Synthesis of some novel D-ring-fused dioxa- and oxazaphosphorinanes in the estrone series

Article abstract of DOI:10.1016/j.tetlet.2005.12.038

New types of P-heterocyclic-fused steroids, such as dioxa- and oxazaphosphorinane derivatives, were synthetized from estrone-1,3-dihydroxy and 1,3-aminoalcohol precursors by cyclization with phenylphosphonic dichloride.

Full text of DOI:10.1016/j.tetlet.2005.12.038

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1105–1108
Synthesis of some novel D-ring-fused dioxa- and
oxazaphosphorinanes in the estrone series
a,
a
b,c
Eva Frank, Brigitta Kazi, Krisztina Ludanyi and Gyo¨rgy Keglevichd
´
*
´
aDepartment of Organic Chemistry, University of Szeged, H-6720 Szeged, Hungary
bHungarian Academy of Sciences, Chemical Research Center, H-1525 Budapest, Hungary
cDepartment of Pharmaceutics, Faculty of Pharmacy, Semmelweis University, H-1092 Budapest, Hungary
dDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
Received 4 October 2005; revised 30 November 2005; accepted 7 December 2005
Available online 27 December 2005
Abstract—New types of P-heterocyclic-fused steroids, such as dioxa- and oxazaphosphorinane derivatives, were synthetized from
estrone-1,3-dihydroxy and 1,3-aminoalcohol precursors by cyclization with phenylphosphonic dichloride.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The reactions of diols and amino-alcohols with phos-
phonic dichlorides are well known and is a method for
the formation of phosphorus-containing heterocycles.1
Oxazaphosphorinanes especially are of great interest,
since cyclophosphamide, one of the most potent drugs
in the treatment of human cancers, contains this type
of heterocyclic ring.2 Besides evaluation of their bio-
logical activity,3 a number of conformational studies
have also been carried out to investigate the steric and
electronic effects of various substituents in different
positions of the parent oxazaphosphorinane ring.3
which is readily available from estrone 3-methyl ether
via multistep pathway, were used as starting materials
(Scheme 1). When the 1,3-diol 1 was reacted with
O
OH
R
H
H
H
H
H
H
MeO
MeO
1 R = OH
1. p-TsCl, py
One of the major aims of steroid chemistry is to develop
new heterocyclic derivatives to extend the already wide
range of biological activity of these compounds. Forma-
tion of a hetero ring on the sterane skeleton is one of the
possible methods of modifying the natural framework.4
To the best of our knowledge, only a few phosphorus
17-spiro-compounds have so far been synthesized.5
2. NaN3, DMF
3. Raney-Ni, NH2NH2
2 R = NH2
PhPOCl2
Et3N
CH2Cl2, reflux
3'
1'
4'
2'
5'
O
P
O
P
6'
This letter describes efficient syntheses of some new D-
ring-fused dioxa- and oxazaphosphorinane ring systems
via the reactions of estrone precursors with phenylphos-
phonic dichloride. For the transformations, 17b-hydr-
oxy-16b-hydroxymethylestrone 3-methyl ether 16 and
the corresponding 16b-aminomethyl derivative 2,7
O
X
O
X
16a
17
+
16
H
H
H
H
MeO
3b
3a
4
Keywords: Steroids; Estrone derivatives; Dioxaphosphorinanes; Oxaza-
phosphorinanes.
3 X = O (93% from 1 as a 1:1 diastereomeric mixture of 3a and 3b)
4 X = NH (15% from 2 as a single diastereomer)
*
Corresponding author. Tel.: +36 62 544275; fax: +36 62 544200;
e-mail: frank@chem.u-szeged.hu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.038

´
E. Frank et al. / Tetrahedron Letters 47 (2006) 1105–1108
1106
PhP(O)Cl2 in the presence of Et3N, the epimeric oxaza-
phosphorinanes 3a and 3b were formed in good yield in
a nearly 1:1 ratio.8 The diastereomeric pair was sepa-
rated by column chromatography.
unstable and difficult to isolate (Scheme 2).10 After treat-
ment of imine 5 with sodium borohydride in THF/
MeOH solution, secondary amine 6 was obtained in
good yield. Alternatively, this compound could also be
synthesized from 16-methylene-estrone 3-methyl ether
711 via the Michael-type addition of benzylamine and
subsequent reduction of the C-17 keto function of inter-
mediate 8.
Ring closure of the corresponding amino-alcohol 2 with
PhP(O)Cl2 under similar conditions resulted in only a
single diastereomer 4. The low yield of oxazaphosphor-
inane 4 is not surprising, as a primary amino function is
usually not very active in such reactions.9
The benzyl-substituted aminoalcohol 6 was then con-
verted to oxazaphosphorinane 11 in a much better yield
than was found for the cyclization of intermediate 2 with
a primary amine function. The heterocyclic product was
formed as a mixture of the two possible diastereomers
(11a and 11b) in a ratio of 3:2.12
Next, 17b-hydroxy-16b-aminomethylestrone 3-methyl
ether 2 was reacted with benzaldehyde to furnish the
corresponding imine 5, which could be isolated as a crys-
talline product in spite of the fact that imines are usually
O
H
H
H
MeO
2
7
abs. EtOH
reflux
R
NH2
O
C
cat. KOH. r.t.
H
CH
OH
N
O
NH R
H
H
H
H
H
H
MeO
MeO
8
9
R = Bn (85%)
R = -Pr (not isolated)
5 (89%)
n
NaBH4
THF/MeOH, r.t.
NaBH4
THF/MeOH, r.t.
OH NH R
H
H
H
MeO
6
R = Bn (95% from 5, 82% from 8)
10 R =
n-Pr (75% from 7)
PhP(O)Cl2
Et3N
CH2Cl2, reflux
O
P
O
P
O
N R
O
N
R
+
H
H
H
H
MeO
11a, 12a
11b, 12b
11 R = Bn (82% from 6 as a 3:2 diastereomeric mixture of 11a and 11b)
12 R = -Pr (35% from 10 as a 3:2 diastereomeric mixture of 12a and 12b)
n
Scheme 2.

´
E. Frank et al. / Tetrahedron Letters 47 (2006) 1105–1108
1107
´
Wo¨lfling, J.; Schneider, Gy.; Peter, A. J. Chromatogr., A
1999, 852, 433–440.
In order to study the substituent effect of the amine pre-
cursor of the oxazaphosphorinane, the analogous trans-
formation was carried out with 7, using n-propylamine,
but the conversion of intermediate 10 to the correspond-
ing oxazaphosphorinane 12 was sluggish. The epimeric
ratio was found to be the same (12a:12b = 3:2).
7. Hajnal, A.; Wo¨lfling, J.; Schneider, Gy. Collect. Czech.
Chem. Commun. 1998, 63, 1613–1622.
8. To a stirred solution of triethylamine (0.43 ml, 4 mmol)
and 2 (316 mg, 1 mmol) in dichloromethane (15 ml),
phenylphosphonic dichloride (0.15 ml, 1 mmol) was added
dropwise at room temperature under a nitrogen atmo-
sphere. The reaction mixture was refluxed for 2 h and then
left to stir overnight at room temperature. The resulting
mixture was poured into water, and extracted with
dichloromethane (3 · 10 ml), and the combined organic
phases were dried over Na2SO4, and evaporated in vacuo.
Crude product 3 was separated by column chromatogra-
phy on silica gel, using ethyl acetate/dichloromethane
(20:80) as eluent. The fast-eluting isomer 3a was crystal-
lized from ethyl acetate/dichloromethane, while the slow-
eluting isomer 3b was crystallized from dichloromethane/
hexane to give colorless crystals.
The structures of the products were determined by
NMR spectroscopy, demonstrated here on representa-
tive compounds 3 and 11. The 1H NMR spectra
revealed an important difference between the related
epimers (3a and 3b or 11a and 11b). The doublet for
17-H in 3a appears at 3.97 ppm (3.93 ppm for 11a) with
a coupling constant of 9.5 Hz (the same for 11a), while
the corresponding signals for 3b and 11b occur at higher
chemical shifts (4.61 ppm with 9.0 Hz for 3b, and
4.51 ppm with 11.5 Hz for 11b). The significant upfield
shift for 17-H in 3a and 11a can be explained by the
magnetic anisotropic effect of the P-phenyl group. This
fact confirms the a position of the aromatic ring in these
diastereomers. In the 13C NMR spectra, the split signals
of the carbon atoms in the proximity of the phosphorus
proved to be of diagnostic value.
Compound 3a: mp 194–197 ꢁC. 31P NMR (CDCl3):
d = 13.8. 1H NMR (500 MHz, CDCl3): d = 1.03 (s, 3H,
18-H3), 1.16–1.30 (m, 3H), 1.35 (m, 1H), 1.53 (m, 2H),
1.87 (m, 1H), 1.94 (m, 1H), 2.06 (m, 1H), 2.18 (m, 1H),
2.28 (m, 1H), 2.76 (m, 1H, 16-H), 2.86 (m, 2H, 6-H2), 3.77
(s, 3H, 3-OMe), 3.97 (d, 1H, J = 9.5 Hz, 17-H), 4.37 (m,
2H, 16a-H2), 6.62 (d, 1H, J = 2.5 Hz, 4-H), 6.70 (dd, 1H,
J = 8.5 Hz, J = 2.5 Hz, 2-H), 7.17 (d, 1H, J = 8.5 Hz,
1-H), 7.49 (m, 2H, 30-H and 50-H), 7.57 (m, 1H, 40-H),
7.84 (m, 2H, 20-H and 60-H). 13C NMR (75 MHz, CDCl3):
d = 13.2 (C-18), 26.2, 27.2, 27.6, 29.7, 37.4, 37.7 (d,
J = 5.1 Hz, C-16), 38.1, 43.8, 45.1 (d, J = 6.4 Hz, C-13),
49.1, 55.3 (3-OMe), 68.7 (d, J = 5.6 Hz, C-16a), 86.8 (d,
J = 8.7 Hz, C-17), 111.7 (C-2), 114.0 (C-4), 126.4 (C-1),
128.4 (d, J = 190.2 Hz, C-10), 128.6 and 128.8 (C-30 and
C-50), 131.7, 131.8, and 132.0 (C-20, C-40, and C-60), 132.7
(d, J = 3.1 Hz, C-10), 137.7 (C-5), 157.7 (C-3). HRMS
(FAB), (M+H)+ found 439.2020, C26H32O4P requires
439.2038.
Acknowledgments
This work was supported financially by the Hungarian
Scientific Research Fund (OTKA T042673, T049366,
and T042479).
References and notes
Compound 3b: mp 219–222 ꢁC. 31P NMR (CDCl3):
d = 16.0. 1H NMR (500 MHz, CDCl3): d = 1.01 (s, 3H,
18-H3), 1.16 (m, 1H), 1.34 (m, 1H), 1.40–1.58 (m, 4H),
1.90 (m, 1H), 1.96 (m, 1H), 2.10 (m, 1H), 2.26 (m, 1H),
2.35 (m, 1H), 2.89 (m, 2H, 6-H2), 3.06 (m, 1H, 16-H), 3.79
(s, 3H, 3-OMe), 4.06 (m, 1H) and 4.29 (m, 1H): [16a-H2],
4.61 (d, 1H, J = 9.0 Hz, 17-H), 6.65 (d, 1H, J = 2.5 Hz,
4-H), 6.73 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz, 2-H), 7.21 (d,
1H, J = 8.5 Hz, 1-H), 7.49 (m, 2H, 30-H and 50-H), 7.59
(m, 1H, 40-H), 7.87 (m, 2H, 20-H and 60-H). 13C NMR
(75 MHz, CDCl3): d = 13.5 (C-18), 26.2, 27.4, 27.7, 29.8,
37.5, 38.2, 38.7 (d, J = 6.6 Hz, C-16), 43.8, 45.2 (d, J =
7.4 Hz, C-13), 48.8, 55.4 (3-OMe), 69.3 (d, J = 5.5 Hz, C-
16a), 84.5 (d, J = 7.4 Hz, C-17), 111.8 (C-2), 114.0 (C-4),
126.5 (C-1), 128.5 (d, J = 183.5 Hz, C-10), 128.6 and 128.8
(C-30 and C-50), 131.5, 131.6, and 132.2 (C-20, C-40, and C-
60), 132.8 (d, J = 3.1 Hz, C-10), 137.8 (C-5), 157.8 (C-3).
HRMS (FAB), (M+H)+ found 439.2021, C26H32O4P
requires 439.2038.
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E. Frank et al. / Tetrahedron Letters 47 (2006) 1105–1108
1108
12. A solution of 2 (315 mg, 1 mmol) and benzaldehyde
(0.10 ml, 1 mmol) in abs ethanol (15 ml) was refluxed for
2 h under a nitrogen atmosphere and then left to stir
overnight at room temperature. The mixture was cooled
and the crystals that separated out were filtered off to give
359 mg (89%) of pure 5. Imine 5 was then dissolved in
MeOH/THF = 1:2 (30 ml), and NaBH4 (150 mg, 4 mmol)
was added portionwise. After stirring for 2 h the mixture
was neutralized with dilute HCl and partially evaporated.
The precipitate of the crude amine 6 was collected, washed
with water, and dried (343 mg, 95% from 5).
J = 12.0 Hz, J = 3.0 Hz): [16a-H2], 3.76 (s, 3H, 3-OMe),
3.93 (d, 1H, J = 9.5 Hz, 17-H), 4.12 (m, 2H, benzyl-H2),
6.60 (d, 1H, J = 2.5 Hz, 4-H), 6.69 (dd, 1H, J = 8.5 Hz,
J = 2.5 Hz, 2-H), 7.15 (d, 1H, J = 8.5 Hz, 1-H), 7.24–7.40
(m, 5H, 200-H, 300-H, 400-H, 500-H, and 600-H), 7.50 (m, 2H,
30-H and 50-H), 7.60 (m, 1H, 40-H), 7.93 (m, 2H, 20-H and
60-H). 13C NMR (75 MHz, CDCl3): d = 13.5 (C-18), 26.3,
27.7, 29.1, 29.8, 37.6, 38.2, 39.2 (d, J = 2.0 Hz, C-16), 43.9,
45.0 (d, J = 6.9 Hz, C-13), 49.3, 49.4 (d, J = 7.7 Hz, Ph–
CH2), 51.1 (d, J = 5.0 Hz, C-16a), 55.4 (3-OMe), 87.4 (d,
J = 9.4 Hz, C-17), 111.7 (C-2), 114.0 (C-4), 126.5 (C-1),
127.7, 128.6 (2C), 128.7, 128.8 (3C), 128.9, 130.6 (d, J =
173.7 Hz, C-10), 132.3, 132.5, 132.7, 137.6 (d, J = 5.0 Hz,
C-10), 137.8 (C-5), 157.7 (C-3). HRMS (FAB), (M+H)+
found 528.2643, C33H39NO3P requires 528.2668.
To a stirred solution of triethylamine (0.43 ml, 4 mmol)
and 6 (343 mg, 0.85 mmol) in dichloromethane (15 ml),
phenylphosphonic dichloride (0.13 ml, 0.85 mmol) was
added dropwise at room temperature under a nitrogen
atmosphere. The reaction mixture was refluxed for 6 h and
then left to stir overnight at room temperature. The
mixture was poured into water, and extracted with
dichloromethane (3 · 10 ml), and the combined organic
phases were dried over Na2SO4, and evaporated in vacuo.
The crude product was subjected to column chromato-
graphy on silica gel, using ethyl acetate/dichloromethane
(20:80) as eluent to give the fast-eluting 11a in pure form.
Compound 11a was crystallized from ethyl acetate/
dichloromethane to afford colorless crystals. Compound
11b could not be isolated in pure form, but the slow-
eluting epimeric mixture of 11a and 11b, in a ratio of 1:3,
permitted the assignment of 11b from the spectra.
1
Compound 11b: 31P NMR (CDCl3): d = 18.6. H NMR
(500 MHz, CDCl3): d = 0.95 (s, 3H, 18-H3), 1.03–2.32 (m,
11H), 2.67 (m, 1H, 16-H), 2.83 (m, 2H, 6-H2), 2.94 (m, 1H)
and 3.15 (t, 1H, J = 16.0 Hz): [16a-H2], 3.76 (s, 3H, 3-
OMe), 4.05 (m, 1H) and 4.21 (m, 1H): [benzyl-H2], 4.51 (d,
1H, J = 11.5 Hz, 17-H), 6.61 (d, 1H, J = 3.0 Hz, 4-H),
6.69 (dd, 1H, J = 11.0 Hz, J = 3.0 Hz, 2-H), 7.18 (d, 1H,
J = 11.0 Hz, 1-H), 7.23–7.39 (m, 5H, 200-H, 300-H, 400-H,
500-H, and 600-H), 7.45 (m, 2H, 30-H and 50-H), 7.51 (m,
1H, 40-H), 7.86 (m, 2H, 20-H and 60-H). 13C NMR
(75 MHz, CDCl3): d = 13.8 (C-18), 26.3, 27.8, 28.8, 29.9,
37.7, 38.2, 40.7 (d, J = 4.5 Hz, C-16), 43.9, 45.3 (d,
J = 8.0 Hz, C-13), 49.0, 49.3 (d, J = 8.5 Hz, Ph–CH2),
50.8 (d, J = 6.0 Hz, C-16a), 55.4 (3-OMe), 84.3 (d,
J = 8.2 Hz, C-17), 111.7 (C-2), 114.0 (C-4), 126.5 (C-1),
127.5, 128.4 (2C), 128.5, 128.6 (3C), 128.7, 131.5, 131.6,
132.2, (d, J = 181.0 Hz, C-10), 132.4, 137.9 (C-5), 138.6 (d,
J = 4.3 Hz, C-10), 157.8 (C-3).
Compound 11a: mp 120–122 ꢁC. 31P NMR (CDCl3):
d = 19.5. 1H NMR (500 MHz, CDCl3): d = 0.98 (s, 3H,
18-H3), 1.09–1.35 (m, 4H), 1.48 (m, 2H), 1.84 (m, 1H),
2.00 (m, 1H), 2.11 (m, 2H), 2.24 (m, 1H), 2.64 (m, 1H, 16-
H), 2.83 (m, 2H, 6-H2), 3.01 (m, 1H) and 3.21 (td, 1H,