Stille/diels-alder reaction sequences: Diversity-oriented access to novel steroids

Article abstract of DOI:10.1021/ol062878m

An efficient, diversity-oriented approach to novel steroid analogues possessing a C-5β configuration begins with the Stille cross-coupling of enantiomerically pure cycloalkenylstannane trans-2 and enol triflate 3. The resulting diene trans-4 engages in Di

Full text of DOI:10.1021/ol062878m

ORGANIC
LETTERS
2007
Vol. 9, No. 3
517-520
Stille/Diels−Alder Reaction Sequences:
Diversity-Oriented Access to Novel
Steroids
Hans Wolf Su
Armin de Meijere*,†
1 1
nnemann,† Anja Hofmeister,‡ Jorg Magull,‡ Martin G. Banwell,§ and
Institut fu¨r Organische und Biomolekulare Chemie and Institut fu¨r Anorganische
Chemie der Georg-August-UniVersita¨t, Tammannstrasse 2-4, 37077 Go¨ttingen,
Germany, and Research School of Chemistry, Institute of AdVanced Studies,
The Australian National UniVersity, Canberra, ACT 0200, Australia
armin.demeijere@chemie.uni-goettingen.de
Received November 27, 2006
ABSTRACT
An efficient, diversity-oriented approach to novel steroid analogues possessing a C-5
enantiomerically pure cycloalkenylstannane trans-2 and enol triflate 3. The resulting diene trans-4 engages in Diels
with a range of dienophiles to give, after removal of protecting groups, biologically interesting 6,7-disubstituted steroid analogues.
â
configuration begins with the Stille cross-coupling of
−Alder cycloaddition reactions
Analogues of natural steroids are important compounds that
possess a wide spectrum of attractive biological properties.
For example, although the use of glucocorticoids as phar-
maceuticals can be accompanied by a range of undesirable
side effects,1 certain synthetic variants have been shown to
retain the desired biological activities while displaying none
of the adverse effects associated with their natural congeners.2
Despite the consequent and intense interest in synthetic
steroids,3 it is noteworthy that among the large arsenal of
established approaches to such compounds,4 diversity-
oriented access to steroidal skeleta capable of delivering large
collections of analogues is essentially unknown. Herein, we
report a new approach to the tetracyclic steroidal skeleton
that follows a convergent A + CD f ACD f ABCD ring-
assembling strategy utilizing a simple sequence of Stille
cross-coupling and Diels-Alder cycloaddition reactions that
achieves rapid increases in molecular complexity. The route
involved generates interesting and, thus far, rarely investi-
gated steroids incorporating substituents at C-6 and C-75 that
have been reported to enhance the biological activities of
steroids lacking groups at these positions.6
† Institut fu¨r Organische und Biomolekulare Chemie der Georg-August-
Universita¨t.
(4) (a) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1979, 101,
215-217. (b) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P.
S. Angew. Chem., Int. Ed. 2000, 39, 44-122.
‡ Institut fu¨r Anorganische Chemie der Georg-August-Universita¨t.
§ The Australian National University.
(1) Refojo, D.; Liberman, A. C.; Holsboer, F.; Arzt, E. Immunol. Cell
Biol. 2001, 79, 385-394.
(5) (a) Rickard, C. E. F.; Le Quesne, P. W. J. Org. Chem. 1998, 63,
1736. (b) Allevi, P.; Longo, A.; Anastasia, M. Tetrahedron 1999, 55, 4167-
4176. (c) Bondarenko, L.; Lorenc, L.; Bla¨ser, D.; Boese, R. Eur. J. Org.
Chem. 2004, 3526-3534.
(2) Fannon, S. A.; Vidaver, R. M.; Marts, S. A. J. Appl. Physiol. 2001,
91, 1854-1859.
(3) Cepa, M. M. D. S.; Tavares da Silva, E. J.; Correia-da-Silva, G.;
Roleira, F. M. F.; Teixeira, N. A. A. J. Med. Chem. 2005, 48, 6379-6385.
(6) Labaree, D. C.; Zhang, J.-x.; Harris, H. A.; O’Connor, C.; Reynolds,
T. Y.; Hochberg, R. B. J. Med. Chem. 2003, 46, 1886-1904.
10.1021/ol062878m CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

The reaction sequence starts (Scheme 1) with the selective
conversion of the readily available and enantiomerically
pure bicyclic enone 17 into either the cis- or trans-ring-
fused forms of the hexahydroindenylstannane 2 by sub-
jection of the former compound to appropriate reduction
conditions and then trapping of the resulting enolates to
generate the corresponding cis- or trans-configured enol
triflate in 71 and 83% yield, respectively.8-10 These last
species were then treated with lithium tri-n-butylstan-
nyl cuprate11 to give cis-2 or trans-2 in 85 and 92% yield,
respectively. The other partner required for the foresha-
dowed Stille cross-coupling reaction12 was the enol triflate
3, and this was prepared from the commercially available
monoethylene acetal of cyclohexane-1,4-dione by a new
protocol employing sodium bistrimethylsilylamide in di-
ethyl ether that allows the conversion of ketones into enol
triflates with the relatively inexpensive reagent trifluoro-
methanesulfonic acid anhydride.13 The best conditions for
carrying out the Stille cross-coupling of stannanes cis-2 and
trans-2 with compound 3 involved a procedure employing
Pd2(dba)3 with a copper(I) cocatalyst in the presence of
lithium chloride. By such means, the dienes cis-4 and trans-4
were obtained in 73 and 77% yield, respectively.
The cis-4 and trans-4 diastereomers each appear to be
reasonably well set up for participation in Diels-Alder
reactions to generate steroid-like adducts, although, in the
event, these dienes needed to be treated with rather reactive
dienophiles such as maleic acid derivatives so that the desired
cycloaddition reaction occurred. For example, upon heating
diene trans-4 with 1.5 equiv of fumaronitrile in refluxing
toluene (Scheme 2), the steroid analogue trans-5 was formed
in 84% yield. The structure of trans-5 follows from a single-
crystal X-ray analysis.14 An analogous reaction conducted
in benzene15 at 95 °C and employing N-methylmaleimide
as a dienophile afforded the adduct trans-6 in 79% yield.
The less reactive dienophile dimethyl acetylenedicarboxylate
engaged in the expected cycloaddition reaction with diene
trans-4 to give, in 65% yield, the steroidal compound trans-7
incorporating a 1,4-diene residue within the B-ring. The use
of unsymmetrically substituted dienophiles such as 2-chlo-
roacrylonitrile in these types of reactions afforded mixtures
of two regioisomeric adducts of trans-8 in a combined yield
of 67%. Such reactions did not proceed in significantly
greater yield when performed under high pressure. The novel
heterocyclic steroid analogue trans-9 was obtained in 77%
yield when N-phenyl-1,2,4-triazoline-3,5-dione was em-
ployed as a dienophile. Similarly, reaction of diene trans-4
with maleic anhydride produced, in 80% yield, adduct trans-
10 as proven by X-ray crystal structure analysis.14 Product
trans-10 should serve as a precursor to various interesting
steroidal diacid derivatives.
Scheme 1
All of the abovementioned steroids, viz. trans-5, trans-6,
trans-7, trans-8, trans-9, and trans-10, are new compounds
and were obtained as single diastereoisomers that must
necessarily be formed by endo-selective attack of the
dienophiles at the face of diene trans-4 opposite to the
angular methyl group attached at C-7a. It is important to
note that these steroid analogues possess the nonnatural
configuration at C-5.16 Furthermore, polar substituents at C-3
and C-17, which often confer beneficial biological properties
on steroids, are conveniently introduced using this Stille/
Diels-Alder sequence involving diene trans-4. Of course,
all of the steroidal products described herein are obtained in
(7) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland, L.
A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40,
675-681.
(8) (a) Goth, U.; Ko¨hler, T.; Taapken, T. Tetrahedron 1991, 47, 7583-
7592. (b) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835-3837.
(9) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(10) The trans-configured enol triflate was prepared by a multistep
procedure involving initial reduction of enone 1 with DIBAL-H/tert-BuCu
and treatment of the resulting diisobutylaluminum enolate with trimethylsilyl
chloride. The ensuing trimethylsilyl enol ether was cleaved with MeLi in
the presence of catalytic 4,4′-bipyridyl to form the more reactive lithium
enolate that was then treated with N,N-bis(trifluoromethylsulfonyl)aniline.
(11) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D.
Tetrahedron Lett. 1988, 29, 4795-4798.
(13) Standard conditions involving the presence of trimethylamine or
sodium carbonate failed to provide the desired product in satisfactory yield.
(14) The data relating to the single-crystal X-ray analyses of compounds
trans-5 and trans-10 (respectively) are contained in the files CCDC-611592
and CCDC-613303, and these have been deposited at the Cambridge
Crystallographic Data Centre. They can be accessed, free of charge, via
http://www.ccdc.cam.ac.uk/products/csd/request/.
(15) Using benzene instead of toluene as solvent generally provided the
cycloaddition products in significantly higher yields.
(16) For examples of steroids incorporating this configuration and
exhibiting interesting biological activities, see: (a) Kaufmann, G.; Schlegel,
J.; Eychenne, B.; Schubert, K. Exp. Clin. Endocrinol. 1983, 81, 222-227.
(b) Oettel, M.; Kaufmann, G.; Kurischko, A. Pharmazie 1993, 48, 541-
545.
(12) For reviews on the Stille cross-coupling reaction, see: (a) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652. (b)
Kosugi, M.; Fugami, K. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley: New York,
2002; pp 263-284. (c) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; pp 125-161.
518
Org. Lett., Vol. 9, No. 3, 2007

Scheme 2
enantiomerically pure form by virtue of the analogous nature
diene and the reduced capacity, therefore, of the angular
methyl and tert-butoxy groups to exert directing effects in
the cycloaddition process.
To generate compounds suitable for biological testing, the
capacity to effect cleavage of the ethylene acetal and tert-
butyl ether moieties within certain of the abovementioned
Diels-Alder adducts was examined (Scheme 4). In particu-
of the starting materials and the fact that there is no
possibility for racemization of preset stereogenic centers
during the course of the reaction sequences being employed.
The diastereoselectivity observed in the Diels-Alder
reaction between N-methylmaleimide and diene cis-4 (Scheme
3) was not as high as that associated with the analogous
Scheme 4
Scheme 3
process involving isomer trans-4. Thus, a 3:2 mixture of the
two possible adducts, cis-6R-11 and cis-6â-11, was obtained
in 62% combined yield. This outcome is attributed to the
more highly curved molecular architecture of the former
lar, the 1,3-dioxolane moieties within compounds trans-5 and
trans-6 were efficiently removed (95-99%) in aqueous
acetone using p-toluenesulfonic acid as a catalyst, and the
Org. Lett., Vol. 9, No. 3, 2007
519

tert-butyl ether residues within the resulting 3-oxo com-
pounds were best cleaved with trifluoroacetic acid in
dichloromethane.17 By such means, the steroids trans-12
and trans-13 were obtained in yields of 91 and 79%,
respectively.
Dehydrogenation of the steroidal diene trans-7 can gen-
erate new and interesting steroid analogues incorporating
an aromatic B-ring.18 Thus, treatment of trans-7 with
DDQ (Scheme 5) under previously reported conditions19
afforded a chromatographically separable mixture of com-
pound trans-14 (69% yield) and congener 15 (5%) incor-
porating a double bond in the D-ring.20
Acknowledgments. The State of Niedersachsen as well
as BASF AG, Schering AG, and Chemetall GmbH (Chemi-
cals) supported this work. H.W.S. is indebted to the German
Merit Foundation (Studienstiftung des Deutschen Volkes)
for a graduate student fellowship. The authors thank Dr.
Burkhard Knieriem, Go¨ttingen, for his careful proofreading
of the manuscript.
Supporting Information Available: Preparation and
1
characterization of selected compounds; H and 13C NMR
Scheme 5
spectra of compounds 3, cis-4, trans-4, trans-5, trans-6,
trans-7, trans-8, trans-9, trans-10, a mixture of cis-6R-11
and cis-6â-11, trans-12, trans-13, the monodeprotected
derivative of trans-6, the monodeprotected derivative of
trans-5, trans-14, and 15; and atomic displacement ellipsoid
plots for compounds trans-5 and trans-10. This material is
available free of charge via the Internet at http://
pubs.acs.org.
OL062878M
(18) (a) Numazawa, M.; Osawa, Y. J. Steroid Biochem. 1987, 26, 137-
143. (b) Neef, G.; Cleve, A.; Depke, G.; Eckle, E. Tetrahedron Lett. 1997,
38, 3897-3900.
(19) (a) Yamato, T.; Miyamoto, S.; Hironaka, T.; Miura, Y. Org. Lett.
2005, 7, 3-6. (b) Hilt, G.; Luers, S.; Smolko, K. I. Org. Lett. 2005, 7,
251-253.
(20) When an excess of DDQ and extended reaction times were
employed, compound 15 became the major product of reaction.
(17) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
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