Chitosan aerogel beads as a heterogeneous organocatalyst for the asymmetric aldol reaction in the presence of water: An assessment of the effect of additives

Article abstract of DOI:10.1002/ejoc.201201187

The catalytic properties of chitosan aerogel for the direct asymmetric aldol reaction in water assisted by various surfactants and acid co-catalysts have been evaluated by employing a range of donor and acceptor systems. A beneficial effect on both the yi

Full text of DOI:10.1002/ejoc.201201187

FULL PAPER
DOI: 10.1002/ejoc.201201187
Chitosan Aerogel Beads as a Heterogeneous Organocatalyst for the
Asymmetric Aldol Reaction in the Presence of Water: An Assessment of the
Effect of Additives
Claudio Gioia,[a] Alfredo Ricci,*[a] Luca Bernardi,[a] Khadidja Bourahla,[b]
Nathalie Tanchoux,[b] Mike Robitzer,[b] and Françoise Quignard*[b]
Keywords: Aldol reactions / Biopolymer / Organocatalysis / Green chemistry / Water chemistry
The catalytic properties of chitosan aerogel for the direct
asymmetric aldol reaction in water assisted by various surfac-
tants and acid co-catalysts have been evaluated by em-
ploying a range of donor and acceptor systems. A beneficial
effect on both the yields and enantioselectivities was ob-
served, and the combination of surfactants and acid co-cata-
lysts has proven particularly useful in the case of heterocyclic
ketone donors.
Introduction
Catalytic transformations involving “organocatalysts”
have attracted considerable interest in recent years.[1] The
advantages, such as the ready separation of products and
the reusability of catalysts, which are very important in
large-scale production, has recently led to the development
of strategies involving the functionalization of both inor-
ganic and polymeric supports with organic catalysts.[2] On
the other hand, the emphasis on environmentally friendly
and sustainable resources and processes is leading to an in-
creasing use of natural materials in catalysis.[3] Biopolymers,
a diverse and versatile class of materials that are cheap and
widely abundant in Nature,[4] have therefore attracted in re-
cent years great interest as supports for catalysts.[5] Among
polysaccharides, chitosan (Figure 1), produced by the alka-
line deacetylation of chitin, the most abundant biopolymer
in Nature after cellulose, is a widely used support for cata-
lytic applications.[6] In this context, the chiral organic cata-
lyst l-proline was recently supported on chitosan and was
successful in promoting a heterogeneous asymmetric aldol
reaction in various organic solvents and in the presence of
water.[7]
Figure 1. Chitosan monomer.
Although chitosan is a chiral polyamine, its direct use in
heterogeneous organocatalysis has been the subject of only
a limited number of investigations. Chitosan microspheres
have been used as a green catalyst in the synthesis of mono-
glyceride by the addition of fatty acid to glycidol,[8,9]
whereas chitosan hydrogels have found applications in aldol
and Knoevenagel reactions.[10] Very recently, a comprehen-
sive assessment has been made of the efficiency of chitosan
beads as recyclable and heterogeneous organocatalysts for
a variety of C–C bond-forming reactions.[11] However, no
significant induction of stereoselectivity caused by the
backbone chirality of the chitosan polymer was noted in
any of these reports.
As a part of our current interest in organocatalysed
asymmetric reactions,[12] we recently succeeded in de-
veloping the first direct asymmetric aldol reaction in the
presence of water catalysed by chemically unmodified chito-
san, thus demonstrating that this biopolymer-derived mate-
rial is efficient not only as a heterogeneous recyclable or-
ganocatalyst, but also as a source of chirality.[13] Chitosan
aerogel microspheres[14] were preferred over commercial
chitosan or hydrogel chitosan. The aerogel formulation of
chitosan gives a well-characterized material with a defined
molecular weight distribution, (high) surface area and
(high) accessibility to the amine function. This guarantees
a better reproducibility compared with commercial chito-
san, the molecular weight and composition of which are
dependent on the natural source, and even a slightly better
catalytic efficiency compared with hydrogel chitosan.[13] In
[a] Department of Organic Chemistry “A. Mangini”, University of
Bologna,
V. Risorgimento 4, 40136 Bologna, Italy
Fax: +39-051-2093654
E-mail: alfredomarco.ricci@unibo.it
Homepage: www.industrial-chemistry.unibo.it/en/research/
organic-chemistry
[b] Institut Charles Gerhardt-Montpellier, Matériaux Avancés
pour la Catalyse et la Santé, UMR5253 CNRS-ENSCM-UM2-
UM1,
8 rue de l’Ecole Normale, 34296 Montpellier, France
Fax: +33-4-67163470
E-mail: quignard@enscm.fr
Homepage: www.macs.icgm.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201187.
588
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Asymmetric Aldol Reactions
addition, the solid, spongy morphology of the chitosan aer- nitrobenzaldehyde as aldol acceptor and cyclohexanone as
ogel microsphere allowed for easier handling compared pro-nucleophile (Table 1). Several organic solvents, such as
with its hydrogel formulation and facilitated filtration for DMSO and THF, were screened, but very little or no aldol
recycling.
product was detected (Entries 1 and 2), and the same out-
Herein, we report a thorough investigation of the role of come was observed (Entry 3) when the reaction was per-
different kinds of additives on the chemical and stereo- formed in neat cyclohexanone. Conversely, the reaction per-
chemical outcomes of the aldol reaction catalysed by chito- formed with water as the bulk medium[15] turned out to be
san aerogel microspheres, ultimately resulting in a remark- successful, no substantial variations being noticed on vary-
able improvement in both reaction scope and efficiency.
ing the amount of water within the range of 0.3 and 0.5 mL
(compare Entries 4 and 5).
To expand the scope of the reaction beyond the acceptor
Results and Discussion
systems previously studied,[13] a series of acceptor aldehydes
An intriguing aspect of the use of the chitosan aerogel were examined under the conditions optimized with cyclo-
as an organocatalyst is related to its efficacy in the interac- hexanone as the ketone donor. As shown in Table 1, not
tion of donor and acceptor systems in the absence or pres- only aromatic and heteroaromatic aldehydes (Entries 5–7),
ence of water. This aspect being closely related to the con- but also variously structured acceptor systems (Entries 9–
struction of the optimal reaction medium, we performed a 11) in the presence of water afforded the aldol products in
series of initial tests on the prototype reaction between 4- fairly high yields, moderate diastereoselectivities and signifi-
Table 1. Chitosan aerogel organocatalysed asymmetric aldol reaction between aldehydes and cyclohexanone in the presence of water.[a]
[a] Reagents and conditions: 4.9 mg of chitosan AG, which corresponds to 20 mol-% of free amino units with respect to the aldehyde,
0.10 mmol of acceptor aldehyde, 2 mmol of cyclohexanone donor (donor/acceptor ratio = 20:1), 48 h, 25 °C. [b] Isolated yield after
chromatography on silica gel. [c] Determined by 1H NMR analysis of the crude mixture (n.d. = not determined). [d] Determined by
chiral stationary phase HPLC analyses (results in parentheses refer to the minor diastereoisomer). [e] Determined on the crude mixture.
[f] After benzoylation.
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cant enantiomeric excesses. Only in the case of water-mis-
Compared with the advantages induced by the additive
cible formaldehyde (Entry 8) did the reaction fail, which in the prototype reaction, a more sizeable improvement was
was predictable[16] and attributed to the fact that this ac- detected (Table 3) in the reaction with formaldehyde as the
ceptor system in bulk water is strongly hydrated,[17] re- acceptor. Only by using these additives was it possible to
sulting in a low concentration of the reactive form.
obtain the expected aldol product 1d, although the yields
We then turned our attention to the effect of different were only moderate and enantioselectivities not satisfactory.
types of additives. Surfactants such as PEG and SDS are The benefits induced by additives such as SDS when using
frequently employed when reactions are performed in aque- formaldehyde in the presence of water have been very re-
ous media, and this strategy has also been attempted under cently highlighted in the aminomethylation of oxindoles by
conditions of organocatalysis.[18] Moreover, the use of a three-component Mannich reaction.[18c]
acidic co-catalysts is common practice[19] in direct aldol re-
actions proceeding via an enamine intermediate and per-
formed under homogeneous conditions, and chitosan is
between formaldehyde and cyclohexanone in the presence of
Table 3. Effects of additives on the asymmetric direct aldol reaction
water.[a]
known to be a lipid binder as demonstrated by its use in
pharmaceutical chemistry as an anti-lipidemic.[20] These
considerations prompted us to consider that lipid moieties
appended with an acidic head group might prove beneficial
for catalysis in pure water, because they would simulta-
neously act as efficient acidic co-catalysts and assist in solu-
bilizing the organic substrates with their lipophilic tail. It is
also conceivable that the proven affinity of saturated and
unsaturated fatty acids for chitosan[21] might provide an ad-
ditional asset, favouring the recognition of the reagents by
the catalyst.
As shown in Table 2, a general improvement in yield and
enantiomeric excess was observed in the presence of anionic
(SDS; Entry 2) and neutral (PEG; Entry 3) surfactants as
well as acidic additives (Entries 4–7). With the acidic addi-
tives, the beneficial effect does not seem only related to their
pKa values, as they are very similar [2,4-dinitrophenol
(DNP): pKa = 4.11, Entry 4; acetic acid, pKa = 4.76, En-
try 5; linoleic acid: pKa = 4.78,[22a] Entry 6; stearic acid: pKa
= 4.7,[22b] Entry 7]. Presumably, the chain lipophilicity of
Entry
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
–
SDS
PEG
Ͻ10
40
25
35
30
n.d.
57
46
44
48
stearic acid
linoleic acid
[a] Reagents and conditions: 34.3 mg of chitosan AG, which corre-
sponds to 20 mol-% of free amino units with respect to formalde-
hyde (0.70 mmol), 14 mmol of cyclohexanone donor (donor/ac-
ceptor ratio = 20:1), 25 °C. [b] Isolated yield after chromatography
on silica gel. [c] Determined by chiral stationary phase HPLC
analysis after benzoylation (n.d. = not determined).
Despite the large variety of aldol acceptors that can now-
the additives also affects the catalytic process. However, its adays be used in direct aldol reactions, the range of donors
efficacy under the conditions employed might be depressed remains quite small. Moreover, although the prototype re-
by the presence of a conspicuous amount of organic phase action is good for establishing the potential usefulness of
coming from the excess (20:1) of the donor (cyclohexanone) the new catalysts, it leads to products lacking functional-
acting as organic co-solvent.
group diversity typical of drug-like building blocks. Re-
Table 2. Effect of additives on the asymmetric direct aldol reaction between 4-nitrobenzaldehyde and cyclohexanone in the presence of
water.[a]
Entry
Additive
Time [h]
Conv. [%][b]
Yield [%][c]
anti/syn[b]
ee [%][d]
1
2
3
4
5
6
7
–
SDS
PEG
DNP
48
48
48
24
48
48
48
90
98
98
90
95
98
90
85
90
92
85
90
95
88
70:30
70:30
66:34
76:24
66:34
70:30
69:31
84
90
86
92
74
87
93
AcOH
linoleic acid
stearic acid
[a] Reagents and conditions: 4.9 mg of chitosan AG, which corresponds to 20 mol-% of free amino units with respect to 4-nitrobenzalde-
hyde (0.10 mmol), 2 mmol of cyclohexanone donor (donor/acceptor ratio = 20:1), 25 °C. [b] Determined by 1H NMR analysis of the
crude mixture. [c] Isolated yield after chromatography on silica gel. [d] Determined by chiral stationary phase HPLC analysis, refers to
the major anti diastereoisomer.
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Asymmetric Aldol Reactions
cently, several highly stereoselective aldol reactions of Table 4. Effect of additives on the reference reactions performed
with a reduced donor/acceptor ratio.[a]
heterocyclic ketones such as tetrahydro-4H-thiopyran-4-one
(2) and 1-Boc-4-piperidone (3) have been reported in or-
ganic media,[23] under solvent-free conditions[24] and in the
presence of water,[25] thus prompting us to expand the chi-
tosan aerogel catalysed aldol reaction beyond the prototype
cyclohexanone to include these donors. However, these do-
nors are not the cheapest. In addition, both ketones 2 and
Entry
Additive 1
Additive 2 Yield [%][b] anti/syn[c] ee [%][d]
3, as well as the acceptor 4-nitrobenzaldehyde and the cata-
lyst, are water-insoluble solids, making the reaction more
difficult to perform due to the mixing of large amounts of
solids. The use of a large excess of these ketones to push the
reactions, as in our original procedure with cyclohexanone,
should thus be avoided. To this end, we examined the effect
of lowering the ketone/aldehyde ratio to 2:1, first for the
aldol addition of cyclohexanone to 4-nitrobenzaldehyde
using chitosan aerogel as the organocatalyst (Table 4).
The reaction, run for the standard time of 48 h in the
absence of additives, occurs with strongly reduced yields
and a sizeable erosion of the enantioselectivity (Table 4, En-
try 1). On the other hand, satisfactory yields and to some
extent lower but still remarkably good enantiomeric ex-
1
2
3
4
5
6
–
–
–
–
SDS
SDS
SDS
45
65
68
75
85
86
66:34
65:35
67:33
70:30
63:37
71:29
70 (60)
77 (63)
80 (66)
87 (82)
84 (35)
90 (77)
linoleic acid
stearic acid
–
linoleic acid
DNP
[a] Reagents and conditions: 4.9 mg of chitosan AG, which corre-
sponds to 20 mol-% of free amino units with respect to 4-nitrobenz-
aldehyde (0.10 mmol), 0.2 mmol of cyclohexanone donor (donor/
acceptor ratio = 2:1), 25 °C. [b] Isolated yield after chromatography
on silica gel. [c] Determined by 1H NMR analysis of the crude
mixture. [d] Determined by chiral stationary phase HPLC analysis
(results in parentheses refer to the minor diastereoisomer).
cesses as compared with the reaction performed with the excess of nucleophile required to shift the involved equilib-
previously employed 20:1 ketone/aldehyde ratio were ob- ria can be avoided without substantially affecting the ste-
served (Table 4, Entries 2–6) when the reaction was per- reochemical outcome, although, as expected, the reaction
formed in the presence of additives. Note, the significant rate is normally lower.
quantities of the aldol elimination product formed in the
Having established the feasibility of the benchmark di-
absence of additives (Entry 1), or in smaller amounts in the rect aldol reaction under these new conditions, the reaction
presence of lipophilic acids (Entries 2 and 3), were almost was extended to heterocyclic donors (Table 5). In the colloi-
completely suppressed (Entries 4–6) in the presence of SDS. dal dispersions formed in water in the presence of SDS, the
Under these reaction conditions, the normally used strong reaction of tetrahydro-4H-thiopyran-4-one (2) and 1-Boc-
Table 5. Heterocyclic ketones as donors in the aldol reactions with 4-nitrobenzaldehyde.[a]
[a] Reagents and conditions: 4.9 mg of chitosan AG, which corresponds to 20 mol-% of free amino units with respect to aldehyde,
0.10 mmol of acceptor aldehyde, 2 mmol of heterocyclic ketone donor (donor/acceptor ratio = 2:1), 48 h, 25 °C. [b] Isolated yield after
chromatography on silica gel. [c] Determined by 1H NMR analysis of the crude mixture. [d] Determined by chiral stationary phase HPLC
analysis of the crude mixture (results in parentheses refer to the minor diastereoisomer).
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phase, which contains the chitosan beads, was then extracted with
EtOAc (3ϫ 5 mL). The combined organic phases were concen-
trated, and the crude product was analysed by 1H NMR spec-
troscopy to determine the diastereomeric ratio. The aldol adducts
1 were finally obtained by chromatographic purification or as out-
lined below.
4-piperidone (3) occurred, albeit in poor yields and enantio-
selectivities (Entries 1 and 4). The susceptibility to syn/anti
isomerization by enolization[25a] as well as the occurrence
of a retro-aldol reaction of 1h in the presence of bases and
the marked tendency of 1i to racemize[24] account for these
drawbacks in the presence of anionic surfactant. Some im-
provement was noted (Entries 5 and 6) by performing the
reaction in the presence of acidic co-catalysts, with the lipo-
philic linoleic acid proving advantageous over DNP in
terms of yields. Finally, the heterocyclic donors 1h and 1i
readily reacted with 4-nitrobenzaldehyde in the presence of
both SDS and acid co-catalysts leading to the aldol prod-
ucts 1h and 1i, respectively (Entries 2, 3, 7 and 8), in satis-
factory to good yields with still moderate diastereoselectivi-
ties but fairly high enantioselectivities. These results for the
heterogeneous organocatalysis promoted by chitosan aero-
gel in the aldol reactions provided further support[25] for
the beneficial effect of combining anionic surfactants with
acidic additives when reactions are performed in bulk water.
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (1a): According to
the general procedure (2.0 mmol of donor) and performing the re-
action without additives (48 h reaction time), the title compound
was obtained in 85% yield as a white solid and as a mixture of
diastereoisomers after chromatography on silica gel (n-hexane/
EtOAc from 85:15 to 75:25). The diastereomeric ratio, as deter-
1
mined by H NMR analysis of the crude mixture, was found to be
70:30 in favour of the anti isomer. The enantiomeric excess of the
product was determined by HPLC analysis (Daicel Chiralpak
ADH column, flow 0.75 mL/min, n-hexane/iPrOH, 90:10; anti iso-
mer: tmaj = 43.9 min, tmin = 33.1 min, 84% ee; syn isomer: tmaj
=
29.5 min, tmin = 26.1 min, 60% ee). The spectral and analytical data
are consistent with literature values.[27] The absolute configuration
of the major anti diastereoisomer was assigned as (1ЈR,2S) by com-
parison of the HPLC retention times of its two enantiomers with
literature values.[28]
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone (1b): According to
the general procedure (2.0 mmol of donor) and performing the re-
action without additives (48 h reaction time), the title compound
was obtained in 70% yield as a white solid and as a mixture of
diastereoisomers after chromatography on silica gel (n-hexane/
EtOAc from 85:15 to 75:25). The diastereomeric ratio, as deter-
Conclusions
The ability of chitosan aerogel to promote stereoselective
direct aldol reactions in the presence of water represents a
“green” complement to the previously described procedures
and has been successfully applied to a range of acceptor
and donor systems. The use of surfactants and acid co-cata-
lysts in the chitosan-catalysed aldol reaction had a benefi-
cial effect on the outcome of the reaction. In particular, a
new protocol for this reaction that avoids the use of a large
excess of the ketone donor has been developed by combin-
ing an ionic surfactant with an acidic co-catalyst. This new
protocol has allowed us to broaden the scope of this reac-
tion to heterocyclic ketone donors.
1
mined by H NMR analysis of the crude mixture, was found to be
69:31 in favour of the anti isomer. The enantiomeric excess of the
product was determined by HPLC analysis (Daicel Chiralpak
ADH column, flow 1 mL/min, n-hexane/iPrOH, 90:10; anti isomer:
tmaj = 20.1 min, tmin = 25.1 min, 80% ee; syn isomer: tmaj
=
17.7 min, tmin = 16.8 min, 60% ee). The spectral and analytical data
are consistent with literature values.[29]
2-[Hydroxy(pyridin-2-yl)methyl]cyclohexanone (1c): According to
the general procedure (2.0 mmol of donor) and performing the re-
action without additives (48 h reaction time), the title compound
was obtained in 70% yield as a white solid and as a mixture of
diastereoisomers after flash chromatography on silica gel (n-hex-
ane/EtOAc = 70:30). The diastereomeric ratio, as determined by
1H NMR analysis of the crude mixture, was found to be 67:33 in
favour of the anti isomer. The enantiomeric excess of the product
was determined by HPLC analysis of the crude mixture, as signifi-
cant epimerization was observed during the chromatographic puri-
fication (Daicel Chiralpak OJ-H column, flow 1 mL/min, n-hexane/
iPrOH, 99:1; anti isomer: tmaj = 23.7 min, tmin = 26.0 min, 70% ee;
syn isomer: tmaj = 21.0 min, tmin = 18.7 min, 62% ee). The spectral
and analytical data are consistent with literature values.[29]
Experimental Section
General Methods and Materials: Analytical grade solvents were
from commercial sources. All the reagents were commercially avail-
able and used as received, except for 3-phenylpropiolaldehyde syn-
thesized according to a literature procedure.[26] Chromatographic
purifications were performed with 70–230 (chromatography) or
230–400 mesh silica gel (flash chromatography). Racemic samples
were prepared by using rac-proline as the catalyst. Chitosan aerogel
microspheres (4.06 mmol/g accessible NH2 groups) were prepared
as described previously.[14] 1H NMR spectra were recorded with
Varian AS 400 or 600 spectrometers. Enantiomeric excesses (ees) of
products were determined by chiral stationary phase HPLC (Daicel
Chiralpak AD-H, Chiralcel OJ-H, Chiralcel AS, Phenomenex Lux)
using a UV detector operating at 254 nm.
2-(Hydroxymethyl)cyclohexanone (1d): According to the general
procedure on a larger scale (0.7 mmol of formaldehyde, 1.4 mmol
of cyclohexanone, 3.5 mL of H2O) and performing the reaction by
using SDS as additive, the title compound was obtained in 40%
yield after 48 h. The ee was determined by HPLC after benzo-
ylation (see below). The spectral and analytical data are consistent
with literature values.[16,30]
General Procedure for the Aldol Reactions: Chitosan aerogel micro-
spheres (4.9 mg, which corresponds to 20 mol-% of free amino
units with respect to the acceptor), aldol acceptor (0.10 mmol), ad-
ditive (0.020 mmol, 20 mol-%), H2O (0.5 mL) and ketone donor
(2.0 or 0.2 mmol) were sequentially added to a vial. A second addi-
tive (0.020 mmol, 20 mol-%) was added as indicated. The mixture
was gently stirred with a shaker at 25 °C for the stated time. EtOAc
was then added, and the phases were separated. The aqueous
Ethyl 2-Hydroxy-2-(2-oxocyclohexyl)acetate (1e): According to the
general procedure (2.0 mmol of donor) and performing the reac-
tion in the absence of additives (48 h reaction time), the title com-
pound was obtained in 90% yield as a colourless oil and as a mix-
ture of diastereoisomers after chromatography on silica gel (n-hex-
ane/EtOAc = 80:20). The diastereomeric ratio, as determined by
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Asymmetric Aldol Reactions
1H NMR analysis of the crude mixture, was found to be 53:47 in
favour of the anti isomer. The enantiomeric excess of the product
was determined by HPLC analysis after benzoylation (see below).
The spectral and analytical data are consistent with literature val-
ues.[31]
General Procedure for the Benzoylation of Products 1d,e: Purified
aldol product 1 (1 equiv., 0.1 mmol), CH2Cl2 (0.5 mL), benzoyl
chloride (2 equiv., 0.2 mmol) and pyridine (5 equiv., 0.5 mmol)
were sequentially added to a vial. After stirring at room tempera-
ture for 2 h, the reaction was quenched with H2O. The mixture was
extracted with CH2Cl2, and the organic layer was washed with
brine and dried with anhydrous Na2SO4. After filtration, the sol-
vents were evaporated, and the residue was purified by short-col-
umn chromatography.
2-(1-Hydroxy-3-phenylprop-2-ynyl)cyclohexanone (1f): According to
the general procedure (2.0 mmol of donor) and performing the re-
action without additives (48 h reaction time), the title compound
was obtained in 90% yield as a colourless oil and as a mixture
of diastereoisomers after chromatography on silica gel (n-hexane/
EtOAc from 80:20). The diastereomeric ratio, as determined by 1H
NMR analysis of the crude mixture, was found to be 57:43 in
favour of the anti isomer. The enantiomeric excess of the product
was determined by HPLC analysis (Daicel Chiralpak OJ-H col-
(2-Oxocyclohexyl)methyl Benzoate: After purification of the crude
mixture by chromatography on silica gel (n-hexane/EtOAc, 90:10),
the enantiomeric excess of the product was determined to be 57%
by HPLC analysis (Phenomenex Lux column, flow 1 mL/min, n-
hexane/iPrOH, 98:2; tmaj = 13.0 min, tmin = 16.2 min). The spectral
and analytical data are consistent with literature values.[30]
umn, flow 1 mL/min, n-hexane/iPrOH, 90:10; anti isomer: tmaj
=
11.0 min, tmin = 14.7 min, 70% ee; syn isomer: tmaj = 16.5 min, tmin
= 13.0 min, 77% ee). The spectral and analytical data are consistent
with literature values.[32]
2-Ethoxy-2-oxo-1-(2-oxocyclohexyl)ethyl Benzoate: After purifica-
tion of the crude mixture by chromatography on silica gel (n-hex-
ane/EtOAc, 90:10), the enantiomeric excess of the product was de-
termined by HPLC analysis (Daicel Chiralpak ADH +AS column,
2-(1-Hydroxy-2-oxo-2-phenylethyl)cyclohexanone (1g): According
to the general procedure (2.0 mmol of donor) and performing the
reaction without additives (48 h reaction time), the title compound
was obtained in 80% yield as a colourless oil and as a mixture of
diastereoisomers after flash chromatography on silica gel (n-hex-
flow 0.9 mL/min, n-hexane/iPrOH, 90:10; anti isomer: tmaj
=
30.0 min, tmin = 26.9 min, 5% ee; syn isomer: tmaj = 28.9 min, tmin
= 37.7 min, 62% ee). The spectral and analytical data are consistent
with literature values.[31]
1
ane/EtOAc, 80:20). The diastereomeric ratio, as determined by H
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for compounds 1.
NMR analysis of the crude mixture, was found to be 53:47 in fav-
our of the anti isomer. The enantiomeric excess of the product was
determined by HPLC analysis (Daicel Chiralpak AS column, flow
1 mL/min, n-hexane/iPrOH, 90:10; anti isomer: tmaj = 16.9 min, tmin
= 37.6 min, 48% ee; syn isomer: tmaj = 56.5 min, tmin = 26.7 min,
64% ee). The spectral and analytical data are consistent with litera-
ture values.[33]
Acknowledgments
Financial support was provided by the University of Bologna. We
acknowledge the Università Italo-Francese for covering travel ex-
penses (Galileo program, project number 25966NE, “AEROCAT”).
We thank Silvia Mariotti for preliminary experiments.
Tetrahydro-3-[hydroxy(4-nitrophenyl)methyl]thiopyran-4-one (1h):
The procedure based on a 2:1 donor/acceptor ratio was applied.
By starting from 0.2 mmol of donor and with SDS and linoleic
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mixture, was found to be 73:27 in favour of the anti isomer. The
enantiomeric excess of the product was determined by HPLC
analysis of the crude mixture as significant epimerization was ob-
served during the chromatographic purification (Daicel Chiralpak
AD-H column, flow 1 mL/min, n-hexane/iPrOH, 80:20; anti iso-
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=
41.4 min, tmin = 46.7 min, 85% ee; syn isomer: tmaj = 34.6 min, tmin
= 36.8 min, 60% ee). The spectral and analytical data are consistent
with literature values.[23]
Eur. J. Org. Chem. 2013, 588–594
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: September 4, 2012
Published Online: November 27, 2012
594
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 588–594