Chiral surfactant-type catalyst for asymmetric reduction of aliphatic ketones in water

Article abstract of DOI:10.1021/ja308357y

A novel chiral surfactant-type catalyst is developed. Micelles formed in water by association of the catalysts themselves, and this was confirmed by TEM analyses. Asymmetric transfer hydrogenation of aliphatic ketones catalyzed by the chiral metallomicellar catalyst gave good to excellent conversions and remarkable stereoselectivities (up to 95% ee). Synergistic effects between the metal-catalyzed center and the hydrophobic microenvironment of the core in the metallomicelle led to high enantioselectivities.

Full text of DOI:10.1021/ja308357y

Communication
pubs.acs.org/JACS
Chiral Surfactant-Type Catalyst for Asymmetric Reduction of
Aliphatic Ketones in Water
Jiahong Li,†,§ Yuanfu Tang,†,§ Qiwei Wang,† Xuefeng Li,# Linfeng Cun,† Xiaomei Zhang,† Jin Zhu,†
Liangchun Li,‡ and Jingen Deng*,‡
†Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
‡Key Laboratory of Drug-Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041,
China
#College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China
§Graduate University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
increasing attention due to its safety and easy operation.12
ABSTRACT: A novel chiral surfactant-type catalyst is
Among the catalysts explored so far, the Noyori−Ikariya
developed. Micelles formed in water by association of the
catalysts themselves, and this was confirmed by TEM
analyses. Asymmetric transfer hydrogenation of aliphatic
ketones catalyzed by the chiral metallomicellar catalyst
gave good to excellent conversions and remarkable
stereoselectivities (up to 95% ee). Synergistic effects
between the metal-catalyzed center and the hydrophobic
microenvironment of the core in the metallomicelle led to
high enantioselectivities.
catalysts (Ru, Rh, and Ir complexes of TsDPEN (1, Figure
1))12d,e and their modifications have been found to be highly
s the demand for environmentally friendly methods
Aincreases, water as a solvent is of great interest. Although
water has the advantages of being safe, nontoxic, environ-
mentally benign, and inexpensive, the insolubility of many
organic compounds in water limits its application in various
chemical transformations. An efficient way to address this
matter is to introduce surfactant additives or use surfactant-like
catalysts. Generally, amphiphilic surfactants can form micelles
in water as microreactors1 to increase not only the solubility of
nonpolar substrates and catalysts but also the reactivity and
stereoselectivity of reactions due to the hydrophobic interaction
and the preorganizing function of micelles.2 Thus, the use of
micellar surfactants as additives or catalysts has attracted
considerable attention in aqueous reactions in recent years.2−8
However, there are few reports of successful asymmetric
synthesis with high enantioselectivity in chiral micellar
systems,2,4−6 especially metallomicellar catalysts with chiral
surfactants as the ligands.2,5b Actually, lower enantioselectivity
was usually observed with chiral metallomicellar catalysts
compared to the corresponding chiral molecular catalysts in
micelles.5,6
Figure 1. Chiral diamine ligands.
efficient for ATH of aromatic ketones,12a−c but limitations arise
in the case of aliphatic ketones.11a−d Herein, we report a novel
chiral surfactant-type metal catalyst with ligand 4 for efficient
ATH of aliphatic ketones in neat water in air.
In our previous work, we found that the reactivity and
selectivity for ATH of aromatic ketones and imines catalyzed by
lipophilic7 and hydrophilic8 catalysts, respectively, could be
improved by adding cationic surfactant CTAB to form micelles
in water, around which positive charges of the surfactants
elevated the concentration of formate ions via the electrostatic
attraction between them. Moreover, our preliminary experi-
ments indicated that, in the presence of surfactant CTAB or
SDS, the selectivy (54% ee with either surfactant) of ATH of
octan-2-one (7b) was markedly improved with a cationic water-
soluble ligand 2 (Figure 1) in water (Table 1, entries 4 and 5).
Anionic surfactant SDS provided lower conversion (60% vs
94%), although in the absence of surfactant the reduction was
sluggish (15% conv) and 35% ee was obtained (entry 3), similar
to the results obtained with lipophilic ligands 1 (37% ee, entry
1) and 3 (39% ee).11c However, only a small increase in ee was
observed with CTAB as surfactant using 1 or 3 as ligand (42%
ee with either) in ATH of 7b (entries 2 and 6). These
observations inspired us to develop amphiphilic surfactant-type
ligand 4 (Figure 1) based on chiral and cationic 2 as the
Asymmetric reduction of ketones catalyzed by transition-
metal complexes is a key and practical technology for synthesis
of optically active alcohols. Although asymmetric catalyzed
reduction of aromatic ketones is well documented, the
development of efficient catalytic systems for asymmetric
reduction of aliphatic ketones with high enantioselectivities and
wide-ranging substrates is a challenge.9−11 Recently, asym-
metric transfer hydrogenation (ATH) of ketones has attracted
Received: August 23, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja308357y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. ATH of Octan-2-one with Different Metal
Precursors and Ligands in Different Solvents
b
c
entry
1
ligand
metal
solvent
conv. (%)
ee (%)
1
1
2
2
2
3
4
4
4
4
4
4
Rh
Rh
Rh
Rh
Rh
Rh
Ru
Ir
H2O
93
97
15
94
60
99
72
98
94
98
5
37 S
42 S
35 S
54 S
54 S
42 S
40 S
82 S
84 S
75 S
7 S
d
2
H2O
3
H2O
d
4
H2O
e
5
d
H2O
Figure 3. Effect of temperature on ATH of octan-2-one catalyzed by
Rh−4 complex.
6
H2O
7
8
9
H2O
H2O
was promoted from 0 to 10 °C and then decreased. A dramatic
drop in conversion was observed on going from 40 to 60 °C. It
was possible that increasing the reaction temperature disfavored
micelle formation.13
Rh
Rh
Rh
Rh
H2O
d
10
H2O
11
12
CH2Cl2
i-PrOH
22
33 S
The above results showed that the reaction may proceed in
chiral metallomicelles only formed from surfactant-type Rh−4
complexes in water (Figure S1). In fact, spherical micelle
particles were observed during the reaction by TEM analyses.
Figure 4 shows TEM micrographs of precatalyst 5, catalyst 6,
a
b
Reaction conditions: see Supporting Information. Conversion was
determined by GC analysis using decane as internal standard.
c
Enantiomeric excess was determined by GC analysis. The absolute
configuration was assigned by comparing the retention time (GC)
with (S)-octan-2-ol. 10 mol% CTAB was added. 10 mol% SDS was
d
e
used.
hydrophilic headgroup, of which metal complexes might form
chiral metallomicelles in water by self-association.
Precatalyst 5 (Figure 2) was prepared by mixing 4 and
[Cp*RhCl2]2 in water at 40 °C for 2 h, and then it was applied
Figure 4. TEM images of micelles of (a) precatalysts, (b) catalysts, (c)
and reaction mixture.
and the reaction mixture.14 The micelle size in the reaction
mixture, with an average diameter of 66.8
bigger than in both precatalyst 5 (20.9 2.5 nm) and catalyst 6
(22.3 5.7 nm) because 7b was incorporated into the
15.6 nm, was
metallomicelles.
We also found that the alkyl length of aliphatic ketones
greatly influenced the reactivity and enantioselectivity (Table
2). For linear alkyl methyl ketones (7a−7f), the enantiose-
lectivity increased with the length of the alkyl chain from 76%
to 94% ee (entries 1−5), but the ee did not increase from 7e to
7f. These results show that there may be a hydrophobic
interaction between the long alkyl group of aliphatic ketones
and the long chain of 6 in the metallomicelle (Figure 5). When
the methyl group of 7c was substituted with ethyl and propyl
groups, the reactivities were very low, and the reaction
proceeded at a lower molar ratio of substrate to catalyst (s/c
= 50), in 74% conversion with 81% ee for 7g and in 45%
conversion with 72% ee for 7h after 48 h (entries 7 and 8). For
the alkyl methyl ketones with terminal branch chains 7i and 7j,
7i gave better results than the corresponding linear ketone 7a,
and even 7j was comparable to 7b in both rate and selectivity
(entries 9 and 10 vs entries 1 and 2). A wider range of aliphatic
ketones (7k−7q), even bearing functional groups, has
successfully given 80−95% ee (entries 11−17). 7m, with a
cyclic hexyl group, was reduced in 95% ee, which was higher
than that of 7b (90% ee) with a linear hexyl group (entry 13 vs
2). 7o was hydrogenated in 92% ee to give tert-butyl 3-
Figure 2. Structures of precatalyst 5 and catalyst 6.
to catalyze ATH of 7b with HCO2Na as hydrogen source in
water. To our surprise, excellent conversion (94%) and high
enantiomeric excess (84%) were obtained in 24 h with catalyst
6 (Figure 2) produced in situ (entry 9). Different metal
precursors, [RuCl2(p-cymene)]2, [Cp*IrCl2]2, and
[Cp*RhCl2]2, were tested using 4 as a ligand, and the Rh
complex turned out to be the most selective (84% ee, entry 9 vs
entries 7 and 8). It is interesting that the ee decreased (75%)
with catalyst 6 when CTAB was added to the reaction mixture
(entry 10). In organic media, very low conversion (5%) and ee
value (7%) were obtained in dichloromethane (entry 11), and
22% conversion and 33% ee were obtained in isopropanol
(entry 12).
Furthermore, the reaction was strongly dependent on
reaction temperature (Figure 3). With increasing temperature,
the ee value gradiently decreased. The highest ee value (90%)
was obtained at 0 and 5 °C; however, the conversion was low
(42%) at 0 °C. The conversion increased when the temperature
B
dx.doi.org/10.1021/ja308357y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 2. ATH of Ketones with Surfactant-Type Catalyst
Figure 5. Proposed mechanism of reduction of aliphatic ketones in the
metallomicelle formed from catalyst 6. (a) Schematic representation of
the metallomicelle. (b) Probable transition states of the reaction.
stereochemistry implies that the reaction mechanism of
metallomicellar catalyst 6 resembles the concerted process
suggested by Noyori and co-workers.16 In contrast to aryl alkyl
ketones, for which a transition state was stabilized by CH−π
interaction between the substrate and the catalyst (Figure
S7),17 we propose that in this transition state, the large alkyl
group of the aliphatic ketone is far away from the Cp*
(1,2,3,4,5-pentamethylcyclopentadiene) ligand of the catalyst,
due to steric hindrance between them,17c leading to (S)-
aliphatic alcohols (Figure 5). Furthermore, the steric
interaction allows the large alkyl group to be orientated toward
the long-chain sulfonylamino group of the catalyst and thereby
the core of the self-assembled metallomicelle.16a On the other
hand, amphiphilic catalyst 6, bearing a large hydrophilic
headgroup with two positive charges, may favor the formation
of metallomicelles, leading to strongly hydrophobic interaction
between the chain of the catalyst and the alkyl chain of the
substrate in the core. Therefore, synergistic effects between the
metal-catalyzed center and the hydrophobic microenvironment
of the metallomicelle core facilicate the reduction, proceeding
with higher stereochemical induction compared to the catalysts
formed from the corresponding ligands 1−3 (Table 1),11c
which is an important feature of enzyme catalysis.2b
In conclusion, a novel surfactant-type ligand was designed
and synthesized. A rhodium complex with this ligand was
successfully applied in asymmetric transfer hydrogenation of a
broad range of aliphatic ketones, especially those bearing
functional groups that might form key intermediates of
bioactive compounds15 and natural products.18 Good to
excellent conversions and remarkable enantioselectivities (up
to 95%) were obtained, with substrate-to-catalyst ratios as high
as 100. The reactivity and enantioselectivity depended on the
solvent, the temperature, and the chain length of the aliphatic
ketones. Furthermore, TEM analyses showed that the
precatalyst and catalyst formed metallomicelles in water, and
the reaction proceeded in micelles. A probable transition state
was proposed on the basis of the absolute configuration of the
products, in which the stereochemistry was controlled by the
steric interaction between the alkyl groups of the aliphatic
ketone and the Cp* ligand of the amphiphilic catalyst.
Hydrophobic interactions between the alkyl chains of aliphatic
ketones and the catalyst in the metallomicelle may lead to high
a
Reaction conditions: 0.004 mmol of ligand 4, 0.002 mmol of
[Cp*RhCl2]2, 1 mL of H2O, 2 mmol of HCOONa, 0.4 mmol of
b
ketone, 5 °C, s/c = 100. Conversion was determined by GC analysis
using decane as internal standard. Enantiomeric excess was
determined by GC analysis. Absolute configurations: see Supporting
c
d
e
Information. 2 mL of H2O was used for the solid substrate. s/c = 50.
f
Z/E ratio was 38.8:61.2 for both 7l and 8l, and the configuration of
g
h
both E- and Z-isomers was (S)-form. At 40 °C. At 10 °C.
hydroxylpyrrolidine-1-carboxylate (8o) as a key intermediate of
factor Xa inhibitor DX-9065a (entry 15).15 Acetophenone (7r)
was also tested for the reaction scope, and 97% ee was obtained
(entry 18). These results indicated that catalyst 6 was effective
for the reduction of not only aliphatic ketones but also aromatic
ketones.
The absolute configuration of 1-phenylethanol (8r) was
opposite to those of aliphatic alcohols except for 8o (Table 2).
For comparison, the Rh complex of (R,R)-TsDPEN (1) was
also used for reduction of 7r and 7m, to give (R)-8r in 97% ee
and (S)-8m in 82% ee, which was much higher than the 37% ee
of (S)-8b (Table 1, entry 1) in water at 40 °C. The identical
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
■
S
* Supporting Information
(c) Ahlford, K.; Lind, J.; Maler, L.; Adolfsson, H. Green Chem. 2008,
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Experiment procedures; spectral data of ligands. This material is
available free of charge via the Internet at http://pubs.acs.org.
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C.; Xiao, J. Platinum Metals Rev. 2010, 54, 3. (b) Wang, C.; Wu, X.;
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AUTHOR INFORMATION
Corresponding Author
jgdeng@cioc.ac.cn
Notes
■
The authors declare no competing financial interest.
(13) (a) Sinou, D.; Rabeyrin, C.; Nguefack, C. Adv. Synth. Catal.
ACKNOWLEDGMENTS
■
2003, 345, 357. (b) Forster, S.; Plantenberg, T. Angew. Chem., Int. Ed.
̈
We thank National Natural Science Foundation of China
(Grant No. 20972154), National Basic Research Program of
China (973 Program, No. 2010CB833300), and Sichuan
University for financial support. Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, and West China
School of Pharmacy, Sichuan University, contributed equally to
this work.
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