Abnormal Beckmann fragmentation/ring closing metathesis route for preparation of 18-nor-Δ13(17)-androgens and their 18-nor-13,17-epoxide derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.09.027

The synthesis of 18-nor-Δ¹³⁽¹⁷⁾-androgens and the structurally related 13,17-epoxides is described. The synthetic route involves the cleavage of 17-ketosteroids by an abnormal Beckmann rearrangement, modification of the D-ring cleavage product

Full text of DOI:10.1016/j.tetlet.2006.09.027

Tetrahedron Letters 47 (2006) 7837–7839
Abnormal Beckmann fragmentation/ring closing metathesis
route for preparation of 18-nor-D13(17)-androgens and their
18-nor-13,17-epoxide derivatives
Cunde Wang,a Nigam P. Rathb and Douglas F. Coveya,*
aDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110, USA
bDepartment of Chemistry and Biochemistry, University of Missouri St. Louis, 8001 Natural Bridge Road, St. Louis, MO 63121, USA
Received 14 July 2006; revised 1 September 2006; accepted 6 September 2006
Available online 26 September 2006
Abstract—The synthesis of 18-nor-D13(17)-androgens and the structurally related 13,17-epoxides is described. The synthetic route
involves the cleavage of 17-ketosteroids by an abnormal Beckmann rearrangement, modification of the D-ring cleavage product
to obtain an intermediate tricyclic diene and ring closing metathesis of the diene to the 18-nor-D13(17)-androgen. (3a,5a)-18-Norand-
rost-13(17)-en-3-ol and the derivative 13a,17a- and 13b,17b-epoxides were prepared by this route.
Ó 2006 Elsevier Ltd. All rights reserved.
The modification of 3a-hydroxysteroids has attracted
considerable attention from medicinal and synthetic
organic chemists because many compounds in both the
androgen and pregnane series are potent modulators
of ion channels in the central nervous system of
animals.1–5 For example, spiroepoxide 1 (Fig. 1) potently
enhances the actions of c-aminobutyric acid (GABA)
O
O
H
H
HO
HO
H
H
1
2a: 16α,17α
2b: 16β,17β
at type-A GABA (GABAA) receptors and is
a
general anesthetic in mice.6 However, neither the
16a,17a- nor the 16b,17b-epoxides 2a and 2b, respec-
tively, are as potent modulators of GABAA receptors
as spiroepoxide 1.6
O
H
HO
H
The actions of the 13a,17a- and 13b,17b-epoxides (3a
and 3b) have not been described and, to our knowledge,
synthetic routes to 13,17-epoxysteroids are not reported
in the literature. To evaluate GABAA receptor actions
of these compounds, a synthetic route for their prepara-
tion that proceeds through the intermediate 18-nor-
D13(17)-steroid was developed. The retrosynthetic analy-
sis shown in Scheme 1 utilizes alkene-nitrile 6, obtained
from an abnormal Beckmann rearrangement of the
oxime of the corresponding 17-ketosteroid, as a precur-
3a: 13α,17α
3b: 13β,17β
Figure 1. Structures of known (1, 2a,b) neurosteroid modulators of
GABAA receptors and the previously unknown modulators (3a,b)
prepared herein.
sor for the diene intermediate 5. Ring closure via a ring
closing metathesis reaction gives regiospecifically the
18-nor-D13(17)-steroid 4, and peracid oxidation of the
double bond yields the desired epoxides 3a and 3b.
Keywords: Olefin metathesis; 18-Nor-D13(17)-steroids; 18-Nor-13,17-
epoxysteroids; Abnormal Beckmann rearrangement; Neurosteroids.
*
Thus, the commercially available (3b,5a)-3-hydroxy-
androstan-17-one was converted into (3a,5a)-3-(benz-
Corresponding author. Tel.: +1 314 362 1726; fax: +1 314 362
7058; e-mail: dcovey@wustl.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.027

7838
C. Wang et al. / Tetrahedron Letters 47 (2006) 7837–7839
O
CN
H
H
H
H
HO
HO
HO
BzO
H
H
H
H
3a: 13α,17α
3b: 13β,17β
5
4
6
Scheme 1. Retrosynthetic analysis for the synthesis of epoxides 3a and 3b.
oyloxy)androstan-17-one (9, 92% yield) by a Mitsunobu
reaction (Scheme 2).7 Using a standard method, oxime
10 was obtained in 98% yield by treating steroid 9 with
H2NOHÆHCl and NaOAc. The required alkene-nitrile 6
was conveniently synthesized from oxime 10 in 83%
closure of diene 5 was carried out using a second gener-
ation Grubbs’ catalyst.11,12 The 18-nor-D13(17)-steroid 4
was obtained in nearly quantitative yield (98%) under
mild conditions and with a short reaction time.13 Epox-
idation of steroid 4 in dry benzene using mCPBA at
room temperature gave a mixture of 13,17-epoxides 3a
and 3b which was easily purified by chromatography
to yield the less polar 13b,17b-epoxide (3b) and the more
polar 13a,17a-epoxide (3a) (4.8:1, 87% in total
yield).14,15 The overall yield for the synthesis of the
epoxides was 38%.
yield using
a
recently reported method (TFA,
CH(OMe)3, THF) that minimizes production of the lac-
tam product of the Beckmann rearrangement.8 Due to
the presence of TFA employed in this method, neutral-
ization with 10% Na2CO3 during workup to avoid iso-
merization of the exocyclic double bond to the 12,13
and 13,14 positions in the secosteroid C-ring is crucial.
The stereochemistry for the 13,17-epoxide products was
established by single crystal X-ray diffraction analysis of
steroid 3b (Fig. 2).16 Preliminary biological evaluation
of epoxide 3b indicates that the actions of this epoxide
at GABAA receptors are weak. As expected, based on
Treatment of carbonitrile 6 with DIBALH at ꢀ78 °C
yielded carboxaldehyde 7 in 85% yield.9 A Wittig reac-
tion employing Ph3P+MeBrꢀ/KOBut in dry THF in
the usual manner provided diene 5 in 70% yield.10 Ring
O
O
H
H
a
H
H
H
H
HO
BzO
H
H
b
c
8
9
NOH
H
H
CN
H
H
H
H
H
BzO
d
BzO
H
H
6
10
e
H
H
H
H
CHO
H
H
H
H
H
H
HO
HO
HO
HO
H
H
f
5
7
O
g
H
H
H
4
3a: 13α,17α
3b: 13β,17β
Scheme 2. Reagents and conditions: (a) BzOH, Ph3P, DEAD, THF, room temperature, 12 h, 92%; (b) H2NOHÆHCl, NaOAc, EtOH, reflux, 12 h,
98%; (c) TFA, CH(OMe)3, THF, N2, 60 °C, 2 h, 83%; (d) DIBALH, N2, CH2Cl2, ꢀ78 °C, 1 h, 85%; (e) Ph3P+MeBrꢀ, KOBut, THF, room
temperature, 60 min, 70%; (f) Grubbs’ catalyst second generation, CH2Cl2, N2, 45 °C, 1 h, 98%; (g) mCPBA, benzene, room temperature, 30 min,
87% (3a, 72%; 3b, 15%). Total yield of the synthetic route is 38%.

C. Wang et al. / Tetrahedron Letters 47 (2006) 7837–7839
7839
4. Belelli, D.; Lambert, J. J. Nat. Rev. Neurosci. 2005, 565–
575.
5. Todorovic, S. M.; Covey, D. F.; Zorumski, C. F.;
Jevtovic-Todorovic, V. Curr. Med. Chem.—Central Ner-
vous System Agents 2005, 5, 157–164.
6. 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.
7. Experimental procedures are available online as Supple-
mentary data.
Figure 2. Crystal structure shown with 50% thermal ellipsoids of one
of the two unique forms of epoxide 3b.16
8. Wang, C.; Jiang, X.; Shi, J.; Lu, J.; Hu, Y.; Hu, H. J. Org.
Chem. 2003, 68, 1997–1999.
20
9. Data for 7: oil; ½aꢁD ꢀ24.58 (c 0.86, CHCl3); IR 3401,
; d 9.71 (t,
3080, 2718, 1722, 1643 cmꢀ1 1H NMR
previous structure–activity studies of epoxide 2a,6 epox-
ide 3a has little, if any, effect on GABAA receptor func-
tion. Full pharmacological details will be included in a
larger study that includes biological data for additional
analogues and will be reported elsewhere.
J = 1.2 Hz, 1H), 4.67 (s, 1H), 4.41 (s, 1H), 3.97 (m, 1H),
0.63 (s, 3H); 13C NMR d 202.74, 150.60, 104.69, 66.06,
53.17, 47.63, 42.04, 41.92, 38.25, 36.82, 36.18, 35.47, 31.95,
31.51, 28.72, 28.25, 27.14, 19.26, 10.90. Anal. Calcd
for C19H30O2: C, 78.57; H, 10.41. Found: C, 78.70; H,
10.24.
20
10. Data for 5: oil; ½aꢁD ꢀ34.52 (c 0.17, CHCl3); IR 3350,
In summary, a general and practical method for the
preparation of 18-nor-D13(17)-steroids has been devel-
oped. The sequence features the use of an abnormal
Beckmann rearrangement/ring closing metathesis
reaction sequence to obtain an 18-nor-D13(17)-steroid.
Isomeric 18-nor-D12-steroids and 18-nor-D13-steroids
are not formed. The synthetic method was used to extend
structure–activity studies of neurosteroid modulators of
GABAA receptors.
3078, 1641, 1445, 1005 cmꢀ1 1H NMR d 5.82 (m, 1H),
;
5.02 (m, 2H), 4.72 (s, 1H), 4.55 (s, 1H), 4.03 (m, 1H), 0.70
(s, 3H); 13C NMR d 151.35, 139.34, 113.82, 104.60, 66.36,
53.43, 47.87, 41.89, 38.46, 37.08, 36.32, 35.64, 32.07, 31.72,
30.61, 28.88, 28.47, 27.26, 26.68, 11.00. Anal. Calcd for
C20H32O: C, 83.27; H, 11.18. Found: C, 83.14; H, 11.20.
11. Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751–
1753.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
13. Data for 4: white solid; mp 118–120 °C (EtOAc–hexanes),
20
½aꢁD ꢀ18.9 (c 0.50, CHCl3); IR 3435, 1635, 1444, 1014
cmꢀ1; 1H NMR d 5.21 (s, 1H), 4.04 (m, 1H), 0.71 (s, 3H);
13C NMR d 146.04, 119.95, 66.67, 52.77, 52.44, 45.67,
38.86, 36.40, 36.07, 32.61, 32.47, 31.50, 29.73, 29.14, 28.65,
28.52, 25.87, 11.33. Anal. Calcd for C18H28O: C, 83.02; H,
10.84. Found: C, 83.07; 10.79.
Acknowledgements
This work was supported by NIH grant GM47969.
Instrumentation for crystallographic studies was made
possible by NSF Grant CHE-0420497.
14. Data for 3b: colorless crystals; mp 170–172 °C (from
20
EtOAc/hexanes); ½aꢁD ꢀ17.4 (c 0.34, CHCl3); IR 3421,
3335, 1456, 1434, 896 cmꢀ1; 1H NMR d 4.05 (m, 1H), 3.41
(s, 1H), 0.78 (s, 3H); 13C NMR d 68.10, 66.29, 62.54,
52.69, 46.75, 39.47, 38.73, 36.19, 35.78, 32.25, 32.00, 28.89,
28.72, 28.18, 27.29, 23.56, 22.85, 11.14. Anal. Calcd
for C18H28O2: C, 78.21; H, 10.21. Found: C, 77.98; H,
10.12.
Supplementary data
Supplementary data associated with this article includes
procedures for the preparation of compounds 3a,b, 4–7,
9, 10 and can be found in the online version, at
doi:10.1016/j.tetlet.2006.09.027.
15. Data for 3a: white solid; mp 144–146 °C (from EtOAc/
20
hexanes); ½aꢁD ꢀ45.7 (c 0.54, CHCl3); IR 3434, 1445, 1432,
1
731 cmꢀ1; H NMR d 4.06 (m, 1H), 3.24 (s, 1H), 0.72 (s,
3H); 13C NMR d 68.85, 66.67, 63.72, 51.91, 46.92, 39.33,
38.86, 36.52, 36.00, 32.86, 32.41, 29.22, 28.99, 28.63, 26.64,
24.48, 23.54, 11.31. Anal. Calcd for C18H28O2: C, 78.21;
H, 10.21. Found: C, 77.94; H, 10.00.
References and notes
1. Phillips, G. H. J. Steroid Biochem. 1975, 6, 607–613.
2. Hamilton, N. M. Curr. Top. Med. Chem. 2002, 2, 897–902.
3. Eisenman, L. N.; He, Y.; Covey, D. F.; Zorumski, C. F.;
Mennerick, S. In Potentiation and Inhibition of GABAA
Receptor Function by Neuroactive steroids; Smith, S. S.,
Ed.; Neurosteroid Effects in the Central Nervous System:
the Role of the GABAA Receptor; CRC Press: Boca
Raton, 2004; pp 95–117.
16. Crystallographic data (excluding structure factors) for the
structure in this letter have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 612073. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 330633 or email: deposit@ccdc.cam.ac.uk].