Construction of novel steroidal isoxazolidinone derivatives under Vilsmeier-Haack conditions

Article abstract of DOI:10.1016/j.tetlet.2012.11.105

A novel expeditious and convenient synthesis of 5α-cholestano-[5,6-c] -isoxazolidin-5′-ones based on the reaction of 5α-6- hydroxyiminocholestanes with Vilsmeier-Haack reagent (DMF/POCl₃) is described. The systems presented here, are novel scaffolds and have not been described before. Structural assignment of newly synthesized compounds was performed by IR, ¹H NMR, ¹³C NMR, 2D ¹H- ¹H COSY, MS and analytical data.

Full text of DOI:10.1016/j.tetlet.2012.11.105

Tetrahedron Letters 54 (2013) 874–877
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of novel steroidal isoxazolidinone derivatives under
Vilsmeier–Haack conditions
a,
⇑
a
a
b
Shamsuzzaman , Hena Khanam , Ashraf Mashrai , Nazish Siddiqui
a
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India
Department of Illmul, Advia Ajmal Khan Tibbiya College, Aligarh Muslim University, Aligarh 202002, India
b
a r t i c l e i n f o
a b s t r a c t
0
Article history:
A novel expeditious and convenient synthesis of 5
a
-cholestano-[5,6-c]-isoxazolidin-5 -ones based on the
Received 11 September 2012
Revised 22 November 2012
Accepted 24 November 2012
Available online 1 December 2012
reaction of 5a-6-hydroxyiminocholestanes with Vilsmeier–Haack reagent (DMF/POCl ) is described. The
3
systems presented here, are novel scaffolds and have not been described before. Structural assignment of
newly synthesized compounds was performed by IR, 1H NMR, C NMR, 2D H– H COSY, MS and analyt-
13
1
1
ical data.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
6
-Hydroxyiminocholestane
Isoxazolidinone
Vilsmeier reagent
Steroid
Isoxazolidinones are well-established building blocks in syn-
thetic organic chemistry. One of the reasons the isoxazolidinones,
particularly 5-isoxazolidinones, are of considerable interest to or-
ganic chemists is that they are good precursors to unnatural b-ami-
no acids: these are, indeed, unmasked forms of 5-isoxazolidinones.
cently.11 Significant effort continues to be directed into the devel-
opment of efficient methodologies to new isoxazolidinone-based
structures.
The Vilsmeier–Haack reagent (halomethyleniminium salt)
formed from the interaction of dialkyl formamide such as DMF
1
,2
These structures exhibit a wide range of biological activities.
3
with POCl has attracted the attention of synthetic organic chem-
1
2
These type of compounds are an important class of heterocyclic
structures, that can be applied in drug and pharmaceutical fields.
These compounds have attracted scientific interest because of their
ists since its discovery in 1927. It is one of the most commonly
used reagents for the introduction of an aldehydic (CHO) group
1
3
into electron rich aromatic systems. However, the scope of the
Vilsmeier reagent is not confined to the aromatic formylation reac-
3
potential cytotoxic, pro-apoptotic and antimicrobial capabilities.
1
4
15
Furthermore, they can be used for the preparation of nucleoside
tion alone. A wide variety of alkene derivatives, carbonyl com-
4
16
analogues. Nucleoside analogues have emerged in recent years
pounds, activated methyl and methylene
groups exhibit
as highly promising candidates for the development of new effi-
cient drugs against cancer and viral infections, particularly that
of the HIV. Moreover, Parnafungins, natural products containing
reactivity towards the Vilsmeier reagent. In addition to the carbon
1
7
18
nucleophiles, some oxygen and nitrogen nucleophiles are also
reactive towards Vilsmeier reagent. Numerous transformations of
the iminium salts into products other than aldehydes have been
5
an isoxazolidinone ring, have been isolated from Fusarium larvarum
1
9,20
and have been shown to be potent inhibitors of the fungal polyad-
achieved
and these transformations enhance the scope and
6
enosine polymerase. Because of the importance of these scaffolds
versatility of the Vilsmeier–Haack reaction. Following our inter-
2
1
in synthetic organic chemistry and their usefulness as pharmaco-
logical molecules, much attention has been focused on their
synthesis.
est on the synthesis of new steroidal derivatives we herein
report a prompt and novel strategy for the synthesis of 5
ano-[5,6-c]-isoxazolidin-5 -ones (7–9) based on the reaction of
a
-cholest-
0
Synthetic routes to them are numerous, including the enantio-
selective conjugate addition of hydroxylamines to pyrazolidinone
5a-6-hydroxyiminocholestanes (4–6) with Vilsmeier reagent.
Interestingly, the reaction proceeded smoothly and the desired
acrylamides, propenoates, crotonic acid esters9 and
7
8
a,b-unsatu-
steroidal 5 -isoxazolidinone derivatives (7–9) were obtained in
0
1
0
rated-d-lactones. The 1,3-dipolar cycloaddition of nitrones with
good yield (80–87%). With the best of our knowledge there
ynolates to give isoxazolidinones has been developed quite re-
are no reports, however, describing the synthesis of steroidal
0
5
-isoxazolidinones via Vilsmeier–Haack reaction.
2
2
The 5a-6-hydroxyiminocholestanes (4–6) employed for the
⇑
Corresponding author. Tel.: +91 9411003465.
E-mail address: shamsuzzaman9@gmail.com ( Shamsuzzaman).
present investigation, were conveniently obtained from the corre-
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.105

Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
875
sponding steroidal ketones23 (1–3) by the known literature meth-
od. Treatment of compounds (4–6) with DMF/POCl at room tem-
Table 1
Effect of temperature on rate of reaction
3
perature furnished corresponding steroidal isoxazolidinone
derivatives (7–9) (Scheme 1). To search for optimum reaction con-
ditions and establish a reproducible procedure, the temperature of
reaction was increased. Reaction time was interestingly reduced
when it was carried out at 60–65 °C (Table 1). Moreover, to exam-
ine the solvent effects, we applied the same conditions with sol-
vents of different polarity. DMF with medium polarity was found
to be the best solvent among acetonitrile, chloroform, dichloro-
methane and toluene in terms of yield and rate (Table 2). With ace-
tonitrile (most polar) and toluene (least polar) even at refluxing
temperature did not improve rate and yield significantly. With sol-
vents other than DMF poor yield of products was observed (<40%).
Thus most appropriate conditions for this important conversion
were found to be (a) 60–65 °C temperature and (b) solvent: DMF.
Detailed experimental procedure and spectral data (Figs. S1–S15)
can be found in Supplementary data.
Compound
Time (h): rt
Time (min): 60–65 °C
7
8
9
6
4
3
50
45
30
Table 2
Effect of solvent on rate and yield of reaction at 60–65 °C temperature
Compound
Solvent
Time (h)
Yield (%)
7
CH3CN
DMF
CHCl3
CH2Cl2
C7H8
CH3CN
DMF
CHCl3
CH2Cl2
C7H8
CH3CN
DMF
CHCl3
CH2Cl2
C7H8
16
50 (min)
12
14
20
12
45 (min)
11
10
17
10
30 (min)
9
8
16
22
87
35
30
25
20
84
32
26
20
18
84
30
24
18
8
9
Elucidation of the proposed structures (7–9) was based on their
1
13
correct elemental analyses and compatible IR, H NMR, C NMR,
1
1
2
D H– H COSY and MS spectral data. The mass spectrum of com-
pound 7 displayed the molecular ion [M ] peak at m/z 487. The IR
absorption showed peaks at 3310 cm for stretching of the N–H
group and at 1759 cm for stretching of the C@O group. The
+Å
ꢀ1
ꢀ
1
1
H
NMR spectrum (400 MHz, CDCl ) of compound 7 featured a signal
3
as singlet at d 8.70 integrating for one hydrogen, which is the char-
acteristic signal of the N–H proton, while another downfield signal
as doublet of doublets at d 3.22 (J = 4.24, 13.52 Hz) was assigned to
interruption at C-5. Thus N–H is attached to this carbon. A doublet
of doublet at d 3.20–3.25 was attributed to H-6 which showed
cross peaks with the signals at d 1.59 and 1.40 due to H-7b and
the C-6 methine proton. The 13C NMR spectra (100 MHz, CDCl
)
3
showed distinct signals. Resonance at d 167.26 was diagnostic sig-
nals for the carbonyl carbon of heterocyclic ring. Based on these
spectral data, the formation of isoxazolidinone ring attached to ste-
roidal skeleton was confirmed. However, the position of the ring
was still undecided, and this was determined with the help of
H-7a. All these data clearly suggest the fusion of heterocyclic moi-
ety to the 5, 6 position of steroid. The other compounds 8 and 9
were characterized in the same way.
Mechanistically, we assume that aminooxymethylene-di-
methyl-ammonium derivative of cholestane is formed from cho-
lesteryl oxime and chloromethyleniminium intermediate (formed
2
D-NMR experiments.
The signal at d 8.70 in the H NMR spectrum of compound 7 was
1
in situ from DMF/POCl ) followed by intramolecular cyclization
3
unambiguously assigned to the spin system containing the N–H
function. It did not show any cross peak with any of the protons
in the 2D spectrum, clearly suggesting that there are no adjacent
protons which are coupled to N–H proton. The signal at d 4.67
to form a four membered spiro intermediate which undergoes
1,2-hydride shift and simultaneous intramolecular rearrangement
to give corresponding products (7–9) as depicted in Scheme 2.
The stereochemistry at C-6 can be established on the basis of
the mechanism as well as on the coupling constant (J) value of
C6-proton. The proposed reaction mechanism gives rise to a chiral
was assigned to H-3
.66, 1.57 (H-2b, H-2
-4 proton showed any cross peaks, indicating that there is an
a
, which further showed cross-peaks at d
1
a
) and at d 2.00, 1.88 (H-4b, H-4 ). Neither
a
H
2
6
centre at C6 with C –CO bond being equatorially (a) oriented,
H
H
H
NH OH.HCl/CH COONa
2
3
H
O
H
DMF/POCl3
stirring at 0
H
N
H
H
H
C2H5OH/reflux, 4 h
°
C
X
X
X
C
H
for 15 min,
H
HN
then at 60-65
°
C
OH
O
O
1
-3
4-6
OAc (4)
7-9
OAc (7)
OAc (1)
Cl
H
(2)
(3)
Cl
H
(5)
(6)
Cl
H
(8)
(9)
Scheme 1. Synthesis of steroidal isoxazolidinone derivatives.

8
76
Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
O
O
O
C
P
H C
Cl
3
P
Cl
N
H
CH3
CH3
N
H
+
O
Cl
Cl
Cl
C
N
H C
3
Cl
H3C
H
Cl
CH3
Reactive species
H
O
H
H
-
HCl
H
H
H
H
H
H
Cl
CH3
CH3
X
X
H
X
+
N
NH
H
C
N
C
N
N
H
H
OH
O
N
C
H
H
H
H
H O
2
1
&
,2 hydride shift
rearangement
H
H
H
H
N
H
H
H
X
X
HN
X
C
HN
N
O
O
HN
O
O
Scheme 2. A tentative mechanism for the synthesis of steroidal isoxazolidinones 7–9.
resulting in cis geometry of isoxazolidinone ring which might be
due to the fact that during the rearrangement hydride ion ap-
proaches from the axial (b) side to push the bulky group already
lidinones, which, to the best of our knowledge, is unprecedented.
Further studies to broaden the scope towards the synthesis of
the novel steroidal derivatives are under investigation in our
laboratory.
present at C-6 to the less hindered equatorial (
a) side to avoid
1
,3-diaxial interaction due to C-10 methyl group. It is further sup-
Acknowledgments
ported by coupling constant (J) values of C
6
–H that appeared as a
–H (equatorial) pro-
tons with J = 13.52 and 4.24 Hz, respectively, strongly supporting
the dihedral angle between C –H and neighbouring two C -protons
which should be ꢁ180°(anti, axial–axial relationship) and ꢁ60°
gauche, axial–equatorial relationship)24,25 As anticipated, the
above results are in excellent agreement with the cis geometry of
7 7
doublet of doublet due to C –H (axial) and C
We are very grateful to the Department of Chemistry, A.M.U.,
Aligarh, for providing necessary research facilities. Facilities pro-
vided by SAP (DRS-I) for their generous research support are also
gratefully acknowledged. We also thank SAIF Punjab University
Chandigarh for providing spectral data.
6
7
(
isoxazolidinone ring (C
6
–bH) and S configuration at C6.2
1a
In conclusion, we have developed an efficient synthetic ap-
proach for the synthesis of a novel class of steroidal isoxazolid-
Supplementary data
inones via Vilsmeier reagent (DMF/POCl
3
). This is a simple, mild
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.105. These data include MOL files and InChiKeys of the most
important compounds described in this article.
and straightforward reaction, which completes in a short span of
time. The novelty of the entire process lies in the Vilsmeier
cyclization of 6-hydroxyiminocholestanes into steroidal isoxazo-

Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
877
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