A novel, versatile D→BCD steroid construction strategy, iIIustrated by the enantioselective total synthesis of estrone

Article abstract of DOI:10.1021/ol902638w

Chemical Equation presented A general steroid synthesis Is presented that relies on prior formation of three stereogenlc centers (C8, C13, and C14) on a D ring template, followed by C- and B-ring cyclizatlons. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation process, allows Introduction of structural variety as required. The method Is illustrated by the total synthesis of estrone via a C-ring closing metathesis and a B-ring Heck cyclization.

Full text of DOI:10.1021/ol902638w

ORGANIC
LETTERS
2010
Vol. 12, No. 4
680-683
A Novel, Versatile DfBCD Steroid
Construction Strategy, Illustrated by the
Enantioselective Total Synthesis of
Estrone
Vincent Foucher,† Benedetta Guizzardi,‡,† Marinus B. Groen,§ Mark Light,† and
Bruno Linclau*,†
UniVersity of Southampton, School of Chemistry, Highfield,
Southampton SO17 1BJ, United Kingdom and Organon, Molenstraat 110,
P.O. Box 20, 5340 BH Oss, The Netherlands
bruno.linclau@soton.ac.uk
Received November 18, 2009
ABSTRACT
A general steroid synthesis is presented that relies on prior formation of three stereogenic centers (C8, C13, and C14) on a D ring template,
followed by C- and B-ring cyclizations. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation
process, allows introduction of structural variety as required. The method is illustrated by the total synthesis of estrone via a C-ring closing
metathesis and a B-ring Heck cyclization.
Steroids are a very large class of compounds and display a
wide range of biological activities. Many steroid derivatives
have been synthesized as their biological evaluation is of
high interest.1 While their synthesis most commonly proceeds
via a hemisynthetic approach,2 many ingenious total syn-
theses continue to be reported.2,3
Scheme 1. Steroid Construction Strategy
A well-known problem in steroid synthesis is the formation
of the trans-fused CD ring junction without contamination
by the corresponding cis-isomer.4 Apart from employing
† University of Southampton.
trans-CD ring building blocks, this problem can be circum-
vented by employing a C ring cyclization strategy that
commences from a D ring precursor (or vice versa) already
‡ In memory of Benedetta Guizzardi.
§ Organon (currently part of Schering-Plough).
(1) (a) Shi, J.; Shigehisa, H.; Guerrero, C. A.; Shenvi, R. A.; Li, C.-C.;
Baran, P. S. Angew. Chem., Int. Ed. 2009, 48, 4328–4331. (b) Su¨nnemann,
H. W.; Hofmeister, A.; Magull, J.; de Meijere, A. Chem.-Eur. J. 2007,
13, 3739–3756, and refs cited therein.
(3) Selected examples: (a) Surendra, K.; Corey, E. J. J. Am. Chem. Soc.
2008, 130, 8865–8869. (b) Pattenden, G.; Stoker, D. A.; Thomson, N. M.
Org. Biomol. Chem. 2007, 5, 1776–1788. See also examples in ref 7.
(4) Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron 1998, 54, 12071–
12150.
(2) (a) Chapelon, A.-S.; Morale´da, D.; Rodriguez, R.; Ollivier, C.;
Santelli, M. Tetrahedron 2007, 63, 11511–11616. (b) Nising, C. F.; Bra¨se,
S. Angew. Chem., Int. Ed. 2008, 47, 9389–9391, and refs cited therein.
10.1021/ol902638w  2010 American Chemical Society
Published on Web 01/22/2010

Scheme 2. Retrosynthetic Analysis
containing the correct stereochemistry at the positions of the
future CD ring junction (C13 and C14), and this approach
has been widely exploited.2a,4,5
bond configuration being translated into the relative config-
uration of the sp3-centers of the formed C-C bond.8 The
desired relative C8-C14 configuration requires a Z-config-
uration of the phosphonate double bond. An enantioselective
synthesis is possible, eg by using a homochiral phosphona-
mide auxiliary as described by Hanessian.9 From 2, the
C-ring of estrone would be obtained via a ring closing
metathesis, followed by a B-ring Heck cyclization.7j
The extension of this concept, in which three stereocenters
C8, C13, and C14 would be established prior to C- and
B-ring cyclization, as illustrated by the sketch shown in
Scheme 1, has hardly been exploited.6 Hence, we envisioned
establishing a general approach to steroid synthesis featuring
a one-pot stereoselective assembly of a D-ring intermediate
A, which would then be subjected to appropriate cyclization
reaction groups to give a B-C-D skeleton.
Key requirements for this to be an attractive and versatile
synthetic strategy include convenient access to the intermedi-
ate A in a highly diastereo- and enantioselective fashion,
and, crucially, the viability to easily introduce suitable R1-
R4 groups in order to enable the synthesis of structurally
diverse steroid targets via a range of suitable cyclization
reactions. In this communication we will showcase our
approach toward steroid synthesis by the enantioselective
total synthesis of estrone 1.7
Hence, the corresponding retrosynthetic analysis of 1
(Scheme 2) involves a B- and C-ring disconnection to give
the key intermediate 2. This intermediate was envisioned to
be directly accessible by a one-pot process involving a
conjugate addition of an allylic phosphonate/phosphonamide
3, to be synthesized from 3-methyl anisole 5, to 2-methyl-
2-cyclopentenone acceptor 4, followed by diastereoselective
alkylation of the resulting enolate with allyl bromide.
Conjugate addition reactions of allylic phosphonates are
known to be very diastereoselective, with the allylic double
In general, this approach would allow convenient synthesis
of a D-ring intermediate (A, Scheme 1) with possible
introduction of R1-R3 groups by appropriate choice of starting
materials. The R4 group, restricted to an E-vinylic phospho-
namide/phosphonate, was thought of as a versatile reactive
handle to achieve the B and C ring cyclizations.
The synthesis of the substrates 3 for the conjugate addition
is shown in Scheme 3. Starting from the known dibromide
6, accessible in one step from 3-methyl anisole 5,10 benzylic
displacement with allenyl magnesium bromide11 followed
by one-carbon extension led to the propargylic alcohol 7.
Diastereoselective alkyne reduction (>98% Z) was achieved
with Zn/BrCH2CH2Br,12 which proved consistently repro-
ducible even upon upscaling, unlike more conventional
methods using poisoned heterogeneous Pd-catalysts. Conver-
sion to the Z-allylic chloride 8 using hexachloroacetone,13
and final Arbuzov reaction with triethyl phosphite gave 3a
in excellent overall yield. The homochiral phosphonamide
3b was obtained by reaction of 8 with homochiral phos-
pholane 9.14
The key conjugate addition/allylation sequence was in-
vestigated next (Scheme 4). Deprotonation of 3a with BuLi,
followed by addition to 2-methyl-2- cyclopentenone 4 and
final alkylation with allyl bromide, gave 2a as the only
observable diastereomer in excellent yield. The conjugate
(5) Early examples in estrone synthesis of this approach: (a) Lentz,
C. M.; Posner, G. H. Tetrahedron Lett. 1978, 40, 3769–3772. (b) Kametani,
T.; Matsumoto, H.; Nemoto, H.; Kukumoto, K. J. Am. Chem. Soc. 1978,
100, 6218–6220. (c) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1980, 102, 5253–5261. (d) Quinkert, G.; Schwartz, U.; Stark, H.; Weber,
W.-D.; Baier, H.; Adam, F.; Du¨rner, G. Angew. Chem., Int. Ed. 1980, 19,
1029–1030. (e) Oppolzer, W.; Roberts, D. A. HelV. Chim. Acta 1980, 63,
(8) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. ReV. 1999,
99, 665–722.
1703–1705
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2090.
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(9) (a) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve´, Y.; Beaudoin,
S. J. Org. Chem. 1993, 58, 5032–5034. (b) Hanessian, S.; Gomtsyan, A.;
Malek, N. J. Org. Chem. 2000, 65, 5623–5631. Reviews: (c) Molt, O.;
Schrader, T. Synthesis 2002, 2633–2670. (d) Bennani, Y. L.; Hanessian, S.
Chem. ReV. 1997, 97, 3161–3195.
(7) Examples of recent estrone syntheses: (a) Canales, E.; Corey, E. J.
Org. Lett. 2008, 10, 3271–3273. (b) Soorukam, D.; Knochel, P. Org. Lett.
2007, 9, 1021–1023. (c) Hakuba, H.; Kitagaki, S.; Mukai, C. Tetrahedron
2007, 63, 12639–12645. (d) Yeung, Y.-Y.; Chein, R.-J.; Corey, E. J. J. Am.
Chem. Soc. 2007, 129, 10346–10347. (e) Cai, Z. Y.; Covey, D. F. Steroids
2007, 72, 351–359. (f) Pattenden, G.; Gonzalez, M. A.; McCulloch, S.;
Walter, A.; Woodhead, S. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12024–
12029. (g) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 5984–5986. (h) Tanaka, K.; Nakashima, H.; Taniguchi, T.; Ogasawara,
K. Org. Lett. 2000, 2, 1915–1917. (i) Rigby, J. H.; Warshakoon, N. C.;
Payen, A. J. J. Am. Chem. Soc. 1999, 121, 8237–8245. (j) Tietze, L. F.;
No¨bel, T.; Spesha, M. J. Am. Chem. Soc. 1998, 120, 8971–8977.
(10) Hoye, T. R.; Mi, L. J. Org. Chem. 1997, 62, 8586–8588.
(11) (a) Hopf, H.; Bohm, I.; Kleinschroth, J. Org. Synth. 1981, 60, 41–
48. (b) Do¨tz, K. H.; Gerhardt, A. J. Organomet. Chem. 1999, 578, 223–
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(12) Aerssens, M. H. P. J.; Brandsma, L. J. Chem. Soc.; Chem. Commun.
1984, 735–736.
(13) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. Tetrahedron Lett.
1977, 35, 2999–3002.
(14) Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. J. Am. Chem.
Soc. 1984, 106, 5754–5756.
Org. Lett., Vol. 12, No. 4, 2010
681

Scheme 3. Synthesis of the Phosphonate/Phosphonamide Conjugate Addition Substrates
Scheme 4. Diastereoselective Conjugate Addition-Alkylation
addition/alkylation process with the homochiral allylic phos-
desired relative configuration of the C8, C13, and C14
phonamide 3b proceeded in a slightly lower yield, leading
to 2b as the only isolated diastereomer. In both cases, the
corresponding nonallylated product 10 was also isolated, as
well as, surprisingly, a diallylation product 11. It is believed
that the formation of both byproducts originate from the same
process, in that the obtained enolate after conjugate addition
reaction deprotonates already formed allylation product 2 to
give 10 and a new enolate, which is then allylated to give
11. Both byproducts are separable by chromatography. It was
important to use a limited excess (1.1 equiv) of BuLi to avoid
concomitant bromine- lithium exchange, which led to the
formation of the corresponding debrominated products (not
shown). Fortunately, the relative configuration of 2a could
be unambiguously established by X-ray crystallographic
analysis (Figure 1), which confirmed the formation of the
stereogenic centers.
With the key intermediates 2 in hand, the subsequent
cyclization reactions to give estrone were accomplished
(Scheme 5). The C-ring closure by ring closing metathesis
to the trans-hydrindene ring15 was investigated first using
the racemic phosphonate 2a. RCM reaction using the
Hoveyda-Grubbs II catalyst in toluene16 at 70 °C17 afforded
trans-hydrindene rac-12 in good yield. Small amounts (up
to 3%) of debrominated product18sseparable by chromato-
graphyscould be observed (NMR) when the Grubbs II
catalyst19 was used. From rac-12 onward, the estrone
synthesis is similar to the Tietze estrone synthesis (in which
the C17 ketone was protected as tbutyl ether).7j The ∆9,11
double bond resulting from the RCM reaction is ideally
positioned for the subsequent Heck B-ring closure, which
proceeded in quantitative yield under conditions developed
by Tietze. This led to 13, with the undesired 9ꢀ-configura-
tion. This can be converted to the desired configuration under
particular conditions in which the ∆11,12 double bond in
13 is isomerized to its conjugated position, followed by
hydrogenation, a process also developed by Tietze. In our
case, the isomerization/hydrogenation process from 13 led
to a 7:3 mixture of O-methyl estrone 14 and its 9ꢀ-epimer,
(15) (a) Ho¨lder, S.; Blechert, S. Synlett 1996, 505–506. RCM to give
strained olefins: (b) Collins, S. K. J. Organomet. Chem. 2006, 691, 5122–
5128.
(16) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799. (b) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168–8179. (c) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett.
2000, 41, 9973–9976.
Figure 1. Crystal structure of 2a.
(17) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K. Chem.sEur.
J. 2008, 14, 806–818.
682
Org. Lett., Vol. 12, No. 4, 2010

Scheme 5. Successive Cyclizations to Achieve the Estrone Synthesis
in almost quantitative yield. Presumably, the different C17
functionalization is the reason for the difference in stereo-
chemical outcome compared to Tietze’s report. Our results
are in accord with a literature report in which ∆9,11-O-
methyl estrone was converted to a 65:35 mixture of 14 and
9ꢀ-14 using H2, Pd/C.20 Estrone methyl ether could be
obtained pure by crystallization, and estrone 1 was then
obtained by conventional deprotection.21
An enantioselective synthesis was achieved from 3b.
Unfortunately, the RCM reaction only proceeded well after
prior hydrolysis of the phosphonamide group to the corre-
sponding phosphonic acid 2c. Starting from 2b, only 6% of
12 was obtained. The thus synthesized enantioenriched 12
was then taken through to O-methyl estrone 14, of which
optical rotation compared well with the reported value for
authentic estrone methyl ether.22
obtain the desired steroid target by a chosen B and C-ring
cyclization event. We have validated this strategy with the
synthesis of estrone. Importantly, it was shown that a
phosphonate/phosphonamide-based congugate addition/eno-
late alkylation process led to the desired key intermediate
in diastereomerically pure form, and that by using a
homochiral auxiliary an enantioselective synthesis is possible.
Our work also demonstrated an extension in scope of the
Hanessian conjugate addition by using a more complex
allylic substituent. We expect that this methodology will be
useful for the synthesis of a wide range of unnatural steroids
including steroid hybrids,23 and further work toward this goal
is in progress.
Acknowledgment. We thank Organon and the EPSRC for
studentships to B.G. and V.F.
In conclusion, we have proposed a potentially versatile
steroid construction strategy based on the formation of an
intermediate that contains the correct C8, C13, and C14
configuration with suitable functionalization to subsequently
Supporting Information Available: Experimental pro-
1
cedures and spectral data, including copies of H and 13C
NMR spectra, for compounds 1-3, 7, 8, 10-14, and the
debrominated product arising from the RCM reaction. The
crystal information file for compound 2a is also included.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The starting material 2a was not contaminated with debrominated
side-product.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(20) Hutchinson, J. H.; Money, T. Can. J. Chem. 1987, 65, 1–6.
(21) Node, M.; Ohta, K.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K.
Chem. Pharm. Bull. 1983, 31, 4178–4180.
OL902638W
(23) Reviews: (a) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew.
Chem., Int. Ed. 2003, 42, 3996–4028. (b) Salunke, D. B.; Hazra, B. G.;
Pore, V. S. Curr. Med. Chem. 2006, 13, 813–847.
(22) Taber, D. F.; Raman, K.; Gaul, M. D. J. Org. Chem. 1987, 52,
28–34.
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