One-step convergent synthesis of the steroid ring system via the coupling of gamma,delta-unsaturated Fischer carbene complexes with o-ethynylbenzaldehyde.

Article abstract of DOI:10.1021/ol0166404

[reaction: see text]. Simultaneous and stereoselective construction of the steroid B and C rings is observed in a tandem process involving the coupling of o-ethynylbenzaldehyde with 2-alkenylcyclopentylcarbene-chromium complexes.

Full text of DOI:10.1021/ol0166404

ORGANIC
LETTERS
2
001
Vol. 3, No. 22
535-3538
One-Step Convergent Synthesis of the
Steroid Ring System via the Coupling of
γ,δ-Unsaturated Fischer Carbene
3
Complexes with o-Ethynylbenzaldehyde
†
,†
‡
Binay K. Ghorai, James W. Herndon,* and Yiu-Fai Lam
Department of Chemistry & Biochemistry, New Mexico State UniVersity, MSC 3C,
Las Cruces, New Mexico 88003, and Department of Chemistry & Biochemistry,
UniVersity of Maryland, College Park, Maryland, 20742-2021
jherndon@nmsu.edu
Received August 23, 2001
ABSTRACT
Simultaneous and stereoselective construction of the steroid B and C rings is observed in a tandem process involving the coupling of
o-ethynylbenzaldehyde with 2-alkenylcyclopentylcarbene−chromium complexes.
Nearly one-third of all currently prescribed medications
the starting material and often necessitate a lengthy synthetic
procedure, thus destroying the overall convergency and
flexibility of the method. In a recent publication, we reported
1
contain the steroid ring system. Many medicinally important
2
steroid derivatives do not occur in nature and must be
synthesized in the laboratory. In addition, recently discovered
marine sterols of unusual structure have proven to be
(
2) Recent citations: (a) Cook, C. E.; Raje, P.; Lee, D. Y. W.; Kepler,
J. A. Org. Lett. 2001, 3, 1013-1016. (b) Fortin, D.; Gaudette, F.; Marsault,
E.; Deslongchamps, P. Tetrahedron 2001, 57, 4167-4177. (c) Anderson,
A.; Boyd, A. C.; Clark, J. K.; Fielding, L.; Gemmell, D. K.; Hamilton, N.
M.; Maidment, M. S.; May, V.; McGuire, R.; McPhail, P.; Sansbury, F.
H.; Sundaram, H.; Taylor, R. J. Med. Chem. 2000, 43, 4118-4125. (d)
Cabeza, M.; Quiroz, A.; Heuze, I.; Bratoeff, E.; Herrera, H.; Ramirez, E.;
Murillo, E. Proc. West. Pharmacol. Soc. 2000, 43, 31-32. (e) Sperry, T.
S.; Thomas, P. Biol. Reprod. 1999, 61, 1152-1161. (f) Hastings, N. B.;
Orchinik, M.; Aubourg, M. V.; McEwen, B. S. Endocrinology 1999, 140,
3
promising candidates for new pharmaceuticals. Total syn-
4
thesis of steroids from simple components can potentially
provide a more diverse array of steroidal therapeutic agents
than simple derivatization of naturally occurring steroids. A
variety of reaction processes exist for the construction of
the steroid ring system; however, most of these processes
involve multistep synthetic transformations. A few recent
reports highlight the construction of the steroid ring system
4
1
459-4469. (g) Little, R. J.; Bodor, N.; Loftsson, T. Pharm. Res. 1999,
6, 961-967. (h) Park-Chung, M.; Malayev, A.; Purdy, R. H.; Gibbs, T.
T.; Farb, D. H. Brain Res. 1999, 830, 72-87. (i) Nedvidkova, J.; Haluzik,
5
M.; Pacak, K.; Schreiber, V.; Starka, L. J. Steroid Biochem. Mol. Biol. 1998,
through tandem reaction processes. Historically, some of
6
1
7, 359-362. (j) Hult, M.; Jornvall, H.; Oppermann, U. C. T. FEBS Lett.
the most notable demonstrations of this approach utilize
998, 441, 25-28. (k) Gonzalez-Vidal, M. D.; Cervera-Gaviria, M.; Ruelas,
6
R.; Escobar, A.; Morali, G.; Cervantes, M. Arch. Med. Res. 1998, 29, 117-
intramolecular Diels-Alder reactions of o-quinonedimethanes
1
24. (l) Lemus, A. E.; Jaimez, R.; Lemini, C.; Menjivar, M.; Silva, G.;
7
and occasionally isobenzofurans. A disadvantage of this
Rubio-Poo, C.; Valenzuela, F.; Larrea, F. Steroids 1998, 63, 433-438. (m)
Dijkema, R.; Schoonen, W. G. E. J.; Teuwen, R.; Van Der Struik, E.; De
Ries, R. J. H.; Van Der Kar, B. A. T.; Olijve, W. J. Steroid Biochem. Mol.
Biol. 1998, 64, 147-156. (n) Hoffmann, K.; Auer, T.; Stucker, M.;
Hoffmann, A.; Altmeyer, P. J. Eur. Acad. Dermatol. Venereol. 1998, 10,
137-142.
(3) Lerch, M. L.; Faulkner, D. J. Tetrahedron 2001, 57, 4091-4094.
(4) (a) Zeelen, F. J. Nat. Prod. Rep. 1994, 11, 607-612. (b) Groen, M.
B.; Zeelen, F. J. Recl. TraV. Chim. Pays-Bas 1986, 105, 465-487.
approach is that most of the carbons are already in place in
†
New Mexico State University.
University of Maryland.
‡
(1) (a) Makin, H. L. J.; Trafford, D. J. H.; Nolan, J. Mass Spectra and
GC Data of Steroids; Wiley-VCH: Weinheim, 1998. (b) Zeelen, F. J.
Medicinal Chemistry of Steroids; Elsevier: Amsterdam, 1990.
1
0.1021/ol0166404 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/04/2001

Scheme 1
that isobenzofurans (e.g., 3, Scheme 1) can be generated from
ever, this reaction was only successful using 2-propenyl-
lithium. Alternatively, the requisite carbene complexes could
be prepared from the corresponding acid chlorides (10,
the couplings of Fischer carbene complexes (e.g., 2) with
8
o-alkynylbenzaldehyde derivatives (e.g., 1) and that these
intermediates are captured moderately efficiently through
intermolecular Diels-Alder reactions with electron deficient
alkenes. In this Letter, the coupling of 2-ethynylbenzaldehyde
with 2-alkenylcyclopentylcarbene complexes (6) will be
discussed, which ultimately results in a compound containing
Scheme 3) using pentacarbonylchromate dianions.11
A
Scheme 3
9
the steroid ring system (8) in a single operation from two
components featuring only the steroid A and D rings intact.
The same reaction that joins the A and D rings also generates
the reactiVe intermediates leading to the B and C rings.
Requisite trans 2-alkenylcyclopentylcarbene complexes (6)
were readily prepared using the series of reactions in
Schemes 2 and 3. Michael addition of alkenyllithium reagents
general synthetic route to ester analogues of acid chloride
0 is depicted in Scheme 4. Michael addition of sulfoxide-
stabilized carbanions (e.g., 16) to ω-iodo-R,â-unsaturated
1
Scheme 2
12
N
ester derivatives (e.g., 15), followed by intramolecular S 2
(7) (a) Peters, O.; Debaerdemaeker, T.; Friedrichsen, W. J. Chem. Soc.,
Perkin Trans. 1 1999, 59-70. (b) Hildebrandt, K.; Friedrichsen, W.
Heterocycles 1989, 29, 1243-1246.
(
8) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267-1269.
(9) Previous utilization of Fischer carbene complexes for steroid ring
construction has been documented; however, they are unrelated to the
reaction under discussion in this paper. (a) Bao, J.; Dragisch, V.;
Winglowsky, S.; Wulff, W. D. J. Am. Chem. Soc. 1991, 113, 9873-9875.
to cyclopentenylcarbene complex 9 offers the most straight-
forward route to the desired substrates (Scheme 2); how-
(
b) Aumann, R.; Meyer, A, G.; Fr o¨ lich, R. J. Am. Chem. Soc. 1996, 118,
1
0
10853-10861. (c) Woodgate, P. D.; Sutherland, H. S.; Rickard, C. E. F. J.
Organomet. Chem. 2001, 627, 206-220.
(10) For recent examples of successful Michael Additions using alkyl-
(
5) (a) Michellys, P. Y.; Marin, P.; Toupet, L.; Pellissier, H.; Santelli,
lithiums and aryllithiums, see: (a) Barluenga, J.; Montserrat, J. M.; Florez,
J.; Garcia-Granda, S.; Martin, E. Angew. Chem., Int. Ed. Engl. 1994, 33,
1392-1394. (b) Barluenga, J.; Bernad, P. L., Jr.; Concellon, J. M.; Pinera-
Nicolas, A.; Garcia-Granda, S. J. Org. Chem. 1997, 62, 6870-6875. (c)
Barluenga, J.; Bernad, P. L. Jr.; Concellon, J. M. Tetrahedron Lett. 1995,
36, 3937-3940.
(11) (a) Schwindt, M. A.; Lejon, T.; Hegedus, L. S. Organometallics
1990, 9, 2814-2819. (b) Semmelhack, M. F.; Lee, G. R. Organometallics
1987, 6, 1839-1844. (c) For specific use of this reaction for the synthesis
of γ,δ-unsaturated carbene complexes, see: Moser, W. H. Hegedus, L. S.
J. Am. Chem. Soc. 1996, 118, 7873-7880.
M. J. Org. Chem. 2001, 66, 115-122. (b) Tietze, L. F.; N o¨ bel, T.; Spescha,
M. J. Am. Chem. Soc. 1998, 120, 8971-8977.
(
6) (a) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. ReV. 1980, 9, 41-
6
1. (b) For the most recent example, see: Cachoux, F.; Ibrahim-Ouali, M.;
Santelli, M. Tetrahedron Lett. 2001, 42, 843-845. (c) Kametani, T.;
Nemoto, H. Tetrahedron 1981, 37, 3-16. (d) Nicolaou, K. C.; Barnette,
W. E.; Ma, P. J. Org. Chem. 1980, 45, 1463-1470. (e) Oppolzer, W.;
Petrzilka, M.; Baettig, K. HelV. Chim. Acta 1977, 60, 2964-2967. (f)
Quinkert, G.; Weber, W. D.; Schwartz, U.; Stark, H.; Baier, H. Duerner,
G. Liebigs Ann. Chem. 1981, 2335-2371.
3536
Org. Lett., Vol. 3, No. 22, 2001

chromatographic purification. The initial Diels-Alder prod-
uct 8A appears to be unstable with respect to ring opening
Scheme 4
13
processes. The cis hydrindane was the major isomer (about
0:40); however, the isomer ratio was not consistent over
6
several experiments. The isomers of 19A differ at the position
R to the ketone; 19A cis and trans were interconverted by
treatment with p-toluenesulfonic acid. Both products result
14
from intramolecular exo selective Diels-Alder reaction in
isobenzofuran intermediate 7A, which also proceeds with a
very high degree of relative asymmetric induction relative
to the allylic stereocenter in the starting carbene complex.
Subsequent ring opening of the initial Diels-Alder product
8
A followed by proton transfer and hydrolysis affords the
observed products, isomers of steroid derivative 19A. As
further verification of the steroid structure, treatment of 19A
with hydrochloric acid resulted in naphthalene derivative 20.
This reaction process was tested for a variety of similar
compounds (Scheme 6). Carbene complex 6B, which features
Scheme 6
reaction of the resulting enolate and spontaneous sulfoxide
elimination (conversion of 15 to 17), is the key step in this
synthetic sequence. A carbene complex derivative featuring
1
1c
a six-membered ring has previously been reported.
Coupling of carbene complex 6A (Scheme 5) with alkynyl
aldehyde 1A afforded tetracyclic compound 19A as a mixture
of two separable diastereomers in a combined yield of 66%.
The crude reaction mixture also showed an impurity con-
sistent with enol ether 18A, which hydrolyzed to 19A during
Scheme 5
an R methyl group, afforded tetracyclic compound 19B as a
single diastereomer in 49% yield. A trace amount of the
oxanorbornene-intact compound 8B could be observed in the
crude reaction mixture. Carbene complex 6C, which features
a six-membered ring, also afforded the expected compound
1
9C as a single diastereomer in 75% yield, assigned as the
trans diastereomer. The stereochemical configuration at the
carbon R to the ketone appears to be under thermodynamic
control since compounds 19A and 19C are of the opposite
(
12) Nakamura, S.; Watanabe, Y.; Toru, T. J. Org. Chem. 2000, 65,
1
758-1766. We have noticed that sulfoxide elimination from the initial
adduct of 15 and 16 is surprisingly rapid at room temperature; the literature
suggests the use of fluoride ion for simultaneous silicon and sulfoxide
elimination.
(
13) The sensitivity of the initial isobenzofuran Diels-Alder adducts is
well-noted. (a) Friedrichsen, W.; AdV. Heterocycl. Chem. 1999, 73, 1-96.
b) Rodrigo, R. Tetrahedron 1988, 44, 2093-2135.
(
(
14) For discussions of endo-exo selectivity in intramolecular Diels-
Alder reactions of isobenzofurans and related compounds, see: (a) Meegalla,
S. K.; Rodrigo, R. Synthesis 1989, 942-944. (b) Yamaguchi, Y.; Yamada,
H.; Hayakawa, K.; Kanematsu, K. J. Org. Chem. 1987, 52, 2040-2046.
(c) Tobia, D.; B. Rickborn, B. J. Org. Chem. 1987, 52, 2611-2615.
Org. Lett., Vol. 3, No. 22, 2001
3537

configuration at this carbon. The observed isomeric prefer-
synthesis of other pharmaceutically important compounds
is currently under examination.
15
ences parallel well-known trends in hydrindane and decalin
chemistry.16 An additional example featuring a 1,1-disub-
stituted alkene (6D) also afforded the desired steroidal
product (19D) in 60% yield. Formation of the trans hydrin-
dane system might be due to an unfavorable 1,3-diaxial
interaction between the methyl group and the five-membered
ring in the cis isomer in this case.
In summary, a one-step synthesis of the steroid ring system
from readily available components has been presented.
Further examination of this reaction for biologically relevant
steroids and application of the key reaction process for the
Acknowledgment. We thank the National Institutes of
Health (S01-GM08136-26), the NSF, and the Petroleum
Research Fund, administered by the American Chemical
Society, for financial support of this research. BKG is
thankful to the Bengal Engineering College (Deemed Uni-
versity), Howrah, India for Sabbatical Leave.
Supporting Information Available: Experimental pro-
cedures, characterization data for carbene complexes and
steroid derivatives, and discussion of stereochemical assign-
ments. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
15) (a) Lo Cicero, B.; Weisbuch, F.; Dana, G.; J. Org. Chem. 1981,
4
1
6, 914-919. (b) Allinger, N. L.; Tribble, M. T. Tetrahedron 1972, 28,
191-1202.
(
16) Thompson, H. W.; Long, D. J. J. Org. Chem. 1988, 53, 4201-
4
209.
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