Proline-cyclodextrin conjugates: Synthesis and evaluation as catalysts for aldol reaction in water

Article abstract of DOI:10.1016/j.tet.2012.06.089

The synthesis of six conjugates of l-proline and β-cyclodextrin and their evaluation as catalysts of aldol reaction in water are described. The results indicated that the nature of the linker between proline and β-cyclodextrin is important for catalytic activity; the one with the most flexible linker gave the best results. Inhibition experiments showed that the cavity of β-cyclodextrin plays a role in the catalysis. Permethylation of the cyclodextrin hydroxyl groups led to higher conversion rates.

Full text of DOI:10.1016/j.tet.2012.06.089

Tetrahedron 68 (2012) 7345e7354
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
Prolineecyclodextrin conjugates: synthesis and evaluation as catalysts for aldol
reaction in water
y
*
€
ꢀ
Elisa G. Doyaguez , Alfonso Fernandez-Mayoralas
ꢀ
ꢀ
Departamento de Química Bioorganica, Instituto de Química Organica General, CSIC (IQOG-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 April 2012
Received in revised form 18 June 2012
Accepted 21 June 2012
Available online 28 June 2012
The synthesis of six conjugates of L-proline and b-cyclodextrin and their evaluation as catalysts of aldol
reaction in water are described. The results indicated that the nature of the linker between proline and
-cyclodextrin is important for catalytic activity; the one with the most flexible linker gave the best
results. Inhibition experiments showed that the cavity of -cyclodextrin plays a role in the catalysis.
Permethylation of the cyclodextrin hydroxyl groups led to higher conversion rates.
Ó 2012 Elsevier Ltd. All rights reserved.
b
b
Keywords:
Aldol reaction
Organocatalyst
Proline
b
-Cyclodextrin
1. Introduction
which proline has been covalently anchored to a hydroxyl group of
the cyclodextrin, exhibiting a free cavity of the cyclic sugar; how-
ever, no data regarding stereoselectivity were reported.
Interest in the field of organocatalysis has increased intensively
over the last years.1 During the first half of the 2000s decade,
proline has been the most successful organocatalyst for a variety of
reactions,2 including aldol additions and Mannich reactions.2e From
a mechanistic point of view, proline-catalyzed aldol additions have
been considered a minimalistic version of aldolase enzymes,3 par-
ticularly of type I aldolases, since both proceed through an enamine
intermediate. However, the catalytic efficiency of proline in water is
very poor. Unlike enzymes, proline lacks of reaction pockets
wherein the substrates can bind and reaction takes place with ex-
clusion of water. Considerable effort has been directed to the de-
velopment of proline analogs with hydrophobic residues that can
catalyze reactions in water.4 Cyclodextrins are well-known com-
pounds for their ability to form inclusion complexes with organic
compounds in water, due to the hydrophobic character of their
internal cavity.5 There are few examples describing organocatalysts
that combine the catalytic properties of proline with the ability of
cyclodextrin to form inclusion complex.6,7 However, in most of
these examples an inclusion complex between a cyclodextrin and
a hydrophobic proline is formed with capacity to catalyze aldol
reactions in water.6 There is one case described by Breslow et al.7 in
Herein, we report on the synthesis of several covalently linked
prolineecyclodextrin conjugates and their evaluation as catalysts of
aldol reactions in water. The role played by the cyclodextrin ring
and the effect of the linker on the conversion and stereoselectivity
of the reaction are studied and the results discussed.
2. Results and discussion
2.1. Synthesis of prolineecyclodextrin conjugates
We prepared six conjugates of L-proline and b-cyclodextrin
linked through different functional groups (Fig. 1). In compound 1,
previously used by Breslow,7 the proline is directly bound to 6-
amino-6-deoxy-cyclodextrin through the carboxylic group, form-
ing a prolinamide. Three of the conjugates present the cyclodextrin
bound to the C-4 position of proline, thus displaying the amino acid
functions free, using linkers of different nature: succinamide, tri-
azol ring, and carbamate (compounds 2, 3, and 4, respectively). Two
additional compounds 5 and 6 are also prolinamides but with
a residue of D- or L-serine intercalated between the cyclodextrin
and the proline. The hydroxyl group of the serine could form hy-
drogen bonds and contributes to the catalysis, as it has been sug-
gested with related hydroxyl-prolinamides.8
* Corresponding
author.
E-mail
ꢀ
addresses:
alfonso.mayoralas@csic.es,
Compound 1 was synthesized from 6I-amino-6I-deoxy-
b-cy-
mayoralas@iqog.csic.es (A. Fernandez-Mayoralas).
clodextrin (7)9 in two chemical steps (Scheme 1). Thus, the reaction
of 7 with commercially available proline derivative 8 in the
y
ꢀ
Present address: Centro de Química Organica Lora Tamayo, CSIC
(CENQUIOR-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.089

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Fig. 1. Prolineecyclodextrin conjugates proposed as catalysts.
Azide 13 was also used for the synthesis of carbamate 4. The
hydroxyl groups of 13 were protected with benzyl groups (com-
pound 16, Scheme 4) and then the azido was reduced with trime-
thylphosphine to give amine 17, which was reacted with 18 to
afford protected carbamate 19. Hydrogenation of 19 in a Parr re-
actor led to the deprotection of the carboxyl and amine group, as
well as the 20 benzyl groups present in the molecule, giving
compound 4.
Scheme 1. Synthesis of cyclodextrin derivative 1.
presence of DIC and HOBt gave amide 9, and then deprotection of
Cbz group by hydrogenation furnished target 1.
For the synthesis of 2, the known monofunctionalized b-cyclo-
dextrin derivative 1010 was coupled with amine 1111 to give 12
(Scheme 2). Afterward, carboxyl and amino groups were simulta-
neously deprotected to afford 2.
Scheme 4. Synthesis of cyclodextrin derivative 4.
The synthesis of serine-containing catalysts 5 and 6 was carried
out from perbenzylated aminocylodextrin 17 (Scheme 5). Amida-
tion reaction between the amino group of 17 and the carboxylate
group of the protected serine derivative 20/21 gave 22/23. Removal
of the Boc in the serine moiety with TFA gave the free amine 24/25,
which reacted with the carboxylate group of proline 8 to afford the
protected conjugates 26/27. Removal of benzyloxycarbonyl and
benzyl groups in 26/27 by hydrogenation furnished 5/6.
Scheme 2. Synthesis of cyclodextrin derivative 2.
The triazol-tethered conjugate 3 was readily synthesized by
Huisgen cycloaddition12 between compounds 1313 and 14 (Scheme
3), followed by hydrogenation of the protected conjugate 15.
2.2. Evaluation of conjugates 1e6 as catalysts for aldol
reaction
The synthesized compounds were tested as catalysts for a model
aldol reaction between 4-nitrobenzaldehyde (28, 260 mM) and
dioxanone (29, 520 mM) in water, in the presence of the conjugates
1e6 (20 mol %). The results are summarized in Table 1. Compounds
3e6 were found to be poor catalysts, leading to minimal formation of
aldol products after 24 h (entries 3e6). Catalyst performance was
observed with prolinamide 1 and succinamide 2 (entries 1 and 2,
Scheme 3. Synthesis of cyclodextrin derivative 3.

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Scheme 5. Synthesis of cyclodextrin derivatives 5 and 6.
seems that the flexibility of the succinamyl moiety in compound 2 is
beneficial for catalytic activity. Further work was focused on testing
Table 1
Evaluation of prolinee
between 28 and 29
b-cylodextrin conjugates 1e6 as catalysts for aldol reaction
the influence of the
of 2 in water. With this aim, we synthesized (4S)-4-N-acetyl-4-
amino- -proline 31 as an analog of 2 without the -cyclodextrin
b-cyclodextrin ring on the catalytic performance
L
b
moiety and tested its properties as catalyst (Fig. 2). No reaction was
observed with 31 alone after 48 h (entry 9, Table 1), but a slight
conversionwas observed when b-cyclodextrinwas added (entry 10),
which may indicate that the cyclodextrin is assisting in dissolving
the reagents. These results indicate that the cyclodextrin covalently
linked to the proline is important for the catalytic activity of 2.
Entry
Catalyst
Time (h)
Conv.a (%)
anti/syna
eeb (%)
1
2
3
4
5
6
1
2
3
4
5
6
2
2
48
24
24
24
24
24
48
24
48
48
30
57
<5
<5
<5
<5
70
68
<5
8
1:1
1:1.5
d
4
8
d
d
d
d
2
40
d
74
d
d
d
7
1:1
1.6:1
d
8c
9
31
31þ
10
b-CD
3:1
a
Determined by NMR and HPLC.
b
c
Determined by HPLC. They are referred to the major isomer.
2-Nitrobenzaldehyde was used as aldehyde.14
Fig. 2. Model catalyst 31.
Table 1), which gave aldol product 30 with modest (30%) and mod-
erate (57%) conversions, but without stereoselectivity. The conver-
sionwith 2 was increased to 70% after 48 h of reaction (entry 7). Also,
catalysis with 2 was more efficient when 2-nitrobenzaldehyde was
used as aldehyde, though diastereo- and enantioselectivity were still
low (entry 8). No reaction was observed when 2 was used with non-
activated aldehydes such as benzaldehyde or 4-chlorobenzaldehyde
(results not shown). The results obtained with the conjugates 1e6
Furthermore, in order to know if the substrate is accommodated
in the cavity of the
b-cyclodextrin during the reaction, experiments
were carried out in the presence of sodium 2-naphthalenesulfonate,
a salt known to form a strong inclusion complex with
b-cyclo-
dextrin.5a,15 For the inhibition experiments the reaction time was
fixed at 8 h (Fig. 3). At this time the conversion is high enough to
accurately measure product formation but, at the same time, is low
so as to minimize the formation of competing inclusion complexes
indicate that the nature of the linker between proline and
b-cyclo-
between b-cyclodextrin and aldol product.
dextrin is important for the activity as catalyst. Assuming that the
presence of the cyclodextrin affects the activity of the proline, it
As can be seen from Table 2, the conversion decreased as the
amount of added sodium 2-naphthalenesulfonate (32) increased

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7348
from 1 to 5 equiv. Therefore, the cavity of the b-cyclodextrin plays
a role in the catalytic function of 2 in water, probably by binding the
aromatic aldehyde substrate.
Finally, to check if the hydroxyl groups of the b-cyclodextrin
moiety of 2 affect the course of the reaction, the permethylated
derivative 37 was synthesized from azide 13 (Scheme 6). Thus,
permethylation of 13 gave 33, which was submitted to hydrogena-
tion to furnish amine 34. Reaction of 34 with succinic anhydride
followed by coupling of the resulting acid 35 with amine 11 gave
conjugate 36, which, after hydrogenolysis, led to 37. Conjugate 2 and
37 were assayed as catalysts for the aldol reactions between 4-
nitrobenzaldehyde and three different ketones: dioxanone (29),
cyclohexanone (38), and acetone (39). Results are shown in Table 3.
In all the cases, the conversions were higher with the permethylated
derivative 37, which gave high values when cyclohexanone and
acetone were used as ketones. Nevertheless, the stereoselectivity
was poor or absent. The higher efficiency observed with 37 suggests
Fig. 3. Conversion versus time for the model aldol reaction catalyzed by 2.
that the methyl groups at the surface of the b-cyclodextrin ring may
Table 2
Kinetics of aldol reaction between aldehyde 28 and ketone 29 catalyzed by 2
interact with the ketone substrates, and this hydrophobic in-
teraction brings the ketone close to the catalytic proline unit.
The lack of stereoselectivity observed in all the reactions studied
could be understood considering the proposed transition state in
the mechanism of proline-catalyzed aldol reactions (Fig. 4). This
transition state involves a chair-like arrangement of enamine and
carbonyl atoms, with the substituent of the aldehyde in a pseudoe-
quatorial position, and the nucleophilic attack of the enamine taking
place on the re-face of the aldehyde.16 Hydrogen bonding seems to
be essential to stabilize the transition state. Under these consider-
ations, water molecules can disrupt hydrogen bonding in the tran-
sition state and, therefore, reduce stereoselectivity. Some proline
derivatives with hydrophobic groups4 as well as polystyrene-
supported proline catalysts17 have been shown to promote stereo-
selective reactions in water. These catalysts could form a hydro-
phobic microenvironment with the hydrophobic reactants, where
the reaction can take place away from the bulk of the water and thus
proceeds with stereoselectivity. In our prolineecyclodextrin
Entry
32 (equiv)
Conv.a (%)
anti/syna
eeb (%)
1
2
3
4
0
1
2
5
16
11
5
1:1.4
1:1.2
1:1.5
1:1.4
8
6
0
0
2
a
Determined by NMR and HPLC.
Determined by HPLC. They are referred to the major isomer.
b
Scheme 6. Synthesis of permethylated cyclodextrin derivative 37.

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obtained as previously described.18 Thin-layer chromatography
(TLC) was performed on aluminum sheets 60 F254 Merck silica gel
and compounds were visualized by irradiation with UV light and/or
by treatment with a solution of Ce2MoO4 in water, a solution of
ninhydrin in n-BuOH/EtOH or H2SO4 (5%) in EtOH or followed by
heating. NMR (1H, 13C NMR) spectra were recorded on a 300 MHz
(Inova 300 or Bruker 300), 400 MHz (Inova 400 or Mercury 400),
and 500 MHz (Inova 500) spectrometers, using CDCl3, DMSO-d6,
CD3OD, or D2O as solvents at room temperature. Chemical shift
Table 3
Aldol reaction between aldehyde 28 with different ketones (29, 38, and 39) cata-
lyzed by 2 or 37a
values are reported in parts per million (d) relative to tetrame-
thylsilane (TMS) in 1H and CDCl3
(d
¼77.0) in 13C NMR. Coupling
constants (J values) are reported in hertz (Hz), and spin multiplic-
ities are indicated by the following symbols: s (singlet), d (doublet),
t (triplet), q (quartet), and m (multiplet). Diastereomeric and en-
antiomeric excess were calculated by NMR and HPLC Dionex P680
with DAD detector (lecture at 254 nm). Mass spectra were recorded
on a HP series 1100 MSD spectrometer or in an Agilent 6250 Ac-
curate Mass Q-TOF spectrometer. Elemental analyses were carried
out on a Heraus CHNeO Rapid analyzer and compositions are
expressed in percentage.
Entry
Ketone
Catalyst
Conv.b (%)
anti/synb
eec (%)
1
2
3
4
5
6
29
38
39
29
38
39
2
2
2
37
37
37
57
27
21
89
69
1:1.4
1.5:1
d
8
10
6
1:1
1:1
10d
54e
6f
100
d
4.2. 6I-[(2S)-1-Benzyloxycarbonylpyrrolidin-2-yl]-
a
carbonylamino-6I-deoxy-
b-cyclodextrin (9)
Reaction conditions: 28 (0.013 mmol), catalyst (20 mol %), ketone (29,
0.026 mmol; 38, 0.065 mmol; 39, 0.325 mmol), in water (0.05 mL).
b
Determined by NMR and HPLC.
Determined by HPLC.
Referred to anti diastereoisomer.
Referred to syn diastereoisomer.
c
To
a
solution of N-carboxybenzyl- -proline (8) (200 mg,
L
d
0.489 mmol) in anhydrous DMF (18 mL), DIC (0.246 mL,
1.587 mmol) and HOBt (246 mg, 1.587 mmol) were added succes-
sively. The reaction mixture was stirred under Ar atmosphere for
1 h at room temperature, and then 7 (370 mg, 0.326 mmol) dis-
solved in 18 mL of anhydrous DMF was added. The mixture was
stirred for 48 h at room temperature. After this time, solvent was
evaporated under reduced pressure, and acetone was added over
the residue obtained, giving a white precipitate that was filtered
and washed with acetone. The precipitate was purified by flash
chromatography (MeCN/H2O 7:1). Compound 9 was obtained
(0.342 g, 77%) as a white foam. 1H NMR (300 MHz, DMSO-d6):
e
f
R Enantiomer was the major product.
Fig. 4. Transition state model for the proline-catalyzed aldol reactions.
d
7.4e7.2 (m, 5H), 5.8e5.6 (m, 14H), 5.2e5.0 (m, 2H), 4.9e4.8 (m,
7H), 4.6e4.4 (m, 6H), 4.3e4.2 (m, 1H), 3.7e3.4 (m, 28H), 3.4e3.2
(m, overlaps with HOD), 2.1e2.0 (m, 2H), 1.9e1.7 (m, 2H); MS (ESI)
m/z 1364.9 [MþH]þ. Anal. Calcd (%) for C55H84N2O37: C, 48.39; H,
6.20; N, 2.05. Found: C, 48.68; H, 6.63; N, 1.92.
conjugates, the CeC bond formation would occur away from the
hydrophobic cavity of the cyclodextrin and exposed to the bulk
water, which should result in loss of stereoselectivity.
3. Conclusions
4.3. 6I-[(2S)-Pyrrolidin-2-yl]-carbonylamino-6I-deoxy-
b-
cyclodextrin (1)
In summary, a variety of proline and prolinamides covalently
anchored to
catalysts for aldol reactions in water. The structure of the linker
between proline and -cyclodextrin was important for catalytic
b-cyclodextrin have been synthesized and evaluated as
To a suspension of 9 (50 mg, 0.036 mmol) in water (2.5 mL)
PdeC (10%, 11.44 mg) was added. The mixture was stirred under H2
(45 psi) in a Parr reactor for 48 h at room temperature. Then, Pd was
filtered through Celite, and water was freeze-dried. Compound 1
b
activity, the most flexible succinamide derivative 2 giving the best
results. Inhibition experiments showed that the internal cavity of
the cyclodextrin plays a role in the catalysis, probably by formation
of inclusion complexes with the aromatic aldehyde substrate. Per-
methylation of the cyclodextrin residue of compound 2 led to
higher conversion rates, which also showed that the substitution of
the oxygens in the rim of the cyclodextrin cone is important for
catalysis. Although there is room for the improvement in the ster-
eoselectivity and in the catalysis with non-activated aldehydes, the
present work provides some useful results for designing improved
was obtained (0.044 g, 100%) as a white foam. ½a D25
þ76.9 (c 0.13,
ꢀ
H2O); 1H NMR (500 MHz, D2O):
d 4.9e4.8 (m, 6H), 4.8e4.7 (m, 1H),
4.4e4.2 (m, 1H), 3.8e3.6 (m, 28H), 3.5e3.3 (m, 14H), 3.3e3.2 (m,
2H), 2.4e2.2 (m, 2H), 1.8e1.7 (m, 2H); 13C NMR (125 MHz, D2O):
d
168.4, 102.3e101.7, 81.6e81.2, 73.1e71.9, 59.9, 58.9, 45.7, 30.6,
23.3. MS HRMS (ESIþ) m/z (%) calcd for C47H78N2O35: 1230.4385,
found: 1230.4387.
4.4. 6I-[N0-(2S,4S)-1,2-dibeNzyloxycarbonylpyrrolidin-4-yl]
catalysts based on the conjugation of proline and b-cyclodextrin.
aminocarbonylethylcarbonylamino-6I-deoxy-
b-cyclodextrin (12)
4. Experimental section
4.1. General
To a solution of 10 (164 mg, 0.133 mmol) in anhydrous DMF
(6 mL) were added successively DIC (0.08 mL, 0.516 mmol) and HOBt
(80 mg, 0.516 mmol). The reaction mixture was stirred under Ar at-
mosphere for 1 h at room temperature, and then (2S,4S)-4-amino-
1,2-dibenzyloxycarbonylpyrrolidine (11)11 (58 mg, 0.162 mmol) dis-
solved in 6 mL of anhydrous DMF was added. The reaction mixture
Chemicals were purchased puriss p.A. from commercial sup-
pliers or purified by standard techniques. Dioxanone 29 was

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was stirred for 48 h at room temperature. Then, solvent was evapo-
rated under reduced pressure, and acetone was added over the res-
idue obtained, giving a white precipitate that was filtered and
washed with acetone. The precipitate was purified by flash chro-
matography (MeCN/H2O 5:1) obtaining 12 (0.177 g, 85%) as a white
4.3e4.2 (m, 1H), 4.0e3.9 (m, 1H), 3.7e3.4 (m, 28H), 3.4e3.2 (m,
overlaps with HOD), 3.1e3.0 (m, 1H), 2.9e2.8 (m, 1H), 2.4e2.2(m,
1H), 2.0e1.9 (m, 1H); 13C NMR (125 MHz, DMSO-d6):
d 172.2, 153.6,
144.1, 136.5e136.0, 129.5e126.3, 125.9, 102.2, 81.4, 79.8, 73.9e72.0,
75.1, 66.2, 61.2, 60.1, 57.6, 50.2, 30.7. HRMS (ESI) m/z (%) calcd for
C65H93N4O39 [MþH]þ: 1553.5417, found: 1553.5534.
foam. ½a 2D5
ꢀ
þ58.6 (c 0.5, DMSO-d6); 1H NMR (400 MHz, DMSO-d6):
d
7.4e7.2 (m, 10H), 5.8e5.6 (m, 14H), 5.2e5.0 (m, 4H), 4.9e4.8 (m,
7H), 4.6e4.4 (m, 6H), 4.3e4.2 (m, 1H), 4.2e4.1 (m, 1H), 3.8e3.4 (m,
28H), 3.4e3.2 (m, overlaps with HOD), 3.2e3.1 (m, 2H), 2.6e2.5 (m,
1H), 2.4e2.2(m, 4H),1.9e1.8 (m,1H); 13C NMR (100 MHz, DMSO-d6):
4.8. 6I-[[(2S,4R)-2-Carboxypyrrolidin-4-yl]4-oxymethyl]-1H-
1,2,3-triazol-1-yl-6I-deoxy-
b-cyclodextrin (3)
d
172.2,171.7,171.5,153.5,136.6e135.9,128.4e128.3,101.9, 83.4, 81.6,
To a suspension of 15 (250 mg, 0.161 mmol) in water (6 mL)
PdeC (10%, 51.2 mg) was added. The mixture was stirred under H2
(45 psi) in a Parr reactor for 48 h at room temperature. Then, Pd was
filtered through Celite and the filtrate was freeze-dried, obtaining 3
81.4, 66.2, 59.9, 59.8, 57.2, 47.0, 40.0, 30.4. HRMS (ESI)m/z (%) calcd for
C66H96N3O40 [MþH]þ: 1570.5570, found: 1570.5585.
4.5. 6I-[N0-(2S,4S)-2-Carboxypyrrolidin-4-yl]
(0.190 g, 89%) as a white foam. ½a D25
ꢀ
þ44.8 (c 0.52, H2O); 1H NMR
aminocarbonylethylcarbonylamino-6I-deoxy-
b-cyclodextrin (2)
(300 MHz, D2O):
d
7.91 (s, 1H), 5.01 (d, J¼3.4 Hz, 1H) 4.9e4.8 (m,
6H), 4.4e4.3 (m,1H), 4.2e4.0 (m,1H), 3.9e3.6 (m, 24H), 3.6e3.3 (m,
20H) 3.1e2.9 (d, 1H, J¼12.1 Hz), 2.7e2.6 (m, 1H), 2.5e2.4 (m, 1H),
To a suspension of 12 (128 mg, 0.081 mmol) in water (10 mL),
PdeC (10%, 25.8 mg) was added. The mixture was stirred under H2
(45 psi) in a Parr reactor for 48 h at room temperature. Then, Pd was
filtered through Celite, and the filtrate was freeze-dried. Compound
2.1e1.9 (m,1H); 13C NMR (125 MHz, DMSO-d6):
d 174.2,143.9,126.9,
102.2, 102.1, 102.0, 101.6, 83.3, 81.5, 81.3, 80.9, 78.0, 73.3e72.0, 71.9,
71.7, 70.7, 61.4, 60.5, 60.1, 59.4, 50.6 (CH2), 35.1. MS (ESI) m/z 1329.9
(MþH); HRMS (ESI) m/z (%) calcd for C50H81N4O37 [MþH]þ:
1329.4580, found: 1329.4563. Anal. Calcd (%) for C50H80N4O37: C,
45.18; H, 6.07; N, 4.22. Found: C, 44.89; H, 6.21; N, 4.18.
a 25
2 was obtained (0.108 g, 100%) as a white foam. ½ ꢀD þ31.2 (c 0.1,
H2O); 1H NMR (400 MHz):
d
4.9e4.8 (m, 7H), 4.26 (q, J¼9.0 Hz, 1H)
3.98 (t, J¼9.0 Hz, 1H), 3.8e3.6 (m, 28H), 3.5e3.3 (m, 14H), 3.3e3.1
(m, 2H), 2.6e2.5 (m, 1H), 2.4e2.2 (m, 4H), 1.8e1.7 (m, 1H); 13C NMR
(100 MHz, D2O):
d
174.5, 173.8, 173.5, 101.8, 81.1, 73.0, 71.9, 71.6,
4.9. 6I-Azido-6I-deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
60.3, 57.1, 49.9, 48.9, 40.1, 34.2, 30.6. MS (ESI) m/z 1346.9 [MþH]þ.
Anal. Calcd (%) for C51H83N3O38: C, 45.50; H, 6.21; N, 3.12. Found: C,
45.80; H, 6.03; N, 3.40.
b-cyclodextrin (16)
To a solution of 13 (600 mg, 0.517 mmol) in anhydrous DMSO
(12.6 mL) NaH (0.856 g, 18.6 mmol) was added, and the mixture
was stirred at room temperature for 30 min under Ar atmosphere.
Then, the reaction was cooled at 0 ꢂC and benzyl chloride (2.14 mL,
18.6 mmol) was added. The mixture was stirred for 30 min at 0 ꢂC,
and then at room temperature overnight. Then, 10 mL of water
were added to stop the reaction, and it was extracted with ether
(4ꢃ10 mL) and washed with brine. Organic phases were dried
(Na2SO4) and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (hexane/EtOAc
4.6. (2S,4R)-1,2-Dibenzyloxycarbonyl-4-(prop-2-inyloxy)
pyrrolidine (14)
A
solution of (2S,4R)-1,2-dibenzyloxycarbonyl-4-hydroxypy
rrolidine11 (440 mg, 0.985 mmol) in DMF (3.5 mL), was added
over a suspension of sodium hydride (48 mg, 1.63 mmol) in DMF
(3.5 mL) at ꢁ20 ꢂC under argon atmosphere. The mixture was stir-
red for 20 min and then propargyl bromide (0.205 mL, 1.63 mmol)
was added. The reaction mixture was stirred at ꢁ20 ꢂC for 1 h, and
then it was stirred at room temperature for 16 h. After this time,
MeOH (2.5 mL) was added, and it was extracted with CH2Cl2
(3ꢃ2.5 mL) and washed with brine. The organic phases were dried
(Na2SO4), and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography (hexane/
EtOAc 4:1). Compound 14 was obtained (0.300 g, 75%) as a colorless
5:1). Compound 16 was obtained (1.16 g, 76%) as a yellow oil. ½a D25
ꢀ
þ57.0 (c 8.2, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d 7.4e7.05 (m,
100H), 5.4e5.3 (m, 1H), 5.3e5.0 (m, 12H), 4.9e4.7 (m, 10H), 4.8e4.3
(m, 24H), 4.2e3.8 (m, 24H), 3.7e3.4 (m, 18H); 13C NMR (100 MHz,
CDCl3):
d
140.8, 139.3e139.2, 139.0, 138.3e137.9, 128.5,
128.4e126.9, 98.7e98.1, 97.8, 80.8e80.6, 79.5e78.7, 76.7e75.1,
73.3e73.2, 72.8e72.5, 71.7e70.7, 69.4e68.9, 65.3. MS (ESI) m/z
2962.9 [MþH]þ. Anal. Calcd (%) for C182H189N3O34: C, 73.79; H, 6.43;
N, 1.42. Found: C, 73.57; H, 6.75; N, 1.17.
oil. ½a 2D5
ꢀ
ꢁ32.4 (c 0.83, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d 7.4e7.2
(m, 10H), 5.3e5.0 (m, 4H), 4.6e4.4 (m, 1H), 4.4e4.3 (m, 1H), 4.2e4.1
(m, 2H), 3.8e3.6 (m, 2H), 2.5e2.3 (m, 2H), 2.2e2.0 (m,1H); 13C NMR
(100 MHz, CDCl3):
d
172.2, 162.5, 128.5e127.8, 79.1, 76.2, 75.5, 77.1,
4.10. 6I-Amino-6I-deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-
benzyl-b-cyclodextrin (17)
66.9, 58.0, 56.3, 51.6, 35.2. MS (ESI) m/z 394.2 [MþH]þ, 416.2
[MþNa]þ. Anal. Calcd (%) for C23H23NO5: C, 70.21; H, 5.89; N, 3.56.
Found: C, 69.82; H, 6.15; N, 3.58.
To a solution of 16 (970 mg, 0.327 mmol) in THF (9.34 mL), PMe3
(solution 1 M in THF; 3.93 mL, 3.93 mmol) and H2O (2.33 mL) were
added. The reaction mixture was stirred at 50 ꢂC for 24 h. Then
solvent was evaporated under reduced pressure, and the residue
was extracted with EtOAc and water (3ꢃ25 mL). Organic phases
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography (tolu-
ene/EtOAc 20:1/1:1). Compound 17 was obtained (0.650 g, 70%)
4.7. 6I-[[(2S,4R)-1,2-Dibenzyloxycarbonylpyrrolidin-4-yl]4-
oxymethyl]-1H-1,2,3-triazol-1-yl-6I-deoxy-
b-cyclodextrin (15)
To a solution of 13 (500 mg, 0.427 mmol) in DMF/H2O (1:1 (v/v),
20 mL), were added successively 14 (168 mg, 0.427 mmol),
CuSO4$5H2O (80.9 mg, 0.324 mmol), and sodium ascorbate
(57.8 mg, 0.324 mmol). The reaction mixture was heated in the
microwave at 80 ꢂC (200 W) for 5 h. Then, solvent was evaporated
under reduced pressure, and the residue was purified by flash
chromatography (MeCN/H2O 6:1). Compound 15 was obtained
as a white foam. ½a D25
ꢀ
þ54.8 (c 2.9, CH2Cl2); 1H NMR (400 MHz,
CDCl3):
d 7.4e7.05 (m, 100H), 5.3e4.9 (m, 21H), 4.8e4.6 (m, 12H),
4.6e4.2 (m, 28H), 3.7e3.3 (m, 28H), 3.0e2.8 (m, 2H); 13C NMR
(100 MHz, CDCl3): 139.2, 138.3e138.1, 128.3, 128.2e126.9,
d
(0.500 g, 75%) as a white foam. ½a D25
ꢀ
þ57.6 (c 0.5, DMSO-d6); 1H
98.9e98.1, 97.8, 80.9e80.6, 79.5e78.7, 76.7e75.1, 73.3e73.2,
72.8e72.7, 71.6e71.1, 69.2e68.9. HRMS (ESI) m/z (%) calcd for
C182H192NO34 [MþH]þ: 2935.3326, found: 2935.3306. Anal. Calcd
NMR (500 MHz, DMSO-d6):
d 8.1e7.9 (m, 1H), 7.4e7.2 (m, 10H),
5.8e5.6 (m,14H), 5.2e5.0 (m, 4H), 4.9e4.8 (m, 7H), 4.6e4.4 (m, 8H),

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E.G. Doyaguez, A. Fernandez-Mayoralas / Tetrahedron 68 (2012) 7345e7354
7351
(%) for C182H191NO34: C, 74.44; H, 6.56; N, 0.48. Found: C, 74.26; H,
6.56; N, 0.19.
1.006 mmol) and HOBt (156 mg, 1.006 mmol) were added succes-
sively. The reaction mixture was stirred under Ar atmosphere at
room temperature for 1 h and 17 (600 mg, 0.204 mmol) dissolved
in 12 mL of anhydrous DMF was added. The reaction was stirred for
2 h at room temperature. After this time, solvent was evaporated
under reduced pressure, and the residue was dissolved in 20 mL of
CH2Cl2 and it was extracted with brine (3ꢃ10 mL). The organic
phase was dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The residue was purified by column chroma-
tography (hexane/EtOAc 3:1), obtaining 22 (0.650 g, 99%) as a white
4.11. (2S,4R)-1,2-Dibenzyloxycarbonyl-4-(1H-imidazol-1-
carbonyloxy)pyrrolidine (18)
To a solution of (2S,4R)-1,2-dibenzyloxycarbonyl-4-hydroxypy
rrolidine11 (370 mg, 1.036 mmol) in anhydrous THF (20.5 mL) N,N0-
carbonyldiimidazole (323.82 mg, 2.072 mmol) was added. The re-
action mixture was stirred under Ar atmosphere at 40 ꢂC for 24 h.
Then, solvent was evaporated under reduced pressure and the resi-
due was purified by flash chromatography (hexane/EtOAc 1:4),
foam. ½a 2D5
ꢀ
þ56.4 (c 1.37, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
7.3e7.0 (m, 105H), 5.4e5.0 (m, 7H), 5.0e4.8 (m, 12H), 4.8e4.6 (m,
obtaining 18 (0.380 g, 82%) as awhite solid. ½a D25
ꢀ
ꢁ31.1 (c 1.3, CH2Cl2);
8H), 4.5e4.3 (m, 28H), 4.1e3.9 (m, 25H), 3.8e3.6 (m, 2H), 3.6e3.4
mp: 57e60 ꢂC; 1H NMR (400 MHz, CDCl3):
d 8.10 (s, 1H), 7.4e7.2 (m,
(m, 11H), 3.4e3.2 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3):
10H), 7.2e7.1 (m, 1H), 7.08 (s, 1H), 5.6e5.5 (m, 1H), 5.3e5.0 (m, 4H),
4.58 (dt, J¼7.8 Hz, 31.8 Hz, 1H), 3.9e3.8 (m, 2H), 2.7e2.6 (m, 1H),
d 170.3, 155.4, 139.2, 138.5, 128.4e127.1, 98.7e97.6, 81.2e81.0,
79.1e78.8, 77.5, 75.8e75.2, 73.5e73.4, 72.9e72.5, 71.8e71.6,
69.5e69.3, 53.8, 42.9, 28.3. Anal. Calcd (%) for C197H210N2O38: C,
73.62; H, 6.59; N, 0.87. Found: C, 73.37; H, 6.59; N, 1.10.
2.5e2.3 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 171.5, 171.1, 155.8,
147.8, 137.2, 130.8, 128.8e128.2, 76.2, 67.5, 67.2, 57.5, 52.1, 36.4, 35.3.
MS (ESI) m/z 450.2 [MþH]þ. Anal. Calcd (%) for C24H23N3O6: C, 64.13;
H, 5.16; N, 9.35. Found: C, 63.87; H, 5.10; N, 9.12.
4.15. 6I-[(1S)-N-tert-Butoxycarbony-1-amino-2-benzyloxyethyl]
carbonylamino-6I-deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
4.12. 6I-[(2S,4R)-1,2-Dibenzyloxycarbonylpyrrolidin-4-yl]-
oxycarbonylamino-6I-deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-
b-cyclodextrin (23)
benzyl-b-cyclodextrin (19)
N-Boc-O-Benzyl- -serine (21) (90.36 mg, 0.204 mmol) was dis-
L
solved in anhydrous DMF (12 mL), and then DIC (0.156 mL,
1.006 mmol) and HOBt (156 mg, 1.006 mmol) were added succes-
sively. The reaction mixture was stirred under Ar atmosphere at
room temperature for 1 h and 17 (600 mg, 0.204 mmol) dissolved
in 12 mL of anhydrous DMF was added. The reaction was stirred for
2 h at room temperature. After this time, solvent was evaporated
under reduced pressure, and the residue was dissolved in 20 mL of
CH2Cl2 and it was extracted with brine (3ꢃ10 mL). The organic
phase was dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The residue was purified by column chroma-
tography (hexane/EtOAc 3:1), obtaining 23 (0.530 g, 81%) as a white
To a solution of 18 (366.4 mg, 0.816 mmol) in anhydrous THF
(2.5 mL), Et3N (726.22 mL) and 17 (600 mg, 0.204 mmol) were
added. The reaction mixture was stirred at 60 ꢂC for 48 h. Then,
solvent was eliminated under reduced pressure, and the residue was
purified by column chromatography (hexane/EtOAc 2:1). Com-
pound 19 was obtained (0.530 g, 83%) as a white foam. ½a D25
þ45.9 (c
ꢀ
1.4, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d 7.4e7.0 (m,110H), 5.3e4.8
(m, 18H), 4.8e4.6 (m, 10H), 4.6e4.2 (m, 25H), 4.0e3.8 (m, 24H),
3.8e3.6 (m, 1H), 3.6e3.4 (m, 18H) 3.4e3.2 (m, 1H), 2.4e2.2 (m, 1H),
2.2e2.0 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 172.0, 171.8, 155.4,
154.7, 154.0, 139.4e139.2, 138.9, 138.4e138.1, 128.6, 128.4e126.9,
98.8e97.8, 81.0e80.2, 79.3e78.8, 75.7e74.8, 73.6e73.0, 72.9e72.4,
72.2e72.0, 71.7, 71.4, 70.1, 69.4e69.1, 68.6, 67.3, 67.1, 66.9, 57.9, 57.7,
41.3, 29.6. Anal. Calcd (%) for C203H210N2O40: C, 73.49; H, 6.38; N,
0.84. Found: C, 73.37; H, 6.53; N, 0.92.
foam. ½a 2D5
ꢀ
þ41.0 (c 1.41, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d
7.3e7.0 (m, 105H), 5.4e5.0 (m, 7H), 5.0e4.8 (m, 12H), 4.8e4.6 (m,
8H), 4.5e4.3 (m, 28H), 4.1e3.9 (m, 25H), 3.8e3.6 (m, 2H), 3.6e3.4
(m, 11H), 3.3e3.1 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
170.3, 155.4, 139.1, 138.3, 128.5e126.9, 98.7e97.6, 81.2e81.0,
79.1e78.8, 77.5, 75.8e75.2, 73.5e73.4, 72.9e72.5, 71.8e71.6,
69.5e69.3, 53.8, 42.9, 28.3. Anal. Calcd (%) for C197H210N2O38: C,
73.62; H, 6.59; N, 0.87. Found: C, 73.25; H, 6.35; N, 0.71.
4.13. 6I-[(2S,4R)-2-Carboxypyrrolidin-4-yl]-oxycarbonylamino-
6I-deoxy-
b-cyclodextrin (4)
To a solution of 19 (176 mg, 0.053 mmol) in MeOH/EtOAc (1:1,
5 mL) PdeC (10%, 300 mg) and TFA (cat.) were added. The mixture
was stirred under H2 (45 psi) in a Parr reactor for 48 h at room
temperature. Then, Pd was filtered through Celite, and washed with
MeOH and water. Most of the solvents were evaporated under re-
duced pressure, and the residue was freeze-dried. Compound 4 was
4.16. 6I-[(1R)-1-Amino-2-benzyloxyethyl]carbonylamino-6I-
deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
b-cyclodextrin(24)
Compound 22 (620 mg, 0.193 mmol) was dissolved in CH2Cl2
(37 mL), and TFA was added (0.911 mL). The mixture was stirred
overnight at room temperature, and then the solvent was evapo-
rated under reduced pressure. The residue was dissolved in 20 mL
of EtOAc and Et3N (0.887 mL) and 10 mL of H2O were added. The
mixture was stirred for 30 min, and it was extracted with brine
(3ꢃ10 mL). The organic phase was dried (Na2SO4), and the solvent
was evaporated under reduced pressure, obtaining 24 (0.600 g,
obtained (57.3 mg, 87%) as a white foam. ½a D25
þ40.9 (c 0.55, H2O);
ꢀ
1H NMR (400 MHz, D2O):
d 5.17 (s, 1H), 4.90 (s, 6H), 4.4e4.2 (m,1H),
3.8e3.6 (m, 25H), 3.5e3.4 (m, 18H), 3.4e3.2 (m, 1H), 3.2e3.0 (m,
1H), 2.5e2.4 (m, 1H), 2.3e2.1 (m, 1H); 13C NMR (125 MHz, CDCl3):
d
172.5, 156.9, 102.1, 83.3, 81.4e81.0, 74.0, 73.2e72.1, 71.9, 70.7, 79.9,
60.3, 60.1, 59.4, 51.4, 41.5, 35.2. MS (ESI) m/z 1291.7 [MþH]þ. HRMS
(ESI) m/z (%) calcd for C48H79N2O38 [MþH]þ: 1291.4311, found:
1291.4335. Anal. Calcd (%) for C48H78N2O38: C, 44.65; H, 6.09; N,
2.17. Found: C, 44.17; H, 6.08; N, 2.47.
100%) as a white foam. ½a D25
ꢀ
þ61.2 (c 0.92, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 7.4e7.0 (m, 105H), 5.4e5.0 (m, 7H), 5.0e4.8 (m,
12H), 4.8e4.6 (m, 8H), 4.5e4.3 (m, 28H), 4.1e3.9 (m, 25H), 3.7e3.3
(m, 14H). Anal. Calcd (%) for C192H202N2O36: C, 74.06; H, 6.54; N,
0.90. Found: C, 74.69; H, 6.80; N, 0.60.
4.14. 6I-[(1R)-N-tert-Butoxycarbonyl-1-amino-2-benzyloxyethyl]
carbonylamino-6I-deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
b-
4.17. 6I-[(1S)-1-Amino-2-benzyloxyethyl]carbonylamino-6I-
cyclodextrin (22)
deoxy-2IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
b-cyclodextrin (25)
N-Boc-O-Benzyl-
D-serine (20) (90.36 mg, 0.204 mmol) was dis-
Compound 23 (450 mg, 0.140 mmol) was dissolved in CH2Cl2
solved in anhydrous DMF (12 mL), and then DIC (0.156 mL,
(27 mL), and TFA was added (0.656 mL). The mixture was stirred

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E.G. Doyaguez, A. Fernandez-Mayoralas / Tetrahedron 68 (2012) 7345e7354
7352
overnight at room temperature, and then solvent was evaporated
under reduced pressure. The residue was dissolved in 20 mL of
EtOAc and Et3N (0.639 mL) and 10 mL of H2O were added. The
mixture was stirred for 30 min, and it was extracted with brine
(3ꢃ10 mL). The organic phase was dried (Na2SO4), and the solvent
was evaporated under reduced pressure, obtaining 25 (0.410 g,
1H NMR (300 MHz, D2O):
d 4.9e4.8 (m, 7H), 4.4e4.2 (m, 4H),
4.0e3.2 (m, 42H), 2.4e2.2 (m, 2H), 2.0e1.8 (m, 4H). HRMS (ESI) m/z
(%) calcd for C50H84N3O37 [MþH]þ: 1318.4784, found: 1318.4803.
4.21. 6I-[(1S)-1-[(2S)-Pyrrolidin-2-yl]-carbonylamino-2-
hydroxyethyl]carbonylamino-6I-deoxy-
b-cyclodextrin (6)
94%) as a white foam. ½a D25
ꢀ
þ154.9 (c 0.9, CH2Cl2); 1H NMR
(400 MHz, CDCl3):
d
7.4e7.0 (m, 105H), 5.4e5.0 (m, 7H), 5.0e4.8 (m,
To a solution of 27 (170 mg, 0.050 mmol) in MeOH/AcOEt (1:1,
5 mL), PdeC (10%, 320 mg) and TFA (cat.) were added. The mixture
was stirred under H2 (45 psi) in a Parr reactor for 48 h at room
temperature. Then, Pd was filtered through Celite, and washed with
MeOH and water. Most of the solvents were evaporated under re-
duced pressure, and the residue was freeze-dried. Compound 6 was
12H), 4.8e4.6 (m, 8H), 4.5e4.3 (m, 28H), 4.1e3.9 (m, 25H), 3.7e3.3
(m, 14H); Anal. Calcd (%) for C192H202N2O36: C, 74.06; H, 6.54; N,
0.90. Found: C, 74.56; H, 6.07; N, 1.10.
4.18. 6I-[(1R)-1-[(2S)-1-Benzyloxycarbonylpyrrolidin-2-yl]
carbonylamino-2-benzyloxyethyl]carbonylamino-6I-deoxy-
obtained (65.8 mg, 100%) as a white foam. ½a D25
þ44.0 (c 0.1, H2O);
ꢀ
2
IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
b-cyclodextrin (26)
1H NMR (300 MHz, D2O):
d 4.9e4.8 (m, 7H), 4.4e4.2 (m, 4H),
4.0e3.2 (m, 42H), 2.4e2.2 (m, 2H), 2.0e1.8 (m, 4H); 13C NMR
(100 MHz, D2O): 165.7, 165.6, 102.2, 82.0e80.9, 73.6, 72.5e71.5,
N-Carboxybenzyl-
L-proline (8) (109.76 mg, 0.269 mmol) was
d
dissolved in anhydrous DMF (16 mL), and DIC (0.168 mL,
1.083 mmol) and HOBt (168 mg, 1.083 mmol) dissolved in anhy-
drous DMF (2.5 mL) were added successively. The reaction mixture
was stirred under Ar at room temperature for 1 h. Then, 24 (560 mg,
0.179 mmol) dissolved in anhydrous DMF (16 mL) was added. The
reaction mixture was stirred at room temperature overnight. Then,
solvent was evaporated under reduced pressure, and the residue
was dissolved in 20 mL of CH2Cl2 and extracted with brine
(3ꢃ10 mL). The organic phase was dried (Na2SO4), and the solvent
was evaporated under reduced pressure. The residue was purified
by column chromatography (hexane/EtOAc 3:1), obtaining 26
61.8, 60.8e59.7, 56.2, 46.9, 37.3, 30.2, 23.8. HRMS (ESI) m/z (%) calcd
for C50H84N3O37 [MþH]þ: 1318.4784, found: 1318.4809.
4.22. General procedure for aldol reaction catalyzed by
cyclodextrin derivatives (1e6), between p-nitrobenzaldehyde
(28) and dioxanone (29)
To
a
suspension/solution of p-nitrobenzaldehyde (28)
(0.013 mmol) and the catalyst (20% mol) in water (0.05 mL), diox-
anone (29) (0.026 mmol) was added. The mixture was stirred at
room temperature for the time indicated in Tables 1 and 2. Then,
water was added (0.3 mL), and the mixture was extracted with
CH2Cl2 (3ꢃ0.3 mL). Organic phase was concentrated under reduced
pressure. Conversions and stereoselectivities are shown in Table 1.
(0.520 g, 87%) as a white foam. ½a D25
ꢀ
þ40.8 (c 1.18, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 7.4e6.8 (m, 110H), 5.3e4.9 (m, 7H), 4.9e4.6 (m,
14H), 4.5e4.1 (m, 31H), 4.1e3.7 (m, 29H), 3.6e3.2 (m, 18H), 2.0e1.5
(m, 4H); Anal. Calcd (%) for C205H215N3O39: C, 73.61; H, 6.48; N, 1.26.
Found: C, 73.73; H, 6.50; N, 1.16.
4.23. (3S,4S)-4-p-Nitrophenyl-1,3,4-trihydroxy-1,3-O-
isopropyliden-butan-2-one (30)
4.19. 6I-[(1S)-1-[(2S)-1-Benzyloxycarbonylpyrrolidin-2-yl]
carbonylamino-2-benzyloxyethyl]carbonylamino-6I-deoxy-
1H NMR (300 MHz, CDCl3):
d
(major isomer) 8.21 (d, J¼8.1 Hz,
2
IeVII,3IeVII,6IIeVII-eicosakis-O-benzyl-
b-cyclodextrin (27)
2H, ArH), 7.60 (d, J¼8.1 Hz, 2H, ArH), 5.01 (d, J¼7.5 Hz, 1H, CHOH),
4.5e4.1 (m, 3H), 3.8e3.7 (m, 1H), 1.39 (s, 3H, Me), 1.21 (s, 3H, Me);
N-Carboxybenzyl-
L-proline (8) (70.55 mg, 0.173 mmol) was
13C NMR (75 MHz, CDCl3, 298 K):
d 210.6 (C]O), 146.5 (Ar), 138.3
dissolved in anhydrous DMF (10 mL), and DIC (0.102 mL,
0.657 mmol) and HOBt (102 mg, 0.657 mmol) dissolved in anhy-
drous DMF (2 mL) were added successively. The reaction mixture
was stirred under Ar at room temperature for 1 h. Then, 25 (360 mg,
0.115 mmol) dissolved in anhydrous DMF (10 mL) was added. The
reaction mixture was stirred at room temperature overnight. Then,
solvent was evaporated under reduced pressure, and the residue
was dissolved in 20 mL of CH2Cl2 and extracted with brine
(3ꢃ10 mL). The organic phase was dried (Na2SO4), and the solvent
was evaporated under reduced pressure. The residue was purified
by column chromatography (hexane/EtOAc 3:1), obtaining 27
(Ar), 127.9 (Ar), 123.2 (Ar), 101.4 (Ac), 75.8 (C-4), 71.7 (C-3), 66.6 (C-
1), 23.4 (CH3), 23.3 (CH3); MS (EI): m/z 585.3 (2Mþ23). Anal. Calcd
(%) for C13H15NO6: C, 55.51; H, 5.38; N, 4.98. Found: C, 55.33; H,
5.22; N, 5.18. All the spectroscopic data matched with literature.19
Retention time (HPLC, Daicel Chiralpak OD-H, hexane/i-
PrOH¼90:10, flow rate 1 mL/min, ¼254 nm): tR¼11.17 (anti, ma-
l
jor), tR¼12.79 (anti, minor), tR¼16.62 (syn). Retention time (HPLC,
Daicel Chiralpak AD-H, hexane/i-PrOH¼96:4, flow rate 1 mL/min,
l
¼254 nm): tR¼25.88 min (anti, major), tR¼27.98 min (anti, minor),
tR¼44.49 min (syn, minor), tR¼60.62 min (syn, major).
(0.320 g, 83%) as a white foam. ½a D25
ꢀ
þ30.3 (c 0.61, CH2Cl2); 1H NMR
4.24. (2S,4S)-4-Acetamido-1,2-dibenzyloxycarbonylpyrrolidine
(400 MHz, CDCl3): d 7.4e6.8 (m, 110H), 5.3e4.9 (m, 7H), 4.9e4.6 (m,
14H), 4.5e4.1 (m, 31H), 4.1e3.7 (m, 29H), 3.6e3.2 (m, 18H), 2.0e1.5
(m, 4H); Anal. Calcd (%) for C205H215N3O39: C, 73.61; H, 6.48; N, 1.26.
Found: C, 73.43; H, 6.55; N, 1.59.
To a solution of (2S,4S)-4-amino-1,2-dibenzyloxycarbonylpy
rrolidine (11)11 (200 mg, 0.563 mmol) in pyridine (0.8 mL), acetic
anhydride (184.10 mL) was added. The mixture was stirred at room
temperature overnight. Then, solvent was evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (CH2Cl2/MeOH 20:1) to give the title compound (0.150 g,
4.20. 6I-[(1R)-1-[(2S)-Pyrrolidin-2-yl]-carbonylamino-2-
hydroxyethyl]carbonylamino-6I-deoxy-
b-cyclodextrin (5)
67%) as a yellow oil. ½a D25
ꢀ
ꢁ137.5 (c 0.24, CH2Cl2); 1H NMR
To a solution of 26 (85.7 mg, 0.026 mmol) in MeOH/AcOEt (1:1,
2.5 mL), PdeC (10%, 148 mg) and TFA (cat.) were added. The mix-
ture was stirred under H2 (45 psi) in a Parr reactor for 48 h at room
temperature. Then, Pd was filtered through Celite, and washed with
MeOH and water. Most of the solvents were evaporated under re-
duced pressure, and the residue was freeze-dried. Compound 5 was
(300 MHz, CDCl3):
d
7.4e7.2 (m, 10H), 6.6e6.5 (d, J¼9 Hz, 1H),
5.3e5.0 (m, 4H), 4.7e4.6 (m, 1H), 4.43 (dd, J¼12 Hz, 21 Hz, 1H),
3.7e3.5 (m, 2H) 2.6e2.4 (m, 1H), 2.1e1.9 (m, 1H), 1.80 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 174.1, 169.9, 155.0, 154.3, 136.3, 135.3, 135.1,
129.1e128.1, 68.4, 67.8, 67.7, 58.6, 58.2, 57.7, 53.9, 53.7, 53.4, 49.2,
48.6, 48.3, 47.6, 37.2, 36.9, 36.7, 36.2, 35.9, 35.6, 23.8, 23.5, 23.2,
22.9. MS (ESI) m/z 397.2 [MþH]þ, 419.2 [MþNa]þ. Anal. Calcd
obtained (34.2 mg, 100%) as a white foam. ½a D25
þ92.0 (c 0.2, H2O);
ꢀ

€
ꢀ
E.G. Doyaguez, A. Fernandez-Mayoralas / Tetrahedron 68 (2012) 7345e7354
7353
(%) for C22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.27; H,
6.46; N, 6.80.
1414.7144. Anal. Calcd (%) for C62H111NO34: C, 52.64; H, 7.91; N, 0.99.
Found: C, 52.37; H, 8.21; N, 1.03.
4.25. (2S,4S)-4-Acetamido-2-carboxypyrrolidine (31)
4.29. 6I-Succinylamido-6I-deoxy-permethylated-
cyclodextrin (35)
b-
To a solution of (2S,4S)-4-acetamido-1,2-dibenzyloxycarbonylp
yrrolidine (100 mg, 0.252 mmol) in MeOH (5 mL), PdeC (10%,
475 mg) was added. The mixture was stirred under H2 (42 psi) in
a Parr reactor for 24 h at room temperature. Then, Pd was filtered
through Celite, and the solvent was evaporated under reduced
pressure. Compound 31 was obtained (0.043 g, 100%) as a yellow
A solution of succinic anhydride (14.7 mg, 0.113 mmol) in an-
hydrous DMF (0.5 mL), was added over a solution of 34 (160 mg,
0.113 mmol) in anhydrous DMF (4 mL). The reaction mixture was
stirred under Ar at room temperature overnight. Then, solvent was
evaporated under reduced pressure. The residual syrup was puri-
fied by column chromatography (CH2Cl2/MeOH 15:1), obtaining 35
solid. ½a 2D5
ꢀ
ꢁ23.9 (c 0.23, H2O); 1H NMR (400 MHz, D2O):
d 4.26 (q,
J¼6.6 Hz, 1H), 4.02 (dd, J¼7.7 Hz, 9.0 Hz, 1H), 3.42 (dd, J¼7.1 Hz,
12.4 Hz, 1H), 3.17 (dd, J¼5.7 Hz, 12.5 Hz, 1H), 2.51 (ddd, J¼6.8 Hz,
8.8 Hz,13.6 Hz,1H), 2.0e1.8 (m,1H),1.79 (s, 3H); 13C NMR (100 MHz,
(0.130 g, 93%) as a colorless oil. ½a D25
ꢀ
þ115.7 (c 0.3, MeOH); 1H NMR
(300 MHz, CDCl3):
d
5.17 (d, J¼3 Hz, 1H), 5.14 (d, J¼3 Hz, 1H),
5.13e5.04 (m, 5H), 3.9e3.7 (m, 14H), 3.7e3.5 (m, 30H), 3.5e3.4 (m,
30H), 3.4e3.3 (m, 20H), 3.2e3.1 (m, 8H), 2.7e2.6 (m, 2H), 2.5e2.4
D2O):
d 174.5, 173.7, 60.19, 49.4, 48.8, 33.9, 21.8. Spectroscopic data
are in agreement with those described in literature.20 MS (ESI) m/z
173.0 [MþH]þ, 195.0 [MþNa]þ. Anal. Calcd (%) for C7H12N2O3: C,
48.83; H, 7.02; N, 16.27. Found: C, 48.75; H, 7.15; N, 16.43.
(m, 2H); 13C NMR (75 MHz, CDCl3):
d 172.5, 99.3, 98.9, 98.4, 82.2,
81.9, 81.8, 81.6, 80.7, 80.4, 79.8, 71.5, 71.1, 70.2, 61.7, 61.6, 61.5, 59.6,
58.8, 58.7, 58.6, 52.0, 50.7, 40.8, 31.3, 29.3. HRMS (ESI) m/z (%) calcd
for C66H115NO37Na [MþNa]þ: 1536.7046, found: 1536.7063.
4.26. General procedure for aldol reaction catalyzed by
proline derivative 31, between p-nitrobenzaldehyde (28) and
dioxanone (29)
4.30. 6I-[N0-(2S,4S)-1,2-Dibenzyloxycarbonylpyrrolidin-4-yl]
aminocarbonylethylcarbonylamino-6I-deoxy-permethylated-
To a solution of p-nitrobenzaldehyde (28) (0.013 mmol) and the
catalyst 31 (20% mol) with or without b-cyclodextrin (20% mol) in
b-cyclodextrin (36)
H2O (0.05 mL), dioxanone (29) (0.026 mmol) was added. The
mixture was stirred at room temperature for 48 h. Then, water was
added (0.3 mL), and the mixture was extracted with CH2Cl2
(3ꢃ0.3 mL). Organic phase was concentrated under reduced pres-
sure. Conversions and stereoselectivities are shown in Table 1.
To a solution of 35 (130 mg, 0.086 mmol) in anhydrous DMF
(4 mL) were added successively DIC (0.052 mL, 0.335 mmol)
and HOBt (52 mg, 0.335 mmol). The reaction mixture was stirred
under Ar atmosphere for 1 h at room temperature, and then
(2S,4S)-4-amino-1,2-dibenzyloxycarbonylpyrrolidine (11) (37.6 mg,
0.112 mmol) dissolved in 4 mL of anhydrous DMF was added. The
reaction mixture was stirred for 48 h at room temperature. Then,
the solvent was evaporated under reduced pressure, and the resi-
due was purified by column chromatography (EtOAc/MeOH 10:1),
4.27. 6I-Azido-6I-deoxy-permethylated-
b-cyclodextrin (33)
To a solution of 13 (300 mg, 0.26 mmol) in anhydrous DMF
(10 mL) NaH (0.750 g, 31 mmol) was added. The mixture was
sonicated at room temperature for 15 min in a water bath. Then,
MeI (3 mL) was added, and the reaction mixture was sonicated for
15 additional minutes. The reaction mixture was diluted with water
and it was extracted with CH2Cl2 (4ꢃ10 mL). Organic phases were
dried (Na2SO4), and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography
(CH2Cl2/EtOH 20:1). Compound 33 was obtained (0.32 g, 86%) as
obtaining 36 (0.110 g, 70%) as a colorless oil. ½a D25
þ52.0 (c 1.62,
ꢀ
MeOH); 1H NMR (300 MHz, CDCl3):
d 7.4e7.2 (m, 10H), 5.2e4.9 (m,
11H), 4.6e4.4 (m, 1H), 4.3e4.2 (m, 1H), 3.9e3.7 (m, 14H), 3.7e3.3
(m, 80H), 3.2e3.1 (m, 10H), 2.5e2.4 (m, 5H), 2.4e2.2 (m, 1H); 13C
NMR (75 MHz, CD3OD):
d 173.9, 172.9, 172.8, 163.7, 128.4e127.8,
124.0, 123.9, 117.5, 111.3, 98.4e97.9, 82.5e81.0, 80.0e78.6,
71.6e70.4, 60.7, 60.6, 58.6, 58.3, 57.8, 56.2, 40.1, 35.8, 34.7, 30.8,
30.5, 28.5. Anal. Calcd (%) for C86H135N3O40: C, 55.80; H, 7.35; N,
2.27. Found: C, 55.92; H, 7.25; N, 2.56.
a yellow oil. ½a 2D5
ꢀ
þ5.7 (c 0.53, CH2Cl2); 1H NMR (300 MHz, CD3OD):
d
5.2e5.1 (m, 7H), 4.0e3.7 (m, 14H), 3.7e3.4 (m, 60H), 3.4e3.3 (m,
20H), 3.2e3.1 (m, 8H); 13C NMR (75 MHz, CD3OD):
d 98.7, 98.4, 98.2,
82.3, 82.1, 81.3, 79.7, 71.6, 71.2, 60.7, 58.2, 57.8, 52.0. Spectroscopic
data are in agreement with those described in literature.21 HRMS
(ESI) m/z (%) calcd for C62H109N3O34Na [MþNa]þ: 1462.6790, found:
1462.6818.
4.31. 6I-[N0-(2S,4S)-2-Carboxypyrrolidin-4-yl]
aminocarbonylethylcarbonylamino-6I-deoxy-permethylated-
b
-cyclodextrin (37)
To a solution of 36 (80 mg, 0.043 mmol) in MeOH (2 mL), PdeC
4.28. 6I-Amino-6I-deoxy-permethylated-
b
-cyclodextrin (34)
(10%, 13.7 mg) was added. The mixture was stirred under H2
(45 psi) in a Parr reactor for 48 h at room temperature. Then, Pd was
filtered through Celite, and washed with MeOH and water. Solvent
was evaporated under reduced pressure, and the residue was
purified by column chromatography (EtOAc/MeOH 4:1) obtaining
To a solution of 33 (300 mg, 0.208 mmol) in MeOH (25 mL)
PdeC (10%, 58 mg) was added. The reaction mixture was stirred
under H2 at room temperature for 48 h. Then, Pd was filtered
through Celite, it was washed with MeOH and EtOH and the solvent
was evaporated under reduced pressure. The residue was purified
by column chromatography (CH2Cl2/EtOH 10:1). Compound 34 was
37 (56 mg, 80%) as a colorless oil. ½a D25
ꢀ
þ104.1 (c 1.46, MeOH); 1H
NMR (400 MHz, CD3OD):
d 5.3e5.1 (m, 7H), 4.45e4.35 (m, 1H),
4.3e4.1 (m, 1H), 3.9e3.7 (m, 12H), 3.65e3.45 (m, 59H), 3.4e3.3 (m,
24H), 3.2e3.1 (m, 7H), 2.95e2.90 (m, 1H), 2.85e2.80 (m, 1H),
2.6e2.4 (m, 5H), 1.7e1.9 (m, 1H); 13C NMR (125 MHz, CD3OD):
obtained (0.160 g, 57%) as a white foam. ½a D25
þ10.3 (c 0.33, CH2Cl2);
ꢀ
1H NMR (300 MHz, CDCl3):
d
5.14 (d, J¼3 Hz, 1H), 5.09 (d, J¼3 Hz,
1H), 5.08e5.02 (m, 5H), 3.9e3.7 (m,14H), 3.7e3.4 (m, 60H), 3.4e3.3
d 177.0, 174.5, 173.7, 99.6, 99.5, 99.3, 99.25, 99.2, 99.1, 98.9,
(m, 20H), 3.2e3.1 (m, 8H); 13C NMR (75 MHz, CDCl3):
d
99.6, 99.2,
83.6e82.6, 82.8, 81.1e80.3, 72.7e72.2, 71.5, 64.4, 62.5, 62.4,
61.9e61.6, 59.7e58.8, 56.4, 55.6, 53.9, 53.1, 50.4, 49.8, 38.6, 32.1,
32.2. Anal. Calcd (%) for C71H123N3O38: C, 52.42; H, 7.62; N, 2.58.
Found: C, 52.67; H, 7.45; N, 2.32.
99.0, 98.8, 82.6, 82.2, 81.8, 80.7, 80.3, 72.5, 71.7, 71.4, 71.2, 71.1, 61.7,
61.5, 61.4, 59.4, 59.2, 58.9, 58.8, 58.6, 58.5, 58.4, 50.6, 42.5. HRMS
(ESI) m/z (%) calcd for C62H112NO34 [MþH]þ: 1414.7066, found:

€
ꢀ
E.G. Doyaguez, A. Fernandez-Mayoralas / Tetrahedron 68 (2012) 7345e7354
7354
2. (a) List, B.; Lerner, R.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396;
(b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386e7387; (c) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260e5267; (d)
4.32. General procedure for aldol reaction catalyzed by 2 or 37
between p-nitrobenzaldehyde (28) and ketones 29, 38, and 39
€
Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529e532; (e) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138e5175.
3. Mase, N.; Barbas, C. F., III. Org. Biomol. Chem. 2010, 8, 4043e4050.
4. Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687e6703.
5. (a) Rekharsky, M.; Inoue, Y. Chem. Rev. 1998, 98, 1875e1917; (b) Connors, K.
Chem. Rev. 1997, 97, 1325e1357.
To
a
suspension/solution of p-nitrobenzaldehyde (28)
(0.013 mmol) and the catalyst (20% mol) in water (0.05 mL), the
corresponding ketone (29, 0.026 mmol; 38, 0.065 mmol; or 39,
0.325 mmol) was added. The mixture was stirred at room tem-
perature for 24 h. Then, water was added (0.3 mL), and the mixture
was extracted with CH2Cl2 (3ꢃ0.3 mL). Organic phase was con-
centrated under reduced pressure. Conversions and stereo-
selectivities are shown in Table 3.
6. (a) Watanabe, K.-I.; Yamada, Y.; Goto, K. Bull. Chem. Soc. Jpn. 1985, 58,
1401e1406; (b) Shen, Z.; Ma, J.; Liu, Y.; Jiao, C.; Li, M.; Zhang, Y. Chirality 2005,
€
17, 556e558; (c) Liu, K.; Haussinger, D.; Woggon, W.-D. Synlett 2007,
2298e2300; (d) Huang, J.; Zhang, X.; Armstrong, D. W. Angew. Chem., Int. Ed.
2007, 46, 9073e9077.
7. Yuan, D.-Q.; Dong, S. D.; Breslow, R. Tetrahedron Lett. 1998, 39, 7673e7676.
8. Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5755e5760.
4.33. (2S,10R)-2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-
1-one (40)
ꢀ
9. Baussanne, I.; Benito, J. M.; Ortiz Mellet, C.; García Fernandez, J. M.; Law, H.;
Defaye, J. Chem. Commun. 2000, 1489e1490.
10. Auzely-Velty, R.; Perly, B.; Tache, O.; Zemb, T.; Jehan, P.; Guenot, P.; Dalbiez, J.-P.;
ꢀ
ꢀ
ꢀ
1H NMR (300 MHz, CDCl3, 298 K):
d (major isomer) 8.19 (d,
Djedaïni-Pilard, F. Carbohydr. Res. 1999, 318, 82e90.
ꢀ
ꢀ
ꢀ
ꢀ
11. Calderon, F.; Fernandez, R.; Sanchez, F.; Fernandez-Mayoralas, A. Adv. Synth.
J¼8.7 Hz, 2H, ArH), 7.49 (d, J¼8.7 Hz, 2H, ArH), 4.88 (d, J¼8.4 Hz, 1H,
CHOH), 4.02 (wide singlet,1H), 2.63e2.54 (m,1H), 2.50e2.33 (m,1H),
2.31e2.21 (m,1H), 2.14e2.06 (m,1H),1.83e1.79 (m,1H),1.73e1.52 (m,
3H), 1.49e1.28 (m, 1H). All the spectroscopic data matched with lit-
erature.17a,22 Retention time (HPLC, Daicel Chiralpak AD-H, hexane/i-
Catal. 2005, 347, 1395e1403.
12. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565e598; (b) Kolb, H. C.;
Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004e2021; (c)
Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057e3064; (d)
Rostovtsed, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596e2599.
13. Tsujihara, K.; Kurita, H.; Kawazu, M. Bull. Chem. Soc. Jpn. 1977, 50,
1567e1571.
PrOH¼80:20, flow rate 0.5 mL/min, ¼254 nm): tR¼23.79 (syn, mi-
l
nor), tR¼25.40 (syn, major), tR¼27.30 (anti, minor), 34.60 (anti, major).
14. All the spectroscopic data of the aldol product (3R,4R)-4-(o-nitrophenyl)-
1,3,4-trihydroxy-1,3-O-isopropyliden-butan-2-one matched with literature:
Luo, S.; Xu, H.; Zhang, L.; Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653e656 retention
time (HPLC, Daicel Chiralpak AD-H, hexane/i-PrOH¼90:10, flow rate 0.8 mL/
4.34. (4R)-4-Hydroxy-4-(40-nitrophenyl)butan-2-one (41)
min,
l
¼254 nm): tR¼14.17 (anti, minor), tR¼16.53 (anti, major), tR¼20.19 (syn,
1H NMR (300 MHz, CDCl3, 298 K):
d
(major isomer) 8.21 (d,
minor), 20.97 (syn, major).
15. Inoue, Y.; Hakushi, T.; Liu, Y.; Tong, L.-H.; Shen, B.-J.; Jin, D.-S. J. Am. Chem. Soc.
J¼8.8 Hz, 2H, ArH), 7.54 (d, J¼8.8 Hz, 2H, ArH), 5.27 (dd, J¼2.9, 3.3 Hz,
1H, CHOH), 3.59 (d, J¼3.3 Hz,1H), 2.85 (d, J¼2.9 Hz, 2H), 2.22 (s, 3H).
All the spectroscopic data matched with literature.22 Retention time
(HPLC, Daicel Chiralpak AD-H, hexane/i-PrOH¼96:4, flow rate 1 mL/
1993, 115, 475e481.
16. (a) Alleman, C.; Gordillo, R.; Clemente, F. R.; Ha-Yeon Cheonga, P.; Houk, K. N.
ꢀ
€
Acc. Chem. Res. 2004, 37, 558e569; (b) Calderon, F.; Doyaguez, E. G.; Ha-Yeon
ꢀ
Cheong, P.; Fernandez-Mayoralas, A.; Houk, K. N. J. Org. Chem. 2008, 73,
7916e7920.
min,
l¼254 nm): tR¼37.50 (S, minor), tR¼38.50 (R, major).
ꢁ
17. (a) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericas, M. A. Org. Lett. 2008, 10,
337e340; (b) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Meo, P. L.;
€
Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 4688e4698; (c) Doyaguez, E. G.;
Acknowledgements
ꢀ
ꢀ
Corrales, G.; Garrido, L.; Rodríguez-Hernandez, J.; Gallardo, A.; Fernandez-
Mayoralas, A. Macromolecules 2011, 44, 6268e6276.
18. (a) Enders, D.; Voith, M.; Ince, S. J. Synthesis 2002, 1775e1779; (b) Enders, D.;
Bockstiegel, B. Synthesis 1989, 493e496.
19. Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1383e1385.
20. Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A: Chem. 2007, 263,
186e194.
This work was supported by the Comunidad de Madrid (S2009/
PPQ-1752), the Spanish Ministry of Economy and Competitiveness
(CTQ2010-15418), and the CSIC (I3P-BPD2005 fellowship to E.G.D.)
21. Yuan, D.-Q.; Lu, J.; Atsumi, M.; Yan, J.-M.; Kai, M.; Fujita, K. Org. Biomol. Chem.
2007, 5, 2932e2939.
22. Guillena, G.; Hita, M. C.; Najera, C.; Viozquez, S. F. J. Org. Chem. 2008, 73,
5933e5943.
References and notes
ꢀ
ꢀ
1. MacMillan, D. W. C. Nature 2008, 455, 304e308.