Cycloaddition-mediated strategies for synthesis of perhydrobenzo[14,15]-14β-19-norsteroids

Article abstract of DOI:10.1039/b005129m

Methods are described for sequential cycloaddition-fragmentation-recombination and cycloaddition-rearrangement-mediated processes for synthesis of the title compounds. Reaction of methyl vinyl ketone with 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl aceta

Full text of DOI:10.1039/b005129m

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Cycloaddition-mediated strategies for synthesis of
perhydrobenzo[14,15]-14ꢀ-19-norsteroids
James R. Bull* and Eugene S. Sickle
1
Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
E-mail: bull@psipsy.uct.ac.za
Received (in Cambridge, UK) 27th June 2000, Accepted 26th September 2000
First published as an Advance Article on the web 7th November 2000
Methods are described for sequential cycloaddition–fragmentation–recombination and cycloaddition–
rearrangement-mediated processes for synthesis of the title compounds. Reaction of methyl vinyl ketone with
3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate 1 gives a cycloadduct 2, which undergoes retroaldol
cleavage followed by intramolecular Michael reaction, to generate 3-methoxy-5Ј,6Ј-dihydro-15αH-benzo[14,15]-
14β-estra-1,3,5(10)-triene-4Ј(3ЈH),17-dione 4. Similarly, it is shown that various 16α-alkenyl-14α,17α-etheno-
estradiols undergo ready [3,3]-sigmatropic rearrangement to give functional variants of this pentacyclic system.
Synthetic routes to novel (perhydrobenzo)[14,15]-14β-analogues of estradiol are described, and aspects of the
chemistry of 14β,16β-propano-19-norsteroids derived from alternative intramolecular reaction pathways are
outlined.
In further studies to extend the scope of cycloaddition-
mediated methodology in the synthesis of new structural vari-
ants of bioactive 19-norsteroids, based upon the introduction
of hydrophobic and sterically demanding structural elements
in ring D, an investigation was undertaken of the cycloaddi-
tion of methyl vinyl ketone (MVK) and 3-methoxyestra-
1,3,5(10),14,16-pentaen-17-yl acetate 1.
We have shown in previous work1–5 that this substrate is a
remarkably versatile source of structurally modified estradiol
analogues, mediatedbycycloaddition–rearrangementandcyclo-
addition–fragmentation strategies. Many of these sequences
rely on regioselective formation of cycloadducts in which the
dienophile-derived functionality is juxtaposed with the bridge-
head oxy group at C-17, thus allowing for simple secondary
reactions. Thus, cycloaddition of acrolein to 1, followed by
functional-group modification and fragmentation furnished 14-
allyl-3-methoxy-14β-estra-1,3,5(10),15-tetraen-17-one, which
served as the key intermediate in stereocontrolled synthesis
of the 14α,17α-ethano analogue of estriol3 and the 14β,17β-
propano and 14β,15β-cyclopropa analogues of estradiol.4,5 The
latter structural type revealed the intriguing retention of estro-
gen receptor-binding affinity in representative hormone
analogues, suggesting that the inclusion of sterically demand-
ing hydrophobic substructures in this region of the estradiol
template is compatible with the steric demands in the ligand-
binding domain of the receptor.6,7 It was reasoned that the
analogous chemistry of an MVK-derived cycloadduct would
provide an entry to intermediates for conversion into perhydro-
benzo[14,15]-14β-estradiols and perhaps, other expressions of
ring -bridged hormone analogues.
Results and discussion
Scheme 1 Reagents and conditions: i, CH2᎐᎐CHCOCH3, BF3ؒEt2O,
THF, 0 ЊC; ii, KOH, MeOH, 24 ЊC; iii, KOH, MeOH, reflux; iv,
LiHMDS, CeCl3, THF, Ϫ78 ЊC; v, SmI2, THF, Ϫ78 to 20 ЊC.
The reaction of MVK with 1 in THF at 0 ЊC, in the presence of
catalytic boron trifluoride–diethyl ether complex (25 mol%),
gave the expected cycloadduct 2 (94%) (Scheme 1), the struc-
ture of which was confidently assigned by analogy as well as
subsequent transformations. As expected, 2 underwent ready
hydrolysis–retroaldol fragmentation in methanolic 1 M KOH
at 24 ЊC, to give the 14β-3Ј-oxobutyl ∆15-17-ketone 3 (93%).
Further treatment of 3 with methanolic 0.03 M KOH under
reflux resulted in smooth intramolecular Michael reaction to
give the pentacyclic 4Ј,17-dione 4 (94%), which was also pre-
pared by direct treatment of 2 under similar conditions. An
experiment in which 3 was treated in a more concentrated
alkaline medium resulted in formation of a reduced yield of 4
(74%), accompanied by a small amount of the product 5 (4%)
arising from conjugate addition of methoxide followed by
intramolecular aldol reaction.
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005129m

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Spectroscopic and analytical data confirmed that the dione 4
is indeed the first example of a novel (perhydrobenzo)[14,15]-
14β-steroidal ring system, and provided insight into the
connectivity and conformational properties of this product.
1
Although H NMR spectroscopy in deuteriochloroform was
complicated by some signal overlap, the fully dispersed 400
MHz spectrum in deuteriopyridine, aided by COSY spectro-
scopy, revealed a pattern of proton signals consistent with the
spiro-fused ring system in which ring E adopts a chair (14C 4Ј)
conformation, and the steroid template is undeformed. Molecu-
lar modelling suggested that an alternative chair (14C4Ј) con-
formation can only be accommodated if ring C adopts a boat
conformation, but this is clearly excluded by the presence of the
expected8,9 ring C signals for the ring B half-chair, ring C chair
conformation of the 14β-estradiol system.
In the light of earlier work on the synthesis of 14,17-alkano
analogues of estradiol,1,4 it was also of interest to ascertain
whether 3 could be induced to undergo an alternative intra-
molecular closure via aldol reaction between C-4Ј and C-17.
Indeed, low-temperature reaction of 3 with lithium hexa-
methyldisilazide (LiHMDS) in the presence of cerium() chlor-
ide, followed by flash chromatography of the crude reaction
product, gave a modest yield (≈38%) of impure material, which
revealed spectroscopic properties consistent with the 14β,17β-
butano 172-ketone 6. However, attempts to improve the conver-
sion yield and to develop the chemistry of this novel ring system
were frustrated by the lability of 6, which underwent ready
retroaldol opening to regenerate the dione 3.
In another experiment, prompted by the successful intra-
molecular reductive cyclisation in analogous 14β-formylethyl
∆15-17-ketones,4 compound 3 was subjected to treatment with
samarium() iodide in THF at low temperature, to give a
separable mixture (≈3:5; 98%) of cyclopenta[14,15] com-
pounds 7 and 8, arising from exclusive ketyl–olefin coupling
at the expense of the alternative, pinacol pathway. This result
is complementary to that reported previously,4 but reveals a
distinctive difference in stereoselectivity of closure, associated
with the steric influence of the terminal methyl group in 3. The
3Ј-configuration of the respective isomers 7 and 8 was con-
firmed with the aid of nuclear Overhauser effect (NOE)
experiments.
The retroaldol–Michael reaction sequence 2 → 3 → 4 is
well precedented in the analogous conversion of bridgehead-
functionalised bicyclo[2.2.2]oct-5-en-2-ones into cis-decalins,10
and in the successful application of this principle in numerous
syntheses of target compounds incorporating such sub-
structures.11 Related target systems are also accessible through
[3,3]-sigmatropic processes of structurally similar, functionally
modified substrates,12 and the cycloadducts 93 and 2 invited
consideration of this alternative approach to assemble the
(perhydrobenzo)[14,15] ring system. Compounds 9 and 2 were
readily converted into the 16α-vinyl and 16α-isopropenyl com-
pounds 10 and 11, respectively, which were heated in toluene
at 150 ЊC (sealed tube) for 48 h, to give the corresponding prod-
ucts 12 (67%) and 13 (64%) of Cope rearrangement (Scheme 2).
The obvious expedient of first hydrolysing the bridgehead
ester function of 10 and 11 with lithium aluminium hydride
(LAH) furnished the respective substrates 14 and 15, which
were amenable to the milder conditions of anionic oxy-Cope
rearrangement.12 The desired reactions proceeded cleanly and
efficiently within 2 h in the presence of potassium hydride in
refluxing THF, to give the corresponding 17-ketones 16 (87%)
and 17 (84%), which were also accessed via mild alkaline
hydrolysis of the respective enol acetates 14 and 15. NMR evi-
dence furnished conclusive evidence for the structures of the
products 14–17.
+
Scheme 2 Reagents and conditions: i, Ph3PCH3 IϪ, t-BuLi, THF,
25 ЊC; ii, CH2Br2, Zn, TiCl4, THF, CH2Cl2, 24 ЊC; iii, C6H5CH3, 150 ЊC;
iv, LAH, THF, 25 ЊC; v, KH, THF, reflux; vi, KOH, MeOH, 24 ЊC; vii,
+
Ph3PCH2OCH2C6H5 ClϪ, t-BuLi, THF, 25 ЊC; viii, CH2᎐᎐CHMgBr,
THF, 24 ЊC; ix, KH, THF, Ϫ78 ЊC.
respective products. Furthermore, [3,3]-sigmatropic rearrange-
ment of 2Ј-functionalised alkenyl systems derived from 9 or 2
could be envisaged, leading to new ring E functional variants of
the pentacyclic system. To this end, the 16α-formyl compound 9
was treated with benzyloxymethylene(triphenyl)phosphorane
to give a separable mixture (≈1:2; 86%) of the E- and Z-isomers
18 and 19. Treatment of the E-17-alcohol 20 (derived from 18)
with potassium hydride in refluxing THF was complete within
1 h, and gave the expected rearrangement product 22 (79%),
whereas similar treatment of the Z-isomer 21 (derived from 19)
required 3 h reaction time, and gave a reduced yield (67%) of
the same product 22. Although the 3Ј-configuration of 22 was
not evident from the NMR signal of the attached proton,
an NOE correlation between those of the benzylic and C-16
positions was diagnostic. The reaction times for the respective
rearrangements are not necessarily significant, but the form-
ation of a common product implies that they are mediated by a
common transition state or that the simpler conversion of 20
proceeds stereospecifically via an allowable chair-like transition
The complementarity of the sigmatropic and retroaldol–
Michael processes was evident in subsequent synthetic trans-
formations, which provided scope for exploiting alternative
pathways for chemodifferentiation of functionality in the
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487
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state, whereas that of the Z-isomer 21 is sterically constrained
to proceed non-concertedly.12
In a further experimental sequence, vinylation of the 16-
ketone 2313 proceeded efficiently and stereoselectively, to give
the 16α-vinyl 16β,17β-diol 24, which was set up for a doubly
potentiated anionic oxy-Cope rearrangement. Indeed, com-
pound 24 underwent impressively convenient rearrangement in
the presence of potassium hydride in THF at Ϫ78 ЊC for 15
min, to give the 5Ј,17-dione 25 in 78% yield.
The foregoing experiments demonstrated that cycloaddition–
fragmentation–recombination or cycloaddition–rearrangement
reaction sequences provide ready access to an array of variously
functionalised (perhydrobenzo)[14,15]-14β-estradiols, and it
remained to complete the conversion into the parent estradiol
analogues. Chemoselective differentiation of the 4Ј,17-dione
4 was demonstrated through borohydride reduction, which
gave a high yield of the corresponding 4Јβ- and 4Јα-hydroxy 17-
ketones 26 (60%) and 27 (30%) (Scheme 3), revealing also the
stereoselectivity imposed by the relatively congested β-face
environment of the 4Ј-oxo group.
This chemoselectivity was exploited to realise the purpose
in hand, through treatment of 4 with ethanedithiol–boron
trifluoride–diethyl ether complex in dichloromethane at 24 ЊC,
to give exclusively the 4Ј,4Ј-ethylenedithio 17-ketone 28 (98%).
Raney nickel-mediated desulfurisation of 28 proceeded readily
to give the 17-ketone 29. Alternatively, catalytic hydrogen-
ation of the 4Ј,5Ј-didehydro 17-ketone 16 furnished 29 directly.
Lithium aluminium hydride reduction of 29 displayed slight
stereoselectivity in favour of α-face entry of hydride, to give
the respective 17β- and 17α-alcohols 30 (49%) and 31 (31%),
which were deprotected at C-3 to the corresponding estradiol
analogues 32 and 33 by treatment with diisobutylaluminium
hydride (DIBAL-H) in toluene under reflux.
A similar approach was adopted for synthesis of 15-isomers
of the foregoing hormone analogues. Thus, selective 4Ј-
ketalisation of 4 proceeded as expected, and the derived inter-
mediate 34 was subjected to sequential enol silylation–dehydro-
silylation to give the 4Ј,4Ј-ethylenedioxy ∆15-17-ketone 35.
Catalytic hydrogenation of 35 proceeded with the expected high
β-face selectivity, to give the 4Ј,4Ј-ethylenedioxy 15β-17-dione
37, which was deprotected at C-4Ј to furnish the 15β-4Ј,17-
dione 38. Chemoselective dithioketalisation of 38 proceeded
similarly to the 15α-isomer 4, and Raney nickel desulfurisation
of the product 39 gave the 15β-17-ketone 40. Following opti-
misation of the oxy-Cope route to the 4Ј,5Ј-didehydro-17-
ketone 16, it proved more expedient to access 40 in a shorter,
more efficient reaction sequence via the 15α-17-ketone 29. Thus,
enol silylation–dehydrosilylation of 29 gave the ∆15-17-ketone
36, catalytic hydrogenation of which yielded 40 directly, in an
overall yield of 87% from 29. Hydride reduction of 40 gave a
separable mixture of the 17β- and 17α-alcohols 41 (46%) and 42
(38%), which were deprotected at C-3 to furnish the respective
estradiol analogues 43 and 44.
The first objectives of this study were thus achieved, and it
remained to explore the scope for elaborating other modes of
ring D bridging from the MVK cycloadduct 2 and the derived
retroaldol product 3. For example, the question of a preferred
pathway for the intramolecular aldol reaction of the 15,16-
dihydro derivative of 3 raises the intriguing prospect of
accessing 14β,16β-propano- or 14β,17β-butano-analogues of
estradiol. With this in view, the cycloadduct 2 was hydrogenated
to give the 14α,17α-ethano compound 45 (Scheme 4). Treat-
ment of 45 with methanolic potassium hydroxide at 0 ЊC
furnished a quantitative yield of a product formulated as the
14β,16β-propano 17-ketone 47, arising from sequential bridge-
head hydrolysis, retroaldol cleavage and subsequent intra-
molecular aldol reaction. Attempts to intervene in the reaction
and isolate any of the obligatory intermediates failed, suggest-
ing that the rate-limiting step may be retroaldol cleavage.
Spectroscopic and analytical data for 47 were consistent with
Scheme 3 Reagents and conditions: i, NaBH4, THF–MeOH, 0 ЊC;
ii, (CH2SH)2, BF3ؒEt2O, CH2Cl2, 24 ЊC; iii, Ra-Ni, EtOH, 50 ЊC; iv, Pd–
C, H2, EtOAc; v, LAH, THF, 24 ЊC; vi, DlBAL-H, C6H5CH3, reflux; vii,
(CH2OH)2, p-TsOH, C6H5CH3, reflux; viii, (a) LiNPr2, Et2O, Ϫ78 ЊC;
then Me3SiCl, 0 ЊC; (b) Pd(OAc)2, CH3CN, 25 ЊC; ix, C5H5NؒTsOH,
Me2CO, 25 ЊC.
the assigned structure, and the configuration at C-161 was
deduced from NOE correlations. The alternative, stepwise
method entailed catalytic hydrogenation of the enedione 3,
which yielded the 3Ј,17-diketone 46 in moderate yield (61%),
but accompanied by significant amounts of the derived aldol
product 47. However, treatment of 3 with methylcopper–
DIBAL-H–hexamethylphosphoric triamide (HMPA)14 pro-
ceeded more cleanly to give the 3Ј-oxobutyl 17-ketone 46
in 84% yield. As expected, 46 underwent intramolecular closure
to 47 in the presence of methanolic alkali, but surprisingly,
not as readily as the foregoing reaction, 45 → 47, implies.
This invites questions about the nature of the intermediate dur-
ing the sequential process; it is conceivable that the primary
enolate species arising from retroaldol cleavage is favour-
ably oriented for intramolecular protonation via 16β-H, and
simple proximity-induced closure. Hydride reduction of 47 pro-
ceeded highly stereoselectively to give only the corresponding
17β-alcohol 48.
The simple and exclusive aldol closure to 47, mediated by a
ring D enolate, is in accordance with the expectation that the
product is thermodynamically favoured, but it was of interest
to ascertain whether chemoselective enolisation of the 3Ј-oxo
group could be induced under conditions of kinetic control,
possibly leading to the elusive 14β,17β-butano product. How-
ever, attempts to conduct this step at low temperature, in the
presence of various hindered bases and with the aid of trapping
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J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487

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intervenes, aided by the resultant generation of a chair-like
six-membered transition state, in which the strongly oxophilic
samarium centre on 17-O coordinates with the 3Ј-oxo group,
and results in 3Ј,16-bond formation. A closed transition state
of this nature would give rise to an aldol reaction under kinetic
control, in contrast to the process governed by base-mediated
aldol reaction of 46.
The (perhydrobenzo)[14,15]-14β- analogues of estradiol pre-
pared in this study were assayed for affinity toward the estradiol
receptor,15 which revealed that the 17β-alcohol 32 is highly
competitive [competition factor15 (CF) 1.5], whereas the corre-
sponding 17α-alcohol 33 shows diminished competition (CF
14). These results parallel those of the closely related cyclo-
penta[14,15]-14β- series.5 The corresponding data for 43 and 44
reveal that both isomers are unresponsive toward the receptor.
Overall these findings reinforce the trend in observations
on analogous compounds,1,4,5 that the ligand-binding domain
(LBD) of the estrogen receptor6 is relatively accommodating
to sterically demanding, hydrophobic substructures in selected
sectors of the ring D environment. Although it is premature to
speculate on the precise bounds of this region of the LBD, the
results contribute toward an emerging picture of the constraints
in an idealised ligand for optimum binding, which can be
expected to contribute toward predictive design of estrogen
agonists and antagonists.
Experimental
For general directions see ref. 5.
Scheme 4 Reagents and conditions: i, Pd–C, H2, EtOAc; ii, MeCu,
DIBAL-H, HMPA, Ϫ78 ЊC; iii, KOH, MeOH, 0 ЊC; iv, LAH, THF,
21 ЊC; v, SmI2, t-BuOH, THF, reflux; vi, SmI2, THF, Ϫ78 to 20 ЊC;
vii, SmI2, THF, reflux; viii, KOH, MeOH, 20 ЊC; ix, Dess–Martin
periodinane, CH2Cl2, 20 ЊC.
16ꢁ-Acetyl-3-methoxy-14,17ꢁ-ethenoestra-1,3,5(10)-trien-17ꢀ-
yl acetate 2
Boron trifluoride–diethyl ether (0.1 cm3, 0.82 mmol) was added
to a solution of 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl
acetate 1 (648 mg, 2 mmol) and MVK (0.9 cm3, 10.8 mmol) in
dry THF (15 cm3) at 0 ЊC under nitrogen. The reaction mixture
was stirred at 0 ЊC for 3 h, then ice–water was added and the
mixture was extracted with ethyl acetate. The combined extract
was washed successively with aq. sodium hydrogen carbonate
and brine, dried (MgSO4), and evaporated under reduced pres-
sure. The residue (756 mg) was chromatographed on silica gel
(65 g) using ethyl acetate–hexane (3:7) as eluent to give the
cycloadduct 2 (740 mg, 94%), mp 141–142 ЊC (from Me2CO–
MeOH); [α]D ϩ78 (c 1.1) (Found: C, 76.1; H, 7.9%; Mϩ, 394.
C25H30O4 requires C, 76.1; H, 7.7%; M, 394); νmax/cmϪ1 1729
(CO); δH (400 MHz) 0.98 (3H, s, 13β-Me), 1.13 (1H, ddd,
J 13.3, 3.6 and 2.9, 12β-H), 1.36 (1H, ddd, J 2 × 11.6 and 2.6,
8β-H), 1.38 (1H, dddd, J 2 × 13.3, 11.6 and 3.6, 11β-H), 1.62
(1H, dd, J 11.9 and 8.4, 15β-H), 1.74 (1H, dd, J 11.9 and 4.3,
15α-H), 2.13 and 2.16 (each 3H, s, 17β-OAc and 16-Ac), 2.20
(1H, dddd, J 13.3, 4.4, 3.8 and 2.9, 11α-H), 2.30 (1H, ddd,
J 2 × 13.3 and 4.4, 12α-H), 2.48 (1H, ddd, J 2 × 11.6 and 3.8,
9α-H), 3.40 (1H, dd, J 8.4 and 4.3, 16β-H), 3.77 (3H, s, 3-OMe),
6.04 and 6.14 (each 1H, d, J 6.1, 171- and 172-H), 6.61 (1H, d,
J 2.8, 4-H), 6.70 (1H, dd, J 8.6 and 2.8, 2-H) and 7.18 (1H,
d, J 8.6, 1-H); δC (100 MHz) 14.9 (q, C-18), 21.6 (q, 16-COMe),
23.8 (t, C-7), 27.2 (t, C-11), 29.5 (t, C-12), 30.2 (t, C-6), 30.4 (q,
17-OCOMe), 30.6 (t, C-15), 39.4 (d, C-8), 40.2 (d, C-9), 55.3 (d,
C-16), 55.4 (q, 3-OMe), 61.8 and 61.9 (each s, C-13 and C-14),
95.9 (s, C-17), 111.8 (d, C-2), 113.8 (d, C-4), 127.1 (d, C-1),
129.9 and 132.3 (each d, C-171 and -172), 132.4 (s, C-10), 137.9
(s, C-5), 157.5 (s, C-3), 169.8 (s, 17-OCOMe) and 207.6 (s,
C-161).
agents, were frustrated by poor selectivity, and the only product
detected in these experiments was 47.
Attention was turned to the scope for performing an intra-
molecular reductive cyclisation upon the 3Ј,17-diketone 46,
in expectation of generating a 171-methyl 14β,17β-propano
17,171-diol, by analogy with precedent for a 14β-formylethyl
17-ketone.4 Surprisingly, treatment of 46 with samarium()
iodide in THF at Ϫ78 ЊC gave a single product (87%), iso-
meric with starting material, which was assigned the structure
49. A pattern of NMR signals for product 49, reminiscent of
those assigned to the bicyclo[3.2.1]octanoid substructure of 47,
provided persuasive evidence that it is an isomeric aldol reac-
tion product! The assignment of configuration at C-161 was
facilitated by transannular NOE correlations and evidence of
intramolecular hydrogen bonding. When the experiment was
performed on 46 in the presence of an excess of samarium()
iodide in refluxing THF, the derived 161,17-diols 50 (13%) and
51 (68%) were isolated. This reaction outcome was reproduced
by similar reaction of the 17-ketone 49, and demonstrates that
the slow reduction favours formation of the 17α-alcohol 51.
By contrast, reduction of 49 with LAH proceeded rapidly and
highly stereoselectively through α-face entry of hydride, to give
only the 17β-alcohol 50, paralleling the course of reduction
in the isomer 47. Interestingly, forcing reduction of the
isomeric 17-ketone 47 with samarium() iodide in refluxing
THF followed the course of LAH reduction, to give only the
17β-alcohol 48.
A decisive experiment entailed treatment of the SmI2-derived
161-hydroxy 17-ketone 49 with methanolic potassium hydroxide
at 20 ЊC to give, after 5 h, the isomeric product 47, thus con-
firming their structural relationship through retroaldol–aldol-
mediated equilibration. It remains to speculate upon the
unusual course of reaction of 46 with samarium() iodide,
giving rise to an ‘abnormal’ aldol reaction product 49.
It is surmised that the expected single-electron-transfer step is
sterically hindered, and that samarium() 17-enolate formation
3-Methoxy-14ꢀ-(3Ј-oxobutyl)estra-1,3,5(10),15-tetraen-17-one 3
The cycloadduct 2 (1.94 g, 4.93 mmol) was suspended in
methanolic 1 M potassium hydroxide (10 cm3, 10 mmol) and
the suspension was stirred at 24 ЊC for 2.5 h. Saturated aq.
ammonium chloride was added and the mixture was extracted
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with ethyl acetate. The combined organic phase was washed
(brine, water), dried (MgSO4), and evaporated under reduced
pressure to give a residue (1.87 g), which was chromatographed
on silica gel (100 g) using toluene as eluent, to give compound 3
(1.61 g, 93%), mp 114–116 ЊC (from Me2CO–MeOH); [α]D
ϩ123 (c 1.1) (Found: C, 78.4; H, 8.3%; Mϩ, 352. C23H28O3
chromatography as described in the foregoing experiments,
gave the 4Ј,17-dione 4 (296 mg, 74%) followed by (161R)-
161-hydroxy-3,15α-dimethoxy-161-methyl-14,16β-propano-14β-
estra-1,3,5(10)-trien-17-one 5 (18 mg, 4%), mp 123–124 ЊC
(from EtOAc–hexane); [α]D ϩ83 (c 1.1) (Found: C, 74.8; H,
8.2%; Mϩ, 384. C24H32O4 requires C, 75.0; H, 8.4%; M, 384);
νmax/cmϪ1 3611 (OH) and 1725 (CO); δH (400 MHz; CDCl3),
1.09 (3H, s, 13β-Me), 1.35 (3H, s, 161-Me), 2.54 (1H, d, J 1.8,
16α-H), 3.16 (1H, td, J 2 × 11.8 and 3.7, 9α-H), 3.22 (3H, s,
15α-OMe), 3.78 (3H, s, 3-OMe), 4.19 (1H, s, 15β-H), 6.68 (1H,
d, J 2.8, 4-H), 6.75 (1H, dd J 8.5 and 2.8, 2-H) and 7.10 (1H, d,
J 8.5, 1-H); δH (400 MHz; C6D6) 0.88 (1H, ddd, J 13.9, 5.5 and
1.8, 163-Hn), 1.00 (3H, s, 13β-Me), 1.0–1.17 (3H, m, 8β-H and
162-H2), 1.14 (3H, s, 161-Me), 1.24 (1H, qd, J 3 × 13.0 and 3.4,
11β-H), 1.55 (1H, dt, J 13.0 and 2 × 3.4, 12β-H), 1.57 (1H, qd,
J 12.5, 11.5, 11.0 and 6.7, 7α-H), 1.90 (1H, dq, J 12.5 and
3.4, 7β-H), 1.93 (1H, ddd, J 13.9, 11.8 and 7.5, 163-Hx), 2.14
(1H, dddd, J 13.0, 3.8, 3.7 and 3.4, 11α-H), 2.38 (1H, d, J 1.4,
16α-H), 2.41 (1H, td, J 2 × 13.0 and 3.8, 12α-H), 2.68–2.74 (2H,
m, 6-H2), 2.89 (3H, s, 15α-OMe), 3.23 (1H, td, J 2 × 13.0 and
3.7, 9α-H), 3.39 (3H, s, 3-OMe), 4.06 (1H, s, 15β-H), 6.70 (1H,
d, J 2.8, 4-H), 6.75 (1H, dd, J 8.5 and 2.8, 2-H) and 7.10 (1H, d,
J 8.5, 1-H); δC (100 MHz) 17.5 (q, C-18), 23.6 (t, C-7), 25.4
(t, C-11), 28.4 (q, 161β-Me), 30.7 (t, C-6), 30.8 (t, C-163), 33.1
(t, C-12), 34.1 (t, C-162), 38.4 (d, C-9), 43.4 (d, C-8), 48.4
and 49.2 (each s, C-13 and -14), 55.2 (q, 3-OMe), 56.2 (q,
15α-OMe), 62.3 (d, C-16), 73.5 (s, C-161), 85.5 (d, C-15), 111.4
(d, C-2), 113.6 (d, C-4), 125.9 (d, C-1), 134.2 (s, C-10), 137.7
(s, C-5), 157.4 (s, C-3) and 221.9 (s, C-17).
requires C, 78.4; H, 8.0%; M, 352); νmax/cmϪ1 1627 (C᎐C) and
᎐
1709br (CO); δH (200 MHz) 1.07 (3H, s, 13β-Me), 2.13 (3H, s,
3Ј-Me), 2.80 (2H, m, 6-H2), 3.76 (3H, s, 3-OMe), 6.20 (1H, d,
J 5.8, 16-H), 6.59 (1H, d, J 2.8, 4-H), 6.70 (1H, dd, J 8.7 and
2.8, 2-H), 7.08 (1H, d, J 8.7, 1-H) and 7.33 (1H, d, J 5.8, 15-H);
δC (50 MHz) 19.7 (C-18), 24.7 (3Ј-Me), 27.4 (C-11), 27.6 (C-7),
30.3 (C-6), 30.9 (C-1Ј), 32.5 (C-12), 36.4 (C-2Ј), 39.0 (C-8), 42.2
(C-9), 51.7 and 54.0 (C-13 and -14), 55.2 (3-OMe), 112.2 (C-2),
113.2 (C-4), 127.8 (C-1), 131.3 (C-15), 132.6 (C-10), 137.2
(C-5), 157.5 (C-3), 164.6 (C-16), 207.5 (C-3Ј) and 213.8 (C-17).
3-Methoxy-5Ј,6Ј-dihydro-15ꢁH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-triene-4Ј(3ЈH),17-dione 4
(a) The 14β-3Ј-oxobutyl ∆15-17-ketone 3 (1.32 g, 3.75 mmol)
was dissolved in methanol (20 cm3) and methanolic 0.1 M
potassium hydroxide (10 cm3) was added. The mixture was
heated under reflux for 4 h then cooled to 24 ЊC and saturated
aq. ammonium chloride was added. The mixture was extracted
with ethyl acetate, and the combined extract was washed (brine,
water), dried (MgSO4), and the solvent was evaporated under
reduced pressure. The residue (1.26 g) was chromatographed on
silica gel (50 g), using ethyl acetate–toluene (3:7) as eluent, to
give the 4Ј,17-dione 4 (1.24 g, 94%), mp 86–88 ЊC (from MeOH–
Et2O); [α]D ϩ76 (c 1.2) (Found: C, 78.5; H, 8.1%; Mϩ, 352.
C23H28O3 requires C, 78.4; H, 8.0%; M, 352); νmax/cmϪ1 1701
(4Ј-CO) and 1724 (17-CO); δH (400 MHz; CDCl3) 1.06 (3H, s,
13β-Me), 1.70 (1H, ddd, J 15.4, 9.6 and 6.0, 6Јβ-H), 1.79 (1H,
dd, J 19.9 and 9.0, 16β-H), 1.99 (1H, dddd, J 15.4, 6.7, 6.4 and
1.4, 6Јα-H), 2.18 (1H, dddd, J 17.1, 6.4, 6.0 and 1.7, 5Јβ-H), 2.39
(1H, ddd, J 15.9, 2.1 and 1.7, 3Јβ-H), 2.55 (1H, ddd, J 17.1, 9.6
and 6.7, 5Јα-H), 2.67 (1H, dd, J 15.9 and 5.0, 3Јα-H), 2.86 (1H,
dd, J 19.9 and 10.2, 16α-H), 2.92 (2H, m, 6-H2), 3.20 (1H, m,
15α-H), 3.78 (3H, s, 3-OMe), 6.63 (1H, d, J 2.8, 4-H), 6.68 (1H,
dd, J 8.6 and 2.8, 2-H) and 7.23 (1H, d, J 8.6, 1-H); δH (400
MHz; C5D5N) 1.02 (3H, s, 13β-Me), 1.20 (1H, td, J 2 × 13.0
and 3.5, 8β-H), 1.25 (1H, dt, J 14.1 and 2 × 3.2, 12β-H), 1.57
(1H, ddd, J 15.2, 10.1 and 6.1, 6Јβ-H), 1.67 (1H, ddd, J 14.4, 14.1
and 4.0, 12α-H), 1.73 (1H, ddd, J 15.2, 6.6 and 6.1, 6Јα-H), 1.95
(1H, dd, J 19.4 and 9.0, 16β-H), 2.18 (1H, dtd, J 16.9, 2 × 6.1
and 1.9, 5Јβ-H), 2.37 (1H, ddd, J 15.7, 2.4 and 1.9, 3Јβ-H), 2.55
(1H, ddd, J 16.9, 10.1 and 6.6, 5Јα-H), 2.67 (1H, dd, J 15.7 and
5.1, 3Јα-H), 2.73 (1H, ddd, J 13.0, 11.1 and 4.0, 9α-H), 2.84
(2H, m, 6-H2), 2.85 (1H, dd, J 19.4 and 10.1, 16α-H), 3.20 (1H,
m, 15α-H), 3.74 (3H, s, 3-OMe), 6.81 (1H, d, J 2.7, 4-H), 6.96
(1H, dd, J 8.5 and 2.7, 2-H) and 7.32 (1H, d, J 8.5, 1-H); δC (100
MHz) 14.8 (q, C-18), 26.6 (t, C-11), 27.1 (t, C-7), 31.0 (t, C-6Ј),
31.7 (t, C-6), 32.5 (d, C-15), 32.9 (t, C-12), 38.4 (d, C-8), 38.9 (t,
C-5Ј), 40.7 (t, C-16), 43.2 (t, C-3Ј), 44.5 (s, C-13), 45.8 (d, C-9),
55.2 (s, C-14), 56.1 (q, 3-OMe), 112.3 (d, C-2), 113.3 (d, C-4),
127.5 (d, C-1), 131.4 (s, C-10), 137.1 (s, C-5), 157.7 (s, C-3),
211.7 (s, C-4Ј) and 218.9 (s, C-17).
17ꢁ-Hydroxy-3-methoxy-14,17ꢀ-butano-14ꢀ-estra-1,3,5(10),15-
tetraen-172-one 6
Cerium() chloride heptahydrate (300 mg, 0.81 mmol) was
dried under reduced pressure at 150 ЊC for 2 h, then cooled
under nitrogen to 24 ЊC, and THF (5 cm3) was added. A solu-
tion of the 14β-3Ј-oxobutyl ∆15-17-ketone 3 (130 mg, 0.37
mmol) in THF (8 cm3) was added and the mixture was cooled
to Ϫ78 ЊC. A solution of LiHMDS [formed by the addition of
1.6 M n-butyllithium (0.3 cm3, 0.38 mmol) to hexamethyl-
disilazane (0.15 cm3, 0.72 mmol) in THF (10 cm3) at Ϫ78 ЊC,
followed by stirring for 30 min at 0 ЊC], also cooled to Ϫ78 ЊC,
was added and the mixture was stirred at Ϫ78 ЊC for 1 h. Satur-
ated aq. ammonium chloride was added, and the mixture was
extracted with ethyl acetate. The combined organic phase was
washed (water, brine), dried (MgSO4), and the solvent was evap-
orated under reduced pressure. Flash chromatography of the
residue (119 mg) on silica gel (15 g), using ethyl acetate–toluene
(7:13) as eluent, gave starting material 3 (67 mg, 49% recovery)
followed by a labile fraction (50 mg, 38%) containing the
14β,17β-butano compound 6, νmax/cmϪ1 1702 (CO) and 3567
(OH); δH (200 MHz) 1.06 (13β-Me), 2.54 and 2.62 (each 1H, d,
J 16.9, 171α- and 171β-H), 3.76 (3-OMe), 5.69 and 5.82 (each
1H, d, J 6.7, 15- and 16-H), 6.60 (1H, d, J 2.7, 4-H), 6.71 (1H,
dd, J 8.8 and 2.7, 2-H) and 7.10 (1H, d, J 8.7, 1-H); m/z 352
(Mϩ).
Reductive coupling of the 14ꢀ-3Ј-oxobutyl ꢂ15-17-ketone 3
(b) The cycloadduct 2 (2 g, 5.1 mmol) was suspended in
methanol (10 cm3) and methanolic 1 M potassium hydroxide
(11 cm3) was added. The resultant mixture was heated under
reflux for 4.5 h until all starting material had been consumed
(TLC), then was cooled to 24 ЊC. Saturated aq. ammonium
chloride was added and the product (1.97 g) was isolated by
extraction with ethyl acetate, and purified by filtration through
silica gel (100 g), using ethyl acetate–toluene (3:7) as eluent, to
give compound 4 (1.88 mg, 94%).
Samarium() iodide (12 cm3 of a 0.1 M solution in THF, 1.2
mmol) was added to a solution of compound 3 (178 mg, 0.51
mmol) in THF (15 cm3) cooled to Ϫ78 ЊC. The mixture was
stirred at Ϫ78 ЊC for 30 min, then was allowed to warm to 20 ЊC
and was neutralised by the addition of 0.1 M hydrochloric acid
(10 cm3). The mixture was extracted with chloroform. The
combined organic phase was washed successively with hydro-
chloric acid, aq. sodium thiosulfate, aq. sodium hydrogen
carbonate and water, then dried (MgSO4). The solvent was
evaporated under reduced pressure to give a residue (171 mg),
which was chromatographed on silica gel (18 g), using ethyl
acetate–toluene (3:5) as eluent, to give 3Јβ-hydroxy-3-methoxy-
(c) Treatment of the 14β-3Ј-oxobutyl ∆15-17-ketone 3 (400
mg, 1.14 mmol) with methanolic 0.5 M potassium hydroxide
(10 cm3) under reflux for 2.5 h, followed by work-up and
4480
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487

View Article Online
3Јα-methyl-4Ј,5Ј-dihydro-15αH-cyclopenta[14,15]-14β-estra-
1,3,5(10)-trien-17(3ЈH)-one 7 (64 mg, 36%), mp 167–170 ЊC
(from Me2CO–MeOH); [α]D Ϫ6.6 (c 1.3) (Found: C, 77.7; H,
8.2%; Mϩ, 354. C23H30O3 requires C, 77.9; H, 8.5%; M, 354);
νmax/cmϪ1 3537 (OH) and 1727 (CO); δH (400 MHz; C6D6) 0.86
(3H, s, 3Јα-Me), 1.17 (3H, s, 13β-Me), 1.82 (1H, dd, J 10.7 and
3.9, 15α-H), 2.01 (1H, dd, J 19.3 and 10.7, 16α-H), 2.49 (1H,
dd, J 19.3 and 3.9, 16β-H), 2.27 (2H, m, 6-H2), 3.37 (3H, s,
3-OMe), 6.63 (1H, d, J 2.8, 4-H), 6.70 (1H, dd, J 8.5 and 2.8,
2-H) and 6.90 (1H, d, J 8.5, 1-H), followed by 3Јα-hydroxy-3-
methoxy-3Јβ-methyl-4Ј,5Ј-dihydro-15αH-cyclopenta[14,15]-14β-
estra-1,3,5(10)-trien-17(3ЈH)-one 8 (111 mg, 62%), mp 143–
145 ЊC (from Me2CO–MeOH); [α]D Ϫ26.5 (c 0.98) (Found: C,
77.9; H, 8.8%; Mϩ, 354); νmax/cmϪ1 3564 (OH) and 1728 (CO);
δH (400 MHz; C6D6) 0.94 (3H, s, 3Јβ-Me), 1.01 (3H, s, 13β-Me),
1.75 (1H, dd, J 19.2 and 7.2, 16β-H), 2.03 (1H, dd, J 10.6 and
7.2, 15α-H), 2.42 (1H, dd, J 19.2 and 10.6, 16α-H), 3.42 (3H, s,
3-OMe), 6.68 (1H, d, J 2.8, 4-H), 6.85 (1H, dd, J 8.4 and 2.8,
2-H) and 7.14 (1H, d, J 8.4, 1-H).
Mϩ, 392. C26H32O3 requires C, 79.6; H, 8.2%; M, 392); νmax
/
cmϪ1 1728 (OAc); δH (400 MHz) 0.97 (3H, s, 13β-Me), 1.13 (1H,
dt, J 13.4 and 2 × 3.2, 12β-H), 1.33 (1H, dd, J 12.1 and 4.5, 15α-
H), 1.39 (1H, td, J 2 × 11.5 and 2.6, 8β-H), 1.76 (3H, s, 1Ј-Me),
1.78 (1H, dd, J 12.1 and 8.8, 15β-H), 2.09 (3H, s, 17β-OAc),
2.23 (1H, dtd, J 13.4, 2 × 3.7 and 3.2, 11α-H), 2.36 (1H, td,
2 × 13.4 and 3.7, 12α-H), 2.50 (1H, td, 2 × 11.5 and 3.7, 9α-H),
2.85–2.90 (2H, m, 6-H2), 3.08 (1H, dd, J 8.8 and 4.5, 16β-H),
3.77 (3H, s, 3-OMe), 4.64 (1H, dq, J 4.1 and 3 × 1.8, 2Ј-Hcis),
4.80 (1H, dq, J 4.1 and 3 × 0.8, 2Ј-Htrans), 5.96 and 6.18 (each
1H, d, J 6.1, 171- and 172-H), 6.64 (1H, d, J 2.8, 4-H), 6.72 (1H,
dd, J 8.6 and 2.8, 2-H) and 7.22 (1H, d, J 8.6, 1-H).
Cope rearrangement of the 1,5-dienes 10 and 11
(a) A solution of the 16α-vinyl compound 10 (85 mg, 0.22
mmol) in dry toluene (5 cm3) was purged with nitrogen and then
heated in a sealed tube at 150 ЊC (oil-bath) for 48 h. The cooled
reaction mixture was filtered through Celite, and the filtrate was
evaporated under reduced pressure. The residue (61 mg) was
chromatographed on silica gel (7 g), using ethyl acetate–toluene
(1:9) as eluent, to give 3-methoxy-3Ј,6Ј-dihydro-15αH-benzo-
[14,15]-14β-estra-1,3,5(10),16-tetraen-17-yl acetate 12 (57 mg,
67%), mp 163–164 ЊC (from EtOAc–hexane); [α]D ϩ278 (c 1.0)
(Found: C, 79.5; H, 7.9%; Mϩ, 378. C25H30O3 requires C, 79.3;
H, 8.0%; M, 378); νmax/cmϪ1 1729 (CO); δH (400 MHz) 1.08 (3H,
s, 13β-Me), 2.12 (3H, s, 17β-OAc), 2.76–2.80 (2H, m, 6-H2),
3.02 (1H, m 15α-H), 3.77 (3H, s, 3-OMe), 4.84 (1H, d, J 5.7,
16-H), 5.34 and 5.57 (each 1H, m, 4Ј- and 5Ј-H), 6.62 (1H, d,
J 2.7, 4-H), 6.71 (1H, dd, J 8.5 and 2.7, 2-H) and 7.19 (1H,
d, J 8.5, 1-H).
(b) Similar treatment of the 16α-isopropenyl compound 11
(67 mg, 0.17 mmol) gave 3-methoxy-4Ј-methyl-3Ј,6Ј-dihydro-
15αH-benzo[14,15]-14β-estra-1,3,5(10),16-tetraen-17-yl acet-
ate 13 (42 mg, 64%), mp 147–149 ЊC (from EtOAc–hexane); [α]D
ϩ306 (c 0.9) (Found: C, 79.8; H, 8.3%; Mϩ, 392. C26H32O3
requires C, 79.6; H, 8.2%; M, 392); νmax/cmϪ1 1728 (CO);
δH (400 MHz) 1.12 (3H, s, 13β-Me), 1.74 (3H, q, J 3 × 1.8,
4Ј-Me), 2.09 (3H, s, 17-OAc), 2.72–2.81 (2H, m, 6-H2), 3.11
(1H, m, 15α-H), 3.78 (3H, s, 3-OMe), 4.69 (1H, d, J 6.1, 16-H),
5.37 (1H, m, 5Ј-H), 6.61 (1H, d, J 2.7, 4-H), 6.73 (1H, dd, J 8.5
and 2.7, 2-H) and 7.19 (1H, d, J 8.5, 1-H).
3-Methoxy-16ꢁ-vinyl-14,17ꢁ-ethenoestra-1,3,5(10)-trien-17ꢀ-yl
acetate 10
1.7 M tert-Butyllithium (0.7 cm3) was added to a suspension of
methyltriphenylphosphonium iodide (485 mg, 1.2 mmol) in
THF (5 cm3) at 0 ЊC. The mixture was stirred at 0 ЊC for 1 h.
Compound 9 (300 mg, 0.79 mmol) as a solution in dry THF
(3 cm3) was added to the orange solution and the mixture was
stirred at 25 ЊC for 2 h. Water (10 cm3) was added and the
mixture was extracted with ethyl acetate. The combined extract
was washed (0.1 M HCl, aq. NaHCO3, brine), dried (MgSO4),
and the solvent was evaporated under reduced pressure. Flash
chromatography of the residue (275 mg) on silica gel (30 g),
using ethyl acetate–toluene (1:9) as eluent, gave the 16α-vinyl
compound 10 (245 mg, 82%), mp 147–150 ЊC (from Me2CO–
MeOH); [α]D ϩ176 (c 1.0) (Found: C, 79.3; H, 7.8%; Mϩ, 378.
C25H30O3 requires C, 79.3; H, 7.9%; M, 378); νmax/cmϪ1 1734
(OAc); δH (400 MHz) 0.95 (3H, s, 13β-Me), 1.12 (1H, dd, J 11.9
and 3.8, 15α-H), 1.16 (1H, ddd, J 13.5, 4.3 and 2.7, 12β-H),
1.26 (1H, qd, J 2 × 13.5, 11.6 and 4.3, 11β-H), 1.38 (1H, td,
J 2 × 11.6 and 2.5, 8β-H), 2.08 (3H, s, 17-OAc), 2.21 (1H, dddd,
J 13.5, 4.4, 3.0 and 2.7, 11α-H), 2.30 (1H, tdd, J 2 × 13.5, 4.4
and 0.93, 12α-H), 2.50 (1H, td, J 2 × 11.6 and 3.0, 9α-H), 2.83–
2.90 (2H, m, 6-H2), 3.01 (1H, ddd, J 8.8, 8.3 and 3.8, 16β-H),
3.77 (3H, s, 3-OMe), 4.98 (1H, ddd, J 10.2, 2.0 and 0.8, 2Ј-Hcis),
5.04 (1H, ddd, J 17.1, 2.0 and 0.8, 2Ј-Htrans), 5.60 (1H, ddd,
J 17.1, 10.2 and 8.3, 1Ј-H), 6.03 and 6.25 (each 1H, d, J 6.1,
171- and 172-H), 6.62 (1H, d, J 2.8, 4-H), 6.71 (1H, dd, J 8.5 and
2.8, 2-H) and 7.20 (1H, d, J 8.5, 1-H).
Preparation of the 17ꢀ-alcohols 14 and 15
(a) LAH (106 mg, 2.7 mmol) was added to a solution of the
17β-acetate 10 (250 mg, 0.66 mmol) in dry THF (10 cm3) at 0 ЊC
under nitrogen, and the mixture was stirred at 25 ЊC for 20 min.
Aq. sodium sulfate was added to the solution at 0 ЊC until a
white precipitate formed. Diethyl ether (10 cm3) was added and
the mixture was stirred for 30 min, then filtered through mag-
nesium sulfate and Celite. The filter pad was washed with
chloroform and the filtrate was evaporated under reduced pres-
sure to give 3-methoxy-16α-vinyl-14,17α-ethenoestra-1,3,5(10)-
trien-17β-ol 14 (182 mg, 82%), mp 237–239 ЊC (from EtOAc–
hexane); [α]D ϩ156 (c 1.0) (Found: C, 82.3; H, 8.3%; Mϩ, 336.
C23H28O2 requires C, 82.1; H, 8.3%; M, 336); νmax/cmϪ1 3430
(OH); δH (400 MHz) 0.95 (3H, s, 13β-Me), 1.17 (1H, dd, J 12.2
and 4.0, 15α-H), 1.23 (1H, ddd, J 12.9, 4.3 and 2.7, 12β-H), 1.40
(1H, td, J 2 × 11.6 and 2.9, 8β-H), 1.94 (1H, dd, J 12.2 and 8.5,
15β-H), 2.10 (1H, td, J 2 × 12.9 and 4.3, 12α-H), 2.48 (1H, td,
J 2 × 11.6 and 4.2, 9α-H), 2.75 (1H, ddd, J 8.8, 8.5 and 4.0,
16β-H), 2.83–2.90 (2H, m, 6-H2), 3.78 (3H, s, 3-OMe), 5.02
(1H, ddd, J 10.1, 2.0 and 0.7, 2Ј-Hcis), 5.12 (1H, ddd, J 17.1, 2.0
and 1.0, 2Ј-Htrans), 5.60 (1H, ddd, J 17.1, 10.1 and 8.8, 1Ј-H),
5.80 and 6.08 (each 1H, d, J 6.0, 171- and 172-H), 6.63 (1H, d,
J 2.7, 4-H), 6.72 (1H, dd, J 8.7 and 2.7, 2-H) and 7.22 (1H,
d, J 8.7, 1-H).
16ꢁ-Isopropenyl-3-methoxy-14,17ꢁ-ethenoestra-1,3,5(10)-trien-
17ꢀ-yl acetate 11
Dibromoethane (0.1 cm3, 1.43 mmol) was added to a stirred
suspension of zinc powder (130 mg, 2 mmol) in THF (5 cm3)
under nitrogen. The mixture was cooled to Ϫ40 ЊC (solid CO2–
acetone bath) and titanium() chloride (0.15 cm3, 1.4 mmol)
was added dropwise over a period of 15 min. The mixture was
stirred at 5 ЊC for 2 h, then dichloromethane (5 cm3) was added
to the dark grey slurry. Compound 2 (394 mg, 1.0 mmol) as a
solution in dichloromethane (5 cm3) was added and the result-
ant mixture was stirred at 24 ЊC for 1.5 h. The mixture was
diluted with pentane (10 cm3) and aq. sodium hydrogen carb-
onate was added slowly until effervescence ceased. The organic
phase was separated and the aqueous phase was extracted with
dichloromethane. The combined organic phase was washed (aq.
NaHCO3, water, brine), dried (MgSO4), and evaporated under
reduced pressure to give a residue (374 mg). Chromatography
on silica gel (40 g), using ethyl acetate–toluene (1:9) as eluent,
afforded compound 11 (303 mg, 77%), mp 167–169 ЊC (from
Me2CO–MeOH); [α]D ϩ209 (c 1.0) (Found: C, 79.4; H, 8.2%;
(b) Similar treatment of the 17β-acetate 11 (170 mg, 0.43
mmol) gave 16α-isopropenyl-3-methoxy-14,17α-ethenoestra-
1,3,5(10)-trien-17β-ol 15 (116 mg, 77%), mp 217–220 ЊC (from
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487
4481

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Me2CO–MeOH); [α]D ϩ197 (c 1.1) (Found: C, 82.2; H, 8.4%;
organic phase was washed (aq. HCl, aq. NaHCO3, brine), dried
Mϩ, 350. C24H30O2 requires C, 82.2; H, 8.6%; M, 350); νmax
/
(MgSO4), and evaporated under reduced pressure. Flash
chromatography of the residue (478 mg) on silica gel (50 g),
using ethyl acetate–toluene (1:19) as eluent, gave the (1ЈE)-
compound 18 (121 mg, 25%), mp 213–215 ЊC (from Me2CO–
MeOH); [α]D ϩ307 (c 1.2) (Found C, 79.6; H, 7.2%; Mϩ, 484.
C32H36O4 requires C, 79.3; H, 7.4%; M, 484); νmax/cmϪ1 1734
(OAc); δH (400 MHz) 0.93 (3H, s, 13β-Me), 1.02 (1H, dd, J 11.9
and 3.6, 15α-H), 1.13 (1H, dt, J 13.4 and 2 × 3.1, 12β-H),
1.26 (1H, tdd, J 2 × 13.4, 11.6 and 3.1, 11β-H), 1.37 (1H, td,
J 2 × 11.6 and 2.4, 8β-H), 1.63 and 1.80 (each 1H, m, 7α- and
7β-H), 1.88 (1H, dd, J 11.9 and 8.8, 15β-H), 2.05 (3H, s,
17-OAc), 2.20 (1H, ddt, J 13.4, 4.2 and 2 × 3.1, 11α-H), 2.32
(1H, td, J 2 × 13.4 and 4.2, 12α-H), 2.51 (1H, td, J 2 × 11.6
and 3.1, 9α-H), 2.82–2.88 (3H, m, 16β-H, 6-H2), 3.78 (3H,
s, 3-OMe), 4.61 (1H, dd, J 12.5 and 9.4, 1Ј-H), 4.71 (2H, s,
OCH2C6H5), 6.03 and 6.21 (each 1H, d, J 6.3, 171- and 172-H),
6.38 (1H, d, J 12.5, 2Ј-H), 6.64 (1H, d, J 2.7, 4-H), 6.72 (2H, dd,
J 8.6 and 2.7, 2-H), 7.22 (1H, d, J 8.6, 1-H) and 7.29–7.40 (5H,
m, OCH2C6H5), followed by the (1ЈZ)-compound 19 (296 mg,
61%), mp 231–232 ЊC (from Me2CO–MeOH); [α]D ϩ267 (c 1.1)
(Found: C, 79.6; H, 7.3%; Mϩ, 484); νmax/cmϪ1 1731 (OAc);
δH (400 MHz) 0.76 (1H, dd, J 11.7 and 3.8, 15α-H), 1.0 (3H, s,
13β-Me), 1.60 and 1.78 (each 1H, m, 7α- and 7β-H), 1.97 (1H,
dd, J 11.7 and 8.9, 15β-H), 2.04 (3H, s, 17-OAc), 2.82–2.90
(2H, m, 6-H2), 3.60 (1H, ddd, J 2 × 8.9 and 3.8, 16β-H), 3.77
(3H, s, 3-OMe), 4.25 (1H, dd, J 8.9 and 6.2, 1Ј-H), 4.70 (2H,
s, OCH2C6H5), 6.01 (1H, d, J 6.2, 2Ј-H), 6.08 and 6.33 (each
1H, d, J 6.2, 171- and 172-H), 6.62 (1H, d, J 2.8, 4-H), 6.71 (1H,
dd, J 8.6 and 2.8, 2-H), 7.20 (1H, d, J 8.6, 1-H) and 7.28–7.30
(5H, m, OCH2C6H5).
cmϪ1 3475 (OH); δH (200 MHz) 1.01 (3H, s, 13β-Me), 1.25 (1H,
dd, J 12.7 and 4.6, 15α-H), 1.81 (3H, br s, 1Ј-Me), 1.83 (1H, dd,
J 12.7 and 8.5, 15β-H), 3.05 (1H, dd, 8.5 and 4.6, 16β-H), 3.77
(3H, s, 3-OMe), 4.56 and 4.73 (each 1H, m, 2Ј-H2), 5.99 and
6.24 (each 1H, d, J 8.4, 171- and 172-H), 6.61 (1H, d, J 2.8, 4-H),
6.71 (1H, dd, J 8.6 and 2.8, 2-H) and 7.22 (1H, d, J 8.6, 1-H).
3-Methoxy-3Ј,6Ј-dihydro-15ꢁH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-trien-17-one 16
(a) Potassium hydride (35% suspension in mineral oil; 97 mg,
0.85 mmol) was washed with pentane to remove the oil, then
dried by the passage of nitrogen and suspended in THF (3 cm3).
A solution of the 16α-vinyl compound 14 (160 mg, 0.48 mmol)
in THF (3 cm3) was added and the mixture was heated at reflux
for 1 h. The mixture was cooled and the reaction was quenched
by the slow addition of ethanol (10 cm3). Water was added
and the resultant solution was extracted with ethyl acetate.
The combined organic phase was washed with water, dried
(MgSO4), and evaporated under reduced pressure. The residue
(149 mg) was chromatographed on silica gel (20 g), using ethyl
acetate–toluene (1:4) as eluent, to give compound 16 (140 mg,
87%), mp 176–178 ЊC (from EtOAc–hexane); [α]D ϩ213 (c 1.1)
(Found: C, 82.1; H, 8.4%; Mϩ, 336. C23H28O2 requires C, 82.1;
H, 8.3%; M, 336); νmax/cmϪ1 1724 (CO); δH (400 MHz) 1.03 (3H,
s, 13β-Me), 2.00 (1H, dd, J 19.2 and 11.3, 16α-H), 2.58 (1H, dd,
J 19.2 and 8.3, 16β-H), 2.76–2.80 (2H, m, 6-H2), 2.88 (1H,
td, J 2 × 11.6 and 4.0, 9α-H), 2.96 (1H, m, 15α-H), 3.78 (3H, s,
3-OMe), 5.64 (1H, m, 4Ј-H), 5.81 (1H, m, 5Ј-H), 6.60 (1H, d,
J 2.7, 4-H), 6.74 (1H, dd, J 8.5 and 2.7, 2-H) and 7.22 (1H,
d, J 8.5, 1-H).
16ꢁ-(2Ј-Benzyloxyethenyl)-3-methoxy-14,17ꢁ-ethenoestra-
1,3,5(10)-trien-17ꢀ-ols 20 and 21
(b) The enol acetate 12 (20 mg, 0.05 mmol) was suspended in
methanol (3 cm3) and methanolic 0.1 M potassium hydroxide
(1 cm3) was added. The mixture was stirred at 24 ЊC for 30 min,
then saturated aq. ammonium chloride was added. Standard
work-up followed by filtration of the crude product (18 mg)
through silica gel (2 g), using toluene as eluent, gave 16 (15 mg,
84%).
(a) LAH (15 mg, 0.4 mmol) was added to a solution of the
(1ЈE)-17β-acetate 18 (100 mg, 0.21 mmol) in dry THF (5 cm3)
at 0 ЊC under nitrogen, then the mixture was stirred at 25 ЊC for
20 min. Aq. sodium sulfate was added to the solution at 0 ЊC
until a white precipitate formed. Diethyl ether (10 cm3) was
added and the mixture was stirred for 30 min, then filtered
through magnesium sulfate and Celite. The filter pad was
washed with chloroform and the filtrate was evaporated
under reduced pressure to give the (1ЈE)-17β-alcohol 20 (79 mg,
85%), mp 254–255 ЊC (from EtOAc–hexane); [α]D ϩ311 (c 1.0)
(Found: C, 81.6; H, 7.8%; Mϩ, 442. C30H34O3 requires C, 81.4;
H, 7.7%; M, 442); νmax/cmϪ1 3467 (OH); δH (400 MHz) 0.92
(3H, s, 13β-Me), 1.06 (1H, dd, J 12.1 and 3.8, 15α-H), 1.95 (1H,
dd, J 12.1 and 8.6, 15β-H), 2.59 (1H, ddd, J 9.9, 8.6 and 3.8,
16β-H), 2.82–2.88 (2H, 6-H2), 3.77 (3H, s, 3-OMe), 4.59 (1H,
dd, J 12.5 and 9.9, 1Ј-H), 4.71 (2H, s, OCH2C6H5), 5.78 and
6.07 (each 1H, d, J 6.0, 171- and 172-H), 6.46 (1H, d, J 12.5,
2Ј-H), 6.62 (1H, d, J 2.7, 4-H), 6.70 (1H, dd, J 8.6 and 2.7, 2-H),
7.20 (1H, d, J 8.6, 1-H) and 7.29–7.40 (5H, m, OCH2C6H5).
(b) Similar treatment of the (1ЈZ)-17β-acetate 19 (200 mg,
0.42 mmol) gave the (1ЈZ)-17β-alcohol 21 (150 mg, 81%), mp
217–219 ЊC (from EtOAc–hexane); [α]D ϩ212 (c 1.1) (Found:
C, 81.4; H, 7.9%; Mϩ, 442); νmax/cmϪ1 3478 (OH); δH (400 MHz)
0.97 (3H, s, 13β-Me), 1.03 (1H, dd, J 11.9 and 3.8, 15α-H), 2.01
(1H, dd, J 11.9 and 8.2, 15β-H), 2.82–2.91 (2H, m, 6-H2), 3.32
(1H, ddt, J 2 × 8.2, 3.8 and 1.5, 16β-H), 3.77 (3H, s, 3-OMe),
4.20 (1H, dd, J 8.2 and 6.2, 1Ј-H), 4.82 (2H, s, OCH2C6H5), 5.86
and 6.0 (each 1H, d, J 6.2, 171- and 172-H), 6.09 (1H, dd, J 6.2
and 1.5, 2Ј-H), 6.62 (1H, d, J 2.8, 4-H), 6.71 (1H, dd, J 8.6 and
2.8, 2-H), 7.20 (1H, d, J 8.6, 1-H) and 7.26–7.30 (5H, m,
OCH2C6H5).
3-Methoxy-4Ј-methyl-3Ј,6Ј-dihydro-15ꢁH-benzo[14,15]-14ꢀ-
estra-1,3,5(10)-trien-17-one 17
(a) Treatment of the 16α-isopropenyl compound 15 (110 mg,
0.31 mmol) with potassium hydride (0.56 mmol) in refluxing
THF (5 cm3) for 2 h, as described in the foregoing experiment
(for 14), followed by similar work-up and chromatography on
silica gel (10 g) gave compound 17 (90 mg, 82%), mp 211–214 ЊC
(from EtOAc); [α]D ϩ284 (c 0.8) (Found: C, 82.4; H, 8.8%; Mϩ,
350. C24H30O2 requires C, 82.2; H, 8.6%; M, 350); νmax/cmϪ1
1725 (CO); δH (400 MHz) 1.02 (3H, s, 13β-Me), 1.68 (3H, br s,
4Ј-Me), 2.0 (1H, dd, J 19.0 and 11.4, 16α-H), 2.58 (1H, dd,
J 19.0 and 8.3, 16β-H), 2.88 (1H, td, J 11.8 × 2 and 3.6, 9α-H),
2.95 (1H, m, 15α-H), 3.77 (3H, s, 3-OMe), 5.49 (1H, m, 5Ј-H),
6.60 (1H, d, J 2.8, 4-H), 6.74 (1H, dd, J 8.7 and 2.8, 2-H) and
7.21 (1H, d, J 8.7, 1-H).
(b) Treatment of the enol acetate 13 (23 mg, 0.06 mmol) with
methanolic 0.025 M potassium hydroxide (4 cm3) at 24 ЊC for
30 min, followed by standard work-up and filtration through
silica gel (2 g), gave 17 (18 mg, 87%).
16ꢁ-(2Ј-Benzyloxyethenyl)-3-methoxy-14,17ꢁ-ethenoestra-
1,3,5(10)-trien-17ꢀ-yl acetates 18 and 19
1.7 M tert-Butyllithium in pentane (0.8 cm3) was added to a
suspension of benzyloxymethyl(triphenyl)phosphonium chlor-
ide (585 mg, 1.4 mmol) in THF (12 cm3) at 0 ЊC, and the
mixture was stirred at 0 ЊC for 1 h. A solution of the 16α-
carbaldehyde 9 (380 mg, 1 mmol) in dry THF (8 cm3) was
added and the mixture was stirred at 25 ЊC for 3 h, then diluted
with water and extracted with ethyl acetate. The combined
3Јꢀ-Benzyloxy-3-methoxy-3Ј,6Ј-dihydro-15ꢁH-benzo[14,15]-
14ꢀ-estra-1,3,5(10)-trien-17-one 22
(a) Potassium hydride (10.5 mg, 0.26 mmol) in THF (4 cm3) was
4482
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487

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added to a solution of the (1ЈE)-17β-alcohol 20 (60 mg,
0.14 mmol) in THF (5 cm3) and the mixture was heated at
reflux for 1 h. Ethanol (10 cm3) was added slowly to the
cooled reaction mixture, followed by water, and the solution
was extracted with ethyl acetate. The combined organic phase
was washed with water, dried (MgSO4), and the solvent was
removed under reduced pressure. The residue (57 mg) was
chromatographed on silica gel (10 g), using ethyl acetate–
toluene (1:9) as eluent, to give compound 22 (49 mg, 79%),
mp 256–258 ЊC (from CHCl3–hexane); [α]D ϩ356 (c 0.9)
(Found: C, 81.4; H, 7.9%; Mϩ, 442. C30H34O3 requires C,
81.4; H, 7.7%; M, 442); νmax/cmϪ1 1727 (CO); δH (400 MHz)
1.04 (3H, s, 13β-Me), 2.26 (1H, dd, J 19.8 and 11.2, 16α-H),
2.60 (1H, dd, J 19.8 and 8.3, 16β-H), 2.72–2.90 (2H, m,
6-H2), 3.24 (1H, m, 15α-H), 3.78 (3H, s, 3-OMe), 4.32 (1H, m,
3Јα-H), 4.58 (2H, d, J 1.6, OCH2C6H5), 5.72 (1H, m, 4Ј-H),
5.84 (1H, m, 5Ј-H), 6.61 (1H, d, J 2.7, 4-H), 6.75 (1H, dd,
J 8.5 and 2.7, 2-H), 7.22 (1H, d, J 8.5, 1-H) and 7.28–7.35 (5H,
m, OCH2C6H5).
Hydride reduction of the 4Ј,17-dione 4
Sodium borohydride (28 mg, 0.74 mmol) was added slowly
to a stirred solution of the 4Ј,17-dione 4 (252 mg, 0.72 mmol)
in THF–methanol (3:1; 12 cm3) at 0 ЊC under nitrogen.
After 10 min at 0 ЊC the reaction was complete (TLC). Aq.
ammonium chloride was added and the mixture was extracted
with ethyl acetate. The combined extract was washed (aq.
NH4Cl, water), dried (MgSO4), and evaporated under reduced
pressure. Chromatography of the residue (242 mg) on silica gel
(25 g), using ethyl acetate–toluene (1:5) as eluent, gave 4Јβ-
hydroxy-3-methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15αH-benzo[14,15]-
14β-estra-1,3,5(10)-trien-17-one 26 (153 mg, 60%), mp 80–
82 ЊC (from Me2CO); [α]D ϩ45 (c 1.0) (Found: C, 77.7; H,
8.4%; Mϩ, 354. C23H30O3 requires C, 77.9; H, 8.5%; M, 354);
νmax/cmϪ1 3606 (OH) and 1721 (CO); δH (400 MHz) 1.01
(3H, s, 13β-Me), 2.76 (1H, dd, J 19.2 and 10.4, 16α-H), 3.18
(1H, dd, J 19.2 and 7.5, 16β-H), 3.32 (1H, m, 15α-H), 3.77
(3H, s, 3-OMe), 4.22 (1H, q, J 3.4, 4Јα-H), 6.60 (1H, d,
J 2.9, 4-H), 6.72 (1H, dd, J 8.6 and 2.9, 2-H) and 7.21 (1H,
d, J 8.6, 1-H), followed by 4Јα-hydroxy-3-methoxy-3Ј,4Ј,5Ј,6Ј-
tetrahydro-15αH-benzo[14,15]-14β-estra-1,3,5(10)-trien-17-one
27 (77 mg, 30%), mp 104–105 ЊC (from Me2CO); [α]D ϩ53
(c 1.2) (Found: C, 77.9; H, 8.3%; Mϩ, 354); νmax/cmϪ1 3603
(OH) and 1727 (CO); δH (400 MHz) 0.98 (3H, s, 13β-Me),
2.20 (1H, dd, J 19.9 and 8.8, 16β-H), 2.75 (1H, dd, J 19.9
and 10.6, 16α-H), 3.07 (1H, m, 15α-H), 3.78 (3H, s, 3-OMe),
3.88 (1H, tt, J 2 × 11.3 and 2 × 5.0, 4Јβ-H), 6.55 (1H, d,
J 2.4, 4-H), 6.68 (1H, dd, J 8.8 and 2.4, 2-H) and 7.16 (1H,
d, J 8.8, 1-H).
(b) Reaction of the (1ЈZ)-17β-alcohol 21 (110 mg, 0.25
mmol) with potassium hydride (14 mg, 0.35 mmol) in THF
(10 cm3) at reflux for 3 h, followed by similar work-up and
chromatography, gave 22 (74 mg, 67%).
3-Methoxy-16ꢁ-vinyl-14,17ꢁ-ethenoestra-1,3,5(10)-triene-
16ꢀ,17ꢀ-diol 24
The 14α,17α-etheno 16-ketone 23 (212 mg, 0.65 mmol) was
added to a solution of vinylmagnesium bromide [prepared from
vinyl bromide (0.1 cm3, 0.93 mmol) and magnesium turnings
(24 mg, 1 mmol)] in THF (10 cm3) and the mixture was stirred
at 24 ЊC for 3 h. Aq. sodium hydrogen carbonate was added and
the mixture was stirred for 15 min, then extracted with ethyl
acetate. The combined organic phase was washed (water, brine),
dried (MgSO4), and the solvent was evaporated under reduced
pressure. Flash chromatography of the residue (198 mg) on
silica gel (20 g), using ethyl acetate–toluene (3:7) as eluent, gave
compound 24 (193 mg, 83%), mp 182–184 ЊC (from CHCl3–
MeOH); [α]D ϩ213 (c 0.9) (Found: C, 78.1; H, 8.6%; Mϩ,
354. C23H28O3 requires C, 77.9; H, 8.6%; M, 354); νmax/cmϪ1
3460br (OH); δH (400 MHz) 1.19 (3H, s, 13β-Me), 1.84 and
1.95 (each 1H, d, J 12.5, 15α- and 15β-H), 2.50 (1H, td,
J 2 × 11.6 and 3.4, 9α-H), 2.78–2.90 (2H, m, 6-H2), 3.78 (3H, s,
3-OMe), 5.11 (1H, dd, J 10.6 and 1.2, 2Ј-Hcis), 5.25 (1H, dd,
J 17.3 and 1.2, 2Ј-Htrans), 5.87 and 5.99 (each 1H, d, J 6.1,
171- and 172-H), 5.97 (1H, dd, 17.3 and 10.6, 1Ј-H), 6.63 (1H,
d, J 2.8, 4-H), 6.72 (1H, dd, J 8.6 and 2.8, 2-H) and 7.23
(1H, d, J 8.6, 1-H).
3-Methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15ꢁH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-trien-17-one 29
(a) A solution of the 4Ј,17-dione 4 (120 mg, 0.34 mmol) in
dichloromethane (2 cm3) at 0 ЊC was treated with ethanedithiol
(0.4 cm3, 4.8 mmol) and boron trifluoride–diethyl ether (0.2
cm3, 4.7 mmol). The solution was kept at 24 ЊC for 30 min,
then poured into aq. sodium hydrogen carbonate. The mixture
was extracted with chloroform and the extract was washed
(aq. NaHCO3, water), dried (MgSO4), and evaporated under
reduced pressure to yield the 4Ј,4Ј-ethylenedithio 17-ketone 28
(142 mg, 98%), mp 242–244 ЊC (from CHCl3–MeOH); [α]D
ϩ32 (c 0.97) (Found: C, 70.2; H, 7.5; S, 14.6%; Mϩ, 428.
C25H32O2S2 requires C, 70.1; H, 7.5; S, 15.0%; M, 428); νmax
/
cmϪ1 1727 (CO); δH (200 MHz) 1.02 (3H, s, 13β-Me), 3.20–3.40
(2H, m, SCH2CH2S), 3.77 (3H, s, 3-OMe), 6.60 (1H, d, J 2.9,
4-H), 6.72 (1H, dd, J 8.7 and 2.9, 2-H) and 7.18 (1H, d,
J 8.7, 1-H).
Raney nickel (Aldrich W2, 0.5 g) was washed by decan-
tation with absolute ethanol (×4), then suspended in ethanol
(2 cm3). A solution of dithioketal 28 (158 mg, 0.36 mmol)
in ethanol (2 ml) was added and the mixture was stirred at
50 ЊC for 1 h. Chloroform (3 ml) was added and the mix-
ture was filtered through Celite. The filtrate was evapor-
ated under reduced pressure to give a solid residue (131 mg),
crystallisation of which gave the 17-ketone 29 (112 mg,
90%), mp 137–138 ЊC (from Me2CO–EtOH); [α]D ϩ23 (c 1.1)
(Found: C, 81.7; H, 8.7%; Mϩ, 338. C23H30O2 requires C,
81.6; H, 8.9%; M, 338); νmax/cmϪ1 1728 (CO); δH (200 MHz)
0.89 (3H, s, 13β-Me), 3.70 (3H, s, 3-OMe), 6.54 (1H, d, J 2.8,
4-H), 6.66 (1H, dd, J 8.6 and 2.8, 2-H) and 7.15 (1H, d,
J 8.6, 1-H).
3-Methoxy-3Ј,6Ј-dihydro-15ꢁH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-triene-5Ј(4ЈH),17-dione 25
Reaction of the 16α-vinyl-16β,17β-diol 24 (130 mg, 0.37 mmol)
with potassium hydride (16 mg, 0.4 mmol) in THF (8 cm3) at
Ϫ78 ЊC for 15 min, followed by standard work-up and flash
chromatography of the product (113 mg) on silica gel (10 g),
using ethyl acetate–toluene (1:4) as eluent, gave the 5Ј,17-dione
25 (105 mg, 78%), mp 106–109 ЊC (from MeOH–Pri2O); [α]D
ϩ267 (c 1.0) (Found: C, 78.4; H, 8.0%; Mϩ, 352. C23H28O3
requires C, 78.7; H, 8.0%; M, 352); νmax/cmϪ1 1698 and 1725
(CO); δH (400 MHz) 0.98 (3H, s, 13β-Me), 1.61 (1H, dd, J 19.7
and 10.3, 16β-H), 1.94 (1H, d, J 15.5, 6Јα-H), 2.20 (1H, dd,
J 15.5 and 1.7, 6Јβ-H), 2.78 (1H, d, J 19.7 and 9.9, 16α-H), 3.09
(1H, dddd, J 10.3, 9.9, 5.0 and 2.4, 15α-H), 3.77 (3H, s, 3-OMe),
6.60 (1H, d, J 2.8, 4-H), 6.74 (1H, dd, J 8.7 and 2.8, 2-H) and
7.20 (1H, d, J 8.7, 1-H); δC (50 MHz) 13.9 (C-18), 26.1 (C-11),
26.2 (C-3Ј), 27.4 (C-7), 30.0 (C-6), 31.5 (C-12), 31.7 (C-4Ј), 34.9
(C-15), 38.1 (C-8), 46.2 (C-9), 48.7 (C-6Ј), 52.0 (C-13), 55.2
(3-OMe), 55.8 (C-14), 112.4 (C-2), 113.4 (C-4), 127.2 (C-1),
131.2 (C-10), 137.4 (C-5), 157.6 (C-3), 211.4 (C-5Ј) and 219.4
(C-17).
(b) The ∆4Ј-17-ketone 16 (22 mg, 0.07 mmol) as a solution in
ethyl acetate (5 cm3) at 24 ЊC was hydrogenated at atmospheric
pressure in the presence of palladium on carbon (10%; 5 mg).
After 3 h the mixture was filtered, and the filtrate was evapor-
ated under reduced pressure. Filtration of the residue (19 mg)
through silica gel (2 g) using toluene as eluent gave 29 (18
mg, 81%), identical to material obtained in the foregoing
experiment.
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487
4483

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Hydride reduction of the 17-ketone 29
lithium diisopropylamide [formed by the addition of n-butyl-
lithium (1.6 M; 0.6 cm3) to diisopropylamine (0.14 cm3, 0.80
mmol) in diethyl ether (10 cm3) at Ϫ78 ЊC, followed by stirring
for 30 min at 0 ЊC] cooled to Ϫ78 ЊC. The mixture was stirred at
Ϫ78 ЊC for 1 h then chlorotrimethylsilane (0.2 cm3, 1.6 mmol)
was added and the mixture was allowed to warm to 0 ЊC. Satur-
ated aq. ammonium chloride was added and the mixture was
extracted with ethyl acetate. The combined organic phase was
washed successively with water and brine, dried (MgSO4), and
the solvent was evaporated under reduced pressure. The residue
(327 mg) was dissolved in acetonitrile (12 cm3) and added to a
mixture of palladium() acetate (173 mg, 0.76 mmol) and
sodium hydrogen carbonate (30 mg, 0.42 mmol) in dry aceto-
nitrile (8 cm3). The mixture was stirred at 25 ЊC for 4 h, then
filtered through Celite. The Celite was washed with ethyl acetate
and the combined filtrate was washed successively with water
and brine, dried (MgSO4), and evaporated under reduced pres-
sure. Flash chromatography of the crude material (251 mg) on
silica gel (20 g), using ethyl acetate–hexane (1:4) as eluent,
gave 4Ј,4Ј-ethylenedioxy-3-methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydrobenzo-
[14,15]-14β-estra-1,3,5(10),15-tetraen-17-one 35 (237 mg,
79%), mp 178–180 ЊC (from CHCl3–MeOH); [α]D ϩ278 (c 1.0)
(Found: C, 76.3; H, 7.6%; Mϩ, 394. C25H30O4 requires C, 76.1;
H, 7.6%; M, 394); νmax/cmϪ1 1708 (CO); δH (400 MHz) 1.06 (3H,
s, 13β-Me), 2.56 (1H, td, J 2 × 11.5 and 3.7, 9α-H), 2.69–
2.74 (2H, m, 6-H2), 3.76 (3H, s, 3-OMe), 3.84–3.88 [4H, m,
O(CH2)2O], 5.82 (1H, s, 16-H), 6.63 (1H, d, J 2.7, 4-H), 6.70
(1H, dd, J 8.8 and 2.7, 2-H) and 7.08 (1H, d, J 8.8, 1-H).
LAH (100 mg, 2.7 mmol) was added in portions to a stirred
solution of the ketone 29 (300 mg, 0.89 mmol) in THF (25 cm3)
at 0 ЊC under nitrogen, then the mixture was stirred at 24 ЊC for
10 min. Water was added dropwise until evolution of hydrogen
ceased, followed by chloroform. The mixture was filtered and
the precipitate was washed repeatedly with chloroform. The
chloroform phase was washed with water, dried (MgSO4), and
evaporated under reduced pressure. The residue (236 mg) was
chromatographed on silica gel (30 g), using ethyl acetate–
toluene (1:4) as eluent, to give 3-methoxy-3Ј,4Ј,5Ј,6Ј-tetra-
hydro-15αH-benzo[14,15]-14β-estra-1,3,5(10)-trien-17β-ol 30
(135 mg, 49%), mp 136–137 ЊC (from EtOAc–MeOH); [α]D
ϩ77 (c 1.2) (Found: C, 81.4; H, 9.2%; Mϩ, 340. C23H32O2
requires C, 81.1; H, 9.4%; M, 340); νmax/cmϪ1 3578 (OH); δH
(200 MHz) 1.05 (3H, s, 13β-Me), 3.62 (1H, dd, J 6.4 and 5.2,
17α-H), 3.77 (3H, s, 3-OMe), 6.59 (1H, d, J 2.8, 4-H), 6.70 (1H,
dd, J 8.6 and 2.8, 2-H) and 7.22 (1H, d, J 8.6, 1-H), followed by
3-methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15αH-benzo[14,15]-14β-estra-
1,3,5(10)-trien-17α-ol 31 (86 mg, 31%), mp 144–145 ЊC (from
CH2Cl2–MeOH); [α]D ϩ56 (c 1.0) (Found: C, 81.2; H, 9.6%;
Mϩ, 340); νmax/cmϪ1 3566 (OH); δH (200 MHz) 0.96 (3H, s,
13β-Me), 4.14 (1H, t, J 2 × 8.6, 17β-H), 3.77 (3H, s, 3-OMe),
6.59 (1H, d, J 2.8, 4-H), 6.72 (1H, dd, J 8.6 and 2.8, 2-H) and
7.24 (1H, d, J 8.6, 1-H).
Deprotection of the 3-methyl ethers 30 and 31
(a) 1.2 M DIBAL-H in toluene (1.5 cm3, 1.8 mmol) was added
to a stirred solution of the 17β-alcohol 30 (100 mg, 0.29 mmol)
in dry toluene (10 cm3) and the mixture was heated at reflux
under nitrogen for 48 h. The mixture was cooled, acidified
with dil. hydrochloric acid, and extracted with chloroform.
The combined organic phase was washed with brine, dried
(MgSO4), and evaporated under reduced pressure to give a
solid residue (81 mg). Recrystallisation (Me2CO–MeOH) gave
3Ј,4Ј,5Ј,6Ј-tetrahydro-15αH-benzo[14,15]-14β-estra-1,3,5(10)-
triene-3,17β-diol 32 (72 mg, 75%), mp 179–181 ЊC; [α]D ϩ82
(c 1.1) (Found: C, 80.8; H, 9.5%; Mϩ, 326. C22H30O2 requires C,
80.9; H, 9.3%; M, 326).
(b) Treatment of the 17-ketone 29 (338 mg, 1 mmol) as
described in the foregoing experiment gave 3-methoxy-3Ј,4Ј,
5Ј,6Ј-tetrahydrobenzo[14,15]-14β-estra-1,3,5(10),15-tetraen-17-
one 36 (284 mg, 91%), mp 161–163 ЊC (from CHCl3–MeOH);
[α]D ϩ202 (c 1.0) (Found: C, 82.4; H, 8.4%; Mϩ, 336. C23H28O2
requires C, 82.1; H, 8.3%; M, 336); νmax/cmϪ1 1702 (CO);
δH (400 MHz) 0.99 (3H, s, 13β-Me), 2.57 (1H, td, J 2 × 11.1 and
3.9, 9α-H), 2.68–2.74 (2H, m, 6-H2), 3.72 (3H, s, 3-OMe), 5.87
(1H, s, 16-H), 6.61 (1H, d, J 2.7, 4-H), 6.68 (1H, dd, J 8.7 and
2.7, 2-H) and 7.08 (1H, d, J 8.7, 1-H).
Hydrogenation of the ꢂ15-17-ketone 35
(b) Similar treatment of the 17α-alcohol 31 (100 mg, 0.29
mmol) gave 3Ј,4Ј,5Ј,6Ј-tetrahydro-15αH-benzo[14,15]-14β-
estra-1,3,5(10)-triene-3,17α-diol 33 (69 mg, 72%), mp 196–
198 ЊC (from Me2CO–MeOH); [α]D ϩ49 (c 1.1) (Found: C, 81.0;
H, 9.4%; Mϩ, 326).
The enone 35 (200 mg, 0.51 mmol) as a solution in ethyl acetate
(5 cm3) was hydrogenated for 5 h at 24 ЊC in the presence of
palladium on carbon (10%; 81 mg). The mixture was filtered
and the filtrate was evaporated under reduced pressure. Flash
chromatography of the residue (200 mg) on silica gel (20 g),
using ethyl acetate–hexane (1:5) as eluent, gave 34 (10 mg,
5%) followed by 4Ј,4Ј-ethylenedioxy-3-methoxy-3Ј,4Ј,5Ј,6Ј-tetra-
hydro-15βH-benzo[14,15]-14β-estra-1,3,5(10)-trien-17-one 37
(188 mg, 93%), mp 156–157 ЊC (from CHCl3–MeOH); [α]D
ϩ218 (c 1.2) (Found: C, 75.6; H, 8.2%; Mϩ, 396. C25H32O4
requires C, 75.8; H, 8.1%; M, 396); νmax/cmϪ1 1729 (CO);
δH (400 MHz) 0.97 (3H, s, 13β-Me), 1.62 (1H, dd, J 18.7 and
11.1, 16β-H), 2.52 (1H, td, J 2 × 11.1 and 3.9, 9α-H), 2.63 (1H,
dd, J 18.7 and 8.4, 16α-H), 2.73–2.79 (2H, m, 6-H2), 3.04 (1H,
m, 15β-H), 3.77 (3H, s, 3-OMe), 3.81–3.85 [4H, m, O(CH2)2O],
6.64 (1H, d, J 2.7, 4-H), 6.67 (1H, dd, J 8.8 and 2.7, 2-H) and
7.21 (1H, d, J 8.8, 1-H).
4Ј,4Ј-Ethylenedioxy-3-methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15ꢁH-
benzo[14,15]-14ꢀ-estra-1,3,5(10)-trien-17-one 34
Toluene-p-sulfonic acid (21 mg, 0.11 mmol) was added to a
solution of the dione 4 (400 mg, 1.13 mmol) in toluene–ethylene
glycol (30 cm3; 9:1) and the mixture was heated under reflux for
7 h with azeotropic removal of water. The solution was cooled
to 25 ЊC and poured into saturated aq. sodium hydrogen
carbonate. The mixture was extracted with ethyl acetate and the
organic phase was washed successively with water and brine,
dried (MgSO4), and the solvent was evaporated under reduced
pressure. Flash chromatography of the residue (371 mg) on
silica gel (30 g), using ethyl acetate–hexane (1:4) as eluent, gave
compound 34 (353 mg, 79%), mp 189–190 ЊC (from CHCl3–
MeOH); [α]D ϩ337 (c 1.1) (Found: C, 75.6; H, 7.9%; Mϩ, 396.
C25H32O4 requires C, 75.8; H, 8.1%; M, 396); νmax/cmϪ1 1727
(CO); δH (200 MHz) 0.98 (3H, s, 13β-Me), 3.12 (1H, m, 15α-H),
3.76 (3H, s, 3-OMe), 3.87–3.93 [4H, m, O(CH2)2O], 6.62 (1H,
d, J 2.8, 4-H), 6.75 (1H, dd, J 8.5 and 2.8, 2-H) and 7.14 (1H, d,
J 8.5, 1-H).
3-Methoxy-5Ј,6Ј-dihydro-15ꢀH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-triene-4Ј(3ЈH),17-dione 38
Pyridinium toluene-p-sulfonate (59 mg, 0.37 mmol) was added
to a solution of the ketal 37 (140 mg, 0.35 mmol) in acetone (10
cm3) and the mixture was stirred at 25 ЊC for 4 h. Saturated aq.
sodium hydrogen carbonate was added and the mixture was
extracted with ethyl acetate. The combined organic phase was
washed successively with water and brine, dried (MgSO4), and
evaporated under reduced pressure. The residue (117 mg) was
chromatographed on silica gel (15 g), using ethyl acetate–hexane
(3:7) as eluent, to give the dione 38 (107 mg, 87%), mp 178–
Dehydrogenation of the 17-ketones 34 and 29
(a) The 4Ј,4Ј-ethylenedioxy 17-ketone 34 (300 mg, 0.76 mmol)
as a solution in diethyl ether (10 cm3) was added to a solution of
4484
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180 ЊC (from Me2CO–MeOH); [α]D ϩ118 (c 1.0) (Found: C,
78.5; H, 8.2%; Mϩ, 352. C23H28O3 requires C, 78.4; H, 8.0%; M,
352); νmax/cmϪ1 1707 (4Ј-CO) and 1731 (17-CO); δH (400 MHz)
1.02 (3H, s, 13β-Me), 1.82 (1H, dd, J 19.1 and 11.2, 16β-H),
2.21 (1H, ddd, J 16.2, 5.8 and 1.4, 3Јβ-H), 2.47 (1H, dd, J 16.2
and 7.9, 3Јα-H), 2.58 (1H, td, J 2 × 10.9 and 4.1, 9α-H), 2.69
(1H, dd, J 19.1 and 9.3, 16α-H), 2.73–2.92 (2H, m, 6-H2), 3.01
(1H, m, 15β-H), 3.78 (3H, s, 3-OMe), 6.65 (1H, d, J 2.7, 4-H),
6.73 (1H, dd, J 8.8 and 2.7, 2-H) and 7.22 (1H, d, J 8.8, 1-H);
δC (100 MHz) 16.7 (q, C-18), 26.8 (t, C-11), 27.3 (q, C-7), 30.4,
30.7 and 31.2 (each t, C-6, -6Ј and -12), 34.1 (d, C-15), 38.9
(d, C-8), 39.4 (t, C-5Ј), 43.8 (t, C-3Ј), 42.2 (t, C-16), 44.7 (d,
C-9), 49.5 and 52.8 (each s, C-13 and -14), 55.2 (q, 3-OMe),
112.1 (d, C-2), 113.3 (d, C-4), 127.4 (d, C-1), 131.9 (s, C-10),
137.2 (s, C-5), 157.7 (s, C-3), 209,8 (s, C-4Ј) and 214.7 (s, C-17).
under reduced pressure. The residue (236 mg) was chromato-
graphed on silica gel (30 g), using ethyl acetate–toluene (2:8) as
eluent, to give 3-methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15βH-benzo-
[14,15]-14β-estra-1,3,5(10)-trien-17β-ol 41 (139 mg, 46%), mp
172–174 ЊC (from CH2Cl2–MeOH); [α]D ϩ218 (c 1.1) (Found:
C, 81.2; H, 9.6%; Mϩ, 340. C23H32O2 requires C, 81.1; H, 9.4%;
M, 340); νmax/cmϪ1 3613 (OH); δH (400 MHz) 0.98 (3H, s, 13β-
Me), 2.58 (1H, td, J 2 × 11.2 and 4.1, 9α-H), 3.09 (1H, m, 15β-
H), 3.77 (3H, s, 3-OMe), 3.91 (1H, dd, J 9.7 and 3.4, 17α-H),
6.62 (H, d, J 2.8, 4-H), 6.71 (1H, dd, J 8.8 and 2.8, 2-H) and 7.2
(1H, d, J 8.8, 1-H) followed by 3-methoxy-3Ј,4Ј,5Ј,6Ј-tetra-
hydro-15βH-benzo[14,15]-14β-estra-1,3,5(10)-trien-17α-ol 42
(115 mg, 38%), mp 191–193 ЊC (from CH2Cl2–MeOH); [α]D
ϩ179 (c 1.2) (Found: C, 81.0; H, 9.3%; Mϩ, 340); νmax/cmϪ1
3609 (OH); δH (400 MHz) 1.03 (3H, s, 13β-Me), 2.54 (1H, td,
J 2 × 11.4 and 3.9, 9α-H), 3.17 (1H, m, 15β-H), 3.77 (3H, s,
3-OMe), 3.87 (1H, dd, J 10.2 and 8.9, 17β-H), 6.59 (1H, d,
J 2.6, 4-H), 6.73 (1H, dd, J 8.7 and 2.6, 2-H) and 7.21 (1H,
d, J 8.7, 1-H).
3-Methoxy-3Ј,4Ј,5Ј,6Ј-tetrahydro-15ꢀH-benzo[14,15]-14ꢀ-estra-
1,3,5(10)-trien-17-one 40
(a) A solution of the 4Ј,17-dione 38 (125 mg, 0.36 mmol) in
dichloromethane (5 cm3) was cooled to 0 ЊC, and ethanedithiol
(0.4 cm3, 4.8 mmol) was added followed by boron trifluoride–
diethyl ether (0.2 cm3, 4.7 mmol). The solution was stirred at
24 ЊC for 90 min, then water was added and the resultant mix-
ture was poured into aq. sodium hydrogen carbonate. The
mixture was extracted with dichloromethane and the combined
organic phase was washed successively with aq. sodium hydro-
gen carbonate and water, dried (MgSO4), and evaporated under
reduced pressure to yield a solid residue (158 mg). Recrystallis-
ation gave the 4Ј,4Ј-ethylenedithio 17-ketone 39 (124 mg, 81%),
mp 231–234 ЊC (from CHCl3–MeOH); [α]D ϩ107 (c 1.3)
(Found: C, 70.1; H, 7.2; S, 14.6%; Mϩ, 428. C25H32O2S2 requires
C, 70.1; H, 7.5; S, 14.9%; M, 428); νmax/cmϪ1 1724 (CO); δH (400
MHz) 1.13 (3H, s, 13β-Me), 3.27–3.42 [4H, m, S(CH2)2S], 3.78
(3H, s, 3-OMe), 6.61 (1H, d, J 2.8, 4-H), 6.73 (1H, dd, J 8.6 and
2.8, 2-H) and 7.14 (1H, d, J 8.6, 1-H).
Raney nickel (Aldrich W2, 350 mg) was washed (4×) by
decantation with absolute ethanol, and suspended in further
ethanol (2 cm3). A solution of the dithioketal 39 (100 mg, 0.23
mmol) in ethanol (3 cm3) was added and the resultant mixture
was heated with stirring at 50 ЊC for 2.5 h. The mixture was
cooled to 25 ЊC and chloroform (5 cm3) was added. The mixture
was filtered through Celite and the filtrate was evaporated
under reduced pressure to give a solid residue (73 mg).
Recrystallisation gave the 17-ketone 40 (68 mg, 87%), mp
136 ЊC (from CHCl3–MeOH); [α]D ϩ298 (c 0.9) (Found: C,
81.8; H, 9.0%; Mϩ, 338. C23H30O2 requires C, 81.6; H, 8.9%; M,
338); νmax/cmϪ1 1731 (CO); δH (400 MHz) 0.97 (3H, s, 13β-Me),
2.09 (3H, dd, J 19.1 and 4.3, 16β-H), 2.44 (1H, dd, J 19.1 and
7.6, 16α-H), 2.60 (1H, td, J 2 × 10.9 and 4.5, 9α-H), 3.13 (1H,
m, 15β-H), 3.76 (3H, s, 3-OMe), 6.59 (1H, d, J 2.7, 4-H), 6.68
(1H, dd, J 8.6 and 2.7, 2-H) and 7.19 (1H, d, J 8.6, 1-H).
(b) The ∆15-17-ketone 36 (250 mg, 0.74 mmol) as a solution in
ethyl acetate (8 cm3) at 24 ЊC was hydrogenated at atmospheric
pressure in the presence of palladium on carbon (10%; 78 mg).
After 5 h the mixture was filtered, and the filtrate was evapor-
ated under reduced pressure. Flash chromatography of the resi-
due on silica gel (30 g), using ethyl acetate–hexane (1:5) as
eluent, gave 15α-H ketone 29 (8 mg, 3%) followed by 15β-H
isomer 40 (237 mg, 95%).
Deprotection of the 3-methyl ethers 41 and 42
(a) 1.2 M DIBAL-H in toluene (1.0 cm3, 1.2 mmol) was added
to a stirred solution of the 17β-alcohol 41 (80 mg, 0.24 mmol)
in dry toluene (20 cm3) and the mixture was refluxed under
nitrogen for 48 h. The mixture was cooled to 24 ЊC, acidified
with hydrochloric acid (10%; 10 cm3), and extracted with
chloroform. The combined organic phase was washed with
brine, dried (MgSO4), and evaporated under reduced pressure
to give a crystalline residue (69 mg). Recrystallisation (Me2-
CO–MeOH) gave 3Ј,4Ј,5Ј,6Ј-tetrahydro-15βH-benzo[14,15]-
14β-estra-1,3,5(10)-triene-3,17β-diol 43 (62 mg, 80%), mp 178–
179 ЊC; [α]D ϩ286 (c 1.0) (Found: C, 80.9; H, 9.0%; Mϩ, 326.
C22H30O2 requires C, 81.0; H, 9.2%; M, 326).
(b) Similar treatment of the 17α-alcohol 42 (100 mg, 0.29
mmol) and crystallisation (Me2CO–MeOH) of the reaction
product (83 mg) gave 3Ј,4Ј,5Ј,6Ј-tetrahydro-15βH-benzo[14,15]-
14β-estra-1,3,5(10)-triene-3,17α-diol 44 (79 mg, 82%), mp 212–
214 ЊC; [α]D ϩ301 (c 1.1) (Found: C, 81.2; H, 9.2%; Mϩ, 326).
16ꢁ-Acetyl-3-methoxy-14,17ꢁ-ethanoestra-1,3,5(10)-trien-
17ꢀ-yl acetate 45
The 14α,17α-etheno compound 2 (192 mg, 0.48 mmol) as a
solution in ethyl acetate (10 cm3) at 24 ЊC was hydrogenated at
atmospheric pressure in the presence of palladium on carbon
(10%; 50 mg). After 3 h the mixture was filtered, and the filtrate
was evaporated under reduced pressure. Filtration of the resi-
due (195 mg) through silica gel (10 g), using toluene as eluent,
gave the 14α,17α-ethano compound 45 (191 mg, 100%), mp 163–
164 ЊC (from Me2CO–MeOH); [α]D ϩ37 (c 1.2) (Found: C, 75.5;
H, 8.0%; Mϩ, 396. C25H32O4 requires C, 75.7; H, 8.1%; M, 396);
νmax/cmϪ1 1728 (OAc) and 1705 (CO); δH (200 MHz) 1.0 (3H, s,
13β-Me), 2.07 (1H, s, 17β-OAc), 2.17 (3H, s, 16α-COMe), 3.34
(1H, ddd, J 11.1, 4.4 and 2.6, 16β-H), 3.76 (3H, s, 3-OMe), 6.61
(1H, d, J 2.7, 4-H), 6.70 (1H, dd, J 8.5 and 2.7, 2-H) and 7.2
(1H, d, J 8.5, 1-H).
3-Methoxy-14ꢀ-(3Ј-oxobutyl)estra-1,3,5(10)-trien-17-one 46
(a) The 14β-3Ј-oxobutyl ∆15-17-ketone 3 (100 mg, 0.28 mmol)
as a solution in ethyl acetate (8 cm3) at 24 ЊC was hydrogenated
at atmospheric pressure in the presence of palladium on carbon
(10%; 30 mg). After 90 min the mixture was filtered, and the
filtrate was evaporated under reduced pressure. Flash chrom-
atography of the residue (532 mg) on silica gel (55 g), using
ethyl acetate–toluene (1:9) as eluent, gave the dihydro compound
46 (61 mg, 61%), mp 147–149 ЊC (from Me2CO–MeOH); [α]D
Ϫ47 (c 0.9) (Found: C, 77.7; H, 8.6%; Mϩ, 354. C23H30O3
requires C, 77.9; H, 8.5%; M, 354); νmax/cmϪ1 1727 (CO);
δH (200 MHz) 1.04 (3H, s, 13β-Me), 2.13 (3H, s, 3Ј-Me), 2.82–
Hydride reduction of the 17-ketone 40
The 17-ketone 40 (300 mg, 0.89 mmol) was treated with LAH
(100 mg, 2.7 mmol) in THF (12 cm3) at 0 ЊC for 30 min then at
24 ЊC for 10 min. Saturated aq. ammonium chloride was added
dropwise to the solution until the evolution of hydrogen ceased,
and chloroform was added. The mixture was filtered and the
precipitate was washed repeatedly with chloroform. The com-
bined filtrate was extracted with chloroform, and the organic
phase was washed with water, dried (MgSO4), and evaporated
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487
4485

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2.92 (2H, m, 6-H2), 3.79 (3H, s, 3-OMe), 6.63 (1H, d, J 2.8,
4-H), 6.67 (1H, dd, J 8.6 and 2.8, 2-H) and 7.21 (1H, d, J 8.6,
1-H), followed by compound 47 (31 mg, 31%) (see following
experiment).
dd, J 12.7 and 7.3, 15α-H), 2.46 (1H, td, J 11.4 × 2 and 2.1,
9α-H), 2.78–2.84 (2H, m, 6-H2), 3.76 (3H, s, 3-OMe), 3.99 (1H,
d, J 6.8, 17α-H), 6.61 (1H, d, J 2.7, 4-H), 6.70 (1H, dd, J 2.7 and
8.6, 2-H) and 7.2 (1H, d, J 8.6, 1-H).
(b) 5% Methyllithium in diethyl ether (0.14 cm3, 0.3 mmol)
was added to a stirred suspension of copper() iodide (57 mg,
0.3 mmol) in dry THF (5 cm3) at 0 ЊC under nitrogen. The
suspension of methylcopper was cooled to Ϫ78 ЊC and HMPA
(2 cm3, 11.4 mmol) and 1.2 M DIBAL-H in toluene (0.3 cm3,
4 mmol) were added successively. The mixture was stirred at
Ϫ78 ЊC for 30 min, then a solution of compound 3 (352 mg,
1 mmol) in dry THF (2 cm3) was added. The mixture was
stirred at Ϫ78 ЊC for 1.5 h, then 1 M hydrochloric acid
(5 cm3) was added and the mixture was extracted with
chloroform. The extract was washed (1 M HCl, aq. NaHCO3,
brine), dried (MgSO4), and evaporated under reduced pres-
sure to give a solid residue (310 mg). Filtration through silica
gel (30 g) with toluene yielded the 3Ј,17-dione 46 (296 mg,
84%).
(b) A solution of the 161-hydroxy 17-ketone 47 (60 mg, 0.17
mmol) in THF (5 cm3) and tert-butyl alcohol (0.1 cm3) was
treated with 0.1 M samarium() iodide (4 cm3, 0.4 mmol) at
reflux for 1 h. 0.1 M Hydrochloric acid (10 cm3) was added and
the mixture was extracted with ethyl acetate. The organic phase
was washed (aq. NaHCO3, aq. Na2S2O3, water, brine), dried
(MgSO4), and evaporated under reduced pressure. The residue
(57 mg) was chromatographed on silica gel (6 g), using ethyl
acetate–toluene (2:3) as eluent, to give the 161,17β-diol 48
(59 mg, 82%).
Reaction of the 3Ј,17-dione 46 with samarium(II) iodide
(a) 0.1 M Samarium() iodide (10 cm3, 1 mmol) was added to a
solution of the 3Ј,17-dione 46 (150 mg, 0.42 mmol) in THF
(5 cm3) at Ϫ78 ЊC. After 6 h at Ϫ78 ЊC the mixture was allowed
to warm to 20 ЊC and was neutralised by the addition of 0.1 M
hydrochloric acid (10 cm3). The mixture was extracted with
chloroform and the combined organic phase was washed
(0.1 M HCl, aq. NaHCO3, aq. Na2S2O3, water) and dried
(MgSO4). The solvent was evaporated under reduced pressure
to give a residue (129 mg), which was chromatographed on silica
gel (12 g), using ethyl acetate–toluene (1:4) as eluent, to give
(161S)-161-hydroxy-3-methoxy-161-methyl-14,16β-propano-
14β-estra-1,3,5(10)-trien-17-one 49 (130 mg, 87%), mp 132–
134 ЊC (from EtOAc–MeOH) (Found: C, 77.9; H, 8.5%; Mϩ,
354. C23H30O3 requires C, 78.0; H, 8.5%; M, 354); νmax/cmϪ1
3530 (OH), 1718 (CO); δH (400 MHz) 1.08 (3H, s, 13β-Me), 1.34
(3H, s, 161-Me), 1.62 (1H, d, J 12.8, 15β-H), 2.24 (1H, ddd,
J 12.8, 6.2 and 3.2, 15α-H), 2.38 (1H, dd, J 6.2 and 1.8, 16α-H),
2.60 (1H, td, J 2 × 11.3 and 3.5, 9α-H), 2.84–2.89 (2H, m,
6-H2), 3.78 (3H, s, 3-OMe), 6.62 (1H, d, J 2.8, 4-H), 6.72
(1H, dd, J 8.6 and 2.8, 2-H) and 7.20 (1H, d, J 8.6, 1-H);
δC (100 MHz) 13.8 (q, C-18), 23.5 (t, C-7), 25.1 (q, 161-Me),
26.0 (t, C-11), 29.8 (t, C-163), 30.6 (t, C-6), 30.7 (t, C-15),
30.8 (t, C-12), 36.1 (t, C-162), 37.4 (d, C-9), 41.95 (d, C-8),
45.9 (s, C-13), 49.7 (s, C-14), 55.2 (q, 3-OMe), 56.6 (d, C-16),
72.5 (s, C-161), 111.8 (d, C-2), 113.5 (d, C-4), 126.6 (d, C-1),
132.1 (s, C-10), 137.7 (s, C-5), 157.6 (s, C-3) and 224.4
(s, C-17).
(b) The foregoing reaction was conducted with 46 (200 mg,
0.56 mmol) and samarium() iodide (2.4 mmol) in THF (5 cm3)
at reflux for 4.5 h. Similar work-up and chromatography of the
product (187 mg) on silica gel (20 g), using ethyl acetate–
toluene (3:2) as eluent, gave (161S)-3-methoxy-161-methyl-
14,16β-propano-14β-estra-1,3,5(10)-triene-161,17β-diol 50 (26
mg, 13%), mp 184–186 ЊC (from Me2CO–MeOH) (Found: C,
77.6; H, 9.4%; Mϩ, 356. C23H32O3 requires C, 77.5; H, 9.1%; M,
356); νmax/cmϪ1 3400br (OH); δH (400 MHz) 1.03 (3H, s, 13β-
Me), 1.27 (3H, s, 161-Me), 1.37 (1H, d, J 12.7, 15β-H), 1.74 (1H,
ddd, J 12.7, 5.7 and 3.3, 15α-H), 2.30 (1H, ddd, J 6.8, 5.7 and 1.8,
16α-H), 2.40 (1H, td, 2 × 11.4 and 3.3, 9α-H), 2.80–2.85 (2H,
m, 6-H2), 3.77 (3H, s, 3-OMe), 4.11 (1H, d, J 6.8, 17α-H), 6.61
(1H, d, J 2.7, 4-H), 6.7 (1H, dd, J 2.7 and 8.6, 2-H) and 7.2 (1H,
d, J 8.6, 1-H), followed by (161S)-3-methoxy-161-methyl-14,16β-
propano-14β-estra-1,3,5(10)-triene-161,17α-diol 51 (137 mg,
68%), mp 197–198 ЊC (from Me2CO–MeOH) (Found: C, 77.8;
H, 9.2%; Mϩ, 356); νmax/cmϪ1 3400br (OH); δH (400 MHz)
1.08 (3H, s, 13β-Me), 1.23 (1H, d, J 12.4, 15β-H), 1.31 (3H, s,
161-Me), 1.44 (1H, ddd, J 14.1, 6.6 and 3.6, 12β-H), 1.78 (1H,
d, J 6.0, 16α-H), 2.00 (1H, td, J 2 × 14.1 and 3.6, 12α-H), 2.09
(1H, ddd, J 12.4, 6.4 and 3.1, 15α-H), 2.29 (1H, dq, J 13.1 and
3 × 3.6, 11α-H), 2.46 (1H, td, J 2 × 11.6 and 3.6, 9α-H), 2.80
(2H, m, 6-H2), 3.76 (3H, s, 3-OMe), 4.15 (1H, s, 17β-H), 6.61
(1H, d, J 2.8, 4-H), 6.71 (1H, dd, J 2.8 and 8.6, 2-H) and 7.24
(1H, d, J 8.6, 1-H).
(161R)-161-Hydroxy-3-methoxy-161-methyl-14,16ꢀ-propano-
14ꢀ-estra-1,3,5(10)-trien-17-one 47
(a) The 14α,17α-ethano compound 45 (100 mg, 0.25 mmol) was
suspended in methanolic 1 M potassium hydroxide (2.5 cm3,
2.5 mmol) and the mixture was stirred at 0 ЊC. After 1.5 h the
reaction was complete (TLC), and saturated aq. ammonium
chloride was added. The mixture was extracted with ethyl
acetate, and the combined organic phase was washed (brine,
water), dried (MgSO4), and evaporated under reduced pressure.
The residue (100 mg) was filtered through silica gel (10 g), using
toluene as eluent, to give the title compound 47 (99 mg, 99%), mp
195–197 ЊC (from Me2CO–MeOH); [α]D Ϫ78 (c 1.1) (Found: C,
77.8; H, 8.6%. Mϩ, 354. C23H30O3 requires C, 77.9; H, 8.5%;
M, 354); νmax/cmϪ1 3597 (OH) and 1726 (CO); δH (400 MHz)
1.08 (3H, s, 13β-Me), 1.26 (1H, dddd, J 13.6, 5.8, 3.1 and 2.0,
163-Hn), 1.33 (3H, s, 161-Me), 1.33 (1H, ddd, J 15.0, 13.6
and 5.8, 162-Hn), 1.58 (1H, qt, J 15.0, 5.9 and 2 × 2.0, 162-Hx),
2.04 (1H, ddd, J 12.2, 5.6 and 3.1, 15α-H), 2.18 (1H, d, J 12.2,
15β-H), 2.24 (1H, td, J 2 × 13.6 and 5.9, 163-Hx), 2.41 (1H, dd,
J 5.6 and 2.2, 16α-H), 2.62 (1H, td, J 2 × 11.9 and 3.6, 9α-H),
3.20–3.51 (2H, m, 6-H2), 3.78 (3H, s, 3-OMe), 6.64 (1H, d, J 2.8,
4-H), 6.73 (1H, dd, J 8.5 and 2.8, 2-H) and 7.22 (1H, d, J 8.5,
1-H); δC (50 MHz) 15.2 (q, C-18), 23.6 (t, C-7), 26.2 (t, C-11),
27.5 (t, C-15), 28.2 (q, 161-Me), 29.3 (t, C-163), 30.7 (t, C-6),
31.7 (t, C-12), 34.1 (t, C-162), 37.3 (d, C-9), 42.6 (d, C-8),
45.3 and 49.2 (each s, C-13 and -14), 55.2 (q, 3-OMe), 57.2
(d, C-16), 71.0 (s, C-161), 111.7 (d, C-2), 113.5 (d, C-4), 126.6
(d, C-1), 131.4 (s, C-10), 137.9 (s, C-5), 157.6 (s, C-3) and 221.3
(s, C-17).
(b) The 14β-3Ј-oxobutyl 17-ketone 46 (100 mg, 0.28 mmol)
was suspended in methanolic 1 M potassium hydroxide (10 cm3,
10 mmol) and the mixture was stirred at 24 ЊC. After 2.25 h the
reaction was complete (TLC), and work-up and chromato-
graphy as described in the foregoing experiment gave 47 (85 mg,
85%).
(161R)-3-Methoxy-161-methyl-14,16ꢀ-propano-14ꢀ-estra-
1,3,5(10)-triene-161,17ꢀ-diol 48
(a) The 161-hydroxy 17-ketone 47 (100 mg, 0.28 mmol) was
treated with LAH (20 mg, 0.5 mmol) in THF (3 cm3) at 21 ЊC
for 20 min. The product was isolated by extraction with chloro-
form and chromatographed on silica gel (10 g), using ethyl
acetate–toluene (1:1) as eluent, to give the 161,17β-diol 48 (93
mg, 92%), mp 226–227 ЊC (from Me2CO) (Found: C, 77.6; H,
8.9%; Mϩ, 356. C23H32O3 requires C, 77.5; H, 9.1%; M, 356);
νmax/cmϪ1 3400br (OH); δH (400 MHz) 0.97 (3H, s, 13β-Me),
1.12 (1H, tdd, J 13.3, 3.6 × 2 and 2.8, 162-Hx), 1.24 (1H, td,
J 11.4 × 2 and 2.4, 8β-H), 1.42 (3H, s, 161-Me), 1.60 (1H, ddd,
J 7.3, 6.8 and 2.8, 16α-H), 1.98 (1H, d, J 12.7, 15β-H), 2.07 (1H,
4486
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487

View Article Online
Isomerisation of (161S)-161-hydroxy 17-ketone 49
Acknowledgements
Treatment of compound 49 (10 mg, 0.03 mmol) with
methanolic 0.5 M potassium hydroxide (4 cm3) at 20 ЊC for
5 h, followed by acidification and isolation by extraction with
ethyl acetate, gave the pure (161R)-161-hydroxy 17-ketone 47
(10 mg).
We thank the National Research Foundation, the University of
Cape Town and Schering AG for financial and material
support.
References
Reduction of the 161-hydroxy 17-ketone 49
1 J. R. Bull and R. I. Thomson, J. Chem. Soc., Perkin Trans. 1, 1990,
241.
2 J. R. Bull and L. M. Steer, Tetrahedron, 1991, 47, 7377.
3 J. R. Bull, P. G. Mountford, G. Kirsch, G. Neef, A. Muller-Fahrnow
and R. Wiechert, Tetrahedron, 1994, 50, 6363.
4 J. R. Bull, C. Hoadley, P. G. Mountford and L. M. Steer, J. Chem.
Soc., Perkin Trans. 1, 1997, 1179.
5 J. R. Bull and P. G. Mountford, J. Chem. Soc., Perkin Trans. 1, 1999,
1581.
6 A. M. Brzozowski, A. C. W. Pike, Z. Dauter, R. E. Hubbard,
T. Bonn, O. Engstrom, L. Ohman, G. L. Greene, J.-A. Gustaffson
and M. Carlquist, Nature, 1997, 389, 753.
7 J.-M. Wurtz, U. Egner, N. Heinrich, D. Moras and A. Muller-
Fahrnow, J. Med. Chem., 1998, 41, 1803.
8 J. R. Bull, J. Floor and M. A. Sefton, J. Chem. Soc., Perkin Trans. 1,
1987, 37.
(a) A solution of the 161-hydroxy 17-ketone 49 (100 mg, 0.28
mmol) in THF (5 cm3) and tert-butyl alcohol (0.1 cm3) was
treated with 0.1 M samarium() iodide (6 cm3, 0.6 mmol) at
reflux for 1 h. The product was isolated as described in the
previous experiment, and chromatographed on silica gel (10 g),
using ethyl acetate–toluene (3:2) as eluent, to give diols 50 (15
mg, 15%) and 51 (66 mg, 65%).
(b) Treatment of the 161-hydroxy 17-ketone 49 (30 mg, 0.08
mmol) with LAH (10 mg, 26 mmol) in THF (3 cm3) at 21 ЊC for
20 min, followed by standard work-up and chromatography of
the product on silica gel (5 g), using ethyl acetate–toluene (1:1)
as eluent, gave diol 50 (23 mg, 79%).
9 J. R. Bull, J. L. M. Dillen and M. A. Sefton, Tetrahedron, 1990, 46,
8143.
Oxidation of the diols 50 and 51
10 A. J. Birch and J. S. Hill, J. Chem. Soc. C, 1966, 419; 1967, 125;
M. L. Elliot and F. J. Urban, J. Org. Chem., 1985, 50, 1752.
11 G. S. R. Subba Rao, L. Uma Devi and U. J. Sheriff, J. Chem. Soc.,
Perkin Trans. 1, 1991, 964; G. Mehta, K. S. Rao, M. M. Bhadbhade
and K. Venkatesan, J. Chem. Soc., Chem. Commun., 1981, 755;
G. S. R. Subba Rao, D. K. Banerjee, L. Uma Devi and U. Sheriff,
Aust. J. Chem., 1992, 45, 187.
12 S. R. Wilson, Org. React., 1993, 43, 93 and references cited therein.
13 J. R. Bull, C. Grundler, H. Laurent, R. Bohlmann and A. Muller-
Fahrnow, Tetrahedron, 1994, 50, 6347.
14 T. Tsuda, T. Hayashi, H. Salori, T. Kawamoto and T. Saegusa,
J. Org. Chem., 1986, 51, 537.
15 Competitive receptor-binding assays were conducted at the Institute
of Medicinal Chemistry, Schering AG, Berlin, in accordance with
standard protocols for competition with estradiol, as described
by K. Lubke, E. Schillinger and M. Topert, Angew. Chem., Int. Ed.
Engl., 1976, 15, 741.
(a) The 161,17β-diol 50 (52 mg, 0.14 mmol) as a solution in
dry dichloromethane (5 cm3) was treated with periodinane
(650 mg, 1.6 mmol) at 20 ЊC for 2 h. Diethyl ether (10 cm3)
was added and the mixture was poured into aq. sodium
hydrogen carbonate (10 cm3) containing solid sodium thio-
sulfate (1 g). The mixture was stirred for 15 min until all the
solid material had dissolved. The organic layer was separ-
ated and washed successively with aq. sodium hydrogen
carbonate (20 cm3) and water (20 cm3), dried (MgSO4),
and evaporated to dryness to give a solid residue (47 mg).
Recrystallisation (CHCl3–MeOH) gave pure compound 49
(42 mg, 79%).
(b) Similar treatment of the 161,17α-diol 51 (80 mg, 0.22
mmol) gave compound 49 (69 mg, 85%).
J. Chem. Soc., Perkin Trans. 1, 2000, 4476–4487
4487