Synthesis of 17α-amino-5α-androst-2-ene from epiandrosterone

Article abstract of DOI:10.1007/s10600-006-0108-4

17α-Amino-5ga-androst-2-ene was synthesized from epiandrosterone via formation of the tosylate followed by nucleophilic substitution by azide and reduction with LiAlH₄. The structures of the products were proved by NMR and IR spectroscopy and mass spectrometry. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-006-0108-4

Chemistry of Natural Compounds, Vol. 42, No. 3, 2006
SYNTHESIS OF 17
α-AMINO-5α-ANDROST-2-ENE FROM
EPIANDROSTERONE
M. I. Merlani,1 L. Sh. Amiranashvili,1 E. P. Kemertelidze,1
K. Papadopulos,2 and E. Yannakopulu2
UDC 547.92
17α-Amino-5α-androst-2-ene was synthesized from epiandrosterone via formation of the tosylate followed
by nucleophilic substitution by azide and reduction with LiAlH . The structures of the products were proved
4
by NMR and IR spectroscopy and mass spectrometry.
Key words: aminosteroids, synthesis.
Steroidal compounds with NH -, N-alkyl-, N-alkyloxy-, and N,N′-dialkyl-substituents in the C-17 position exhhibit a
2
broad spectrum of biological activity[1-5]. Among these compounds, amines of the 5α-androstane series are also encountered.
However, the biological activity of 17-amino-5α-androst-2-ene and its derivatives has not been reported.
We have previously reported the preparation of a mixture of epimers of 17β- and 17α-amino-5α-androst-2-ene as
intermediates in the synthesis of 17β-amino-5α-androstane, a compound known to have anti-inflammatory and fungicidal
activity [1]. Because crystallization of the mixture of epimers formed upon reduction of 17-hydroxyimino-5α-androst-2-ene
or 17β-formamido-5α-androst-2-ene could isolate only the 17β-epimer in 60% yield, we developed a scheme for preparing
17α-amino-5α-androst-2-ene (1) using epiandrosterone that provides for the stereoselective synthesis of this epimer
(Scheme 1).
OH
OTs
O
H
H
3
4
5
H
H
N
3
NH
2
6
1
Scheme 1. Synthesis of 17α-amino-5α-androst-2-ene from epiandrosterone.
Epiandrosterone (2) was transformed to 5α-androst-2-ene-17-one (3) by the previously described method [6]. Ketone
(3) was reduced using NaBH in CH OH to give stereospecifically 17β-hydroxy-5α-androst-2-ene (4), reaction of which with
4
3
p-toluenesulfonyl chloride in anhydrous pyridine gave 17β-(4-methylphenylsulfonyloxy)-5α-androst-2-ene (5). We used the
Streitweiser—Shaeffer method, which provides for nucleophilic substitution ofthe 17β-tosyloxygroup byazide through an S 2
N
1) I. G. Kutatelazde Institute ofPharmaceutical Chemistry, AcademyofSciences ofGeorgia, Tbilisi, 0159, fax (99532)
25 00 26, e-mail: maiamer@mail.ru; 2) Institute of Physical Chemistry, National Scientific Research Center Demokritos,
Athens, Greece. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 257-258, May-June, 2006. Original article
submitted March 2, 2006.
0009-3130/06/4203-0313 ©2006 Springer Science+Business Media, Inc.
313

mechanism, to invert the configuration at C-17 [7]. This method was modified by carrying out the substitution reaction using
NaN in DMF containing water (10%) at 105-110°C instead of N-methyl-2-pyrrolidone at 150°C. This formed over 48 h an
3
oily mixture, chromatography of which over a silica-gel column isolated 17α-azido-5α-androst-2-ene (6) in 80% yield. Then
reduction of azide (6) by an excess of LiAlH in THF led to the target 17α-amino-5α-androst-2-ene (1) in 80% yield. Using
4
LiAlH to reduce the azide gives selective reduction that does not involve the C2–C3 double bond.
4
Thus, we performed a stereoselective transformation of 2 into 1 using a modified Streitweiser—Schaeffer method.
The structures of the synthesized compounds were confirmed by NMR and IR spectroscopy and mass spectrometry.
-1
The IR spectra exhibit characteristic absorption bands for the functional groups. Strong absorptions at 1372 and 1182 cm in
-1
5 were assigned to tosyl SO stretching vibrations; at 2098 cm , to the azide of 6. The NH stretches of 1 appeared near
3459 cm .
2
2
-1
The PMR spectra of 1, 5, and 6 contained signals for C-10 and C-13 methyls as singlets with chemical shifts in the
range δ 0.74-0.88 ppm. A doublet at δ 3.33-3.55 ppm with SSCC J = 6.2 Hz corresponds to the 17β-proton in 6 and 1. Signals
for vicinal protons of the C2–C3 double bond of 1, 5, and 6 appeared as a distorted triplet at δ 5.59 ppm with SSCC J = 6.8 Hz.
13
The C NMR spectra of1, 5, and 6 had signals for C-18 and C-19 at δ 11.67-11.89 and 14.07-20.28 ppm, respectively;
for the C C bond of 1, 5, and 6, at δ 125.8 ppm; for tosylate C–O of 5, at δ 90.04 ppm; for C–N of 6, at δ 71.64 ppm; and for
3
C–NH of 1, at δ 60.11 ppm.
2
The mass spectra of 1, 5, and 6 exhibited peaks for the molecular ions corresponding to the molecular weights of these
+
+
+
compounds at 274 [M + 1] , 428 [M] , and 300 [M + 1] , respectively.
The biological activity of 1 and its 17β-epimer is being studied.
EXPERIMENTAL
Melting points were determined on a Gallenkamp block and are uncorrected. IRspectra were recorded on a Magna-IR
spectrometer 550 in KBr disks. Mass spectra were recorded in a Finnigan AQA Navigator instrument (EI, 70 eV). NMR
1
13
spectra were obtained on a Bruker AC 500 instrument (500 MHz working frequency for H and 125 MHz for C). Chemical
shifts of protons are given on the δ (ppm) scale with TMS internal standard and DMSO-d and CDCl solvents. Elemental
6
3
analyses were found on a Perkin—Elmer CHN 2004. Analyses of all compounds corresponded with those calculated. The
course of reactions and purity of products were monitored by TLC on Silufol 254 plates (Kavalier, Czech Rep.) using
CHCl :CH OH(15:1). Spots were developed byspraying with phosphomolybdic acid (10%) in ethanol and subsequent heating.
3
3
17β-Hydroxy-5α-androst-2-ene (4). A solution of3 (2 g, 7.3 mmol) in CH OH(20mL) at 0°C was treated in portions
3
with NaBH (0.4 g, 10.5 mmol), stirred at 20 C for 1 h, treated with acetic acid (2 mL), and poured into water (100 mL).
4
The precipitate was filtered offand washed with water. Recrystallization from CH OH afforded 4 (1.81 g, 90%), mp 161-162°C
3
-1
(lit. [8] mp 163°C), IR spectrum (ν, cm ): 3455 (OH).
17β-(4-Methylphenylsulfonyloxy)-5α-androst-2-ene (5). Asolution of4(1g, 3.64mmol)in freshlydistilledpyridine
(20 mL) at 0°C was treated in portions with p-toluenesulfonyl chloride (1.4 g, 7.28 mmol), held at 0°C for 48 h, and poured
into icewater (100 mL). The precipitate was filtered off and washed with water. Recrystallization from benzene:hexane (1:4)
-1
+
afforded 5 (1.42 g, 85%), mp 96-98°C. IRspectrum (ν, cm ): 1372 and 1182 (SO ). Mass spectrum (m/z, I , %): 482 (5) [M] ,
2
rel
257 (100).
PMR spectrum (δ, ppm, J/Hz): 0.74 (3H, s, CH -18), 0.81 (3H, s, CH -19), 2.46 (3H, s, CH -OTs), 4.30 (1H, dd,
3
3
3
J = 9.0, 7.7, H-17α), 5.59 (2H, dist. t, J = 6.8, H-2, H-3), 7.33 (2H, d, J = 8.2, OTs-17), 7.80 (2H, d, J = 8.2, OTs-17).
13
C NMR spectrum (δ, ppm): 11.89 (C-18), 20.28 (C-19), 23.21 (CH -OTs), 90.04 (C-17), 125.8 (C-2, C-3), 127.80,
3
129.60, 134.54, and 144.55 (C-arom.).
17α-Azido-5α-androst-2-ene (6). A mixture of 5 (1.5 g, 3.49 mmol), NaN (1.5 g, 23.8 mmol), DMF (30 mL), and
3
water (3 mL) was heated at 105-110°C for 48 h, cooled to 20°C, and poured into icewater (100 mL). The resulting oilyproduct
was chromatographed over a column (silica gel L 100/160, eluent petroleum ether:ethylacetate, 50:1) toisolate6, (0.83 g, 80%),
-1
+
mp 58-60°C. IR spectrum (ν, cm ): 2098 (N ). Mass spectrum (m/z, I , %): 300 (5) [M + 1] , 272 (100).
3
rel
PMR spectrum (δ, ppm, J/Hz): 0.76 (3H, s, CH -18), 0.87 (3H, s, CH -19), 3.55 (1H, d, J = 6.87, H-17β), 5.59 (2H,
3
3
13
dist. t, J = 6.8, H-2, H-3). C NMR spectrum (δ, ppm): 11.67 (C-18), 17.71 (C-19), 71.64 (C-17), 125.8 (C-2, C-3).
17α-Amino-5α-androst-2-ene (1). A suspension of LiAlH (1.5 g, 39.47 mmol) in THF (100 mL) at 20°C was treated
4
314

with 6 (1.5 g, 5.0 mmol) in THF (20 mL) and boiled for 6 h. The excess of LiAlH was destroyed by adding water (1.5 mL),
4
aqueous NaOH (1.5 mL, 15%), and water again (4.5 mL). The reaction mixture was filtered. The precipitate was washed with
THF (3 × 30 mL). The mother liquor was acidified with HCl until the pH was 2. The solvent was removed in vacuo. The solid
dissolved with heating in water (200 mL). The solution was filtered. The precipitate that formed when the mother liquor was
made basic (NaOH to pH 8) was separated by filtration. Crystallization from benzene:hexane (1:2) afforded 1 (1.09 g, 80%),
-1
+
mp 138-140°C. IR spectrum (ν, cm ): 3459 (NH). Mass spectrum (m/z, I , %): 274 (15) [M + 1] , 257 (100).
rel
PMR spectrum (δ, ppm, J/Hz): 0.84 (3H, s, CH -18), 0.88 (3H, s, CH -19), 3.33 (1H, br.d, J = 6.2, H-17β), 5.59 (2H,
3
3
13
dist. t, J = 6.8, H-2, H-3). C NMR spectrum (δ, ppm): 11.73 (C-18), 14.07 (C-19), 60.11 (C-17), 125.83 (C-2, C-3).
ACKNOWLEDGMENT
The work was supported by grant NATO FEL.RIG 987703. We thank Dr. Leondios Leondiadis, Head of the Mass
Spectrometry Laboratory, National Scientific Research Center Demokritos, for his work.
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