First total syntheses of (±)-3-aza-11-selena and (±)-3-aza-11-tellura steroids

Article abstract of DOI:10.1016/j.tet.2011.03.080

An efficient synthesis of 11-selena and 11-tellura steroids bearing a pyridine as an A ring was achieved via an intramolecular Diels-Alder cycloaddition of o-quinodimethanes, which were generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal. The major isomer matches the trans-anti-trans ring configuration of natural products. Finally, the vinyl groups of the synthesized 11-hetero steroids have been oxidized by the Wacker process in good yields. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.

Full text of DOI:10.1016/j.tet.2011.03.080

Tetrahedron 67 (2011) 3668e3676
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First total syntheses of (ꢀ)-3-aza-11-selena and (ꢀ)-3-aza-11-tellura steroids
a
,
a
b
*
ꢀ
Malika Ibrahim-Ouali , Eugenie Romero , Hocine Bouleghlem
ˇ
a
Institut des Sciences Mol ꢀe culaires de Marseille UMR 6263 CNRS and Universit ꢀe d’Aix Marseille III, Facult ꢀe des Sciences et Techniques de Saint J ꢀe rome,
Avenue Escadrille Normandie Ni ꢀe men, 13397 Marseille Cedex 20, France
Laboratoire de Chimie Organique Appliqu ꢀe e, Groupe de Chimie Bioorganique, Facult ꢀe des sciences, Universit ꢀe d’Annaba, Annaba, Algeria
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 11-selena and 11-tellura steroids bearing a pyridine as an A ring was achieved
via an intramolecular DielseAlder cycloaddition of o-quinodimethanes, which were generated from
a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal. The major isomer matches the trans-anti-trans ring
configuration of natural products. Finally, the vinyl groups of the synthesized 11-hetero steroids have
been oxidized by the Wacker process in good yields. The characteristic 1H and C NMR spectroscopic
features of the synthesized compounds are reported.
Received 4 February 2011
Received in revised form 21 March 2011
Accepted 23 March 2011
Available online 30 March 2011
13
Keywords:
Aza steroids
Ó 2011 Elsevier Ltd. All rights reserved.
Pyridine
Intramolecular DielseAlder reaction
Wacker-type oxidation
1. Introduction
intramolecular cycloaddition of o-xylylenes to generate the BC ring
12
system, which was developed by Oppolzer and Kametani. We
were now interested by the syntheses of 11-selena and 11-tellura
steroids possessing a pyridine as an A ring using our general ap-
proach for elaborating the steroidal skeleton. To the best of our
knowledge, there are no total syntheses described in the literature
though their biological potential. Indeed, compounds containing
selenium can possess biological properties and have been used as
antiviral, antihypertensive, anti-bacterial, or chemopreventive an-
Steroids constitute an extensive and important class of bi-
ologically active polycyclic compounds that are widely used for
therapeutic purposes. Despite decades of research, the total syn-
thesis of steroid nuclei by improved strategies continues to receive
considerable attention. Numerous methods have been exploited for
the total synthesis of steroids, which are widely distributed in na-
ture and which possess practical medical importance.
1
13
Recently hetero steroids have received much attention for
ticancer agents. There are several reports in the literature de-
scribing the antitumoral activity of selenium compounds via
apoptosis in cancer cells induced by the generation of ROS in a pro-
2
pharmacological interest and their structure have been widely
3
studied.
14
This is particularly the case for aza steroids due to the presence
of a nitrogen atom, which is known to give rise to biologically in-
oxidant fashion. Likewise, organotellurium compounds have
attracted a great deal of attention because of their synthetic
4
5
15
teresting properties. For example, anti-bacterial and neuromus-
cular-blocking activities6 have been found for some aza steroids.
Though many aza steroids have been reported, curiously and much
to our surprise, 3-aza-1,3,5(10)-trieno steroids have been reported
utility.
We report herein the first total syntheses of 3-aza-11-selena and
3-aza-11-tellura steroids. We show that we can introduce by our
method two heteroatoms at two key positions of the steroidal
skeleton. We report here the full details of the study and we make
a comparative study on the selectivity of the key thermolysis re-
action between 11-hetero steroids and 3,11-dihetero steroids
(Scheme 1).
7
only once and it was not a total synthesis. Nevertheless, a steroidal
pyridine-N-oxide proved to be a potent inhibitor of the enzyme 5a-
reductase (5AR), which catalyzes the conversion of testosterone to
8
the more potent androgen dihydrotestosterone.
Recently, we have described the first total syntheses of 11-
9
10
selena and 11-tellura steroids based on our general strategy for
2. Results and discussion
11
elaborating the steroid skeleton. This strategy involved the
In 2005, we have reported the synthesis of a 3-aza-7-iodo-
16
bicyclo[4.2.0]octa-1,3,5-triene 2 (Scheme 2). The key step of this
synthesis is the [2þ2] cycloaddition of a 3,4-didehydropyridine and
a ketene dialkyl acetal leading to 3-azabicyclo[4.2.0]octa-1,3,5-
*
Corresponding author. Tel.: þ33 491288416; fax: þ33 491983865; e-mail address:
malika.ibrahim@univ-cezanne.fr (M. Ibrahim-Ouali).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.080

M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
3669
I
OH
OH
X
X11
N
X
3
N
N
OH
X = Se, Te
X
Scheme 1. Retrosynthetic pathway.
OR
O
1
) 2 eq. LiHMDS
OR
TFA / acetone / H O
2
N
1
N
9 / 1 / 0.1
2 h, 80 °C, 85%
N
OR
Br
2
) 5 eq.
1
2
OR
R = OEt; 25%
O
OH
OMs
I
NaBH , EtOH
MsCl, NEt , CH Cl
3 2 2
4
NaI,
h, -20 °C, 90%
N
0.5 h, -10 °C, 77%
N
, 81 %
N
3
4
5
Scheme 2. Synthesis of 3-aza-7-iodo-bicyclo[4.2.0]octa-1,3,5-triene 2.
trien-7-one ketal 1. Cycloaddition proceeded regioselectively. After
deprotection of the ketal, 4-azabenzocyclobutenone 2 was reduced
trieno steroids (Scheme 4) and secondly 3-aza-11-tellura-1,3,5(10)-
trieno steroids (Scheme 5). Thus, the starting iodhydrine 9 was
9
with NaBH
4
in ethanol to the corresponding azabenzocyclobutenol
easily accessible by a procedure reported previously by us via
3
. This latter was converted to the corresponding iodide 5 via its
a treatment with NaI of 14, prepared by condensation of BISTRO 13
with chloroacetic anhydride. Iodhydrine 9 was dissolved in acetone
containing potassium selenocyanate and heated under reflux for
48 h, to give selenocyanate 6 in 53% yield. This latter, dissolved in
mesylate 4. Thus, iodobenzocyclobutene 5 was obtained in 12%
overall yield.
17
9
We recently described the first total syntheses of 11-selena and
10
11-tellura-1,3,5(10) trieno steroids (Scheme 3). Our strategy is
4
tetrahydrofuran/ethanol, was treated with NaBH at room tem-
based on an intramolecular DielseAlder cycloaddition of o-quino-
dimethanes, which are generated by thermal ring opening of
a benzocyclobutene.11
As a continuation of our synthetic and stereochemical studies on
heterocyclic steroidal systems containing two heteroatoms, a simi-
lar strategy was used to obtain firstly 3-aza-11-selena-1,3,5(10)-
perature for 24 h, then the reductive product generated in this
manner has been alkylated in situ with 3-aza-7-iodo-bicyclo[4.2.0]
octa-1,3,5-triene 5, leading to (ꢀ)-cyclobutene 15. Thermolysis of
15 afforded a mixture of two selena steroids 16a and 16b in 72%
yield and a 7/1 ratio, which were easily separable by flash chro-
matography on silica gel.
OH
OH
OH
X
1
) NaBH
4
, THF-EtOH
MeO
1) Na
2
Te, EtOH
NCSe
I
I
MeO
2) 7,
2
)
2
5%
(
± )-6
(± )-9
62%
7
(± )-8 X = Se, 62% from 6
± )-10 X = Te, 25% from 9
(
o-xylene
30 °C, 12 h
1
OH
OH
H
X
H
X
H
H
H
MeO
MeO
+
H
(
± )-11a X = Se
(± )-11b X = Se
(± )-12b X = Te
(± )-12a X = Te
11a : 11b = 9 / 1; 80%
12a : 12b = 8 / 2; 58%
Scheme 3. Synthesis of 11-selena steroids 11 and 11-tellura steroids 12.

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M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
SiMe3
O
O
O
OH
OH
TiCl4
CH Cl , MeNO
2
NaI, acetone
, 24 h, 88%
Cl
Cl
+
2
2
Cl
I
-
60 °C, 12 h, 74%
SiMe
3
13
(± )-14
(± )-9
OH
KSeCN
acetone
OH
1
) NaBH
4
, THF-EtOH
I
Se
NCSe
,
24 h
3%
N
5
2)
N
(
± )-6
58%
5
(± )-15
OH
H
OH
Se
Se
H
H
H
9
+
o-xylene
30 °C, 12 h, 72%
8
1
H
H
N
N
(± )-16a
7 : 1
(± )-16b
Scheme 4. Synthesis of 3-aza-11-selena steroids 16.
OH
OH
1
) Na
2
Te, EtOH
Te
tetracycle 16a or 18a, indicating the C/D trans ring junction. No
cross peak has been observed between H-(8) and H-(14). On the
other hand, the trans relationship between H-(8) and H-(9) was
I
I
,
N
2
)
N
3
(± )-9
5
22%
(± )-17
confirmed by the vicinal coupling constant JH(8)eH(9) of the order of
10 Hz. The cycloadducts 16a and 18a result from an exo approach of
the (E)-o-xylylene intermediate during the cyclization.
In the case of 16b or 18b, NOESY cross peaks have been observed
between H-(15b), H-(9) and H-(12b). A similar interaction proved
OH
OH
H
Te
Te
H
H
9
+
o-xylene
30 °C, 12 h, 55%
8
H
H
H
the syn relationship H-(14) and OH-(18). Finally, the doublet signal
of H-(9) corresponds to a cis relationship with H-(8) (J w4.5 Hz).
The steroid 16b or 18b, which exhibits cis-anti-cis ring fusion ste-
reochemistry comes from a cycloaddition process involving the
vinyl group syn to the benzocyclobutene moiety. This steroid could
result from an endo approach of the (E)-o-xylylene intermediate.
It is worth pointing out the similarity of the results between
11-hetero steroids and 3,11-dihetero steroids. The isomer’s ratio
observed by introducing a heteroatom at the three-position is quite
the same (Schemes 3e5), and on top of that in favour of the isomer
matching the trans-anti-trans ring fusion of natural product. So,
interesting is to note the good stereoselectivity of the thermolysis
step, the relative configurations of five stereogenic centres were
controlled during the cycloaddition process. To the best of our
knowledge, there is no total synthesis of such compounds reported
in the literature.
N
N
1
(
± )-18a
(± )-18b
5
: 1
Scheme 5. Synthesis of 3-aza-11-tellura steroids 18.
We turned then our attention to the synthesis of 3-aza-11-tel-
lura-1,3,5(10)-trieno steroids (Scheme 5). Thus, iodhydrine 9 was
18
dissolved in dry ethanol containing sodium telluride and heated
under reflux for 48 h, to give an intermediate, which was alkylated
in situ with 3-aza-7-iodo-bicyclo[4.2.0]octa-1,3,5-triene 5, pro-
viding a convenient way to produce the key intermediate 17. This
latter, sensitive to oxygen, was used in the following step without
further purification. Thermolysis of (ꢀ)-cyclobutene 17 yielded a 5/
1
mixture of two diastereoisomers 18a and 18b in a 55% overall
yield. These tellura steroids were separated by flash chromatogra-
phy on silica gel and stored under an argon atmosphere (Scheme 5).
The torquoselectivity in the electrocyclic conversion of benzo-
Having achieved the stereoselective formation of the steroid
carbocyclic framework, we turned then our attention to the in-
troduction of an acetyl group present in numerous steroids at the C-
17 position. Wacker-type oxidation is well established as a syn-
19
cyclobutenes into o-xylylenes has been previously discussed.
Generally, a pronounced preference for outward rotation is ob-
served in the case of electron-donating substituents borne by the
benzocyclobutene.
The relative stereochemistry of our new dihetero steroids 16 and
8 has been determined by a series of 1D NMR, COSY and NOESY
experiments (400 MHz). The steroids 16a/18a and 16b/18b have,
respectively, a trans-anti-trans and a cis-anti-cis ring fusion. In-
terestingly, in the two cases the main product 16a/18a matches the
trans-anti-trans ring fusion configuration of natural products. Phase
mode NOESY experiments (Scheme 6) confirm the vicinal re-
2
0
thetic organic reaction.
As reported previously on thia steroids and more recently on
21
9
10
selena steroids 11 and tellura steroids 12, the Wacker-type oxida-
tion applied on these compounds always failed to give the desired
ketone. To overcome this problem, selenium or tellurium atoms were
1
2
2
firstly oxidized using common oxidants before doing the Wacker
oxidation. So, we undertook several attempts on steroids 11a and 12a,
matching the trans-anti-trans ring fusion of natural products. Thus,
fair yields (15e30%) were obtained with hydrogen peroxide (H O /
2
2
ꢁ
ꢁ
lationship between the axial protons H-(9), H-(14), H-(12
a
) of the
CH COOH/0 C), tert-butyl hydroperoxide (t-BuOOH/EtOH/0 C) or
3

M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
3671
Scheme 6. Stereochemistry of major and minor isomers 16 and 18.
ꢁ
ozone (O
3
/ꢂ80 C). On the other hand, oxidation of selenide 11a and
OH
H
OH
H
telluride 12a to the corresponding selenoxide 19 and telluroxide 20
was effected with MCPBA at low temperature in good yields. And
Scheme 7) to undergo clean oxidation, it was necessary to use THF
O
X
H
X
H
2
3
H
H
m-CPBA
(
THF
rather than CH
2
Cl
2
as the solvent.
N
N
0
°C, 1h
O
1
6a X = Se
21 X = Se; 86%
22 X = Te; 78%
OH
H
OH
H
O
18a X = Te
X
X
H
H
H
MeO
MeO
Scheme 9. Synthesis of selenoxide 21 and telluroxide 22.
MCPBA/THF/0 °C
H
the heteroatom are deshielded on passing from selenides or tellu-
rides to the corresponding selenoxides or telluroxides.
1
1a X = Se
19 X = Se; 92%
20 X = Te; 85%
12a X = Te
Having transformed our steroids into their corresponding ox-
ides, we turned then our attention to the Wacker-type oxidation.
Indeed, terminal olefins can be regarded as masked methyl ketones.
The Wacker process, using palladium acetate/benzoquinone in the
Scheme 7. Synthesis of selenoxide 19 and telluroxide 20.
It is worth pointing out that no elimination reaction occurred and
our selenoxides were stables. Moreover, we observed the formation
of only one isomer, which is the axial isomer. Indeed, this result was
not surprising since our steroids possess a hydroxyl substituent at
2
4
presence of perchloric acid, was first applied to 11-hetero steroids
9 and 20, and then to 3,11-dihetero steroids 21 and 22 matching
the trans-anti-trans ring fusion of natural products (Scheme 10).
Thus, in the two cases, oxidation of the 17 -vinyl groups according
to the Miller and Wayner procedure, afforded the expected 17
1
a
the 13b position. So, we are in the case in which the oxygen atom of
a
-
the selenoxide or telluroxide gave a hydrogen bond with a close
acidic hydrogen atom (Scheme 8). Interesting is also to note that
similar results of oxidation were obtained for the two series.
acetyl derivatives in good yields. However, minor amounts of the
unexpected terminal aldehydes resulting from an anti-Markovni-
2
5
kov hydroxypalladation were obtained besides ketones.
H
O
Finally, in order to develop novel steroids matching various
functionalities, and particularly to introduce different substituents
at C-13 via conjugate additions, we decided to create an unsatu-
ration between C-13 and C-17 (Scheme 11). Thus, reaction of ste-
MeO
O
X
X = Se, Te
Scheme 8. Stereochemistry of 19 and 20.
2
6
roids 23, 25, 27 and 29 with BF
3
$Et
2
O
in dichloromethane led to
the corresponding -unsaturated ketones 31, 32, 33 and 34, re-
a,b
spectively, in good yields.
In the case of dihetero steroids 16a and 18a (Scheme 9), during
this reaction the nitrogen atom of the pyridyl ring was also oxi-
ꢁ
dized. Thus, the use of 3-chloroperbenzoic acid in THF at 0 C led to
3. Conclusion
the corresponding N-oxide steroids 21 and 22 in good yields. Here
too, a single product was observed. We are in the same conditions
as those described above for the aromatic analogous.
Selenoxides 19 and 21 and telluroxides 20, 22 showed the
characteristic spectroscopic data (see Experimental section). In
particular, in the 13C NMR spectra, carbons (C-9 and C-12) bearing
In summary, we have shown herein that our strategy is com-
patible with the synthesis of a wide range of steroids and particu-
larly steroids possessing a pyridine as an A ring and a selenium or
a tellurium atom in a biologically important position of the ste-
roidal skeleton. Otherwise, the functionalisation realized on our

3672
M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
O
H
OH
H
OH
H
O
OH
H
O
O
O
X
H
X
H
X
H
H
H
H
MeO
MeO
MeO
a
+
1
9 X = Se
0 X = Te
23 X = Se; 75%
25 X = Te; 66%
24 X = Se;12%
26 X = Te; 8%
2
O
OH
H
OH
O
OH
O
X
H
O
X
H
O
X
H
H
a
H
H
H
H
H
N
N
+
N
O
O
O
2
1 X = Se
27 X = Se; 72%
29 X = Te; 64%
28 X = Se; 10%
30 X = Te; 15%
22 X = Te
(
a) Pd(OAc) , benzoquinone, 0.3M HClO , CH CN, H O, 2 h, rt.
2
4
3
2
Scheme 10. Wacker-type oxidation of selenoxides and telluroxides.
OH
O
O
O
17
O
and 2-methylen-1,3-dioxepane (2 equiv) in THF (approximatively
3 mL/mmol of bromopyridine) was stirred at reflux. The reaction
was monitored by TLC. The reaction mixture was allowed to cool
to room temperature and poured carefully onto crushed ice. The
product was extracted with ether and the combined ether extracts
were then washed with water and brine and dried over anhydrous
X
H
X
H
1
3
H
H
MeO
MeO
BF
3
.Et
2
O
H
H
CH
2
Cl
2
, r.t.
2
2
3
5
X = Se
X = Te
31 X = Se; 86%
32 X = Te; 72%
4
MgSO . Removal of the solvent left a brown oil. Hydrolysis of the
ketal was effected by stirring the brown oil in a THF/water/HCl
mixture (89/10/1) until completion of the reaction (TLC). The
OH
H
O
O
O
X
O
X
H
H
BF
3
.Et
2
O
residue was diluted and extracted with CH
extracts were then washed with water and brine and dried over
anhydrous MgSO . Removal of the solvent and purification by flash
2 2
Cl . The combined
H
H
H
N
CH Cl , r.t.
N
2
2
O
O
4
2
2
7
9
X = Se
X = Te
33 X = Se; 82%
34 X = Te; 68%
chromatography (petroleum ether/ethyl acetate: 5/5) afforded the
pure azabenzocyclobutenone (55% yield for the two steps) as
Scheme 11. Synthesis of
a,
b
-unsaturated ketones 31, 32, 33 and 34.
ꢂ1
1
a colourless oil. IR (film, cm ): 2965, 1732, 1456. H NMR
300 MHz, CDCl ):
¼8.89 (1H, s), 8.72 (1H, d, J¼4.7 Hz), 7.15 (1H,
d, J¼4.7 Hz), 4.11 (2H, s). C NMR (75 MHz, CDCl
49.3, 145.9, 144.9, 113.5, 53.5. HRMS (EI): calcd for C
(
3
d
steroids allows us to envisage the introduction of numerous func-
tionalities and particularly a methyl group at C-13. We are currently
pursuing our research towards more complex target systems.
13
3
):
d
¼187.7, 155.7,
NO
1
7 5
H
119.0371, found 119.0374.
4
4
. Experimental section
4
.1.2. 4-Azabenzocyclobuten-1-ol (3). A flask equipped with a mag-
netic stirring bar and an argon outlet was charged with NaBH
1.27 g, 33.6 mmol) and absolute ethanol. The solution was cooled
4
.1. General
(
ꢁ
at ꢂ20 C and then the azabenzocyclobutenone 2 (4 g, 26 mmol) was
All reactions were performed underanargonatmosphere inoven-
added. Aftercompletionof the reaction(TLC), it wasquenchedbythe
2 5
driedglassware. DichloromethanewasfreshlydistilledfromP O and
addition of aqueous saturated NH
4
Cl and extracted with CH
2 2
Cl
tetrahydrofuran (THF) over sodium/benzophenone. Other reagents
and solvents were obtained from commercial sources and used as
received. Flash column chromatography (FC): Merck 230e400 mesh
silica gel; EtOAc, Et O and petroleum ether as eluents. Thin-layer
2
chromatography (TLC): MachereyeNagel silica gel UV254 analytical
(
3ꢃ20 mL). The extracts were dried over MgSO
4
, filtered and then
concentrated under vacuum. The residue was chromatographed on
silica gel (diethyl ether: 100%) to give pure alcohol 3 (3.6 g, 90% yield)
ꢂ1
1
as an oil. IR (film, cm ): 3385, 2923, 1604, 1470. H NMR (300 MHz,
CDCl ):
¼8.28 (1H, d, J¼4.5 Hz), 8.14 (1H, s), 7.08 (1H, dd, J¼4.5,
1.2 Hz), 5.28 (1H, dd, J¼4.7,1.9 Hz), 3.62 (1H, dd, J¼14.5, 4.7 Hz), 3.11
3
d
plates; detection either with UV, or by dipping in revealing solution.
1
13
ꢁ
H and C NMR spectra were recorded at 25 C in CDCl
3
solutions at
13
(
1
1
1H, d, J¼14.5 Hz). C NMR (75 MHz, CDCl
38.8, 117.6, 70.8, 41.7. HRMS (EI): calcd for C
21.0530.
3
):
d
¼158.3, 147.3, 143.5,
5
00 or 300, and 125 or 75 MHz, respectively, using a Bruker Advance
7 7
H NO 121.0528, found
DPX 500 or AC300 spectrometers. Chemicalshift
d
inparts per million
: 7.24 ppm for
relative to CDCl
3
(signals for residual CHCl
3
in the CDCl
3
1
13
H NMR and 77.16 ppm (central) for C NMR).
2
7
4.1.3. Mesylate of 4-azabenzocyclobuten-1-yle (4). A solution of 3
(0.56 g, 4.62 mmol) in anhydrous CH
(ꢀ)-1-Chloromethyl-2,5-divinylcyclopentol
14 and 1-iodo-5-
2
8
2
Cl
2
(10 mL) was cooled
methoxybenzocyclo-butene 7 are prepared according to the pre-
viously described procedure.
ꢁ
to ꢂ10 C and NEt
3
freshly distilled (1.3 mL, 9.24 mmol) and mesyl
chloride (0.54 mL, 6.93 mmol) were added. After stirring 1 h, the
mixture was hydrolysed with water and extracted with CH Cl
3ꢃ20 mL). The organic layer was washed with a saturated solution
2
2
4.1.1. 4-Azabenzocyclobuten-1-one (2). A mixture of 3-bromopyr-
(
idine (1 equiv), lithium hexamethyl disilazide (LiHMDS) (2 equiv)

M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
3673
of NaCl (10 mL), dried over MgSO
vacuum. The residue was chromatographed on silica gel (AcOEt:
4
and then concentrated under
2H), 1.72e1.38 (m, 6H). 13C NMR (75 MHz, CDCl
138.9, 137.7, 134.1, 124.1, 116.8, 116.5, 115.8, 107.5, 82.7, 55.4, 54.3,
51.3, 44.2, 39.0, 38.4, 28.9, 27.8. HRMS (EI): calcd for C19
364.0942, found 364.0947.
3
):
d
¼159.8, 146.2,
ꢁ
1
00%) to afford 0.71 g (77% yield) of 4 as a solid. Mp¼110 C; IR
24 2
H O Se
ꢂ1
1
(film, cm ): 2931, 1601, 1476. H NMR (300 MHz, CDCl
3
):
d¼8.62
(
1H, d, J¼4.7 Hz), 8.47 (1H, s), 7.26 (1H, dd, J¼4.7, 1.3 Hz), 5.91 (1H,
dd, J¼4.5, 1.9 Hz), 3.84 (1H, dd, J¼14.9, 4.5 Hz), 3.55 (1H, d,
4.1.8. (ꢀ)-1-(4-Methoxybenzocyclobutenetellanylmethyl)-2,5-di-
vinylcyclopentanol (10). A mixture of powdered tellurium (130 mg,
1.02 mmol), Rongalite (sodium hydroxy-methane sulfinate)
(340 mg) and aqueous sodium hydroxide (70 mg in 1 mL of water)
13
J¼14.9 Hz). C NMR (75 MHz, CDCl
18.4, 73.8, 39.3, 38.5. HRMS (EI): calcd for C
found 199.0307.
3
):
d
¼151.3, 148.8, 144.5, 138.1,
1
H
8 9
NO S 199.0303,
3
ꢁ
was stirred at 60 C for 2 h under argon, to produce sodium tellu-
4
.1.4. 1-Iodo-4-azabenzocyclobutene (5). To a stirred solution of
ride. The wine-coloured solution was evaporated to dryness under
reduced pressure. To the pale-yellow residue was added a solution
of iodhydrine 9 (100 mg, 0.36 mmol) in dry ethanol (2 mL). The
mixture was heated under reflux for 24 h, then 1-iodo-5-methox-
ybenzocyclobutene 7 was added (0.12 g, 0.46 mmol) and heated
under reflux 24 h. The reaction was quenched by the addition of
a 10% ammonium sulfate solution (5 mL), and the organic layer was
extracted with diethyl ether (3ꢃ20 mL). The ethereal extract was
washed with water (10 mL), dried over anhydrous sodium sulfate,
and evaporated, to give crude cyclobutene 10, which was stored
mesylate 4 (1.36 g, 6.82 mmol) in anhydrous acetone (30 mL) under
argon was added NaI (2.04 g, 13.64 mmol). The mixture was stirred
2
and concentrated under vacuo. The residue was purified by flash
chromatography on silica gel (diethyl ether: 100%) to give 5 (1.27 g,
8
4 h at reflux then cooled to room temperature, filtered over Celite
ꢁ
ꢂ1
1% yield) as a yellowish solid. Mp¼62 C; IR (film, cm ): 2925,
1
1607, 1586. H NMR (300 MHz, CDCl
3
):
d
¼8.57 (1H, d, J¼4.8 Hz),
8
.28 (1H, s), 7.02 (1H, d, J¼4.8 Hz), 5.46 (1H, dd, J¼4.7, 2.1 Hz), 4.00
13
(
1H, dd, J¼15.0, 4.7 Hz), 3.56 (1H, d, J¼15.0 Hz). C NMR (75 MHz,
CDCl
for C
3
):
H
d
¼156.4,149.1,143.8,138.3,117.5, 44.7,11.1. HRMS (EI): calcd
under an argon atmosphere. This latter was used in the following
1
7
6
IN 230.9545, found 230.9548.
step without further purification. H NMR (300 MHz, CDCl
3
):
d
¼7.02 (d, J¼8.1 Hz, 1H), 6.76 (d, J¼2.0 Hz, 1H), 6.64 (dd, J¼8.1,
4
.1.5. (ꢀ)-1-Iodomethyl-2,5-divinylcyclopentol (9). To a stirred so-
2.0 Hz, 1H), 5.58 (2H, m), 5.01 (4H, m), 3.68 (s, 3H), 3.10e2.85 (m,
1
3
lution of alcohol 14 (1.5 g, 8 mmol) in anhydrous acetone (30 mL)
under argon was added NaI (2.4 g, 13.64 mmol). The mixture was
stirred 24 h at reflux then cooled to room temperature, filtered over
Celite and concentrated under vacuo. The residue was purified by
flash chromatography on silica gel (diethyl ether: 100%) to give 9
3H), 2.45 (m, 2H), 1.68e1.36 (m, 6H). C NMR (75 MHz, CDCl
¼157.8, 142.2, 136.9, 137.0, 128.7, 128.6, 115.8, 115.6, 112.8, 109.5,
81.9, 55.6, 54.6, 51.1, 44.6, 39.1, 27.9, 27.6, 25.4.
3
):
d
4.1.9. (ꢀ)-1-(4-Azabenzocyclobuteneselanylmethyl)-2,5-divinylcy-
clopentanol (15). Compound 6 (1.32 mmol, 0.3 g) was dissolved in
ꢁ
ꢂ1
(
3
1.95 g, 88% yield) as a yellowish solid. Mp¼123 C; IR (film, cm ):
1
410, 2960, 1362, 1064. H NMR (300 MHz, CDCl
.03 (m, 2H), 3.21 (m, 2H), 2.28 (m, 2H), 2.04 (br s, 1H), 1.65 (m, 2H),
):
3
):
d
¼5.74 (m, 2H),
anhydrous EtOH (5 mL) under argon. The solution was cooled at
ꢁ
5
0 C and NaBH
4
(0.06 g, 1.59 mmol) was added. After stirring at this
1
8
2
.38 (m, 2H). 13C NMR (75 MHz, CDCl
3
d
¼137.6, 137.2, 116.1, 115.9,
temperature for 4 h, 0.18 g (1.59 mmol) of t-BuOK and 1.72 mmol of
azabenzocyclobutene 5 were added. After stirring at room tem-
perature for 24 h, the resulting mixture was hydrolysed with
4.7, 52.9, 51.6, 27.9, 25.1, 15.2. HRMS (EI): calcd for C10
78.0168, found 278.0171.
H15IO
a saturated solution of NH
extracted with Et
O (3ꢃ25 mL). The organic phase was dried over
MgSO , filtered and concentrated in vacuo. The residue was purified
4
Cl (10 mL). The aqueous layer was
4
.1.6. (ꢀ)-1-Selenocyanomethyl-2,5-divinylcyclopentanol
2
(6). Iodhydrine 9 (0.5 g, 1.8 mmol) and potassium selenocyanate
4
(
2
0.27 g, 1.8 mmol) in acetone (30 mL) were heated under reflux for
4 h. After evaporation of the solvent, the product was dissolved in
by flash chromatography (petroleum ether/ether: 9.5/0.5) to afford
15 (0.25 g, 58% yield) as an oil. IR (film, cm ): 3447, 2940, 2128,
ꢂ1
1
diethyl ether (20 mL). The solution was washed with saturated
brine and with water (10 mL) and dried over anhydrous magnesium
sulfate. Evaporation of the solvent left a residue, which was chro-
matographed on silica gel, eluted with petroleum ether/diethyl
ether: 7/3. Compound 6 was isolated in 53% yield (0.24 g) as an oil.
1608. H NMR (300 MHz, CDCl
3
):
d
¼8.46 (1H, d, J¼4.8 Hz), 8.24 (1H,
d, J¼2.0 Hz), 7.05 (1H, d, J¼4.8 Hz), 5.74 (m, 2H), 5.02 (m, 4H), 4.54
(1H, dd, J¼5.1, 2.4 Hz), 3.58 (1H, dd, J¼12.8 Hz), 3.14 (1H, dd,
J¼14.6 Hz), 2.73 (1H, d, J¼12.8 Hz), 2.54 (1H, m), 2.35 (1H, m),
13
2.13e1.41 (4H, m). C NMR (75 MHz, CDCl
3
):
d¼155.5, 148.1, 143.3,
ꢂ1
1
IR (film, cm ): 3348, 2931, 2150, 1651, 1386. H NMR (300 MHz,
CDCl ):
¼5.76 (m, 2H), 5.04 (m, 2H), 2.32 (m, 2H), 2.02 (br s, 1H),
.60 (s, 2H), 1.65 (m, 2H), 1.40 (m, 2H). C NMR (75 MHz, CDCl
¼138.2, 137.4, 116.3, 115.7, 101.4, 81.5, 66.9, 53.6, 50.6, 28.6, 24.2.
HRMS (EI): calcd for C11 15NOSe 257.0319, found 257.0325.
139.2, 138.6, 137.4, 117.0, 115.9, 82.8, 54.2, 54.6, 45.6, 39.3, 38.5, 28.6,
27.4. HRMS calcd for C17 21NOSe 335.0788, found 335.0793.
3
d
H
13
1
d
3
):
4.1.10. (ꢀ)-1-(4-Azabenzocyclobutenetellanylmethyl)-2,5-divinylcy-
clopentanol (17). Using the same procedure described above for
H
compound 10, reaction of 1 g (3.6 mmol) of 9 and 1 g (4.3 mmol) of
ꢂ1
4
.1.7. (ꢀ)-1-(4-Methoxybenzocyclobuteneselanylmethyl)-2,5-di-
5 gave, after purification, 0.3 g (22%) of 17 as an oil. IR (film, cm
)
1
vinylcyclopentanol (8). Selenocyanate (1.32 mmol, 0.2 g) derivative
6
lution was cooled at 0 C and NaBH
After stirring at this temperature for 4 h, 0.49 g (4.36 mmol) of
t-BuOK and 4.71 mmol of 1-iodobenzocyclobutene 7 was added.
After stirring at room temperature for 24 h, the resulting mixture
3447, 2940, 1608. H NMR (300 MHz, CDCl
3
):
d
¼8.52 (d, J¼6.1 Hz,
was dissolved in anhydrous EtOH (5 mL), under argon. The so-
1H), 8.48 (br s, 1H), 7.19 (d, J¼6.1 Hz, 1H), 5.65 (2H, m), 5.03 (4H, m),
ꢁ
13
4
(0.04 g, 4.36 mmol) was added.
3.68 (s, 3H), 3.12e2.88 (m, 3H), 2.25 (m, 2H), 1.62e1.38 (6H, m).
NMR (75 MHz, CDCl ):
C
3
d
¼152.4, 148.8, 146.2, 138.9, 137.6, 135.5,
117.9, 117.7, 115.6, 82.3, 54.6, 52.3, 45.3, 39.1, 38.2, 28.6, 27.4.
was hydrolysed with a saturated solution of NH
aqueous layer was extracted with Et
O (3ꢃ25 mL). The organic
phase was dried over MgSO , filtered and concentrated in vacuo.
4
Cl (20 mL). The
4.2. Experimental procedure for the preparation of 16 and 18
2
4
A solution of 15 or 17 (3 mmol) in o-xylene (40 mL) was stirred
ꢁ
The residue was purified by flash chromatography (petroleum
ether/ether: 9.5/0.5) to afford 8 (0.82 g, 62% yield) as an oil. IR (film,
under argon at 130 C. The progress of the reaction was followed by
TLC analysis. After cooling at room temperature, the solvent was
removed under reduced pressure (1 mmHg). The resulting oil was
purified by flash chromatography on silica gel (petroleum ether/
diethyl ether: 1/1 to 2/8).
ꢂ1
1
cm ): 3447, 2940, 2128, 1608. H NMR (300 MHz, CDCl
(
5
3
):
d¼6.95
d, J¼8.2 Hz, 1H), 6.78 (d, J¼2.0 Hz, 1H), 6.59 (dd, J¼8.2, 2.0 Hz, 1H),
.64 (m, 2H), 5.05 (m, 4H), 3.69 (s, 3H), 3.12e2.90 (m, 3H), 2.43 (m,

3674
M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
4
.2.1. (ꢀ)-(8
trien-13
981, 1370, 1048. H NMR (300 MHz, CDCl
b
,9
a
,14
a
)-3-Aza-17
a
-vinyl-11-selenagona-1,3,5(10)-
4.3.2. (ꢀ)-(8
(10)-trien-13
3401, 2927, 1610, 820 cm . H NMR (CDCl
b,9a,14a)-2-Methoxy-17a-vinyl-11-telluragona–1,3,5
ꢂ1
b
-ol (16a). Yield, 0.6 g (63%). Oil. IR (film, cm ): 3352,
b
-ol-11-oxide (20). Yield, 0.95 g (85%). Oil. IR (neat)
1
ꢂ1 1
2
3
):
d¼8.29 (br s, 2H), 7.41
3
): 7.03 (d, J¼8.2 Hz, 1H),
(
d, J¼5.1 Hz, 1H), 5.61 (m, 1H), 5.00 (m, 2H), 3.64 (d, J¼10.9 Hz, 1H),
6.95 (d, J¼2.6 Hz, 1H), 6.82 (dd, J¼2.6, 8.2 Hz, 1H), 5.78 (m, 1H), 5.22
3
1
3
.26 (s, 1H), 2.95 (d, J¼13.4 Hz, 1H), 2.77 (m, 3H), 2.68 (d, J¼13.4 Hz,
(m, 2H), 3.76 (s, 3H), 3.87 (d, J¼10.6 Hz, 1H), 2.75 (m, 3H), 1.80 (m,
13
H), 2.17 (m, 1H), 2.01 (m, 1H), 1.82 (m, 2H), 1.56 (m, 4H), 1.43 (m,
8H),1.54 (d, J¼12.8 Hz,1H),1.36 (d, J¼12.8 Hz,1H). C NMR (CDCl
3
):
13
H). C NMR (75 MHz, CDCl
22.4, 116.1, 76.8, 53.6, 51.2, 47.8, 42.1, 40.2, 28.2, 27.4, 26.9, 26.4.
HRMS (EI): calcd for C17 21NOSe 335.0788, found 335.0792.
3
):
d¼150.9, 147.6, 144.0, 139.6, 132.5,
157.3, 139.8, 137.6, 130.2, 128.8, 115.7, 114.8, 111.4, 76.8, 67.5, 55.9,
55.0, 53.6, 42.6, 36.2, 28.1, 27.6, 26.6, 22.2. HRMS (EI): calcd for
1
H
C
19
24
H O
3
Te 430.0788, found 430.0792.
4
.2.2. (ꢀ)-(8
b
,9
b
,14
a
)-3-Aza-17
a
-vinyl-11-selenagona-1,3,5(10)-
4.3.3. (ꢀ)-(8
b
,9 ,14 )-3-Aza-17 -vinyl-11-selenagona-1,3,5(10)-
a
a
a
ꢂ1
trien-13
a
-ol (16b). Yield, 90 mg (9%). Oil. IR (film, cm ): 3353,
trien-13
b
-ol-11-oxide (21). Yield, 0.82 g (86%). Oil. IR (neat) 3353,
1
ꢂ1 1
2
1
3
982, 1374, 1038. H NMR (300 MHz, CDCl
3
):
d¼8.39 (d, J¼5.2 Hz,
2982, 1374, 820 cm . H NMR (CDCl
3
): 8.16 (d, J¼1.2 Hz, 1H), 8.02
H), 8.31 (s, 1H), 7.85 (d, J¼5.2 Hz, 1H), 5.29 (m, 1H), 4.88 (m, 2H),
(dd, J¼1.2, 6.9 Hz, 1H), 7.86 (d, J¼6.9 Hz, 1H), 5.72 (1H, m), 4.96 (2H,
m), 3.36 (d, J¼11.1 Hz,1H), 3.28 (d, J¼13.9 Hz,1H), 3.16 (d, J¼13.9 Hz,
1H), 2.69 (2H, m), 2.32 (2H, m), 1.95 (2H, m), 1.88 (1H, m), 1.56 (1H,
m), 1.38 (3H, m). C NMR (CDCl
124.3, 116.1, 78.0, 63.1, 54.6, 48.7, 37.2, 35.1, 27.6, 26.4, 24.4, 24.9.
HRMS calcd for C17 Se 367.0687, found 367.0691.
.76 (d, J¼4.3 Hz, 1H), 2.76 (m, 2H), 2.65 (td, J¼9.0, 2.9 Hz, 1H), 2.46
(
2
m, 1H), 2.37 (d, J¼13.5 Hz, 1H), 2.32 (d, J¼13.5 Hz, 1H), 2.12 (m, 1H),
13
.03 (m, 1H), 1.92 (m, 1H), 1.87 (m, 1H), 1.57 (m, 1H), 1.34 (m, 1H),
3
): 140.0, 138.9, 137.4, 136.9, 125.6,
13
1
1
2
.29 (td, J¼11.9, 7.4 Hz, 1H). C NMR (75 MHz, CDCl
47.7, 144.4, 139.1, 131.5, 123.1, 115.5, 76.7, 53.6, 42.1, 41.8, 37.2, 35.3,
7.3, 26.7, 26.3, 25.6. HRMS (EI): calcd for C17 21NOSe 335.0788,
found 335.0794.
3
):
d¼150.2,
H21NO
3
H
4.3.4. (ꢀ)-(8
b,9a,14a)-3-Aza-17a-vinyl-11-telluragona-1,3,5(10)-
-ol-11-oxide (22). Yield, 0.84 g (78%). Oil. IR (neat) 3353,
trien-13
b
ꢂ1 1
4
.2.3. (ꢀ)-(8
b
,9
a
,14
a
)-3-Aza-17
a
-vinyl-11-telluragona-1,3,5(10)-
2982, 1374, 820 cm . H NMR (CDCl
3
): 7.96 (1H, d, J¼7.2 Hz), 7.90
ꢂ1
trien-13
b
-ol (18a). Yield, 0.53 g (46%). Oil. IR (film, cm ): 3352,
(1H, s), 7.38 (1H, d, J¼7.2 Hz), 5.65 (1H, m), 5.01 (2H, m), 4.04 (1H, d,
J¼11.5 Hz), 2.81 (2H, m), 1.44 (4H, m), 2.68 (1H, m), 1.83 (2H, m),
1
2
1
3
981, 1370, 1048. H NMR (300 MHz, CDCl
H), 8.31 (br s, 1H), 7.41 (d, J¼4.9 Hz, 1H), 5.61 (m, 1H), 5.02 (m, 2H),
.89 (d, J¼10.0 Hz, 1H), 2.82 (m, 2H), 2.70 (m, 1H), 2.24 (m, 1H), 2.01
3
):
d¼8.36 (d, J¼4.9 Hz,
13
1.72 (1H, d, J¼11.2 Hz), 1.48 (1H, d, J¼11.2 Hz), 1.61 (2H, m). C NMR
3
(CDCl ): 141.4, 139.2, 137.9, 136.1, 134.6, 124.1, 115.2, 76.6, 51.4, 48.2,
(
m, 1H), 1.86 (m, 2H), 1.65 (d, J¼11.4 Hz, 1H), 1.53 (m, 4H), 1.32 (d,
36.5, 32.7, 28.9, 27.4, 26.1, 24.7, 24.2. HRMS calcd for C17
417.0584, found 417.0589.
3
H21NO Te
1
3
J¼11.4 Hz, 1H). C NMR (75 MHz, CDCl
3
):
d
¼150.0, 147.4, 145.1,
1
38.6, 131.1, 119.6, 115.3, 75.3, 50.6, 49.1, 39.8, 32.6, 28.5, 27.2, 25.2,
2
4.9, 24.8. HRMS (EI): calcd for C17H21NOTe 385.0685, found
4.4. General procedure for the Wacker-type oxidation
3
85.0692.
A 25 mL three-necked flash equipped with an argon inlet,
4
.2.4. (ꢀ)-(8
b
,9
b
,14
a
)-3-Aza-17
a
-vinyl-11-telluragona-1,3,5(10)-
a magnetic stirring bar and a septum cap was charged with Pd
ꢂ1
trien-13
b
-ol (18b). Yield, 0.1 g (9%). Oil. IR (film, cm ) 3353, 2982,
(OAc)
A solution of CH
2
(0.02 g, 0.09 mmol) and benzoquinone (0.088 g, 0.82 mmol).
CN/H O (7/1) (10.2 mL) and HClO (0.3 M) is
1
1374, 1038. H NMR (300 MHz, CDCl
3
):
d¼8.37 (d, J¼4.5 Hz, 1H),
3
2
4
8
.33 (s,1H), 7.45 (d, J¼4.5 Hz,1H), 5.89 (m,1H), 5.15 (m, 2H), 3.97 (d,
added. The resulting solution was stirred at room temperature for
1 h and steroid 19, 20, 21 or 22 (0.9 mmol) is then added. The re-
action mixture is stirred at this temperature for 2 h and hydrolysed
with a NaOH solution (30%). The aqueous phase is extracted with
J¼4.6 Hz, 1H), 2.79 (m, 2H), 2.66 (m, 1H), 2.13 (m, 1H), 1.94 (m, 3H),
13
1
(
5
C
.68 (d, J¼11.2 Hz, 1H), 1.48 (m, 4H), 1.25 (d, J¼11.2 Hz, 1H). C NMR
75 MHz, CDCl ):
¼150.0, 147.4,145.1,138.6, 131.1, 119.6,115.3, 75.3,
0.6, 49.1, 39.8, 32.6, 28.5, 27.2, 25.2, 24.9, 24.8. HRMS (EI): calcd for
21NOTe 385.0685, found 385.0691.
3
d
ether, and the organic layers are dried (MgSO
orated. After purification by flash chromatography, the corre-
sponding ketones 23 (CH Cl /MeOH: 99/1 to 95/5), 25 (CH Cl
MeOH: 97/3), 27 (CH Cl /MeOH: 99/1) or 29 (CH Cl /MeOH: 95/5
to 9/1) and aldehydes 24, 26, 28 or 30 are obtained.
4
), filtered and evap-
17
H
2
2
2
2
/
2
2
2
2
4
.3. Experimental procedure for the preparation of
selenoxides 16, 18 and telluroxides 20, 22
4
.4.1. (ꢀ)-(8
(10)-trien-13
(neat) 3317, 2930, 1703, 1609, 820 cm
b a,14a)-2-Methoxy-17a-acetyl-11-selenagona-1,3,5
,9
Compounds 11a, 12a, 16a and 18a (2.6 mmol) were dissolved in
anhydrous THF (15 mL), under argon. The solution was cooled at
b-ol-11-oxide 23 from 19. Yield, 0.27 g (75%). Oil. IR
ꢂ1
1
3
. H NMR (CDCl ): 7.03
ꢁ
0
C and m-CPBA (1.28 g, 5.2 mmol) was added. After stirring at this
(d, J¼2.4 Hz,1H), 7.02 (d, J¼8.6 Hz,1H), 6.75 (dd, J¼2.4, 8.6Hz,1H), 5.80
(br s, 1H), 3.75 (s, 3H), 3.64 (d, J¼10.9 Hz, 1H), 3.15 (dd, J¼3.1, 9.6 Hz,
1H), 2.75 (m, 2H), 2.19 (s, 3H),1.80 (m, 8H),1.52 (d, J¼14.1 Hz,1H),1.36
temperature for 1 h, the mixture was hydrolysed with a saturated
solution of NaHCO . The aqueous layer was extracted with CH Cl
, filtered and
3
2
2
13
(
3ꢃ25 mL). The organic phase was dried over MgSO
4
(d, J¼14.1 Hz, 1H). C NMR (75 MHz, CDCl
3
):
d
¼210.8, 158.3, 131.2,
concentrated in vacuo. The residue was purified by flash chroma-
130.4,129.6,114.1,112.2, 80.4, 64.1, 62.2, 55.2,51.8, 43.6,36.5,30.3, 28.1,
tography (typically eluting with petroleum ether/ethyl acetate: 9/1
24 4
26.6, 26.1, 22.7. HRMS (EI): calcd for C19H O Se 396.084, found
to 8/2) to give a major diastereoisomer 19
b, 20b, 21b, or 22b.
396.0843.
4
.3.1. (ꢀ)-(8
b
,9
a
,14
a
)-2-Methoxy-17
a
-vinyl-11-selenagona-1,3,5
4.4.2. (ꢀ)-(8
b,9a,14a)-2-Methoxy-17a-(2-oxoethyl)-11-selenagona-
(
10)-trien-13
b-ol-11-oxide (19). Yield, 0.9 g (92%). Oil. IR (neat)
1,3,5(10)-trien-13
b
-ol-11-oxide 24 from 19. Yield, 0.043 g (12%). IR
ꢂ1 1
ꢂ1 1
3
401, 2927, 1610, 820 cm . H NMR (CDCl
3
): 7.05 (d, J¼2.5 Hz, 1H),
(neat) 3431,1638,1264, 820 cm . H NMR (CDCl ): 9.71 (s,1H), 7.24
3
7
5
.04 (d, J¼8.2 Hz, 1H), 6.75 (dd, J¼2.5, 8.2 Hz, 1H), 5.66 (br s, 1H),
.58 (m, 1H), 5.02 (m, 2H), 3.74 (s, 3H), 3.48 (d, J¼10.4 Hz, 1H), 2.70
m, 3H), 1.80 (m, 8H), 1.46 (d, J¼14.2 Hz, 1H), 1.31 (d, J¼14.2 Hz, 1H).
(d, J¼2.3 Hz, 1H), 7.03 (d, J¼8.6 Hz, 1H), 6.76 (dd, J¼2.3, 8.2 Hz, 1H),
5.69 (br s, 1H), 3.76 (s, 3H), 3.50 (d, J¼11.3 Hz, 1H), 2.80 (m, 2H), 2.15
(
(m, 2H), 1.72 (m, 8H), 1.58 (d, J¼13.7 Hz, 1H), 1.36 (d, J¼13.7 Hz, 1H).
1
3
13
C NMR (CDCl
8.9, 64.5, 55.3, 55.2, 51.5, 43.5, 37.5, 28.4, 27.3, 26.5, 25.2. HRMS
EI): calcd for C19 Se 380.0891, found 380.0895.
3
): 158.4, 138.6, 138.4, 131.1, 130.8, 116.3, 113.8, 112.4,
C NMR (75 MHz, CDCl
3
):
d¼201.2, 158.3, 131.0, 131.1, 130.4, 114.1,
7
(
112.3, 81.9, 64.6, 55.5, 51.6, 48.7, 47.5, 44.5, 30.6, 28.5, 27.9, 26.6,
23.8. HRMS (EI): calcd for C19 Se 396.084, found 396.0843.
H
24
O
3
24 4
H O

M. Ibrahim-Ouali et al. / Tetrahedron 67 (2011) 3668e3676
3675
4
(
(
.4.3. (ꢀ)-(8
10)-trien-13
neat) 2930, 1705, 1609, 820 cm
b
,9
a
,14
a
)-2-Methoxy-17
a
-acetyl-11-telluragona-1,3,5
argon at room temperature during 12 h. The mixture was hydro-
lysed with a saturated solution of NaHCO . The aqueous layer was
extracted with CH Cl
(3ꢃ25 mL). The organic phase was dried over
MgSO , filtered and concentrated in vacuo. The residue was purified
by flash chromatography (petroleum ether/ethyl acetate: 6/4) to
give 31, 32, 33 or 34.
b
-ol-11-oxide 25 from 20. Yield, 0.265 g (66%). Oil. IR
3
ꢂ1
1
.
H NMR (CDCl
3
): 7.74 (d,
2
2
J¼2.1 Hz, 1H), 7.02 (d, J¼8.5 Hz,1H), 6.81 (dd, J¼2.1, 8.5 Hz, 1H), 4.23
br s, 1H), 4.15 (d, J¼10.9 Hz, 1H), 3.76 (s, 3H), 3.18 (dd, J¼2.8,
0.3 Hz, 1H), 2.82 (m, 2H), 2.19 (s, 3H), 1.85 (m, 8H), 1.58 (d,
4
(
1
13
J¼14.0 Hz, 1H), 1.34 (d, J¼14.0 Hz, 1H). C NMR (75 MHz, CDCl
3
):
d
¼210.6, 158.2, 131.0, 130.5, 129.7, 114.0, 112.0, 81.4, 64.2, 62.1, 55.4,
4.5.1. (ꢀ)-(8
b,9a,14a)-2-Methoxy-17-acetyl-11-selenagona-1,3,5
5
1.9, 44.8, 34.9, 30.4, 28.5, 26.56, 26.2, 22.1. HRMS (EI): calcd for
(10),13(17)-tetraene-11-oxide 31. Yield, 0.16 g (86%). Oil. IR (neat)
ꢂ1 1
C
H O
19 24 4
Te 446.0737, found 446.0743.
3432, 1692, 905, 820 cm . H NMR (CDCl
3
): 7.76 (d, J¼2.6 Hz, 1H),
7
.00 (d, J¼8.5 Hz,1H), 6.78 (dd, J¼2.6, 8.5 Hz,1H), 3.75 (s, 3H), 3.12 (d,
4
.4.4. (ꢀ)-(8
b
,9
a
,14
a
)-2-Methoxy-17
a
-(2-oxoethyl)-11-telluragona-
J¼11.1 Hz, 1H), 2.76 (m, 5H), 2.32 (m, 1H), 2.21 (s, 3H), 2.18 (d,
1,3,5(10)-trien-13
b
-ol-11-oxide 26 from 20. Yield, 0.032 g (8%). Oil.
J¼15.5 Hz,1H), 2.08 (m, 2H),1.86 (d, J¼15.5 Hz,1H),1.72 (m,1H),1.43
ꢂ1 1
13
IR (neat)1640,1265, 910, 820 cm . H NMR(CDCl
3
):9.70 (s,1H), 7.75
(m,1H). C NMR (75 MHz, CDCl
3
):
d¼197.8,157.7,142.3,139.2,130.8,
(
5
d, J¼2.4 Hz, 1H), 7.04 (d, J¼8.5 Hz, 1H), 6.83 (dd, J¼2.4, 8.5 Hz, 1H),
130.4, 126.6, 115.5, 113.4, 65.6, 55.2, 54.7, 52.2, 44.3, 33.2, 30.6, 28.8,
27.3, 27.1. C19 Se (378.07):C 60.48, H 5.88;found C 60.09, H6.12.
.30 (br s,1H), 3.77 (s, 3H), 3.90 (d, J¼10.3 Hz,1H), 2.84 (m, 2H), 2.28
22 3
H O
(
m, 2H), 1.83 (m, 8H), 1.56 (d, J¼13.7 Hz, 1H), 1.32 (d, J¼13.7 Hz, 1H).
3
1
C NMR (75 MHz, CDCl
12.9, 79.4, 67.1, 59.1, 55.5, 50.7, 47.5, 42.8, 36.6, 28.9, 28.9, 26.7, 22.8.
HRMS (EI): calcd for C19 Te 446.0737, found 446.0744.
3
):
d
¼200.3, 157.9, 130.0, 130.3, 126.5, 115.4,
4.5.2. (ꢀ)-(8
b,9a,14a)-2-Methoxy-17-acetyl-11-telluragona-1,3,5
1
(10),13(17)-tetraene-11-oxide 32. Yield, 0.15 g (72%). Oil. IR (neat)
ꢂ1 1
24
H O
4
3385, 1696, 1610, 820 cm . H NMR (CDCl
3
): 8.05 (d, J¼8.7 Hz, 1H),
6
.75 (dd, J¼2.8, 8.7 Hz,1H), 6.65 (d, J¼2.8 Hz,1H), 3.76 (s, 3H), 3.19 (d,
4
.4.5. (ꢀ)-(8
b
,9
a
,14
a
)-3-Aza-17
a
-acetyl-11-selenagona-1,3,5(10)-
J¼10.9 Hz, 1H), 2.78 (m, 5H), 2.31 (m, 1H), 2.24 (s, 3H), 2.12 (d,
trien-13
b
-ol-11-oxide 27 from 21. Yield, 0.25 g (72%). Oil. IR (neat)
J¼15.1 Hz, 1H), 2.06 (m, 2H), 1.88 (d, J¼15.1 Hz, 1H), 1.70 (m, 1H), 1.44
ꢂ1 1
13
3
8
1
424, 1709, 1269, 820 cm . H NMR (CDCl
3
): 8.13 (d, J¼1.7 Hz, 1H),
(m, 1H). C NMR (75 MHz, CDCl
3
):
d¼197.9, 159.4, 142.5, 140.2, 139.4,
.07 (dd, J¼1.7, 7.0 Hz, 1H), 7.89 (d, J¼7.0 Hz, 1H), 3.53 (d, J¼10.9 Hz,
130.6, 117.8, 114.9, 112.9, 65.1, 55.2, 54.6, 52.4, 44.1, 33.0, 30.0, 29.8,
H), 3.15 (dd, J¼2.5, 9.2 Hz, 1H), 2.74 (2H, m), 2.18 (3H, s), 1.72 (8H,
22 3
27.4, 26.3. C19H O Te (428.06): C 53.57, H 5.21; found C 53.12, H 5.76.
13
m), 1.64 (d, J¼13.8 Hz, 1H), 1.36 (d, J¼13.8 Hz, 1H). C NMR (CDCl
3
):
2
10.2, 138.6, 137.3, 136.9, 125.8, 78.1, 63.9, 61.9, 59.8, 49.2, 34.4, 32.0,
6.1, 25.4, 25.0, 22.7. HRMS (EI): calcd for C17 Se 383.0636,
found 383.0641.
4.5.3. (ꢀ)-(8
b
,9
a
,14 )-3-Aza-17-acetyl-11-selenagona-1,3,5(10),13
a
2
H21NO
4
(17)-tetraene-11-oxide 33. Yield, 0.15 g (82%). Oil. IR (neat) 3509,
ꢂ1 1
1690, 1510, 820 cm . H NMR (CDCl
3
): 8.09 (d, J¼1.8 Hz,1H), 8.07 (dd,
J¼1.8, 7.6 Hz, 1H), 7.82 (d, J¼7.6 Hz, 1H), 2.98 (d, J¼10.9 Hz, 1H), 2.78
4
.4.6. (ꢀ)-(8
b,9a,14a)-3-Aza-17a-(2-oxoethyl)-11-selenagona-1,3,5
(2H, m), 2.19 (3H, s), 2.09(d, J¼14.1 Hz, 1H), 1.87 (d, J¼14.1 Hz,1H),1.75
13
(
(
(
10)-trien-13
neat) 3430, 1640, 907, 820 cm . H NMR (CDCl
d, J¼1.7 Hz, 1H), 8.08 (dd, J¼1.7, 7.0 Hz, 1H), 7.92 (d, J¼7.0 Hz, 1H),
b
-ol-11-oxide 28 from 21. Yield, 0.035 g (10%). Oil. IR
(8H, m). C NMR (75 MHz, CDCl
3
):
d¼196.8, 146.2, 141.9, 139.9, 138.2,
ꢂ1 1
3
): 9.62 (s, 1H), 8.13
137.4, 137.1, 126.2, 54.9, 50.7, 48.2, 42.3, 33.6, 32.1, 29.8, 28.9, 25.3.
17 3
C H19NO Se (365.05): C 56.05, H 5.26; found C 55.79, H 5.62.
3
.47 (d, J¼11.1 Hz, 1H), 2.74 (m, 2H), 2.60 (m, 2H), 2.33 (m, 2H), 1.75
13
(
(
6
m, 7H), 1.51 (d, J¼13.8 Hz, 1H), 1.28 (d, J¼13.8 Hz, 1H). C NMR
75 MHz, CDCl ):
3.7, 59.5, 48.8, 48.0, 47.1, 34.7, 28.3, 26.5, 24.9, 22.6. HRMS (EI):
4.5.4. (ꢀ)-(8
b,9a,14a)-3-Aza-17-acetyl-11-telluragona-1,3,5(10),13
3
d¼202.8, 138.6, 136.4, 137.9, 125.6, 124.8, 78.3,
(17)-tetraene-11-oxide 34. Yield, 0.14 g (68%). Oil. IR (neat) 3395,
ꢂ1 1
2975,1696, 820 cm . H NMR (CDCl
3
): 8.05(d, J¼1.6Hz,1H), 8.02(dd,
calcd for C17
H24NO
4
Se 383.0636, found 383.0639.
J¼1.6, 7.5 Hz, 1H), 7.86 (d, J¼7.5 Hz, 1H), 3.02 (d, J¼11.1 Hz, 1H), 2.77
2H, m), 2.18 (3H, s),1.98 (d, J¼14.4 Hz, 1H), 1.89 (d, J¼14.4 Hz,1H),1.76
(
13
4
.4.7. (ꢀ)-(8
b
,9
a
,14
a
)-3-Aza-17
a
-acetyl-11-telluragona-1,3,5(10)-
(8H, m). C NMR (75 MHz, CDCl
137.4, 137.1, 126.0, 54.1, 49.6, 46.2, 42.1, 33.4, 30.9, 29.1, 27.9, 25.6.
Te (415.04): C 49.45, H 4.64; found C 49.01, H 4.98.
3
):
d¼196.5, 145.9, 142.0, 139.6, 138.3,
trien-13
3
8
b
-ol-11-oxide 29 from 22. Yield, 0.25 g (64%). Oil. IR (neat)
ꢂ1 1
425, 1708, 1265, 820 cm . H NMR (CDCl
3
): 8.11 (d, J¼1.9 Hz, 1H),
17 3
C H19NO
.07 (dd, J¼1.9, 7.5 Hz, 1H), 7.89 (d, J¼7.5 Hz, 1H), 3.18 (dd, J¼2.8,
1
0.3 Hz, 1H), 3.13 (d, J¼10.9 Hz, 1H), 2.84 (2H, m), 2.19 (3H, s), 1.76
Acknowledgements
13
(
8H, m), 1.59 (d, J¼13.7 Hz, 1H), 1.38 (d, J¼13.7 Hz, 1H). C NMR
CDCl ): 209.9, 138.9, 137.6, 136.8, 126.1, 77.9, 64.2, 61.8, 59.5, 48.8,
4.6, 32.2, 26.4, 25.8, 25.2, 22.6. HRMS (EI): calcd for C17 Te
33.0533, found 433.0538.
(
3
4
3
We are indebted to Dr. R. Faure for his assistance in NMR mea-
surements and to Pr N. Aouf (Universit eꢀ d’Annaba, Alg eꢀ rie) for
helpful comments.
H21NO
4
4
.4.8. (ꢀ)-(8
b,9a,14a)-3-Aza-17a-(2-oxoethyl)-11-telluragona-1,3,5
References and notes
(
10)-trien-13
b
-ol-11-oxide 30 from 22. Yield, 0.06 g (15%). Oil. IR
ꢂ1 1
(
neat) 3430, 1640, 820 cm . H NMR (CDCl ): 9.72 (s, 1H), 8.15 (d,
3
1. (a) Amagata, T.; Amagata, A.; Tenney, K.; Valeriote, F. A.; Lobkovsky, E.; Clardy,
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(
d, J¼10.3 Hz, 1H), 2.81 (m, 2H), 2.29 (m, 3H), 1.76 (m, 9H), 1.56 (d,
13
2
3
4
J¼13.7 Hz, 1H), 1.31 (d, J¼13.7 Hz, 1H). C NMR (75 MHz, CDCl
¼201.8, 138.9, 136.6, 137.8, 125.8, 124.3, 78.1, 63.2, 59.1, 48.2, 47.9,
7.2, 34.6, 28.1, 26.6, 24.3, 22.2. HRMS (EI): calcd for C17 Te
3
):
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d
. (a) Dolle, R. E.; Allaudeen, H. S.; Kruse, L. I. J. Med. Chem. 1990, 33, 877; (b)
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4
H21NO
4
4
33.0533, found 433.0539.
5
. (a) Chesnut, R. W.; Durham, N. N.; Mawsdsley, E. A.; Berlin, R.-A. Steroids 1976,
5
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3 2
$Et O
1
1979, 305.
(
1.5 mmol, 0.19 mL) in anhydrous CH Cl (5 mL) was stirred under
2
2
7. Morgan, L. R. Chem. Ind. 1963, 293.

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