A new electrochemical system for stereoselective allylic hydroxylation of cholesteryl acetate with dioxygen induced by iron picolinate complexes

Article abstract of DOI:10.1248/cpb.52.756

The oxygenation reaction of cholesteryl acetate 1 was examined with the Fe^III(PA)₃/O₂/MeCN system using an electrochemical method. The constant potential technique gave mainly the 7-hydroxylated product stereoselectively, along with the 7-oxo product. This oxygenation system is mechanistically unique, requiring iron catalyst, dioxygen, and both cathode and anode.

Full text of DOI:10.1248/cpb.52.756

756
Chem. Pharm. Bull. 52(6) 756—759 (2004)
Vol. 52, No. 6
A New Electrochemical System for Stereoselective Allylic Hydroxylation of
Cholesteryl Acetate with Dioxygen Induced by Iron Picolinate Complexes
*
Iwao OKAMOTO, Wataru FUNAKI, Kyosuke NAKAYA, Eiichi KOTANI, and Tetsuya TAKEYA
Showa Pharmaceutical University; 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received March 4, 2004; accepted April 5, 2004; published online April 8, 2004
The oxygenation reaction of cholesteryl acetate 1 was examined with the FeIII(PA)3/O2/MeCN system using
an electrochemical method. The constant potential technique gave mainly the 7-hydroxylated product stereose-
lectively, along with the 7-oxo product. This oxygenation system is mechanistically unique, requiring iron cata-
lyst, dioxygen, and both cathode and anode.
Key words allylic hydroxylation; iron catalysis; electrochemical oxidation; 7a-hydroxylation
[reagent system (A)] or FeII(PA)2/O2/MeCN [reagent system
Many investigations of oxygenation reactions using vari-
(B)] and electrolysis without hydrogen peroxide.
ous chemical or electrochemical systems mimicking mono-
oxygenase enzymes have been reported. Among these oxy-
genation models, studies on chemical systems using iron(III)
picolinate (FeIII(PA)3) or iron(II) picolinate (FeII(PA)2) com-
plexes as catalysts have been reported under various condi-
tions and in various solvents.1—5) We are interested in stere-
oselective oxidation reactions, especially 7a-hydroxylation
of 3b-acetoxy-D5-steroids, including cholesterol and oxy-
sterols, from the viewpoints of their metabolism and biosyn-
thesis.6—8)
In the preceding paper, we reported a convenient oxidation
system using FeIII(PA)3/H2O2/MeCN (acetonitrile) as an al-
ternative to the chemical Gif model system (GoAggIII),
which is effective for stereoselective allylic hydroxylation of
steroids.9—11) However, hydrogen peroxide is potentially ex-
plosive, and is undesirable for large-scale reactions. On the
other hand, the electrochemical method is useful for a variety
of oxidations, because the redox potential can be controlled
easily, and sometimes the reaction provides unique products
and mechanisms. Recently Maki et al. have applied electro-
chemical methods to biomimetic oxidation systems.12—14) We
herein report new and unique electrochemical systems for
oxygenation, particularly stereoselective allylic hydroxyla-
tion, involving the combination of FeIII(PA)3/O2/MeCN
Results and Discussion
The reactions were conducted under similar conditions in
all cases. Cholesteryl acetate (0.3 mmol) was dissolved in a
0.1 M solution of tetra n-butyl ammonium tetrafluoroborate as
a supporting electrolyte in acetonitrile. The H-shaped one-
compartment glass cell equipped with platinum mesh elec-
trodes (cathode and anode) was filled with the above solu-
tion, and O2 gas was bubbled through the mixture with mag-
netic stirring for 1 h at ambient temperature.
First, we investigated the reactions under constant current
conditions. The results are summarized in Table 1 and Chart
1. The yields are isolated yields, and the ratios of 2a : 2b
were calculated from the integration values in 1H-NMR mea-
surements of mixtures of the two isomers.10,15) Runs 1 and 2
show the results of the electrochemical reaction of 1 with the
reagent system (A) containing FeIII(PA)3 (0.06 mmol) as a
catalyst. In the case of run 1, the 7-hydroxylated compound 2
was the major product (21% conversion yield), as in the oxy-
genation reaction with the FeIII(PA)3/H2O2/MeCN system
mentioned above.10) Increased current did not improve the
yield, and caused decomposition of the substrate and prod-
ucts.
Table 1. Electrochemical Oxygenation of Cholesteryl Acetate (1) with Iron Complexes and Dioxygen in Acetonitrile under Constant Current Conditions
Product (%)b)
Runa)
Iron catalyst
Current (mA)
Ratio of 2a : 2b
2c)
3
4c)
1 (recovery)
1
2
3
4
5
6
FeIII(PA)3
FeIII(PA)3
25
50
25
50
25
50
7.1 (21)
4.7 (4.9)
19 (27)
9.2 (9.3)
2.9 (6.9)
4.7 (6.7)
4.0 (12)
6.6 (6.9)
8.7 (12)
12 (13)
4.7 (11)
6.4 (9.1)
1.4 (4.2)
1.7 (1.8)
2.6 (3.6)
2.7 (2.7)
2.1 (5.0)
2.9 (4.1)
67
4.3
29
0.7
58
30
100 : 7
100 : 9
100 : 5
100 : 3
100 : 8
100 : 7
FeII(PA)2
FeII(PA)2
Fe(ClO4)2-PA-Py
Fe(ClO4)2-PA-Py
a) The reaction was run in a one-compartment cell. b) Isolated yield, and conversion yield are shown in parentheses. c) A mixture of a- and b-isomers.
Chart 1. Oxygenation of Cholesteryl Acetate (1)
∗ To whom correspondence should be addressed. e-mail: takeya@ac.shoyaku.ac.jp
© 2004 Pharmaceutical Society of Japan

June 2004
757
Table 2. Electrochemical Oxygenation of Cholesteryl Acetate (1) with Iron Complexes and Dioxygen in Acetonitrile under Constant Potential Conditions
Product (%)a)
Potential of
Run
Iron catalyst
Ratio of 2a : 2b
working electrode
2b)
3
4b)
1 (recovery)
7c)
8c)
FeIII(PA)3
FeII(PA)2
FeII(ClO4)2
FeIII(PA)3
FeII(PA)2
FeIII(PA)3
FeIII(PA)3
FeIII(PA)3
—
ꢀ0.1 V
ꢀ0.1 V
ꢀ0.1 V
—
—
ꢀ0.1 V
ꢀ0.1 V
ꢁ2.0 V
ꢁ2.0 V
21 (28)
29 (38)
13 (19)
No reaction
No reaction
1.4
No reaction
8.3
9.0
11 (15)
14 (18)
13 (19)
No reaction
No reaction
0.9
No reaction
4.3
5.6
Trace
Trace
Trace
No reaction
No reaction
—
No reaction
—
26
24
33
100 : 8
100 : 7
100 : 70
9c)
10c)
11c)
12c,e)
13d)
14d)
15d)
16d)
17d,f)
77
100 : 62
77
56
30
52
100 : 66
100 : 64
—
—
Trace
FeIII(PA)3
FeIII(PA)3
ꢁ2.5 V
—
—
1.5
ꢀ0.1 V, then ꢁ2.0 V
12
100 : 19
a) Isolated yield, and conversion yield are given in parentheses. b) A mixture of a- and b-isomers. c) The reaction was run in the undivided cell. d) The reaction was
run in the divided cell. e) The reaction was conducted under argon bubbling. f) The reaction time and conditions are different from those of other runs, see the text.
The electrochemical reaction with the reagent system (B) glass filter. In contrast, the anodic reaction (ꢁ2.0 V vs.
containing FeII(PA)2 (0.06 mmol) as a catalyst gave similar Ag/AgCl) of 1 using reagent system (A) in the divided cell
results under constant current conditions with both 25 and afforded 2 (8.3%) and 3 (4.3%), but the stereoselectivity for
50 mA current, as shown in runs 3 and 4. The reagent system 2a was poor (run 14, 2a : 2bꢂ100 : 66). This decreased
(B), prepared in situ, resulted in moderate yield (runs 5 and stereoselectivity suggests that the oxygenation reaction in
6), but the 7-keto product 3 predominates in comparison with run 14 may proceed without the participation or influence of
other systems. In all of these constant current reactions, the iron complex containing PA; in other words, substrate 1 is
7-hydroxylation showed a-preference (ratio of over 100 : 9).
not oxidized by the iron complex generated from the electrol-
Next, we investigated the reactions in the constant poten- yses of the reagent system (A) or (B),17) but rather, direct an-
tial mode using a one-compartment cell under the following odic oxidation may occur. In fact, in run 15, the direct anodic
conditions. Since the redox potential of FeIII(PA)3 in acetoni- oxidation (ꢁ2.0 V vs. Ag/AgCl) of 1 with continuous bub-
trile was ꢀ0.08 V vs. Ag/AgCl, the cathode potential was set bling of dioxygen gas in acetonitrile gave a similar result to
to ꢀ0.1 V. This potential is considered to be suitable, since it run 14 in terms of product yields and stereoselectivity. Al-
permits the one-electron reduction of FeIII(PA)3 in acetoni- though increasing the potential caused a decrease of the re-
trile, and is not effective for reduction of dioxygen.16) Other covered substrate 1, no product such as 2 or 3 was formed in
reaction conditions were similar to those in the constant cur- run 16. These results showed that direct anodic reaction of 1
rent electrolysis reactions, and the results are summarized in could not give a similar result to run 7 or 8 in terms of the
Table 2.
yield or stereoselectivity; in other words, our oxygenation
The result of run 7 showed that the electrochemical reac- system is different from direct anodic reaction.
tion of 1 using reagent system (A) containing FeIII(PA)3 as a
Finally, in order to confirm the reaction sequence in our
catalyst gave the 7-hydroxylated product 2 (21%) as the electrochemical oxygenation in run 7, the stepwise electro-
major product along with the ketone 3 (11%) and a trace chemical reaction with reagent system (A) was carried out
amount of epoxide 4. In the case of the electrochemical reac- (run 17) under a constant potential condition in a divided
tion using reagent system (B) containing FeII(PA)2, a similar cell. The procedure was carried out in the working electrode
result was obtained (run 8). The hydroxylation in both runs 7 compartment of the divided cell, and the counter electrode
and 8 stereoselectively afforded the 7a-hydroxylated product compartment was filled with the solution of ammonium salt
in better yield than constant current conditions. When the in acetonitrile.
iron(II) perchlorate, which lacks the PA moiety as a ligand,
Cathodic electrolysis at ꢀ0.1 V (vs. Ag/AgCl) of FeIII(PA)3
was used as a catalyst in run 9, the oxidation proceeded to (1.0 equiv.) in acetonitrile was performed for 5 min with bub-
give a product mixture of 2, 3 and 4, including the 7a-hy- bling of argon gas. After the first electrolysis was stopped, O2
a
droxylated product 2 , along with significant amount of the was bubbled through the resulting reaction mixture, and then
b
b-isomer 2 . This result indicated that iron complex with PA substrate 1 was added. The working electrode was switched
as a ligand is essential for stereoselective 7a-hydroxylation.
to the anode, and the above acetonitrile solution containing
In order to research the requirements for the reaction in the substrate 1 was subjected to anodic electrolysis at ꢁ2.0 V
runs 7 and 8, the following reactions were conducted. The re- (vs. Ag/AgCl) with bubbling of argon gas for 15 min. These
action using reagent system (A) or (B) without electrolysis reactions finally afforded 2 (12%) stereoselectively as a
gave no product (runs 10 and 11). In run 12, when the elec- major product, a result similar to those of runs 7 and 8. This
trochemical reaction was conducted using the reagent system result in run 17 provides some clues to the reaction mecha-
(A) with bubbling of argon instead of O2, the reaction did not nism of electrochemical oxygenation of 1.
proceed to any great extent.
In the present electrochemical oxygenation using reagent
On the other hand, in run 13, no reaction took place under systems (A) and (B), the precise mechanism remains to be
similar conditions to run 7, but using a divided cell, in which investigated in detail, but some aspects of above results de-
the anode and the cathode compartments are separated with a serve comment. This oxygenation, including stereoselective

758
Vol. 52, No. 6
Chart 2. Proposed Mechanism for the Oxygenation of Cholesteryl Acetate
Chart 3. Oxygenation of Methyl 3-O-Acetyl-oleanolate (5)
allylic hydroxylation, did not proceed at all without electroly- posed by us for the oxygenation with the chemical system
ses (both reduction and oxidation) or under conditions which FeIII(PA)3/H2O2/MeCN.10) Because the stereoselectivity of the
omitted any one of the reagents, dioxygen or iron complex 7-hydroxylation requires PA as a ligand, a steric effect can be
with PA as a ligand; in other words, the “FeIII(PA)3 or considered as the main reason for the selectivity. After the
FeII(PA)2/O2/cathodic reduction/anodic oxidation” system as oxygenation of 1 by complex VI, cathodic reduction of com-
a whole is essential to promote the reaction. From this point plex VII in the presence of PA and protons, which are gener-
of view, our electrochemical system is definitely different ated by the former step, takes place to form complex II as
from the Gif-Orsay system18,19) or the electrochemical system the hydrated form. In the case of the electrochemical reaction
using both electrodes reported by Maki et al.20)
with the reagent system (B), a similar mechanism can be pro-
A likely mechanism for the electrochemical oxygenation posed except for the first stage, i.e. the formation of FeII com-
using system (A) is summarized in Chart 2. As we reported plex.
before, iron(III) picolinate is in an equilibrium of hydrated
Finally, our electrochemical oxygenation using system (A)
and anhydrous forms in acetonitrile. That is, in the first stage, was applied to the reaction of methyl 3-O-acetyl-oleanolate
the cathodic reduction of FeIII(PA)3(H2O) (I) to the FeII com- (5). The reaction was run in constant potential manner, like
a
plex (II) take place. This is supported by the change in color run 7, and yielded the 11-a hydroxylated compound 6
from pale-yellow to deep-red. In the next step, dioxygen gas (21%) stereoselectively without the formation of the b-iso-
a
is adsorbed on the resulting iron complex II, which under- mer, and the ketone 7 (14%) (Chart 3). The yield of 6 was
goes auto-oxidation by O2 to form the iron m-oxo-dimer, better than that of the oxidation using chemical system
FeIII–O–FeIII complex.21,22) This dioxygen adsorption was FeIII(PA)3/H2O2/MeCN, reported previously by us.11)
confirmed in another experiment using a gas burette, show-
ing that 0.5 equivalent amount of dioxygen to iron catalyst Conclusion
was adsorbed. Subsequently, the anodic oxidation of complex
We present a new method of stereoselective allylic hydrox-
III proceeds to yield the high valence species, the ylation using electrochemical method. This reaction is
FeIV–O–FeIV complex (IV), in which water oxidation is in- unique in the sense that it requires dioxygen, iron(III) picoli-
duced by the FeIV atom, and ring closure proceeds to form nate complex and both anode and cathode.
the Fe2-m(O)2 complex (V) along with deprotonation.23—26)
Experimental
After that, the ring cleavage of complex V results in the
All melting points are uncorrected. Infrared (IR) spectra were recorded
formation of the dimeric FeIII–FeV manifold complex,
with a JASCO IR-700 spectrometer, and 1H- and 13C-NMR spectra with
(H2O)(PA)2FeIII–O–FeVꢂO(PA)2 (VI) as an active intermedi-
JEOL JNM-EX90, JNM-GX270, JNM-AL300, and JNM-GSX500 spec-
ate that can work as a monooxygenating species for 1.27,28) In trometers, with tetramethylsilane as an internal standard (CDCl3 solution).
Chemical shifts are recorded in ppm, and coupling constants (J) are
the oxygenation of 1, the oxygen source for hydroxyl and ke-
tone formation at the C7 position in 2 and 3 is considered to
be either dioxygen or water via complex I, though the details
recorded in Hz. Mass spectra were recorded on a JEOL JMS-D300 spec-
trometer. Elemental analyses were performed on a Yanaco CHN-MT-3 appa-
ratus and a Amco Flash EA 1112 instrument. Wako silica gel C-200 (200
mesh) and Merck Kieselgel 60 F254 were used for column chromatography
are not clear. The mechanism of stereoselective 7a-hydroxy-
and thin-layer chromatography (TLC), respectively. Preparative HPLC
a
lation leading to the formation of 2 is analogous to that pro-

June 2004
759
(high-performance liquid chromatography) was carried out with a JASCO
HPLC system (pump, JASCO 880; RI detector, JASCO 830) using a silica-
3301-N (Senshu Pac, 8 f3300 mm i.d.) column.
tor, and the residue was flash-chromatographed (ethyl acetate : hexane
ꢂ1 : 20), affording 3 (1.5%), a trace amount of 4, 52% recovery of 1, and 2
(12%) as an a/b mixture (100 : 19).
Preparation of Iron(III) Picolinate Complexes Iron(III) perchlorate
was a commercial product, used without further purification. Each iron com-
plex was prepared as follows, and checked by elemental analysis.
Electrochemical Oxygenation Reaction of Methyl 3-O-Acetyl-
oleanolate (5) Methyl 3-O-acetyl-oleanolate (5) (51.5 mg) and iron cata-
lyst (0.02 mmol) were dissolved in 0.1 M solution of tetra n-butylammonium
FeIII(PA)3·4H2O A solution of iron(III) perchlorate 9-hydrate (1.58 g, tetrafluoroborate in 40 ml of acetonitrile. In the H-shaped undivided glass
3.3 mmol) in 10 ml of water was added to a solution of picolinic acid (1.23 g,
cell, this reaction mixture was electrolyzed at ꢀ0.1 V with dioxygen gas
10 mmol) and sodium hydroxide (0.4 g, 10 mmol) in 10 ml of water with stir- bubbling. After 30 min, the resulting mixture was poured into ice-water, and
ring at ambient temperature. The resulting pale yellow powder was collected extracted with ether. The combined organic layer was washed with 10% hy-
by filtration and dried in vacuo. Anal. Calcd for C18H14N3O7Fe: C, 51.21; H, drochloric acid, saturated sodium bicarbonate, and brine, then dried over
2.87; N, 9.95; Found: C, 51.24; H, 3.01; N, 9.97.
magnesium sulfate, and filtered. The solvent was removed with an evapora-
tor, and the residue was flash-chromatographed (ethyl acetate : hexane
ꢂ1 : 20), affording 6a (21%), 7 (14%), recovered 5 (22%), and trace
FeIII(PA)3 The hydrated complex obtained as above was recrystallized
from anhydrous acetonitrile, and pale green prisms were obtained mp 285—
287 °C. Anal. Calcd for C18H12N3O6Fe: C, 49.12; H, 3.21; N, 9.55; Found: C, amounts of 12,13-epoxide and 12-oxo compounds. The 1H-NMR peaks were
49.97; H, 3.16; N, 9.52.
identical to those we reported before.11)
FeII(PA)2·4H2O A solution of iron(II) perchlorate hexahydrate (1.81 g,
5 mmol) in 10 ml of water was added to a solution of picolinic acid (1.23 g,
10 mmol) and sodium hydroxide (0.4 g, 10 mmol) in 10 ml of water29,30) in an
argon atmosphere using an AtmosBag. The resulting red-orange crystals
were filtered under an argon stream, and used without further purification.
General Procedure for Electrochemical Reactions Cholesteryl acetate
(0.3 mmol) and iron catalyst (0.06 mmol) in hydrated form were dissolved in
a 0.1 M solution of tetra n-butylammonium tetrafluoroborate in 40 ml of ace-
tonitrile. In the H-shaped glass cell equipped with platinum mesh electrodes
(cathode and anode), this reaction mixture was electrolyzed under each con-
dition with gas bubbling. After 1 h, the resulting mixture was poured into
ice-water, and extracted with ether. The combined organic layer was washed
with 10% hydrochloric acid, saturated sodium bicarbonate, and brine, then
dried over magnesium sulfate, and filtered. The solvent was removed with
an evaporator, and the residue was flash-chromatographed (ethyl
acetate : hexaneꢂ1 : 20), affording 3, recovered 1, a mixture of 2a and 2b,
and a mixture of 4a and 4b were given. The product ratio of 2a/2b was
measured in terms of the integration ratio of the C7 proton peak. Further
separation of these a/b products was performed with HPLC. Spectroscopic
characteristics for each product were identical with those we reported before
and those in the literature.10,11) The characteristic 1H-NMR signals are as fol-
lows:
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Electrochemical Reaction in Run 17 The working electrode compart-
ment of the divided cell was filled with a solution of 44.0 mg (0.1 mmol) of
iron catalyst in 20 ml of 0.1 M solution of n-butylammonium tetrafluorobo-
rate in acetonitrile, and the counter electrode compartment was filled with
20 ml of a solution of 0.1 M electrolyte in acetonitrile. After the bubbling of
argon for 10 min, electrolysis was done at ꢀ0.1 V for 5 min with argon bub-
bling, then stopped. The working electrode compartment of the divided cell
was bubbled with dioxygen for 15 min, then the substrate 1 was added. After
the bubbling of argon for 10 min, electrolysis was done at ꢁ2.0 V for 15 min
with argon bubbling. The resulting mixture was poured into ice water, and
extracted with ether. The combined organic layer was washed with 10% hy-
drochloric acid, saturated sodium bicarbonate, and brine, then dried over
magnesium sulfate, and filtered. The solvent was removed with an evapora-
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