Bismuth(III) triflate-catalyzed direct conversion of corticosteroids into highly functionalized 17-ketosteroids by cleavage of the C17-dihydroxyacetone side chain

Article abstract of DOI:10.1021/jo9018478

(Chemical Equation Presented) The use of bismuth(III) triflate as catalyst for the direct conversion of corticosteroids into highly functionalized 17-ketosteroids by cleavage of the C17-dihydroxyacetone side chain is reported. This catalytic process is very chemoselective, since functionalities of the starting corticosteroids, such as Δ⁴-3-keto, Δ1,4-3-keto, 11β-hydroxyl, and 9β,11β-epoxide, remained intact.

Full text of DOI:10.1021/jo9018478

pubs.acs.org/joc
and by gut microflora, the enzyme responsible for this
biotransformation has not been identified yet.4
Bismuth(III) Triflate-Catalyzed Direct Conversion
of Corticosteroids into Highly Functionalized
17-Ketosteroids by Cleavage of the
The degradation of the C17-dihydroxyacetone moiety of
corticosteroids has been performed by several classical oxi-
dative chemical procedures, such as those that use CrO3,
Pb(OAc)4, HIO4, and NaBiO3.5 Among these reactants, the
best results have been achieved with NaBiO3;5 however the
need of various equivalents of this reactant is not compatible
with the actual paradigm of green chemistry6-10 and green
pharmaceutical chemistry.11
C17-Dihydroxyacetone Side Chain
Rui M. A. Pinto,† Jorge A. R. Salvador,*,†,‡
§
Christophe Le Roux, and Jose A. Paixao
ꢀ
~
†
´
^
Laboratoꢀrio de Quımica Farmaceutica, Faculdade de
ꢀ
Farmacia, Universidade de Coimbra, 3000-548, Coimbra,
Portugal, ‡Instituto Pedro Nunes-Labpharm, Rua Pedro
Nunes, 3030-199 Coimbra, Portugal, §Laboratoire
The use of basic reaction conditions for the cleavage of the
C17-dihydroxyacetone side chain has been reported by Simons
and co-workers.12 Later, an optimized procedure that uses 5.0
equiv of sodium methoxide in refluxing 1,4-dioxane has been
described.13 More recently, the direct conversion of corticos-
teroids into 17-ketosteroids by using iodine in the presence of
an excess of aqueous ammonia has also been reported.14
The lack of selectivity and the moderate reaction yields of
some of the classical methods associated with the use of large
amounts of oxidative or basic reactants make the classical
approaches for the cleavage of the corticosteroid side chain
inconvenient at laboratory scale and inadequate for the
large-scale synthesis of 17-ketosteroids. In this context,
new catalytic processes that use environmentally friendly,
cheap, and easily available reactants to perform the one-step
conversion of corticosteroids into 17-ketosteroids would be
of considerable interest.
ꢀ ꢀ
Heterochimie Fondamentale et Appliquee, Universite Paul
Sabatier, 118, route de Narbonne, 31062 Toulouse Cedex 9,
ꢀ
ꢀ
´
France, and CEMDRX, Departamento de Fısica, Faculdade
de Ciencias e Tecnologia, Universidade de Coimbra, 3004-516
^
Coimbra, Portugal
salvador@ci.uc.pt
Received September 2, 2009
Bismuth(III) salts15-21 have emerged in the past few years
as suitable reagents for the development of new chemical
processes22-24 under more “ecofriendly” reaction conditions.
(4) Shackleton, C. H. L.; Neres, M. S.; Hughes, B. A.; Stewart, P. M.;
Kater, C. E. Steroids 2008, 73, 652–656.
The use of bismuth(III) triflate as catalyst for the direct
conversion of corticosteroids into highly functionalized
17-ketosteroids by cleavage of the C17-dihydroxyacetone
side chain is reported. This catalytic process is very
chemoselective, since functionalities of the starting corti-
costeroids, such as Δ4-3-keto, Δ1,4-3-keto, 11β-hydroxyl,
and 9β,11β-epoxide, remained intact.
(5) Oliveto, E. P. Synthesis and degradation of the pregnane side-chain.
In Organic reactions in steroid chemistry; Fried, J., Edwards, J. A., Eds.; Van
Nostrand Reinhold Company: New York, 1972; Vol. 2, pp 127-236.
(6) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281.
(7) Clark, J. H. Pure Appl. Chem. 2001, 73, 103–111.
(8) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686–694.
(9) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2169–2173.
(10) Sheldon, R. A. Chem. Commun. 2008, 3352–3365.
(11) Tucker, J. L. Org. Process Res. Dev. 2006, 10, 315–319.
(12) Simons, S. S.; Merchlinsky, M. J.; Johnson, D. F. Steroids 1981, 37,
281–289.
(13) Le Pera, A.; Leggio, A.; Siciliano, C.; Di Gioia, M. L.; Napoli, A.;
Sindona, G.; Liguori, A. Steroids 2003, 68, 139–142.
(14) Sun, L.; Geng, X.; Liu, L. H.; Jiang, C. G.; Wang, C. J. Chem. Res.
(S) 2009, 22–23.
(15) Suzuki, H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249–267.
(16) Suzuki, H.; Matano, Y., Organobismuth chemistry; Elsevier:
Amsterdam, The Netherlands, 2001.
(17) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58,
8373–8397.
(18) Gaspard-Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004,
2517–2532.
(19) Gaspard-Iloughmane, H.; Le Roux, C. Trends Org. Chem 2006, 11,
65–80.
(20) Gaspard-Iloughmane, H.; Le Roux, C. Bi(III) Lewis acids. In Acid
catalysis in modern organic chemistry; Yamamoto, H., Ishihara, K., Eds.;
John Wiley & Sons: Weinheim, Germany, 2008; pp 551-588.
(21) Hua, R. M. Curr. Org. Synth. 2008, 5, 1–27.
(22) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114.
(23) Anzalone, P. W.; Baru, A. R.; Danielson, E. M.; Hayes, P. D.;
Nguyen, M. P.; Panico, A. F.; Smith, R. C.; Mohan, R. S. J. Org. Chem. 2005,
70, 2091–2096.
(24) Ollevier, T.; Bouchard, J. E.; Desyroy, V. J. Org. Chem. 2008, 73,
331–334.
The industrial production of corticosteroids, an important
drug class in the treatment of clinical situations ranging from
moderate skin rash to severe acute inflammatory disorders,1
reaches several tones per year.2 In fact, these compounds are
readily available from a number of commercial sources.
The metabolization of corticosteroids to C19-steroids by
side-chain cleavage at position C17 is a well-known process
that occurs in vivo.3 Although corticosteroid side chain
removal has been shown to occur in adrenal glands, kidney,
(1) Avery, M. A.; Woolfrey, J. R. Anti-inflammatory steroids. In Burger’s
Medicinal Chemistry and Drug Discover, Vol. 3, Cardiovascular Agents and
Endrocrines, 6th ed.; Abraham, D. J., Ed.; John Wiley & Sons, Inc.: New
York, 2003; pp 747-853.
(2) McGhie, S.; Strachan, C.; Aitken, S. Org. Process Res. Dev. 2002, 6,
898–900.
(3) Kornel, L.; Saito, Z. J. Steroid Biochem. 1975, 235, 2246–2252.
8488 J. Org. Chem. 2009, 74, 8488–8491
Published on Web 10/02/2009
DOI: 10.1021/jo9018478
r
2009 American Chemical Society

Pinto et al.
JOCNote
Moreover, the application of bismuth(III) salts to the synthe-
sis of compounds of pharmaceutical interest is rapidly
increasing.25-31 As part of our current interest on the deve-
lopment of new bismuth-based processes32 applied to natural
product chemistry,33-38 we report herein the bismuth(III)
triflate-catalyzed direct conversion of corticosteroids into
highly functionalized 17-ketosteroids by cleavage of the
C17-dihydroxiketone side chain.
SCHEME 1. Bi(OTf)3 xH2O-Catalyzed Synthesis of Δ4,9(11)
3,17-Diketosteroid 2
-
3
Quite recently, we reported the use of Bi(OTf)3 xH2O as
3
catalyst in the Wagner-Meerwein rearrangement of terpene
derivatives. Under appropriated reaction conditions, a dou-
ble rearrangement has been observed in lupane compounds,
involving contraction of the six-membered ring A, along
with expansion of ring E and formation of an additional
O-containing ring. The reactivity observed at ring A was
TABLE 1. Catalyst Screening for the C-17 Side-Chain Cleavage of
Hydrocortisone 1a
triggered by the Bi(OTf)3 xH2O-promoted dehydration of
3
the 3β-hydroxyl group.38 This nonexpected reactivity of
Bi(OTf)3 xH2O turned our attention to the study of other
3
chemical transformations involving a possible dehydration
of suitable hydroxyl groups. Thus we decided to study the
reactivity of bismuth(III) salts toward several corticoster-
oids, which typically contain the tertiary 17R-hydroxyl
group, the 21-hydroxy-20-keto moiety at C17 side chain,
and several other chemical functions, including, in most
cases, additional hydroxyls at position C11.
entry
catalyst (mol %)
time (h)
product
Yield (%)b,c
1
2
3
4
5
6
7
8
Bi(OTf)3 xH2O (10)
3
6.5
8
3
3
3
3
84
93 (75)d
71
Bi(OTf)3 xH2O (5)
3
Bi(OTf)3 xH2O (5)e
Bi(OTf)3 xH2O (2)
22.5
22
24
24
24
7
3
3
90
BiBr3 (10)
BiCl3 (10)
1 þ 3
1 þ 3
1 þ 3
77 (33:67)f
81 (34:66) f
86 (57:43)f
La(OTf)3 (10)
HOTf (15)
Initially, we performed the reaction of hydrocortisone
(cortisol) 1under the reaction conditions previously established
for the double Wagner-Meerwein rearrangement of lupanes
g
-
aReaction conditions: 0.5 mmol of 1; 15 mL of 1,4-dioxane, 80 °C.
bYield of the reaction crude after aqueous workup obtained as colorless
oil. c1H NMR spectrum of the reaction crude showed the selective
synthesis of 3, along with unidentified nonsteroidal side products in
variable amounts (δ 3.50-4.10 ppm, several multiplets and 8.04-8.10
ppm, singulet). Isolated yield by flash column chromatography. The
reaction was performed at 50 °C. fRatio between 1 and 3, as determined
by integration of their 4-H signals (1, δ 5.72, br s; 3, δ 5.67, br s) in the 1H
NMR spectrum of the reaction crude. gFull conversion of 1 was
observed, but several products were seen on the TLC plate, after 7 h
of reaction.
(20 mol % of Bi(OTf)3 xH2O, at refluxing CH2Cl2). Although
3
some reactivity has been detected, low selectivity and substrate
conversion were obtained, after 24 h of reaction, as observed by
TLC control. Other solvents, temperatures, and catalyst load-
ings were tested. For instance, when compound 1 was treated
d
e
with 5 mol % of Bi(OTf)3 xH2O, in CH3NO2, at 100 °C, full
3
conversion was observed after 6.5 h. Although several products
were visible on the TLC plate, the major one was isolated in
34% yield, by flash column chromatography. Analysis of its
spectroscopic data indicated that cleavage of the side chain had
occurred as well as dehydration of the 11β-hydroxyl group to
afford the Δ4,9(11)-3,17-diketosteroid 239 (Scheme 1).
Despite the low yield, this result was quite interesting
because catalytic amounts of Bi(III) salt were enough to
induce the cleavage of the C17-dihydroxyacetone side chain
of corticosteroid 1. The rough reaction conditions were most
likely responsible for the loss of the 11β-hydroxyl function.
The use of 1,4-dioxane as solvent, at a lower temperature,
significantly improved the selectivity of the reaction. Thus,
(25) Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883–3885.
(26) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H. R.
J. Am. Chem. Soc. 2003, 125, 14702–14703.
(27) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed.
Engl. 2005, 44, 3895–3899.
treatment of 1 with either 10 mol % or 5 mol % of Bi(OTf)3
xH2O, in 1,4-dioxane/80 °C, gave the 11β-hydroxy-Δ4-3,17-
(28) Slade, J. S.; Vivelo, J. A.; Parker, D. J.; Bajwa, J.; Liu, H.; Girgis, M.;
Parker, D. T.; Repic, J.; Blacklock, T. Org. Process Res. Dev. 2005, 9, 608–
620.
(29) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005, 3421–3423.
(30) Salvador, J. A. R.; Pinto, R. M. A.; Silvestre, S. M. Mini-Rev. Org.
Chem. 2009, 6, 241–274.
3
diketosteroid 3,13 in good yields (Table 1, entries 1 and 2).
1
Analysis of the H NMR spectrum of the crude product
showed that unidentified nonsteroidal side products were
formed along with 3. Their presence probably arises from the
acid-catalyzed polymerization of the R-hydroxy ketone moi-
ety derived from the cleavage of the corticosteroid side chain.
Thus, purification by flash chromatography was needed to
obtain pure 11β-hydroxy-Δ4-3,17-diketosteroid 3 (Table 1,
entry 2).
(31) Salvador, J. A. R.; Pinto, R. M. A.; Silvestre, S. M. Curr. Org. Synth.
2009, 6, 426–470.
(32) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C. Catal. Commun.
2008, 9, 465–469.
(33) Salvador, J. A. R.; Silvestre, S. M. Tetrahedron Lett. 2005, 46, 2581–
2584.
(34) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C. Synlett 2006, 2047–
2050.
(35) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C. Tetrahedron 2007,
63, 9221–9228.
(36) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C.; Carvalho, R. A.;
The conversion of hydrocortisone 1 with 5 mol % of
Bi(OTf)3 xH2O, in 1,4-dioxane, at 50 °C, afforded the
3
~
Silva, M. R.; Beja, A. M.; Paixao, J. A. Steroids 2008, 73, 549–561.
(37) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C.; Carvalho, R. A.;
17-ketosteroid 3, in 71% yield, after 22.5 h (Table 1, entry
3). A similar reaction time was observed when the reaction
~
Beja, A. M.; Paixao, J. A. Tetrahedron 2009, 65, 6169–6178.
(38) Salvador, J. A. R.; Pinto, R. M. A.; Santos, R. C.; Le Roux, C.; Beja,
A. M.; Paixao, J. A. Org. Biomol. Chem. 2009, 7, 508–517.
(39) Zhao, Q. J.; Li, Z. S. Synth. Commun. 1993, 23, 1473–1478.
was carried out in the presence of only 2 mol % of Bi(OTf)3
xH2O, at 80 °C (Table 1, entry 4). The use of bismuth(III)
3
J. Org. Chem. Vol. 74, No. 21, 2009 8489

Pinto et al.
JOCNote
SCHEME 2. HOTf-Catalyzed Reaction of Hydrocortisone 1 in
1,4-Dioxane/80 °C
TABLE 2. Bi(OTf)3 xH2O-Catalyzed Cleavage of the C17-Dihy-
3
droxyacetone Side Chain of Corticosteroidsa
halides have also been tested (Table 1, entries 5 and 6);
however, the reaction of 1 was not complete after 24 h of
reaction. The use of La(OTf)3 as a Lewis acid40 and HOTf as
a Bronsted acid was also evaluated (Table 1, entries 7 and 8).
After 24 h, the reaction of 1 with 10 mol % of La(OTf)3
afforded only partial conversion of the starting corticoster-
oid 1 to the 17-ketosteroid 3 (Table 1, entry 7), whereas in the
presence of 15 mol % of HOTf, a complex mixture of several
products was obtained, after 7 h (Table 1, entry 8).
When the reaction of 1 with 15 mol % of HOTf was
stopped after 1 h, the 11β-hydroxy-17-ketosteroid 3 was
isolated in 11% yield, along with 21-(1,3-dioxalan-2-yl)-
11β-hydroxypregn-4-ene-3,20-dione 4, in 45% yield, as the
major reaction product (Scheme 2). The formation of pro-
duct 4 may be explained by the acid-catalyzed reaction of the
R-hydroxy ketone derived from the cleavage of the side chain
of one molecule with the primary alcohol group of substrate
1, involving dehydration of the 17R-hydroxyl. The 11β-
hydroxy-Δ4-3,17-diketosteroid 3 was also obtained as by-
product, showing that the degradation reaction may occur
unselectively under Bronsted acid catalysis.
entry
substrate
time (h)
product
yield (%)b
1
2
3
4
5
6
5
7
9
11
13
15
5
14
5
5.5
5
6
8
10
12
14
16
85
78
84
68
74
45
1.5
aReaction conditions: 0.5 mmol of substrate; 5 mol % of Bi(OTf)3
3
xH2O, 15 mL of 1,4-dioxane, 80 °C. bIsolated yield by flash column
chromatography.
Bearing in mind our recent reports on the participation of
an in situ formed Bronsted acid species from Bi(OTf)3 xH2O,
3
in the reaction mechanism of Wagner-Meerwein-type rearr-
agements,37,38 we carried out the Bi(OTf)3 xH2O-catalyzed
in 78% yield, after 14 h of reaction with Bi(OTf)3 xH2O/
3
3
1,4-dioxane (Table 2, entry 2).
reaction of hydrocortisone 1 in the presence of 2,6-di-tert-
butylpyridine (DTBP), a known proton scavenger.38 Interest-
ingly, full substrate conversion was observed after 20 h of
When beclomethasone 9 was used as substrate, the corre-
sponding 9R-chloro-11β-hydroxy-16β-methyl-Δ1,4-3,17-dike-
tosteroid 10, a new steroid compound, was obtained in 84%
yield (Table 2, entry 3). Both the epimeric 9R-fluoro-11β-
hydroxy-16β-methyl-Δ1,4-3,17-diketosteroid 1242 and 9R-
fluoro-11β-hydroxy-16R-methyl-Δ1,4-3,17-diketo derivative
1443 were efficiently prepared from betamethasone 11 and
dexamethasone 13, respectively, in 68% and 74% yield, under
similar reaction conditions (Table 2, entries 4 and 5).
The reaction of the 9β,11β-epoxy-16β-methyl derivative
15, an intermediate in the synthesis of betamethasone,44 with
reaction [0.5 mmol of 1, 5 mol % of Bi(OTf)3 xH2O, and
3
15 mol % of DTBP, in 1,4-dioxane, at 80 °C, 81% isolated
yield].
Therefore, although Bronsted acid catalysis was observed,
this set of results seems to show that the Bi(OTf)3 xH2O-
3
catalyzed cleavage of the C17-dihydroxyacetone side chain
of corticosteroids is mediated by Lewis acid catalysis. In the
absence of proton scavenger, Bronsted acid-assisted Lewis
acid catalysis41 is observed, as suggested by the higher
reaction rate.
5 mol % of Bi(OTf)3 xH2O, in 1,4-dioxane, at 80 °C,
3
afforded the 9β,11β-epoxy-16β-methyl-Δ1,4-3,17-diketoster-
oid 16,42 in 45% yield (Table 2, entry 6). The lower isolated
yield of 16 may be explained in light of our recent findings
related to the reactivity of bismuth(III) salts toward
epoxysteroids.34-37 Compound 16 has already been synthe-
sized by starting from the corresponding 11β-hydroxy-16β-
methylcorticosteroid, in five synthetic steps.42 Advanta-
geously, our approach gave directly in one step the useful
9β,11β-epoxy-16β-methyl-Δ1,4-3,17-diketosteroid 16 from
After these studies that allowed us to gain more insight on
the conversion of hydrocortisone 1 into the highly functiona-
lized 11β-hydroxy-Δ4-3,17-diketosteroid 3, other corticoster-
oids were efficiently transformed into the corresponding
17-ketosteroids with use of this process (Table 2).
The reaction of cortisone 5 under the optimized conditions
gave the corresponding 17-ketosteroid 6,13 in 85% yield
(Table 2, entry 1). When 3-keto-Δ1,4-corticosteroids were used
as substrates, similar results were obtained. Thus, predniso-
lone 7 afforded the 11β-hydroxy-Δ1,4-3,17-diketosteroid 8,12
(42) Rausser, R.; Oliveto, E. P. C-16-alkylated 1,4-androstadienes, U.S.
Patent 3,010,958, 1961.
(40) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem.
Rev. 2002, 102, 2227–2302.
(41) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924–
(43) Gut, M.; Worcester, M.; Selective degradation of 16-methyl-17-OH-
20-keto steroids, U.S. Patent 3,539,598, 1970.
(44) Fu, X. Y.; Tann, C. H.; Thiruvengadam, T. K. Org. Process Res. Dev.
2001, 5, 376–382.
1942.
8490 J. Org. Chem. Vol. 74, No. 21, 2009

Pinto et al.
JOCNote
the relatively easily available 9β,11β-epoxy-16β-methyl
derivative 15.44 The molecular structure of compound 16
was confirmed by single crystal X-ray analysis. The corres-
ponding ORTEP diagram is depicted in the Supporting
Information (Figure A7) and some features of its structure
are briefly discussed.
magnetic stirring, at 80 °C, full conversion of the starting
compound was observed, as verified by TLC control. The
solvent was removed under reduced pressure and the resulting
mixture was purified by flash column chromatography [toluene/
ethyl acetate 2:1 (v/v)] to afford 11β-hydroxyandrost-4-ene-
3,17-dione 3, as a white solid (113.4 mg, 75% yield). Mp
(acetone/n-hexane) 185-188 °C (lit.13 mp 188-190 °C); TLC
[CH2Cl2/MeOH 9:1 (v/v)] Rf 0.67; IR 3473, 2927, 1736, 1663,
1617, 1450, 1051 cm-1; 1H NMR (CDCl3, 400 MHz) see Table
A1 in the SI; 13C NMR (CDCl3, 100 MHz) see Table A1 in the
SI; EI-MS m/z (%) 302 (100) Mþ, 266 (20), 248 (9), 226 (11), 189
(27), 163 (50), 145 (13), 91 (23).
All these obtained 17-keto derivatives are very expensive
steroid compounds, specially those bearing the 3-keto-Δ1,4
-
moiety. Therefore, our new catalytic process stands as an
attractive method to obtain highly functionalized 17-ketos-
teroids directly from corticosteroids bearing a diversity of
chemical functionalities. In fact, C19-steroids bearing an oxy-
gen function at C11 are synthetically and biologically45,46
important molecules. For instance, 11β-hydroxyandrostanes
have been efficiently converted into Δ9(11)-3,17-diketoster-
oids,39,47 which can then be readily transformed into estrone
derivatives by aromatization of ring A.48 The 17-ketosteroids
prepared herein are also suitable intermediates for the synthe-
sis of 17-substituted steroids, by simple modification of the
C17-carbonyl group.49
In conclusion, we have developed a highly practical protocol
for the conversion of corticosteroids into highly functionalized
17-ketosteroids, by cleavage of the C17-dihydroxyacetone side
chain using the “ecofriendly” bismuth(III) triflate as catalyst.
Due to the commercial availability of corticosteroids, this
process is an easy route to C17-ketosteroids bearing a
variety of chemical functions in rings A, B, C, and D. The
17-ketosteroids prepared herein are interesting molecules from
the pharmaceutical point of view and are currently under
biological evaluation.
9r-Chloro-11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-
dione, 10. Under the reaction conditions mentioned above,
compound 10 was obtained in 84% yield after purification by
flash column chromatography [toluene/ethyl acetate 3:1 (v/v)].
Mp (acetone/n-hexane):208-212 °C; TLC [CH2Cl2/MeOH 9:1
(v/v)] Rf 0.73; IR 3425, 2934, 1731, 1660, 1614, 1448, 884 cm-1
;
1H NMR (CDCl3, 400 MHz) see Table A2 in the SI; 13C NMR
(CDCl3, 100 MHz) see Table A2 in the SI; EI-MS m/z (%) 348
(75) Mþ, 331 (17), 311 (49), 293 (46), 193 (17), 89 (100), 75 (40),
73 (31). Anal. Calcd for C20H25ClO3: C, 68.86; H, 7.22. Found:
C, 69.01; H, 7.20.
9r-Fluoro-11β-hydroxy-16r-methylandrosta-1,4-diene-3,17-
dione, 14. Under the reaction conditions mentioned above,
compound 14 was obtained in 74% yield after purification by
flash column chromatography [toluene/ethyl acetate 3:1 (v/v)].
Mp (acetone/n-hexane) 241-243 °C (lit.43 mp 245-249 °C);
TLC [CH2Cl2/MeOH 9:1 (v/v)] Rf 0.68; IR 3450, 2935, 1734,
1663, 1619, 1452, 889 cm-1; 1H NMR (CDCl3, 400 MHz) see
Table A2 in the SI; 13C NMR (CDCl3, 100 MHz) see Table A2
in the SI; EI-MS m/z (%) 332 (100) Mþ, 311 (22), 293 (14), 265
(13), 208 (8), 186 (9), 89 (52), 75 (33).
Experimental Section
~
Acknowledgment. R.M.A.P. thanks Fundac-ao para a
Ciencia e Tecnologia for a grant (SFRH/BD/18013/2004).
J.A.R.S. thanks Universidade de Coimbra for financial sup-
port. The authors are grateful to Hovione FarmaCiencia SA,
Portugal, for kindly supplying some of the corticosteroids
used in this study.
^
General Procedure for the Cleavage of the C17-Dihydroxya-
cetone Side Chain of Corticosteroids. To a solution of hydro-
cortisone 1 (181.2 mg, 0.50 mmol) in 1,4-dioxane (15 mL) was
added Bi(OTf)3 xH2O (18.2 mg, 0.025 mmol). The color of the
3
reaction mixture gradually turned pale yellow. After 8 h, under
(45) Suzuki, Y.; Nakagawa, M.; Sato, F.; Iichikawa, Y.; Mizushima, Y.,
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Supporting Information Available: The experimental pro-
cedures of compounds prepared herein as well as some con-
siderations about their structural elucidation, including spectral
data the 1H NMR spectra of all compounds obtained herein, the
13C NMR spectra of compounds 4 and 10, and the CIF file of
compound 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8491