Convenient stereoselective synthesis of some 3-aminosteroid scaffolds

Article abstract of DOI:10.1080/00397911.2019.1590602

An efficient stereoselective synthesis 3α- and 3β-aminoandrostan-17-one and 3α-amino dehydroepiandrosten-17-one based on a Mitsunobu reaction has been developed, using azide as the ammonia equivalent. All the products were isolated in high yield.

Full text of DOI:10.1080/00397911.2019.1590602

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Convenient stereoselective synthesis of some 3-
aminosteroid scaffolds
Eirik Johansson Solum & Yasser Mahmoud A. Mohamed
To cite this article: Eirik Johansson Solum & Yasser Mahmoud A. Mohamed (2019): Convenient
stereoselective synthesis of some 3-aminosteroid scaffolds, Synthetic Communications, DOI:
10.1080/00397911.2019.1590602
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https://doi.org/10.1080/00397911.2019.1590602
Convenient stereoselective synthesis of some
3-aminosteroid scaffolds
Eirik Johansson Soluma and Yasser Mahmoud A. Mohamedb
b
aFaculty of Health Sciences, NORD University, Namsos, Norway; Photochemistry Department, National
Research Center, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 4 January 2019
An efficient stereoselective synthesis 3a- and 3b-aminoandrostan-17-
one and 3a-amino dehydroepiandrosten-17-one based on
a
Mitsunobu reaction has been developed, using azide as the ammo-
nia equivalent. All the products were isolated in high yield.
KEYWORDS
Aminosteroids; Staudinger
reaction;
GRAPHICAL ABSTRACT
Mitsunobu reaction
Introduction
Steroids and steroid-like molecules are an important class of biologically active com-
pounds, essential for the control of a variety of biological responses. One class of ste-
roids, the aminosteroids have gained considerable attention lately.[1] Compounds within
this class have shown great therapeutic potential both as anticancer, anti-angiogeneic,
anti-inflammatory, antimicrobial agents as well as neuromuscular blocking agents, see
Figure 1.[1–4] Furthermore, several natural products of this class have both been synthe-
sized and isolated from a variety of natural sources.[5,6] Many different approaches have
been utilized for the introduction of a 3-amino group at the steroidal skeleton. However,
disadvantages like lack of stereoselectivity and the use of protecting groups have resulted
in a low overall yield. The classical approach with the reduction of the corresponding
3-oximes with reducing reagents such as LiAlH4 or catalytic hydrogenation does not pro-
ceed in a stereospecific manner because the lack of facial selectivity exhibited by the
reducing agent.[7,8] The LiAlH4 reduction of a 3-oxime provided a 6:1 diastereomeric
mixture of the corresponding 3b- and 3a-aminosteroids, and PtO2-mediated reduction
CONTACT Eirik Johansson Solum
eirik.j.solum@nord.no
Faculty of Health Sciences, NORD University, 7800
Namsos, Norway.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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E. J. SOLUM AND Y. M. A. MOHAMED
Scheme 1. One pot synthesis of 3a-aminoandrostan-17-one (6). Reagents and conditions: (i) PPh3,
DIAD, DPPA, THF. (ii) P(CH3)3, 1M NaOH, THF. 69% overall yield.
of the same material gave a 1:1 mixture.[7] Furthermore, a sodium metal mediated oxime
reduction in iso-propanol of a 3-ketosteroid provided a 2:1 diastereomeric mixture of the
corresponding 3b:3a aminosteroids.[1b,4]
A more recent approach is by the use of Mitsunobu chemistry. With this approach
phtalimide, 2-nitrobenzenesulfonyl and azide acted as equivalents of the amino group.
In the published procedures, the ketone groups in 17–position of the steroids are either
protected as the acetal or not present in the molecule.[3,5a,9] In the procedure presented
in this study, it is demonstrated that the synthesis of 3-aminosteroids can be accom-
plished without recourse to protection of the ketone, and the OH group at 3-position
can easily be converted to the corresponding amine by a simple procedure. Within this
work we describe the stereoselective synthesis of 3a- and 3b-amino-5a-androstan-17-
ones (6 and 9) and 3-aminoandrost-5-en-17-one (11) using an azide based Mitsunobu-
Staudinger reaction sequence. The stereochemistry of the synthesized compounds was
1
verified by comparison with the reported H NMR data in the literature.[7–9]
Results and discussion
In the first set of experiments, the synthetic approach for the synthesis of 3a-amino-5a-
androstan-17-one (6) was initiated through a Mitsunobu reaction, using trimethylphos-
phine, diisopropyl azidocarboxylate (DIAD), and diphenylphosphorylazide (DPPA) as
the amine equivalent. A Staudinger reaction was then employed to transform the pre-
pared azide to the desired steroidal amine through a one-pot methodology. Using the
reactive trimethylphosphine as the reducing agent in the Staudinger reaction, the phos-
phor-nitrogen bond cleavage proceeds under mild conditions. Furthermore, the formed
trimethylphosphonium oxide is water-soluble and easily removed during the work up of
the reaction.[10] The 3a-amino-5a-androstan-17-one (6) was isolated in 69% yield (see
Scheme 1).
In the second set of experiments, the synthesis of the corresponding 3b-amino-5a-
androstan-17-one (9) was conducted as depicted in Scheme 2. 3b-hydroxyandrostane
(5) was subjected to a Mitsunobu reaction with benzoic acid, inverting the stereochem-
istry of the 3-hydroxy group cleanly to afford the benzoate (7) in 74% yield. It is worth
to note that the benzoate precipitated from the reaction mixture as it formed and was
subsequently collected by filtration as a single diastereoisomer with high chemical purity
(>98%) using NMR analysis. Subsequent sodium methoxide mediated cleavage of the
ester provided the 3a-hydroxyandrostane (8) as a single diastereoisomer. The amine

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3
Scheme 2. Synthesis of 3b -aminoadrostan-17-one (9). Reagents and conditions: (i) PPh3, DIAD, ben-
zoicacid, THF, 74% yield. (ii) MeONa/MeOH, MeOH, DCM, 65% yield. (iii) PPh3, DIAD, DPPA, THF.
(iv) P(CH3)3, 1M NaOH, THF.
Scheme 3. One pot synthesis of 3a-aminoandrost-5-en-17-one (11). Reagents and conditions: (i)
PPh3, DIAD, DPPA, THF. (ii) P(CH3)3, 1M NaOH, THF. Compound 11 was isolated in 63% overall yield.
was then introduced using the described Mitsunobu–Staudinger sequence. The chemical
purity of compound 9 was >98% using NMR analysis, and no evidence of the 3a-dia-
stereoisomer in the isolated product. The isolated yield for this reaction was in the
same range as described above.
In a final set of experiments, the preparation of 3a-aminoadrosten-17-one (11) from
compound (10) was performed in one-pot procedure (Scheme 3). This class of steroids
had been reported to undergo an allylic rearrangement, along with the desired activa-
tion of the OH-group, upon treatment with triphenylphosphine.[11] The rearranged
byproducts were hard to remove during work up, especially with the amines masked as
either azide, phtalimide, or any other chemical group with no hydrogen bond donor
properties. However, in this report, the adduct (11) was easily isolated from reaction
mixture with a simple chromatographic separation.
Experimental
General
All reagents and solvents were used as purchased without further purification unless
stated otherwise. Melting points are uncorrected. Analytical TLC was performed using
silica gel 60 F254 aluminum plates (Merck). Flash column chromatography was per-
formed on silica gel 60 (40–63 mm) produced by Merck. NMR spectra were recorded
on a Bruker Avance DPX-300 MHz, DPX-400 MHz, or DPX-600 MHz spectrometer for
1 H NMR, and 75 MHz, 101 MHz or 151 MHz for 13C NMR. Coupling constants (J) are
reported in Hertz, and chemical shifts are reported in parts per million relative to
1
CDCl3 residual protio-solvent (7.26 ppm for H and 77.0 ppm for 13C). Mass spectra
were recorded at 70 eV with Fison’s VG Pro spectrometer. High-resolution mass spectra

4
E. J. SOLUM AND Y. M. A. MOHAMED
Figure 1. Structure of some biologically active 3-aminosteroidal compounds.
were performed with a VG Prospec mass spectrometer and with a Micromass Q-TOF-
2TM. The HPLC analyses were performed on an Agilent Technologies 1200 Series
instrument with an Eclipse XDB-C18 (5 mm 4.6 # 150 mm) column. Optical rotations
were measured using a 1 ml cell with 1.0 dm path length on Perkin-Elmer 341 polarim-
eter in dedicated solvent. Protocols for the preparation, physical and spectral data of the
prepared compounds are presented in the ESI.
General procedure for the conversion of steroidal 3-OH-group to a 3-amino group
To a solution of triphenyl phosphine (2.89 g, 11.0 mmol, 1.1 equiv.) in THF (100 mL),
diethyl azodicarboxylate (2.4 mL, 12.0 mmol, 1.2 equiv.) was added at 0 ꢀC. The solution
was stirred for 15 min, and then the steroid (10.0 mmol, 1.0 equiv.) was added. After
additional 10 min stirring, diphenylphosphoryl azide (2.8 mL, 13.0 mmol, 1.3 equiv.) was
added. The reaction mixture was allowed to warm to room temperature. After 12 h
sodium hydroxide solution (1.0 N, 50 mL) was added, and the reaction was stirred for
10 min. Then, a 1.0N solution of trimethylphosphine in tetrahydrofuran (30.0 mL,
30 mmol, 3 equiv.) was added, and the reaction was allowed to stir for additional 3 h.
Upon completion, the reaction mixture was poured into sodium hydroxide solution
(0.1 N, 50 mL) and extracted with dichloromethane (5 ꢁ 50 mL). The combined organic
extracts were washed with saturated aqueous sodium chloride solution (20 mL), and the
organic phase was dried over sodium sulfate. The dried solution was filtered and the fil-
trate was concentrated. The residue was purified using flash-column chromatography
(10% MeOH in dichloromethane on SiO2).

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Conclusion
A novel one-pot synthetic approach that was capable of providing 3a- and 3b-amino-
5a-androstan-17-ones (6 and 9) as well as 3a-aminoandrost-5-en-17-one (11) as single
diastereoisomers was developed. The methodology was successfully applied on a multi-
gram scale and the compounds were isolated in good overall yields. The key stage in
this procedure was the azide based Mitsunobu reaction and the trimethylphosphine
mediated Staudinger reduction. The chemical purity of the compounds was determined
1
to be > 98% by H NMR analysis and the diastereoselectivity was verified by compari-
1
son with the reported H NMR data in the literature as well as optical rotation, see sup-
plementary material.[7–9] In contrast to previously reported methods for the synthesis of
3-aminosteroid scaffolds, no use of protection groups was required. The methodology
was also successfully applied on didehydroepiandrostenone (10), containing, in this
regard, a problematic D5-double bond, which further consolidates the efficiency and
novelty of the methodology.
Acknowledgment
The authors are grateful to and NORD University (Norway) and to the National Research Center
(Egypt) for providing the facilities.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
[1] (a) Mousseau, G.; Clementz, Mark A.; Bakeman, Wendy N.; Nagarsheth, N.; Cameron,
M.; Shi, J.; Baran, P.; Fromentin, R.; Chomont, N.; Valente, Susana T. An analog of the
natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcrip-
tion. Cell Host Microbe. 2012, 12, 97–108. DOI: 10.1016/j.chom.2012.05.016. (b) Khan,
S. N.; Kim, B. J.; Kim, H.-S. Synthesis and antimicrobial activity of 7-fluoro-3-aminoste-
roids. Bioorganic Med. Chem. Lett. 2007, 17, 5139–5142. DOI: 10.1016/j.bmcl.2007.07.001.
(c) Krieg, R.; Jortzik, E.; Goetz, A.-A.; Blandin, S.; Wittlin, S.; Elhabiri, M.; Rahbari, M.;
Nuryyeva, S.; Voigt, K.; Dahse, H.-M.; et al. Arylmethylamino steroids as antiparasitic
agents. Nat. Comms. 2017, 8, 14478–14478. DOI: 10.1038/ncomms14478.
[2] Solum, E. J.; Cheng, J.-J.; Sylte, I.; Vik, A.; Hansen, T. V. Synthesis, biological evaluation
and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol:
potent inhibitors of angiogenesis. RSC Adv. 2015, 5, 32497–32504. DOI: 10.1039/
C5RA03570H.
ꢀ
€
[3] Czako, B.; KuRti, L. s.; Mammoto, A.; Ingber, D. E.; Corey, E. J. Discovery of Potent and
Practical Antiangiogenic Agents Inspired by Cortistatin A. J. Am. Chem. Soc. 2009, 131,
9014–9019. DOI: 10.1021/ja902601e.
[4] Docherty, J. R.; McGrath, J. C. Sympathomimetic effects of pancuronium bromide on the
cardiovascular system of the pithed rat: a comparison with the effects of drugs blocking
the neuronal uptake of noradrenaline. Br. J. Pharmacol. 1978, 64, 589–599. DOI: 10.1111/
j.1476-5381.1978.tb17321.x.
[5] (a) Gans, M.; Bracher, F. First total synthesis of the marine steroid alkaloid plakinamine
B. Tetrahedron 2014, 70, 1084–1090. DOI: 10.1016/j.tet.2013.11.065. (b) Nicolaou, K. C.;
Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y. K. Total Synthesis of (þ)-Cortistatin A.

6
E. J. SOLUM AND Y. M. A. MOHAMED
Angew. Chem. 2008, 120, 7420–7423. DOI: 10.1002/ange.200803550. (c) Shenvi, R. A.;
Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. Scalable Synthesis of Cortistatin A and
Related Structures. J. Am. Chem. Soc. 2008, 130, 7241–7243. DOI: 10.1021/ja202103e.
[6] Watanabe, Y.; Aoki, S.; Tanabe, D.; Setiawan, A.; Kobayashi, M. Cortistatins E, F, G, and
H, four novel steroidal alkaloids from marine sponge Corticium simplex. Tetrahedron
2007, 63, 4074–4079. DOI: 10.1016/j.tet.2007.02.112.
ꢀꢁ
[7] Matyas, L.; Kasal, A.; Riera, Z. B.; Sunol, C. E. Effects of 3a-Amino-5a-pregnan-20-one on
GABAA Receptor: Synthesis, Activity and Cytotoxicity. Collect. Czech. Chem. Commun.
2004, 69, 1506–1516. DOI: 10.1135/cccc20041506.
€
ꢀ
[8] Reyes, M.; Rosado, A.; Alvarez, Y. M.; Ruiz, J. A.; Aguero, J.; Velez, H. Synthesis of
3b-Amino-5a-androstan-17-one from Epiandrosterone. J. Chem. Res. (S) 2003, 4,
234–235. DOI: 10.3184/030823403103173615.
[9] Hitchin, J. R.; Hamilton, N. M.; Jordan, A. M.; Lyons, A. J.; Ogilvie, D. J. A novel scalable
and stereospecific synthesis of 3a- and 3b-amino-5a-androstan-17-ones and 3a- and
3b-amino-5a-pregnan-20-ones. Tetrahedron Lett. 2012, 53, 2868–2872. DOI: 10.1016/
j.tetlet.2012.03.124.
ꢀ
[10] (a) Ariza, X.; Urpı, F.; Viladomat, C.; Vilarrasa, J. One-pot conversion of azides to Boc-
protected amines with trimethylphosphine and Boc-ON. Tetrahedron Lett. 1998, 39,
ꢀ
9101–9102. DOI: 10.1016/S0040-4039(98)02006-1. (b) Ariza, X.; Urpı, F.; Vilarrasa, J. A
practical procedure for the preparation of carbamates from azides. Tetrahedron Lett. 1999,
40, 7515–7517. DOI: 10.1016/S0040-4039(99)01449-5.
[11] Hanson, J. R.; Hitchcock, P. B.; Reese, P. B.; Truneh, A. Steroidal allylic and homoallylic
rearrangements during halogenation with triphenylphosphine and carbon tetrachloride.
J. Chem. Soc, Perkin Trans. 1 1988, 1469–1472. DOI: 10.1039/p19880001469.