Reactivity at the interface of chiral amphiphilic dendrimers. High asymmetric reduction by NaBH4 of various prochiral ketones

Article abstract of DOI:10.1021/ja000378x

New amphiphilic dendrimers derived from PAMAM and D-gluconolactone were found to induce chirality in the reduction of prochiral ketones by NaBH₄, in heterogeneous (THF) and homogeneous (water) conditions. The third generation of these amphiphilic dendrimers, G(3)G, was found to be a good chiral ligand for the reduction of various prochiral ketones in heterogeneous conditions. Even with substrates well-known to give poor results (especially linear ketones), good enantioselectivities were obtained. It is also important to notice that under heterogeneous conditions (THF) the dendrimer could be recovered by filtration, regenerated, and recycled (up to 10 times), leading to reproducible results in asymmetric reduction of ketones. We have also discussed the reduction of acetophenone in water. Evidence is presented that the selectivity is dominated by the architecture of the dendrimer and some supramolecular ordering in the position of the ketone at the chiral solvating interface. The results obtained showed a correlation between stereoselectivity of the reduction and the compact character of the dendritic particles.

Full text of DOI:10.1021/ja000378x

5956
J. Am. Chem. Soc. 2001, 123, 5956-5961
Reactivity at the Interface of Chiral Amphiphilic Dendrimers. High
Asymmetric Reduction by NaBH4 of Various Prochiral Ketones
A. R. Schmitzer,§ S. Franceschi,§ E. Perez,§ I. Rico-Lattes,*,§ A. Lattes,§ L. Thion,†
M. Erard,† and C. Vidal‡
Contribution from the Laboratoire des Interactions Mole´culaires et Re´actiVite´ Chimique et Photochimique,
UMR no. 5623 CNRS, UniVersite´ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex, France,
Institut de Pharmacologie et de Biologie Structurale, UMR 5089 CNRS, 205 Route de Narbonne,
31077 Toulouse Cedex, France, and SerVice Commun Informatique Chimie, FR 1744,
UniVersite´ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex, France
ReceiVed February 1, 2000. ReVised Manuscript ReceiVed January 4, 2001
Abstract: New amphiphilic dendrimers derived from PAMAM and D-gluconolactone were found to induce
chirality in the reduction of prochiral ketones by NaBH4, in heterogeneous (THF) and homogeneous (water)
conditions. The third generation of these amphiphilic dendrimers, G(3)G, was found to be a good chiral ligand
for the reduction of various prochiral ketones in heterogeneous conditions. Even with substrates well-known
to give poor results (especially linear ketones), good enantioselectivities were obtained. It is also important to
notice that under heterogeneous conditions (THF) the dendrimer could be recovered by filtration, regenerated,
and recycled (up to 10 times), leading to reproducible results in asymmetric reduction of ketones. We have
also discussed the reduction of acetophenone in water. Evidence is presented that the selectivity is dominated
by the architecture of the dendrimer and some supramolecular ordering in the position of the ketone at the
chiral solvating interface. The results obtained showed a correlation between stereoselectivity of the reduction
and the compact character of the dendritic particles.
Introduction
We described recently new chiral amphiphilic dendrimers
prepared from polyamidoamine (PAMAM) and gluconolactone
(generations 1-4)8 (Figure 1). These dendrimers can act as
chiral rigid unimolecular micelles. We recently reported9 that
sodium borohydride reduces prochiral aromatic ketones at the
chiral interface of these amphiphilic dendrimers, to the corre-
sponding chiral alcohols, with both high yields and high
enantioselectivities in heterogeneous conditions.
Dendrimers1 are highly branched, fractal macromolecules of
defined three-dimensional size, shape, and topology which can
be prepared with extremely narrow molecular weight distribu-
tion. Dendrimer chemistry is now occupying a unique position,
not only in polymer and material chemistry but also in other
areas of chemistry.
The introduction of chirality into a dendritic structure will
create an asymmetric macromolecule having a chiral surface
environment with internal cavities.2 Chiral dendrimers are
therefore potentially useful materials in mediating chiral rec-
ognition and enantioselective binding of guest molecules.
Furthermore, the use of chiral dendrimers as promoters or
catalysts in asymmetric synthesis is also one of the prime
objectives in dendrimer chemistry.3-7
The purpose of this paper is to understand in greater detail
the mechanism of this chiral induction and to show the generality
of the phenomenon with various ketones.
Experimental Section
1H NMR spectra were recorded on either a Bruker AC200 (200
MHz) spectrometer or a Bruker AC400WB (400 MHz) spectrometer
with either the solvent reference or TMS as internal standard.
13C NMR spectra were recorded on a Bruker AC200 (50 MHz)
spectrometer or a Bruker AC400WB (100.6 MHz) spectrometer.
Molecular Simulation. Simulations were carried out using the CVFF
force field as implemented in the Discover program running on a Silicon
Graphics Indigo 2 Workstation. We evaluated the multitude of
conformations available for the molecule by refining the energy of a
model-built structure and evaluated configurations of the system. The
whole assembly was minimized using the conjugated gradients method
and a water layer of 0.5 nm. Dendrimer structures were first minimized
for 10 000 iterations. To obtain a global minimum, molecular dynamics
simulations were used. Dynamics were performed at constant 500 K
temperature. The lowest energy conformer obtained in the molecular
dynamics simulation was further minimized by 10 000 iterations.
* Author to whom correspondence should be addressed. Fax: (33) 5 61
55-81-55. E-mail: rico@iris.ups-tlse.fr.
§ Laboratoire des Interactions Mole´culaires et Re´activite´ Chimique et
Photochimique, Universite´ Paul Sabatier.
† Institut de Pharmacologie et de Biologie Structurale.
‡ Service Commun Informatique Chimie, Universite´ Paul Sabatier.
(1) (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III Angew. Chem.
Int. Ed. Engl. 1990, 29, 138. (b) Tomalia, D. A.; Durst, H. D. Top. Curr.
Chem. 1993, 165, 193. (c) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F.
Dendritic Molecules, Concepts, Syntheses, PerspectiVes; VCH Publishers:
Meinheim, 1996.
(2) (a) Mansfield, M. L.; Klushin, L. I. Macromolecules 1993, 26, 4262.
(b) Peerlings, H. W. I.; Meijer, E. Chem. Eur. J. 1997, 3, 1563.
(3) Brunner, H.; Fu¨rst, J. Tetrahedron 1994, 50, 4303.
(4) (a) Brunner, H.; Net, G. Synthesis 1995, 423. (b) Brunner, H. J.
Organomet. Chem. 1995, 500, 39.
(5) Chan, T. H.; Zheng, G. Z. Can. J. Chem. 1997, 75, 629.
(6) Sanders-Hovens, M. S. T. H.; Jansen, J. F. G. A.; Vekemans, J. A.
J. M.; Meijer, E. W. Polym. Mater. Sci. Eng. 1995, 73, 338.
(7) Seebach, D.; Marti, R. E.; Hintermann, T. HelV. Chim. Acta 1996,
79, 1710.
(8) Schmitzer, A.; Perez, E.; Rico-Lattes, I.; Lattes, A. Langmuir 1999,
15, 4397.
(9) Schmitzer, A. R.; Perez, E.; Rico-Lattes, I.; Lattes, A. Tetrahedron
Lett. 1999, 40, 2947.
10.1021/ja000378x CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/30/2001

ReactiVity of Chiral Amphiphilic Dendrimers
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5957
Figure 1. Synthesis and structure of the chiral amphiphilic dendrimers G(m)G.
Thin-layer chromatography (TLC) was carried out on aluminum
sheets coated with Kieselgel 60 F254 (Merck).
All rotations were measured on a Perkin-Elmer 241 polarimeter
(at 589.3 nm).
Gas chromatography was performed on a DELSI NERMAG
DN200 chromatograph and a VARIAN Chrompack CP 3800 gas
chromatograph.
For octan-2-ol: â DEX 2,3,6-M-19, 130 °C, tR for the R isomer is 7.9
min, tR for the S isomer is 9.5 min. For 1-(2-pyridyl)-ethan-1-ol: â
DEX 110, 110 °C, tR for the S isomer is 14.9 min, tR for the R isomer
is 15.2 min. For 1-(3-pyridyl)-ethan-1-ol: â DEX 110, 110 °C, tR for
the S isomer is 14.5 min, tR for the R isomer is 14.9 min. For 1-(4-
pyridyl)-ethan-1-ol: â DEX 110, 110 °C, tR for the S isomer is 14.8
min, tR for the R isomer is 15.1 min.
Circular Dichroism. All measurements were performed at 25 °C
using a Jobin Yvon Mark VI Dichrograph in the 190-350 nm spectral
range. The scan speed was 0.2 nm/s. All the solutions, either in pure
water or in sugar-dendrimer aqueous solutions, were prepared by
allowing the solvent to remain overnight undisturbed and in contact
with the solute (the ketone) at 40 °C. The dendrimer concentration we
used for the spectra was always 2.5 × 10-6 M in a 0.1 cm path length
quartz cell. Results were normalized in molar ellipticity [θ] based on
a unit molecular mass of 110 Da.
Comparison with the racemic and optically pure alcohols (aromatic
compounds) purchased from Aldrich was realized under the same
chromatographic conditions. By this technique, the purity of the alcohols
was also ascertained, confirming the 1H and 13C NMR data. For linear
alkyl and pyridyl alcohols, optically pure alcohols are not commercially
available: their absolute configurations were determined by optical
rotation, by comparison with the reported values in the literature.
General Procedure for Coupling the Poly(amidoamine) Den-
drimers (PAMAM Dendrimers) with the D-Glucono-1,5-lactone.
Chemicals, including D-glucono-1,5-lactone and PAMAM dendrimers
(generations 1-4), were purchased from Aldrich. The PAMAM
dendrimers samples used in this report were stored in methanol solution.
All solvents were obtained from Aldrich and used without further
purification. The solvents were preserved with molecular sieves (4 Å).
In a two-necked, round-bottomed flask equipped with a thermometer
and a magnetic stir bar were introduced 7.25 × 10-4 mol of PAMAM
dendrimers (generation n ) 1, 2, 3, and 4) in 5 mL of dry CH3OH,
under argon. A 10% molar excess of 4, 8, 16, or 32 × 7.25 × 10-4
mol of d-glucono-1,5-lactone in 3 mL of DMSO was added to the
solution by a syringe with stirring. The mixture was stirred at 40 °C
for 24 h under argon atmosphere. The reaction was followed by TLC
using CHCl3/CH3OH (80/20, v/v) as eluent.
Methods for the Characterization of Alcohols. The isolated
1
alcohols were identified by comparing their H and 13C NMR spectra
with the spectra of authentic samples.
The enantiomeric excess (ee) of the obtained alcohols was determined
by gas chromatography with a chiral separation column (SUPELCO R
DEX 120, â DEX 110 fused silica capillary column with a 30 m ×
0.25 mm × 0.25 µm film thickness and a VARIAN â DEX 2,3,6-M-
19 column with a 50 m × 0.25 mm × 0.39 µm film thickness). The
isotherm temperature program with N2 as the gas vector (0.5 to 1.2
mL/mn depending of the compounds) was used. For 1-phenylethan-
1-ol: â-DEX 110, 110 °C, tR for the S isomer is 13.1 min, tR for the
R isomer is 13.4 min. For 1-phenylcyclohexan-1-ol: R-DEX 120, 160
°C, tR for the S isomer is 10.2 min, tR for the R isomer is 10.4 min.
For 1-phenylbutan-1-ol: R-DEX 120, 130 °C, tR for the S isomer is
18.2 min, tR for the R isomer is 18.5 min. For 1-phenylpropan-1-ol:
â-DEX 110, 100 °C, tR for the S isomer is 9.2 min, tR for the R isomer
is 9.5 min. For pBr-1-phenylethan-1-ol: â-DEX 110, 110 °C, tR for
the S isomer is 14.4 min, tR for the R isomer is 14.6 min. For pentan-
2-ol: â DEX 2,3,6-M-19, 110 °C, tR for the R isomer is 23.6 min, tR
for the S isomer is 25.8 min. For heptan-2-ol: â DEX 2,3,6-M-19,
130 °C, tR for the R isomer is9.9 min, tR for the S isomer 1 is 1.5 min.
The solution was poured into an amount of propan-2-ol (IPA). The
azeotrope formed by DMSO with IPA was removed under vacuum.
Gluconamidopoly(amidoamine) dendrimer was isolated after vigor-
ous washing of the reaction mixtures with methanol (these compounds
showed hydrophilic properties and were soluble in water and DMSO;
they were insoluble in methanol and chloroform which dissolved the
D-glucono-1.5-lactone). The precipitate was lyophilized to yield a white
powder.

5958 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Schmitzer et al.
The linking of the sugars is achieved by amide bond formation,
provided that the reaction proceeds quantitatively or nearly so (G(1)G
yield 95%, G(2)G yield 93%, G(3)G yield 96%, G(4)G yield 94%,).
The compounds exhibited high hygroscopic behavior, which increased
with each subsequent generation.
Table 1. Enantioselective Reduction of Acetophenone in THF at
0 °C by NaBH4 in the Presence of Different Chiral Supports
The isolated dendrimers were characterized by specific physico-
chemical methods, similar to our previous work.8
For the chiral supports (gluconamidopolynorbornene and glucon-
amidoalkanes), the procedures were similar to previous work.10,11
General Procedure for Reduction of Prochiral Ketones in
Organic Medium. A stoichiometric quantity of sodium borohydride
(NaBH4) (32 mol equiv, 96 mg; 2.5 × 10-3 mol) was added to a solution
of glucose-persubstituted PAMAM dendrimers (8 × 10-5 mol) in 25
mL of THF. The mixture was stirred under reflux for 10 h. Then the
mixture was cooled to room temperature and the ketone (2.5 × 10-3
mol) was added to it with stirring. After complete reduction (12 h),
the THF was evaporated to dryness. A large amount of CH3OH was
added to the resulting solid. After filtration of the dendrimer, a 1 M
HCl solution was added to the CH3OH layer. Evaporation of CH3OH
led to the alcohol. All compounds were obtained in high chemical yields
and showed satisfactory NMR characteristics. The ee of products were
determined by gas chromatography with a chiral separation column
(SUPELCO R DEX 120, â DEX 110 fused silica capillary column
with a 30 m × 0.25 mm × 0.25 µm film thickness and a VARIAN
CP-Cyclodextrin-â-2,3,6-M-19 column with a 50 m × 0.25 mm × 0.39
µm film thickness) (see below).
a Determined by GC using a â DEX 110 column (see the Experi-
mental Section).
The procedure for the reduction of prochiral ketones in the presence
of the gluconamidopolynorbornane and bis-gluconamido alkanes was
the same.
various chiral objects such as fibers, helices,13 and the supra-
molecular expression of chirality, which is directly linked to
the headgroup organization.
The results for the reduction in the presence of these different
chiral supports are summarized in Table 1.
Under these heterogeneous conditions, good results were only
obtained with the third-generation dendrimer G(3)G. All the
other dendrimer generations (G(1)G, G(2)G, and G(4)G), linear
polymer, or even bolaform chiral auxiliaries were not able to
selectively induce chirality.
General Procedure for Reduction of Prochiral Ketones in
Aqueous Medium. Glucose-dendrimer aqueous solution with methyl
phenyl ketone in excess was allowed to remain for 12 h undisturbed at
40 °C. The maximum concentration of ketone in a 10-3 M aqueous
solution of glucose-persubstituted PAMAM dendrimers was equal to
2 × 10-5 M for generation 3 and 10-4M for generation 4. Sodium
borohydride was added to 10 mL of this saturated solution. The mixture
was stirred for 2 h, followed by two successive extractions with CCl4.
After evaporation of the solvent, the methylphenylcarbinol was obtained
and analyzed.
General Procedure for the Regeneration of the Dendrimer. The
boron-modified dendrimer (5 g; 3.96 × 10-4 mol) was stirred at room
temperature in 0.1 N HCl aqueous solution. The mixture was neutralized
with an aqueous solution of 0.1 N NaOH and ultrafiltered on a Millipore
microporous membrane system. The complete system consisted of a
Millipore filter holder, torque wrench, low shear peristaltic pump and
appropriate filter packets, and retentate separators (polysulfone 10 000
NMWL).
According to molecular simulations (Figure 2), low genera-
tions of gluconamido-persubstituted PAMAM (generations 1 and
2) possess a highly asymmetric, open “starfish-like” shape.
Similarly, bolaform structures and even gluconamidopolynor-
bornene are open structures. In contrast, the G(3)G dendrimer
has a spherical symmetry and presents a more closed and
densely packed structure which is effectively the most stable
form of the dendrimer as shown in the different steps of the
modelization (Figure 3). Moreover this compactness is con-
13
No significant difference was observed on conversion and enantio-
selectivity between the initial and regenerated dendrimer (even with
10 cycles).
firmed by C NMR relaxation times showing rigidity of the
branches of G(3)G.14 Therefore, this compactness of the surface
seems to play a key role in an asymmetric induction. The
dendrimer G(4)G became too highly sterically hindered at its
periphery, leading to difficulties for the gluconamido end groups
in adopting a favorable conformation for chiral induction.
In summary, the results obtained showed a correlation
between stereoselectivity of the reduction and the isotropic and
compact character of the external surface of the molecule. It
seems that better selectivities are obtained as a result of the
compromise between the steric clutter and the global compact-
ness of the surface. It is also important to notice that under
heterogeneous conditions (THF) the dendrimer could be recov-
ered by filtration, regenerated in HCl/MeOH, and recycled (up
to 10 times), leading every time to the same results in
asymmetric reduction of ketones.
Results and Discussion
Asymmetric Reduction of Acetophenone by NaBH4 in
THF, at the Solid-Liquid Interface of Amphiphilic Chiral
Supports. Reduction of acetophenone by NaBH4 was carried
out in THF, which is usually a solvent used for this type of
reaction.12 The reaction was carried out in the presence of
various chiral supports with the same sugar group (gluconamido)
and structural modulations summarized in Figure 2. This
gluconamido group was selected since it allowed us to obtain
(10) Puech, L.; Perez, E.; Rico-Lattes, I.; Bon, M.; Lattes, A. New J.
Chem. 1997, 21, 1229.
(11) Brisset, F.; Garelli-Calvet, R.; Azema, J.; Chebli, C.; Rico-Lattes,
I.; Lattes, A.; Moisand, A. New J. Chem. 1996, 20, 595.
(12) (a) Hirao, A.; Ohwa, M.; Itsuno, S.; Yamazaki, N. Bull. Chem. Soc.
Jpn. 1981, 54, 1424. (b) Hirao, A.; Itsuno, S.; Ohwa, M.; Yamazaki, N. J.
Org. Chem. 1980, 45, 4231. (c) Hirao, A.; Ohwa, M.; Itsuno, S.; Yamazaki,
N.; Nagami, S J. Chem. Soc., Perkin Trans. 1 1981, 900. (d) Hirao, A.;
Ohwa, M.; Itsuno, S.; Yamazaki, N.; Nagami, S Agric. Biol. Chem. 1981,
45, 693.
Asymmetric Reduction of Acetophenone by NaBH4 at the
Interface of Amphiphilic Chiral Supports in Water. The
(13) Emmanouil, V.; El Ghoul, M.; Andre´-Barre`s, C.; Guidetti, C; Rico-
Lattes, I.; Lattes, A. Langmuir 1998, 14, 5389.
(14) Schmitzer, A.; Laupreˆtre, F.; Perez, E.; Rico-Lattes, I. To be
submitted for publication.

ReactiVity of Chiral Amphiphilic Dendrimers
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5959
Figure 2. Structures of different chiral supports.
topology of the chiral surface could be also influenced by
hydrogen bonding and solvation of the sugar heads. To
investigate the influence of these two parameters, we performed
the reduction of acetophenone in the presence of these amphi-
philic dendrimers in water. In this case the reaction takes place
under homogeneous conditions.
The aim of this study was as well to obtain evidence of the
formation of complex inclusion in our dendrimers in water and
thereby to understand how the acetophenone is positioned to
affect the face selectivity. For this purpose, NMR 13C in water
was used to obtain details of the structure and dynamics of the
inclusion complex.
As above, the reaction was carried out with various chiral
supports and the results are summarized in Table 2.
In these homogeneous conditions, only G(4)G gave high
enantioselectivity; all the other chiral supports lead to poor
results.
The first information obtained from a comparison of the
spectra in Figure 4a,b concerns the formation of the dendrimer-
AcPh complex by hydrogen bonds. A simple observation of
the signals from the dendrimer moiety (32 to 176 ppm) shows
that no important variations are produced indicating that the

5960 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Schmitzer et al.
Table 2. Enantioselective Reduction of Acetophenone in Water at
25 ˚C by NaBH4 in the Presence of Different Chiral Supports
a Determined by GC using a â DEX 110 column (see the Experi-
mental Section).
Figure 4. (a) NMR spectra of acetophenone in D2O, in the presence
of G(3)G dendrimer. (b) NMR spectra of acetophenone in D2O.
Figure 3. (a) G(3)G after the first energy minimization (fist step), (b)
G(3)G at T ) 37.2 ps of the dynamic simulation (second step), and (c)
final conformation of G(3)G. Dynamic modelization of G(3)G.
complex between the dendrimer and AcPh is not affected
significantly, at least as far as the stability is concerned.
However, a very important observation can be made concerning
the signal of the carbonyl and methyl groups of AcPh. The
carbonyl group normally appears at 185 ppm and the methyl
group appears at 24.5 ppm. In the present case, they disappeared.
The possible explanation is to consider that the carbonyl group
is strongly immobilized by a hydrogen bond.
Stimulated by the observation of induced chirality of chro-
mophores dissolved into chiral bilayers and micelles15 and to
get direct proof of the effect of the dendrimer in the process,
the induced circular dichroism (ICD) spectra of the acetophe-
none encapsulated in the dendritic cavities were recorded. ICD
spectroscopy is based on the transfer of chirality from the
environment to an achiral ketone (the carbonyl chromophore
displays an intramolecular ICD in the first allowed n f π*
Figure 5. Induced circular dichroism of acetophenone in the presence
of chiral amphiphilic dendrimers.
transition around 190 to 300 nm due to perturbation from the
surrounding chiral environment). In Figure 5 the results are
described for the acetophenone in the presence of all chiral
dendrimer generations.
Although four samples show identical UV spectra, a signifi-
cant difference is observed in their induced CD spectra. The
generations 0-2 did not exhibit an induced CD spectrum.
However, an exciton-coupled spectrum is observed when
acetophenone is encapsulated in G(3)G and G(4)G. Moreover,
this exciton coupling indicates the closer proximity of chro-
mophores with a certain fixed orientation, in the case of G(4)G,
due to hydrogen-bonded coordination with the chiral dendrimer
(15) (a) Kunitake, T.; Nakashima, N.; Moritsu, K. Chem. Lett. 1982,
1347. (b) Focher, B.; Savelli, G.; Torri, G.; Vecchio, G.; McKenzie, D. C.;
Bunton, C. A. Chem. Phys. Lett. 1989, 158, 491.

ReactiVity of Chiral Amphiphilic Dendrimers
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5961
Table 3. Enantioselective Reduction of Prochiral Ketones in THF
by NaBH4 in the Presence of G(3)G
The examination of Table 3 leads to the following com-
ments: (a) Rigidity of the chiral complex is a factor controlling
the topology of the reducing reagent, so decreasing temperature
resulted in a significant improvement in the chiral induction.
(b) The optical induction is larger for aromatic and short linear
substrates than for ketones where the carbonyl is attached to a
long paraffinic chain. In this last case, the steric hindrance at
the chiral interface of the dendrimer is probably the limiting
effect.
NeVertheless the high asymmetric inductions obtained with
linear alkyl ketones are, to our knowledge, the best result
presented in the literature for this type of ketones.16
Finally, the enantioselectivity depends on the variation of the
position of the carbonyl group on the pyridine moiety. We
noticed that better results were obtained through the 2-acetyl-
pyridine. This is probably due to the competition of the
complexation of the NaBH4 on the N of pyridine and the
hydroxyl dendrimer groups.
chemical
yield (%)
ketone
T, °C
% eea
cyclohexyl phenyl
butyl phenyl
propyl phenyl
methyl phenyl
methyl phenyl
methyl p-Br phenyl
2-pentanone
2-pentanone
2-heptanone
2-heptanone
2-octanone
25
25
25
25
0
25
0
-20
-20
-80
-20
-80
0
97
96
90
82
94
94
94
88
94
96
92
85
90
60
45
97 (S)
100 (S)
100 (S)
82 (S)
99 (S)
78 (S)
55 (S)
85 (S)
28 (S)
96 (S)
25 (S)
50 (S)
90 (S)
59 (S)
25 (S)
2-octanone
2-acetylpyridine
3-acetylpyridine
4-acetylpyridine
0
0
a Determined by GC using R DEX 120, â DEX 110, or â DEX 2,3,6-
M-19 columns depending of the compounds (see the Experimental
Section).
Conclusion
interface. These ICD effects have been exploited to assess the
relatively well-ordered structures of the ketone at the dendrimer
hydrophilic chiral interface. These results suggest that the
procedure employed here with dendrimers produces unimo-
lecular structure (direct “micelle-like”) in which guest molecules
can be encapsulated and for which the orientation in the dendritic
cavity is directly linked to the external dendrimer surface. The
ketones are more highly orientated and better fixed in the G(4)G
dendrimer because its periphery is more compact and the
presence of H-bonds between sugar moieties greatly enhances
the rigidity of the system. Therefore G(4)G seems to act in water
as G(3)G in THF. As in THF, all the other chiral supports are
not compact enough to give high enantioselectivities.
New amphiphilic dendrimers derived from PAMAM and
D-gluconolactone have been found to induce chirality in the
reduction of prochiral ketones by NaBH4. The enantioselec-
tivities obtained appear to be directly influenced by the external
surface of the structure.
The third generation of these amphiphilic dendrimers, G(3)G,
was found to be a good chiral ligand for the reduction of various
prochiral ketones in heterogeneous conditions. Even with
substrates well-known to give poor results (specially linear
ketones), good enantioselectivities are obtained. It is also
important to notice that under heterogeneous conditions (THF)
the dendrimer could be recovered by filtration, regenerated in
HCl/MeOH, and recycled, leading every time to the same results
in asymmetric reduction of ketones.
In THF, the heterogeneous conditions allowing the recovery
and its regeneration, we investigated the efficiency of the
procedure with other ketones.
We have also discussed the reduction of acetophenone in
water. It appears that the selectivity is dominated by the
architecture of the dendrimer and some supramolecular ordering
in the position of the ketone at the chiral solvating interface.
Asymmetric Reduction of Various Ketones by NaBH4, in
THF, at the Solid-Liquid Interface of Amphiphilic Chiral
Dendrimer G(3)G. In previous work, we were able to reduce
9
aromatic prokiral ketones with high enantioselectivities. We
show here that the process is also efficient with linear ketones
and also with some functionalized ketones. The results are
summarized in Table 3.
JA000378X
(16) Fehring V.; Selke R. Angew. Chem., Int. Ed. Engl. 1998, 37, 1827.