Synthesis of (±)-3-methoxyestra-1,3,5(10)-trienes by the repetitive use of Negishi reagent

Article abstract of DOI:10.1021/ol053119r

The repetitive use of Cp₂ZrBu₂ (Negishi reagent) was applied in the synthesis of three 3-methoxyestra-1,3,5(10)-trienone isomers within four steps from the advanced intermediate 11. The overall synthesis is based on three zirconium-m

Full text of DOI:10.1021/ol053119r

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1315-1318
Synthesis of
)-3-Methoxyestra-1,3,5(10)-trienes by
the Repetitive Use of Negishi Reagent†
(±
Pavel Herrmann,‡,§ Martin Kotora,*,‡,§ Milosˇ Budeˇsˇ´ınsky´,§ David Saman,§ and
ˇ
|
Ivana C´ısarˇova´
Department of Organic and Nuclear Chemistry, Faculty of Science, Charles
UniVersity, HlaVoVa 8, 128 43 Praha 2, Czech Republic, Institute of Organic
Chemistry and Biochemistry, FlemingoVo na´m. 2, 166 10 Praha 6, Czech Republic,
and Department of Inorganic Chemistry, Faculty of Science, Charles UniVersity,
HlaVoVa 8, 128 43 Praha 2 Czech Republic
kotora@natur.cuni.cz
Received December 23, 2005
ABSTRACT
The repetitive use of Cp2ZrBu2 (Negishi reagent) was applied in the synthesis of three 3-methoxyestra-1,3,5(10)-trienone isomers within four
steps from the advanced intermediate 11. The overall synthesis is based on three zirconium-mediated reactions: (a) oxidative addition of a
benzyl ether, (b) cyclization of an allyl-ene compound, and (c) cyclocarbonylation of a diene. The presented synthesis demonstrates that
complex organic compounds can be prepared by the repetitive use of one reagent.
The introduction of transition-metal compounds into organic
synthesis has been responsible for an unprecedented explo-
sion of new and efficient C-C bond formation reactions.
Their use in syntheses of natural compounds has often been
regarded as the touchstone of their synthetic utility.1 In this
regard, one of the favorite targets is steroids and their
derivatives. There have been reported several syntheses of
the steroid framework that relied in one of their key steps
on a transition-metal-based reaction such as Co-catalyzed
[2 + 2 + 2]-cyclotrimerization of alkynes,2,3 Pd-catalyzed
Heck reaction4,5 and cascade cyclization of polyenes and
polyynes,6-8 Rh-catalyzed dimerization of diallenes,9 zir-
conocene-mediated cyclization of dienes,10 or oxidative
addition to zirconocene.11 Nonetheless, to the best of our
knowledge, there has not been a report in which the synthesis
of the whole steroid framework bearing the corresponding
functional groups would be accomplished by the repetitive
use of one transition-metal-based reagent. Herein, we would
like to report on a new synthetic strategy for the synthesis
(4) (a) Tietze, L. F.; No¨bel, T.; Spescha, M. J. Am. Chem. Soc. 1998,
120, 0, 8971-8977. (b) Tietze, L. F.; J. Wiegand, M.; Vock, C. J.
Organomet. Chem. 2003, 687, 346-352.
(5) Sinnemann, H. W.; de Meijere, A. Angew. Chem., Int. Ed. 2004, 43,
895-897.
† Dedicated to Professor Ei-ichi Negishi on the occasion of his 70th
birthday.
(6) Zhang, Y.; Wu, G.; Agnel, G.; Negishi, E. J. Am. Chem. Soc. 1990,
112, 8590-8592.
‡ Department of Organic and Nuclear Chemistry, Charles University.
§ Institute of Organic Chemistry and Biochemistry.
(7) Gauthier, V.; Cazes, B.; Gore, J. Tetrahedron Lett. 1991, 32, 915-
918.
| Department of Inorganic Chemistry, Charles University.
(1) (a) Nicolaou, K. C.; Sorensen, E. J.Classics in Total Synthesis; Wiley-
VCH: Weinheim, Germany, 1996. (b) Nicolaou, K. C.; Snyder, S. A.
Classics in Total Synthesis II; Wiley-VCH: Weinheim, Germany, 2003.
(2) (a) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 2,
5253-5261. (b) Lecker, S. H.; Nguyen, N. H.; K. P. C. J. Am. Chem. Soc.
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4495-4498.
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10.1021/ol053119r CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/01/2006

Scheme 1. Synthesis of Estratrienes 7-9
of steroids based on the exclusive application of known
(Scheme 1) to verify its feasibility. The starting compound,
styrene 3, was prepared in two steps (62% yield) by
benzylation of the commercially available iodobenzyl alcohol
2 followed by Stille coupling under standard conditions.13
The oxidative addition of the ether C-O bond14,15 of 3 to
Cp2ZrBu2 (easily prepared from Cp2ZrCl2 and n-BuLi)
followed by CuCl-catalyzed reaction with 3,4-dichlo-
robutene16 yielded the unstable chloroallyl-ene 4 (83%),
which was immediately converted into the methoxyallyl-ene
5 by the reaction with MeONa (66%). The cyclization of 5
with Cp2ZrBu2 gave a monorganozirconium species17,18 that
reacted with methallyl chloride in the presence of a catalytic
amount of CuCl to furnish the trans-diene 6.
zirconocene methodology. The construction of steroid frame-
work including the required functional groups is demon-
strated in the total synthesis of stereoisomers of (()-3-
methoxyestra-1,3,5(10)-trien-16-ones 1a-c (Figure 1).
Treatment of diene 6 with Cp2ZrBu2 and CO afforded after
quenching with molecular iodine a complex reaction mixture.
Out of it was isolated the ketone 7 (12%), the iodoketone 8
(13%), a mixture of compounds that, according to NMR
analysis, seemed to be a mixture alcohols 9 (11%), and a
fraction that was a mixture of the alcohols 9 and the ketone
7 (10%). Thus, the total amount of isolated tetracyclic
compounds was 46%. The ketone 7 was desired target
compound (12%), however, with an unnatural cis configu-
ration on the fusion of the ring C and D. The formation of
the iodoketone 8 was rather surprising because, to the best
Figure 1. Three stereoisomers of (()-3-methoxyestra-1,3,5(10)-
triene-16-one.
The initial impetus for this venture was our interest in
synthesis of complex organic compounds (e.g., natural
compounds) by the repetitive use of one reagent that would
act as a molecular “monkey-wrench” and would introduce
various structural features of the target compound in each
step. In this regard, we focused on the use of zirconocene-
based methodology because of its well-known ability to form
various types of organozirconium species that participate in
a plethora of C-C bond formation reactions. The main
advantage of the zirconocene methodology is that organozir-
conium species are usually easily prepared by a simple
reaction of Cp2ZrBu2 (Negishi reagent) with various sub-
strates.12
(13) McKeaw, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org.
Chem. 1987, 52, 422-424.
(14) (a) Hanzawa, Y.; Ikeuchi, Y.; Nakamura, T.; Taguchi, T. Tetrahe-
dron Lett. 1995, 36, 6503-6506. (b) Ikeuchi, Y.; Taguchi, T.; Hanzawa,
Y. Tetrahedron Lett. 2004, 45, 3717-3720. (c) Ikeuchi, Y.; Taguchi, T.;
Hanzawa, Y. J. Org. Chem. 2005, 70, 756-759.
(15) For other oxidative addition reactions to Cp2ZrBu2, see: (a) Rousset,
C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E. Tetrahedron Lett. 1989, 30,
5105-5108. (b) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992,
33, 1295-1298. (c) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y.
Tetrahedron Lett. 1992, 33, 3769-3772. (d) Ito, H.; Taguchi, T.; Hanzawa,
Y. J. Org. Chem. 1993, 58, 774-775. (e) Takahashi, T.; Kotora, M.; Fischer,
R.; Nishihara, Y.; Nakajima, K. J. Am. Chem. Soc. 1995, 117, 11039-
11040. (f) Liard, A.; Marek, I. J. Org. Chem. 2000, 65, 7218-7220.
(16) For other 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.
Initially, we decided to apply the above-mentioned meth-
odology in the synthesis of the estra-1,3,5(10)-triene skeleton
(12) (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.
(17) Takahashi, T.; Kondakov, D. Y.; Suzuki, N. Organometallics 1994,
13, 3411-3412.
(18) Knight, K. S.; Waymouth, R. M. Organometallics 1994, 13, 2575-
2577.
1316
Org. Lett., Vol. 8, No. 7, 2006

Scheme 2. Synthesis of 3-Methoxyestratrienes 1a-c
of our knowledge, the formation of an iodoketone in this
organozirconium intermediate with methallyl chloride af-
forded the trans-diene 14 in good 93% yield. Carbonylation
of the zirconacyclopentane formed by treatment of 14 with
Cp2ZrBu2 afforded, after workup and column chromatogra-
phy, a mixture of trans-anti-cis 1a22 and cis-anti-cis 1b in
combined yield of 49% in 3:1 ratio. In contrast to the
previous method, the reaction mixture was quenched with 3
M HCl to avoid the formation of iodoketone. Since it has
been shown that intramolecular reaction of dienes with Cp2-
ZrBu2 can be carried out under conditions of either kinetic
or thermodynamic control,19,23 the zirconacycle formed by
the reaction of the diene 14 with Cp2ZrBu2 was equilibrated
at 80 °C for 4 h before carbonylation. Although considerable
thermal degradation was observed under these conditions,
the product 1c with the natural trans-anti-trans relative
stereochemistry24 was isolated in 11% yield along with a
number of other unidentified products.
reaction has not been reported before. (On the other hand,
the formation of R-iodoketones in steroids was reported under
similar conditions.)19 The structure and stereochemistry of
8 was derived from NMR spectra and confirmed by a single-
crystal X-ray diffraction analysis (see the Supporting Infor-
mation). The iodoketone 8 was transformed into the ketone
7 by reductive dehalogenation with tributyltin hydride in 39%
yield, confirming that the both compounds have the same
stereochemistry.
Although the final cyclization proceeded with cis-stereo-
selectivity20 and the final target compounds had unnatural
trans-anti-cis relative stereochemistry, this result proved that
our strategy was correct, and we decided not to optimize
the synthetic steps, but instead to embark directly on the
synthesis of (()-3-methoxyestra-1,3,5(10)-trien-16-ones 1.
The starting point of our synthesis of 3-methoxyestra-
1,3,5(10)-trien-16-ones 1 (Scheme 2) was styrene 11, which
was prepared from the commercially available benzoic acid
10 by reduction with BH3‚THF, alkylation with BnBr,14c and
vinylation under Suzuki conditions (57% for three steps).21
(It is necessary to note that Suzuki coupling was unexpect-
edly accompanied by reductive dehalogenation of the starting
material to 3-methoxybenzyl ether (30%), which was in-
separable from 11. Thus, it was necessary to use the mixture
of both compounds in the next step.)
The structure of 1a was confirmed by a single-crystal
X-ray analysis (see Figure 2). The relative configurations at
carbon atoms 8, 9, 13, and 14 in compounds 7-9 and 1a-c
were also established from detailed analysis of NMR spectra.
The observed characteristic vicinal J(H,H) and NOE contacts
in stereoisomers 1a-c are shown in Figure 3.
In the synthesis of three estratrienes 1a-c that is sum-
marized in Scheme 2, the steroid framework was established
in three zirconium-mediated steps: (a) oxidative addition of
The oxidative addition of the styrene 11 to Cp2ZrBu2
followed by CuCl-catalyzed reaction with 3,4-dichlorobutene
yielded the desired chloroallyl-ene 12 in 67% isolated yield.
Methoxylation of 12 with MeONa proved to be rather
troublesome; nonetheless, a reasonable yield of the methoxy
derivative 13 (67%) was achieved in DMF (carrying out the
reaction in MeOH as in the previous case furnished 13 in
13% yield only). The stereoselective cyclization of 13 with
Cp2ZrBu2 and CuCl-catalyzed alkylation of the formed
(22) 1H and 13C NMR data of 1a were in agreement with published
data: (a) Nambara, T. Chem. Pharm. Bull. 1972, 20, 2156-2162. (b)
Mernya´k, E.; Scho¨necker, B.; Lange, C.; Ko¨tteritzsch, M.; Go¨rls, H.;
Wo¨lfling, J.; Schneider, G. Steroids 2003, 68, 289-295.
(23) (a) Akita, M.; Yasuda, H.; Yamamoto, H.; Nakamura, A. Polyhedron
1991, 10, 1-9. (b) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.;
Dixon, D. A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457-9463.
For application of zirconacycle isomerization in syntheses of natural
products, see also: (c) Taber, D. F.; Wang, Y. J. Am. Chem. Soc. 1997,
119, 22-26. (d) Taber, D. F.; Wang, Y. Tetrahedron Lett. 1995, 36, 6639-
6642. (e) Tuckett, M. W.; Watkins, W. J.; Whitby, R. J. Tetrahedron Lett.
1998, 39, 123-126. (f) Taber, D. F.; Cambell, C. L.; Louey, J. P.; Wang,
Y.; Zhang, W. Curr. Org. Chem. 2000, 4, 809-819.
(19) Mueller, G. P.; Johns, W. F. J. Org. Chem. 1961, 26, 2403-2413.
(20) For cis-selective cyclization, see: Takahashi, T.; Kotora, M.; Kasai,
K. J. Chem. Soc., Chem. Commun. 1994, 2693-2694.
(21) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866-
867.
(24) 1H and 13C NMR data of 1c were in agreement with published
data: (a) Wittstruck, T. A.; Williams, K. I. H. J. Org. Chem. 1973, 38,
1542-1548. (b) Erker, G.; Mollenkopf, C.; Grehl M.; Scho¨necker, B. Chem.
Ber. 1994, 127, 2341-2345.
Org. Lett., Vol. 8, No. 7, 2006
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cyclization of 5 to 6 and 13 to 14 proceeded with more than
98% stereoselectivity to give the desired trans isomers,
despite the fact that zirconium-mediated cyclizations usually
give preferentially cis-products when six-membered rings are
formed.12,21 Another interesting phenomenon is the formation
of isomer 1b during the final cyclocarbonylation. However,
the origin of its formation is at the moment unclear. Attempts
to isomerize 1a into 1b under the cyclocarbonylation or
workup conditions were not met with success. One of the
possible explanations may be based on the reversible 1,3-
hydrogen shift caused by the abstraction of the allylic
hydrogen on C-8 atom prior to the cyclization of the diene
14.25 Hopefully, future reactions with chiral intermediates
will provide clear-cut clues at what carbon atom and in which
stage of cyclocarbonylation actually a change of configura-
tion takes place.
Figure 2. Overall view of 1a. The displacement ellipsoids are
drawn at the 50% probability level (PLATON).
In conclusion, the presented results demonstrate a proof
of the principle, i.e., synthesis of a complex organic
compound can be achieved by the repetitive use of one
reagent, which acts as a molecular “monkey-wrench”. In this
manner, stereoisomeric (()-3-methoxyestra-1,3,5(10)-trienes
1a-c were synthesized in four steps from the advanced
intermediate styrene 11 or seven steps from the commercially
available benzoic acid 10. Optimization of individual steps,
the scope of this methodology with respect to the synthesis
of other steroid derivatives, and enantioselective synthesis
are currently under investigation.
Acknowledgment. This project was supported by Project
No. 1M0508 to the Centre for New Antivirals and Antineo-
plastics from Ministry of Education of the Czech Republic.
Supporting Information Available: Detailed experi-
1
mental procedures, characterization data, and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 3. Characteristic vicinal coupling constants and NOE
contacts in 1a-c.
OL053119R
a benzyl ether, (b) cyclization of an allyl-ene, and (c)
cyclocarbonylation of a diene. It is noteworthy that the
(25) Negishi, E.; Maye, J. P.; Choueiry, D. Tetrahedron 1995, 51, 4447-
4462.
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Org. Lett., Vol. 8, No. 7, 2006