Asymmetric phase-transfer catalytic sulfanylation of some 2-methylsulfinyl cyclanones. Modeling of the stereochemical course of the aldol reaction of (SS,2S)-2-methylsulfinyl-2-methylsulfanylcyclohexanone

Article abstract of DOI:10.1016/j.tetlet.2010.08.010

Increased diastereoisomeric excesses are obtained for the sulfanylation reactions of some 2-methylsulfinyl cyclanones under phase-transfer catalysis using the chiral catalyst QUIBEC instead of TEBA. The optically pure (SS,2S)-2-methylsulfinyl-2-methylsulf

Full text of DOI:10.1016/j.tetlet.2010.08.010

Tetrahedron Letters 51 (2010) 5344–5348
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Tetrahedron Letters
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Asymmetric phase-transfer catalytic sulfanylation of some 2-methylsulfinyl
cyclanones. Modeling of the stereochemical course of the aldol reaction
of (SS,2S)-2-methylsulfinyl-2-methylsulfanylcyclohexanone
⇑
Alessandro Rodrigues, Blanka Wladislaw , Claudio Di Vitta, José Eduardo Pandini Cardoso Filho,
Liliana Marzorati, Mauro Alves Bueno, Paulo Roberto Olivato
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP CEP 05508-000, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Increased diastereoisomeric excesses are obtained for the sulfanylation reactions of some 2-methylsulfi-
nyl cyclanones under phase-transfer catalysis using the chiral catalyst QUIBEC instead of TEBA. The opti-
cally pure (SS,2S)-2-methylsulfinyl-2-methylsulfanylcyclohexanone thus prepared reacts with ethyl
acetate lithium enolate affording, after hydrolysis, (R)-2-[(ethoxycarbonyl)methyl]-2-hydroxycyclohexa-
none in 60% ee. Density functional theory calculations (at the B3LYP/6-311++G(d,p) level) can success-
fully explain the origin of this result as the kinetically favored axial attack of the nucleophile to the
Received 5 July 2010
Accepted 4 August 2010
Available online 9 August 2010
Keywords:
Asymmetric phase-transfer catalysis
Aldol reaction
carbonyl group of the most stable conformer of the cyclanone, in which the CH
are at the equatorial and axial positions, respectively.
3 3
SO and CH S groups
Density functional theory calculations
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
O
O
S
S
O
O
S
RSSO CH
2
3
Although the sulfinyl group has been used as chiral auxiliary in
K2CO3
CH3
R
CH3
X
aldol reactions, most examples are confined to the presence of this
group in the nucleophilic species. Only two examples of such reac-
tions using electrophiles bearing the sulfinyl moiety are reported in
TEBA
X
CH2
1
r.t.
CH2
a-c
2a-c R = CH3;
2c' R = p-Tol
1
2
2a
the literature. Ruano et al. studied the addition of lithium ester
enolates to 2-tolylsulfinylcyclohexanones and concluded that the
observed 1,2-asymmetric induction resulted from nucleophilic at-
tack at the carbonyl group via an equatorial approach, forming a
stable tricoordinated lithium species, with the sulfinyl moiety lying
in an equatorial position. However, no rationalization was pre-
sented to explain the stereochemical course of the addition of ethyl
acetate lithium enolate to the 2-alkylsulfanyl-, or 2-p-tolylsulfanyl-
X= -(CH ) -: (a);
(b);
-(CH2)3-: (c)
2
2
Scheme 1. PTC sulfanylation of (±)-2-methylsulfinyl cyclanones 1a–c.
*
*
the determination of its (SS ,2S ) relative configuration. This com-
pound, in its optically pure form, would be of great importance for
the elucidation of the role of the thioketal S-oxide carbon in the
mentioned aldolic 1,2-asymmetric induction process.
The sulfanylation of (±)-2-methylsulfinylcyclanones 1a and 1b
by the previously reported PTC procedure furnished compounds
2
-p-tolylsulfinylcyclohexanones, due to the instability of such
2
b
p-tolylsulfinyl derivatives.
3
2
. Results and discussion
In a previous communication from this laboratory, we reported
(
±)-2a and (±)-2b in 100% and 70% de, respectively. However, in
3
the case of sulfanylation of 1c, the obtained de (20%) for 2c made
this method unsuitable for the preparation of the corresponding
optically pure compound. Previous results from this laboratory4
concerning the PTC sulfanylation of open chain b-ketosulfoxides
indicated that de could be obtained by using QUIBEC instead of
TEBA. This fact prompted us to perform the sulfanylation of
the sulfanylation of some 2-methylsulfinyl cyclanones by the PTC
method, employing as catalyst triethylbenzylammonium chloride
,5
(
(
TEBA) (Scheme 1). In the case of 2-methylsulfinylcyclohexanone
1c), the methylsulfanylated product (2c) proved to be a stable
compound, in contrast to the p-tolylsulfinyl derivative, allowing
(
±)-2-methylsulfinyl-cyclanones 1a–c using chiral catalysts.
When the chiral catalyst A (QUIBEC; see Fig. 1) was substituted
0
⇑
Corresponding author. Tel.: +55 11 3091 2167; fax: +55 11 3815 5579.
E-mail address: bwlad@iq.usp.br (B. Wladislaw).
for TEBA, 2b,c and 2c were obtained in increased de (see Table 1).
However, no improvements in yield or in de for 2c were observed
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.010

A. Rodrigues et al. / Tetrahedron Letters 51 (2010) 5344–5348
5345
was subsequently hydrolyzed, yielding (ꢀ)-2-[(ethoxycarbonyl)-
methyl]-2-hydroxycyclohexanone ((ꢀ)-5) in 76% overall yield
(ee = 60% by chiral GC) (Scheme 3). The R absolute configuration
for the major enantiomer of this product could be assigned by
comparison of the optical rotation value with the previously
R''
N
N+
R'
2
b
OR
reported one.
Assuming the chelation model proposed by Ruano et al.2a for
the addition of ester enolates to 2-tolylsulfinylcyclohexanones,
the nucleophilic axial and equatorial attacks on (ꢀ)-2c would lead
to chelates D and E, respectively (Fig. 2).
This rationalization seems to be unsuitable for explaining our
results, because: (i) chelate D should be more difficult to form
A: (QUIBEC): R= H; R'= Ph; R"= OMe
B: R=H; R'= 9-Anthracenyl; R"= H
C: R=Bn; R'= 9-Anthracenyl; R"= H
Figure 1. Chiral phase-transfer catalysts.
2 2
due to steric destabilizing 1,3-interactions between the CH CO Et
and methylsulfinyl groups; (ii) the more stable chelate E, once
formed, would lead to (+)-5 of S configuration at the newly formed
stereogenic center, which is contrary to our observation.
Table 1
PTC sulfanylation of some (±)-2-methylsulfinyl cyclanones 1a–c
Compound
Sulfanylated product
Catalyst
TEBA de (yield; %)
In our opinion, conformational investigations on the axial/equa-
torial equilibrium of disubstituted cyclohexanone (ꢀ)-2c (Scheme
A de (yield; %)
4), and the influence of steric and electronic effects on the confor-
1
1
1
1
a
b
c
c
2a
2b
2c
100 (80)
70 (85)
20 (75)
40 (93)
100 (75)
80 (84)
mational flexibility properties are essential to rationalize the ste-
reocontrol of the aldol addition reaction. Thus, an experimental
and theoretical conformational analysis of (ꢀ)-2c was performed.
Carbonyl compounds are excellent targets for conformational anal-
a,b
70 (93)
0
2c
74 (84)
a
For catalyst B: de = 70% (yield 89%).
For catalyst C: de = 30% (yield 65%).
b
10
ysis purposes by means of infrared spectroscopy as the key tool.
Therefore, IR spectra for compound (ꢀ)-2c were registered in a
range of different polarity solvents. Table 2 presents the stretching
frequencies and the absorbance percentage of the analytically re-
solved carbonyl bands of compound (ꢀ)-2c. In all cases a doublet
of ca. 80:20 relative intensity in favor of the higher frequency com-
ponent was observed.
C H
6
5
O
O
S
O
O
S
N
1
) LDA
K CO3
2
CH3
CH3 QUIBEC
2
) (S,S)-MeSO2DAG
SCH3
MeSSO2Me
Aiming to attribute each component of the observed doublet to
the representative conformations of (ꢀ)-2c, a density functional
theory (DFT) calculation was performed. Thorough geometry opti-
mization and frequency calculations resulted in the three more sta-
3
(S,S)-1c
(SS,2S)-2c
2
5
[
α]D
- 210
Scheme 2. Synthesis of enantiomerically pure (SS,2S)-2-methylsulfinyl-2-
methylsulfanylcyclohexanone.
ble conformations I–III which present
DEgas values lower than
2
.0 kcal/mol. (Fig. 3). The sulfinyl group adopted geometry, as well
when catalyst B was employed. In contrast, a lower de was ob-
served for the reaction performed in the presence of catalyst C
bearing an alkylated oxygen. This result reinforces the importance
of hydrogen-bond formation between the OH group of the catalyst
and both enolate and sulfinyl oxygens.5
O
S
O
CH3
Having improved the diastereoselectivity of the sulfanylation
reaction, we turned our attention to the enantiomerically pure
SCH3
-)-(2S,SS)-2c
(
2
-methylsulfinylcyclohexanone (1c) which, after sulfanylation,
LiCH CO Et
2
2
would provide the new stereogenic center of known absolute con-
figuration. Compound 1c, of SS configuration was obtained in 75%
yield as a mixture of epimers (7:3), starting from cyclohexylideni-
OC H
Li
2
5
6
,7
O
O
mine (3) and employing 1,2:5,6-di-O-isopropylidene-
a
-
D
-gluco-
O
H C
O
2
8
,9
CH3
furanosyl (ꢀ)-(SS)-methane-sulfinate ((SS)-MeSO
2
-DAG)
as
Li
OC H
2 5
O
S
chiral sulfinylating agent. The sulfanylation of SS-1c by the PTC
method, employing as the catalyst QUIBEC, afforded (ꢀ)-(SS,2S)-
S
O
CH3
H CS
SCH3
(1S,2S,SS)-E
3
2
c as the major diastereoisomer, isolated in 56% yield and
(
1R,2S,SS)-D
(
+)-(SS,2R)-2c in 14% yield (Scheme 2).
With (ꢀ)-2c in hand, this compound was submitted to the
Figure 2. Possible chelates formed by attack of lithium ethyl acetate enolate at the
two faces of the carbonyl group of (ꢀ)-2c.
reaction with ethyl acetate lithium enolate. The crude product 4
CO Et
O
O
S
S
2
O
HO
O
S
OH
NBS
LiCH CO Et
CH3
2
2
CO Et
2
CH3
S
CH3
H O/acetone
2
CH3
(
SS,2S)-2c
5; ee=60%
4
Scheme 3. Aldol reaction of (ꢀ)-2c followed by hydrolysis.

5
346
A. Rodrigues et al. / Tetrahedron Letters 51 (2010) 5344–5348
dꢀ
dþ
O
ꢁ ꢁ ꢁ S
electrostatic interaction (3.188 Å, as depicted in
ðsoÞ
ðcoÞ
Fig. 3) arises in lieu of the attractive interaction observed in con-
formers I and II. In brief, it is quite reasonable to associate con-
formers I and II to the more intense component of the carbonyl
doublet, and the less intense one to conformer III. The computed
carbonyl frequencies for conformers I–III are practically coincident
within ca. 3 cm . However, from previous results on b-ketosulf-
oxide, it is well established that the higher carbonyl frequency
component, in solution, should correspond to the more-populated
equatorial conformers I and II, while the lower frequency compo-
nent to the less-populated axial conformer III.
Scheme 4. Axial/equatorial equilibrium of (SS,2S)-2-methylsulfinyl-2-methylsulfa-
nylcyclohexanone ((ꢀ)-2c).
ꢀ1
11
Table 2
co; cmꢀ1) and intensities (P; in % of absorbance) for the carbonyl
m
Frequencies (
stretching bands in the IR spectra of (ꢀ)-2c
Once having established the most important conformations for
compound (ꢀ)-2c, we decided to investigate the origins of the
asymmetric induction on the aldol reaction using DFT method
and to propose a mechanistic model that would account for our re-
sults. Having in mind that the aldol addition to I and II would lead
to the same stereochemical result, we considered only conformers
I and III. The B3LYP/6-311++G(d,p) transition-state structures were
obtained by full optimization without constraints, and are pre-
sented along with their relative energies in Figure 4.
n-Hexane CCl CHCl
4
3
CH
2
Cl
2
3
CH CN
m
CO
P
m
CO
P
m
CO
P
m
CO
P
m
CO
P
1
1
713
697
81
19
1710
1689
85
15
1706
1682
84
16
1705
1679
80
20
1705
1679
77
23
as the relative energy (DEgas), and free energy (DGgas) calculated at
the B3LYP/6-311++G(d,p) level, and population (P) for each con-
former are presented in Table 3.
The first step for the attack of lithium enolate to the carbonyl
group of cyclohexanone (ꢀ)-2c is the formation of a reactant-like
complex precursor followed by the positioning of the lithium cat-
ion from the enolate next to the oxygen atom of the carbonyl group
of the cyclohexanone, resulting in distorted half-chair six-member
ring-transition states. In all cases, the lithium cation plays a funda-
mental role by forming a bis-coordinate transition-state complex,
Conformers I and II bearing the sulfinyl group in equatorial, and
the sulfanyl group in the axial positions are stabilized by a very
short intramolecular contact (ca. 2.947 Å) between the negative
carbonyl oxygen and the positively charged sulfur atom of sulfinyl
dꢀ
dþ
group, resulting in strong O ꢁ ꢁ ꢁ S
electrostatic and charge
ðcoÞ
ðsoÞ
transfer interactions as depicted in Figure 3. These intramolecular
attractive interactions have been considered as the key behavior
governing the relative stability of conformers of b-ketosulfoxide
2
a
as previously proposed. Calculations for the aldol reaction involv-
ing the addition to both faces of conformers I and III resulted in
four TS potential structures (Fig. 4). As for conformer I, the
computed free energies relative to reactants were 7.83 for the axial
attack (TS-I-ax) and 10.04 kcal/mol for the equatorial attack
1
1
and related compounds.
As for conformer III the sulfinyl group lies in the axial position
and the sulfanyl in the equatorial one. In this geometry an
Figure 3. Selected minimum energy conformations for (ꢀ)-2c at the B3LYP/6-311++G(d,p) level.

A. Rodrigues et al. / Tetrahedron Letters 51 (2010) 5344–5348
5347
Table 3
Dihedral angles,a relative energy (
level
D
E
gp),b relative free energy (
D
G
gp)b and populations (P)c for the most stable conformers of (ꢀ)-2c, as characterized at the B3LYP/6-311++G(d,p)
1
α = O -C -C -S
4
1
2
3
O
2
3
5
β
=
C2-C3-S4-O5
γ = C -C -S -C
4
O
6
CH3
S
2
3
4
6
δ = O -C -C -S
8
S
1
2
3
7
7
ω = C -C -S -C
H C
2 3 7 8
3
Conformer
SOCH
3
position
a
b
c
d
x
D
E
gp
D
G
gp
P
I
II
III
eq
eq
ax
16.6
27.8
102.9
178.1
170.9
52.7
ꢀ71.7
ꢀ79.1
163.2
ꢀ106.3
ꢀ98.7
ꢀ13.2
ꢀ164.0
29.6
52.2
0
1.5
1.8
0
1.5
1.6
87.4
7.1
5.5
a
b
c
In degrees.
In kcal/mol, in the gas phase.
In %.
O SOMe
C
MeS(O) O
MeS
or
C
Nu
Nu
MeS
axial addition to I
equatorial addition to I
MeS O
O SMe
or
SOMe
C
C
Nu
Nu
SOMe
axial addition to III equatorial addition to III
Figure 5. Staggered transition-state representations for nucleophilic attack on to
conformers I and III.
agreement with the obtained enantiomeric ratio for compound 5
(
80:20 in THF; ꢀ78 °C).
Figure 4. Optimized TSs geometries for the reaction of ethyl acetate lithium enolate
to (ꢀ)-2c. Selected distances are in Å. Free energies relative to reactants in the gas
phase (in parentheses) are in kcal/mol. The hydrogen atoms were omitted for
clarity.
3
. Conclusion
The use of chiral catalysts A and B instead of TEBA increased the
diastereoselectivity of the sulfanylation reaction of 1b,c. DFT calcu-
lations at the B3LYP/6-311++G(d,p) level suggest that the kineti-
cally favored axial attack to the most stable conformer I of
(
TS-I-eq), respectively, indicating the preference of axial addition
(
(
SS,2S)-2c is responsible for the observed enantiomeric excess of
ꢀ)-5. Further studies on the full scope of these reactions are in
as compared to the equatorial pathway. In the case of conformer
III, axial attack (TS-III-ax) is also predominant (8.30 kcal/mol ver-
sus 14.03 kcal/mol for TS-III-eq). Therefore, it may be concluded
that the best direction for the nucleophilic addition to the carbonyl
carbon atom is anti to the axial substituent in both conformers I
and III (see Fig. 5). The lowest energy structures for the formation
progress and will be reported in due course.
Acknowledgments
We acknowledge CNPq (for Grants B.W. and P.R.O.) and FAPESP
for the financial support. We also thank Professor F. H. Quina for
revising the manuscript and Dr. L. H. de Andrade for ee determina-
tions. The LCCA-Laboratory of Advanced Scientific Computation of
the University of São Paulo is acknowledged for access to
resources.
of diastereomers 4 are those in which /
1
is ꢀ176.7° for the axial
addition to I, and 173.1° for the axial addition to III, respectively.
This diastereofacial selectivity can also be predicted by the Fel-
kin–Anh model for which, in this particular case, the TS is stabi-
3
lized by the presence of the antiperiplanar CH S group, and is
able to delocalize the nucleophile electron density into the anti-
ꢂ
12
bonding
r
orbital.
cꢀs
The computed free activation energy barriers for the addition
reaction suggests that re addition to (ꢀ)-2c should be favored, giv-
ing 4 in a 76:24 diastereomeric ratio, according to the calculated
Boltzmann distribution (gas phase; ꢀ78 °C), which is in very good
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.010.

5
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A. Rodrigues et al. / Tetrahedron Letters 51 (2010) 5344–5348
7.
Carrñeo, M. C.; García Ruano, J. L.; Pedregal, C.; Rubio, A. J. Chem. Soc., Perkin
Trans. 1 1989, 1335–1337.
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