Mechanistic study of the enantioselective reduction of ketones in the presence of glycodendrimers

Article abstract of DOI:10.1016/j.tetasy.2003.09.014

Prochiral ketones were sodium borohydride reduced at the chiral interface of amphiphilic dendrimers bearing sugar moieties at their ends. In water, stereoselectivities were improved by using the fourth generation of these amphiphilic dendrimers [G(4)G]. Under heterogeneous conditions (THF) the third generation [G(3)G] gave the best enantioselectivities. Mechanistic studies of such asymmetric induction were performed by molecular modeling, ¹³C NMR spectroscopy, Induced Circular Dichroism, as well as reaction parameters: influence of the temperature, cations, molecular structure of the sugar ends and of dendrimer links with the sugars:-in homogeneous conditions (water), the main factor is the ordering and specific orientation of the ketone at the chiral interface;-in heterogeneous conditions (THF) enantioselectivities are due to a chiral intermediate with the C(3) and C(4) sites of the sugar part, and to the C(2) site whose structure is important for ketone positioning.

Full text of DOI:10.1016/j.tetasy.2003.09.014

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3719–3730
Mechanistic study of the enantioselective reduction of ketones in
the presence of glycodendrimers
Andreea Schmitzer, Emile Perez, Isabelle Rico-Lattes and Armand Lattes*
Laboratoire des interactions mole´culaires et Re´activite´ Chimique et Photochimique, UMR 5623, CNRS-Universite´ Paul Sabatier,
118 route de Narbonne, 31062 Toulouse Cedex 4, France
Received 28 July 2003; accepted 9 September 2003
Abstract—Prochiral ketones were sodium borohydride reduced at the chiral interface of amphiphilic dendrimers bearing sugar
moieties at their ends. In water, stereoselectivities were improved by using the fourth generation of these amphiphilic dendrimers
[G(4)G]. Under heterogeneous conditions (THF) the third generation [G(3)G] gave the best enantioselectivities. Mechanistic
studies of such asymmetric induction were performed by molecular modeling, 13C NMR spectroscopy, Induced Circular
Dichroism, as well as reaction parameters: influence of the temperature, cations, molecular structure of the sugar ends and of
dendrimer links with the sugars:
– in homogeneous conditions (water), the main factor is the ordering and specific orientation of the ketone at the chiral interface;
– in heterogeneous conditions (THF) enantioselectivities are due to a chiral intermediate with the C(3) and C(4) sites of the sugar
part, and to the C(2) site whose structure is important for ketone positioning.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
results were only obtained with the third-generation
dendrimer: [G(3)G];
Dendrimers are chemically well-defined, highly
branched molecules which are constructed in a genera-
(ii) under homogeneous conditions (water), good
results were only obtained with the fourth-generation
dendrimer: [G(4)G];
tion-wise manner starting from
a
central core
molecule.1 They can be designed to form unimolecular
micelles (when they are amphiphilic) possessing cavities
able to accommodate guest molecules.2 Dendrimers can
also be functionalized, for example with sugars giving
glycodendrimers mimicking the multi-antennary carbo-
hydrate moieties of the glycoconjugates exposed on the
surface of mammalian cells.3
This indicated a correlation between the stereoselectiv-
ity of the reduction and the confinement of the prochi-
ral molecule in a chiral environment. To explain this
behavior we postulated two hypotheses:
– in THF, the third generation dendrimer is rela-
tively open, and allows substrate molecules to reside
at the solid-liquid interface,
– in water, with generation four, the maximum
enhancement in enantioselectivity is dominated by
the position of the ketone at the chiral solvating
interface.6
Recently we described new glycodendrimers prepared
from polyamidoamine (PAMAM) and gluconolactone
(generations [G(n)G], n=1–4).4 These glycodendrimers
have a chiral surface environment with internal cavities,
and can act as rigid chiral unimolecular micelles.
Sodium borohydride reduces prochiral ketones in the
presence of these amphiphilic dendrimers, to give the
corresponding chiral alcohols with both high yields and
high enantioselectivities:5
Herein we describe different physicochemical methods
to gain a better understanding of the mechanisms of
these reactions.
(i) under heterogeneous conditions (THF) good
2. Results and discussion
Figure
1 shows the synthesis and structure of
* Corresponding
(33)5.61.55.81.55; e-mail: lattes@chimie.ups-tlse.fr
author.
Tel.:
(33)5.61.55.62.73;
fax:
amphiphilic dendrimer [G(3)G].
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.014

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
Figure 1. Synthesis and structure of amphiphilic dendrimers [G(n)G]. The G(n) symbol is applied to all the PAMAM dendrimer
and the letter after indicates the nature of the sugar: G in the case of glucose. Ex.: [G(1)G] points out the first PAMAM generation
functionalized with glucose.
2.1. Asymmetric reduction of acetophenone by NaBH4
at the interface of amphiphilic chiral supports in water
in water.6 This study showed that these new
amphiphilic dendrimers were able to dissolve or encap-
sulate increasing quantities of hydrophobic compounds
(pyrene or aromatic ketones) in water, depending on
the number of microcavities in each dendrimer.4 To
investigate the effect related to the hydrophobicity of
2.1.1. Capping of prochiral ketones. In a previous study
the physicochemical properties of glucose-persubsti-
tuted poly(amidoamine) dendrimers were investigated

A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
3721
the compounds, we studied the incorporation of differ-
ent ketones having different hydrophobicities. To do
so, we used the partition coefficient between water and
1-octanol, expressed by its logarithm: log P, calculated
with the atomic increment method (Table 1).
large amounts of pyrene to gain access to the hydro-
phobic core. We chose this dendrimer to study the
solubility of ketones in aqueous solution. The concen-
tration of the dissolved ketones was found to increase
linearly with the concentration of dendrimer (Fig. 2).
We have shown before that dendrimer generation 3
provided the best water protection to the dissolved
pyrene molecules indicating that this structure allowed
Besides, the more hydrophobic the ketone, the greater
the solubility. These results agree with the accessibility
of the ketones to the hydrophobic core.
Table 1. Ketones log P lipophilicity parameters
Figure 2. Ketones solubility in water versus the [G(3)G] concentration (24.00 h at 40°C; UV analysis at 25°C).

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
2.1.2. Reduction of prochiral ketones. Scheme 1 summa-
rizes the general procedure for reduction of prochiral
ketones in aqueous media the dendrimer being insolu-
ble in methanol, it was very easy to recover it by
filtration.
– better insertion of the hydrophobic molecule into
the cavity, with a better orientation,
– a diminution of the quantity of ketone dissolved
due to the external surface compactness.
In our opinion, another parameter should be consid-
ered: the aggregation of the dendrimers. In an earlier
work we investigated these aggregation properties in
water by Transmission Electron Microscopy4 when
Molecular simulation was essential to gain insight into
the nature of the aggregates.
2.1.2.1. Reduction of acetophenone in water, in the
presence of [G(n)G] dendrimers. We chose acetophe-
none, because of its strong hydrophobic character, with
a concentration of 10−2 M in aqueous dendrimer solu-
tion, to achieve a good arrangement between both
components: the reaction then takes place under homo-
geneous conditions. Under these conditions, the enan-
tioselectivity depends on the dendrimer generation.
With the highest generation tested,[G(4)G], giving 98%
enantiomeric excess in the favor of (S), two important
parameters have to be considered:
2.1.3. Molecular modeling study. Figure 3 shows the
result of the molecular simulation of the aggregation of
four [G(3)G] dendrimer molecules, in water, with
minimization.
Scheme 1. Reduction of prochiral ketones in water.
Figure 3. Molecular simulation of the aggregation of four [G(3)G] dendrimer molecules in water.

A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
3723
This study showed:
drimer host, with a water layer 0.5 nm thick, the
minimization calculation was carried out only on the
guest molecule (ketone) taking into account its macro-
molecule environment. At the beginning, the ketone is
in the water layer, outside of the dendrimer, but during
the calculation it penetrates into one of the hydropho-
bic cavities The lowest energy conformer fits position-
ing by hydrogen bonding with a hydroxylic group (Fig.
4).
– the high solvation of hydroxylic groups by water,
– the strong association of [G(3)G] molecules.
The association, due to the intermolecular hydrogen
bonding between the sugar moieties which persists in
aqueous solutions, could prevent the ketone from pene-
trating into the hydrophobic cavities: in this case, the
actual quantity of encapsulated ketone would be less
than theoretical. Another point concerns the compact-
ness of the chiral outer surface which evolves depending
on the generation of the dendrimer: high for the third
generation (with maximum ketone encapsulation), the
denser outer layer of the fourth generation dendrimer
leads to steric hindrance accounting for the low quanti-
ties of acetophenone penetrating the hydrophobic core.
Schematically, the mechanism of the reaction with the
hydride ion can be described as in Scheme 2. After
inclusion and positioning of the ketone in the cavity,
due to the hydrogen bonding with the hydroxylic group
in the position of the terminal amide bond, there is a
selective attack of the carbonyl group by the hydride
anion. This attack occurs from below the double bond
and leads to the (S)-enantiomer, owing to the steric
hindrance on the other side. Taking this model into
The ketone encapsulation phenomenon in the dendritic
cavities of [G(3)G] was also simulated by the same
molecular modeling method. After ‘gelling’ the den-
Figure 4. Acetophenone positioning in the dendritic cavity (red: O, grey=H, green: dendrimer C atoms, yellow=carbonyl group
of the ketone, magenta: ketone framework, blue: N of the amido group and water molecules).
Scheme 2. Mechanism of the hydride reaction.

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
account, we can explain the results obtained with the
different generations:
– [G(1)G] and [G(2)G] dendrimers possess an open
‘starfish-like’ shape, not rigid enough to provide sta-
ble orientation for the ketone,
– from [G(3)G] to [G(4)], the cavities become more
compact forcing the ketone to adopt a favorable
orientation, but limiting the quantity of ketone
incorporated.
2.2. Asymmetric reduction of ketones by NaBH4 in
THF at the solid–liquid interface of amphiphilic chiral
supports
Reduction of ketones by NaBH4 was carried out in
THF which is the usual solvent used for this type of
reaction in the presence of carbohydrate molecules.9–11
Scheme 3 shows the general procedure for the reduction
of prochiral ketones in THF.
13C NMR was then used to validate the simulation: the
change of the environment carbonyl group shifting its
resonance.
The NaBH4–dendrimer complex formed during the first
step of this procedure was not soluble in THF, so the
reduction was performed under heterogeneous condi-
tions. These conditions allowed the recovery of the
dendrimer by filtration. After recovery it was possible
to regenerate this chiral support: the recycled glycoden-
drimer led to the same asymmetric reduction of
ketones.
2.1.4. 13C NMR studies. The ketone 13C NMR spectra
in D2O and in dendrimers solution in D2O, provide
some important data:
– with the generations 0–1, we did not observe any
change of the 13C signal with or without dendrimer:
it is a mixture of ketone and dendrimer spectra;
– with the second generation, the 13C carbonyl group
signal was a slightly deshielded;
2.2.1. Reduction of acetophenone. To determine the best
stoichiometry for the reduction, we studied the molar
ratio: NaBH4/acetophenone; in the presence of [G(3)G],
chemical yields decrease to 72% and enantiomeric
excess to 16% (S) when we use 1:2 molar ratio.
– with the third generation, the 13C methyl signal
disappeared and the carbonyl group signal shifted
downfield.
The last changes can be attributed to the positioning of
the ketone in the cavity; the hydrogen bond between
CꢀO and OH groups rigidifies the system generating a
change in the relaxation times.
This result leads to the following comments:
1) two hydrides seem to be involved in the reaction;
2) the asymmetric induction strongly decreases with
a 1:2 stoichiometry.
These results agree with the molecular modeling studies
corroborating the localization of the ketone at the
chiral interface of the dendritic cavity.
With a 1:1 stoichiometry, which was the one previously
used in water, acetophenone reduction at 25°C gave
different enantioselectivities depending on the den-
drimer generation
2.1.5. Induced circular dichroism spectra. Incorporating
acetophenone in dendritic cavities by direct contact
with the [G(3)G] dendrimer solution at 40°C for 24 h,
we observed a slight shift of circular dichroism of
absorption bands in comparison with the UV spectra
(Fig. 5). Only with the [G(3)G] did we find an induced
CD spectrum indicating closer proximity of chro-
mophores with the chiral dendrimer interface.8
As in water solution, low generation dendrimers, but
also [G(4)G], were not able to selectively induce chiral-
ity (2–5% ee); good results were only obtained with the
third generation [G(3)G] (82%):
– with generations 1 and 2, the arrangement is too
open;
– with generation 4, the dendrimer becomes too
highly sterically hindered at its periphery.
All three methods: Molecular modeling, 13C NMR
spectra and induced circular dichroism converged to
account for our results in water by specific positioning
of the ketone inside the dendritic cavities and specific
orientation induced by the dendrimer chiral interface.
The behavior of the last generation in water and in
THF can be explained by competition for hydrogen
bonds between intermolecular water solvation and
‘intramolecular’ sugar moiety hydroxylic groups. The
Figure 5. A: Acetophenone UV spectrum in aqueous solution. B: Acetophenone CD spectrum in aqueous solution of [G(3)G].

A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
3725
Scheme 3. Reduction of prochiral ketones in THF.
solvation by water was able to open out the chiral ends,
allowing a well-ordered structure of the ketone and
enhancing penetration through the interface.
agent or by solvation of the sodium cation, limiting the
electrophilic activation of the ketone.12
2.2.4. Cation effect. We compared the effect of the
cation by reducing the ketone with KBH4 and LiBH4 in
THF: the decrease of the enantioselectivity is of the
same order as ketone electrophilicity enhancement by
complexation with the cation: Li+>Na+>K+. With
LiBH4, the reactivity was the best (98% yield) while
selectivity decreased (27%S). With KBH4, the reaction
was slower, the cation being less complexed, and the
anion reactivity lowered (70% yield; 33%S).
In THF, the [G(4)G] dendrimer became too highly
sterically hindered because of the compactness due to
the intramolecular H-bonds between the sugar moieties.
2.2.2. Influence of temperature. Decreasing the tempera-
ture from 25 to 0°C resulted in a significant improve-
ment in the asymmetric induction: at 0°C the
enantiomeric excess was more than 99%. This result can
be explained by the slowdown of exchange between the
NaBH4 and the sugars, but also by a different partition
coefficient of the ketone between THF and dendrimer.
The selectivity of the reduction is strongly influenced by
the solvent cation pair. The problem is finding a good
compromise between the solvation of the cation and its
electrophilic assistance.
2.2.3. Influence of the solvent. For a better explanation
of the influence of the solvent on the enantioselectivity,
we performed the reduction in two solvents: THF and
dichloromethane (DCM) which were used for both
reaction steps: Transformation of the chiral inductor
and reduction of the ketone. Examination of the results
leads to the following comments: with DCM as solvent
for the whole process, the global yield was reduced and
the enantiomeric excess was very low (6%); when THF
was used in the first step and DCM in the second, the
enantiomeric excess was 70%, but only 4% when the
solvents were reversed. This shows the importance of
the THF during the formation of the chiral reducing
agent, which is also important in the second step owing
to the lower enantioselectivity in DCM. The mechanism
in THF can be explained by different phenomena, by
increasing the interaction between sodium borohydride
and sugars, favoring the formation of the reducing
2.2.5. Influence of the sugar molecular structure. Owing
to this surprising selectivity and to explain the role of
the dendrimer structure, it was essential to evaluate the
influence of the stereogenic carbon atom configuration
on the reaction enantioselectivity. Therefore, we synthe-
sized PAMAM-type dendrimers substituted with
epimeric
D-mannose and D-galactose moieties. In this
way we synthesized third generation PAMAM den-
drimers functionalized with galactose [G(3)Gala] and
mannose [G(3)M], by direct coupling between den-
drimer and
tone (Fig. 6).
D
-galactonic-g-lactone or mannonic-g-lac-
The results obtained for acetophenone reduction at 0°C
in THF, in the presence of these dendrimers can be
interpreted as following:

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
Figure 6. Functionalized PAMAM dendrimer with epimeric sugars.
2.2.5.1. C(2) configuration. On changing the configu-
ration of the C(2) centre, we did not observe asymmet-
ric induction [G(3)M, 3%S]. It seems therefore that this
C(2) configuration is of crucial importance for the
enantioselectivity. Besides, molecular modeling in water
has shown that it was this hydroxylic group on C(2)
which was involved in the formation of hydrogen bonds
between the ketone and hydrophilic part of the
dendrimer.
Figure 7. Reduced [G(3)G].
2.2.5.2. C(4) configuration. We carried out the same
reduction in the presence of [G(3)Gala]: in this case the
Figure 8.
L-Gluconolactone substituted G(3).
configuration change is located on C(4). With the orig-
inal C(2) configuration maintained. The enantiomeric
excess was 60% showing a slight decrease of selectivity,
but this decrease was not as great as with the change of
C(2) carbon atom configuration.
13C NMR in DMSO, gave a comparison between the
dendrimer structures and the carbon framework
motions with those of the complex. Measuring T1 longi-
tudinal relaxation times provided information on the
molecular dynamics of [G(3)G] and its complex with
boron; the latter compound being short of reducing
agent. Table 2 shows the terminal chiral part of [G(3)G]
and the assignment of the signals. All the chemical
shifts are the same for [G(3)G] and [G(3)G/8NaBH4]
but, with the complex, C(2), C(3), C(4) and C(5) signals
are not split unlike [G(3)G]. This splitting can be
attributed to two preferential conformers and their
disappearance in the presence of the reducing agent
supports the involvement of amido groups in the com-
plexation. New signals appear at 75.6, 74.6 and 64.1
ppm, with [G(3)G]/8NaBH4 assigned to the complexa-
tion of the dendrimer sugar moiety with borohydride.
In Figure 9 both the dendrimer and the complex are
visible (new signals in red), the exchange between den-
drimer and borohydride being very low at the NMR
time scale. The new signals with added boron hydride
most probably correspond to carbon atoms of the
complexed sites.
2.2.5.3. Amide bond influence. To estimate the contri-
bution of the amide bond, we reduced the amido
groups with BH3 in THF to get the corresponding
amines (Fig. 7): When we used the new dendrimer
obtained to reduce acetophenone at 0°C, the enan-
tiomeric excess was only 20%: the alcohol being, this
time, enhanced in (R)-enantiomer, displaying the influ-
ence of the amide bond in the proximity of the stereo-
genic centers. In seems that the pair: amide bond-C(2)
configuration as a whole, plays a very significant role in
reduction enantioselectivity. We proved this hypothesis
using
L-gluconolactone as the capping groups of the
dendrimer (Fig. 8): Reversing the configurations of all
stereogenic carbons, the enantiomeric excess (S enan-
tiomer) obtained by reducing acetophenone at 0°C, was
only 20%. These results were confirmed by NMR
spectroscopy.
2.2.5.4. 13C NMR studies. After studying the influ-
ence of the dendrimer chiral moieties, we investigated
the structure of the reducing agent formed with [G(3)G]
and NaBH4 in THF at 60°C. We separated the complex
generated and tested it to verify its activity: The enan-
tioselectivity was maintained during the acetophenone
reduction.
This exchange however was underlined by varying the
temperature: increasing the temperature speeded up the
exchange bringing the signals closer together. From 25
to 90°C it was impossible to observe coalescence of the
peaks showing that the exchange was slow in this
temperature range. Chemical shift variation of each

A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
3727
Table 2. 13C NMR chemical shifts of [G(3)G] and [G(3)G]/8NaBH4
2.2.6. Influence of the ketone. We successively studied
the reduction in the presence of [G(3)G] of the aro-
matic, aliphatic, heterocyclic and substituted aromatic
ketones. Table 3 shows the results obtained with aro-
matic ketones at 25°C in THF. In all cases, whatever
the nature of the R group, the quantity of (S)-alcohol
formed is enhanced: the enantioselectivity being better
in heterogeneous than in homogeneous media. With
substituted aromatic ketones, enantioselectivites were
less than with unsubstituted aromatic ketones: the
decrease can be explained by an increased total volume
of the molecule, hence steric hindrance during contact
between the reactants.
carbon atom of the sugar moiety versus the tempera-
ture was greatest for C(3) and C(4) carbon atoms: We
can postulate that both corresponding sites are com-
plexed with the borohydride. This result is in agreement
with the previous stoichiometric study: the reducing
agent seems to have two active hydrides required for
the reduction. So, the chiral intermediate formed with
[G(3)G] and NaBH4 should be obtained with the C(3)
and C(4) sites of the sugar moiety. The reversibility of
the complexation was confirmed by going back to room
temperature: chemical shifts were then the same as
before.
Another hypothesis is the covalent reaction of a very
small quantity of NaBH4 with sugar, owing to the
presence of traces of water. However, the very small
quantity of this compound cannot explain the high
enantioselectivity of the reaction.
This reducing method is general, as shown in Table 4,
with a limitation for the linear aliphatic ketones: even
at very low temperature (−80°C) it was impossible to
obtain ees above 25% with 2-nonanone.
This 13C NMR study combined with the sugar effects
suggests a complexation between the C(2) site and the
ketone, while C(3) and C(4) sites are complexed with
NaBH4.
With acetylpyridines, yields and enantioselectivities
depended on the position of the carbonyl group rela-
tively to the nitrogen atom. The best result was
obtained with 2-acetylpyridine, owing to a possible

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
Figure 9. 13C NMR spectra of [G(3)G]/8NaBH4.
Table 3. Prochiral aromatic ketones reduction (THF, 25°C, [G(3)G)]
hydrogen bond with hydroxylic group of the dendrimer
(Fig. 10).
between dendrimer and the salt and gel filtration dem-
ineralization. In both cases the dendrimer was recycled
for further ketone reduction: after ten cycles we
observed neither lowering of the activity or stereoselec-
tivity in the reduction of acetophenone.
Another hypothesis is the formation of a cyclic complex
where the reactant is at first complexed with both the
carbonyl group and the heteroatom13 (Fig. 11): such
complexation is impossible with acetyl in 3 or 4
position.
3. Conclusion
2.2.7. Dendrimer reconditioning and recycling. The most
important advantage of the reaction in heterogeneous
phase is the recovery of the dendrimer by filtration at
the end of the reaction. To do so it was necessary to
transform organic boron compounds by adding acidic
aqueous solution. Then we used two methods of recon-
ditioning ultrafiltration, owing to the difference in size
The study of the reduction of ketones in the presence of
a new family of glycodendrimers, has shown that it is
possible to get very high enantioselectivity:– in homo-
geneous water solution, with the fourth generation den-
drimer, showing that its rigidity and compacity are
essential for high stereoselectivity;– in heterogeneous
THF medium, with the third generation dendrimer,

A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
Table 4. Enantioselective prochiral ketones reduction (THF, [G(3)G)]
3729
tion between C(3) and C(4) sites of the sugar part, the
ketone positioning depending on the structure of the
C(2) carbon atom.
4. Experimental
PAMAM dendrimers, lactone, ketones, borohydrides
and THF were purchased from ALDRICH; DCM was
obtained from NORMAPUR. The general procedure
for coupling the PAMAM dendrimers with the
D-glu-
Figure 10. Hydrogen bonding of 2-acetylpyridine with
cono-1,5-lactone has been previously described as well
as the general procedure for the reduction of prochiral-
ketones in organic or aqueous media.6 The general
procedure for the regeneration of the boron-modified
dendrimer was also described in the same paper.6 Fol-
lowing reduction in water recovery of the dendrimer
was carried out by ultrafiltration. 1H NMR spectra
were recorded on either a BRUKER AC 200 (200
MHz) spectrometer, or a BRUKER AC 400 WB (400
MHz) spectrometer with either the solvent as reference
or TMS as internal standard. 13C NMR spectra were
recorded on a BRUKER AC200 (50 MHz) spectrome-
ter or a BRUKER AC 400 WB (100.6 MHz) spectrom-
eter. Circular dichroism spectra were recorded at 25°C
using a Jobin Yvon Mark VI dichrograph. Log P val-
ues were calculated using the TSAR 2.02 software,
Oxford Molecular. Molecular simulation. Simulations
were carried out using the CVFF force field as imple-
mented in the Discover program running on a Silicon
Graphics Indigo 2 workstation. Details of the study of
[G(3)G].
Figure 11. Cation coordination with carbonyl group and
nitrogen atom.
giving a very useful system for practical synthesis and
recovery of the reactant.
In THF, we showed that enantioselectivity is
attributable to a chiral intermediate obtained by reac-

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A. Schmitzer et al. / Tetrahedron: Asymmetry 14 (2003) 3719–3730
dendrimer structures are described in Ref. 7. General
procedures for reduction of prochiral ketones in
aqueous or organic media are described in Ref. 7 as
well as the methods used for the characterization of the
alcohols. UV spectra were recorded with a Hewlett-
Packard HP 845LA diode-array UV–vis spectrometer.
4. Schmitzer, A.; Perez, E.; Rico-Lattes, I.; Lattes, A.;
Rosca, S. Langmuir 1999, 15, 4397.
5. Schmitzer, A.; Perez, E.; Rico-Lattes, I.; Lattes, A. Tetra-
hedron Lett. 1999, 40, 2947.
6. Schmitzer, A.; Franceschi, S.; Perez, E.; Rico-Lattes, I.;
Lattes, A.; Thion, L.; Erard, M.; Vidal, C. J. Am. Chem.
Soc. 2001, 123, 5957.
7. Rico-Lattes, I.; Schmitzer, A.; Perez, E.; Lattes, A. Chi-
rality 2001, 13, 24.
References
8. Focher, B.; Savelli, G.; Torri, G.; Vecchio, G.; Bunton,
C. A. Chem. Phys. Lett. 1989, 6, 491.
9. Kunz, H.; Ru¨ck, K. Angew. Chem., Int. Ed. Engl. 1993,
32, 336 and references cited therein.
10. (a) Hirao, A.; Nakahama, S.; Mochizuki, H.; Yamazaki,
N. J. Org. Chem. 1980, 45, 4231; (b) Hirao, A.; Naka-
hama, S.; Mochizuki, H.; Itsuno, S.; Zoorov, H. A.;
Yamazaki, N. J. Chem. Soc., Perkin Trans. 1 1981, 900.
11. Loupy, A.; Haudrechy, A. Effets de milieu en synthe`se
organique, Masson, 1996.
12. Sharma, L. Indian J. Chem. 1997, 796.
13. Be´nard, C.; Maurette, M. T.; Lattes, A. Bull. Soc. Chim.
Fr. 1976, 146.
1. (a) Flory, P. J. J. Am. Chem. Soc. 1941, 63, 3083, 3091
and 3096; (b) Tomalia, D. A.; Naylor, A. M.; Goddard,
W. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 138.
2. (a) Pistolis, G.; Malliaris, A.; Paleos, C. M.; Tsiourvas,
D. Langmuir 1997, 13, 5870; (b) Naylor, A. M.; God-
dard, W. A.; Kiefer, G. E; Tonalia, D. A. J. Am. Chem.
Soc. 1989, 111, 2339; (c) Watkins, D. M.; Sayed-Sweet,
Y.; Klimash, J. W.; Turro, N. J.; Tomalia, D. A. Lang-
muir 1997, 13, 3136.
3. (a) Zanini, D.; Park, W. K. C.; Roy, R. Tetrahedron Lett.
1995, 36, 7383; (b) Roy, R.; Park, W. K. C.; Wu, Q.;
Wang, S. Tetrahedron Lett 1995, 36, 4377; (c) Roy, R.;
Zanini, D. J. Chem. Soc., Chem. Commun. 1993, 1869.