First total synthesis of N-oxido-3-aza-1,3,5(10)-trieno Steroids

Article abstract of DOI:10.1055/s-2005-869879

An efficient synthesis of 3-aza-steroids bearing a pyridine as an A ring was achieved via intramolecular cycloaddition of orthoquinodimethanes, which were generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869879

LETTER
1695
First Total Synthesis of N-Oxido-3-aza-1,3,5(10)-trieno Steroids
First
Total
S
ynthes
h
is of
N
-Oxid
a
o-3-aza-1,3
l
,5(10)-
i
trieno
Steroids Oumzil, Malika Ibrahim-Ouali,* Maurice Santelli*
UMR 6180 CNRS and Université d’Aix Marseille III, ‘Chirotechnologies: catalyse et biocatalyse’ Laboratoire de Synthèse Organique
associé au CNRS, Faculté des Sciences de Saint Jérôme, 13397 Marseille Cedex 20, France
E-mail: m.santelli@univ.u-3mrs.fr; E-mail: m.ibrahim@univ.u-3mrs.fr
Received 18 April 2005
We have recently reported the first [2 + 2]-cycloaddition
Abstract: An efficient synthesis of 3-aza-steroids bearing a pyri-
of a 3,4-didehydropyridine and a ketene dialkylacetal
dine as an A ring was achieved via intramolecular cycloaddition of
leading to 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal
orthoquinodimethanes, which were generated from a 3-azabicy-
clo[4.2.0]octa-1,3,5-trien-7-one ketal.
(3; Scheme 2).16 The intermediate 3,4-pyridyne 2 was
obtained by treatment of 3-bromopyridine 1 with a base.
Key words: aza-steroid, pyridine, intramolecular Diels–Alder re-
Of note was the remarkable regioselectivity of the elimi-
nation reaction where the 3,4-pyridyne was formed exclu-
sively. Moreover, the cycloaddition reaction was also
found to be fully regioselective.
action, Wacker oxidation
The steroid literature is vast,1 and recently heterosteroids
have received much attention due to their pharmacologi-
cal interest2 and their structure has been widely studied.3,4
This is particularly the case for aza-steroids due to the
presence of a nitrogen atom, which is known to result in
biologically interesting properties.5 For example, some
aza-steroids have been found to exhibit anti-bacterial6 and
neuromuscular-blocking activities.7 Though many aza-
steroids have been reported, curiously and much to our
surprise, 3-aza-1,3,5(10)-trieno steroids have been report-
ed only once and this was not a total synthesis.8 Neverthe-
less, a steroidal pyridine-N-oxide proved to be a potent
inhibitor of the enzyme 5a-reductase (5AR), which cata-
lyzes the conversion of testosterone to the more potent
androgen dihydrotestosterone.9
We described previously the total synthesis of 11-thia-,10
11-oxa-,11 and 11-aza-steroids12 based on our general
strategy for elaborating the steroid skeleton.13 This
strategy involved the intramolecular cycloaddition of
o-xylylenes to generate the BC-ring system, which was
developed by Oppolzer14 and Kametani.15
2 equiv LiHMDS
N
N
Br
1
2
OR
OR
OR
5 equiv
OR
N
∆, 72 h
R = OEt; 25%
3
Scheme 2
The next step of the synthesis was the deprotection of the
ketal (Scheme 3). In this paper, we wish to make a correc-
tion and to give a new result concerning this reaction. The
hydrolysis of the ketal compound 3 to the ketone 4, had
appeared before to be problematic.16 Several known acid-
promoted cleavage conditions17 employed gave no prod-
uct. We attributed this lack of reactivity to the presence of
the nitrogen atom of the pyridine ring. Eventually, we
found that the amount of acetone and acid was critical for
this reaction. Thus, in a solution of trifluoroacetic acid–
acetone–water (9:1:0.1),18 ketal 3 hydrolyzed cleanly to
provide 4-azabenzocyclobutenone 4 in 85% yield, within
two hours at 80 °C.
We are now interested in applying our method to the prep-
aration of new aza-steroids bearing this time a pyridine as
the A ring. In this communication, we wish to report an
efficient method for the preparation of N-oxido-3-aza-
1,3,5(10)-trieno steroids, using the thermolysis of 4-aza-
benzocyclobutenes as the key step.
OR
O
OR
TFA / acetone / H2O
N
N
9 / 1 / 0.1
3
4
2 h, 80 °C, 85%
Scheme 3
N
N
Scheme 1
Satisfied with this result which constitutes a novel route to
compound 4, we continued our synthesis using our gener-
al scheme. Reduction of 4 with sodium borohydride in
ethanol at –20 °C afforded alcohol 5 in 90% yield. 4-Aza-
benzocyclobutenol 5 was found to be readily converted to
the corresponding mesylate 6 in good yield.
SYNLETT 2005, No. 11, pp 1695–1698
Advanced online publication: 09.06.2005
0
7
.0
7
.2
0
0
5
DOI: 10.1055/s-2005-869879; Art ID: G09705ST
© Georg Thieme Verlag Stuttgart · New York

1696
K. Oumzil et al.
LETTER
O
O
O
OH
O
O
NaBH4, EtOH
NaCN
N
N
1 h, –20 °C, 90%
DMSO
4
5
8
+
N
N
90 °C
OMs
MsCl, NEt3, CH2Cl2
0.5 h, –10 °C, 77%
10
N
6
O
O
O
O
H
O
O
Scheme 4
∆
H
H
H
+
+
200 °C,
Having achieved the formation of 6 in only four steps, we
turned our attention to the steroid precursor 8 (Scheme 5).
Thus, the alkylation of the activated spirolactone 719 was
carried out in refluxing acetone in the presence of an-
hydrous potassium carbonate and our 4-azabenzo-
cyclobutenic derivative 6.20 A mixture of two cyclobutene
diastereoisomers 8 (2.5:1) was isolated in 82% yield.
Upon thermolysis of 8, an inseparable mixture of two
cycloadducts 9a and 9b was obtained in a 70:30 ratio and
80% overall yield. Unfortunately, at this step of the
synthesis, it was not possible to determine the relative
stereochemistry of the 8-, 9-, and 14-positions of these
steroids.
24 h, 85%
H
H
H
H
H
N
N
N
11b
11a : 11b : 11c = 3 / 2 / 1
11a
11c
Scheme 6
Structures were characterized on the basis of spectroscop-
ic properties, including a series of NMR experiments
(COSY and phase NOESY, 400 MHz). The structure of
11a was confirmed unequivocally by both spectroscopic
methods and X-ray crystallography.22
It has been reported that a steroidal N-oxido-3-aza-
1,3,5(10)-triene proved to be a good inhibitor of the
enzyme 5a-reductase.9 Oxidation of our major steroid was
considered (Scheme 7). The pyridine nitrogen of aza-
steroid 11a was oxidized with MCPBA23 in dichlo-
romethane to produce the target N-oxide 12, in good yield.
O
OMs
O
MeO2C
K2CO3
N
+
acetone
7
6
∆
O
O
O
O
MeO2C
O
H
O
H
O
O
H
H
H
N
MCPBA
MeO2C
H
H
H
CH2Cl2
∆
N
N
+
O
H
1 h, 86%
N
200 °C, 16 h, 80%
11a
12
O
O
9a + 9b : 70:30
Scheme 7
MeO2C
N
Furthermore, we proceeded to functionalize the terminal
chain of the N-oxide steroid 12 by a Wacker-type oxida-
tion (Scheme 8).24 The introduction of an acetyl group at
the C-17 position was then effected using palladium ace-
tate/benzoquinone in the presence of perchloric acid.25
The expected corresponding ketone 13 was isolated in
65% yield accompanied with a minor amount of terminal
aldehyde 14 resulting from an anti-Markovnikov hydro-
xypalladation.26
8
Scheme 5
With the aim to access pure steroids with natural stereo-
chemistry, we performed a demethoxycarbonylation of 8
according to the Krapcho procedure (NaCN/DMSO21)
(Scheme 6). Epimerization occurred and an inseparable
mixture of 4-azabenzocyclobutene diastereoisomers 10
was isolated in 91% yield. Heating 10 at 200 °C in 1,2,4-
trichlorobenzene for 24 hours yielded three isomeric ste-
roids 11a, 11b, and 11c. Fortunately, these aza-steroids
were easily separated by flash chromatography on silica
gel. Steroid 11a exhibits a cis-anti-trans structure, while
the isomer 11b matches the trans-anti-trans ring-fusion
configuration found in the natural products. Isomer 11c
possesses a trans-anti-cis structure.
In conclusion, we have developed the first short and effi-
cient synthesis of aza-steroids bearing a pyridine as the A
ring.27 Application of this strategy is in progress to pre-
pare variously substituted 3-aza-1,3,5(10)-trieno steroids.
Acknowledgment
We thank Dr. R. Faure for his assistance in NMR measurements and
Dr. M. Giorgi for providing the X-ray analysis of 11a.
Synlett 2005, No. 11, 1695–1698 © Thieme Stuttgart · New York

LETTER
First Total Synthesis of N-Oxido-3-aza-1,3,5(10)-trieno Steroids
1697
O
H
O
O
O
O
H
O
O
H
O
H
H
H
H
Pd(OAc)2
benzoquinone
HClO4, H2O
r.t., 3 h
H
H
H
+
N
N
N
O
O
O
78%
13
12
14
13 : 14 = 8:1
Scheme 8
(17) (a) Mash, E. A.; Math, S. K.; Flann, C. J. Tetrahedron Lett.
1988, 29, 2147. (b) Grieco, P. A.; Nishizawa, M.; Oguri, T.;
Burke, S. D.; Marinovic, N. J. Am. Chem. Soc. 1977, 99,
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Chem. Soc., Chem. Commun. 1971, 858. (d) Bauduin, G.;
Bondon, D.; Pietrasantra, Y.; Pucci, B. Tetrahedron 1978,
34, 3269. (e) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.
M.; Quesnel, Y.; Marko, I. E. Tetrahedron Lett. 1999, 40,
1799.
(18) Khim, S. K.; Nuss, J. M. Tetrahedron Lett. 1999, 40, 1827.
(19) Pellissier, H.; Wilmouth, S.; Santelli, M. Bull. Soc. Chim. Fr.
1995, 132, 627.
(20) (a) Barco, A.; Benetti, S.; Pollini, G. P. Synthesis 1973, 316.
(b) Kataoka, H.; Yamada, T.; Goto, K.; Tsuji, J. Tetrahedron
1987, 43, 4107.
(21) (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron
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(c) Krapcho, A. P. Synthesis 1982, 893.
(22) The crystallographic data (CCDC 272301) can be obtained
free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; e-mail:
deposit@ccdc.cam.ac.uk.
(23) Iwama, T.; Matsumoto, H.; Shimizu, H.; Kataoka, T.;
Muraoka, O.; Tanabe, G. J. Chem. Soc., Perkin Trans. 1
1998, 1569.
(24) Tsuji, J.; Shimizu, I.; Yamamoto, K. Tetrahedron Lett. 1976,
2975.
References
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Berlin, R. A. Steroids 1976, 525. (b) Lange, C.; Holzhey,
N.; Schönecker, B.; Beckert, R.; Möllmann, U.; Dahse, H.-
M. Bioorg. Med. Chem. 2004, 12, 3357.
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Trans. 1 1973, 1204. (b) Singh, H.; Paul, D. J. Chem. Soc.,
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(10) Cachoux, F.; Ibrahim-Ouali, M.; Santelli, M. Synlett 2000,
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Lett. 2000, 41, 1767.
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(b) Ouvrard, P.; Tubul, A.; Santelli, M. Bull. Soc. Chim. Fr.
1993, 130, 772. (c) Pellissier, H.; Santelli, M. Tetrahedron
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(27) All compounds showed satisfactory spectroscopic data as
well as microanalytical data. Diastereomeric ratios were
established from the 1H NMR spectrum of the crude product.
Experimental procedure for the preparation of 11: A
solution of 10 (0.75 g, 2.53 mmol) in 1,2,4-trichlorobenzene
(50 mL) was stirred under argon at 200 °C for 24 h. After
cooling, the solvent was removed under reduced pressure
(0.2 Torr). The resulting oil was purified by flash
chromatography on silica gel (EtOAc–Et2O, 2:8 to 5:5) to
afford compounds 11a (0.336 g; 41%), 11b (0.232 g; 29%),
and 11c (0.12 g; 15%) in 85% overall yield.
11a: White solid; mp 146–147 °C. IR (film): 3083, 2932,
1773, 1610 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.30 (d,
J = 11.9 Hz, 1 H), 1.52 (m, 3 H), 1.92 (m, 3 H), 2.14 (m, 3
H), 2.73 (d, J = 3.8 Hz, 1 H), 2.76 (m, 1 H), 2.84 (dt, J = 8.5
Hz, J = 12.4 Hz, 1 H), 3.23 (m, 1 H), 3.34 (m, 1 H), 4.98 (m,
2 H), 5.42 (m, 1 H), 7.06 (d, J = 5.3 Hz, 1 H), 8.35 (m, 2 H).
13C NMR (250 MHz, CDCl3): d = 21.6, 23.8, 27.5; 28.9,
34.2, 35.1, 37.0, 43.2, 44.8, 49.1, 96.7, 116.6, 121.3, 132.7,
137.2, 144.1, 147.5, 151.0, 177.2. Anal. Calcd for
C19H21NO2: C, 77.26; H, 7.17. Found: C, 77.48; H, 7.26.
11b: Oil. IR (film): 2930, 2880, 1762, 1550 cm–1. 1H NMR
(500 MHz, CDCl3) : d = 1.49 (m, 1 H), 1.62 (m, 1 H), 1.64
(16) Mariet, N.; Ibrahim-Ouali, M.; Santelli, M. Tetrahedron
Lett. 2002, 42, 5789.
Synlett 2005, No. 11, 1695–1698 © Thieme Stuttgart · New York

1698
K. Oumzil et al.
LETTER
(m, 1 H), 1.69 (m, 1 H), 1.71 (m, 1 H), 1.80 (d, J = 11.8 Hz,
1 H), 2.03 (m, 1 H), 2.12 (m, 1 H), 2.26 (m, 1 H), 2.52 (dd,
J = 5.4, 11.8 Hz, 1 H), 2.65 (d, J = 10.5 Hz, 1 H), 2.89 (m, 1
H), 3.44 (d, J = 5.4 Hz, 1 H), 5.11 (d, J = 9.5 Hz, 1 H), 5.14
(d, J = 17.0 Hz, 1 H), 5.64 (dt, J = 9.9, 17.2 Hz, 1 H), 7.32
(d, J = 5.0 Hz, 1 H), 8.34 (s, 1 H), 8.39 (d, J = 5.0 Hz, 1 H).
13C NMR (250 MHz, CDCl3): d = 25.8, 27.0, 27.1, 29.5,
38.9, 40.4, 41.7, 43.8, 49.1, 49.4, 96.3, 116.7, 119.8, 132.0,
137.2, 144.4, 147.1, 150.4, 175.5. HRMS (EI): m/z calcd for
C19H21NO2 [M+]: 295.1572; found: 295.1571.
MHz, CDCl3): d = 1.09 (qd, J = 5.7, 12.2 Hz, 1 H), 1.49 (qd,
J = 2.7, 11.1 Hz, 1 H), 1.59 (m, 1 H), 1.91 (m, 2 H), 2.01 (d,
J = 12.2 Hz, 1 H), 2.07 (dd, J = 4.2, 12.2 Hz, 1 H), 2.08 (m,
1 H), 2.12 (qd, J = 5.4, 11.9 Hz, 1 H), 2.12 (m, 1 H), 2.45 (td,
J = 7.6, 11.3 Hz, 1 H), 2.90 (m, 1 H), 5.09 (m, 1 H), 5.88 (m,
1 H), 7.18 (d, J = 5.1 Hz, 1 H), 8.32 (s, 1 H), 8.37 (d, J = 5.1
Hz, 1 H). 13C NMR (250 MHz, CDCl3): d = 25.7, 26.7, 29.8,
31.6, 32.9, 39.5, 39.8, 41.0, 51.4, 51.9, 94.3, 116.7, 119.0,
132.4, 135.4, 147.2, 147.5, 150.3, 179.7. HRMS (EI): m/z
calcd for C19H21NO2 [M+]: 295.1572; found: 295.1569.
11c: Oil. IR (film): 2928, 1771, 1609 cm–1. 1H NMR (500
Synlett 2005, No. 11, 1695–1698 © Thieme Stuttgart · New York