Synthesis and conformational preferences of novel steroidal 16-spiro-1, 3, 2-dioxaphosphorinanes

Article abstract of DOI:10.2174/157017809788489927

The diastereomeric pairs a and b of novel 16-spiro-dioxaphosphorinanes 3-11 were synthesised via the phosphorylation of 16, 16-bis(hydroxymethyl)estrone 3-methyl ether (1) and its 17β-hydroxy analogue (2) and their stereostructures were investigated by di

Full text of DOI:10.2174/157017809788489927

340
Letters in Organic Chemistry, 2009, 6, 340-344
Synthesis and Conformational Preferences of Novel Steroidal
16-Spiro-1,3,2-Dioxaphosphorinanes
Éva Frank*, László Sipos, János Wölfling and Gyula Schneider
Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary
Received November 04, 2008: Revised March 09, 2009: Accepted March 12, 2009
Abstract: The diastereomeric pairs a and b of novel 16-spiro-dioxaphosphorinanes 3ꢀ11 were synthesised via the phos-
phorylation of 16,16-bis(hydroxymethyl)estrone 3-methyl ether (1) and its 17ꢁ-hydroxy analogue (2) and their
stereostructures were investigated by different NMR methods.
Keywords: Steroids, spiro compounds, phosphorylations, dioxaphosphorinanes, stereostructure.
INTRODUCTION
PhOP(O)Cl2 in refluxing CH2Cl2 in the presence of an amine
base gave the diastereomeric pairs a and b of dioxaphos-
phorinane 3 in high yield, in a ratio of 2:3 (Table 1). In order
to study the electronic and steric effects of different P sub-
stituents on the conformation of the hetero ring, we carried
out the analogous reactions with PhP(O)Cl2, POCl3 and
bis(2-chloroethyl)phosphoramidic dichloride [6] to afford 4-
6, as 1:2 mixtures of the related isomers a and b for 4 and 6,
and as a 3:1 mixture for 5a and 5b. The overall yields of the
desired products decreased in the sequence 3 > 4 > 5 > 6.
The diastereomers a and b of 3-6 were separated by column
chromatography.
Mono- and bicyclic 1,3,2-dioxaphosphorinanes, includ-
ing natural and synthetic cyclic nucleotides, have attracted
much attention during the past few decades from both phar-
macological and stereochemical aspects [1]. The main
driving force behind the stereostructural studies was the
desire to investigate the unique conformational behaviour of
differently substituted six-membered P-containing hetero
rings [2]. It has been demonstrated that, especially in
conformationally biased bulky molecules, one of the two
alternative chair forms or intermediate twist [3a] half-chair
[3b] or boat [3c] conformations of the P heterocycle can
predominate in solution. Furthermore, the conformational
distribution of 2-oxo-1,3,2-dioxaphosphorinanes may be
highly sensitive to the solvent, i.e. a more polar solvent may
stabilize non-chair conformations [3d].
In view of the low yield of 6 from 1 with the bis(2-
chloroethyl) reagent, the phosphorylations of 2 to furnish 7-9
were performed only with the other three P(V) reagents. The
conversion of 2 proved poorer than that of 1 because of the
more polar character and hence the lower solubility of 2 in
the reaction solvent. Moreover, the presence of the
17-hydroxy group in 2 permitted the formation of minor
side-products. Besides the major isomers 7a and 7b, cyclic
phosphates 12a and 12b were obtained from 2 on reaction
with PhOP(O)Cl2, both pairs in ratios of close to 1:1,
whereas the ring closure of 2 with PhP(O)Cl2 led to only a
single by-product 13b, the major product comprising a 2:3
mixture of 8a and 8b. Ring closure of 2 with POCl3 under
similar conditions resulted in only a single diastereomer 9a.
The isomers a and b of 7 and 8 were also synthesised from
the separated diastereomers of 3 and 4 with KBH4, respec-
tively. Six-membered P heterocycles are known to be
relatively stable under both acidic and alkaline hydrolytic
conditions [7] and undergo reduction without decomposition.
In order to achieve lower polarity and facilitate the NMR
characterisation, the 17ꢁ-acetates 10 and 11 of 7 and 8 were
also prepared.
The construction of a dioxaphosphorinane ring on a rela-
tively rigid sterane skeleton furnishes an excellent possibility
via which to restrict the conformational flexibility of the
hetero ring, though only a few examples of such systems
have been described so far [4]. In this regard, we recently
reported the synthesis and conformational analysis of
diastereomeric dioxaphosphorinano[16,17ꢀd]-estrone deriva-
tives, where the geometry of the P-containing ring was
strongly influenced by the condensed sterane framework,
and an unusual distorted-boat conformation predominated in
most cases, regardless of the P configuration and substituent
preferences [4b].
RESULTS AND DISCUSSION
As an extension of our earlier work, we now describe the
synthesis of some new 16-spiro-dioxaphosphorinanes via the
phosphorylation of estrone precursors with four P(V)-
reagents. The transformations were performed on 16,16-
bis(hydroxymethyl)estrone 3-methyl ether 1 [5] and the cor-
responding 17ꢁ-hydroxy derivative 2, which is readily avail-
able from 1 by reduction (Scheme 1). The reaction of 1 with
The structures of the 16-spiro-dioxaphosphorinanes 3-11
were investigated by solution-state multinuclear (1H, 13C and
31P) NMR techniques. The sequence of 31P chemical shifts
for diastereomers a and b of 3ꢀ11 is ꢂ31P(a) < ꢂ31P(b), which
suggests that the Y substituent on P is axial in isomers a and
equatorial in diastereomers b [8] (Table 2). The orientation
of Y may be axial in two chair conformations (Aax. and Bax.),
in which the P configurations are opposite (Table 3). The
*Address correspondence to this author at the Department of Organic
Chemistry, University of Szeged, H-6720 Szeged, Dóm tér 8., Hungray;
Fax: +36-62-544199; E-mail: frank@chem.u-szeged.hu
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Synthesis and Conformational Preferences of Novel Steroidal
Letters in Organic Chemistry, 2009, Vol. 6, No. 4
341
Y
Y
YP(O)Cl2
Et3N
CH2Cl2
reflux
R
R
O
R
O
OH
P
P
O
O
17
O
O
OH
16
H
+
H
H
H
H
MeO
KBH4
KBH4
MeOH
CH2Cl2
KBH4
MeOH
CH2Cl2
3a-6a R = O
7a-9a R =ꢀOH,H
10a, 11a R =ꢀOAc,H
3b-6b R = O
7b-9b R = ꢀOH,H
10b, 11b R = ꢀOAc,H
1 R = O
MeOH
THF
2 R = ꢀOH,H
OPh
O
Y
O
O
Y
P
P
O
O
O
3, 7, 10, 12
4, 8, 11, 13
5, 9
OPh
Ph
Cl
OH
OH
6
N(CH2CH2Cl)2
H
H
12b, 13b
12a
Scheme 1.
Table 1. Dioxaphosphorinanes Afforded by the Phosphorylation of 1 and 2
Entry
Substrate
Reagent
Product(s)
Overall Yielda [%]
Diastereomeric Ratiob (a:b)
1
2
3
4
5
1
1
1
1
2
PhOP(O)Cl2
PhP(O)Cl2
POCl3
3
4
91
86
40
13
69
8
2:3
1:2
3:1
1:2
1:1
1:1
5
MucP(O)Cl2
6
PhOP(O)Cl2
7
12
8
6
2
PhP(O)Cl2
POCl3
55
2
2:3
d
13b
9a
d
7
2
12
aAfter purification by column chromatography.
bDetermined from the 1H NMR spectra of the crude products.
cMu = N(CH2CH2Cl)2.
dsingle diastereomer.
same is true for the equatorial Y in diastereomers b, where
chair forms Aeq. and Beq. may be considered. In order to
determine the configuration, 10a and 11b, in which chair
conformations were expected to predominate with regard to
the substituent preferences, were subjected to NOESY meas-
urements. The two-dimensional spectra of 10a and 11b
revealed unambiguous cross-peaks between the 16b-protons
and 17-H. The proximity of the equatorial 16a-Hb to 18-CH3
was also confirmed. The observed relationship is impossible
in conformer Bax. for 10a and in Beq. for 11b, and the pre-
dominant population of chair conformation A is therefore
suggested for both diastereomers a and b. A typical feature
of 2-oxo-1,3,2-dioxaphosphorinanes, which are mainly in
one conformation in solution, is the combination of large
3J(H,P) values for those protons equatorial and hence anti-
pling constants of 3ꢀ11 (Table 3). Accordingly, the chair
conformation Aax. is assigned to the hetero ring in 3a, 5a, 7a,
9a and 10a, which is evident from the small values (< 3.2
Hz) for J(16a-Ha,P) and J(16b-Ha,P) and the large values (>
22.2 Hz) for J(16a-Hb,P) and J(16b-Hb,P). The conforma-
tional equilibrium can be regarded as anancomeric in these
cases, which is not surprising considering the strong axial
preferences of the electronegative OPh and Cl substituents
due to the anomeric effect [9]. However, substituent in 6a
proved to be insufficiently strong to drive the equilibrium
towards conformation Tps.eq. to a major extent, and the large
contribution of conformer Aax. therefore also seems certain.
The large four-bond couplings JW ꢁ 2.8 Hz, confirm the W
arrangement of 16a-Hb and 16b-Hb in 3a, 5aꢀ7a, 9a and 10a.
In contrast with 6a, extensive depopulation of the chair con-
formation occurred for 4a, 8a and 11a, as indicated by the
increased J(16a-Ha,P) values of about 17 Hz and the
decreased J(16a-Hb,P) values of around 6 Hz. Conformation
Aax., which places the. P-Ph in an unfavourable axial posi-
3
periplanar to P, and small J(H,P) values for the axial pro-
tons synclinal to P. The relatively great differences in chemi-
cal shifts within the pairs 16a-Ha/16a-Hb and 16b-Ha/16b-Hb
at 400 MHz allowed an accurate analysis of the vicinal cou-

342 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Frank et al.
tion, is largely converted to the twist form with the Ph
pseudo-equatorial. The results are somewhat surprising, as
the preference of NR2 for an equatorial position has been
reported to be usually stronger than that of Ph [10]. Although
16a-Ha and 16a-Hb are essentially interchanged in conform-
ers Aax. and Tps.eq., the coupling pattern of the 16b-protons
remains almost unchanged relative to that in the chair con-
formation Aax.. The predominant twist conformer Tps.eq. was
also demonstrated by the NOESY spectrum of 11a, which
showed cross-peaks between both of the 16a-protons and the
angular CH3 on C-13. The conformational analysis of the b
series of compounds was performed similarly to that in the a
series. The small couplings of the equatorial 16a-Ha and 16b-
Ha with the P and the large values of J(16a-Hb,P) and J(16b-
Hb,P) led to the conclusion that the hetero ring in 4b and 6b
is exclusively in conformation Aeq. with the Ph and bis(2-
chloroethyl)amino substituent in their favoured equatorial
orientation. The conformational equilibrium likewise seems
to be strongly shifted towards the Aeq. conformer in 3b, 8b
and 11b. For 5b, 7b and 10b, however, the contribution of
the twist conformer Tps.ax. is assumed to be larger since
J(16a-Ha,P) > J(16a-Hb,P). This can be explained by OPh
and Cl striving to take up an axial position. The minor popu-
lation of Bax. is also conceivable in these latter cases in view
of the increased J(16b-Ha,P) and decreased J(16b-Hb,P)
values. A further interesting conclusion emerges from a
comparison of the conformational preferences of the differ-
ently substituted 16-spiro-dioxaphosphorinanes 3b-11b.
C-17 in the sterane skeleton is sp2 hybridised in 3b-6b, but in
a sp3 hybridisation state in 7b-11b. This causes a slight
change in the conformation of ring D and seems to affect the
conformational equilibrium of the connected hetero ring.
While the chair conformation Aeq. is assumed to predominate
for 3b, despite the unfavourable equatorial orientation of
OPh, depopulation of this conformer towards Tps.ax. and to a
small extent Bax. can occur in 7b and 10b. The same
tendency may be observed by comparing 4b with 8b and
11b. 4b is highly biased toward the population of Aeq., while
a certain presence of the twist form can be predicted from the
coupling constants for 8b and 11b. These results suggest that
the more rigid cyclopentanone-like ring D in 3bꢀ6b some-
what restricts the conformational mobility of the
P-containing ring and thus overcompensates the substituent
preferences to some degree.
In summary, we have synthesised novel steroidal
16-spiro-1’3’,2’-dioxaphosphorinanes. Stereostructural study
of the hetero rings revealed that a conformational bias in
favour of one or other conformer can be induced by the joint
sterane framework.
EXPERIMENTAL
General
TLC: silica gel 60 F254 plates (0.25 mm; Merck). Column
chromatography: silica gel 60 (0.040-0.063 mm; Merck).
Melting points: Kofler block; uncorrected; EI-MS: Varian
1
MAT 311A spectrometer with ionisation energy 70eV. H
NMR (400 or 500 MHz), 13C NMR (100 or 125 MHz) and
31P NMR (121 MHz) spectra: Bruker DRX 400 or Bruker
DRX 500 in CDCl3 at 300 K; TMS as internal standard (1H,
13C) and H3PO4 as external standard (31P); chemical shifts in
ppm.
Table 2. Selected 31P and 1H Chemical Shifts of 3-11 in CDCl3
ꢁ (ppm)
Compd
31P
16a-Ha
16a-Hb
16b-Ha
16b-Hb
3a
3b
-13.9
-11.3
14.4
18.0
-7.5a
-2.7a
6.3
4.73
4.76
4.28
4.98
4.70
4.44
4.75
4.82
4.69
4.79
4.30
5.10
4.68
4.31
4.59
4.32
4.70
4.22
4.20
4.37
4.12
4.27
4.52
4.12
4.08
4.29
4.27
4.36
4.25
4.35
4.26
4.25
4.08
4.19
4.56
4.62
4.24
4.80
4.52
4.33
4.59
4.65
4.48
4.21
4.17
4.89
4.47
4.66
4.27
4.30
4.69
4.11
4.09
4.16
3.99
4.16
4.46
4.02
3.97
3.95
4.42
4.10
3.91
3.98
4.01
4.39
4.20
3.93
4a
4b
5a
5b
6a
6b
6.5
7a
-12.2
-10.9
15.1
7b
8a
8b
18.4
b
9a
10a
10b
11a
11b
-12.8
-12.2
14.9
17.9
ameasured in DMSO-d6.
bnot measured.

Synthesis and Conformational Preferences of Novel Steroidal
Letters in Organic Chemistry, 2009, Vol. 6, No. 4
343
Table 3. Selected Coupling Constants J(H,P) and J(H,H) for the Hetero Rings of 3-11
Y
Ha
eq.
Ha
R
R
R
O
O
Hb
Y
P
Hb
Ha
Ha
O
Y
ax.
O
16b
O
16b
ps.eq.
P
17
16
17
16
17
16
16b
Hb
Hb
P
16a
O
16a O
O
Hb
Ha
16a
O
18
18
18
Ha
Hb
Tps.eq.
H
H
H
H
H
H
Aax.
Beq.
J (Hz)
Predicted
Conformational
Preferences
16a-Ha,P
16a-Hb,P
16b-Ha,P
16b-Hb,P
16a-Ha,16a-Hb
16b-Ha,16b-Hb
Jw
b
Compd
R
Y
3a
4a
O
O
OPh
Ph
0.8
17.6
2.8
23.2
5.9
0
23.5
17.7
28.2
20.8
22.8
16.6
28.2
23.5
17.1
-11.2
-11.2
-11.3
-11.3
-11.6
-11.6
-11.8
-11.2
-11.4
-11.2
-11.3
-11.5
-11.2
-11.0
-11.0
-11.1
-11.2
-11.2
3.0
2.2
3.2
3.1
2.8
1.8
3.1
2.8
2.0
Aax.
(Aax.
)
Tps.eq.
5.7
0
5a
O
Cl
28.3
20.0
23.2
7.2
Aax.
(Tps.eq.
Aax.
)
6a
O
Mua
OPh
Ph
4.3
2.1
0
7a
ꢀOH,H
ꢀOH,H
ꢀOH,H
ꢀOAc,H
ꢀOAc,H
2.0
Aax.
(Aax.
)
Tps.eq.
8a
17.0
3.2
6.1
0
9a
Cl
28.4
22.2
7.3
Aax.
Aax.
10a
11a
OPh
Ph
2.8
0
(Aax.
)
Tps.eq.
17.0
5.0
O
Ha
Ha
16b
R
R
R
O
O
Hb
P
ax.
Hb
Ha
Ha
O
O
O
16b
17
16
O
O
Y
16b
eq.
Y
P
17
17
16
16a
Hb
Hb
16a
P
ps.ax.
Y
16
O
Hb
Ha
16a
Ha
18
18
18
Hb
Tps.ax.
H
H
H
H
H
H
Aeq.
Bax.
J (Hz)
Predicted
Conformational
Preferences
b
Compd
R
Y
16a-Ha,P
16a-Hb,P 16b-Ha,P
16b-Hb,P
16a-Ha,16a-Hb 16b-Ha,16b-Hb
Jw
Aeq.
(Tps.ax.
)
3b
4b
O
O
OPh
Ph
4.7
2.4
19.4
20.4
11.3
22.6
10.6
18.8
8.8
4.7
0
19.4
20.8
15.6
22.6
14.3
18.2
15.4
19.2
-11.3
-11.2
-11.6
-11.3
-11.2
-11.4
-11.2
-11.3
-11.3
-11.2
-11.3
-11.2
-11.2
-11.0
-11.2
-11.1
2.3
2.6
0
Aeq.
Aeq.
Tps.a x.
Bax.
5b
O
Cl
13.2
0.8
9.3
0
6b
O
Mua
OPh
Ph
3.1
1.0
2.2
1.3
2.3
Aeq.
Aeq.
Tps.a x.
Bax.
7b
ꢀOH,H
ꢀOH,H
ꢀOAc,H
ꢀOAc,H
13.0
3.8
9.5
3.9
8.8
4.4
Aeq.
Tps.ax.
Tps.a x.
(Tps.ax.
8b
Aeq.
Bax.
10b
11b
OPh
Ph
14.8
3.3
Aeq.
)
18.7
aMu = N(CH2CH2Cl)2.
bcouplings of the equatorial protons on C-16a and C-16b.
A Typical Procedure is as Follows
dichloromethane (20:80) as eluent. Compound 4a: Mp. 247-
250 °C; 13C NMR (100 MHz, CDCl3): ꢂ = 14.1 (C-18), 25.6
(CH2), 26.6 (CH2), 29.5 (CH2), 30.9 (CH2), 31.8 (CH2), 37.8
(CH), 44.0 (CH), 47.5 (CH), 49.7 (C-13), 52.0 (d, J = 7.2
Hz, C-16), 55.2 (3-OMe), 71. 5 (d, J = 6.7 Hz, C-16b), 74.2
(d, J = 6.7 Hz, C-16a), 111.8 (C-2), 113.9 (C-4), 125.8 (d, J
= 182.9 Hz, C-1’), 126.2 (C-1), 129.1 (d, 2C, J = 15.3 Hz, C-
2’ and C-6’), 131.3 (C-10), 131.4 (d, 2C, J = 10.5 Hz, C-3’
and C-5’), 133.0 (d, J = 3.0 Hz, C-4’), 137.6 (C-5), 157.8 (C-
3), 216.2 (C-17). MS(EI): m/z = 466 (100) [M+], 389 (12),
341 (11). Compound 4b: Mp. 117-120 °C; 13C NMR (100
4a and 4b: To a stirred solution of Et3N (0.43 ml, 4
mmol) and 1 (344 mg, 1 mmol) in dichloromethane (15 ml),
PhP(O)Cl2 (0.17 ml, 1.2 mmol) was added drop-wise at
room temperature under a nitrogen atmosphere. The reaction
mixture was refluxed for 3 h then was poured into water, and
extracted with dichloromethane (3 ꢁ 10 ml), and the com-
bined organic phases were dried over Na2SO4, and evapo-
rated in vacuo. The crude product 4 was separated by column
chromatography on silica gel, using ethyl acetate/

344 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Frank et al.
G.; Rowell, R. J. Am. Chem. Soc., 1979, 101, 4925; (d) Sartillo-
Piscil, F.; Sánchez, M.; Cruz-Gregorio, S.; Quintero, L.
Tetrahedron, 2004, 60, 3001.
MHz, CDCl3): ꢀ = 13.9 (C-18), 25.6 (CH2), 26.7 (CH2), 29.5
(CH2), 30.6 (CH2), 31.6 (CH2), 37.8 (CH), 44.0 (CH), 47.4
(CH), 49.4 (C-13), 52.7 (d, J = 5.3 Hz, C-16), 55.2 (3-OMe),
69.1 (d, J = 6.2 Hz, C-16b), 72.7 (d, J = 6.2 Hz, C-16a),
111.7 (C-2), 113.9 (C-4), 125.7 (d, J = 196.9 Hz, C-1’),
126.2 (C-1), 128.5 (d, 2C, J = 15.7 Hz, C-2’ and C-6’), 131.4
(C-10), 132.2 (d, 2C, J = 10.4 Hz, C-3’ and C-5’), 133.0 (d, J
= 3.0 Hz, C-4’), 137.4 (C-5), 157.7 (C-3), 215.7 (C-17).
MS(EI): m/z = 466 (100) [M+], 341 (20), 172 (24).
[3]
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This work was supported financially by the Hungarian
Scientific Research Fund (OTKA PD-72403 and T-49366).
The authors thank I. Simon (University of Szeged) and R.
Machinek (University of Göttingen, Germany) for the NMR
spectra. É. Frank’s work was supported by the award of a
Bolyai János Research Fellowship.
[8]
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