Synthesis of an (±)-estrone precursor: The scope of Zr- And co-mediated cycloannulations

Article abstract of DOI:10.1002/ejoc.200900937

The synthesis of an estrone intermediate based on a new approach was studied. The construction of the basic framework was carried out in three steps from, a simple styrene derivative. The crucial reaction sequence for the steroid skeleton construction rel

Full text of DOI:10.1002/ejoc.200900937

FULL PAPER
DOI: 10.1002/ejoc.200900937
Synthesis of an (؎)-Estrone Precursor: The Scope of Zr- and Co-Mediated
Cycloannulations
Robert Betík,[a] Pavel Herrmann,[a,b] and Martin Kotora*[a,b]
Dedicated to John M. Birmingham on the occasion of his 80th birthday
Keywords: Zirconium / Cobalt / Cyclization / Carbonylation / Steroids
The synthesis of an estrone intermediate based on a new ap-
proach was studied. The construction of the basic framework
was carried out in three steps from a simple styrene deriva-
tive. The crucial reaction sequence for the steroid skeleton
construction relied on a Zr-mediated cyclization (Zr-ene reac-
tion)/propargylation followed by a Co-mediated diastereo-
Li to tetracyclic ketone 11a aiming at the installation of the
angular methyl group in the 13-position gave rise exclusively
to product 12 with unnatural trans-anti-cis stereochemistry
The successful synthesis of known estrone intermediate 4
with natural trans-anti-trans stereochemistry was ac-
complished by chemoselective reduction of the carbonyl
group of ketone 11b. Attempts to use other metallo-ene reac-
tions to affect the synthesis of steroid B-ring are also de-
scribed.
selective Pauson–Khand reaction that afforded various
D-
ring-substituted tetracyclic ketones 11 with natural trans-anti
stereochemistry. The conjugated addition reaction of Me2Cu-
Co-catalyzed intermolecular co-cyclotrimerization of a
diyne with an alkyne,[13] Rh-catalyzed intramolecular C–H
activation in diazoketo esters,[14] Tl-mediated fragmentation
of an androstane precursor,[15] Pd-catalyzed inter- and in-
tramolecular double Heck reaction of a halovinylaryl ha-
lide,[16] Cu-catalyzed intermolecular allylic substitution,[17]
and Ru-catalyzed diene metathesis.[18] Despite these
achievements there has been an ever-continuing interest in
the development of new synthetic strategies as well as appli-
cation of various synthetic methods for estrone preparation.
In our last report,[19] we demonstrated that a consecutive
sequence of several zirconium-mediated reactions (oxidative
addition/allylation and two cyclization/allylation sequences)
followed by ring-closing metathesis could be used for the
synthesis of estratetraene 4, an intermediate in the synthesis
of estrone,[20] from simple starting styrene 1 (Scheme 1). Es-
pecially, the first cyclization/allylation sequence of suitably
substituted allylene 2 with a stoichiometric amount of di-
butyl zirconocene (also known as the Negishi reagent) pro-
ceeded with high trans selectivity (Ͼ98%), giving alkylzirco-
nium compound 2a, which was easily alkylated with a
number of allyl or acyl halides to give bicyclic compounds
3 (Scheme 1).[19b] Out of these compounds only fluorodiene
3a, so far, was utilized in further transformations to estrate-
traene 4, the direct precursor of estrone (in total, seven
steps from a commercially available starting material).
Since the above-mentioned procedures represented com-
paratively easy synthetic operations, we wanted to explore
whether also other alkylation products, such as bromodiene
3b, could be used for the alternative preparation of estrone
Introduction
The discovery of estrone (oestrone) almost 80 years ago
was a milestone in the chemistry of steroids.[1] Soon there-
after, an era of its total syntheses started and it continues
to span to the present day. The first synthesis of estrone was
based on the hydrogenation of equilenine,[2] also a natural
hormone, and was soon followed by a total synthesis.[3]
Starting with pioneering synthetic work in the 1940s,[4]
a
number of other syntheses based on condensation reac-
tions,[5] the Diels–Alder reaction,[6] cleavage of the cyclobu-
tane ring,[7] a radical cascade reaction,[8] Friedel–Crafts al-
kylation,[9] and photochemically induced cycloaddition,[10]
to name a few, appeared. Some of the early syntheses still
serve even today as an inspiration for more sophisticated
approaches, Torgov’s intermediate being a typical exam-
ple.[11] However, since the advent of organometallic chemis-
try the scope of possible synthetic strategies has greatly ex-
panded. One of such early examples was the utilization of
the Cu-catalyzed conjugate addition of Grignard rea-
gents.[12] Soon it was followed by other transition-metal-
mediated or -catalyzed reactions. Typical examples include
[a] Department of Organic and Nuclear Chemistry, Faculty of Sci-
ence, Charles University in Prague,
Hlavova 8, 12843 Praha 2, Czech Republic
Fax: +420-221-951-326
E-mail: kotora@natur.cuni.cz
[b] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic,
Flemingovo n. 2, 16610 Praha 6, Czech Republic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900937.
646
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Synthesis of an (Ϯ)-Estrone Precursor
Scheme 1. Synthesis of estratetraene 4 from styrene 1.
derivatives that would enable greater synthetic flexibility. In with nBuLi followed by the addition of MeI, strong depen-
this regard, it was conceived that its dehydrobromination dence of the course of the reaction on the conditions used
could yield enyne 5a, a potential candidate for Pauson– was observed. Except for desired enyne 5b, variable
Khand reaction, a procedure by which the steroid C and D amounts of compound 6 were also found. When the solu-
rings could be easily assembled in one step. Moreover, the tion of lithiated enyne 5a-Li (the metalation was done with
presence of the carbonyl group and the conjugated double 1.1 equiv. of nBuLi to ensure quantitative metalation of the
bond would ensure their further transformation into es- terminal triple bond) was warmed to 20 °C, the formation
trone or its derivatives.
of 6 in 79% yield along with 5b in 20% yield was observed
after the addition of MeI. The formation of the five-mem-
bered ring can be explained by lithiation of the propargylic
position, followed by intramolecular carbolithiation of the
Results and Discussion
In the first step, dehydrohalogenation of 3b was at- double bond. The lithiation of the propargylic position of
tempted. Since we observed problems accompanying dehy- terminal alkynes is known to proceed in the presence of
drohalogenation of 3b and its chloride derivative in the an excess amount of alkyllithiums.[22] Also, intramolecular
presence of strong bases,[19b] the elimination was carried out cyclization of unsaturated organolithium compounds is not
under mild conditions by using tetra-n-butylammonium surprising and was observed previously.[23] However, the
fluoride (TBAF) in DMF[21] to avoid any potential undesir- catalytic nature of the observed cyclization is rather unique
able side reactions. The reaction proceeded smoothly and and could be rationalized in the following terms
uneventfully, yielding enyne 5a in high 94% isolated yield (Scheme 3): After initial lithiation of terminal alkyne 5a to
(Scheme 2). Having 5a in hand, further functionalization of 5a-Li, the unreacted nBuLi lithiated the propargylic posi-
the terminal alkynyl group was done to extend the series of tion, giving 7; then ensued intramolecular carbolithiation,
compounds for the Pauson–Khand reaction to assess its yielding cycloalkyllithium 8. Since iso-organolithiums are
scope with respect to the substitution pattern.
strong bases,[24] the newly formed cycloalkyllithium 8 acted
Further functionalization of enyne 5a into 5b–f was car- as a strong base and intermolecularly lithiated the propar-
ried out by using several commonly used procedures gylic position in 5a-Li through Li–H exchange to form 9,
(Scheme 2). When the standard procedure for methylation which after addition of MeI afforded 6 (its configuration
of the terminal triple bond was applied, that is, lithiation was determined by analogy with related compounds[19]). To
Scheme 2. Dehydrobromination of bromodiene 3b to enyne 5a and its conversion into enynes 5b–f, followed by cyclocarbonylation to 11.
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avoid the above-mentioned cyclization, a modified ap-
proach was used. It relied on the lithiation of 5a below 0 °C,
followed by the addition of MeI, yielding enyne 5b in 91%
isolated yield (it is important to emphasize that both reac-
tants should be meticulously dried prior to the reaction).
Scheme 4. Preparation of bromoallene 10 and one-pot synthesis of
5b.
moiety.[31] Interestingly, despite its synthetic scope it has
found just one application in the synthesis of steroids:[32]
cyclocarbonylation of steroidal enynes having different spa-
tial arrangement of the double and triple bonds in compari-
son with 5b.[33] The Pauson–Khand reaction of prepared
enynes 5 was studied under various reaction conditions
(Table 1). The best results were obtained with the classical
procedure (method A), relying on the use of a stoichiomet-
Scheme 3. Organolithium-catalyzed cyclization of 5a-Li and forma-
tion of 6.
The same method was also applied for the preparation ric amount of Co2(CO)8, followed by decomplexation of the
of trimethylsilyl derivative 5c. Lithiation of 5a followed by formed complex with DMSO instead of N-methylmorph-
the addition of trimethylsilyl chloride produced, after isola- oline N-oxide (NMO).[33] Under these conditions, the corre-
tion, 5c in 86% yield. The attachment of various aryl sponding estratetraenes 11a, 11b, 11d–f were isolated in
groups was done through Sonogashira coupling under stan- high yields (84–95%; Table 1, Entries 1, 2, 4–6). Only in the
dard conditions;[25] the corresponding aryl enynes 5d–f were case of enyne 5c did cyclocarbonylation afford the corre-
obtained in good isolated yields (68–80%; Scheme 2).
sponding product 11c in mediocre 41% isolated yield. An
Obviously, construction of enyne 5b in a one-step (or attempt to carry out the cyclocarbonylation of enyne 5a by
one-pot) procedure from advanced intermediate 2 would using Mo(CO)6 (method B)[34] was not met with success, as
constitute a synthetic shortcut in terms of yield and effi- not even a trace amount of the expected product was de-
ciency in comparison with the above-mentioned three-step tected. To exploit the catalytic cyclocarbonylation reaction
procedure. In this regard, the SN2Ј alkylation of bromo- by avoiding the use of gaseous CO,[35] the carbonylation of
allene with an organotitanium compound in the presence of enyne 5e with 2-naphthaldehyde in the presence of
a catalytic amount of CuCl provided us a necessary hint.[26] Rh(BF4)(cod)2/dppp[36] [method C; cod = cis,cis-1,5-cyclo-
Thus, it was envisioned that the reaction of intermediate 2a octadiene, dppp = 1,3-bis(diphenylphosphanyl)propane]
with 3-bromo-1,2-butadiene (10) could yield desired enyne was attempted. Disappointingly, the reaction did not pro-
5b in a one-pot procedure. Since the only procedure for its ceed and the starting material was recovered. Similar results
preparation was based on the use of organomercury com- were obtained also with 4-trifluoromethylbenzaldehyde
pounds,[27] we opted for a two-step sequence, avoiding ma- (method D). The last tested method was Negishi’s protocol
nipulation with hazardous organomercury compounds for cyclocarbonylation (method E),[37] which is based on the
(Scheme 4). In the first step, 1-trimethylsilylbut-2-yne was reaction of “in situ” formed zirconacyclopentenes with CO.
prepared by lithiation of 2-butyne with the subsequent ad- This method proved to be superior in the case of trimethyl-
dition of Me3SiCl in 89% yield,[28] then reaction with ele- silyl-substituted enyne 6c: the corresponding estratetraene
mental bromine afforded 3-bromo-1,2-butadiene.[29] The re- 11c was obtained in 58% isolated yield (Table 1, Entry 8).
action was carried out in chloroethane instead of dichloro- It is worth mentioning that the cyclocarbonylations af-
methane to partially circumvent problems associated with forded only products with the required natural trans-anti
the separation of the product from the solvent. Nonetheless, stereochemistry on ring junctions in all cases.
10, of suitable purity for further synthetic use, was obtained
Conjugated enone 11a (Scheme 5) seemed to be an ideal
in overall 24% isolated yield (low thermal stability of the intermediate for the installation of the angular methyl
product can also account for the low isolated yield). Thus, group of the estrone skeleton. The conjugate addition was
carrying out the one-pot cyclization of 2 with dibutyl zir- carried out under various conditions (Table 2). Initially it
conocene followed by the reaction with freshly prepared was attempted to carry out the catalytic conjugate addition
bromoallene 10 afforded 5b in 87% isolated yield.
with Me3Al/Ni-cat.,[38] Me3Al/Cu-cat.,[39] or Me2Zn/Cu-
Since its discovery in the early 1970s,[30] the Pauson– cat.[40] systems. In no case was any conjugate addition prod-
Khand reaction, that is, the three-component coupling of uct obtained, and the starting material remained intact. The
an alkyne, an alkene, and CO, has become an indispensable low reactivity could be probably attributed to the β,β-disub-
synthetic tool for the construction of the cyclopentenone stituted enone arrangement and steric hindrance caused by
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Synthesis of an (Ϯ)-Estrone Precursor
Table 1. Cyclocarbonylation of 5 to 11 under various conditions.
Entry Enyne 5
Method[a] Enone 12 Yield [%][b]
1
2
3
4
5
6
7
8
5a, R = H
5b, R = Me
5c, R = TMS
5d, R = Ph
5e, R = 4-MeOOCPh
5f, R = 3-C5H3N
5b, R = Me
A
A
A
A
A
A
E
11a
11b
11c
11d
11e
11f
11b
11c
95
88
41
92
84
88
31
58
Figure 1. Approach of Me– to the conjugated double bond in 11a
from the least-hindered side [the structure of 11a was calculated by
using B3LYP/6-311G(2d,p)].
5c, R = TMS
E
[a] Method A: 1. Co2(CO)8 (1.3 equiv.), toluene, 20 °C, 4 h; 2.
DMSO (5 equiv.), 80 °C, overnight. Method E: 1. Cp2ZrBu2
(1.05 equiv.), THF; 2. CO. [b] Isolated yield.
reductions.[41] The first method relied on the known combi-
nation of Et3SiH/BF3·Et2O.[42] Although the reduction pro-
ceeded reasonably well in terms of the reduction of the car-
bonyl group, the C–C double bond was reduced as well,
giving rise to an inseparable mixture of estratetraene 4, es-
tratriene 13, and other unidentified products. Varying the
molar ratios of the reactants with respect to enone 11b did
not have any dramatic effect on the ratio of obtained prod-
ucts 4 and 13 or on the chemoselectivity of the reaction. It
should be added that the use of classic reduction methods
such as the Wollf–Kishner reaction or its modifications re-
sulted in the formation of intractable reaction mixtures.[43]
Next we switched to aluminum hydride based procedures.
The aluminum hydrides of general formula AlHxCly, gener-
ated from AlCl3 and LiAlH4 depending on the molar ratios
(0.33 ≈ 4:1), are capable of reducing the carbonyl group[44]
to the methylene group, including the one in the enone sys-
tem.[45] Similarly to the above-mentioned silane-induced re-
ductions, the reaction proceeded well with high yields but
was plagued by the formation of a mixture of 4/13 in vari-
ous ratios. Gratifyingly, changing the AlCl3/LiAlH4 ratio to
4.8:1.2 with respect to 11b resulted in the selective reduction
of the carbonyl group with only minimal reduction of the
double bond (combined yield of 95%). Thus, desired estra-
tetraene 4 (Scheme 6) was obtained in 90% isolated yield
containing only Ͻ5% of estratriene 13.
the rigid tetracyclic framework. A partial success was ob-
served in the conjugate addition of MeMgBr catalyzed by
CuI (10 mol-%) in the presence of the activating Lewis acid
BF3·Et2O, where product 12 (with unnatural cis-stereo-
chemistry on the junction of the C and D rings) was ob-
tained in 5–30% yields (Table 2, Entries 1–3). Interestingly,
the reaction in the presence of a stoichiometric amount of
CuI did not lead to an improved yield (Table 2, Entry 4).
The most successful reaction was the conjugate addition of
cuprate Me2CuLi, which yielded diastereoselectively 12 in
80% yield (Table 2, Entry 5). The origin of the observed
stereoselectivity can be easily explained by attack of the
double bond at C13 from the less-hindered (bottom) side
of 11a (Figure 1). Additional unfavorable steric hindrance
preventing the attack from the top side could also be exer-
cised by the hydrogen atoms on C8 and C11.
Scheme 5. Conjugate additions to 11a.
Table 2. Conjugate additions to 11a.
Entry
Me-metal
Catalyst[a]
Additive
Solvent
Yield [%][b]
1
2
3
4
5
MeMgBr
MeMgBr
MeMgBr
MeMgBr
Me2CuLi
CuOTf
CuI
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
THF
THF
Et2O
Et2O
Et2O
≈5
≈30
≈30
≈25
80
CuI
CuI[c]
–
[a] 10 mol-% unless otherwise noted. [b] Isolated yield. [c] 100 mol-
%.
Since the conjugate addition failed to give the product
with desired natural stereochemistry, we had to look for an
alternative method. As the next candidate for the synthesis
of estrone, conjugated enone 11b was chosen. We conceived
Scheme 6. Reduction of the carbonyl group in enone 11b to estrate-
traene 4.
Although the dibutyl zirconocene mediated cyclization
that the reduction of the carbonyl group would afford estra- of 1 proved to be highly efficient and stereoselective, we
tetraene 4, which is a known intermediate of estrone.[20] The wanted to look for an alternative methodology that would
reduction of the carbonyl group to the methylene group was enable cyclization under simpler or catalytic conditions. In
attempted by using known methods based on metal hydride this regard, Oppolzer’s metallo-ene reaction of Grignard
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reagents seemed to be a method worthy to try.[46] Com- catalytic cyclization of 2 by using chiral zirconocene [(R,R)-
pound 14 was chosen as the Grignard reagent precursor, (ebthi)ZrCl2][19d] [ebthi = ethylenebis(4,5,6,7-tetrahydro-1-
and it was prepared by the previously reported method indenyl)] in the presence of a Grignard reagent did not fur-
from 1.[19] After considerable experimentation, required nish the expected organomagnesium intermediates and, in
Grignard reagent 15 (Scheme 7) was generated from 14 and addition, the diastereo- and enantioselectivity was not good
Rieke magnesium in high yield. Initially, the metallo-ene enough.[19d] Thus, we decided to use a different approach.
reaction was run at 60 °C for 24 h. After hydrolysis an in- It was shown that titanium-mediated cyclization of enynes
separable mixture of uncyclized and cyclized products was carrying a chiral acetal moiety yielded chiral cycloalkanes
obtained in 88% isolated yield. It was composed of a mix- with reasonable selectivity; we assumed that the zir-
ture of cis- and trans-17 (31%), 19 (31%), and a mixture of conocene-mediated reaction of a diene carrying a chiral
cis- and trans-18 (15 and 11%). Carrying out the reaction ether moiety could bring about asymmetric cyclization. The
at 100 °C for 24 h gave the identical substances in 70% iso- reaction of 14 with the potassium salt of (S)-(2-naphthyl)-
lated yield; however, their distribution was shifted in favor ethanol 21 gave rise to the diene-carrying chiral ether
of the cyclized products: cis- and trans-18 (45 and 21%), a moiety 22 (Scheme 9). Although the ensuing zirconocene-
mixture cis- and trans-17 (Ͻ2%), and 19 (Ͻ2%). Heating mediated cyclization afforded expected product 18 with the
of the reaction mixture to 140 °C for 24 h did not change usual trans-selectivity in 70% isolated yield, no asymmetric
the cis/trans ratio of 18.
induction was observed.
Scheme 9. Cyclization of chiral ether 22 with Cp2ZrBu2.
Scheme 7. Oppolzer’s magnesio-ene reaction of 15.
Next, a Pd-catalyzed[47] variant of Oppolzer’s metallo-
ene reaction with diethylzinc was tested. Starting acetate 20
(Scheme 8) was prepared by the reaction of 14 with potas-
sium acetate in DMSO (100 °C, 10 min) in 82% isolated
yield. The cyclization was run under two different condi-
tions, A and B. Under conditions A, only a minor amount
of the starting material was converted almost exclusively
into cis-18 (14%) (the amount of trans-18 was Ͻ1%); the
major products were uncyclized compounds 17 and 19. Un-
der conditions B, no cyclization was observed at all.
Conclusions
In summary, we have demonstrated that the sequential
application of Zr- and Co-mediated cyclizations is a suit-
able synthetic pathway to compounds with the steroidal
skeleton. The former process, Cp2ZrBu2-mediated cycliza-
tion/allylation (propargylation), selectively furnished com-
pounds with a trans-substituted steroidal B ring, and the
latter process, Co2(CO)8-mediated cyclocarbonylation, gave
rise diastereoselectively to unsaturated tetracyclic ketones
with natural trans-anti stereochemistry. It could be also sub-
stituted by the Cp2ZrBu2-mediated cyclocarbonylation re-
action (Negishi protocol). Further elaboration of the se-
lected ketones either by diastereoselective conjugate ad-
dition or by chemoselective reduction of the carbonyl group
yielded steroidal compounds with the unnatural trans-anti-
cis stereochemistry or compounds with natural trans-anti-
trans stereochemistry, respectively. In this regard, estratetra-
ene 4, the known intermediate in estrone synthesis, could
be prepared in just seven steps from commercially available
2-bromo-5-methoxybenzoic acid in 51% yield overall. Thus,
the above-described strategy provides a simple and reliable
synthesis of the steroid framework. Attempts to substitute
Scheme 8. Palladium-catalyzed metallo-ene reaction of 20.
Since the zirconocene-mediated cyclization of 2 is a con- the Zr-mediated cyclization (Zr-ene reaction) by a Mg-me-
venient method for the synthesis of bicyclic intermediates diated or Pd-catalyzed process did not meet expectations
3, we wanted to explore a possible enantioselective variant with respect to synthetic generality, clearly demonstrating
of this method. In our previous reports we showed that the the synthetic power of zirconium-based chemistry.
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Synthesis of an (Ϯ)-Estrone Precursor
CH3), 1.8–1.9 (m, 2 H, CH2), 1.91–2.00 (m, 1 H, CH), 2.08–2.16
(m, 2 H, CH2), 2.38–2.46 (m, 1 H, CH), 2.66–2.80 (m, 3 H, CHH,
CH2), 3.77 (s, 3 H, OCH3), 4.96–5.02 (m, 1 H, CH=CHH), 5.04–
5.10 (m, 1 H, CH=CHH), 5.82 (ddd, J = 17.4, 10.4, 7.6 Hz, 1 H,
CH=CH2), 5.98–6.02 (m, 1 H, Ar-H), 6.10–6.14 (m, 1 H, Ar-H),
7.08–7.12 (m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
3.49 (CH3), 16.03 (CH2), 25.67 (CH2), 27.08 (CH2), 35.38 (CH2),
40.88 (CH), 41.20 (CH), 55.11 (OCH3), 75.78 (CϵC), 79.17 (CϵC),
112.07 (CH, Ar), 113.26 (CH, Ar), 114.21 (C=C), 130.01 (CH, Ar),
130.99 (C, Ar), 137.89 (C, Ar), 142.15 (C=C), 157.39 (COMe, Ar)
Experimental Section
General Methods: All solvents unless otherwise stated were used as
obtained. THF and Et2O were distilled from LiAlH4, DCM and
Et3N from CaH2, toluene from sodium benzophenone ketyl. All
other reagents were obtained from commercial sources. 1H and 13
C
NMR spectra were recorded with a Varian UNITY 400 (1H at
400 MHz, 13C at 100.6 MHz) and Varian UNITY 300 (1H at
300 MHz, 13C at 75 MHz) spectrometers as solutions in CDCl3 or
C6D6 at 25 C sharply. Melting points (uncorrected) were deter-
mined by using a Kofler apparatus. Mass spectra were recorded
with a ZAB-SEQ (VG-Analytical) instrument. Infrared spectra
were recorded with a Bruker IFS 55 spectrometer as THF solu-
tions. Fluka 60 silica gel was used for flash chromatography. TLC
was performed on silica gel 60 F254-coated aluminum sheets
(Merck). All reactions were carried out under an argon atmosphere
with the use of flasks. Compound 3b was prepared by a previously
reported procedure.[19a,19c]
ppm. IR (KBr): ν = 2953, 2885, 1721, 1442, 1183, 1062, 1035, 988,
˜
923 cm–1. MS (EI): m/z (%) = 254.2 (35) [M+], 225 (40), 200 (50),
187.1 (100), 185.1 (55), 159.1 (25), 115 (25). HRMS (EI+): calcd.
for C18H22O 254.1671; found 254.1677. Rf (hexane/CH2Cl2, 1:1) =
0.65.
(؎)-anti-6-Methoxy-1-(4-trimethylsilylbut-3-ynyl)-2-vinyl-1,2,3,4-
tetrahydronaphthalene (5c): nBuLi (1.65 mmol, 1.03 mL, 1.6  in
hexanes) was added to a stirred solution of 5a (1.5 mmol, 359 mg)
in Et2O (10 mL) at –78 °C. After 1 h, TMSCl (3 mmol, 327 mg)
was added, and the reaction mixture was warmed gradually to
20 °C and kept for 3 h at this temperature. Then, the volatiles were
removed under reduced pressure, and column chromatography of
the residue on silica gel (hexane/CH2Cl2, 1:1) yielded the title com-
pound as a colorless viscous liquid (401 mg, 86 %). 1H NMR
(400 MHz, CDCl3): δ = 0.14 [s, 9 H, -Si(CH3)3], 1.60–1.70 (m, 1
H, CHH), 1.84–2.00 (m, 3 H, CH2, CH), 2.18–2.26 (m, 2 H, CH2),
2.4–2.5 (m, 1 H, CH), 2.68–2.82 (m, 3 H, CHH, CH2), 3.76 (s,
3 H, OCH3), 4.96–5.01 (m, 1 H, CH=CHH), 5.03–5.10 (m, 1 H,
CH=CHH), 5.81 (ddd, J = 17.4, 10.2, 7.6 Hz, 1 H, CH=CH2),
6.57–6.6 (m, 1 H. Ar-H), 6.68–6.74 (m, 1 H, Ar-H), 7.06–7.10
(m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 0.14
[Si(CH3)3], 17.35 (CH2), 25.55 (CH2), 27.02 (CH2), 35.09 (CH2),
40.92 (CH), 40.96 (CH), 55.12 (OCH3), 84.84 (CϵC), 107.51
(CϵC), 112.12 (CH, Ar), 113.30 (CH, Ar), 114.27 (C=C), 130.021
(CH, Ar), 130.92 (C, Ar), 137.91 (C, Ar), 142.02 (C=C), 157.43 (C,
(؎)-anti-1-But-3-ynyl-6-methoxy-2-vinyl-1,2,3,4-tetrahydronaph-
thalene (5a): Tetrabutylammonium fluoride (15.5 mmol, 4.9 g) was
added to a solution of 3b[19c] (3.1 mmol, 1 g) in DMF (20 mL), and
the reaction mixture was stirred at 60 °C for 2 h. Then, DMF was
removed under reduced pressure and water (150 mL) was added.
The reaction mixture was extracted with CH2Cl2 (3ϫ15 mL), and
the combined organic fractions were dried with anhydrous MgSO4.
Volatiles were removed under reduced pressure, and column
chromatography of the residue on silica gel (hexane/CH2Cl2, 1:1)
yielded the title compound as a colorless viscous liquid (0.7 g,
1
94%). H and 13C NMR spectra were in agreement with the pre-
viously reported data.[19c]
(؎)-anti-6-Methoxy-1-pent-3-ynyl-2-vinyl-1,2,3,4-tetrahydronaphthal-
ene (5b)
Alkylation of 5a with MeI: nBuLi (1.13 mmol, 0.7 mL, 1.6  in hex-
anes) was added to a stirred solution of 5a (1 mmol, 240 mg) in
THF (5 mL) at –78 °C. The reaction mixture was warmed grad-
ually to –30 °C and stirred for 1 h at this temperature; then it was
cooled again to –78 °C followed by the addition of MeI (dried with
anhydrous MgSO4 prior to use; 1.5 mmol, 213 mg). The mixture
was warmed to 20 °C and stirred for 5 h. Then, water (100 mL)
and HCl (10%, 5 mL) were added, the mixture was extracted with
CH2Cl2 (3 ϫ 15 mL), and the combined organic fractions were
dried with anhydrous MgSO4. Volatiles were removed under re-
duced pressure, the residue was dissolved in toluene (5 mL), and
the solvent was evaporated under reduced pressure (repeated 2ϫ)
to remove residual MeI. Column chromatography of the residue on
silica gel (hexane/CH2Cl2, 1:1) yielded of title compound as a color-
less viscous liquid (230 mg, 91%).
Ar) ppm. IR (KBr): ν = 2954, 2886, 1720, 1439, 1275, 1180, 1061,
˜
1035, 988, 857 cm–1. MS (EI): m/z (%) =312 (50) [M+], 297 (30),
200 (65), 187 (100), 73 (55). HRMS (EI+): calcd. for C20H28OSi
312.1909; found 312.1917. Rf (hexane/CH2Cl2, 1:1) = 0.7.
General Method for the Sonogashira Coupling of 5a with Aryl Ha-
lides: To a stirred solution of 5a (1 mmol, 239 mg), Pd(PPh3)4
(0.01 mmol, 11 mg), and CuI (0.02 mmol, 5 mg) in a mixture of
THF (6 mL) and Et3N (2 mL) was added the corresponding substi-
tuted phenyl iodide (1.1 mmol). The reaction was stirred for 10 h
and then filtered through a short pad of Celite, and the volatiles
were removed under reduced pressure. Column chromatography of
the residue on silica gel furnished the desired products.
Alkylation of 2 with 3-Bromobuta-1,2-diene (10): nBuLi (3.4 mmol,
2.13 mL, 1.6  in hexanes) was added to a stirred solution of
Cp2ZrCl2 (1.7 mmol, 498 mg) in THF (15 mL) at –78 °C. After 1 h,
(؎)-anti-6-Methoxy-1-(4-phenylbut-3-ynyl)-2-vinyl-1,2,3,4-tetra-
hydronaphthalene (5d): Iodobenzene (1.1 mmol, 224 mg) was used.
Column chromatography of the residue on silica gel (hexane/
methoxydiene 2 (1.63 mmol, 377 mg) in THF (1 mL) was added, CH2Cl2, 1:1) yielded the title compound as a colorless viscous li-
and the reaction mixture was warmed gradually to 20 °C over 2 h.
Then, 3-bromobuta-1,2-diene (2.44 mmol, 325 mg) and CuCl
(0.16 mmol, 16 mg) were added, and the reaction mixture was
stirred for 2 h. Solvents were removed under reduced pressure, and
the residue was dissolved in CH2Cl2 (5 mL) and hexane (20 mL)
and filtered through Celite. Volatiles were removed under reduced
pressure, and column chromatography of the residue on silica gel
(hexane/CH2Cl2, 1:1) furnished the title compound as a colorless
viscous liquid (358 mg, 87%). 1H NMR (400 MHz, CDCl3): δ =
1.61–1.7 (p, J = 6 Hz, 1 H, CHH), 1.79 (t, J = 2.4 Hz, 3 H, CϵC-
quid (249 mg, 79%). 1H NMR (400 MHz, CDCl3): δ = 1.62–1.7
(m, 1 H, CHH), 1.94–2.04 (m, 3 H, CH2, CH), 2.38–2.52 (m, 3 H,
CH2, CH), 2.70–2.78 (m, 2 H, CH2), 2.82–2.90 (m, 1 H, CHH),
3.77 (s, 3 H, OCH3), 4.98–5.02 (m, 1 H, CH=CHH), 5.06–5.14 (m,
1 H, CH=CHH), 5.83 (ddd, J = 17.6, 10.4, 7.4 Hz, 1 H, CH=CH2),
6.58–6.62 (m, 1 H, Ar-H), 6.70–6.75 (m, 1 H, Ar-H), 7.10–7.16 (m,
1 H, Ar-H), 7.23–7.29 (m, 3 H, 3 ϫ Ar-H), 7.36–7.40 (m, 2 H,
2ϫAr-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.80 (CH2),
25.72 (CH2), 27.13 (CH2), 35.03 (CH2), 40.99 (CH), 41.22 (CH),
55.14 (OCH3), 80.99 (CϵC), 90.23 (CϵC), 112.15 (CH, Ar), 113.35
Eur. J. Org. Chem. 2010, 646–655
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
651

R. Betík, P. Herrmann, M. Kotora
FULL PAPER
(CH, Ar), 114.36 (C=C), 123.99 (C, Ar), 127.51 (CH, Ar), 128.18
(2ϫCH, Ar), 130.04 (CH, Ar), 130.88 (C, Ar), 131.53 (2ϫCH,
Ar), 137.98 (C, Ar), 142.09 (C=C), 157.45 (COMe, Ar) ppm. IR
fied by distillation under reduced pressure to yield the product as
a colorless liquid (0.5 g, 24%). H NMR (300 MHz, CDCl3): δ =
1
2.26 (t, J = 3.3 Hz, 3 H, CH3), 4.79 (q, J = 3.3 Hz, 2 H, C=CH2)
(KBr): ν = 2955, 2886, 1720, 1442, 1342, 1183, 1060, 1036, 987, ppm. 13C NMR (75 MHz, CDCl3): δ = 37.94 (CH3), 80.54 (=CH2),
˜
923, 857 cm–1. MS (EI): m/z =316 (85) [M+], 262 (40), 187 (100),
171 (20), 158 (25), 146 (30), 128 (25), 115 (65), 83 (45). HRMS
(EI+): calcd. for C20H28OSi 316.1827; found 316.1832. Rf (hexane/
CH2Cl2, 1:1) = 0.6.
87.42 (=CBrMe), 204.53 (=C=) ppm.
General Method for the Pauson–Khand Reaction: To a solution of
enyne 5a–f (1 mmol) in toluene (5 mL) was added Co2(CO)8
(1.3 mmol, 445 mg), and the reaction mixture was stirred at 20 °C
for 4 h. Then, DMSO (5 mmol, 354 µL, 390 mg) was added, and
the reaction mixture was stirred at 80 °C for 5 h. It was quenched
with HCl (1%, 100 mL) and extracted with CH2Cl2 (3ϫ15 mL);
the combined organic fractions were dried with anhydrous MgSO4,
and the volatiles were removed under reduced pressure. Column
chromatography of the residue on silica gel yielded the desired
products.
(؎)-anti-6-Methoxy-1-[4-(4-methoxycarbonylphenyl)but-3-ynyl]-2-
vinyl-1,2,3,4-tetrahydronaphthalene (5e): Methyl 4-iodobenzoate
(1.1 mmol, 288 mg) was used. Column chromatography on silica
gel (CH2Cl2) yielded the title compound as a colorless viscous li-
1
quid (298 mg, 80%). H NMR (400 MHz, CDCl3): δ = 1.61–1.72
(m, 1 H, CHH), 1.96–2.08 (m, 3 H, CH, CH2), 2.34–2.54 (m, 3 H,
CH, CH2), 2.70–2.78 (m, 2 H, CH2), 2.82–2.88 (m, 1 H, CHH),
3.77 (s, 3 H, OCH3), 3.91 (s, 3 H, COOCH3), 4.98–5.04 (m, 1 H,
CH=CHH), 5.06–5.14 (m, 1 H, CH=CHH), 5.83 (ddd, J = 17.5,
10, 7.3 Hz, 1 H, CH=CH2), 6.58–6.62 (m, 1 H, Ar-H), 6.70–6.76
(m, 1 H, Ar-H), 7.10–7.16 (m, 1 H, Ar-H), 7.40–7.46 (m, 2 H,
2 ϫ Ar-H), 7.92–7.98 (m, 2 H, 2 ϫ Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.80 (CH2), 25.85 (CH2), 27.21 (CH2),
34.68 (CH2), 41.01 (CH), 41.31 (CH), 52.12 (COOCH3), 55.13
(OCH3), 80.50 (CϵC), 93.76 (CϵC), 112.17 (CH, Ar), 113.38 (CH,
Ar), 114.41 (C=C), 128.80 (C, Ar), 128.86 (C, Ar), 129.38 (2ϫCH,
Ar), 129.92 (CH, Ar), 130.64 (C, Ar), 131.44 (2ϫCH, Ar), 138.03
(C, Ar), 142.03 (C=C), 157.49 (COMe, Ar), 166.63 (COOMe) ppm.
(؎)-3-Methoxy-16-ketoestra-1,3,5(10),13(17)-tetraene (11a): Enyne
5a (1 mmol, 239 mg) was used. Column chromatography of the res-
idue on silica gel (CH2Cl2/MeOH, 50:1) followed by recrystalli-
zation (MeOH) yielded the title compound as a colorless solid
1
(254 mg, 95%). M.p. 114–115 °C. H NMR (400 MHz, CDCl3): δ
= 1.18–1.30 (m, 1 H, CH), 1.36–1.48 (m, 1 H, CHH), 1.52–1.66
(m, 1 H, CHH), 1.96–2.04 (m, 1 H, CHH), 2.12–2.22 (m, 1 H,
CHH), 2.44–2.74 (m, 5 H, 2ϫCH, CH2, CHH), 2.82–2.90 (m, 2
H, CH2), 2.98–3.04 (m, 1 H, CHH), 3.78 (s, 3 H, OCH3), 5.89 (s,
1 H, C=CH), 6.61–6.65 (m, 1 H, Ar-H), 6.71–6.77 (m, 1 H, Ar-H),
7.19–7.25 (m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
28.47 (CH2), 30.11 (CH2), 30.63 (CH2), 31.58 (CH2), 40.65 (CH2),
41.75 (CH), 47.16 (CH), 48.06 (CH), 55.19 (OCH3), 112.04 (CH,
Ar), 113.72 (CH, Ar), 126.91 (CH, Ar), 127.04 (C=C), 130.50 (C,
Ar), 137.86 (C, Ar), 157.72 (C, Ar), 183.15 (C=C), 208.81 (C=O)
IR (KBr): ν = 2956, 2887, 2170, 1757, 1720, 1441, 1247, 1182, 1061,
˜
1035, 987, 923, 844 cm–1. MS (EI): m/z (%)= 374.2 (100) [M+], 345
(40), 320 (85), 261 (50), 187 (100), 158 (50), 146 (30), 128 (20), 115
(25), 91 (15). HRMS (EI+): calcd. for C25H26O3 374.1882; found
374.1878. Rf (hexane/CH2Cl2, 1:1) = 0.65.
ppm. IR (KBr): ν = 3014, 2952, 2933, 2865, 2854, 2836, 1699, 1674,
˜
1616, 1498, 1449, 1434, 1278, 1256, 1198, 1145, 1045, 1027, 863,
845 cm–1. MS (EI): m/z (%) = 268 (100) [M+], 239 (10), 211 (10),
173 (35), 159 (15), 147 (30), 115 (20), 91 (15). HRMS (EI+): calcd.
for C18H20O2 268.1463; found 268.1459. Rf (CH2Cl2/MeOH, 50:1)
= 0.3.
(؎)-anti-6-Methoxy-1-[4-(3-pyridyl)but-3-ynyl]-2-vinyl-1,2,3,4-tetra-
hydronaphthalene (5f): 3-Iodopyridine (1.1 mmol, 225 mg) was
used. Column chromatography on silica gel (CH2Cl2/Et2O, 20:1)
yielded the title compound as a colorless viscous liquid (215 mg,
1
68%). H NMR (400 MHz, C6D6): δ = 1.40–1.52 (m, 1 H, CHH),
1.70–1.80 (m, 1 H, CH), 1.85–1.93 (m, 2 H, CH2), 2.21–2.32 (m, 3
H, CH, CH2), 2.46–2.64 (m, 2 H, CH2), 2.72–2.79 (m, 1 H, CHH),
3.38 (s, 3 H, OCH3), 4.92–4.98 (m, 1 H, CH=CHH), 5.00–5.06 (m,
1 H, CH=CHH), 5.72 (ddd, J = 17.5, 10.3, 7.5 Hz, 1 H, CH=CH2),
6.52–6.58 (m, 1 H, pyr-H), 6.60–6.62 (m, 1 H, Ar-H), 6.70–6.75
(m, 1 H, Ar-H), 7.00–7.04 (m, 1 H, Ar-H), 7.35–7.40 (m, 1 H, pyr-
H), 8.32–8.38 (m, 1 H, pyr-H), 8.95 (br. s, 1 H, pyr-H) ppm. 13C
NMR (100 MHz, C6D6): δ = 17.84 (CH2), 27.19 (CH2), 28.42
(CH2), 35.90 (CH2), 42.32 (CH), 42.71 (CH), 55.66 (OCH3), 79.5
(CϵC), 94.97 (CϵC), 113.63 (CH, Ar), 114.89 (CH, Ar), 115.37
(C=C), 123.81 (CH, pyr), 122.21 (C, pyr), 131.12 (CH, Ar), 131.56
(C, Ar), 138.89 (C, Ar), 139.02 (CH, pyr), 143.27 (C=C), 149.41
(؎)-3-Methoxy-17-methyl-16-ketoestra-1,3,5(10),13(17)-tetraene
(11b): Enyne 5b (1 mmol, 253 mg) was used. Column chromatog-
raphy of the residue on silica gel (CH2Cl2/MeOH, 100:1) followed
by recrystallization (MeOH) yielded the title compound as a color-
less solid (247 mg, 88 %). M.p. Ͼ220 °C (decomp.). 1H NMR
(400 MHz, CDCl3): δ = 1.10–1.20 (m, 1 H, CH), 1.30–1.42 (m, 1
H, CHH), 1.50–1.64 (m, 1 H, CHH), 1.72 (s, 3 H, CH3), 1.96–2.04
(m, 1 H, CHH), 2.08–2.18 (m, 1 H, CHH), 2.32–2.44 (m, 1 H, CH),
2.44–2.52 (m, 1 H, CHH), 2.58–2.74 (m, 3 H, CH, 2ϫCHH), 2.82–
2.88 (m, 2 H, CH2), 2.98–3.08 (m, 1 H, CHH), 3.78 (s, 3 H, OCH3),
6.62–6.64 (m, 1 H, Ar-H), 6.72–6.76 (m, 1 H, Ar-H), 7.21–2.25 (m,
1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 7.68 (CH3),
28.25 (CH2), 28.52 (CH2), 30.13 (CH2), 31.22 (CH2), 39.48 (CH2),
42.10 (CH), 45.67 (CH), 47.92 (CH), 55.19 (OCH3), 111.99 (CH,
Ar), 113.70 (CH, Ar), 126.88 (CH, Ar), 130.79 (C, Ar), 133.15
(C=C), 137.98 (C, Ar), 157.67 (C, Ar), 174.17 (C=C), 208.87 (C=O)
(CH, pyr), 153.85 (CH, pyr), 159.25 (C, Ar) ppm. IR (KBr): ν =
˜
3352, 2951, 2886, 2224, 1769, 1721, 1607, 1440, 1343, 1183, 1061,
1035, 989, 924, 858, 706 cm–1. MS (EI): m/z (%) = 317.1 (100) [M+],
263.1 (45), 187.1 (90), 158 (30), 146 (40), 128 (25), 115 (45), 103
(25), 91 (30), 77 (25). HRMS (EI+): calcd. for C22H23NO 317.1780;
found 317.1783. Rf (CH2Cl2/Et2O, 20:1) = 0.25.
ppm. IR (KBr): ν = 3013, 2936, 2858, 1690, 1694, 1607, 1498, 1447,
˜
1264, 1148, 1042, 866, 819, 789 cm–1. MS (EI): m/z (%) = 282.2
(100) [M+], 253.1 (25), 219 (20), 173.1 (75), 159.1 (35), 147.1 (90),
115.1 (25). C19H22O2 (282.38): calcd. C 80.82, H 7.85; found 81.05,
H 8.13. HRMS (EI+): calcd. for C19H22O2 282.1620; found
282.1617. Rf (CH2Cl2/MeOH, 50:1) = 0.4.
3-Bromobuta-1,2-diene (10): A solution of Br2 (15.5 mmol, 2.5 g) in
chloroethane (10 mL) was added dropwise to a stirred solution of
1-trimethylsilylbut-2-yne (16.2 mmol, 2 g)[2] in chloroethane
(30 mL) at –78 °C. The reaction mixture was stirred for 1 h at
–78 °C. Then, silica gel (2 g) was added at –78 °C, and the suspen-
sion was filtered through silica gel (5 g). Chloroethane was allowed
(؎)-3-Methoxy-17-trimethylsilyl-16-ketoestra-1,3,5(10),13(17)-
tetraene (11c): Enyne 5c (1 mmol, 312 mg) was used. Column
to evaporate at room temperature, and the residue was further puri- chromatography of the residue on silica gel (CH2Cl2) yielded the
652
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 646–655

Synthesis of an (Ϯ)-Estrone Precursor
title compound as a colorless viscous liquid (139 mg, 41%). 1H
1H NMR (400 MHz, C6D6): δ = 0.61–0.72 (m, 1 H, CH), 0.87–
NMR (400 MHz, CDCl3): δ = 0.23 [s, 9 H, Si(CH3)3], 1.20–1.27 0.99 (m, 1 H, CHH), 1.05–1.17 (m, 1 H, CHH), 1.42–1.50 (m, 1
(m, 1 H, CH), 1.35–1.46 (m, 1 H, CHH), 1.53–1.64 (m, 1 H, CHH), H, CHH), 1.77–1.90 (m, 3 H, 2ϫCHH, CH), 2.10–2.20 (m, 2 H,
1.95–2.00 (m, 1 H, CHH), 2.07–2.15 (m, 1 H, CHH), 2.40–2.75 (m, CH, CHH), 2.27–2.37 (m, 1 H, CHH), 2.52–2.59 (m, 2 H, CH2),
5 H, 2ϫCH, CH2, CHH), 2.82–2.87 (m, 2 H, CH2), 3.15–3.23 (m,
2.75–2.84 (m, 1 H, CHH), 3.41 (s, 3 H, OCH3), 6.64–6.68 (m, 1 H,
1 H, CHH), 3.78 (s, 3 H, OCH3), 6.62–6.64 (m, 1 H, Ar-H), 6.70– Ar-H), 6.76–6.80 (m, 1 H, Ar-H), 6.88–6.98 (br. s, 1 H, pyr-H),
6.76 (m, 1 H, Ar-H), 7.20–7.24 (m, 1 H, Ar-H) ppm. 13C NMR 6.98–7.03 (m, 1 H, Ar-H), 7.72–7.79 (m, 1 H, pyr-H), 8.50–9.00
(100 MHz, CDCl3) δ = C), 137.88 (C, Ar), 157.69 (C, Ar), 189.96
(br. d, 2 H, 2ϫpyr-H) ppm. 13C NMR (100 MHz, C6D6): δ = 29.29
(CH2), 29.47 (CH2), 30.87 (CH2), 32.11 (CH2), 40.62 (CH2), 42.57
(CH), 46.18 (CH), 48.31 (CH), 55.46 (OCH3), 113.00 (CH, Ar),
114.76 (CH, Ar), 127.75 (CH, Ar), 131.51 (C, Ar), 134.79 (C=C),
137.26 (CH, pyr), 138.56 (C, Ar), 159.15 (C, Ar), 176.39 (C=C),
(C=C), 212.12 (C=O) ppm. IR (KBr): ν = 2948, 2912, 2858, 2833,
˜
1686, 1591, 1499, 1449, 1279, 1246, 1198, 1140, 1044, 841 cm–1.
MS (EI): m/z (%) = 340.2 (100) [M+], 325.2 (90), 174.1 (45), 147.1
(35), 115 (20), 73 (70). HRMS (EI+): calcd. for C21H28O2Si
340.1859; found 340.1859. Rf (CH2Cl2) = 0.2.
204.81 (C=O) ppm. IR (KBr): ν = 3031, 2951, 2921, 2858, 1702,
˜
1692, 1608, 1501, 1414, 1252, 1237, 1141, 1043, 927, 808, 713 cm–1.
MS (EI): m/z (%) = 345 (100) [M+], 316 (10), 175 (45), 159 (10),
147 (35), 115 (5). HRMS (EI+): calcd. for C23H23O2N 345.1729;
found 345.1729. Rf (CH2Cl2/MeOH, 50:1) = 0.4.
(؎)-3-Methoxy-17-phenyl-16-ketoestra-1,3,5(10),13(17)-tetraene
(11d): Enyne 5d (1 mmol, 315 mg) was used. Column chromatog-
raphy of the residue on silica gel (CH2Cl2/MeOH, 100:1) followed
by recrystallization (MeOH) yielded the title compound as a color-
less solid (315 mg, 92%). M.p. 178–181 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.25–1.50 (m, 2 H, CH, CHH), 1.55–1.72 (m, 1 H,
CHH), 2.01–2.10 (m, 1 H, CHH), 2.25–2.35 (m, 1 H, CHH), 2.46–
2.57 (m, 1 H, CH), 2.62–2.95 (m, 6 H, 2ϫCH2, CH, CHH), 3.18–
3.27 (m, 1 H, CHH), 3.79 (s, 3 H, OCH3), 6.63–6.67 (m, 1 H, Ar-
H), 6.71–6.77 (m, 1 H, Ar-H), 7.19–7.24 (m, 1 H, Ar-H), 7.27–7.37
(m, 3 H, 3ϫPh-H), 7.38–7.46 (m, 2 H, 2ϫPh-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.55 (CH2), 28.94 (CH2), 30.09 (CH2),
31.50 (CH2), 40.14 (CH2), 41.95 (CH), 45.60 (CH), 48.08 (CH),
55.16 (OCH3), 112.00 (CH, Ar), 113.70 (CH, Ar), 126.84 (CH, Ar),
127.67 (CH, Ph), 128.28 (2ϫCH, Ph), 129.23 (2ϫCH, Ph), 130.61
(C, Ar), 131.32 (C=C), 137.87 (C, Ar), 157.70 (C, Ar), 176.03
General Method for Cyclocarbonylation with Cp2ZrBu2 (Negishi
Protocol): nBuLi (2.1 mmol, 1.36 mL, 1.6  in hexanes) was added
to a stirred solution of Cp2ZrCl2 (1.05 mmol, 306 mg) in THF
(10 mL) at –78 °C. After 1 h, enyne 5b–c (1 mmol) in THF (1 mL)
was added, and the reaction mixture was warmed gradually to
20 °C, after 2 h followed by CO bubbling through the reaction mix-
ture for 20 min at 20 °C. Then, it was quenched with HCl (1%,
30 mL) and extracted with CH2Cl2 (3ϫ15 mL). The combined or-
ganic fractions were dried with anhydrous MgSO4, and the volatiles
were removed under reduced pressure. Column chromatography of
the residue on silica gel yielded the desired products.
(؎)-3-Methoxy-17-methyl-16-ketoestra-1,3,5(10),13(17)-tetraene
(11b): Enyne 5b (1 mmol, 253 mg) was used. Column chromatog-
raphy of the residue on silica gel (CH2Cl2/MeOH, 100:1) yielded
the title compound as a colorless solid (87 mg, 31%).
(C=C), 206.42 (C=O) ppm. IR (KBr): ν = 3054, 2925, 2856, 2836,
˜
1696, 1608, 1499, 1443, 1366, 1234, 1137, 1043, 698 cm–1. MS (EI):
m/z (%) = 344.1 (100) [M+], 173 (60), 147 (80), 128 (30), 115 (50),
91 (25), 69 (40), 57 (50), 43 (55). HRMS (EI+): calcd. for C24H24O2
344.1776; found 344.1780. Rf (CH2Cl2/MeOH,100:1) = 0.5.
(؎)-3-Methoxy-17-trimethylsilyl-16-ketoestra-1,3,5(10),13(17)-
tetraene (11c): Enyne 5c (1 mmol, 312 mg) was used. Column
chromatography of the residue on silica gel (CH2Cl2) yielded the
title compound as a colorless viscous liquid (196 mg, 58%).
(؎)-3-Methoxy-17-(4-methoxycarbonylphenyl)-16-ketoestra-
1,3,5(10),13(17)-tetraene (11e): Enyne 5e (1 mmol, 373 mg) was
used. Column chromatography of the residue on silica gel (CH2Cl2/
MeOH, 100:1) followed by recrystallization (MeOH) yielded the
title compound as a colorless solid (336 mg, 84 %). M.p. 182–
(؎)-3-Methoxy-17-methylestra-1,3,5(10),13(17)-tetraene (4): To a
solution of LiAlH4 (0.6 mmol, 23 mg) in Et2O (2 mL) was added
AlCl3 (2.4 mmol, 319 mg) at 20 °C. The resulting suspension was
stirred for 15 min at 20 °C, and then it was left to stand for 10 min,
allowing the insoluble materials to deposit. The solution was sepa-
rated and added dropwise to a solution of 11b (0.5 mmol, 140 mg)
in Et2O (8 mL) at –10 °C. The reaction mixture was then stirred at
20 °C for 30 min followed by quenching with HCl (5%, 3 mL).
Water (100 mL) was added, and the mixture was extracted with
CH2Cl2 (3ϫ15 mL) and dried with anhydrous MgSO4, and the
volatiles were removed under reduced pressure. Filtration over a
short pad of silica gel (5 g) in CH2Cl2 yielded the title compound
as a colorless solid (126 mg, 95%). Spectral characteristics were in
agreement with the previously reported data.[20] Rf (CH2Cl2/hex-
ane, 2:1) = 0.6.
1
185 °C. H NMR (400 MHz, CDCl3): δ = 1.28–1.50 (m, 2 H, CH,
CHH), 1.60–1.72 (m, 1 H, CHH), 2.02–2.10 (m, 1 H, CHH), 2.28–
2.36 (m, 1 H, CHH), 2.48–2.61 (m, 1 H, CH), 2.64–2.84 (m, 4 H,
CH, CH2, CHH), 2.84–2.92 (m, 2 H, CH2), 3.15–3.22 (m, 1 H,
CHH), 3.78 (s, 3 H, OCH3), 3.93 (s, 3 H, COOCH3), 6.62–6.66 (m,
1 H, Ar-H), 6.71–6.77 (m, 1 H, Ar-H), 7.18–7.24 (m, 1 H, Ar-H),
7.36–7.42 (m, 2 H, 2ϫAr-H), 8.04–8.12 (m, 2 H, 2ϫAr-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 28.58 (CH2), 29.05 (CH2), 30.08
(CH2), 31.52 (CH2), 40.15 (CH2), 41.94 (CH), 45.81 (CH), 48.15
(CH), 52.12 (COOCH3), 55.19 (OCH3), 112.05 (CH, Ar), 113.74
(CH, Ar), 126.84 (CH, Ar), 129.27 (2ϫCH, Ar), 129.54 (2ϫCH,
Ar), 130.42 (C, Ar), 136.11 (C, Ar), 136.63 (C=C), 137.82 (C, Ar),
157.76 (C, Ar), 166.86 (COO), 177.33 (C=C), 205.77 (C=O) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, experimental details, and copies of the
1H and 13C of spectra.
IR (KBr): ν = 3001, 2930, 2857, 1719, 1695, 1607, 1497, 1433, 1285,
˜
1108, 1031, 927, 776, 706 cm–1. MS (EI): m/z (%) = 402 (45) [M+],
344 (5), 256 (5), 173 (30), 147 (35), 97 (40), 83 (45), 69 (65), 55
(90), 43 (100). HRMS (EI+): calcd. for C26H26O4 402.1831; found
402.1838. Rf (CH2Cl2/MeOH, 100:1) = 0.3.
Acknowledgments
(؎)-3-Methoxy-17-(3-pyridyl)-16-ketoestra-1,3,5(10),13(17)-
tetraene (11f): Enyne 5f (1 mmol, 316 mg) was used. Column This work was supported by the Ministry of Education of the
chromatography of the residue on silica gel (CH2Cl2/MeOH, 50:1)
followed by recrystallization (MeOH/petroleum ether) yielded the
title compound as a colorless solid (302 mg, 88%). M.p. 48–51 °C.
Czech Republic (grant project 1M0508 and MSM0021620857). The
authors would like to thank to Dr. Jana Roithová for calculation
of the structure presented in Figure 1.
Eur. J. Org. Chem. 2010, 646–655
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
653

R. Betík, P. Herrmann, M. Kotora
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Received: August 17, 2009
Published Online: December 18, 2009
Eur. J. Org. Chem. 2010, 646–655
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
655