Synthesis and structure-activity studies of 8α- and 9β-analogues of 14,17-ethanoestradiol

Article abstract of DOI:10.1039/a908375h

Synthetic routes to the title compounds are described, commencing with readily available 19-norsteroid precursors. The reaction of 3-methoxy-8α-estra-1,3,5(10),14,16-pentaen-17-yl acetate 3 with phenyl vinyl sulfone at 150 °C proceeded in high yield, but

Full text of DOI:10.1039/a908375h

View Online / Journal Homepage / Table of Contents for this issue
Synthesis and structure–activity studies of 8ꢀ- and 9ꢁ-analogues of
14,17-ethanoestradiol
James R. Bull* and Pieter D. de Koning
1
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Received (in Cambridge, UK) 19th October 1999, Accepted 23rd December 1999
Synthetic routes to the title compounds are described, commencing with readily available 19-norsteroid
precursors. The reaction of 3-methoxy-8α-estra-1,3,5(10),14,16-pentaen-17-yl acetate 3 with phenyl vinyl sulfone
at 150 ЊC proceeded in high yield, but with poor selectivity, to give a mixture of 14α,17-cycloadducts, which
underwent convergent functional group modification, to furnish 14α,17α-ethano-8α-estradiol 13. The feasibility
of performing similar cycloaddition chemistry on analogous 9β-precursors was demonstrated, but the preferred
synthetic route entailed configurational inversion at C-9, of 14α,17α-ethanoestradiol 25, via moderately
stereoselective hydrogenation of a 9,11-dehydro intermediate, leading to 14α,17α-ethano-9β-estradiol 32. The
estrogen receptor binding affinities of 13 and 32 are reported, and discussed in terms of superimpositional
modelling on estradiol.
spectrum displayed cross-peaks consistent with the structure 4
Introduction
(Fig. 1). The diagnostic enhancements are those between 172 -H
and 8α- and 9α-H, and between the vinylic 15- and 16-H and
the 13β-methyl protons, which verified the α-face, endo-oriented
presence of the dienophile-derived bridging elements, and the
location of the PhSO2 group at C-172.
The interpretation of structure–activity relationships in ster-
oidal estrogens has been the subject of much attention in recent
years,1 and has been further stimulated by the first structural
study of the receptor-bound complex of estradiol2 and of
molecular modelling approaches to predictive design of
estradiol analogues.3 The emerging picture of the hydrogen-
bonded contacts and steric demand in the environment of ring
D is of particular interest as an aid to our systematic study of
the structure–activity patterns in estradiol analogues featuring
ring D alkano bridges4–6 and alkyl groups.7 The highly competi-
tive affinity of 14,17α-ethanoestra-1,3,5(10)-triene-3,17α-diol8
toward the estradiol receptor invites speculation on the possible
influence of 14,17-alkano bridges upon the estrogenicity of
backbone-inverted analogues of estradiol. Previous studies
have identified 8α-estradiol and some of its derivatives as
moderately competitive estrogens9 and, although 9β-estradiol
displays negligible estrogenicity,10a surprisingly high levels of
activity are found in a number of its functionally modified
variants.10b–d Accordingly, the synthesis of the 14α,17α-ethano
analogues of 8α- and 9β-estradiol was undertaken, in order
to evaluate their affinity toward the estradiol receptor, and to
explore the implications of these outcomes, in terms of
comparative structural and conformational studies.
Although no further structural information could be gleaned
from the properties of the primary cycloaddition mixture, the
additional components 5 and 6 were isolated during ensuing
transformations of the mixture, and their structures similarly
assigned with the aid of high-field NMR spectroscopy, includ-
ing NOESY correlations (Fig. 1).
The foregoing cycloaddition finding poses some questions
about the underlying factors leading to the observed pattern of
stereo- and regio-selectivity. In contrast to the ‘natural’ series,
in which cycloaddition of PVS to the corresponding dienyl
acetate proceeds with exclusive β-face, endo- and head-to-head
selectivity,4 this result shows that retention of β-face selectivity
is diminished (to ~80% of product), and accompanied by
significant regioreversal (to 75% of β-face product), whilst the
α-face addition is exclusively head-to-tail.
Alkaline treatment of the total cycloaddition product 4–6
furnished the expected product 7 (17%) arising from retrograde
cleavage of the head-to-head component 5, accompanied
by an inseparable mixture of the 17-alcohols 8 and 9, thus
demonstrating the regiochemistry of their respective precur-
sors. Furthermore, reacetylation of the mixture 8 ϩ 9 gave the
17-acetates 4 and 6, which were separated by fractional crys-
tallisation, thereby enabling characterisation of the major
cycloadduct 6.
The primary purpose, of converting the cycloadducts 4–6
into the bridged estradiol analogue 13, was not adversely influ-
enced by the complexity of the cycloaddition reaction, since all
of the products could be regarded as convergent precursors,
through catalytic hydrogenation and desulfonylation. In fact,
this sequence was first attempted. Catalytic hydrogenation of
4–6 in chloroform, in the presence of palladium on carbon,
appeared to proceed readily at 60 ЊC/50 bar, but work-up of the
reaction after 2 h, and chromatography of the product, revealed
a remarkable chemodifferentiation, in that an inseparable
mixture of dihydro products 10 and 11 (82%), clearly derived
from the respective precursors 4 and 6, was accompanied
Results and discussion
8ꢀ-Series
8α-Estrone 3-methyl ether 19a was readily converted into the
∆15-17-ketone 2 (100%), via conventional enol silylation–
dehydrosilylation, and hence into the corresponding dienyl
acetate 3 (78%) (Scheme 1). Treatment of 3 with phenyl vinyl
sulfone (PVS) in benzene at 150 ЊC (sealed tube) resulted in
slow formation (140 h) of a chromatographically homogeneous
fraction (79%), estimated from preliminary NMR examination
to comprise a ~1:1:3 mixture of the cycloadducts 4–6. Frac-
tional crystallisation of this material furnished a highly
crystalline minor product 4, which was more exhaustively char-
acterised. Although the NMR chemical shifts and coupling
constants of pertinent ring D protons did not yield unambigu-
ous evidence for any one of eight possible isomers, a NOESY
DOI: 10.1039/a908375h
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
This journal is © The Royal Society of Chemistry 2000
1003

View Online
Scheme 1 Reagents and conditions: i, LDA , THF, Ϫ78 ЊC, then TMSCl; ii, Pd(OAc)2, MeCN, reflux; iii, CH2᎐᎐CH(OAc)CH3, Ac2O, p-TsOH, reflux;
iv, C6H5SO2CH᎐CH2, C6H6, 150 ЊC (sealed tube); v, KOH, MeOH, 25 ЊC; vi, Ac2O, C5H5N, DMAP, 25 ЊC.
᎐
with sodium–liquid ammonia had the virtue of achieving con-
comitant bridgehead hydrolysis, but gave a significantly reduced
yield (53%) of the product 12. In another experiment, reversal
of the reduction sequence for the cycloaddition mixture proved
to be unrewarding. In the first instance, desulfonylation of 4–6
gave a poor yield (36%) of an inseparable mixture comprising
the expected 14,17-etheno compounds 16 and 17 (~50%), and
the secondary products 14 and 15 (~50%) arising from olefinic
bond participation during desulfonylation. This reaction out-
come was inferred from catalytic hydrogenation of the mixture,
to give the 14,17-ethano compound 12 (47%) and a mixture of
14 and 15 (52%), from which pure 14 was recovered by crystal-
lisation, and characterised by comparison of spectroscopic
properties with those of structurally related analogues.4,5
9ꢁ-Series
Two possible approaches to the synthesis of the 9β-analogue
of 14α,17α-ethanoestradiol were considered (Scheme 3). In the
first, the intention was to convert an estrone derivative A into
an 11-oxo-9β-intermediate, using adaptations and variations of
reported methods,10c,12,13 and hence, to deoxygenate at C-11 to
give the 9β-estrone analogue B. Subsequent elaboration of ring
D functionality for cycloaddition mediated introduction of the
14,17-ethano bridge (leading to C) was expected to follow
the precedent of the natural series (A→D). This approach has
the additional advantage of affording scope for investigating
cycloaddition mediated approaches to other, possibly bioactive
ring D modified 9β-estradiols. Alternatively, formal configur-
ational inversion of a 14α,17α-ethanoestradiol derivative D at
C-9 would lead directly to the target system C.
Estrone 3-methyl ether was first converted into the 9β-11-
ketone 18 (overall yield, 15%), following a described pro-
cedure.12 Although attempted 11-deoxygenation of 18 failed,
the derived 11α-alcohol was converted into the S-methyl 11α-
dithiocarbonate 19, which underwent Barton–McCombie
deoxygenation14 in modest yield to give, after 17-deprotection,
the target compound 21 (28%). In an alternative approach,
Fig. 1 Ring C/D region of the cycloadducts 4–6, showing signal
enhancements observed through cross-peaks in NOESY correlation
spectra.
by unreacted 5 (18%) (Scheme 2). The cause of this chemo-
selectivity is not apparent, but it provided serendipitous access
to pure 5, thus enabling characterisation of each constituent
of the chromatographically inseparable, primary cycloaddition
products.
The dihydro mixture 10 ϩ 11 was smoothly desulfonylated
with samarium() iodide–HMPA,11 and subsequent alkaline
hydrolysis gave 12 (78%), which was deprotected at C-3 to
give 14,17α-ethano-8α-estra-1,3,5(10)-triene-3,17β-diol 13. The
overall conversion efficiency for 3→13 is ~41%, but there is
scope for optimisation of certain steps.
Among the preliminary experiments directed toward this
goal, attempted desulfonylation of the dihydro mixture 10 ϩ 11
1004
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013

View Online
Scheme 2 Reagents and conditions: i, Pd-C, H2, CHCl3; ii, SmI2, HMPA, THF, Ϫ20 ЊC, then KOH, MeOH, 20 ЊC; iii, Na, NH3, THF; iv, BBr3,
CH2Cl2, 0 ЊC.
derivatives, was examined. It was expected that the critical step
would entail efficient introduction of central ring unsaturation,
since the presence of a 14α,17α-ethano bridge was likely to
facilitate β-face stereoselectivity during hydrogenation of a
∆
9(11)- or ∆8-bond.
Treatment of 14α,17α-ethanoestradiol 25 with DDQ in
methanol at 25 ЊC followed by acetylation (Ac2O–DMAP,
25 ЊC) of the reaction product gave an inseparable mixture
(65%) comprising a ~2:1 mixture of the ∆9(11) compound 28
and the diacetate 26 of starting material. Similar treatment of
the 3-methyl ether 27 gave a less favourable ~1:1 mixture of the
desired product 29 and starting material, and an attempt to
apply more forcing conditions (DDQ–p-TsOH, reflux) resulted
in exhaustive dehydrogenation to give the hexaene 30.
Catalytic hydrogenation of the mixture of 26 ϩ 28 gave a
separable mixture (~5:2) of 26 and 31, implying that the reduc-
tion of the ∆9(11) component 28 proceeded with slight β-face
selectivity. Alkaline hydrolysis of the diacetate 31 furnished
14,17α-ethano-9β-estra-1,3,5(10)-triene-3,17β-diol 32.
Although the latter pathway to this target compound is
clearly superior to the former, the overall efficiency is still com-
promised by the modest success of the dehydrogenation step
and the marginally favourable stereoselectivity of reduction.
Nevertheless, it provided ready access to material for biological
evaluation and conformational analysis.
Scheme
3
Inversion–cycloaddition (A→B→C) vs. cycloaddition–
inversion (A→D→C) reaction pathways leading to 14α,17α-ethano-9β-
estradiol.
estrone was dehydrogenated with DDQ, and the derived 17,17-
ethylenedioxy compound was hydrogenated, to give 9β-estrone
as the minor product (15%), and hence, the 3-methyl ether 21.
Numerous variations in the foregoing reaction sequences
were explored in attempts to improve the overall conversion
to this key intermediate 21, but to no avail. However, the
remaining steps toward constructing the 14,17-bridged system
proceeded satisfactorily. Thus, 21 was dehydrogenated via silyl
enol ether formation and dehydrosilylation, to give the ∆15-17-
ketone 22 (52%). The derived dienyl acetate 23 was treated with
phenyl vinyl sulfone in benzene at 140 ЊC (sealed tube) for 48 h,
to give a product (73%) comprising of a mixture of cyclo-
adducts (~7:1, by NMR), from which the major component
was partially separated by careful chromatography. NMR data
were consistent with the structure 24.
Structure–activity investigation
Competitive binding affinities of the bridged estradiol anal-
logues 13 and 32, toward the estradiol receptor [expressed as
‘competition factor’ (CF), the ratio of concentration of the test
sample (ctest) to that of estradiol (cref) at 50% competition15]
were determined in accordance with conventional protocols for
uterine cytosol fractions, and revealed that the 8α-isomer 13
(CF 2.2) is a competitive estradiol mimic (by comparison with
a CF value of unity for estradiol), where the 9β-isomer 32
(CF 7.9) displays relatively diminished competition. Studies on
selectivity of the response toward the recently described estro-
gen receptor subtypes-α and -β1c are incomplete, but prelimin-
ary findings reveal little evidence of differentiation.
Although these experiments demonstrated the feasibility of
accessing the target compound via this reaction pathway, its
practical implementation will necessitate a greatly improved
synthetic route to the 9β-estrone derivative 21. Accordingly, the
alternative approach, via 9-inversion of 14,17-ethanoestradiol
A first consideration, in search of a structure based rational-
isation of these results, is the comparison of the degree of
estradiol mimicry, expressed in the preferred conformations
and steric demand of the analogue structures. The recent
progress in understanding the nature of the ligand bound
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
1005

View Online
Scheme 4 Reagents and conditions: i, NaBH4, THF, H2O, 20 ЊC; ii, NaH, Imidazole, THF, then CS2 followed by MeI; iii, p-TsOH, Me2CO, H2O; iv,
Bu3SnH, AIBN, C6H5Me, reflux; v, (a) DDQ, MeOH, (b) (CH2OH)2, (COOH)2, C6H6, reflux, (c) Pd-C, H2, THF, (d) HCl, MeOH, H2O, (e) Me2SO4,
K2CO3, Me2CO, H2O; vi, LDA, THF, Ϫ78 ЊC, then TMSCl; vii, Pd(OAc)2, MeCN, reflux; viii, CH2᎐᎐CH(OAc)CH3, Ac2O, p-TsOH, reflux; ix,
C6H5SO2CH᎐CH2, C6H6, 140 ЊC (sealed tube); x, DDQ, MeOH; xi, Ac2O, DMAP, C5H5N; xii, DDQ, p-TsOH, MeOH, reflux; xiii, R-Ni, H2, THF–
᎐
MeOH, 50 ЊC, 50 bar; xiv, KOH, MeOH.
receptor1–3 provides scope for using this approach as a basis for
determining the compatibility of the 14,17-ethano bridge with
the binding domain, and hence, determining the influence of
this feature, combined with backbone inversion, on bioactivity.
A first approach entails determination of feasible conform-
ations of 13 and 32, and their superimposability on that of
estradiol.
In the absence of X-ray crystallographic data on the com-
pounds, the first resort was to examine the spectroscopic prop-
erties of appropriate derivatives for evidence of any preferred
ground state conformations. In the 8α-series, the NMR data
confirmed the inference drawn from molecular models that the
ring system is conformationally quite rigid, and that a ring B
half-chair, ring C chair conformation is fully reconcilable with
observed couplings and NOE correlations. Similarly, these data
in the 9β-series, furnished no evidence of significant deviation
from a ring C chair conformation, despite the attendant α-face
steric congestion imposed by the cis ring-junction. The latter
observation is reminiscent of earlier findings on a 14α-methyl
9β-analogue of estradiol,16 in which similar steric factors are
present.
A conformational search was conducted on the respective
hormone analogues to determine their respective, global mini-
mum energy structures (Table 1), and confirmed that both the
8α- and 9β-isomers 13 and 32 adopt preferred ring B half-chair,
ring C chair (7H8,8C12) conformations 13a and 32a respectively.
In the case of the 9β-isomer 32, three additional, higher energy
conformations 32b, 32c and 32d were also identified. The first
of these, 32b, entails the minimal energy-demand modification
of ring B to a boat-like (6,9B) conformation, whereas 32c and
32d reveal the more radical deformation of ring C to a twist
(9T14) conformation.
The energy minimisation confirms that 13 is indeed con-
formationally rigid, despite the presence of a cis B,C-ring junc-
tion and, although a molecular dynamics simulation revealed
that a transient 6,9B conformation can be attained, it has no
influence on the overall ground-state conformation. No ring C
inversion could be detected during this simulation. By contrast,
the relative steric energies of the two lower energy forms of the
9β-isomer 32a and 32b are very similar, and a molecular dyn-
amics simulation demonstrated that the 7H8 and 6,9B states
of ring B are readily interconvertible, and that the latter is
1006
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013

View Online
Table 1 Steric energies of discrete conformers of 14,17α-ethano-8α-estradiol 13 and 14,17α-ethano-9β-estradiol 32, showing respective puckering
parameters of rings B and Ca
Ring B
Ring C
Compound
E (kcal molϪ1
)
Q/Å
φ
θ
Conf.
Q/Å
φ
θ
Conf.
8α-isomer 13a
99.9
93.0
93.9
98.2
99.8
0.458
0.439
0.601
0.434
0.504
207.7
200.8
116.1
57.2
44.7
44.8
90.4
130.0
73.4
7H8
7H8
6,9B
E7
0.522
0.542
0.528
0.680
0.640
205.7
259.4
246.2
267.6
274.4
4.0
6.9
8.1
88.4
88.7
8C12
8C12
8C12
9T14
9T14
9β-isomer 32a
32b
32c
32d
275.7
7S6
a Steric energies are represented by E, and puckering parameters by Q, φ and θ, and conformational descriptors are defined in accordance with
described practice.17
relatively persistent. Although ring C retains its 8C12 state more
tenaciously in this simulation, conformational inversion to a
9T14 state is nevertheless observed, implying that the higher
energy flexible structures represented by 32c and 32d are
attainable.
An initial approach to comparing these analogues with
estradiol entailed superimpositions of the feasible conformers
upon the energy minimised structure of the parent hormone.
For this purpose, the ring A carbon atoms and the oxygen
atoms at C-3 and C-17 were chosen as the elements for super-
imposition, using a root mean-square fitting protocol.
The ‘fit’ achieved by superimposing the minimum energy
structure of the 8α-analogue 13a upon estradiol (Fig. 2)
revealed reasonably good overlap of the polar termini, with
ring D and the ethano bridge occupying the space in the α-face
region of estradiol. This region has been shown to be capable
of accommodating sterically demanding hydrophobic struc-
tures without adversely influencing the ligand affinity for the
estradiol receptor,5,8 and provides a working hypothesis to
explain the moderately high competition factor exhibited by 13.
The poor alignment of the central-ring elements in this super-
imposition suggests why the affinity is not more competitive
with that of estradiol, and is probably responsible for inherently
lower binding affinities in the 8α-series.9 It is concluded there-
fore, that the 14,17-ethano bridge is not inimical to receptor
binding in this series, although more comparative studies based
upon definitive comparison of X-ray crystal structures would
be required to substantiate this conclusion.
In the case of the 9β-analogue 32, the superimposition of the
lower energy forms 32a and 32b on estradiol is extremely poor
(Fig. 3). This result is unsurprising, given the profound influ-
ence of 9-inversion upon the overall conformation. However,
consideration of the higher energy states, represented by the
flexible conformers 32c and 32d, reveals that reasonable align-
ment of the polar termini with those of estradiol is possible,
particularly in 32c, despite the consequent intrusion of ring D
and 14,17-ethano bridge elements into the ring D β-space of
estradiol and some deviance in the central-ring superimposition
(Fig. 3). The partial occupancy of α-space by the 14,17-ethano
bridge in the conformer 32c is compatible with the proven
tolerance of the receptor toward steric demand in this region,
but the very weak receptor binding affinity of the parent
Fig. 2 Superimposition on estradiol (light), of the minimum-energy
7H8,8C12-conformation 13a of 14α,17α-ethano-8α-estradiol (dark).
Fig. 3 Superimposition on estradiol (light), of 14α,17α-ethano-9β-estradiol (dark): (i) 7H8,8C12-conformation 32a; (ii) 6,9B,8C12-conformation 32b;
(iii) E7,9T14-conformation 32c; (iv) 7S6,9T14-conformation 32d.
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
1007

View Online
9β-estradiol precludes a meaningful interpretation of any
binding contribution of this factor. Nevertheless, it is perhaps
remarkable that the ethano analogue 32 reveals any affinity for
the estradiol receptor, and suggests that the binding which is
observed may be attributable to the adoption of a higher energy
conformation during the interaction with the receptor. The
attendant energy demand is feasible, given the energy release
associated with receptor binding.18 The alternative option, of a
receptor–substrate interaction, in which 32 retains the ground
state conformation, can conceivably be accommodated by the
steric latitude of the binding domain above and below rings B
and C, but at the cost of a proximal relationship, for hydrogen
bonding contact, between the 17-hydroxy group and the
histidine-524 residue of the receptor.2
Although the findings presented here, provide a basis for a
working hypothesis of structure–activity in backbone-inverted
analogues of 14α,17α-ethanoestradiol, it is evident that more
refined modelling, based upon X-ray crystal structure data, are
necessary to substantiate some of the provisional conclusions
presented in this study.
80.8; H, 7.9%; M, 282); νmax/cmϪ1 1707 (C᎐O); δ (400 MHz)
᎐
H
1.24 (3H, s, 13β-Me), 2.41 (H, m, 8α-H), 2.66–2.85 (3H, m, 6-H2
₁
and 9α-H), 2.97 (1H, m, W 8, 14α-H), 3.77 (3H, s, 3-OMe),
₂
6.09 (1H, dd, J 6.0 and 3.4, 16-H), 6.61 (1H, d, J 2.7, 4-H), 6.73
(1H, dd, J 8.4 and 2.7, 2-H), 7.08 (1H, d, J 8.4, 1-H) and 7.59
(1H, ddd, J 6.0, 2.0 and 0.6, 15-H); δC (100 MHz) 22.8 (C-7),
23.3 (C-18), 28.5 (C-11), 30.3 (C-12), 31.6 (C-6), 37.8 (C-8), 40.8
(C-9), 52.0 (C-13), 54.0 (C-14), 55.2 (3-OMe), 112.3 (C-2), 113.5
(C-4), 130.1 (C-1), 131.9 (C-16), 132.9 (C-10), 137.4 (C-5),
157.5 (C-3), 160.4 (C-15) and 212.8 (C-17).
3-Methoxy-8ꢀ-estra-1,3,5(10),14,16-pentaen-17ꢁ-yl acetate 3
A solution of the ∆15-17-ketone 2 (1.4 g, 4.9 mmol) and toluene-
p-sulfonic acid (200 mg) in a mixture of isopropenyl acetate (15
cm3) and acetic anhydride (15 cm3) was heated under reflux for
2 h. The mixture was then poured into ice-water and stirred
for 1.5 h, with the regular addition of solid sodium hydrogen
carbonate until effervescence ceased. The resulting mixture was
extracted into diethyl ether, and the extract was washed (satd.
aq. NaHCO3, water), dried (MgSO4) and evaporated under
reduced pressure to give a residue (1.5 g) which was flash
chromatographed on silica gel (50 g), eluting with toluene–
hexane (1:1), to give the dienyl acetate 3 (1.25 g, 78%), mp 107–
110 ЊC (from methanol); [α]D ϩ108 (c 0.3) (Found: C, 77.9; H,
7.7%; Mϩ, 324. C21H24O3 requires C, 77.7; H, 7.5%; M, 324);
νmax/cmϪ1 1748 (C᎐O); δ (400 MHz) 1.21 (3H, s, 13β-Me), 1.94
Experimental
Mps were determined on a Reichert-Jung hot-stage microscope
and are uncorrected. Unless otherwise stated, spectra were
recorded as follows: IR, Perkin-Elmer 983 or Perkin-Elmer
᎐
H
1
Paragon 1000, chloroform solutions; H NMR, Varian VXR
(1H, dt, J 12.8 and 2 × 3.1, 12β-H), 2.21 (3H, s, 17-OAc), 2.61
(1H, dt, J 11.6 and 2 × 5.5, 9α-H), 2.79 (2H, m, 6-H2), 2.94 (1H,
ddd, J 13.3, 5.4 and 2.6, 8α-H), 3.77 (3H, s, 3-OMe), 5.98 (1H,
d, J 3.0, 15-H), 6.08 (1H, d, J 3.0, 16-H), 6.62 (1H, d, J 2.6,
4-H), 6.71 (1H, dd, J 8.4 and 2.6, 2-H) and 7.02 (1H, d, J 8.4,
1-H).
(200 MHz) or Varian Unity (400 MHz), deuteriochloroform
solutions (J values in Hz; Jx refers to exo; Jn refers to endo);
mass spectra, VG Micromass 16F (low resolution, electron
impact) and VG-70E (accurate masses). Optical rotations were
measured on a Perkin-Elmer 141 polarimeter for chloroform
solutions at 20 ЊC, and [α]D values are given in 10Ϫ1 deg cm2 gϪ1
.
Microanalyses were determined using a Fisons EA 1108
instrument. Silica gel for chromatography refers to Merck
Kieselgel 60, 63–200 µm (gravity) and 40–63 µm (flash).
Cycloaddition of dienyl acetate 3 with phenyl vinyl sulfone (PVS)
A mixture of the dienyl acetate 3 (400 mg, 1.23 mmol) and PVS
(1 g, 5.95 mmol) in anhydrous benzene (10 cm3) was heated at
150 ЊC for 140 h in a sealed tube. The cooled solution was
adsorbed on silica gel (50 g) and eluted with ethyl acetate–
toluene (1:9) to give unidentified products (144 mg), followed
by an inseparable mixture of cycloadducts 4, 5 and 6 (476 mg,
79%). Recrystallisation from chloroform–methanol afforded
(172R)-3-methoxy-172-phenylsulfonyl-14,17α-ethano-8α-estra-
1,3,5(10),15-tetraen-17β-yl acetate 4, mp 286–287 ЊC; [α]D ϩ92
(c 0.4) (Found: C, 70.4; H, 6.6; S, 6.4%; Mϩ, 492. C29H32O5S
Computational results were obtained using software pro-
grammes from Molecular Simulations Inc (San Diego, USA).
Energy minimisations were performed using the CVFF force-
field in the Discover programme (version 2.9.8), applying a
combination of steepest descents, conjugate gradient and
Newton–Raphson minimisation techniques incorporated in the
software, and superimpositions were similarly carried out with
the aid of the ‘superimpose’ command in the software. Molecu-
lar dynamics simulations were performed using a constant
volume, constant temperature (NVT) ensemble at 298 K with a
Verlet leapfrog integrator and a 1 fs timestep. An initial 10 ps
equilibration period was followed by a 100 ps data collection
period in which structures were sampled every 50 fs.
requires C, 70.7; H, 6.5; S, 6.5%; M, 492); νmax/cmϪ1 1739 (C᎐O),
᎐
1318, 1147 (SO2Ph); δH (400 MHz) 1.03 (3H, s, 13β-Me), 2.05
(3H, s, 17β-OAc), 2.14 (1H, dd, J 12.2 and 9.4, 171 -H), 2.57
x
(1H, dd, J 12.2 and 4.3, 171 -H), 2.79 (2H, m, 6-H2), 3.09 (2H,
n
m, 8α-H and 9α-H), 3.78 (3H, s, 3-OMe), 4.25 (1H, dd, J 9.4
and 4.3, 172 -H), 6.33 (1H, d, J 6.0, 15-H), 6.40 (1H, d, J 6.0,
3-Methoxy-8ꢀ-estra-1,3,5(10),15-tetraen-17-one 2
x
16-H), 6.62 (1H, d, J 2.8, 4-H), 6.72 (1H, dd, J 8.4 and 2.8,
2-H), 7.04 (1H, d, J 8.4, 1-H), 7.50 (2H, m, m-H of PhSO2), 7.58
(1H, m, p-H of PhSO2) and 7.80 (2H, m, o-H of PhSO2); δC (100
MHz) 16.9 (C-18), 21.3 (17-OCOCH3), 22.6 (C-11), 27.2 (C-7),
28.1 (C-12), 31.1 (C-171), 31.3 (C-6), 34.6 (C-8), 35.4 (C-9), 55.2
(3-OMe), 60.3 (C-13), 61.1 (C-14), 66.3 (C-172), 92.4 (C-17),
112.4 (C-2), 113.2 (C-4), 128.1 (C-2Ј and C-6Ј), 129.2 (C-3Ј and
C-5Ј), 130.4 (C-1), 132.5 (C-15), 132.7 (C-10), 133.3 (C-4Ј),
135.5 (C-16), 137.6 (C-5), 141.3 (C-1Ј), 157.6 (C-3) and 170.4
(17-OCOCH3).
A solution of the 17-ketone 1 (800 mg, 2.8 mmol) in THF (20
cm3) was added to a solution of lithium diisopropylamide [pre-
pared from n-butyllithium (2.5 mol dmϪ3 in hexanes, 6 cm3, 15
mmol) and diisopropylamine (2 cm3, 15.3 mmol) in THF
(10 cm3)] at Ϫ78 ЊC and the mixture was stirred for 30 min.
Chlorotrimethylsilane (1.9 cm3, 15 mmol) was added and the
mixture was stirred for 10 min and then allowed to warm up to
25 ЊC. Saturated aqueous ammonium chloride was added and
the resultant mixture was extracted into ethyl acetate. The com-
bined organic phase was washed (water), dried (MgSO4) and
concentrated under reduced pressure to give a residue (1.2 g)
which was refluxed with palladium acetate (670 mg, 3 mmol) in
acetonitrile (70 cm3) for 1 h. The solids were filtered off, and the
filtrate was evaporated under reduced pressure to give a solid
residue (1.01 g) which was flash chromatographed on silica gel
(75 g) with toluene as eluent to afford the ∆15-17-ketone 2 (795
mg, 100%), mp 115–116 ЊC (from diisopropyl ether); [α]D Ϫ39
(c 0.2) (Found: C, 81.0; H, 8.0%; Mϩ, 282. C19H22O2 requires C,
Base hydrolysis of cycloaddition mixture 4, 5 and 6
A solution of the mixture of cycloadducts 4 ϩ 5 ϩ 6 (55 mg,
0.11 mmol) in methanolic potassium hydroxide (1%; 5 cm3) was
stirred for 18 h at 25 ЊC. The mixture was poured into saturated
aqueous sodium hydrogen carbonate (10 cm3) and extracted
into ethyl acetate. The combined organic phase was washed
(water), dried (MgSO4) and evaporated under reduced pressure
1008
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013

View Online
to give a crude residue (39 mg) which was chromatographed on
silica gel (4.5 g), with ethyl acetate–toluene (1:9) as eluent, to
give 3-methoxy-14-phenylsulfonylethyl-8α,14β-estra-1,3,5(10),
15-tetraen-17-one 7 (9 mg, 17%), as an oil, [α]D ϩ14 (c 0.8)
under reduced pressure to give a solid residue (483 mg) which
was adsorbed on silica gel (50 g). Elution with ethyl acetate–
toluene (1:19) gave an inseparable mixture of (172R)-3-
methoxy-172-phenylsulfonyl-14,17α-ethano-8α-estra-1,3,5(10)-
trien-17β-yl acetate 10 and 3-methoxy-15α-phenylsulfonyl-
14,17α-ethano-8α-estra-1,3,5(10)-trien-17β-yl acetate 11 (375
mg, 82%).
(Found: Mϩ, 450.185. C27H30O4S requires M, 450.186); νmax
/
cmϪ1 1708 (C᎐O), 1307, 1152 (SO Ph); δH (200 MHz) 1.08 (3H,
᎐
2
s, 13β-Me), 3.76 (3H, s, 3-OMe), 6.20 (1H, d, J 5.9, 16-H), 6.60
(1H, d, J 2.8, 4-H), 6.70 (1H, dd, J 8.4 and 2.8, 2-H), 6.92 (1H,
d, J 8.4, 1-H) and 7.14–7.90 (6H, m, PhSO2 and 15-H) followed
by an inseparable mixture of (172R)-3-methoxy-172-phenyl-
sulfonyl-14,17α-ethanoestra-1,3,5(10),15-tetraen-17β-ol 8 and
3-methoxy-15α-phenylsulfonyl-14,17α-ethenoestra-1,3,5(10)-
trien-17β-ol 9 (33 mg, 66%) as an oil, m/z 450; νmax/cmϪ1 3599,
3412 (OH), 1307, 1148 (SO2Ph); δH (400 MHz) for 9 (~70%)
0.95 (3H, s, 13β-Me), 3.76 (3H, s, 3-OMe), 4.00 (1H, dd, J 8.7
and 4.7, 15β-H), 5.96 (1H, d, J 5.9, 172-H), 6.06 (1H, d, J 5.9,
171-H), 6.57 (1H, d, J 2.6, 4-H), 6.66–6.74 (1H, m, 2-H), 6.98
(1H, d, J 8.4, 1-H) and 7.48–7.88 (5H, m, 15α-SO2Ph); δH (400
MHz) for 8 (~30%) 1.00 (1H, s, 13β-Me), 3.77 (3H, s, 3-OMe),
Recrystallisation from chloroform–methanol afforded 11,
mp 312–313 ЊC; [α]D ϩ7 (c 0.3) (Found: C, 70.0; H, 6.9; S, 6.3%;
Mϩ, 494. C29H34O5S requires C, 70.4; H, 6.9; S, 6.5%; M, 494);
νmax/cmϪ1 1734 (C᎐O), 1306, 1147 (SO Ph); δH (200 MHz) 1.01
᎐
2
(3H, s, 13β-Me), 2.00 (3H, s, 17β-OAc), 3.79 (3H, s, 3-OMe),
3.99 (1H, ddd, J 11.7, 4.3 and 2.4, 15β-H or 172 -H), 6.62 (1H,
x
d, J 2.7, 4-H), 6.74 (1H, dd, J 8.5 and 2.7, 2-H), 7.06 (1H, d,
J 8.5, 1-H), 7.58 (3H, m, m- and p-H of PhSO2) and 7.88 (2H,
m, o-H of PhSO2). Further elution with ethyl acetate–toluene
(1:19) gave 3-methoxy-16α-phenylsulfonyl-14,17α-etheno-8α-
estra-1,3,5(10)-trien-17β-yl acetate 5 (82 mg, 18%), mp 218–
220 ЊC (from chloroform–methanol); [α]D ϩ22 (c 0.2) (Found:
C, 70.8; H, 6.7; S, 6.3%; Mϩ, 492. C29H32O5S requires C, 70.7;
4.17 (1H, dd, J 7.8 and 5.4, 172 -H), 6.06 (1H, d, J 5.9, 15-H),
x
6.31 (1H, d, J 5.9, 16-H), 6.61 (1H, d, J 2.8, 4-H), 6.66–6.74
H, 6.5; S, 6.5%; M, 492); νmax/cmϪ1 1746 (C᎐O), 1320, 1152
᎐
(1H, m, 2-H), 7.02 (1H, d, J 8.4, 1-H), 7.48–7.99 (5H, m, 172 -
(SO2Ph); δH (400 MHz) 0.91 (1H, dt, J 13.8 and 2 × 3.2, 12β-H),
0.95 (3H, s, 13β-Me), 1.44 (1H, qd, J 3 × 13.8 and 3.8, 11β-H),
1.63 (3H, s, 17β-OAc), 1.72 (1H, dd, J 12.6 and 4.6, 15α-H),
2.18 (1H, ddd, J 13.5, 4.6 and 2.4, 8α-H), 2.31 (1H, tdd, J 13.8,
2 × 4.2 and 0.8, 12α-H), 2.52 (1H, dd, J 12.6 and 9.0, 15β-H),
2.74 (2H, m, 6-H2), 2.85 (1H, dt, J 12.6 and 2 × 4.2, 9α-H), 3.76
(3H, s, 3-OMe), 4.05 (1H, dd, J 9.0 and 4.6, 16β-H), 5.96 (1H,
d, J 6, 172-H), 6.43 (1H, d, J 6, 171-H), 6.60 (1H, d, J 2.6, 4-H),
6.70 (1H, dd, J 8.6 and 2.6, 2-H), 7.00 (1H, d, J 8.6, 1-H), 7.62
(3H, m, m- and p-H of PhSO2) and 7.91 (2H, m, o-H of PhSO2);
δC (100 MHz) 16.5 (13β-Me), 20.1 (C-7), 20.9 (17-OCOCH3),
28.2 (C-11), 28.9 (C-15), 29.2 (C-12), 30.5 (C-6), 37.8 (C-8), 38.2
(C-9), 55.2 (3-OMe), 54.4 (C-13), 61.2 (C-14), 67.2 (C-16), 95.1
(C-17), 112.3 (C-2), 113.2 (C-4), 128.5 (C-2Ј and C-6Ј), 129.1
(C-3Ј and C-5Ј), 129.2 (C-171), 130.4 (C-1), 133.3 (C-4Ј), 133.4
(C-10), 136.3 (C-172), 136.9 (C-5), 140.9 (C-1Ј), 157.6 (C-3) and
168.9 (17-OCOCH3).
n
SO2Ph).
(172R)-3-Methoxy-172-phenylsulfonyl-14,17ꢀ-ethano-8ꢀ-estra-
1,3,5(10),15-tetraen-17ꢁ-ol 8
A solution of the 17β-acetate 4 (20 mg, 0.05 mmol) in meth-
anolic potassium hydroxide (1%, 2 cm3) was stirred for 18 h at
25 ЊC. Work-up, as in the previous experiment, gave a crude
residue (17 mg) which was chromatographed on silica gel (1.5 g)
with ethyl acetate–hexane (1:1) as eluent to give the 17β-alcohol
8 (13 mg, 73%) as an oil (Found: Mϩ, 450.185. C27H30O4S
requires M, 450.186); νmax/cmϪ1 3599, 3412 (OH), 1306, 1148
(SO2Ph); δH (400 MHz) 1.00 (3H, s, 13β-Me), 1.90 (1H, br s,
17β-OH), 3.77 (3H, s, 3-OMe), 4.17 (1H, dd, J 7.8 and 5.4,
172 -H), 6.06 (1H, d, J 5.9, 15-H), 6.31 (1H, d, J 5.9, 16-H),
x
6.61 (1H, d, J 2.8, 4-H), 6.71 (1H, dd, J 8.6 and 2.8, 2-H), 7.02
(1H, d, J 8.6, 1-H) and 7.48–7.80 (5H, m, 172 -SO2Ph).
n
3-Methoxy-14,17ꢀ-ethano-8ꢀ-estra-1,3,5(10)-trien-17ꢁ-ol 12
Acetylation of the mixture of alcohols 8 and 9
(a) A solution of 1,2-diiodoethane (1.9 g, 6.8 mmol) in THF (68
cm3) was added slowly to samarium (1.1 g, 7.6 mmol) and the
mixture was allowed to stir at 25 ЊC until a deep-blue solution
was formed (~90 min). Hexamethylphosphoramide (HMPA)
(5.5 cm3) was added and the mixture was stirred for 1 h at 25 ЊC
to give a dark-purple solution which was cooled to Ϫ20 ЊC. A
solution of the mixture of sulfones 10 ϩ11 (366 mg, 0.7 mmol)
in THF (35 cm3) was added and the mixture was stirred at
Ϫ20 ЊC for 4 h. Saturated aqueous ammonium chloride was
added and the mixture was extracted into ethyl acetate. The
combined organic phase was washed (water, saturated aq.
Na2S2O3, brine), dried (MgSO4) and evaporated under reduced
pressure to give a residue (382 mg) which was chromatographed
on silica gel (40 g), with ethyl acetate–toluene (1:19) as eluent,
to give starting material (5 mg), preceded by a fraction (206 mg)
which was stirred in a methanolic potassium hydroxide solution
(1%, 10 cm3) for 18 h. The mixture was poured into water and
extracted with ethyl acetate. The combined organic phase was
washed (water, brine), dried (MgSO4) and evaporated under
reduced pressure to give a solid residue (181 mg) which was
chromatographed on silica gel (20 g), with ethyl acetate–toluene
(1:19) as eluent, to give 3-methoxy-14,17α-ethano-8α-estra-
1,3,5(10)-trien-17β-ol 12 (180 mg, 78%), mp 146–148 ЊC (from
methanol); [α]D Ϫ34 (c 0.3) (Found: C, 80.5; H, 9.1%; Mϩ, 312.
C21H28O2 requires C, 80.7; H, 9.0%; M, 312); νmax/cmϪ1 3601,
3438br (OH); δH (200 MHz) 1.00 (3H, s, 13β-Me), 2.6–3.2
(3H, m, 6-H2 and 9α-H), 3.78 (3H, s, 3-OMe), 6.62 (1H, d, J 2.8,
4-H), 6.74 (1H, dd, J 8.4 and 2.8, 2-H) and 7.08 (1H, d, J 8.4,
1-H).
The mixture of alcohols 8 ϩ 9 (26 mg, 0.05 mmol) and 4-
(dimethylamino)pyridine (DMAP) (5 mg) in pyridine (2 cm3)
was stirred for 4 h at 25 ЊC. Saturated aqueous ammonium
chloride was added and the resultant mixture was extracted into
ethyl acetate. The combined organic phase was washed [aq. HCl
(1 mol dm3), satd. aq. NaHCO3, water, brine], dried (MgSO4)
and evaporated under reduced pressure to give a residue
(30 mg) which was chromatographed on silica gel (2 g), with
ethyl acetate–toluene (1:19) as eluent, to give a mixture of the
17β-acetates 4 and 6 (25 mg; 88%). Recrystallisation from
chloroform–methanol afforded 17β-acetate 4, mp 285–287 ЊC.
Evaporation of the mother liquor afforded 3-methoxy-15α-
phenylsulfonyl-14,17α-ethenoestra-1,3,5(10)-trien-17β-yl acet-
ate 6 as an oil, [α]D Ϫ1 (c 1.4) (Found: Mϩ, 492. C29H32O5S
requires M, 492); νmax/cmϪ1 1739 (C᎐O), 1319, 1149 (SO Ph);
δH (400 MHz) 1.00 (3H, s, 13β-Me), 2.05 (3H, s, 17β-OAc), 2.09
(1H, dd, J 12.3 and 9.0, 16β-H), 2.63 (1H, dd, J 12.3 and
4.8, 16α-H), 3.77 (3H, s, 3-OMe), 4.03 (1H, dd, J 9.0 and 4.8,
15β-H), 6.00 (1H, d, J 6.0, 172-H), 6.37 (1H, d, J 6.0, 171-H),
6.59 (1H, d, J 2.7, 4-H), 6.70 (1H, dd, J 8.4 and 2.7, 2-H), 7.00
(1H, d, J 8.4, 1-H), 7.55 (2H, m, m-H of PhSO2), 7.63 (1H, m,
p-H of PhSO2) and 7.88 (2H, m, o-H of PhSO2).
᎐
2
Hydrogenation of the mixture of cycloadducts 4, 5 and 6
The mixture of cycloadducts 4 ϩ 5 ϩ 6 (460 mg, 0.9 mmol) was
stirred with palladium on carbon (10%, 100 mg) in chloroform
(10 cm3) under hydrogen (50 bar) at 60 ЊC for 5 h. The solu-
tion was filtered through Celite and the filtrate was evaporated
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
1009

View Online
(b) A solution of the sulfones 10 ϩ 11 (320 mg, 0.65 mmol) in
THF (10 cm3) was added to a solution of sodium (700 mg, 30
mmol) in a mixture of ammonia (40 cm3, freshly distilled from
sodium) and THF (5 cm3) at Ϫ33 ЊC. The resulting solution was
stirred for 2 h at Ϫ33 ЊC. Solid ammonium chloride was added
and the ammonia was allowed to evaporate. Water was added
and the resulting mixture was extracted into ethyl acetate. The
combined organic phase was washed (water, brine), dried
(MgSO4) and evaporated under reduced pressure to give a
solid residue (133 mg) which was chromatographed on silica
gel (13 g), eluting with ethyl acetate–toluene (1:19), to give
compound 12 (108 mg, 53%), identical in all respects (mp and
[α]D) to that synthesised previously.
with the same solvent afforded 3-methoxy-14α,17α-ethano-8α-
estra-1,3,5(10)-trien-17β-ol 12 (16 mg, 47%), mp 145–147 ЊC
(from methanol).
S-Methyl O-(3-methoxy-11-oxo-9ꢁ-estra-1,3,5(10)-trien-11ꢀ-
yl)dithiocarbonate 20
Sodium borohydride (500 mg, 12.5 mmol) was added to a solu-
tion of 17,17-ethylenedioxy-3-methoxy-9β-estra-1,3,5(10)-trien-
11-one 1812 (465 mg, 1.4 mmol) in a mixture of THF (10 cm3)
and water (1 cm3) and the mixture was stirred for 2 h. Water
was added and the mixture was extracted into ethyl acetate.
The combined organic phase was washed (water, brine), dried
(MgSO4) and evaporated under reduced pressure. The crude
11α-alcohol (430 mg, 1.3 mmol), sodium hydride (0.5 g of a
60% suspension in mineral oil, 12.5 mmol) and imidazole (10
mg) were refluxed in THF (20 ml) for 90 min. Carbon disulfide
(0.2 cm3, 3 mmol) was added and the mixture was refluxed for
30 min, then methyl iodide (0.2 cm3, 3 mmol) was added. The
resulting mixture was refluxed for 30 min. Acetic acid (2 cm3)
was added to the cooled solution and the mixture was extracted
into ethyl acetate. The combined organic phase was washed
(water, brine), dried (MgSO4) and evaporated under reduced
pressure to give a residue (826 mg) which was chromatographed
on silica gel (50 g) with ethyl acetate–hexane (1:9) as eluent to
give the 11α-dithiocarbonate 19 (402 mg, 74%), as an oil, [α]D
14,17ꢀ-Ethano-8ꢀ-estra-1,3,5(10)-triene-3,17ꢁ-diol 13
A solution of boron tribromide (1.0 mol dmϪ3 in dichloro-
methane, 3 cm3, 3 mmol) was added to a solution of the
3-methyl ether 12 (206 mg, 0.7 mmol) in dichloromethane (20
cm3) at 0 ЊC and the mixture was stirred at 0 ЊC for 90 min. The
mixture was poured into water and extracted with ethyl acetate.
The combined organic phase was washed (water, brine), dried
(MgSO4) and concentrated under reduced pressure to give a
residue (186 mg) which was adsorbed onto silica gel (18 g) and
eluted with methanol–chloroform (1:9) to give the 3,17β-diol
13 (160 mg, 81%), mp 248–249 ЊC (from methanol); [α]D Ϫ34
(c 0.8 in THF) (Found: C, 80.5; H, 8.9%; Mϩ, 298. C20H26O2
requires C, 80.5; H, 8.8%; M, 298); νmax/cmϪ1 (in THF) 3442,
3320br (OH).
ϩ50 (c 0.3) (Found: Mϩ, 434. C23H30O4S2 requires M, 434); νmax
/
cmϪ1 1235, 1120, 1052 (C᎐S); δ (200 MHz) 1.09 (3H, s, 13β-
᎐
H
Me), 2.56 (3H, s, 11α-OCS2Me), 3.50 (1H, t, J 2 × 4.3, 9β-H),
3.75–3.9 (4H, m, 17,17-OCH2CH2O), 3.78 (3H, s, 3-OMe), (1H,
dt, J 10.9 and 2 × 4.3, 11β-H), 6.63 (1H, d, J 2.7, 4-H), 6.73
(1H, dd, J 8.8 and 2.7, 2-H) and 7.61 (1H, d, J 8.8, 1-H). Treat-
ment of a portion of this product with toluene-p-sulfonic acid
in a mixture of acetone and water (7:1) at 25 ЊC for 22 h, fol-
lowed by standard work-up, and chromatography of the residue
on silica gel with ethyl acetate–toluene (1:19) as eluent gave the
17-ketone 20 (85%), mp 152–154 ЊC (from acetone–hexane);
[α]D ϩ161 (c 0.4) (Found: C, 64.9; H, 6.9; S, 16.4%; Mϩ, 390.
Desulfonylation of the mixture of phenyl vinyl sulfone cyclo-
adducts 4, 5 and 6
A solution of the phenyl vinyl sulfone cycloadducts 4 ϩ 5 ϩ 6
(700 mg, 1.4 mmol) in THF (20 cm3) was added to a solution of
sodium (700 mg, 30 mmol) in a mixture of ammonia (40 cm3;
freshly distilled from sodium) and THF (5 cm3) at Ϫ33 ЊC. The
resulting mixture was stirred for 2 h at Ϫ33 ЊC. Solid ammo-
nium chloride was added, and the ammonia was allowed to
evaporate. Water was added and the resulting mixture was
extracted into ethyl acetate. The combined organic phase was
washed (water, brine), dried (MgSO4) and evaporated under
reduced pressure to give a residue (616 mg). Chromatography
on silica gel (60 g) with ethyl acetate–toluene (1:19) as eluent
gave two unidentified fractions (50 and 12 mg), followed by
an inseparable mixture of products 14, 15, 16 and 17 (157
mg, 36%), mp 83–85 ЊC (from methanol) (Found: C, 81.1; H,
8.7%; Mϩ, 310. C21H26O2 requires C, 81.3; H, 8.4%; M, 310);
νmax/cmϪ1 3598 (OH); δH (200 MHz) 0.97 and 0.98 (each 3H, s,
13β-Me), 3.77 (3H, s, 3-OMe), 5.75 (0.5H, d, J 5.9), 5.90 (0.5H,
d, J 5.9), 6.60 (1H, m, 4-H), 6.70 (1H, m, 2-H) and 7.01–7.05
(1H, m, 1-H).
C21H26O3S2 requires C, 64.6; H, 6.7; S, 16.4%; M, 390); νmax
/
cmϪ1 1734 (C᎐O), 1239, 1150, 1055 (C᎐S); δ (200 MHz)
᎐
᎐
H
1.11 (3H, s, 13β-Me), 2.53 (3H, s, 11α-OCS2Me), 3.50 (1H, t,
J 2 × 4.7, 9β-H), 3.77 (3H, s, 3-OMe), 6.31 (1H, dt, J 8.3 and
2 × 4.6, 11β-H), 6.64 (1H, d, J 2.6, 4-H), 6.72 (1H, dd, J 8.5 and
2.6, 2-H) and 7.51 (1H, d, J 8.5, 1-H).
3-Methoxy-9ꢁ-estra-1,3,5(10)-trien-17-one 21
(a) A solution of the 17,17-ethylenedioxy-11α-dithiocarbonate
19 (100 mg, 0.2 mmol), tributylstannane (1 g, 3.4 mmol) and
α,αЈ-azobis(isobutyronitrile) (AIBN) (30 mg) in toluene (5 cm3)
was refluxed for 3 h. The cooled mixture was adsorbed onto
silica gel (20 g) and eluted with toluene (to remove the tin
residues) followed by ethyl acetate–toluene (1:19) to give an
oily residue (36 mg, 0.1 mmol) which was dissolved in a mixture
of acetone and water (7:1; 10 cm3) and stirred with toluene–p-
sulfonic acid (10 mg) for 18 h. The acetone was removed under
reduced pressure and the resulting solution was extracted with
ethyl acetate. The combined organic phase was washed (satur-
ated aq. NaHCO3, water, brine), dried (MgSO4) and evaporated
under reduced pressure to give a residue (25 mg) which was
filtered through silica gel (0.5 g) with ethyl acetate–toluene
(1:19) to give 3-methoxy-9β-estra-1,3,5(10)-trien-17-one 21 (18
mg, 28%) as an oil, [α]D ϩ40 (c 0.2) (lit.,12 [α]D ϩ43) (Found:
Hydrogenation of the desulfonylation mixture 14, 15, 16 and 17
A solution of the mixture of products 14 ϩ 15 ϩ 16 ϩ 17 (33
mg, 0.1 mmol) in ethyl acetate (2 cm3) at 25 ЊC was stirred with
palladium on carbon (10%, 3 mg) under hydrogen for 3 h. After
filtration of the catalyst (Celite), evaporation of the filtrate gave
a residue (34 mg) which was chromatographed on silica gel (5 g)
with ethyl acetate–toluene (1:19) as eluent to give a mixture of
compounds 14 and 15 (17 mg, 52%). Recrystallisation from
methanol afforded 3-methoxy-15,172-cyclo-14,17α-ethano-8α-
estra-1,3,5(10)-trien-17β-yl acetate 14, mp 77–80 ЊC; [α]D ϩ2
(c 0.5) (Found: C, 81.1; H, 8.6%; Mϩ, 310. C21H26O2 requires C,
81.3; H, 8.4%; M, 310); νmax/cmϪ1 3596 (OH); δH (400 MHz)
0.76 (1H, dt, J 5.8 and 2 × 1.5, 172-H), 0.98 (3H, s, 13β-Me),
Mϩ, 284. C19H24O2 requires M, 284); νmax/cmϪ1 1728 (C᎐O);
᎐
δH (400 MHz) 0.97 (3H, s, 13β-Me), 1.24 (1H, td, J 2 × 12.8
and 3.8, 12α-H), 2.20 (1H, m, 8β-H), 2.70 (1H, dt, J 16.8 and
2 × 4.6, 6β-H), 2.80 (1H, td, J 2 × 16.8 and 8.8, 6α-H), 3.01
1.44 and 1.48 (each 1H, dd, J 9.7 and 1.5, 16α-H and 171 -H),
(1H, br s, W 10, 9β-H), 3.77 (3H, s, 3-OMe), 6.62 (1H, d, J 2.7,
₁
n
₂

1.81 and 1.90 (each 1H, dt, J 9.7 and 2 × 1.6, 16β-H and 171 -
4-H), 6.72 (1H, dd, J 8.6 and 2.7, 2-H) and 7.22 (1H, d, J 8.6,
1-H); δC (100 MHz) 13.4 (13β-Me), 21.8 (C-15), 24.2 (C-11),
24.8 (C-7), 26.0 (C-6), 27.4 (C-12), 33.8 (C-8), 35.4 (C-16), 37.3
x
H), 3.77 (3H, s, 3-OMe), 6.60 (1H, d, J 2.7, 4-H), 6.72 (1H, dd,
J 8.4 and 2.7, 2-H) and 7.06 (1H, d, J 8.4, 1-H). Further elution
1010
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013

View Online
(C-9), 42.3 (C-14), 47.9 (C-13), 55.2 (3-OMe), 112.0 (C-2), 113.9
(C-4), 127.4 (C-1), 129.6 (C-10), 138.4 (C-5), 157.5 (C-3) and
220.8 (C-17).
3-Methoxy-9ꢁ-estra-1,3,5(10),14,16-pentaen-17-yl acetate 23
A solution of the ∆15-17-ketone 22 (114 mg, 0.4 mmol) and
toluene-p-sulfonic acid (20 mg) in a mixture of acetic anhydride
(2 cm3) and isopropenyl acetate (2 cm3) was refluxed for 3 h.
The cooled reaction mixture was poured into a mixture of ice
and solid sodium hydrogen carbonate and was stirred for 1 h,
with the addition of further sodium hydrogen carbonate to
quench the acid generated. The resulting mixture was extracted
into ethyl acetate (3×), the combined organic phase was washed
with water and brine, dried and evaporated under reduced pres-
sure to give a residue (178 mg) which was chromatographed on
silica gel (10 g) with toluene–hexane (7:3) as eluent to give the
product 23 (114 mg, 88%) as an oil, [α]D ϩ36 (c 0.2) (Found:
Mϩ, 324.172. C21H24O3 requires M, 324.1725); νmax/cmϪ1 1744
(b) A solution of DDQ (1.8 g, 7.9 mmol) in dry methanol (10
cm3) was added to a suspension of estrone 21 (2 g, 7.4 mmol) in
dry methanol (320 cm3) and the resulting dark-red solution was
stirred for 5 h at 45 ЊC, during which time the solution faded to
a dark orange. The methanol was removed under reduced pres-
sure and the residue was triturated with chloroform (200 cm3)
and allowed to stand for 18 h. Activated charcoal was added
and the mixture was stirred for 5 min then filtered through
Celite and concentrated under reduced pressure. The resultant
residue (1.9 g) was dissolved in a mixture of benzene (100 cm3)
and ethanediol (10 cm3) and was refluxed with oxalic acid (200
mg) for 18 h with azeotropic removal of water. The cooled
reaction mixture was poured into saturated aqueous sodium
hydrogen carbonate (100 cm3) and the mixture was extracted
with chloroform. The combined organic phase was washed with
water and brine, dried (MgSO4) and concentrated under
reduced pressure to give a dark-blue solid (1.8 g), which was
dissolved in THF (40 cm3) and stirred with palladium on
carbon catalyst (10%, 200 mg) under hydrogen (30 bar) for 72 h
at 40 ЊC. The catalyst was removed by filtration through Celite
and the residue after removal of the solvent (1.9 g) was dis-
solved in a mixture of methanol (40 ml), water (4 ml) and
hydrochloric acid (10 mol dmϪ3, 2 cm3) and the mixture was
stirred for 30 min. Water was added and the resulting precipi-
tate was collected by filtration (1.5 g). Recrystallation from a
mixture of ethanol (40 cm3) and water (5 cm3) afforded estrone
(390 mg). Chromatography of the mother liquor material (900
mg) on silica gel with ethyl acetate–chloroform (1:9) as eluent
afforded further estrone (447 mg) followed by 3-hydroxy-9β-
estra-1,3,5(10)-trien-17-one (300 mg, 15%), mp 182–184 ЊC
(from methanol–water) (lit.,12 186–189 ЊC), methylation of
which gave the product 21 (264 mg, 84%).
(C᎐O); δH (400 MHz) 1.10 (1H, td, J 2 × 13.2 and 3.4, 12α-H),
᎐
1.16 (3H, s, 13β-Me), 1.68 (1H, dt, J 13.2 and 2 × 3.4, 12β-H),
1.95–2.12 (2H, m, 7-H and 11β-H), 2.16 (3H, s, 17β-OAc), 2.24
(1H, m, 7-H), 2.37 (1H, dq, J 13.2 and 3 × 3.4, 11α-H), 2.73
(1H, ddd, J 17.4, 7.3 and 3.4, 6β-H), 2.86 (1H, m, 8β-H), 3.10–
3.20 (2H, m, 6α-H and 9β-H), 3.75 (3H, s, 3-OMe), 5.96 (1H, t,
J 2.2, 15-H), 6.03 (1H, d, J 2.2, 16-H), 6.59 (1H, d, J 2.8, 4-H),
6.63 (1H, dd, J 8.7 and 2.8, 2-H) and 7.06 (1H, d, J 8.7, 1-H).
Cycloaddition of phenyl vinyl sulfone to dienyl acetate 23
A solution of the dienyl acetate 23 (80 mg, 0.25 mmol) and
phenyl vinyl sulfone (400 mg, 2.4 mmol) in dry, deoxygenated
benzene (2 cm3) was heated in a sealed tube for 48 h at 140 ЊC.
The cooled reaction mixture was chromatographed on silica gel
(10 g) with ethyl acetate–hexane (1:9) as eluent to give a mix-
1
ture of cycloadducts (80 mg, 73%) (estimated at 7:1 by H
NMR). Careful rechromatography using diethyl ether–pentane
(1:1) as eluent resulted in partial separation to give 3-methoxy-
16α-phenylsulfonyl-14,17α-etheno-9β-estra-1,3,5(10)-trien-17β-
yl acetate 24 as a glassy solid, [α]D ϩ135 (c 4.2) (Found: C, 70.0;
H, 6.7; S, 6.2%; Mϩ, 492.195. C29H32O5S requires C, 70.7; H,
6.55; S, 6.5%; M, 492.196); νmax/cmϪ1 1745 (C᎐O); δ (400
᎐
H
3-Methoxy-9ꢁ-estra-1,3,5(10),15-tetraen-17-one 22
MHz) 0.88 (1H, dt, J 13.6 and 2 × 4.0, 12β-H), 0.96 (3H, d,
J 0.4, 13β-Me), 1.50 (1H, m, 7α-H), 1.62 (3H, s, 17β-OAc), 1.77
(1H, m, 11β-H), 1.83 (1H, dd, J 12.7 and 4.7, 15α-H), 1.96 (1H,
dd, J 12.7 and 9.1, 15β-H), 2.10–2.16 (2H, m, 7β-H and 8β-H),
2.21 (1H, m, 11α-H), 2.35 (1H, td, J 2 × 13.6 and 4.2, 12α-H),
2.60–2.76 (2H, m, 6-H2), 2.80 (1H, m, 9β-H), 3.80 (3H, s,
3-OMe), 4.13 (1H, dd, J 9.1 and 4.7, 16β-H), 5.10 (1H, d, J 6.2,
172-H), 5.98 (1H, d, J 6.2, 171-H), 6.70–6.75 (2H, m, 2-H and
4-H), 7.10 (1H, d, J 8.2, 1-H), 7.54 (2H, m, m-HЈs), 7.61 (1H, m,
p-H) and 7.82 (2H, m, o-HЈs); δC (100 MHz) 14.9 (C-18), 21.0
(17β-OAc), 22.6 (C-11), 23.7 (C-7), 25.4 (C-12), 28.2 (C-6), 31.8
(C-15), 33.9 (C-8), 34.3 (C-9), 52.3 (C-13), 55.2 (3-OMe), 62.5
(C-14), 66.3 (C-16), 95.1 (C-17), 111.4 (C-2), 112.9 (C-4), 125.9
(C-1), 127.6 (C-171), 128.4 (o-CЈs), 129.0 (m-CЈs), 131.7 (C-10),
132.8 (C-172), 133.2 ( p-C), 140.2 (C-5), 140.9 (ipso-C), 157.6
(C-3) and 169.0 (17β-OAc).
A solution of the 17-ketone 21 (264 mg, 0.93 mmol) in THF (10
cm3) was added to a freshly prepared solution of LDA [from
diisopropylamine (0.6 cm3, 4.6 mmol) and n-BuLi (2.5 mol
dmϪ3 in hexanes, 1.8 cm3, 4.5 mmol) in THF (15 cm3)] at
Ϫ78 ЊC and the resulting mixture was stirred for 1 h at Ϫ78 ЊC.
Chlorotrimethylsilane (0.6 cm3, 4.6 mmol) was added and the
mixture was allowed to warm up to 25 ЊC. Saturated aqueous
ammonium chloride was added and the reaction mixture was
extracted into diethyl ether (3×). The combined organic phase
was washed with water and brine, dried (MgSO4) and concen-
trated under reduced pressure to afford an oily residue (450 mg)
which was dissolved in acetonitrile (50 cm3) and refluxed with
palladium() acetate (225 mg, 1 mmol) and potassium carbon-
ate (500 mg) for 30 min. The solids were removed by filtration
and the residue after concentration was chromatographed on
silica gel (25 g) with ethyl acetate–toluene (1:19) as eluent to
give starting material 21 (89 mg, 33%) followed by the product
22 (132 mg, 52%) as an oil, [α]D ϩ24 (c 0.3) (Found: C, 80.2;
H, 8.0%; Mϩ, 282.162. C19H22O2 requires C, 80.8; H, 7.9%;
M, 282.162); νmax/cmϪ1 1703 (C᎐O); δ (400 MHz) 1.21 (3H,
s, 13β-Me), 1.55 (1H, m, obscured, 12α-H), 1.66 (1H, dt,
J 13.0 and 2 × 4.0, 12β-H), 1.74–2.16 (3H, m, 7-H2 and 11-H),
2.36–2.48 (2H, m, 8β-H and 11-H), 2.61 (1H, ddd, J 12.2, 3.2
and 2.1, 14α-H), 2.76 (2H, m, 6-H2), 3.11 (1H, m, 9β-H), 3.77
(3H, s, 3-OMe), 6.00 (1H, dd, J 6.0 and 3.2, 16-H), 6.63 (1H,
d, J 2.8, 4-H), 6.75 (1H, dd, J 8.5 and 2.8, 2-H), 7.28 (1H, d,
J 8.5, 1-H) and 7.56 (1H, ddd, J 6.0, 2.1 and 0.8, 15-H);
δC (100 MHz) 20.8 (C-18), 24.3 (C-11), 24.9 (C-7), 25.7 (C-12),
26.3 (C-6), 31.1 (C-8), 37.5 (C-9), 48.9 (C-14), 51.6 (C-13),
55.2 (3-OMe), 112.3 (C-2), 113.8 (C-4), 127.8 (C-1), 129.5
(C-10), 131.6 (C-16), 138.2 (C-5), 157.5 (C-3), 159.1 (C-15) and
213.2 (C-17).
Dehydrogenation of 14ꢀ,17ꢀ-ethano compounds
(a) A solution of 14,17α-ethanoestra-1,3,5(10)-triene-3,17β-
diol 254 (390 mg, 1.3 mmol) in dry methanol (60 cm3) was
stirred at 25 ЊC while a solution of DDQ (320 mg, 1.4 mmol) in
dry methanol was added over 2 min. The dark-red solution was
stirred at 40 ЊC for 3 h, during which time the colour faded to
a light orange. The methanol was evaporated under reduced
pressure and the residue was dissolved in ethyl acetate (50 cm3).
This solution was washed [aq. K2CO3 (1 mol dmϪ3), aq. Na2SO3
(2 mol dmϪ3), aq. K2CO3 (1 mol dmϪ3), water, brine]. The com-
bined washings were extracted with ethyl acetate, and these
extracts were combined with the original solution, and the
resulting mixture was washed (water, brine), dried (MgSO4) and
evaporated under reduced pressure to give a residue (428 mg).
This was dissolved in a mixture of pyridine (5 cm3) and acetic
᎐
H
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
1011

View Online
anhydride (5 cm3) and stirred with DMAP (20 mg) at 25 ЊC for
24 h. Water and solid sodium hydrogen carbonate were added,
and once effervescence ceased the mixture was extracted with
ethyl acetate. The combined organic phase was washed [satur-
ated aq. NaHCO3, aq. HCl (1 mol dmϪ3), water, brine], dried
(MgSO4) and evaporated under reduced pressure to give a resi-
due (515 mg) which was adsorbed onto silica gel (50 g) and
eluted with ethyl acetate–hexane (1:9) to give an inseparable
mixture of the diacetate 26 and 14,17α-ethanoestra-1,3,5(10),
9(11)-tetraene-3,17β-diyl diacetate 28 (324 mg, 65%), m/z 382
requires C, 75.4; H, 7.9; M, 382); νmax/cmϪ1 1750, 1727 (C᎐O);
᎐
δH (400 MHz) 0.94 (1H, ddd, J 13, 9.8 and 5.2, 172 -H), 1.03
n
(3H, s, 13β-Me), 1.16 (1H, dt, J 13 and 2 × 3.5, 172 -H), 1.99
x
(3H, s, 17β-OAc), 2.27 (3H, s, 3-OAc), 2.44 (1H, br d, J 15,
11α-H), 2.55 (1H, ddd, J 15, 11 and 5.6, 6α-H), 2.66 (1H,
dt, J 15 and 2 × 5.2, 6β-H), 2.84 (1H, br t, J 2 × 6.2, 9β-H),
6.82 (1H, d, J 2.5, 4-H), 6.89 (1H, dd, J 8.5 and 2.5, 2-H)
and 7.31 (1H, d, J 8.5, 1-H); δC (100 MHz) 14.2 (13β-Me), 21.2
(3-OCOCH3), 21.6 (17β-OCOCH3), 21.8 (C-11), 23.2 (C-7),
24.5 (C-12), 28.4 (C-6), 28.8 (C-172), 29.1 (C-171), 31.8 (C-16),
33.8 (C-15), 34.3 (C-9), 35.3 (C-8), 45.2 (C-14), 48.7 (C-13), 89.8
(C-17), 118.8 (C-2), 120.3 (C-4), 124.5 (C-1), 139.3 (C-10),
141.2 (C-5), 148.1 (C-3), 169.7 (17β-OCOCH3) and 170.9
(3-OCOCH3); δH (400 MHz, C6D6) 0.68 (1H, ddd, J 12.6, 9.9
and 380; νmax/cmϪ1 1729 (C᎐O); δH (400 MHz) (28, ~65%) 0.93
᎐
(3H, s, 13β-Me), 2.03 (3H, s, 17β-OAc), 2.28 (3H, s, 3-OAc),
6.29 (1H, dt, J 5.4 and 2 × 2.7, 11-H), 6.80 (1H, d, J 2.5, 4-H),
6.85 (1H, dd, J 8.7 and 2.5, 2-H) and 7.66 (1H, d, J 8.7, 1-H);
(26, ~35%) 0.93 (3H, s, 13β-Me), 2.03 (3H, s, 17β-OAc), 2.28
(3H, s, 3-OAc), 6.78 (1H, d, J 2.5, 4-H), 6.84 (1-H, dd, J 8.5 and
2.5, 2-H) and 7.30 (1H, d, J 8.5, 1-H).
and 5.1, 172 -H), 0.92 (3H, s, 13β-Me), 1.00 (1H, m, 7β-H), 1.28
n
(1H, dt, J 12.6 and 2 × 4.1, 12β-H), 1.46 (1H, m, 171 -H), 1.65
n
(3H, s, 17β-OAc), 1.76 (3H, s, 3-OAc), 2.44 (1H, br t, J 2 × 6.7,
9β-H), 6.88 (1H, d, J 2.3, 4-H), 6.93 (1H, dd, J 8.3 and 2.3, 2-H)
and 7.07 (1H, d, J 8.3, 1-H); δC (100 MHz, C6D6) 14.4 (13β-
Me), 20.6 (3-OCOCH3), 21.1 (17β-OCOCH3), 22.0 (C-11), 23.4
(C-7), 25.0 (C-12), 28.6 (C-6), 28.9 (C-172), 29.4 (C-171), 32.3
(C-16), 33.9 (C-15), 34.4 (C-9), 35.4 (C-8), 45.4 (C-14), 48.9
(C-13), 89.7 (C-17), 119.4 (C-2), 120.8 (C-4), 124.5 (C-1), 139.2
(C-10), 141.2 (C-5), 149.1 (C-3), 168.6 (17β-OCOCH3) and
169.8 (3-OCOCH3). The mixed fractions were rechromato-
graphed on silica gel (15 g) eluting with ethyl acetate–toluene
(1:99) to give further 26 (150 mg, 15%) and 31 (33 mg, 10%).
(b) To a stirred solution of 3-methoxy-14,17α-ethanoestra-
1,3,5(10)-trien-17β-ol 274 (2.7 g, 8.7 mmol) in dry methanol
(430 cm3) at 25 ЊC was added DDQ (2 g, 8.8 mmol) in meth-
anol (25 cm3) over a period of 2 min. After stirring for 1 h,
during which time the solution faded from a deep red to a pale
orange, the methanol was evaporated under reduced pressure
and the residue was triturated with hot chloroform (50 cm3) and
then allowed to stand at 4 ЊC for 16 h. After stirring with activ-
ated charcoal for 5 min the solution was filtered through Celite
to give a pale-yellow solution which was concentrated under
reduced pressure to give a residue (3.74 g) which was absorbed
onto alumina (activity III, 100 g) and eluted with ethyl acetate–
toluene (3:17) to give an inseparable mixture of starting
material 27 and 3-methoxy-14,17α-ethanoestra-1,3,5(10),9(11)-
tetraen-17β-ol 29 (2.7 g), m/z 312 and 310; δH (200 MHz) (27,
~50%) 0.89 (3H, s, 13β-Me), 3.76 (3H, s, 3-OMe), 6.6–6.9 (2H,
m, 2- and 4-H) and 7.20 (1H, d, J 8.5, 1-H); δH (200 MHz) (29,
~50%) 0.89 (3H, s, 13β-Me), 3.76 (3H, s, 3-OMe), 6.20 (1H, m,
11-H), 6.6–6.8 (2H, m, 2- and 4-H) and 7.60 (1H, d, J 8.8, 1-H).
(c) A solution of 3-methoxy-14α,17α-ethanoestra-1,3,5(10)-
trien-17β-ol 27 (270 mg, 0.9 mmol) and toluene-p-sulfonic acid
(300 mg, 1.74 mmol) in dry methanol (50 cm3) was stirred at
25 ЊC while a solution of DDQ (400 mg, 1.76 mmol) in dry
methanol (5 cm3) was added dropwise. The reaction was stirred
for 18 h at 25 ЊC followed by 2 h at reflux. The solvent was
removed under reduced pressure and the residue was dissolved
in chloroform (20 cm3). This solution was washed (saturated aq.
NaHCO3), dried (MgSO4) and evaporated to give a residue (220
mg). Chromatography on silica gel (25 g) with ethyl acetate–
toluene (1:9) as eluent gave the hexaene 30 (154 mg, 58%), mp
198–200 ЊC (from methanol); [α]D Ϫ31 (c 0.2) (Found: C, 82.4;
H, 7.5; Mϩ, 306. C21H22O2 requires C, 82.3; H, 7.2; M, 306);
νmax/cmϪ1 3609, 3464 (OH); δH (200 MHz) 0.85 (3H, s, 13β-Me),
1.70 (1H, s, D2O exch., 17β-OH), 3.92 (3H, s, 3-OMe), 6.65 (1H,
d, J 9.8, 12-H), 7.12 (1H, d, J 2.7, 4-H), 7.15 (1H, d, J 9.8,
11-H), 7.18 (1H, dd, J 9.3 and 2.7, 2-H), 7.21 (1H, d, J 8.3,
7-H), 7.64 (1H, d, J 8.3, 6-H) and 8.60 (1H, d, J 9.3, 1-H).
14ꢀ,17ꢀ-Ethano-9ꢁ-estra-1,3,5(10)-triene-3,17ꢁ-diol 32
A solution of the 3,17β-diacetate 31 (46 mg, 0.1 mmol) in
methanolic potassium hydroxide (1%, 10 cm3) was stirred for
24 h at 25 ЊC. Water was added and the mixture was extracted
into ethyl acetate. The combined organic phase was washed
(water, brine), dried (MgSO4) and evaporated under reduced
pressure to give a residue (40 mg) which was chromatographed
on silica gel (5 g) with ethyl acetate–toluene (1:4) as eluent to
give the 3,17β-diol 32 (33 mg, 91%), mp 208–209 ЊC (from
chloroform); [α]D ϩ48 (c 0.5) (Found: Mϩ, 298.192. C20H26O2
requires M, 298.193).
Acknowledgements
We thank the National Research Foundation and Schering AG
for financial and material support.
References
1 (a) T. Ojasoo, J.-P. Raynaud and J.-P. Mornon, in Comprehensive
Medicinal Chemistry, vol. 3, ed. J. C. Emmet, Pergamon, Oxford,
1990, p. 1193 and references cited therein; (b) G. M. Anstead,
K. E. Carlson and J. A. Katzenellenbogen, Steroids, 1997, 62, 268;
(c) G. Gao, J. A. Katzenellenbogen, R. Garg and C. Hansch, Chem.
Rev., 1999, 99, 723 and references cited therein.
2 A. M. Brzozowski, A. C. W. Pike, Z. Dauter, R. E. Hubbard,
T. Bonn, O. Engstrom, L. Ohman, G. L. Greene, J.-A. Gustafsson
and M. Carlquist, Nature (London), 1997, 389, 753.
3 J.-M. Wurtz, U. Egner, N. Heinrich, D. Moras and A. Mueller-
Fahrnow, J. Med. Chem., 1998, 41, 1803.
4 J. R. Bull and R. I. Thomson, J. Chem. Soc., Perkin Trans. 1, 1990,
241.
5 J. R. Bull, C. Hoadley, P. G. Mountford and L. M. Steer, J. Chem.
Soc., Perkin Trans. 1, 1997, 1179.
6 J. R. Bull, P. G. Mountford, G. Kirsch, G. Neef, A. Mueller-
Fahrnow and R. Wiechert, Tetrahedron, 1994, 50, 6363.
7 J. R. Bull and M. C. Loedolff, J. Chem. Soc., Perkin Trans. 1, 1996,
1269.
8 J. R. Bull, R. I. Thomson, H. Laurent, H. G. Schroeder and
R. Wiechert, Ger. Offen., DE 3 628 189 (Chem. Abstr., 1988, 109,
129451w).
14,17ꢀ-Ethano-9ꢁ-estra-1,3,5(10)-triene-3,17ꢁ-diyl diacetate 31
A solution of the tetraene 28 (contaminated with 26) (324 mg,
0.9 mmol) in THF (10 cm3) and ethanol (10 cm3) was stirred
with Raney nickel (Aldrich W-2, 10 cm3) at 50 ЊC under a
hydrogen atmosphere (50 bar) for 48 h. The cooled solution was
filtered through Celite, the catalyst was washed thoroughly with
ethyl acetate and chloroform. The residue (272 mg) after evap-
oration of the solvent was adsorbed onto silica gel (35 g) and
eluted with ethyl acetate–toluene (1:99) to give 14,17α-
ethanoestra-1,3,5(10)-triene-3,17β-diyl diacetate 26 (121 mg,
37%), mp 138–140 ЊC (from acetone–hexane), mixed fractions
(109 mg), and 14,17α-ethano-9β-estra-1,3,5(10)-triene-3,17β-
diyl diacetate 31 (27 mg, 9%), mp 106–109 ЊC (from propan-2-
ol); [α]D ϩ46 (c 0.4) (Found: C, 75.2; H, 8.0; Mϩ, 382. C24H30O4
9 (a) C. Rufer, E. Schroeder and H. Gibian, Liebigs Ann. Chem., 1967,
705, 211; (b) F. B. Gonzalez, G. Neef, U. Eder, R. Wiechert,
E. Schillinger and Y. Nishino, Steroids, 1982, 40, 171 and references
cited therein; (c) P. Kaspar and H. Witzel, J. Steroid Biochem., 1985,
23, 259 and references cited therein.
1012
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013

View Online
14 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin
Trans. 1, 1975, 1574.
15 K. Lubke, E. Schillinger and M. Topert, Angew. Chem., Int. Ed.
Engl., 1976, 15, 741.
16 J. R. Bull, K. Bischofberger and A. A. Chalmers, S. Afr. J. Chem.,
1990, 43, 46.
17 (a) D. Cremer and J. A. Pople, J. Am. Chem. Soc., 1975, 97, 1354;
(b) J. C. A. Boeyens, J. Cryst. Mol. Struct., 1978, 8, 317.
18 T. E. Wiese, D. Dukes and S. C. Brooks, Steroids, 1995, 60, 802 and
references cited therein.
10 (a) N. K. Uberoi, L. B. Hendry, T. G. Muldoon, R. B. Myers,
A. Segaloff, E. D. Bransome and V. D. Mahesh, Steroids, 1985,
45, 326; (b) A. Segaloff, R. B. Gabbard, A. Flores, R. F. Borne,
J. K. Baker, W. L. Duax, P. D. Strong and D. C. Rohrer, Steroids,
1980, 35, 335; (c) R. B. Gabbard, L. F. Hamer and A. Segaloff,
Steroids, 1981, 37, 243; (d) R. B. Gabbard and A. Segaloff, Steroids,
1983, 42, 555.
11 H. Kunzer, M. Stahnke, G. Sauer and R. Wiechert, Tetrahedron
Lett., 1991, 32, 1949.
12 D. J. Collins and J. Sjövall, Aust. J. Chem., 1983, 36, 339 and
references cited therein.
13 C. D. Liang, J. S. Baran, N. L. Allinger and Y. Yuh, Tetrahedron,
1976, 32, 2067.
Paper a908375h
J. Chem. Soc., Perkin Trans. 1, 2000, 1003–1013
1013