Neurosteroid Analogues. 7. A Synthetic Route for the Conversion of 5β-Methyl-3-ketosteroids into 7(S)-Methyl-Substituted Analogues of Neuroactive Benz[e]indenes

Full text of DOI:10.1021/jo991953m

2
264
J . Org. Chem. 2000, 65, 2264-2266
Neu r oster oid An a logu es. 7. A Syn th etic
Rou te for th e Con ver sion of
a tedious separation of C-7 epimers (benz[e]indene num-
bering system ) is required at a late stage of the
synthesis.
Continuation of our pharmacological studies has re-
quired us to prepare benz[e]indene 4 by a route that does
not require separation from the diastereomeric benz[e]-
indene 3. We report here a new route from a 5â-methyl-
1
0
5
â-Meth yl-3-k etoster oid s in to
(S)-Meth yl-Su bstitu ted An a logu es of
Neu r oa ctive Ben z[e]in d en es
7
Chun-min Zeng, Mingcheng Han, and
Douglas F. Covey*
1
9-norsteroid precursor that accomplishes this goal. The
route (Scheme 1) utilizes commercially available 19-
nortestosterone (5) as a starting material and gives the
desired product in 12 steps with an overall yield of 7.6%.
Department of Molecular Biology and Pharmacology,
Washington University School of Medicine, 660 South
Euclid Avenue, St. Louis, Missouri 63110
Resu lts a n d Discu ssion
Received December 21, 1999
4
The 1,4-addition of CH
3
MgX to ∆ -3-ketosteroids in the
We previously reported that benz[e]indenes 1 and 2
presence of copper salts is known to yield exclusively 5â-
enhance the actions of the inhibitory neurotransmitter
1,12
receptors.1
-7
methyl-3-ketosteroids in high yield.1 Accordingly, CH
MgI was reacted in the presence of Cu(OAc) with 19-
nortestosterone (5) to yield steroid 6 in 81% yield.
Bromination of compound 6 with Br followed by dehy-
drobromination using CaCO in refluxing dimethyl-
3
-
γ-aminobutyric acid (GABA) at GABA
A
2
Because of this pharmacological action, the compounds
are of interest as lead compounds for identifying new
drug candidates with anticonvulsant, sedative-hypnotic,
and anesthetic activities. Conceptually, compounds 1 and
are accessible from 19-norsteroids by breaking the
A-ring between C-2 and C-3 and then removing C-1 and
2
3
1
acetamide gave the ∆ -3-ketosteroid 8 as the major
product. A minor product assigned as structure 7 on the
basis of it’s H NMR spectrum [δ 7.06 (1H, dd, J ) 10.2,
.0 Hz), 6.09 (1H, d, J ) 10.2 Hz), 5.17 (1H, s)] was
converted into steroid 8 when reduced with Zn dust in
AcOH. The overall yield for the conversion of steroid 6
into product 8 was 84%. Oxidation of steroid 8 with PDC
gave product 9 in 97% yield.
2
1
C-2. Indeed, we have prepared benz[e]indene 1 from
6
(
5R,17â)-17-hydroxyestran-3-one by this route (ozonolysis
2
of a ∆ -enol derivative followed by removal of C-1 and
C-2).3
,8
The cleavage of the A-ring of steroid 9 into a compound
that was readily converted into benz[e]indene 11 in high
yield was unexpectedly difficult. A variety of methods
were investigated for this purpose. These methods in-
cluded the following: (1) epoxidation of the double bond
followed by ring opening using the Tanabe-Eschenmoser
rearrangement;1
(
3,14
(2) OsO
15
4
3 2
-Ba(ClO ) oxidation; and
3) ozonolysis. While it was possible to cleave the A-ring
Benz[e]indene 2 could not be similarly prepared from
5â,17â)-17-hydroxyestran-3-one by this method because
using any of these methods, only the ozonolysis method
gave a product, which could be expeditiously converted
into benz[e]indene 11. Ozonolysis of steroid 9 in CH Cl
containing AcOH, followed by reduction of the initial
ozonolysis products with Zn dust in AcOH gave a complex
mixture of carboxylic acid products. Treatment of these
(
the preferred direction of enolization of the 3-keto group
2
2
9
is toward C-4. Instead, this compound was prepared by
4
total synthesis. However, this route is not optimal since
(
1) Rodgers-Neame, N. T.; Covey, D. F.; Hu, Y.; Isenberg, K. E.;
Zorumski, C. F. Mol. Pharmacol. 1992, 42, 952.
2) Covey, D. F.; Hu, Y.; Bouley, M. G.; Holland, K. D.; Rodgers-
Neame, N. T.; Isenberg, K. E.; Zorumski, C. F. J . Med. Chem. 1993,
2 2
products with CH N gave a mixture of methyl esters that
was separated by flash column chromatography. The
components of this mixture that were isolated included
the expected aldehyde 10a (28%), the diester 10b [14%,
(
3
3
1
6, 6, 627.
3) Hu, Y.; Zorumski, C. F.; Covey, D. F. J . Med. Chem. 1993, 36,
956.
(
1
characterized only by H NMR δ 3.67 (3H, s), 3.65 (3H,s)],
(4) Han, M.; Hu, Y.; Zorumski, C. F.; Covey, D. F. J . Med. Chem.
and benz[e]indene 11 (4%). The formation of compound
995, 38, 4548.
(
1
1 was unexpected, and the structure of the oxidized
5) Zorumski, C. F.; Wittmer, L. L.; Isenberg, K. E.; Hu, Y.; Covey,
D. F. Neuropharmacol. 1996, 35, 1161.
6) Hu, Y.; Wittmer, L. L.; Kalkbrenner, M.; Evers, A. S.; Zorumski,
C. F.; Covey, D. F. J . Chem. Soc., Perkin Trans 1 1997, 3665.
7) Zorumski, C. F.; Mennerick, S. J .; Covey, D. F. Synapse 1998,
9, 162.
intermediate that gives rise to this minor product was
not determined. Aldehyde 10a is an unstable oil that
readily rearranges to multiple products. For this reason,
it was characterized spectroscopically and then im-
mediately decarbonylated using Wilkinson’s catalyst in
(
(
2
(
(
8) Hu, Y.; Covey, D. F. J . Chem. Soc., Perkin Trans. 1 1993, 417.
9) (a) Marker, R. E.; Rohnmann, E. J . Am. Chem. Soc. 1940, 62,
7
3. (b) Rapala, R. T.; Farkas, E. J . Am. Chem. Soc. 1958, 80, 1008.
10) In addition to the different numbering system for steroids and
(
(11) Birch, A. J .; Smith, M. Proc. Chem. Soc. 1962, 356.
(12) Fetizon, M.; Gramain, J . C. Bull. Soc. Chim. Fr. 1968, 3301.
(13) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967,
3943.
(14) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967,
50, 708.
benz[e]indenes, the nomenclature used for the assignment of the R and
â stereodescriptors for benz[e]indenes and steroids is also different.
For benz[e]indenes, the R-side of the reference plane is that side on
which the preferred substituent lies at the lowest-numbered stereo-
genic position. See Chemical Abstracts Index Guide-Appendix IV;
American Chemical Society: Washington, DC, 1994; ¶ 203, pp 195I-
(15) Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, S. J .
J . Am. Chem. Soc. 1977, 99, 6066.
1
96I.
1
0.1021/jo991953m CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/14/2000

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2265
Sch em e 1a
13
or 75 MHz ( C). IR spectra were recorded as films for liquids
or KBr disks for solids. Elemental analyses were carried out by
M-H-W Laboratories, Phoenix, AZ. Solvents were used either
as purchased or dried and purified by standard methodology.
2 4
Organic extracts were dried over anhydrous Na SO . Column
chromatography was performed using silica gel (32-63 microns)
purchased from Scientific Adsorbents, Atlanta, GA. The 19-
nortestosterone was purchased from Steraloids, Inc., Newport,
RI.
(
5â,17â)-17-Hyd r oxy-5-m eth ylestr a n -3-on e (6). CH
34.0 mL, 3.0 M solution in EtOEt, 102.0 mmol) was added to a
stirred THF (400 mL) solution containing 19-nortestosterone (5,
3
MgI
(
1
0
1.05 g, 40.2 mmol) and Cu(OAc)
2
‚H
2
O (812 mg, 4.07 mmol) at
°C for 1.5 h under N . After addition, the ice bath was removed,
2
and the resulting mixture was stirred at room temperature
overnight. Saturated aqueous NH Cl (200 mL) was added to
4
quench the reaction at 0 °C. The reaction mixture was extracted
with EtOAc, which was washed with water, brine and dried.
After solvent removal, the crude product was purified by column
chromatography (silica gel eluted with 20% EtOAc in hexanes)
to give product 6 (9.47 g, 81%) as a colorless solid: mp 158-160
12
°
3
C (lit.16 mp 157.5-159.5 °C; lit. mp 160-162 °C); IR (KBr)
-
1 1
3
406, 2949, 2914, 2840, 1701 cm ; H NMR (CDCl ) δ 3.68 (1H,
t, J ) 8.4 Hz), 2.71 (1H, d, J ) 14.4 Hz), 0.95 (3H, s), 0.77 (3H,
1
3
s); C NMR (CDCl
4
2
3
) δ 213.48, 81.89, 50.15, 48.12, 45.48, 42.82,
1.35, 39.88, 39.56, 38.94, 36.63, 36.21, 30.44, 29.23, 26.49, 25.81,
3.03, 22.73, 10.91. Anal. Calcd for C19 : C, 78.57; H, 10.41.
30 2
H O
Found: C, 78.68, H, 10.23.
5â,17â)-17-Hyd r oxy-5-m eth ylestr -1-en -3-on e (8). Br
M in CHCl , 8.85 mL, 7.08 mmol) was added dropwise during
.5 h at room temperature to a solution of ketone 6 (2.06 g, 7.08
mmol) in CHCl (70 mL). The solution was stirred further for
2 h and then diluted with EtOAc (400 mL), washed successively
with saturated aqueous NaHCO , water, and brine, and dried.
(
2
(0.8
3
1
3
1
3
After solvent removal, the residue was dissolved in dimethyl-
acetamide (10 mL), added during 20 min to boiling dimethyl-
acetamide (50 mL) containing CaCO (2.15 g, 21.5 mmol), and
3
refluxed for 0.5 h. Following filtration and solvent removal, the
residue was extracted with EtOAc. The extract was washed
successively with water and brine and dried. After solvent
removal, the residue was purified by column chromatography
(silica gel eluted with 20% EtOAc in hexanes) to give pure enone
8
(1.07 g) and a mixture of products 7 and 8 (794 mg).
The mixture of products 7 and 8 (794 mg) was stirred with
Zn dust (410 mg, 6.27 mmol) in AcOH (9 mL) at room temper-
ature for 2 h and then poured into 100 mL saturated aqueous
NaHCO (100 mL). After extraction with EtOAc, washing of the
3
extract with water and brine, and drying, the EtOAc was
removed and the residue purified by column chromatography
a
Reagents (a) CH3MgI, Cu(OAc)2‚H2O; (b) (1) Br2, CHCl3; (2)
CaCO3, dimethylacetamide, reflux; (c) Zn, AcOH; (d) PDC, CH2Cl2;
e) (1) O3, CH2Cl2, AcOH, -40 to -45 °C; (2) Zn, AcOH; (3) CH2N2;
f) [(Ph)3P]3RhCl, benzonitrile, reflux; (g) (1) KCN, AcOH; (2)
(
(
POCl3, pyridine; (h) 10% Pd/C, EtOAc; (i) LiBH4, THF, 50 °C.
(
(
silica gel eluted with 15% acetone in hexanes) to give enone 8
638 mg).
refluxing benzonitrile to obtain benz[e]indene 11 (84%
yield). The total yield of compound 11 obtained from
steroid 9 by this ozonolysis-decarbonylation sequence was
7%.
The remaining steps in the conversion of compound 11
into benz[e]indene 4 are straightforward. Compound 11
was first converted into an R-cyanohydrin using KCN in
AcOH and the product was immediately dehydrated to
the R,â-unsaturated nitrile 12 (overall yield 49%). Cata-
lytic hydrogenation (10% Pd/C) of compound 12 followed
by selective reduction of the methyl ester group with
LiBH in THF gave the required benz[e]indene 4 (87%
4
yield for the two steps combined). Preliminary experi-
ments have shown that benz[e]indene 4 potentiates
GABA receptors and causes anesthesia in mice when
A
injected intravenously through the tail vein. Details of
the pharmacological profile of benz[e ]indene 4 will be
published elsewhere.
The total amount of product 8 obtained as a colorless solid
was 1.71 g (84%): mp 140-142 °C; IR (KBr) 3529, 2956, 2915,
-
1 1
2853, 1664 cm ; H NMR (CDCl
Hz), 5.98 (1H, d, J ) 10.2 Hz), 3.65 (1H, t, J ) 8.4 Hz), 2.76
1H, d, J ) 17.1 Hz), 0.99 (3H, s), 0.79 (3H, s); 13C NMR (CDCl
δ 200.53, 153.76, 127.90, 81.80, 49.46, 48.92, 46.69, 45.01, 42.99,
0.84, 38.89, 36.42, 36.12, 30.18, 28.70, 26.45, 26.21, 23.02, 10.95.
3
) δ 7.07 (1H, dd, J ) 10.2, 6.0
2
(
3
)
4
Anal. Calcd for C19H28O : C, 79.12; H, 9.78. Found: C, 79.30,
2
H, 9.59.
(
5â)-5-Meth ylestr -1-en e-3,17-d ion e (9). Enone 8 (961 mg,
.33 mmol) was oxidized by mixing with PDC (2.43 g, 6.46 mmol)
in CH Cl (50 mL). The mixture was stirred at room temperature
3
2
2
for 16 h and diluted with EtOEt (500 mL). The organic layer
was washed with water (5 × 70 mL) and brine and dried. After
solvent removal, the residue was purified by column chroma-
tography (silica gel eluted with 15% EtOAc in hexanes) to give
compound 9 (926 mg, 97%) as a white solid: mp 155-156 °C;
IR (KBr) 2922, 1738, 1670, 1449, 1249, 770 cm-
1
;
1
H NMR
) δ 7.08 (1H, dd, J ) 10.2, 6.3 Hz), 5.99 (1H, d, J ) 10.2
Hz), 2.77 (1H, d, J ) 17.1 Hz), 2.46 (1H, dd, J ) 18.6, 8.7 Hz),
(CDCl
3
13
1
1
3
3
.02 (3H, s), 0.92 (3H, s); C NMR (CDCl ) δ 220.63, 199.90,
52.94, 127.90, 49.62, 48.50, 47.44, 46.38, 44.74, 40.02, 38.51,
5.92, 35.31, 31.09, 28.45, 25.83, 25.28, 21.26, 13.47. Anal. Calcd
Exp er im en ta l Section
for C19
26 2
H O : C, 79.68; H, 9.15. Found: C, 79.77, H, 9.21.
Gen er a l Meth od s. Melting points are uncorrected. NMR
1
spectra were recorded at ambient temperature at 300 MHz ( H)
(16) Mori, H. Chem. Pharm. Bull. 1962, 10, 382.

2
266 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
[
3a S-(3a r,5a â,6â,7â,9a r,9b â)]-6-F or m yl-3a ,7-d im et h yl-
mL) and POCl
3
(0.8 mL, 8.58 mmol) and refluxed for 6 h under
d od eca h yd r o-3-oxo-1H- ben z[e]in d en e-7-a cetic Acid Meth -
yl Ester (10a ). Ozone was bubbled into a solution of enone 9
241 mg, 0.84 mmol) in CH
2
N . The reaction mixture was poured into 5 N HCl (80 mL) at 0
°C. The aqueous solution was extracted with EtOEt (4 × 150
mL), and the combined extracts were washed with water and
brine and dried. After solvent removal, the residue was purified
by column chromatography (silica gel eluted with 10-15%
EtOAc in hexanes) to give recovered starting material 11 (76
mg) and product 12 (211 mg, 49%) as an oil: IR (film) 2915,
(
-
2 2
Cl (60 mL) and AcOH (0.3 mL) at
40 to -45 °C until TLC showed that the enone 9 was no longer
present. The excess ozone was discharged with a stream of
oxygen. After solvent removal at room temperature, the residue
was dissolved in AcOH (6 mL) and mixed with zinc dust (200
mg, 3.06 mmol). The mixture was stirred at room temperature
for 9 h and then extracted with EtOAc. The EtOAc was washed
with water and brine and dried. After solvent removal, the
residue was dissolved in EtOAc and methylated using an EtOEt
-
1 1
2212, 1732, 1589, 1456, 957 cm ; H NMR (CDCl
m), 3.57 (3H, s), 2.25 (2H, s), 0.95 (3H, s), 0.85 (3H, s); C NMR
(CDCl ) δ 172.84, 147.20, 127.43, 115.73, 54.75, 50.90, 48.68,
44.31, 41.14, 39.61, 39.33, 37.30, 33.67, 32.17, 29.61, 28.86, 26.27,
3
) δ 6.55 (1H,
13
3
+
solution of CH
2
N
2
. The products were purified by column
2
16.19; HRMS FAB (m/e) calcd for C19H27NO Li (M + Li)
308.2202, found 308.2201.
chromatography (silica gel eluted with 10-20% EtOAc in
hexanes) to give in order of elution: compound 11 (10 mg, 4%),
compound 10b (41 mg, 14%), and aldehyde 10a (75 mg, 28%) as
an unstable oil: H NMR (CDCl
[3S-(3r,3a r,5a â,7â,9a r,9bâ)]-3a ,7-Dim eth yld od eca h yd r o-
7-(2-h yd r oxyet h yl)-1H -b en z[e]in d en e-3-ca r b on it r ile (4).
Compound 12 (259 mg, 0.86 mmol) was hydrogenated using 10%
Pd/C (101 mg) catalyst in EtOAc (40 mL) containing AcOH (1.5
mL). The catalyst was removed by filtration, and the filtrate was
diluted with EtOEt (300 mL). The EtOEt was washed with water
and brine and dried. After solvent removal, crude product 13
1
3
) δ 9.68 (1H, d, J ) 4.8 Hz),
3
7
.66 (3H, s), 2.79 (1H, d, J ) 13.5 Hz), 2.46 (1H, dd, J ) 18.6,
.8 Hz), 2.27 (1H, d, J ) 13.5 Hz), 1.17 (3H), 0.88 (3H, s); 13
) δ 220.52, 205.53, 171.93, 64.72, 51.32, 49.90, 47.82,
C
NMR (CDCl
3
3
2
9.85, 38.82, 37.85, 37.12, 36.77, 35.36, 31.14, 27.65, 26.18, 24.75,
1.21, 13.66.
[
oxo-1H-ben z[e]in d en e-7-a cetic Acid Meth yl Ester (11). The
aldehyde 10a (17 mg, 0.05 mmol) was decarbonylated by
refluxing with [(Ph)
(262 mg) was obtained. Compound 13 had: 1H NMR (CDCl
3.58 (3H, s), 2.24 (2H, s), 2.23 (1H, t, J ) 9.6 Hz), 0.94 (3H, s),
0.86 (3H, s); 13C NMR (CDCl
) δ 173.09, 121.34, 53.05, 51.06,
44.99, 44.31, 41.58, 41.26, 40.12, 38.76, 37.59, 36.89, 33.72, 29.73,
29.11, 26.59, 26.37, 23.90, 14.28.
) δ
3
3a S-(3a r,5a â,7â,9a r,9bâ)]-3a ,7-Dim eth yld od eca h yd r o-3-
3
3 3
P] RhCl (77 mg, 0.08 mmol) in benzonitrile
(3 mL) for 5 h. The precipitate was removed by filtration and
Product 13 (262 mg), without further purification, was
the solvent was removed in vacuo. The residue was extracted
with EtOAc and the extract was washed with water, brine and
dried. After solvent removal, the residue was purified by column
chromatography (silica gel eluted with 15% EtOAc in hexanes)
to give product 11 (13 mg, 84%) as an oil: IR (film) 2922, 1732,
reduced with LiBH
THF (90 mL) at 50 °C for 40 h under N
4
(2M solution in THF, 3.6 mL, 7.2 mmol) in
. The reaction mixture
2
was quenched by addition of 10% HCl (12 mL) at 0 °C. Most of
the THF was removed on a rotary evaporator, and the remaining
aqueous residue was extracted with EtOEt. The EtOEt was
washed with water and brine and dried. After solvent removal,
the residue was purified by column chromatography (silica gel
eluted with 20% EtOAc in hexanes) to give benz[e]indene 4 (207
mg, 87%): mp 113-115 °C; IR (KBr) 3501, 2915, 2246, 1450,
-
1
1
1
1
453 cm ; H NMR (CDCl
8.9, 8.4 Hz), 2.32 (2H, s), 1.03 (3H, s), 0.89 (3H, s); C NMR
) δ 221.23, 172.97, 50.96, 50.11, 48.30, 44.43, 41.17, 40.70,
9.11, 37.39, 35.60, 33.72, 31.32, 29.68, 28.73, 25.45, 21.21, 13.69.
3
) δ 3.65 (3H, s), 2.45 (1H, dd, J )
13
(CDCl
3
3
-
1
1
Anal. Calcd for C18
H, 9.44.
H
28
O
3
: C, 73.93; H, 9.65. Found: C, 73.74,
1028 cm
; H NMR (CDCl ) δ 3.64 (2H, t, J ) 7.8 Hz), 2.30
3
13
3
(1H, t, J ) 9.6 Hz), 0.92 (3H, s), 0.90 (3H, s); C NMR (CDCl )
[
3a S-(3a r,5a â,7â,9a r,9b â)]-3-Cya n o-3a ,4,5,5a ,6,7,8,9,9a ,
b-decah ydr o-3a,7-dim eth yl-1H-ben z[e]in den e-7-acetic Acid
Meth yl Ester (12). Compound 11 (491 mg, 1.68 mmol) in EtOH
60 mL) was mixed with KCN (2.99 g, 45.9 mmol), and the flask
δ 121.41, 59.34, 53.14, 45.01, 44.43, 41.67, 40.11, 38.86, 38.57,
9
37.89, 36.94, 32.47, 29.85, 29.23, 26.48, 26.36, 23.90, 14.28; Anal.
Calcd for C18H29NO: C, 78.49; H, 10.61; N, 5.09. Found: C,
78.53; H, 10.49; N, 5.22.
(
was sealed with a rubber septa. AcOH (4 mL) was added via a
syringe, and the reaction mixture was stirred for 18 h at room
temperature. The reaction mixture was diluted with EtOEt (500
mL) and the EtOEt was washed with water, brine and dried.
After solvent removal, the residue was mixed with pyridine (20
Ack n ow led gm en t. The work was supported by NIH
grant GM 47969.
J O991953M