Novel sulfonylpolystyrene-supported prolinamides as catalysts for enantioselective aldol reaction in water

Article abstract of DOI:10.1016/j.tet.2013.10.093

Five novel prolinamides derived from 1,n-diamines supported on commercially available sulfonylpolystyrene have been synthesized and successfully applied in diastereo- and enantioselective aldol reaction in water or, in one case, neat conditions. Excellent

Full text of DOI:10.1016/j.tet.2013.10.093

Tetrahedron 69 (2013) 10811e10819
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel sulfonylpolystyrene-supported prolinamides as catalysts
for enantioselective aldol reaction in water
*
*
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ꢀ
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Rafael Pedrosa , Jose M. Andres , Ana Gamarra, Ruben Manzano, Cesar Perez-Lopez
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Instituto CINQUIMA and Departamento de Química Organica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belen 7, 47011 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Five novel prolinamides derived from 1,n-diamines supported on commercially available sulfonylpo-
lystyrene have been synthesized and successfully applied in diastereo- and enantioselective aldol re-
action in water or, in one case, neat conditions. Excellent dr and er were obtained by reaction of different
cyclohexanone derivatives with aromatic and heteroaromatic aldehydes in the presence of the catalysts
and AcOH as co-catalyst. The supported organocatalysts work in low loading (5 mol %) exhibiting similar
performances than homogeneous prolinamides, and can be reused, after activation, without loss of
activity.
Received 4 September 2013
Received in revised form 21 October 2013
Accepted 28 October 2013
Available online 1 November 2013
Keywords:
Aldol reaction
Organocatalysis
Prolinamides
Ó 2013 Elsevier Ltd. All rights reserved.
Supported catalysts
Supported prolinamides
1. Introduction
catalysts, requiring a high mol % of catalyst loading, and the tedious
preparation of complex molecules to be anchored to the polymer.
Organocatalysis has reached the mature age in the last decade,
and a lot of organocatalysts have been described for the enantio-
selective version of different reactions.1 One of the most important
subject related with that transformations is the searching for sup-
ported catalysts2 able to promote enantioselective transformations
in water.3 To this end, the anchorage of the homogeneous catalysts
on an insoluble polystyrene matrix constitutes a method leading to
materials, which are easily manipulated, separated, recovered, and
reused from the reaction mixtures.
Enantioselective aldol reaction catalyzed by proline derivatives
is probably one of the most important reaction, and catalysts able to
promote that transformation have been thoroughly developed.4 In
that way, proline derivatives have been supported on micelle-
forming species,5 polyethylene glycol,6 dendrimers,7 polystyrene,8
cyclodextrines,9 ionic liquids,10 polyvinylidene chloride,11 or in-
organic supports.12 Copolymers derived from methacrylates and 4-
hydroxy proline13 or cinconine derivatives with acrylonitrile14 have
been also described. Recently, 4-(1-triazolyl) proline has been
immobilized on DVB-PS support, and used as catalyst for
continuous-flow enantioselective aldol reaction with excellent
results.15
Nevertheless, the search for novel efficient supported catalysts
capable of promoting the aldol reaction with low loading, high
stereoselection, and preferably in water is an important research
area. The practical applicability of the catalysts is dependent on
their activity, robustness, recyclability, and easy preparation, in few
steps, from cheap and easily accessible starting compounds. Re-
cently, we have demonstrated that prolinamides derived from 1,2-
diamines worked very well as bifunctional organocatalysts for the
inter- and intramolecular aldol reaction in organic solvents16 and
water.17 Based on those perspectives, we present now a short
synthesis of novel supported prolinamides and their use as cata-
lysts for the enantioselective aldol reaction in water and solvent-
free conditions.
A supported prolinamide (3a) previously described by us,17b and
four novel supported sulfonyl prolinamides (3bee) were prepared
to study the influence of the length of the tether chain connecting
the sulfonyl group of the polymer and the carboxamide group
(3aec), the substitution on the nitrogen atom at the sulfonamide
(3d), and the presence of an additional stereocenter at the amine
component (3e) on the stereoselection of the reaction.
Some of the most common problems founded when using those
materials are related with the loss of activity of the supported
2. Results and discussion
All the supported catalysts were prepared in three or four steps
from Boc-proline as summarized in Scheme 1. Prolinamide 1a and
ent-1a, derived from 1,2-ethylene diamine, were prepared by
* Corresponding authors. E-mail address: pedrosa@qo.uva.es (R. Pedrosa).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.093

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R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
Scheme 1. Reagents and conditions: (i) 1. ClCO2Et, NMM, CH2Cl2, ꢀ5 ꢁC, 30 min. 2. H2N(CH2)nCH2NH2, CH2Cl2, ꢀ78 ꢁC to rt. (ii) Sulfonyl chloride polymer bound, CH2Cl2, Et3N, rt,
4 days. (iii) TFA, CH2Cl2, rt, 6 h, then MeOH/Et3N 98:2. (iv) 1. ClCO2Et, NMM, THF, ꢀ15 ꢁC. 2. H2NCH2CH2OH, THF, ꢀ15 ꢁC to rt. (v) MsCl, Et3N, CH2Cl2, then CH3NH2 (aq), Et2O.
a modification of a previously described method,18 by condensation
of 1,2-ethylene diamine with the anhydride formed by reaction of
Boc-(L)-proline or Boc-(D)-proline, respectively, and ethyl chlor-
oformate. In the same way, prolinamides 1b,c were synthesized
from 1,4-butane diamine and 1,6-hexane diamine, respectively.
Methyl-substituted prolinamide 5 was obtained, in two steps, from
sulfonamide group. The analytical data of the nitrogen and sulfur
atoms allowed the calculation of the yield of linkage and the ef-
fective functionalization f (prolinamide content per gram of resin)
of the functionalized polymers (Table 1).
We first studied the ability of the different catalysts in pro-
moting the enantioselective aldol reaction in water, taking the re-
action of cyclohexanone and p-nitrobenzaldehyde as a model. To
Boc-(
L)-proline by condensation with ethanolamine to 4 and sub-
sequent mesylation, and displacement with aqueous methylamine.
this end,
a mixture of cyclohexanone (1 mmol), p-nitro-
Compound 6, derived from Boc-(
L
)-proline and (
L
)-valine was pre-
benzaldehyde (0.5 mmol), the corresponding catalyst (5 mol %), and
AcOH (10 mol %) was stirred in water (1 mL) at 0 ꢁC for 24 h, and the
results are collected in Scheme 2 and Table 2.
The results show that the best catalysts, in terms of chemical
yield and stereoselection, were 3a and ent-3a yielding the anti-al-
dol product 7a preferentially (er: 96/4) in 92/8 anti/syn ratio and its
enantiomer, respectively (entries 1 and 6 in Table 2).
Interestingly, poorer diastereo- and enantioselectivities were
obtained with catalyst 3b and 3c derived from 1,4-butane diamine
and 1,6-hexane diamine, respectively, indicating that the longer is
the tether connecting the proline to the polymer, the poorer is the
stereoselection (entries 2, 3 in Table 2). On the contrary, the N-
methyl substituted sulfonamide 3d behaves in a similar way than
do 3a (compare entries 1 vs 4 in Table 2), pointing to that the acidic
hydrogen in the sulfonamide component in catalyst 3a does not
participate in the complex responsible for the stereocontrol. Finally,
the supported catalyst 3e, with an additional stereocenter at the
diamine tether, gave the same stereochemical results than 3a, in-
dicating that, as previously described,16 additional stereocenters on
the catalysts do not improve the stereoselection, which is dictated
by the proline component.
Taking 3a as the best catalyst, we screened the optimal reaction
conditions varying the acid acting as co-catalyst, the reaction
temperature, the molar ratio of cyclohexanone, and the catalyst
loading in aqueous medium or without solvent. Some of the results
are collected in Table 3.
Both the temperature and the nature of the acidic additive play
an important role on the stereoselection of the aldol reaction. At rt,
the reaction of p-nitrobenzaldehyde with 5 equiv of cyclohexanone
and 20 mol % of 3a, and 40 mol % of AcOH yielded anti-7a with
moderate diastereoselection (78/22 dr) and enantioselection (90/
10 er), whereas the diastereoselectivity was increased to 90/10 dr,
and the enantioselectivity to 96/4 er when the reaction was carried
out at 0 ꢁC for 14 h (compare entries 1 and 2 in Table 3).
pared as previously described.16
The linkage of amino prolinamides 1aec, ent-1a, 5, and 6 to the
sulfonylpolystyrene resin was studied taking 1a as a model. To this
end, a mixture of 1a and the commercially available chlor-
osulfonylpolystyrene19 was stirred in DCM and triethylamine at rt
for 4 days. The solid was filtrated, and thoroughly washed with
water and methanol and dried in vacuo. The IR spectrum of this
material showed characteristic bands at 1670, 1158, and 1313 cmꢀ1
corresponding to the Boc- and sulfonamide functionalities, re-
spectively. This material was subjected to hydrolysis of the pro-
tecting group by treatment with TFA, leading to the supported
material (3a) with yields that are dependent on the molar ratio of
the reactants. Only 79% yield of support was obtained when the
polymer was treated with 1 equiv of 1a, but the support was
quantitative in the reaction with 2 equiv of prolinamide (entries 1
and 2 in Table 1). The excess of 1a was recovered during the
washing step.
The described methodology was extended to the linkage of
amino prolinamides 1b,c, 5, 6, and ent-1a, and the results are col-
lected in Table 1. The polymeric materials were characterized by the
IR absorptions at 1154 and 1318 cmꢀ1, corresponding to the
Table 1
Preparation of resins 3aee and ent-3a
a
Entry
Prolinamide (equiv)
Polymer
f (mmol gꢀ1
)
% Linkage
1
2
3
4
5
6
7
1a (1)
1a (2)
1b (2)
1c (2)
5 (2)
3a
3a
3b
3c
3d
3e
ent-3a
1.38
1.55
1.52
1.25
1.69
1.58
1.68
79
100
91
86
100
97
6 (2)
ent-1a (2)
97
a
Calculated on the basis of the elemental analysis of nitrogen and sulfur atoms.

R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
10813
Scheme 2. Diastereo- and enantioselective aldol reaction of cyclohexanone and p-nitrobenzaldehyde catalyzed by 3aee and ent-3a.
In the same reaction conditions, the change of acetic acid to
benzoic acid (entry 3) or to p-nitrobenzoic acid (entry 4) as co-
catalysts produced a significant decrease in both the diastereo-
and enantioselection of the reaction. The reduction of the loading of
3a to 10 mol % or 5 mol % did not have significant effect on the
stereoselection, although at expenses to increase the reaction time
to 20 h in the last case (entries 5 and 6 in Table 3). It is interesting to
note that the reaction also worked well with 5 mol % of 3a in neat
conditions or in the absence of AcOH as co-catalyst, although rel-
atively low diastereo- and enantioselectivities were obtained (en-
tries 7 and 8 in Table 3), but a decrease in the yield was observed
and a high increase in the reaction time was necessary when the
reaction was carried out in brine as a solvent (entry 9).
The molar ratio ketone/aldehyde also play significant effect on
the reactivity. While the reaction worked very well when the molar
ratio was decreased to 2 equiv of ketone (entry 10 in Table 3), the
yield decreased to 30% when an equimolar mixture of cyclohexa-
none and p-nitrobenzaldehyde was reacted for 24 h in the presence
of 5 mol % of 3a (entry 11). The yield increased to 86%, maintaining
the stereoselection, in the presence of 10 mol % of catalyst (entry 12
in Table 3). The reaction was scaled up by using 5 mmol of p-
nitrobenzaldehyde and 10 mmol of cyclohexanone with 5 mol % of
3a in 10 mL of water for 72 h at 0 ꢁC, yielding 7a in excellent yield
and diastereo- and enantioselectivities (entry 13 in Table 3).
The recyclability of the catalysts was tested for 3a in two dif-
ferent conditions. In the first one, the reaction was carried out with
1 mmol of cyclohexanone and 0.5 mmol of p-nitrobenzaldehyde in
1 mL of water at 0 ꢁC in the presence of 20 mol % of catalyst. After
completion of the reaction, the catalyst was recovered by filtration,
washed with water and EtOAc, dried, and reused in the next cycle.
This procedure was repeated four times, and the results are col-
lected in Table 4 (entries 1e4).
It was observed that the catalyst provided high chemical yield
and constant levels of diastereo- and enantioselection in all cases,
although at expenses to increase the reaction time in each cycle. A
second set of experiments was done by stirring a mixture of 2 mmol
of cyclohexanone, 1 mmol of aldehyde, and 5 mol % of 3a in 2 mL of
water at 0 ꢁC. In those conditions, the reaction was nearly com-
pleted after 24 h, leading to the anti-aldol in excellent yield and
stereoselectivity (entry 5 in Table 4), but in the second cycle, the
recycled catalyst was able to promote the reaction with only 48% of
conversion (entry 6). The recovered catalyst also shown a drop of
activity when used in a third cycle because 19% of aldehyde was
unreacted after 72 h of reaction (entry 7). Catalysts 3c and 3d
showed the same behavior than 3a. The conversion of the reaction
decreased to 48% and 53%, respectively, after 24 h of reaction in the
Table 2
Screening of catalyst 3aee and ent-3a in the direct asymmetric aldol reaction be-
tween cyclohexanone and 4-nitrobenzaldehyde in watera
Entry Catalyst Time (h) Yieldb (%) Product anti/sync erd
1
2
3
4
5
6
3a
3b
3c
3d
3e
ent-3a
24
24
24
24
24
24
91
82
90
83
76
81
7a 92/8
7a 88/12
7a 86/14
7a 91/9
7a 93/7
7a 92/8
96:4 (2S, 10R)
93:7 (2S, 10R)
89:11 (2S, 10R)
95:5 (2S, 10R)
96:4 (2S, 10R)
96:4 (2R, 10S)
a
Reaction conditions: 1 mL of water, 1 mmol cyclohexanone, 0.5 mmol aldehyde,
0.025 mol of catalyst, 0.05 mol of HOAc 0 ꢁC.
b
Yields determined after chromatographic purifications.
c
Diastereomeric excess determined by 1H NMR of crude reaction mixture.
d
Enantiomeric ratio determined by chiral HPLC analysis for anti-diastereomers.
Table 3
Optimization of reaction conditions for the direct enantioselective aldol reaction of
cyclohexanone with p-nitrobenzaldehyde catalyzed by 3aa
Entry Catalyst (mol %) T (ꢁC) Time (h) Yieldb (%) Product anti/sync erd
1
3a (20)
3a (20)
3a (20)
3a (20)
3a (10)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (10)
3a (5)
20
0
0
0
0
0
0
0
0
0
0
0
0
8
14
14
14
14
20
7
14
100
24
24
24
72
81
90
76
81
89
90
80
79
55
91
30
86
92
7a 78/22
7a 90/10
7a 75/25
7a 88/12
7a 90/10
7a 89/11
7a 85/15
7a 87/13
7a 91/9
90:10
96:4
93:7
95:5
94:6
94:6
90:10
92:8
94:6
96:4
93:7
94:6
96:4
2
3e
4f
5
6
Table 4
7g
8h
9i
Recycling experiments using 3aed in water at 0 ꢁC
Entry Catalyst Cycle Time (h) Conversion (%) Yielda (%) drb
erc
10j
11k
12k
13l
7a 92/8
7a 89/11
7a 95/5
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3c
3c
3d
3d
1d
2d
3d
4d
1e
2e
3e
4e,f
1e
2e
1e
2e
24
40
120
120
24
24
72
24
24
100
100
100
100
95
48
81
88
100
48
86
82
70
88
90
40
70
78
90
38
85
44
93/7
92/8
95/5
93/7
92/8
93/7
91/9
91/9
86/14 90/10
86/14 88/12
90/10 95/5
90/10 95/5
96:4
96:4
96:4
96:4
96:4
96:4
96:4
96:4
7a 92/8
a
Reaction conditions: 1 mL of water, 2.5 mmol cyclohexanone, 0.5 mmol alde-
hyde, x mol % catalyst, 2x mol % HOAc, as stated in the Table.
b
Yields determined after chromatographic purifications.
c
Diastereomeric excess determined by 1H NMR of crude reaction mixture.
9
d
Enantiomeric ratio determined by chiral HPLC analysis for anti-diastereomer.
40 mol % benzoic acid as additive.
40 mol % PNBA as additive.
Reaction performed ‘neat’, without water.
Reaction performed without HOAc.
Reaction performed in brine.
Reaction performed with 2 equiv of cyclohexanone.
Reaction performed with 1 equiv of cyclohexanone.
10
11
12
24
24
24
e
94
53
f
g
h
a
Yields determined after chromatographic purifications.
i
b
c
d
e
f
Diastereomeric excess determined by 1H NMR of crude reaction mixture.
Enantiomeric ratio determined by chiral HPLC analysis for anti-diastereomer.
The reactions were carried out by using 20 mol % of catalyst.
The reactions were carried out by using 5 mol % of catalyst.
Reaction promoted by regenerated 3a.
j
k
l
Reaction was performed using 5 mmol of p-nitrobenzaldehyde and 10 mmol of
cylohexanone.

10814
R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
second cycle, although the stereoselection was maintained in both
cases (entries 9 and 11 vs 10 and 12 in Table 4).
diastereo- and enantioselection, but increasing the catalyst loading
to 20 mol % (entries 8, 9 in Table 5).
A similar loss of activity, and its regeneration, in related sup-
ported prolinamides had been previously observed by Grutta-
dauria,8d,f and was ascribed to the partial inactivation of the
catalyst by formation of imidazolidinones. The displacement of
25 cmꢀ1 of the amide band at higher frequency in the catalyst 3a,
after 3 cycles, with respect to the starting or regenerated catalysts
(see SD), points to the formation of the proposed imidazolidinone.
Additionally, the nitrogen and sulfur contents of the three times
recycled catalyst increased from 6.15% to 6.53% or decreased from
5.04 to 4.84, respectively, supporting the partial incorporation of
p-nitrobenzaldehyde molecules to the catalyst. Fortunately, the
activity of catalyst 3a can be regenerated by treatment with formic
acid as previously reported,8f and used in a new cycle, recovering
the activity to promote the reaction in excellent yield and ster-
eoselection (entry 8 in Table 4).
Specially interesting is the result obtained in the desymmetri-
zation20 of 4-methyl cyclohexanone, as an alternative to the
metal21 or enzyme22 desymmetrizations. In our case, the reaction
of the ketone with p-nitrobenzaldehyde in water and 5 mol % of the
supported
catalyst
3a
yielded
(2S,4S)-2[(R)-hydroxy-(4-
nitrophenyl)methyl]-4-methyl cyclohexanone23 (7k) in good yield
and excellent diastereo- and enantioselection (entry 10 in Table 5).
Very good stereoselection was also observed in the aldol reaction
with tetrahydrothiopyranone in a mixture 1/1 of ethanol/water as
solvent, although in lower yield (entry 11), whereas both tetrahy-
dropyranone (entry 12) and N-Boc-piperidone (entry 13) reacted
very quickly, leading to the anti-aldol products 7m and 7n, re-
spectively, with moderate diastereoselectivity but excellent enan-
tioselectivity. Finally, cyclopentanone also participates in the aldol
reaction with p-nitrobenzaldehyde leading to syn-aldol 7o as major
diastereoisomer, but both the diastereo- and enantioselection were
low (entry 14 in Table 5).24
Finally, the generality of the aldol reaction was tested by re-
action of different aromatic aldehydes with cyclopentanone and
cyclohexanone derivatives in the presence of only 5 mol % of cat-
alyst 3a, and the results are summarized in Scheme 3 and Table 5.
The high yields and excellent levels of diastereo- and enantio-
control can be attributed the hydrophobic effect exerted by the
polymer and to the formation of hydrogen bonds between the
water molecules surrounding the complex and the oxygen of the
amide groups.23b These hydrogen bonds also increase the acidity of
the NH groups making a more compact transition state and in-
creasing the rate of the reactions.25,26
The stereochemical discrimination of the reaction can be
explained in agreement with a simplified transition state as
depicted in Scheme 4 for the aldol-desymmetrization of 4-methyl
cyclohexanone. That model indicates that the stereochemistry of
the major isomer is determined by the stereocenter of the proline
component of the catalyst. The presence of additional stereocenters
at the amine counterpart of the prolinamides has little or no in-
fluence in the stereo-discrimination.17a The stereochemical results
can be explained by accepting that two different regioisomeric
enamines (A and B in Scheme 4) could be initially formed from 4-
methyl cyclohexanone, but enamines A1 and B1, anti to the car-
boxamide group are more stable than the syn arrangements A2 and
B2.27 Otherwise, the aldehyde is activated by the formation of
a hydrogen bond with the carboxamide, and its approach is much
more hindered in the enamine B1 than in A1 because the steric
hindrance of the methyl group in the same face. Then, the TS D is
more favorable than C, and the reactions occur by approaching the
aldehyde, by its re face to the re face of the enamine, leading to 7k
as major enantiomer.
Scheme 3. Diastereo- and enantioselective aldol reaction of cyclopentanone and cy-
clohexanone derivatives with different aldehydes.
The aldehydes with electron-withdrawing substituents at the
phenyl group easily reacted with cyclohexanone, yielding the anti-
aldol products 7bef in excellent yields and diastereo- and enan-
tioselection (entries 1e5 in Table 5). Benzaldehyde also give the
anti-aldol 7g with good stereoselectivity, but in lower yield and
increasing the reaction time (entry 6), and furfural yielded 7h in
moderate yield and lower diastereoselection (er 88:12), although
good enantioselection in the same reaction conditions (entry 7).
The less reactive 2-naphtaldehyde and p-tolualdehyde also lead to
the anti-aldol products 7i and 7j, respectively, with excellent
Table 5
Aldol reaction of different aldehydes with cyclic ketones catalyzed by 3aa
Entry Ar/X
Time (h) Yieldb (%) Product anti/sync erd
1
2
3
4
5
6
7
o-NO2Ph/CH2
24
24
48
44
72
144
144
90
120
48
48
144
24
87
78
77
95
74
68
40
88
60f
80
66
86
87
80
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
90/10
94/6
92/8
96/4
94/6
95/5
88/12
93/7
91/9
94/6
93/7
80/20
78/22
32/68
94:6
96:4
96:4
96:4
98:2
96:4
96:4
98:2
95:5
95:5
98:2
93:7
95/5
87/13h
3. Conclusions
m-NO2Ph/CH2
p-NCPh/CH2
p-CF3Ph/CH2
p-ClPh/CH2
Ph/CH2
2-Furyl/CH2
2-Naphtyl/CH2
p-CH3Ph/CH2
p-NO2Ph/CHMe
p-NO2Ph/S
In conclusion, we have prepared prolinamides supported on
a matrix of sulfonylpolystyrene in few steps from cheap and easily
accessible starting materials. The simplest ethylene diamine-
derived organocatalyst 3a, and AcOH as co-catalyst, was found to
be the most promising catalyst for diastereo- and enantioselective
aldol reaction in water or without solvent, because it exhibits
performances similar to those found for the homogeneous coun-
terpart. The catalyst can be recycled, after regeneration, for four
times without significant loss of activity leading to the anti-aldol
products with excellent yield and stereoselectivities.
8e
9e
10
11g
12
13g
14
p-NO2Ph/O
p-NO2Ph/NBoc
p-NO2Ph/e
24
a
Reaction conditions: 1 mL of water, 1 mmol ketone, 0.5 mmol aldehyde,
0.025 mol of catalyst, 0.05 mol of HOAc, 1 ꢁC.
b
4. Experimental section
4.1. General
Yields determined after chromatographic purifications.
c
Diastereomeric excess determined by 1H NMR of crude reaction mixture.
d
Enantiomeric ratio determined by chiral HPLC analysis for anti-diastereomer.
20 mol % catalyst.
18% Unreacted aldehyde.
Reaction performed in a 1:1 water/ethanol mixture as solvent.
e
f
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded in CDCl3 as solvent. Chemical shifts for protons are re-
ported in parts per million from TMS with the residual CHCl3
g
h
The er corresponds to the minor anti-diastereoisomer. The er for the major syn-
diastereoisomer was 52/48.

R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
10815
Scheme 4. Proposed TS for diastereo- and enantioselective desymmetrization of 4-methyl cyclohexanone.
resonance as internal reference. Chemical shifts for carbons are
reported in ppm from TMS and are referenced to the carbon reso-
nance of the solvent. Data are reported as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad), coupling constants in Hertz, and in-
tegration. Specific rotations were measured on a digital polarimeter
using a 5-mL cell with a 1-dm path length, and a sodium lamp, and
concentration is given in g per 100 mL. Infrared spectra were
recorded on a FT-IR spectrometer and are reported in frequency of
absorption (only the structurally most important peaks are given).
Melting points were obtained with open capillary tubes and are
uncorrected. Flash chromatography was carried out using silica gel
(230e240 mesh). Chemical yields refer to pure isolated substances.
TLC analysis was performed on glass-backed plates coated with
silica gel 60 and an F254 indicator, and visualized by either UV ir-
radiation or by staining with phosphomolybdic acid solution. Chiral
HPLC analysis was performed on an instrument equipped with
dichloromethane (150 mL) previously cooled to ꢀ78 ꢁC. When the
addition was complete, the mixture was stirred for 10 min at that
temperature and then warmed to rt and stirred overnight. The re-
action mixture was concentrated in vacuo to a volume of about
50 mL, and extracted with aqueous HCl 1 M (2ꢂ20 mL). The
aqueous layer was basified with concentrated ammonia and it was
thoroughly extracted with chloroform (10ꢂ25 mL). The organic
phases were combined, dried over MgSO4, filtered, and the solvent
was evaporated in vacuo. The pure compound was obtained as
colorless oil (940 mg, 3.3 mmol, 82% yield). ½a D25
ꢀ76.8 (c 1.1, CHCl3).
ꢃ
1H NMR (400 MHz, CDCl3, 330 K):
d 1.26 (br s, 2H); 1.45 (s, 9H);
1.48e1.58 (m, 4H); 1.80e2.05 (m, 3H); 2.24 (m, 1H); 2.70 (t, 2H,
J¼6.7 Hz); 3.24 (m, 2H); 3.40 (m, 2H); 4.22 (dd, 1H, J¼8.2, 2.7 Hz);
6.75 (br s, 1H). 13C NMR (101 MHz, CDCl3, 330 K)
d 24.1 (CH2); 27.0
(CH2); 28.3 (CH3); 30.9 (CH2); 39.2 (CH2); 41.6 (CH2); 47.0 (CH2);
60.7 (CH); 80.2 (C(CH3)3); 155.2 (COt2Bu); 172.1 (CON). IR (neat):
3302, 1690, 1659, 1545, 1390, 1246, 1163, 1121, 755 cmꢀ1. HRMS
calcd for C14H27N3O3þHþ: 286.2125; found, 286.2131.
a
quaternary pump, using a Daicel Chiralcel OD Column
(250ꢂ4.6 mm) or Chiralpak AD-H Column (250ꢂ4.6 mm). UV de-
tection was monitored at 220 or at 254 nm.
4.2.2. N-(6-Aminohexyl)-N0-(tert-butoxycarbonyl)-
(1c). Obtained by monoacylation reaction of hexanemethylenedi-
amine (2.6 mL, 20 mmol, 5 equiv) with Boc- -proline (860 mg,
L-prolinamide
Racemic samples were prepared by using racemic proline as the
catalyst in DMSO. Organic compounds were used as received. Sol-
L
ꢁ
vents were dried and stored over microwave-activated 4 A mo-
4.0 mmol) by the procedure described for the preparation of 1b. The
lecular sieves. The synthesis of catalysts 3a and ent-3a has been
pure compound was obtained as colorless oil (940 mg, 3.0 mmol,
previously published.17b
75% yield). ½a 2D5
ꢃ
ꢀ69.1 (c 0.9, CHCl3). 1H NMR (400 MHz, CDCl3,
330 K): d 1.32 (m, 4H); 1.46 (s, 9H); 1.40e1.55 (m, 2H); 1.75e2.05 (m,
2H); 2.25 (m, 1H); 2.67 (t, 2H, J¼6.8 Hz); 3.22 (m, 2H); 3.40 (m, 2H);
4.2. Preparation of catalysts 3bee
4.10 (m,1H); 4.58 (br s, 2H); 6.50 (br s,1H).13C NMR (101 MHz, CDCl3,
4.2.1. N-(4-Aminobutyl)-N0-(tert-butoxycarbonyl)-
(1b). To a solution of Boc- -proline (860 mg, 4.0 mmol) and 4-
L
-prolinamide
330 K): d 24.1 (CH2); 26.4 (CH2); 26.6 (CH2); 28.3 (CH3); 29.6 (CH2);
30.0 (CH2); 33.6 (CH2); 39.2 (CH2); 42.0 (CH2); 47.0 (CH2); 60.5 (CH);
80.3 (C(CH3)3); 156.6 (COt2Bu); 172.0 (CON). IR (neat): 3308, 1690,
1664, 1540, 1390, 1364, 1251, 1163, 1127, 729 cmꢀ1. HRMS calcd for
L
methylmorpholine (0.44 mL, 4.0 mmol) in anhydrous dichloro-
methane (40 mL) was dropped ethyl chloroformate (0.42 mL,
4.4 mmol) at ꢀ5 ꢁC. After 20 min of stirring, the reaction mixture
was washed successively with a cold solution of citric acid (5%
aqueous, 20 mL), a solution of sodium bicarbonate (10%, 20 mL) and
water (20 mL). The organic layer was dried over MgSO4, filtered,
and diluted with dichloromethane to a volume of 150 mL. This
solution was added dropwise (30e60 min) to a vigorously stirred
solution of 1,4-diaminobutane (2.0 mL, 20 mmol, 5 equiv) in
C
16H31N3O3þHþ: 314.2438; found: 314.2447.
4.3. Preparation of resin 3b
Chlorosulfonyl polystyrene (432 mg, 0.82 mmol) was added to
a solution of Boc-prolinamide 1b (466 mg, 1.64 mmol, 2 equiv) and
Et3N (0.12 mL, 0.82 mmol, 1 equiv) in anhydrous CH2Cl2 (30 mL) at

10816
R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
rt. The resulting mixture was stirred for four days. The polymer was
then filtered off and washed successively with methanol, water,
methanol/water (1:1), and methanol. The material was dried under
vacuum to give 625 mg of polymer 2b, which corresponds to ap-
proximately 94% of ligand incorporation calculated on the basis of
elemental analysis and weight difference (found: C, 69.08; H, 7.36;
N, 5.98, S, 4.87). IR (ATR): 3302, 1664, 1395, 1318, 1152, 1090,
a 40% aqueous solution of methylamine was added (6.6 mL,
76 mmol). The reaction mixture was stirred overnight at rt. The
phases were separated and the aqueous layer was thoroughly
extracted with chloroform. The combined organic phases were
dried over MgSO4, filtered off, and evaporated in vacuo. The crude
product was purified by silica gel column chromatography (eluent
dichloromethane/methanol/ammonia 6:4:0 to 6:4:0.1). The pure
product was isolated as a colorless oil (605 mg, 2.3 mmol, 50%
651 cmꢀ1
.
A portion of this resin (615 mg) was suspended in dichloro-
methane/trifluoroacetic acid (3 mL/0.75 mL) and stirred at rt for
6 h. After this period, the resin was filtered and washed with MeOH/
Et3N 98:2 (100 mL), water (100 mL), and diethyl ether (100 mL). The
yellow resin was dried under vacuum to give 544 mg of polymer 3b,
which corresponds to approximately 91% of ligand incorporation
and 1.52 mmol gꢀ1 of ligand attached to the resin calculated on the
basis of elemental analysis (found: C, 70.81; H, 7.38; N, 6.37, S, 5.38).
yield). ½a 2D5
ꢃ
ꢀ71.9 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
d 1.46 (s,
9H); 1.87 (m, 2H); 2.04 (m, 1H); 2.20 (m, 1H); 2.43 (s, 3H); 2.75 (t,
J¼5.9 Hz, 2H); 3.38 (m, 2H); 3.42 (m, 2H); 4.22 (dd, 1H, J¼8.1,
3.2 Hz); 6.82 (br s, 1H). 13C NMR (101 MHz, CDCl3): 24.0 (CH2); 28.3
((CH3)3C); 35.5 (CH3); 38.5 (CH2); 47.0 (CH2); 50.5 (CH2); 60.6
(CHN); 80.1 (C(CH3)3); 155.0 (COt2Bu); 172.6 (CON). IR (neat): 3318,
2977, 1664, 1390, 1365, 1163, 1122, 750 cmꢀ1. HRMS calcd for
C
13H25N3O3þHþ: 272.1969; found: 272.1969.
IR (ATR): 3287, 1649, 1530, 1313, 1153, 1096, 574 cmꢀ1
.
4.5. Preparation of resin 3d
4.4. Preparation of resin 3c
The same procedure for resin 3b was followed, using chlor-
osulfonyl polystyrene (242 mg, 0.46 mmol) and 5 (500 mg,
1.84 mmol) as the Boc-prolinamide reactant to give 349 mg of
polymer 2d, which corresponds to approximately 100% of ligand
incorporation calculated on the basis of elemental analysis and
weight difference (found: C, 67.99; H, 7.22; N, 6.29, S, 4.84). IR
The same procedure for resin 2b was followed, using chlor-
osulfonyl polystyrene (716 mg, 1.36 mmol) and 1c (853 mg,
2.72 mmol) as the Boc-prolinamide reactant to give 1.01 g of
polymer 2c, which corresponds to approximately 88% of ligand
incorporation calculated on the basis of elemental analysis and
weight difference (found: C, 70.59; H, 7.55; N, 5.40, S, 4.70). IR
(ATR): 3680, 3344,1675,1530,1390,1334,1153,1091, 703, 574 cmꢀ1
.
(ATR): 3271, 1669, 1401, 1323, 1153, 1096, 755, 698, 574 cmꢀ1
.
A portion of this resin (340 mg) was treated with TFA as de-
scribed for 3b to give 299 mg of polymer 3d, which corresponds to
approximately 100% of ligand incorporation and 1.69 mmol gꢀ1 of
ligand attached to the resin calculated on the basis of elemental
analysis (found: C, 68.66; H, 7.16; N, 7.10, S, 5.31). IR (ATR): 3297,
A portion of this resin (1.0 g) was treated with TFA as described
for 2b to give 850 mg of polymer 3c, which corresponds to ap-
proximately 86% of ligand incorporation and 1.25 mmol gꢀ1 of li-
gand attached to the resin calculated on the basis of elemental
analysis (found: C, 73.87; H, 7.54; N, 5.25, S, 4.64). IR (ATR): 3282,
1649, 1530, 1411, 1328, 1153, 1090, 905, 698 cmꢀ1
.
1649, 1530, 1447, 1318, 1153, 1096, 698, 574 cmꢀ1
.
4.5.1. (S)-tert-Butyl 2-((S)-1-amino-3-methylbutan-2-ylcarbamoyl)
pyrrolidine-1-carboxylate (6). Boc- -Proline (740 mg, 3.44 mmol,
4.4.1. N-(2-Hydroxyethyl)-N0-(tert-butoxycarbonyl)-
L
-prolinamide
L
(4). To a solution of Boc-proline (2.15 g, 10.0 mmol) and 4-
methylmorpholine (1.10 mL, 10.0 mol) in anhydrous THF (30 mL)
at ꢀ15 ꢁC was added dropwise another solution of ethyl chlor-
oformate (0.96 mL,10.0 mmol) inTHF (5 mL). After 20 min of stirring
at that temperature was added ethanolamine (0.60 mL, 10.0 mmol)
in one portion. It was slowly warmed to rt and stirred overnight. The
volatiles were removed in vacuo and the resulting solid was parti-
tioned between chloroform (30 mL) and a 10% aqueous solution of
sodium carbonate (15 mL). The phases were separated and the
aqueous solution was thoroughly extracted with chloroform
(10ꢂ20 mL). The combined organic phases were washed with
a single portion of HCl 2 M (2 mL). The organic layer was dried over
MgSO4, filtered, and evaporated in vacuo. The resulting yellowish
solid was recrystallized (hexane/ethyl acetate) and the pure com-
pound was isolated as a white solid (1.80 g, 7 mmol, 70% yield). Mp
1.25 equiv) and DCC (709 mg, 3.44 mmol, 1.5 equiv) were dissolved
in dichloromethane (25 mL) and cooled to 0 ꢁC. The solution was
stirred for 30 min, then a solution of (R)-N1, N1-dibenzyl-3-
methylbutane-1,2-diamine15 (776 mg, 2.75 mmol, 1 equiv) in
dichloromethane (25 mL) was added dropwise over 10 min. After
the addition was complete, the mixture was warmed to rt and
stirred for a further 10 h. After filtration and removal of solvent
under reduced pressure, the residue was purified by flash column
chromatography on silica gel (hexane/EtOAc, 4:1) to provide
dibenzylated prolinamide (1.07 g, 2.23 mmol, 81%) as a colorless
oil; ½a 2D5
ꢃ
ꢀ65.8 (c 0.9, CHCl3). 1H NMR (400 MHz, CDCl3, 330 K):
d
0.60 (d, 3H, J¼6.8 Hz); 0.80 (d, J¼6.9 Hz, 3H); 1.45 (s, 9H);
1.58e2.15 (m, 5H); 2.39 (dd, 1H, J¼12.9, 6.9 Hz); 2.49 (dd, 1H,
J¼12.9, 7.5 Hz); 3.40 (m, 2H); 3.51 (d, 2H, J¼13.6 Hz); 3.69 (d, 2H,
J¼13.6 Hz); 4.06 (m, 1H); 4.25 (m, 1H); 7.19e7.35 (m, 10H). 13C NMR
157e158 ꢁC (from hexane/ethylacetate). ½a 2D5
ꢃ
ꢀ83.4 (c 1.0, CHCl3).1H
(101 MHz, CDCl3, 330 K): d 16.0 (CH3); 19.6 (CH3); 24.6 (CH2); 28.5
NMR (400 MHz, CDCl3, 330 K):
d
1.47 (s, 9H); 1.89 (m, 2H); 2.05 (m,
(CH3); 29.0 (CH2); 31.8 (CH); 47.0 (CH2); 51.8 (CHN); 55.0 (CH2N);
58.8 (CH2Ph); 60.5 (CHCO); 80.2 (C(CH3)3); 125.9 (CHar); 128.2
(CHar); 129.1 (CHar); 139.4 (Car); 154.2 (COt2Bu); 171.8 (CON). IR
1H); 2.22 (m, 1H); 3.42 (m, 4H); 3.70 (t, J¼5.1, 2H); 4.22 (dd, J¼8.1,
3.5 Hz, 1H); 6.75 (br s, 1H). 13C NMR (101 MHz, CDCl3, 330 K):
d
24.2
(CH2); 28.3 (CH3); 42.3 (CH2); 47.1 (CH2); 60.7 (CHN); 61.9 (CH2); 80.5
(C(CH3)3); 155.5 (COt2Bu); 173.3 (CON). IR (neat): 3371, 3309, 1661,
1562, 1412, 1245, 1167, 1079, 861, 689 cmꢀ1. HRMS calcd for
(neat): 3323, 2930, 1685, 1664, 1390, 1163, 1121, 745, 698 cmꢀ1
.
HRMS calcd for C29H41N3O3þHþ: 480.3221; found: 480.3205.
To a solution of dibenzylated prolinamide (960 mg, 2.0 mmol) in
MeOH (20 mL), was added Pd(OH)2eC (240 mg) in one portion. The
mixture was stirred under H2, at atmospheric pressure, for 4 h and
the catalyst was removed by filtration and washed with methanol.
The solvent was evaporated under reduced pressure and the resi-
due was purified by flash column chromatography on silica gel
(EtOAc/methanol, 5:1) to give 6 (491 mg, 1.64 mmol, 82%) as
C
12H22N2O4þNaþ: 281.1472; found: 281.1468.
4.4.2. N-(2-Methylaminoethyl)-N0-(tert-butoxycarbonyl)-
L-prolina-
mide (5). To a solution of previously synthesized alcohol 4 (1.18 g,
4.6 mmol) and triethylamine (0.99 mL, 7.1 mmol) in dry dichloro-
methane (25 mL), was added dropwise mesyl chloride (0.42 mL,
5.3 mmol) at 0 ꢁC. The reaction mixture was stirred for 3 h until
disappearance of starting alcohol (TLC). The solvent was removed
in vacuo, the residue was redissolved in diethyl ether (25 mL) and
a colorless oil. ½a D25
ꢃ
ꢀ95.6 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
d
0.87 (d, J¼6.8 Hz, 3H); 0.90 (d, J¼6.7 Hz, 3H); 1.47 (s, 9H); 1.77 (m,
1H); 1.90 (br s, 2H); 2.03 (m, 3H); 2.33 (m, 1H); 2.65 (m, 1H); 2.83

R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
10817
(m, 1H); 3.43 (m, 2H); 3.71 (m, 1H); 4.31 (m, 1H). 13C NMR
(101 MHz, CDCl3, 330 K): 17.7 (CH3); 19.1 (CH3); 24.1 (CH2); 28.4
(CH3); 29.9 (CH2); 32.0 (CH); 43.4 (CH2NH2); 47.1 (CH2NBoc); 56.5
(CHN); 60.7 (CHCO); 80.2 (C(CH3)3); 155.1 (COt2Bu); 172.4 (CON). IR
(neat): 3308, 1685, 1659, 1390, 1365, 1163, 1117, 729 cmꢀ1. HRMS
calcd for C15H29N3O3þHþ: 300.2282; found: 300.2277.
d
¼1.30e1.85 (m, 6H); 2.32e2.43 (m, 1H); 2.48e2.53 (m, 1H);
2.58e2.67 (m, 1H); 4.13 (br s, 1H); 4.90 (d, J¼9.0 Hz, 1H); 7.53 (t,
J¼7.9 Hz, 1H); 7.67 (d, J¼7.5 Hz, 1H); 8.16 (d, J¼7.9 Hz, 1H); 8.21 (d,
J¼1.7 Hz, 1H); HPLC analysis Chiracel OD (hexane/i-PrOH¼95/5,
1.5 mL/min, 254 nm, 20 ꢁC) tR¼16.5 min (major) and tR¼23.7 min
(minor); er: 96:4.
4.6. Preparation of resin 3e
4.8.4. (2S,10R)-2-Hydroxy-(4-cyanophenyl)methyl]cyclohexan-1-one
(7d).7a,26 Yield: 77%; anti/syn: 92/8. 1H NMR (400 MHz, CDCl3):
The same procedure for resin 3b was followed, using chlor-
osulfonyl polystyrene (112 mg, 0.21 mmol) and 6 (126 mg,
0.42 mmol) as the Boc-prolinamide reactant to give 174 mg of
polymer 2e, which corresponds to approximately 100% of ligand
incorporation calculated on the basis of elemental analysis and
weight difference (found: C, 68.57; H, 7.50; N, 5.90, S, 4.51).
A portion of this resin (170 mg) was treated with TFA as de-
scribed for 2a to give 142 mg of polymer 3e, which corresponds to
approximately 97% of ligand incorporation and 1.58 mmol gꢀ1 of
ligand attached to the resin calculated on the basis of elemental
analysis (found: C, 70.04; H, 7.47; N, 6.64, S, 5.24). IR (ATR): 3292,
d
¼1.35e2.14 (m, 6H); 2.30e2.50 (m, 2H); 2.53e2.61 (m, 1H); 4.07
(br s, 1H); 4.83 (d, J¼8.8 Hz, 1H); 7.45 (d, J¼8.3 Hz, 2H); 7.65 (d,
J¼8.3 Hz, 2H); HPLC analysis Chiracel OD (hexane/i-PrOH¼95/5,
1.0 mL/min, 220 nm, 20 ꢁC) tR¼29.5 min (major) and tR¼45.5 min
(minor); er: 96:4.
4.8.5. (2S,10R)-2-Hydroxy-(4-trifluoromethylphenyl)methyl]cyclo-
hexan-1-one (7e).29 Yield: 95%; anti/syn: 96/4. 1H NMR (400 MHz,
CDCl3):
2.35e2.60 (m, 3H); 4.07 (br s, 1H); 4.85 (d, J¼8.3 Hz, 1H); 7.45 (d,
J¼7.9 Hz, 2H); 7.61 (d, J¼7.9 Hz, 2H); HPLC analysis Chiracel OD
(hexane/i-PrOH¼95/5, 1 mL/min, 220 nm, 20 ꢁC) tR¼12.3 min
(major) and tR¼15.3 min (minor); er: 96:4.
d¼1.26e1.36 (m. 1H); 1.54e1.80 (m, 4H); 2.05e2.10 (m, 1H);
1649, 1525, 1318, 1153, 1091, 827, 698 cmꢀ1
.
4.7. Typical procedure for aldol reaction
4.8.6. (2S,10R)-2-Hydroxy-(4-chlorophenyl)methyl]cyclohexan-1-one
A mixture of the corresponding catalyst 3 (0.025 mmol), acetic
(7f).26 Yield: 74%; anti/syn: 94/6. 1H NMR (400 MHz, CDCl3):
acid (12 mL, 0.05 mmol), and ketone (1.0 mmol), in water (1 mL) at
0
d
¼1.26e2.11 (m, 6H); 2.31e2.49 (m, 2H); 2.52e2.59 (m,1H); 3.61 (s,
ꢁC was stirred for 15 min in a wheaton vial, and then aldehyde
1H); 4.76 (d, J¼8.4, 1H); 7.25 (d, J¼8.4 Hz, 2H); 7.31 (d, J¼8.8 Hz,
2H); HPLC analysis Chiracel OD (hexane/i-PrOH¼95/5, 1.0 mL/min,
220 nm, 20 ꢁC) tR¼13.9 min (major) and tR¼20.5 min (minor); er:
98:2.
(0.5 mmol) was added. The reaction mixture was stirred until the
aldehyde was consumed (monitored by TLC). The mixture was fil-
tered, the catalyst was successively washed with water and EtOAc,
and the aqueous phase was extracted with EtOAc (3ꢂ5 mL). The
combined organic phases were washed with brine, dried over an-
hydrous MgSO4, and concentrated to give the aldol, which was
purified by flash column chromatography on silica gel (hexane/
ethyl acetate). Diastereoselectivity was determined by 1H NMR
analysis of the crude aldol product. The enantiomeric excess was
determined by chiral-phase HPLC analysis using mixtures of hex-
ane/isopropanol as eluent. Absolute stereochemistry was de-
termined by comparison with the literature data.
4.8.7. (2S,10R)-2-Hydroxy(phenyl)methyl]cyclohexan-1-one
(7g).26,28 Yield: 68%; anti/syn: 95/5. 1H NMR (400 MHz, CDCl3):
d
¼1.27e2.13 (m, 6H); 2.31e2.52 (m, 2H); 2.55e2.67 (m, 1H); 3.99
(br s, 1H); 4.79 (d, J¼8.8 Hz, 1H); 7.29e7.40 (m, 5H); HPLC analysis
Chiracel OD (hexane/i-PrOH¼90/10, 1.0 mL/min, 220 nm, 20 ꢁC)
tR¼10.0 min (major) and tR¼14.9 min (minor); er: 96:4.
4.8.8. (2S,10R)-2-Hydroxy-(2-furyl)methyl]cyclohexanone
(7h).30 Yield: 40%; anti/syn: 88/12. 1H NMR (400 MHz, CDCl3):
4.8. Procedure for catalyst regeneration
d
¼1.36 (m. 1H); 1.68 (m, 3H); 1.84 (m, 1H); 2.11 (m, 1H); 2.38 (m,
1H); 2.47 (m, 1H); 2.92 (m, 1H); 3.89 (br s, 1H); 4.84 (d, J¼8.4 Hz,
1H); 6.29 (d, J¼3.3 Hz, 1H); 6.34 (dd, J¼3.3, 1.8 Hz, 1H); 7.39 (dd,
J¼1.8, 0.8 Hz, 1H); HPLC analysis Chiralpak AD-H (hexane/i-
PrOH¼90/10, 1.0 mL/min, 220 nm, 20 ꢁC) tR¼18.5 min (major) and
tR¼20.0 min (minor), er: 96:4.
Catalyst 3a was placed in a wheaton vial and HCOOH was added
(usually 250 mL for 100 mg of catalyst). The mixture was stirred for
2.5 h, then filtered and successively washed with water, aqueous
NaHCO3, water, MeOH, and diethyl ether. Finally, the product was
dried for 30 min under vacuum at 60 ꢁC.
4.8.9. (2S,10R)-2-Hydroxy-(naphthalene-2-yl)methyl]cyclohexan-1-
4.8.1. (2S,10R)-2-Hydroxy-(4-nitrophenyl)methyl]cyclohexan-1-one
one (7i).7a,26 Yield: 88%; anti/syn: 93/7. 1H NMR (400 MHz, CDCl3):
(7a).26,28 Yield: 91%; anti/syn: 92/8; 1H NMR (400 MHz, CDCl3):
d
¼1.27e1.41 (m, 1H); 1.50e1.78 (m, 4H); 2.07e1.12 (m, 1H);
d
¼1.22e1.84 (m, 6H); 2.30e2.41 (m, 1H); 2.46e2.63 (m, 2H); 4.11
2.33e2.44 (m, 1H); 2.49e2.54 (m, 1H); 2.68e2.77 (m, 1H); 4.10 (br
s, 1H); 4.98 (d, J¼8.8 Hz, 1H); 7.48e7.51 (m, 3H); 7.77 (s, 1H);
7.83e7.87 (m, 4H); HPLC analysis Chiracel OD (hexane/i-PrOH¼85/
15, 1.0 mL/min, 254 nm, 20 ꢁC) tR¼10.5 min (major) and
tR¼12.7 min (minor), er: 98:2.
(d, J¼3.0 Hz, 1H); 4.89 (dd, J¼8.3, 2.9 Hz, 1H); 7.50 (d, J¼8.6 Hz, 2H);
8.19 (d, J¼8.6 Hz, 2H); HPLC analysis Chiracel OD (hexane/i-
PrOH¼95/5, 1.5 mL/min, 220 nm, 20 ꢁC) tR¼18.4 min (major) and
tR¼25.2 min (minor); er: 96:4.
4.8.2. (2S,10R)-2-Hydroxy-(2-nitrophenyl)methyl]cyclohexan-1-one
4.8.10. (2S,10R)-2-Hydroxy-(4-methylphenyl)methyl]cyclohexanone
(7b).7a,28 Yield: 87%; anti/syn: 90/10. 1H NMR (400 MHz, CDCl3):
(7j).29 Yield: 60%; anti/syn: 91/9. 1H NMR (400 MHz, CDCl3):
d
¼1.57e1.88 (m, 6H); 2.07e2.13 (m, 1H); 2.33e2.49 (m, 2H);
d
¼1.51e1.80 (m, 5H); 2.05e2.11 (m, 1H); 2.34 (s, 3H); 2.41e2.50 (m,
2.74e2.78 (m, 1H); 5.45 (d, J¼7.0 Hz, 1H); 7.44 (t, J¼7.5 Hz, 1H); 7.76
(t, J¼7.5 Hz, 1H); 7.77 (d, J¼8.1 Hz, 1H); 7.85 (d, J¼8.1 Hz, 1H); HPLC
analysis Chiracel OD (hexane/i-PrOH¼95/5, 1.0 mL/min, 254 nm,
20 ꢁC) tR¼16.9 min (major) and tR¼20.0 min (minor); er: 94:6.
2H); 2.57e2.64 (m, 1H); 3.94 (br s, 1H); 4.76 (d, J¼8.8 Hz, 1H); 7.16
(d, J¼8.3 Hz, 2H); 7.21 (d, J¼8.3 Hz, 2H); HPLC analysis Chiracel OD
(hexane/i-PrOH¼95/5, 1.0 mL/min, 220 nm, 20 ꢁC) tR¼13.1 min
(major) and tR¼18.4 min (minor), er: 95:5.
4.8.3. (2S,10R)-2-Hydroxy-(3-nitrophenyl)methyl]cyclohexan-1-one
4.8.11. (2S,4S,10S)-2-Hydroxy-(4-nitrophenyl)methyl]-4-
(7c).7a,28 Yield: 78%; anti/syn: 94/6. 1H NMR (400 MHz, CDCl3):
methylcyclohexan-1-one (7k).20d,23,30 Yield: 80%; anti/syn: 94/6. 1H

10818
R. Pedrosa et al. / Tetrahedron 69 (2013) 10811e10819
62, 243e502; (g) Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487e631; (h)
NMR (400 MHz, CDCl3):
d
¼1.06 (d, J¼7.0 Hz, 3H); 1.30e2.12 (m,
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138e5175.
2. (a) Kristensen, T. E.; Hansen, T. Eur. J. Org. Chem. 2010, 3179e3204; (b) Giac-
alone, F.; Gruttadauria, M.; Noto, R. Chim. Ind. 2010, 92, 108e115; (c) Trindade,
A. F.; Gois, P. M. P.; Afonso, C. A. M. Chem. Rev. 2009, 109, 418e514; (d) Corma,
A.; García, H. Adv. Synth. Catal. 2006, 348, 1391e1412; (e) Cozzi, F. Adv. Synth.
Catal. 2006, 348, 1367e1390; (f) Chiral Catalyst Immobilization and Recycling; De
Vos, D. E., Vankelecom, I., Jacobs, P. M., Eds.; Wiley-VCH: Weinheim, Germany,
2000.
5H); 2.36e2.79 (m, 3H); 3.94 (br s, 1H); 4.93 (d, J¼8.8 Hz, 1H); 7.51
(d, J¼8.8 Hz, 2H); 8.22 (d, J¼8.8 Hz, 2H); HPLC analysis Chiralpak
AD-H (hexane/i-PrOH¼90/10, 1.0 mL/min, 254 nm, 20 ꢁC)
tR¼37.2 min (major) and tR¼41.7 min (minor), er: 95:5.
4.8.12. (3S,10R)-3-[10-Hydroxy-10-(4-nitrophenyl)methyl]-tetrahy-
drothiopyran-4-one (7l).32 Yield: 66%; anti/syn: 93/7. 1H NMR
3. (a) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc. Rev. 2008, 37, 1666e1688;
(b) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33e57;
(c) Simon, M.-O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415e1427.
(400 MHz, CDCl3):
d
¼2.49e2.54 (m, 1H); 2.65e2.73 (m, 1H);
2.78e2.85 (m, 2H); 2.98e2.06 (m, 3H); 3.64 (br s, 1H); 5.06 (d,
J¼7.9 H, 1H); 7.55 (d, J¼8.8 Hz, 2H); 8.25 (d, J¼8.8 Hz, 2H); HPLC
analysis Chiralpak AD-H (hexane/i-PrOH¼90/10, 1.0 mL/min,
254 nm, 20 ꢁC) tR¼58.0 min (minor) and tR¼101.0 min (major), er:
98:2.
4. (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
ꢀ
ꢀ
2004; Vol. 1e2; (b) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry
2007, 18, 2249e2293; (c) Zlotin, S. G.; Kucherenko, A. S.; Beletskaya, I. P. Russ.
Chem. Rev. 2009, 78, 737e784; (d) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev.
2010, 39, 1600e1632.
5. Lipshutz, B. H.; Ghorai, S. Org. Lett. 2012, 14, 422e425.
6. (a) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal. 2001, 343, 171e173;
(b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. Adv. Synth.
Catal. 2002, 344, 533e542.
4.8.13. (3S,10R)-3-[10-Hydroxy-10-(4-nitrophenyl)methyl]-tetrahy-
dropyran-4-one (7m).33 Yield: 86%; mixture of anti/syn: 80/20, 1H
7. (a) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417e4420;
(b) Paladhi, S.; Das, J.; Mishra, P. K.; Dash, J. Adv. Synth. Catal. 2013, 355,
274e280.
NMR (400 MHz, CDCl3):
d
¼2.50e2.57 (m, 1H); 2.64e2.74 (m, 1H);
2.85e2.93 (m, 1H); 3.42e3.49 (m, 1H); 3.70e3.79 (m, 3H);
4.18e4.24 (m, 1H); 4.99 (d, J¼7.9 Hz, 0.8H, anti); 5.54 (d, J¼2.6 Hz,
0.2H, syn); 7.52 (d, J¼8.8 Hz, 2H); 8.23 (d, J¼8.8 Hz, 2H); analysis
Chiralpak AD-H (hexane/i-PrOH¼80/20, 1.0 mL/min, 254 nm, 20 ꢁC)
tR¼24.6 min (minor) and tR¼28.6 min (major), er: 93:7.
8. (a) Liu, Y.-X.; Sun, Y.-N.; Tan, H.-H.; Liu, W.; Tao, J.-C. Tetrahedron: Asymmetry
2007, 18, 2649e2656; (b) Liu, Y.-X.; Sun, Y.-N.; Tan, H.-H.; Liu, W.; Tao, J.-C.; Liu,
L. R. Catal. Lett. 2008, 120, 281e287; (c) Gruttadauria, M.; Giacalone, F.; Mar-
culescu, A. M.; Lo Meo, P.; Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 4688e4698;
(d) Gruttadauria, M.; Pia Salvo, A. N.; Giacalone, F.; Agrigento, P.; Noto, R. Eur. J.
Org. Chem. 2009, 5437e5444; (e) Gruttadauria, M.; Marculescu, A. M.; Noto, R.
Adv. Synth. Catal. 2008, 350, 1397e1405; (f) Gruttadauria, M.; Marculescu, A. M.;
ꢂ
Salvo, A. M. P.; Noto, R. Arkivoc 2009, 8, 5e15; (g) Font, D.; Jimeno, C.; Pericas,
4.8.14. (3S,10R)-3-[10-Hydroxy-10-(4-nitrophenyl)methyl]-4-
M. A. Org. Lett. 2006, 8, 4653e4655; (h) Font, D.; Sayalero, S.; Bastero, A.; Ji-
oxopiperidine-1-carboxylic acid tert-butyl ester (7n).34 Yield: 87%;
ꢂ
ꢀ
~ꢀ
meno, C.; Pericas, M. A. Org. Lett. 2008, 10, 337e340; (i) Banon-Caballero, A.;
mixture of anti/syn: 78/22, 1H NMR (400 MHz, CDCl3):
d
¼1.40 (br s,
Guillena, G.; Najera, C. Green Chem. 2010, 12, 1599e1606.
9. Shen, Z.; Ma, J.; Liu, Y.; Jiao, C.; Li, M.; Zhang, Y. Chirality 2005, 17, 556e558.
10. Kochetkov, S. V.; Kucherenko, A. S.; Zlotin, S. G. Eur. J. Org. Chem. 2011,
6128e6133.
9H); 2.49e2.56 (m, 2H); 2.77 (br s, 1H); 2.93 (t, J¼11.0 Hz, 1H); 3.27
(br s, 1H); 3.70e3.83 (m, 1H); 3.87 (d, J¼3.6 Hz, 1H); 4.19 (m, 1H);
4.97 (dd, J¼7.9, 3.1 Hz, 0.96H, anti); 5.48 (br s, 0.04H, syn); 7.56 (d,
J¼8.4 Hz, 2H); 8.24 (d, J¼8.8 Hz, 2H); analysis Chiralpak AD-H
(hexane/i-PrOH¼90:10, 1.0 mL/min, 254 nm, 20 ꢁC) tR¼22.3 min
(major) and tR¼24.6 min (minor), er: 95:5.
11. Zhang, X.; Zhao, W.; Yang, L.; Cui, Y. J. Appl. Polym. Sci. 2013, 3537e3542.
ꢀ
12. (a) Fuerte, A.; Corma, A.; Sanchez, F. Catal. Today 2005, 107e108, 404e409; (b)
€
ꢀ
ꢀ
ꢀ
Doyaguez, E. G.; Calderon, F.; Sanchez, F.; Fernandez-Mayoralas, A. J. Org. Chem.
€
2007, 72, 9353e9356; (c) Zamboulis, A.; Moitra, N.; Moreau, J. J. E.; Cattoen, X.;
Chi Man, M. W. J. Mater. Chem. 2010, 20, 9322e9338; (d) Massi, A.; Cavazzini,
A.; Del Zoppo, L.; Pandoli, O.; Costa, V.; Pasti, L.; Giovannini, P. P. Tetrahedron
€
Lett. 2011, 52, 619e622; (e) Monge-Marcet, A.; Pleixats, R.; Cattoen, X.; Chi Man,
4.8.15. 2-Hydroxy-(4-nitrophenyl)methyl]cyclopentan-1-one
ꢀ
M. V.; Alonso, D. A.; Almasi, D.; Najera, C. New J. Chem. 2011, 35, 2766e2772; (f)
(7o).31 Yield: 80%; anti/syn: 32/68; anti-diastereomer (2S, 10R), 1H
€
ꢀ
~ꢀ
Monge-Marcet, A.; Cattoen, X.; Alonso, D. A.; Najera, C.; Chi Man, M. W.;
Pleixats, R. Green Chem. 2012, 14, 1601e1610; (g) Banon-Caballero, A.; Guillena,
G.; Najera, C.; Faggi, E.; Sebastian, R. M.; Vallribera, A. Tetrahedron 2013, 69,
NMR (400 MHz, CDCl3):
d
¼1.51e1.80 (m, 3H); 1.98e2.07 (m, 1H);
ꢀ
ꢀ
2.21e2.52 (m, 3H); 4.78 (s, 1H); 4.85 (d, J¼9.2 Hz, 1H); 7.54 (d,
J¼8.8 Hz, 2H); 8.22 (d, J¼8.8 Hz, 2H); HPLC analysis Chiralpak ADH
(hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm, 20 ꢁC) tR¼55.4 min
(minor) and tR¼58.2 min (major); er: 87:13. syn-diastereomer (2R,
1307e1315.
13. (a) Kristensen, T. E.; Vestli, K.; Jacobsen, M. G.; Hansen, F. K.; Hansen, T. Org. Lett.
2009, 11, 2968e2971; (b) Kristensen, T. E.; Vestli, K.; Fredkinsen, K. A.; Hansen,
F. K.; Hansen, T. J. Org. Chem. 2010, 75, 1620e1629.
14. Zhou, J.; Wan, J.; Ma, X.; Wang, W. Org. Biomol. Chem. 2012, 10, 4179e4185.
10R), 1H NMR (400 MHz, CDCl3):
d
¼1.65e1.76 (m, 2H); 1.96e2.22
ꢂ
15. Ayats, C.; Henseler, A. H.; Pericas, M. A. ChemSusChem 2012, 5, 320e325.
ꢀ
16. Andres, J. M.; Manzano, R.; Pedrosa, R.; Rodríguez, P. Eur. J. Org. Chem. 2010,
(m, 3H); 2.36e2.52 (m, 2H); 2.69 (br s, 1H); 5.43 (d, J¼2.2 Hz, 1H);
7.53 (d, J¼8.8 Hz, 2H); 8.22 (d, J¼8.8 Hz, 2H). HPLC analysis Chir-
alpak ADH (hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm, 20 ꢁC)
tR¼35.0 min (minor) and tR¼45.1 min (major); er: 52:48.
5310e5319.
ꢀ
ꢀ
ꢀ
17. (a) Pedrosa, R.; Andres, J. M.; Manzano, R.; Roman, D.; Tellez, S. Org. Biomol.
ꢀ
ꢀ
Chem. 2011, 9, 935e940; (b) Pedrosa, R.; Andres, J. M.; Manzano, R.; Perez-
ꢀ
Lopez, C. Tetrahedron Lett. 2013, 54, 3101e3104.
€
18. Schlunsen, J.; Manecke, G. Makromol. Chem. 1987, 188, 3005e3016.
19. Chlorosulfonyl polystyrene PS-1%DVB, 100e200 mesh, nominal charge:
1e2 mmol gꢀ1
.
Acknowledgements
20. (a) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetra-
hedron 2006, 62, 317e328; (b) Jiang, J.; He, L.; Luo, S.-W.; Cun, L. F.; Gong, L.-Z.
Chem. Commun. 2007, 736e738; (c) Karmakar, A.; Maji, T.; Wittmann, S.; Raiser,
O. Chem.dEur. J. 2011, 17, 11024e11029; (d) Agarwal, J.; Peddinti, R. K. Eur. J. Org.
We acknowledge the financial support provided by the Spanish
DGICYT (Project CTQ 2011-28487). C.P.-L. thanks the Universidad of
Valladolid for a fellowship.
~
Chem. 2012, 6390e6406; (e) Martínez-Castaneda, A.; Poladura, B.; Rodríguez-
ꢀ
Solla, H.; Concellon, C.; del Amo, V. Org. Lett. 2011, 13, 3032e3035; (f) Fotaras,
S.; Kokotos, C. G.; Kokotos, G. Org. Biomol. Chem. 2012, 10, 5613e5619; (g)
Revelou, P.; Kokotos, C. G.; Mouteuelis-Minakakis, P. Tetrahedron 2012, 68,
8732e8738.
Supplementary data
21. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921e2944.
22. García-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313e354.
23. (a) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Zheng, X.; Cheng, J. P. Tetrahedron 2007, 63,
11307e11314; (b) Visnumaya, M. R.; Singh, V. K. J. Org. Chem. 2009, 74,
4289e4297.
24. The change in the diastereoselection for the aldol reaction of cyclopentanone
had been previously observed: (a) See Ref. 32 and references cited therein. (b)
Fotaras, S.; Kokotos, G. C.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011,
CopiesofIR(ATR)spectraforsupportedcatalysts,copiesof1HNMR
and 13C NMR spectra for all new compounds and copies of the HPLC
chromatograms are available. Supplementary data related to this ar-
ticle can be found at http://dx.doi.org/10.1016/j.tet.2013.10.093.
References and notes
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