Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction

Article abstract of DOI:10.1016/j.tet.2012.11.097

Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intramolecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained under similar homogeneous reaction conditions using an organocatalyst of related structure. For the intermolecular process, the aldol products were obtained at room temperature and using only 2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts can be used in the intramolecular aldol reaction allowing the synthesis of the Wieland-Miescher and ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on the obtained results.

Full text of DOI:10.1016/j.tet.2012.11.097

Tetrahedron 69 (2013) 1307e1315
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Recoverable silica-gel supported binam-prolinamides as
organocatalysts for the enantioselective solvent-free intra- and
intermolecular aldol reaction
a
a
,
a
,
b
*
*
~ꢀ
ꢀ
Abraham Banon-Caballero , Gabriela Guillena , Carmen Najera , Enrico Faggi ,
b
b,
*
ꢀ
Rosa María Sebastian , Adelina Vallribera
Departamento de Química Organica e Instituto de Síntesis Organica, Universidad de Alicante, Apdo. 99, Facultad de Ciencias, E-03080 Alicante, Spain
a
ꢀ
ꢀ
b
ꢁ
ꢁ
Departamento de Química, Universitat Autonoma de Barcelona, Cerdanyola del Valles, 08193 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intra-
molecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic
stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained
under similar homogeneous reaction conditions using an organocatalyst of related structure. For the
intermolecular process, the aldol products were obtained at room temperature and using only
2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction
conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be
reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts
can be used in the intramolecular aldol reaction allowing the synthesis of the WielandeMiescher and
ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on
the obtained results.
Received 4 September 2012
Received in revised form 26 November 2012
Accepted 29 November 2012
Available online 6 December 2012
Keywords:
Solvent-free
Organocatalysis
Aldol reaction
Enantioselective
WielandeMiescher ketone
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
techniques,11 in order to allow the efficient mixing of reagents.
However, using different binam-prolinamides12 derivatives
1
The demand of sustainable processes, due to the environmental
concerns of our society, has led to the development of greener
methods for chemical synthesis.1 The environmental impact or E-
factor,2 defined as the ratio of the mass of waste per unit of product,
in the pharmaceutical industry is bigger than in other industry
segments.3 The use of solvents supposes more than 80% of the mass
of any pharmaceutical batch processes.4 Therefore, the imple-
mentation of solvent-free methodologies for the synthesis of drugs
are essential, especially if those processes are run with stereo-
chemical control.5 One of these processes is the asymmetric aldol
reaction,6 with the use of organocatalysts,7 such as proline or
prolinamides derivatives, for this transformation providing excel-
lent results under solvent-free conditions.8 Under these reaction
conditions, the normally used excess of nucleophile, required to
shift the involved equilibrium, can be reduced to a minimum
amount and the rate of the reaction is normally increased. More-
over, most of the aldol organocatalyzed reactions9 required only
mild temperatures and therefore could be considered as an ener-
getic sustainable process. Usually, the use of solvent-free conditions
in the aldol reaction10 is accompanied by the use of ball-milling
(Fig. 1) as organocatalysts for the intermolecular and intra-
molecular aldol reaction under solvent-free conditions, we have
demonstrated that the use of conventional magnetic stirring is
enough to allow the reaction to proceed with excellent results.10eeh
Fig. 1. Binam-prolinamide derivatives used as organocatalyst under solvent-free
* Corresponding authors. E-mail address: gabriela.guillena@ua.es (G. Guillena).
conditions.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.097

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A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1308
Thus, when C2-symmetrical prolinamide derivative 1a was used
reacted with TEOS (tetraethoxysilane) and NH4F to form a white
solid, which after work-up was dried in vacuo for several hours to
afford supported catalyst 3 as a white powder. The catalyst loading
was determined by elemental analyses being in average 0.32 mmol
per gram of silica.
as catalyst under solvent free-conditions, both the amount of cat-
alyst and of nucleophilic ketone were reduced (5 mol % of 1a and
2 equiv) compared to the required amounts used in solution. The
results, in terms of yields and selectivities, were similar to those
achieved when the reaction was carried out in solvents, such as
DMF, DMF/water mixtures or just water, with the rate of the re-
action being increased from days to hours. Furthermore, the best
results were obtained using conventional magnetic stirring, both
for the intra- and the intermolecular aldol reaction and the catalyst
was recovered after the reaction completion by a simple acid-base
work-up.10f The use of binam-sulphonamide prolinamide de-
rivative 1b (5 mol %) under solvent-free conditions, and 1 mol % of
benzoic acid as co-catalyst, led also to a similar performance for the
intermolecular aldol reaction.10g,h In addition, catalyst 1b showed
to be particularly efficient for the intramolecular aldol reaction,
allowing the gram scale synthesis of the WielandeMiescher ketone
and analogues, following a convenient one-pot two-step proce-
dure.10g,h,13 Notwithstanding, the recovery of the catalyst was only
possible by chromatographic techniques.
Once the catalyst was immobilized, the reaction conditions
parameters, such as catalyst loading, amount of acid added as co-
catalyst, amount of nucleophile, addition of water and tempera-
ture were evaluated in the model aldol reaction between cyclo-
hexanone and p-nitrobenzaldehyde. Initially, the need of the use of
benzoic acid (5 mol %) as co-catalyst under solvent-free conditions
was explored, finding that was determinant in order to accelerate
the reaction and to achieve higher diastereo- and enantioselectiv-
ities (Table 1, compare entries 1 and 2). Then, the addition of small
amount of water to the reaction mixture was evaluated, with the
addition of 12 equiv of water providing the best results in terms of
reaction time, diastereo- and enantioselectivities (Table 1, Entries
3e7). Under the presence of 12 equiv of water, the effect of the
temperature was studied (Table 1, entries 8 and 9). Decreasing the
temperature at 5 ꢀC, led to an increase of the reaction time, with
slightly higher diastereo- and enantioselectivity being achieved
(Table 1, entry 9). The required catalyst loading was evaluated un-
der solvent-free conditions in the presence of water at 25 ꢀC (Table
1, entries 10 and 11), with 10 mol % of catalyst 3 leading to the best
results.
As the use of a supported organocatalyst14 would allow the re-
covery of the catalyst, increasing the global efficiency of the pro-
cess,15 we have recently synthesized
a polymer supported
prolinamide system 1c and a cross-linked supported prolinamide
system 1d, which were very efficient for the intermolecular aldol
reaction under solvent-free conditions.16 However, the application
of this supported organocatalyst for the more interesting intra-
molecular10g,h,13 version of this reaction failed, and as far as our
knowledge, only unsatisfactory results were achieved by using
other supported organocatalysts for this transformation.17
Therefore, we thought of interest to design a supported binam-
prolinamide derivative, which could be used for the general inter-
and intramolecular aldol reaction under solvent-free conditions. In
order to have a cheap and robust support we decided to anchor our
catalytic system to silica-gel.
Table 1
Optimization of the intermolecular aldol reaction catalyzed by 3a
Here, we report a recoverable silica-gel supported organo-
catalyst able to catalyze not only the intermolecular but also the
intramolecular aldol reaction with high efficiency under mild and
solvent-free conditions, which meets all the criteria of a green
process.
Entry Solvent
H2O
T (ꢀC) t (h) Conversion (%)b anti/sync ee (%)d
(0.15 mL) (equiv)
1e
2
d
d
d
25
25
25
25
25
25
25
10
5
24 99
70:30
93:7
92:8
94:6
93:7
93:7
88:12
97:3
80
90
92
92
92
92
88
93
93
92
92
88
63
82
36
88
73
d
6
9
4
3
5
7
96
97
91
96
97
97
3
d
3
4
d
6
12
25
50
12
12
12
12
d
d
d
d
d
d
5
d
2. Results and discussion
6
d
7
d
8
d
15 71
24 91
The immobilization of the binam-prolinamide derivative 2 was
carried out by a solegel procedure.18 First, a photoinduced thiol-
ene coupling (TEC)16,19 strategy was used to prepare the required
silicon precursor (Scheme 1). Hence, the styrylsulfonyl binam-
derivative 2 was obtained by reacting commercially available so-
dium 4-vinylbenzenesulfonate with thionyl chloride to give the
expected sulfonyl chloride derivative, which was further reacted
with (Ra)-1,10-binaphthyl-2,20-diamine. The achieved binam-
9
d
94:6
10f
11g
12
13
14
15
16
17
d
25
25
25
25
25
25
25
25
6
96
93:7
92:8
d
24 91
48 80
72 74
120 70
120 48
Hexane
DMF
CH2Cl2
MeOH
H2O
4a
90:10
60:40
86:14
65:35
88:12
75:25
7
97
72 99
sulfonyl derivative was subsequently coupled with N-Boc-D-pro
a
General reaction conditions: the reaction was carried out using 4-
nitrobenzaldehyde (0.15 mmol) cyclohexanone (0.3 mmol), benzoic acid (5 mol %,
otherwise stated), H2O and catalyst 3 (20 mol %, otherwise stated).
followed by deprotection with trifluoroacetic acid. A solution of
compound 2 was added to 3-(triethoxysilyl)propane-1-thiol and
AIBN to afford the required intermediate silicon derivative as
a glassy pale yellow solid in 66% yield. This intermediate was
b
Conversion based on the amount of the unreacted aldehyde.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral phase HPLC analysis for the anti-6aa isomer.
The reaction was carried out in the absence of benzoic acid.
10 mol % of catalyst 3 was used.
5 mol % of catalyst 3 was used.
e
f
g
The use of several solvents (0.15 mL), such as hexane, DMF,
dichloromethane, methanol, water and cyclohexanone as reaction
media was tested (Table 1, entries 12e17), with the best results in
being encountered in hexane and pure water (Table 1, entries 12
Scheme 1. Synthesis of the silica-gel supported organocatalyst.

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A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1309
and 16) at 25 ꢀC. So, the optimal reaction conditions were 2 equiv of
nucleophilic ketone, 10 mol % of catalyst 3 in the presence of
5 mol % of benzoic acid as co-catalysts and 12 equiv of water at
room temperature (Table 1, entry 10). Under those conditions,
mainly the anti-isomer 6aa was formed in high yield, diastereo- and
enantioselectivity. These results were comparable to those ach-
ieved using binam-derived prolinamides (product anti-6aa was
obtained in 80% yield, 80% de, 86% ee and 94% yield, 98% de, 88% ee
using catalyst 1a and 1b, respectively) and slightly better than
those obtained using the related polymer supported prolinamide
catalysts (catalyst 1c afforded product anti-6aa in 83% yield, 90% de,
88% ee; catalyst 1d afforded product anti-6aa in 88% yield, 88% de,
92% ee) under similar solvent-free conditions.10feh,16
Under the optimal reaction conditions, the scale and the scope of
the process were studied (Table 2). Thus, the catalyst was applied in
the synthesis of product anti-6aa in gram scale, with the product
being achieved in 86% yield and 89% ee (Table 2, entry 1). The reaction
between cyclohexanone and several aromatic aldehydes proceeded
to give the corresponding anti-products 6 in high yields, diastereo-
and enantioselectivities (Table 2, entries 1e6). Longer reaction times
were required when non-activated aldehydes, such as benzaldehyde
or m-methylbenzaldehyde were used as electrophiles (Table 2, entry
3 and 6). However, the reaction failed when aliphatic aldehydes, such
as cyclohexanecarbaldehyde, decanal or acetaldehyde were used as
electrophiles. Then, the influence of the ketone structure was eval-
uated. As occurred with other prolinamides of similar structures, the
reaction between cyclopentanone and p-nitrobenzaldehyde led to
the formation of mainly the syn-isomer 6ba albeit in low enantiose-
lectivity (Table 2, entry 7). More efficient was the reaction between
tetrahydro-4-pyranone and p-nitrobenzaldehyde giving anti-6ca in
96% ee (Table 2, entry 8). Then, some acyclic ketones were tested in
this reaction. The reaction with acetone gave compound 6da in high
yield and good enantioselectivity (Table 2, entry 9). When asym-
metric ketones were used as nucleophile, also the corresponding iso-
isomer could be formed depending on the structure of the ketone.
Thus, while the use of 2-butanone and
to formation of mainly the iso-isomer 7ea and iso-7ga, respectively, in
good enantioselectivities (Table 2, entries 10 and 12), the use of
a-methylsulfanyl acetone led
a-
methoxyacetone gave mainly the anti-isomer 6fa with good results
(Table 2, entry 11). In general, these results are superior to those
obtained with the related polymer supported prolinamides with
shorter reaction times being required for the reaction.16
Table 2
Solvent-free intermolecular aldol reaction catalyzed by 3a
Entry
1e
Major product
t (h)
Yield (%)b
90 (86)
6/7
anti/sync
ee (%)d
95 (89)
6 (6)
d
94/6 (90/10)
2
3
4
5
6
7f
24
72
24
24
384
24
91
85
86
90
82
80
d
d
d
d
d
d
93/7
93/7
94/6
95/5
90/10
29/71
89
91
93
98
90
50
(continued on next page)

~ꢀ
A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1310
Table 2 (continued )
Entry
Major product
t (h)
Yield (%)b
6/7
anti/sync
ee (%)d
96
8
6
95
d
93/7
9
24
48
93
67
d
79
88
10
32/68
d
11
12
24
25
92
48
93/7
85/15
89
81
30/70
d
a
Reaction conditions: 4 (0.6 mmol), 5 (0.3 mmol), benzoic acid (5 mol %), H2O (12 equiv) and catalyst 3 (10 mol %).
Yield of the pure product after purification by column chromatography.
Determined by 1H NMR of the crude product.
Determined by chiral phase HPLC analysis.
In parenthesis, the results achieved starting from 16 mmol of cyclohexanone and 8 mmol of p-nitrobenzaldehyde. The reaction was carried out at 0 ꢀC.
b
c
d
e
Catalyst 3 (20 mol %) in the presence of 5 mol % benzoic acid and
Table 3
Recycling studies of catalyst by 3a
12 equiv of water was able to promote the cross aldol reaction
between two aldehydes: propanal with p-nitrobenzaldehyde and
p-cyanobenzaldehyde. In this case, 5 equiv of propanal were re-
quired in order to obtain, after reduction with NaBH4, the corre-
sponding anti-1,3-diols 8 with moderate results (Scheme 2). The
extension of this process to the cross aldol reaction between two
aliphatic aldehydes, such as isobutyraldehyde and decanal was,
however, unsuccessful.
Cycle
Yield (%)b
anti/sync
ee (%)d
1
2
3
4
5
6
7
8
9
88
90
87
85
85
82
79
77
73
93/7
93/7
92/8
94/6
93/7
95/5
93/7
94/6
94/6
92
91
92
94
92
93
94
90
93
a
Scheme 2. Solvent-free cross aldol between aldehydes catalyzed by 3.
Reaction conditions: 4a (0.6 mmol), 5a (0.3 mmol), benzoic acid (5 mol %) and
catalyst 3 (10 mol %).
b
Next, the recovery and reuse of catalyst 3 was tested with the
results summarized in Table 3. The catalyst can be recovered by
filtration and reused up to nine times without changes in the
achieved diastereo- and enantioselectivities. Only a small decrease
of the yield was observed after the fifth cycle. This could be at-
tributed to two causes: one the occlusion of benzoic acid in the
silica supported catalyst, the other being the simple catalyst
leaching. To confirm the last, the silica supported catalyst coming
for the last cycle (cycle 9) was resubmitted to elemental analysis
showing 0.18 mmol per gram of catalyst loading.
More challenging was the application of the silica supported
catalyst to the intramolecular aldol reaction to give the interesting
and useful WielandeMiescher ketone and analogous.21 Recently,
we described the use of Binam-Pro-sulfonamide 1b as excellent
catalyst for the intramolecular aldol reaction under solvent-free
Yield of the pure product after purification by column chromatography.
c
Determined by 1H NMR of the crude product.
d
Determined by chiral phase HPLC analysis.
conditions.10f,g,13 However, the use of the related polymer sup-
ported catalysts 1c and 1d, for these transformations under similar
conditions, failed.16 This process, which has been deeply studied
under homogeneous conditions, has been scarcely reported using
supported catalysts under heterogeneous conditions,17 probably
due to poor reactivity displayed by ketones 9 compared to the in-
termolecular aldol reaction. In order to achieve the right configured
WielandeMiescher ketone 9a, catalyst ent-3 was used in this pro-
cess. First, some optimization of the reaction conditions was per-
formed (Table 4).

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A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1311
Table 4
Table 5
Optimization of the reaction conditions for the intramolecular aldol reactiona
Intramolecular aldol reaction catalyzed by ent-3.a
Entry Solvent (0.15 mL) H2O (equiv) T (ꢀC) t (d) Conversion (%)b ee (%)c
Entry
n
R
t (d)
Product
Yield (%)b
ee (%)c
1
2
2
2
1
2
2
2
2
2
2
Me
Me
Me
Me
Allyl
Bn
Me
Me
Me
Me
5
5
7
7
7
10
5
5
5
5
10a
10a
10a
10b
10c
10d
10a
10a
10a
10a
88
91
81
85
77
73
90
87
83
75
80
88
84
88
92
91
82
80
77
79
1
H2O
DMF/H2O
Hexane
d
25
7
27
70
2d
3e
4
2
3
4
5
d
d
d
d
d
d
12
d
d
25
25
25
0
25
25
25
50
25
7
3
5
7
3
3
3
3
3
0
99
99
0
67
55
25
63
10
d
73
81
d
75
66
69
71
d
5
6
d
7f
8g
9h
10i
6d
7e
8
d
d
a
9
d
Reaction conditions: 9 (0.1 mmol), benzoic acid (5 mol %) and catalyst ent-3
10f
(20 mol %).
b
c
d
e
f
a
After purification by column chromatography.
Determined by chiral phase HPLC analysis.
The reaction was carried out starting from 4 mmol of ketone 9a (800 mg).
One-pot two-step procedure, with the Michael addition taking place in 3 h.
Second run.
Third run.
Fourth run.
Fifth run.
General reaction conditions: the reaction was carried out using 0.3 mmol 9a,
20 mol % of catalyst ent-3 and 5 mol % of benzoic acid (otherwise stated).
b
Conversion based on the amount of the unreacted ketone.
Determined by chiral phase HPLC analysis for the 10a isomer.
40 mol % of catalyst was used.
10 mol % of benzoic acid was used.
c
d
g
h
i
e
f
Performed in a ball mill at rotation speed of 900 rpm.
When the reaction was performed in solution (Table 4, entries
1e3), the best results were achieved in hexane (entry 3) while the
reaction failed when was carried out in a mixture of DMF/H2O
(entry 2). Better yield and enantioselectivity was achieved under
solvent free-conditions, with compound 10a being obtained with
81% ee (Table 4, entry 4). Lowering the temperature at 0 ꢀC de-
creased the activity of the catalyst under solvent-free conditions,
with no product formation being detected after 7 d reaction time
(Table 4, entry 5). In order to accelerate the reaction rate, a double
amount of catalyst loading (40 mol %) was essayed (Table 4, entry
6), but the encountered yield of the reaction after 3 d was signifi-
cantly lower than using 20 mol % of catalyst. Increasing the amount
of the benzoic acid catalyst to 10 mol %, adding a small amount of
water or increasing the temperature at 50 ꢀC (Table 4, entries 7e9)
did not have a positive effect on the reaction results. Finally the
effect of the use of the ball-milling technique in order to achieve
a better mixing of the reagents was explored (Table 4, entry 10),
with the results being very poor. Hence, the best results were
achieved under solvent-free conditions, using conventional mag-
netic stirring, giving product 10a in 88 yield and 80% ee (Table 4,
entry 4) under solvent-free conditions and using conventional
magnetic stirring. Although these results were slightly inferior to
those achieved using homogeneous catalyst 1b (95% yield, 90% ee),
this is, as far as our knowledge, the best result for this important
reaction under heterogeneous conditions.
ketones analogues with interesting applications in natural product
synthesis leading to the expected product in good yield and enan-
tioselectivity (Table 5, entries 4e6).10h,20 Then, the recovery and
reuse of catalyst ent-3 for this annulation process was evaluated. As
for the intermolecular process, the catalyst can be recovered by fil-
tration. In this case it was reused for five times without changes in
the achieved enantioselectivities, with only a small decrease of the
yield was observed after the fifth cycle (Table 5, entries 7e10).
Very interesting was the possible application of catalyst 3 in the
kinetic resolution of the racemic keto ester 11 by an intramolecular
aldol reaction (Scheme 3), affording compound 12 in good results.
The achieved compound 12 has been recently synthesized with
similar results using either a chiral phosphoric acids,22 or Cinchona
ammonium salts as PTC23 by an enantioselective Michael addition
of the corresponding keto ester to methyl vinyl ketone followed by
an aldol reaction. This product serves as a starting material for the
synthesis of dihydrocoumarins.24
Once the best conditions for this reaction were found (20 mol %
of catalyst ent-3, 5 mol % of benzoic acid, solvent-free, 25 ꢀC), these
were applied to other cyclization process with the results being
summarized in Table 5. The possibility of carrying out this process
on a large scale was also explored, finding that the reaction proceed
even with slightly better results (Table 5, entry 2). Recently, we
have reported the synthesis of compound 10a (n¼2) using a one-
pot two-step procedure starting from the 1,3 diketone and
methyl vinyl ketone catalyzed by a N-tosyl-binam-prolinami-
de.10h,13 The application of this procedure using catalyst ent-3 was
also possible achieving similar results to those obtained in the di-
rect intramolecular process (Table 5, compare entries 1 and 3).
This process was extended to the synthesis of the five membered
bicyclic compound 10b (n¼1) and to other WielandeMiescher
Scheme 3. Intramolecular aldol reaction of racemic b-keto ester 11.
3. Conclusions
In summary, silica supported binam-S-prolinamide sulphona-
mide is an effective catalyst, which promotes not only the in-
termolecular aldol reaction between aldehydes and ketones and the
cross aldol reaction between aldehydes, but also the more interesting
intramolecular aldol reaction, under solvent-free conditions using
magnetic stirring. The catalyst can be recovered and reused several
times. In addition, only 2 equiv of ketone as nucleophiles can be used.
This procedure allows the synthesis of high interesting building

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A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1312
blocks under solvent-free conditions using a recyclable catalysts
meeting almost all the criteria of sustainable chemistry.
125.6,126.4,127.4,127.45,127.6,127.7,128.1,128.6,130.1,130.5,130.7,
131.1, 132.1, 133.5, 135.0, 138.0, 142.0, 173.4. Anal. Calcd for
C
33H29N3O3S: C, 72.4; H, 5.3; N 7.7; S 5.8. Found: C, 72.6; H, 5.4; N 7.7;
S 5.7.
To a solution of product 2 (250 mg, 0.46 mmol) in 8 mL of
4. Experimental section
All reactions for the catalyst preparation were carried out under
argon. Dry DMF, dry toluene, dry CH2Cl2, dry THF, pyridine and
triethylamine and all others reagents were commercially available
and used without further purification. Aldehydes were distilled
prior to use. Only the structurally most important peaks of the IR
spectra are listed. 1H NMR (300 MHz, 400 MHz) and 13C NMR
(75 MHz) spectra were obtained spectra were obtained at 25 ꢀC on
a Bruker AC-300 at 25 ꢀC using CDCl3 as solvent and TMS as internal
standard, unless otherwise stated. Optical rotations were measured
on a Perkin Elmer 341 polarimeter. HPLC analyses were performed
on an Agilent 1100 series equipped with a chiral column (detailed
for each compound below), using mixtures of n-hexane/isopropyl
alcohol (IPA) as mobile phase, at 25 ꢀC. Analytical TLC was per-
formed on Schleicher & Schuell F1400/LS silica gel plates and the
spots were visualized under UV light (l¼254 nm). For flash chro-
matography we employed Merck silica gel 60 (0.063e0.2 mm).
Elemental analysis was carried out in the Research Technical Ser-
vices of the University of Alicante.
chloroform were added 3-(triethoxysilyl)-propyl thiol (175 mg,
0.73 mmol) and AIBN (12 mg, 0.07 mmol); the mixture was
degassed using the freeze-and-thaw method (3 cycles) and then
refluxed overnight. Reaction progress was monitored via 1H NMR
(disappearance of olefinic signals). The solvent was evaporated and
the crude product was purified via flash column chromatography
(starting with hexane/EtOAc 1:2, then polarity was increased). In-
termediate product 2a was obtained as a glassy, pale yellow solid
(240 mg, 66% yield): 1H NMR (300 MHz, CDCl3):
d 9.37 (br s, 1H),
8.80 (d, J¼9.0 Hz, 1H), 8.17 (d, J¼9.1 Hz, 1H), 8.10e7.87 (m, 4H), 7.53
(d, J¼8.4 Hz, 2H), 7.45e7.37 (m, 2H), 7.25e7.16 (m, 4H), 6.94 (d,
J¼8.5 Hz, 1H), 6.88 (d, J¼8.3 Hz, 1H), 3.82 (q, J¼7.0 Hz, 6H), 3.37 (dd,
J¼9.4, 4.1 Hz, 1H), 2.95e2.87 (m, 2H), 2.77 (d, J¼7.0 Hz, 2H), 2.55
(dd, J¼7.5, 7.3 Hz, 2H), 2.30e2.21 (m, 1H), 1.84e1.57 (m, 4H), 1.23 (t,
J¼7.0 Hz, 9H), 1.28e1.20 (m, 2H), 0.91e0.87 (m, 1H), 0.76e0.70
(m, 2H).
To a solution of 2a (230 mg, 0.29 mmol) in ethanol (5 ml) and
chloroform (3 ml) were added TEOS (tetraethoxysilane, 2.44 g, 11.7
mmol). A second solution containing water (850
ml, 47.3 mmol)
4.1. General procedure for synthesis of catalyst 3
and NH4F (1M solution, 120 l, 0.12 mmol) in 3 ml of ethanol was
m
added slowly, under stirring, to the first one. After 15e20 min
a white solid was formed. It was stirred for additional 2 h and then
left standing overnight. The solid was washed with water, ethanol
and diethyl ether. Finally it was dried in vacuo for several hours.
800 mg of catalyst 3 as a white powder was obtained. Catalyst
load: 0.32 mmol/g (calculated on the percentage of nitrogen found
in the elemental analysis). Nitrogen percentage calcd for 100%
incorporation: 1.52 (0.36 mmol/g); found: 1.36 (corresponds to
89.5% incorporation). Nitrogen percentage found after 9 reaction
cycles: 0.77 (corresponds to 50.6% incorporation or 0.18 mmol/g
loading).
To a solution of 4-vinylbenzenesulfonate (1.1 g, 5.3 mmol) in dry
toluene (30 mL) were added SOCl2 (2 mL, 27.6 mmol) and a few drops
of dry DMF. The resulting solutionwas heated to 80 ꢀC for 15 h and all
the volatiles were removed under reduced pressure (0.1 Torr) to yield
the corresponding sulfonyl chloride derivative. This compound was
dissolved in dry CH2Cl2 (20 mL) under inert atmosphere and added to
a solution of (Ra)-1,1-binaphthyl-2,2-diamine (1 g, 3.5 mmol) in
20 mL of dry CH2Cl2 and dry pyridine (3.5 mL, 43.44 mmol). The
resulting mixture was stirred for 12 h at rt, and then treated with
a HCl 5%solution(3ꢁ15 mL). Theorganiclayerwasdried overNa2SO4,
filtered off and the solvents were removed under reduced pressure
(15 Torr). The resulting crude product was purified by column chro-
matography (hexane/ethyl acetate) to give the (R)-N-(2-amino-1,1-
binaphthyl-2-yl)-4-vinylbenzenesulfonamide in 65% yield.
4.2. General procedure for the aldol reaction
4.2.1. General procedure for the aldehydeeketone aldol reaction
catalyzed by silica supported binam-prolinamide 3. To a mixture of
the corresponding aromatic aldehyde (0.3 mmol), catalyst 3
(0.03 mmol,100 mg) and benzoic acid (0.015 mmol, 2.0 mg) at 25 ꢀC
was added the corresponding ketone (0.6 mmol) and H2O
To a solution of Boc-D-proline (0.215 g, 1.0 mmol) and triethyl-
amine (0.14 mL, 1.0 mmol) in dry THF (7.5 mL) at 0 ꢀC was dropwise
added ethyl chloroformate (0.102 mL, 1.0 mmol). After stirring the
resulting solutionfor30minat 0 ꢀC, a solution of(R)-N-(2-amino-1,1-
binaphthyl-2-yl)-4-vinylbenzenesulfon-amide (0.45 g, 1.0 mmol)
dissolved in dry THF (7.5 mL) was added over 15 min. The ice-bath
was removed and the reaction was refluxed for 48 h. The solvents
were removed under reduced pressure (15 Torr) and the resulting
solid residue was dissolved in dichloromethane (7.5 mL) and tri-
fluoroacetic acid (2 mL) was added. The resulting mixture was stirred
for 1 h. NaOH (3 M) was added to the reaction mixture until pH 7 and
the resulting solution was washed with water (3ꢁ7 mL). The organic
layer was dried over MgSO4, filtered and the solvents were removed
under reduced pressure (15 Torr). The resulting crude product 2 was
purified by column chromatography (hexane/ethyl acetate) to give
product 2 (0.380 g, 70%) as a white solid: mp 210e212 ꢀC (EtOAc);
(3.6 mmol, 64 mL). The reaction was stirred until the aldehyde was
consumed (monitored by TLC). Then, the mixture was filtered and
washed with EtOAc (10e15 mL). The solvents were removed under
reduced pressure and the residue was purified by flash chroma-
tography (with 25e30 mL of hexanes/EtOAc) to yield the pure aldol
product. After the filtration, the catalyst was dried under vacuum
and reused for the next reaction cycle using the same reaction
conditions and amount of reagents and catalysts in each cycle.
4.2.1.1. (R)-2-((S)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone
(anti-6aa).25 Yield (0.067 g, 90%) 1H NMR (300 MHz, CDCl3):
d
1.28e1.49 (m, 1H), 1.52e1.73 (m, 3H), 1.79e1.83 (m, 1H), 2.06e2.14
HPLC (HPLC Chiralpak AD-H, n-hexane/i-PrOH: 80/20,1.0 mL minꢂ1),
(m, 1H), 2.31e2.45 (m, 1H), 2.45e2.55 (m, 1H), 2.55e2.66 (m, 1H),
4.12 (br s, 1H), 4.90 (d, J¼8.4 Hz, 1H), 7.49 (d, J¼8.7 Hz, 2H), 8.19 (d,
20
tR¼51.29; Rf¼0.28 (EtOAc); [
a
]
111.7 (c 1.0 in CHCl3); 1H NMR
D
(300 MHz, CDCl3):
d
0.66 (m, 1H), 1.17 (m, 2H), 1.58 (m, 1H), 1.73 (m,
J¼8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 24.6, 27.5, 30.6, 42.6, 57.1,
1H), 2.18 (m, 1H), 3.27 (dd, J¼4.1 Hz, 9.6, 1H), 5.42 (d, J¼10.8 Hz, 1H),
5.48 (d, J¼17.6 Hz,1H), 6.67 (dd, J¼10.8 Hz,17.6,1H), 6.84 (d, J¼8.4 Hz,
1H), 6.92 (d, J¼8.4 Hz,1H), 7.17 (m, 2H), 7.31 (d, J¼8.2 Hz, 2H), 7.39 (m,
2H), 7.50 (d, J¼8.6 Hz, 2H), 7.86 (d, J¼8.2 Hz, 1H), 7.93 (d, J¼8.2 Hz,
1H), 8.00 (d, J¼9.0 Hz, 1H), 8.06 (d, J¼9.2 Hz, 1H), 8.21 (d, J¼9.2 Hz,
1H), 8.83 (d, J¼9.0 Hz, 1H), 9.26 (s, 1H); 13C NMR (75 MHz, CDCl3):
73.9,123.5,127.8,147.4,148.3, 214.6; HPLC Chiralpak AD (n-hexane/i-
PrOH: 90/10, 0.7 mL/min), anti: tR¼36.232 (major), tR¼48.639 (mi-
nor), syn: tR¼28.446 (major), tR¼33.033 (minor).
4.2.1.2. 4-((S)-Hydroxy((R)-2-oxocyclohexyl)methyl)benzonitrile
(anti-6ab).26 Yield (0.063 g, 91%) 1H NMR (300 MHz, CDCl3):
d
25.2, 30.5, 46.0, 60.4, 116.8, 117.9, 119.1, 119.2, 120.6, 124.0, 125.1,
d 1.28e1.49 (m,1H),1.52e1.84 (m, 4H), 2.04e2.17 (m,1H), 2.30e2.47

~ꢀ
A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1313
(m, 1H), 2.50e2.61 (m, 2H), 4.07 (s, 1H), 4.84 (d, J¼8.4 Hz, 1H), 7.45
(d, J¼8.3 Hz, 2H), 7.65 (d, J¼8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
280 nm, (n-hexane/i-PrOH: 80/20, 1.0 mL/min), anti: tR¼19.021 (mi-
nor), tR¼22.454 (major), syn: tR¼13.727 (minor), tR¼15.700 (major).
d
24.6, 27.6, 30.6, 42.6, 57.0, 74.1, 111.6, 118.6, 127.7, 132.2, 146.3,
-
214.8; HPLC Chiralpak AD (n-hexane/i-PrOH: 95/05, 1.0 mL/min),
anti: tR¼44.854 (major), tR¼59.214 (minor), syn: tR¼29.828 (minor),
tR¼38.261 (major).
4.2.1.9. (S)-4-Hydroxy-(4-nitrophenyl)butan-2-one (6da).25
Yield (0.058 g, 93%) 1H NMR (300 MHz, CDCl3):
d 2.22 (s, 3H),
2.86 (d, J¼1.8 Hz,1H), 2.88 (s,1H) 3.70 (s,1H), 5.27 (dd, J¼2.9, 3.3 Hz,
1H), 7.54 (d, J¼8.8 Hz, 2H), 8.21 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz,
4.2.1.3. (R)-2-((S)-Hydroxy(phenyl)methyl)cyclohexanone (anti-
CDCl3): d 30.6, 51.4, 68.8, 123.7, 126.3, 147.3, 149.9, 208.2; HPLC
6ac).26 Yield (0.052 g, 85%) 1H NMR (300 MHz, CDCl3):
d
1.27e1.36
Chiralpak AS-H column at 280 nm, (n-hexane/i-PrOH: 85/15,1.0 mL/
min), tR¼25.755 (minor), tR¼34.741 (major).
(m, 1H), 1.50e1.80 (m, 4H), 2.04e2.12 (m, 1H), 2.30e2.42 (m, 1H),
2.43e2.54 (m, 1H), 2.58e2.67 (m, 1H), 4.05 (br s, 1H), 4.78 (d,
J¼8.9 Hz, 1H), 7.29e7.37 (m, 5H); 13C NMR (75 MHz, CDCl3):
d
24.7,
4.2.1.10. (S)-1-Hydroxy-1-(4-nitrophenyl)pentan-3-one (7ea).25
-
27.8, 30.8, 42.6, 57.4, 74.7, 127.0, 127.9, 128.3, 140.8, 215.5; HPLC
Chiralcel OD-H column at 210 nm, (n-hexane/i-PrOH: 95/5, 0.5 mL/
min), anti: tR¼23.507 (minor), tR¼31.015 (mayor), syn: tR¼18.107
(mayor), tR¼20.340 (minor).
Yield (0.045 g, 67%) 1H NMR (300 MHz, CDCl3):
d
1.09 (t, J¼7.3 Hz,
3H), 2.48 (q, J¼7.3 Hz, 2H), 2.82 (m, 2H), 3.67 (d, J¼3.3 Hz, 1H), 5.27
(dt, J¼3.5 Hz, 7.7,1H), 7.53 (d, J¼8.6 Hz, 2H), 8.21 (d, J¼9.8 Hz, 2H); 13
C
NMR (75 MHz, CDCl3): d 7.4, 36.8, 50.2, 69.1, 123.7, 126.4, 147.3, 150.1,
211.4; HPLC Chiralpak AS-H column at 280 nm, (n-hexane/i-PrOH:
95/05, 1.0 mL/min), tR¼63.672 (minor), tR¼125.772 (major).
4.2.1.4. (R)-2-((S)-Hydroxy(2-nitrophenyl)methyl)cyclohexanone
(anti-6ad).27 Yield (0.064 g, 86%) 1H NMR (300 MHz, CDCl3):
d
1.27e1.36 (m,1H),1.50e1.80 (m, 4H), 2.04e2.12 (m,1H), 2.30e2.42
4.2.1.11. (3R,4R)-4-Hydroxy-3-methoxy-4-(4-nitrophenyl)butan-
(m,1H), 2.43e2.54 (m,1H), 2.58e2.67 (m,1H), 4.05 (br s,1H), 4.78 (d,
2-one (anti-6fa).29 Yield (0.066 g, 92%) 1H NMR (300 MHz, CDCl3):
d
J¼8.9 Hz, 1H), 7.29e7.37 (m, 5H); 13C NMR (75 MHz, CDCl3):
d
24.7,
2.16 (s, 3H), 3.32 (s, 3H), 3.70 (d, J¼6.2 Hz,1H), 5.02 (d, J¼6.2 Hz,1H),
27.8, 30.8, 42.6, 57.4, 74.7, 127.0, 127.9, 128.3, 140.8, 215.5; HPLC
Chiralpak AD column at 280 nm, (n-hexane/i-PrOH: 95/05, 0.7 mL/
min), anti: tR¼45.038 (minor), tR¼47.244 (major), syn: tR¼32.131
(minor), tR¼33.738 (major).
7.56 (d, J¼8.8 Hz, 2H), 8.22 (d, J¼8.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3):
d 27.5, 59.6, 73.3, 89.6, 123.4, 127.7, 146.7, 147.7, 209.9; HPLC
Chiralcel OD-H column at 280 nm, (n-hexane/i-PrOH: 90/10, 0.7 mL/
min), anti: tR¼17.047 (minor), tR¼18.578 (major), syn tR¼21.181
(major), tR¼25.327 (minor).
4.2.1.5. (R)-2-((S)-Hydroxy(3-nitrophenyl)methyl)cyclohexanone
4.2.1.11.1. (R)-4-Hydroxy-1-(methylthio)-4-(4-nitrophenyl)butan-
(anti-6ae).27 Yield (0.067 g, 90%) 1H NMR (300 MHz, CDCl3):
2-one (7ga).29 Yield (0.037 g, 48%) 1H NMR (300 MHz, CDCl3):
d 2.06
d
1.55e1.87 (m, 5H), 2.04e2.17 (m, 1H), 2.28e2.49 (m, 2H),
(s, 3H), 3.06 (d, J¼6.2 Hz, 2H), 3.19 (s, 2H), 5.29 (t, J¼6.1 Hz, 1H), 7.57
2.71e2.80 (m, 1H), 4.19 (br s, 1H), 5.45 (d, J¼7.2 Hz, 1H), 7.40e7.46
(d, J¼8.5 Hz, 2H), 8.22 (d, J¼8.8 Hz, 2H);13C NMR (75 MHz, CDCl3):
(m, 1H), 7.61e7.66 (m, 1H), 7.73e7.80 (m, 1H), 7.82e7.88 (m, 1H);
d
15.6, 43.3, 48.0, 69.3, 123.7, 126.7, 147.4, 149.8, 204.7; HPLC Chir-
13C NMR (75 MHz, CDCl3):
d
24.9, 27.7, 31.0, 42.8, 57.2, 69.7, 124.0,
alcel OD-H column at 280 nm, (n-hexane/i-PrOH: 95/05, 1.0 mL/
min), tR¼42.461 (major), tR¼47.734 (minor).
128.3, 128.9, 133.0, 136.5, 148.6, 214.9; HPLC Chiralpak AD column
at 254 nm, (n-hexane/i-PrOH: 95/05, 0.7 mL/min), anti: tR¼50.356
(minor), tR¼64.643 (major), syn: tR¼39.063 (minor), tR¼44.716
(major).
4.2.2. General procedure for the aldol reaction between aldehydes
catalyzed by 3. To a mixture of the corresponding aromatic aldehyde
(0.3 mmol), catalyst 3 (0.06 mmol, 200 mg) and benzoic acid
(0.015 mmol, 2 mg) at 25 ꢀC was added the propanal (1.5 mmol,
4.2.1.6. (R)-2-((S)-Hydroxy-(3-methylphenyl)methyl)cyclohexa-
none (anti-6af).28 Yield (0.053 g, 82%) 1H NMR (300 MHz, CDCl3):
110 mL) and H2O (64 mL). The reaction was stirred until the aldehyde
d
1.24e1.32 (m, 1H), 1.52e1.70 (m, 3H), 1.73e1.83 (m, 1H), 2.03e2.13
was consumed (monitored by TLC). Then, the mixture was filtered
and washed with 10e15 mL of EtOAc. The solvents were removed
under reduced pressure and the residue was diluted with MeOH
(1 mL) then NaBH4 (0.3 mmol, 12 mg) was added at 0 ꢀC, and the
mixturewasstirredfor 1 h. The resultingresiduewaspurified by flash
chromatography (hexanes/EtOAc; 4/1) to yield the pure product.
(m,1H), 2.30e2.40 (m,1H), 2.35 (s, 3H), 2.45e2.53 (m,1H), 2.57e2.67
(m, 1H), 4.75 (d, J¼8.8 Hz, 1H), 7.07e7.12 (m, 2H), 7.15 (s, 1H), 7.22 (t,
J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): 13C NMR (75 MHz, CDCl3)
d
21.4, 24.1, 27.8, 30.9, 42.7, 57.3, 74.7, 124.2, 127.6, 128.2, 128.6, 138.1,
140.8, 215.7; HPLC Chiralcel OD-H column at 210 nm, (n-hexane/i-
PrOH: 95/05,1.0mL/min), anti: tR¼10.783 (minor), tR¼13.176 (major).
4.2.2.1. (1S,2S)-2-Methyl-1-(4-nitrophenyl)propane-1,3-diol
4.2.1.7. (R)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclo-
(anti-8a).10f Yield (0.047 g, 75%) 1H NMR (300 MHz, CDCl3):
d 0.78
pentanone (anti-6ba).29 Yield (0.056 g, 80%) 1H NMR (300 MHz,
CDCl3): d 1.72e1.75 (m, 2H), 1.90e2.55 (m, 5H), 2.95 (s,1H, syn), 4.77
(d, J¼7.0 Hz, 3H), 2.01e2.06 (m, 1H), 2.74 (br s, 1H), 3.72e3.85 (m,
3H), 4.72 (d, J¼7.8 Hz, 1H anti), 7.54 (d, J¼8.7 Hz, 2H), 8.23 (d,
(s, 1H, anti), 4.84 (d, J¼9.1 Hz, 1H, anti), 5.42 (s, 1H, syn), 7.52 (d,
J¼8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 13.6, 41.5, 67.4, 79.3,
123.6, 127.5, 147.4, 150.5; HPLC Chiralpak AD, (hexanes/i-PrOH: 96/
04, 0.9 mL/min), tR¼72.965 (minor), tR¼74.885 (mayor).
J¼8.4 Hz, 2H), 8.21 (d, J¼8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
syn
20.2, 22.2, 38.8, 56.0, 70.3, 123.6, 126.3, 147.0, 150.2, 219.6; anti 20.2,
26.7, 38.5, 55.0, 74.3, 123.5, 127.3, 147.2, 148.5, 222.8; HPLC Chiralpak
AD column at 280 nm, (n-hexane/i-PrOH: 97/03, 1.0 mL/min), anti:
tR¼75.661 (minor), tR¼83.634 (major), syn: tR¼43.228 (minor),
tR¼65.514 (major).
4.2.2.2. 4-((1S,2S)-1,3-Dihydroxy-2-methylpropyl)benzoni-
trile(anti-8b).30 Yield (0.040 g, 70%) 1H NMR (300 MHz, CDCl3):
d
0.75 (d, J¼7.0 Hz, 3H), 1.94e2.10 (m, 1H), 3.64e3.74 (m, 1H),
3.76e3.84 (m, 1H), 4.64 (d, J¼7.8 Hz, 1H anti), 7.47 (d, J¼8.1 Hz, 2H),
4.2.1.8. (R)-3-((S)-Hydroxy(4-nitrophenyl)methyl)dihydro-2H-
7.65 (d, J¼8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 13.7, 41.4, 67.5,
pyran-4(3H)-one (anti-6ca).27 Yield (0.072 g, 95%) 1H NMR
(300 MHz, CDCl3): d 2.50e2.60 (m,1H), 2.63e2.73 (m,1H), 2.85e2.93
79.7, 111.4, 118.8, 127.4, 132.2, 148.7; HPLC with a Chiralpak AD col-
umn at 230 nm, (n-hexane/i-PrOH: 95/05, 1.0 mL/min), tR¼41.956
(minor), tR¼43.957 (mayor).
(m, 1H), 3.46 (dd, J¼11.4, 9.6 Hz, 1H), 3.73e3.81 (m, 2H), 3.9 (s, 1H),
4.16e4.27 (m, 1H), 5.00 (d, J¼9.8 Hz, 1H), 7.52 (d, J¼8.7 Hz, 2H), 8.23
(d, J¼8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
42.7, 57.5, 68.2, 69.7,
4.2.3. General procedure for the aldol intramolecular reaction cata-
lyzed by ent-3. To the catalyst ent-3 (0.06 mmol, 200 mg) and
71.2, 123.8, 127.4, 147.4, 147.7, 209.1; HPLC Chiralpak AD-H column at

~ꢀ
A. Banon-Caballero et al. / Tetrahedron 69 (2013) 1307e1315
1314
benzoic acid (0.015 mmol, 2 mg) at 25 ꢀC was added the ketone 8
or 11 (0.3 mmol). The reaction was stirred during the days re-
quired (monitored by TLC). Then, the mixture was filtered and
washed with 10e15 mL of EtOAc. The solvents were removed
under reduced pressure and the resulting residue was purified by
flash chromatography (hexanes/EtOAc 7/3) to yield the pure
product.
4.3. Typical procedure for catalyst recovery
To a mixture of the p-nitrobenzaldehyde (0.3 mmol), catalyst 3
(0.03 mmol,100 mg) and benzoic acid (0.015 mmol, 2.0 mg) at 25 ꢀC
was added the cyclohexanone (0.6 mmol) and H2O (3.6 mmol,
64 mL). The reaction was stirred until the aldehyde was consumed
(monitored by TLC). Then, the mixture was filtered and washed
with EtOAc (10e15 mL). The solvents were removed under reduced
pressure and the residue was purified by flash chromatography
(with 25e30 mL of hexanes/EtOAc) to yield the pure aldol product.
After the filtration, the catalyst was dried under vacuum and reused
for the next reaction cycle using the same reaction conditions and
amount of reagents and catalysts in each cycle.
4.2.4. General procedure for the aldol intramolecular reaction cata-
lyzed by ent-3 (one-pot reaction). To 2-methylcyclohexane-1,3-
dione (0.3 mmol, 38 mg) in a standard glass vial with stirrer bar
was added methyl vinyl ketone (0.33 mmol, 23
mL) followed by Et3N
(0.003 mmol, 1 L). The initial thick suspension slowly became
m
more fluid as the solid slowly dissolved to give a yellow/orange
solution/oil. After 3 h the mixture was concentrated on a rotary
evaporator and then kept under high vacuum with stirring for 3 h.
Catalyst ent-3 (0.06 mmol, 200 mg) and benzoic acid (0.015 mmol,
2 mg) were added and the resulting mixture was stirred for 7 days.
Then, the mixture was filtered and washed with 10e15 mL of
EtOAc. The solvents were removed under reduced pressure and the
resulting residue was purified by flash chromatography (hexanes/
EtOAc 7/3) to yield the pure product.
Acknowledgements
This research was supported by the Ministerio de Ciencia e
ꢀ
Innovacion (MICINN: Projects CTQ2007-62771/BQU, CTQ2010-
20387, CTQ2008-05409-C02-01, CTQ2011-22649 and Consolider
Ingenio 2010 CSD2007-00006), FEDER, the Generalitat Valenciana
(Project PROMETEO/2009/039), the DURSI-Generalitat de Cata-
lunya (2009SGR-1441), the University of Alicante and the EU (ORCA
action CM0905). A.B.-C. thanks the Spanish MICINN for a pre-
doctoral fellowship (FPU AP2009-3601).
4.2.4.1. (S)-8a-Methyl-3,4,8,8a-tetrahydronaphthalene-
1,6(2H,7H)-dione(10a).31 Yield (0.047 g, 88%) 1H NMR (300 MHz,
CDCl3): d 1.46 (s, 3H),1.65e1.77 (m,1H), 2.10e2.20 (m, 3H), 2.44e2.57
Supplementary data
(m, 4H), 2.67e2.79 (m,1H), 5.86 (d, J¼1.6 Hz, 1H); 13C NMR (75 MHz,
Supplementary data: 1H and 13C NMR spectra for compound 2.
NMR spectra and HLPC chromatograms from aldol products. Sup-
plementary data related to this article can be found online at http://
dx.doi.org/10.1016/j.tet.2012.11.097.
CDCl3):
d 22.7, 23.1, 29.5, 31.6, 33.4, 37.5, 50.4, 125.6, 166.0, 198.4,
211.0; HPLC Chiralcel OD-H (n-hexane/i-PrOH: 96/04, 0.8 mL/min),
tR¼25.356 (mayor), tR¼28.756 (minor).
4.2.4.2. (S)-7a-Methyl-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-
dione (10b).32 Yield (0.042 g, 85%) 1H NMR (300 MHz, CDCl3):
d 1.32
References and notes
(s, 3H), 1.81e1.90 (m, 1H), 2.09e2.14 (m, 1H), 2.39e2.58 (m, 3H),
2.72e2.84 (m, 2H), 2.91e3.01 (m, 1H), 5.97 (d, J¼2.4 Hz, 1H); 13C
1. (a) Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice; Oxford
University: Oxford, 1998; (b) Noyori, R. Chem. Commun. 2005, 1807e1811; (c)
Methods and Reagents for Green Chemistry; Tundo, P., Perosa, A., Zecchini, F.,
Eds.; John Wiley & Sons: Hoboken, NJ, USA, 2007.
2. Sheldon, R. A. Chem. Commun. 2008, 3352e3365.
3. Shearouse, W. C.; Waddell, D. C.; Mack, J. Curr. Opin. Drug Discovery Dev. 2009,
NMR (75 MHz, CDCl3): d 20.5, 26.7, 29.1, 32.8, 35.8, 48.6,123.8,169.7,
198.1, 216.5; HPLC Chiralcel OJ column at 230 nm, (n-hexane/i-PrOH:
96/04, 0.5 mL/min), tR¼34.915 (mayor), tR¼39.283 (minor).
12, 772e783.
4.2.4.3. (R)-8a-Allyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-
ꢀ
ꢀ
4. Constable, J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org. Process Res. Dev.
2007, 11, 133e137.
5. Asymmetric Synthesis: The Essentials; Christmann, M., Brase, S., Eds.; Wiley-VCH:
dione (10c).10h Yield (0.047 g, 77%) 1H NMR (300 MHz, CDCl3):
d
€
1.62e1.80 (m,1H), 2.00e2.29 (m, 3H), 2.38e2.47 (m, 2H), 2.46e2.60
Weinheim, 2007.
(m, 3H), 2.61e2.73 (m, 2H), 2.74e2.85 (m, 1H), 5.06e5.21 (m, 2H),
6. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1
and 2.
7. (a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007; (b) Enantioselective Organocatalyzed Reactions; Mahrwald, R., Ed.;
Springer: 2011; Vols. 1 and 2.
5.60 (ddt, J¼15.8 Hz, 11.2, 7.4, 1H), 5.90 (d, J¼1.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 23.3, 26.2, 31.9, 33.3, 38.4, 39.8, 54.6, 119.5, 126.5,
131.5,164.9,198.2, 209.3; HPLC Chiralcel OD-H column at 210 nm, (n-
hexane/i-PrOH: 96/04, 1.0 mL/min), tR¼30.126 (minor), tR¼32.287
(mayor).
8. (a) Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim, 2003; (b)
Walsh, P. J.; Li, C.; de Parrodi, C. A. Chem. Rev. 2007, 107, 2503e2545; (c) Mar-
vaniya, H. M.; Modi, K. N.; Sen, D. J. Int. J. Drug Dev. Res. 2011, 3, 34e73; (d)
ꢀ
Hernandez, J. G.; Juaristi, E. Chem. Commun. 2012, 48, 5396e5409.
ꢀ
ꢀ
4.2.4.4. (R)-8a-Benzyl-3,4,8,8a-tetrahydronaphthalene-
9. (a) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18,
2249e2293; (b) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20,
131e173; (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; (e) Guillena, G.; Ramon, D. J.; Najera, C. In Enantioselective
Organocatalyzed Reactions II; Mahrwald, R., Ed.; Springer: 2011; pp 245e342;
Cap. 4.
1,6(2H,7H)-dione (10d).32 Yield (0.056 g, 73%)1H NMR (300 MHz,
CDCl3):
2.46e2.80 (m, 4H), 3.18 (q, J¼13.6 Hz, 2H), 5.97 (d, J¼1.6 Hz, 1H),
6.98e7.10 (m, 2H), 7.20e7.36 (m, 3H); 13C NMR (75 MHz, CDCl3):
23.1,
d 1.54e1.83 (m, 1H), 1.93e2.23 (m, 3H), 2.23e2.46 (m, 2H),
ꢀ
ꢀ
d
27.5, 32.6, 33.6, 39.1, 42.7, 55.8, 127.0, 127.5, 128.6, 129.5, 135.5, 165.0,
198.2, 210.0; HPLC Chiralcel OD-H column at 230 nm, (n-hexane/i-
PrOH: 96/04, 0.6 mL/min), tR¼30.971 (minor), tR¼35.311 (mayor).
10. (a) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem.
Commun. 2007, 957e959; (b) Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem.
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dEur. J. 2007, 13, 4710e4722; (c) Guillena, G.; Hita, M. C.; Najera, C.; Viozquez,
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ꢀ
Najera, C. Adv. Synth. Catal. 2009, 351, 1123e1131; (e) Almas¸ i, D.; Alonso, D. A.;
4.2.4.5. (R)-Methyl
carboxylate (12).22 Yield (0.034 g, 47%) H NMR (300 MHz, CDCl3):
2.16 (m, 1H), 2.49e2.59 (m, 2H), 2.72e2.82 (m, 1H), 3.06 (d,
3-oxo-2,3,9,9a-tetrahydro-1H-fluorene-9a-
ꢀ
Najera, C. Adv. Synth. Catal. 2008, 350, 2467e2472; (f) Guillena, G.; Hita, M. C.;
1
ꢀ
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Najera, C.; Viozquez, S. F. J. Org. Chem. 2008, 73, 5933e5943; (g) Guillena, G.;
ꢀ
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Najera, C.; Viozquez, S. F. Synlett 2008, 3031e3035; (h) Bradshaw, B.;
d
ꢀ
ꢀ
Etxebarría-Jardi, G.; Bonjoch, J.; Viozquez, S. F.; Guillena, G.; Najera, C. Adv.
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J¼16.6 Hz, 1H), 3.57 (d, J¼16.6 Hz, 1H), 3.63, (s, 3H), 6.37 (s, 1H),
7.28e7.37 (m, 2H), 7.38e7.45 (m, 1H), 7.58e7.64 (m, 1H); 13C NMR
ꢀ
2425e2428; (j) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464e1467;
ꢀ
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(k) Hernandez, J. G.; Juaristi, E. Tetrahedron 2011, 68, 6953e6959; (l) Hernandez,
(75 MHz, CDCl3): d 32.9, 35.1, 43.0, 52.9, 54.4,119.1,122.9,125.3,127.7,
131.9,138.0,145.6,164.4,173.8,198.7;HPLCChiralcel OD-H(n-hexane/
i-PrOH: 99/01, 1.0 mL/min), tR¼¼5.908 (mayor), tR¼8.698 (minor).
ꢀ
J. G.; García-Lopez, V.; Juaristi, E. Tetrahedron 2012, 68, 92e97; (m) Martínez-
~
ꢀ
Castaneda, A.; Poladura, B.; Rodríguez-Solla, H.; Concellon, C.; del Amo, V.
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2257e2281; (c) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic,
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́