Chiral auxiliary-mediated enantioenrichment of (±)-ibuprofen, under steglich conditions, with secondary alcohols derived from (R)-carvone

Article abstract of DOI:10.1590/S0103-50532010000600011

The synthesis of a series of chiral secondary alcohols derived from (R)-carvone, and the stereochemical outcome of their reaction with (±)-ibuprofen, is reported. The racemic drug was transformed into the corresponding diastereomeric esters mediated by DC

Full text of DOI:10.1590/S0103-50532010000600011

J. Braz. Chem. Soc., Vol. 21, No. 6, 1017-1036, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen, under Steglich
conditions, with Secondary Alcohols derived from (R)-Carvone
Marcela Amongero, Damian Visnovezky and Teodoro S. Kaufman*
Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y
Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
A síntese de uma série de álcoois secundários derivados da (R)-carvona, assim como o curso
estereoquímico da esterificação destes derivados com ( )-ibuprofeno é apresentada. O composto
comercial racêmico foi transformado nos respectivos ésteres diastereoisoméricos através do
acoplamento mediado por DCC/DMAP, fornecendo o par de diastereoisômeros derivados de
(S)- ou (R)-ibuprofeno em relação até 5.7:1, dependendo do tipo de auxiliar quiral empregado.
The synthesis of a series of chiral secondary alcohols derived from (R)-carvone, and the
stereochemical outcome of their reaction with ( )-ibuprofen, is reported. The racemic drug was
transformed into the corresponding diastereomeric esters mediated by DCC/DMAP, affording up
to 5.7:1 diastereomeric ratios of the esters derived from either (S)- or (R)-ibuprofen, depending
on the type of chiral auxiliary employed.
Keywords: ibuprofen, carvone, Steglich esterification, chiral auxiliaries, chiral secondary
alcohols
Introduction
into their active enantiomers through a thioester-mediated
epimerization process which involves the Co-enzyme A
(CoA).3 However, these acyl-CoA thioester derivatives
are chemically reactive and may become involved in a
transacylation reactions with endogenous nucleophiles,
leading to covalent binding of the drug to proteins, the
clinical consequences of which relate to the toxicity of this
pharmaceutically active ingredient.4 It is also suspected
that the acyl-CoA intermediate derived from (R)-ibuprofen
may be responsible for the formation of mixed glyceryl
esters, which once deposited in fatty tissue could cause
unknown long-term effects, transforming (R)-ibuprofen
into a pharmacological uncertainty.5
Therefore, the selective preparation of (S)-ibuprofen
has been the subject of intense research and numerous
stereoselective chemical approaches have been explored for
that purpose.6 In addition, resolutions of the racemate by
means of crystallization of diastereomeric salts,7 as well as
chemoenzimatic transformations including esterificacion,
trans-esterification,8 enantioselective hydrolysis of
esters,9 amides10 and nitriles11 and other enzyme-mediated
strategies,12 and a yeast-mediated selective degradation of
the unwanted enantiomer,13 have also been reported.
Carvone is a naturally-occurring cyclohexylic terpenoid
which is isolated from Carum carvi, Anethum graveolans
During the past two decades, the preparation of optically
active drugs has received considerable attention both, from
academics and industry. The reasons behind this interest
are threefold, including the medical benefit from using
a single chemical entity, the changing pharmaceutical
regulations, which now require the development of optically
active drugs as single stereoisomers, and also advances in
strategies for the synthesis of optically pure compounds,
which facilitated the task.1
Ibuprofen (1, Figure 1) is a non-steroidal anti-
inflammatory agent of the class of the a-arylpropionic
acids, which also includes flurbiprofen (2, Figure 1),
fenoprofen (3, Figure 1), ketoprofen (4, Figure 1) and
naproxen (5, Figure 1), amongst its most prominent
members. The drug is marketed mostly as the racemate
despite that it has been shown that the (S)-enantiomer is
the main responsible for the therapeutic effect. The pure
enantiomer is also available, being prescribed only for
certain specific conditions.2
It has been demonstrated that (R)-ibuprofen as well as
its congeners can be stereoselectively interconverted in vivo
*e-mail: kaufman@iquir-conicet.gov.ar

1018
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
Me
J. Braz. Chem. Soc.
Me
Me
OH
O
OH
Me
O
O
O
F
HO
Me
ibuprofen (1)
flurbiprofen (2)
fenoprofen (3)
Me
O
O
Me
Me
OH
OH
O
O
MeO
Me
ketoprofen (4)
naproxen (5)
R-carvone (6)
Figure 1. Chemical structures of ( )-ibuprofen (1), other relevant a-arylpropionic acid type non-steroidal anti-inflammatory agents (2-5) and R-carvone (6).
1
and Mentha spicata, being available in both of its
enantiomeric forms. It has been extensively employed
as building block in organic synthesis.14 Interestingly,
however, the use of carvone derivatives as chiral auxiliaries
has only few and scattered precedents.15
The chiral auxiliary-mediated dynamic kinetic
resolution of a-substituted carboxylic acids has been
recently recognized as an approach towards the preparation
of enantioenriched a-aminoacids, as well as their
a-mercapto-, a-halo- and a-hydroxy- congeners. This is an
effective alternative, provided configurational lability can
be induced at the stereogenic a-carbonyl center.16
examination of their H NMR spectra, which revealed that
H-3 was considerably more deshielded in 7a (d 3.89 ppm)
than in 7b (d 2.91 ppm) and 7c (d 3.29 ppm), pointing out to
apseudo-axialorientationoftheheteroatomicsubstituent.The
preferential generation of 7a and 8 under kinetic conditions is
consistent with an axial Michael addition of the thiols from
the a-face of carvone, driven by stereoelectronic effects,
and subsequent protonation of the resulting enolate from the
oppositeandlesshinderedb-face. Compounds7band7cmay
result from the base-mediated equilibration of 7a under the
reaction conditions.23
Diastereoselective reduction of ketones 7a, 7b and
8 with K-Selectride in anhydrous THF,24 from the less
encumbered b-face of their corresponding carbonyl
moiety,25 provided alcohols 9a, 9b and 10 (Scheme 1) in
58, 66 and 56%, respectively.
Recently, Amoroso and coworkers17,18 reported
the preparation of different a-arylpropionic acids in
their enantioenriched forms, by using lactamide-type
chiral auxiliaries. The diastereomeric mixtures of the
corresponding lactamic esters were obtained in good yields
and reasonable diastereoselectivities depending upon
the solvent and chiral auxiliary used. Therefore, here we
wish to report the synthesis of chiral secondary alcohols
derived from (R)-carvone (6, Figure 1) and their reaction
with racemic ibuprofen under Steglich conditions,19 as a
stereodivergent entry to enantioenriched mixtures of esters
derived from either (S)- or (R)-ibuprofen, depending on the
type of chiral auxiliary employed.
Thioether 7b was further elaborated by oxidation with
H2O2 under (NH4)6Mo7O24 catalysis.26 This furnished 12
(Scheme 1) (47%), 11 (Scheme 1) (5%) and recovered 7b
(30%) when limiting amounts of the oxidant were employed,
andaseparablemixtureconsistingof 11(52%)and12(24%),
when a five-fold excess of H2O2 was used. Next, compounds
11 and 12 were stereoselectively reduced with K-selectride,
providing 13 and 14 (Scheme 1) in 45 and 44% yield,
respectively. Low yields were caused by elimination of the
sulfur-bearing moiety. However, in an improved approach,
the required sulfone-alcohol 13 was accessed in 60% yield
throughthe(NH4)6Mo7O24-catalyzedoxidationofalcohol 9b.
For the second series, where the aromatic substituent
is directly attached to a cyclohexenic six-membered ring,
(R)-carvone was subjected to the direct addition of three
different Grignard reagents. The procedure stereoselectively
furnished alcohols 15a-c (Scheme 2), as result of an anti-
periplanar attack of the Grignard reagent with respect to the
isopropenyl group.27 In turn, these tertiary allylic alcohols
were treated with PCC/Al2O3, producing an oxidative allylic
transposition28 to the corresponding 3-phenyl-(S)-carvone
derivatives 16a-c (Scheme 2) in yields ranging from 71
to 86%.29
Results and Discussion
Three series of secondary alcohols were prepared. In
the first one, (R)-carvone was submitted to a conjugate
addition reaction with thiophenol under thermodynamic
conditions,20 furnishing thioethers (7a-c, Scheme 1) in
4, 34 and 16% yield, respectively. On the other hand,
reaction with PhSH and 2-naphthalenethiol under kinetic21
conditions afforded sulfides (7a and 8, Scheme 1) in 60 and
92% yield, respectively.
The stereochemistry of these products was deduced by
comparisonwithliteraturedata,22 analysisoftheenhancement
ofsignalsinnuclearOverhausereffect(nOe)experimentsand

Vol. 21, No. 6, 2010
Amongero et al.
1019
7
Me
Me
Me
Me
2'
5'
2
1'
1
O
O
S
O
S
O
S
3'
4'
a
Ar
+
3
4
+
5
8
6
6'
10
H
H
9b
Me
Me
Me
Me
H
H
9a
7a Ar = Ph
7c
8
Ar = 2-Naphth
6
7b
c
h
b
d
Me
O
Me
HO
Me
O
S
Me
O
S
S
O
HO
S
Ar
O
+
Me
Me
Me
Me
9a Ar = Ph
10 Ar = 2-Naphth
9b
11
12
e
g
f
H
H
O
H
Me
O
S
Me
O
S
H
CH3
S
H3C
HO
HO
O
H
H
H
H
H
H
Me
Me
14
7b
13
Scheme 1. Reagents and conditions: a) PhSH (5 equiv.), Et3N, CHCl3, reflux 3 days (7a, 4%; 7b, 34%; 7c, 16%), or PhSH (1 equiv.), Et3N (cat.), hexane,
0 ºC, 8 h (7a, 60%), or 2-NaphthSH (1 equiv.), Et3N (0.5 equiv.), hexane, 0 ºC, 8 h (8, 92%); b) K-Selectride, THF, –78 ºC, 2 h (9a, 58%; 10, 56%);
c) K-Selectride, THF, –78 ºC, overnight (66%); d) H2O2 (5 equiv.), (NH4)6Mo7O24, EtOH, 0 ºC (11, 52%; 12, 24%); e) H2O2 (5 equiv.), (NH4)6Mo7O24
(cat.), EtOH, 0 ºC, 24 h (60%); f) K-Selectride, THF, –78 ºC, overnight (45%); g) K-Selectride, THF, –78 ºC, overnight (44%); h) H2O2 (1.05 equiv.),
(NH4)6Mo7O24, EtOH, 0 ºC, 3 h (11, 5%; 12, 47%).
These ketones were stereoselectively reduced with
sodium borohydride in a MeOH-THF mixture, furnishing
the secondary allylic alcohols 17a-c (Scheme 2) in 83-94%
yield. Their configuration was determined as 1S,5S based on
literature precedents30 and the results of a nOe experiment,
where signal enhancement of H-5 was observed upon
irradiation of H-1.
The third group of chiral alcohols was obtained after
subjecting (R)-carvone to conjugate addition reactions with
aryl and 1-naphthyl Grignard reagents in the presence of
copper(I) iodide31 to which TMSCl was added in order to
ensure efficient transformations.32
These gave the corresponding silyl enol ether
intermediates 18a and 18b (Scheme 3) in high yields, as
single diastereomers to which the (3S,5R)- configuration
was assigned on the basis of literature precedents,33 an
exhaustive NMR analysis of 18b and knowledge of the role
of the isopropenyl group in determining the stereochemistry
of the conjugate addition product. The stereochemical
result of this reaction is consistent with the outcome of the
reductions of ketones 16a-c, resulting from a nucleophilic
attack anti-periplanar to the bulky isopropenyl group.
In turn, these were desilylated by careful treatment
with TBAF in Et2O in order to avoid the production of
Scheme 2. Reagents and conditions: a) R-C6H4MgBr, THF or Et2O, –20 ºC (15a, 75%; 15b, 54%; 15c, 59%); b) PCC/Al2O3, CH2Cl2, rt (16a, 82%; 16b,
86%; 16c, 71%); c) NaBH4, THF-MeOH (5:3), 0 ºC (17a, 88%; 17b, 94%; 17c, 83%).

1020
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
Me
Me
Me
Me
O
TMSO
Ar
O
Ar
HO
Ar
a
b
c
(R)
Me
Me
18a Ar = Ph
Me
19a Ar = Ph
Me
20a Ar = Ph
6
18b Ar = 1-Naphth
19b Ar = 1-Naphth
20b Ar = 1-Naphth
Scheme 3. Reagents and conditions: a) ArMgBr, CuI, TMSCl, THF, 0 ºC (18a, 95%; 18b, 96%); b) TBAF, Et2O, rt (19a, 96%; 19b, 90%); c) K-Selectride,
THF, –70 ºC (20a, 80%; 20b, 80%).
diastereomeric mixtures at the stereocenter adjacent to
the carbonyl, due to the base-catalyzed epimerization of
the initial product.34 In this process, protonation of the
trapped intermediate enolate from the less hindered face
anti-periplanar to the C-5 substituent, furnished ketones 19a
and 19b (Scheme 3) in 96 and 90% yields, respectively.
Finally, ketones 19a,b were stereoselectively reduced with
K-selectride to the corresponding secondary alcohols 20a
and 20b (Scheme 3) in 80% yield.
Interestingly, the stereochemical outcome of the
reduction was different from that previously observed with
the sulfur-containing alcohols and could be attributed to a
different preferred conformation of the starting ketones,
where the bulky aryl substituents are located equatorially,
flipping the isopropenyl moiety to a pseudo-axial position,
thus hindering the approach of the reducing agent from the
side of the isopropenyl group.
This speculation was confirmed by nOe experiments
on 19a and 19b, which revealed that irradiation of the
methylene carbon of the isopropenyl moiety excerted
signal enhancement of H-3 (Figure 2). On the other hand,
detection of H-3 signal enhancement in 20a upon irradiation
of the C-2 methyl group and also of H-9b confirmed
that they were located on the same side of the molecule.
Furthermore, the axial nature of the hydroxyl group was
established from the values of the coupling constants
between H-1 and its neighbours in its 1H NMR spectrum
(4.5 and 5.9 Hz) and its lack of nOe signal enhancement
of H-1 upon irradiation of H-9b.
with ( )-ibuprofen, under the conditions described by
Steglich,19 which employ the DCC-DMAP reagent system
as condensing agent.
As shown in Table 1, alcohol 9a provided up to a
28:72 mixture of diastereomeric esters in 89% combined
yield, when the reaction was carried out in CHCl3
at –50 ºC (entry 1). Furthermore, when the bulkier
2-naphthyl thioether 10 was used as chiral auxiliary, a
slight improvement in the diastereomeric ratio (26:74)
was observed, at the expense of a slight decrease in yield
of product (entry 10). On the other hand alcohol 9b, a
diastereomer of 9a, furnished essentially equimolecular
mixtures of diastereomeric esters (entries 4-9), according
to NMR and HPLC peak area integration, regardless the
solvent and temperature conditions employed.
In an attempt to improve the product diastereomeric
ratio, the reactions with the related sulfoxide 13 and sulfone
14 were explored. However, essentially no chiral induction
was observed among the resulting esters (entries 11-14).
Chiral auxiliaries 17a-c gave diastereomeric ratios
nearing 2:1 (Table 2), always favouring the same ester which
as discussed below, was demonstrated to be that derived
from (S)-ibuprofen. The best results in terms of chemical
and optical yields were obtained with alcohol 17a, when
subjected to esterification in toluene at –20 ºC (entry 3).
When chiral alcohols 20a and 20b were subjected
to esterification with ( )-ibuprofen under Steglich
conditions (Table 3), it was observed that the best
results were obtained when chloroform was employed
as solvent (entries 1, 2 and 13) and that the product was
enantioenriched in the ester derived from (R)-ibuprofen.
The performance of the chiral auxiliaries was evaluated
through their submission to esterification reactions
H
H9a
Me
Me
H
H
H9b
OH
Me
O
H
H
H
H
H3
O
H
H
H
H
H
H
Me
H
H
Me
Me
H
H
H
H
H
H
H
19a
19b
20a
Figure 2. Signal enhancements in the nOe experiments of compounds 19a, 19b and 20a.

Vol. 21, No. 6, 2010
Amongero et al.
1021
Table 1. Esterification of ( )-ibuprofen with chiral auxiliaries 9a, 9b, 10, 13 and 14
(O)n
Me
(O)n
S
R
Me
*
O
Me
Me
DCC
HO (S)
Me
S
R
O (S)
Me
DMAP
OH
Ar
Ar
+
(S)
(S)
O
Me Me
Temperature
Me Me
Entry
No.
Chiral
Auxiliary No.
Yield
(%)
Product
No.
Diaster.
ratioa
Ar (n)
R
Solvent
(ºC)
–50 → rt
–20
0
1
9a
9a
9a
9b
9b
9b
9b
9b
9b
10
13
14
14
14
Ph (0)
Ph (0)
Ph (0)
Ph (0)
Ph (0)
Ph (0)
Ph (0)
Ph (0)
Ph (0)
b-H
b-H
b-H
a-H
a-H
a-H
a-H
a-H
a-H
b-H
a-H
a-H
a-H
a-H
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhMe
PhMe
PhMe
PhH
89
95
85
44
38
65
72
52
49
69
95
81
40
62
21
21
21
22
22
22
22
22
22
23
24
25
25
25
72:28
2
67:32
3
ca. 50:50
ca. 50:50
ca. 50:50
ca. 50:50
ca. 50:50
ca. 50:50
ca. 50:50
74:26
4
–50
rt
5
6
–50
–20
rt
7
8
9
rt
10
11
12
13
14
Naphthyl
Ph (2)
CHCl3
CHCl3
PhMe
CHCl3
CHCl3
0 → rt
0
ca. 50:50
ca. 50:50
58:42
Ph (1)
–20
–20
0
Ph (1)
Ph (1)
ca. 50:50
aComparison with esters prepared with pure (S)-ibuprofen indicated that the major diastereomer is that derived from (R)-ibuprofen.
Table 2. Esterification of ( )-ibuprofen with chiral auxiliaries 17a-c
R
R
Me
Me
*
Me
(S)OH
Me
(S) O
DCC
DMAP
OH
+
(S)
(S)
O
O
Me Me
Me Me
Me
Me
Chiral Auxiliary
No.
Temperature
(ºC)
Yield
(%)
Product
No.
Entry No.
R
Solvent
R/Sa
1
17a
17a
17a
17a
17a
17b
17b
17b
17c
17c
17c
H
H
CHCl3
CHCl3
PhMe
PhMe
PhMe
PhMe
CHCl3
THF
0
–20
–20
0
40
70
81
32
72
66
21
39
90
85
72
26
26
26
26
26
27
27
27
28
28
28
42:58
48:52
37:63
45:55
39:61
38:62
37:63
38:62
40:60
41:59
38:62
2
3
H
4
H
5
H
rt
6
Me
Me
Me
MeO
MeO
MeO
rt
7
0
8
0
9
PhMe
PhMe
PhMe
rt
10
11
–20
rt
aDeduced by comparison with esters prepared with pure (S)-ibuprofen.

1022
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
Interestingly, slightly improved diastereomeric ratios
were obtained when a five-fold excess of ibuprofen was
employed, while changing the order of addition of the
reagents, preincubation of a mixture of the acid and
the alcohol with activated 4Å molecular sieves and the
addition of triethylamine (entries 3-5) did not improve the
diastereomeric ratios of ester products.
In addition, a trend was observed, indicating that the
bulkier 1-naphthyl derivative 20b slightly outperformed
its congener 20a, probably by leading to a chiral auxiliary
with a conformationally more rigid cyclohexyl ring. Under
the typical conditions, a ratio of products up to 82:18 was
observed (entry 13). These levels of enantioenrichment
are similar to those previously informed by the group of
Amoroso.17
For the sake of comparison, the effect of placing a
bulkier group near the secondary alcohol was examined
with (–)menthol (31, Scheme 4), the esterification of which
with ( )-ibuprofen in CHCl3 at 0ºC gave 55% of a nearly
1:1 mixture of diasteromeric esters 32 (Scheme 4).
Therefore, the more hindered alcohol 35 (Scheme 4)
was synthesized by K2Cr2O7-H2SO4 oxidation of 31 to
menthone (33, Scheme 4),35 followed by a Claisen-Schmidt
condensation of the latter with 4-bromobenzaldehyde36 to
furnish 43% of 34 (Scheme 4), which was finally reduced
with NaBH4 in 66% yield. However, Steglich esterification
of 35 with ( )-ibuprofen provided a diastereomeric mixture
of esters 36 (Scheme 4) in 97% yield and in a 65:35 (R/S)
diastereomeric ratio.
The group ofAmoroso has demonstrated that ibuprofen
and other a-substituted carboxylic acids undergo a
dynamic kinetic resolution process when subjected to the
Steglich esterification.19 As shown in Scheme 5, when an
a-substituted carboxylic acid (I) reacts with DCC and
DMAP, enantiomeric acyl-DMAP derivatives II and III
are formed as intermediates. Under these conditions, it
has been proposed that the stereogenic center becomes
labile and the enantiomeric acyl-DMAP derivatives are
thus capable of being interconverted. When a chiral alcohol
(R*OH) is added to the reaction medium, both acyl-DMAP
intermediates can react to furnish diastereomeric ester
products (IV and V). Two main conditions are required
for a successful dynamic kinetic resolution. One of them
is that interconversion between the acyl-DMAP derivatives
II and III should proceed at a faster rate than formation
of the ester products and the other is that the acyl-DMAP
intermediates should react at very different rates with the
chiral auxiliary.
In order to gain further understanding on the studied
esterification, a series of esterifications were carried out
Table 3. Esterification of ( )-ibuprofen with chiral auxiliaries 20a and 20b
Me
Me
Me
*
O
Me
DCC
DMAP
O (R)
Me
Ar
(R)
OH
HO
Ar
+
(R)
(R)
O
Me Me
Me Me
Me
Entry
No.
Chiral
Auxiliary No.
Temperature
(ºC)
Yield
(%)
Product
Ar
Solvent
R/Sa
No.
1
20ab
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhH
–40 → rt
69
76
96
84
83
62
64
44
69
64
78
72
58
29
29
29
29
29
29
29
29
29
29
29
30
30
85:15
80:20
72:28
69:31
61:39
62:38
65:35
72:28
66:34
71:29
62:38
73:27
82:18
2
20ab
0 → rt
3
20ac,d
20ad,e
20ae
–
4
0
5
0
6
20a
rt
7
20a
PhH
40
8
20a
CH2Cl2
CH2Cl2
THF
0
9
20a
40
10
11
12
13
20a
–40 → rt
20ad
PhMe
PhMe
CHCl3
0
0
20b
1-Naphthyl
1-Naphthyl
20b
rt
aDeduced by comparison with esters prepared with pure (S)-ibuprofen. bFive-fold excess of ibuprofen. cThe chiral alcohol added as the last reactant.
dPre-incubated with activated 4Å molecular sieves (200 mg). eEt3N (2 equiv.) were added to the reaction mixture.

Vol. 21, No. 6, 2010
Amongero et al.
1023
7
Me
Me
5
3'
4'
Me
Me
2'
6
(S)
4
3
(R)
(S)
2
a
O
5'
*
OH
Me
O
1
1'
6'
Me
10
8
Me
Me
Me
9
31
32
Br
Br
4'
Br
b
5'
6'
Me
3'
2'
7
Me
Me
Me
1'
3"
3
4"
5"
Me
Me
2"
d
e
c
(R)
(S)
4
5
H
H
H
O
2
(S)
*
OH
O
O
1"
1
O
Me
6
6"
Me
10
8
Me 9
Me
Me
Me
Me
Me
34
Me
33
35
36
Scheme 4. Reagents and conditions: a) DCC (1.0 equiv.), DMAP (1.0 equiv.), ibuprofen (1.0 equiv.), CHCl3, 0 ºC (55%); b) K2Cr2O7, H2SO4, rt 50 ºC
(82%); c) 4Br-C6H4-CHO, KtBuO, DMSO, 12 h, rt (43%); d) NaBH4, THF-MeOH, 30 min, 0 ºC (66%); e) DCC (1.0 equiv.), DMAP (1.0 equiv.), ibuprofen
(1.0 equiv.), CHCl3, 0 ºC (97%).
O
DCC, DMAP
DCC, DMAP
ibuprofen esters, that their performance is similar to that
of other chiral alcohols and that depending on the chosen
chiral auxiliary, production of (R)- or (S)- ibuprofen derived
esters may be favoured.
R
HO
X
I
O
R
O
Epimerization
R
N+
N+
X
X
Experimental
Me2N
Me2N
III
II
O
O
Melting points were taken on an Ernst Leitz Wetzlar
model 350 hot-stage microscope and are reported
uncorrected. Specific rotation data were obtained with a
Jasco DIP 1000 photopolarimeter, fitted with 1 dm cells.
FT-IR spectra were determined employing a Shimadzu
Prestige 21 spectrophotometer as solid dispersions in
KBr disks, or as thin films held between NaCl cells. The
1H and 13C NMR spectra were acquired in CDCl3 in a
Bruker Avance spectrometer (300.13 and 75.48 MHz for
1H and 13C, respectively), with tetramethylsilane (TMS)
as internal standard. The chemical shifts are reported in
ppm downfield from TMS and coupling constants (J) are
given in Hertz. DEPT 135 and DEPT 90 experiments
aided the interpretation and assignment of the fully
decoupled 13C NMR spectra. In special cases, 2D-NMR
(COSY, HMBC, HMQC and J-resolved spectra) and
selective nOe experiments were also employed. Pairs of
signals marked with “#”, “‡” or with an asterisk, “*”,
as superscripts indicate that their assignments may be
exchanged.
R*OH
R*OH
R
X
R
*RO
*RO
X
IV
V
Diastereomeric esters
Scheme 5. Proposed mechanism of the DCC-DMAP mediated dynamic
kinetic resolution of a-substituted carboxylic acids.
with pure (S)-ibuprofen.After examination of the products,
it was observed that when the reaction was carried out with
alcohol 20a the resulting major diastereomers where those
carrying the (R)-configuration on the ibuprofen a-carbonyl
stereocenter. On the contrary, when the esterifications
where carried out with alcohols 17a-c, the prevailing
diastereomers were those derived from (S)-ibuprofen
(Tables 1-3).
However, composition of the mixtures was different
from those arising from the racemic acid, pointing out to
poor compliance of the studied transformations with the
requirements for a successful dynamic kinetic resolution.
Particularly, the experiments revealed that interconversion
of the enantiomeric acyl-DMAP intermediates is not fast
enough, compared with their reaction with the chiral
auxiliary, to grant a more optically efficient transformation.
In conclusion, it was demonstrated that secondary
alcohols derived from naturally-occurring (R)-carvone are
able to provide good yields of enantioenriched mixtures of
The reactions were carried out under dry Nitrogen or
Argon atmospheres, employing oven-dried glassware.
Reagents were used as received. Dry hexane, benzene and
toluenewerepreparedbydistillationfromNa-benzophenone
ketyl.Anhydrous CH2Cl2 and CHCl3 were prepared by a 4 h
reflux over P2O5 followed by distillation. Anhydrous Et3N

1024
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
was obtained by distillation, after a 4 h reflux over CaH2.
Anhydrous solvents were stored in dry Young ampoules.
In the conventional work-up procedure, the reaction
was diluted with brine (5-10 mL) and the products were
extracted with EtOAc (4-5 × 20 mL). The combined organic
extracts were then washed once with brine (5 mL), dried
over Na2SO4 and concentrated under reduced pressure. The
residue was submitted to flash column chromatography
with silica gel 60 H. Elution was carried out with hexane-
EtOAc mixtures, under positive pressure and employing
gradient of solvent polarity techniques.
All new compounds gave single spots on TLC plates
run in different hexane-EtOAc and CH2Cl2-toluene solvent
systems. Chromatographic spots were detected by exposure
to UV light (254 nm), followed by spraying with ethanolic
ninhydrin (amines) or with ethanolic p-anisaldehyde/
sulfuric acid reagent and careful heating of the plates for
improving selectivity.
5-Isopropenyl-2-methyl-3-phenylsulfanyl-cyclo-
hexanones 7a-c under thermodynamic conditions: A
solution of thiophenol (5.15 mL, 50 mmol) and Et3N
(1.0 mL, 14 mmol) in CHCl3 (30 mL), was treated dropwise
with (R)-carvone (1.56 mL, 10 mmol) and the resulting
reaction mixture was stirred 3 days under reflux. Then the
reaction was diluted with brine (5 × 10 mL) and the products
were extracted with EtOAc (3 × 10 mL). The combined
organic extracts were dried under Na2SO4, concentrated
under reduced pressure, leaving an oily residue which was
flash-chromatographed (hexane-EtOAc, slow gradient from
99.5:0.5 to 95:5), furnishing three relevant fractions.
(2S,3R,5S)-5-Isopropenyl-2-methyl-3-phenyl-
sulfanylcyclohexanone 7a: Yield = 105 mg, 4%. Melting
point, specific rotation and spectral data in agreement
with the compound previously accessed under kinetic
conditions.21
The diastereomeric esters of ibuprofen were best
separated on a Varian ProStar liquid chromatograph fitted
with a 250 × 4.6 mm C-18 Luna column (Phenomenex, 5 mm
particle size), using a 80:20 mixture of MeOH:50 mmol L-1
phosphate buffer, pH 5.5 as mobile phase, pumped at
1 mL min-1. Detection wavelength was 254 nm.
(2S,3S,5S)-5-Isopropenyl-2-methyl-3-phenyl-
sulfanylcyclohexanone 7b: Yield = 889 mg, 34%. White
25
solid, mp 67-69 ºC (hexane-AcOEt). [a]D –95.0 (c 0.96,
25
CHCl3). Lit.: mp 68-69 ºC.20 [a]D –95 (c 4, CHCl3).
IR (KBr, nmax/cm-1): 3071, 2927, 2850, 1707, 1643, 1436,
1379, 1210, 902, 749 and 692. 1H NMR: d 1.33 (d, 3H, J 6.5,
H-7), 1.69 (s, 3H, H-10), 1.74-1.84 (m, 1H, H-4ax), 2.23-2.42
(m, 4H, H-2, H-4eq, H-5 and H-6eq), 2.46 (dd, 1H, J 2.3 and
9.2, H-6ax), 2.91 (dt, 1H, J 3.7 and 12.1, H-3), 4.69 (s, 1H,
H-9b), 4.75 (s, 1H, H-9a), 7.16-7.39 (m, 3H, ArH-3’, ArH-
5’ and ArH-4’) and 7.40-7.54 (m, 2H, ArH-2’ and ArH-6’).
13C NMR: d 12.6 (C-7), 20.2 (C-10), 39.1 (C-4), 43.9 (C-5),
46.3 (C-6), 49.5 (C-2), 53.3 (C-3), 110.2 (C-9), 127.7 (ArC-
4’), 128.9 (2C, ArC-3’ and ArC-5’), 133.1 (ArC-1’), 133.5
(2C, ArC-2’ and ArC-6’), 146.3 (C-8) and 209.5 (C-1).
(2S,3R,5S)-5-Isopropenyl-2-methyl-3-phenyl-
sulfanylcyclohexanone 7a under kinetic control
conditions: Thiophenol (110 mg, 1.0 mmol) was added
to a stirred solution of (R)-carvone (150 mg, 1.0 mmol)
and Et3N (0.2 mL) in hexane (3 mL), cooled at 0 ºC. The
resulting solution was stirred 8 h at 0 ºC while a white
precipitate was formed. The precipitate was separated
from the solution, washed twice with hexane (5 mL)
and dried under vacuum, affording 7a (156 mg, 60%),
as a white solid mp 62.5-64 ºC (hexane-EtOAc. Lit.:
25
63-65 ºC21). [a]D –100.4 [c 1.20, CHCl3. Lit.:21 –91.0
(2R,3S,5S)-5-Isopropenyl-2-methyl-3-phenyl-
(c 10, CH2Cl2)]. IR (film, nmax/cm-1): 2977, 2854, 1700,
1663, 1439, 1290, 1147, 897, 749 and 692. 1H NMR: d
1.21 (d, 3H, J 6.8, H-7), 1.65 (bs, 3H, H-10), 1.84 (ddd,
1H, J 2.9, 11.4 and 13.8, H-4ax), 2.06 (ddt, 1H, J 2.1, 3.8
and 13.8, H-4eq), 2.28 (ddd, 1H, J 1.0, 12.5 and 13.7,
H-6ax), 2.52 (ddd, 1H, J 2.1, 4.3 and 13.7, H-6eq), 2.88
(ddq, 1H, J 1.1, 4.8 and 6.7, H-2), 3.02 (ddt, 1H, J 3.8,
11.4 and 12.5, H-5), 3.89 (bdt, 1H, J 3.5 and 4.8, H-3),
4.70 (bs, 1H, H-9b), 4.76 (bs, 1H, H-9a), 7.21-7.32 (m,
3H, H-3’, H-4’ and H-5’) and 7.38-7.42 (m, 2H, H-2’
and H-6’). 13C NMR: d 12.7 (C-7), 20.8 (C-10), 35.3
(C-4), 40.4 (C-5), 45.9 (C-6), 48.5 (C-2), 53.4 (C-3),
110.2 (C-9), 127.4 (C-4’), 129.1 (2C, C-3’ and C-5’),**
132.5 (2C, C-2’ and C-6’),** 134.6 (C-1’), 146.9 (C-8)
and 209.7 (C-1).
sulfanylcyclohexanone 7c: Oil. Yield = 419 mg, 16%.
25
[a]D +37.9 (c 1.57, CHCl3). IR (film, nmax/cm-1): 2971,
2934, 1712, 1644, 1584, 1480, 1439, 1377, 1280, 1216,
1089, 1025, 749 and 692. 1H NMR: d 1.29 (d, 3H, J 6.9,
H-7), 1.65 (s, 3H, H-10), 1.95 (ddd, 1H, J 4.1, 7.5 and 14.2,
H-4ax), 2.20 (ddd, 1H, J 3.7, 7.8 and 14.2, H-4eq), 2.39-2.50
(m, 1H, H-2), 2.43 (dd, 1H, J 6.1 and 14.2, H-6ax), 2.56
(dd, 1H, J 7.3 and 14.2, H-6eq), 2.77-2.88 (m, 1H, H-5),
3.29 (dt, 1H, J 3.7 and 7.5, H-3), 4.68 (bs, 1H, H-9b), 4.82
(bs, 1H, H-9a), 7.25-7.37 (m, 3H, Ar-3’, ArH-4’andAr-5’)
and 7.39-7.46 (m, 2H, Ar-2’ and Ar-6’). 13C NMR: d 15.1
(C-7), 21.4 (C-10), 32.4 (C-4), 39.9 (C-5), 43.2 (C-6), 49.1
(C-2), 49.9 (C-3), 111.5 (C-9), 127.6 (ArC-4’), 129.0 (2C,
ArC-3’andArC-5’), 133.1 (2C,ArC-2’andArC-6’), 133.4
(ArC-1’), 146.2 (C-8) and 211.0 (C-1).

Vol. 21, No. 6, 2010
Amongero et al.
1025
(2S,3R,5S)-5-Isopropenyl-2-methyl-3-(naphthalen-2-
ylsulfanyl)-cyclohexanone 8: 2-Naphthalenethiol (303 mg,
1.9 mmol) was added to a stirred solution of (R)-carvone
(285 mg, 1.9 mmol) and Et3N (0.7 mL, 0.95 mmol) in
anhydrous hexane (10 mL), cooled at 0 ºC. The resulting
solution was stirred 8 h at 0 ºC while a white precipitate was
formed. The precipitate was separated from the solution,
washed twice with hexane (2 × 5 mL) and dried under
reduced pressure, affording 8 (540 mg, 92%), as a white solid
mp 113-116ºC (hexane-EtOAc). [a]D25 –96.7 (c 1.0, CHCl3).
IR (KBr, nmax/cm-1): 3054, 2925, 2844, 1711, 1443, 1378,
1208, 1141, 1015, 889, 858, 825 and 744. 1H NMR: d 1.25
(d, 3H, J 7.5, H-7), 1.64 (s, 3H, H-10), 1.92 (ddd, 1H, J 3.2,
4.9 and 13.9, H-4ax), 2.10 (ddt, 1H, J 2.1, 3.6 and 13.9, H-4eq),
2.30 (ddd, 1H, J 1.2, 12.6 and 13.7, H-6ax), 2.56 (ddd, 1H, J
2.0, 4.3 and 13.6, H-6eq), 2.92 (ddq, 1H, J 1.2, 4.8 and 7.5,
H-2), 3.08 (ttd, J 4.1 and 12.0, H-5), 4.02 (dq, 1H, J 1.3 and
7.5, H-3), 4.71 (d, 1H, J 0.6, H-9b), 4.76 (d, 1H, J 0.6, H-9a),
7.45-7.50 (m, 3H, H-3’, H-6’ and H-7’), 7.70-7.80 (m, 3H,
H-4’, H-5’ and H-8’) and 7.88 (bs, 1H, H-1’). 13C NMR: d
12.8 (C-7), 20.8 (C-10), 35.4 (C-4), 40.5 (C-5), 46.0 (C-6),
48.5 (C-2), 53.3 (C-3), 110.3 (C-9), 126.3 (C-6’),# 126.7
(C-7’),# 127.3 (C-4’),‡ 127.8 (C-5’),‡ 128.8 (C-8’),‡129.6
(C-3’),# 131.2 (C-1’), 131.9 (C-2’),* 132.4 (C-8a’),* 133.7
(C-4a’),* 146.9 (C-8) and 209.8 (C-1).
(1S,2S,3R,5S)-5-Isopropenyl-2-methyl-3-phenyl-
sulfanylcyclohexanol 9a: A solution of ketone 7a (22 mg,
0.08 mmol) in THF (5 mL), was cooled to –78 ºC and
treated with K-Selectride (0.24 mL, 0.12 mmol). The
mixture was stirred 2 h at –78 ºC, then acetone (0.1 mL) was
added to destroy the remainder of the reducing agent and
the solvent was removed under reduced pressure, leaving
an oily residue, which was chromatographed, yielding 9a
(13 mg, 58%), as an oil. [a]D25 –28.6 (c 1.42, CHCl3). IR
(film, nmax/cm-1): 3421, 2927, 2872, 2360, 1645, 1436,
1024, 975, 949 and 889. 1H NMR: d 1.25 (ddd, 1H, J 10.7,
12.0 and 12.2, H-6ax), 1.26 (d, 3H, J 6.7, H-7), 1.49 (ddd,
1H, J 3.4, 12.2 and 13.4, H-4ax), 1.63 (bs, 1H, OH), 1.69
(s, 3H, H-10), 1.73-1.83 (m, 1H, H-2), 1.93 (dq, 1H, J 4.1
and 13.4, H-4eq), 2.05-2.13 (m, 1H, H-6eq), 2.67 (tt, 1H, J
3.1 and 12.2, H-5), 3.57 (dd, 1H, J 3.4 and 7.0, H-3), 3.63
(dt, 1H, J 4.5 and 10.7, H-1), 4.71 (s, 2H, H-9), 7.18-7.32
(m, 3H, H-3’, H-4’ and H-5’) and 7.38-7.45 (m, 2H, H-2’
and H-6’). 13C NMR: d 16.3 (C-7), 21.1 (C-10), 36.8 (C-4),
38.3 (C-5), 40.6 (C-6), 43.7 (C-2), 53.8 (C-3), 71.9 (C-1),
109.1 (C-9), 126.8 (C-4’), 129.0 (2C, C-3’and C-5’), 131.
9 (2C, C-2’ and C-6’), 136.3 (C-1’) and 148.6 (C-8).
(1S,2S,3R,5S)-5-Isopropenyl-2-methyl-3-phenyl-
sulfanylcyclohexanol 9b: K-Selectride (0.214 mL,
0.107 mmol) was added dropwise to a solution of ketone
7b (18.6 mg, 0.071 mmol) in anhydrous THF (2 mL), kept
at –78 ºC, and the reaction was further stirred 24 h at this
temperature. Then, the solvent was removed under reduced
pressure and the residue was subjected to chromatography,
furnishing 9b (13 mg, 66%), as an oil. [a]D25 +118.7 (c 0.94,
CHCl3). IR (film, nmax/cm-1): 3447, 2928, 2359, 1643, 1582,
1437, 1180, 949, 889, 743 and 691. 1H NMR: d 1.33 (d, 3H,
J 6.5, H-7), 1.29-1.49 (m, 2H, H-4ax and H-6ax), 1.50-1.61
(m, 1H, H-2), 1.67 (d, 3H, J 1.1, H-10), 1.91 (ddt, 1H, J
2.5, 3.3 and 12.6, H-6eq), 2.12 (ddt, 1H, J 2.5, 3.3 and 13.0,
H-4eq), 2.43 (tt, 1H J 3.3 and 12.7, H-5), 3.19 (dt, 1H J 3.3
and 11.8, H-3), 4.01 (d, 1H, J 2.5, H-1), 4.66 (dd, 1H, J
0.9 and 1.8, H-9b), 4.68 (s, 1H, H-9a), 7.18-7.34 (m, 3H,
ArH-3’, ArH-4’ and ArH-5’) and 7.37-7.47 (m, 2H, ArH-
2’ and ArH-6’). 13C NMR: d 16.9 (C-7), 20.7 (C-10), 38.2
(C-6), 38.3 (C-5), 39.7 (C-4), 40.9 (C-2), 48.4 (C-3), 71.8
(C-1), 109.0 (C-9), 126.7 (ArC-4’), 128.7 (2C, ArC-3’and
ArC-5’), 132.2 (2C, ArC-2’ and ArC-6’), 134.7 (ArC-1’)
and 148.8 (C-8).
(1S,2S,3R,5S)-5-Isopropenyl-2-methyl-3-(naphthalen-
2-ylsulfanyl)-cyclohexanol 10: A solution of 8 (140 mg,
0.45 mmol) in THF (3 mL), was cooled to –78 ºC and
treated dropwise with K-Selectride (2.7 mL, 1.34 mmol).
The reaction was stirred at –78 ºC during 2 h, when acetone
(0.1 mL) was added to destroy the remaining reducing agent,
and the solvent was removed under reduced pressure leaving
an oily residue, which was chromatographed, furnishing
10 (93 mg, 66%), as a yellow solid, mp 56-59 ºC (hexane-
EtOAc). [a]D25 –88.0 (c 0.75, CHCl3). IR (KBr, nmax/cm-1):
3462, 3052, 2927, 1643, 1624, 1587, 1500, 1448, 1375, 1193,
1133, 1052, 944, 888, 857, 814, 746 and 602. 1H NMR: d
1.29 (d, 3H, J 7.1, H-7), 1.51 (ddd, 1H, J3.0, 12.0 and 14.2,
H-6ax), 1.56 (ddd, 1H, J 3.0, 12.0 and 14.9, H-4ax), 1.68 (s,
3H, H-10), 1.98-2.11 (m, 3H, H-2, H-4eq and H-6eq), 2.81 (tt,
1H, J3.0, 12.0 and 12.0, H-5), 3.66 (dt, 1H, J 3.6 and 3.8,
H-3), 3.95 (dt, 1H, J 3.0 and 3.1, H-1), 4.71 (bt, 1H, J 0.9,
H-9), 4.72 (bt, 1H, J 0.9, H-9), 7.44-7.51 (m, 3H, H-3’, H-6’
and H-7’), 7.73-7.81 (m, 3H, H-4’, H-5’and H-8’) and 7.88
(d, 1H, J 1.7, H-1’). 13C NMR: d 16.2 (C-7), 21.1 (C-10),
32.7 (C-5), 36.1 (C-4), 38.0 (C-6), 39.0 (C-2), 50.6 (C-3),
71.4 (C-1), 109.1 (C-8), 125.8 (C-6’),# 126.3 (C-7’),# 127.1
(C-4’),‡ 127.5 (C-5’),‡ 128.3 (C-8’),‡ 129.1 (C-3’),# 129.8
(C-1’), 132.0 (C-2’),* 133.6 (C-8a’),* 133.8 (C-4a’)* and
148.9 (C-8).
(2S,3R,5S)-3-Benzenesulfonyl-5-isopropenyl-2-
•
methylcyclohexanone 11: A solution of (NH4)6Mo7O24 4H2O
(30 mg, 0.0237 mmol) and 30% H2O2 (0.140 mL,
0.138 mmol) was cooled to 0 ºC and added through a cannula
to ketone 7b (55 mg, 0.212 mmol) dissolved in ethanol

1026
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
(2 mL). The reaction mixture was stirred 3 h at 0 ºC, brine
was added, and the reaction products were extracted with
Et2O (5 × 10 mL). The combined organic extracts were
dried (Na2SO4) concentrated under reduced pressure and
the residue was chromatographed, affording sulfone 11 (32
mg, 52%), as a white solid mp 73-74 ºC (hexane-EtOAc).
cooled in an ice bath, and the resulting mixture was stirred
24 h at 0 ºC.Then, brine (10 mL) was added and the products
were extracted with Et2O (5 × 10 mL). The combined
extracts were washed with brine (5 mL), dried over Na2SO4
and concentrated under reduced pressure, leaving a residue
which was chromatographed, furnishing alcohol 13 (92 mg,
60%) as a white solid mp 116-118 ºC (hexane-EtOAc).
25
[a]D –27.0 (c 0.91, CHCl3). IR (KBr, nmax/cm-1): 2924,
1713, 1447, 1305, 1144, 1083, 898, 747 and 690. 1H NMR:
d 1.36 (d, 3H, J 6.6, H-7), 1.66 (s, 3H, H-10), 1.71-1.88 (m,
1H, H-4ax), 2.04 (ddd, 1H, J 2.8, 3.9 and 11.7, H-4eq), 2.18-
2.32 (m, 1H, H-5), 2.20-2.34 (m, 1H, H-6eq), 2.42-2.58 (m,
1H, H-6ax), 2.75 (dq, 1H J 6.6 and 12.8, H-2), 3.14 (ddd, 1H,
J 3.9, 11.3 and 12.8, H-3), 4.68 (s, 1H, H-9b), 4.78 (s, 1H,
H-9a), 7.55-7.73 (m, 3H, ArH-3’, ArH-4’ and ArH-5’) and
7.87-7.94 (m, 2H, ArH-2’ and ArH-6’). 13C NMR: d 13.3
(C-7), 20.0 (C-10), 31.7 (C-4), 42.3 (C-5), 44.1 (C-2), 45.5
(C-6), 67.8 (C-3), 111.0 (C-9), 128.6 (2C,ArC-2 andArC-6),
129.3 (2C, ArC-3 and ArC-5), 134.0 (ArC-4), 137.9 (ArC-
1), 145.5 (C-8) and 207.7 (C-1). Increasing solvent polarity
afforded sulfoxide 12 (14 mg, 25%).
[a]D +22.3 (c 0.47, CHCl3). IR (KBr, nmax/cm-1): 3504,
25
2938, 1437, 1282, 1141, 1086, 752, 719 and 690 cm-1.
1H RMN: d 1.29 (ddd, 1H, J 12.5, 12.6 and 12.6, H-4ax),
1.36 (dt, 1H, J 2.7 and 12.0, H-6ax), 1.37 (d, 3H, J 6.8,
H-7), 1.62 (s, 3H, H-10), 1.75 (ddd, 1H, J 2.7, 3.3 and
12.6, H-4eq), 1.83-1.90 (m, 1H, H-6eq), 1.90-1.97 (m, 1H,
H-2), 2.39 (tt, 1H, J 2.7 and 12.5, H-5), 3.31 (ddd, 1H, J
3.3, 11.2 and 12.6, H-3), 3.93-3.99 (m, 1H, H-1), 4.62 (s,
1H, H-9b), 4.69 (s, 1H, H-9a), 7.51-7.60 (m, 2H, ArH-3’
and ArH-5’), 7.60-7.68 (m, 1H, ArH-4’) and 7.83-7.91
(m, 2H, ArH-2’and ArH-6’). 13C NMR: d 17.5 (C-7), 20.5
(C-10), 32.1 (C-4), 36.5 (C-5),** 36.7 (C-2),** 37.6 (C-6),
63.7 (C-3), 72.5 (C-1), 109.6 (C-9), 128.4 (2C, ArC-2’and
ArC-6’), 128.9 (2C, ArC-3’ and ArC-5’), 133.4 (ArC-4’),
138.5 (ArC-1’) and 147.8 (C-8).
(2S,3R,5S)-3-Benzenesulfinyl-5-isopropenyl-2-
methylcyclohexanone 12:A solution of (NH4)6Mo7O24.4H2O
(27mg, 0.0211mmol)and30%H2O2 (0.05mL, 0.062mmol)
was cooled to 0 ºC and added through a cannula to ketone 7b
(49mg, 0.19mmol)dissolvedinethanol(2mL).Thereaction
mixture was stirred 3 h at 0 ºC, brine was added, and the
reaction products were extracted with Et2O (5 × 10 mL). The
combined organic extracts were dried (Na2SO4)concentrated
underreducedpressureandtheresiduewaschromatographed,
affordingsulfone11(2.4mg, 5%). Increasingsolventpolarity
afforded sulfoxide 12 (23 mg, 47%), as a white solid mp
103-105 ºC (hexane-EtOAc). [a]D25 +93.3 (c 0.95, CHCl3).
IR (KBr, nmax/cm-1): 2932, 1713, 1442, 1215, 1084, 1039,
902, 746 and 700. 1H NMR: d 1.34 (ddd, 1H, J 3.0, 3.9 and
13.0, H-4eq), 1.47 (d, 3H, J 6.5, H-7), 1.61 (s, 3H, H-10),
2.05 (ddd, 1H J 12.2, 12.5 and 13.0, H-4ax), 2.21 (tt, 1H, J
3.0 and 12.2, H-5), 2.33 (dd, 1H, J 12.2 and 12.6, H-6ax),
2.42 (dt, 1H, J 3.9 and 12.5, H-3), 2.45 (dd, 1H, J 3.0 and
12.6, H-6eq), 2.88 (dq, 1H, J 6.5 and 12.5, H-2), 4.66 (s, 1H,
H-9b), 4.71 (s, 1H, H-9a), 7.47-7.56 (m, 5H,ArH). 13C NMR:
d 12.1 (C-7), 19.8 (C-10), 24.2 (C-4), 43.0 (C-5), 44.4 (C-2),
45.8 (C-6), 68.2 (C-3), 110.8 (C-9), 124.0 (2C, ArC-2’ and
ArC-6’), 129.1 (2C, ArC-3’ and ArC-5’), 130.7 (ArC-4’),
140.8 (ArC-1’), 146.0 (C-8) and 209.1 (C-1).
(1S,2S,3S,5S)-3-Benzenesulfinyl-5-isopropenyl-2-
methylcyclohexanol 14: A solution of sulfoxide 12 (71 mg,
0.257 mmol) in THF (5 mL) was cooled to –78 ºC, treated
dropwise with K-Selectride (0.32 mL, 0.385 mmol) and
the resulting mixture was stirred 2 days at –78 ºC. Then,
the solvent was removed under reduced pressure and the
remaining oil was chromatographed, furnishing alcohol 14
(32 mg, 44%) as a white solid, mp 125-127 ºC (hexane-
EtOAc). [a]D25 +32.7 (c 0.55, CHCl3). IR (KBr, nmax/cm-1):
3404, 2925, 1643, 1443, 1084, 1014, 885, 740 and 668.
1H NMR: d 1.15 (ddd, 1H, J 3.5, 3.7 and 12.6, H-4eq), 1.43
(ddd, 1H, J 2.4, 12.6 and 13.4 H-6ax), 1.44 (d, 3H, J 6.8,
H-7), 1.58 (s, 3H, H-10), 1.60 (ddd, 1H, J 12.0, 12.6 and
12.6, H-4ax), 1.85 (ddd, 1H, J 2.2, 3.5 and 13.4, H-6eq), 2.02
(ddq, 1H, J 2.2, 6.8 and 12.0, H-2), 2.34 (tt, 1H, J 3.5 and
12.6, H-5), 2.58 (dt, 1H, J 3.7 and 12.0, H-3), 4.08 (ddd,
1H, J 2.2, 2.2 and 2.4, H-1), 4.61 (s, 1H, H-9b), 4.63 (s, 1H,
H-9a) and 7.41-7.50 (m, 5H,ArH). 13C NMR: d 16.3 (C-7),
20.3 (C-10), 24.2 (C-4), 36.0 (C-5), 36.8 (C-2), 38.0 (C-6),
63.7 (C-3), 71.6 (C-1), 109.5 (C-9), 124.2 (2C, ArC-2’and
ArC-6’), 128.8 (2C, ArC-3’ and ArC-5’), 130.2 (ArC-4’),
141.2 (ArC-1’) and 148.5 (C-8).
(1S,2S,3S,5S)-3-Benzenesulfonyl-5-isopropenyl-2-
methylcyclohexanol 13: A solution of alcohol 9b (137 mg,
0.521 mmol) in ethanol (10 mL) was cooled to 0 ºC and
(1R,5R)-5-Isopropenyl-2-methyl-1-phenylcyclohex-2-
enol 15a: A suspension of Mg turnings (35 mg, 1.46 mmol)
in anhydrous Et2O (8 mL) was submitted to reflux and
treated dropwise with the bromobenzene (0.15 mL,
1.4 mmol) during 30 min, and the resulting mixture was
•
added dropwise to a solution of (NH4)6Mo7O24 4H2O
(74 mg, 0.059 mmol) in 30% H2O2 (0.32 mL, 2.85 mmol)

Vol. 21, No. 6, 2010
Amongero et al.
1027
further heated to reflux during 1 h. The Grignard reagent
was cooled to –20 ºC and treated with (R)-carvone
(0.10 mL, 0.67 mmol) at room temperature. After 30
min, the solvent was removed under reduced pressure and
the residue was chromatographed, yielding alcohol 15a
(114.7 mg, 75%) as an oil. [a]D25 –122.4 (c 1.19, CHCl3).
IR (film, nmax/cm-1): 3448, 1646, 1448, 1029, 934, 889, 768
and 703. 1H NMR: d 1.62 (s, 3H, H-10), 1.65 (s, 3H, H-7),
1.93-2.19 (m, 4H, H-4ax, H-5, H-6ax and H-6eq), 2.20-2.31
(m, 1H, H-4eq), 4.62 (s, 1H, H-9b), 4.65 (s, 1H, H-9a), 5.79
(m, 1H, H-3), 7.22-7.28 (m, 1H, ArH-4’), 7.30-7.37 (m,
2H, ArH-2’ and ArH-6’) and 7.44-7.49 (m, 2H, ArH-3’
and ArH-5’). 13C NMR: d 17.8 (C-7), 20.6 (C-10), 31.1
(C-4), 37.8 (C-5), 45.1 (C-6), 77.2 (C-1), 108.8 (C-9),
125.8 (ArC-4’), 126.2 (2C, ArC-2’ and ArC-6’), 126.9
(C-3), 127.9 (2C, ArC-3’ and ArC-5’), 135.8 (C-2), 145.6
(ArC-1’) and 148.6 (C-8).
and the residue was chromatographed, yielding alcohol 15c
(102 mg, 59%), as an oil. [a]D –153.3 (c 4.88, CHCl3).
25
IR (film, nmax/cm-1): 3431, 2916, 1608, 1508, 1248, 1175,
1036 and 833. 1H NMR: d 1.64 (s, H-10), 1.68 (s, 3H, H-7),
1.92-2.18 (m, 3H, H-4ax, H-5 and H-6eq), 1.95 (t, 1H, J 13.0,
H-6ax), 2.19-2.31 (m, 1H, H-4eq), 3.81 (s, 3H, OMe), 4.64
(s, 1H, H-9b), 4.67 (s, 1H, H-9a), 5.78 (dd, 1H, J 1.5 and
4.8, H-3), 6.89 (d, 2H, J 8.8, ArH-3’and ArH-5’) and 7.41
(d, 2H, J 8.8, ArH-2’andArH-6’). 13C NMR: d 17.8 (C-7),
20.5 (C-10), 31.1 (C-4), 37.8 (C-5), 45.2 (C-6), 54.9 (OMe),
76.7 (C-1), 108.7 (C-9), 113.1 (2C, ArC-3’ and ArC-5’),
125.5 (C-3), 127.3 (2C, ArC-2’ and ArC-6’), 136.0 (ArC-
1’), 137.7 (C-2), 148.5 (C-8) and 158.3 (ArC-4’).
(5S)-5-Isopropenyl-2-methyl-3-phenylcyclohex-2-
enone 16a: 18% PCC on Al2O3 (9.34 g, 7.8 mmol) was
added portionwise to a solution of alcohol 15a (741 mg,
3.25 mmol) in anhydrous CH2Cl2 (30 mL), and the resulting
suspension was stirred 3 days at room temperature. The
solids were separated by filtration through Celite and the
filter was washed with CH2Cl2 (3 × 15 mL). The filtrates
were concentrated under reduced pressure and the residue
was chromatographed, furnishing ketone 16a (599 mg,
(1R,5R)-5-Isopropenyl-2-methyl-1-p-tolylcyclohex-
2-enol 15b: A suspension of Mg turnings (212 mg,
8.71 mmol) in anhydrous THF (8 mL) was heated to 60 ºC
and treated dropwise with a solution of bromotoluene
(1.37 g, 8.06 mmol) in THF (2 mL) during 30 min and
the resulting mixture was further refluxed during 1 h. The
Grignard reagent was cooled to –20 ºC and treated with
(R)-carvone (1.0 mL, 6.7 mmol) at room temperature.After
1 h, the solvent was removed under reduced pressure and
the residue was chromatographed, yielding alcohol 15b
25
82%), as an oil. [a]D +152.6 (c 0.85, CHCl3). IR (film,
n
max/cm-1): 2923, 1668, 1442, 1108, 893, 765 and 701.
1H NMR: d 1.73 (s, 3H, H-7), 1.77 (s, 3H, H-10), 2.45
(dd, 1H, J 13.0 and 16.2, H-4ax), 2.56-2.76 (m, 3H, H-4eq,
H-6ax and H-6eq), 2.82 (ddd, 1H J 4.2, 9.2 and 17.7, H-5),
4.80 (s, 1H, H-9b), 4.83 (s, 1H, H-9a), 7.18-7.23 (m, 2H,
ArH-2’ and ArH-6’) and 7.28-7.43 (m, 3H, ArH-3’, ArH-
4’ and ArH-5’). RMN de 13C: d 12.6 (C-7), 20.4 (C-10),
37.9 (C-4), 41.6 (C-5), 42.5 (C-6), 110.5 (C-9), 127.0 (2C,
ArC-2’andArC-6’), 127.8 (ArC-4’), 128.3 (2C,ArC-3’and
ArC-5’), 131.4 (C-2), 141.1 (ArC-1’), 146.4 (C-8), 155.4
(C-3) and 199.7 (C=O).
25
(877 mg, 54%) as an oil. [a]D –154.2 (c 2.50, CHCl3).
IR (film, nmax/cm-1): 3420, 2918, 1645, 1508, 1447, 1375,
1
1022, 934, 899 and 820. H NMR: d 1.62 (s, 3H, H-7),
1.64 (s, 3H, H-10), 1.87-2.17 (m, 4H, H-4ax, H-5, H-6ax
and H-6eq), 2.29 (ddd, 1H, J 1.6, 3.1 and 16.5, H-4eq), 2.33
(s, 3H, ArMe), 4.61 (s, 1H, H-9b), 4.64 (s, 1H, H-9a), 5.75
(ddq, 1H, J 1.3, 2.8 and 3.7, H-3), 7.12 (dd, 2H, J 1.9 and
8.3, ArH-3’ and ArH-5’) and 7.34 (dt, 2H, J 1.9 and 8.3,
ArH-2’and ArH-6’). 13C NMR: d 17.8 (C-10), 20.4 (C-7),
20.7 (PhMe), 31.0 (C-4), 37.7 (C-5), 45.0 (C-6), 76.8 (C-1),
108.6 (C-9), 125.3 (C-3), 126.0 (2C, ArC-2’ and ArC-6’),
128.4 (2C, ArC-3’and ArC-5’), 136.0 (ArC-4’), 136.2 (C-
2), 142.6 (ArC-1’) and 148.4 (C-8).
(5S)-5-Isopropenyl-2-methyl-3-p-tolylcyclohex-2-
enone 16b: 18% PCC on Al2O3 (5.17 g, 4.32 mmol) was
added portionwise to a solution of alcohol 15b (435 mg,
1.80 mmol) in anhydrous CH2Cl2 (15 mL), and the resulting
suspension was stirred 3 days at room temperature. The
solids were separated by filtration through Celite and the
filter was washed with CH2Cl2 (3 × 10 mL). The filtrates
were concentrated under reduced pressure and the residue
was chromatoraphed, furnishing ketone 16b (373 mg,
(1R,5R)-5-Isopropenyl-2-methyl-1-(4-methoxyphenyl)-
cyclohex-2-enol 15c:A suspension of Mg turnings (35 mg,
1.46 mmol) in anhydrous THF (5 mL) was heated to 60 ºC
and treated dropwise with a solution of bromoanisole
(262 mg, 1.4 mmol) in THF (2 mL) during 30 min, and
the resulting mixture was further refluxed during 1 h. The
Grignard reagent was cooled to –20 ºC and treated with
(R)-carvone (0.1 mL, 0.68 mmol) at room temperature.
After 1 h, the solvent was removed under reduced pressure
25
86%), as an oil. [a]D +134.2 (c 0.85, CHCl3). IR (film,
n
max/cm-1): 2920, 1666, 1510, 1437, 1377, 1342, 1107, 893
and 816 cm-1. 1H NMR: d 1.74 (s, 3H, H-7), 1.77 (s, 3H,
H-10), 2.38 (s, 3H, ArMe), 2.44 (dd, 1H, J 12.9 and 16.1,
H-4ax), 2.54-2.75 (m, 3H, H-4eq, H-6ax and H-6eq), 2.81 (ddd,
1H, J 4.4, 9.8 and 13.7, H-5), 4.79 (s, 1H, H-9b), 4.83 (s,

1028
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
1H, H-9a), 7.12 (d, 2H, J 8.0, ArH-2’andArH-6’) and 7.21
(d, 2H, J 8.0, ArH-3’ and ArH-5’). 13C NMR: d 12.7 (C-
7), 20.4 (C-10), 21.1 (ArMe), 38.0 (C-4), 41.6 (C-5), 42.5
(C-6), 110.4 (C-9), 127.1 (2C, ArC-2’ and ArC-6’), 128.9
(2C, ArC-3’ and ArC-5’), 131.2 (C-2), 137.8 (ArC-1’),
138.1 (ArC-4’), 146.6 (C-8), 155.6 (C-3) and 199.8 (C=O).
(38 mg, 1 mmol) in a 5:3 THF:MeOH (8 mL) mixture
cooled at 0 ºC. After 3 h, acetone (0.5 mL) was added,
the solvent was removed under reduced pressure and
the residue was chromatographed, affording alcohol 17b
25
(230 mg, 94%), as an oil. [a]D +101.6 (c 2.7, CHCl3).
IR (film, nmax/cm-1): 3340, 2918, 2856, 1643, 1512, 1441,
1
1039, 972, 888 and 816. H NMR: d 1.55-1.70 (m, 1H,
(5S)-5-Isopropenyl-2-methyl-3-(4-methoxyphenyl)-
cyclohex-2-enone 16c: 18% PCC on Al2O3 (1.09 g,
0.91 mmol) was added portionwise to a solution of alcohol
15c (98 mg, 0.38 mmol) in anhydrous CH2Cl2 (15 mL),
and the resulting suspension was stirred 1 day at room
temperature. The solids were separated by filtration through
Celite and the filter was washed with CH2Cl2 (3 × 10 mL).
The filtrates were concentrated under reduced pressure and
the residue was chromatoraphed, furnishing ketone 16c
H-6ax), 1.66 (s, H-7), 1.77 (s, 3H, H-10), 2.16-2.46 (m, 7H,
H-5, H-4ax, H-4eq and H-6eq), 2.38 (s, 3H, ArMe), 4.34 (t,
1H, J 7.7, H-1), 4.76 (s, 1H, H-9a), 4.78 (s, 1H, H-9b), 7.05
(d, 2H, J 8.0, ArH-2’ and ArH-6’) and 7.15 (d, 2H, J 8.0,
ArH-3’and ArH-5’). 13C NMR: d 15.8 (C-7), 20.6 (C-10),
21.0 (ArMe), 37.6 (C-4),** 37.7 (C-6),** 39.9 (C-5), 71.9
(C-1), 109.2 (C-9), 128.0 (2C, ArC-2’ and ArC-6’), 128.7
(2C, ArC-3’ and ArC-5’), 130.9 (C-2), 134.9 (C-3), 136.0
(ArC-1’), 139.9 (ArC-4’) and 148.8 (C-8).
25
(69 mg, 71%), as an oil. [a]D +190.6 (c 1.13, CHCl3).
IR (film, nmax/cm-1): 2953, 1665, 1607, 1510, 1441, 1287,
1250, 1179, 1107, 1034 and 831. 1H NMR: d 1.76 (s, 3H,
H-7),** 1.78 (s, 3H, H-10),** 2.43 (dd, 1H, J 13.0 and 15.9.
H-6ax), 2.56-2.81 (m, 3H, H-4ax, H-4eq and H-6eq), 2.76-2.90
(m, 1H, H-5), 3.84 (s, 3H, OMe), 4.80 (s, 1H, H-9b), 4.83
(s, 1H, H-9a), 6.93 (d, 2H, J 8.9, ArH-3’ and ArH-5’) and
7.18 (d, 2H, J 8.9, ArH-2’ and ArH-6’). 13C NMR: d 13.0
(C-7), 20.6 (C-10), 38.1 (C-4), 41.6 (C-5), 42.6 (C-6), 55.3
(OMe), 110.5 (C-9), 113.7 (2C,ArC-3’andArC-5’), 128.8
(2C, ArC-2’ and ArC-6’), 131.2 (C-2), 133.3 (ArC-1’),
146.7 (C-8), 155.3 (C-3), 159.4 (ArC-4’) and 199.9 (C-
(1S,5S)-5-Isopropenyl-2-methyl-(4-methoxyphenyl)-
cyclohex-2-enol 17c: A solution of ketone 16c (69 mg,
0.27 mmol) in THF (5 mL) was transferred to a suspension
of NaBH4 (20.2 mg, 0.54 mmol) in a 5:3 THF:MeOH
(8 mL) mixture cooled at 0ºC. After 2 h, acetone (0.5 mL)
was added, the solvent was removed under reduced pressure
and the residue was chromatographed, affording alcohol
17c (58 mg, 83%), as a white solid mp 94-96 ºC (hexane-
EtOAc). [a]D25 +111.4 (c 1.21, CHCl3). IR (KBr, nmax/cm-1):
3392, 2913, 1643, 1609, 1512, 1441, 1240, 1173, 1028,
903, 829 and 584. 1H NMR: d 1.64 (dt, 1H, J 9.8 and 12.3,
H-6ax), 1.70 (s, 3H, H-7), 1.79 (s, 3H, H-10), 2.17 (dd,
1H, J 5.9 and 12.3, H-6eq), 2.26-2.53 (m, 3H, H-4ax, H-4eq
and H-5), 3.43 (s, 3H, OMe), 4.21 (m, 1H, H-1), 4.85 (s,
1H, H-9a), 4.90 (s, 1H, H-9b), 6.89 (d, 2H, J 8.8, ArH-3’
and ArH-5’) and 7.14 (d, 2H, J 8.8, ArH-2’ and ArH-6’).
13C NMR: d 16.3 (C-7), 20.6 (C-10), 38.4 (C-4), 38.4 (C-
6), 40.6 (C-5), 54.8 (OMe), 71.9 (C-1), 109.5 (C-9), 114.0
(2C, ArC-3’ and ArC-5’), 129.7 (2C, ArC-2’ and ArC-6’),
132.2 (C-2), 134.3 (ArC-1’), 135.7 (C-3), 149.0 (C-8) and
158.8 (ArC-4’).
(1S,5S)-5-Isopropenyl-2-methyl-3-phenylcyclohex-2-
enol 17a: A solution of ketone 16a (575 mg, 2.54 mmol)
in THF (5 mL) was transferred to a suspension of NaBH4
(97 mg, 2.54 mmol) in a 5:3 THF-MeOH (8 mL) mixture
cooled at 0 ºC. After 1 h, the solvent was removed under
reduced pressure and the residue was chromatographed,
25
affording alcohol 17a (504 mg, 88%), as an oil, [a]D
+81.0 (c 0.57, CHCl3). IR (film, nmax/cm-1): 3355, 2921,
1442, 1043, 890, 765 and 700. 1H NMR: d 1.58-1.73 (m,
1H, H-6ax), 1.66 (s, 3H, H-7), 1.77 (s, 3H, H-10), 2.19-
2.49 (m, 4H, H-4ax, H-4eq, H-5 and H-6eq), 4.32 (m, 1H,
H-1), 4.77 (s, 1H, H-9a), 4.79 (s, 1H, H-9b), 7.12-7.18 (m,
2H, ArH-2’ and ArH-6’), 7.20-7.27 (m, 1H, ArH-4’) and
7.29-7.37 (m, 2H, ArH-3’ and ArH-5’). 13C NMR: d 15.8
(C-7), 20.6 (C-10), 37.6 (C-6), 37.7 (C-4), 39.9 (C-5), 71.9
(C-1), 109.3 (C-9), 126.4 (ArC-4’), 128.1 (2C, ArC-3’and
ArC-5’), 128.1 (2C,ArC-2’andArC-6’), 131.1 (C-2), 135.1
(C-3), 142.9 (ArC-1’) and 148.7 (C-8).
( 2 S , 3 R , 5 R ) - 5 - I s o p ro p e n y l - 2 - m e t h y l - 3 -
phenylcyclohexanone 19a: CuI (500 mg, 2.64 mmol) was
added to a stirred 1.18M THF solution of PhMgBr (8 mL,
5.28 mmol), cooled to 0 ºC.After stirring 15 min, a solution
of (R)-carvone (209 mg, 1.39 mmol) and TMSCl (772 mg,
7.1 mmol) in THF (2 mL) was introduced dropwise and
the reaction was further stirred 45 min at 0 ºC. Then, the
mixture was treated with saturated NH4Cl and the reaction
products were extracted with EtOAc (4 × 50 mL). The
combined organic extracts were washed with brine (10 mL),
dried (Na2SO4) and concentrated under reduced pressure.
The resulting residue was filtered through a short plug of
(1S,5S)-5-Isopropenyl-2-methyl-3-p-tolylcyclohex-2-
enol 17b: A solution of ketone 16b (241 mg, 1 mmol) in
THF (5 mL) was transferred to a suspension of NaBH4

Vol. 21, No. 6, 2010
Amongero et al.
1029
silica gel, furnishing 18a (380 mg, 96%), as a yellowish
oil. Without further purification, a stirred solution of the
silyl ether 18a (100 mg, 0.35 mmol) in Et2O (10 mL) was
cooled to 0 ºC and treated with 1M TBAF in THF (0.42 mL,
0.42 mmol). After 2 h at this temperature, the volatiles
were removed under reduced pressure and the residue was
chromatographed affording ketone 19a (72 mg, 95%), as
4.66, d, 1H, J 1.5, H-9), 7.36 (dd, 1H, J 1.1 and 7.1, H-2’),
7.42-7.61 (m, 3H, H-6’and H-7’), 7.77 (d, 1H, J 8.1, H-4’),
7.89 (dd, 1H, J 3.3 and 6.2, H-3’), 7.92 (dd, 1H, J 1.4 and
8.1, H-5’) and 8.20 (d, 1H, J 8.3, H-8’). 13C NMR: d 1.0
(3C, Me3Si), 15.6 (C-7), 20.8 (C-10), 34.3 (C-4), 36.0
(C-6), 37.1 (C-5), 41.3 (C-3), 109.0 (C-9), 112.4 (C-2),
123.4 (C-8’), 125.2 (C-6’), 125.9 (2C, C-7’ and C-2’),
126.8 (C-4’), 127.9 (C-3’), 129.0 (C-5’), 132.0 (C-4a’),
134.3 (C-8a’), 139.9 (C-1’), 146.1 (C-1) and 146.9 (C-8).
Without further purification, a solution of silyl ether 18b
(140 mg, 0.40 mmol) in Et2O (20 mL) was treated with a
1M solution of TBAF in THF (0.48 mL, 0.48 mmol) and
the resulting mixture was stirred 2 h at room temperature.
Then, brine (10 mL) was added and the organic products
were extracted with EtOAc (4 × 15 mL). The combined
organic extracts were washed with brine (1 × 10 mL),
drier (Na2SO4) and concentrated under reduced pressure.
The residue was chromatographed, furnishing 19b
(100 mg, 90%) as a solid, mp 77-79 ºC (hexane-EtOAc).
25
a pale yellow oil. [a]D –55.8 (c 1.76, CHCl3). IR (film,
n
max/cm-1): 2970, 2875, 1709, 1643, 1496, 1377, 1211,
1
1146, 1030, 900, 756 and 701. H NMR: d 0.86 (d, 3H,
J 6.4, H-7), 1.74 (s, 3H, H-10), 2.14 (bdd, 2H, J 4.6 and
7.4, H-4), 2.58 (dq, J 0.8 and 6.4, H-2), 2.60-2.72 (m, 1H,
H-3), 2.64 (dd, 1H, J 7.7 and 14.3, H-6ax), 2.74 (bd, 1H, J
14.3, H-6eq), 2.78-2.84 (m, 1H, H-5), 4.77 (s, 1H, H-9b),
4.94 (s, 1H, H-9a), 7.19 (dd, 2H, J 1.5 and 7.2, H-2’ and
H-6’), 7.18-7.26 (m, 1H, H-4’) and 7.32 (dd, 2H, J 1.5 and
7.2, H-3’ and H-5’). 13C NMR: d 12.4 (C-7), 22.0 (C-10),
35.9 (C-4), 40.9 (C-5), 44.3 (C-6), 46.4 (C-3), 50.1 (C-
2), 112.6 (C-9), 126.4 (C-4’), 127.1 (2C, C-2’ and C-6’),
128.5 (2C, C-3’ and C-5’), 143.7 (C-8),** 146.1 (C-1’)**
and 211.8 (C-1).
25
[a]D –19.9 (c 1.10, CHCl3). IR (film, nmax/cm-1): 3058,
2966, 2863, 1703, 1641, 1510, 1448, 1376, 1213, 1141,
906, 800 and 783. 1H NMR: d 0.93 (d, 3H, J 6.5, H-7), 1.79
(s, 3H, H-10), 2.10-2.25 (m, 2H, H-4), 2.71 (dd, 1H, J 6.9
and 15.1, H-6ax), 2.78-2.84 (bs, 3H, H-2, H-5 and H-6eq),
3.74 (bt, J 3.2 and 7.8, 1H, H-3), 4.87 (s, 1H, H-9a), 5.05 (s,
1H, H-9b), 7.44-7.55 (m, 4H, H-2’, H-3’, H-6’ and H-7’),
7.75 (d, 1H, J 6.3, H-4’), 7.88 (dd, 1H, J 2.9 and 6.6, H-5’)
and 8.00 (d, 1H, J 8.8, H-8’). 13C NMR: d 13.0 (C-7), 22.3
(C-10), 36.0 (C-4), 39.6 (C-3), 41.3 (C-5), 44.7 (C-6), 50.3
(C-2), 112.9 (C-9), 122.4 (C-8’), 123.3 (C-2’), 125.6 (2C,
C-6’ and C-7’), 126.2 (C-3’), 127.0 (C-4’), 129.1 (C-5’),
131.9 (C-8a’), 134.0 (C-4a’), 140.0 (C-1’), 146.7 (C-8)
and 212.8 (C-1).
(2S,3R,5R)-5-Isopropenyl-2-methyl-3-naphthalen-
1-yl-cyclohexanone 19b: To an ultrasonically irradiated
mixture of magnesium turnings (160 mg, 6.67 mmol)
and a crystal of iodine in dry Et2O (10 mL) under argon
was added dropwise a solution of 1-bromonaphthalene
(833 mg, 3 mmol) in anhydrous Et2O (5 mL) over a
30 min period. During the addition the temperature of the
water bath increased due to sonication and maintained
the reaction at rapid reflux. After addition was complete,
sonication was continued for another 2 h to ensure complete
consumption of the 1-bromonaphthalene. Then, the
reaction was cooled to 0 ºC, CuI (360 mg, 1.87 mmol) was
added, and 15 min later, the mixture was treated dropwise
with a solution of (R)-carvone (282 mg, 1.82 mmol)
and TMSCl (204 mg, 1.87 mmol) in THF (2 mL). After
stirring 45 min, the reaction was quenched with saturated
NH4Cl (10 mL) and the organic products were extracted
with EtOAc (4 × 25 mL). The combined organic layers
were washed once with brine (10 mL), drier over Na2SO4,
concentrated under reduced pressure and the remaining
oily residue was chromatographed, furnishing (5R,3S)-
5-isopropenyl-2-methyl-3-naphthalen-1-yl-cyclohex-1-
enyloxy)-trimethylsilane (18b, 380 mg, 96%), as a yellowish
(1R-2S,3R,5R)-5-Isopropenyl-2-methyl-3-
phenylcyclohexanol 20a: A stirred solution of ketone
19a (70 mg, 0.31 mmol) in THF (5 mL), was cooled to
–78 ºC and treated dropwise with a 0.5 mol L-1 solution
of K-Selectride (0.94 mL, 0.47 mmol). Stirring continued
for 2 h, when acetone was added to destroy the unreacted
reducing agent. The mixture was left to attain room
temperature, brine (10 mL) was added and the reaction
products were extracted with EtOAc (4 × 15 mL). The
organic phases were combined, washed with brine (5 mL)
and dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was chromatographed,
affording alcohol 20a (56 mg, 80%), as an oil. [a]D25 –36.3
(c 1.13, CHCl3). IR (film, nmax/cm-1): 3415, 2935, 2874,
25
oil. [a]D –32.9 (c 0.85, CHCl3). IR (film, nmax/cm-1):
3066, 2959, 2857, 1685, 1508, 1448, 1337, 1252, 1187,
1063, 929, 842, and 779. 1H NMR: d 0.35 (s, 3H, Me3Si),
1.61 (s, 3H, Me-7), 1.64 (s, 3H, Me-10),1.90-2.10 (m, 2H,
H-4), 2.10-2.25 (m, 1H, H-6), 2.26-2.38 (m, 2H, H-5 and
H-6), 4.32 (bd, 1H, J 1.2, H-3), 4.64 (d, 1H, J 1.5, H-9),
1
1650, 1495, 1447, 1066, 889 and 699. H NMR: d 0.87
(d, 3H, J 6.9, H-7), 1.71 (bs, 1H, w1/2= 13, OH), 1.75-2.25
(m, 5H, H-4, H-2 and H-6), 1.87 (s, 3H, H-10), 2.38 (bdd,

1030
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
1H, J 4.9 and 9.7, H-5), 2.90 (dt, 1H, J 3.9 and 13.9, H-3),
3.90 (dt, 1H, J 4.5 and 5.9, H-1), 4.92 (s, 1H, H-9a), 5.01
(s, 1H, H-9b) and 7.15-7.40 (m, 5H, ArH). 13C NMR: d
15.4 (C-7), 22.4 (C-10), 34.2 (C-4 and C-6), 38.2 (C-5),
40.6 (C-2), 41.6 (C-3), 71.8 (C-1), 109.7 (C-9), 126.0
(C-4’), 127.4 (2C, C-2’ and C-6’), 128.4 (2C, C-3’ and
C-5’), 145.2 (C-1’) and 149.7 (C-8).
d 0.88 (d, 6H, J 6.6, ArCH2CHMe2). 0.99 (d, 3H, J 6.9,
H-7), 1.41 (ddd, 1H, J 2.6, 11.7 and 14.3, H-6), 1.52-1.58
(m, 1H, H-4), 1.61(d, 3H, J 7.3, ArCHMe), 1.63 (s, 3H,
H-10), 1.83 (septet, 1H, J ArCH2CHMe2), 1.86-1.94 (m,
1H, H-6), 1.97-2.02 (m, 1H, H-4), 2.03-2.11 (m, 1H, H-2),
2.44 (d, 2H, J 7.3, ArCH2CHMe2), 2.66 (tt, 1H, J 5.9 and
11.5, H-5), 3.40 (dd, 1H, J 4.3 and 8.4, H-3), 3.79 (q, 1H,
J 7.3, ArCHMe), 4.65 (s, 1H, H-9), 4.70 (s, 1H, H-9), 5.00
(dd, 1H, J 3.2 and 6.6, H-1), 7.10 (d, 2H, J 8.0, H-3”’ and
H-5”’), 7.18-7.22 (m, 1H, H-4’), 7.24-7.32 (m, 2H, H-3’and
H-5’), 7.36 (d, 2H, J 8.0, H-2”’ and H-6”’) and 7.40 (dd,
2H, J 1.2 and 8.1, H-2”’ and H-6”’). 13C NMR: d 15.7 (C-
7), 18.0 (ArCHMe), 21.2 (C-10), 22.3 (2C,ArCH2CHMe2),
30.2 (ArCH2CHMe2), 33.7 (H-5), 34.7 (H-6), 36.3 (H-4),
37.9 (H-2), 45.1 (ArCH2), 46.0 (ArCHMe), 51.4 (C-3),
72.9 (H-1), 109.2 (C-9), 126.5 (C-4 PhS), 127.5 (2C,
C-2”’ and C-6”’), 128.9 (C-3’ and C-5’), 129.2 (C-3”’ and
C-5”’), 131.5 (2C, C-2’and C-6’), 137.7 (C-1’), 138.0 (C-
1”’), 140.5 (C-4”’), 148.6 (C-8) and 174.4 (C=O). Minor
(1R,2S,3R,5R)-5-Isopropenyl-2-methyl-3-naphthalen-
1-yl-cyclohexanol 20b: A solution of ketone 19b (98 mg,
0.35 mmol) in THF (5 mL), was cooled to –78 ºC and
treated with K-Selectride (2.1 mL, 1.06 mmol). After
2 h, acetone was added to destroy the unreacted reducing
agent and the solution was warmed to room temperature.
Then, the solvent was removed under reduced pressure
and the residue was chromatographed, furnishing 20b
(71 mg, 80%), as a solid mp 57-59 ºC (hexane-EtOAc).
25
[a]D –88.0 (c 0.75, CHCl3). IR (film, nmax/cm-1): 3416,
2960, 2873, 1642, 1597, 1449, 1396, 1119, 1009, 890, 778
and 733. 1H NMR: d 0.89 (d, 3H, J 6.8, H-7), 1.75-1.90 (m,
1H, H-2), 1.90 (ddd, 1H, J 3.3, 5.8 and 14.0, H-6ax), 1.94 (s,
3H, H-10), 1.96 (ddd, 1H, J 5.0, 9.6 and 14.6, H-4ax), 2.15
(ddd, 1H, J 3.1, 7.0 and 9.0, H-3), 2.21 (ddt, 1H, J 1.7, 4.7
and 14.5, H-4eq), 2.32 (ddt, 1H, J 1.7, 5.3 and 14.0, H-6eq),
2.54 (dt, 1H, J 5.0 and 10.0, H-x), 3.85 (dt, 1H, J 4.3 and
9.2, H-1), 4.00 (bs, 1H, OH), 5.00 (s, 1H, H-9), 5.14 (s,
1H, H-9), 7.44-7.56 (m, 4H, H-2’, H-3’, H-6’ and H-7’),
7.74 (dd, 1H, J 2.9 and 6.3, H-4’), 7.88 (dd, 1H, J 1.7 and
7.9, H-5’) and 8.17 (d, 1H, J 8.0, H-8’). 13C NMR: d 15.4
(C-7), 22.6 (C-10), 34.2 (C-6), 34.8 (C-4), 35.4 (C-3), 38.8
(C-2), 41.9 (C-5), 72.3 (C-1), 109.7 (C-9), 123.3 (C-8’),
123.5 (C-2’),** 125.4 (C-6’),** 125.6 (C-3’),** 125.9
(C-7’),** 126.6 (C-4’), 129.1 (C-5’), 132.3 (C-8a’), 134.1
(C-4a’), 142.2 (C-1’) and 150.0 (C-8).
1
diastereomer, (1S,2S,2”S,3R,5S)-21: H NMR: d 0.89 (d,
6H, J 6.6, ArCH2CHMe2). 1.15 (d, 3H, J 6.9, H-7), 1.45-
1.60 (m, 2H, H-4 and H-6), 1.61(d, 3H, J 7.3, ArCHMe),
1.71 (s, 3H, H-10), 1.83 (septet, 1H, J ArCH2CHMe2),
1.86-1.94 (m, 1H, H-6), 1.97-2.02 (m, 1H, H-4), 2.03-2.11
(m, 1H, H-2), 2.44 (d, 2H, J 7.3, ArCH2CHMe2), 2.66 (tt,
1H, J 5.9 and 11.5, H-5), 3.38 (dd, 1H, J 4.3 and 8.4, H-3),
3.79 (q, 1H, J 7.3, ArCHMe), 4.55 (s, 1H, H-9), 4.65 (s,
1H, H-9), 5.00 (dd, 1H, J 3.2 and 6.6, H-1), 7.10 (d, 2H,
J 8.0, H-3”’ and H-5”’), 7.18-7.22 (m, 1H, H-4’), 7.24-
7.32 (m, 2H, H-3’ and H-5’), 7.36 (d, 2H, J 8.0, H-2”’ and
H-6”’) and 7.40 (dd, 2H, J 1.2 and 8.1, H-2”’ and H-6”’).
13C NMR: d 14.1 (C-7), 17.9 (ArCHMe), 21.1 (C-10), 22.3
(2C, ArCH2CHMe2), 29.4 (ArCH2CHMe2), 31.9 (H-5),
34.0 (H-6), 36.3 (H-4), 37.9 (H-2), 45.4 (ArCH2), 45.5
(ArCHMe), 51.4 (C-3), 73.3 (H-1), 109.0 (C-9), 125.5
(C-4 PhS), 127.2 (2C, C-2”’ and C-6”’), 128.9 (C-3’ and
C-5’), 129.2 (C-3”’and C-5”’), 131.4 (2C, C-2’and C-6’),
137.7 (C-1’), 138.0 (C-1”’), 140.4 (C-4”’), 148.5 (C-8)
and 174.4 (C=O).
Typical procedure for the preparation of ( )-ibuprofen
esters under Steglich conditions: A solution of DCC
(1.0 equiv.) in the reaction solvent (0.5 mL) was added
to a mixture of the chiral auxiliary (20 mg, 1.0 equiv.),
( )-ibuprofen (1.0 equiv.) and DMAP (1.0 equiv.),
dissolved in the reaction solvent (3 mL). The reaction was
stirred (0.5-3 days) at the designated temperature until
complete, then the solvent was removed under reduced
pressure and the residue was chromatographed.
(1S,2S,2”R,3S,5S) and (1S,2S,2”S,3S,5S)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-
3-phenylsulfanyl-cyclohexyl ester 22a,b: Yield = 65%. IR
(film, nmax/cm-1): 3436, 2954, 1728, 1452, 1166, 890, 743
and 692 cm-1. 1H NMR: d 0.86 (d, 6H, J 6.6, H-9”’), 1.10
and 1.21 (d, 3H, J 6.8, H-7), 1.16-1.38 (m, 2H, H-4ax and
H-6ax), 1.47 and 1.59 (s, 3H, H-10), 1.49-1.55 (m, 4H, H-2”
and H-3”), 1.69-2.17 (m, 5H, H-4eq, H-5, H-6eq and H-8”’),
2.42 and 2.46 (d, 2H, J 7.0, H-7”’), 2.92 and 2.94 (dt, 1H,
J 3.9, and 11.9, H-3), 3.72 and 3.73 (q, 1H, J 7.2, H-2),
4.44 and 4.57 (s, 1H, H-9b), 4.57 and 4.65 (s, 1H, H-9a),
(1S,2S,2”R,3R,5S)- and (1S,2S,2”S,3R,5S)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-
3-phenylsulfanyl-cyclohex-1-yl ester 21a,b: Oil. Yield =
25
95%. [a]D –39.3 (c 0.31, CHCl3). IR (film, nmax/cm-1):
2954, 2927, 2869, 1730, 1451, 1247, 1165, 1050, 887 and
692. Major diastereomer, (1S,2S,2”R,3R,5S)-21: 1H NMR:

Vol. 21, No. 6, 2010
Amongero et al.
1031
5.05 and 5.07 (dd, 1H, J 2.8 and 5.6, H-1), 7.07-7.12 (m,
2H, ArH-3’ and ArH-3’) and 7.16-7.41 (m, 7H, ArH-2’,
ArH-4’,ArH-6’,ArH-2”’,ArH-3”’,ArH-5”’andArH-6”’).
13C NMR: d 16.1 and 16.4 (C-7), 17.6 and 17.6 (C-3”),
20.4 and 20.5 (C-10), 22.2 (2C, C-9”’), 30.1 (C-8”’), 35.0
and 35.2 (C-4), 38.7 and 39.0 (C-5), 39.1 and 39.3 (C-6),
39.7 and 40.0 (C-2), 44.9 (C-7”’), 45.2 and 45.6 (C-2”),
48.9 and 49.0 (C-3), 74.2 and 74.4 (C-1), 108.9 and 109.2
(C-9), 126.8 and 126.9 (ArC-4’), 127.0 and 127.1 (2C,
ArC-2”’ and ArC-6”’), 128.6 and 128.7 (2C, ArC-3”’ and
ArC-5”’), 129.1 and 129.2 (2C,ArC-3’andArC-5’), 132.4
(2C, ArC-2’andArC-6’), 134.3 and 134.4 (ArC-1’), 137.6
and 137.7 (ArC-1”’), 140.4 and 140.5 (ArC-4”’), 148.1 and
148.1 (C-8), and 173. 8 and 173.8 (C=O).
and H-5”’), 7.43-7.51 (m, 3H, Naphth), 7.38 (d, 2H, J 8.0,
H-2”’ and H.6”’) and 7.77-7.84 (m, 4H, Naphth).
(1S,2S,2”R,3S,5S)- and (1S,2S,2”S,3S,5S)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-
3-phenylsulfonyl-cyclohexyl ester 24a,b: Yield = 95%. IR
(film, nmax/cm-1): 2954, 1731, 1447, 1305, 1145, 1085 and
691 cm-1. 1H NMR: d 0.85 and 0.87 (d, 6H, J 6.7, H-9”’),
0.94 and 1.01 (d, 3H, J 6.7, H-7), 1.08-1.27 (m, 2H, H-4ax
and H-6ax), 1.42 and 1.46 (d, 3H, J 7.2, H-3”), 1,54 and
1.56 (s, 3H, H-10), 1.68-1.93 (m, 4H, H-4eq, H-5, H-6eq and
H-8”’), 1.94-2.05 (m, 1H, H-2), 2.41 and 2.44 (d, 2H, J 7.2,
H-7”’), 3.04 and 3.06 (ddd, 1H, J 3.5, 11.2 and 12.6, H-3),
3,71 (q, 1H, J 7.2, H-2”), 4.38 and 4.53 (s, 1H, H-9b), 4.57
and 4.66 (s, 1H, H-9a), 4.96-5.03 (m, 1H, H-1), 7.04-7.22
(m, 4H, ArH-2”’, ArH-3”’, ArH-5”’ and ArH-6”’), 7.52-
7.70 (m, 3H, ArH-3’, ArH-4’ and ArH-5’) and 7.80-7.88
(m, 2H, ArH-2’ and ArH-6’). 13C NMR: d 16.8 and 17.1
(C-7), 17.6 and 17.7 (C-3”), 20.1 and 20.2 (2C, C-9”’),
20.3 and 20.4 (C-10), 30.1 and 30.3 (C-8”’), 31.9 (C-4),
34.4 and 34.6 (C-6), 35.4 and 35.6 (C-5), 37.1 and 37.4
(C-2”), 44.9 (C-7”’), 45.0 and 45.5 (C-2), 64.5 (C-3), 74.
8 and 74.9 (C-1), 109.6 and 109.9 (C-9), 126.9 and 127.0
(2C, ArC-2”’ and ArC-6”’), 128.4 and 128.5 (2C, ArC-2’
and ArC-6’), 129.0 (2C, ArC-3’ and ArC-5’), 129.2 and
129.3 (2C, ArC-3”’ and ArC-5”’), 133.5 (ArC-4’), 137.3
and 137.8 (ArC-1”’), 138.1 and 138.2 (ArC-1’), 140.5 and
140.6 (ArC-4”’), 147.0 and 147.1 (C-8) and 173.6 (C=O).
(1S,2S,2”R,3R,5S)- and (1S,2S,2”S,3R,5S)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-3-
(naphthalen-2-ylsulfanyl)-cyclohex-1-yl ester 23a,b: Oil.
Yield=69%.[a]D25 +53.2(c0.27,CHCl3).IR(film,nmax/cm-1):
3435, 2955, 2927, 1729, 1646, 1453, 1247, 1165,
1050, 887, 849, 814 and 744. Major diastereomer,
1
(1S,2S,2”R,3R,5S)-23: H NMR: d 0.88 (d, 6H, J 6.6,
ArCH2CHMe2), 1.03 (d, 3H, J 7.0, H-7), 1.43 (ddd, 1H, J
2.7, 11.7 and 14.2, H-6), 1.52-1.62 (m, 1H, H-4), 1.63 (d,
3H, J 7.3, ArCHMe), 1.64 (s, 3H, H-10), 1.84 (septet, 1H,
J 6.6, ArCH2CHMe2), 1.90-1.98 (m, 1H, H-6), 2.02-2.08
(m, 1H, H-4), 2.09-2.15 (m, 1H, H-2), 2.45 (d, 2H, J 7.2,
ArCH2CHMe2), 2.70 (tt, 1H, J 5.9 and 11.5, H-5), 3.55
(dd, 1H, J 3.8 and 8.0, H-3), 3.81 (q, 1H, J 7.3, ArCHMe),
4.66 (s, 1H, H-9), 4.70 (s, 1H, H-9), 5.04 (dd, 1H, J 3.1 and
6.3, H-1), 7.11 (d, 2H, J 8.0, H-3”’ and H-5”’), 7.43-7.51
(m, 3H, Naphth), 7.38 (d, 2H, J 8.0, H-2”’ and H.6”’) and
7.77-7.84 (m, 4H, Naphth). 13C NMR: d 15.8 (C-7), 18.0
(ArCHMe), 21.3 (C-10), 22.4 (2C, ArCH2CHMe2), 30.2
(ArCH2CHMe2), 33.8 (H-5), 34.8 (H-6), 36.3 (H-4), 37.95
(H-2), 45.1 (ArCH2), 46.0 (ArCHMe), 51.1 (C-3), 72.9
(H-1), 109.3 (C-9), 125.8 (Naphth), 126.4 (Naphth), 127.2
(Naphth), 127.6 (2C, C-2”’ and C-6”’), 127.7 (Naphth),
128.4 (Naphth), 129.2 (4C, 2 × Naphth, C-3”’ and C-5”’),
132.0 (Naphth-8’),* 133.8 (Naphth-4’),* 135.4 (C-1’
Naphth),* 137.7 (C-1”’), 140.5 (C-4”’), 148.6 (C-8) and
174.4 (C=O). Minor diastereomer, (1S,2S,2”S,3R,5S)-23:
1H NMR: d 0.89 (d, 6H, J 6.6,ArCH2CHMe2), 1.19 (d, 3H,
J 7.0, H-7), 1.43 (ddd, 1H, J 2.7, 11.7 and 14.2, H-6), 1.52-
1.62 (m, 1H, H-4), 1.61 (d, 3H, J 7.3,ArCHMe), 1.64 (s, 3H,
H-10), 1.84 (septet, 1H, J 6.6, ArCH2CHMe2), 1.90-1.98
(m, 1H, H-6), 2.02-2.08 (m, 1H, H-4), 2.09-2.15 (m, 1H,
H-2), 2.46 (d, 2H, J 7.2, ArCH2CHMe2), 2.70 (tt, 1H, J 5.9
and 11.5, H-5), 3.56 (dd, 1H, J 3.8 and 8.0, H-3), 3.83 (q,
1H, J 7.3, ArCHMe), 4.56 (s, 1H, H-9), 4.64 (s, 1H, H-9),
4.96 (dd, 1H, J 3.1 and 6.3, H-1), 7.12 (d, 2H, J 8.0, H-3”’
(1S,2S,2”R,3S,5S)- and (1S,2S,2”S,3S,5S)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-
3-phenylsulfinyl-cyclohexyl ester 25a,b: Yield = 81%. IR
(film, nmax/cm-1): 2954, 1732, 1444, 1168, 1088, 1045 and
750 cm-1. 1H NMR: d 0.81 and 0.87 (d, 6H, J 6.6, H-9”’),
0.99 and 1.27 (d, 3H, J 6.7, H-7), 0.99-1.40 (m, 3H, H-4ax,
H-6ax and H-8”’), 1.51 and 1.53 (d, 3H, J 7.2, H-3”), 1.40
and 1.53 (s, 3H, H-10), 1.53-2.16 (m, 4H, H-2, H-4eq, H-5
and H-6eq), 2.23 and 2.30 (ddd, 1H, J 3.5, 11.8 and 11.9,
H-3), 2.39 and 2.46 (d, 2H, J 7.2, H-7”’), 3.70 and 3.72
(q, 1H, J 7.6, H-2”), 4.40 and 4.55 (s, 1H, H-9a), 4.53 and
4.62 (s, 1H, H-9b), 5.11-5.21 (m, 1H, H-1), 7.01-7.24 (m,
5H, ArH-3’, ArH-4’, ArH-5’ , ArH-2”’ and ArH-6”’) and
7.40-7.61 (m, 4H, ArH-2’, ArH-6’, ArH-3”’andArH-5”’).
13C NMR: d 15.4 and 15.8 (C-7), 17.5 and 17.6 (C-3”),
20.1 and 20.2 (C-10), 22.2 (2C, C-9”’), 23.8 and 23.9 (C-
4), 30.0 and 30.1 (C-8”’), 34.5 (C-6), 34.8 and 35.1 (C-5),
37.2 and 37.6 (C-2”), 44.8 and 44.9 (C-7”’), 45.1 and 45.4
(C-2), 64.2 (C-3), 74.1 and 74.4 (C-1), 109.5 and 109.8
(C-9), 124.1 and 124.2 (2C,ArC-2’andArC-6’), 127.0 and
127.2 (2C, ArC-2”’ and ArC-6”’), 129.2 (2C, ArC-3”’ and
ArC-5”’), 129.9 (2C, ArC-3’andArC-5’), 130.3 (ArC-4’),

1032
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
137.7 and 137.8 (ArC-1”’), 140.5 and 140.6 (ArC-4”’),
141.1 and 141.2 (ArC-1’), 147.6 and 147.7 (ArC-8), and
173.5 and 173.6 (C=O).
(C-7), 18.1 (ArCHMe), 20.4 (C-10), 21.0 (PhMe), 22.2 (2C,
C-9”’), 30.1 (ArCH2CHMe2), 33.8 (C-6), 37.4 (C-4), 39.8
(C-5), 44.9 (ArCH2CHMe2), 45.4 (C-2”), 74.5 (C-1), 109.3
(C-9), 127.9 (2C, ArC-2’and ArC-6’), 128.0 (2C, ArC-2”’
andArC-6”’), 128.6 (2C,ArC-3”’andArC-5”’), 129.1 (2C,
ArC-3’andArC-5’), 136.0, 136.4, 137.6, 137.8, 139.5 and
140.3 (6C, C-2, C-3, C-1’, C-4’, C-1”’and C-4”’), 148.0 (C-
8) and 174.4 (C=O). Minor diastereomer, (1S,2”R,5S)-27:
1H NMR: d 0.88 (d, 6H, J 6.7, ArCH2CHMe2), 1.44 (s,
3H, H-3”), 1.49-1.63 (m, 4H, H-6ax and H-7), 1.68 (s, 3H,
H-10), 1.84 (tq, 1H, J 6.8 and 6.8, H-8”’), 2.38-2.50 (m,
6H, H-4ax, H-4eq, H-6eq and H-7’), 2.38-2.51 (m, 3H, H-5
and H-7”’), 3.73 (q, 1H, J 7.1, H-2”), 4.68 (m, 1H, H-9a),
4.70 (m, 1H, H-9b), 5.53 (bs, 1H, H-1), 6.96-7.17 (m, 6H,
ArH) and 7.19-7.27 (m, 2H, ArH). 13C NMR: d 15.6 (C-
7), 18.4 (ArCHMe), 20.4 (C-10), 21.0 (PhMe), 22.2 (2C,
C-9”’), 30.1 (ArCH2CHMe2), 33.4 (C-6), 37.4 (C-4), 39.9
(C-5), 44.9 (ArCH2CHMe2), 45.4 (C-3), 74.4 (C-1), 109.3
(C-9), 127.1 (2C, ArC-2’and ArC-6’), 128.1 (2C, ArC-2”’
andArC-6”’), 128.7 (2C,ArC-3”’andArC-5”’), 129.1 (2C,
ArC-3’andArC-5’), 136.0, 136.4, 137.6, 137.8, 139.5 and
140.3 (6C, C-2, C-3, C-1’, C-4’, C-1”’ and C-4”’), 148.0
(C-8) and 174.6 (C=O).
(1S,2”R,5S)- and (1S,2”S,5S)-2-(4-Isobutylphenyl)-
propionic acid 5-isopropenyl-2-methyl-3-phenyl-cyclohex-
2-enyl ester 26a,b: Oil. Yield = 40%. [a]D25 +81.0 (c 0.65,
CHCl3). IR (film, nmax/cm-1): 2924, 1729, 1513, 1450, 1375,
1190,956,890and798.Majordiastereomer,(1S,2”S,5S)-26:
1H NMR: d 0.85 (d, 6H, J 6.6, ArCH2CHMe2), 1.15 (s, 3H,
H-7), 1.50-1.64 (m, 4H, H-6ax and H-3”), 1.73 (s, 3H, H-10),
1.81 (tq, 1H, J 6.6 and 7.0, H-8”’), 2.08-2.34 (m, 3H, H-4ax,
H-4eq and H-6eq), 2.34-2.51 (m, 3H, H-5 and H-7”’), 3.72
(q, 1H, J 7.1, H-2”), 4.74 (m, 2H, H-9a and H-9b), 5.48-
5.62 (m, 1H, H-1), 7.02-7.11 (m, 4H, ArH) and 7.17-7.37
(m, 5H, ArH). 13C NMR: d 15.1 (C-7), 18.1 (ArCHMe),
20.4 (C-10), 22.2 (2C, C-9”’), 30.1 (ArCH2CHMe2), 33.8
(C-6), 37.4 (C-4), 39.9 (C-5), 44.9 (ArCH2CHMe2) 45.4
(ArCHMe), 74.4 (C-1), 109.4 (C-9), 126.4 (ArC-4’), 127.1
(2C, ArC-2”’and ArC-6”’), 128.0 (2C, ArC-3’and Ar-5’),
128.0 (2C, ArC-2’ and ArC-6’), 128.3 (C-2), 129.1 (2C,
ArC-3”’ and ArC-5”’), 136.5 (ArC-1”’), 137.8 (ArC-4”’),
140.4 (ArC-1’), 142.5 (C-3), 147.9 (C-8) and 174.4 (C=O).
Minor diastereomer, (1S,2”R,5S)-26: 1H NMR: d 0.88 (d,
6H, J 6.6, ArCH2CHMe2), 1.44 (s, 3H, H-3”), 1.53 (d, 3H,
J 7.2, H-7), 1.69 (s, 3H, H-10), 1.84 (tq, 1H, J 6.6 and 7.0,
H-8”’), 2.08-2.33 (m, 3H, H-4ax, H-4eq y H-6eq), 2.33-2.51
(m, 4H, H-5, H-6ax and H-7”’), 3.75 (q, 1H, J 7.1, H-2”),
4.69 (s, 1H, H-9a), 4.71 (s, 1H, H-9b), 5.48-5.62 (m, 1H,
H-1), 7.02-7.17 (m, 4H,ArH) and 7.17-7.37 (m, 5H,ArH).
13C NMR: d 15.51 (C-7), 18.36 (ArCHMe), 20.41 (C-10),
22.19 (2C, C-9”’), 30.08 (ArCH2CHMe2), 33.4 (C-6), 37.4
(C-4), 39.8 (C-5), 44.9 (ArCH2CHMe2) 45.4 (ArCHMe),
74.3 (C-1), 109.4 (C-9), 126.5 (ArC-4’), 127.1 (2C,ArC-2”’
and ArC-6”’), 128.0 (2C, ArC-3’ and ArC-5’), 128.1 (2C,
ArC-2’ and ArC-6’), 128.3 (C-2), 129.1 (2C, ArC-3”’ and
ArC-5”’), 136.8 (ArC-1”’), 137.6 (ArC-4”’), 140.4 (ArC-
1’), 142.5 (C-3), 148.0 (C-8) and 174.6 (C=O).
(1S,2”R,5S)- and (1S,2”S,5S)-2-(4-Isobutylphenyl)-
propionic acid 5-isopropenyl-2-methyl-3-(4-
methoxyphenyl)-cyclohex-2-enyl ester 28a,b: Oil. Yield =
25
90%. [a]D +114.4 (c 1.21, CHCl3). IR (film, nmax/cm-1):
3057, 2932, 1731, 1646, 1581, 1484, 1449, 1419, 1180,
1088, 893, 801 and 780. Major diastereomer, (1S,2”S,5S)-28:
1H NMR: d 0.85 (d, 6H, J 6.2, H-9”’), 1.16 (s, 3H, H-7),
1.52 (d, 3H, J 7.2, H-3”), 1.52-1.64 (m, 1H, H-6ax), 1,73 (s,
3H, H-10), 1.74-1.90 (m, 1H, H-8”’), 2.07-2.34 (m, 3H,
H-4eq, H-4ax y H-6eq), 2.34-2.49 (m, 3H, H-5 and H-7”’),
3.72 (q, 1H, J 7.2, H-2”), 3.79 (s, 3H, OMe), 4.73 (m, 2H,
H-9a and H-9b), 5.47-5.61 (m, 1H, H-1), 6.80-6.91 (m, 2H,
ArH-3’ and ArH-5’), 6.99-7.13 (m, 4H, ArH-2’, ArH-6’,
ArH-3”’ and ArH-5”’) and 7.19-7.28 (m, 2H, ArH-2”’ and
ArH-6”’). 13C NMR: d 15.3 (C-7), 18.1 (C-3”), 20.4 (C-10),
22.2 (2C, C-9”’), 30.2 (C-8”’), 33.8 (C-6), 37.5 (C-4), 39.8
(C-5), 44.9 (C-7”’), 45.4 (C-2”), 55.1 (OMe), 74.5 (C-1),
109.3 (C-9), 113.3 (2C, ArC-3’ and ArC-5’), 127.1 (2C,
ArC-2”’ and ArC-6”’), 128.1 (C-2), 129.1 (2C, ArC-2’ and
ArC-6’), 129.2 (2C, ArC-3”’andArC-5”’), 134.7 (ArC-1’),
136.0 (ArC-1”’), 137.8 (C-3), 140.3 (ArC-4”’), 148.0 (C-
8), 158.1 (ArC-4’) and 174.4 (C=O). Minor diastereomer,
(1S,2”R,5S)- and (1S,2”S,5S)-2-(4-Isobutylphenyl)-
propionic acid 5-isopropenyl-2-methyl-3-p-tolylcyclohex-
25
2-enyl ester 27a,b: Oil. Yield = 26%. [a]D +101.5
(c 2.66, CHCl3). IR (film, nmax/cm-1): 2924, 1730, 1512,
1452, 1375, 1315, 1199, 1165, 956, 891 and 818. Major
1
diastereomer, (1S,2”S,5S)-27: H NMR: d 0.85 (d, 6H, J
6.2, ArCH2CHMe2), 1.16 (s, 3H, H-3”), 1.49-1.63 (m, 4H,
H-6ax and H-7), 1.72 (s, 3H, H-10), 1.81 (tq, 1H, J 6.8 and
6.8, H-8”’), 2.07-2.37 (m, 6H, H-4ax, H-4eq, H-6eq and H-7’),
2.37-2.50 (m, 3H, H-5 and H-7”’), 3.72 (q, 1H, J 7.1, H-2”),
4.73 (m, 2H, H-9a and H-9b), 5.52 (bs, 1H, H-1), 6.96-7.17
(m, 6H,ArH) and 7.19-7.26 (m, 2H,ArH). 13C NMR: d 15.2
1
(1S,2”R,5S)-28: H NMR: d 0.88 (d, 6H, J 6.7, H-9”’),
1.36-1.49 (m, 4H, H-6ax and H-7), 1.53 (d, 3H, J 7.2, H-3”),
1.68 (s, 3H, H-10), 1.74-1.93 (m, 1H, H-8”’), 2.07-2.50 (m,
6H, H-4eq, H-4ax, H-5, H-6eq and H-7”’), 3.75 (q, 1H, J 7.2,
H-2”), 3.80 (s, 3H, OMe), 4.68 (s, 1H, H-9b), 4.71 (s, 1H,

Vol. 21, No. 6, 2010
Amongero et al.
1033
H-9a), 5.47-5.61 (m, 1H, H-1), 6.80-6.91 (m, 2H, ArH-3’
and ArH-5’), 6.99-7.13 (m, 4H, ArH-2’, ArH-6’, ArH-3”’
andArH-5”’) and 7.19-7.28 (m, 2H,ArH-2”’andArH-6”’).
13C NMR: d 15.6 (C-7), 18.4 (C-3”), 20.4 (C-10), 22.2 (2C,
C-9”’), 30.1 (C-8”’), 33.4 (C-6), 37.5 (C-4), 39.8 (C-5),
44.9 (C-7”’), 45.4 (C-2”), 55.1 (OMe), 74.5 (C-1), 109.3
(C-9), 113.4 (2C, ArC-3’ and ArC-5’), 127.1 (2C, ArC-2’”
and ArC-6”’), 127.8 (C-2), 129.1 (2C, ArC-2’and ArC-6’),
129.2 (2C, ArC-3”’ and ArC-5”’), 134.8 (ArC-1’), 136.3
(ArC-1”’), 137.6 (C-3), 140.3 (ArC-4”’), 148.0 (C-8), 158.1
(ArC-4’) and 174.6 (C=O).
C-5’), 129.2 (C-3”’ and C-5”’), 138.0 (C-1”’), 140.4 (C-
4”’), 144.7 (C-1’), 148.2 (C-8) and 174.3 (C=O).
(1R,2S,2”R,3R,5R)- and (1R,2S,2”S,3R,5R)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-3-
naphthalen-1-yl-cyclohexyl ester 30a,b: Oil. Yield = 72%.
25
[a]D –16.3 (c 1.00, CHCl3). IR (film, nmax/cm-1): 3057,
2932, 1731, 1646, 1581, 1484, 1449, 1419, 1180, 1088, 893,
801 and 780. Major diastereomer, (1R,2S,2”R,3R,5R)-30:
1H NMR: d 0.40 (d, 3H, J 6.9, H-7), 0.75 (d, 3H, J 6.6,
ArCH2CHMe2), 0.76 (d, 3H, J 6.6, ArCH2CHMe2), 1.55 (d,
3H, J 7.1, ArCHMe), 1.77 (s, 3H, H-10), 1.78 (septet, J 6.6,
ArCH2CHMe2), 1.83-1.94 (m, 2H, H-5, H-6), 2.10-2.21
(m, 2H, H-2 and H-4), 2.30 (ddt, 1H, J 1.6, 5.8 and 13.8,
H-6), 2.39 (d, 2H, J 7.2, ArCH2CHMe2), 3.69 (q, 1H, J 7.1,
ArCHMe), 3.77 (dt, 1H, J 4.5 and 9.3, H-3), 4.88 (bd, 1H, J
1.5, H-9), 4.91 (s, 1H, H-9), 5.19 (dt, 1H, J 2.9 and 5.8, H-1),
7.08 (d, 2H, J 8.1, H-3”’and H-5”’), 7.23 (d, 2H, J 8.1, H-2”’
and H-6”’), 7.42-7.57 (m, 4H, H-2’, H-3’, H-6’ and H-7’),
7.69 (dd, 1H, J 3.1 and, 6.2, H-4’), 7.85 (dd, 1H, J 1.6 and
8.0, H-5’)and8.01(bd, 1H, J8.0, H-8’). 13CNMR:d14.7(C-
7), 17.6 (ArCHMe), 22.2 (C-10),** 22.3 (ArCH2CHMe2),**
22.4 (ArCH2CHMe2),** 30.1 (ArCH2CHMe2), 31.7 (C-
6),** 35.1 (C-4),** 35.6 (C-3), 38.3 (C-5), 39.8 (C-2), 45.0
(ArCH2), 45.4 (ArCHMe), 74.1 (C-1), 108.7 (C-9), 123.2
(C-8’),# 123.3 (C-2’),# 125.2 (C-6’),** 125.6 (C-3’),** 125.7
(C-7’),** 126.4 (C-4’), 127.4 (2C, C-2”’ and C-6”’), 129.0
(C-5’), 129.2(C-3”’andC-5”’), 132.2(C-8a’), 134.0(C-4a’),
138.1 (C-1”’), 140.4 (C-4”’), 141.9 (C-1’), 148.2 (C-8) and
174.4 (C=O). Minor diastereomer, (1R,2S,2”S,3R,5R)-30:
1H NMR: d 0.67 (d, 3H, J 6.9, H-7), 0.75 (d, 3H, J 6.6,
ArCH2CHMe2), 0.76 (d, 3H, J 6.6, ArCH2CHMe2), 1.56 (d,
3H, J 7.1, ArCHMe), 1.77 (s, 3H, H-10), 1.78 (septet, J 6.6,
ArCH2CHMe2), 1.83-1.94 (m, 2H, H-5, H-6), 2.10-2.21
(m, 2H, H-2 and H-4), 2.30 (ddt, 1H, J 1.6, 5.8 and 13.8,
H-6), 2.43 (d, 2H, J 7.2, ArCH2CHMe2), 3.69 (q, 1H, J 7.1,
ArCHMe), 3.83 (dt, 1H, J 4.5 and9.3, H-3), 4.79 (bd, 1H,
J 1.5, H-9), 4.89 (s, 1H, H-9), 5.22 (dt, 1H, J 2.9 and 5.8,
H-1), 7.10 (d, 2H, J 8.1, H-3”’ and H-5”’), 7.25 (d, 2H, J
8.1, H-2”’ and H-6”’), 7.42-7.57 (m, 4H, H-2’, H-3’, H-6’
and H-7’), 7.70 (dd, 1H, J 3.1 and 6.2, H-4’), 7.87 (dd, 1H, J
1.6 and 8.0, H-5’) and 8.11 (bd, 1H, J 8.0, H-8’). 13C NMR:
d 15.2 (C-7), 18.2 (ArCHMe), 22.3 (ArCH2CHMe2),** 22.4
(ArCH2CHMe2),** 22.7 (C-10),** 30.1 (ArCH2CHMe2),
31.9 (C-6),** 34.7 (C-4),** 36.1 (C-3), 38.3 (C-5), 39.4 (C-
2), 45.0 (ArCH2), 45.8 (ArCHMe), 74.3 (C-1), 108.8 (C-9),
123.2 (C-8’),# 123.4 (C-2’),# 125.2 (C-6’),** 125.6 (C-3’),**
125.8 (C-7’),** 126.5 (C-4’), 127.4 (2C, C-2”’ and C-6”’),
129.1 (C-5’), 129.2 (C-3”’and C-5”’), 132.2 (C-8a’), 134.1
(C-4a’), 138.1 (C-1”’), 140.4 (C-4”’),141.8 (C-1’), 148.2
(C-8) and 174.4 (C=O).
(1R,2S,2”R,3R,5R)- and (1R,2S,2”S,3R,5R)-2-(4-
Isobutylphenyl)-propionic acid 5-isopropenyl-2-methyl-
3-phenylcyclohexyl ester 29a,b: Oil. Yield = 96%.
25
[a]D –28.6 (c 1.42, CHCl3). IR (film, nmax/cm-1): 2957,
1729, 1602, 1514, 1454, 1382, 1213, 1204, 1069, 757
and 701. Major diastereomer, (1R,2S,2”R,3R,5R)-29:
1H NMR: d 0.44 (d, 3H, J 6.9, H-7), 0.88 (s, 3H, J 6.6,
ArCH2CHMe2), 0.90 (d, 3H, J 6.6,ArCH2CHMe2), 1.53 (d,
3H, J 7.1,ArCHMe), 1.75 (s, 3H, H-10), 1.89 (septet, J 6.6,
ArCH2CHMe2), 1.80-1.93 (m, 2H, H-5, H-6), 2.00-2.20 (m,
2H, H-2 and H-4), 2.30 (bdt, 1H, J 4.6 and 10.6, H-6), 2.41
(d, 2H, J 7.2, ArCH2CHMe2), 2.87 (dt, 1H, J 4.0 and 8.1,
H-3), 3.67 (q, 1H, J 7.1, ArCHMe), 4.84 (s, 1H, H-9), 4.86
(s, 1H, H-9), 5.09 (dt, 1H, J 3.4 and 6.9, H-1), 7.18 (d, 2H,
J 8.1, H-3”’ and H-5”’), 7.20-7.33 (m, 5H, ArH) and 7.24
(d, 2H, J 8.1, H-2”’ and H-6”’). 13C NMR: d 14.6 (C-7),
17.6 (ArCHMe), 22.3 (C-10), 22.3 (2C, ArCH2CHMe2),
30.2 (ArCH2CHMe2), 31.4 (C-6),** 33.8 (C-4),** 37.6 (C-
3), 38.0 (C-5), 42.1 (C-2), 45.0 (ArCH2), 45.3 (ArCHMe),
73.5 (C-1), 108.8 (C-9), 125.9 (C-4’), 127.3 (2C, C-2’and
C-6’), 127.4 (2C, C-2”’ and C-6”’), 128.4 (2C, C-3’ and
C-5’), 129.2 (C-3”’ and C-5”’), 138.0 (C-1”’), 140.4 (C-
4”’), 144.7 (C-1’), 148.2 (C-8) and 174.3 (C=O). Minor
diastereomer, (1R,2S,2”S,3R,5R)-29: 1H NMR: d 0.69 (d,
3H, J 6.9, H-7), 0.88 (s, 3H, J 6.6, ArCH2CHMe2), 0.90 (d,
3H, J 6.6, ArCH2CHMe2), 1.54 (d, 3H, J 7.1, ArCHMe),
1.75 (s, 3H, H-10), 1.89 (septet, J 6.6, ArCH2CHMe2),
1.80-1.93 (m, 2H, H-5, H-6), 2.00-2.20 (m, 2H, H-2 and
H-4), 2.30 (bdt, 1H, J 4.6 and 10.6, H-6), 2.41 (d, 2H, J
7.2, ArCH2CHMe2), 2.93 (dt, 1H, J 4.0 and 8.1, H-3), 3.69
(q, 1H, J 7.1, ArCHMe), 4.80 (s, 1H, H-9), 4.82 (s, 1H,
H-9), 5.10 (dt, 1H, J 3.4 and 6.9, H-1), 7.18 (d, 2H, J 8.1,
H-3”’ and H-5”’), 7.20-7.33 (m, 5H, ArH) and 7.24 (d,
2H, J 8.1, H-2”’ and H-6”’). 13C NMR: d 14.9 (C-7), 17.8
(ArCHMe), 22.0 (C-10), 22.3 (2C, ArCH2CHMe2), 30.2
(ArCH2CHMe2), 31.3 (C-6),** 33.7 (C-4),** 37.6 (C-3),
38.0 (C-5), 42.1 (C-2), 45.0 (ArCH2), 45.8 (ArCHMe),
73.6 (C-1), 108.8 (C-9), 125.9 (C-4’), 127.3 (2C, C-2’and
C-6’), 127.4 (2C, C-2”’ and C-6”’), 128.4 (2C, C-3’ and

1034
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
(1S,2S,2”R,5R)- and (1S,2S,2”S,5R)-2-(4-Isobutyl-
0.13 mmol) in THF-MeOH (2:1, 2 mL) kept at 0 ºC. After
30 min, acetone (0.5 mL) was added and 5 min later the
organic solvent was removed under reduced pressure and
the residue was chromatographed, furnishing 35 (28 mg,
66%) as a white solid mp 128-130 ºC (hexane-EtOAc).
phenyl)-propionic acid 2-isopropyl-5-methyl-cyclohexyl
ester 32: Oil. Yield = 97%. IR (film, nmax/cm-1): 2930,
2121, 1730, 1513, 1451, 1360, 1258, 1241, 1203, 1170,
1094, 1048, 956, 891, 845 and 799. 1H NMR: d 0.49 and
0.70 (d, 3H, J 6.9, H-9),** 0.66 and 0.81 (s, 3H, J 6.9,
H-10),** 0.77-1.15 (m, 1H, H-6), 0.81 (d, 3H, J 6.9, H-7),
0.88 (d, 6H, J 6.6, ArCH2CHMe2), 1.18-1.40 (m, 3H, H-3,
H-4), 1.46 and 1.48 (d, 3H, J 6.0, ArCHMe), 1.80-2.00
(m, 1H, H-6), 2.44 (d, 2H, J 7.4, ArCH2), 3.15-3.23 (m,
1H, H-2), 3.63 and 3.65 (q, 1H, J 7.5, ArCHMe), 4.60 and
4.61 (q, 1H, H-1), 7.06 and 7.07 (d, 2H, J 7.8, ArH-3’ and
ArH-5’)** and 7.17 and 7.19 (d, 2H, J 7.8, ArH-2’ and
ArH-6’).** 13C NMR: d 15.9 and 16.2 (C-9),** 18.2 and
18.3 (ArCHMe), 20.5 and 20.7 (C-10),** 21.9 and 22.0
(ArCH2CHMe2),# 22.2 and 22.3 (ArCH2CHMe2),# 23.2 and
23.4 (C-7),# 24.5 and 25.5 (C-3), 26.1 (C-8), 30.1 and 30.2
(ArCH2CHMe2), 31.3 and 31.4 (C-5), 34.3 and 34.9 (C-4),
40.4 and 40.9 (ArCHMe), 45.0 and 45.4 (ArCH2), 46.9 and
47.1 (C-6), 55.7 (C-2), 74.2 and 74.3 (C-1), 127.0 and 127.1
(2C, C-2’and C-6’),** 129.1 (2C, C-3’and C-5’),** 137.9
and 138.2 (C-1’), 140.3 (C-4’) and 174.2 and 174.3 (C=O).
25
[a]D –70.3 (c 1.05, CHCl3). IR (KBr, nmax/cm-1): 2453,
2951, 2897, 1650, 1484, 1383, 1077, 1009, 977, 867, 760,
717 and 633. 1H NMR: d 0.92 (d, 3H, J 7.0, H-9),** 0.96
(d, 3H, J 7.0, H-10),** 1.13 (d, 3H, J 7.3, H-7), 1.31 (m,
1.27-1.36, 1H, H-6), 1.44-1.56 (m, 4H, H-4 and H-5),
2.25 (d-septet, 1H, J 2.9 and 7.0, H-8), 3.10-3.18 (m, 1H,
H-3), 4.26 (dd, 1H, J 1.2 and 13.5, H-1), 6.52 (d, 1H, J 1.8,
ArCH=), 7.05 (d, 2H, J 8.4, H-2’ and H-6’) and 7.42 (d,
2H, J 8.4, H-3’ and H-5’). 13C NMR: d 15.9 (C-9),** 18.4
(C-5), 18.8 (C-10),** 20.8 (C-7), 26.7 (C-8), 31.2 (C-3),
32.3 (C-4), 52.6 (C-6), 70.3 (C-1), 117.3 (ArCH=), 119.8
(C-4’), 130.3 (2C, C-2’ and C-6’), 130.9 (2C, C-3’ and
C-5’), 137.7 (C-1’) and 150.0 (C-2).
(1S,2”R,3R,6S)- and (1S,2”S,3R,6S)-2-(4-
Isobutylphenyl)-propionic acid 2-(4-bromobenzylidene)-
6-isopropyl-3- methyl-cyclohexyl ester 36a,b: DMAP
(8.6 mg, 0.07 mmol) and ibuprofen (18.2 mg, 0.07 mmol)
were successively added to a stirred solution of alcohol
35 (22.7 mg, 0.07 mmol) in CHCl3 (3 mL). The mixture
was treated with a solution of DCC (18.2 mg, 0.07 mmol)
in CHCl3 (0.5 mL). After stirring overnight at room
temperature, the organic solvent was removed under
reduced pressure and the residue was chromatographed,
(3R,6S)-2-(4-Bromobenzylidene)-6-isopropyl-3-
methyl-cyclohexanone 34: A solution of (-)-menthone
(33, 260 mg, 1.68 mmol) and 4-bromobenzaldehyde
(312 mg, 1.68 mmol) in DMSO (10 mL), was treated
with KtBuO (20 mg, 0.17 mmol). After stirring 12 h at
room temperature, saturated NH4Cl (15 mL) and water
(15 mL) were added and the organic product was extracted
with EtOAc (4 × 50 mL). The combined organic extracts
were washed with brine (10 mL), dried over Na2SO4,
concentrated under reduced pressure and the residue was
chromatographed, furnishing 34 (145.2 mg, 43%) as a white
solid, mp 100-102 ºC (hexane-EtOAc). [a]D25 –53.3 (c 1.33,
CHCl3). IR (KBr, nmax/cm-1): 2954, 2931, 1674, 1608, 1438,
1398, 1170, 1095, 1068, 1004, 835 and 756. 1H NMR: d
0.89 (d, 3H, J 7.1, H-9), 0.96 (d, 3H, J 7.1, H-10), 1.16 (d,
3H, J 7.1, H-7), 1.75-1.82 (m, 1H, H-4), 1.82-1.90 (m, 3H,
H-4 and H-5), 2.22 (ddd, 1H, J 3.6, 8.6 and 10.0, H-6), 2.54
(d-septet, 1H, J 3.3 and 6.8, H-8), 3.28-3.38 (bs, 1H, H-3),
7.01 (s, 1H, =C-H), 7.20 (d, 2H, J 8.1, H-3’ and H-5’) and
7.49 (d, 2H, J 8.1, H-2’and H-6’). 13C NMR: d 17.8 (C-9),
18.7 (C-5), 19.7 (C-7), 20.4 (C-10), 26.6 (C-8), 30.5 (C-4),
31.7 (C-3), 56.0 (C-6), 122.2 (C-4’), 131.0 (3C, C-2’, C-6’
and ArCH-C), 131.6 (2C, C-3’and C-5’), 134.8 (C-1’),
145.5 (C-2) and 204.7 (C=O).
25
furnishing 36 as an oil (34.9 mg, 97%). [a]D –40.4 (c
1.60, CHCl3). IR (film, nmax/cm-1): 2957, 1742, 1486, 1164,
1010, 852 and 812. Major diastereomer, (1S,2”R,3R,6S)-36:
1H NMR: d 0.60 (d, 3H, J 6.9, H-9),** 0.70 (d, 3H, J 6.9,
H-10),** 0.88 (d, 6H, J 6.6, ArCH2CHMe2), 1.17 (d, 3H,
J 7.2, H-7), 1.30-1.55 (m, 6H, H-4, H-5, H-6 and H-8),
1.55 (d, 3H, J 7.1, ArCHMe), 1.80 (septet, 1H, J 6.9,
ArCH2CHMe2), 2.44 (d, 2H, J 7.1, ArCH2CHMe2), 3.04-
3.14 (m, 1H, H-3), 3.81 (q, 1H, J 7.1, ArCHMe), 5.41 (bd,
J 8.4, 1H, H-1), 5.95 (s, 1H, ArCH=C), 6.97 (d, 2H, J 8.0,
H-3’ and H-5’), 7.08 (d, 2H, J 8.3, H-3” and H-5”), 7.25
(d, 2H, J 8.3, H-2” and H-5”) and 7.40 (d, 2H, J 8.0, H-2’
and H-6’). 13C NMR: d 15.5 (C-9),** 17.8 (ArCHMe), 18.3
(C-7), 18.4 (C-5), 20.5 (C-10),** 22.3 (2C,ArCH2CHMe2),
26.2 (C-8), 30.1 (ArCH2CHMe2), 31.4 (C-3), 32.2 (C-4),
45.0 (ArCHMe), 45.5 (ArCH2CHMe2), 50.1 (C-6), 72.4
(C-1), 117.2 (ArCH=C), 119.8 (C-4’), 127.3 (2C, C-2”
and C-6”), 129.3 (2C, C-3” and C-5”), 130.5 (2C, C-2’
and C-6’), 131.1 (2C, C-3’ and C-5’), 136.8 (C-1’), 137.6
(C-1”), 140.7 (C-4”), 145.5 (C-2) and 173.7 (C=O). Minor
diastereomer, (1S,2”S,3R,6S)-36: 1H NMR: d 0.60 (d, 3H,
J 6.9, H-9), 0.70 (d, 3H, J 6.9, H-10), 0.84 (d, 6H, J 6.6,
(1S,3R,6S)-2-(4’-Bromobenzylidene)-6-isopropyl-
3-methyl-cyclohexanol 35: NaBH4 (20 mg, 0.52 mmol)
was added to a stirred solution of ketone 34 (42 mg,

Vol. 21, No. 6, 2010
Amongero et al.
1035
ArCH2CHMe2), 1.14 (d, 3H, J 7.2, H-7), 1.30-1.55 (m,
6H, H-4, H-5, H-6 and H-8), 1.54 (d, 3H, J 7.1, ArCHMe),
1.82 (septet, 1H, J 6.9, ArCH2CHMe2), 2.39 (d, 2H, J 7.1,
ArCH2CHMe2), 3.04-3.14 (m, 1H, H-3), 3.81 (q, 1H, J
7.1, ArCHMe), 5.44-5.46 (m, 1H, H-1), 6.30 (s, 1H,
ArCH=C), 6.76 (d, 2H, J 8.0, H-3’ and H-5’), 7.05 (d,
2H, J 8.3, H-3” and H-5”), 7.25 (d, 2H, J 8.3, H-2” and
H-5”) and 7.32 (d, 2H, J 8.0, H-2’ and H-6’). 13C NMR:
d 16.0 (C-9),** 18.1 (ArCHMe), 18.3 (C-7), 18.7 (C-5),
20.7 (C-10),** 22.3 (2C, ArCH2CHMe2), 26.9 (C-8), 30.2
(ArCH2CHMe2), 31.3 (C-3), 32.2 (C-4), 45.0 (ArCHMe),
45.3 (ArCH2CHMe2), 49.9 (C-6), 72.1 (C-1), 117.3
(ArCH=C), 119.8 (C-4’), 127.4 (2C, C-2” and C-6”),
129.4 (2C, C-3” and C-5”), 130.3 (2C, C-2’ and C-6’),
131.0 (2C, C-3’and C-5’), 136.7 (C-1’), 137.7 (C-1”),
140.7 (C-4”), 145.0 (C-2) and 173.7 (C=O).
Kulkarni, D. G.;Ahuja, J. R.; Tetrahedron: Asymmetry 1991, 2,
251; Oppolzer, W.; Rosset, S.; De Brabander, J.; Tetrahedron
Lett. 1997, 38, 1539; Ishibashi, H.; Maeki, M.; Yagi, J.; Ohba,
M.; Kanal, T.; Tetrahedron 1999, 55, 6075; Beaulieu, C.; Spino,
C.; Tetrahedron Lett. 1999, 40, 1637; Jung, M. E.; Anderson,
K. L.; Tetrahedron Lett. 1997, 38, 2605; Jang, E. J.; Lee, K. H.;
Lee, J. S.; Kim,Y. G.; J. Molec. Catal. A: Chem. 1999, 138, 25;
For a review on arylpropionic acids, see Sonawane, H.; Bellur,
N. S.; Ahuja, J. R.; Kulkarni, D. G.; Tetrahedron: Asymmetry
1992, 3, 163.
7. Lam, W. H.; Ng, K. M.; AIChE J. 2007, 53, 429; Bhattacharya,
A.; Org. Process Res. Dev. 2003, 7, 717.
8. da Silva, V. C. F.; Contesini, F. J.; Carvalho, P. D.; J. Braz.
Chem. Soc. 2008, 19, 1468; Henke, E.; Schuster, S.; Yang, H.;
Bornscheuer, U. T.; Monatsh. Chem. 2000, 131, 633.
9. Kumar, I.; Manju, K.; Jolly, R.; Tetrahedron: Asymmetry 2001,
12, 1431; Cauwenberg, V.; Vergossen, P.; Stankiewicz, A.;
Kierkels, H.; Chem. Eng. Sci. 1999, 54, 1473; Senanayake, C.
H.; Bill, T. J.; Larsen, R. D.; Leazer, J.; Reider, P. J.; Tetrahedron
Lett. 1992, 33, 5901.
Acknowledgements
The authors are thankful to CONICET, ANPCyT,
SECyT-UNR and Fundación Josefina Prats for their
generous financial assistance. M. A. thanks ANPCyT and
CONICET for her fellowships.
10. Hirrilinger, B.; Andreas, S.; Kanckmuss, H. J.; J. Bacteriol.
1996, 178, 3501; Yamamoto, K.; Kazumasa, O.; Akira, M.;
Takahiko, H.; Isao, F.; Ken-Ichi, K.; Appl. Environ. Microbiol.
1996, 62, 152; Effenberger, F.; Graef, B. W.; Osswald, S.;
Tetrahedron: Asymmetry 1997, 8, 2749.
References
11. Cohen, M. A.; Parrat, J. S.; Turner, N. J.; Tetrahedron:
Asymmetry 1992, 3, 1543; Kakeya, H.; Sakai, N.; Sugai, T.;
Ohta, H.; Tetrahedron Lett. 1991, 32, 1343; Yamamoto, K.;
Ueno, Y.; Otsubo, K.; Kawakami, K.; Komatsu, K.; Appl.
Environ. Microbiol. 1990, 56, 3125.
1. Reddy, I. K.; Mehva, R.; Chirality in Drug Design and
Development. Marcel Dekker: New York, 2004; Francotte, E.;
Linder,W.; Chirality in Drug Research.Wiley-VCH:Weinheim,
2006.
2. Kaehler, S. T.; Phleps, W.; Hesse, E.; Inflammopharmacology
2003, 11, 371.
12. Bando, T. ; Namba, Y. ; Shishido, K.; Tetrahedron:
Asymmetry 1997, 8, 2159.
3. Knadler, M. P.; Hall, S. D.; Chirality 1990, 2, 67; Tracy, T. S.;
Wirthwein, D. P.; Hall, S. D.; Drug Metab. Dispos. 1993, 21,
114; Hall, S. D.; Xiaotao, Q.; Chem.-Biol. Interact. 1994, 90,
235; Sanins, S. M.; Adams, W. J.; Kaiser, D. G.; Halstead, G.
W.; Baillie, T. A.; Drug Metab. Dispos. 1990, 18, 527.
4. Li, C.; Benet, L. Z.; Grillo, M. P.; Chem. Res. Toxicol. 2002,
15, 1480; Grillo, M. P.; Hua, F.; Chem. Res. Toxicol. 2008, 21,
1749.
13. Tanaka, J.-I.; Oda, S.; Ohta, H.; J. Biosci. Bioeng. 2001, 91,
314.
14. Srikrishna, A.; Nagaraju, S.; Jagadeeshwar Reddy, T.;
Venkateswarlu, S.; Pure Appl. Chem. 1996, 68, 699; Ho, T.-
L.; Enantioselective Synthesis: Natural Products from Chiral
Terpens. Wiley: Chichester, 1992; Abad, A.; Agullo, C.;
Castelblanque, L.; Cunar, A. C.; Navarro, I.; de Arellano, M.
C. R.; J. Org. Chem. 2000, 65, 4189.
5. Rainsford, K. D.; Ibuprofen. A Critical Bibliographic Review.
Taylor and Francis: London, 1999; Hutt, A. J.; Caldwell, J.;
J. Pharm. Pharmacol. 1983, 35, 693; Bertola, M. A.; U.S.
Pat. 5,108,917, 1992; Williams, K.; Day, R.; Kinhinicki, R.;
Duffield, A.; Biochem. Pharmacol. 1986, 35, 3403.
6. Polet, D.; Alexakis, A.; Tetrahedron Lett. 2005, 46, 1529;
Acemoglu, L.; Williams, J. M. J.; J. Mol. Catal. A: Chem.
2003, 196, 3; Sonawane, H. R.; Bellur, N. S.; Kulkarni, D.
G.; Ayyangar, N. R.; Tetrahedron 1994, 50, 1243; Hamon, D.
P. G.; Massy-Westropp, R. A.; Newton, J. L.; Tetrahedron:
Asymmetry 1993, 4, 1435; Sonawane, H. R.; Nanjundiah, B. S.;
15. Corey, E. J.; Gin, D.; Kania, R. S.; J. Am. Chem. Soc. 1996,
118, 9202; Grygorenko, O. O.; Kopylova, N. A.; Mikhailiuk,
P. K.; Meissner, A.; Komarov, I. V.; Tetrahedron: Asymmetry
2007, 18, 290; Rossi, J. C.; Marull, M.; Boiteau, L.; Taillades,
J.; Eur. J. Org. Chem. 2007, 662.
16. For reviews, see: Pellisier, H.; Tetrahedron 2003, 59, 8291;
Ward, R. S.; Tetrahedron: Asymmetry 1995, 6, 1475; Pellisier,
H.; Tetrahedron 2008, 64, 1563.
17. Ammazzalorso,A.;Amoroso, R.; Bettonia, G.; De Filippis, B.;
Giampietro, L.; Pierini, M.; Tricca, M. L.; Tetrahedron Lett.
2002, 43, 4325.

1036
Chiral Auxiliary-Mediated Enantioenrichment of ( )-Ibuprofen
J. Braz. Chem. Soc.
18. Ammazzalorso, A.; Amoroso, R.; Bettoni, G.; De Filippis, B.;
28. Mehta, G.; Umarye, J. D.; Gagliardini, V.; Tetrahedron Lett.
2002, 43, 6975; Srikrishna, A.; Dethe, D. H.; Org. Lett. 2004,
6, 165; Mehta, G.; Chattopadhyay, S. K.; Umarye, J. D.;
Tetrahedron Lett. 1999, 40, 4881.
Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Tricca, M. L.;
Eur. J. Org. Chem. 2006, 4088.
19. Neises, B.; Steglich, W.; Angew. Chem., Int. Ed. 1978, 17, 522;
Wiener, H.; Gilon, C.; J. Mol. Catal. 1986, 37, 45.
20. Hargreaves, M. K.; Rabari, L. F.; Monatsh. Chem. 1983, 114,
195
29. Srikrishna, A.; Ramasastry, S. S. V.; Tetrahedron Lett. 2006,
47, 335; Srikrishna, A.; Dethe, D. H.; Tetrahedron Lett. 2005,
46, 3381.
21. Rodrigues deAlmeida, Q.A.; de Oliveira Pereira, M. L.; Bezerra
Coelho, R.; Martins de Carvalho, E.; Kaiser, C. R.; Jones Jr.;
J.; Martins da Silva, F.; J. Braz. Chem. Soc. 2008, 19, 894.
22. Smitt, O.; Hoegberg, H. E.; J. Chem. Res. (S) 2002, 11, 527;
Bakuzis, P.; Bakuzis, M. L. F.; J. Org. Chem. 1981, 46, 235.
23. Cohen, T.; Yu, L.-C.; J. Org. Chem. 1985, 50, 3266.
24. Nicolaou, K. C.; Groneberg, R. D.; J. Am. Chem. Soc. 1990,
112, 4085.
30. Sakagami, M.; Muratake, H.; Natsume, M.; Chem. Pharm. Bull.
1994, 42, 1393.
31. Solladié, G.; Gehrold, N.; Maignan, J.; Tetrahedron: Asymmetry
1999, 10, 2739.
32. Chiba, S.; Kitamura, M.; Narasaka, K.; J. Am. Chem. Soc. 2006,
128, 6931; Asao, N.; Lee, S.;Yamamoto, Y.; Tetrahedron Lett.
2003, 44, 4265.
33. Meulemans, T. M.; Stork, G. A.; Jansen, B. J. M.; de Groot, A.;
Tetrahedron Lett. 1998, 39, 6565.
25. Miyashita, M.; Suzuki, T.;Yoshikoshi, A.; J. Org. Chem. 1985,
50, 3377.
34. Verstejen-Haaksma, A. A.; Swarts, H. J.; Jansen, B. J. M.; de
Groot, A.; Tetrahedron 1994, 50, 10073.
26. García-Gutiérrez, J. L.; Fuentes, G. A.; Hernández-Terán, M.
E.; García, P.; Murrieta-Guevara, F.; Jiménez-Cruz, F.; Appl.
Catal., A 2008, 334, 366.
35. Sandborn, L. T.; Org. Synth. 1941, 1, 340.
36. Vashchenko, V.; Kutulya, L.; Krivoshey, A.; Synthesis 2007,
2125.
27. Srikrishna, A.; Chikkana, D.; Tetrahedron: Asymmetry 2005,
16, 2203.
Received: October 20, 2009
Web Release Date: March 4, 2010