Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids

Article abstract of DOI:10.1002/chem.202100446

The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.

Full text of DOI:10.1002/chem.202100446

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&
Steroids
Electrochemically Enabled One-Pot Multistep Synthesis of C19
Androgen Steroids
[a, b]
[a, b]
[a, b]
Florian Sommer,
C. Oliver Kappe,*
and David Cantillo*
Abstract: The synthesis of many valuable C19 androgens
can be accomplished by removal of the C17 side chain from
more abundant corticosteroids, followed by further derivati-
zation of the resulting 17-keto derivative. Conventional
chemical reagents pose significant drawbacks for this syn-
thetic strategy, as large amounts of waste are generated,
and quenching of the reaction mixture and purification of
the 17-ketosteroid intermediate are typically required.
Herein, we present mild, safe, and sustainable electrochemi-
cal strategies for the preparation of C19 steroids. A reagent
and catalyst free protocol for the removal of the C17 side
chain of corticosteroids via anodic oxidation has been devel-
oped, enabling several one-pot, multistep procedures for
the synthesis of androgen steroids. In addition, simultaneous
anodic C17 side chain cleavage and cathodic catalytic hydro-
genation of a steroid has been demonstrated, rendering a
convenient and highly atom economic procedure for the
synthesis of saturated androgens.
Introduction
the synthesis of C19 steroids entails the generation of a 17-ke-
tosteroid precursor via cleavage of the side chain of more
[
7]
Steroids constitute a large and important class of both natural
products and pharmaceutical ingredients. Their biosynthesis by
plants and animals is fundamental for many physiological pro-
cesses, as steroids play key roles in signaling, as hormones,
abundant corticosteroids (Figure 1a). Removal of the C17
side chain of corticosteroids has traditionally involved the use
[
8]
of excess amounts of strong oxidizing agents such as NaBiO ,
3
[
9]
[10]
[11]
NaBH /NaIO , CrO
3
or MnO2. Additional methods involv-
4
4
[1]
[12]
[13]
and as membrane constituents. Due to their key biological
properties, a significant number of medicines have been devel-
oped based on steroid derivatives, with a wide range of appli-
cations including anti-inflammatory, contraceptive, antibiotic or
ing excess I /NH3 and strong bases have also been devel-
2
oped, although with either moderate yields or limited applica-
bility. More recently, cleavage of hydroxyacetone side chains
[
14]
with bismuth(III) catalysts has been reported.
Due to the
[2]
antihistamine treatments. The vital importance of steroids in
modern medicine is underscored by the fact that many of
shortcomings of these methods and the difficulties associated
with the selective side chain removal without degradation of
the androstane skeleton, microbial approaches from phytoster-
[3]
them are among the top selling drugs, and several are also
[4]
included in the WHO list of essential medicines. It is therefore
not surprising that, over the past few decades, significant re-
search efforts have focused on the discovery of novel steroid
drugs and the development of more efficient methods for
[
5]
their synthesis.
Within the family of steroidal compounds, C19 steroids,
based on the androstane skeleton, are also relevant natural
hormones and synthetic or semisynthetic active ingredients, in-
[6]
cluding over 40 marketed drugs. A convenient strategy for
[
a] F. Sommer, Prof. Dr. C. O. Kappe, Dr. D. Cantillo
Institute of Chemistry
University of Graz
Heinrichstrasse 28, 8010 Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
david.cantillo@uni-graz.at
[
b] F. Sommer, Prof. Dr. C. O. Kappe, Dr. D. Cantillo
Center for Continuous Flow Synthesis and Processing (CC FLOW)
Research Center Pharmaceutical Engineering GmbH (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
Figure 1. Multistep synthesis of C19 androgens via (a) classical methods and
https://doi.org/10.1002/chem.202100446.
(b) proposed electrochemical strategy.
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[15]
ols have been intensely investigated. However, the low solu-
bility of steroids in aqueous systems severely limits product
17-ketosteroid 2a (Table 1, entry 1). Next, a screen of the opti-
mal reaction conditions was carried out. MeCN/H O 40:1
2
[15]
yield and productivity.
indeed proved to be the most suitable solvent mixture. Metha-
The classical chemical methods for the removal of the C17
side chain outlined above typically require a quench or neu-
tralization of the excess of reagents, in addition to work-up
and purification steps to isolate the corresponding 17-ketoste-
roid before it can be further derivatized to the target com-
nol (entry 2) and THF/H O (entry 3) provided lower conversion
2
or selectivity. Other solvent systems (EtOH, acetone/water) and
other proportions of MeCN/H O resulted in lower conversions
2
as well (see Table S1 in the Supporting Information). When
sodium and lithium perchlorate were used as the supporting
electrolyte instead of the tetraalkylammonium salt, lower con-
versions and a significantly lower selectivity was observed (en-
tries 4 and 5). Interestingly, other anode materials such as
glassy carbon, reticulated vitreous carbon (RVC) or platinum
performed very poorly (entries 6–8), with very low conversions
of the substrate (<5% in all cases and rather poor selectivity).
Modification of other reaction parameters, including higher
current densities and different substrate or supporting electro-
lyte concentrations (Table S1) did not improve the results.
Once the optimal reaction conditions had been established
[
7,16]
pound (Figure 1a).
We hypothesized that cleavage of the
a-hydroxyketone C17-C20 bond might be possible via anodic
oxidation in a catalyst- and reagent-free fashion (Figure 1b).
Electrochemistry has been shown as a safe and green method-
[17,18]
ology to induce organic redox transformations.
Such
methodology for the generation of 17-ketosteroids, in the ab-
sence of external reagents, would permit direct derivatization
of the intermediate without additional work-up or purification
steps, resulting in a convenient and sustainable one-pot proce-
dure for the multistep preparation of essential C19 steroids.
(
0.2m substrate concentration in MeCN/H O 40:1, 5 mA con-
2
stant current with graphite as the anode and stainless steel as
the cathode material), the amount of charge was gradually in-
creased (Table 1, entries 9 and 10). To our delight, full conver-
sion of the starting material and excellent selectivity towards
Results and Discussion
To test our hypothesis, the electrolysis of hydrocortisone 1a
was initially investigated as model reaction (Table 1). In a typi-
cal experiment, the corticosteroid and a supporting electrolyte
were placed in an undivided electrochemical cell (5 mL IKA
ElectraSyn vial) and, after addition of a solvent, the mixture
was electrolyzed under constant current at room temperature.
Gratifyingly, a first attempt in acetonitrile/water 40:1 with
À1
the target 17-ketosteroid 2a was achieved after 4 Fmol of
charge had been passed. The excellent selectivity of the reac-
tion enabled a very simple work-up procedure, which consist-
ed of evaporation of the solvent, dilution of the crude mixture
with a saturated aqueous solution of NaHCO3 (or distilled
water) and extraction of the product with DCM. Evaporation of
the organic solvent provided a quantitative yield of 2a.
Et NBF4 as the supporting electrolyte and graphite as the
4
anode, provided a promising 79% conversion of the starting
material and an excellent selectivity towards the corresponding
The scope and applicability of this electrochemical C17 side
chain cleavage protocol was subsequently investigated. Thus,
several key 17-ketosteroids 2 were prepared from their corre-
sponding corticosteroid precursors (Figure 2). As mentioned
above, 11b-hydroxyandrostenedione 2a was obtained in quan-
titative yield (Figure 2a). When cortisone and cortexolone were
used as starting materials, Reichstein’s substance G (adrenos-
terone) 2b and androstenedione 2c were obtained in quanti-
tative and excellent yield, respectively. Anodic side chain cleav-
age of the more sensitive prednisone and prednisolone also
provided satisfactory results, and 17-ketosteroids 2d and 2e
were obtained in excellent yields. Importantly, it could also be
shown that this reagent-free electrochemical procedure does
not require the presence of a hydroxyketone side chain, a
rather common limitation of some conventional chemical
cleavage methods. Thus, 17a-hydroxyprogesterone 3, which
contains a methylketone side chain, could be cleanly electro-
lyzed to the corresponding 17-ketosteroid 2c in quantitative
yield (Figure 2b). In contrast, the presence of the 17-hydroxyl
group proved to be essential for the side chain cleavage. Thus,
when the standard electrolysis conditions were applied to cor-
ticosterone, 17-ketosteroid formation was not observed.
Table 1. Optimization of the reaction conditions for the anodic C17 side
chain cleavage of hydrocortisone 1a.
[a]
[b]
Entry Conditions
Conv /Select
[
c]
(
%)
1
2
3
4
5
6
7
8
9
1
MeCN:H
MeOH
2
O (40:1) Et
Et
4
4
4
NBF
NBF
NBF
4
4
4
(+)G/Fe(À)
(+)G/Fe(À)
(+)G/Fe(À)
(+)G/Fe(À)
(+)G/Fe(À)
2 F/mol 79/99
2 F/mol 65/92
2 F/mol 78/91
2 F/mol 47/73
2 F/mol 35/73
THF:H
2
O (10:1)
Et
MeCN:H
MeCN:H
MeCN:H
MeCN:H
MeCN:H
MeCN:H
2
2
2
2
2
2
O (40:1) NaClO
O (40:1) LiClO
4
4
O (40:1) Et
O (40:1) Et
O (40:1) Et
O (40:1) Et
4
4
4
4
NBF
NBF
NBF
NBF
4
4
4
4
(+)GC/Fe(À) 2 F/mol <1/–
(+)RVC/Fe(À) 2 F/mol 9/67
(+)Pt/Fe(À) 2 F/mol 11/75
(+)G/Fe(À)
(+)G/Fe(À)
3 F/mol 84/99
0
MeCN:H
2
O (40:1) Et
4
NBF
4
4 F/mol 99/98
[
1
a] Undivided cell (Electrasyn 2.0, 5 mL vial), 0.6 mmol 1a, 3 mL solvent,
000 rpm stirring speed, constant current electrolysis at rt. [b] Deter-
As mentioned above, the preparation of many C19 andro-
gen steroids require several reaction steps. Side chain cleavage
utilizing conventional reagents complicate these multistep syn-
thetic routes, as quench and workup procedures for the purifi-
cation of the 17-ketosteroid intermediates are required. The
mined by HPLC peak area percent (254 nm). [c] Determined by HPLC
peak area percent (254 nm) as the percentage of product with respect to
all other peaks except the substrate. G: graphite. GC: glassy carbon. RVC:
reticulated vitreous carbon. Fe: stainless steel.
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Figure 3. One-pot multistep synthesis of several 17-keto and 17-hydroxy ste-
roids based on anodic side chain cleavage of C21 precursors.
Figure 2. Scope of the anodic generation of 17-ketosteroids 2 via (a) hydrox-
yacetone side chain cleavage and (b) alkylketone side chain cleavage.
the first step. TEMPO catalyzed anodic oxidations are favored
[
21b]
catalyst and reagent free electrochemical procedure presented
herein permitted the execution of several multistep C19 ste-
roid syntheses in one pot, by simply adding additional re-
agents or catalysts to the electrochemical cell (Figure 3). For
example, anodic oxidation of cortisone (1b) followed by addi-
tion of NaBH4 to the undivided cell (Figure 3a) unlocked a
simple and convenient one-pot protocol for the synthesis of
by moderately basic pH.
In an additional multistep transfor-
mation, following the hydroxyketone side chain cleavage of
cortisone (1b), androstane-3,11,17-trione (6) was prepared by
Pd/C catalyzed hydrogenation of the C4-C5 double bond (Fig-
ure 3c). In this case, once the electrolysis had ended, 10 mol%
Pd/C was added to the electrochemical cell and the mixture
stirred under H atmosphere at room temperature for 2 h. Fil-
2
[19]
11-ketotestosterone (4), an important androgen. Using a sim-
tration of the reaction solution and extraction with distilled
ilar strategy and cortexolone (1c) as the substrate, 4-androste-
nediol (5), a testosterone precursor, could be efficiently pre-
pared in very good yield.
water or aqueous NaHCO /DCM provided an excellent yield
3
[20]
(91%) of the reduced androgen 6. Compound 6 is an impor-
[
22]
tant steroid with androgenic properties, and an intermediate
[
23]
An open-pot two-step electrooxidative transformation for
the synthesis of adrenosterone (2b) from hydrocortisone (1a)
was also developed (Figure 3b). In this process, during the
electrolysis of hydrocortisone 1a, TEMPO was added to the cell
in the synthesis of deoxycholic acid and other synthetic ster-
[
24]
oidal bile acids.
The above successful preparation of androstane-3,11,17-
trione (6), following a one-pot electrochemical side chain
cleavage/catalytic hydrogenation sequence, led us to infer that
the same transformation could probably be accomplished in a
single electrochemical reaction. This is due to the fact that
[21]
À1
as an electrocatalyst after 4 Fmol had already been ap-
plied. Thus, the anodic generation of the 17-ketosteroid inter-
mediate (2a) was immediately followed by electrocatalytic oxi-
dation of the C11 hydroxyl group, leading to the 11-oxo deriva-
tive (2b). This transformation, which proved more challenging
to achieve in one-pot without intermediate purification, re-
quired an optimization of the second electrooxidative step
during the anodic side chain cleavage H gas is produced at
2
the cell cathode (the proposed reaction mechanism is depicted
in Figure S1). Such synthetic strategy would result in a highly
convenient and atom economic procedure for the synthesis of
6 and a number or related saturated androgens. To test this
hypothesis, cortisone (1b) was electrolyzed under the optimal
reaction conditions for the cleavage of the side chain in the
presence of a suspension of 10 mol% Pd/C (Figure 4).
(
see Table S2 in the Supporting Information). Ultimately, a high
yield of 2b (78%) was obtained by adding to the cell a combi-
nation of TEMPO (30 mol%) and an aqueous solution of
Na CO (1 equiv) to neutralize the glycolic acid present from
2
3
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À2
experiments (3.3 mAcm ), the cell current could be increased
2
to 40 mA by immersing ca. 12 cm of electrode surface into
the reaction mixture. Gratifyingly, application of the optimal
electrolysis conditions for small scale (cf. Figure 2a) with
4
0 mA to a 90 mL solution resulted excellent conversion and
selectivity toward 2b. Simple extractive workup resulted in
7% isolated yield (2.62 g) of the pure 17-ketosteroid
9
(
Figure 5).
The proposed mechanism for the C17 side chain cleavage
might involve direct oxidation of the hydroxyketone moiety or
initial formation of a hydrate intermediate (Figure 6a). Forma-
tion of a hydrate would result in a CÀC bond cleavage similar
to that of a 1,2-diol, which is known to be relatively facile
[
26]
under electrochemical conditions. Indeed, cyclic voltamme-
try of hydrocortisone 1a in the absence and the presence of
water (Figure 6b) revealed that the oxidation is easier when
water is present. Additionally, the reaction performed best
with water as additive compared with other less nucleophilic
Figure 4. Simultaneous anodic removal of the C17 side chain and cathodic
catalytic hydrogenation of 1b.
In this experiment, the reaction vial was tightly closed to
protic solvents (H O>MeOH>EtOH) (Table S1). In both cases,
2
ensure that the H generated at the cathode could not easily
the cleavage is a 2-electron process in which glycolic acid is re-
2
escape the cell. To our delight, HPLC monitoring of the reac-
tion mixture revealed disappearance of both the starting ste-
roid 1b and the 17-ketosteroid intermediate 2b. Compound 6,
generated by simultaneous anodic oxidation and cathodic cat-
alytic hydrogenation of 1b was obtained in nearly quantitative
yield (97%). It should be emphasized that, while examples of
„
ex-cell“ exploitation of the H generated in electrochemical re-
2
[25]
actions have been reported, in situ utilization „in-cell“ for the
catalytic reduction of a molecule that is simultaneously being
oxidized is unprecedented.
The synthetic usefulness of the electrochemical protocol was
further demonstrated by performing a multigram scale experi-
ment (9 mmol). The side chain cleavage of cortisone (1b), lead-
ing to 17-ketosteroid 2b, was selected as model (Figure 5). For
this experiment, a cell with higher electrode area was em-
ployed to increase the productivity and avoid the prolonged
electrolysis times that would be needed with the standard IKA
cell (see Supporting Information for details). Thus, while keep-
ing constant the current density with respect to the small-scale
Figure 6. (a) Suggested mechanism for the electrochemical side chain cleav-
age and (b) cyclic voltammetry of hydrocortisone 1a in the presence and
the absence of water.
Figure 5. Multigram scale electrochemical synthesis of 17-ketosteroid 2b.
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1
3
leased as byproduct. Notably, when a C NMR spectrum of a
crude reaction mixture was recorded after partial evaporation
of the solvent, no glycolic acid could be observed (Figure S1).
In fact, no other carbons in addition to the reaction product,
the supporting electrolyte and the solvent were present. This
was ascribed to further electrochemical oxidation of glycolic
acid under the electrolysis conditions to gaseous products
Acknowledgements
The CC FLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET Pro-
gram by the Austrian Federal Ministry of Transport, Innovation
and Technology (BMVIT), the Austrian Federal Ministry of Sci-
ence, Research and Economy (BMWFW), and by the State of
Styria (Styrian Funding Agency SFG).
(
probably CO and formaldehyde), which would explain that
2
À1
more than 4 Fmol are always needed to obtain full conver-
sion of the steroid starting material. This hypothesis could be
confirmed by electrolyzing a sample of glycolic acid under the Conflict of interest
standard reaction conditions. Thus, NMR monitoring of a reac-
tion mixture containing glycolic acid as substrate showed com-
plete disappearance of this material under electrolysis (Fig-
ure S2). In addition, cyclic voltammetry of glycolic acid (Fig-
ure S3) showed that this compound can indeed by oxidized
under the same potentials as the steroid substrates.
The authors declare no conflict of interest.
Keywords: anodic oxidations · electroorganic synthesis · one-
pot reactions · steroids · sustainable chemistry
To put the electrochemically-enabled, one pot procedure for
the synthesis of C19-androgen steroids described herein into
perspective, it was compared with the standard side chain
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4
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many 17-ketosteroids 2, and their direct functionalization with-
out the need of intermediate purification was demonstrated
with several examples (Figures 3 and 4). From the economical
viewpoint, the electrochemical methodology also provides sig-
nificant advantages with respect to the conventional reagents.
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