Enantiopure Peptide-Functionalized Metal-Organic Frameworks

Article abstract of DOI:10.1021/jacs.5b05327

We present herein the first example of metal-organic frameworks postfunctionalized with peptides. Our microwave-assisted postsynthetic modification method yields enantiopure peptides anchored inside MOF cavities. Al-MIL-101-NH₂, In-MIL-68-NH

Full text of DOI:10.1021/jacs.5b05327

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Article
Enantiopure Peptide-Functionalized Metal-Organic Frameworks
Jonathan Bonnefoy, Alexandre Legrand, Elsje Alessandra Quadrelli, Jerome Canivet, and David Farrusseng
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jun 2015
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Enantiopure Peptide-Functionalized Metal-Organic Frame-
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Jonathan Bonnefoy,† Alexandre Legrand,† Elsje Alessandra Quadrelli,‡ Jérôme Canivet*,† and David
Farrusseng†
† IRCELYON, Université Lyon 1 ꢀ CNRS, UMR 5256, 2, Av. Albert Einstein, 69626 Villeurbanne, France
‡ C2P2, Université Lyon 1 ꢀ CPE Lyon ꢀ CNRS, UMR 5265, 43, Bvd du 11 Novembre 1918, 69616 Villeurbanne, France
ABSTRACT: We present herein the first example of MetalꢀOrganic Frameworks postꢀfunctionalized with peptides. Our microꢀ
waveꢀassisted postꢀsynthetic modification method yields enantiopure peptides anchored inside MOF cavities. AlꢀMILꢀ101ꢀNH2, Inꢀ
MILꢀ68ꢀNH2 and ZrꢀUiOꢀ66ꢀNH2 were chosen as starting platforms. A single amino acid and various oligopeptides are grafted with
yields up to 60% after a 30ꢀminutes microwaveꢀassisted couplingꢀdeprotection sequence. This allows efficient preparation of a
library of functional hybrid solids for molecular recognition applications such as sensing, separation or asymmetric catalysis, as
demonstrated here for the chiral aldol reaction.
(SPPS) for the enhancement of yields and reactivity.12 In the
case of hybrid porous materials, Cohen and coꢀworkers recentꢀ
Introduction
MetalꢀOrganic Frameworks (MOFs) constitute a new class of
functional hybrid nanoporous solids with promising applicaꢀ
tions in gas storage and separation. In addition, the developꢀ
ment of MOFs for high addedꢀvalue applications is attracting
increasing interest in domains such as enantioselective heteroꢀ
geneous catalysis,1 solar energy harvesting through photocaꢀ
talysis,2 chiral separation1d,3 and sensing.4 MOFs exhibiting
properties that are useful for the aforementioned domains are
often referred to as “artificial enzymes.” Some of these MOFs
further reduce the gap with enzymes through the incorporation
of peptide moieties inside the MOF cavities, thereby providing
a typical apoenzyme environment.
ly reported the copperꢀmediated aryl halide cyanation of the 2ꢀ
bromotherephthalate ligand in UiOꢀ66 under microwave irraꢀ
diation.13
We present herein the first example of microwaveꢀassisted
covalent grafting of an amino acid and various oligopeptides
(up to tetrapeptides) inside MOF cavities, for the design of
chiral hybrid solids. Typically, the use of microwave irradiaꢀ
tion during the functionalization process increases the grafting
yield while preventing the racemization of the peptide. Raceꢀ
mization, a known pitfall in related strategies,9,14 is shown to
be successfully avoided. Also, proofꢀofꢀconcept experiments
demonstrate the asymmetric nature of the MOFꢀbased cataꢀ
lysts.
From a synthetic point of view, peptideꢀcontaining MOFs
designed as artificial metalloenzymes5 are obtained either by
selfꢀassembly using amino acid ligands (MetalꢀPeptide
Frameworks)3b,6 or by postꢀsynthetic functionalization starting
from easilyꢀaccessible aminoꢀcontaining frameworks.7 When
the synthetic process involves a thermal treatment such as the
removal of peptideꢀterminal protecting groups, the racemizaꢀ
tion of chiral grafts often takes place, thereby jeopardizing the
enantioselective properties needed for asymmetric applicaꢀ
tions. Recent studies report either an enantiomeric purity of
80%8 or full racemization9 of proline functions after protecting
groups have been thermally removed from the cavities of selfꢀ
assembled MOF materials. Indeed, if a high yield of deprotecꢀ
tion can be achieved under harsh conditions (high temperature,
long time), this is often detrimental to the purity of sensitive
biomolecules or the quality of the final material. To the best of
our knowledge, no methodology that combines high yield and
high quality/purity has yet been reported for the production of
bioꢀfunctionalized materials.
Three different MOF starting platforms have been investigatꢀ
ed. All of them bear the 2ꢀaminoterephthalate linker, but they
present different topology, dimensionality, pore sizes and
window sizes for investigating the scope of the methodology
(Scheme 1).
InꢀMILꢀ68ꢀNH2, patented as IHMꢀ2,15 is isostructural to MILꢀ
6816 and has a oneꢀdimensional rodꢀshaped structure formed of
indium octahedra and 2ꢀaminoterephthalates (BDCꢀNH2) as
bridging linkers. It is composed of hexahedral and triangular
1ꢀD channels with diameters of 16 and 6 Å, respectively. Alꢀ
MILꢀ101ꢀNH2 is isostructural to the threeꢀdimensional Crꢀ
MILꢀ10117 and is formed of octahedral trimeric aluminum (III)
clusters linked by 2ꢀaminoterephthalate ligands.18 Related to
its giantꢀpore MOF parent with pore diameters of 29 and 34 Å,
this AlꢀMILꢀ101ꢀNH2 can be considered an ideal candidate
thanks to its high pore volume, which is able to accommodate
larger grafts and/or high graft density. ZrꢀUiOꢀ66ꢀNH2 is
based on Zr6O6 clusters linked by 2ꢀaminoterephthalates.19 It is
also threeꢀdimensional but has smaller accessible cavities with
pore diameters of 7.5 and 11 Å.
Since its first reported use by Gedye et al.10 in the 1980s,
microwave irradiation has been widely used in organic syntheꢀ
sis in order to enhance the reactivity of functional groups and
shorten the reaction time.11 It is also applied in solid surface
modification and especially in solidꢀphase peptide synthesis
The grafting process we applied here was based on a variation
of solidꢀphase peptide synthesis (SPPS).20 The peptide (or
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single amino acid) is anchored on the MOF support through a
pling agent25 (see Scheme 1), all of which have demonstrated
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peptide coupling between the amino group at the MOF wall
and the carboxylic acid function of the Nꢀprotected amino acid
(or polypeptide), followed by the removal of the protecting
group to liberate the terminal NH of the amino acid (or polyꢀ
peptide) moiety that was grafted.21 Coupling agents are necesꢀ
sary elements of the synthetic procedure, because they activate
the carboxylic acid, and no coupling reaction is observed in
their absence.22 Traditional peptide coupling can efficiently
proceed using dicyclohexylcarbodiimide (DCC) as coupling
agent. However, the DCC is transformed during the coupling
into dicyclohexylurea (DCU), an insoluble white solid, which
cannot be isolated from the MOFs. We therefore investigated
only coupling agents that are soluble in organic solvents, in
order to allow the purification of the solid MOF materials
through the use of washing cycles. The coupling agents that
we investigated are bromotripyrrolidinophosphonium hexꢀ
their effectiveness for difficult peptide coupling reactions,
combined with a base such as N,Nꢀdimethylaminopyridine
(DMAP) or diisopropylethylamine (DIEA). The concomitant
protection of the terminal amino functionality of the incoming
amino acid or peptide is also essential here, because the amino
groups at the MOF walls are less nucleophilic than their hoꢀ
mogeneous counterparts due to the electronꢀwithdrawing
effect of the carboxylates coordinated to metals at the MOF
nodes. Tertꢀbutyloxycarbonyl (Boc) was chosen as the Nꢀ
protecting group, because its thermolability to gaseous prodꢀ
ucts (carbon dioxide and isobutene at temperatures above
110°C)8ꢀ9,14a allows its removal without the use of additional
chemicals that could possibly remain blocked inside the MOF
pores (see Scheme 1 for an overview of the method).
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Experimental section
afluorophosphate
(PyBrOP),23
chlorotripyrrolidinoꢀ
Synthetic methods. In a typical coupling procedure under
microwave irradiation, 0.45 mmol of coupling agent, 0.6
mmol of base, 0.45 mmol of Bocꢀprotected peptide and
phosphonium hexafluorophosphate (PyClOP)24 and 2ꢀchloroꢀ
Nꢀmethylpyridinium iodide, known as the Mukaiyama couꢀ
Scheme 1. Parameters investigated for the optimization of the two-step peptide grafting process into various MOFs.
the desired amount of MOFꢀNH2 (ca. 0.45 mmol ꢀNH2) were
suspended in 5 mL of anhydrous dichloromethane. Unless
otherwise specified, the L enantiomer of the peptide was used.
The resulting suspension was allowed to react under microꢀ
wave irradiation for 20 minutes at 80°C (300 watts) under air
cooling. The suspension was then centrifuged, and the solid
obtained was washed with dichloromethane (3 x 5 mL) and
dried under vacuum at room temperature to give the desired
product as a fine yellow powder.
The deprotection procedure, i.e., Boc removal, consisted in
suspending the desired MOFꢀNHꢀ(peptide)ꢀBoc in 5 mL of
anhydrous dichloromethane. The suspension was then allowed
to react under microwave irradiation for 10 minutes at 150°C
(300 watts). After centrifugation, the solid was washed with
dichloromethane (3 x 5 mL) and dried under vacuum at room
temperature to give the desired product as a fine yellow powꢀ
der. The grafting yields of amino acid or peptide obtained for
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the various MOFs under these conditions are summarized in
20 mol% of 2ꢀaminoterephthalate linker leaches into the
1
Table 1.
solution (Figures S3 and S4).
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The postꢀsynthetic modification yields represent the percentꢀ
age of modified terephthalate linkers in the MOF framework.
They were measured using the integration of the H NMR
spectra peaks after digestion of the solid sample in deuterated
dimethylsulfoxide (dmso) solution: DClꢀD2O/dmsoꢀd6 for
MILꢀ6823a and HFꢀH2O/dmsoꢀd6 for UiOꢀ66 and MILꢀ101
materials (Figure 1 and Supporting Information).26 All of the
functionalized solids obtained remained crystalline, as deterꢀ
mined by powder Xꢀray diffraction, and porous, according to
nitrogen adsorption isotherms (Supporting Information).
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Catalytic aldol reaction. In a typical catalytic trial, 45 mg
of AlꢀMILꢀ101ꢀNHꢀPro or 10 mg of AlꢀMILꢀ101ꢀNHꢀGlyꢀPro
(corresponding to 0.030 mmol of proline moiety) were susꢀ
pended in a solution of pꢀnitroꢀbenzaldehyde (30 mg, 0.200
mmol) in acetone (1 mL) in the presence of water (50 ꢀL).
The suspension was allowed to react at 22°C for seven days, in
a similar fashion to the previouslyꢀreported experimental
procedure for a MOFꢀcatalyzed asymmetric aldol reaction.8,27
Then, after centrifugation, the solution was quenched with an
aqueous ammonium chloride solution, and the organic prodꢀ
ucts were extracted using diethyl ether. In parallel, the solid
catalyst was washed twice with diethyl ether. The organic
phases were combined, dried using magnesium sulfate and
analyzed by HPLC for the measurements of conversion and
enantiomeric excess (e.e.) (Supporting Information).
Results and discussion
Amino acid and dipeptide coupling in the MIL-101
framework. In the case of AlꢀMILꢀ101ꢀNH2, microwave
irradiation enables higher grafting yields in a much shorter
time for both proline and prolineꢀglycine compared to convenꢀ
tional heating in an oil bath (Table 1, entries 1 ꢀ 6). The pepꢀ
tide coupling proceeds 200 times more quickly with microꢀ
wave irradiation, for a higher ratio of functionalized ligands.
(Table 1, entries 2 and 5). It is noteworthy that under convenꢀ
tional heating at 80°C, no peptide coupling is detected after 20
minutes. This evidence rules out a simple thermal effect on
the effectiveness of peptide coupling,28 and shows the pivotal
role of microwave assistance in the synthetic procedure. Simiꢀ
larly, the stability of the parent AlꢀMILꢀ101ꢀNH2 under miꢀ
crowave irradiation is assessed by using dmfꢀd7 as solvent. 1H
NMR analysis of the supernatant after reaction shows that less
than 1.5 mol% of 2ꢀaminoterephthalate linker is released in the
solution under the harshest conditions (300 W, 150°C, 10
minutes). For comparison, when AlꢀMILꢀ101ꢀNH2 is placed at
150°C in dmfꢀd7 in an autoclave for 8 hours, conditions that
are close to those reported for deprotection with other MOFs,8ꢀ
Figure 1. Characterizations of AlꢀMILꢀ101ꢀNHꢀGlyꢀPro grafted
with 60% dipeptide. (A) Liquid H NMR spectrum of dissolved
1
MOF sample in HFꢀH2O/dmso d6. Unmodified BDCꢀNH2 and
functionalized linker are indicated by circles and squares, respecꢀ
tively. (B) Powder Xꢀray diffraction pattern of parent AlꢀMILꢀ
101ꢀNH2 compared to AlꢀMILꢀ101ꢀNHꢀGlyꢀPro. (C) N2 sorption
isotherms at 77 K for parent AlꢀMILꢀ101ꢀNH2 compared to Alꢀ
MILꢀ101ꢀNHꢀGlyꢀPro. Filled and open symbols correspond to
adsorption and desorption, respectively.
Table 1. Grafting yields in MOF-Pro and MOF-oligopeptide after coupling-deprotection sequences.[a] (More data can be
found in Supporting Information.)
entry
MOF starting platform
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
Amino acid or Peptide
HOꢀPro
Heating method [b] / T [°C] / time
CH / 37 / 96 h
Grafting yield [%][c]
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7
10
15
7
HOꢀPro
MW / 80 / 20 min
CH / 80 / 96 h
HOꢀPro
HOꢀGlyꢀPro
HOꢀGlyꢀPro
HOꢀGlyꢀPro
HOꢀGlyꢀGly
CH / 37 / 96 h
50
60
45
55
MW / 80 / 20 min
CH / 80 / 96 h
MW / 80 / 20 min
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AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
AlꢀMILꢀ101ꢀNH2
InꢀMILꢀ68ꢀNH2
InꢀMILꢀ68ꢀNH2
InꢀMILꢀ68ꢀNH2
InꢀMILꢀ68ꢀNH2
ZrꢀUiOꢀ66ꢀNH2
ZrꢀUiOꢀ66ꢀNH2
ZrꢀUiOꢀ66ꢀNH2
ZrꢀUiOꢀ66ꢀNH2
HOꢀGlyꢀGlyꢀGly
HOꢀSarꢀGlyꢀAla
HOꢀGlyꢀGlyꢀGlyꢀAla
HOꢀGlyꢀPheꢀGlyꢀGly
HOꢀPro
MW / 80 / 20 min
MW / 80 / 20 min
MW / 80 / 20 min
MW / 80 / 20 min
CH / 37 / 96 h
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18
< 5
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HOꢀPro
MW / 80 / 20 min
CH / 37 / 96 h
HOꢀGlyꢀPro
HOꢀGlyꢀPro
HOꢀPro
MW / 80 / 20 min
CH / 37 / 96 h
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< 2
10
< 2
< 2
HOꢀPro
MW / 80 / 20 min
CH / 37 / 96 h
HOꢀGlyꢀPro
HOꢀGlyꢀPro
MW / 80 / 20 min
[a] AminoꢀMOF (0.45 mmol ꢀNH2, MILꢀ101: 100 mg, MILꢀ68: 71 mg and UiOꢀ66: 76 mg), N-Bocꢀprotected amino acid (0.45 mmol),
coupling agent (0.45 mmol), aminated base (0.90 mmol), dichloromethane (5 mL) under described conditions, followed by deprotection in
dichloromethane at 150°C under 300 W microwave irradiation for 10 minutes. [b] CH = conventional heating, MW = microwave heating
(300 W). [c] Determined by liquid 1H NMR of the dissolved MOF sample.
The choice of solvent is also critical for the effectiveness of
the process (solvents such as nꢀhexane, dichloromethane, ethyl
acetate, acetonitrile, dmf and dmso were tested, see Table S1).
Although SPPS is usually performed in N,Nꢀ
dimethylformamide (dmf),29 the best solvent here is diꢀ
chloromethane, possibly because it combines the advantages
of a low dielectric constant, which is a key parameter in miꢀ
crowaveꢀassisted synthesis,30 and the ability to dissolve target
organic reactants.
Application to MIL-68 and UiO-66 frameworks. The
efficiency of microwave irradiation is also observed for the
Bocꢀprotected proline upon moving from the MILꢀ101 MOF
platform to InꢀMILꢀ68ꢀNH2: the same yields are observed
after 96 h of conventional heating or 20 minutes of microwave
irradiation. In the case of the larger dipeptide BocꢀProꢀGlyꢀ
OH, no grafting yield enhancement is observed using microꢀ
wave irradiation (Table 1, entries 12 – 15). This lack of graftꢀ
ing yield enhancement could be caused by the more stringent
diffusion limitation for this larger organic compound and
amplified by the very short reaction time under microwave
irradiation.
Regarding the coupling agent / aminated base combination,
both PyBrOP/DMAP and Mukaiyama agent/DIEA yield 15%
functionalization in the case of AlꢀMILꢀ101ꢀNHꢀPro synthesis
(see Table S1). In the case of AlꢀMILꢀ101ꢀNHꢀGlyꢀPro, the
Mukaiyama agent/DIEA combination gives the highest graftꢀ
ing yield (60%, Table 1, entry 5) of the various systems invesꢀ
tigated (see Table S1).
The benefits of microwave irradiation remain for both Proꢀ
and ProꢀGlyꢀfunctionalized MILꢀ68 systems during the deproꢀ
tection step. Indeed, as previously shown for MILꢀ101, chemiꢀ
cal removal using trifluoroacetic acid and conventional heatꢀ
ing at 110°C are detrimental to the integrity of the MILꢀ68
structure. Although InꢀMILꢀ68ꢀNH2 has been described as
thermally sensitive,23a the microwave heating nevertheless
allows thermal Boc removal from the functionalized MOF
without structure loss (Figure S14). The final InꢀMILꢀ68ꢀNHꢀ
Pro and InꢀMILꢀ68ꢀNHꢀGlyꢀPro are obtained after a microꢀ
waveꢀassisted deprotection step, with 10 and 15% yields,
respectively. The PXRD patterns of InꢀMILꢀ68ꢀNHꢀPro and
InꢀMILꢀ68ꢀNHꢀGlyꢀPro correspond to that of the parent Inꢀ
MILꢀ68ꢀNH2. The BET surface area decreases from 1200
m2·gꢀ1 for the starting aminoꢀMILꢀ68 to 850 and 800 m2·gꢀ1 for
the proline and glycineꢀproline MOFs, respectively.
Thermal Boc removal under conventional heating is detriꢀ
mental: heating the functionalized AlꢀMILꢀ101 samples at
110°C for 2 hours,8 either in dichloromethane (in a pressurized
vessel) or in dmf under conventional heating, leads to a loss of
grafted groups and to structural decomposition (Figure S2). In
contrast, under microwave irradiation, the grafting yield, poꢀ
rosity and crystallinity of the functionalized solids are preꢀ
served (Figure 1 and Supporting Information).
Indeed, the PXRD patterns of AlꢀMILꢀ101ꢀNHꢀPro and Alꢀ
MILꢀ101ꢀNHꢀGlyꢀPro correspond to that of the parent Alꢀ
MILꢀ101ꢀNH2 (Figures 1B and S14). Meanwhile, the BET
surface area decreases from 3000 m2·gꢀ1 for the starting amiꢀ
noꢀMILꢀ101 to 330 and 800 m2·gꢀ1 for the prolineꢀ and glyꢀ
cineꢀprolineꢀfunctionalized MOFs, respectively.
In the case of ZrꢀUiOꢀ66ꢀNH2, the proline coupling yield is
enhanced using microwave irradiation, reaching 10% for Zrꢀ
UiOꢀ66ꢀNHꢀPro (Table 1, entries 16 and 17). The PXRD
pattern of ZrꢀUiOꢀ66ꢀNHꢀPro, obtained after microwaveꢀ
assisted Boc removal, corresponds to that of the parent Zrꢀ
UiOꢀ66ꢀNH2. The BET surface area decreases from 552 m2·gꢀ1
for the starting ZrꢀUiOꢀ66ꢀNH2 to 355 m2·gꢀ1 for the prolineꢀ
functionalized MOF. No dipeptide coupling is achieved either
under conventional heating or with microwave assistance.
Most likely, the size of the UiOꢀ66 pore aperture is too small
to be able to accommodate the protected prolineꢀglycine diꢀ
peptide (Table 1, entries 18 and 19).
In summary, this optimized methodology is a fast and efficient
route to peptideꢀcontaining MILꢀ101 solids AlꢀMILꢀ101ꢀNHꢀ
Pro and AlꢀMILꢀ101ꢀNHꢀGlyꢀPro with loadings correspondꢀ
ing to 15 and 60 proline units per cavity, respectively, on a
100 mg scale, in less than one hour. It is worth noting that
higher grafting yields are obtained for glycineꢀproline than for
proline. We suggest that the glycine could act as a spacer by
increasing the distance between the bulky, rigid Bocꢀproline
and the MOF wall, limiting steric hindrance due to both the
Boc group and the curvature of the framework cavity.
Enantiopurity. In order to evaluate the enantiomeric purity
of the peptideꢀfunctionalized linker, we used liquid chromaꢀ
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tography to analyze two separate MOF samples obtained from
removal from DUTꢀ32ꢀProꢀBoc.9 The detailed study showed
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AlꢀMILꢀ101ꢀNH2 and either (D)ꢀProꢀGlyꢀOH or the (L)ꢀProꢀ
GlyꢀOH, respectively followed by digestion using 0.5 vol%
trifluoroacetic acid in water. The HPLC trace obtained for the
AlꢀMILꢀ101ꢀGlyꢀPro sample shows two peaks corresponding
to its ligands, i.e., 2ꢀaminoꢀterephthalic acid and 2ꢀ(2ꢀ
(pyrrolidineꢀ2ꢀcarboxamido)acetamido)terephthalic acid (Figꢀ
ure 2 and Supporting Information). The signals obtained for
the (D)ꢀProꢀGlyꢀ or the (L)ꢀProꢀGlyꢀfunctionalized MILꢀ101
are 2 minutes apart in retention time. In both chromatograms,
a peak is observed at 77 minutes; it corresponds to the nonꢀ
functionalized 2ꢀaminoterephthalic acid ligand. In the case of
AlꢀMILꢀ101ꢀNHꢀ(L)ꢀGlyꢀPro, an enantiomeric excess (e.e.) of
97% is found for the functionalized ligand by integrating the
peaks in the HPLC trace. With our methodology, the enantioꢀ
meric purity of the graft is almost fully preserved, in contrast
to the previouslyꢀdescribed prolineꢀfunctionalized MOF. Inꢀ
deed, Telfer et al. reported thermal Boc removal from
IRMOFꢀProꢀBoc.8 The latter was made by selfꢀassembly using
a preꢀfunctionalized linker containing Bocꢀproline moieties.
The full Boc removal was performed at 165°C for 4 hours
under microwave irradiation and led to an e.e. of 80% for the
functional ligand. More recently and using the same Bocꢀ
proline preꢀfunctionalized linker, Kaskel reported thermal Boc
an acceleration of the racemization of the organic linker in
solution by increasing the temperature from 100 to 140°C. In
the case of the functionalized DUTꢀ32 solid, a temperature of
170°C was required to achieve the Boc removal and led to the
complete racemization of the chiral proline graft (e.e. = 0).
Extension to grafting of polypeptides on MIL-101. In
order to assess the scope of our method, we performed peptide
coupling between AlꢀMILꢀ101ꢀNH2 and a different dipeptide
(BocꢀGlyꢀGlyꢀOH) or longer terminal NꢀBocꢀprotected triꢀ
and quadripeptides, namely Bocꢀ(Gly)3ꢀOH (NꢀBocꢀ
(glycine)3), BocꢀAlaꢀGlyꢀSarꢀOH (NꢀBocꢀalanineꢀglycineꢀ
sarcosine), BocꢀAlaꢀ(Gly)3ꢀOH (NꢀBocꢀalanineꢀ(glycine)3) and
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Bocꢀ(Gly)2ꢀPheꢀGlyꢀOH
glycine).
(NꢀBocꢀ(glycine)2ꢀphenylalanineꢀ
Under the best conditions established for glycineꢀproline,
these grafting trials proceed with yields from 17 to less than 5
% (Scheme 2 and Table 1, entries 7 – 11). Indeed, from dipepꢀ
tide to tripeptide, the grafting yield drops from 50ꢀ60% to
20%. In these cases, steric repulsion between the protected
peptide and the MOF walls cannot explain such a decrease,
because the glycine spacer is always present.
Figure 2. HPLC chromatograms of dissolved MOF samples in 0.5 vol% aqueous trifluoroacetic acid solution: AlꢀMILꢀ101ꢀNHꢀ(D)ꢀGlyꢀ
Pro (red trace) and AlꢀMILꢀ101ꢀNHꢀ(L)ꢀGlyꢀPro (blue trace).
Scheme 2. Grafting in the Al-MIL-101 material, from a single amino acid to quadripeptides.
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Large triꢀ and quadripeptides seem unable to diffuse inside the
is found to give the conditions most favorable for yield and
enantiomeric excess, which nevertheless plateaus at 35% e.e.
(Table 2).
MILꢀ101, a situation that could arise either from strong adꢀ
sorption of the peptides or from blocking at the pore windows.
Moving from (Gly)3 to (Gly)3ꢀAla does not seem to affect the
grafting yield and shows that functionalization is not limited
here by the size of the peptide. In contrast, the presence of
phenylalanine (Phe) in the last quadripeptide is detrimental to
grafting yield. Hindered diffusion in the pores, possible π−π
stacking of the phenylalanine residues, and peptide folding
and conformation could contribute to explaining the slightness
of this grafting.
MOF-catalyzed asymmetric aldol reaction. As proofꢀofꢀ
concept for the application of chiral peptide MOFs as asymꢀ
metric catalysts, we tested the prolineꢀfunctionalized solids in
the asymmetric aldol reaction between acetone and 4ꢀnitroꢀ
benzaldehyde, which has already been reported to be catalyzed
by homogeneous prolinamides (Scheme 3).
Since the native AlꢀMILꢀ101ꢀNH2 does not catalyze the aldol
reaction in contrast to InꢀMILꢀ68ꢀNH2 (Table S3) and since
the MILꢀ101 cavity is large enough to accommodate both the
anchored organocatalyst and the reactants, this platform was
chosen for our asymmetric aldol reaction studies.
As shown in Table 2, we found that, using 15 mol% of proline
moieties anchored in MILꢀ101 at room temperature in the
presence of water, AlꢀMILꢀ101ꢀNHꢀGlyꢀPro catalyzes the
reaction to give the aldol product 4ꢀhydroxyꢀ4ꢀ(4ꢀ
nitrophenyl)butanꢀ2ꢀone with 25% enantiomeric excess,
whereas AlꢀMILꢀ101ꢀNHꢀPro shows an enantiomeric excess
of 18%. The MOFꢀbased catalysis appears to occur at substanꢀ
tially lower rates than homogeneous catalysis: while almost
full conversion is observed in solution at room temperature, all
of the solid catalysts show a plateau at yields below 30% after
seven days (Table 2). The reaction performed at 45°C gives
almost full conversion but with a lower e.e. value (17%).
Using one equivalent of proline moiety in AlꢀMILꢀ101ꢀNHꢀ
GlyꢀPro compared to 4ꢀnitroꢀbenzaldehyde leads to 80% yield
with similar enantioselectivity (e.e. = 27%).
Scheme 3. Prolinamide-catalyzed asymmetric aldol reac-
tion.
Table 2. Observed yield and enantiomeric excess in the
asymmetric aldol reaction.[a]
This reaction requires the presence of a proton source, in this
case water, to proceed efficiently, as already reported for
homogeneous systems.31
Using (R)ꢀNꢀphenylpyrrolidineꢀ2ꢀcarboxamide31a as homogeꢀ
Yield [b]
[%]
E.e. [b]
[%]
Catalyst
Ref.
AlꢀMILꢀ101ꢀNH2
< 5
< 2
this work
neous catalyst, a solution containing acetone and 1 vol% water
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Supporting Information. Synthetic procedures, characterizaꢀ
tions and catalysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
AlꢀMILꢀ101ꢀNHꢀPro
18
26
80[c]
> 95[d]
> 95[c]
n.d.
18
25
27
17
29
0
this work
this work
this work
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7
AlꢀMILꢀ101ꢀNHꢀGlyꢀPro
AlꢀMILꢀ101ꢀNHꢀGlyꢀPro
AlꢀMILꢀ101ꢀNHꢀGlyꢀPro
IRMOFꢀPro
AUTHOR INFORMATION
this work
8
Corresponding Author
9
DUTꢀ32ꢀPro
* Jerome.canivet@ircelyon.univꢀlyon1.fr
Author Contributions
8
9
> 95
35
this work
The manuscript was written through contributions of all authors.
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[a] Reaction performed using 15 mol% of catalytic species (0.03
mmol of proline derivative either in MOF or as pure organic), pꢀ
nitroꢀbenzaldehyde (0.2 mmol), water (50 ꢀL) in acetone (5 mL)
at room temperature for seven days. [b] Determined by HPLC
using Chiralpak ASꢀH column. (n.d. = not determined). [c] Result
obtained using 100 mol% of proline moiety compared to 4ꢀ
nitrobenzaldehyde. [d] Reaction performed at 45°C.
ACKNOWLEDGMENT
The authors thank the ANR project HOPFAME (ANRꢀ13ꢀBS07ꢀ
0002ꢀ01) for funding and are very grateful to the IRCELYON
scientific services.
ABBREVIATIONS
Reverse nomenclature is used for isolated peptides and MOFꢀ
grafted peptides: for example ProꢀGlyꢀOH, in which the amino
acidꢀbearing terminal NH is the first listed, is grafted to give Alꢀ
MILꢀ101ꢀNHꢀGlyꢀPro, in which the amino acidꢀbearing terminal
NH becomes the last one listed. Pro = proline, Gly = glycine, Sar
= sarcosine, Ala = alanine, Phe = phenylalanine.
At the same time and very satisfactorily, the functionalized
MOF catalysts are proven to attain e.e. values close to those of
their homogeneous counterparts. A leaching test shows that no
active proline moieties are released in the solution during the
course of the reaction (Figure S22). The enantioselectivities
observed here with the postꢀfunctionalized MOFs are also
similar to that reported by Telfer using the selfꢀassembled
IRMOFꢀPro with 1 equivalent of proline supported in the
MOF compared to 4ꢀnitroꢀbenzaldehyde substrate (29% e.e.).8
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The catalytic activity of AlꢀMILꢀ101ꢀNHꢀGlyꢀPro is probably
limited by diffusion in the nanoporous structure. This result is
not surprising, as we can expect strong adsorption of pꢀnitroꢀ
benzaldehyde to the MOF through both hydrogen bonding and
πꢀπ interactions.32 This model asymmetric reaction further
confirms the absence of racemization, and thus the chiral
induction is maintained after postꢀsynthetic grafting using our
procedure.
The precise conformations of the grafted peptides, as well as
their alignment inside the cavity, are expected to affect the
catalytic performances. Given the high number of possible
confirmations for the isolated peptides as well as all the possiꢀ
ble interactions between the MOF and the peptides, a dedicatꢀ
ed study is currently ongoing to address this aspect.
Conclusion
In conclusion, we report herein a fast and easily applicable
method for grafting bioꢀderived chiral moieties inside MOF
cavities. With coupling conditions that are optimized in terms
of activator, base and solvent, and thanks to the use of microꢀ
wave irradiation, the anchoring inside the solid pores proceeds
with reasonable yields from a single amino acid to tetrapepꢀ
tides. It is noteworthy that following this new methodology,
no racemization of the peptide occurs during the graftingꢀ
deprotection process inside MOF cavities. This makes it posꢀ
sible to design a library of porous crystalline hybrid solids
with confined asymmetric active groups combining high chiral
graft density and diversity. This opens a new perspective for
the rapid development of MOFꢀbased liquidꢀphase chiral
applications such as asymmetric catalysis, chromatography
and sensing.
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Journal of the American Chemical Society
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ACS Paragon Plus Environment