry dichloromethane solution
of 19 (101 mg, 0.21 mmol) and stirred for 24 h. After usual
work-up, the crude product was purified by preparative TLC in
hexane to yield 14 (19 mg, 19%), 15 (18 mg, 18%), 12a (11 mg,
11%) and 16 (10 mg, 10%). 15: (Found: C, 85.6; H, 10.7;
C33H50O requires C, 85.6; H, 10.9%); δH(200 MHz, CDCl3)
0.7 (3H, s, H-18), 0.8 (3H, s, H-19), 0.9–2.3 (21H, m, steroid
skeleton), 5.6 (1H, s, OH), 5.7 (1H, m, H-2), 6.8–7.0 (2H, m,
Ar-H), 7.0–7.1 (2H, m, Ar-H).
1-Benzofuro[2Ј,3Ј:2,3]-5ꢁ-cholest-2-ene 16
BF3ؒOEt2 (2.5 ml) was added to a dichloromethane solution
of 6b (807 mg, 1.42 mmol) at room temperature and was stirred
460
J. Chem. Soc., Perkin Trans. 1, 2000, 453–461

View Article Online
(h) Y. Fukuyama, M. Nakahara, H. Minami and M. Kodama,
Chem. Pharm. Bull., 1996, 44, 1418.
Acknowledgements
The authors thank the National Science Foundation (OTKA,
Grant No. T-23687) and the Ministry of Education (Grant No.
46/1997) for the financial support. We express our thanks to Dr
Z. Dinya (Department of Organic Chemistry, Lajos Kossuth
University, Debrecen) for the mass spectra.
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