Metal-Free Allylic Oxidation of Steroids Using TBAI/TBHP Organocatalytic Protocol

Article abstract of DOI:10.1002/asia.201800256

A mild, efficient and organocatalytic allylic oxidation of steroids using a TBAI/TBHP protocol has been developed. A range of bioactive Δ⁵-en-7-ones can be easily prepared from the corresponding Δ⁵-steroids. The methodology features several advantages, including readily available starting materials, environmentally benign oxidant, high functional group compatibility, and metal-free catalysis.

Full text of DOI:10.1002/asia.201800256

CHEMISTRY
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Accepted Article
Title: Metal-free Allylic Oxidation of Steroids Using TBAI/TBHP
Organocatalytic Protocol
Authors: Ying-Pong Lam and Ying-Yeung Yeung
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Chemistry - An Asian Journal
10.1002/asia.201800256
COMMUNICATION
Metal-free Allylic Oxidation of Steroids Using TBAI/TBHP
Organocatalytic Protocol
[a]
[a]
Ying-Pong Lam and Ying-Yeung Yeung*
Abstract: A mild, efficient and organocatalytic allylic oxidation of
our group developed an allylic oxidation protocol using the
hypervalent iodine reagent diacetoxyiodobenzene (DIB) and
TBHP (Scheme 1, eq. 1). While a board substrate scope has
been achieved under very mild conditions, significant amount of
by-product was generated since stoichiometric amount of DIB
was used in the transformation.
steroids using the TBAI/TBHP protocol was developed. A range of
5
[19]
bioactive  -en-7-ones can be easily prepared from the
5
corresponding  -steroids. The methodology features advantages
including readily available starting materials, environmentally benign
oxidant, high functional group compatibility, and metal-free catalysis.
Allylic oxidation of olefins is a useful organic transformation. The
corresponding ,-unsaturated enone products are common
[
1]
pharmacophores and building blocks in organic synthesis.
5
5
Allylic oxidation of  -steroids to  -en-7-ones is of particular
interest since  -en-7-ones exhibit outstanding potential in the
5
pharmaceutical aspect. For instances, 7-oxo-cholesterol shows
high potency in anti-cancer treatment[2] and 7-oxo-
dehydroepiandrosterone (7-oxo-DEHA) was found to be
effective in inducing thermogenic enzymes and enhancement of
memory in old mice.[3,4]
Classical methods for allylic oxidation involve the use of
[
5]
chromium (VI) reagents such as chromium trioxide, chromium
pyridinium chlorochromate[ and chromium trioxide-pyridine
complex.[ However, environmentally hazardous chromium
residues are produced in the processes. Besides, the tedious
work-up procedures cause immense inconvenience on
commercial-scale production. Methodologies using other
6]
7]
Scheme 1. Metal-free allylic oxidation of steroids.
metallic reagents or catalysts such as copper,[ cobalt,
8]
[9]
palladium,[ iron,[11] manganese,[12] rhodium[13] and bismuth[14]
for allylic oxidation of olefins and steroids are also documented.
While reasonably high reaction yields were obtained in these
cases, however, methods using metallic reagents or catalysts
encounter some problems such as low functional group
tolerance, high cost, low regioselectivity and/or difficult catalyst
preparation, which diminish the attractiveness of these methods
from the industrial and environmental points of view.
10]
The
combination
of
catalytic
amount
tetra-n-
butylammonium iodide (TBAI) and stoichiometric amount TBHP
was discovered to be a powerful catalytic system, which has
been subjected to various oxidation reactions.[20] It is believed
that the hypoiodite species could be generated in-situ in the
TBAI/TBHP protocol.[21-23] We hypothesized that the TBAI/TBHP
protocol might be applicable in the allylic oxidation of olefins.
Herein, we are pleased to report an efficient metal-free allylic
oxidation of steroids using catalytic amount of TBAI (Scheme 1,
eq. 2). To the best of our knowledge, this report represents the
first case of organocatalytic allylic oxidation of olefins that results
in the formation of ,-unsaturated ketones.
The increasing concern on environmental issue led
chemists to develop greener and metal-free allylic oxidation
protocols. Metal-free systems can also be adopted in the
preparation of compounds that do not tolerate metal
contamination such as pharmaceutical products.[15] In 1996,
Ochiai reported a seminal work on using the stable peroxy
compound 1-(tert-butylperoxy)-1,2-benziodoxol-3(1H)-one as the
stoichiometric amount of oxidant for allylic oxidation reactions.[16]
Sodium hypochlorite in combination with aqueous tert-butyl
hydroperoxide (TBHP) was also reported to perform allylic and
benzylic oxidations.[17] Later, sodium chlorite in combination with
either TBHP or N-hydroxyphthalimide was found to be useful in
the allylic oxidation of a range of olefinic substrates.[18] Recently,
To test the hypothesis, cholesteryl acetate (1a) was used
as the olefinic substrate with dichloromethane as the solvent at
o
23 C. To our delight, it was found that 1a could be oxidized to
5
the corresponding ∆ -en-7-one 2a in 37% yield after 48 hours in
the presence of 20 mol% of TBAI and 2 equivalents TBHP
(Scheme 2, eq. 1). 7β-hydroxycholes-5-en-3β-yl acetate (2a’)
(10%) was also isolated together with the recovery of 30% of the
starting material. This result revealed the potential of using TBAI
as a catalyst for the allylic oxidation of steroids in the presence
of TBHP as the co-oxidant. Next, cholesterol (1b) was subjected
to the investigation. Many of the allylic oxidation methods[ are
not compatible with unprotected hydroxyl group at the C(3)
carbon of cholesterol since it can be oxidized to ketone readily.
Surprisingly, the TBAI/TPHP catalytic protocol could oxidize 1b
to yield 3β-hydroxycholest-5-en-7-one (2b) as the major product
in 37% yield, suggesting that the allylic oxidation protocol has
high functional group compatibility (Scheme 2, eq. 2).
2c]
[
a]
Mr. Y.-P. Lam, Prof. Dr. Y.-Y. Yeung
Department of Chemistry
The Chinese University of Hong Kong
Shatin, N.T., Hong Kong (China)
E-mail: yyyeung@cuhk.edu.hk
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
TBAI was found to be the optimal catalyst loading (entries 2, 5
and 6). Prolonging the reaction time (entry 7) or varying the
temperature (entries 8 and 9) was found to be ineffective in
improving the conversion. The catalytic activity of TBAI was
found to be superior to tetra-n-butylammonium chloride (TBAC)
and tetra-n-butylammonium bromide (TBAB) (entries 10 and 11).
A number of steroidal substrates 1 were subjected to the
evaluation under the optimized conditions (Table 2). Generally,
Table 2. Scope of the allylic oxidation.
Scheme 2. Preliminary study on the TBAI-catalyzed allylic oxidation.
After verifying our hypothesis, the reaction was further
optimized by varying the parameters. The amount of TBHP was
first evaluated. Reducing the amount of TBHP returned a lower
conversion (Table 1, entry 1). On the other hand, the reaction
yield was improved when applying 4 equivalents of TBHP (entry
3). Further increasing the amount of TBHP did not result in a
significant improvement of the reaction yield (entry 4). The
amount of catalyst loading was also investigated and 20 mol% of
Table 1. Reaction optimization.
Entry[a]
TBAI (mol%)
TBHP (equiv)
Temp ( C)
o
Yield (%)[b]
1
20
20
20
20
15
25
20
20
20
20
20
1
2
4
8
4
4
2
2
2
4
4
23
23
23
23
23
23
23
0
25
30
53
56
45
53
37
36
30
30
45
2
3
4
5
6
7[c]
8
9
10
23
23
1
0[d]
1[e]
1
[
a] The reactions were performed using 1b (0.2 mmol), TBAI, and TBHP in
CH Cl (1 mL) for 48 h under the conditions indicated in the Table. [b]
Isolated yield. [c] The reaction time was 120 h. [d] TBAC was used instead
of TBAI. [e] TBAB was used instead of TBAI.
2
2
[
a] The reactions were performed using 1 (0.3 mmol), TBAI (0.06 mmol),
(1.5 mL) at 23 oC for 48 h. The yields were
TBHP (1.2 mmol) in CH Cl
isolated yields. [b] The reaction was conducted at 1.0 g scale.
2
2
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COMMUNICATION
the steroids
corresponding  -en-7-ones
1
were successfully transformed into the
proton from olefin 1 to form the allyl radical A, which could then
couple with another tert-butyl peroxy radical to give the peroxy
species B. The existence of the peroxy intermediate B was
evidenced by the successful tracing of the peroxy ether derived
from 1b using mass spectrometry (see Supporting Information
for detail). Further oxidation process might collapse the peroxy
species B to give the enone product 2 together with the
regeneration of TBAI.
5
2
with good conversions and
regioselectivity using the TBAI/TBHP catalytic protocol. Other
than the protected cholesterol 1a (entry 1) and unprotected
cholesterol 1b (entry 2), chlorinated cholesterol 1c also worked
well to give the desired enone product 2c (entry 3). The reaction
was also found to be compatible with other functionalities at the
C(3) position including silyl ether, trityl, and benzoate (entries 5–
7
). Diosgenin 1g and its acetyl derivative 1h that bear an acid-
sensitive acetal could survive under the mild reaction conditions
entries and 9). Pregnenolone (1i and 1j) and
(
8
dehydroepiandrosterone (1k and 1l) that contain ketone
functionalities could also give rise to the corresponding enones
2i–2l smoothly (entries 10–13). The results revealed great
chemoselectivity of the oxidation system towards the allylic
position. In addition, gram-scale allylic oxidation of cholesterol
1b was conducted and comparable reaction yield of the desired
product 2b was obtained (entry 3 vs 2).
To get a better understanding on the mechanistic picture,
several controlled experiments were conducted. First, no
reaction was observed and the starting material 1b was
recovered quantitatively upon the addition of radical scavenger
butylated hydroxytoluene (BHT), suggesting that
a radical
mechanism might be involved (Scheme 3, eq. 1). Second, allylic
oxidation of 1b was examined using molecular iodine (1
equivalent)
and
tetra-n-butylammonium
hydroxide
(2
equivalents) in place of TBAI and TBHP, and no reaction was
observed (Scheme 3, eq. 2). Since it is known that the putative
active species tetra-n-butylammonium hypoiodite could be
generated from the reaction between iodine and tetra-n-
butylammonium hydroxide,[22,24] this result suggests that tetra-n-
butylammonium hypoiodite, which is also believed to be the
active species in the reaction with TBAI/TBHP,[21-23] is insufficient
to drive the allylic oxidation and TBHP might play a separated
role.
Scheme 4. A plausible reaction mechanism.
In summary, a mild, efficient, regioselective, and metal-free
allylic oxidation catalytic protocol using TBAI as the catalyst and
TBHP as the stoichiometric oxidant has been developed. A
number of pharmaceutically important 5-en-7-ones were
successfully prepared using this metal-free catalytic protocol
Experimental Section
General procedure for the allylic oxidation using TBAI and TBHP
To a solution of steroid 1 (0.3 mmol, 1.0 equiv.) in dichloromethane (1.5
mL) was added tetra-n-butylammonium iodide (22 mg, 0.06 mmol) at 23
C. The resultant suspension was vigorously stirred and a solution of tert-
Scheme 3. Controlled experiments.
o
butylhydroperoxide (6.0 M in decane, 200 휇L, 1.2 mmol) was added. The
resultant mixture was further stirred for 48 h at the same temperature
under protection of inert atmosphere. The reaction was concentrated
under reduced pressure and the residue was purified by column
While a more detailed study is needed in order to elucidate
a clearer mechanistic picture, at this stage we speculate that
TBAI might be oxidized to generate tetra-n-butylammonium
hypoiodite and tetra-n-butylammonium iodite in-situ (Scheme
5
chromatography on silica gel to yield the corresponding  -en-7-ones 2.
4
).[21-23] We suspect that quaternary ammonium hypoiodite and
iodite might further react with TBHP to give tert-butyl peroxy
radical.[20] The tert-butyl peroxy radical might abstract the allylic
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COMMUNICATION
[
11] D. R. H. Barton, V. N. Le Gloahec, Tetrahedron 1998, 54, 15457–
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We thank the Hong Kong Special Administrative Region
University Grant Council (RGC Ref. No. CUHK14315716) and
The Chinese University of Hong Kong Direct Grant (Project
code: 4053203) for financial supports. The equipment was
partially supported by the Faculty Strategic Fund for Research
from the Faculty of Science of the Chinese University of Hong
Kong.
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Keywords: allylic oxidation • enone • hypoiodite •
organocatalysis • steroid
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COMMUNICATION
COMMUNICATION
Ying-Pong Lam and Ying-Yeung Yeung*
Page No. – Page No.
Metal-free Allylic Oxidation of
Steroids Using TBAI/TBHP
Organocatalytic Protocol
A mild, efficient and organocatalytic allylic oxidation of steroids using the
5
TBAI/TBHP protocol was developed. A range of bioactive  -en-7-ones can be
5
easily prepared from the corresponding  -steroids. The methodology features
advantages including readily available starting materials, environmentally benign
oxidant, high functional group compatibility, and metal-free catalysis.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.