Proline-coated gold nanoparticles as a highly efficient nanocatalyst for the enantioselective direct aldol reaction in water

Article abstract of DOI:10.1039/c3ra22955f

Reported is an efficient approach to the synthesis of water-soluble proline-coated gold nanoparticles through a place exchange reaction between pentanethiolate stabilized gold nanoparticles and a proline-tethered amphiphilic thiol. Preliminary studies sho

Full text of DOI:10.1039/c3ra22955f

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Proline-coated gold nanoparticles as a highly efficient
nanocatalyst for the enantioselective direct aldol
reaction in water3
Cite this: RSC Advances, 2013, 3, 3861
Received 20th November 2012,
Accepted 18th January 2013
Noureddine Khiar,*a Raquel Navas,a Eleonora Elhalem,a Victoria Valdiviaab
b
DOI: 10.1039/c3ra22955f
´
and Inmaculada Fernandez*
www.rsc.org/advances
Reported is an efficient approach to the synthesis of water-
soluble proline-coated gold nanoparticles through place
exchange reaction between pentanethiolate stabilized gold
nanoparticles and proline-tethered amphiphilic thiol.
aldolases) mechanism.6 Since the seminal work by List et al.7 on
the intermolecular application of the proline-catalyzed direct
asymmetric aldol reaction, many other transformations have been
successfully catalysed by proline.8 Unlike natural enzymatic
reactions, organocatalytic reactions mimicking the class I aldolase
mode of action have typically been carried in organic solvents such
as DMSO, DMF, or CHCl3, which are far from being considered as
green solvents.9 In the presence of bulk water aldolase-type
organocatalytic reactions generally result in very poor yield and
stereoselectivity. Additionally, the high organocatalyst loading
required generally for driving the reaction to completion
constitutes a serious purification problem when the product and
the catalyst do not have good separation factors. Thus an
approach that allows an aldolase-type organocatalytic reaction to
occur in water and permits an easy separation of the catalyst from
the reaction medium is highly desirable. Many attempts were
made to conduct the reaction in aqueous media,10 including
attaching hydrophobic groups to the catalyst,11 conducting the
reaction in micelles,12 or the use of host–guest catalytic systems.13
The strategies for the separation, recuperation and reuse of
catalysts are numerous and include tethering to organic14 and
inorganic supports,15 ionic liquids,16 magnetite,17 dendrimers,18
and DNA,19 with the immobilization of proline on organic
supports making up the bulk of the literature reports. While
often successful in the removal of the catalyst from the products,
supported catalysts often suffer from lower activities (diffusion
effects) and selectivities (site heterogeneity) when compared with
their unsupported analogues. The emergence of nanotechnology
has brought a large number of nanomaterials which can be used
as semi-heterogeneous catalyst supports combining the advan-
tages of high reactivity and easy separation.20 Their very high
specific surface area confer them with high activity, while the
recent advances in nanofiltration, precipitation–flocculation,
facilitate their separation from the products. Functional gold
nanoparticles stabilized by alkanethiol self-assembled monolayers
(SAMs) exhibit excellent size, solubility, and agglomeration
behaviour which qualify them quite naturally to act as nanometric
supports for catalyst immobilization, Fig. 1.
a
a
Preliminary studies show that the nanocatalyst is highly active
in an enamine type aldolisation leading to the desired product
with nearly perfect diastereoselectivity and enantioselectivity
using water as an innocuous solvent.
Introduction
While great advances have been achieved with metal promoted
asymmetric catalysis,1 the recent advent of organocatalysis has
boosted the field in such a way that ‘‘man-made enzymes’’ are no
more a utopia, but realistic targets.2 A paradigmatic example of
this qualitative jump is the advances made in the aldol reaction,
one of the most powerful transformations in organic chemistry.3
Many powerful processes, mainly stoichiometric, were developed
by chemists in order to tackle the challenging issues of chemo-,
regio-, diastereo-, and enantioselectivity presented by the aldol
condensation. While these advances have allowed the total
synthesis of complex polyhydroxylated products4 and large-scale
production of enantiopure active pharmaceutical ingredients
(API),5 they suffer from the production of stoichiometric by-
products, and do not compete with other catalytic green
transformations. In biological systems, the aldol reaction is
carried out by two types of aldolases, which catalyse the reaction
through an enamine (type I aldolases) or zinc enolate (type II
a
´
´
Instituto de Investigaciones Quımicas, C.S.I.C-Universidad de Sevilla, c/. Americo
Vespucio, 49., Isla de la Cartuja, 41092 Sevilla, Spain. E-mail: khiar@iiq.csic.es;
Fax: +34 954460565;; Tel: +34 954489559
b
´
´
´
Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia,
´
´
Universidad de Sevilla, c/. Professor Garcıa Gonzalez, 2, 41012 Sevilla, Spain.
E-mail: inmaff@us.es; Fax: +34 954556737; Tel: +34 954555993
Electronic supplementary information (ESI) available: Experimental procedures for
3
the synthesis of compounds 2–8, the pentanethiolate stabilized gold nanoparticle 9,
the place exchange reaction for the synthesis of nanocatalyst I, 1H, and 13C spectra of
all the products as well as those of gold nanoparticles 9 and I are given. See DOI:
10.1039/c3ra22955f
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Scheme 2 Synthesis
of
proline-tethered
amphiphilic
thiol
8.
(a)
N,N9-diisopropylcarbodiimide (DIC), DMAP, CH2Cl2, 71%. (b) Pd/C, CH2Cl2, 45%.
(c) TBTU, DIPEA, DMF, 95%. (d) TFA, Et3SiH, CH2Cl2, 80%.
Fig. 1 Structure of proline coated nanocatalyst I.
tethered amphiphilic spacer, we used as starting material the
proline derivative 3 obtained from inexpensive, commercially
available trans-hydroxy proline (L-Hyp). Ester bond formation
using bifunctional spacer 2 obtained in three steps from
Results and discussion
While peptides and proteins containing proline including A3
peptide,21 gelatin22 and the cell penetrating peptide SAP23 have
been used for the biofunctionalization of gold nanoparticles, there
are no reports on the use of proline-coated gold nanoparticles as a
nanocatalyst.24 In this communication we report the design and
first use of gold nanoparticles as a nanometric scaffold for the
synthesis of a proline-coated water-soluble nanocatalyst I. The
immobilization of proline on a support can be seen as a
minimalistic version of an aldolase type I, with the proline playing
the role of the enzyme’s active site and the gold nanoparticle that
of an oversimplified peptide backbone not directly involved in the
catalytic activity. The catalyst design will be validated by using the
obtained nanocatalyst I in an enamine type catalysis in bulk water,
Scheme 1.
For the synthesis of our nanocatalyst with controlled density
and environment of the proline on the gold surface, and to tailor
the particle size, we chose to employ the place exchange reaction
pioneered by Murray et al.25 This 2 step approximation is based on
the synthesis of gold nanoparticles stabilized with alkanethiolates
which are exchanged in a second step by the catalyst functiona-
lized with a reactive thiol. The gold nanoparticles stabilized by
alkanethiolates are generally hydrophobic and insoluble in water,
thus, our design to enhance the water solubility of the sought
catalyst was the use of an amphiphilic spacer, containing both an
alkyl chain to promote the exchange reaction, and a hydrophilic
part derived from tetraethylene glycol to enhance the solubility of
the catalyst in water. For the synthesis of the sought proline-
tetraethylene glycol 1 (see ESI ), followed by azide reduction leads
3
to the amine 5. Next, the reaction of the amine 5 with trityl
protected mercaptoundecanoic acid 6 using O-(benzotriazol-1-yl)-
N,N,N9,N9-tetramethyluronium tetrafluoroborate (TBTU) and
N,N-diisopropylethylamine (DIPEA) in methylene chloride as
solvent afforded the amide intermediate 7 in good yield.
Subsequently, trifluoroacetic acid treatment of compound 7 led
to the concomitant deprotection of the Boc and trityl functions,
affording the desired proline appended amphiphilic spacer 8,
Scheme 2.
Gold nanoparticles stabilized with pentanethiolate groups were
synthesized using the method of Brust, Schiffrin et al. by a sodium
borohydride reduction of tetrachloroaureate in a biphasic system
using tetraoctylammonium chloride as a phase transfer agent in
the presence of pentanethiol.26 The obtained nanoparticles 9, with
a size of 2 nm, were characterized by NMR, UV-Vis and
transmission electron microscopy. TEM analysis shows that the
mean particle size is about 2 nm, which corresponds to 250 gold
atoms per nanoparticle, while elemental analysis shows that there
are 97 pentanethiol molecules per nanoparticle. The place
exchange reaction was conducted in methylene chloride using
an excess of the thiol 8 in order to assure a total coating of the
nanoparticle with the catalyst. Interestingly, in the course of the
reaction the desired nanoparticle precipitated in methylene
chloride as a black suspension, indicating that the outer face of
the nanoparticle is no longer hydrophobic. After 48 h and through
evaporation of methylene chloride, the black solid was found to be
highly soluble in water. Dialysis to remove the excess of the active
thiol, followed by lyophilization of the mixture afforded the
desired water-soluble proline-coated gold nanoparticle I in pure
form, Scheme 3.
1H NMR analysis shows that the place exchange reaction takes
place in quantitative yield and that mostly all the pentanethiolates
on the gold nanoparticle surface were exchanged with the
Scheme 1 Enantioselective direct aldol reaction in water.
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Conclusions
In conclusion, we have reported an efficient approach for the
synthesis of a type I aldolase mimic nanocatalyst by a place
exchange approach between a proline tethered-amphiphilic thiol
and a gold nanoparticle stabilized with pentanethiolate ligands.
The obtained 2 nm nanoparticles, containing 0.48 mmol g21 of
the catalyst, are highly soluble in water. The nanocatalyst is highly
active in an enamine type direct aldol reaction, as only 2.5 mol% is
needed to afford the desired product in quantitative yield with
nearly perfect diastereoselectivity and enantioselectivity using
water as a green solvent. Work directed toward the determination
of the scope of the catalyst in other catalytic processes, as well as to
improve the experimental conditions in order to recycle the
catalyst efficiently are under active investigation and will be
reported in due course.
Acknowledgements
Scheme 3 Place exchange synthesis and TEM image of AuNP I.
This work was supported by the Ministerio de Economia y
Competitividad (grant no. CTQ2010-21755-CO2-00), and the
functional thiol (see ESI ). Elemental analysis indicates a ratio of
3
´
Junta de Andalucıa (P07-FQM-2774). We acknowledge CITIUS
92 molecules of the catalyst per 250 gold atoms, corresponding to
a molecular weight of 195 kD, and to 0.48 mmol of ligand per
gram of the nanoparticle.
for TEM and NMR facilities.
Notes and references
Once obtained, the nanocatalyst was used in the model
reaction of the direct aldol reaction between p-nitrobenzaldehyde
10 and cyclohexanone 11 in pure water as solvent (Scheme 4).
We were delighted to find that the nanocatalyst I is highly
efficient in the direct aldol reaction as the product 12 was
obtained in quantitative yield with nearly total diastereoselection
and enantioselection in favor of the 12-anti isomer (Scheme 4).
The first assays were conducted using 30 mol% of the catalyst,
typical in this transformation, but in view of the efficiency of the
nanocatalyst, the catalyst loading could be reduced to 2.5 mol%
without any loss in the diastereoselectivity nor in the enantios-
electivity. Interestingly, in all cases, once the reaction had finished
(24 h), a simple extraction with methylene chloride led to
compound 12-anti as a single isomer in pure form, as catalyst I
remained in the aqueous phase. Preliminary attempts to recycle
the catalyst were tried, and show that the catalyst is still highly
enantioselective until the third run (90% de, and 98% ee), even
though the yield dropped significantly (30%). Taking into account
the smoothness of the experimental conditions, the leaching of
the catalyst27 can be ruled out, and the decrease of the chemical
yield could be due to the aggregation of the nanoparticles during
the extraction step.
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