A new flexible synthesis of (D-homo) steroids

Article abstract of DOI:10.1016/j.tetlet.2004.10.102

A short, flexible and efficient procedure has been developed for the synthesis of C17 substituted steroid skeletons and D-homo steroid skeletons using a ZnBr₂ catalysed coupling of a silyl enol ether containing ring D precursor with a Torgov type reagent, followed by acid catalysed cyclisation of the adducts to (D-homo) steroid skeletons.

Full text of DOI:10.1016/j.tetlet.2004.10.102

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9431–9433
A new flexible synthesis of (D-homo) steroids
*
`
Florence C. E. Saraber and Aede de Groot
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
Received 20 August 2004; revised 11 October 2004; accepted 19 October 2004
Available online 5 November 2004
Abstract—A short, flexible and efficient procedure has been developed for the synthesis of C17 substituted steroid skeletons and D-
homo steroid skeletons using a ZnBr2 catalysed coupling of a silyl enol ether containing ring D precursor with a Torgov type rea-
gent, followed by acid catalysed cyclisation of the adducts to (D-homo) steroid skeletons.
Ó 2004 Elsevier Ltd. All rights reserved.
The construction of ring C as the final stepin total syn-
theses of skeletons of steroids is well known because of
the good results using the Torgov reaction.1–12 Recently
we published a short approach to the synthesis of (D-
homo) steroids, where the closure of ring C relies on
the construction of the C12–C13 bond via a Lewis acid
catalysed intramolecular reaction of a Torgov type inter-
mediate with a silyl enol ether in ring D.13 Ring C clo-
sure in this way leads to a cis fused CD-ring system in
the (D-homo) steroid.
products from the normal Torgov reaction (Scheme 1).
Selective (catalytic) reduction of the double bonds
should then complete the synthesis of the trans CD fused
(D-homo) steroids. Examples of the Lewis acid cata-
lysed alkylations of silyl enol ethers with suitable carbo-
cation precursors are known and showed good
precedent for such an approach.15–17
The silyl enol ether containing ring D precursors 2 were
obtained by conjugate addition followed by capture of
the enolate with a silylating agent, via Mukaiyama
Michael reactions on enones with transfer of the silyl
groupfrom the starting silyl enol ether to the enol of
the adduct, or by direct silylation of ketones. Our
experience with the synthesis of CD cis fused (D-homo)
steroid skeletons had shown that tert-butyldimethylsilyl
(TBDMS) enol ethers are often the best compromise
between stability and reactivity in Lewis acid catalysed
reactions, but sometimes the more reactive trimethylsilyl
It seemed feasible to developa short synthesis for trans
CD fused (D-homo) steroids using similar chemistry. An
intermolecular Lewis acid catalysed reaction of a Torgov
type reagent 1 with a silyl enol ether containing ring D
precursor 2 should give quick access to C8–C14 seco
steroid skeletons 3.14 Acid catalysed closure of ring C
should lead to (D-homo) steroid skeletons 4 with a sim-
ilar set of double bonds in the C and D rings as in the
R
R
R
12
17
13
n
n
OH
ZnBr2
n
pTsOH
O
14
TBDMSO
8
MeO
MeO
MeO
1
2 n = 1,2
3 n = 1,2
4 n = 1,2
Scheme 1.
Keywords: Torgov type reactions; Silyl enol ethers; Steroid synthesis.
*
Corresponding author. Tel.: +31 317482370; fax: +31 317484914; e-mail: aede.degroot@wur.nl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.102

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F. C. E. Saraber, A. de Groot / Tetrahedron Letters 45 (2004) 9431–9433
9432
Table 1.
Silyl enol ethers
Coupling product (% yield)
Cyclisation product (% yield)
O
TBDMSO
TBDMSO
5
19 (87%)
12 (84%)
MeO
MeO
MeO
O
20 (82%)
2 isomers 2:1
13 (83%)
2 isomers 2:1
6
MeO
O
TMSO
21 (79%)
14 (83%)
7
MeO
MeO
MeO
∗
∗
∗
COOMe
COOMe
COOMe
a
O
TMSO
TMSO
8
15 (57%)
2 isomers 7:5
22 (91%)
2 isomers 7:5
MeO
2 isomers 7:5
O
MeO
MeO
16 (64%)
2 isomers 2:1
23 (87%)
2 isomers 2:1
9
b
O
TBDMSO
TBDMSO
10
MeO
MeO
17 (72%)
MeO
MeO
24 (88%)
O
18 (20%)
2 isomers 2:1
25 (75%)
2 isomers 2:1
11
a For both isomers of 22 the depicted stereochemistry was confirmed using NOE experiments.
b Using P2O5 as a catalyst.
(TMS) enol ethers had to be used. ZnBr2 was chosen as
the Lewis acid catalyst16 and all coupling reactions were
performed at À10°C, in CH2Cl2 as solvent.
The ring closure reactions of the seco steroids to the
unsaturated steroids 19–23 all gave good results using
mildly acidic conditions (catalytic pTsOH in benzene,
40°C).19
Under these conditions reactions of the Torgov reagent
1 with silyl enol ethers of the substituted cyclopenta-
nones 5–9 giving seco steroids 12–16 proceeded in good
to excellent yields, as can be seen in Table 1. Steric hin-
drance did not hamper the yields and, indeed, improved
the stereoselectivity from good to excellent as can be
seen for compounds 13 and 14. Even when the silyl enol
ether had an ethyl groupat C2, as in 9, a good yield of
its coupling product with the Torgov reagent could be
achieved, leading to the seco steroid 16 with an angular
ethyl group. 2-Ethyl substituted cyclopentanone deriva-
tives often show lower reactivity than their 2-methyl
congeners.18
Similar reactions with TBDMS enol ethers derived
from cyclohexanones, ultimately leading to D-homo
steroids, gave more diverse results. The reaction of the
2-methylcyclohexanone derivative 10 with the Torgov
reagent proceeded in good yield, but the more substi-
tuted silyl enol ether 11 gave only moderate results.
Apparently for the six-membered rings, steric hindrance
influences the yield to a larger extent than in the corre-
sponding five-membered rings. TMS enol ethers derived
from cyclohexanones were also tried in this addition
reaction but afforded similar results to the TBDMS
derivatives.

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F. C. E. Saraber, A. de Groot / Tetrahedron Letters 45 (2004) 9431–9433
9433
Et3SiH,
CF3COOH
Pd/CaCO3
H
H
H
H
MeO
MeO
MeO
21
26 93%
27 86%
Scheme 2.
2. Ananchenko, S. N.; Limanov, V. Y.; Leonov, V. N.;
Rzheznikov, V. N.; Torgov, I. V. Tetrahedron 1962, 18,
1355.
3. Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963,
5, 1553.
4. Gaidamovich, N. N.; Torgov, I. V. Steroids 1964, 4, 729.
5. Zakharychev, A. V.; Ananchenko, S. N.; Torgov, I. V.
Steroids 1964, 4, 31.
6. Kuo, C. H.; Taub, D.; Wendler, N. L. J. Org. Chem. 1968,
33, 3126.
7. Makk, N.; Toth, G.; Tomorkeny, E. Steroids 1975, 25, 611.
8. Garland, R. B.; Palmer, J. R.; Pappo, R. J. Org. Chem.
1976, 41, 531.
9. Magriotis, P. A.; Johnson, F. J. Org. Chem. 1984, 49,
1460.
In the D-homo series, the ring closure reactions also
gave good results and the unsaturated D-homo steroids
24 and 25 could be isolated in good yields. However, in
the case of compound 17 the cyclisation had to be car-
ried out in the presence of P2O5 since with pTsOH the
reaction yielded a low, 19% yield of compound 24 to-
gether with a 27% yield of the D9,11-14-hydroxycom-
pound in which dehydration had not taken place after
the cyclisation step. Similar problems with the cyclisa-
tion step have been reported previously for compounds
with a carbonyl at C17a2 although good cyclisations of
these compounds have also been reported using
pTsOH.20
10. Groen, M. B.; Zeelen, F. J. Recl. Trav. Chim. Pays-Bas
1986, 105, 465, and references cited therein.
´
11. Gauthier, V.; Cazes, B.; Gore, J. Tetrahedron Lett. 1991,
The double bonds in the C and D rings in the steroid
and D-homo steroid skeletons can be reduced catalyti-
cally to give C,D-trans fused steroids following literature
procedures.9,21–24 This reduction was tested on com-
pound 21 using Pd/CaCO3 as the catalyst and gave the
13,14-trans-reduced compound 26 in a 93% yield
(Scheme 2). Further reduction to the all-trans ring sys-
tem has been extensively reported in literature. Usually
reduction in liquid ammonia is used for the trans-reduc-
tion of the D8,9 double bond. The Birch reduction can be
applied when reduction of ring A to an enone is also de-
sired. A large variation in yields is reported under these
conditions8,9,21–29 and an ionic reduction using trieth-
ylsilane and trifluoroacetic acid21 was more effective
and reliable in our hands.30
32, 915.
12. Gauthier, V.; Cazes, B.; Gore, J. Bull. Soc. Chim. Fr. 1996,
133, 563.
´
13. Dratch, S.; Charnikhova, T.; Saraber, F. C. E.; Jansen, B.
J. M.; de Groot, A. Tetrahedron 2003, 59, 4287.
14. Steroid numbering is used throughout the discussion.
15. Grieco, P. A.; May, S. A.; Kaufman, M. D. Tetrahedron
Lett. 1998, 39, 7047.
16. Djuric, S.; Sarkar, T.; Magnus, P. J. Am. Chem. Soc. 1980,
102, 6885.
17. Meulemans, T. M.; Stork, G. A.; Jansen, B. J. M.; de
Groot, Ae. Tetrahedron Lett. 1998, 39, 6565.
18. Corey, E. J.; Huang, A. X. J. Am. Chem. Soc. 1999, 121,
710.
19. Throughout this paper all spectral data (NMR, IR, MS
and accurate mass measurements) were in accordance with
the given structures.
20. Rao, G. S. R. S.; Banerjee, D. K.; Devi, L. U.; Sheriff, U.
Aust. J. Chem. 1992, 45, 187.
In conclusion, a short, flexible and efficient procedure
has been developed for the synthesis of steroid and D-
homo steroid skeletons. A variety of substituted silyl
enol ether containing ring D precursors can be prepared
and then used for the preparation of C17 substituted
steroid skeletons by Lewis acid catalysed coupling with
a Torgov type reagent, followed by acid-catalysed clo-
sure of ring C.
21. Quinkert, G.; Del Grosso, M.; Do¨ring, A.; Do¨ring, W.;
Schenkel, R. I.; Bauch, M.; Dambacher, G. T.; Bats, J.
W.; Zimmermann, G.; Durner, G. Helv. Chim. Acta 1995,
¨
78, 1345, and references cited therein.
22. Broess, A. I. A.; van Vliet, N. P.; Groen, M. B.;
Hamersma, H. Steroids 1992, 57, 514.
23. Blazejewski, J.-C.; Dorme, R.; Wakselman, C. J. Chem.
Soc., Perkin Trans. 1 1986, 337.
Acknowledgements
24. Zhuang, Z.-P.; Zhou, W.-S. Tetrahedron 1985, 41, 3633.
25. Pillai, K. M. R.; Murray, W. V.; Shooshani, I.; Williams,
D. L.; Gordon, D.; Wang, S. Y.; Johnson, F. J. Med.
Chem. 1984, 27, 1131.
26. Bijoy, P.; Ramachandran, U.; Rao, G. S. R. S. J. Chem.
Soc., Perkin Trans. 1 1994, 16, 2331.
The authors gratefully acknowledge financial support
from the Dutch Technology Foundation (Grant CW/
STW-project 790.35.215) and from Organon Interna-
tional. The authors thank B. van Lagen for NMR and
IR spectroscopic data, and M.A. Posthumus for mass
spectroscopic measurements.
27. Kunzer, H.; Sauer, G.; Wiechert, R. Tetrahedron Lett.
¨
1991, 32, 743.
28. Kurosawa, T.; Niitsu, U.; Tohma, M. Chem. Pharm. Bull.
1987, 35, 585.
References and notes
29. Rufer, C.; Schro¨der, E.; Gibian, H. Justus Liebigs Ann.
Chem. 1971, 752, 1.
1. Nazarov, I. N.; Torgov, I. V.; Verkholetova, G. N. Dokl.
Akad. Nauk. SSSR 1957, 112, 1067.
30. The all trans configuration of compound 27 was confirmed
by X-ray analysis.