Iridium-catalysed highly selective reduction-elimination of steroidal 4-en-3-ones to 3,5-dienes in water

Article abstract of DOI:10.1039/c9gc00654k

Steroidal 3,5-diene is an important structural motif in steroid drugs. In this report, an iridium-catalyzed reduction-elimination of readily available steroidal 4-en-3-ones is realized to prepare steroidal 3,5-dienes. At a low catalyst loading (S/C = 200), heating 4-en-3-ones in a water-mixed organic solvent with formic acid without inert atmosphere protection afforded the desired 3,5-dienes in moderate to excellent yields. In a gram-scale preparation, recrystallization is used instead of column chromatography to purify products. Excellent functionality tolerance and regioselectivity are featured. Structural moieties such as alkanols (primary, secondary and tertiary), esters (except for formate), tolylates, and ketones (endocyclic or exocyclic) are not affected. Surprisingly, the reduction-elimination only takes place at A-ring 4-en-3-ones. In addition, bicyclic 4-en-3-ones are also viable substrates. Synthetic applications of steroidal 3,5-dienes are demonstrated. Our method can also lead to steroidal 3,5-dienes-3-d (>99% d-incorporation) when DCO₂D and D₂O are used together.

Full text of DOI:10.1039/c9gc00654k

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Iridium-catalysed highly selective reduction–
elimination of steroidal 4-en-3-ones to 3,5-dienes
Cite this: DOI: 10.1039/c9gc00654k
in water†
a
b,c
d
a
a
Jide Li, Weiping Tang, Demin Ren, Jiaxi Xu * and Zhanhui Yang
*
Steroidal 3,5-diene is an important structural motif in steroid drugs. In this report, an iridium-catalyzed
reduction–elimination of readily available steroidal 4-en-3-ones is realized to prepare steroidal
3,5-dienes. At a low catalyst loading (S/C = 200), heating 4-en-3-ones in a water-mixed organic solvent
with formic acid without inert atmosphere protection afforded the desired 3,5-dienes in moderate to
excellent yields. In a gram-scale preparation, recrystallization is used instead of column chromatography
to purify products. Excellent functionality tolerance and regioselectivity are featured. Structural moieties
such as alkanols (primary, secondary and tertiary), esters (except for formate), tolylates, and ketones
(endocyclic or exocyclic) are not affected. Surprisingly, the reduction–elimination only takes place at
A-ring 4-en-3-ones. In addition, bicyclic 4-en-3-ones are also viable substrates. Synthetic applications of
steroidal 3,5-dienes are demonstrated. Our method can also lead to steroidal 3,5-dienes-3-d (>99%
Received 22nd February 2019,
Accepted 14th March 2019
DOI: 10.1039/c9gc00654k
rsc.li/greenchem
2 2
D-incorporation) when DCO D and D O are used together.
steps. For example, following the installation of a leaving
group, pyrolysis or photolysis can afford the desired olefin
Introduction
5
6
Steroid compounds play an extremely important role in the (Scheme 1a, i). In the presence of strong dehydration reagents
pharmaceutical industry. A very large number of steroid medi- or acids, 5-en-3-ols can be directly converted to
2
1
7
cations have been developed to treat different kinds of dis- (Scheme 1a, ii). A 2,3-Wittig rearrangement protocol has also
eases. Among the top 200 pharmaceutical products by pre- been developed by treating benzyl-protected 2 with butyl
1
2
8
scriptions in 2016, there are around 20 steroid derivatives.
lithium (Scheme 1a, iii). Alternatively, steroidal 4-en-3-ones
Thus, developing new methods for structural modification of (3) are also good starting materials to produce 3,5-dienes (1).
steroid compounds is indispensable in both organic and med- 1,2-Reduction of 3 leads to allylic alcohol 4, which can
icinal chemistries. Steroidal 3,5-dienes, which contain two undergo either Pd-catalysed olefination after leaving group
9
conjugated CvC double bonds across the A and B rings, serve installation (Scheme 1b, iv) or direct dehydration (Scheme 1b,
3
10
as not only key structural motifs, but also important synthetic v) to form 1. Transformation of 3 into enol triflates 5 has
4
precursors of a variety of bioactive structures (Fig. 1).
also been developed by sequential pseudohalogen–lithium
The synthesis of steroidal 3,5-dienes (1) from steroidal 5-en- exchange reaction and protonation of the resulting carbanions,
-ols (2) or steroidal 4-en-3-ones (3) generally requires multiple which requires rather basic and harsh conditions
3
1
1
(
Scheme 1c). Another protocol involving the protection of 3
to dithioketal 6, allylic chlorination with PhSeCl, ring enlarge-
ment, and desulfurization with RANEY® Ni was also estab-
a
State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, P. R. China. E-mail: zhyang@mail.buct.edu.cn,
jxxu@mail.buct.edu.cn; Fax: +86 10 64435565
b
School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue,
Madison, Wisconsin 53705, USA
c
Department of Chemistry, University of Wisconsin-Madison, Madison,
Wisconsin 53706, USA
d
Hunan Provincial Key Laboratory of Controllable Preparation and Functional
Application of Fine Polymers, Hunan University of Science and Technology,
Xiangtan 411201, China
†
Electronic supplementary information (ESI) available: A detailed experimental
1
13
procedure, analytical data and NMR ( H and C) spectra of 1, 8, 9, 10, 11 and
3. See DOI: 10.1039/c9gc00654k
1
Fig. 1 Bioactive structures with steroid 3,5-diene as key subunits.
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a
Table 1 Optimization of reaction conditions
b
Entry
Cat.
S/C
2
HCO H (x)
Cosolvent
Yield /%
1
2
3
4
5
6
7
8
9
1
11
1
1
1
TC-1
TC-2
TC-3
TC-4
TC-5
TC-6
TC-7
TC-8
LC-1
LC-2
LC-3
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
TC-4
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
100
500
1000
200
200
200
200
24
24
24
24
24
24
24
24
24
24
24
12
12
12
12
12
12
12
12
12
12
12
12
12
8
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
EtOH
i-PrOH
t-BuOH
TFE
50
47
42
66
34
55
48
61
20
47
31
25
33
49
55
74
32
14
30
80
0
Scheme 1 Established steroidal 3,5-diene synthesis and this work.
1
2
lished (Scheme 1d). Notably, the Shapiro-type olefination of
0
1
3
3
does not yield 3,5-dienes, but 2,4-dienes instead.
2
3
4
Despite the above advances, problems still exist in steroidal
,5-diene syntheses. The highly reactive leaving group precur-
3
sors, strong dehydration agents/acids, strong bases, and other 15
1
1
1
6
7
8
factors lead to poor functional group tolerance. For example,
most of the reaction conditions are not compatible with other
DMF
DMSO
THF
hydroxyl groups present in the molecules. Other ketone moi- 19
10a,
20
MeCN
eties generally cannot be tolerated during the reduction of 3.
c
2
2
1
2
2
H O
b,e
Due to the above issues, the reported procedures were only
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
67
7
5
49
87
94
tested in very limited examples and their applications in synthe- 23
2
2
2
4
5
6
sizing structurally different steroidal 3,5-dienes with sensitive
10a,b,e,12
functional groups are quite rare.
Furthermore, from a
16
24
16
14
green-chemistry standard, there still lacks a satisfactory and 27
d
e
28
90 (85)
operationally simple method to produce a diverse range of phar-
maceutically important steroidal 3,5-diene intermediates.
Recently, we developed a new type of iridium catalyst with
differently substituted 2-(4,5-dihydroimidazol-2-yl)pyridine
a
b
In all the reactions, deionized water was used. Yields determined by
1
c
H NMR with 4-nitroiodobenzene as an internal standard. Only water
d
e
used. Reaction time 4 h. Isolated yield.
1
5
ligands. The catalysts showed extremely high efficiency and
selectivity in the transfer hydrogenation–reduction of alde-
1
5b
15c
hydes and ketones, and the deoxygenation of alkanols, in
2
00 S/C ratio (entries 1–11) revealed that our catalyst TC-4 gave
1
5d
1
7
aqueous formic acid solution.
planned to chemoselectively reduce enones 3 to allylic alcohols
with our catalysts. To our surprise, experimentally, allyl
Based on this, we initially
a higher yield (66%, entry 4) than other catalysts (entries
–11). The catalyst precursor [Cp*IrCl exhibits no catalytic
9
2 2
]
4
activity, indicating the indispensability of the 2-(4,5-dihydroi-
midazol-2-yl)pyridine ligands. We presume that the ligand
effect mainly lies in the formic acid decomposition step and is
similar to that reported for cyclometalated iridium(III) com-
alcohol 4 underwent dehydration under the reaction con-
ditions, providing a green and convenient method to syn-
thesize structurally diverse steroidal 3,5-dienes 1 from the
1
6
1
8
corresponding 4-en-3-ones 3 in water (Scheme 1e).
plexes.
Solvent screening (entries 12–21) disclosed that
mixed MeCN–water (volume ratio v/v = 1 : 1) was the best com-
bination and the yield of 3a was improved to 80% (entry 20).
1
4d,e,h
According to the Pfizer solvent selection guide,
the use of
Results and discussion
acetonitrile is acceptable in green-chemistry synthesis. The
Testosterone (3a) was selected as the model substrate to opti- reduction–elimination did not occur in only water (entry 21),
mize the reaction conditions (Table 1). Catalyst screening at probably because of the insolubility of 1a in water. Thus,
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organic solvents were added to improve the solubility. Table 2 Iridium-catalysed reduction–elimination of different steroidal
a
4-en-3-ones
However, only formylation occurred in organic solvent alone,
such as acetonitrile. Increasing the catalyst loading (S/C = 100)
gave a lower yield (entry 22), possibly due to the resulting
accelerated decomposition of formic acid. The decrease of
catalyst loading afforded poor yields (entries 23 and 24). The
equivalents of formic acid, which acted as both reducing Entry
agents and dehydration promotors, also affected the reaction
significantly (entries 25–27). A 94% yield was obtained when
b
Substrate (3)
Product (1)
Yield (%)
2
4 equivalents of formic acid were used (entry 27). In the pres-
ence of 16 equivalents of formic acid, extending the reaction
time to 4 hours also resulted in 90% NMR yield and 85% iso-
lated yield (entry 28).
With the optimal conditions in hand, structurally diverse
steroidal 4-en-3-ones were tested (Table 2). Not only testoster-
1
2
1
2
1
2
3
4
5
6
R = R = H, 3a
R = R = H, 1a
85
63
76
c
1
2
1
2
R = H, R = Me, 3b
R = H, R = Me, 1b
1 2
d
1
2
e
R = CHO, R = H, 3c
R = CHO, R = H, 1c
d
1
2
1
2
R = Ac, R = H, 3d
R = Ac, R = H, 1d
62
75
50
d, f
1
2
1
2
R = Ts, R = H, 3e
R = Ts, R = H, 1e
g
1
0b
one (3a, entry 1),
verted to the corresponding diene 1b in 63% isolated yield
entry 2). In both cases, the secondary or tertiary alkanolic
hydroxyl group remained intact. This is in sharp contrast to
17α-methyltestosterone (3b) was also con-
(
d
7
35
7
a
Scetiri’s dehydration protocol. The reaction of testosterone
7-formate (3c) delivered the desired product 1c in 31% yield
1
and the deformylation product 1a in 45% yield (76% in total,
entry 3). However, in the reaction of testosterone 17-acetate
(
3d) and tosylate (3e), no hydrolysis of acetate and tosylate
took place (entries 4 and 5). Nandrolone phenylpropionate
3f), a marketed medication used to treat breast cancer and
c
h
8
9
1
1
R = Me, 3h
R = H, 3i
R = Me, 1h
R = H, 1i
78 (80)
49
71
i
0
1
2
R = CH OH, 3j
2
R = CH OH, 1j
(
d, j
77
osteoporosis, was selectively reductively olefinated in 50%
yield, without affecting the ester moiety (entry 6). Surprisingly,
the electron-deficient C1vC2 bond in metandienone (3g) was
transfer hydrogenated during the reduction–elimination of the
enone moiety (entry 7). In this case, 1b was produced in 35%
yield, with other unidentified mixtures. Androst-4-ene-3,17-
dione (3h) and 19-norandrost-4-ene-3,17-dione (3i) readily
underwent the desired reactions to afford dienes 1h and 1i in
c
12
13
14
R = H, 3l
R = OH, 3m
R = H, 1l
R = OH, 1m
77
70
62
d, j
k
7
8% and 49% yields (entries 8 and 9), respectively. The reac-
tion of 19-hydroxyandrost-4-ene-3,17-dione (3j) gave diene 1j in
1% yield (entry 10). 6-Methyleneandrost-4-ene-3,17-dione (3k)
7
first underwent reduction at the electrophilic 6-methylene
moiety, followed by reduction–elimination of the resultant
4
-en-3-one intermediate to generate diene 1k in 77% yield
entry 11). In entries 8–11, the endocyclic 17-oxo groups were
well tolerated, because of the steric environment nearby.
Progesterone (3l), 17α-hydroxyprogesterone (3m), and medrox- 18
yprogesterone 17-acetate (3n) were all reductively olefinated in
excellent selectivity, giving the desired products 1l, 1m, and 1n
in 77%, 70%, and 62% yields (entries 12–14), respectively. The
exocyclic ketone moieties also remained intact.
After learning that 17-hydroxy, 17-oxo, 17-acetyl, and
various esters in different positions can be tolerated, we
sought to test functional groups at other positions.
Gratifyingly, corticosterone (3o) and hydrocortisone (3p), with 20
two new hydroxyl groups (11-hydroxy and exocyclic hydroxy)
and an exocyclic ketone, both exclusively gave the desired pro-
ducts 1o and 1p in 36% and 61% yields, respectively (entries
(
d
1
1
6
R = H, 3o
R = OH, 3p
R = H, 1o
R = OH, 1p
36
61
81
7d, j
d,k
d,k
1
9
41
58
1
6 and 17). Notably, the 11-oxo group in cortisone acetate (3q)
also well survived from the highly reductive conditions, with
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Table 2 (Contd.)
b
Entry
Substrate (3)
Product (1)
Yield (%)
k
21
No reaction
NA
k
22
No reaction
NA
a
The reactions of 3g and 3i were performed on a 0.15 mmol scale, and
that of 3j on a 0.2 mmol scale. The remaining were performed on a Scheme 2 Selected previous syntheses of 1a, 1h, and 1l with sensitive
b
c
d
0
(
.1 mmol scale. Isolated yield. Reaction time 2 h. HCOOH
functional groups.
e
f
32 equiv.). Total yield of 1c (31%) and 1a (45%). TFE–H O (1 : 1) as
2
g
h
the solvent. Based on the recovery of the starting material. Yield of a
i
1
mmol-scale reaction. Total yield of 1j (55%) and its formate (16%).
j
k
2
Reaction time 8 h. HFIP–H O (1 : 1) as the solvent.
deacetylation at C20 hydroxyl, and oxidation with pyridinium
chlorochromate (PCC), to obtain 1l in 39% total yield. In con-
trast, our reduction–elimination protocol delivered 1a, 1h, and
the desired product isolated in 81% yield (entry 18). In 1l in 85%, 78%, and 77% isolated yields, respectively, in only
addition, the one-step reduction–elimination of cholest-4-en-3- one step (Table 2, entries 1, 8, and 12). The high efficiency of
1
9
one (3r) and diosgenone (3s) occurred smoothly. Among the our reduction–elimination protocol is also demonstrated by
9
,11,7a
numerous synthetic procedures to access 1r,
the present the facile access to 1o, 1p, and 1q (Table 2, entries 16–18).
one provides
conditions.
a
simple solution under green-chemistry
Bicyclic enones such as nootkatone (7a) and Wieland–
Miescher ketone (7b) are also viable substrates (Scheme 3). In
7
-Keto-dehydroepiandrosterone (3t) and its acetate (3u), as the former case, triene 8a was isolated in 56% yield. In the
well as enoxolone (3v) and its derivatives 3w and 3x, showed latter case, dienone 8b and dienol 9b were prepared in 34%
no reactivity toward the iridium-catalysed reduction–elimin- and 22% yields, respectively. The formation of dienol 9b was
ation (Table 2, entries 21 and 22). This demonstrates that our due to the sterically less-congested environment around the
reduction–elimination protocol is also highly regioselective. carbonyl of 7b or 8b (11% yield from 8b to 9b under the same
Reactions only occurred at the A-ring 4-en-3-ones, while B- or conditions). The bicyclic diene backbone is an important
C-ring enones were left intact.
subunit in lovastatin, a naturally occurring compound and pre-
Previously established protocols for the synthesis of ster- scription drug used for treating dyslipidemia and preventing
oidal 3,5-dienes suffered from functionality tolerance. When cardiovascular disease.
sensitive functional groups were present, tedious protection
In the gram-scale synthesis of 1a (Scheme 4), the addition
and deprotection operations were inevitable. For example, a of formic acid three times is required to obtain a high conver-
tedious sequence including acetyl protection of hydroxyl,
Li(t-BuO) AlH reduction of carbonyl, dehydration with SOCl ,
3
2
and deprotection was used to convert testosterone 3a into 1a
1
0b
in total 43% yield (Scheme 2, i–iv). Previous syntheses of 1h
were also tedious. For example, product 1h was prepared from
3
h in less than 45% total yield, following a three-step pro-
1
2
cedure under harsh conditions (Scheme 2, vi–viii), while
another five-step synthesis of 1h only gave 16% total yield
1
0b
(Scheme 2, i–v).
Although the synthesis of 1l from 3l was
realized by the reduction/dehydration/oxidation sequence, oxi-
dation in the last step was required to restore the acetyl group,
1
0a
which was over-reduced in the first step (Scheme 2, ix–x). In
another method for the preparation of progesterone receptor
1
0e
antagonists (Scheme 2, xi–xvi),
it involved a six-step
sequence including double reduction, double acetylation,
selective deacetylation at C3 hydroxyl, 3,5-diene formation, Scheme 3 Reduction–elimination of bicyclic enones.
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Scheme 4 Gram-scale synthesis of 1a (left) and the recrystalized
product from ethyl acetate (right).
sion. We also need to treat the crude mixture with sodium car-
bonate in methanol to release 1a from its formate ester.
Recrystallization from ethyl acetate gave 1a in 78% yield
Scheme 6 Proposed mechanism for the reduction–elimination of ster-
oidal 4-en-3-ones.
(
1.47 g).
We further examined the mechanistic details of the
reduction–elimination (Scheme 5). Reduction of testosterone
3a) delivered allylic alcohol 4a, which was converted to 1a in
(
8
1
5b
and electronically sensitive.
Thus, in the reduction of 3,
1
5% H NMR yield upon treatment with formic acid in MeCN–
only sterically least demanding 3-oxo moiety is reactive. In
other words, the good tolerance of other ketone moieties and
high regioselectivity are a result of steric sensitive reduction.
water. The reaction of deuterium-labelled alcohol d-4a suggests
that the elimination involves the loss of the proton at the C6
position instead of C3. In the iridium-catalyzed reaction, the
2
On the other hand, the relatively weak acidity of HCO H and
use of DCO
2 2
D or D O (H/D = 33 : 67 under Conditions A, H/D =
the use of water as the co-solvent only dehydrate the active
allylic alcohol, leaving other hydroxyls intact. These factors
contribute to the high chemo- and regioselectivity of the
iridium-catalyzed reduction–elimination.
8
6 : 14 under Conditions B) demonstrated that the hydrogen at
the C3 position of 3,5-dienes primarily comes from formic
acid. The incomplete D-incorporation under Conditions A was
caused by the H–D exchange between [Ir]-D and H
2
O. Similar
The synthesized steroidal 3,5-dienes are also useful build-
ing blocks. For example, treating 1a with ethynylmagnesium
bromide and (pyridin-2-ylmethyl)lithium afforded 3,5-dienyl
propargyl alcohol 10 and anticancer agent 11 (also referred to
as II in Fig. 1) in 59% and 92% yields, respectively (Scheme 7).
It should be noted that the reaction of ethisterone 3y under
our conditions could not deliver 10, although we tried
different conditions in the presence of various amounts of
formic acid and co-solvents. It was reported that propargyl
alcohol 10 showed significant biological activity in animal
exchange between [Ir]-H and D O under Conditions B was also
observed. When DCO D and D O were used together, efficient
2 2
2
preparation of steroidal 3,5-dienes-3-d was realized with com-
plete D-incorporation (Scheme 5, Conditions C, H/D < 1 : 99).
1
5
Based on the above information and our previous studies,
a plausible mechanism is proposed (Scheme 6). Reduction of
-en-3-ones 3 with iridium hydride C, which is generated
4
through iridium formate B from iridium chloride A and formic
acid, affords allylic alcohols 4 as the key intermediates. Under
acidic conditions, dehydration of 4 gives carbocation D/E.
Subsequent removal of the proton at the C6 position of D/E
yields dienes 1. Most likely, the rate-determining step is not
2
0
studies. The Horner–Wadsworth–Emmons olefination of 1h
with phosphate 12 gave triene 13 in 51% yield. We expect that
1
5b
the dehydration of 4 but the 1,2-reduction of 3.
The
reduction of ketones with iridium hydride C is both sterically
Scheme 5 Mechanistic studies.
Scheme 7 Synthetic applications of steroidal 3,5-dienes.
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the introduction of a cyano group to 13 would make it a useful
intermediate for further derivatizations.
(b) E. A. Djurendic, J. J. Ajdukovic, M. N. Sakac,
J. J. Csanádi, V. V. Kojic, G. M. Bogdanovic and
K. M. P. Gasi, Eur. J. Med. Chem., 2012, 54, 784;
(
c) S. Z. Kovačević, S. O. Podunavac-Kuzmanović,
Conclusions
L. R. Jevrić, P. T. Jovanov, E. A. Djurendić and
J. J. Ajduković, Eur. J. Pharm. Sci., 2016, 93, 1;
We have developed a new method to prepare steroidal 3,5-
dienes by means of reduction–elimination of steroidal 4-en-3-
ones in water. By simply heating steroidal 4-en-3-ones in a
water-mixed solvent with formic acid in the presence of our
recently developed iridium catalysts, steroidal 3,5-dienes are
obtained in moderate to excellent yields in one single oper-
ation. All the reactions are performed without inert atmo-
sphere protection. In the gram-scale preparation, the product
is isolated by recrystallization. Our reduction–elimination
shows extremely high functionality tolerance. Primary, second-
ary and tertiary hydroxys are well tolerated. No hydrolysis is
observed when steroidal esters (except for formates) or toly-
lates are used. Surprisingly, under the reductive conditions,
the endocyclic or exocyclic ketone moieties are not affected. In
addition, our method also features excellent regioselectivity.
The reduction–elimination only takes place at A-ring 4-en-3-
ones, while B- or C-ring enones are unreactive. Simple bicyclic
(
d) D. S. Jakimov, V. V. Kojic, L. D. Aleksic,
G. M. Bogdanovic, J. J. Ajdukovic, E. A. Djurendic,
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2
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1
6
7
D. H. R. Barton, S. Achmatowicz, P. D. Magnus,
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1
971, 1014.
(a) F. D’Onofrio and A. Scettri, Synthesis, 1985, 1159;
b) T. Nishiguchi, N. Machida and E. Yamamoto,
4
-en-3-ones are also viable substrates. Mechanistic studies
indicate that the process consists of two consecutive reactions,
namely (i) iridium-catalyzed selective reduction of enones to
enols and (ii) acid-promoted selective dehydration of enols to
dienes. Synthetic applications of the resulting steroidal 3,5-
dienes are also demonstrated. Furthermore, this reduction–
elimination can also be used to efficiently prepare steroidal
(
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Conflicts of interest
(b) C. L. Varela, F. M. F. Roleira, S. C. P. Costa,
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Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (No. 21602010 to Z. Y.), and the
Fundamental Research Funds for the Central Universities
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