6,19-carbon-bridged steroids. Synthesis of 6,19-methanoprogesterone.

Article abstract of DOI:10.1039/b211974a

6,19-Methanoprogesterone (4) was synthesized in nine steps from the readily available 3 beta,20 beta-diacetyloxy-5 alpha-bromo-6,19-oxidopregnane (5) in 14% overall yield. The additional carbon atom was introduced by reaction of a C-19 aldehyde with Ph3PC

Full text of DOI:10.1039/b211974a

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6
,19-Carbon-bridged steroids. Synthesis of 6,19-methano-
progesterone
María Joselevich, Alberto A. Ghini and Gerardo Burton*
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EGA Buenos Aires,
Argentina
Received 5th December 2002, Accepted 21st January 2003
First published as an Advance Article on the web 14th February 2003
6
6
,19-Methanoprogesterone (4) was synthesized in nine steps from the readily available 3β,20β-diacetyloxy-5α-bromo-
,19-oxidopregnane (5) in 14% overall yield. The additional carbon atom was introduced by reaction of a C-19
aldehyde with Ph PCHOCH under salt free conditions and subsequent hydrolysis to give the homologous aldehyde.
3
3
Intramolecular addition of the newly incorporated carbonyl (C-19a) to the olefinic C-6 in ring B was achieved by
means of a Prins reaction with TiCl as Lewis acid.
4
7
Introduction
analogues, the electronic effects that sulfur, oxygen or other
bridging heteroatoms may exert on the observed activities
should be absent. This would allow a better assessment of
the contribution of overall molecular shape per se. Further-
more, compared to oxygen- and sulfur-bridged steroids, carbon
bridges are expected to confer better metabolic stability and
hence longer half-lives in vivo. We now describe the first syn-
thesis of the simplest progesterone derivative, 6,19-methano-
progesterone (4) starting from commercially available steroids.
Over the past 20 years, the biochemistry of steroids has
advanced very rapidly. These developments have been impor-
tant in the search for new drugs, leading to a renewed interest in
1
these compounds, a large number of which are used in therapy.
Many of the natural steroid hormones and synthetic analogues
4
contain a ∆ -3-keto moiety in their structure, a typical func-
tionality associated to receptor interaction. This moiety, gives
ring A a 1α-envelope to 1α half chair conformation. The
4
introduction of a 6,19-oxido bridge into ∆ -steroids bends the
molecule at the A/B ring junction changing the ring A con-
formation to a 1β-envelope. Some of these bridged steroids
Results and discussion
2
The key steps in the synthesis of 4 were the introduction of an8
additional carbon atom at C-19 and its cyclization onto C-6.
With these guidelines in mind, we used the Wittig olefination
with (methoxymethylidene)triphenylphosphorane to introduce
have been shown to possess unusual activities; thus the 21-
hydroxyprogesterone analogue 1, is a selective antiglucocorti-
3
coid devoid of mineralocorticoid and progestational activities4
and the pregnanolone analogue 2 is a potent anticonvulsant.
9
10
a carboxaldehyde group at C-19 and the Prins reaction for its
intramolecular addition to the olefinic C-6 in ring B. The syn-
thetic sequence starting from 6,19-oxidosteroid 5 is outlined in
the Scheme 1; this compound was obtained from commercially
available pregnenolone acetate following essentially the pro-
6
,19-Sulfur bridges (e.g. 3) give rise to similar activities but with
a slightly less torsioned steroid nucleus due to the longer C–S
5
bonds. Introduction of oxygen atoms on the bridging sulfur
(
i.e. sulfoxide and sulfone derivatives) cause major changes in
the biological properties.
11
cedure described by de Armas et al.. Cleavage of the
bromoether moiety in 5 with Zn in acetic acid, followed by
oxidation of the 19-hydroxy derivative 6 with pyridinium
chlorochromate (PCC), gave aldehyde 7 in 68% yield (from 5).
The homologation step was first attempted with (methoxy-
methylidene)triphenylphosphorane, generated from the corre-
sponding phosphonium salt and n-BuLi in THF. It had been
claimed that under these conditions, the resulting ylide gave
12
satisfactory yields with similar substrates although, several
contradictory reports on related transformations are described
13
in the literature. In our hands, the yield obtained under these
conditions did not exceed 35%. We then turned to salt free
conditions and, after several attempts, found that a stable
(
methoxymethylidene)triphenylphosphorane solution resulted
from the addition of powdered sodium amide to a suspension
of the phosphonium salt in toluene and exposure to ultra-
sound. The deep red ylide solution, converted 7 into the hom-
14
ologated enol ether 8 in excellent yield (75%). A small amount
of 3-deacetylated product was also obtained (ca. 16%); acetyl-
ation to give 8 increased the overall yield of the Wittig reaction
to 90%. The stereochemistry of the newly generated double
bond in 8 was evident from the coupling constants between
The incorporation of short carbon atom bridges spanning
characteristic positions of the steroid backbone, has been used
in the search for new biologically active steroid hormone
analogues. Although semiempirical AM1 calculations predict
that the overall molecular shape of 6,19-methano-bridged
steroids should be very similar to that of the sulfur-bridged
1
H-19 and H-19a in the H NMR spectra. Thus, in the E-isomer
6
H-19 and H-19a appeared as two doublets at 4.48 and 6.09 ppm
respectively, with a mutual coupling of 13 Hz, while in the
Z-isomer these hydrogens appeared at 3.88 and 5.91 ppm with a
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 9 3 9 – 9 4 3
939

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i
Scheme 1 Reagents and conditions. (a) Zn, AcOH, Pr OH; (b) PCC, BaCO , Cl CH ; (c) CH OCHPPh , toluene; (d) 4N HCl, acetone; (e) TiCl ,
3
2
2
3
3
4
Cl CH ; (f ) 1. CS , DBU, DMF; 2. CH I; (g) Ph SiH , AIBN, toluene; (h) LiAlH , THF; (i) Al O , Et O
2
2
2
3
2
2
4
2
3
2
2
1
coupling of 7 Hz. In the presence of lithium salts, the E/Z ratio
of 8 (determined by H NMR) ranged from 1 : 3 to almost
using the Altona equation. This is the expected stereo-
chemistry for the product on the basis of steric considerations,
as the coordination of the Lewis acid at the C-19a carbonyl
oxygen, increases steric hindrance. This favours the approach of
C19a to C-6, with the more sterically demanding group prefer-
entially placed over the less hindered ring A.
1
1
00% of the Z isomer; when using salt free conditions, the E
isomer was the major product (E/Z ratio ca. 11 : 1). Reagent-
dependent differences in the stereochemical outcome of Wittig
reactions with these and similar reagents, have been described
15
for other steroids; however, the reasons for the stereo-
16
selectivity patterns in those cases were not clearly discerned.
Transformation of 8 into the homologous aldehyde 9 was first
attempted with perchloric acid in diethyl ether (45% yield)
and finally carried out using hydrochloric acid in acetone
1
7
(
98% yield).
Titanium tetrachloride has been the Lewis acid of choice for
Type II Prins reactions of β,γ-unsaturated aldehydes to give
18
bridged chloroalcohols. Treatment of 9 with TiCl4 in di-
chloromethane triggered a stereocontrolled intramolecular
Prins reaction giving a mixture of 6,19-methano steroids 10
and 11 in a 1:4 ratio. The structures of both compounds
were established from H and C NMR spectra, 2D-NMR
experiments and selective irradiation of H-19a in the H NMR
spectrum of 11. Diagnostic signals in the H NMR spectra
Removal of the 19a-hydroxyl group in alcohol 11 was
22
achieved using the Barton deoxygenation procedure. The
19
23
crude mixture of methano-bridged steroids (10 and 11), was
1
13
converted into the 19a-xanthates and treated with diphenyl-
silane/AIBN in toluene. The 6,19-methanopregnane 12 was
obtained in 37% yield (from 8). The spectroscopic data for this
compound (absence of a hydroxymethine resonance at 3.5–
4.5 ppm) indicated the success of this reaction. The acetate
groups in 12 were removed by reduction with lithium aluminum
hydride, and the resulting 3β,20β-diol 13 oxidized to the
diketone with PCC (90% yield for the last two steps). Dehydro-
halogenation of the latter compound with basic alumina in
dichloromethane gave the target compound 4 in 14 % overall
yield (from 5).
1
1
of both 10 and 11 were those assigned to H-19a at 4.14 and
4
.26 ppm respectively, and the absence of the characteristic
resonances of aldehydic and olefinic protons. The 3-chloro-
derivative 10 may result from substitution of the allylic acetate
20
group in 15 (the other plausible product of the Prins reaction)
and subsequent acid catalyzed addition of water to the highly
strained 4,5-double bond during workup. The multiplicity and
coupling constants of H-19a (J
= 4 Hz, J19a,19pro-S = 8 Hz
19a,19pro-R
1
and J19a,6 ∼ 0 Hz) in the H NMR spectrum of 11, allowed
assignment of the R stereochemistry to C-19a, in accordance
with the calculated coupling constants on the AM1 geometry,
Preliminary assays indicate that, as with 6,19-oxidoproges-
2
5
terone and 6,19-sulfanylprogesterone, 6,19-methanoproges-
terone lacks glucocorticoid activity.
9
40
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 9 3 9 – 9 4 3

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Conclusions
(C-21), 21.4 and 21.3 (acetates), 21.5 (C-11), 24.0 (C-15), 25.4
C-16), 28.1 (C-2), 31.2 (C-7), 33.1 (C-1 and C-8), 38.2 (C-4),
(
The above procedure may be used to introduce 6,19-methano
bridges in a variety of steroids. Furthermore, the cyclized inter-
mediate 11 has a functionalized bridging atom, which allows for
further derivatization at this position (ester derivatives, ketone,
carbon chains, etc.).
3
5
1
3
9.3 (C-12), 41.5 (C-10), 42.3 (C-13), 50.3 (C-9), 54.9 (C-17),
6.8 (C-14), 62.7 (C-19), 72.8 (C-20), 73.4 (C-3), 127.8 (C-6),
34.7 (C-5), 170.4 (acetates); m/z (EI, 70 eV) 366 (7), 354 (2),
31 (4), 263 (4), 155 (19), 117 (20), 91 (32), 43 (100).
3
ꢀ,20ꢀ-Diacetyloxypregn-5-en-19-al, 7
Pyridinium chlorochromate (1.38 g, 6.4 mmol), barium car-
Experimental
Melting points were taken on a Fisher–Johns apparatus and are
uncorrected. IR spectra were recorded in thin films using KBr
bonate (0.83 g, 2.4 mmol) and 4 Å molecular sieves (0.64 g)
3
in dry dichloromethane (95 cm ) were vigorously stirred at
room temperature under a nitrogen atmosphere for 15 min and
1
disks on a Nicolet Magna IR 550 FT-IR spectrometer. H and
then compound 6 (0.667 g, 1.60 mmol) was added. After 1 h,
13
C NMR spectra were measured in a Bruker AC-200 (200.13
3
the reaction mixture was diluted with diethyl ether (50 cm ),
and 50.32 MHz) or AM-500 (500.13 and 125.72 MHz) NMR
spectrometer in deuteriochloroform (using TMS as internal
standard). The J values are given in Hz. Spectra were assigned
by analysis of the DEPT, COSY 45, HETCOSY and HMBC
spectra and by comparison with those of progesterone. The
electron impact mass spectra (EI) were measured in a Shimadzu
QP-5000 mass spectrometer at 70 eV or in a VG-Trio 2 at
and percolated through silica gel with dichloromethane.
Evaporation of the solvent gave aldehyde 7 (0.638 g, 96%)
homogeneous by TLC (R = 0.63 hexane–ethyl acetate 7 : 3),
F
mp 100–105 ЊC (from i-PrOH); (Found C 71.9; H 8.9. C H O
25
36
5
24
Ϫ1
requires C 72.1; H 8.7%); νmax (KBr)/cm 2939, 2871, 2368,
732, 1244, 1032; δH (500 MHz) 0.59 (3H, s, H-18), 1.15 (3H,
d, J = 6, H-21), 2.00 (3H,s, acetate), 2.01 (3H, s, acetate), 4.59
1H, tt, J = 5 and 11, H-3), 4.81 (1H, dq, J = 10 and 6, H-20),
.87 (1H, m, H-6), 9.65 (1H, d, J = 1, H-19); δ (125 MHz) 12.3
1
2
0 eV, by direct inlet. All solvents used were reagent grade.
(
Solvents were evaporated at ca. 45 ЊC under vacuum. Column
chromatography was performed on silica gel Merck 9385
5
C
(
(
(
(
(
(
(
C-18), 19.9 (C-21), 21.3, 21.5 (acetates), 22.1 (C-11), 24.0
C-15), 25.4 (C-16), 28.8 (C-2), 30.3 (C-1), 31.3 (C-7), 32.8
C-8), 39.1 (C-4), 39.5 (C-12), 42.1 (C-13), 48.8 (C-9), 53.6
C-10), 54.9 (C-17), 55.9 (C-14), 64.5 (C-3), 72.7 (C-20), 128.3
C-6), 131.7 (C-5), 170.4, 170.6 (acetates), 204.8 (C-19); m/z
(
6
0.0040–0.0063 mm). TLC analysis was performed on silica gel
0 F254 (0.2 mm thick). The homogeneity of all compounds
was confirmed by TLC.
β,20β-Diacetyloxy-5α-bromo-6,19-oxidopregnane
3
5 was
obtained from pregnenolone acetate (3β-acetyloxypregn-5-
en-20-one) following essentially the procedure described by
de Armas et al., by reduction with sodium borohydride in
ϩ
EI, 70 eV) 416 (M , 0.1%), 356 (10), 327 (34), 267 (78), 143
43), 91 (46), 43 (100).
10
methanol/dichloromethane followed by acetylation to give
3ꢀ,20ꢀ-Diacetyloxy-19-(methoxymethylidene)pregn-5-ene, 8
3
β,20β-diacetyloxypregn-5-ene, formation of the 5,6-bromo-
Preparation of the ylide. (Methoxymethylidene)triphenyl-
hydrin with N-bromoacetamide and radical cyclization with
DIB/I (63% overall yield).
phosphonium chloride (1.00 g, 2.92 mmol) was suspended in
2
3
dry toluene (10 cm ), an excess of finely powdered sodium
amide (0.12 g, 3.08 mmol) was added and the mixture sonicated
in an ultrasound bath for 30 min. The suspension was then
centrifuged and degassed under vacuum (0.5 torr) to give a
dark-red solution.
3
ꢀ,20ꢀ-Diacetyloxy-5ꢁ-bromo-6,19-oxidopregnane, 5
A sample of bromoether 5, homogeneous by TLC (R = 0.55,
hexane–ethyl acetate 7 : 3), had mp 150–153 ЊC (from ethanol–
F
water); (Found C 60.4; H 7.5. C H BrO requires C 60.4;
H 7.5%); νmax(KBr)/cm 2945, 1733, 1369, 1248, 1091, 1042;
δH (200 MHz) 0.67 (3H, s, H-18), 1.15 (3H, d, J = 6, H-21), 2.01
25
37
5
Ϫ1
Wittig reaction. To a solution of aldehyde 7(0.5 g, 1.2 mmol)
in dry toluene (0.5 cm ), the ylide solution (5 cm , containing
.5 mmol of ylide) was added, and the solution was stirred for
3
3
1
1
(
3H, s, acetate), 2.03 (3H, s, acetate), 4.84 (1H, dq, J = 10 and 6,
6 h under a nitrogen atmosphere. A second portion of ylide
H-20), 5.20 (1H, tt, J = 11 and 5, H-3); δ (50 MHz) 13.0 (C-18),
C
3
solution (5 cm ) was added and the stirring continued for 16 h.
The reaction mixture was directly applied to a silica gel column;
1
2
9.9 (C-21), 21.3 and 21.5 (acetates), 22.5 (C-11), 23.3 (C-7),
3.4 (C-15), 25.5 (C-16), 26.9 (C-2), 32.8 (C-1), 33.2 (C-8), 39.1
elution with hexane–ethyl acetate 9 : 1 gave enol ether 8 (0.4 g,
(
5
(
4
C-12), 41.3 (C-4), 43.0 (C-13), 45.9 (C-10), 48.8 (C-14),
3.8 (C-9), 54.8 (C-17), 67.5 (C-19), 70.0 (C-3), 72.8 (C-20), 74.5
C-5), 82.2 (C-6), 170.4 and 170.5 (acetates); m/z (EI, 70 eV):
1
7
5%) as an E/Z mixture (11:1 as determined by H NMR).
An analytical sample of the E isomer homogeneous by TLC
(R = 0.60, hexane–ethyl acetate 7 : 3), had mp 132–136 ЊC
from Pr OH); (Found C 72.9; H 9.0. C H O requires C 72.9;
ϩ
F
38 (M Ϫ AcOH, 1%), 436 (1), 399 (1), 357 (5), 297 (14), 267
i
(
2
7
40
5
(
8), 121 (20), 43 (100).
Ϫ1
H 9.1%); νmax (KBr)/cm 2939, 2360, 1732, 1244, 1034; δ (500
H
MHz) 0.57 (3H, s, H-18), 1.15 (3H, d, J = 6, H-21), 2.02 (6H,
3
ꢀ,20ꢀ-Diacetyloxy-19-hydroxypregn-5-ene, 6
s, acetates), 3.52 (3H, s, CH O), 4.48 (1H, d, J = 13, H-19), 4.62
3
Zinc powder (0.255 g) was added to a solution of 3β,20β-
diacetyloxy-5α-bromo-6,19-oxidopregnane (5, 0.100 g, 0.20
(1H, tt, J = 5 and 11, H-3), 4.83 (1H, dq, J = 10 and 6, H-20),
5.55 (1H, dd, J = 2 and 3, H-6), 6.09 (1H, d, J = 13, H-19a);
δC (125 MHz) 12.3 (C-18), 19.9 (C-21), 21.2 (C-11), 21.3 and
21.5 (acetates), 24.3 (C-15), 25.4 (C-16), 28.1 (C-2), 30.9 (C-8),
31.7 (C-7), 36.5 (C-1), 38.2 (C-12), 39.0 (C-4), 41.2 (C-13 and
i
3
mmol) in recently distilled Pr OH (20 cm ) and heated to 75 ЊC.
3
Acetic acid (0.2 cm ) was added, the mixture was vigorously
stirred for 45 min at that temperature, filtered and the solvent
evaporated. The resulting residue was taken with dichloro-
methane, washed with aqueous NaHCO3 and dried with
sodium sulfate. Purification by flash chromatography gave
C-10), 50.2 (C-9), 54.8 (C-17), 55.3 (C-14), 55.9 (CH O), 72.8
3
(C-20), 73.9 (C-3), 106.1 (C-19), 124.7 (C-6), 136.6 (C-5), 150.5
ϩ
(C-19a), 170.4 and 170.5 (acetates); m/z (EI, 70 eV): 384 (M –
1
(
9-hydroxy steroid 6 (0.059 g, 71%) homogeneous by TLC
RF = 0.52, hexane–ethyl acetate 7 : 3), mp 70–74 ЊC (from
ethanol-water); (Found C 69.1; H 9.3. C H O .H O requires
AcOH, 22%), 326 (48), 266 (12), 162 (29), 130 (37), 91 (46), 43
(100). An analytical sample of the Z isomer homogeneous by
TLC (R = 0.62, hexane–ethyl acetate 7 : 3), had δ (500 MHz)
25
38
5
2
F
H
C 68.8; H 9.2%); δ (200 MHz) 0.70 (3H, s, H-18), 1.15 (3H, d,
0.61 (3H, s, H-18), 1.15 (3H, d, J = 6, H-21), 2.01 (3H, s,
H
J = 6, H-21), 2.02 (3H, s, acetate), 2.03 (3H, s, acetate), 3.72
acetate), 2.02 (3H, s, acetate), 3.50 (3H, s, CH O), 3.88 (1H, d,
3
(
1H, d, J = 12, Ha-19), 3.84 (1H, d, J = 12, Hb-19), 4.64 (1H,
tt, J = 11 and 5, H-3), 4.84 (1H, dq, J = 10 and 6, H-20), 5.76
1H, dd, J = 3 and 2, H-6); δC (50 MHz) 12.6 (C-18), 19.8
J = 7, H-19), 4.62 (1H, tt, J = 5 and 11, H-3), 4.83 (1H, dq,
J = 10 and 6, H-20), 5.36 (1H, dd, J = 2 and 3, H-6), 5.91 (1H, d,
J = 7, H-19a).
(
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 9 3 9 – 9 4 3
941

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ϩ
Further elution with hexane–ethyl acetate 6 : 4 gave 20β-
(M –AcOH, 26%), 370 (406-HCl, 34), 362 (370-C H O, 57),
2 4
acetyloxy-3β-hydroxy-19-(methoxymethylidene)pregn-5-ene
326 (406 Ϫ HCl–C H O, 100), 266 (326 Ϫ AcOH, 87), 197 (23),
142 (40), 117 (34).
2 4
1
(
0.077 g, 16%) as an E/Z mixture (5 : 1 as determined by H
NMR), which upon acetylation (acetic anhydride/pyridine)
gave 8 (0.079 g, 93%).
3ꢀ,20ꢀ-Diacetyloxy-5ꢁ-chloro-6,19-methanopregnane, 12
To a solution of the crude mixture of 10 and 11 obtained above
3
ꢀ,20ꢀ-Diacetyloxypregn-5-en-19-carboxaldehyde, 9
3
(
0.300 g) in dimethylformamide (2.53 cm ), were added DBU
3
3
3
4
M hydrochloric acid (0.8 cm ) was added to a solution of
(0.361 cm , 2.42 mmol) and CS (3.35 cm ) under a nitrogen
2
3
enol ether 8 (0.200 g, 0.449 mmol) in acetone (8 cm ), and
the resultant mixture was stirred for 16 h under a nitrogen
atmosphere. The solvent was evaporated and water was added.
Extraction with dichloromethane gave a mixture of products
that was then dissolved in dichloromethane (1 cm ) and
acetylated with acetic anhydride (0.6 cm ) and pyridine
atmosphere. The mixture was stirred at room temperature for
3
90 min and methyl iodide (6.21 cm ) was added. After 90 min,
excess methyl iodide was evaporated under a nitrogen stream,
and the mixture was washed with KHSO and evaporated. The
4
3
3
residue (0.216 g) was dissolved in dry toluene (3.1 cm ) and
diphenylsilane (0.163 cm , 0.885 mmol) was added under a
3
3
3
(
0.6 cm ) for 16 h at room temperature. Extractive workup gave
nitrogen atmosphere. The resulting solution was heated to
3
aldehyde 9 (0.19 g, 98%), homogeneous by TLC (R = 0.44,
hexane–ethyl acetate 7 : 3); νmax (KBr)/cm 2938, 1726, 1384,
90 ЊC and treated with ten portions of 0.336 cm of a solution
F
Ϫ1
Ϫ3
of AIBN in toluene (0.044 g cm ) at 30 min intervals. After a
1
248, 1034; δ (500 MHz) 0.57 (3H, s, H-18), 1.15 (3H, d, J = 6,
further 30 min the mixture was evaporated to give, after purifi-
cation by flash chromatography, methano steroid 12 (0.125 g,
H
H-21), 2.01 (3H, s, acetate), 2.04 (3H, s, acetate), 2.33 (1H, d,
J = 15, Ha-19), 2.71 (1H, d, J = 15, Hb-19), 4,68 (1H, tt, J = 5
and 11, H-3), 4.82 (1H, dq, J = 10 and 6, H-20), 5.55 (1H, t,
37%, three steps) homogeneous by TLC (R = 0.49, hexane–
F
ethyl acetate 8:2); mp 121–124 ЊC (from ethanol–water); (Found
C 69.0; H 8.7. C H ClO requires C 69.2; H 8.7); ν (KBr)/
J = 3, H-6), 9.76 (1H, dd, J = 1 and 5, H-19a); δ (125 MHz)
C
26 39
4
max
Ϫ1
1
2
2.4 (C-18), 19.9 (C-21), 21.3 and 21.4 (acetates), 21.5 (C-11),
4.0 (C-15), 25.3 (C-16), 27.6 (C-2), 31.3 (C-7), 32.7 (C-8), 36.6
cm 2945, 1740, 1369, 1241, 1091, 1035; δH (500 MHz) 0.65
(3H, s, H-18), 1.14 (3H, d, J = 6, H-21), 2.00 (3H, s, acetate),
2.01 (3H, s, acetate), 4.84 (1H, dq, J = 10 and 6, H-20), 5.16
(1H, tt, J = 5 and 11, H-3); δC (125 MHz) 13.0 (C-18), 19.9
(C-21), 21.5 and 21.4 (acetates), 22.1 (C-11), 23.7 (C-15), 24.3
(C-19), 25.6 (C-16), 25.7 (C-19a), 25.9 (C-1), 27.0 (C-2), 32.4
(C-7), 33.2 (C-8), 39.3 (C-12), 41.3 (C-4), 43.0 (C-10), 45.5
(C-6), 45.7 (C-13), 48.3 (C-14), 54.2 (C-9), 55.0 (C-17),
(
(
(
(
(
C-1), 38.2 (C-4), 39.1 (C-12), 40.5 (C-10), 42.2 (C-13), 45.5
C-19), 50.5 (C-9), 54.8 (C-17), 56.7 (C-14), 72.8 (C-20), 73.2
C-3), 125.6 (C-6), 135.6 (C-5), 170.3 and 170.4 (acetates), 203.9
C-19a); m/z (EI, 70 eV) 370 (M Ϫ AcOH, 3%), 326 (19), 266
8), 142 (21), 43 (100). Attempts to recrystallize this compound
ϩ
were unsuccessful, resulting in extensive decomposition.
7
0.2 (C-3), 72.8 (C-20), 82.7 ϩ(C-5), 170.3 and 170.5
3
ꢀ,20ꢀ-Diacetyloxy-5-chloro-19a-hydroxy-6,19-methano-
(acetates);m/z (EI, 70 eV) 450 (M , 0.14%), 414 (M Ϫ HCl,
pregnane, 11
0.7%), 330 (14), 137 (37), 119 (42), 55 (87), 43 (100).
To a stirred solution of 9 (0.32 g, 0.744 mmol) in dry dichloro-
6
,19-Methanopregn-4-ene-3,20-dione, 4
3
methane (11 cm ) at Ϫ70 ЊC was added a solution of TiCl (1
4
3
3
cm ) in dichloromethane (10 cm ) under a nitrogen atmosphere.
The reaction mixture was stirred at Ϫ30 ЊC for 2 h, Pr OH–
water 1 : 3 (12 cm ) was added and the resulting solution was
Diacetate 12 (0.032 g, 0.07 mmol) was stirred with lithium
aluminum hydride (0.048 g, 1.3 mmol) in dry diethyl ether
(0.7 cm ) for 90 min under a nitrogen atmosphere. Ethyl acetate
i
3
3
further stirred at 0 ЊC for 15 min. The organic layer was washed
was added and the mixture was washed with aqueous
with water and aqueous NaHCO , dried, filtered and con-
KHSO and extracted with diethyl ether to give diol 13 (0.025 g,
3
4
centrated to give a mixture of 6,19-methano steroids 10 and 11
97%) homogeneous by TLC (R = 0.43, hexane–ethyl acetate
F
1
(
(
1:4 by H NMR). An analytical sample of 10 had R = 0.43
hexane–ethyl acetate 6:4); δH (500 MHz) 0.64 (3H, s, H-18),
1:1); δ (200 MHz) 0.77 (3H, s, H-18), 1.12 (3H, d, J = 6, H-21),
F
H
3.70 (1H, dq, J = 10 and 6, H-20), 4.05 (1H, tt, J = 5 and 11,
1
2
.13 (3H, d, J = 6, H-21), 1.56 (1H, dd, J = 4 and 14, H-19proR),
.01 (3H, s, acetate), 2.26 (1H, dd, J = 8 and 14, H-19proS), 2.50
H-3); δ (125 MHz) 12.7 (C-18), 22.0 (C-11), 23.2 (C-21), 23.7
C
(C-19a), 24.1 (C-19), 25.4 (C-16), 25.6 (C-1), 26.1 (C-15), 30.2
(C-2), 32.3 (C-7), 32.9 (C-8), 39.6 (C-12), 42.9 (C-10), 44.6
(C-4), 45.4 (C-6 and C-13), 48.2 (C-14), 54.0 (C-17), 54.1 (C-9),
66.2 (C-20), 70.1 (C-3), 83.5 (C-5).
(
1H, br s, H-6), 4.14 (1H, dd, J = 4 and 8, H-19a), 4.61 (1H, tt,
J = 5 and 11, H-3), 4.83 (1H, dq, J = 11 and 6, H-20); δ (125
MHz) 12.9 (C-18), 19.9 (C-21), 21,5 (acetate), 22.4 (C-11), 23.5
C
(
(
(
(
C-15), 25.4 (C-16), 28.3 (C-1), 31.1 (C-2), 31.9 (C-7), 33.3
C-8), 39.1 (C-12), 40.0 (C-4), 42.9 (C-19 and C-13), 45.2
C-14), 50.1 (C-10), 54.7 (C-17), 54.9 (C-9), 55.3 (C-6), 55.9
Compound 13 (0.059 g, 0.15 mmol) was oxidized with pyrid-
inium chlorochromate as described above yielding diketone 14
(0.051 g, 93%) homogeneous by TLC (R = 0.61, hexane–ethyl
F
C-3), 72.6 (C-20), 77.6 (C-19a), 95.5 (C-5), 170.4 (acetate);
acetate 1:1); δH (200 MHz) 0.67 (3H, s, H-18), 2.12 (3H, s,
H-21), 2.57 (1H, d, J = 15, H-4β), 2.86 (1H, d, J = 15, H-4α);
δC (125 MHz) 13.8 (C-18), 22.2 (C-11), 22.8 (C-19a), 23.9
(C-15), 25.8 (C-16), 25.9 (C-19), 28.4 (C-2), 31.5 (C-21), 32.0
(C-7), 33.2 (C-8), 36.8 (C-1), 38.8 (C-12), 44.6 (C-10), 44.8
(C-6), 46.0 (C-13), 48.3 (C-14), 51.5 (C-4), 54.9 (C-9), 63.5
(C-17), 83.6 (C-5), 207.8 (C-20), 209.5 (C-3). A solution of
ϩ
m/z (EI, 20 eV) 388 (M –HCl, 1%), 370 (388-H O, 18), 326
(
1
2
370-C H O, 100), 266 (326 Ϫ AcOH, 57), 198 (26), 161 (44),
2 4
41 (55), 116 (60).
An analytical sample of 11 had R = 0.25 (hexane–ethyl acet-
F
ate 6:4); mp 110–115 ЊC (from ethanol–water); (Found C 66.6;
H 8.4. C H ClO requires C 66.9; H 8.4%); ν (KBr)/cm
3
(
Ϫ1
26
39
5
max
3
415, 2938, 2360, 1733, 1255, 1084, 1034; δH (500 MHz) 0.63
3H, s, H-18), 1.14 (3H, d, J = 6, H-21), 1.78 (1H, dd, J = 4 and
5, H-19proR), 1.98 (1H, dd, J = 8 and 15, H-19proS), 2.00 (3H, s,
diketone 14 (0.050 g, 0.138 mmol) in dichloromethane (2.8 cm )
was stirred for 3 h in the presence of aluminum oxide (0.3 g).
Filtration, evaporation of the solvent and purification by flash
chromatography, gave 6,19-methanoprogesterone 4 (0.035 g,
70%) homogeneous by TLC (RF = 0.40 hexane–ethyl acetate
6:4); (Found C 81.1; H 9.3. C H O requires C 80.9; H 9.3%);
1
acetate), 2.01 (3H, s, acetate), 2.06 (1H, br s, H-6), 4.26 (1H, dd,
J = 4 and 8, H-19a), 4.83 (1H, dq, J = 11 and 6, H-20), 5.15 (1H,
tt, J = 5 and 11, H-3); δ (125 MHz) 13.0 (C-18), 19.9 (C-21),
2
2
C
22 30
2
Ϫ1
1.4 and 21.5 (acetates), 22.1 (C-11), 23.5 (C-15), 25.5 (C-16),
5.9 (C-1), 26.8 (C-2), 30.4 (C-7), 34.0 (C-8), 36.6 (C-19), 39.1
νmax(KBr)/cm 2930, 1740, 1697, 1661, 1447, 1248, 1077,
1034; mp 125–127 ЊC (from ethanol–water); δH (500 MHz)
0.69 (3H, s, H-18), 1.30 (1H, m, H-7α), 1.34 (1H, dt, J = 4 and
13, H-19proS), 1.63 (1H, m, H-19aproS), 1.72 (1H, td, J = 8
and 14, H-1β), 1.75 (1H, m, H-7β), 2.00 (1H, tt, J = 6 and 13,
(
(
(
C-12), 41.5 (C-4), 43.1 (C-10), 47.6 (C-14), 48.0 (C-13), 54.1
C-6 and C-9), 54.9 (C-17), 70.4 (C-19a), 72.7 (C-20), 73.4
C-3), 82.3 (C-5), 170.4 and 170,5 (acetates); m/z (EI, 20 eV) 406
9
42
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 9 3 9 – 9 4 3

View Article Online
H-19aproR), 2.12 (3H, s, H-21), 2.23 (1H, ddd, J = 5, 3 and 14,
H-1α), 2.25 (1H, m, H-2α), 2.29 (1H, m, H-2β), 2.79 (1H, ddd,
J = 2, 4 and 6, H-6), 5.75 (1H, s, H-4); δC (125 MHz) 13.8
9 B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863–927.
1
0 B. Snider, in Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon Press, New York, 1991, Vol. 2, p. 527–561.
1 P. de Armas, J. I. Concepcion, C. G. Francisco, R. Hernandez,
J. A. Salazar and E. Suarez, J. Chem. Soc. Perkin Trans 1, 1989,
1
(
(
C-18), 23.0 (C-16), 23.3 (C-19a), 23.4 (C-11), 24.1 (C-15), 30.8
C-1), 31.4 (C-21), 32.6 (C-19), 33.9 (C-2 and C-8), 38.6 (C-12),
4
05–411.
4
1.2 (C-7), 42.9 (C-6), 44.8 (C-13), 45.3 (C-10), 51.6 (C-9), 55.3
12 P. Kocovsky and F. Turecek, Tetrahedron, 1983, 39, 3621–3626.
13 P. A. Marcotte and C. H. Robinson, Steroids, 1982, 39, 325–342;
P. Kocovsky, Coll. Czech. Chem. Commun., 1983, 48, 3618–3628 and
references cited therein.
(
(
(
C-14), 63.3 (C-17), 115.8 (C-4), 181.1 (C-5), 199.7 (C-3), 209.2
C-20); m/z (EI, 70 eV): 326 (M , 23%), 284 (16), 241 (16), 147
17), 135 (34), 43 (100).
ϩ
1
4 For other alternatives see E. Vedejs, G. P. Meier and K. H. J. Snoble,
J. Am. Chem. Soc., 1981, 103, 2823–2831 and references cited
therein.
Acknowledgements
1
5 See for example W. E. Childers, P. S. Furth, M-J. Shih and
C. H. Robinson, J. Org. Chem., 1988, 53, 5947–5951 (for sulfur
ylides) S. R. Schow and T. C. McMorris, J. Org. Chem., 1979, 44,
3760–3765 (for Wittig reactions with steroids).
This work was supported by grants from Universidad de
Buenos Aires and CONICET (Argentina).
1
6 At least two distinct mechanism are operative for the Wittig reaction
depending on the presence or absence of a metal ion at the site of
oxaphosphetane formation and this is probably reflected in the
observed stereoselectivity. W. J. Ward, Jr. and W. E. McEwen, J. Org.
Chem., 1990, 55, 493–500 and references cited therein; E. Vedejs and
C. F. Marth, J. Am. Chem. Soc., 1989, 111, 1519–1520 and references
cited therein.
References
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A. S. Campos Neves, M. L. Sá e Melo, M. J. S. M. Moreno,
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therein.
17 E. Ottow, R. Rohde, W. Schwede and R. Wiecher, Tetrahedron Lett.,
1993, 34, 5253–5256.
2
3
G. Burton, M. Galigniana, S. de Lavallaz, A. L. Brachet-Cota,
E. M. Sproviero, A. A. Ghini, C. P. Lantos and M. C. Damasco,
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18 N. H. Andersen, S. W. Hadley, J. D. Kelly and E. R. Bacon, J. Org.
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G. P. Vicent, M. C. Monteserín, A. S. Veleiro, G. Burton,
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19 In a preliminary approach, other Lewis acids (BF .Et O, ZnI ) and
3
2
2
solvents, as well as the direct transformation of enol ethers 8 (E/Z)
7
49–753.
with mineral acid were tried. However, TiCl was the most effective
4
4
5
6
A. S. Veleiro, R. Rosenstein, M. L. Grilli, C. Jaliffa, F. Speroni and
G. Burton, Bioorg. Med. Chem. Lett., 2003, 13, 343–346.
even without optimization.
20 We have observed similar substitutions of 3β-acetyloxy and 3β-t-
5
G. Burton, C. P. Lantos and A. S. Veleiro, PCT Int. Appl. WO 02
butyldimethylsilyloxy groups in ∆ -steroids, with either SnCl
4
2
2,647, 21 Mar 2002, EP Appl. EP 00,119,495.0, 18 Sept 2000.
or TiCl in dichloromethane at low temperature (Ϫ20Њ to 0Њ); in all
4
5
H. Klinzer, D. Bittler, D. Rosenberg, G. Sauer and R. Wiecher,
Tetrahedron Lett., 1990, 31, 6171–6174 and references cited therein.
J. P. Burkhart, E. W. Huber, F. M. Lanskovics and N. P. Peet, J. Org.
Chem., 1992, 57, 5150–5154.
cases 3β-chlorosteroids result. In ∆ -steroids, substituents at C-3
are prone to give SN1 reactions due to the stabilization of the
intermediate homoallylic carbocation, the allylic acetate in 15 would
show a similar reactivity.
7
8
For a comparison of the X-ray crystallographic structures of 1 and
21 C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona,
Tetrahedron, 1980, 36, 2783–2792.
22 D. H. R. Barton, D. O. Jang and J. Cs. Jaszberenyi, Tetrahedron,
1993, 49, 7193–7214, and references cited therein.
3
, see ref. 5. Excellent correspondence has been observed between
these structures and those calculated using the AM1 semiempirical
method.
Functionalization of C-19 was achieved by a hypoiodite remote
functionalization reaction. The other two major routes for the
introduction of substituents at the 10- and/or 19-positions of the
steroid nucleus involve the opening of a 5,10-epoxide, and the [3,3]
sigmatropic rearrangement of an allylic ether tethered on the 11β-
position and a 5,10-double bond. In both cases, the starting
materials are 19-nor steroids. See D. Lesuisse, F. Canu and B. Tric,
Tetrahedron, 1994, 50, 8491–8504 and references cited therein.
23 Chromatographic purification prior to this stage was carried out
with the purpose of characterizing compounds 10 and 11 however,
extensive decomposition was observed (probably by cleavage of the
additional bridge via retroaldolic-type reactions, that would cause a
relief of angular and torsional tension). Better yields were obtained
when purification was carried out after removal of the hydroxyl
group at C-19a (compound 12).
24 T. C. Wong and V. Rutar, J. Am. Chem. Soc., 1984, 106, 7380–7384.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 9 3 9 – 9 4 3
943