Formal total synthesis of (±)-estrone and zirconocene-promoted cyclization of 2-fluoro-1,7-octadienes and ru-catalyzed ring closing metathesis

Article abstract of DOI:10.1021/jo800620d

(Chemical Equation Presented) A new and diastereoselective method for the synthesis of the estrone skeleton from a substituted styrene based on sequential 3-fold use of Cp₂ZrBu₂ (oxidative addition-alkylation and two cyclization-alkylation sequences) and a ruthenium complex catalyzed RC-metathesis of a sterically hindered diene was developed. The prepared estratetraene was obtained in 7 steps from a commercially available starting material and thus the overall synthesis of estrone could be accomplished in 9 steps. Moreover, we have also found that the course of the reaction of substrates bearing the 2-halo-1,7-diene moiety with Cp₂ZrBu ₂, i.e., cyclization or oxidative addition to the C-X bond, could be controlled by the nature of the halogen leaving group.

Full text of DOI:10.1021/jo800620d

Formal Total Synthesis of (()-Estrone and Zirconocene-Promoted
Cyclization of 2-Fluoro-1,7-octadienes and Ru-Catalyzed Ring
Closing Metathesis
Pavel Herrmann,†,‡ Milosˇ Budeˇsˇ´ınsky´,‡ and Martin Kotora†,‡,
*
Department of Organic and Nuclear Chemistry, and Centre for New AntiVirals and Antineoplastics,
Faculty of Science, Charles UniVersity, HlaVoVa 8, 128 43 Praha 2, Czech Republic and Institute of
Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
FlemingoVo nám. 2, 166 10 Praha 6, Czech Republic
kotora@natur.cuni.cz
ReceiVed March 19, 2008
A new and diastereoselective method for the synthesis of the estrone skeleton from a substituted styrene
based on sequential 3-fold use of Cp2ZrBu2 (oxidative addition-alkylation and two cyclization-alkylation
sequences) and a ruthenium complex catalyzed RC-metathesis of a sterically hindered diene was developed.
The prepared estratetraene was obtained in 7 steps from a commercially available starting material and
thus the overall synthesis of estrone could be accomplished in 9 steps. Moreover, we have also found
that the course of the reaction of substrates bearing the 2-halo-1,7-diene moiety with Cp2ZrBu2, i.e.,
cyclization or oxidative addition to the C-X bond, could be controlled by the nature of the halogen
leaving group.
Introduction
examples of the application of Zr-mediated reactions such as
cyclocarbonylation of a diene4 or oxidative addition of benzyl
ethers5 should not be omitted. From the synthetic point of view
the Zr-based methodology for oxidative dimerization of dienes
to cyclic compounds is especially attractive because the formed
intermediate organozirconium compounds can be used in further
C-C bond-formation reactions. Thus Zr-mediated cyclizations
of dienes and their derivatives were used in the synthesis of
various natural compounds, such as the dolabellane skeleton,6
dendrobine,7 kainic acid,8 haliclonadiamine,9 elemol,10 pisifera-
nol,11 phorbole,12 and a decahydroquinoline (+)-trans-195A.13
Since the zirconocene-based chemistry with respect to
transformations of various functional groups is very rich,14 we
have become interested in its repetitive application in the
synthesis of complex organic compounds. In this regard, we
have recently reported a short pathway to 16-ketoestratrienes
from an advanced styrene derivative that was based on three
consecutive dibutylzirconocene (Cp2ZrBu2, a.k.a Negishi re-
Steroids have been in the center of synthetic interest for many
decades. Among them a prominent role is reserved for estrone
that since its first synthesis1 has been an object of unabating
synthetic interest due to its high molecular complexity and
biological properties. In this regard a special place is occupied
by methodologies exploiting transition metal based reactions.2
Co-catalyzed cyclotrimerization,2a,b Pd-catalyzed coupling
reactions,2c,d Ru-catalyzed metathesis,2e and others3 can be
considered as typical examples. In this regard, also the early
* Address correspondence to this author. Phone: (+420) 221 951 326.
‡ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of
the Czech Republic.
† Charles University.
(1) Synthesis of equlenin constituted a formal total synthesis of estrone:
Bachmann, W. E.; Cole, W.; Wilds, A. L. J. Am. Chem. Soc. 1939, 61, 974–
975. Its conversion to estrone: Marker, R. E. J. Am. Chem. Soc. 1938, 60, 1897–
1980. For details, see: Reed, J. W.; Hudlicky´, T. In The Way of Synthesis; Wiley-
VCH; Weinheim, Germany, 2007.
(2) For Co-based methodology, see: (a) Funk, R. L.; Vollhardt, K. P. C. J. Am.
Chem. Soc. 1980, 102 (2), 5253–5261. (b) Lecker, S. H.; Nguyen, N. H.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 856–858. For Pd-based
methodology, see: (c) Tietze, L. F.; No¨bel, T.; Spescha, M. J. Am. Chem. Soc.
1998, 120, 8971–8977. (d) Soorukam, D.; Knochel, P. Org. Lett. 2007, 9, 1021–
1023. For Ru-based methodology, see: (e) Hanada, K.; Miyazawa, N.; Ogasawara,
K. Chem. Pharm. Bull. 2003, 51, 104–106.
(4) (a) Taber, D. F.; Zhang, W.; Campbell, C. L.; Rheingold, A. L. J. Am.
Chem. Soc. 2000, 122, 4813–4814. For the first application of Zr-mediated
cyclocarbonylation see: (b) Swanson, D. R. J. Org. Chem. 1989, 54, 3521-
3523. (c) Rousset, C. J. Tetrahedron Lett. 1989, 30, 5105–5108.
(5) Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 2004, 45, 4495–
4498.
(3) Skoda-Fo¨ldes, R.; Kolla´r, L. Chem. ReV. 2003, 103, 4095–4129.
(6) Luker, T.; Whitby, R. J. Tetrahedron Lett. 1996, 37, 7661–7664.
6202 J. Org. Chem. 2008, 73, 6202–6206
10.1021/jo800620d CCC: $40.75 2008 American Chemical Society
Published on Web 07/16/2008

Synthesis of (()-Estrone
SCHEME 1. A Plan for the Construction of C and D
Steroid Rings
SCHEME 2. Formation of 2a
agent15)-mediated reactions.16a These comprised (i) oxidative
addition of dibenzyl ether followed by alkylation, (ii) metallo-
ene reaction followed by alkylation, and finally (iii) cyclocar-
bonylation. One of the important results obtained in this study
was the finding that zirconocene-mediated cyclization aiming
at B-ring closure proceeded with trans stereochemistry that is
common in natural steroids.16,17 Moreover, this relative con-
figuration controls the relative configuration of other stereogenic
centers in further steroid framework build-up. Our next goal
was the expansion of this methodology for estrone synthesis.
Herein we would like to report a successful accomplishment of
this task, which is based on a combination of Zr and Ru
chemistry for the construction of the steroid C and D rings.
a Reagents and conditions: (a) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2)
3,4-dichlorobutene, CuCl (10 mol %), 20 °C, 2 h, (3) 3 M HCl; (b) MeONa,
DMF, 20 °C, 2h; (c) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2) 2,3-
dihalopropene, CuCl (10 mol %), 20 °C, 2 h, (3) 3 M HCl.
of dibutylzirconocene followed by CuCl-catalyzed alkylation
with 2,3-dichloro- or 2,3-dibromoropene afforded the required
2-chloro- and 2-bromo-1,7-dienes 2a and 2b in 84% and 83%
isolated yields, respectively (Scheme 2).16c
Next, the cyclization-alkylation sequence was attempted.
However, the reaction of 2a with dibutylzirconocene followed
by the CuCl-catalyzed reaction with 2,3-dichloropropene re-
sulted in the formation of several products. Unfortunately, the
expected product, i.e., halodiene 3, was formed only in about
10% yield. The major reaction path proceeded via oxidative
addition of dibutylzirconocene into the C-Cl bond to give a
vinyl zirconium compound21 that upon the reaction with 2,3-
dichloropropene gave rise to dimer 422 and the allylation product
5 in 20% and 45% yields, respectively (Scheme 3). A change
of the substrate to bromodiene 2b (more reactive C-Br bond)
did not improve the situation and after workup of the reaction
mixture halodiene 3 was not detected at all. The cyclization
was also attempted with the Ti(O-i-Pr)4/i-PrMgX system,23 but
the reaction did not proceed and the starting compound 2a was
recovered.
Results and Discussion
At the outset, we envisioned that the application of rarely
used zirconcocene-mediated cyclization of 2-halo-R,ω-dienes18
could provide a useful tool for the formation of steroid C and
D rings (Scheme 1). Thus it was expected that the cyclization
of an intermediate bearing the 2-halo-R,ω-diene moiety with
dibutylzirconocene followed by alkylation with an 1,2-dihalo-
propene would yield 1-(2-halobut-1-en-4-yl)-2-methylidenecy-
cloalkane. Then again its reaction with dibutylzirconocene
should yield a product having a methylidenecyclopentane ring
(a direct precursor of estrone).
The starting allylically substituted diene compound 1 was
prepared according to the previously reported reaction
sequence16a (oxidative addition of dibenzyl ether to dibutyl
zirconocene,5,19 allylation of the formed organozirconium
intermediate with 3,4-dichlorobutene,20 and methoxylation of
the formed allyl chloride). Its further cyclization in the presence
Because the zirconocene methodology failed, the intramo-
lecular carbolithiation was attempted in the next step (Scheme
4).24 Thus treatment of the chloroderivative 2a with t-BuLi
(7) (a) Mori, M.; Uesaka, N.; Shibasaki, M. J. Org. Chem. 1992, 57, 3519–
3521. (b) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date,
T. J. Org. Chem. 1994, 59, 5633–5642.
(19) (a) Hanzawa, Y.; Ikeuchi, Y.; Nakamura, T.; Taguchi, T. Tetrahedron
Lett. 1995, 36, 6503–6506. (b) Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y. J. Org.
Chem. 2005, 70, 756–759. For other oxidative addition reactions to Cp2ZrBu2,
see: (c) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E. Tetrahedron
Lett. 1989, 30, 5105–5108. (d) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron
Lett. 1992, 33, 1295–1298. (e) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y.
Tetrahedron Lett. 1992, 33, 3769–3772. (f) Ito, H.; Taguchi, T.; Hanzawa, Y. J.
Org. Chem. 1993, 58, 774–775. (g) Liard, A.; Marek, I. J. Org. Chem. 2000,
65, 7218–7220.
(8) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans 1 2000, 3194–3204.
(9) Taber, D. F.; Wang, Y. J. Am. Chem. Soc. 1997, 119, 22–26.
(10) Taber, D. F.; Wang, Y. Tetrahedron Lett. 1995, 36, 6639–6642.
(11) Tuckett, M. W.; Watkins, W. J.; Whitby, R. J. Tetrahedron Lett. 1998,
39, 123–126.
(12) (a) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956–
4958. (b) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997,
119, 7897–7898.
(20) For CuCl-catalyzed reactions with alkyl halides, see: (a) Takahashi, T.;
Kotora, M.; Kasai, K.; Suzuki, N. Tetrahedron Lett. 1994, 35, 5685–5688. (b)
Takahashi, T.; Kotora, M.; Xi, Z. J. Chem. Soc., Chem. Commun. 1995, 1503–
1504. (c) Kasai, K.; Kotora, M.; Suzuki, N.; Takahashi, T. J. Chem. Soc., Chem.
Commun. 1995, 109–110. (d) Takahashi, T.; Nishihara, Y.; Hara, R.; Huo, S.;
Kotora, M. Chem. Commun. 1997, 1599–1600. (e) Ikeuchi, Y.; Taguchi, T.;
Hanzawa, Y. Tetrahedron Lett. 2004, 45, 3717–3720.
(13) Holub, N.; Neidho¨fer, J.; Blechert, S. Org. Lett. 2005, 7, 1127–1129.
(14) For reviews see: (a) Negishi, E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon; Oxford, UK, 1991; Vol. 5, pp 1163-
1184. (b) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-
VCH; Weinheim, Germany, 2002. (c) Negishi, E. Dalton Trans. 2005, 827–
848.
(21) Takahashi, T.; Kotora, M.; Fischer, R.; Nishihara, Y.; Nakajima, K.
J. Am. Chem. Soc. 1995, 117, 11039–11040.
(15) (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829–2832. (b) Negishi, E. J. Am. Chem. Soc. 1989, 111, 3336–3346.
(22) 2,3-Dichloropropene was shown to promote dimerization of certain
organometallics, e.g., Grignard reagents: (a) Cheng, J. W.; Luo, F. T. Tetrahedron
Lett. 1988, 29, 1293–1294. (b) Wang, W. J.; Huang, C. M.; Luo, F. T. Synth.
Met. 1991, 41, 335–339.
ˇ
(16) (a) Herrmann, P.; Kotora, M.; Budeˇsˇ´ınsky´, M.; Saman, D.; C´ısarˇova´, I.
Org. Lett. 2006, 8, 1315–1318. For related papers, see: (b) Herrmann, P.; Kotora,
M. Tetrahedron Lett. 2007, 48, 3209–3212. (c) Herrmann, P.; Budeˇsˇ´ınsky´, M.;
Kotora, M. Chem. Lett. 2007, 36, 1268–1269.
(23) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835–2886,
and refereces cited therein.
(17) The preference for trans fusion under equilibrating conditions was
observed earlier, see: Akita, N. Polyhedron 1991, 10, 1–9.
(24) For review, see: (a) Normant, J. F. Top. Organomet. Chem. 2003, 5,
287–310, and references cited thereinFor other leading refrences on carbolithiation
of 2-halodienes, see: (b) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch,
C. H. J. Am. Chem. Soc. 1988, 110, 4788–4796. (c) Bailey, W. F.; Jiang, X.-L.;
McLeod, C. E. J. Org. Chem. 1995, 60, 7791–7795. (d) Barluenga, J.; Sanz, R.;
Fan˜ana´s, F. J. Tetrahedron Lett. 1997, 38, 2763–2766.
(18) (a) Takahashi, T.; Kotora, M.; Xi. Z.; Suzuki, N. The 69th Annual
Meeting of Chemical Society of Japan, Kyoto, March 1995, 2H3 43. (b) Millward,
D. B.; Waymouth, R. M. Organometallics 1997, 16, 1153–1155. (c) Kotora,
M.; Gao, G. H.; Li, Z. P.; Xi, Z. F.; Takahashi, T. Tetrahedron Lett. 2000, 41,
7905–7909.
J. Org. Chem. Vol. 73, No. 16, 2008 6203

Herrmann et al.
SCHEME 3. Attempts of the Cp2ZrBu2-Mediated C-Ring Closurea
a Reagents and conditions: (a) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2) 2,3-dichloropropene, CuCl (10 mol %), 20 °C, 2 h, (3) 3 M HCl.
SCHEME 4. Attempts of the C-Ring Closure through Carbolithiationa
a Reagents and conditions: (a) (1) t-BuLi (2 equiv), TMEDA (2.2 equiv), (2) H+.
addition to the C-F bond proceeded only to the extent of 10%.
In this way the construction of the steroid C ring by zirconocene
methodology was successfully accomplished.
Then we embarked on the synthesis of the steroid D ring.
Once again it was presumed that dibutylzirconocene mediated
cyclization of 10 would help us reach the goal. Although the
reaction proceeded well, the oxidative addition of the C-F bond
FIGURE 1. Grubbs 2nd generation and Hoveyda-Grubbs 2nd genera-
to the zirconium atom was prefered over the cyclization. Diene
11, formally originating in the reductive defluorination, was
obtained as the major product (33% after isolation) (Scheme
6). The desired exocyclic alkene 12 was formed only in a
negligible amount (>5%). Its formation was confirmed by
characteristic 1H NMR signals of the exo methylene double bond
(δ 4.72-4.74, m, 2H) and the angular methyl group (δ 1.02, s,
3H). Since the known methylidene derivative prepared from
natural estrone had signals of the exo methylene double bond
and the angular methyl group at 4.67 and 0.81 ppm,25
respectively, it was concluded that compound 12 had an
unnatural cis configuration on the fusion of rings C and D. The
change of solvent from THF to toluene did not have any effect
on the product yields and distribution. Despite the low yield,
the obtained mixture of compounds (11 and 12) was oxidized
by the OsO4/NaIO4 system and GC/MS analysis confirmed the
presence of methoxyestrone (for details see the Supporting
Information). To shift the course of the reaction to cyclization,
the reaction was carried out under various conditions. An attempt
to carry out the cyclization in the presence PMe3 as a stabilizing
agent for the intermediate zirconocene-olefin complex26 did
not have the desired effect on the product distribution (23% of
a mixture of 11 and 12). The use of zirconacyclopentane27
instead of Cp2ZrBu2 led only to a selective substitution of one
ethylene ligand on the zirconium atom by the vinyl fluoride
moiety giving rise to a product with the ethylated double bond
13 in 34% isolated yield. Also an attempt to promote the
cyclization of the oxidative addition intermediate by converting
it to a cationic zirconium species by the addition of MAO18c
failed. An inseparable complex reaction mixture was formed,
tion catalysts.
SCHEME 5. Probable Intermediates During Formation of 9
afforded a complex mixture, from which we isolated alkyne 8,
the product of the dehydrochlorination reaction, and (cycloalkyl)-
alkyne 9 in 8% and 24% yields, respectively. The formation of
the latter could be explained by the following reaction sequence:
lithiation of alkyne 8 then a second lithiation of one of the
propargylic hydrogens followed by intramolecular carbolithia-
tion (Scheme 5). The products of simple dehalogenation of 6
or carbolithiation of 7 were not detected. Similarly, the reaction
of the bromoderivative 2b under identical conditions yielded
only 6 in 75% isolated yield.
Since the carbolithiation also failed, we decided to resort back
to zirconocene methodology and to try to solve the crucial
problem of the cyclization step, i.e., the competition between
oxidative addition to the C-X bond and cyclization of the
alkene moieties. We assumed that using a substrate with a
shorter (stronger) C-X bond and hence less reactive could favor
the cyclization of the double bonds on the zirconium atom over
the oxidative addition. The obvious choice was to use a substrate
with the C-F bond. In this regard, 2-fluoro-1,7-diene 2c was
prepared in 75% yield similarly to the synthesis of 2a and 2b
(Scheme 2).16c Fortunately, in this case the reaction of 2c with
Cp2ZrBu2 proceeded via cyclization of the alkene moieties to
furnish an organozirconium intermediate that upon CuCl-
catalyzed allylation with 3-chloro-2-fluoropropene yielded new
fluorodiene 10 in 62% isolated yield (Scheme 6). The oxidative
(25) Kuhl, A.; Kreiser, W. HelV. Chim. Acta 1998, 81, 2264–2269.
(26) Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755–769.
(27) Xi, Z. F.; Hara, R.; Takahashi, T. J. Org. Chem. 1995, 60, 4444–4448.
6204 J. Org. Chem. Vol. 73, No. 16, 2008

Synthesis of (()-Estrone
SCHEME 6. Reactions of 2c with Negishi Reagent (Cp2ZrBu2) under Various Conditionsa
a Reagents and conditions: (a) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2) 3-chloro-2-fluoropropene, CuCl (10 mol %), 20 °C, 2 h; (b) Cp2ZrBu2, -78 to 20
°C, 1.5 h; (c) Cp2ZrBu2/PMe3, -78 to 20 °C, 1.5 h; (d) Cp2Zr(CH2)4, -78 to 20 °C, 1.5 h; (e) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2) MAO, 20 °C, 2 h.
(15/16 ) 25/75). Since cycloalkene 16 is a known intermediate33
SCHEME 7. D-Ring Closure of the Estrone Framework via
Metathesisa
and was previously converted to 3-methoxyestrone in two
steps,34 the successful formal total synthesis of estrone was
accomplished.
Conclusion
In conclusion, a short formal total synthesis of estrone by
means of two zirconocene and one RC-metathesis step from
a Reagents and conditions: (a) (1) Cp2ZrBu2, -78 to 20 °C, 1.5 h, (2)
methallyl chloride, CuCl (10 mol %), 20 °C, 2 h, 80%; (b) Grubbs 2nd
advanced intermediate 1 was accomplished (totally 9 steps from
the commercially available starting material). As far as the
zirconocene-based methodology is concerned, varying the
halogen leaving group in 2-halodienes can have a profound
effect on the course of the reaction, especially when cyclization
and oxidative addition compete owing to structural features of
the substrate (e.g., steric hindrance). This finding could have a
positive effect on further developments in organozirconium
chemistry and its application in organic synthesis. In addition,
the facile ring closing metathesis of a diene to sterically hindered
tetrasubstituted cycloalkene is also noteworthy and could provide
a useful example for application of this methodology in the
synthesis of compounds with highly substituted double bonds.
generation catalyst, toluene, 90 °C, 16 h, 82%.
1
out of which was identified by H NMR and GC-MS only the
polyene 14 in 43% GC yield (δ 4.64-4.96, m, 4H, dCH2; 5.78,
dt, J ) 15.6, 6.6 Hz, 1H, sCHd; 6.05, d, J ) 15.6 Hz, 1H,
sCHd; m/z 336.3, M+), presumably a product of the reaction
of the cationic zirconium species with 1-butene (the product of
Cp2ZrBu2 decomposition). The reluctance of 10 to cyclize
probably could be attributed to steric hindrance in the vicinity
of the exocyclic double bond resulting in a preferential attack
of the C-F bond by Cp2ZrBu2.
At that moment we decided to switch the synthetic strategy
because the limits of zirconocene-based methodology were
evidently achieved. Nevertheless, Zr-mediated cyclization of 2c
was used once again for the closure of the steroid C ring and
was followed by allylation with methallyl chloride affording
diene 15 in 80% isolated yield.
Experimental Section
anti-1-[(3-Fluorobut-3-en-1-yl)-2-vinyl-6-methoxy]-1,2,3,4-tet-
rahydronaphtalene (2c). n-BuLi (1.6 M solution in hexanes,
26 mmol) was added to a stirred solution of Cp2ZrCl2 (3.68 g,
12.6 mmol) in THF (70 mL) at -78 °C. After 1 h methoxydiene
1 (2.79 g, 12 mmol) in THF (10 mL) was added then the
reaction mixture was warmed gradually to 20 °C and stirred
for 1.5 h. To this solution was added 3-chloro-2-fluoropropene
(1.7 g, 18 mmol) and CuCl (120 mg, 1.2 mmol), and the reaction
mixture was stirred for 2 h. Then, 3 M HCl (aq) was added, the
mixture was stirred for 0.5 h, extracted with hexanes, dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography on
It was presumed that the ring closing metathesis28 of 15 could
bring about the closure of the steroid D ring. Gratifyingly, inspite
of the fact that tetrasubstituted alkenes are difficult to form,29,30
heating of a 0.0033 M toluene solution of 15 with Grubbs second
generation catalyst31 (20 mol %) (Figure 1) at 90 °C resulted
in the quantitative formation of the tetracyclic compound 16,
which was isolated in 82% yield (Scheme 7). The same reaction
carried out with Hoveyda-Grubbs second generation catalyst32
(Figure 1) at 25 °C overnight did not proceed to completion
(28) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446–452. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
(29) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–7318.
(30) For recent advances in the synthesis of tetrasubstituted alkenes by the
metathesis reaction, see: (a) Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl,
F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787–4790. (b) Berlin, J. M.;
Campbell, K.; Ritter, T.; Funk, T. W.; Clenov, A.; Grubbs, R. H. Org. Lett.
2007, 9, 1339–1342. (c) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.;
Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
1
silica gel to afford 2.35 g (75%) of 2c as a colorless oil. H
(32) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. L. J. Am.
Chem. Soc. 2000, 122, 8168–8179. (b) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973–9976.
(33) Spectral data were in agreement with previously reported characteristics:
Ro¨mer, J.; Steinbach, J.; Kasch, H.; Scheller, D. J. Prakt. Chem. 1999, 341,
574–583.
(31) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(34) Bartlett, P. A.; Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 7501–7502.
J. Org. Chem. Vol. 73, No. 16, 2008 6205

Herrmann et al.
NMR (600.1 MHz, CDCl3) δ 1.62-1.69 (m, 1H), 1.85-1.98
(m, 3H), 2.10-2.20 (m, 2H), 2.38-2.42 (m, 1H), 2.70-2.76
(m, 3H), 3.77 (s, 3H), 4.20 (ddt, J ) 50.3, 2.8, 0.9, 0.9 Hz,
1H), 4.49 (dd, J ) 17.6, 2.8 Hz, 1H), 5.00 (ddd, J ) 10.4, 1.8,
0.9 Hz, 1H), 5.06 (ddd, J ) 17.3, 1.8, 1.1 Hz, 1H), 5.79 (ddd,
J ) 17.3, 10.4, 7.8 Hz, 1H), 6.60 (dt, J ) 2.8, 0.5 Hz, 1H),
6.72 (ddt, J ) 8.4, 2.8, 0.8 Hz, 1H), 7.07 (dd, J ) 8.4, 0.5 Hz,
1H); 13C NMR (125.7 MHz CDCl3) δ 26.1, 27.4, 28.6 (d, J(C,F)
) 27.3 Hz), 31.5 (d, J(C,F) ) 1.7 Hz), 41.0, 41.4, 55.1, 89.4
(d, J(C,F) ) 20.5 Hz), 112.2, 113.3, 114.4, 129.7, 130.7, 138.1,
142.1, 157.4, 167.0 (d, J(C,F) ) 256.8 Hz); IR (CCl4) 3079,
3000, 2935, 2836, 1671, 1610, 1578, 1501, 1465, 1257, 1160,
1042, 995, 916, 846; MS-EI (m/z) 259.9 (M+); HR-EI for
C17H21FO calcd 260.1576, found 260.1580. Rf (96/4 hexanes/
Et2O) 0.7.
7-Methoxy-1-(3-methylbut-3-enyl)-2-methylene-1,2,3,4,4a,-
9,10,10a-octahydrophenanthrene (15). n-BuLi (1.6 M solution
in hexanes, 2.1 mmol) was added to a stirred solution of
Cp2ZrCl2 (307 mg, 1.05 mmol) in THF (5 mL) at -78 °C. After
1 h diene 2c (260 mg, 1 mmol) in THF (2 mL) was added and
the reaction mixture was warmed gradually to 20 °C and stirred
for 1.5 h. To this solution was added ꢀ-methallylchloride (136
mg, 1.5 mmol) and CuCl (10 mg, 0.1 mmol), and the reaction
mixture was stirred for 2 h. Then, 3 M HCl (aq) was added, the
mixture was stirred for 30 min, extracted with hexanes, and
dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford 237 mg (80%) of diene
15 as a colorless oil. 1H NMR (600.1 MHz, CDCl3) δ 1.20-1.25
(m, 1H), 1.29-1.35 (m, 1H), 1.37-1.44 (m, 1H), 1.65-1.72
(m, 1H), 1.76 (t, J ) 1.3 Hz, 3H), 1.85-1.92 (m, 2H),
1.99-2.05 (m, 1H), 2.12-2.25 (m, 3H), 2.47-2.54 (m, 3H),
2.81-2.84 (m, 2H), 3.77 (s, 3H), 4.67 (q, J ) 1.6 Hz, 1H),
4.70-4.72 (m, 2H), 4.82 (qd, J ) 1.6, 0.6 Hz, 1H), 6.62 (dt, J
) 2.8, 1.0 Hz, 1H), 6.71 (ddt, J ) 8.6, 2.8, 0.8 Hz, 1H), 7.19
(dd, J ) 8.6, 1.0 Hz, 1H); 13C NMR (150.9 MHz CDCl3) δ
22.7, 26.1, 27.3, 30.4, 32.8, 34.7, 36.1, 42.6, 45.4, 46.9, 55.2,
106.1, 109.4, 111.6, 113.2, 126.6, 132.8, 138.0, 146.5, 150.6,
157.4; IR (CCl4) 3083, 2994, 2936, 2836, 1645, 1611, 1502,
1465, 1443, 1435, 1278, 1257, 1238, 1044, 892; MS-EI (m/z)
296.1 (M+); HR-EI for C21H28O calcd 296.2140, found 296.2136.
Rf (96/4 hexanes/Et2O) 0.75.
(()-3-Methoxy-17-methylestra-1,3,5(10),13(17)-tetraene (16).
Diene 15 (30 mg, 0.1 mmol) was added into a stirred solution
of Grubbs second generation catalyst (17 mg, 20 mol%) in
toluene (30 mL) and the mixture was heated at 90 °C for 16 h.
The mixture was cooled to 20 °C, solvent was removed under
reduced pressure, and the residue was purified on PTLC plate
to afford 22 mg (82%) of 16 as a colorless oil. 1H NMR (600.1
MHz, CDCl3) δ 0.97-1.04 (m, 1H), 1.11-1.18 (m, 1H),
1.35-1.43 (m, 2H), 1.63-1.64 (m, 3H), 1.93-2.00 (m, 2H),
2.10-2.15 (m, 1H), 2.21-2.32 (m, 3H), 2.40 (tm, J ) 10.8
Hz, 1H), 2.44-2.48 (m, 1H), 2.66 (ddd, J ) 14.2, 4.2, 2.3 Hz,
1H), 2.79-2.82 (m, 2H), 3.77 (s, 3H), 6.62 (dt, J ) 2.8, 1.0
Hz, 1H), 6.71 (ddt, J ) 8.8, 2.8, 0.7 Hz, 1H), 7.19 (dd, J )
8.8, 1.0 Hz, 1H); 13C NMR (150.9 MHz CDCl3) δ 13.5, 25.8,
27.6, 27.7, 30.4, 31.5, 37.2, 42.2, 49.0, 52.5, 55.2, 111.6, 113.6,
127.2, 128.6, 132.32, 135.9, 138.5, 157.2; IR (CCl4) 3084, 2930,
2857, 2840, 1688, 1611, 1576, 1501, 1465, 1454, 1257, 1043;
MS-EI (m/z) 268.1 (M+); HR-EI for C19H24O calcd 268.1827,
found 268.1832. Rf (96/4 hexanes/Et2O) 0.75.
Acknowledgment. This work was supported by the grant
project 1M0508 and MSM0021620857 from the Ministry of
Education of the Czech Republic.
Supporting Information Available: Experimental proce-
dures, detailed spectral characterization data, and spectra of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800620D
6206 J. Org. Chem. Vol. 73, No. 16, 2008