New steroid-fused P-heterocycles. Part II. Synthesis and conformational study of oxazaphosphorino[16,17-e]estrone derivatives

Article abstract of DOI:10.1016/j.steroids.2007.02.001

16β-Aminomethyl-17β-hydroxyestrone 3-methyl ether 6 and its N-propyl (17), N-benzyl (18) and N-arylmethyl derivatives (19-22) were subjected to ring closure reactions with phenylphosphonic dichloride in order to synthetize P-epimeric oxazaphosphorinanes 2

Full text of DOI:10.1016/j.steroids.2007.02.001

steroids 7 2 ( 2 0 0 7 ) 446–458
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
New steroid-fused P-heterocycles
Part II. Synthesis and conformational study of
oxazaphosphorino[16,17-e]estrone derivatives
Eva Franka,∗, Brigitta Kazia,1, Zolta´n Mucsib, Krisztina Luda´nyic,d, Gyo¨rgy Keglevichb
´
a
Department of Organic Chemistry, University of Szeged, Hungary
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary
Hungarian Academy of Sciences, Chemical Research Center, Budapest, Hungary
Department of Pharmaceutics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
16␤-Aminomethyl-17␤-hydroxyestrone 3-methyl ether 6 and its N-propyl (17), N-benzyl
(18) and N-arylmethyl derivatives (19–22) were subjected to ring closure reactions with
phenylphosphonic dichloride in order to synthetize P-epimeric oxazaphosphorinanes 23a,
24–29 in which the hetero ring is condensed to ring D of the sterane skeleton. The stereo-
structures of the products were evaluated by 1H, 13C and 31P NMR spectroscopy. The geom-
etry was optimized by utilizing the B3LYP DFT method. The NMR spectral data and the
results of the ab initio calculations demonstrated that the stereostructure of the hetero ring
was strongly affected by the rigid sterane framework condensed to it, and the phosphor-
amidate ring proved to adopt predominantly a distorted-boat conformation, regardless of
the P-configuration.
Received 20 October 2006
Received in revised form
19 January 2007
Accepted 2 February 2007
Published on line 13 February 2007
Dedicated to Professor Gyula
Schneider on the occasion of his
75th birthday.
© 2007 Elsevier Inc. All rights reserved.
Keywords:
Heteroestrone derivatives
Oxazaphosphorinanes
Epimers
Conformational study
1.
Introduction
a number of similar compounds have been studied in order
to acquire more information on the mode of action of these
Six-membered P-heterocycles, especially oxazaphosphori-
nane derivatives, have been subjected to intense research
during the past few decades in consequence of their pharma-
cological activity and their unique conformational behavior.
These hetero rings are of great significance since they are
an integral structural part of the clinically widely used anti-
cancer drug cyclophosphamide and its analogs. Accordingly,
agents and to reveal certain structure–activity relationships
[1–6].
As pointed out by Bentrude and others, the stereostructures
of monocyclic oxazaphosphorinanes differ significantly from
those of cyclohexanes: the P ring relatively easily adopts con-
formations other than a chair, depending on the substitution
pattern. The conformational preference of these heterocycles
∗
Corresponding author at: Department of Organic Chemistry, University of Szeged, Do´m te´r 8., H-6720 Szeged, Hungary. Tel.: +36 62 544275;
fax: +36 62 544199.
´
E-mail address: frank@chem.u-szeged.hu (E. Frank).
1
Present address: Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, Hungary.
0039-128X/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2007.02.001

steroids 7 2 ( 2 0 0 7 ) 446–458
447
is mainly influenced by the steric and electronic properties of
the P substituent, the size of the group on the ring N atom
and the P-configuration [7–12]. Earlier studies concentrated
mainly on derivatives in which the P atom was substituted
with OR [2,11], Cl [13,14] or NR2 groups [2,8], though some
P-Ph hetero rings [14–16] were also examined. Compounds
with hydrogen, Ph [2,8], Bn [17,18] and different alkyl sub-
stituents [19] on the N atom were studied. The results obtained
for the mono- and bicyclic ring systems indicated that the
P-Ph and the P-bis(2-chloroethyl)amino groups prefer to
occupy an equatorial position, while the P-OPh group tends to
locate axially [20]; consequently, the chair conformer is often
forced to adopt twist forms so as to be able to fulfill this pref-
erence. The steric repulsion between the P and N substituents
[2,21] and anomeric effects, however, may modify the predom-
inant conformation considerably [22].
Fig. 1 – D-ring-fused dioxaphosphorinanes studied earlier
Interest has recently shifted towards fused cycloalkane
and heterocycle-condensed derivatives, and new questions
have been raised concerning the bioactivity and conforma-
tional behavior of these compounds [14,15,17,23]. Although
the cyclohexane and six-membered heterocycle-condensed
oxazaphosphorinanes have been thoroughly studied, there
are only a few examples of cyclopentane-fused derivatives
[24,25].
(see footnote 2) [26].
described steroid intermediates 5, 12–22. Our aim was to
investigate the epimeric ratios and the conformational pref-
erences of the D-ring-fused N-unsubstituted (23a), N-Pr (24),
N-Bn (25) and different N-arylmethyl (26–29) P-heterocycles
as compared with the dioxaphosphorinane analog 1. Steroid-
condensed oxazaphosphorinane ring systems have not yet
been studied, though they can also be important from a phar-
macological aspect.
As reported preliminarily, D-ring-fused P-Ph dioxaphos-
phorinane and oxazaphosphorinane derivatives were read-
ily obtained from 17␤-hydroxy-16␤-hydroxymethylestrone
3-methyl ether and 17␤-hydroxy-16␤-aminomethylestrone 3-
methyl ether with phenylphosphonic dichloride as epimeric
mixtures [26]. Further investigations with different P-
substituted dioxaphosphorinanes led to the conclusion that
the conformational preferences of the fused hetero ring
were significantly influenced by the rigid sterane framework.2
The NMR measurements and ab initio calculations supported
by single-crystal X-ray analysis revealed that the phospho-
nate ring of the P-Ph-substituted epimer 1a (P O trans to
17-H) exists in a distorted-boat conformation, with the Ph
group in a pseudoaxial position both in solution and in
the solid state (Fig. 1). An upfield shift of the 17-H signal
generated by the anisotropic shielding effect of the aro-
matic ring, was noted in this case. The preference of the Ph
group for the equatorial position was not strong enough to
effect a conformational conversion. At the same time, the
hetero ring of the corresponding epimer 1b (P O cis to 17-
H) seemed to adopt predominantly a similar distorted-boat
conformation with the P substituent in a pseudoequatorial
position. The shift in the conformational equilibrium toward
the distorted-boat conformer in 1a and 1b was explained
by the rigidity of the fused sterane skeleton. Analogous
results were found for the P-OPh dioxaphosphorinane deriva-
tives.
2.
Experimental
2.1.
General
The NMR spectra were recorded on a Bruker DRX 300, a Bruker
DRX 400 or a Bruker DRX 500 spectrometer in CDCl3, MeOD
or DMSO-d6 solution applying TMS (1H and 13C NMR) as an
internal standard or 85% H3PO4 (
31P NMR) as an external stan-
dard. 13C and 31P NMR spectra were measured at 75 (or 100)
MHz and 121 MHz, respectively. For determination of the 13C
NMR multiplicities, the APT pulse sequence was used. Chem-
ical shifts (ı) are given in ppm, and coupling constants (J) in
Hz. Mass spectra were obtained on Varian MAT 311A and VG-
2ZAB instruments using electron ionization (EI), or fast atom
bombardment (FAB), respectively. Melting points (Mps) were
determined on a Kofler block and are uncorrected. The reac-
tions were monitored by TLC on Kieselgel-G (Merck Si 254
F) layers (0.25 mm thick); flash chromatography: silica gel 60,
40–63 ␮m.
2.2.
3-Methoxy-16ˇ-(N-benzylaminomethyl)estra-
1,3,5(10)-trien-17-one (5)
We now report the synthesis and conformational analy-
sis of novel oxazaphosphorino[e:16␤,17␤]estrone derivatives
23a, 24–29, all containing a P-Ph group, prepared via newly
Compound 3 [28,30] (600 mg, 2.00 mmol) was dissolved in ben-
zylamine (10 mL), and 20% aqueous KOH (2 mL) was added.
The mixture was stirred for 1 h at room temperature, and
then poured into water (10 mL). The precipitate was filtered
off, washed with water and dried to give 5 (687 mg, 85%) as a
white solid. Mp 112-114 ◦C; Rf = 0.53 (MeOH/CH2Cl2 = 5/95); 1H
NMR (400 MHz, CDCl3, ı [ppm]): 0.91 (s, 3H, 18-H3), 2.84 (m,
1H, one of 16a-H2), 2.92 (m, 2H, 6-H2), 2.96 (m, 1H, the other
2
´
Frank E, Ko¨rtve´lyesi T, Czugler M, Mucsi Z, Keglevich Gy.
New steroid-fused P-heterocycles. Part I. Synthesis and confor-
mational study of dioxaphosphorino[16,17]estrone derivatives.
Steroids 2007;72:437–45.

448
steroids 7 2 ( 2 0 0 7 ) 446–458
16a-H2), 3.80 (s, 3H, 3-OMe), 3.83 (s, 2H, benzyl-H2), 6.66 (d, 1H,
J = 2.0 Hz, 4-H), 6.74 (dd, 1H, J = 8.4 Hz, J = 2.0 Hz, 2-H), 6.97 (d,
1H, J = 8.4 Hz, 1-H), 7.27 (m, 1H, 4ꢀ-H), 7.34 (m, 4H, 2ꢀ-H, 3ꢀ-H,
5ꢀ-H and 6ꢀ-H); 13C NMR (100 MHz, CDCl3, ı [ppm]): 13.9 (C-
18), 25.9 (CH2), 26.7 (CH2), 27.2 (CH2), 29.6 (CH2), 31.9 (CH2),
37.9 (CH), 44.1 (CH), 48.6 (C-13), 49.0 (CH), 49.5 (C-16), 51.0 and
54.0 (C-16a and benzyl-C), 55.2 (3-OMe), 111.5 (C-2), 113.9 (C-
4), 126.2 (C-1), 126.9 (C-4ꢀ), 128.0 (2C) and 128.3 (2C): C-2ꢀ, C-3ꢀ,
C-5ꢀ and C-6ꢀ, 132.0 (C-10), 137.7 (C-5), 140.2 (C-1ꢀ), 157.6 (C-3),
221.9 (C-17); FAB-MS m/z (%): 404 (29) [M + H]+, 120 (36), 91 (100),
77 (22); FAB-HRMS (M + H)+ found: 404.2590 (4.3 ppm), requires:
404.2572.
3.74 (dd, 1H, J = 10.0 Hz, J = 4.8 Hz, 17-H), 3.95 (dd, 1H, J = 11.4 Hz,
J = 4.0 Hz, the other 16a-H2), 4.68 (d, 1H, J = 4.8 Hz, OH), 6.58 (d,
1H, J = 2.5Hz, 4-H), 6.66 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz, 2-H), 7.16
(d, 1H, J = 8.5 Hz, 1-H), 7.26 (d, 2H, J = 8.6. Hz, 3ꢀ-H and 5ꢀ-H), 7.78
(dd, 2H, J = 8.6 Hz, J = 5.8 Hz, 2ꢀ-H and 6ꢀ-H), 8.34 (s, 1H, imine-H);
EI-MS (70 eV) m/z (%): 421 (86) [M+], 393 (27), 192 (50), 164 (100),
137 (46), 124 (54), 109 (47); FAB-HRMS (M + H)+ found: 422.2477
(4.3 ppm), requires: 422.2495.
2.3.4. 3-Methoxy-16ˇ-((4ꢀ-chlorobenzylimino)methyl)
estra-1,3,5(10)-trien-17ˇ-ol (15)
In the general procedure, 4-chlorobenzaldehyde (10, 281 mg)
was used. Imine 15 (700 mg, 80%) was obtained. Mp 151–153 ◦C;
1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.74 (s, 3H, 18-H3), 2.74
(m, 2H, 6-H2), 3.32 (m, 1H, one of 16a-H2), 3.68 (s, 3H, 3-OMe),
3.74 (dd, 1H, J = 10.0 Hz, J = 4.7 Hz, 17-H), 3.97 (dd, 1H, J = 11.4 Hz,
J = 4.4 Hz, the other 16a-H2), 4.68 (d, 1H, J = 4.8 Hz, OH), 6.58 (d,
1H, J = 2.5 Hz, 4-H), 6.66 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz, 2-H), 7.16 (d,
1H, J = 8.6 Hz, 1-H), 7.50 (d, 2H, J = 8.4 Hz, 3ꢀ-H and 5ꢀ-H), 7.75 (d,
2H, J = 8.4 Hz, 2ꢀ-H and 6ꢀ-H), 8.34 (s, 1H, imine-H); EI-MS (70 eV)
m/z (%): 439 (34) [M+], 437 (100) [M+], 409 (26), 408 (18), 284 (16),
208 (18), 180 (31); FAB-HRMS (M + H)+ found: 438.2186 (3.2 ppm),
requires: 438.2200.
2.3.
General procedure for the synthesis of
benzylimino alcohols 12–16
Compound 6 [29] (630 mg, 2.00 mmol) was suspended in abso-
lute EtOH (30 mL) and benzaldehyde (7) or para-substituted
benzaldehyde (8–11, 2 mmol) was added. The mixture was
refluxed for 2 h under a nitrogen atmosphere, the solvent was
then partially evaporated off, and the precipitate was filtered
off and dried.
2.3.1. 3-Methoxy-16ˇ-(benzyliminomethyl)
estra-1,3,5(10)-trien-17ˇ-ol (12)
2.3.5. 3-Methoxy-16ˇ-((4ꢀ-nitrobenzylimino)methyl)
estra-1,3,5(10)-trien-17ˇ-ol (16)
In the general procedure, benzaldehyde (7, 0.20 mL) was used.
Imine 12 (720 mg, 89%) was obtained, as a pure product. Mp
145-147 ◦C; 1H NMR (500 MHz, DMSO-d6, ı [ppm]): 0.73 (s, 3H,
18-H3), 2.73 (m, 2H, 6-H2), 3.31 (t, 1H, J = 11.0 Hz, one of 16a-
H2), 3.67 (s, 3H, 3-OMe), 3.73 (dd-like m, 1H, 17-H), 3.96 (dd, 1H,
J = 11.0 Hz, J = 4.0 Hz, the other 16a-H2), 4.71 (d, J = 4.8 Hz, OH),
6.57 (d, 1H, J = 2.5 Hz, 4-H), 6.65 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz, 2-
H), 7.14 (d, 1H, J = 8.5 Hz, 1-H), 7.43 (m, 3H, 3ꢀ-H, 4ꢀ-H and 5ꢀ-H),
7.72 (dd-like m, 2H, 2ꢀ-H and 6ꢀ-H), 8.32 (s, 1H, imine-H). EI-MS
(70 eV) m/z (%): 403 (68) [M+], 375 (22), 202 (14), 174 (66), 146 (100),
106 (48), 91 (44); FAB-HRMS (M + H)+ found: 404.2573 (4.1 ppm),
requires: 404.2590.
In the general procedure, 4-nitrobenzaldehyde (11, 151 mg)
was used. Imine 16 (695 mg, 77%) was obtained. Mp 154–155 ◦C;
1H NMR (500 MHz, DMSO-d6, ı [ppm]): 0.74 (s, 3H, 18-H3),
2.73 (m, 2H, 6-H2), 3.36 (m, 1H, one of 16a-H2), 3.67 (s, 3H,
3-OMe), 3.74 (d, 1H, J = 9.9 Hz, 17-H), 4.03 (dd, 1H, J = 11.4 Hz,
J = 3.7 Hz, the other 16a-H2), 4.74 (d, 1H, J = 4.8 Hz, OH), 6.57 (d,
1H, J = 2.4 Hz, 4-H), 6.65 (dd, 1H, J = 8.6 Hz, J = 2.4 Hz, 2-H), 7.14
(d, 1H, J = 8.6 Hz, 1-H), 7.98 (d, 2H, J = 8.7 Hz, 2ꢀ-H and 6ꢀ-H), 8.28
(d, 2H, J = 10.0 Hz, 3ꢀ-H and 5ꢀ-H), 8.49 (s, 1H, imine-H); EI-MS
(70 eV) m/z (%): 448 (100) [M+], 267 (24), 265 (55), 240 (36), 219 (42),
191 (63), 164 (64), 147 (40), 117 (24), 91 (12); FAB-HRMS (M + H)+
found: 449.2418 (5.0 ppm), requires: 449.2440.
2.3.2. 3-Methoxy-16ˇ-((4ꢀ-methylbenzylimino)
methyl)estra-1,3,5(10)-trien-17ˇ-ol (13)
2.4.
3-Methoxy-16ˇ-(propylaminomethyl)
In the general procedure, 4-methylbenzaldehyde (8, 302 mg)
was used. Imine 13 (626 mg, 75%) was obtained. Mp 156–158 ◦C;
1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.74 (s, 3H, 18-H3), 2.34
(s, 3H, 4ꢀ-H3), 2.75 (m, 2H, 6-H2), 3.29 (m, 1H, one of 16a-
H2), 3.68 (s, 3H, 3-OMe), 3.74 (dd, 1H, J = 10.0 Hz, J = 4.8 Hz,
17-H), 3.94 (dd, 1H, J = 11.4 Hz, J = 4.3 Hz, the other 16a-H2),
4.68 (d, 1H, J = 4.8 Hz, OH), 6.57 (d, 1H, J = 2.0 Hz, 4-H), 6.65
(dd, 1H, J = 8.4 Hz, J = 2.0 Hz, 2-H), 7.14 (d, 1H, J = 8.4 Hz, 1-H),
7.22 (d, 2H, J = 8.0 Hz, 3ꢀ-H and 5ꢀ-H), 7.59 (d, 2H, J = 8.0 Hz,
2ꢀ-H and 6ꢀ-H), 8.27 (s, 1H, imine-H); EI-MS (70 eV) m/z (%):
417 (100) [M+], 389 (38), 188 (33), 160 (68), 120 (21), 105 (34),
91 (9); FAB-HRMS (M + H)+ found: 418.2722 (5.7 ppm), requires:
418.2746.
estra-1,3,5(10)-trien-17ˇ-ol (17)
Compound 3 [28,30] (600 mg, 2.00 mmol) was dissolved in n-
propylamine (5 mL) and 20% aqueous KOH (2 mL) was added.
The mixture was stirred for 30 min at room temperature,
then diluted with MeOH/THF = 1:1 (10 mL), and NaBH4 (150 mg,
4 mmol) was added portionwise. After stirring for 2 h, the
mixture was neutralized with dilute HCl and partially evap-
orated. The precipitate was filtered off, washed with water,
and dried. The white solid was recrystallized from aqueous
MeOH to give 17 (536 mg, 75%) in pure form. Mp 257–259 ◦C;
1H NMR (500 MHz, CDCl3, ı [ppm]): 0.69 (s, 3H, 18-H3), 0.91
(t, 3H, J = 7.5 Hz, 3ꢀ-H3), 1.64 (m, 2H, 2ꢀ-H2), 2.78 (m, 2H, 6-
H2), 2.84 (m, 2H, 1ꢀ-H2), 3.10 (dd, 1H, J = 12.4 Hz, J = 7.8 Hz) and
3.26 (d, 1H, J = 7.8 Hz): 16a-H2, 3.69 (s, 3H, 3-OMe), 3.72 (d,
1H, J = 9.9 Hz, 17-H), 6.59 (d, 1H, J = 2.5 Hz, 4-H), 6.67 (dd, 1H,
J = 8.5 Hz, J = 2.5 Hz, 2-H), 7.05 (d, 1H, J = 8.5 Hz, 1-H); FAB-MS
m/z (%): 358 (51) [M + H]+, 307 (23), 154 (100), 136 (76), 107 (26),
79 (25); FAB-HRMS (M + H)+ found: 358.2746 (5.0 ppm), requires:
358.2728.
2.3.3. 3-Methoxy-16ˇ-((4ꢀ-fluorobenzylimino)
methyl)estra-1,3,5(10)-trien-17ˇ-ol (14)
In the general procedure, 4-fluorobenzaldehyde (9, 0.22 mL)
was used. Imine 14 (590 mg, 70%) was obtained. Mp 161–163 ◦C;
1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.74 (s, 3H, 18-H3), 2.74
(m, 2H, 6-H2), 3.30 (m, 1H, one of 16a-H2), 3.68 (s, 3H, 3-OMe),

steroids 7 2 ( 2 0 0 7 ) 446–458
449
2.5.
General procedure for the synthesis of
2.5.3. 3-Methoxy-16ˇ-((4ꢀ-fluorobenzylamino)methyl)
estra-1,3,5(10)-trien-17ˇ-ol (20)
benzylamino alcohols 18–22
In the general procedure, imino alcohol 14 (590 mg) was
reduced to furnish 20 (445 mg, 75%), as a pure product. Mp
254-258 ◦C; 1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.67 (s, 3H,
18-H3), 2.61 (dd, 1H, J = 11.5, J = 7.1 Hz, one of 16a-H2), 2.76 (m,
2H, 6-H2), 2.91 (dd, 1H, J = 11.5 Hz, J = 8.3 Hz, the other 16a-H2),
3.32 (bs, 1H, NH), 3.69 (s, 3H, 3-OMe), 3.88 (d, 1H, J = 14.0 Hz)
and 3.92 (d, 1H, J = 14.0 Hz): benzyl-H2, 6.60 (d, 1H, J = 2.5 Hz, 4-
H), 6.67 (dd, 1H, J = 8.4 Hz, J = 2.5 Hz, 2-H), 7.15 (d, 1H, J = 8.4 Hz,
1-H), 7.20 (t, 2H, J = 8.8 Hz, 3ꢀ-H and 5ꢀ-H), 7.46 (t-like m, 2H, 2ꢀ-
H and 6ꢀ-H); EI-MS (70 eV) m/z (%): 423 (12) [M+], 314 (22), 138
(100), 109 (94); FAB-HRMS (M + H)+ found: 424.2630 (5.1 ppm),
requires: 424.2651.
Imino alcohol (12–16) (1.40 mmol) was 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 product (18–22, respectively) was
collected, washed with water, and dried.
2.5.1. 3-Methoxy-16ˇ-(benzylaminomethyl)
estra-1,3,5(10)-trien-17ˇ-ol (18)
Method A (from 12): In the general procedure, imino alcohol 12
(605 mg) was reduced to give 18 (466 mg, 82%), as a pure prod-
uct.
2.5.4. 3-Methoxy-16ˇ-((4ꢀ-chlorobenzylamino)methyl)
estra-1,3,5(10)-trien-17ˇ-ol (21)
Method B (from 5): Compound 5 (687 mg, 1.70 mmol) was
dissolved in MeOH/THF = 1:3 (40 mL) and NaBH4 (100 mg,
2.67 mmol) was added portionwise. After stirring for 2 h, the
mixture was neutralized with dilute HCl and partially evap-
orated. The precipitate was collected, washed with water,
and dried to furnish 18 (565 mg, 82%). Mp 248–250 ◦C; 1H
NMR (400 MHz, MeOD, ı [ppm]): 0.77 (s, 3H, 18-H3), 2.81 (m,
2H, 6-H2), 3.01 (dd, 1H, J = 12.0 Hz, J = 5.2 Hz) and 3.25 (t, 1H,
J = 12.0 Hz): 16a-H2, 3.34 (bs, 1H, NH), 3.75 (s, 3H, 3-OMe), 3.89
(d, 1H, J = 9.7 Hz, 17-H), 4.19 (d, 1H, J = 13.2 Hz) and 4.29 (d, 1H,
J = 13.2 Hz): benzyl-H2, 6.61 (d, 1H, J = 2.3 Hz, 4-H), 6.68 (dd, 1H,
J = 8.5 Hz, J = 2.3 Hz, 2-H), 7.16 (d, 1H, J = 8.5 Hz, 1-H), 7.19 (m,
3H, 2ꢀ-H, 4ꢀ-H and 6ꢀ-H), 7.34 (m, 2H, 3ꢀ-H and 5ꢀ-H); 13C NMR
(100 MHz, MeOD, ı [ppm]): 12.9 (C-18), 27.4 (CH2), 28.6 (CH2),
30.7 (CH2), 30.8 (CH2), 37.3 (C-16), 38.4 (CH2), 39.8 (CH), 45.1 (CH),
45.6 (C-13), 50.2 (CH), 50.9 (CH2) and 52.2 (C-16a and benzyl-C),
55.6 (3-OMe), 82.1 (C-17), 112.6 (C-2), 114.7 (C-4), 127.2 (C-1),
130.3 (2C, C-2ꢀ and C-6ꢀ), 130.6 (C-4ꢀ), 130.9 (2C, C-3ꢀ and C-5ꢀ),
132.6 (C-10), 133.5 (C-1ꢀ), 138.8 (C-5), 159.0 (C-3); EI-MS (70 eV)
m/z (%): 405 (9) [M+], 314 (14), 121 (10), 120 (100), 106 (15), 91
(42); FAB-HRMS (M + H)+ found: 406.2719 (6.7 ppm), requires:
406.2746.
In the general procedure, imino alcohol 15 (613 mg) was
reduced to give 21 (561 mg, 91%), as pure product. Mp
127–128 ◦C; 1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.69 (s,
3H, 18-H3), 2.43 (dd-like m, 1H) and 2.69 (t-like m, 1H): 16a-
H2, 2.76 (m, 2H, 6-H2), 3.66 (m, 3H): 17-H and benzyl-H2,
3.68 (s, 3H, 3-OMe), 6.59 (d, 1H, J = 2.3 Hz, 4-H), 6.66 (dd,
1H, J = 8.4 Hz, J = 2.3 Hz, 2-H), 7.15 (d, 1H, J = 8.4 Hz, 1-H), 7.34
(m, 4H, 2ꢀ-H, 3ꢀ-H, 5ꢀ-H and 6ꢀ-H); EI-MS (70 eV) m/z (%):
441 (8) [M+], 439 (20) [M+], 314 (29), 156 (28), 154 (100), 125
(81); FAB-HRMS (M + H)+ found: 440.2331 (5.8 ppm), requires:
440.2356.
2.5.5. 3-Methoxy-16ˇ-((4ꢀ-nitrobenzylamino)methyl)
estra-1,3,5(10)-trien-17ˇ-ol (22)
In the general procedure, imino alcohol 16 (628 mg) was
reduced to give 22 (542 mg, 86%), as a pure product. Mp
242–245 ◦C; 1H NMR (400 MHz, DMSO-d6, ı [ppm]): 0.65 (s, 3H,
18-H3), 2.77 (m, 3H, 6-H2 and one of 16a-H2), 3.14 (m, 1H, the
other 16a-H2), 3.69 (s, 3H, 3-OMe), 3.72 (d, 1H, J = 9.8 Hz, 17-H),
4.31 (m, 2H, benzyl-H2), 6.59 (d, 1H, J = 2.3 Hz, 4-H), 6.67 (dd, 1H,
J = 8.6 Hz, J = 2.3 Hz, 2-H), 7.16 (d, 1H, J = 8.6 Hz, 1-H), 7.88 (d, 2H,
J = 8.6 Hz, 2ꢀ-H and 6ꢀ-H), 8.29 (d, 2H, J = 8.6 Hz, 3ꢀ-H and 5ꢀ-H);
13C NMR (100 MHz, CDCl3, ı [ppm]): 12.6 (C-18), 26.3 (CH2), 27.6
(CH2), 29.8 (CH2), 30.0 (CH2), 37.8 (CH2), 38.1 (CH), 38.7 (C-16),
43.8 (CH), 44.5 (C-13), 49.1 (CH), 52.4 and 53.0 (C-16a and benzyl-
C), 55.2 (3-OMe), 82.4 (C-17), 111.4 (C-2), 113.8 (C-4), 123.7 (2C,
C-3ꢀ and C-5ꢀ), 126.3 (C-1), 128.7 (2C, C-2ꢀ and C-6ꢀ), 132.6 (C-10),
137.8 (C-5), 146.8 and 147.2 (C-1ꢀ and C-4ꢀ), 157.4 (C-3); EI-MS
(70 eV) m/z (%): 450 (11) [M+], 313 (11), 268 (10), 173 (9), 165 (100),
152 (18), 136 (31), 106 (13); FAB-HRMS (M + H)+ found: 451.2567
(6.6 ppm), requires: 451.2597.
2.5.2. 3-Methoxy-16ˇ-((4ꢀ-methylbenzylamino)
methyl)estra-1,3,5(10)-trien-17ˇ-ol (19)
In the general procedure, imino alcohol 13 (585 mg) was
reduced to give 19 (575 mg, 98%), as a pure product. Mp
235–237 ◦C; 1H NMR (400 MHz, MeOD, ı [ppm]): 0.79 (s, 3H,
18-H3), 2.40 (s, 3H, 4ꢀ-H3), 2.84 (m, 2H, 6-H2), 3.01 (dd, 1H,
J = 12.3 Hz, J = 5.2 Hz) and 3.25 (t, 1H, J = 12.3 Hz): 16a-H2, 3.35
(bs, 1H, NH), 3.76 (s, 3H, 3-OMe), 3.91 (d, 1H, J = 9.7 Hz, 17-H),
4.17 (d, 1H, J = 13.2 Hz) and 4.26 (d, 1H, J = 13.2 Hz): benzyl-H2,
6.62 (d, 1H, J = 2.6 Hz, 4-H), 6.68 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz, 2-
H), 7.18 (d, 1H, J = 8.6 Hz, 1-H), 7.30 (d, 2H, J = 8.0 Hz, 3ꢀ-H and
5ꢀ-H), 7.43 (d, 2H, J = 8.0 Hz, 2ꢀ-H and 6ꢀ-H); 13C NMR (100 MHz,
MeOD, ı [ppm]): 12.9 (C-18), 21.3 (4ꢀ-CH3), 27.4 (CH2), 28.6 (CH2),
30.7 (CH2), 30.8 (CH2), 37.3 (C-16), 38.4 (CH2), 39.8 (CH), 45.2
(CH), 45.6 (C-13), 50.2 (CH), 50.7 (CH2) and 51.9 (C-16a and
benzyl-C), 55.6 (3-OMe), 82.0 (C-17), 112.6 (C-2), 114.7 (C-4),
127.2 (C-1), 129.5 (C-1ꢀ), 130.8 (2C) and 130.9 (2C): C-2ꢀ, C-3ꢀ,
C-5ꢀ and C-6ꢀ, 133.5 (C-10), 138.8 (C-5), 140.8 (C-4ꢀ), 159.0 (C-
3); EI-MS (70 eV) m/z (%): 419 (14) [M+], 314 (23), 134 (95), 105
(100); FAB-HRMS (M + H)+ found: 420.2875 (6.6 ppm), requires:
420.2903.
2.6.
(2ꢀS*)-3-Methoxy-2ꢀ-oxo-2ꢀ-phenoxy[1ꢀ,3ꢀ,2ꢀ]oxaza-
phosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]estra-1,3,5(10)-triene (23a)
To a stirred suspension of compound 6 [29] (315 mg, 1.00 mmol)
in CH2Cl2 (15 mL), Et3N (0.5 mL, 5.00 mmol) and phenylphos-
phonic dichloride (0.15 mL, 1.00 mmol) were added at room
temperature under a nitrogen atmosphere. The mixture was
refluxed for 6 h and then left to stir overnight at room tem-
perature. The solution was poured into water, and extracted
with CH2Cl2 (3 × 10 mL), and the combined organic phases
were dried over Na2SO4, and evaporated in vacuo. The crude

450
steroids 7 2 ( 2 0 0 7 ) 446–458
product was purified by column chromatography (silica gel,
MeOH/EtOAc = 10:90 v/v), to give 23a (66 mg, 15%), as a sin-
gle epimer. Mp 248–250 ◦C; Rf = 0.74 (MeOH/EtOAc = 10:90); 1H
NMR (400 MHz, CDCl3, ı [ppm]): 1.01 (s, 3H, 18-H3), 2.56 (m, 1H,
16-H), 2.85 (m, 2H, 6-H2), 3.32 (m, 1H) and 3.38 (m, 1H): 16a-
H2, 3.76 (s, 3H, 3-OMe), 3.85 (dd, 1H, J = 9.5 Hz, J = 1.1 Hz, 17-H),
6.61 (d, 1H, J = 2.6 Hz, 4-H), 6.69 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz, 2-
H), 7.16 (d, 1H, J = 8.6 Hz, 1-H), 7.46 (m, 2H, 3ꢀ-H and 5ꢀ-H), 7.53
(m, 1H, 4ꢀ-H), 7.89 (m, 2H, 2ꢀ-H and 6ꢀ-H); FAB-MS m/z (%): 438
(21) [M + H]+, 307 (17), 154 (100), 136 (81), 107 (31), 91 (22), 77
(34); FAB-HRMS (M + H)+ found: 438.2198 (5.7 ppm), requires:
438.2173.
(C-2), 113.8 (C-4), 126.3 (C-1), 128.1 (CH), 130.0 (d, J = 181.2 Hz, C-
1ꢀꢀ), 131.3 (CH), 131.4 (CH), 131.6 (d, J = 2.8 Hz, C-10), 131.7 (CH),
131.9 (C-4ꢀꢀ), 137.7 (C-5), 157.5 (C-3).
2.8.
General procedure for the synthesis of
N-arylmethyl oxazaphosphorinane derivatives (26-29)
To a stirred suspension of p-arylamino derivative (19–22)
(1.00 mmol), Et3N (0.3 mL, 3.00 mmol) and phenylphosphonic
dichloride (0.15 mL, 1.00 mmol) were added at room tempera-
ture under a nitrogen atmosphere. The mixture was refluxed
for 4 h and then left to stir overnight at room temperature. The
solution was poured into water, and extracted with CH2Cl2
(3 × 10 mL), and the combined organic phases were dried over
Na2SO4, and evaporated in vacuo. The crude product (26–29,
respectively) was purified by column chromatography (silica
gel, EtOAc/CH2Cl2 = 20:80 v/v).
2.7.
3-Methoxy-2ꢀ-oxo-2ꢀ-phenoxy-3ꢀ-propyl[1ꢀ,3ꢀ,2ꢀ]
oxazaphosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]estra-1,3,5(10)-triene
(24)
To a stirred suspension of compound 17 (250 mg, 0.70 mmol)
in CH2Cl2 (15 mL), Et3N (0.5 mL, 5.00 mmol) and phenylphos-
phonic dichloride (0.10 mL, 0.70 mmol) were added at room
temperature under a nitrogen atmosphere. The mixture was
refluxed for 6 h and then left to stir overnight at room temper-
ature. The solution was poured into water, and extracted with
CH2Cl2 (3 × 10 mL), and the combined organic phases were
dried over Na2SO4, and evaporated in vacuo. The crude product
(24a:24b = ca. 3:2 by 1H NMR) was purified by column chro-
matography (silica gel, EtOAc/CH2Cl2 = 20:80 v/v) to give 24a
(80 mg, 17%) as the fast-eluting diastereomer. The less mobile
epimer was identified as isomer 24b (86 mg, 18%), with 24a as
a minor impurity (ca. 3:1 by 1H NMR).
24a: Rf = 0.43 (EtOAc/CH2Cl2 = 20:80); NMR data (assigned
from a 5:1 mixture of 24a and 24b): 31P NMR (121 MHz, CDCl3,
ı [ppm]): 18.9; 1H NMR (500 MHz, CDCl3, ı [ppm]): 0.83 (t, 3H,
J = 7.4 Hz, propyl-H3), 0.99 (s, 3H, 18-H3), 2.66 (m, 1H, 16-H), 2.87
(m, 2H, 6-H2), 3.12 (m, 1H) and 3.42 (m, 1H): 16a-H2, 3.76 (s, 3H,
3-OMe), 3.83 (d, 1H, J = 9.6 Hz, 17-H), 6.61 (d, 1H, J = 2.6 Hz, 4-H),
6.69 (dd, 1H, J = 8.5 Hz, J = 2.6 Hz, 2-H), 7.15 (d, 1H, J = 8.5 Hz, 1-
H), 7.48 (m, 2H, 3ꢀ-H and 5ꢀ-H), 7.54 (m, 1H, 4ꢀ-H), 7.85 (m, 2H,
2ꢀ-H and 6ꢀ-H); 13C NMR (75 MHz, CDCl3, ı [ppm]): 11.3 (propyl-
CH3), 13.3 (C-18), 22.2 (propyl-CH2), 26.0 (CH2), 27.5 (CH2), 28.8
(CH2), 29.7 (CH2), 37.5 (CH2), 38.0 (CH), 39.5 (C-16), 43.8 (CH),
44.8 (d, J = 7.1 Hz, C-13), 49.2 (CH), 49.5 (N-CH2), 50.2 (C-16a),
55.2 (3-OMe), 86.8 (d, J = 9.2 Hz, C-17), 111.5 (C-2), 113.8 (C-4),
126.3 (C-1), 128.3 and 128.5 (C-3ꢀ and C-5ꢀ), 130.7 (d, J = 192.8 Hz,
C-1ꢀ), 131.6 (d, J = 2.8 Hz, C-10), 132.0 (C-4ꢀ), 132.4 and 132.5 (C-
2ꢀ and C-6ꢀ), 137.6 (C-5), 157.5 (C-3). FAB-MS m/z (%): 480 (50)
[M + H]+.
2.8.1. 3-Methoxy-3ꢀ-(4ꢀꢀ-methylbenzyl)-2ꢀ-oxo-2ꢀ-phen-
oxy[1ꢀ,3ꢀ,2ꢀ]oxazaphosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]
estra-1,3,5(10)-triene (26)
In the general procedure, amino alcohol 19 (420 mg) was
used. After purification of the crude product (26a:26b = ca.
3:2 by 1H NMR), compound 26a (148 mg, 27%) as the fast-
eluting diastereomer was obtained. The less mobile epimer
was identified as isomer 26b (150 mg, 28%), with 26a as a minor
impurity (ca. 3:1 by 1H NMR).
26a: Mp 182–184 ◦C; Rf = 0.43 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 19.4; 1H NMR (400 MHz, CDCl3,
ı [ppm]): 0.97 (s, 3H, 18-H3), 2.33 (s, 3H, 4ꢀꢀ-CH3), 2.64 (m, 1H,
16-H), 2.81 (m, 2H, 6-H2), 3.02 (m, 1H) and 3.19 (m, 1H): 16a-H2,
3.75 (s, 3H, 3-OMe), 3.92 (d, 1H, J = 9.7 Hz, 17-H), 4.08 (m, 2H,
benzyl-H2), 6.61 (d, 1H, J = 2.5 Hz, 4-H), 6.68 (dd, 1H, J = 8.6 Hz,
J = 2.5 Hz, 2-H), 7.16 (d, 1H, J = 8.6 Hz, 1-H), 7.25 (d, 2H, J = 8.1 Hz,
3ꢀꢀ-H and 5ꢀꢀ-H), 7.25 (d, 2H, J = 8.1 Hz, 2ꢀꢀ-H and 6ꢀꢀ-H), 7.52 (m,
3H, 3ꢀ-H, 4ꢀ-H and 5ꢀ-H), 7.93 (m, 2H, 2ꢀ-H and 6ꢀ-H); 13C NMR
(100 MHz, CDCl3, ı [ppm]): 13.2 (C-18), 21.1 (4ꢀꢀ-CH3), 26.0 (CH2),
27.5 (CH2), 28.9 (CH2), 29.6 (CH2), 37.4 (CH2), 38.0 (CH), 39.0 (C-
16), 43.7 (CH), 44.8 (d, J = 6.8 Hz, C-13), 49.0 (benzyl-CH2), 49.1
(CH), 50.6 (d, J = 4.5 Hz, C-16a), 55.1 (3-OMe), 87.1 (d, J = 9.5 Hz,
C-17), 111.5 (C-2), 113.8 (C-4), 126.2 (C-1), 128.2 (C-4ꢀ), 128.4 (2C,
C-3ꢀꢀ and C-5ꢀꢀ), 129.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 130.6 (d, J = 183.1 Hz, C-
1ꢀ), 132.0 (2C, C-3ꢀ and C-5ꢀ), 132.1 (C-4ꢀꢀ), 132.3 (d, 2C, J = 9.9 Hz,
C-2ꢀ and C-6ꢀ), 134.3 (d, J = 4.9 Hz, C-1ꢀꢀ), 137.1 (C-10), 137.6 (C-
5), 158.0 (C-3); EI-MS (70 eV) m/z (%): 541 (100) [M+], 400 (60),
260 (48), 105 (32); FAB-HRMS (M + H)+ found: 542.2824 (4.3 ppm),
requires: 542.2801.
24b: Rf = 0.41 (EtOAc/CH2Cl2 = 20:80); NMR data (assigned
from a 1:3 mixture of 24a and 24b): 31P NMR (121 MHz, CDCl3,
ı [ppm]): 18.4; 1H NMR (500 MHz, CDCl3, ı [ppm]): 0.76 (t, 3H,
J = 7.4 Hz, propyl-H3), 0.94 (s, 3H, 18-H3), 2.81 (m, 1H, 16-H), 2.87
(m, 2H, 6-H2), 3.02 (m, 1H) and 3.24 (m, 1H): 16a-H2, 3.77 (s,
3H, 3-OMe), 4.47 (dd, 1H, J = 9.6 Hz, J = 1.4 Hz, 17-H), 6.63 (d, 1H,
J = 2.6 Hz, 4-H), 6.70 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz, 2-H), 7.19 (d,
1H, J = 8.6 Hz, 1-H), 7.43 (m, 2H, 3ꢀ-H and 5ꢀ-H), 7.54 (m, 1H,
4ꢀ-H), 7.82 (m, 2H, 2ꢀ-H and 6ꢀ-H); 13C NMR (75 MHz, CDCl3, ı
[ppm]): 11.2 (propyl-CH3), 13.6 (C-18), 22.6 (propyl-CH2), 26.1
(CH2), 27.6 (CH2), 28.6 (CH2), 29.7 (CH2), 37.5 (CH2), 38.0 (CH),
41.0 (C-16), 43.7 (CH), 45.3 (d, J = 8.3 Hz, C-13), 48.8 (CH), 49.3 (N-
CH2), 49.5 (C-16a), 55.2 (3-OMe), 84.0 (d, J = 6.8 Hz, C-17), 111.5
26b: Rf = 0.41 (EtOAc/CH2Cl2 = 20:80); NMR data (assigned
from a 1:3 mixture of 26a and 26b): 31P NMR (121 MHz, CDCl3, ı
[ppm]): 18.5; 1H NMR (400 MHz, CDCl3, ı [ppm]): 0.94 (s, 3H, 18-
H3), 2.30 (s, 3H, 4ꢀꢀ-CH3), 2.65 (m, 1H, 16-H), 2.81 (m, 2H, 6-H2),
2.96 (m, 1H) and 3.09 (m, 1H): 16a-H2, 3.76 (s, 3H, 3-OMe), 4.00
(m, 1H) and 4.16 (m, 1H, benzyl-H2), 4.51 (d, J = 9.6 Hz, 17-H),
6.61 (m, 1H, J = 2.5 Hz, 4-H), 6.70 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz, 2-
H), 7.18 (d, 1H, J = 8.6 Hz, 1-H), 7.17 (m, 2H), 7.26 (m, 2H), 7.48 (m,
3H), 7.87 (m, 2H); 13C NMR (100 MHz, CDCl3, ı [ppm]): 13.5 (C-
18), 21.1 (4ꢀꢀ-CH3), 26.1 (CH2), 27.5 (CH2), 28.6 (CH2), 29.6 (CH2),
37.5 (CH2), 38.0 (CH), 40.5 (d, J = 3.9 Hz, C-16), 43.6 (CH), 45.1 (d,
J = 8.2 Hz, C-13), 48.8 (CH), 49.0 (benzyl-CH2), 50.3 (d, J = 5.9 Hz,
C-16a), 55.1 (3-OMe), 84.1 (d, J = 7.8 Hz, C-17), 111.5 (C-2), 113.8

steroids 7 2 ( 2 0 0 7 ) 446–458
451
1H NMR), compound 28a (194 mg, 35%) as the fast-eluting
diastereomer was obtained. The less mobile epimer was iden-
tified as isomer 28b (121 mg, 21%).
(C-4), 126.3 (C-1), 128.2 (CH), 128.4 (CH), 128.5 (CH), 129.0 (CH),
131.4 (d, J = 254.7 Hz, C-1ꢀ), 131.3 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 131.7 (2C,
C-3ꢀꢀ and C-5ꢀꢀ), 132.1 (d, J = 180.1 Hz, C-1ꢀ), 132.2 (C-4ꢀꢀ), 135.2 (d,
J = 3.3 Hz, C-1ꢀꢀ), 136.9 (C-10), 137.6 (C-5), 157.5 (C-3).
28a: Mp 242–245 ◦C; Rf = 0.59 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 19.4; 1H NMR (300 MHz, CDCl3,
ı [ppm]): 0.97 (s, 3H, 18-H3), 2.64 (m, 1H, 16-H), 2.83 (m, 2H, 6-
H2), 2.96 (m, 1H) and 3.20 (m, 1H): 16a-H2, 3.76 (s, 3H, 3-OMe),
3.92 (dd, 1H, J = 9.6 Hz, J = 0.9 Hz, 17-H), 4.02 (m, 1H) and 4.15
(m, 1H): benzyl-H2, 6.60 (d, 1H, J = 2.7 Hz, 4-H), 6.69 (dd, 1H,
J = 8.4 Hz, J = 2.7 Hz, 2-H), 7.16 (d, 1H, J = 8.4 Hz, 1-H), 7.28-7.36
(m, 4H, 2ꢀꢀ-H, 3ꢀꢀ-H, 5ꢀꢀ-H and 6ꢀꢀ-H), 7.54 (m, 3H, 4ꢀ-H, 3ꢀ-H e´s
5ꢀ-H), 7.90 (m, 2H, 2ꢀ-H and 6ꢀ-H); 13C NMR (75 MHz, CDCl3, ı
[ppm]): 13.3 (C-18), 26.0 (CH2), 27.5 (CH2), 28.9 (CH2), 29.6 (CH2),
37.4 (CH2), 38.0 (CH), 39.0 (d, J = 2.2 Hz, C-16), 43.7 (CH2), 44.9 (d,
J = 6.9 Hz, C-13), 49.3 (CH), 49.5 (d, J = 2.0 Hz, benzyl-CH2), 50.5
(d, J = 5.1 Hz, C-16a), 55.2 (3-OMe), 87.2 (d, J = 9.5 Hz, C-17), 111.5
(C-2), 113.8 (C-4), 126.3 (C-1), 128.6 (d, 2C, J = 13.4 Hz, C-2ꢀ and
C-6ꢀ), 128.7 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 129.9 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 130.6
(d, J = 217.5 Hz, C-1ꢀ), 132.0 (C-4ꢀꢀ), 132.2 (d, J = 2.9 Hz, C-4ꢀ), 132.3
(d, 2C, J = 10.1 Hz, C-3ꢀ and C-5ꢀ), 133.3 (C-1ꢀꢀ), 136.1 (d, J = 4.2 Hz,
C-10), 137.6 (C-5), 157.5 (C-3); FAB-MS m/z (%): 562 (22) [M + H]+,
154 (100), 136 (78), 107 (33), 69 (41); FAB-HRMS (M + H)+ found:
562.2252 (4.6 ppm), requires: 562.2278.
28b: Mp 188–190 ◦C; Rf = 0.53 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 18.4; 1H NMR (300 MHz, CDCl3,
ı [ppm]): 0.96 (s, 3H, 18-H3), 2.65 (m, 1H, 16-H), 2.84 (m, 2H,
6-H2), 2.94 (m, 1H) and 3.17 (m, 1H): 16a-H2, 3.77 (s, 3H, 3-
OMe), 3.97 (m, 1H) and 4.19 (m, 1H): benzyl-H2, 4.51 (dd, 1H,
J = 9.9 Hz, J = 1.5 Hz, 17-H), 6.62 (d, 1H, J = 2.7 Hz, 4-H), 6.70 (dd,
1H, J = 8.4 Hz, J = 2.7 Hz, 2-H), 7.19 (d, 1H, J = 8.4 Hz, 1-H), 7.22 (m,
3H), 7.31 (m, 1H), 7.54 (m, 3H), 7.87 (m, 2H, 2ꢀ-H and 6ꢀ-H); 13C
NMR (75 MHz, CDCl3, ı [ppm]): 13.6 (C-18), 26.1 (CH2), 27.6 (CH2),
28.6 (CH2), 29.7 (CH2), 37.5 (CH2), 38.0 (CH), 40.7 (d, J = 4.4 Hz,
C-16), 43.7 (CH2), 45.2 (d, J = 7.7 Hz, C-13), 48.7 (CH), 49.4 (d,
J = 3.5 Hz, benzyl-CH2), 50.2 (d, J = 6.2 Hz, C-16a), 55.2 (3-OMe),
84.2 (d, J = 8.1 Hz, C-17), 111.5 (C-2), 113.9 (C-4), 126.3 (C-1), 128.4
(d, 2C, J = 15.9 Hz, C-2ꢀ and C-6ꢀ), 128.6 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 129.6
(2C, C-2ꢀꢀ and C-6ꢀꢀ), 131.4 (d, 2C, J = 9.6 Hz, C-3ꢀ and C-5ꢀ), 131.8
(d, J = 179.9 Hz, C-1ꢀ), 131.9 (d, J = 2.9 Hz, C-4ꢀ), 132.2 (C-4ꢀꢀ), 133.2
(C-1ꢀꢀ), 137.0 (d, J = 4.0 Hz, C-10), 137.6 (C-5), 157.6 (C-3); FAB-MS
m/z (%): 562 (21) [M + H]+, 307 (26), 154 (100), 136 (85), 107 (37),
91 (35); FAB-HRMS (M + H)+ found: 562.2252 (4.6 ppm), requires:
562.2278.
2.8.2. 3-Methoxy-3ꢀ-(4ꢀꢀ-fluorobenzyl)-2ꢀ-oxo-2ꢀ-phen-
oxy[1ꢀ,3ꢀ,2ꢀ]oxazaphosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]
estra-1,3,5(10)-triene (27)
In the general procedure, amino alcohol 20 (424 mg) was
used. After purification of the crude product (27a:27b = ca.
3:2 by 1H NMR), compound 27a (127 mg, 23%) as the fast-
eluting diastereomer was obtained. The less mobile epimer
was identified as isomer 27b (168 mg, 31%), with 27a as a minor
impurity (ca. 3:1 by 1H NMR). With 2 equiv. of PhP(O)Cl2, 27a
(236 mg, 43%) and 27b (222 mg, 41%), latter with 27a as a minor
impurity (ca. 4:1 by 1H NMR), were obtained.
27a: Mp 187–190 ◦C; Rf = 0.46 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 19.3; 1H NMR (400 MHz, CDCl3,
ı [ppm]): 0.97 (s, 3H, 18-H3), 2.64 (m, 1H, 16-H), 2.84 (m, 2H, 6-
H2), 3.00 (m, 1H) and 3.19 (m, 1H): 16a-H2, 3.75 (s, 3H, 3-OMe),
3.92 (d, 1H, J = 9.7 Hz, 17-H), 4.18 (m, 2H, benzyl-H2), 6.60 (d, 1H,
J = 2.6 Hz, 4-H), 6.69 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz, 2-H), 7.00 (t, 2H,
J = 8.6 Hz, 3ꢀꢀ-H and 5ꢀꢀ-H), 7.18 (d, J = 8.6 Hz, 1-H), 7.36 (m, 2H, 2ꢀꢀ-
H and 6ꢀꢀ-H), 7.54 (m, 3H, 3ꢀ-H, 4ꢀ-H and 5ꢀ-H), 7.92 (m, 2H, 2ꢀ-H
and 6ꢀ-H); 13C NMR (100 MHz, CDCl3, ı [ppm]): 13.3 (C-18), 26.0
(CH2), 27.5 (CH2), 28.9 (CH2), 29.6 (CH2), 37.4 (CH2), 38.0 (CH),
38.9 (C-16), 43.7 (CH), 44.8 (d, J = 6.7 Hz, C-13), 49.1 (CH), 49.4
(benzyl-CH2), 50.4 (d, J = 4.4 Hz, C-16a), 55.2 (3-OMe), 87.1 (d,
J = 9.4 Hz, C-17), 111.5 (C-2), 113.8 (C-4), 115.3 (d, 2C, J = 21.2 Hz,
C-3ꢀꢀ and C-5ꢀꢀ), 126.3 (C-1), 128.5 (d, 2C, J = 15.9 Hz, C-2ꢀꢀ and C-
6ꢀꢀ), 130.0 (d, 2C, J = 8.0 Hz, C-3ꢀ and C-5ꢀ), 130.4 (d, J = 148.4 Hz,
C-1ꢀ), 132.1 (C-4ꢀ), 132.2 (C-1ꢀꢀ), 132.3 (d, 2C, J = 10.0 Hz, C-2ꢀ and
C-6ꢀ), 134.0 (C-10), 137.7 (C-5), 157.5 (C-3), 163.5 (C-4ꢀꢀ); FAB-
MS m/z (%): 546 (38) [M + H]+, 154 (100), 136 (67), 109 (45), 77
(30); FAB-HRMS (M + H)+ found: 546.2573 (3.5 ppm), requires:
546.2554.
27b: Rf = 0.44 (EtOAc/CH2Cl2 = 20:80); NMR data (assigned
from a 1:4 mixture of 27a and 27b): 31P NMR (121 MHz, CDCl3, ı
[ppm]): 18.4; 1H NMR (400 MHz, CDCl3, ı [ppm]): 0.95 (s, 3H, 18-
H3), 2.64 (m, 1H, 16-H), 2.84 (m, 2H, 6-H2), 2.93 (m, 1H) and 3.16
(m, 1H): 16a-H2, 3.76 (s, 3H, 3-OMe), 3.98 (m, 2H, benzyl-H2),
4.50 (dd, 1H, J = 9.6 Hz, J = 1.4 Hz, 17-H), 6.61 (d, 1H, J = 2.6 Hz,
4-H), 6.70 (dd, 1H, J = 8.5 Hz, J = 2.6 Hz, 2-H), 6.94 (t, J = 8.6 Hz,
3ꢀꢀ-H and 5ꢀꢀ-H), 7.20 (d, J = 8.6 Hz, 1-H), 7.23 (m, 2H, 2ꢀꢀ-H and
6ꢀꢀ-H), 7.46 (m, 3H, 3ꢀ-H, 4ꢀ-H and 5ꢀ-H), 7.85 (m, 2H, 2ꢀ-H and 6ꢀ-
H); 13C NMR (100 MHz, CDCl3, ı [ppm]): 13.6 (C-18), 26.1 (CH2),
27.6 (CH2), 28.6 (CH2), 29.7 (CH2), 37.5 (CH2), 38.0 (CH), 40.6 (d,
J = 4.0 Hz, C-16), 43.6 (CH), 45.1 (d, J = 7.8 Hz, C-13), 48.8 (CH), 49.3
(benzyl-CH2), 50.0 (d, J = 5.8 Hz, C-16a), 55.2 (3-OMe), 84.2 (d,
J = 7.8 Hz, C-17), 111.5 (C-2), 113.8 (C-4), 115.2 (d, 2C, J = 21.4 Hz,
C-3ꢀꢀ and C-5ꢀꢀ), 126.3 (C-1), 128.4 (d, 2C, J = 15.2 Hz, C-2ꢀꢀ and C-
6ꢀꢀ), 129.8 (d, 2C, J = 7.9 Hz, C-3ꢀ and C-5ꢀ), 130.3 (d, J = 148.9 Hz,
C-1ꢀ), 131.3 (d, 2C, J = 9.6 Hz, C-2ꢀ and C-6ꢀ), 131.8 (C-4ꢀ), 132.2
(C-1ꢀꢀ), 134.1 (C-10), 137.6 (C-5), 157.5 (C-3), 163.4 (C-4ꢀꢀ).
2.8.4. 3-Methoxy-3ꢀ-(4ꢀꢀ-nitrobenzyl)-2ꢀ-oxo-2ꢀ-phen-
oxy[1ꢀ,3ꢀ,2ꢀ]oxazaphosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]
estra-1,3,5(10)-triene (29)
In the general procedure, amino alcohol 22 (451 mg) was used.
After purification of the crude product (29a:29b = ca. 3:2 by
1H NMR), compound 29a (162 mg, 28%) as the fast-eluting
diastereomer was obtained. The less mobile epimer was iden-
tified as isomer 29b (96 mg, 17%).
29a: Mp 266–269 ◦C; Rf = 0.43 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 19.3; 1H NMR (400 MHz, CDCl3,
ı [ppm]): 0.98 (s, 3H, 18-H3), 2.70 (m, 1H, 16-H), 2.83 (m, 2H,
6-H2), 2.96 (m, 1H) and 3.26 (m, 1H): 16a-H2, 3.76 (s, 3H, 3-
OMe), 3.95 (d, 1H, J = 9.6 Hz, 17-H), 4.13 (m, 1H) and 4.32 (m, 1H):
benzyl-H2, 6.60 (d, 1H, J = 2.4 Hz, 4-H), 6.69 (dd, 1H, J = 8.8 Hz,
J = 2.4 Hz, 2-H), 7.16 (d, 1H, J = 8.8 Hz, 1-H), 7.52 (m, 2H), 7.58
2.8.3. 3-Methoxy-3ꢀ-(4ꢀꢀ-chlorobenzyl)-2ꢀ-oxo-2ꢀ-phen-
oxy[1ꢀ,3ꢀ,2ꢀ]oxazaphosphorino[5ꢀ,6ꢀ-e:16ˇ,17ˇ]
estra-1,3,5(10)-triene (28)
In the general procedure, amino alcohol 21 (440 mg) was used.
After purification of the crude product (28a:28b = ca. 3:2 by

452
steroids 7 2 ( 2 0 0 7 ) 446–458
(m, 3H), 7.90 (m, 2H), 8.18 (d, 2H, J = 8.8 Hz, 3ꢀꢀ-H e´s 5ꢀꢀ-H); 13C
NMR (75 MHz, CDCl3, ı [ppm]): 13.3 (C-18), 26.0 (CH2), 27.5
(CH2), 28.8 (CH2), 29.6 (CH2), 37.3 (CH2), 37.9 (CH), 38.8 (d,
J = 2.0 Hz, C-16), 43.7 (CH), 44.8 (d, J = 7.1 Hz, C-13), 49.1 (CH),
50.3 (d, J = 2.3 Hz, benzyl-CH2), 50.9 (d, J = 5.3 Hz, C-16a), 55.1
(3-OMe), 87.3 (d, J = 9.6 Hz, C-17), 111.5 (C-2), 113.8 (C-4), 123.8
(2C, C-3ꢀꢀ and C-5ꢀꢀ) 126.2 (C-1), 128.7 (d, 2C, J = 14.4 Hz, C-2ꢀ
and C-6ꢀ), 129.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 129.8 (d, J = 174.5 Hz, C-
1ꢀ), 132.0 (C-1ꢀꢀ), 132.2 (d, 2C, J = 10.2 Hz, C-3ꢀ and C-5ꢀ), 132.4
(d, J = 2.9 Hz, C-4ꢀ), 137.5 (C-4ꢀꢀ), 145.2 (d, J = 3.3 Hz, C-10), 147.5
(C-5), 157.5 (C-3); EI-MS (70 eV) m/z (%): 572 (100) [M+], 436
(46), 304 (50), 268 (64), 173 (50), 165 (70), 136 (40); FAB-MS m/z
(%): 573 (52) [M + H]+, 305 (24), 154 (100), 138 (94), 107 (38), 77
(36). FAB-HRMS (M + H)+ found: 573.2518 (4.1 ppm), requires:
573.2495.
29b: Mp 221–224 ◦C; Rf = 0.41 (EtOAc/CH2Cl2 = 20:80); 31P
NMR (121 MHz, CDCl3, ı [ppm]): 18.5; 1H NMR (400 MHz, CDCl3,
ı [ppm]): 0.99 (s, 3H, 18-H3), 2.69 (m, 1H, 16-H), 2.84 (m, 2H,
6-H2), 2.92 (m, 1H) and 3.27 (m, 1H): 16a-H2, 3.78 (s, 3H, 3-
OMe), 4.15 (m, 1H) and 4.30 (m, 1H): benzyl-H2, 4.55 (dd, 1H,
J = 9.6 Hz, J = 1.3 Hz 17-H), 6.63 (d, 1H, J = 2.5 Hz, 4-H), 6.72 (dd,
1H, J = 8.6 Hz, J = 2.5 Hz, 2-H), 7.20 (d, 1H, J = 8.6 Hz, 1-H), 7.46 (d,
Scheme 1 – Reagents and conditions: (i) BnNH2, KOH, rt, 1 h; (ii) PrNH2, KOH, rt, 30 min; (iii) abs. EtOH, 78 ◦C, 2 h, N2 atm; (iv)
NaBH4, THF/MeOH, rt, 2 h.

steroids 7 2 ( 2 0 0 7 ) 446–458
453
2H, J = 8.6 Hz, 2ꢀꢀ-H and 6ꢀꢀ-H), 7.50 (m, 2H), 7.56 (m, 1H), 7.87 (m,
2H), 8.13 (d, 2H, J = 8.6 Hz, 3ꢀꢀ-H and 5ꢀꢀ-H); 13C NMR (100 MHz,
CDCl3, ı [ppm]): 13.5 (C-18), 26.1 (CH2), 27.5 (CH2), 28.6 (CH2),
29.6 (CH2), 37.4 (CH2), 38.0 (CH), 40.6 (d, J = 3.8 Hz, C-16), 43.6
(CH), 45.1 (d, J = 7.3 Hz, C-13), 48.7 (CH), 50.0 (d, J = 1.7 Hz, benzyl-
CH2), 50,4 (d, J = 6.2 Hz, C-16a), 55.2 (3-OMe), 84.2 (d, J = 8.3 Hz,
C-17), 111.5 (C-2), 113.8 (C-4), 123.7 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 126.3
(C-1), 128.5 (d, 2C, J = 14.8 Hz, C-2ꢀ and C-6ꢀ), 128.8 (2C, C-2ꢀꢀ and
C-6ꢀꢀ), 130.1 (d, J = 175.0 Hz, C-1ꢀ), 132.2 (d, 2C, J = 9.5 Hz, C-3ꢀ and
C-5ꢀ), 132.1 (C-4ꢀ), 132.7 (C-1ꢀꢀ), 137.6 (C-4ꢀꢀ), 146.3 (d, J = 2.8 Hz, C-
10), 147.3 (C-5), 157.5 (C-3); EI-MS (70 eV) m/z (%): 572 (94) [M+],
268 (100); FAB-MS m/z (%): 573 (21) [M + H]+, 215 (79), 201 (100),
69 (55); FAB-HRMS (M + H)+ found: 573.2518 (3.9 ppm), requires:
573.2496.
3.
Results and discussion
3.1.
Synthetic studies
For the phosphorylation reactions, first the amino alcohols
6 and 17–22 were synthetized (Scheme 1). 17␤-Hydroxy-16␤-
aminomethylestrone 3-methyl ether 6 was obtained from
estrone 3-methyl ether 2 in several steps according to the
procedures described in the literature [27–29]. For compari-
son of the cyclization propensities, 6 containing a primary
amino function, and N-substituted secondary amines such
as N-Pr (17), N-Bn (18) and different N-arylmethyl 19–22
derivatives were also prepared. Compound 17 was synthetized
from 16-methylidene-estrone 3-methyl ether 3 [28,30] via the
1,4-addition of n-propylamine and the in situ reduction of
the C-17 keto group in intermediate 4. Although Michael
adducts of this type are sensitive and exhibit a great ten-
dency to undergo the retro-type reaction in solution,3 the
benzylamino derivative 5 could be isolated during the reac-
tion of 3 with benzylamine. The subsequent reduction with
NaBH4 led to the benzylamino alcohol 18 in high yield. The
addition of both amines to the double bond of 3, and the fol-
lowing reductions of 4 and 5, occurred in a stereoselective
manner, leading to 16␤, 17␤-substituted derivatives 17 and
18.
Scheme 2 – Reagents and conditions: (i) PhP(O)Cl2, Et3N,
CH2Cl2, rt, N2 atm → 40 ◦C, 6 h → rt, 24 h.
8.3 ppm in all cases. No signal indicative of the presence of
the tautomeric 1,3-oxazine (T) could be observed. Reduction of
12–16 with NaBH4 resulted in secondary amines 18–22 in good
yields.
Amino alcohols
6
and 17–22 were cyclized with
phenylphosphonic dichloride in the presence of Et3N. In
most cases, two epimers (a and b), differing in their P
configuration, were formed and were separated by column
chromatography. The ring-closure reaction of 6 proceeded
with complete diastereoselectivity to give 23a; no traces
of the corresponding
P epimer (23b) could be detected
even in the crude product (Scheme 2). However, the yield
was, quite low (15%), which is not surprising at all for a
Compound 18 and its para-substituted benzylamino
analogs 19–22 could also be obtained in an alternative way
from 6 with different benzaldehydes (7–11) to furnish first
the corresponding imino alcohols 12–16, respectively. These
intermediates were characterized only via their 1H NMR spec-
tral data due to their poor solubility in the usually applied
NMR solvents. Benzimino alcohols containing an alcoholic
hydroxyl group and an imino function in the 1,3 position
have been reported to display tendency to ring-chain tau-
tomerism in solution, depending on the substitution pattern
of the aromatic moiety [31,32]. Therefore, they often exist as an
equilibrium mixture of the open-chain imine and the related
1,3-oxazine forms. The 1H NMR spectra of the Schiff bases
12–16 indicated that only the imine form was present in solu-
tion, despite the different substituents in the para position of
the Ph group. The imine proton could be identified at around
primary amine such as
6 [17,33], whereas better yields
(35–82%) were achieved in the phosphorylation reactions
of secondary amines 17–22 with an equivalent amount of
phenylphosphonic dichloride. In the particular case of the
cyclization of 20, a 2-fold excess of the P reagent was applied
in order to improve the conversion. Thus, 84% of 27 could be
obtained, which was commensurable with the yield of the
unsubstituted N-benzyl derivative 25. The epimeric ratios
were determined for the 1H NMR spectra of the reaction
mixtures, which revealed a ratio of a and b of ca.3:2 for 24–
29.
The structures of the oxazaphosphorinanes (23–29) were
confirmed by multinuclear (1H, 13C and 31P) NMR meth-
ods, and the stereostructures were evaluated by means
of B3LYP/3-21G* ab initio calculations. The structure of 1a
was previously determined by single-crystal X-ray analy-
sis (see footnote 2). The 1H and 13C chemical shifts were
assigned with the aid of 2D homonuclear (COSY) and het-
eronuclear (HMQC and HMBC) correlation measurements.
3
Unpublished results in this laboratory.

454
steroids 7 2 ( 2 0 0 7 ) 446–458
In previous studies on isomeric pairs of oxazaphospho-
Table 1 – Selected 1H and 13C chemical shifts in CDCl3
Compound ı [ppm]
16-H␣
rinanes, the 31P NMR chemical shifts of the trans isomer a:
(P O is trans to 17-H) were mostly upfield of those for their
cis counterpart b: (P O is cis to 17-H). Inspection of the 31P
chemical shifts for the epimers of 24–29, however, was in
itself not enough for the configurational assignment, since
there was only a slight difference between the values for the
related isomeric phosphoramidates. Anomalous 31P chemi-
cal shifts for isomeric phosphorinane structures have been
reported [12,38], but have been left unexplained or interpreted
in terms of a chair to chair [39] or a chair to twist-boat
equilibration [12]. Hence, other corroborative NMR parame-
ters, such as characteristic 1H and 13C chemical shifts were
used for identification. The sequence of the 17-H chemi-
cal shifts was found to be very similar to that for 1a and
1b: ı(17-H) for 24a–29a < ı(17-H) for 24b–29b (Table 1), which
can be attributed to the P O effect. Moreover, the difference
between the values was about 0.6 ppm, and therefore the
same anisotropic effect of the P-Ph group cis to 17-H was pre-
sumed for diastereomers a, as was the situation previously
for the corresponding O-containing analog 1a. Since only one
diastereomer of 23 was isolated, the assignment was con-
firmed by comparison of its characteristic 1H chemical shifts
with those of the other isomeric pairs, which revealed good
accordance with the values for the a series of compounds.
With respect to the 13C NMR chemical shifts, C-17 resonates
at somewhat higher field in the b series (around 84 ppm) as
compared with that for the a series of compounds (around
16-H
16-H␤
17-H
C-17
23aa
24a
24b
25ab
25bb
26a
26b
27a
27b
28a
28b
29a
29b
2.56
2.66
2.81
2.64
2.67
2.64
2.65
2.64
2.64
2.64
2.65
2.70
2.69
3.38
3.42
3.24
3.21
3.15
3.19
3.09
3.19
3.16
3.20
3.17
3.26
3.27
3.32
3.12
3.02
3.01
2.94
3.02
2.96
3.00
2.93
2.96
2.94
2.96
2.92
3.85
3.83
4.47
3.93
4.51
3.92
4.51
3.92
4.50
3.92
4.51
3.95
4.55
-
86.8
84.0
87.4
84.3
87.1
84.1
87.1
84.2
87.2
84.2
87.3
84.2
a
Characterized only by 1H NMR.
Values from [26].
b
The 1H chemical shifts and coupling constants were ana-
lyzed by an iterative method with the PERCH NMR software
[34,35].
3.2.
Stereostructures (configuration and conformation)
The phosphorylation reactions resulted in a series of diastere-
omeric pairs and due to the stereogenic atom.
The P-configuration, and thus the orientation of the P
87 ppm), because of the deshielding effect of the axial P
bond.
O
a
b
P
O
Exhaustive studies have been carried out on oxaza-
phosphorinane derivatives fused with cyclohexane- or
six-membered hetero rings to reveal a conformational flexibil-
ity of the P,N-ring for substitution [8,14,15,21–23]. The specific
conformational behavior of these rings has been handled in
terms of a chair-alternative boat or a chair-twist equilibrium,
and the coupling constants 3J(H,H) and 3J(H,P) have been used
as indicators of possible dynamic processes [40]. To the best of
bond, can be determined by different NMR methods. The
following indicators were used earlier for the identifica-
tion of the isomers: (i) 31P NMR chemical shifts [36]; (ii)
1H chemical shifts due to the 1,3-diaxial interactions; (iii)
changes in 13C chemical shifts arising from the shielding
effect of oxygen; (iv) NOE effects between the P substituent
and other ring protons; and (v) 1J(P,N) coupling constants
[37].
Table 2 – Selected coupling constants J(H,H) and J(H,P)
Compound
J [Hz]
16a-H␤, 16a-H␣
16a-H␤, P
16a-H␤, 16-H
16a-H␤, P
16a-H␤, 16-H
17-H, P
1aa
−10.8
−10.7
−12.0
−12.0
−12.7
−12.1
−12.7
−12.0
−12.6
−12.2
−12.8
−12.0
−12.9
−12.0
−12.6
4.6
1.4
3.9
2.6
<1.0
2.8
<1.0
2.3
<1.0
2.6
<1.0
2.4
<1.0
2.0
10.8
12.0
11.8
12.0
12.7
12.0
12.7
12.6
12.6
12.2
12.8
12.0
12.9
12.0
12.6
25.1
21.5
24.1
20.7
20.5
20.7
19.2
20.4
19.5
20.6
19.2
20.4
24.9
19.9
19.0
6.5
6.2
6.0
6.0
6.0
6.1
6.0
6.0
6.0
6.0
6.0
6.3
5.9
6.0
5.8
<1.0
<1.0
1.1
<1.0
1.4
1.4
<1.0
0.9
1.5
<1.0
1.4
0.9
1.5
1ba
23a
24a
24b
25a
25b
26a
26b
27a
27b
28a
28b
29a
29b
<1.0
1.3
<1.0
aSee footnote 2.

steroids 7 2 ( 2 0 0 7 ) 446–458
455
our knowledge, however, the stereostructures of P-substituted
heterocycles cis-fused to a five-membered ring have been
investigated only for 1,3,2-dioxaphosphorinanes [41,42]. Con-
formational restriction is expected in these cases with regard
to the fused strained five-membered ring. Although the
greater length of the P–N bond in oxazaphosphorinanes, as
compared with the P–O in dioxaphosphorinanes, and the pres-
ence of a substituent other than hydrogen on the ring N
atom, should result in appreciable differences in the con-
formational properties [8], the stereostructures described for
cyclopentane-condensed dioxa derivatives [41] and also sug-
gested by the inspection of Dreiding models were taken as
starting points. Consequently, two possible chair (A and B)
and two alternative boat forms (C and D) of the P-hetero
ring can be assumed. These conformers are depicted in
Fig. 2.
Table 3 – Computed relative energies (kcal/mol) for the existing conformers of products 23–29 at the BLYP/6-31G(d) level
of theory.
Epimers a
Epimers b
Cb,1
Ca,1
Ca,2
Ca,3
Da
Bb,1
Bb,2
Cb,2
23
24
25
26
27
28
29
–
1.76
1.56
2.18
2.22
2.45
2.51
2.64
–
4.92
3.54
6.89
6.91
7.18
7.24
7.40
6.50
6.57
7.83
7.81
7.77
7.71
7.60
–
0.00
0.00
0.00
0.00
0.00
0.00
0.00
–
0.59
1.26
1.28
1.22
1.13
1.05
2.14
3.85
3.81
3.74
3.74
3.63
6.42
6.85
6.90
7.13
7.02
7.06
0.16
0.92
0.91
1.03
1.02
0.82

456
steroids 7 2 ( 2 0 0 7 ) 446–458
Cb, 1 forms, bearing the P-Ph group in a pseudoequatorial posi-
tion (23b–29b), are energetically more favorable. The observed
difference in the epimeric ratios of 24–29 (a:b = 3:2) may be
attributed both to the thermodynamic and the kinetic con-
trol of the process. This assumption is supported by the fact
that isomers b are theoretically more stable, whereas 23a was
isolated diastereoselectively, and compounds 24a–29a were
obtained as major isomers. Additionally, conformers B (Ba, Bb,1
and Bb,2) are not preferred in consequence of the steric interac-
tions caused by the unfavorable eclipsed position of the hetero
ring hydrogen atoms. Theoretical calculations precluded the
existence of conformer A which was converted to other confor-
mations due to steric repulsion between the P-group and the
angular methyl group at position 13 of the sterane skeleton.
In summary, epimers of D-ring-fused oxazaphosphori-
nanes (23–29) were prepared via newly described interme-
diates (5, 12–22) in the estrone series, and their preferred
conformations were calculated. In accord with the NMR mea-
surements, the results indicated that the stereostructure of
the hetero ring is mainly determined by the rigidity of the
sterane skeleton. The P-rings of compounds 23–29 adopt pre-
dominantly a distorted-boat conformation, independently of
the P-configuration and the substituent preferences, very sim-
ilarly as for the corresponding dioxaphosphorinane analogs.
Fig. 2 – Possible conformations of the phosphoramidate
ring of 23–29.
A
typical feature of 2-oxo-1,3,2-oxazaphosphorinanes,
which exist predominantly in one conformation in solution, is
the combination of large 3J(H,P) values for the protons equato-
rial and hence antiperiplanar to the P and small 3J(H,P) values
for the axial protons synclinal to the P. In conformations A
and D, the P atom and 17-H are in an antiperiplanar orien-
tation, and thus J(17-H,P) would be >20 Hz. In contrast, the
dihedral angle P–O17–C17–H17 in conformations B and C is
about 90◦, leading to a small J(17-H,P) value, which indeed
holds true for 23–29 (J(17-H,P) ≤ 1.5 Hz) (Table 2). Moreover, the
observed extra upfield shift of 17-H for epimers a can not be
explained in the case of conformer A or D. The 3J(H,P) data on
the 16a protons, however, suggest that all compounds (23–29)
seem to adopt predominantly the distorted-boat conformer C
almost exclusively, regardless of the relative configuration on
the P atom. This is consistent with the combination of a small
3J(16a-H␤, P) with a large 3J(16a-H␣, P) for 23–29. The dihedral
angle P–O16a–C16a–H16–H␤ in conformer B is about 180◦, so that
3J(16a–H␤, P) >20 Hz would be predicted. There is obvious sim-
ilarity between the corresponding coupling constants of 1a
and 23a in Table 2. The small differences may arise from the
stereostructural modification effect caused by the change of
the O atom in 1a to the N atom in 23a. The coupling constants
3J(H,H) and 3J(H,P) for the epimers a and b of the N-substituted
oxazaphosphorinanes 24–29 suggested the same conforma-
tional dominance as noted for 1a and 1b. In order to support
these considerations, B3LYP/6–31 + G(d)) DFT calculations [43]
using Gaussian03 [44] were carried out on diastereomers a and
b of 23–29.
Acknowledgments
The authors thank the Hungarian Scientific Research Fund
(OTKA T 049366 and T 042479) for financial support, Istva´n
Simon (University of Szeged, Hungary) for the NMR spectra,
Mrs. Gyo¨rgyi Udvarnoki (University of Go¨ttingen, Germany) for
the mass spectra and Tam
Hungary) for initial computational calculations.
a´s Ko¨rtve´lyesi (University of Szeged,
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