Optimal TBHP allylic oxidation of Δ5 - Steroids catalyzed by dirhodium caprolactamate

Article abstract of DOI:10.1021/ol7025284

Dirhodium caprolactamate is the most efficient catalyst for the oxidation of Δ⁵-steroids to 7-keto-Δ⁵-steroids by 70% tert-butyl hydroperoxide in water (T-HYDRO). Isolated product yields range from 38 to 87%.

Full text of DOI:10.1021/ol7025284

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5349-5352
Optimal TBHP Allylic Oxidation of
5-Steroids Catalyzed by Dirhodium
Caprolactamate
∆
Hojae Choi and Michael P. Doyle*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
mdoyle3@umd.edu
Received August 10, 2007
ABSTRACT
Dirhodium caprolactamate is the most efficient catalyst for the oxidation of
in water (T-HYDRO). Isolated product yields range from 38 to 87%.
∆
5-steroids to 7-keto-
∆
5-steroids by 70% tert-butyl hydroperoxide
Few substrates have commanded as much attention for allylic
oxidation as have ∆5-steroids. Intense interest has been
emerging concerning the biological effects of the 7-keto
steroid oxidation products that are indicated in their increas-
ingly evident physiological effects.1,2 Selenium dioxide is
inappropriate as an oxidant because this reagent favors
oxidation at the 4-position,3 and stoichiometric chromium-
(VI) oxidations4 are disfavored because of the relative
severity of reaction conditions and environmental concerns.1a
Recently, tert-butyl hydroperoxide has become the oxidant
of choice for steroidal allylic oxidations, but the defining
ingredient in these oxidations is the promoter or catalyst,
and the optimal methodology is unclear. Since 2000 alone,
allylic oxidation methodologies for steroids using tert-butyl
hydroperoxide (TBHP) have been reported to be catalyzed
or promoted by sodium chlorite,5 chromium (VI),6 manga-
nese(III) acetate,7 bismuth(III) salts,8 copper iodide,9 and
cobalt acetate.10 Chromium-mediated oxidations have re-
ceived the most attention,11 but ruthenium(III) chloride
catalysis in large-scale applications was found to be more
advantageous.12 We reported in 2004 a new catalytic system
for allylic oxidations using TBHP that was extraordinarily
effective for simple cyclic systems, providing enone product
with complete regioselectivity and in high yield with the use
of catalyst loadings of between 0.1 and 1.0 mol % of
(1) Reviews: (a) Parish, E. J.; Kizito, S. A.; Qiu, Z. Lipids 2004, 801.
(b) Arsenou, E. S.; Fousteris, M. A.; Koutsourea, A. I.; Nikolaropoulos, S.
S. Mini ReV. Med. Chem. 2003, 3, 557. (c) Smith, L. Lipids 1996, 31, 453.
(d) Peng, S.-K.; Morin, R. J. The Biological Effects of Cholesterol Oxides;
CRC Press: Boca Raton, FL, 1992.
(2) (a) Lee, J. W.; Fuda, H.; Javitt, N. B.; Strott, C. A.; Rodriguez, I. R.
Exp. Eye Res. 2006, 83, 465. (b) Berthier, A.; Lemaire-Ewing, S.; Prunet,
C.; Monier, S.; Athias, A.; Bessade, G.; Paisde Barros, J.-P.; Laubriet, A.;
Gambert, P.; Lizard, G.; Nacel, D. Cell Death Differ. 2004, 11, 897. (c)
Deckert, V.; Duverneuil, L.; Poupon, S.; Monier, S.; de Guern, N.; Lizard,
G.; Masson, D.; Lagrost, L. Brit. J. Pharm. 2002, 137, 655. (d) Steffen,
Y.; Wiswedel, I.; Peter, D.; Schewe, T.; Sies, H. Free Radicals Biol. Med.
2006, 41, 1139. (e) Javitt, N. B. Curr. Opin. Lipidol. 2007, 18, 283.
(3) (a) Rabjohn, N. Org. React. 1976, 24, 261. (b) Crich, D.; Zou, Y.
Org. Lett. 2004, 6, 775.
(4) (a) Hua, Z.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J.
J. Org. Chem. 2005, 70, 9849. (b) Bora, U.; Chaudhuri, M. K.; Dey, D.;
Kalita, D.; Kharmawphlang, W.; Mandal, G. C. Tetrahedron 2001, 57, 2445.
(c) Kasal, A. Tetrahedron 2000, 56, 3559. (d) Li, D.; Spencer, T. A. Steroids
2000, 65, 529. (e) Labaree, D.; Hoyte, R. M.; Hochberg, R. B. Steroids
1998, 63, 454. (f) Parish, E. J.; Wei, T.-Y. Synth. Commun. 1987, 17, 1227.
(g) Dauben, W. G.; Fullertyon, D. S. J. Org. Chem. 1971, 36, 3277.
(5) Silvestre, S. M.; Salvador, J. A. R. Tetrahedron 2007, 63, 2439.
(6) Fousteris, M. A.; Koutsourea, A. I.; Nikolaropoulos, S. S.; Riahi,
A.; Muzart, J. J. Mol. Catal. A: Chem. 2006, 250, 70.
(7) Shing, T. K. M.; Yeung, Y. Y.; Su, P. L. Org. Lett. 2006, 8,
3149.
(8) Salvador, J. A. R.; Silvestre, S. M. Tetrahedron Lett. 2005, 46,
2581.
(9) Arsenou, E. S.; Koutsourea, A. I.; Fousteris, M. A.; Nikolaropoulos,
S. S. Steroids 2003, 68, 407.
(10) Salvador, J. A. R.; Clark, J. H. Chem. Commun. 2001, 33.
(11) (a) Baptistella, L. H.; Sousa, I. M. O.; Gushikem, Y.; Aleixo, A.
M. Tetrahedron Lett. 1999, 40, 2595. (b) Muzart, J. Synth. Commun. 1989,
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(12) Miller, R. A.; Li, W.; Humphrey, G. R. Tetrahedron Lett. 1996,
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10.1021/ol7025284 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/21/2007

dirhodium caprolactamate, Rh2(cap)4.13 The tert-butyl hy-
droperoxide oxidant was the anhydrous reagent in decane
that has been favored by several investigators in order to
avoid hydrolysis of the catalyst. We can now report that
dirhodium caprolactamate is exceptionally effective for the
oxidation of ∆5-steroids and even those that possess oxida-
tively sensitive groups, using the much less expensive 70%
TBHP in water (T-HYDRO).
high product yield, use of T-HYDRO instead of tert-butyl
hydroperoxide in decane, catalyst loading down to 0.1 mol
%, less T-HYDRO than most methods, moderate tempera-
tures and time. In contrast to the other catalysts or promoters,
the oxidized Rh2(cap)4 that is formed upon reaction with
TBHP is soluble in both water and the organic solvent, thus
minimizing operational concerns that are related to two-phase
reaction systems.
Previous reports for oxidations by TBHP cover a wide
range of conditions, so direct comparison is difficult.
However, cholesteryl acetate (1) is common to virtually all
studies, and comparative results for its conversion to the
7-keto-∆5 product (2, eq 1) are described in Table 1, along
The Rh2(cap)4-catalyzed oxidation was performed on a
millimole scale with ∆5-steroids using 0.1-1.0 mol % of
Rh2(cap)4. 1,2-Dichloroethane was added to dissolve the
steroid, the solution was heated to 40 °C, and then T-
HYDRO was added in one portion. The original blue color
of Rh2(cap)4 turned deep-red upon mixing with tert-butyl
hydroperoxide, consistent with formation of Rh(II)/Rh(III)
caprolactamate. The reaction solution was stirred for 20 h
at 40 °C, after which the solution was concentrated under
reduced pressure and subjected to purification by column
chromatography (1 cm diameter, 15 cm long glass column)
using hexane/ethyl acetate.
Isolated yields were determined by mass of the purified
product, and product identity was confirmed by NMR
spectroscopy with comparison, whenever possible, to spectra
of authentic samples.
Oxidation of cholesterol (3) is more challenging than the
oxidation of cholesteryl acetate, and we observe a compara-
tive decrease in the isolated yield of 7-ketocholesterol (4)
of 15-20% with the use of tert-butyl hydroperoxide as the
oxidant.14 Highly polar materials, believed to be acids from
oxidative cleavage, are formed whose identity has been
elusive. However, 7-ketocholesterol is easily isolated from
the reaction mixture in pure form by standard chromatog-
raphy (vide infra), and we have carried out the oxidation in
gram-scale using 0.1 mol % of Rh2(cap)4.
Optimization of this oxidation was achieved by investiga-
tion of the change in % conversion and isolated yield as a
function of temperature, amount of T-HYDRO, solvent, and
additive. Conversion is slow at room temperature, but
complete within 20 h at 40 °C; at 60 °C, oxidation is
considerably faster, but the catalyst undergoes hydrolysis at
a measurable rate. With 2.0 equiv of T-HYDRO, oxidation
reached 83% conversion within 20 h and was at 95%
conversion with 4.0 equiv of T-HYDRO over the same time,
the reason for which is competitive formation of both
stereoisomers of 7-hydroperoxy- (5) and 7-hydroxycholes-
terol (6)15 that undergo slow oxidation to 7-ketocholesterol
(Scheme 1). Dichloroethane was preferred over dichlo-
romethane because of its higher boiling point. The use of
toluene gave comparable results under comparable condi-
tions; however, oxidation was slower in cyclohexane, and
the use of either methanol or water without an organic
cosolvent resulted, as expected from solubility considerations,
Table 1. Method of Comparison for Oxidation of Cholesteryl
Acetate (1) by tert-Butyl Hydroperoxide
catalyst/
additive
(mol %)
TBHP
oxidant (equiv)
time temp yield 2
solvent
MeCN
(h) (°C)
(%)
NaClO2
(116%)
CrO3
(5%)/NMI
Mn3(OAc)9 t-BuOOH/
(10%)
BiCl3
(5%)
CuI (3%)/ T-HYDRO
Bu4NBr
T-HYDRO
10
80
23
48
22
24
60 66
(ref 5)
T-HYDRO
7
PhCF3
EtOAc
MeCN
benzene
40 74
(ref 6)
40 85
(ref 7)
70 82
(ref 8)
70 63
(ref 9)
5
decane
t-BuOOH/
decane
10
7
(6%)
Co(OAc)2 t-BuOOH/
6
benzene
48
70 70
(ref 10)
20 75
(ref 12)
(2.2%)
RuCl3
(0.7%)
decane
T-HYDRO
10
cyclohexane 24
Rh2(cap)4 T-HYDRO
(1.0%)
Rh2(cap)4 T-HYDRO
(0.1%)
5
8
(CH2Cl)2
(CH2Cl)2
20
20
40 80
40 77
with that for the Rh2(cap)4-catalyzed oxidation. As can
be seen from the table, the catalytic use of Rh2(cap)4 has
distinct advantages over other existing methodologies:
(14) Few publications report results for the oxidation of cholesterol;
oxidation of the 3-OH-protected substrate is reported instead.1,5-12
(15) (a) Akihisa, T.; Matsumoto, T.; Sakamaki, H.; Take, M.; Ichinohe,
Y. Bull. Chem. Soc. Jpn. 1986, 59, 680. (b) Dang, H.-S.; Davies, A. G.;
Davison, I. G. E.; Schiesser, C. H. J. Org. Chem. 1990, 55, 1432. (c) Ponce,
M. A.; Ramirez, J. A.; Galagovsky, L. R.; Gros, E. G.; Erra-Balsells, R. J.
Chem. Soc., Perkin Trans. 2 2000, 2351.
(13) Catino, J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
126, 13622.
5350
Org. Lett., Vol. 9, No. 26, 2007

Scheme 1
in a much slower rate of oxidation. Inorganic bases that
The usefulness of this oxidative methodology is linked to
its functional group tolerance, selectivity, and product yield.
Results from oxidations of cholesterol derivatives (7) by
T-HYDRO catalyzed by Rh2(cap)4 under conditions opti-
mized for oxidation of cholesterol suggest high functional
group compatibility (eq 2).
facilitated TBHP allylic oxidations which occurred under
anhydrous conditions13 only inhibited oxidations that oc-
curred with T-HYDRO. When the same amount of TBHP
in decane is used along with 50 mol % of potassium
carbonate, instead of T-HYDRO, % conversion only reaches
40%. Thus, optimum conditions for allylic oxidations of
cholesterol involve the use of 0.1-1.0 mol % of Rh2(cap)4,
4-5 molar equiv of T-HYDRO without base, a moderately
polar organic solvent to dissolve the steroidal reactant, a
temperature of 40 °C, and a reaction time of 20 h. Under
these conditions, 7-ketocholesterol was formed in 63%
isolated yield with 1.0 mol % of Rh2(cap)4 and in 58%
isolated yield with 0.1 mol % of Rh2(cap)4.16
To compare catalysts that are suitable for use with
T-HYDRO under the same conditions that were optimized
for cholesterol oxidation with Rh2(cap)4 catalysis, we sub-
17
stituted RuCl3(hydrate),12 CuI,9 and CuCl2 for Rh2(cap)4,
all at 1.0 mol %. The copper catalysts were inadequate under
these conditions, reaching only 61% conversion for CuI and
76% conversion with CuCl2 but with substantial amounts of
partially oxidized 5 and 6 formed and remaining after 20 h;
however, faster conversion rates occurred under anhydrous
conditions (TBHP in decane) even though these catalysts
were insoluble in the reaction medium. Ruthenium(III)
chloride hydrate, on the other hand, catalyzed the clean
conversion of cholesterol to 7-ketocholesterol, but the isolated
yield of 7-ketocholesterol was only two-thirds of that
obtained with the use of Rh2(cap)4; unlike oxidized Rh2(cap)4,
oxidized RuCl3 is soluble in water but not in DCE. Reactions
catalyzed by Rh2(cap)4 were also performed under conditions
reported to be optimal for RuCl3 (0.7 mol % of catalyst, 10
equiv of T-HYDRO, delivery by syringe pump, cyclohexane
solvent, room temperature),12 and both catalysts gave the
same outcome.
Both acetyl and tert-butyldimethylsilyl cholesterol derivatives
with their common hydroxyl protective groups undergo
allylic oxidation to their respective 7-keto products in high
yield; chloro and trityl derivatives give results comparable
to cholesterol. Further optimization of conditions for specific
substrates may be possible.
Oxidations of ∆5-steroids with functional groups at the
17-position or in the alkyl side chain at the 17-position under
the same conditions gave variable 7-keto-∆5-steroid product
yields (9-12, Figure 1). In addition to results with dehy-
droandrosterone catalyzed by 1.0 mol % of Rh2(cap)4,
oxidation of this substrate with only 0.1 mol % of Rh2(cap)4
formed 9b in 69% yield. Although the presence of oxidizable
functional groups in the alkyl side chain reduces the yield
of 7-keto-∆5-steroid product, only simple chromatography
is required to obtain the allylic oxidation product. Byproducts
from these oxidations were not identified but are of interest
in efforts to further optimize product yields.
(16) Oxidations with 0.1 mol % Rh2(cap)4 were performed with 1.36 M
TBHP (8 molar equiv) whereas those with 1.0 mol % Rh2(cap)4 were with
0.27 M TBHP (5 molar equiv).
(17) Salvador, J. A. R.; Melo, M. L. S.; Neves, A. S. C. Tetrahedron.
Lett. 1997, 38, 119.
Allylic oxidations by TBHP occur through a free radical
pathway for generation of the tert-butylperoxy radical that
Org. Lett., Vol. 9, No. 26, 2007
5351

occur through hydroperoxy radical capture by Rh2(cap)4,
followed by O-O cleavage with hydrogen transfer (Scheme
2, cyclohexene model),24 or form a metal peroxide complex
Scheme 2
leading to, as yet, unprecedented intermediates. They are
viable alternatives to bimolecular disproportionation of two
peroxy radicals that would form alcohol and ketone together
with dioxygen (the Russell mechanism).25 Efforts to deter-
mine the specific pathway or pathways for oxidation
catalyzed by dirhodium compounds and methods to direct
the reaction to a specific pathway are ongoing.
In summary, allylic oxidations of ∆5-steroids to 7-keto-
∆5-steroids by tert-butyl hydroperoxide is optimally con-
ducted with T-HYDRO in dichloroethane with dirhodium
caprolactamate as the catalyst. This method is tolerant of a
variety of functional groups and can be conducted at catalyst
loadings as low as 0.1 mol %.
Figure 1.
is common to metal-catalyzed reactions of hydroperoxides.18
One-electron reduction of TBHP forms an oxidized metal
hydroxide and the tert-butoxy radical that undergoes rapid
hydrogen atom abstraction from tert-butyl hydroperoxide to
produce the more stable tert-butylperoxy radical.19 The tert-
butylperoxy radical imparts selectivity to hydrogen abstrac-
tion reactions;20 these processes are well documented and
universally accepted.13,19-22 Trapping of the allyl radical by
combination with dioxygen is well established.22
Selectivity in the conversion of the allylperoxy radical to
ketone (13 f 14) in competition with hydrogen atom
abstraction (13 f 15) is the core feature of this allylic
oxidation process. Direct conversion of 13 to ketone could
(a) involve a recently described23 hydrogen atom abstraction
from the R-position to form an alkyl hydroperoxy radical,
followed by oxidative transfer of hydroxyl to Rh2(cap)4, (b)
Acknowledgment. The financial support of the National
Institutes of Health (GM 46503) is gratefully acknowledged.
We wish to thank Dr. Norman B. Javitt (Department of
Medicine and Pediatrics, New York University) for his
generous provision of 27-hydroxycholesterol.
Supporting Information Available: Procedures, product
characterization, and full analysis of new compounds. This
material is available free of charge via Internet at http:
//pubs.acs.org.
(18) (a) Nagiev, T. M. Coherent Synchronized Oxidation Reactions by
Hydrogen Peroxide; Elsevier Science, Ltd.: Amsterdam, 2006. (b) Modern
Oxidation Methods; Ba¨ckvall, J., Ed., Wiley-VCH: New York, 2004.
(19) (a) Snelgrove, D. W.; Lusztyk, J.; Banks, J. T.; Mulder, P.; Ingold,
K. U. J. Am. Chem. Soc. 2001, 123, 469. (b) MacFaul, P. A.; Arends, I. W.
C. E.; Ingold, K. U.; Wayner, D. D. M. J. Chem. Soc., Perkin Trans. 2
1997, 135.
OL7025284
(20) Bravo, A.; Bjorsvik, H.-R.; Fontana, F.; Liguori, L.; Minisci, F. J.
Org. Chem. 1997, 62, 3849.
(21) Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(22) Chavez, F. A.; Mascharak, P. K. Acc. Chem. Res. 2000, 33, 539.
(23) Bozzelli, J. W.; Sheng, C. J. Chem. Phys. A 2002, 106, 1113.
(24) Note that Scheme 3 also describes a catalytic interconversion
between Rh2 and Rh2 .
(25) Miyamoto, S.; Martinez, G. R.; Medeiros, M. H. G.; Di Mascio, P.
J. Am. Chem. Soc. 2003, 125, 6172.
5+
4+
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