Investigation on the regioselectivities of intramolecular oxidation of unactivated C-H bonds by dioxiranes generated in Situ

Article abstract of DOI:10.1021/jo0347011

We found that dioxiranes generated in situ from ketones 1-6 and Oxone underwent intramolecular oxidation of unactivated C-H bonds at δ sites of ketones to yield tetrahydropyrans. From the trans/cis ratio of oxidation products 1a and 2a as well as the retention of the configuration at the δ site of ketone 5, we proposed that the oxidation reaction proceeds through a concerted pathway under a spiro transition state. The intramolecular oxidation of ketone 6 showed the preference for a tertiary δ C-H bond over a secondary one. This intramolecular oxidation method can be extended to the oxidation of the tertiary γ′ C-H bond of ketones 9 and 10. For ketone 11 with two δ C-H bonds and one γ′ C-H bond linked respectively by a sp³ hydrocarbon tether and a sp² ester tether, the oxidation took place exclusively at the δ C-H bonds. Finally, by introducing proper tethers, regioselective hydroxylation of steroid ketones 12-14 have been achieved at the C-17, C-16, C-3, and C-5 positions.

Full text of DOI:10.1021/jo0347011

In vestiga tion on th e Regioselectivities of In tr a m olecu la r
Oxid a tion of Un a ctiva ted C-H Bon d s by Dioxir a n es Gen er a ted
in Situ
Man-Kin Wong, Nga-Wai Chung, Lan He, Xue-Chao Wang, Zheng Yan,
Yeung-Chiu Tang, and Dan Yang*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
yangdan@hku.hk
Received May 23, 2003
We found that dioxiranes generated in situ from ketones 1-6 and Oxone underwent intramolecular
oxidation of unactivated C-H bonds at δ sites of ketones to yield tetrahydropyrans. From the trans/
cis ratio of oxidation products 1a and 2a as well as the retention of the configuration at the δ site
of ketone 5, we proposed that the oxidation reaction proceeds through a concerted pathway under
a spiro transition state. The intramolecular oxidation of ketone 6 showed the preference for a tertiary
δ C-H bond over a secondary one. This intramolecular oxidation method can be extended to the
oxidation of the tertiary γ′ C-H bond of ketones 9 and 10. For ketone 11 with two δ C-H bonds
and one γ′ C-H bond linked respectively by a sp3 hydrocarbon tether and a sp2 ester tether, the
oxidation took place exclusively at the δ C-H bonds. Finally, by introducing proper tethers,
regioselective hydroxylation of steroid ketones 12-14 have been achieved at the C-17, C-16, C-3,
and C-5 positions.
In tr od u ction
ation of steroids catalyzed by metalloporphyrin and
metallosalen complexes.4 Furthermore, selective oxida-
tion of remote carbons four bonds away from a hetero-
Selective functionalization of saturated hydrocarbons
is of significant importance for both basic research and
practical applications of organic chemistry. The develop-
ment of efficient methods for regio- and stereoselective
C-H bond activation has attracted considerable attention
over the past decades.1,2 Owing to geometric constraints,
intramolecular reactions represent an effective approach
for regioselective functionalization of C-H bonds.3-6
Notably, transition-metal-catalyzed intramolecular C-H
bond insertion reactions with carbenes and nitrenes have
been extremely useful in organic synthesis.3 Significant
progress has also been made in template-directed remote
functionalization and biomimetic regioselective hydroxyl-
(3) For reviews, see: (a) Moody, C. J . In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 7, Chapter 1.2. (b) Taber, D. F. In Comprehensive Organic
Synthesis; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; Vol. 3,
Chapter 4.2, p 1045. (c) Doyle, M. P. Comprehensive Organometallic
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1998, 98, 911. (e) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
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Interscience: New York, 1998. For recent examples on carbene and
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1998, 4, 990 and references therein. (g) Taber, D. F.; Christos, T. E.;
Guzei, I. A.; Rheingold, A. L. J . Am. Chem. Soc. 1999, 121, 5589. (h)
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10.1021/jo0347011 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/15/2003
J . Org. Chem. 2003, 68, 6321-6328
6321

Wong et al.
SCHEME 1. Selective Oxid a tion of δ C-H Bon d
F IGURE 1. Proposed mechanism of intramolecular C-H
bond oxidation by dioxirane.
atom has been successfully accomplished by using the
radical reactions that undergo intramolecular 1,5-
hydrogen atom abstractions.5 Nevertheless, there is little
progress on the oxidation of more remote unactivated
C-H bonds in flexible molecules.6
Dioxiranes exhibit excellent reactivities in various
oxidation reactions, including epoxidation, heteroatom
oxidation, and hydroxylation of unactivated C-H bonds
under mild conditions.7,8 The hydroxylation reaction is
completely stereospecific and shows strong preference for
tertiary C-H bonds over secondary ones.8 Both concerted
and diradical pathways have been proposed for dioxirane-
mediated C-H bond oxidation on the basis of experi-
mental results.9 Theoretical calculations revealed that
dioxirane-mediated hydroxylation of C-H bonds could
proceed via a concerted spiro transition state as well as
a diradical intermediate.10
proposed a concerted C-H bond oxidation mechanism
(Figure 1). For ketones 1 and 2, the δ site oxidation gave
a mixture of two fused 1-oxadecalin products with a
trans/cis ratio about 4.5:1 (Scheme 1). A spiro transition-
state model (Figure 2), in which the two three-membered
rings adopt a spiro geometry, was proposed to explain
the observed trans selectivity.11,12 This spiro transition-
state model was supported by recent theoretical calcula-
tions.10,13 Here, we report our new investigation on the
scope of this hydroxylation reaction. Moreover, we de-
scribe the discoveries of (1) a new intramolecular oxida-
tion of tertiary γ′ C-H bonds of ketones and (2) a remote
regioselective hydroxylation reaction of steroids.
Resu lts a n d Discu ssion
1. Syn th esis of Keton es 3-13 for In tr a m olecu la r
Oxid a tion Rea ction s. We previously reported that
dioxiranes generated from the electronically activated
ketones, such as 1,1,1-trifluoromethyl ketones and sub-
stituted R-keto esters, showed excellent reactivities in
oxidation of unactivated C-H bonds. Therefore, those two
electronically activated ketone units were then attached
to a series of hydrocarbon chains for oxidation. The
general synthetic routes of ketones 3-13 are summarized
in Scheme 2 (for detailed experimental procedures, see
the Supporting Information).
Following Zard’s protocol,14 1,1,1-trifluoromethyl ke-
tones 3, 12, and 13 were readily synthesized by stirring
the corresponding carboxylic acid chlorides with tri-
fluoroacetic anhydride and pyridine in CH2Cl2. Ketones
4-6 were prepared by coupling of the corresponding
carboxylic acids and (cyanomethylene)phosphorane in the
presence of EDCI followed by oxidative cleavage with
We previously reported a preliminary study of a novel
reaction for oxidation of unactivated C-H bonds at the
δ site of ketones (Scheme 1).11 The observed regioselec-
tivity (i.e., δ selectivity) was different from that of a
typical intramolecular radical reaction, suggesting the
nonradical nature of this oxidation reaction.9,10 We thus
(6) (a) Wagner, P. J .; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G.
J . Am. Chem. Soc. 1972, 94, 7500. (b) Moreira, R. F.; When, P. M.;
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Chem. Soc. 2002, 124, 11856.
(7) For general reviews on dioxirane chemistry, see: (a) Adam, W.;
Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205. (b) Murray,
R. W. Chem. Rev. 1989, 89, 1187. (c) Curci, R. Advances in Oxygenated
Processes; J AI: Greenwich, CT, 1990; Vol. 2, Chapter 1. (d) Adam, W.;
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in Current Chemistry; Springer-Verlag: Berlin, 1993; Vol. 164, p 45.
(f) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995, 67, 811.
(8) For examples on oxidation of unactivated C-H bonds by diox-
iranes, see: (a) Murray, R. W.; J eyaraman, R.; Mohan, L. J . Am. Chem.
Soc. 1986, 108, 2470. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R.
J . Am. Chem. Soc. 1989, 111, 6749. (c) Bovicelli, P.; Lupattelli, P.;
Mincione, E.; Prencipe, T.; Curci, R. J . Org. Chem. 1992, 57, 5052. (d)
Bovicelli, P.; Gambacorta, A.; Lupattelli, P.; Mincione, E. Tetrahedron
Lett. 1992, 33, 7411. (e) Adam, W.; Asensio, G.; Curci, R.; Nunez, M.
E. G.; Mello, R. J . Org. Chem. 1992, 57, 953. (f) Asensio, G.; Nunez,
M. E. G.; Bernardini, C. B.; Mello, R.; Adam, W. J . Am. Chem. Soc.
1993, 115, 7250. (g) Bovicelli, P.; Lupattelli, P.; Fiorini, V.; Mincione,
E. Tetrahedron Lett. 1993, 34, 6103. (h) Kuck, D.; Schuster, A.; Fusco,
C.; Fiorentino, M.; Curci, R. J . Am. Chem. Soc. 1994, 116, 2375. (i)
Curci, R.; Detomaso, A.; Prencipe, T.; Carpenter, G. B. J . Am. Chem.
Soc. 1994, 116, 8112. (j) Curci, R.; Detomaso, A.; Lattanzio, M. E.;
Carpenter, G. B. J . Am. Chem. Soc. 1996, 118, 11089. (k) Asensio, G.;
Castellano, G. Mello, R.; Nunez, M. E. G. J . Org. Chem. 1996, 61, 5564.
(l) Fusco, C.; Fiorentino, M.; Dinoi, A.; Curci, R.; Krause; R. A.; Kuck,
D. J . Org. Chem. 1996, 61, 8681. (m) Adam, W. Curci, R.; D’Accolti,
L.; Fusco, C.; Gasparrini, F. Kluge, R.; Paredes, R.; Schulz, M.; Smerz,
A. K.; Veloza, L. A.; Weinkotz, S.; Winde, R. Chem. Eur. J . 1997, 3,
105. (n) Nunez, M. E. G.; Royo, J .; Castellano, G.; Andreu, C.; Boix,
C.; Mello, R.; Asensio, G. Org. Lett. 2000, 2, 831. (o) Curci, R.; D′Accolti,
L.; Fusco, C. Tetrahedron Lett. 2001, 42, 7087. (p) D’Accolti, L.; Fusco,
C.; Lucchini, V.; Carpenter, G. B.; Curci, R. J . Org. Chem. 2001, 66,
9063. (q) Nunez, M. E. G.; Castellano, G.; Andreu, C.; Royo, J .;
Baguena, M.; Mello, R.; Asensio, G. J . Am. Chem. Soc. 2001, 123, 7487.
(r) D’Accolti, L.; Kang, P.; Khan, S.; Curci, R.; Foote, C. S. Tetrahedron
Lett. 2002, 43, 4649.
(9) For reports on the mechanism of C-H bond oxidation by
dioxiranes, see: (a) Minisci, F.; Zhao, L.; Fontana, F.; Bravo, A.
Tetrahedron Lett. 1995, 36, 1697. (b) Vanni, R.; Garden, S. J .; Banks,
J . T.; Ingold, K. U. Tetrahedron Lett. 1995, 36, 7999. (c) Simakov, P.
A.; Choi, S.-Y.; Newcomb, M. Tetrahedron Lett. 1998, 39, 8187. (d)
Bravo, A.; Fontana, F.; Fronza, G.; Minisci, F.; Zhao, L. J . Org. Chem.
1998, 63, 254. (e) Buxton, P. C.; Marples, B. A.; Toon, R. C. and
Waddington, V. L. Tetrahedron Lett. 1999, 40, 4729.
(10) (a) Shustov, G. V.; Rauk, A. J . Org. Chem. 1998, 63, 5413. (b)
Du, X.; Houk, K. N. J . Org. Chem. 1998, 63, 6480. (c) Glukhovtsev, M.
N.; Canepa, C.; Bach, R. D. J . Am. Chem. Soc. 1998, 120, 10528. (d)
Freccero, M.; Gandolfi, R.; Sarzi-Amade`, M.; Rastelli, A. Tetrahedron
Lett. 2001, 42, 2739.
(11) Yang, D.; Wong, M.-K.; Wang, X.-C.; Tang, Y.-C. J . Am. Chem.
Soc. 1998, 120, 6611.
(12) Bach, R. D.; Andres, J . L.; Su, M. D.; McDouall, J . J . W. J . Am.
Chem. Soc. 1993, 115, 5768.
(13) A similar spiro transition state has been found for dioxirane
epoxidation reactions. See: (a) Baumstark, A. L.; McCloskey, C. J .
Tetrahedron Lett. 1987, 28, 3311. (b) Baumstark, A. L.; Vasquez, P.
C. J . Org. Chem. 1988, 53, 3437. (c) Baumstark, A. L.; Harden. D. B.
J . Org. Chem. 1993, 58, 7615. (d) Bach, R. D.; Andres, J . L.; Su, M.-
D.; McDouall, J . J . W. J . Am. Chem. Soc. 1993, 115, 5768. (e) Tu, Y.;
Wang, Z.-X.; Shi, Y. J . Am. Chem. Soc. 1996, 118, 9806. (f) Yang, D.;
Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem. Soc.
1996, 118, 11311. (g) Houk, K. N.; Liu, J .; DeMello, N. C.; Condroski,
K. R. J . Am. Chem. Soc. 1997, 119, 10147.
(14) Boivin, J .; Kaim, L. E.; Zard, S. Z. Tetrahedron Lett. 1992, 33,
1285.
6322 J . Org. Chem., Vol. 68, No. 16, 2003

Intramolecular Oxidation of Unactivated C-H Bonds
F IGURE 2. Proposed spiro transition state for C-H bond oxidation by dioxirane.
SCHEME 2
and Et3N (Scheme 3). The exclusive formation of the cis
products 3a and 4a may be a result of the closer distance
of Ha than Hb to an oxygen atom of dioxirane under a
spiro transition state (Figure 3). According to the theo-
retical calculations on the oxidation of the C-H bond by
dioxiranes, the transition state was highly polar and
asynchronous, with O-H bond formation much more
advanced than that of the C-O bond.10 Thus, oxidation
of the the C-Ha bond could be much faster than that of
C-Hb bond.
Oxid a tion P r oceed s w ith Reten tion of Con figu -
r a t ion . It was known in the literature that oxidation
of optically active (R)-(-)-2-phenylbutane to (S)-(-)-2-
phenyl-2-butanol by isolated methyl(trifluoromethyl)-
dioxirane and dimethyldioxirane proceeded with com-
plete retention of configuration.8a,e This interesting
observation prompted us to investigate the stereospeci-
ficity of our intramolecular oxidation reactions. Therefore,
ketone 5 with a chiral center at the δ-position was
prepared from (S)-(-)-citronellal (76% ee).17 Oxidation of
ketone 5 afforded the dehydrated cyclic product 5a in 78%
yield together with lactone 5b in 8% yield (Table 1, entry
3). The optical purity of 5a was determined to be 73% ee
by chiral HPLC analysis, indicating that our intra-
molecular oxidation reaction proceeded with retention of
configuration via a concerted oxygen transfer pathway.
The formation of lactone 5b was probably due to the
Baeyer-Villiger rearrangement of the R-keto ester in-
termediate (Scheme 4).
dimethyldioxirane.15,16 Ketones 7-11 were constructed
by the coupling reactions of keto acid chlorides with the
corresponding alcohols in CH2Cl2.
2. δ-Selective In tr a m olecu la r Oxid a tion of Ke-
ton es 3-6. Ketones 3-6 were subjected to the previously
reported conditions for intramolecular C-H bond oxida-
tion reactions. The results summarized in Table 1
revealed the δ-selectivity for oxidation of this series of
ketones.
Interesting stereoselectivities were observed for the
hydroxylation of ketones 3 and 4. In contrast to the
hydroxylation reactions of ketones 1 and 2 bearing a
cyclohexane ring, hydroxylation reactions of trifluoro-
methyl ketone 3 and R-keto ester 4 bearing a cyclopen-
tane ring provided exclusively cis bicyclic products 3a
(74% yield) and 4a (67% yield), respectively (Table 1,
entries 1 and 2). The cis stereochemistry of hemiketal
3a was confirmed by converting 3a into known cis-lactone
3b (75% yield) via heating under alkaline conditions
(Scheme 3). Hemiketal 4a could also undergo dehydration
to afford cis-4b in 82% yield upon treatment with MsCl
A Str on g P r efer en ce for Oxid a tion of Ter tia r y δ
C-H Bon d s over Secon d a r y δ C-H Bon d s. Ketone
6 has a tertiary δ C-H bond and two secondary δ C-H
bonds. Oxidation of 6 took place exclusively at the
tertiary δ C-H bond to give 6a (73% yield), and no
product derived from oxidation of secondary δ C-H bond
(17) The optical purity of the commercially available (S)-(-)-
citronellal was determined to be 76% by optical rotation measurement.
The optical rotation of commercially available (S)-(-)-citronellal was
(15) Wasserman, H. H.; Baldino, C. M.; Coats, S. J . J . Org. Chem.
1995, 60, 8231.
(16) Wong, M.-K.; Yu, C.-W.; Yuen, W.-H.; Yang, D. J . Org. Chem.
2001, 66, 3606.
[R]20 -12.6 (c ) 1, CH2Cl2), and that of optically pure (S)-(-)-
D
citronellal is [R]20D -16.4 (c ) 1, CH2Cl2). See: Becicka, B. T.; Koerwitz,
F. L.; Drtina, G. J .; Baenziger, N. C.; Wiemer, D. F. J . Org. Chem.
1990, 55, 5613.
J . Org. Chem, Vol. 68, No. 16, 2003 6323

Wong et al.
TABLE 1. Selective Oxid a tion of δ C-H Bon d a
a
Unless otherwise indicated, all reactions were carried out with a 10 mM solution of ketone in a 1.5:1 mixture of CH3CN and aqueous
b
Na2‚EDTA solution (0.4 mM) containing 5.0 equiv of Oxone and 15.0 equiv of NaHCO3 for 24 h at room temperature. Isolated yield after
flash column chromatography. c Reaction was carried out for 6 h, and the reaction temperature was increased from 0 °C to room temperature
after the addition of the mixture of Oxone and NaHCO3. 73% ee; determined by HPLC. e 6a was obtained as a 4:1 mixture of diastereomers.
d
SCHEME 3
F IGURE 3. Possible transition state for the oxidation reac-
tions of ketones 3 and 4.
developed a δ-selective C-H bond oxidation method by
connecting hydrocarbons and activated ketone groups
through tethers consisting of sp3 carbon atoms. Subse-
quently, we decided to examine the structural effect of
an ester tether on the intramolecular oxidation of 7-11
(Table 2).
was found (Table 1, entry 4). The complete regioselec-
tivity of this oxidation reaction indicated the strong
intrinsic preference for oxidation of tertiary δ C-H bonds
over secondary ones, in good agreement with the findings
in the literature.8f Note that hemiketal 6a could be
converted into 6b in 97% yield upon treatment with MsCl
and Et3N at room temperature (Scheme 3).
While ketone 7 has a tertiary δ′ C-H bond and ketone
8 bears two benzylic δ′ C-H bonds, both of them have
secondary γ′ C-H bonds adjacent to the oxygen atom of
the ester moiety. After ketones 7 and 8 were subjected
to our oxidation reaction conditions (10 mM) at room
temperature for 72 h, cyclohexanemethanol 7a and
2-phenylethanol 8a were obtained in 75% and 93% yields,
respectively (Table 2, entries 1 and 2), with no oxidized
product detected. Presumably, alcohols 7a and 8a came
3. A New In tr a m olecu la r γ′ C-H Bon d Oxid a tion
of Keton es. As mentioned in the above section, we
6324 J . Org. Chem., Vol. 68, No. 16, 2003

Intramolecular Oxidation of Unactivated C-H Bonds
TABLE 2. Selective Oxid a tion of Keton es
SCHEME 4. P ossible P a th w a y for th e F or m a tion
of La cton e 5b
from the ester hydrolysis of ketones 7 and 8 under the
high salt conditions. To minimize the rate of ester
hydrolysis, we conducted the oxidation at a lower con-
centration (1.5 mM) with portionwise addition of Oxone.
No alcohols could be found under the diluted reaction
conditions (1.5 mM) after 120 h, and ketones 7 and 8
remained unchanged (Table 2, entries 1 and 2).
In contrast, oxidation of C3-epimers 9 and 10, both
bearing a tertiary γ′ C-H bond, afforded androstane-
3,17-dione (9a ) after 120 h as the major product along
with ester hydrolysis products 9b and 10a (Table 2,
entries 3 and 4). In the oxidation of 9, a minor product
9c was also isolated (17% yield), which presumably came
from the Baeyer-Villiger oxidation of 9a by Oxone. Since
the hydrolysis of axial ester was slower than that of the
equatorial one, the overall oxidation yield for 10 (78%)
was higher than that of 9 (61% for the combined yield of
9a and 9c). Control experiments indicated that 9a could
not be generated from the intermolecular oxidation of
androsterone 9b and epiandrosterone 10a by methyl
pyruvate and Oxone at the same substrate concentration
(1.5 mM). We propose that 9a is formed through a
regioselective intramolecular oxidation of the axial and
equatorial tertiary γ′ C-H bonds of 9 and 10, respectively
(Figure 4). The dioxirane generated from the ketone
moieties of 9 and 10 could bend back to oxidize the γ′
C-H bonds under a spiro transition state to afford
hemiketals, which were then hydrolyzed to give 9a .
Overall, the oxidation of 9 and 10 to 9a by Oxone
constitutes an alternative to the known photolysis reac-
tion reported by Binkley.18 The lack of oxidation for 7
and 8 can be explained by the lower activity of their
secondary γ′ C-H bonds as compared to the tertiary ones
in 9 and 10.
δ vs γ′-Selectivity in In tr a m olecu la r C-H Bon d
Oxid a tion Rea ction . The different regioselectivities
(i.e., δ or γ′ selectivity) observed in the intramolecular
oxidation reactions of ketones 1-6 and 9-10 could be
attributed to the structural differences between the sp3
hydrocarbon tether and the sp2 ester tether. To investi-
gate the relative reactivity of the intramolecular δ C-H
bond and the γ′ C-H bond in the oxidation reactions,
ketone 11 was designed for such a competition experi-
ment. On one side of the activated ketone group of 11,
there are two secondary δ C-H bonds connected by a
a
b
5.0 equiv of Oxone and 15.0 equiv of NaHCO3. Yield based
on conversion. c The reaction was carried out with a 1.5 mM
solution of ketone in a 1.5:1 mixture of CH3CN and aqueous
Na2‚EDTA solution (0.4 mM) for 120 h at room temperature.
d
Reactions were carried out with a 10 mM solution of ketone in a
1.5:1 mixture of CH3CN and aqueous Na2‚EDTA solution (0.4 mM)
for 72 h at room temperature. e No reaction. f 100% conversion.
g
h
i
88% conversion. 90% conversion. 76% conversion.
tether of three sp3 carbons. On the other side, there is
an equatorial tertiary γ′ C-H bond linked by a tether of
an ester group (sp2 hybridized). The oxidation of ketone
(18) (a) Binkley, R. W. J . Org. Chem. 1976, 41, 3030. (b) Binkley,
R. W. J . Org. Chem. 1977, 42, 1216.
J . Org. Chem, Vol. 68, No. 16, 2003 6325

Wong et al.
F IGURE 4.
11 was performed at two substrate concentrations, i.e.,
10 mM and 1.5 mM (Table 2, entry 5). Under both
reaction conditions, hemiketal 11a and epiandrosterone
10a were obtained from the oxidation of the δ C-H bond
and the ester hydrolysis, respectively. In particular, δ
oxidation product 11a was isolated in 77% yield on the
basis of 90% conversion at 1.5 mM concentration. Nev-
ertheless, no product from the oxidation of γ′ C-H bond
was detected. The outcome of this competition experiment
suggested that the oxidation of δ C-H bond at saturated
hydrocarbon chains was much more favorable than that
of γ′ C-H bond. The lower activity of γ′ C-H bond of
ketones was probably due to the slight distortion of ester
bond under a spiro transition state for the intramolecular
oxidation reaction (Figure 4).
4. Regioselective Rem ote Hyd r oxyla tion of Ste-
r oid s. Regioselective remote hydroxylation of steroids is
of significant interest in organic synthesis as the oxidized
steroids are useful in the synthesis of artificial hormones
or steroidal drugs. Recently, hydroxylation of steroids has
been achieved by using natural19 or artificial enzymes,20
dimethyldioxirane,21 and other oxidants.22 Most of those
oxidation reactions were carried out in an intermolecular
manner. We previously reported one example of the
regioselective intramolecular hydroxylation of steroids by
using a dioxirane intermediate. Trifluoromethyl ketone
12, prepared from cholic acid triacetate, gave selective
hydroxylation at the 17-position with retention of con-
figuration upon treatment with Oxone (Scheme 5). The
observed excellent selectivity promoted us to further
explore the remote hydroxylation of steroids. Ketone 13
with one carbon atom less in the tether than 12 was
oxidized smoothly at the 16-position (δ-site) to fur-
nish the cis ring junction product 13a in 77% yield
(Scheme 5). These two examples represent a novel
pathway for regio- and stereospecific functionalization of
steroids.
While dioxiranes generated in situ from 9 and 10 could
bend back to oxidize the C-3 hydrogens efficiently and
offered androstan-3,17-dione 9a as the major product
(Table 2, entries 3 and 4), oxidation further away from
the C-3 hydrogens was not observed, probably because
the tether was too short and the dioxirane intermediate
could not reach more remote hydrogens. Through build-
ing molecular models, we expected that the dioxirane
generated from trifluoromethyl ketone 14 might have the
(21) (a) Dixon, J . T.; Holzapfel, C. W.; van Heerden, F. R. Synth.
Commun. 1993, 23, 135. (b) Bovicelli, P.; Gambacorta, A.; Lupattelli,
P.; Mincione, E. Tetrahedron Lett. 1992, 33, 7411. (c) Cerre, C.;
Hofmann, A. F.; Schteingart, C. D.; J ia, W.; Maltby, D. Tetrahedron
1997, 53, 435. (d) Iida, T.; Yamaguchi, T.; Nakamori, R.; Hikosaka,
M.; Mano, N.; Goto, J .; Nambara, T. J . Chem. Soc., Perkin Trans. 1
2001, 2229. (e) Bovicelli, P.; Lupattelli, P.; Fiorini, V.; Mincione, E.
Tetrahedron Lett. 1993, 34, 6103.
(22) (a) Schneider, H. J .; Mueller, W. J . Org. Chem. 1985, 50, 4609.
(b) Tori, M.; Matsuda, R.; Asakawa, Y. Tetrahedron 1986, 42, 1275.
(c) Betancor, C.; Francisco, C. G.; Freire, R.; Suarez, E. J . Chem. Soc.,
Chem. Commun. 1988, 947. (d) Arnone, A.; Cavicchioli, M.; Montanari,
V.; Resnati, G. J . Org. Chem. 1994, 59, 5511. (e) Betancor, C.;
Francisco, C. G.; Freire, R.; Suarez, E. J . Chem. Soc., Chem. Commun.
1988, 14, 947. (f) Bovicelli, P.; Lupattelli, P.; Fracassi, D. Tetrahedron
Lett. 1994, 35, 935.
(19) (a) Holland, H. L.; Brown, F. M.; Chenchaiah, P. C.; Chernish-
enko, M. J .; Khan, S. H.; Rao, J . A. Can. J . Chem. 1989, 67, 268. (b)
Kawaguchi, K.; Hirotani, M.; Furuya, T. Phytochemistry 1991, 30, 1503.
(c) Ortiz de Montellano, P. R., Ed. Cytochrome P450: Structure,
Mechanism and Biochemistry, 2nd ed.; Plenum: New York, 1995. (d)
Woggon, W. D. Top. Curr. Chem. 1996, 184, 39. (e) Boynton, J .; Hanson,
J . R.; Hunter, A. C. Phytochemistry 1997, 45, 951. (f) Farooq, A.;
Hanson, J . R. Bioscience, Biotechnology, Biochemistry 1999, 63, 1798.
(g) Kitamoto, D.; Dieth, S.; Burger, A.; Tritsch, D.; Biellmann, J .-F.
Tetrahedron Lett. 2001, 42, 505.
(20) (a) Yang, J .; Breslow, R. Angew. Chem., Int. Ed. 2000, 39, 2692.
(b) Belvedere, S.; Breslow, R. Bioorg. Chem. 2001, 29, 321. (c) Yang,
J .; Gabriele, B.; Belvedere, S.; Huang, Y.; Breslow, R. J . Org. Chem.
2002, 67, 5057.
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Intramolecular Oxidation of Unactivated C-H Bonds
SCHEME 5
SCHEME 6
SCHEME 7
potential to oxidize the remote C-5 hydrogen of cholestanol.
Ketone 14, prepared in two steps from 3â-cholestanol (see
the Supporting Information), was stirred in CH3CN/H2O
(1 mM) with an excess amount of Oxone/NaHCO3 added
portionwise at room temperature during a 41-day period.
After the reaction, several products were identified
(Scheme 6). A trace amount of 14a (3%) was isolated as
the hydrolysis product of ketone 14. 3-Cholestanone 14b
(4%) was generated from the intramolecular oxidation
of the C-3 hydrogen of 14 by the trifluoromethyl dioxirane
followed by the hemiketal hydrolysis. The mixture of
lactones 14c (17%) and 14d (10%) came from the Baeyer-
Villiger oxidation of ketone 14b by Oxone. The isolation
of diol 14e (3%) and keto alcohol 14f (6%) strongly
indicated that regioselective remote hydroxylation oc-
curred at the C-5 position. As outlined in Scheme 7, the
dioxirane generated in situ from ketone 14 regioselec-
tively oxidized the C-5 hydrogen to give hydroxyl ketone
14g, which underwent subsequent hydrolysis to provide
diol 14e. On the other hand, the ketone group of 14g
could generate another dioxirane, which oxidized the C-3
equatorial hydrogen to give keto alcohol 14f. Though the
yield of C-5 oxidation needs further improvement, this
is the first example demonstrating the use of a covalently
linked dioxirane for regioselective hydroxylation at C-5
positions of steroids.
J . Org. Chem, Vol. 68, No. 16, 2003 6327

Wong et al.
organic layers were dried over anhydrous MgSO4 and concen-
trated. The residue was purified by flash column chromatog-
raphy (10% EtOAc in n-hexane) to give 4a (0.095 g, 67% yield)
as a colorless syrup.
Con clu sion s
In summary, we have discovered a highly regioselective
method for intramolecular C-H bond oxidation mediated
by dioxiranes. The intramolecular oxidation reaction
proceeds with retention of configuration and displays a
strong preference for tertiary C-H bonds over secondary
ones. This δ-selective C-H bond oxidation method allows
incorporation of various substituents into the tetra-
hydropyran products.23 Furthermore, through modifica-
tion of the tether linking the ketone group and C-H
bonds, we have found a novel dioxirane-mediated in-
tramolecular γ′ C-H bond oxidation reaction. Finally, we
have successfully demonstrated the feasibility of using
covalently linked dioxirane for remote regioselective
hydroxylation of steroids.
Gen er a l P r oced u r e for In tr a m olecu la r γ′ C-H Bon d
Oxid a tion (Ta ble 2, En tr y 3). To an acetonitrile solution
(120 mL) of ketone 9 (0.108 g, 0.3 mmol) at room temperature
was added an aqueous Na2‚EDTA solution (80 mL, 0.4 mM).
To this reaction mixture was added a mixture of Oxone (0.184
g, 0.3 mmol) and NaHCO3 (0.076 g, 0.9 mmol) at a 24-h
interval (total amount of Oxone and NaHCO3 added are 5 ×
0.184 g and 5 × 0.076 g, respectively). After the mixture was
stirred at room temperature for 120 h, solid NaCl was added
until the solution became saturated. The reaction mixture was
extracted with EtOAc. The combined organic layers were dried
over anhydrous MgSO4 and concentrated. The residue was
purified by flash column chromatography (20%-50% EtOAc
in n-hexane) to give recovered starting material 9 (0.013 g,
88% conversion), 9a (0.033 g, 78% yield), 9b (0.029 g, 38%
yield), and 9c (0.014 g, 17% yield) as white solids.
Exp er im en ta l Section
Gen er a l P r oced u r e for In tr a m olecu la r δ C-H Bon d
Oxid a tion (Ta ble 1, En tr y 2). To an acetonitrile solution (43
mL) of ketone 4 (0.13 g, 0.71 mmol) at room temperature was
added an aqueous Na2‚EDTA solution (28 mL, 0.4 mM). To
this reaction mixture was added a mixture of Oxone (2.17 g,
3.54 mmol) and NaHCO3 (0.88 g, 10.5 mmol). After being
stirred at room temperature for 24 h, the reaction mixture was
poured into brine and extracted with EtOAc. The combined
Ack n ow led gm en t. This work was supported by the
Hong Kong Research Grants Council, The University
of Hong Kong, and the Generic Drug Research Program.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization data of compounds 3-11, 13, and 14; NOE
assignments of cyclic hemiketals 3a , 4a , and 14a ; and HPLC
analysis of compound 5a . This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Wong, M.-K.; Chung, N.-W.; He, L.; Yang, D. J . Am. Chem. Soc.
2003, 125, 158.
J O0347011
6328 J . Org. Chem., Vol. 68, No. 16, 2003