Influence of a remote sulfinyl group on L-proline-catalyzed direct asymmetric aldol addition of acetone

Article abstract of DOI:10.1016/j.tet.2016.07.035

The addition of acetone to rac-2-methylsulfinyl-benzaldehyde, catalyzed by secondary amines (morpholine, piperidine, L-proline, L-prolinamide and (S)-(–)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether), was realized. Interesting aspects, such as 1,4-asymmetric induction by the remote sulfinyl group of the aldehyde but also the stereochemical control and kinetic resolution of the racemic substrate by the chiral organocatalyst were examined. Finally, an unexpected stereoselective retro-aldol reaction catalyzed by L-proline was pointed out.

Full text of DOI:10.1016/j.tet.2016.07.035

Accepted Manuscript
Influence of a remote sulfinyl group on l-proline-catalyzed direct asymmetric aldol
addition of acetone
Rosaria Villano, Maria Rosaria Acocella, Arrigo Scettri
PII:
S0040-4020(16)30658-5
10.1016/j.tet.2016.07.035
TET 27931
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 April 2016
Revised Date: 1 July 2016
Accepted Date: 7 July 2016
Please cite this article as: Villano R, Acocella MR, Scettri A, Influence of a remote sulfinyl group on
l-proline-catalyzed direct asymmetric aldol addition of acetone, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.07.035.
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Influence of a remote sulfinyl group on L-
proline-catalyzed direct asymmetric aldol
addition of acetone
Leave this area blank for abstract info.
Rosaria Villano*, Maria Rosaria Acocella, Arrigo Scettri
Istituto di Chimica Biomolecolare – CNR, Trav. La Crucca 3, 07100 Sassari (Italy)
OH
O
O
O
H
Rac-3
dr 84 / 16
+
S
S
Stereoselective retro-aldol addition
O
Stereoselective aldol addition
Rac-1
O
+
+
L-Pro
kinetic resolution
kinetic resolution
O
OH
*
O
OH
O
O
H
H
*
S
+
+
*
*
S
S
S
O
O
O
O
3
enantioenriched 3
dr 85 / 15
enantioenriched
dr 84 / 16
opposite configuration
-1
S
R-1

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Influence of a remote sulfinyl group on L-proline-catalyzed direct asymmetric aldol
addition of acetone
Rosaria Villanoa, , Maria Rosaria Acocellab and Arrigo Scettrib
aIstituto di Chimica Biomolecolare – CNR, Trav. La Crucca 3, 07100 Sassari - Italy
bDipartimento di Chimica e Biologia – Università di Salerno, via Ponte Don Melillo, 84084 Fisciano (Salerno) - Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
The addition of acetone to rac-2-methylsulfinyl-benzaldehyde, catalyzed by secondary amines
(morpholine, piperidine, L-proline, L-prolinamide and (S)-(–)-α,α-diphenyl-2-
Received in revised form
Accepted
Available online
pyrrolidinemethanol trimethylsilyl ether), was realized. Interesting aspects, such as 1,4-
asymmetric induction by the remote sulfinyl group of the aldehyde but also the stereochemical
control and kinetic resolution of the racemic substrate by the chiral organocatalyst were
examined. Finally, an unexpected stereoselective retro-aldol reaction catalyzed by L-proline was
pointed out.
Keywords:
Direct aldol reaction
Sulfinyl group
Proline
2009 Elsevier Ltd. All rights reserved
.
Kinetic resolution
Chirality
———
Corresponding author. Fax: +39 079 2841298; e-mail: rosaria.villano@icb.cnr.it

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2
Tetrahedron
Rather surprisingly, the use of a reduced amount of acetone
1. Introduction
resulted in a significant improvement of efficiency without any
decrease in diastereoselectivity (entries 1 and 2), while in the
presence of an excess of the catalyst up to 1.3 eq the formation of
3 occurred again in modest yield (entries 2 and 3).
The direct aldol addition is one of the most powerful methods
for the synthesis of new C-C bonds and, in this context, the
asymmetric version of the reaction is particularly intriguing as an
efficient tool for the synthesis of chiral β-hydroxyketones.1 In
recent years, notable results have been achieved in the
asymmetric direct aldol addition of acetone to aldehydes by
employing secondary amines (above all proline and its
derivatives) as organocatalysts1c,2 and it has been postulated that
this type of reaction procedeed via an enamine mechanism.2a-c,3
Although several functionalized ketones have been used as
nucleophiles with high diastereo- and enantioselectivities, the
influence of a chiral group on the aromatic aldehydes on the
reactivity is still poorly explored, despite the fact that a critical
role of the aldehyde structure has been highlighted in several
reports: in fact the best results for aliphatic aldehydes were
obtained by using α-substituted aliphatic aldehydes2a,b,4 as well
as, for aromatic aldehydes, an increase of enantioselectivity was
observed with ortho-substituents, according to their steric and
electronic properties.5 Moreover, it was found that the nature of
the solvent had a strong effect on the reaction and in particular
the best methodologies were realized in DMSO.2a,4b A density
functional study6 of the proline-catalyzed direct aldol reaction
proved that in the presence of DMSO, the barrier for the initial
complexation between proline and acetone was reduced and that
this solvent was able to stabilize the ionic charges allowing the
reaction to take place through a lower energy pathway.
Interestingly, the presence of a co-solvent like CH2Cl2
enhanced the level of diastereoselectivity (88/12 dr) but reduced
significantly the reaction rate, so that 3 could be isolated in 57%
yield only after 4 days (entries 4 and 5); a similar effect on the
reaction efficiency was also observed by performing the reaction
at 0°C and, furthermore, in this case, the final product showed a
lower diasteromeric ratio (entries 6 and 7). Finally, under the
typical conditions of entry 2 the use of piperidine as basic
catalyst did not afford satisfactory results (entry 8).
Table 1. Optimization of the reaction conditions.
Entrya
morph
oline
Acetone
(equiv)
t/T
Co-
solvent
Yield
(%)b
drc
(equiv)
In the past years 2-methylsulfinyl-benzaldehyde 1 proved to
be a valuable starting material for the synthesis of a variety of bi-
and tetradentate chiral amino- and iminosulfoxides which were
very conveniently used as activators of allyl and crotyl
trichlorosilanes in the highly stereoselective allylation of
aldehydes.7 Notably, while the beneficial effect of an electron-
withdrawing ortho-substituent on the enantioselectivity was
recently pointed out in L-proline catalyzed aldol reaction (vide
supra),5 analogous reports on the possible influence of a chiral
group situated on the aromatic nucleus are not available. Due to
these considerations, 2-methylsulfinyl-benzaldehyde 1, easily
accessible in racemic and enantiomerically enriched form,7a,8
seemed to be the ideal substrate to explore this aspect in the L-
proline catalyzed aldol addition of acetone.
1
2
3
4
5
6
7
8d
0.20
0.20
1.3
27
16
16
16
16
27
27
16
24h/rt
24h/rt
24h/rt
24h/rt
4d/rt
-
50
73
50
-
82/18
83/17
82/18
-
-
-
0.20
0.20
0.20
0.20
0.20
CH2Cl2
CH2Cl2 57
88/12
90/10
74/26
81/19
24h/0°C
4d/0°C
24h/rt
-
-
-
24
58
50
a All reactions were carried out using acetone as reagent and as solvent.
b All yields refer to isolated products.
c
1
Determined by H-NMR spectroscopy of the crude product. According to
2. Results and discussion
the stereochemical assignments in paragraph 2.2, dr was [(SS,R)-3 + (RS,S)-
3]/[(SS,S)-3 + (RS,R)-3].
d Piperidine was used instead of morpholine.
2.1. Direct aldol reaction promoted by non chiral secondary amine
In a preliminary phase, racemic substrate 1 was used as
starting material and the reaction was performed in the presence
of morpholine, as a non-chiral catalyst. The influence of some
reaction parameters (morpholine loading, acetone amount,
reaction temperature and presence of a co-solvent) on yields and
dr was investigated (Table 1).
2.2. Stereochemical assignment of chromatographic peaks
In view of the subsequent employment of a chiral catalyst, the
configuration of all the stereoisomers of the product 3 had to be
assigned. For this reason, after the resolution of the
stereoisomeric mixture of aldols 3 obtained from the experiment
in entry 2 (Table 1) by chiral-phase HPLC on a Daicel Chiralpak
AD-H column, the configurational assignments were established
by two targeted experiments. In a first experiment, the
enantioenriched aldehyde R-1 (73% ee) was submitted to direct
aldol addition of acetone in the presence of morpholine, under the
optimized conditions (Scheme 1).
As shown in Table 1, in all the experiments the formation of
the expected aldol 3 took place in rather modest efficiency, with
the exception of entry 2 where an acceptable yield was obtained.
Conversely, a good diastereoselectivity was generally observed
confirming the important role of the sulfinyl group in addressing
the stereochemical outcome.

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3
Scheme 1. Direct aldol addition of the enantioenriched aldehyde R-1
promoted by morpholine.
At the end of the reaction, the recovered unreacted aldehyde
showed the same ee of starting aldehyde 1, thus allowing the
assignment of the R configuration to the sulfinyl group (RS) of
the most abundant products. On the basis of this finding, the
stereochemistry of the sulfinyl-group could be attributed to each
chromatographic peak.
In order to assign the stereochemistry of the chiral carbon to
each peak in the chromatogram, the following strategy was
adopted (Scheme 2). We realized the stereoselective addition of
acetone to 2-(methylthio)benzaldehyde 4 promoted by L-proline
in the same experimental conditions of entry 1 in Table 1 (L-
proline instead of morpholine); the corresponding aldol 5 was
found to be R-configured, according to the sign of optical
rotation.9 A following not asymmetric sulfoxidation of the
product (tBuOOH, CSA in CHCl3 6h/rt)8 gave the aldol 3 with dr
= 58/42. The observed ee for each diastereoisomer indicated that
peak 1 and peak 4 in the chromatogram are associated to aldols 3
with R-configurated carbon (Scheme 2).
Scheme 3. Direct aldol addition of acetone to racemic aldehyde 1
promoted by chiral secondary amines.
Table 2. Direct aldol addition of acetone to racemic aldehyde 1 promoted
by chiral secondary amines.
Entry Cat (mol Acetone
t/T
Yield
(%)a
drb
eec
%)
(equiv)
O
O
HO
H
LꢀPro
(20 mol %)
O
1
2
3
4
5
6
6 (20 %)
27
24h/rt
9d/0°C
24h/rt
4d/0°C
24h/rt
3d/rt
52
50
50
42
53
51
76
24
90 (SS,R)
55 (RS,R)
H
(R)
+
S
S
ee = 76% (R)
6 (20 %)
6 (40 %)
6 (40 %)
6 (20 %)
6 (20 %)
27
27
27
16
16
79
21
93 (SS,R)
99 (RS,R)
4
2
5
79
21
91 (SS,R)
91 (RS,R)
non stereoselective
sulfoxidation
84
16
92 (SS,R)
99 (RS,R)
O
O
HO
H
HO
H
(R)
(R)
85
15
90 (SS,R)
96 (RS,R)
+
S
S
(R)
(S)
O
O
79
21
61 (SS,R)
90 (RS,R)
(Rs,R)-3
(Ss,R)-3
dr = 58/42
ee (t1) = 75%
ee (t4) = 76%
7d
8d
6 (20 %)
6 (20 %)
16
16
24h/rt
4d/rt
-
-
-
26
85
15
95 (SS,R)
91 (RS,R)
Scheme 2. An alternative synthesis of aldol 3 via a sequence of
asymmetric aldol addition and non stereoselective sulfoxidation.8
9
7 (20 %)
8 (20 %)
16
16
1h/rt
4d/rt
73
54
71
29
10 (SS,R)
20 (RS,R)
10
85
15
5 (SS,R)
8 (RS,R)
2.3. Direct aldol addition promoted by chiral secondary amines
a All yields refer to isolated products.
b Determined by 1H-NMR spectroscopy of the crude product. According to
the stereochemical assignments in paragraph 2.2, dr was [(SS,R)-3 +
(RS,S)-3]/[(SS,S)-3 + (RS,R)-3].
After having studied the direct aldol reaction promoted by non
chiral secondary amines (Table 1) and after having identified all
chromatographic peaks associated to four stereoisomers of aldol
3 (Figure 3), we evaluated the possibility to realize the reaction
by employing chiral secondary amines as catalysts (Scheme 3), in
particular L-proline 6 and its commercially available derivatives
7 and 8.
c
Determined by HPLC analysis with a chiral column (Daicel Chiralpak
AD-H).
d In this experiment CH2Cl2 was used as co-solvent.
As shown in Table 2, L-proline was able to promote the direct
aldol addition of acetone to Rac-1 at room temperature.

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4
Tetrahedron
In the first experiment, the racemic aldehyde 1 was reacted
treatment under the same optimized conditions of entry 5 (Table
2), was converted into the expected R-aldol in 49% yield (only
34% ee) and the corresponding α,β-unsaturated carbonyl
compound in 30% yield (Scheme 4).
with acetone in the presence of 20 mol % of L-proline 6 (Table 2,
entry 1). After 24 h the reaction was interrupted and H NMR
1
analysis on the crude mixture revealed the formation of aldol 3
(60% conversion) in rather modest diastereoselectivity (76/24
dr). The purification procedure afforded 3 in 52% overall yield
and, more interestingly, each diastereoisomer proved to be
enantioenriched, being respectively (SS,R)-3 (90% ee) and
(RS,R)-3 (55% ee) the most abundant products according to
HPLC analysis.
Notably, the favoured R-configuration of the newly formed
carbinolic stereocenter proved to be in agreement with the sense
of asymmetric induction produced by L-proline in analogous
aldol reactions of acetone with aromatic aldehydes.
Scheme 4. Direct aldol addition of acetone to benzaldehyde catalyzed by
L-proline.
Remarkably, L-prolinamide 7 was more active than L-proline
6, so that good conversions were observed after only 1 h (entry
9), but in this case the product 3 was isolated in very low ee.s as
(SS,R)-3 and (RS,R)-3 predominant products, once again in
agreement with the sense of asymmetric induction of L-proline in
analogous aldol additions.
Anyway, this result was interesting because it is known2a that
L-prolinamide was uneffective as catalyst in the direct aldol
addition of acetone to 4-nitrobenzaldehyde in DMSO.
Furthermore, to our surprise, the unreacted aldehyde 1 was
isolated in 39% yield as predominant R-enantiomer (57% ee).
This result could be attributed to significantly lower reactivity of
R-aldehyde compared to the S-enantiomer under the reaction
conditions. This behaviour was further confirmed by the fact that,
when the reaction in Scheme 3 was carried out using as starting
material the enantioenriched R-aldehyde 1 (ee = 73%), a drastic
reduction in reactivity and enantioselectivity was observed so
that, after 24h at rt, the aldol 3 was isolated in only 14% yield
with very low dr (52/48) and, more importantly, the ee of the
recovered aldehyde R-1 (76% yield) raised up to 88% ee.
On the other hand, the proline-derivative 8 showed a reduced
catalytic activity so that 4 days at room temperature were
required in order to isolate the aldol 3 in 54 % yield (dr = 85/15
but very low ee.s, entry 10). The poor enantioselectivity can be
explained based on the fact that a tricyclic hydrogen bonded
framework was required for enantiofacial selectivity2a and in this
case it was not realizable for the presence of a TMSO- group.
These results could be reasonably explained assuming that, in
the examined reaction and under the chosen reaction conditions,
the process of asymmetric synthesis of the new chiral centre is
combined with a process of kinetic resolution of the substrate
1.10,11
In order to improve the results in entry 1, a screening of
several experimental parameters was carried out (entries 2-8). As
well known, conversions of about 50% are desirable for
optimized processes of kinetic resolution, consequently all the
following reactions were monitored via 1H NMR analysis.
2.4. Stereochemical remarks for the L-proline catalyzed reaction
According to the literature,12 the results in Table 2 could be
reasonably explained by considering that a nucleophilic attack is
easier on the Re prochiral face of aldehydic group of S-1 than on
the Si prochiral face, which is shielded by the methyl group of
the sulfoxide (Figure 1). The nucleophilic attack of the enamine
on the Re prochiral face would lead to the formation of a R
stereogenic center. Of course, a specular behaviour was expected
for the aldehyde R-1.
Analogously to morpholine-mediated methodology, a lower
temperature (0°C) resulted in a dramatic reduction of reaction
rate (entry 2): in fact, 9 days were required to obtain 3 in 50%
isolated yield (79/21 dr) while, more importantly, a very
significant enhancement of enantioselectivity (up to 99%) was
found for the less abundant diastereoisomer and, also in this case,
the unreacted aldehyde was enriched in R-enantiomer (82 % ee).
An improved stereoselectivity was observed by using 40 mol
% of catalyst at 0°C (entry 4) since, after 4 days, the aldol 3 was
isolated in 42% yield (84/16 dr) and, respectively, 92% and 99%
ee for two stereoisomeric aldols 3 while the unreacted aldehyde 1
was isolated in 50% yield (58% ee, R predominant enantiomer).
With respect to entry 1 the reduction of acetone amount again
showed to have a beneficial effect (entry 5), although it is known
from the literature that high concentrations of acetone are
required in order to suppress side reactions between aldehyde and
amine.2a
Figure 1. The Re prochiral face of CHO group of S-1 can more easily
undergo a nucleophilic attach with respect to the Si prochiral face.
On the other hand, prolonged reaction times had a negative
effect on selectivity (entry 6) tentatively explained by a partial
equilibration of products via a stereoselective retroaldol reaction,
without any significant increase in yields. This aspect was
specifically investigated in the last paragraph of this work by
carrying out targeted experiments.
On the other hand, such as reported in the literature2 and
confirmed by the experiment in Scheme 4, the direct aldol
addition of acetone to benzaldehyde (or substituted
benzaldehydes) promoted by L-proline fostered the formation of
R-aldol according to a preferential Re-enantiofacial attack on the
aldehyde: so, with L-proline and S-aldehyde 1, configurational
A parallel experiment confirmed the determining role played by
the sulfinyl group in some aspects of the direct aldol addition of
acetone to 1. In fact benzaldehyde, submitted to the usual

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5
and conformational conditions can be transmitted favorably
(“matched”) in the product formation.
In light of the above, it was likely that the results reported in
Table 2 are due to more aspects: a) the asymmetric induction of
the chiral organocatalyst, b) the 1,4-induction of a remote
sulfinyl group and c) a kinetic resolution of the initial racemic
substrate.
In order to account for the observed stereochemical results,
four different transition states could be proposed (Figure 2).
Scheme 5. Direct aldol reaction of the racemic aldehyde 1 catalyzed by
L-proline.
2.5. Retro-aldol addition promoted by L-Proline
It is known that most of the catalysts that are useful in
asymmetric aldol additions are not able to promote
a
stereoselective retro-aldol reaction. Until now, only complexes of
transition metals,13 antibody aldolases14 and some chiral amines15
have been reported to catalyze a stereoselective retro-addition
differently from proline and its derivatives, which were only
involved in non-selective processes.2b
During our studies about the asymmetric aldol addition of
acetone to the aldehyde 1 catalyzed by L-proline, we observed a
drastic reduction of diastereoselectivities and enantioselectivities
by prolonging reaction times (compare entries 5 and 6, Table 2).
This behaviour could be attributed to a mixture equilibration via
a stereoselective retro-aldol process.
So, at the end of this work, we decided to test the behaviour of
L-proline as organocatalyst in the retro-aldol reaction of the aldol
Rac-3, chosen as model substrate (Scheme 6).
Figure 2. Proposed transition states: a) Re-enantiofacial attack on the S-
aldehyde 1 (synthesis of (SS,R)-3); b) Si-enantiofacial attack on the S-
aldehyde 1 (synthesis of (SS,S)-3); c) Re-enantiofacial attack on the R-
aldehyde 1 (synthesis of (RS,R)-3); d) Si-enantiofacial attack on the R-
aldehyde 1 (synthesis of (RS,S)-3).
OH
O
S
Rac-3 (dr = 84 / 16)
O
LꢀPro (20 mol %)
CDCl3, 5 d / rt
As shown in Figure 2, the attack on the aldehydic Si-face
(transition states (b) and (d)) would result in unfavorable steric
interactions among the aromatic ring, the pyrrolidine system and
the methyl group because of the axial position of both Ar and Me
groups. These stereochemical considerations explain why, in the
most abundant diastereoisomer, the predominant stereoisomer is
(SS,R)-3, instead in the other one, (RS,R)-3 is prevalent (Scheme
5).
O
OH
O
OH
O
H
H
O
(S)
(S)
H
+
+
+
S
S
S
(R)
(S)
(S)
2
O
O
O
S-1
(Rs,S)-3
(Ss,S)-3
Yield: 34 %
ee: 74 % (S)
Yield: 60 %
dr: 84 / 16
ee = 14 % (SS,S)
ee = 62 % (RS,S)
Scheme 6. Retro-aldol addition promoted by L-proline.

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6
Tetrahedron
1
A control of the reaction mixture by H-NMR spectroscopy
pointed out how the reaction in CDCl3 was slow. After 5 days at
room temperature, remarkably, diastereoselectivity of recovered
aldol 3 remained unchanged but each diastereoisomer was
enantioenriched. Moreover, the aldehyde produced by the retro-
aldol reaction (yield = 34 %) had an ee of 74 % in S-enantiomer.
These results could be explained by considering the
mechanism for the retro-aldol reaction catalyzed by L-proline
(Scheme 7).
As shown in Scheme 7, the realization of transition states type
A is favored compared to transition states type B (with Ar and
Me groups in axial positions).
Figure 3. Proposed mechanism for the retro-aldol reaction of each
stereoisomer 3 promoted by L-proline.
Scheme 7. Proposed mechanism for the retro-aldol reaction of rac-3
promoted by L-proline.
3. Conclusions
A favored transition state A can be observed with aldols
(SS,R)-3 and (RS,R)-3, instead a disfavored transition state B can
be realized with aldols (SS,S)-3 and (RS,S)-3 (Figure 3).
We have found that the sulfinyl group was able to control the
stereoselectivity during the nucleophilic addition of acetone
catalyzed by secondary amines, via 1,4-asymmetric induction
(remote stereocontrol). Moreover, L-proline was able to catalyze
the stereoselective processes by a chiral induction but it was also
able to differentiate between two enantiomers of the racemic
aldehyde.
In the light of the above, it seemed rational that the
decomposition of the aldols (SS,R)-3 and (RS,R)-3 should be
favored compared to decomposition of the aldols (SS,S)-3 and
(RS,S)-3.
From an experimental point of view, the chiral-phase HPLC
analysis of unreacted aldol 3 showed that the most abundant
diastereoisomer was enriched in (RS,S)-3, whereas the other one
was enriched in (SS,S)-3, according to our hypothesis.
Finally, an unexpected stereoselective retro-aldol reaction
catalyzed by L-proline was identified and this aspect was
particularly interesting. In fact, the slow retro-aldol reaction
could explain why the observed ee.s were reduced by prolonging
reaction times of direct aldol addition. Moreover, in this study it
was pointed out as a single enantiomer of catalyst (L-proline)
was able to produce aldols 3 enantiomerically enriched in
stereoisomers of opposite configurations, depending on the use of
L-proline as catalyst for the direct aldol addition or for the
reverse retro-aldol reaction. In other words, it was possible to
revert the predominant absolute configurations of the products 3
without changing the source of chirality (L-proline). Further
explorations on the retro-aldol reaction with particular attention
to experimental conditions are in progress.
Moreover, with the aldol (SS,R)-3 a sterically less hindered
transition state A was realized compared to the situation with the
aldol (RS,R)-3; this consideration is consistent with the
experimental data and in fact, at the end of the reaction, the
isolated aldehyde was enantiomerically enriched in S-
stereoisomer.
4. Experimental section
4.1. Methods and Characterization

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7
TLC was performed on Merck Kiesegel 60 F 254 plates and
visualized by a 254 nm UV lamp. Column chromatographic
purification of products was carried out using silica gel 60 (70–
230 mesh, Merck). All reagents (Aldrich and Fluka) were used
without further purification. NMR spectra were recorded on a
removed under N2 and the concentrated mixture was purified by
SiO2 flash chromatography employing n-Hexane/EtOAc (8:2) as
eluent to provide the R-configured compound 5 (0.076 mmol,
yield: 61 %).
A solution of aldol 5 (0.076 mmol, 1.0 equiv) in CHCl3 (0.40
mL) was prepared, then CSA (0.008 mmol, 0.10 equiv) and 27.6
ꢁL of a solution 5.5M of tBuOOH in nonane were added. The
mixture was stirred for 6 h at room temperature. After this time,
the mixture was directly loaded to silica gel column employing n-
Hexane/EtOAc (1:1) as eluent to provide the desired compound 3
(dr=58/42; ee= 75% ((SS,R)-3) and ee= 76% ((RS,R)-3).
1
Varian 400 spectrometer by using CDCl3 (δ=7.26 ppm in H
NMR spectra and δ=77.0 ppm in 13C NMR spectra) as solvent
1
(400.135 MHz for H and 100.03 MHz for 13C); mass spectral
data are reported in the form of m/z. Infrared spectra were
recorded on a Bruker 22 series FT-IR spectrometer. HPLC
analysis were performed with Waters Associates equipment
(Waters 2487 Dual
λ
absorbance
Detector) using a
CHIRALPAK AD-H or Chiralcel OB column with mixtures and
flow rate as indicated. The spectroscopic data of compounds 17a
and 59 matched the ones reported in the literature.
4.5. Typical procedure for the retro-aldol reaction (Scheme 6)
A solution of racemic aldol Rac-3 (0.060 mmol, 1.0 equiv, dr
84/16) in CDCl3 (0.40 mL) was prepared and L-proline (0.012
mmol, 0.20 equiv) was added. After 5 days at room temperature
the formation of the aldehyde 1 was evident (TLC and 1H-NMR)
so the mixture was directly loaded to silica gel column
employing n-Hexane/EtOAc (1:1) as eluent to provide the
aldehyde 1 in 34 % of yield and ee of 74 % (S).
4.2. Typical procedure for the aldol addition (Table 1, entry 2)
To a solution of racemic 2-methylsulfinyl-benzaldehyde 1
(0.125 mmol, 1.0 equiv) in acetone (16 equiv), morpholine
(0.025 mmol, 0.20 equiv) was added. The mixture was stirred for
24 h at room temperature, then acetone was removed under N2
and the concentrated mixture was purified by SiO2 flash
chromatography employing n-Hexane/EtOAc (1:1) as eluent to
provide the desired racemic compound 3.
Acknowledgements
We are grateful to MIUR and University of Salerno for
financial support.
4-hydroxy-4-(2-(methylsulfinyl)phenyl)butan-2-one (Rac-3):
light yellow oil; yield: 73 % (20.6 mg). dr = 83/17. H-NMR δ
1
(ppm) 2.22 (s, 3H, major diastereomer), 2.26 (s, 3H, minor
diastereomer), 2.80 (dd, 1H, J = 18.0 Hz, J = 2.4 Hz, major
diastereomer), 2.98-3.01 m (m, 2H, minor diastereomer), 3.26
(dd, 1H, J = 18.0 Hz, J = 10.4 Hz, major diastereomer), 5.33 (dd,
1H, J = 10.4 Hz, J = 2.4 Hz, major diastereomer), 5.38 (dd, 1H, J
= 9.2 Hz, J = 2.8 Hz, minor diastereomer), 7.28-7.57 (m, 3H,
major diastereomer + minor diastereomer), 8.01 (bd, 1H, J = 7.2
Hz, minor diastereomer), 8.17 (bd, 1H, J = 8.0 Hz, major
diastereomer). 13C-NMR δ (ppm) 30.6 (major diastereomer), 30.7
(minor diastereomer), 44.0 (minor diastereomer), 44.5 (major
diastereomer), 49.7 (minor diastereomer), 50.3 (major
diastereomer), 65.3 (minor diastereomer), 70.0 (major
diastereomer), 123.6 (minor diastereomer), 124.2 (major
diastereomer), 125.9 (minor diastereomer), 127.0 (major
diastereomer), 129.3 (major diastereomer), 129.4 (minor
diastereomer), 131.0 (major diastereomer), 131.3 (minor
diastereomer), 139.5, 145.0, 208.9 (minor diastereomer), 209.0
(major diastereomer). HRMS (ESI) calcd for C11H15O3S [M+H]+
227.0736, found: 227.0725. IR νmax (liquid film) 3081, 1720,
1602, 1080, 1012 cm-1. The enantiomeric excess was determined
by chiral HPLC (Chiralpak AD-H, hexane/2-propanol 9:1, 0.7
mL/min, 220 nm, t1 = 17.7 min for (SS,R)-3 stereoisomer, t2 =
21.6 min for (RS,S)-3 stereoisomer, t3 = 24.7 min for (SS,S)-3
stereoisomer, t4 = 31.3 min for (RS,R)-3 stereoisomer).
References and notes
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To a solution of racemic 2-methylsulfinyl-benzaldehyde 1
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