Two-way enantioselective control in the epoxidation of alkenes with the keto bile acid-Oxone system

Article abstract of DOI:10.1016/j.tet.2006.02.052

A number of 3-keto bile acid derivatives has been prepared and evaluated in the asymmetric epoxidation of unfunctionalized olefins with Oxone. The control of the enantioselectivity with the production of both enantiomers is strictly regulated by the bile acid inductor, as a function of substitution at carbons C(7) or C(12). Up to 98% ee has been achieved. The stereochemical outcome of the reaction may be rationalized in terms of spiro transition state model.

Full text of DOI:10.1016/j.tet.2006.02.052

Tetrahedron 62 (2006) 4482–4490
Two-way enantioselective control in the epoxidation of alkenes
with the keto bile acid–Oxonew system
b
b,
b
Olga Bortolini,a, Giancarlo Fantin, Marco Fogagnolo and Lara Mari
*
*
a
`
Dipartimento di Chimica, Universita della Calabria, Via Bucci 12 C, 87036 Rende CS, Italy
b
`
Dipartimento di Chimica, Universita di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
Received 9 November 2005; revised 30 January 2006; accepted 16 February 2006
Available online 22 March 2006
Abstract—A number of 3-keto bile acid derivatives has been prepared and evaluated in the asymmetric epoxidation of unfunctionalized
olefins with Oxone. The control of the enantioselectivity with the production of both enantiomers is strictly regulated by the bile acid
inductor, as a function of substitution at carbons C(7) or C(12). Up to 98% ee has been achieved. The stereochemical outcome of the reaction
may be rationalized in terms of spiro transition state model.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
alkenes, as well as for functionalized carbon–carbon double
bonds.8 In particular, the high enantioselective epoxidation of
styrenesrepresentedanimportantchallengefor manyresearch
groups, with results ranging from good to excellent.10
Optically active epoxides are useful chiral synthons in organic
synthesis and various chemical and biological methods have
been developed for the preparation of these derivatives.1 The
asymmetric epoxidation of alkenes represents the most direct
approach to these compounds2 and impressive results have
been achieved by many research groups in the epoxidation of
allylic alcohols,3 non-activated olefins4,5 and in the nucleo-
philic epoxidation of electron-poor alkenes.6,7 Chiral dioxir-
anesembodyanewgenerationofenantioselectiveoxidantsfor
olefin epoxidation8 and vic-diol oxidation.8c These non-metal
peroxidic oxygen transferring agents are readily prepared
from suitable optically active ketones and potassium
monoperoxysulfate (Oxonew) under buffered and mild
conditions.
With this background and based on our recent work, we have
reported that bile acid-derived ketones 1 of Chart 1, in
association with Oxone, served as efficient oxidant in the
asymmetric epoxidation of electron-poor11 and simple
olefins.12
In this epoxidation procedure, the control of the sense of the
enantioselection was strictly regulated by the bile acid
inductor, as a function of substitution at carbons C(7) or
C(12) of the steroidal framework. As an example, in the
epoxidation of cinnamic acid derivatives, specific and
stereochemically appropriate C(7) substitution led to the
formation of (K) epoxides of (2R,3S) absolute configur-
ation,13 whereas C(12) substituted bile acids promote the
formation of the opposite (C)-(2S,3R) epoxides 2 of Chart
1.11,13 This important stereochemical control has also been
found in the oxidation of mono-, trans-, gem-disubstituted
and trisubstituted unfunctionalized alkenes,12 with a
systematic inversion of the epoxide configuration by
The epoxidation is stereospecific and occurs using the in situ
generated dioxiranes both in stoichiometric and catalytic
conditions.8 Since the first report by Curci et al.9 utilizing an
optically active butanone derivative, various chiral ketones
have been investigated by many laboratories and considerably
high enantiomeric excess values have been reported for
terminal, trans- and cis-disubstituted and trisubstituted
O
Ph
bile acid 1a
Ph
Oxone,water/CH3CN
NaHCO3, pHca.8
O
Ph
R
(1)
R
bile acid 2a
R
up to 98% ee
Keywords: Enantioselective epoxidation; Oxone; Bile acids; Chiral dioxiranes.
*
Corresponding authors. Tel.: C39 0984 492850; fax: C39 0984 493307 (O.B.); fax: C39 0532 240709 (M.F.); e-mail addresses: o.bortolini@unical.it;
fgr@unife.it
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.052

O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
4483
Y
COOH
X = α–OR, H
X = H,H
Y = H,H
Y = α–OR, H
24
12
7
3
1
O
X
Z
Z= H, p-CH3, m-F, p-CH3O, o-Br
H
3
H
HOOC
2
O
(2S,3R)-2
Chart 1. Bile acid-derived ketones 1 and (2S,3R)-cinnamic acid epoxides 2.
changing the position of the C(7)/C(12) substituent on 1,
(Eq. 1).
epoxidation, we have synthesized some new 1-type bile
acid derivatives all having a C(3) carbonyl function and
substituents at C(7) or C(12) of different polarity and
bulkiness. In addition, the stereochemical outcome of the
As part of our efforts to understand the structural
requirements and factors involved in this asymmetric
OR
COOR'
COOR'
O
OR
O
7-substituted bile acid
R
H
R’
H
12-substituted bile acid
3a
3b
4a
4b
O
CH3
OH
O
O
O
CH3
3c
4c
OH
O
H
CH3
3d
--
--
4d
OH
O
O
O
CH3
CH3
3e
3f
4e
4f
OH
O
OH
O
O
3g
3h
CH3
H
4g
4h
HOOC
Chart 2. 3-Keto-5-b-cholan-24-oic acids investigated in this study.

4484
O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
reaction has been rationalized with the help of the spiro
transition state model.8a
obtained from common, low cost and commercially
available bile acids by adapting literature procedures.
The structure of the bile acids is characterized by a remarkable
robustness and rigidity that prevents any distortion, thus
maintaining the chiral elements of the carbonyl function also
after its conversion into dioxirane. The epoxidation reaction
was carried out in water–CH3CN (1/1) EDTA, pH ca. 8 using
equimolar concentrations of substrate and bile acid in the
presence of an excess of Oxone. The results of the epoxidation
of various alkenes are shown in Table 1.
2. Results and discussion
2.1. Epoxidation studies
The systematic study of the role played by the C(7)/C(12)
substituent characteristics and steric size was carried out by
preparing the ketones 3a–h and 4a–h, and by investigating
their performances with respect to enantioselectivity.
Ketones 3a–h and 4a–h, shown in Chart 2, are readily
With all substrates the epoxidation is complete in 12 h at
0 8C, with enantiomeric excesses varying from excellent
Table 1. Asymmetric epoxidation of selected unfunctionalized alkenes with Oxone in the presence of 3-keto-7-substituted and 3-keto-12-substituted bile acidsa
Substrate
7-Substituted bile acids
Yield (%) ee (%) Absolute configuration
12-Substituted bile acids
Yield (%) ee (%) Absolute configuration
1a
1b
1c
1d
1e
1f
90
90
60
92
70
60
80
54
80
80
40
80
70
60
(K)-(S,S)18
(K)-(S,S)19
(C)-S20
2a
2b
2c
2d
2e
2f
55
90
45
45
45
40
50
43
90
80
60
85
70
98
(C)-(R,R)18
(C)-(R,R)19
(K)-R20
Ph
Ph
1g
2hb
1a
1bc
1c
1d
1ee
1f
99
25
99
60
40
95
40
37
70
70
47
60
60
70
2a
80
50
70
10
99
30
20
15
70
50
78
65
55
66
Ph
2bc
2c
2dd
2e
Me
2ff
2h
1g
1a
1b
1c
1d
1e
1f
99
99
60
98
99
60
40
33
50
55
50
57
50
30
2a
2b
2c
2d
2e
2f
75
99
70
70
99
70
40
41
76
65
45
65
40
65
Ph
Me
1g
2h
1a
1b
1c
1d
1e
1f
50
93
70
90
90
70
79
49
57
70
30
60
70
49
(K)-(S,S)21
2a
2b
2c
2d
2e
2f
75
83
70
50
40
90
80
44
20
84
85
75
50
85
(C)-(R,R)21
Ph
Ph
Tol
Me
Ph
1g
2h
1a
1b
1c
1d
1e
1f
40
55
25
80
80
50
40
30
50
50
40
35
30
40
(C)-(S)20
2a
2b
2c
2d
2e
2f
45
65
60
50
70
50
30
34
60
50
40
50
30
70
(K)-(R)20
1g
2h
1a
1b
1c
1d
1e
1f
95
70
40
70
90
30
40
30
58
55
40
45
30
40
(C)-(S)22
2a
2b
2c
2d
2e
2f
65
50
50
50
99
75
45
48
60
60
60
35
50
70
(K)-(R)22
1g
2h
1b
1c
1e
1g
99
60
80
99
33
30
25
20
(C)-(1R,2S)23
2b
2c
2e
2h
45
99
97
99
50
35
30
30
(K)-(1S,2R)23
a Reaction time usually 12 h.
b Reaction time (3 h), after 12 h yield 85%, ee 80%.
c Reaction time (3 h), after 12 h yield 90%, ee 50%.
d Reaction time (1 h), after 12 h yield 85%, ee 52%.
e Reaction time (3 h), after 12 h yield 98%, ee 35%.
f
Reaction time (3 h), after 12 h yield 88%, ee 30%.

O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
4485
(98%) to moderate (30–40%) and with the systematic
inversion of the configuration as a function of C(7)/C(12)
bile acid substitution. The length of the alkyl chain between
the carboxylic functions of the C(7)/C(12) substituent was
shown to play a minor role, since the best results were
obtained with oxalic (3b, 4b) and phthalic (3g, 4h)
derivatives. Short substituents such as formyl gave results
comparable to those obtained with the hydroxyl derivatives
3a and 4a. The protection of the bile acid as a C(24) methyl
ester does not affect the course of the epoxidation reaction.
Stilbene is epoxidized by Oxone in the presence of the
protected derivative 3g in 80% yield (ee 60%, see Table 1)
and with the same yield but slightly higher ee (70%) when in
the presence of the unprotected derivative 4h. On the other
hand, the epoxidation of b-methyl styrene gave 40% yield
(ee 70%, Table 1) and 50% yield (ee 60%) if mediated by
the protected 3g or unprotected bile acid 4h, respectively.
moment, only moderately successful. The oxidation
system may also be applied to the oxyfunctionalization
of cis-alkenes.14 Dihydronaphthalene, used as model
substrate, is quantitatively oxidized to the corresponding
epoxide, either to the (1R,2S) or to the (1S,2R) form,
with enantiomeric excesses of 33 and 50%, respectively,
depending on bile acid (Table 1, last entry).
Many studies reported that halogen substituents strongly
increase the reactivity of the carbonyl group in the dioxirane
mediated epoxidation. The use of fluorine substitution was
first introduced into dioxirane chemistry by Curci et al.15 in
1988 and then applied to chiral ketones for asymmetric
catalysis by many research groups.10c,16 In this frame, we
have investigated 3-keto bile acid derivatives having
halogen substituents near to the carbonyl function,
in particular the 4-bromo derivatives 5 and 6 shown in
Chart 3.17
The a-b, that is, axial–equatorial, stereochemistry of the
C(7) and C(12) substituents of the bile acid has been
extensively reported in a previous paper11a and the results
also confirmed in this case. In particular, an axial
stereochemistry in both these positions is crucial for
efficient enantioselective control on the formation of either
one or the opposite enantiomer (see Fig. 1 for details).
Equatorial substituents at C(7), in fact, gave the same epoxy
enantiomers as axial substituents at C(12).11a Worthy of note,
3-keto-12-substituted bile acids afforded higher enantiomeric
excesses compared with 3-keto-7-substituted homologues.
Both chiral inductors are particularly active in the
epoxidation reaction (yield 99% in 6 h at 0 8C), thus
confirming the effect of halogen substituents on increasing
of the carbonyl electrophilic reactivity.10c The enantiomeric
excesses, however, are modest with values of 23 and 50%,
respectively, using b-methyl styrene. We are currently
encountering serious difficulties in the synthesis of the
corresponding fluorinated bile acids.
Terminal olefins were confirmed difficult in epoxidation
reactions and good enantioselectivities, ca. 70%, are
obtained only after the partial conversion (50%) of the
substrate. In 1999, Furstoss et al.20 reported a detailed study
on the determination of the absolute configuration of
a-methyl styrene oxide and several styrene epoxide
derivatives, that is, p-Cl, m-Cl, o-Cl, p-Br, p-NO2.
Conflicting optical rotation signs and, consequently,
opposite absolute configurations were, in fact, described
by many authors for these enantiomeric molecules. In our
oxidation conditions by using 7-substituted bile acids 3a–h,
the optical rotation signs of the isolated a-methyl styrene
epoxide and styrene epoxide were positive (solvent CHCl3,
cZ1) and therefore assigned to a (S)-configuration
(Table 1). The opposite (K)-R enantiomers were obtained
for oxidations carried out in the presence of 12-substituted
bile acids 4a–h. Note that the optical rotation signs reported
in our preliminary communication were not measured in
chloroform.12 Table 1 also includes the results observed
with para-methyl styrene. A positive rotation sign was
determined on the related isolated epoxide for oxidation
with Oxone mediated by 3a–h (solvent CHCl3, cZ1),
however; no association with an absolute configuration
might be found in the literature. The para-methyl styrene
oxide and the styrene oxide have an identical chromato-
graphic elution order in GC, on the chiral column used for
these analysis, being the second peak the most abundant. On
the other hand, based on the oxidation mechanism discussed
below and depicted in Figure 1, the two alkenes should
approach the dioxirane in a similar way. Following these
considerations but keeping well in mind the cautions in the
use of similar arguments20 we tentatively attribute to para-
methyl styrene oxide a (C)-S absolute configuration.
spiro O1
H
R1
CH3
CH3
12
Ph
R2
1
O
O
H
COOH
7
3
2
O
R
spiroA-transition state
spiro O1
Ph
R2
CH3
CH3
12
O
H
H
1
R1
COOH
O
7
3
2
R
O
spiro B-transition state
Figure 1. Spiro A-transition state for C(7)-substituted bile acids, spiro B-
transition state for C(12)-substituted bile acids.
Ketones 3a–h and 4a–h demonstrated a remarkable
structural durability with minor decomposition (ca. 10%
in 24 h, likely by Baeyer–Villiger oxidation11a), under
the oxidative reaction conditions. However, in some
cases, we observed a decrease of the ee values as a
function of the progress of the reaction. As an example,
when b-methyl styrene is epoxidized with Oxone in the
presence of the chiral ketone 3b an ee value of 70% was
measured after 3 h, that decreases to 50% after the period
required to complete the oxidation (12 h). Attempts to
minimize this parallel unselective oxidation are, at the

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O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
O
COOH
O
COOH
H
O
O
H
O
Br
O
Br
5
6
Chart 3. 3-Keto-4-bromo-5-b-cholan-24-oic acids, b predominant isomer, substituted at C(7) or C(12).
Table 2. Epoxide absolute configuration for the oxidation of cinnamic acid derivatives with Oxone, mediated by 7-substituted and 12-substituted bile acids11a
Substrate
7-Substituted bile acids
12-Substituted bile acids
Epoxide absolute configuration
Epoxide absolute configuration
(K)-(2R,3S)13a
(K)-(2R,3S)13b,d
(C)-(2S,3R)
(C)-(2S,3R)
COOH
COOH
CH3
F
COOH
(K)-(2R,3S)13b,d,e
(C)-(2S,3R)
(C)-(2S,3R)
(K)-(2R,3S)13e,16a
CH3O
COOH
Br
(K)-(2R,3S)13b,d,e
(C)-(2S,3R)
COOH
2.2. Mechanistic studies
reaction for cinnamic acids, that is, R1ZCOOH and R2ZH,
should give rise, on the basis of the absolute configuration of
the resulting epoxides collected in Table 2, to a spiro
A-transition state when the bile acid is C(7) substituted, or a
spiro B-transition state, when C(12) substituted (Fig. 1).
In a previous paper on the epoxidation of cinnamic acid
derivatives with the bile acid–Oxone system we have
evaluated the minimized dioxirane–alkene adducts with the
help of MM2 methods.11a Despite the low level of the
calculations, the theoretical approach is effectively limited
by such large system, evidence was provided for a
preferential approach of the olefin to the lipophilic face of
the bile acid, approach spiro O1, with the phenyl substituent
of the olefin directed toward this face. Computational
studies have shown that spiro transition states are favored
for the epoxidation of ethylene with dimethyldioxirane24
and in the epoxidation of trans-di- and trisubstituted olefins
with Oxone in the presence of fructose-derived ketones.8a,25
On the other hand, the occurrence of an attractive
interaction between p-conjugating substituents and the
lipophilic face of the bile acid may parallel similar
interactions proposed by Shi et al. in fructose mediated
oxidations.8a The importance of asynchronicity in the
dioxirane enantioselective epoxidation has been recently
demonstrated.26 According to the general view tending to
rationalize the stereochemical course of this epoxidation in
terms of a spiro model, the stereochemical outcome of the
The absolute configuration of the resulting cinnamic acid
epoxides is based on literature data13 and recent VCD
calculations.13b,d We have now applied the mechanistic
approach shown in Figure 1 to the epoxidation of the
unfunctionalized alkenes of this study, all containing at least
a phenyl ring. The spiro A-transition state, related to a C(7)
substitution of the bile acids, fully accounts for the
stereochemical outcome of the reaction, as shown in
Table 3.
The switch to a spiro B-transition state, proposed for C(12)
substituted bile acids, gives rise to the opposite enantio-
meric epoxides. From these considerations we may assert
that at least for cinnamic acid-like and unfunctionalized
alkenes, all containing a phenyl ring in the molecular
framework, the proposed spiro model well predicts the
experimental findings. We would like to point out, however,
that, at this stage and taking into account the low level of

O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
4487
dissolved in 1 mL of water containing 4!10K4 M EDTA
were added under stirring. After 1 h reaction time a second
portion of the solution containing the oxidant was added to
the reaction mixture. Samples of the mixture were taken out
at fixed times of 1, 3, 12 h, respectively, extracted with ethyl
acetate and submitted to GC analysis on the chiral column to
estimate both the alkene conversion and the enantiomeric
excess. For the epoxidations carried out on preparative
scale, the reaction mixtures were treated as described above
and the epoxides were separated from the crude mix by
column chromatography over silica gel, characterized by 1H
and 13C NMR analysis and submitted to optical rotation
measurement. The absolute configuration were obtained by
comparison with literature values, see text for details.
Table 3. Expected absolute configuration, based on the proposed spiro
transition state model of Figure 1, and experimentally found absolute
configuration for the epoxidation of the unfunctionalized alkenes of this
study with 3-keto-7-substituted bile acids
Substrate
Expected absolute
configuration
Found absolute
configuration
Ph
(S,S)
(S,S)
(S)
(K)-(S,S)18
(K)-(S,S)19
(C)-(S)20
Ph
Ph
Ph
Me
4.2.1. 3-Keto-7a-hydroxy- and 3-keto-12a-hydroxy-5b-
cholan-24-oic acid (3a, 4a). Three grams (7.6 mmol) of
commercially available chenodeoxycholic or deoxycholic
acid are dissolved in MeOH (30 mL) and reacted with 1 mL
of concentrated H2SO4. The solution is refluxed for 1 h,
concentrated and treated with aqueous saturated NaHCO3
(30 mL). The reaction mixture is extracted with ethyl
acetate and dried over anhydrous Na2SO4. The solvent was
removed in vacuum to give the crude methyl ester in almost
quantitative yield. The further oxidation of the C(3) hydroxy
function was carried out via oxidation with the Oppen-
nauer’s reagent27 according to the following simple and
straightforward procedures. The appropriate ester and
aluminium tert-butoxide (3.6 g, 14.6 mmol) in a mixture
of dry benzene (90 mL) and dry acetone (40 mL) were
boiled under reflux for 18 h. The turbid reaction product was
cooled and poured with stirring into 2 N sulphuric acid
(60 mL). The benzene layer was separated and washed
(twice) with water, aqueous sodium hydrogen carbonate and
water. After drying (Na2SO4), the solvent was removed
under reduced pressure to give the expected carbonyl
derivative. The foregoing precursor was hydrolyzed by
boiling it for 4 h under reflux with 20 mL of 10% NaOH in
methyl alcohol (40 mL). The solution was then diluted with
water (70 mL) and concentrated under reduced pressure to
remove methyl alcohol. After cooling the solution was
acidified with HCl 5%. Crystalline product was filtered off
in nearly 50% yield. Compound 3a: White crystals; mp
111–114 8C (lit.28 113–115 8C); [a]2D0 C13.5 (c 1.7,
CHCl3); selected 1H NMR28,29 resonances (300 MHz,
CD3OD): d 0.69 (s, 3H, CH3-18), 1.01 (d, JZ6.2 Hz, 3H,
CH3-21), 1.07 (s, 3H, CH3-19), 3.52 (dd, JZJ0Z14.6 Hz,
1H, H-4axial), 3.90 (br s, 1H, H-7b). Calcd for C24H38O4: C,
73.80; H, 9.81. Found: C, 73.35; H, 9.80. Compound 4a:
white crystals; mp 154–156 8C (lit.28 155–157 8C); [a]2D0
Me
Ph
Me
Ph
(S,S)
(K)-(S,S)21
Ph
(S)
(S)
(C)-(S)20
(C)-(S)22
Tol
calculations, the alternative spiro O2 approach cannot be
completely excluded. Work is in progress on this important
problem.
3. Conclusions
In summary, we have demonstrated that the use of bile acid
inducers having a carbonyl function at carbon C(3) and
suitable axial C(7) or C(12) substituents has a fundamental
effect on the reactivity and selectivity in asymmetric
epoxidations with Oxone. The two-way enantioselective
control of the stereochemistry of the resulting epoxide is
strictly regulated by the bile acid inductor as a function of
substitutions at carbons C(7) or C(12). Also in this case, the
spiro transition state model may be successfully applied to
predict the stereochemical outcome of the reaction.
4. Experimental
4.1. General methods
1
C44.1 (c 1.6, CHCl3); selected H NMR28,29 resonances
Oxidation reactions were monitored by quantitative GC
analysis using a Megadex DETTBSb capillary column.
Optical rotations were measured in CHCl3. Oxone and the
alkenes of this study are all commercially available products
used as received.
(300 MHz, CD3OD): d 0.69 (s, 3H, CH3-18), 1.05 (d, JZ
5.7 Hz, 3H, CH3-21), 1.08 (s, 3H, CH3-19), 2.87 (dd, JZ
J0Z14.0 Hz, 1H, H-11axial), 4.05 (br s, 1H, H-12b). Calcd
for C24H38O4: C, 73.80; H, 9.81. Found: C, 73.47; H, 9.50.
4.2. General procedure for epoxidation reactions
4.2.2. 3-Keto-7a-succinyloxy-5b-cholan-24-oic acid
(3d).11a Five grams of chenodeoxycholic acid were
suspended in ethyl acetate (30 mL) in the presence of
succinic anhydride (6 g, 60 mmol), triethylamine (1.27 mL,
12.7 mmol) and DMAP (0.15 g, 1.27 mmol). The reaction
mixture, monitored by TLC, was refluxed for 40 h. Ethyl
acetate (20 mL) and 15 mL of water were then added to the
In a 10 mL volumetric flask the alkene (0.085 mmol) and
the chiral ketone 3a–h or 4a–h (0.085 mmol) were
dissolved in 2 mL of CH3CN and mixed with 2 mL of an
aqueous solution of 5% NaHCO3, pH ca. 8. After cooling to
0 8C, 0.255 mmol of Oxone and 0.85 mmol of NaHCO3

4488
O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
mixture. The organic layer was washed with acid water
pH ca.1, dried over anhydrous Na2SO4 and evaporated to
obtain the bis-hemisuccinate. The identity of the intermedi-
ate could be validated by 1H NMR (300 MHz, CDCl3/
CD3OD 1:1 v/v): d 0.69 (s, 3H, CH3-18), 0.87 (s, 3H, CH3-
19), 0.87 (d, JZ6.5 Hz, 3H, CH3-21), 4.55 (m, 1H, H-3b),
4.82 (br s, 1H, H-7b). The C(3) hydrolysis of the product
was obtained by dissolving the it in MeOH–NaOH 5% (1/1
v/v) After 1 h the solution is acidified with dilute H2SO4.
Addition of 50 mL of H2O caused the precipitation of the
3a-hydroxy-7a-hemisuccinate derivative that was recov-
ered by filtration. The further oxidation of the C(3) hydroxy
function was carried out via oxidation with the Jones’
reagent.30 This reagent is obtained by adding 2.2 g of
chromium trioxide to 2.8 mL of concentrated sulfuric acid
and the solution diluted to 10 mL with water. Thus, the
hydoxy bile acid precursor was dissolved in 100 mL of
acetone and treated with Jones’ reagent until a slight
permanent orange color was obtained. After standing for
5 min, several drops of isopropyl alcohol were added to
destroy the oxidant in excess. The reaction mixture was
filtrated over Celite, concentrated under reduced pressure,
diluted with 20 mL of water and extracted with ethyl
acetate. The organic layer was dried over anhydrous
Na2SO4 and the solvent was removed in vacuum to give
3.5 g (70% overall yield) of the expected carbonyl
derivative. Compound 3d: mp 120–125 8C (dec) (hexane–
(s, 3H, CH3-18), 0.81 (d, JZ6.1 Hz, 3H, CH3-21), 1.00
(s, 3H, CH3-19), 2.62 (m, 5H, H-11axial, (COCH2)2), 3.67
(s, 3H, OCH3), 5.15 (br s, 1H, H-12b). Calcd for C29H44O7:
C, 69.02; H, 8.79. Found: C, 68.76; H, 9.11. Compound 1e:
syrup, 72% yield; [a]D20 C4.2 (c 3.5, CHCl3); selected H
1
NMR resonances (300 MHz, CDCl3): d 0.70 (s, 3H, CH3-
18), 0.94 (d, JZ6.0 Hz, 3H, CH3-21), 1.02 (s, 3H, CH3-19),
2.98 (dd, JZJ0Z14.6 Hz, 1H, H-4axial), 3.64 (s, 3H,
OCH3), 5.01 (br s, 1H, 1H, H-7b). Calcd for C31H46O7: C,
70.16; H, 8.74. Found: C, 71.00; H, 8.88. Compound 4e:
1
syrup, 74% yield; [a]D20 C57.5 (c 1.2, CHCl3); selected H
NMR resonances (300 MHz, CDCl3): d 0.75 (s, 3H, CH3-
18), 0.80 (d, JZ5.8 Hz, 3H, CH3-21), 0.99 (s, 3H, CH3-19),
2.68 (dd, JZJ0Z14.0 Hz, 1H, H-11axial), 3.62 (s, 3H,
OCH3), 5.12 (br s, 1H, H-12b). Calcd for C31H46O7: C,
70.16; H, 8.74. Found: C, 71.02; H, 8.18. Compound 3f:
1
syrup, 37% yield; [a]D20 C5.6 (c 1.3, CHCl3); selected H
NMR resonances (300 MHz, CDCl3): d 0.71 (s, 3H, CH3-
18), 0.96 (d, JZ6.2 Hz, 3H, CH3-21), 1.05 (s, 3H, CH3-19),
3.00 (dd, JZJ0Z14.6 Hz, 1H, H-4axial), 3.64 (s, 3H,
OCH3), 5.01 (br s, 1H, H-7b). Calcd for C32H48O7: C,
70.56; H, 8.88. Found: C, 70.12; H, 8.47. Compound 4f:
1
syrup, 40% yield; [a]D20 C61.2 (c 2.5, CHCl3); selected H
NMR resonances (300 MHz, CDCl3): d 0.78 (s, 3H, CH3-
18), 0.80 (d, JZ6.1 Hz, 3H, CH3-21), 1.01 (s, 3H, CH3-19),
2.70 (dd, JZJ0Z14.0 Hz, 1H, H-11axial), 3.66 (s, 3H,
OCH3), 5.15 (br s, 1H, H-12b). Calcd for C32H48O7: C,
70.56; H, 8.88. Found: C, 70.21; H, 8.74.
EtOAc); [a]2D0 C17.3 (c 1.5, CHCl3); selected H NMR
1
resonances (300 MHz, CDCl3): d 0.70 (s, 3H, CH3-18), 0.95
(d, JZ6.5 Hz, 3H, CH3-21), 1.04 (s, 3H, CH3-19), 2.98 (dd,
JZJ0Z14.6 Hz, 1H, H-4axial), 5.05 (br s, 1H, H-7b). Calcd
for C28H42O7: C, 68.54; H, 8.63. Found: C, 68.16; H, 9.01.
4.2.4. 3-Keto-7a-malonyloxy- (3c), 3-keto-12a-malonyl-
oxy-5b-cholan-24-oic methyl ester (4c). One gram
(2.5 mmol) of 3a- or 4a-methyl esters dissolved in
anhydrous toluene (30 mL) were added to a solution
containing 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s
acid, 2.75 mmol). The reaction mixture was kept under
reflux for 4 h, cooled and concentrated under reduced
pressure affording the malonyl derivatives in almost
quantitative yield. Compound 3c: sticky oil; [a]2D0 K1.8
4.2.3. 3-Keto-7a-oxalyloxy- (3b), 3-keto-12a-oxalyloxy-
(4b), 3-keto-12a-succinyloxy- (4d), 3-keto-7a-glutaryl-
oxy- (3e), 3-keto-12a-glutaryloxy- (4e), 3-keto-7a-adi-
poyloxy- (3f), 3-keto-12a-adipoyloxy-5b-cholan-24-oic
methyl ester (4f). One gram (2.5 mmol) of 3a- or 4a-
methyl esters were dissolved in 10 mL of CH2Cl2 contain-
ing TEA (2.5 mmol) and slowly added, under stirring, to a
solution of the appropriate dichloride derivative, that is,
oxalyl, succinyl, glutaryl or adipoyl dichloride, 7.5 mmol
dissolved in 5 mL of CH2Cl2. After 12 h at room
temperature the reaction mixture was treated with 10 mL
of acid water (HCl 5%) and left under stirring for 4 h. The
organic layer was separated, dried on anhydrous Na2SO4,
concentrated and the expected derivatives purified by
column chromatography (petroleum ether/ethyl acetate/
acetic acid 60:40:1). Compound 3b: syrup, 85% yield;
1
(c 2.0, CHCl3); selected H NMR resonances (300 MHz,
CDCl3): d 0.68 (s, 3H, CH3-18), 0.95 (d, JZ6.2 Hz, 3H,
CH3-21), 1.02 (s, 3H, CH3-19), 2.91 (dd, JZJ0Z14.6 Hz,
1H, H-4axial), 3.42 (m, 2H, COCH2CO), 3.64 (s, 3H,
OCH3), 5.03 (br s, 1H, H-7b). Calcd for C29H42O7: C,
69.29; H, 8.42. Found: C, 68.86; H, 8.55. Compound 4c: mp
143–145 8C, (hexane–EtOAc); [a]2D0 C73.1 (c 1.3, CHCl3);
selected 1H NMR resonances (300 MHz, CDCl3): d 0.78 (s,
3H, CH3-18), 0.83 (d, JZ6.4 Hz, 3H, CH3-21), 1.02 (s, 3H,
CH3-19), 2.70 (dd, JZJ0Z14.0 Hz, 1H, H-11axial), 3.42
(m, 2H, COCH2CO), 3.68 (s, 3H, OCH3), 5.21 (br s, 1H, H-
12b). Calcd for C29H42O7: C, 69.29; H, 8.42. Found: C,
68.16; H, 8.57.
1
[a]2D0 K16.2 (c 5.0, CHCl3); selected H NMR resonances
(300 MHz, CDCl3): d 0.70 (s, 3H, CH3-18), 0.93 (d,
JZ6.8 Hz, 3H, CH3-21), 1.07 (s, 3H CH3-19), 3.20 (dd,
JZJ0Z14.6 Hz, 1H, H-4axial), 3.62 (s, 3H, OCH3), 5.17 (br
s, 1H, H-7b). Calcd for C28H40O7: C, 68.83; H, 8.25. Found:
C, 68.36; H, 8.30. Compound 4b: syrup, 83% yield; [a]D20
C74.4 (3.4, CHCl3); selected 1H NMR resonances
(300 MHz, CDCl3): d 0.80 (s, 3H, CH3-18), 0.82 (d, JZ
6.2 Hz, 3H, CH3-21), 1.12 (s, 3H, CH3-19), 2.72 (dd, JZ
J0Z14.0 Hz, 1H, H-11axial), 3.63 (s, 3H, OCH3), 5.32 (br s,
1H, H-12b). Calcd for C28H40O7: C, 68.83; H, 8.25. Found:
C, 68.45; H, 8.09. Compound 4d: 76% yield, mp 138–
141 8C (hexane–EtOAc); [a]2D0 C66.4 (c 2.5, CHCl3);
4.2.5. 3-Keto-7a-phtaloyloxy- (3g), 3-keto-12a-phtaloyl-
oxy-5b-cholan-24-oic methyl ester (4g). To a toluene
solution (40 mL) containing 3a- or 4a-methyl esters (1 g,
2.5 mmol), phtalic anidride (3.75 mmol) and imidazole
(2.5 mmol) were added under stirring. The mixture was
refluxed for 40 h, monitoring the progress of the reaction by
TLC (petroleum ether/ethyl acetate 4:1). After completion
the mixture was washed with acid water (15 mL, HCl 5%)
and extracted with ethyl acetate. The organic layer was
separated, dried on anhydrous Na2SO4, concentrated and the
expected derivatives purified by column chromatography
1
selected H NMR resonances (300 MHz, CDCl3): d 0.78

O. Bortolini et al. / Tetrahedron 62 (2006) 4482–4490
4489
(petroleum ether/ethyl acetate/acetic acid 80:20:1). Yields
83 and 87%, respectively. Compound 3g: mp 105–110 8C
References and notes
(dec), (hexane–EtOAc); [a]2D0 K15.1 (c 1.1, CHCl3);
selected H NMR resonances (300 MHz, CDCl3): d 0.72
1. (a) Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev.
2004, 104, 2857–2899. (b) Behrens, C. H.; Sharpless, K. B.
Aldrichim. Acta 1983, 16, 67–80.
1
(s, 3H, CH3-18), 0.95 (d, JZ6.0 Hz, 3H, CH3-21), 1.08 (s,
3H, CH3-19), 2.92 (dd, JZJ0Z14.6 Hz, 1H, H-4axial), 3.68
(s, 3H, OCH3), 5.35 (br s, 1H, H-7b), 7.44 (d, JZ7.2 Hz,
1H, Ar-H), 7.60 (m, 2H, Ar-H), 7.98 (d, JZ7.0 Hz, 1H, Ar-
H). Calcd for C33H44O7: C, 71.71; H, 8.02. Found: C, 71.24;
2. Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem.
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and references.
1
H, 7.89. Compound 4g: the H NMR spectrum is almost
identical to that of 4h except for the methyl ester resonance
d 3.65 (s, 3H, OCH3).
4. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, 1993; pp 159–202.
5. Katsuki, T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
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4.2.6. 3-Keto-12a-phtaloyloxy-5b-cholan-24-oic acid
(4h). The free bile acid 4h was obtained from 4g upon
reaction with KOH 5% (20 mL) under reflux for 1 h. The
reaction mixture was treated with concentrated HCl and
extracted with ethyl acetate. The organic layer, separated,
dried and concentrated afforded the expected product in
almost quantitative yield. Compound 4h: mp 92–98 8C
(dec), (hexane–EtOAc); [a]2D0 C46.7 (c 1.4, CHCl3);
7. Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47–51.
8. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496. (b) Yang, D.
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1
selected H NMR resonances (300 MHz, CDCl3): d 0.86
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2004, 101, 5794–5798. (b) Chan, W.-K.; Yu, W.-Y.; Che,
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67, 3479–3486. (d) Tian, H.; She, X.; Xu, J.; Shi, Y. Org.
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(s, 3H, CH3-18), 0.98 (d, JZ6.2 Hz, 3H, CH3-21), 1.05 (s,
3H, CH3-19), 2.72 (dd, JZJ0Z14.0 Hz, 1H, H-11axial),
5.44 (br s, 1H, H-12b), 7.60 (m, 3H, Ar-H), 7.90 (d, JZ
7.1 Hz, 1H, Ar-H). Calcd for C32H42O7: C, 71.35; H, 7.86.
Found: C, 72.02; H, 8.20.
4.2.7. 3-Keto-4b-bromo-7a-formyloxy-5b-cholan-24-oic
acid (5). This derivative was prepared from the correspond-
ing 3-keto-7a-formyloxy-5b-cholan-24-oic acid by treat-
ment with bromine in DMF, according with literature
procedures;17,31 diasteromeric a/b ratio 1:9, mp 164–166 8C
11. (a) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Forlani, R.;
Maietti, S.; Pedrini, P. J. Org. Chem. 2002, 67,
5802–5806. (b) Bortolini, O.; Fogagnolo, M.; Fantin, G.;
Maietti, S.; Medici, A. Tetrahedron: Asymmetry 2001, 12,
1113–1115.
1
(hexane–EtOAc); selected H NMR resonances (300 MHz,
CDCl3): d 0.70 (s, 3H, CH3-18), 0.94 (d, JZ5.4 Hz, 3H,
CH3-21), 1.10 (s, 3H, CH3-19), 5.15 (m, 1H, H-7), 5.33 (d,
JZ11.7 Hz, 1H, H-4), 8.08 (s, 1H, 7-CHO).
12. Bortolini, O.; Fantin, G.; Fogagnolo, M.; Mari, L. Tetra-
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4.2.8. 3-Keto-4b-bromo-12a-formyloxy-5b-cholan-24-
oic acid (6). This derivative was prepared from the
corresponding 3-keto-12a-formyloxy-5b-cholan-24-oic
acid by treatment with bromine in DMF, according with
literature procedures17,31; diasteromeric a/b ratio ca. 1:9,
mp 183–184 8C (hexane–Et2O); selected 1H NMR resonances
(300 MHz, CDCl3): d 0.80 (s, 3H, CH3-18), 0.84 (d, JZ
6.3 Hz, 3H, CH3-21), 1.07 (s, 3H, CH3-19), 4.95 (d, JZ
11.7 Hz, 1H, H-4), 5.29 (m, 1H, H-12), 8.11 (s, 1H, 12-CHO).
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Acknowledgements
This work was supported by MURST (Italy) PRIN 2003 and
Universities of Calabria and Ferrara.
´
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.02.
052.
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