Synthesis of novel pregnane-based 20-carboxamides via palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1007/s11696-020-01478-7

20-Carboxamidopregnene derivatives, such as 3β-acetoxy-5α-pregn-20-ene-20-carboxamides and 5α-pregn-20-ene-20-carboxamides were synthesized from the widely accessible 3β-acetoxy-pregn-5,16-dien-20-one (PDA) using selective hydrogenation, hydrazine and iodoalkene formation, as well as palladium-catalysed aminocarbonylation. The 20-iodo-20-ene derivatives, obtained from the corresponding 20-keto derivatives via their hydrazones, served as substrates. 23 new 20-carboxamides were obtained using various N-nucleophiles ranging from simple primary amines to α-amino acid esters. The novelty of this methodology lies in the application of facile, moderate or high-yielding reactions to obtain otherwise hardly accessible steroidal 20-carboxamides of pharmaceutical importance. In other words, instead of the enzymatic or synthetic degradation of e.g., sterols or cholanic acids, functionalization of the basic skeleton (a ‘building-up’ approach) was used.

Full text of DOI:10.1007/s11696-020-01478-7

Chemical Papers (2021) 75:1861–1867
https://doi.org/10.1007/s11696-020-01478-7
ORIGINAL PAPER
Synthesis of novel pregnane‑based 20‑carboxamides
via palladium‑catalysed aminocarbonylation
Gábor Mikle1 · Alexandra Zugó1 · Erzsébet Szatnik1 · Anita Maxim1 · Sándor Mahó2 · László Kollár1,3
Received: 22 July 2020 / Accepted: 16 December 2020 / Published online: 4 January 2021
© The Author(s) 2020
Abstract
20-Carboxamidopregnene derivatives, such as 3β-acetoxy-5α-pregn-20-ene-20-carboxamides and 5α-pregn-20-ene-20-
carboxamides were synthesized from the widely accessible 3β-acetoxy-pregn-5,16-dien-20-one (PDA) using selective hydro-
genation, hydrazine and iodoalkene formation, as well as palladium-catalysed aminocarbonylation. The 20-iodo-20-ene
derivatives, obtained from the corresponding 20-keto derivatives via their hydrazones, served as substrates. 23 new 20-car-
boxamides were obtained using various N-nucleophiles ranging from simple primary amines to α-amino acid esters. The
novelty of this methodology lies in the application of facile, moderate or high-yielding reactions to obtain otherwise hardly
accessible steroidal 20-carboxamides of pharmaceutical importance. In other words, instead of the enzymatic or synthetic
degradation of e.g., sterols or cholanic acids, functionalization of the basic skeleton (a ‘building-up’ approach) was used.
Keywords Iodoalkene · Carboxamide · Pregnane · Palladium · Aminocarbonylation
Introduction
The efciency of homogeneous catalytic reactions, due to
their high activity, as well as chemo-, regio- and enanti-
oselectivity is well known. In the last decades the highly
selective hydrogenation, isomerization, various carbonyla-
tion and cross-coupling reactions, catalysed by various tran-
sition metal complexes, have become important tools of the
synthetic chemist.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s1169
6-020-01478-7.
* László Kollár
Among the homogeneous catalytic functionalization of
various skeletons of practical importance (Cornils et al.
1996; Beller et al. 1998; Omae 1998), that of the steroidal
backbone is of primary interest (Skoda-Földes et al. 2003).
A great variety of transition metal-catalysed reactions, for
instance alkene and carbonyl hydrogenations, various car-
bonylations and coupling reactions were used to introduce
new functionalities. Among these reactions, the synthesis of
carboxamides via palladium-catalysed aminocarbonylation
is one of the most promising one. Several families of these
steroid-based carboxamides possess 5a-reductase inhibitor
properties (see below).
kollar@gamma.ttk.pte.hu
Gábor Mikle
miklegabor8@gmail.com
Alexandra Zugó
zugo.alexandra@gmail.com
Erzsébet Szatnik
szatnikerzsebet@gmail.com
Anita Maxim
maximanita@gmail.com
Sándor Mahó
s.maho@richter.hu
1
Department of Inorganic Chemistry, Faculty of Sciences,
The synthesis of carboxamides from easily available
iodoaromatics (or aryl trifates, their synthetic surrogates)
is a straightforward methodology. The seminal work of
Heck et al. (‘Heck-carbonylation’) (Schoenberg and
Heck 1974a, b, Schoenberg et al. 1974) provided a solid
University of Pécs, Ifúság 6, Pecs 7624, Hungary
2
Chemical Works of Gedeon Richter Plc., Budapest, Hungary
3
János Szentágothai Research Center and MTA-PTE Research
Group for Selective Chemical Syntheses, Ifúság u. 6.,
Pecs 7624, Hungary
Vol.:(0123456789)
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Chemical Papers (2021) 75:1861–1867
basis for the homogeneous catalytic functionalization of
the above substrates. Several reviews and book chapters
have been published on the aminocarbonylation of aryl
halides (Roy et al. 2012; Wu et al. 2011, 2013; Magano
and Dunetz 2011; Grigg and Mutton 2010; Barnard 2008;
Skoda-Földes et al. 2002; Gadge and Bhanage 2014). Even
the importance of the double carbon monoxide insertion
resulting in 2-ketocarboxamides (Ozawa et al. 1984; Son
et al. 1988) has been emphasised, i.e., the chemoselectivity
towards 2-ketocarboxamides/carboxamides is an important
issue. However, the aminocarbonylation of iodoalkenes/
enol trifates is a chemoselective reaction providing unsat-
urated carboxamides only (Kiss et al. 2015). The double
carbon monoxide insertion, i.e., the formation of unsatu-
rated ketocarboxamides requires special triarylphosphite-
based palladium catalysts (Carrilho et al. 2012).
Experimental
Materials and equipment
Celite®, sodium hydroxide, iodine, PPh3, palladium(II)
acetate, PDA (1) and Pd/C catalyst were purchased from
Sigma-Aldrich. Commercial Et3N, primary and secondary
amines including amino acid esters (Sigma-Aldrich) were
used without further purifcation. Toluene and DMF were
dried according to standard procedures; THF, ethyl acetate
and ethanol were used without further purifcation.
The 1H- and 13C-NMR spectra were recorded on a Bruker
500 spectrometer at 500 and 125.721 MHz, respectively.
The chemical shifts are given as δ values (ppm) and refer-
enced to tetramethylsilane. TLC analyses were carried out
using Merck TLC sheets (Silica gel 60 F254) and chloroform,
chloroform/ethyl acetate, and chloroform/methanol mixtures
were used as appropriate eluents. (The exact ratios are given
at the corresponding synthetic procedures.) Mass-spectrom-
etry data have been obtained using a GC–MS system consist-
ing of a Perkin Elmer AutoSystem XL gas-chromatograph
and Perkin Elmer TurboMass mass spectrometer.
The introduction of an amide functionality in steroidal
substrates via palladium-catalysed aminocarbonylation,
especially into the most distinguished position-3 and -17
(in ring A and D, respectively), has long been the aim of
the patent literature as well (Holt et al. 1989, 1990; Cacchi
et al. 1986; Dolle et al. 1987; Tian et al. 2000; McGuire
et al. 1998; Petz et al. 2001). Eforts have been made also
for the synthesis of 11- and 12-carboxamides using the
same methodology, i.e., aminocarbonylation of the corre-
sponding iodoalkene functionalities in the most hindered
positions (Ács et al. 2006, 2007). Although the pharmaco-
logical importance such as inhibition of concise enzymes
in ergosterol biosynthesis (Müller et al. 2015), anti-infam-
matory (Kim et al. 1987), 24-methyl transferase (Lorente
et al. 2005) and anti-microbial activities (Khabnadideh et al.
2000) of 20-carboxamides have been reported, to the best of
our knowledge, only cholenic acid-based multistep proce-
dures have been published for their synthesis. The procedure
includes the activation of 20-acids as nitrophenol esters, fol-
lowed by protection-deprotection sequence. Alternatively,
ergosteryl acetate has been subjected to hydrogenation using
Raney Ni, and the 5α,6-dihydroergosteryl acetate product
has been oxidized to the corresponding acid using potas-
sium permanganate. The acid chloride has been prepared by
oxalyl chloride and reacted further with the corresponding
primary or secondary amine (Giera et al. 2008).
Hydrogenation of 1 and 4
The unsaturated steroid 3β-acetoxy-pregn-5,16-diene-20-
one (‘PDA’) (1) (or in the analogous procedure, 4) (20 g,
56.1 mmol) was dissolved in ethyl acetate (120 mL) under
argon in a 500 mL three-necked fask equipped with a gas
inlet, refux condenser with a balloon at the top. A suspen-
sion of 605 mg of Pd/C (5%) (or 605 mg of Pd/C (10%))
in ethyl acetate (20 mL) was added to the stirred solution
at room temperature, then the atmosphere was changed to
H2 (1 bar). The composition of the reaction mixture was
checked by GC. After completion of the reaction, the mix-
ture was fltered on Celite®. The solvent was removed and
the product was recrystallized from ethyl acetate. Yield: 2:
18.04 g (90%) (when Pd/C (5%) was used); 3: 17.3 g (85%)
(when Pd/C (10%) was used).
Synthesis of 4 via hydrolysis and water elimination
Based on our preliminary investigations with similar
iodoalkene functionalities, i.e., their use in aminocarbon-
ylation/cyclization sequence to obtain oxazoles (Szuroczki
et al. 2018), as well as in asymmetric aminocarbonylation
to obtain diastereoisomers of various carboxamides (Mikle
2017), a systematic investigation regarding the structure of
both substrate and N-nucleophile was decided. In the present
paper, a facile procedure for the synthesis of 20-carboxa-
midopregnenes is described using the 20-keto—20-hydra-
zone—20-iodo-20-ene—20-carboxamido-20-ene reaction
pathway.
The compound saturated in both 5-ene and 16-ene positions
(3) (8.5 g, 23.67 mmol) was dissolved in 240 mL of etha-
nol and 10% NaOH solution (6.3 mL) was added. The reac-
tion mixture was heated for 2 h at 100 °C then concentrated
under reduced pressure. Coldwater (200 mL) and 10% HCl
solution (20 mL) were added. The steroid was fltered and
washed with water to neutral pH, and dried.
The hydrolysed steroid (7.3 g, 22.92 mmol), p-toluene-
sulfonic acid monohydrate (1.75 g, 9.22 mmol) and silica
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Chemical Papers (2021) 75:1861–1867
1863
gel (52.64 g) were dissolved in toluene (460 mL) and stirred
at 120 °C for 5 h. The composition of the reaction mixture
was checked by GC. After the reaction was completed, the
silica was fltered of, washed with toluene (1000 mL) and
the solvent was evaporated. Yield: 4.82 g (70%).
mixture was checked by GC. The solvent was evaporated,
and the residue was dissolved in 20 mL of CHCl3. It was
washed in turn with 20 mL of water, 20 mL portions of
5% HCl, saturated NaHCO3, and brine. The organic layer
was separated, dried over Na2SO4 and evaporated. Column
chromatography (silica gel, 95/5 CHCl3/MeOH, 100/0, 95/5,
90/10, 80/20, or 50/50 CHCl3/EtOAc; the exact composition
of the eluents are given in Supporting Material) resulted in
the target 20-carboxamido-20-ene derivatives (10a-k, 11a-l).
Synthesis of 20‑iodo‑3β‑acetoxy‑5α‑pregn‑20‑ene
(8) and 20‑iodo‑5α‑pregn‑20‑ene (9)
3β-Acetoxy-pregn-5-ene-20-one (2) or 5α-pregnan-20-one
(5) (14 mmol), hydrazine hydrate (15.2 mL, 314 mmol)
and triethylamine (7.8 mL, 55.8 mmol) in ethanol (42 mL)
were stirred for 2.5 h at 100 °C under argon. After cooling,
removal of the solvent resulted in some crystal formation.
Coldwater (100 mL) was added to the mixture. The precipi-
tated material was fltered and washed with water to neutral
pH. The white crystalline hydrazone (6, 7) was dried to con-
stant weight under vacuum.
Results and discussion
Synthesis of 20‑iodo‑20‑ene derivatives from PDA
According to a retrosynthetic analysis (Scheme 1), to
synthesize steroids with carboxamido functionality at the
position-20, pregnene derivatives possessing the 20-iodo/
trifloxy-20-ene moieties have to be obtained. To achieve
this goal, one of the most efcient ways could be the syn-
thesis of the corresponding 20-keto derivatives. In contrary
to previous approaches based on the degradation of sterols
(for instance Giera et al. 2008), our methodology is aimed
at using functionalization of a pregnane skeleton. Although
the oxidative degradation approach, i.e., the oxidation of the
C8–C10 alkenyl chains bound to 17-position, has been used
to obtain pregnane- and androstane-based compounds for
a long time (Giera et al. 2008, Fried et al. 1972), the high
chemoselectivity (practically no steroidal side products) and
the simple protocol encouraged us to follow the ‘bottom-
up’ approach based on 20-keto derivatives. Furthermore,
the synthesis is based on the application of simple ‘small
molecules’, such as carbon monoxide and primary and sec-
ondary amines as building blocks.
The hydrazone (6) (or 7) (13.46 mmol) and triethylamine
(18.8 mL, 134.6 mmol) were dissolved in THF (87 mL)
under argon in a 500 mL three-necked fask. A solution of
iodine (6.84 g, 26.92 mmol) in THF (26 mL) was added
dropwise to the stirred solution. After the addition was
completed, the mixture was stirred for 1 h. The amine salt
was fltered and the mixture was poured dropwise into a
stirred solution of Na2S2O5 (7.06 g, 37.14 mmol) in water
(1000 mL). The precipitated steroid was fltered and washed
with water to neutral pH and dried under vacuum. The ste-
roidal iodoalkene was recrystallized from aqueous ethanol.
General procedure for aminocarbonylation
A steroidal iodoalkene substrate 8 (or 9) (1 mmol),
palladium(II) acetate (5.6 mg, 0.025 mmol), and PPh3
(13.1 mg, 0.05 mmol) were dissolved in 10 mL DMF under
argon. Triethylamine (0.5 ml) and tert-butylamine (a)
(0.525 mL 5 mmol) [or another N-nucleophile 1.5 mmol
(b–e)] were added. (The amino acid methyl esters (f–k)
were used as hydrochloride salts (1.1 mmol) and were added
together with the catalyst.) The atmosphere was changed to
CO (1 bar), and the reaction was conducted at 50 °C for the
appropriate reaction time. The composition of the reaction
3β-Acetoxy-pregn-5,16-diene-20-one (pregna-5,16-
dien-3β-ol-20-one acetate, ‘PDA’) (1) was chosen as start-
ing material. Its heterogeneous catalytic hydrogenation
(Scheme 2) leads to the partially and fully hydrogenated
compounds, 2 and 3 (Shingate et al. 2007), respectively.
The hydrogenation of the double bonds proceeds in a con-
secutive manner, therefore, both compounds (2 and 3) pos-
sessing the required 20-keto functionalities can be obtained
Scheme 1 Retrosynthetic analy-
sis of the synthesis of steroidal
20-carboxamides. (R,R′: H,
alkyl, aryl; X: I, OTf)
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Chemical Papers (2021) 75:1861–1867
as analytically pure compound. The hydrogenation of both
16-ene and 5-ene double bonds are highly stereoselective:
17α-H and 5α-H epimers were obtained with high selectiv-
ity. As expected, heterogeneous hydrogenation takes place
preferably from the α-side.
The 20-iodo-20-ene substrates 8 and 9 were synthesised
from the corresponding ketones (2 and 5) via their hydra-
zones (6 and 7, respectively), using the modifed Barton’s
method (Scheme 4) (Barton et al. 1962, 1983, Krubine et al.
1969).
To synthesize a model compound without 3β-acetoxy
functionality, two pathways were chosen: (1) acetic acid
was eliminated from compound 1, and the resulting mix-
ture of dienes (3,5-diene and 2,4-diene) was hydrogenated
to the hardly separable mixture of the two epimers (5α-
and 5β-prenan-20-one formed mainly from 3,5-diene and
2,4-diene, respectively); (2) the pure 5α-epimer (3) was
subjected to acetate hydrolysis and elimination of water
(D’Onofrio and Scettri 1985), and the hydrogenation of the
mixture of 2-ene and 3-ene (4) resulted in the formation of
5 (Scheme 3). Since the frst methodology proved to be not
feasible, in further syntheses, the latter method, resulting in
practically epimerically pure product (5) was applied.
Synthesis of 20‑carboxamido‑20‑enes
via palladium‑catalysed aminocarbonylation
The iodoalkenes 8 and 9 were reacted as substrates
in palladium-catalysed aminocarbonylation reaction
(Scheme 5). Various primary and secondary amines
were used as N-nucleophiles (tert-butylamine (a), ani-
line (b), benzylamine (c), piperidine (d), morpholine (e),
methyl glycinate (f), methyl alaninate (g), methyl seri-
nate (h), methyl valinate (i), methyl phenylalaninate (j),
methyl prolinate (k)) and α-phenylethylamine (l) in DMF
under atmospheric carbon monoxide in the presence of
Scheme 2 Hydrogenation of 1
Scheme 3 The synthesis of
5α-pregnan-20-one (5)
Scheme 4 Synthesis of
20-iodo-20-ene derivatives (8,
9)
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Chemical Papers (2021) 75:1861–1867
1865
Table 1 Isolated yields of
20-carboxamides (10a–l and
11 a–l)a
N-nucl Products [isolated
yields, (%)]
a
b
c
d
e
f
g
h
i
10a (75)
11a (52)
10b (51) 11b (51)
10c (97)
10d (56) 11d (51)
11c (51)
10e (63)
10f (49)
10g (43)
11e (53)
11f (39)
11g (41)
10h (59) 11h (54)
10i (33)
10j (54)
11i (55)
11j (51)
j
k
l
10k (59) 11k (50)
10l (92)b 11l (75)
aFor reaction conditions see
“General procedure for amino-
carbonylation” (above)
Scheme 5 Aminocarbonylation of iodoalkenes (8, 9) toward 20-car-
boxamides (10, 11)
bMikle et al. 2017
palladium(0)-triphenylphosphine catalysts formed in situ.
Palladium(II) acetate was used as a catalytic precursor.
The formation of highly active coordinatively unsaturated
Pd(0) species was investigated by cyclic voltammetry and
NMR techniques in the presence of mono- and bidentate
phosphines (Csákai et al. 1999, Amatore et al. 1992, 1995).
It has to be noted that triphenylphosphine was used only in
a twofold excess to palladium. One equivalent is responsible
for the reduction of Pd(II) to Pd(0) while it is oxidised to
triphenylphosphine oxide.
amines (Schoenberg and Heck 1974a, b, Schoenberg et al.
1974, Skoda-Földes et al. 2002, Kiss et al. 2015). Using
these steroidal iodoalkene substrates (20-iodo-20-pregnenes)
this efect is even more pronounced.
As mentioned above, the reactions were conducted to
almost complete conversion. In spite of that, the isolated
yield of the target carboxamides can be considered as moder-
ate only, due to the loss of products during chromatographic
work-up of the catalytic reaction mixture. In this way, the
isolated yields of the analytically pure products varied from
33 to 97%. In general, the carboxamides 10 can be isolated
in higher yields than carboxamides 11 (compare for instance
10a and 11a; 10c and 11c; 10e and 11e, etc.). As the only
exception nucleophile i has to be mentioned, i.e., 11i was
isolated in higher yield than 10i.
The resulting Pd(0) intermediate is a highly reactive, low-
ligated intermediate which is apt to activate the iodoalkenyl
substrates (8, 9) in oxidative addition. This type of catalytic
system proved to be efcient also in further steps of the cata-
lytic cycle such as carbon monoxide activation, its insertion
into the alkenyl-palladium bond, amine activation, as well as
reductive elimination in the product-forming step (Table 1).
The iodoalkene functionality (20-iodo-20-ene) reacted
selectively and quantitatively toward the corresponding
20-carboxamido-21-ene derivatives (10a–k, 11a–l) under
mild conditions (atmospheric CO pressure, 50 °C). As
expected, practically no infuence of the structure of the
A-ring on conversion and isolated yields was observed. That
is, the removal of 3β-hydroxy functionality has no measur-
able efect on the reactivity of the 20-iodo-20-ene moiety.
However, the structure of the amine nucleophile has some
efect on the conversion. In general, 1–1.5 h are needed to
achieve close to complete conversion (‘GC-yields’ higher
than 98%). In the case of b, d, e and k nucleophiles 3 h, 5 h,
4.5 h and 4 h reaction times were requested, respectively.
The low reactivity of the less basic aromatic amine (b) is
not surprising in the light of earlier results obtained with
a great variety of iodoalkenes. In general, the secondary
amines, especially k show lower reactivity than the primary
Conclusions
In conclusion, it can be stated, that pregnane skeletons
functionalised at 20-position can be synthesized in yields
of practical interest in palladium-catalysed aminocarbonyla-
tion. 20-Iodo-20-ene functionality, easily accessible from 20
to one, provided a clean, high-yielding aminocarbonylation
towards 20-carboxamido compounds. Although the reactiv-
ity of the amines depends on their basicity, even with less
basic aromatic amines and more bulky ones isolated yields
of practical importance can be obtained.
Acknowledgements This work was supported by the Hungarian Sci-
entifc Research Fund (OTKA K113177) and the GINOP-2.3.2-15-
2016-00049 Grant.
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Chemical Papers (2021) 75:1861–1867
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Funding Open access funding provided by University of Pécs.
Compliance with ethical standards
Conflict of interest On behalf of all authors, the corresponding author
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