A comparative structural study of the steroid epimers: 17β-Amino- 1,3,5(10)estratrien-3-ol, 17α-amino-1,3,5(10)-estratrien-3-ol, and some derivatives by 1H NMR, and x-ray diffraction analysis

Article abstract of DOI:10.1016/S0039-128X(98)00063-4

The epimers 17β-amino-1,3,5(10)-estratrien-3-ol and 17α-amino- 1,3,5(10)-estratrien-3-ol were synthesized. 17β-Amino-1,3,5(10)-estratrien- 3-ol was prepared by catalytic hydrogenation of the estrone-oxime. The 17α- amino epimer was obtained from estradiol

Full text of DOI:10.1016/S0039-128X(98)00063-4

Papers
A comparative structural study of the
steroid epimers: 17␤-amino-1,3,5(10)-
estratrien-3-ol, 17␣-amino-1,3,5(10)-
estratrien-3-ol, and some derivatives
1
by H NMR, and x-ray
diffraction analysis
Cristina Lemini,* Elia Cruz–Ramos,* Rube´n Alfredo Toscano,† and
Raymundo Cruz–Almanza†
*Departamento de Farmacolog´ıa, Facultad de Medicina, Universidad Nacional Auto´noma de
Me´xico (UNAM), CP 04510. Apdo. Postal 70–297 and †Instituto de Qu´ımica, UNAM Circuito
exterior CU, Me´xico D.F., CP 04510, Me´xico
The epimers 17␤-amino-1,3,5(10)-estratrien-3-ol and 17␣-amino-1,3,5(10)-estratrien-3-ol were synthesized.
17␤-Amino-1,3,5(10)-estratrien-3-ol was prepared by catalytic hydrogenation of the estrone–oxime. The 17␣-
amino epimer was obtained from estradiol, via tosylate, followed by nucleophilic displacement by sodium azide
and subsequent reduction with LiAlH4. They were characterized by spectroscopic methods. Determination of the
crystal structures of 3-(toluene-4-sulfonyloxy)-17␣-azido-1,3,5(10)-estratriene, 3-(toluene-4-sulfonyloxy)-17-␣-
amino-1,3,5(10)-estratriene hydrochloride, 17␤-acetylamino-1,3,5(10)-estratriene-3-ol, and 3-acetoxy-17␤-
acetylamino-1,3,5(10)-estratriene enabled us to characterize the structure of the 17␣ and 17␤ amino epimers for
the first time. (Steroids 63:556–564, 1998) © 1998 by Elsevier Science Inc.
Keywords: 17-aminosteroids; 17␣-aminoestrogens; 17␤-aminoestrogens; 1H NMR; X-ray; epimers
NNЈdialkyl C17 substitutions produce anticoagulant ef-
fects,5–10 however, it is unknown whether substitution in the
amino group is required or not to produce such effects. The
effects on blood coagulation of 17␣-aminoestrogens, which are
epimers of 17␤-aminoestrogens have not been studied yet.
To obtain this information, 17␤-amino-1,3,5(10)-estratrien-
3-ol (1) and 17␣-amino-1,3,5(10)-estratrien-3-ol (7) were syn-
thesized and characterized by spectroscopic methods. X-ray
studies of 17␤-acetylamino-1,3,5(10)-estratriene-3-ol (2),
3-acetoxy-17␤-acetylamino-1,3,5(10)-estratriene (3),
3-(toluene-4-sulfonyloxy)-17␣-azido-1,3,5(10)-estratriene (6),
and 3-(toluene-4-sulfonyloxy)-17-␣-amino-1,3,5(10)-
estratriene hydrochloride (8) enabled us to characterize the
structure of the 17␤ and 17␣ amino epimers 1 and 7.
Introduction
17␤-aminosteroids have been used as precursors for the
preparation of peptide derivatives for steroid-protein bind-
ing, and have been evaluated as anticancer drugs against
hormone-dependent tumors, as well as immunoregulatory
and antiarrhythmic agents.1–4
17␤-aminoestrogens produce dose-dependent and pro-
longed anticoagulant effects in rodents,5–10 contrasting with the
procoagulant effects produced by estradiol and other synthetic
estrogens when administered at high doses.11 The anticoagu-
lant effect of the 17␤-aminoestrogens is related to the nitrogen
function attached at the C17 position of the steroid. Com-
pounds which have N-alkyl, N-alkyloxy and N-alkyl-
Address reprint requests to Cristina Lemini, Departamento de Farmacolog´ıa,
Facultad de Medicina, Universidad Nacional Auto´noma de Me´xico, Ciudad
Universitaria, CP 04510, Apdo. Postal 70–297, Me´xico D.F. Mexico.
Received September 11, 1997; accepted July 1, 1998.
Experimental
All solvents and reagents used were of analytical reagent
grade, and were dried and distilled under usual procedures.
Steroids 63:556–564, 1998
© 1998 by Elsevier Science Inc. All rights reserved.
655 Avenue of the Americas, New York, NY 10010
0039-128X/98/$19.00
PII S0039-128X(98)00063-4

1
Synthesis, H NMR, and x-ray of 17␤ and 17␣-aminoestrogens: Lemini et al.
Figure 1 300 MHz1H NMR of 17-H and benzylic protons; (a) epimer 17␤-amino in CDCl3-DMSO-d6; (b) epimer 17␤-amino in C6D6-
DMSO-d6; (c) epimer 17␣-amino in CDCl3-DMSO-d6.
Estrone (3-hydroxy-1,3,5(10)-estratrien-17-one) and estra-
diol (3-hydroxy-1,3,5(10)-estratrien-17␤-ol) were obtained
from Syntex (Mexico City, Mexico). Reagents were pur-
chased from Aldrich (Milwaukee, WI, USA). Reactions
were monitored by thin-layer chromatography (TLC) with
Merck precoated silica gel F254 plates, (0.25 mm thick)
using hexane/ethyl acetate/methanol (5:4:1 v/v) and hexane-
chloroform-methanol (5:4:1 v/v) as eluents. The spots were
detected under ultraviolet light (254 nm and 366 nm) and
revealed with iodine. Products were purified by flash chro-
matography (Merck, silica gel 60, 230–400 mesh ASTM or
aluminum oxide). Proof of chemical purity was established
by spectroscopy (IR, NMR, MS) and analytical techniques
(TLC and chemical analysis). Elemental analyses were per-
formed by Galbraith Laboratories Inc. Knoxville, TN, USA.
Melting points were assessed on an Electrothermal 9100
capillary melting point apparatus, and are uncorrected. Op-
tical rotation data were measured in methanol, ethanol or
acetonitrile solution with a JASCO J-720 spectropolarime-
ter. IR spectra were obtained using a Nicolet FT-5SX or
1
Perkin Elmer 283B spectrophotometer. H NMR spectra
were recorded on a Varian–Gemini 200 MHz and a Varian–
Unity 300 MHz spectrometers, and are reported in ppm
downfield from the internal standard tetramethylsilane. MS
were obtained with a JEOL JMS-AX505HA mass spec-
trometer at 70 eV. The x-ray study was performed with a
Siemens P4 diffractometer.
17␤-Amino-1,3,5(10)-estratrien-3-ol (1)
Compound 1 was prepared by the reduction of estrone–
oxime with sodium-propanol.12–14 The resulting yellow pale
solid was purified by TLC (silica-gel) using hexane-
chloroform-methanol (85:4:1 v/v) and crystallized several
Figure 2 ORTEP-type plot of the 2 molecule. Ellipsoids are drawn at 30% probability level.
Steroids, 1998, vol. 63, November 557

Papers
Table 1 Unit Cell, Data Collection, and Structure Solution Parameters
Compound
2
3
6
8
Molecular formula
Mass
C20H27NO2
313.43
P212121
6.817(1)
14.292(1)
17.771(2)
—
C22H29NO3
355.46
C25H29N3O3
451.57
P212121
6.372(1)
16.624(3)
21.770(2)
—
S
C25 H34 Cl N O4
480.04
P212121
7.4871(3)
7.610(1)
44.260(2)
—
S
Space group
a (Å)
P21
7.0586(2)
30.830(1)
9.3990(4)
97.700(4)
2026.9(1)
4
b (Å)
c (Å)
␤ (°)
V (Å3)
1731.4(3)
4
2306.1(6)
4
2521.8(4)
4
Z
F(000)
680
768
960
1024
Radiation
CuK␣
CuK␣
CuK␣
CuK␣
␮ (mmϪ1
)
0.600
0.608
1.503
2.358
D (calc) (g cmϪ3
)
1.202
1.165
1.301
1.264
Crystal dimensions (mm)
␪ limits (°)
0.80, 0.24, 0.20
1.50–56.75
7, 15, 19 plus
Friedel pairs
2319
0.60, 0.46, 0.26
1.50–56.75
7, 33, 10 plus
Friedel pairs
5421
0.40, 0.14, 0.12
1.50–55.00
6, 17, 23
0.34, 0.26, 0.20
1.50–56.75
7, 8, 48 plus
Friedel pairs
3312
max. h, k, l
N measured
2888
2451
290
N observed [I Ն 2␴(I)]
2199
5052
2945
Number of parameters
215
485
305
Max./min. residual
Electron density (e/Å3)
ϩ0.12/Ϫ0.15
0.056
ϩ0.50/Ϫ0.19
0.058
ϩ0.21/Ϫ0.18
0.048
ϩ0.22/Ϫ0.16
0.0458
R
wR
0.152
0.155
0.126
0.115
wa
w ϭ 1/[␴2(Fo2)
ϩ (0.1026P)2
ϩ 0.3035P]
w ϭ 1/[␴2(Fo2)
ϩ (0.0970P)2
ϩ 0.6211P]
w ϭ 1/[␴2(Fo2)
ϩ (0.0721P)2
ϩ 0.6115P]
w ϭ 1/[␴2(Fo2) ϩ
(0.0521P)2
0.7501P]
ϩ
aP ϭ (Fo2 ϩ 2Fc2)/3.
times from methanol to yield 0.302 g (1.10 mmol, 37%) of
product 1 with m.p. 225–226° C, (lit. m.p. 200° C12 221–
222.5° C15 222–224° C16 223–226° C13 231–233° C1).
[␣]2D5 ϭ ϩ 57.7° (MeOH), [␣]3D0 ϭ ϩ 75.3° (EtOH), (lit.
[␣]2D2 ϭ ϩ 73.4° (EtOH)1. IR (KBr): 3426 and 3286 (N-H,
was filtered off, washed with methanol and the solvent
evaporated under reduced pressure. The solid residue was
crystallized from methanol to give 0.452 g (1.44 mmol, 38%
yield) of product 2, with m.p. 266–268°C (lit. m.p. 264–
265° C17). [␣]D25 ϭ Ϫ37.2° (MeOH) (lit. [␣]2D0 ϭ ϩ 6.5°
(DMF)17. IR (KBr): 3399 and 3309 (NOH, OOH), 1625
O-H), 1611 (aromatic ring), cmϪ1 1H NMR 300 MHz
.
1
(CDCl3-DMSO-d6): ␦ 0.68 (s, 3H, 18-CH3), 1.12–2.32 (m,
12H), 2.78 (m, 4H, 17-CH, benzylic protons), 6.56 (d, J ϭ
2.4 Hz, 1H, H-4), 6.62 (dd, J ϭ 8.1 Hz and 2.4 Hz, 1H,
(CO), cmϪ1. H NMR 200 MHz (CDCl3): ␦ 0.74 (s, 3H,
18-CH3), 1.24–2.62 (m, 10H), 1.95 (s, 3H, OC-CH3), 2.75
(m, 5H, 16-H and benzylic protons), 3.87 (t, J ϭ 9.4 Hz, 1H,
17␣-H), 5.93 (d, J ϭ 8.6 Hz, NH), 6.46 (d, J ϭ 2.4 Hz, 1H,
H-4), 6.52 (dd, J ϭ 8.4 Hz and 2.4 Hz, 1H, H-2), 7.06 (d,
J ϭ 8.4 Hz, 1H, H-1), 8.2 (br, 1H, OH exchangeable with
D2O, -OH). MS m/z 313 (Mϩ, 100%), 254 (19%), 213
(75%), 160 (22%). Analysis calculated for: C20H27NO2
(313.43) C, 76.64; H, 8.68; N, 4.47. Found: C, 76.60; H,
8.67; N, 4.37.
1
H-2), 7.14 (d, J ϭ 8.1 Hz, 1H, H-1). H NMR 300 MHz
(C6D6-DMSO-d6): ␦ 0.54 (s, 3H, 18-CH3), 2.57 (t, J ϭ 8.7
Hz 1H, 17-H), 2.79 (m, 3H, benzylic protons). MS m/z 271
(Mϩ, 95%), 254 (57.8%), 213 (50%), 56 (100%). Analysis
calculated for: C18H25NO (271.40) C, 79.66; H, 9.28; N,
5.16. Found: C, 79.68; H, 9.27; N, 5.27. Compound 1 was
dissolved in methanol at room temperature and concentrated
hydrochloric acid was added. The solution was evaporated
to dryness and the residue was recrystallized from metha-
nol/acetone. The hydrochloride decompound 286°C. [␣]D25
ϭ ϩ 80.2° (MeOH). IR (KBr): 3426–3062 (N-H, O-H),
3-Acetoxy-17␤-acetylamino-1,3,5(10)-estratriene (3)
A mixture of 1.5 g (5.26 mmol) of estrone–oxime was
hydrogenated under the conditions described previously,
maintaining the reaction for 5 days. The crude product 3
was crystallized from methanol/acetone to give 0.510 g
(1.44 mmol, 27% yield), m.p. 225–227°C (lit. m.p. 220–
222° C17). [␣]D25 ϭ Ϫ26.4° (MeOH), [␣]3D0 ϭ Ϫ12.3°
(CHCl3), (lit: [␣]2D1 ϭ Ϫ10° (CHCl3), [␣]D19 ϭ ϩ 4.7°
(DMF)17. IR (KBr): 3393–3259 (N-H), 1760 (O-CO), 1643
1
cmϪ1. H NMR 200 MHz (CDCl3-DMSO-d6): ␦ 0.83 (s,
3H, 18-CH3), 1.18–2.38 (m, 12H), 2.75 (m, 3H, benzylic
protons), 3.00 (br, 1H, 17␣-H), 3.45 (br, 3H, ϩNH3), 6.49
(d, J ϭ 2.5 Hz, 1H, H-4), 6.54 (dd, J ϭ 8.3 Hz and 2.5 Hz,
1H, H-2), 7.00 (d, J ϭ 8.3 Hz, 1H, H-1), 8.2 (br, 1H, OH).
17␤-Acetylamino-1,3,5(10)-estratrien-3-ol (2)
1
(HN-CO) cmϪ1. H NMR 200 MHz (CDCl3-DMSO-d6): ␦
Estrone–oxime (1.08 g, 3.78 mmol) was dissolved in 30 mL
of acetic anhydride and shaken in the presence of 10% Pd/C
and hydrogen at room temperature for 3 days. The catalyst
0.71 (s, 3H, 18-CH3), 1.28–2.40 (m, 12H), 2.0 (s, 3H,
NCOCH3), 2.28 (s, 3H, OCOCH3), 2.85 (m, 3H, benzylic
protons), 4.0 (dd, J ϭ 9.2 Hz and 7.2 Hz, 1H, 17␣-H), 5.38
558 Steroids, 1998, vol. 63, November

1
Synthesis, H NMR, and x-ray of 17␤ and 17␣-aminoestrogens: Lemini et al.
Table 2 Atomic Coordinates (ϫ103) and Equivalent Isotropic
Table 2 (Continued)
Thermal Parameters (ϫ102 Å2)
Atom
x/a
y/b
z/c
Ueq
Atom
C14B
x/a
y/b
z/c
Ueq
Compound 2
O1
4917(5)
5925(6)
4734(6)
3092(5)
1895(5)
5629(15)
6073(10)
379(6)
4923(1)
5200(2)
5626(1)
5561(1)
4922(1)
2235(2)
1793(2)
6011(1)
6252(2)
16842(4)
18081(6)
18003(5)
16759(4)
18019(4)
13921(7)
13817(8)
15788(4)
16114(5)
59(1)
82(1)
72(1)
57(1)
61(1)
134(3)
113(2)
62(1)
83(1)
22123(4)
8452(4)
9919(5)
3289(2)
6532(2)
5602(2)
4654(2)
4427(2)
3502(2)
2835(2)
3065(2)
2312(2)
2552(2)
3535(2)
4241(2)
3992(2)
5255(2)
5491(2)
4800(2)
3805(2)
3207(2)
3870(3)
4840(2)
4901(3)
6380(2)
7054(3)
3650(1)
838(1)
Ϫ1(2)
63(1)
60(1)
60(1)
56(1)
59(1)
51(1)
49(1)
46(1)
53(1)
51(1)
45(1)
45(1)
46(1)
55(1)
52(1)
47(1)
47(1)
67(1)
75(1)
54(1)
67(1)
47(1)
64(1)
C15B
C16B
C17B
C18B
C19B
C20B
C21B
C22B
Compound 6
S1
O2
N1
C1
18216(5)
19900(6)
20496(5)
19469(5)
17786(5)
16766(5)
14645(5)
14545(5)
15147(5)
17100(5)
15040(6)
13057(5)
12544(5)
12550(5)
11544(6)
10045(7)
10394(5)
13953(6)
8977(4)
2796(2)
3190(2)
3223(2)
2825(2)
2415(2)
1971(2)
1779(2)
1441(2)
2051(2)
2417(2)
1769(2)
1408(2)
792(2)
C2
C3
C4
C5
Ϫ1346(8)
C6
C7
1304(2)
2074(6)
Ϫ35(8)
5463(1)
4732(2)
5171(3)
5922(2)
Ϫ426(3)
Ϫ1039(3)
Ϫ1617(3)
3349(3)
4042(3)
4042(3)
3371(3)
2665(3)
1943(3)
1175(3)
1348(2)
1899(3)
2655(2)
2081(3)
1310(3)
803(3)
603(2)
Ϫ43(3)
Ϫ497(3)
Ϫ45(3)
1245(3)
5976(3)
6237(3)
6676(3)
6839(3)
6581(4)
6153(3)
7281(4)
5562(1)
5152(1)
6033(2)
5733(2)
7360(2)
7583(2)
7749(3)
6026(2)
5736(2)
5466(2)
5463(2)
5745(2)
5718(2)
5947(2)
6534(2)
6379(2)
6040(2)
6951(2)
7293(2)
7458(2)
6863(2)
7057(3)
7593(2)
7711(2)
7936(2)
5009(2)
5162(2)
4731(3)
4157(3)
4020(3)
4436(2)
3693(3)
54(1)
60(1)
83(1)
87(1)
64(1)
66(1)
107(2)
47(1)
51(1)
46(1)
46(1)
43(1)
51(1)
47(1)
37(1)
39(1)
37(1)
44(1)
48(1)
42(1)
39(1)
57(1)
56(1)
52(1)
57(1)
46(1)
63(2)
67(2)
62(2)
72(2)
63(2)
84(2)
C8
O1
C9
O2
C10
O3
3086(8)
7220(7)
7923(8)
8731(11)
5482(8)
4762(10)
2866(8)
1599(8)
2322(8)
848(8)
C11
N1
C12
N2
C13
N3
C14
1137(2)
529(2)
C1
C15
C2
C16
161(3)
C3
C17
516(2)
C4
C18
125(2)
C5
C19
186(2)
C6
C20
8562(6)
Ϫ437(2)
C7
1880(8)
3097(7)
4983(7)
4220(7)
6308(8)
6973(8)
5086(8)
3898(7)
2287(9)
3399(8)
5516(8)
3720(9)
Ϫ160(8)
Ϫ2141(10)
Ϫ3326(10)
Ϫ2527(11)
Ϫ487(11)
708(9)
Compound 3
O1A
O2A
O3A
N1A
C1A
C2A
C3A
C4A
C5A
C6A
C7A
C8A
C9A
C10A
C11A
C12A
C13A
C14A
C15A
C16A
C17A
C18A
C19A
C20A
C21A
C22A
O1B
O2B
O2BЈ
O3B
N1B
C1B
C2B
C3B
C4B
C5B
C6B
C7B
C8B
C9B
C10B
C11B
C12B
C13B
C8
1531(4)
4641(6)
Ϫ216(5)
Ϫ590(5)
1678(6)
2192(6)
1184(6)
Ϫ282(6)
Ϫ800(5)
Ϫ2451(6)
Ϫ3196(6)
Ϫ1560(5)
Ϫ355(5)
218(5)
9554(1)
9538(1)
5943(1)
6210(1)
8366(1)
8777(2)
9125(1)
9062(1)
8647(1)
8592(1)
8130(1)
7805(1)
7827(1)
8289(1)
7515(1)
7046(1)
7013(1)
7338(1)
7206(2)
6709(2)
6590(1)
7084(2)
9725(2)
10166(2)
5927(1)
5575(2)
2401(2)
2470(3)
2513(4)
6002(1)
5817(1)
3499(2)
3063(2)
2872(2)
3115(2)
3553(1)
3798(2)
4286(2)
4432(1)
4246(1)
3758(1)
4388(2)
4882(1)
5067(1)
7841(3)
8674(6)
9453(3)
77(1)
123(2)
86(1)
59(1)
69(1)
72(1)
67(1)
63(1)
60(1)
72(1)
72(1)
56(1)
57(1)
58(1)
79(1)
72(1)
54(1)
58(1)
84(1)
81(1)
58(1)
78(1)
74(1)
93(1)
64(1)
85(1)
130(2)
188(6)
255(13)
91(1)
58(1)
123(3)
144(3)
110(2)
85(1)
72(1)
97(2)
88(2)
56(1)
63(1)
69(1)
77(1)
72(1)
49(1)
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C21
C22
C23
C24
C25
C26
C27
Compound 8
C11
S1
11621(4)
8221(4)
7840(5)
8287(4)
9083(4)
9457(4)
10334(5)
10336(5)
10616(4)
9381(4)
9036(4)
1355(6)
704(7)
9634(6)
9836(5)
Ϫ559(5)
Ϫ2194(5)
Ϫ3521(7)
Ϫ3313(7)
Ϫ1699(5)
675(7)
3288(7)
3310(8)
117(6)
1352(8)
5010(9)
5509(25)
7062(41)
804(5)
1422(5)
2981(10)
3259(12)
4873(10)
6183(8)
5927(6)
7373(6)
7232(6)
5154(5)
4038(6)
4302(6)
1943(6)
1729(6)
2820(5)
11025(4)
10735(4)
11842(6)
11957(6)
11073(4)
12483(5)
8046(5)
Ϫ3830(12)
7530(1)
Ϫ3471(2)
Ϫ1406(5)
Ϫ4061(5)
Ϫ4268(7)
8613(6)
6490(5)
1303(5)
193(5)
4065(1)
1059(2)
539(4)
1789(6)
Ϫ496(6)
10077(6)
7372(5)
1599(5)
721(6)
1518(6)
3155(6)
4070(5)
5911(6)
6910(6)
5733(5)
4295(5)
3289(5)
3107(5)
4170(5)
5565(5)
6728(5)
8256(7)
8606(7)
6947(5)
4674(8)
2663(7)
7735(1)
5707(1)
5733(1)
5984(1)
5589(1)
7539(1)
7309(1)
6395(1)
6199(1)
5934(1)
5860(1)
6058(1)
5972(1)
6223(1)
6398(1)
6556(1)
6331(1)
6754(1)
6984(1)
6825(1)
6638(1)
6541(1)
6821(1)
7021(1)
6635(1)
5421(1)
60(1)
77(1)
75(1)
89(1)
118(2)
99(1)
51(1)
52(1)
58(1)
58(1)
60(1)
49(1)
64(1)
68(1)
45(1)
44(1)
46(1)
56(1)
55(1)
47(1)
48(1)
79(2)
81(2)
54(1)
79(2)
66(1)
O1
O2
O3
7429(6)
O4
10781(4)
11519(5)
14920(5)
12792(12)
14068(18)
14561(3)
16891(3)
14535(6)
14366(8)
15024(6)
15887(6)
16098(5)
17132(7)
17013(7)
16877(4)
15496(4)
15385(4)
15269(5)
15349(4)
16710(3)
N1
C1
C2
C3
Ϫ300(6)
305(6)
C4
C5
1403(5)
1985(6)
2907(6)
4168(5)
3079(5)
1921(5)
4244(6)
5350(6)
6471(5)
5212(5)
6423(8)
7562(8)
7445(6)
7943(6)
Ϫ3465(6)
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
Steroids, 1998, vol. 63, November 559

Papers
Table 2 (Continued)
Analysis calculated for: C25H29N3O3S (451.57): C, 66.49;
H, 6.47 N, 9.31. Found: C, 66.51; H, 6.46; N, 9.32.
Atom
C20
C21
C22
C23
C24
C25
x/a
y/b
z/c
Ueq
17␣-Amino-1,3,5(10)-estratrien-3-ol (7)
Ϫ3795(8)
Ϫ3791(9)
Ϫ3444(8)
Ϫ3090(8)
Ϫ3091(8)
Ϫ3463(11)
4371(8)
5647(9)
5239(9)
3542(10)
2223(8)
6645(11)
5498(1)
5278(1)
4984(1)
4913(1)
5129(1)
4743(2)
90(2)
100(2)
91(2)
98(2)
85(2)
135(3)
To a solution of 0.500 g (1.11 mmol) of compound 6 in 10
mL of anhydrous tetrahydrofuran, 1 g of lithium aluminum
hydride was added and the reaction mixture stirred for 24 h
at room temperature. After this time, water was added
carefully, as well as a10% solution of hydrochloric acid to
reach a pH of 1. The reaction mixture was extracted with
ethyl ether, and the aqueous phase was made alkaline by
adding a 10% solution of sodium hydroxide. After extrac-
tion with dichloromethane, the organic layer was dried and
evaporated under reduced pressure. The oily residue was
crystallized from methanol to yield 0.057 g (0.21 mmol,
17%) of product 7, 205 C (decomp) m.p. 226–227°C. [␣]D25
ϭ ϩ 50.9° (MeOH). IR (KBr): 3348 and 3283 (O-H, N-H)
cmϪ1.1 H NMR, 300 MHz (CDCl3-DMSO-d6): ␦ 0.75 (s,
3H, 18-CH3), 1.25–2.39 (m, 12H), 2.79 (m, 3H, benzylic
protons), 3.05 (d, J ϭ 7.2 Hz, 1H, 17␤-H), 6.57 (d, J ϭ 2.4
Hz, 1H, H-4), 6.64 (dd, J ϭ 8.1, J ϭ 2.4 Hz, 1H, H-2), 7.10
(d, J ϭ 8.1 Hz, 1H, H-1). MS m/z 271 (Mϩ52.5%), 254
(35%), 213 (33%), 56 (100%). Analysis calculated for:
C18H25NO (271.40): C, 79.66; H, 9.28, N, 5.16. Found: C,
79.68; H, 9.31; N, 5.20.
(d, J ϭ 9.2 Hz, 1H, H-N), 6.78 (d, J ϭ 2.5 Hz 1H, H-4,),
6.83 (dd, J ϭ 2.5 y 8.2 Hz 1H, H-2), 7.28 (d, J ϭ 8.2 Hz 1H,
H-1). MS m/z 355 (Mϩ, 16%), 313 (100%), 254 (20%), 213
(60%), 160 (16%). Analysis calculated for: C22H29NO3
(355.46) C, 74.33; H, 8.22; N, 3.94. Found: C, 74.36; H,
8.17; N, 3.90.
3,17␤-bis(toluene-4-sulfonyloxy)-1,3,5(10)-
estratriene(5)
This compound was prepared from estradiol (4) using re-
ported procedures19–21 and was obtained with 87% yield, as
pale pinkish white needles with m.p. 155–157°C. [␣]2D5 ϭ ϩ
26.9° (CH3CN). IR (KBr): 1372 and 1178 (SO3), cmϪ1. 1H
NMR 200 MHz (CDCl3): ␦ 0.80 (s, 3H, 18-CH3), 1.01–2.23
(m, 12 H), 2.43 (s, 6H, 2 CH3-OTs), 2.74 (m, 3H, benzylic
protons), 4.33 (d,d J ϭ 9.0 Hz and J ϭ 7.7 Hz, 1H, 17␣-H),
6.63 (dd, J ϭ 8.8 y 2.5 Hz, 1H, H-2), 6.72 (d, J ϭ 2.5 Hz,
1H, H-4), 7.14 (d, J ϭ 8.8 Hz, 1H, H-1), 7.29 (d, J ϭ 8.1
Hz, 2H, 17-OTs), 7.31 (d, J ϭ 8.1 Hz, 2H, 17-OTs), 7.71 (d,
J ϭ 8.5 Hz, 2H, 3-OTs), 7.78 (d, J ϭ 8.5 Hz, 2H, 3-OTs,).
MS m/z 580 (Mϩ 100%), 408 (99%), 253 (100%), 91
(95%). Analysis calculated for: C32H36O6S2 (580.75): C,
66.18; H, 6.25. Found: C, 66.15; H, 6.27.
3-(Toluene-4-sulfonyloxy)-17␣-amino-1,3,5(10)-
estratriene hydrochloride (8)
A solution of 0.740 g (1.64 mmol) of compound 6 in
methanol was added to a mixture of 0.24 g of 10% Pd/C in
30 mL of methanol. The mixture was hydrogenated for 2 h,
filtered over celite, washed with ethyl acetate and methanol.
The solvents were evaporated under reduced pressure, and
the solid obtained was crystallized from methanol to give
0.290 g (0.63 mmol yield 39%) of crystals 170–174°C
(decomp). [␣]2D5 ϭ ϩ 35.4° (MeOH). IR (film): 3393 (N-H),
1372 and 1183 (SO3) cmϪ1. 1H NMR 200 MHz (CDCl3): ␦
0.81 (s, 3H, 18-CH3), 1.2–2.38 (m, 12H), 2.42 (s, 3H,
3-OTs), 2.70 (m, 3H, benzylic protons), 3.33 (br, when
exchanged with D2O d, J ϭ 6.2 Hz, 1H, 17␤-H), 6.58 (dd,
J ϭ 8.5 Hz and J ϭ 2.5 Hz, 1H, H-2), 6.72 (d, J ϭ 2.5 Hz,
1H, H-4), 7.0 (d, J ϭ 8.5 Hz, 1H, H-1), 7.30 (d, J ϭ 8.2 Hz,
2H, 3-OTs), 7.71 (d, J ϭ 8.2 Hz, 2H, 3-OTs), 8.32 (br, 3H,
NH2.HCl). MS m/z 425 (Mϩ 65%), 408 (15%), 270
(38.6%), 253 (43.3%), 56 (100%). Analysis calculated for:
C25H32O3NSCl (462.0): C, 64.98; H, 6.98; N, 3.03. Found:
C, 65.16; H, 6.77; N, 3.06.
3-(Toluene-4-sulfonyloxy)-17␣-azido-1,3,5(10)-
estratriene(6)
To a solution of 5 g (8.61 mmol) of compound 5 in 45 mL
of hexamethylphosphoramide (HMPA), 6 g (92.29 mmol)
of sodium azide was added and the mixture heated between
60–70 C for 5 days. The reaction mixture was poured on
ice, the precipitate filtered and dissolved in ethyl acetate,
washed with water, dried and the solvent removed under
reduced pressure below 70 C. The brown oil obtained was
purified by column chromatography (silica gel) using a
mixture 95:5 (v/v) of hexane/ethyl acetate as eluent, obtain-
ing 2.721 g (6.03 mmol, 70% yield) of compound 6. Crys-
tallization from ethyl acetate-methanol produced colorless
hexagonal prisms, m.p. 94–96°C. [␣]2D5 ϭ ϩ 22.2°
(MeOH). IR (film CHCl3): 2098 (N3), 1187 and 1374
(-SO3) cmϪ1. H NMR 200 MHz (CDCl3): ␦ 0.76 (s, 3H,
1
18-CH3), 1.20–2.35 (m, 12H), 2.44 (s, 3H, C3-OTs), 2.77
(m, 3H, benzylic protons), 3.56 (d, J ϭ 6.2 Hz, 1H, 17␤-H),
6.64 (dd, J ϭ 8.4 y 2.5 Hz, 1H, H-2), 6.73 (d, J ϭ 2.5 Hz,
1H, H-4), 7.14 (d, J ϭ 8.4 Hz, 1H, H-1), 7.30 (d, J ϭ 8.0
Hz, 2H, 3-OTs), 7.72 (d, J ϭ 8.0 Hz 2H, 3-OTs). MS m/z
451 (Mϩ, 86.6%), 423 (23%), 268 (100%), 91 (34%).
560 Steroids, 1998, vol. 63, November

1
Synthesis, H NMR, and x-ray of 17␤ and 17␣-aminoestrogens: Lemini et al.
Figure 3 ORTEP-type plot of the 3 molecule. Ellipsoids are drawn at 30% probability level (top molecule a, bottom molecule b).
tallizations from methanol, we were able to obtain com-
pound 1 free from the epimer 7.
Results and discussion
17␤-Amino-1,3,5(10)-estratrien-3-ol (1, Scheme 1) had
been prepared previously by reduction of estrone–hydra-
zone in the presence of Ni/Ra17 and by sodium reduction of
estrone–oxime in n-propanol.1,2,13,16 In our hands, sodium
reduction of estrone–oxime gave, after recrystallization of
Estrone–oxime, under catalytic hydrogenation over Pd/C
in methanol-acetic anhydride medium, produced the 17␤
acetylamine 2. Under prolonged reaction time 3-acetoxy-
1
17␤-acetylamine 3 was obtained. The H NMR spectra of
1
compound 2 showed the C-18 methyl group at 0.74 ppm and
a triplet signal at 3.87 ppm assigned to the 17␣-H. Com-
pound 3 gave the C-18 methyl signal at 0.71 and a quartet
(d,d) centered at 4.00 ppm corresponding to the 17␣-H.
These compounds were purified by recrystallization, obtain-
ing the pure compounds 2, 3 suitable for x-ray analysis.
Synthesis of 17␣-amino-1,3,5(10)-estratrien-3-ol (7) was
performed as outlined in Scheme 2. The di-tosylate 5,
prepared from estradiol in the usual fashion,19–21 was
the crude product, an 8:2 mixture (calculated from its H
NMR spectrum) of epimers 1 and 7. From this mixture, two
signals for the C-18 methyl group were observed: one at
0.68 ppm assigned to the 17␤-amino epimer and the second
at 0.75 ppm assigned to the 17␣-amino epimer. The proton
attached to C-17 in the 17␤-amino appears as a multiplet
centered at 2.78 ppm, whereas the corresponding proton in
the 17␣-amino is shifted to 3.05 ppm as a doublet signal.
The mixture was purified by TLC and, after several recrys-
Steroids, 1998, vol. 63, November 561

Papers
affording 17␣-azide 6. The stereochemistry of 6 was con-
firmed by x-ray analysis. The 17␣-azide 6 was reduced to
the corresponding amine 7 by treatment with LiAlH4 in
THF yielding 17%. When the reduction reaction was carried
out by catalytic hydrogenation (Pd/C in methanol) the
amine 8 was obtained with 39% yield and identified as its
hydrochloride. The 17␤-H of this compound appears as a
doublet signal at 3.33 ppm. Crystals suitable for x-ray
diffraction analysis of compound 6 and 8 were obtained by
slow crystallization in the appropriate solvent (see Experi-
mental).
Comparison of the pure epimers 1 and 7 by their infrared
spectra, TLC behavior (ethyl acetate-chloroform-methanol
8:9:1 v/v), and HPLC gave nearly identical results. Proton
magnetic resonance spectrum displacements of the individ-
ual 17␤-amino and 17␣-amino epimers exhibited C-18 an-
gular methyl group signals as sharp singlets at 0.68 and 0.75
ppm, respectively. It has been reported that, in general, for
the 17-substituted steroids, the 17␣-H (quasi-axial) is found
treated with sodium azide in hexamethylphosphoramide
(HMPA) under reflux. Since the nucleophilic displacement
of tosylate should follow an SN2 mechanism, the azide ion
attacks from the opposite side of the leaving tosylate group
Figure 4 ORTEP-type plot of the 6 molecule. Ellipsoids are drawn at 30% probability level.
Figure 5 ORTEP-type plot of the 8 molecule. Ellipsoids are drawn at 30% probability level.
562 Steroids, 1998, vol. 63, November

1
Synthesis, H NMR, and x-ray of 17␤ and 17␣-aminoestrogens: Lemini et al.
Table 3 Ring Conformations and the Puckering Parameters
Molecule A
Molecule B
2
3
6
8
B-Ring
7␣, 8␤-half-chair
(␾ ϭ 154.1°, Q ϭ
0.374,
7␣, 8␤-half-chair
(␾ ϭ 155.3°, Q ϭ
0.337, ␪ ϭ 48.0°)
7␣ 8␤-half-chair
(␾ ϭ 161.2°, Q ϭ
0.345, ␪ ϭ 45.3°)
7␣, 8␤-half-chair
(␾ ϭ 160.4°, Q ϭ
0.341, ␪ ϭ 51.1°)
intermediate
between 7␣, 8␤-
half-chair and
8␤-envelope
(␾ ϭ 166.0°, Q ϭ
0.329, ␪ ϭ 50.5°)
chair
(␾ ϭ 267.4°, Q ϭ
0.579, ␪ ϭ 3.2°)
intermediate
between 13␤-
envelope and
13␤, 14␣-half
chair
␪ ϭ 44.3°)
C-Ring
D-Ring
chair
chair
chair
chair
(␾ ϭ 276.4°, Q ϭ
0.577, ␪ ϭ 6.3°)
13␤-envelope
(␾ ϭ 186.6°, Q ϭ
0.470)
(␾ ϭ 5.1°, Q ϭ
0.578, ␪ ϭ 3.2°)
13␤-envelope
(␾ ϭ 188.9°, Q ϭ
0.471)
(␾ ϭ 305.2°, Q ϭ
0.565, ␪ ϭ 3.2°)
13␤-envelope
(␾ ϭ 181.6°, Q ϭ
0.471)
(␾ ϭ 268.9°, Q ϭ
0.582, ␪ ϭ 4.8°)
13␤-envelope
(␾ ϭ 185.3°, Q ϭ
0.453)
(␾ ϭ 204.6°, Q ϭ
0.453)
at a higher field as a triplet signal, whereas the one corre-
sponding to 17␤-H (quasi-equatorial) appeared as a dou-
blet.22 In our spectrum the 17␣-H of the 17␤-amino epimer
1 could not be observed, since it appeared together with the
benzylic protons as a multiplet centered at 2.78 ppm (Figure
1a). Other authors have described this proton as a triplet
centered at 2.60 ppm16 without mentioning the correspond-
Table 1. All the structures were solved by direct methods
(SIR92)23 and refined with all non-hydrogen atoms having
anisotropic temperature factors (SHELXL93).24 Hydrogen
atoms attached to carbon atoms were put at geometrical
positions and forced to ride on their carbons, hydrogen
atoms attached to a heteroatom were located on a difference
Fourier map and their positional parameters refined; in both
conditions an isotropic temperature factor 1.2 times the Ueq
of the parent atoms was assumed.
The final coordinates and equivalent isotropic parame-
ters for the non-H atoms of 2, 3, 6, and 8 are reported on
Table 2.25 The molecular conformations and atomic labeling
schemes for 2, 3, 6, and 8 are shown in Figures 2–5,
respectively, which also depict the spatial arrangement of
the substituents at the chiral center C-17.
Compound 3 crystallized with two chemically similar
but crystallographically different molecules (labeled a and
b) forming “dimers” connected by hydrogen bonds between
the amide groups. Compound 8 crystallized as the amine
hydrochloride monohydrate, with nitrogen in the ammo-
nium form. All bond lengths and bond angles of the four
compounds correlate well with the average values observed
for 1,3,5(10)-estratriene.26 Amide resonance in compounds
2 and 3 (a and b) is evident from the values (1.326(4),
1.321(5), and 1.333(5) Å) of the lengths of NOC(AO)
bonds and a planar hybridization of nitrogen atom (the sums
1
ing signals for the benzylic protons. However, in the H
NMR spectrum of the hydrochloride of 1, the 17␣-H could
be observed as a broad signal shifted at 3.00 ppm separated
from the benzylic protons. When the spectrum of 1 was
determined in C6D6, part of the signal was shifted to a
higher field; and the 17␣-H could be observed as a triplet at
2.57 ppm J ϭ 8.7 Hz (Figure 1b). For the 17␣-amino
epimer 7, 17␤-H appeared as a well-defined doublet cen-
tered a 3.05 ppm with a coupling constant of 7.2 Hz due to
the interaction with a proton in C-16 (Figure 1c). To con-
firm the stereochemistry of the 17␣-amino epimer 7, a NOE
DIF experiment was performed. The doublet signal centered
at 3.05 ppm was irradiated and the signal corresponding to
the methyl group at 0.75 ppm was observed.
Crystallographic studies
X-ray experiments were performed using a Siemens P4/PC
four-circle diffractometer equipped with graphite mono-
chromatized CuK␣ radiation; details are summarized in
Figure 6 Least-square fit of the A rings of crystal structures determined in this work.
Steroids, 1998, vol. 63, November 563

Papers
hydroxypropyl amine, a novel amino-estrogen. Steroids 45:159–
170.
of the bond angles around N are 359.9, 359.9 and 359.3° for
2 and 3 (a and b), respectively. The p-tosyl group in 6
adopts a fully extended conformation (dihedral angle C3-
O1-S1-C21: Ϫ163.3(4)°), whereas the same group in com-
pound 8 is twisted toward the C4 carbon atom (dihedral
angle C3-O1-S1-C21: 88.8(4)°). In both conditions, the
plane of the phenyl group in this moiety bisects the angle
subtended by O1-S1-O3.
7.
Rubio–Po´o C, Lemini C, Garc´ıa–Mondrago´n J, de la Pen˜a A, Jayme
V, Mendoza–Patin˜o N, Zavala E, Silva G, Blickenstaff RT, Fernan-
dez–G JM, Mandoki JJ (1990). The anticoagulant effect of hexo-
lame, N-(3-hydroxy-1,3,5(10)-estratrien-17␤-yl)-6-hydroxyhexyla-
mine, another amino-estrogen with prolonged anticoagulant effect.
Steroids 55:83–86.
Mandoki JJ, Rubio–Po´o C, Lemini C, De la Pen˜a A, Ferna´ndez-G
JM, Garc´ıa–Mondrago´n J, Zavala E, Silva G, Mendoza–Patin˜o N
(1991). The effects of five new 17␤-amino-estrogens, buame, en-
diame, etolame, picae, and proacame on blood clotting time. Proc
West Pharmacol Soc 34:99–106.
Lemini C, Rubio–Po´o C, Silva G, Garc´ıa–Mondrago´n J, Zavala E,
Mendoza–Patin˜o N, Castro D, Cruz–Almanza R, Mandoki JJ
(1993). Anticoagulant and estrogenic effects of two new 17␤-
aminoestrogens, butolame [17␤-(4-hydroxy-1-butylamino)-1,3,5(10)-
estratrien-3-ol] and pentolame [17␤-(5-hydroxy-1-pentylamino)-
1,3,5(10)-estratrien-3-ol]. Steroids 58:457–461.
Rubio–Po´o C, Lemini C, Silva G, Cha´vez–Lara B, Mendoza–Patin˜o
N, Ort´ız R, Mandoki JJ (1997). Effects of 17␤-(N,N-
diethylaminoethyl)amino-1,3,5(10)-estratrien-3-ol, and its andro-
stane analog on blood clotting time. Med Chem Res 7:67–75.
Mandoki JJ, Zavala E, Silva G, Mendoza–Patin˜o N, Rubio–Po´o C,
Medina–Mart´ınez S, Dom´ınguez–Escoto P (1983). The dual effects
of estrogens on blood clotting time. Proc West Pharmacol Soc
26:45–48.
8.
9.
Table 3 presents the conformations and the puckering
parameters27 for rings B, C, and D of each molecule, they
are similar but not identical as can be seen in Figure 6. An
8␤, 9␣-half-chair conformation has been found for ring B of
all molecules studied, although an increasing flattening at
C7 is observed going from compound 2 to compound 8, so
the latter can be described as intermediate between half-
chair and sofa conformations. The distorted chair confor-
mation of ring C found in all four compounds presents a
different direction of the distortion (phase angle ␾, 5.1 and
305.2°) for both molecules of compound 3. Four of the five
molecules, determined in this work, show the 13␤-envelope
conformation of ring D, whereas the steroid molecule in
compound 8 is intermediate between the 13␤-envelope and
the 13␤, 14␣-half-chair conformations.
10.
11.
12.
13.
14.
15.
Goodfriend L, Sehon AH, (1958). Preparation of an estrone-protein
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Weeler OH, Reyes–Zamora C (1969). Steroid derivatives of cys-
teamine and cysteine. Can J Chem 47:160–163.
Regan BM, Hayes N (1956). 17- And 17a-Aza-D-homosteroids
J Am Chem Soc 78:639–643.
The data presented for 1H NMR spectra of compounds 1
and 7 and the determination of the crystal structure of
compounds 2, 3, 6, and 8 enabled us to characterize the
structure of the 17␣ and 17␤ aminoepimers 1 and 7 for the
first time. Pharmacological evaluation of the compounds
synthesized here is in progress.
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Hecker E, Farthofer
G (1963). Ostrogene und antio¨strogene
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Chavis C, de Gourcy Ch, Borgna JL Imbach JL (1982). New
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This work was supported by grants IN205396 from
DGAPA-UNAM and 2400PM from CONACYT, Mexico.
We are indebted to R. Patin˜o, L. Velasco, J. Pe´rez-Flores, R.
Gavin˜o, S. Herna´ndez and B. Quiroz for obtaining the IR,
RMN, MS spectra, and x-ray analysis.
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