An l-proline functionalized metallo-organic triangle as size-selective homogeneous catalyst for asymmetry catalyzing aldol reactions

Article abstract of DOI:10.1039/c1cc11698c

A homochiral metal-organic triangle Co-Pro1 was achieved via self-assembly by incorporating a l-proline moiety within the corresponding ligand. Co-Pro1 comprised l-proline moieties as asymmetric catalytic active sites and a helical-like cavity, it worked

Full text of DOI:10.1039/c1cc11698c

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COMMUNICATION
An L-proline functionalized metallo-organic triangle as size-selective
homogeneous catalyst for asymmetry catalyzing aldol reactionsw
Xiao Wu, Cheng He, Xiang Wu, Siyi Qu and Chunying Duan*
Received 25th March 2011, Accepted 8th June 2011
DOI: 10.1039/c1cc11698c
A homochiral metal–organic triangle Co–Pro1 was achieved via
self-assembly by incorporating a L-proline moiety within the
corresponding ligand. Co–Pro1 comprised L-proline moieties as
asymmetric catalytic active sites and a helical-like cavity, it
worked as an asymmetric catalyst to prompt aldol reactions with
size-, stereo- and enantioselectivity.
construct catalytically active homochiral macro-molecular
complexes, many similar in size to small enzymes.10 These
supramolecular systems either contain an asymmetric catalytic
moiety to control the environment around the active site for
stabilizing the transition-state corresponding to the enantio-
selectivity, or comprise a cavity to mimic the pocket of an
enzyme for accelerating the reaction through proximity effects.
There is still very little overlap that combines aspects of both
into one entity. A promising avenue appears to be the design
of more sophisticated enzyme mimics that combine rate
increase as a consequence of proximity effects with transition-
state stabilization by the functional groups.
Metal–organic macromolecular complexes, discrete molecular
architectures constructed through the coordination of metal ions
and organic linkers, have attracted considerable attention, due
to their intriguing structures, their potential for a variety of
applications and their relevance to biological self-assembly.1,2
These structures are synthesized using modular and high yield
coordination-chemistry-based self-assembled methods, thus the
steric, geometric and electronic characteristics embedded within
the individual components have collectively allowed the
controllable construction, to some extent, of supra-molecular
entities.3 Since nature has served as a dominant source of
inspiration in the area of supramolecular chemistry,4 these
synthetic approaches often attempt to create enzyme-like
systems, in which a cavitand is connected to an active site,
with the aim of mimicking enzyme catalysis. Yet only a few
‘‘artificial systems’’ achieved the magnificent catalysis of
natural enzymes,5,6 because of the difficulties associated with
the generation of specific interactions capable of selective
encapsulation of substrates with suitable orientation, and
accelerating their reactions through proximity effects.7,8
Without doubt, the biggest challenge in supramolecular
catalysis is to develop selective catalysts that convert relevant
substrates into desired products with high selectivity. Enantio-
selective reactions in which only one of the two possible
enantiomers of the product is formed are particularly difficult,
because precise control of the reaction pathways is required and
energy differences in the competing transition states as small as 3
kcal molÀ1 make large differences in selectivity.9 To further
develop conventional supramolecular coordination-chemistry-
based asymmetric catalysts for producing optically pure fine
chemicals, several well-established strategies have been used to
As well-known asymmetric organocatalysts, L-proline and its
derivatives are used to accelerate a variety of enantio-selective
organic reactions, including C–C bond forming aldol and
Michael reactions under homogeneous conditions.11 Through
incorporation of a L-proline moiety within a metallo-helical
triangle formed by assembling metal ions and two tridentate
N2O units containing amide groups within a central benzene ring
at the meta sites, herein, we have developed a new approach to
create a homochiral triangle Co–Pro1. With the asymmetric
catalytic active sites to stabilize the potential transition state
and the helical cavity to increase the local concentration of
the substrates, Co–Pro1 works as an asymmetric enzyme-like
catalyst prompting the well-known aldol reactions with size-,
stereo- and enantioselectivity.
Ligand L-Pro1 was synthesized according to the synthetic
route outlined in Scheme 1. 3 was gained through a formal
amide-formation reaction from N-Boc–L-proline. The reaction of
the unprotected ester 4 with hydrazine hydrate gave 5. Through a
Schiff base reaction with 2-pyridinecarbaldehyde, the final ligand
L-Pro1 was achieved and purified via semipreparatory HPLC and
characterized spectroscopically. Adding NH4PF6 into the
methanol solution of ligand L-Pro1 and Co(NO3)2Á6H2O led to
the formation of the metallohelical triangle Co–Pro1. Electro-
spray ionization mass spectrometry (ESI-MS) spectrum of the
reaction solution exhibited five intense peaks at m/z = 812.76
and 885.77 with the isotopic distribution patterns separated
by 0.50 Da (Fig. 1). These peaks were assignable to
[Co3(L-Pro1)3]2+ and [Co3(L-Pro1)3(PF6) + H]2+, respectively,
through the exact comparison of the experimental peaks with the
simulation results obtained on the basis of natural isotopic
abundances, demonstrating the formation of M3L3 species in
the solution. The coordination of the ligand to the metal ions
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian, 116012, China. E-mail: cyduan@dlut.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details and additional spectroscopic data. See DOI: 10.1039/
c1cc11698c
c
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Chem. Commun., 2011, 47, 8415–8417 8415

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the cobalt complex was quantitative and the complex exhibited
1 : 1 stoichiometry. The presence of a sharp isosbestic point at
330 nm indicated that only two species coexist in the equilibrium
(Fig. 2). This result is quite similar to that observed before
with a M6L4 octahedral nanocage with the three disk-shaped
arm ligands,12 confirming that the cobalt is strongly coordinated
by the tridentate chelators in a pseudo-octahedral coordination
geometry, demonstrating that the M3L3 species was the only
one complexation species and the association constant of the
complexation species is relatively high. Circular dichroism
(CD) measurements of Co–Pro1 in DMSO solution showed
one band at 390 nm with a negative Cotton effect and another
band at 280 nm with a positive Cotton effect, respectively. The
whole spectrum was quite different from that of the chiral
ligand L-Pro1, suggesting the homochirality of the pyrrolidine
moieties in the Co–Pro1 even in solution.
The catalytic activities of Co–Pro1 in asymmetric aldol
reactions between various aromatic aldehydes and cyclo-
hexanone were employed in d6-DMSO media at room
temperature. As shown in Table 1, the loading of only 1.5%
ratio of Co–Pro1 (7.5 mM) catalyst leads to a 42% conversion
of the product corresponding to 4-nitrobenzaldehyde. Inter-
estingly, the catalytic aldol reaction exhibits an excellent
diastereoselectivity of ca. 6 : 1 (anti : syn) as well as a high
enantioselectivity (73% ee). A control experiment with the
unmodified MC-1 (having the same triangle backbone with the
absence of the L-proline moiety)13 and a similar Co-based
triangle in which the pyrrolidyl ring was replaced by a phenyl
group exhibited trace conversion after 10 days.
Scheme 1 Synthetic procedure for Co–Pro1. Conditions: (a) (Boc)2O,
CH2Cl2, rt (73.8%); (b) oxalyl chloride, pyridine, CH2Cl2, 0 1C;
(c) 5-aminoisophthalic acid dimethyl ester, NEt3, CH2Cl2, 0 1C–rt;
(d) 6 N solution of HCl in 1,4-dioxane (40 mL mmolÀ1), 0 1C;
(e) hydrazine hydrate (80%), EtOH, reflux (85%); (f) 2-pyridinecarb-
aldehyde, reflux (85%); (g) Co(NO3)2Á6H2O, NH4PF6, CH3OH, rt (55%).
Importantly, the same reaction when performed with L-Pro1
acting as catalyst resulted in a 36% conversion, significantly
Fig. 1 ESI-TOF spectra of the Co-based triangle Co–Pro1 formed in
CH3OH solution.
could be also identified by the relatively broadened and shifted
resonance signals in 1H NMR spectra. 1H NMR spectra of
Co–Pro1 in d6-DMSO indicated that –CQO–NH– signals of
L-Pro1 were significantly shifted up-field (d = 0.52 ppm), while
–NQCH– signals of L-Pro1 were distinctly shifted downfield
(d = 0.51 ppm). At the same time, only one set of signals were
observed, indicating that all the ligands in each complex were
in an identical environment, possibly located equivalently with a
C3-symmetry.
Ligand L-Pro1 (10 mM) in methanol solution exhibits an
intense band at about 300 nm, assignable to the p–p* and n–p*
charge transfer band. Upon the addition of Co2+ ions, this
band was decreased gradually and a new band at about 376 nm
increased significantly. Both the bands remained constant
after adding approximately 1 equivalent of Co2+. The almost
linear relations between the absorbance at both bands and the
concentration of Co2+ added revealed that the formation of
Fig. 2 (a) UV-Vis spectra of ligand L-Pro1 (10 mM) upon the addition
of
a
standard solution of Co(NO3)2Á6H2O (per
1 mM) up to
1 equivalent. (b) CD spectra of L-Pro1 (black line) and Co–Pro1
(red line) in DMSO solution.
c
8416 Chem. Commun., 2011, 47, 8415–8417
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Table 1 Aldol reactions between aldehydes and cyclohexanonea
of 4-nitrobenzaldehyde revealed the small but significant
high-field shift (ca. 0.1 ppm) of the amide proton signal from
that of the free Co–Pro1 in solution, which could possibly be an
indicator that 4-nitrobenzaldehyde was capsulated within the
pocket of the Co–Pro1 through the hydrogen bonding inter-
actions corresponding to the amide donors.
Con.b dr
eec
We gratefully acknowledge financial support from the
National Natural Science foundation of China (20801008
and 21025102).
Entry Substrates
Cat
(%)
(A/S)b (%)
1
2
3
4
4-Nitrobenzaldehyde
Co–Pro1 42
6 : 1
2 : 1
6 : 1
2 : 1
10 : 1
2 : 1
—
73
50
70
62
62
44
—
—
L-Pro1 36
Co–Pro1 38
L-Pro1 23
Co–Pro1 24
L-Pro1 21
Co–Pro1 Trace
24
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
3-Formyl-1-phenylene-
Notes and references
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(3,5-di-tert-butylbenzoate) L-Pro1
1 : 1
a
The reaction was carried out at room temperature for 10 days with
cyclohexanone (5 mmol) and aldehyde (0.5 mmol) in the presence of
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d6-DMSO (0.5 mL). The conversion and diastereomeric ratio were
b
determined by 1H NMR spectroscopy of crude products. Values
c
represent the major isomer. The ee values were determined by chiral
HPLC on a Chiralcel AD-H column.
lower diastereoselectivity (2 : 1) as well as the decrease of
enantioselectivity (50%, ee) (table entry 1). In fact our metal–
organic catalyst Co–Pro1 exhibited excellent specificity for the
anti conformation of the product corresponding to the aldol
reactions of the nitrobenzaldehydes, which drives the significant
improvements from those of the relative catalytic reaction with
L-Pro1. The better diastereo- and enantio-selection of the
catalytic aldol reaction with Co–Pro1 may originate from
the restricted movement of the substrates in the confined
pocket-like environment in combination with multiple chiral
inductions.
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To further probe whether activation of the carbonyl species
occurs inside the hydrophobic hollow of the catalyst and the
reflection of compound configuration on diastereomers, a
substrate of increasing dimension was tested. While the reaction
between bulky aldehyde 3-formyl-1-phenylene-(3,5-di-tert-
butylbenzoate),14 which is larger than the pocket size of Co–Pro1,
and cyclohexanone in the presence of L-Pro1 gave the conversion
of about 24%, no signals corresponding to the aldol product
were found in the NMR spectra of the reaction mixture under
the same experimental conditions. From a view point of
mechanism, the bowl-like Co–Pro1 first acts as a mimic of
the pocket of an enzyme to accelerate the reaction through
encapsulating the substrates within the pocket, greatly increasing
the local concentration of the substrates and preorganizing the
substrates in the correct orientation to react. These homochiral
pyrrolidine moieties attached within the chiral pocket of
Co–Pro1 interact with the cyclohexanone to form the anti-
enamine transition-state,15 which dominates the asymmetric
aldol reactions that occur via an enamine pathway. Infrared
spectroscopy of the Co–Pro1 solution in the presence of
cyclohexanone exhibited one broad C–O stretch at 1685 cmÀ1
.
The significant red-shift from 1709 cmÀ1 (free cyclohexanone)
supports the encapsulation of cyclohexanone within the pocket
of the catalyst and the possible activation of the substrates
within the pocket of the catalyst through an enamine transition-
state. 1H NMR spectra of the Co–Pro1 solution in the presence
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8415–8417 8417