Polymer-supported manganese porphyrin catalysts - Peptide-linker promoted chemoselectivity

Article abstract of DOI:10.1039/b502149a

Manganese porphyrin catalysts were tethered to polymer-supports via peptide linkers. The reactivity and chemoselectivity of the catalysts were assessed in the epoxidation of limonene. It was found that the inclusion of a peptide linker incorporating a donor heteroatom which could act as an axial ligand led to a supported manganese porphyrin catalyst with unprecedented selectivity and stability. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502149a

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A R T I C L E
Polymer-supported manganese porphyrin catalysts—peptide-linker
promoted chemoselectivity
Emilie Brule´,a King Kuok (Mimi) Hiib and Yolanda R. de Miguel*c
a Department of Chemistry, Organic Chemistry, Royal Institute of Technology, SE-10044,
Stockholm, Sweden
b Department of Chemistry, Imperial College London, South Kensington, UK SW7 2AZ.
E-mail: mimi.hii@imperial.ac.uk
c LABEIN Technological Centre, Calle Geldo, Edificio 700, Parque Tecnolo´gico de Bizkaia,
Derio, 48160, Bizkaia, Spain. E-mail: ydemiguel@labein.es; Fax: +34 94 607 3349
Received 11th February 2005, Accepted 5th April 2005
First published as an Advance Article on the web 18th April 2005
Manganese porphyrin catalysts were tethered to polymer-supports via peptide linkers. The reactivity and
chemoselectivity of the catalysts were assessed in the epoxidation of limonene. It was found that the inclusion of a
peptide linker incorporating a donor heteroatom which could act as an axial ligand led to a supported manganese
porphyrin catalyst with unprecedented selectivity and stability.
quences were tolerated under the oxidation reaction conditions.
Introduction
Limonene is commonly used10 to probe the steric hindrance of
metalloporphyrins and was therefore chosen as the substrate for
testing our new supported porphyrins. Their catalytic activity,
chemoselectivity and recyclability were assessed with respect to
the peptide chain length and constituent amino acid residues.
The reactive site of many hemeproteins comprises a metallopor-
phyrin coordinated by a proximal ligand in the form of an amino
acid residue in the protein scaffold, containing a sulfur, nitrogen
or oxygen donor group in its side chain, e.g. cysteine, histidine
or tyrosine residues are found in very different heme systems.
A significant body of work has demonstrated that the proximal
ligand controls the redox properties of the hemeproteins, thus
determining the types of oxidation they can perform.1 In the
emerging area of protein engineering, there are also several
reports on synthetic heme–peptide complexes with interesting
catalytic, electrochemical and optical properties.2–4
There have been several recent reports of polymer-supported
metalloporphyrins for the oxidation of olefins,5 including our
work on immobilised manganese porphyrin catalysts and their
catalytic activity in the epoxidation of a wide range of alkenes6a
and dienes.6b Many other studies on supported metallopor-
phyrins have also been published.7–9 In our own studies we
have highlighted distinct compatibility issues between the linker
and the activity and recyclability of the supported catalysts. In
particular, Wang-supported manganese porphyrins were found
to display a fairly high regioselectivity in the epoxidation of
limonene (2.7 : 1 in favour of the 1,2-regiomer). Reports by
others8 have also examined the chemoselective epoxidation of
limonene using immobilised manganese porphyrins, as well
as a zeolite-encapsulated ruthenium porphyrin. However, the
chemoselectivities were no higher than 3 : 1 for previously
reported supported manganese porphyrins.
Results and discussion
Utilising solid-phase synthesis, Wang–Ala–Fmoc and Wang–
Ile–Fmoc resins were functionalised with peptide linkers. Suc-
cessive deprotection and coupling with Fmoc-protected amino
acids were carried out using PyBOP–HOBt coupling reagents
(Scheme 1). The yield of each step of the coupling was calculated
by conducting the Fmoc test and the resultant functionalised
polymers were fully characterised by a combination of % N
analysis, single bead transmittance FTIR and gel-phase MAS–
NMR spectroscopy. A library of more than 100 supported
peptides was prepared in this way, but for the present study
the synthesis of three representative supported peptides 1–
3 is presented. They were chosen for their different spacer
chain lengths as well as for their different peptide sequences
containing amino acids with different functionalities (alkyl, N-
or S-containing amino acids).
Previously, the catalytic behaviour of a surface-bound man-
ganese porphyrin–peptide conjugate in the oxidation of a num-
ber of alkenes was studied in the presence of iodosylbenzene.9 It
was found that incorporation of a peptide led to different yields
and ratios of oxidised products, compared to control experi-
ments conducted with the analogue without the peptide. More
interestingly, substrate competition experiments showed that the
catalyst was able to discriminate between alkenes of different
sizes, demonstrating that the peptide chain was able to influence
the reactivity of the metalloporphyrin. These results prompted
us to speculate that peptide linkers may be able to promote the
selectivity of polymer-bound mangenese porphyrins in alkene
epoxidation reactions. Herein, the preparation of three polymer-
supported manganese porphyrins containing different peptide
linkers is described. These three different peptide linkers were
chosen in order to test whether the different amino acid se-
Scheme 1 Preparation of supported peptides: a) Wang resin, MSNT,
MeIm, DCM, rt, 3 h; b) (i) 20% piperidine, DMF, rt, 15 min, (ii)
Fmoc-protected amino acid, PyBOP, HOBt, DIPEA, DCM, DMF, rt,
3 h.
To maximise the interaction between the peptide chain and
the metal centre, the porphyrin ring is attached to the peptide
linker via the ortho-position of one of the peripheral phenyl
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 7 1 – 1 9 7 6
1 9 7 1
©

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groups. Hence, 2-(10,15,20-triphenyl-porphyrin-5-yl)-phenol 411
was initially subjected to an alkylation reaction with ethyl-
4-bromobutyrate, then hydrolysed to give the functionalised
porphyrin 6. Subsequent treatment with MnCl2 at reflux fur-
nished the manganese(III) porphyrin complex 7 (Scheme 2).
Finally, coupling of 7 with functionalised polymers 1–3 was
achieved by using PyBOP–HOBt as coupling reagents, furnish-
ing the corresponding manganese porphyrin–peptide conjugates
WANG–Ala–His–Leu–o-MnP (8), WANG–Ile–Ala–Leu–Pro–
Gly–o-MnP (9) and WANG–Ala–Cys–Leu–Val–Pro–Gly–o-
MnP (10) (Fig. 1). ICP–AES analysis of these dark coloured
beads showed the Mn loading percentage to be between 1.00–
1.93 mmol g−1.
Scheme 3 Regioselective epoxidation of (R)-limonene.
porphyrin 8 displayed an excellent chemoselectivity of 5 : 1 (entry
3), which is the best reported so far for supported metallopor-
phyrin systems. The lowest ratio of 2.8 : 1 (entry 6), obtained
with the pentapeptide–manganese porphyrin conjugate 9, was
comparable to that previously obtained with Wang supported
catalysts without peptide linkers.6 Catalyst 10, with the longest
peptide linker, appears to exhibit intermediate chemoselectivity
(3.7 : 1, entry 9), but both yield and selectivity reached a plateau
at 24 h. Notable also is the increase in chemoselectivity of catalyst
8, which increases as the reaction progresses between 24 and
36 hours (entries 2 and 3). This is an interesting divergence from
the steady chemoselectivity exhibited by the other two catalysts
between 24 and 36 hours. This perhaps suggests the operation
of competitive catalytic pathways with different selectivities
in this particular system. In fact, it is also possible that a
conformational change occurs as the reaction proceeds, leading
to a more sterically-demanding catalyst structure and therefore
to a higher chemoselectivity.
The relative rates of the catalytic turnovers were also mon-
itored (Fig. 2). As expected, fast initial conversions were
displayed by catalysts attached to longer peptide tethers, pre-
sumably due to greater catalyst mobility. However, there is
marked difference in the stability of the catalysts after 12 h.
Although catalyst 8 exhibited the slowest turnover it is the most
stable, continuing to exhibit turnovers beyond 36 h, compared
to catalysts 9 and 10, which reached optimal conversions after
10 h. As the stability is clearly not dependent on the length of the
peptide chain, we postulate that the robustness of catalyst 8 may
be due to the presence of the N-donor group afforded by the
histidine residue, which may act as a coordinating axial ligand
and thus stabilise the reactive manganese metal centre (Fig. 3).
The model also suggests that the epoxidation of the alkene will
occur on the site opposite to the axial ligand and away from any
chiral pocket that may be generated by the peptide chain. Hence,
it is perhaps unsurprising that the reactions proceeded with no
stereoselectivity, with de and ee values <3%.
Scheme 2 Preparation of manganese porphyrins with a flexible tether:
a) BrCH2CH2CH2CO2Et (3.75 eq.), K2CO3, KI, dry DMF, 60 ◦C, 89%;
b) (i) 1M aq. NaOH, THF, 48 h, rt, (ii) 10% w/w aq. AcOH; c) 20 eq.
MnCl2, dry DMF, 30 min, reflux; d) peptide 1, 2 or 3, PyBOP, HOBt,
DIPEA, CH2Cl2, DMF, 3 h, rt.
The activity, selectivity and recyclability of these polymer-
supported catalysts were subsequently examined in the epoxi-
dation of limonene, which has been previously shown10 to be
sensitive to steric effects (Scheme 3). Using previously estab-
lished catalytic assay conditions,6b the epoxidation of limonene
proceeded smoothly, generating the 1,2-limonene oxide 11 as the
major product. As a control experiment, it was checked that no
product was formed in the presence of a Wang supported peptide
without manganese porphyrin, nor with a metal-free porphyrin
as a catalyst. It has also been previously demonstrated6b that
Wang resin is stable during epoxidation reactions using sodium
periodate as an oxidant.
Good chemoselectivity was obtained with all three catalysts
8–10 (Table 1). Most encouragingly, the tripeptide–manganese
Fig. 1 Supported catalysts containing tri-, penta- and hexa-peptide linkers 8–10.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 7 1 – 1 9 7 6
1 9 7 2

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Table 1 Regioselective epoxidation of (R)-limonene catalysed by immobilised peptide–manganese porphyrin conjugates 8–10a
Entry
Catalyst
Time/h
Conversionb (%)
Yieldc 11 (%)
Yieldc 12 (%)
11 : 12
1
2
3
4
5
6
7
8
9
8
6
24
36
6
24
36
6
17
72
85
31
30
37
47
66
66
12
57
70
31
30
37
35
52
52
5
15
15
11
13
13
12
14
14
2.4 : 1
3.8 : 1
5 : 1
2.8 : 1
2.8 : 1
2.8 : 1
2.9 : 1
3.7 : 1
3.7 : 1
9
10
24
36
a Conditions: catalyst, imidazole, alkene, NaIO4 in a molar ratio of 1 : 10 : 23 : 46, CH3CN, H2O (2 : 1). b Determined by GC analysis and corresponds
to the percentage of starting material consumed. c GC yields with respect to starting material, yields were repeatable within 2%.
Furthermore, claims on the recyclability of the supported
catalysts “without significant loss of activity” were rarely backed
up by experimental data and the chemoselectivity of the recycled
catalysts was not discussed. In light of this, we examined
the reuse of the immobilised peptide–manganese porphyrin
conjugates 8, 9 and 10 in the epoxidation of limonene.
UV spectroscopic examination of the catalytic reaction mix-
ture showed the absence of any absorption peak due to free or
manganese porphyrins, which served as the first indication that
no leaching of the catalyst had occurred. This was confirmed
by % Mn analysis of the recovered beads, which showed that
there was no decrease of Mn content after recycling. The FT-IR
spectra of the recovered catalysts were found to be identical to
those of the freshly prepared samples.
Furthermore, the recovered polymer beads remained catalyt-
ically active in a second catalytic run (Fig. 4). With the tri- and
hexapeptide supported catalysts 8 and 10, similar conversions
were obtained over 24 h, despite a slightly slower reactivity of
the recycled catalyst during the initial 12 h. The chemoselectivity
was also identical to that obtained in the first catalytic run
(from the start of the reaction). In contrast, the pentapeptide
supported catalyst 9 was far less active, achieving only half the
conversion in the second catalytic run with a slight erosion in
the chemoselectivity (2.5 : 1).
Fig. 2 Rates of reaction catalysed by 8 (triangles), 9 (diamonds) and
10 (squares).
Conclusions
We have demonstrated that peptide linkers may be used as
effective tethers for manganese porphyrins to polymer-supports.
No catalyst leaching was observed and good chemoselectivity
was obtained (5 : 1) with the tripeptide conjugate catalyst 8.
There seemed to be a correlation between the peptide chain
length and the initial rates of reaction. However, the stability
of these catalysts appears to be far less dependent on the
chain length of the linker than on its constituent amino acid
residues. For example, the presence of a coordinating side chain
in the peptide linker of 8 (Fig. 3) is thought to lead to a
stabilised and sterically-demanding catalyst structure. It exhibits
good chemoselectivity as well as improved stability, which leads
to retained catalytic activity in a second run. Other peptide
Fig. 3 Stabilisation of the catalyst 8 by the peptide linker.
Recyclability
The recovery and reuse of immobilised catalysts is often
challenging since the catalyst may leach from the support
or degrade under the oxidative conditions, resulting in the
deactivation of the supported catalyst at the end of the first cycle
and preventing further reuse. Previously reported recyclability
studies of immobilised epoxidation catalysts were not always
successful.12
Fig. 4 Reaction progress for first (circle) and second (square) catalytic runs for catalysts 8 (left), 9 (middle) and 10 (right).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 7 1 – 1 9 7 6
1 9 7 3

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sequences in 9 and 10 gave poorer chemoselectivities, indicating
that the conformational structure of the peptide–porphyrin
catalyst is important. Future studies will focus on the systematic
variation of the peptide structure in order to prepare and screen
libraries of such olefin epoxidation catalysts.
WG–Ala–His(Trt)–Leu 1. Yield: 100%, calculated from
Fmoc test. mmax/cm−1 3362br (NH), 1720 (C O)ester, 1676
=
=
(C O)amide; dH (400 MHz, CDCl3) 8.45 (br s, NH His), 7.88
(br s, NH Ala), 4.95 (br s, NH2 Leu)), 4.71 (br s, H-a His), 4.54
(br s, H-a Ala), 3.42 (br s, H-a Leu), 3.01 (br s, H-b His), 1.45
(br s, H-c Leu), 1.35 (br s, H-b Ala, H-b Leu), 0.93 (br s, H-d
Leu).
Experimental
WG–Ile–Ala–Leu–Pro–Gly 2.
Materials
WG–Ile–Ala. Yield: 100%, calculated from Fmoc test.
Wang–Ala–Fmoc (1.1 mmol g−1) and WG–Ile–Fmoc
(0.8 mmol g−1) resins are 1% cross-linked with bead sizes
between 100–200 mesh and were purchased from Novabiochem.
Fmoc-protected peptides and the peptide coupling reagents
(MSNT, HOBt and PyBOP) were also purchased from Nov-
abiochem. Anhydrous DMF was bought from Aldrich and
dichloromethane was freshly distilled from CaH2 under nitro-
gen. MnCl2 was purchased from Aldrich with 99.999% purity
and supplied in ampoules, which were stored under nitrogen
after opening.
mmax/cm−1 3375 (NH), 1739 (C O)ester, 1679 (C O)amide; dH
(400 MHz, CDCl3) 7.84 (br s, NH Ile), 4.96 (br s, NH2 Ala),
4.62 (br s, H-a Ile), 3.53 (br s, H-a Ala), 1.96 (br s, H-b Ile), 1.42
(br s, H-cIle), 1.35 (br s, H-b Ala), 1.18 (br s, Hꢀ-cIle), 0.91 (br s,
H-d Ile).
=
=
WG–Ile–Ala–Leu. Yield: 93%, calculated from Fmoc test.
mmax/cm−1 3329br (NH), 1738 (C O)ester, 1670br (C O)amide; dH
(400 MHz, CDCl3) 7.85 (br s, NH Ile, NH Ala), 4. 97 (br s, NH2
Leu), 4.61 (br s, H-aIle, H-aAla), 3.40 (br s, H-aLeu), 1.95 (br s,
H-b Ile), 1.74 (br s, H-b Leu), 1.40 (br s, H-b Ala, H-c Ile, H-c
Leu), 1.19 (br s, Hꢀ-c Ile), 0.98–0.95 (br s, H-d Ile, H-d Leu).
WG–Ile–Ala–Leu–Pro. Yield: 94%, calculated from Fmoc
=
=
Instrumental methods
test. mmax/cm−1 3322br (NH), 1738 (C O)ester, 1671br (C O)amide
.
=
=
The semi-automated peptide synthesiser is a Quest 210 (Arg-
onaut Technologies) and contains twenty reactors with an
internal volume of 5 mL. It is combined with an automated
solvent wash unit. Single bead FT-IR spectra (transmittance)
were recorded on a Perkin Elmer Spectrum One spectrometer
with a beam-condensing accessory (BCA), using a diamond
compressor to flatten the bead. Gel-phase high resolution magic
angle spinning (HR-MAS) NMR spectra were recorded using
a Bruker AVANCE 400 spectrometer with special HR-MAS
probe and the resin was placed in a 4 mm rotor. GC-MS
spectra were recorded on a Varian Saturn 220 spectrometer
equipped with an autosampler. The carrier gas was helium and
the flow rate was 1 mL min−1. The chiral column used for the
asymmetric epoxidation reactions was a cyclodex-B column,
with an isothermal oven temperature of 100 ◦C. The Fmoc
test was performed to determine the yield of peptide coupling
reactions on the polymer-resin.
WG–Ile–Ala–Leu–Pro–Gly 2. Yield: 90%, calculated from
Fmoc test. mmax/cm−1 3313br (NH), 1736 (C O)ester, 1670br
=
=
(C O)amide
.
WG–Ala–Cys(Trt)–Leu–Val–Pro–Gly 3.
WG–Ala–Cys(Trt). Yield: 100%, calculated from Fmoc test.
mmax/cm−1 3382 (NH), 1721 (C O)ester, 1681 (C O)amide; dH
(400 MHz, CDCl3) 8.08 (br s, NH Ala), 4.96 (br s, NH2 Cys),
4.53 (br s, H-a Ala), 3.26 (br s, H-a Cys), 2.60 (br s, H-b Cys),
1.35 (br s, H-b Ala).
=
=
WG–Ala–Cys(Trt)–Leu. Yield: 100%, calculated from Fmoc
test. mmax/cm−1 3363br (NH), 1739 (C O)ester, 1672 (C O)amide
;
=
=
dH (400 MHz, CDCl3) 7.82 (br s, NH Ala), 7.66 (br s, NH Cys),
4.85 (br s, NH2 Leu), 4.59 (br s, H-a Ala), 4.06 (br s, H-a Cys),
3.36 (br s, H-a Leu), 2.60 (br s, H-b Cys), 1.69 (br s, H-c Leu),
1.49 (br s, H-b Leu), 1.35 (br s, H-b Ala), 0.94 (br s, H-d Leu).
WG–Ala–Cys(Trt)–Leu–Val. Yield: 100%, calculated from
Fmoc test. mmax/cm−1 3331br (NH), 1738 (C O)ester, 1674
(C O)amide; dH (400 MHz, CDCl3) 7.74 (br s, NH Ala, NH Cys,
NH Leu), 4.96 (br s, NH2 Val ), 4.60 (br s, H-a Ala), 4.43 (br s,
H-a Cys), 3.75 (br s, H-a Leu), 3.18 (br s, H-a Val ), 2.65 (br s,
H-b Cys), 2.29 (br s, H-b Val ), 1.67 (br s, H-c Leu), 1.46 (br s,
H-b Leu), 1.35 (br s, H-b Ala), 0.97 (br s, H-d Val ), 0.92 (br s,
H-d Val , H-d Leu).
=
General procedure for the synthesis of deprotected supported
peptides (manually or using the peptide semi-automated
synthesiser)
=
The appropriate N-deprotected WG–peptide (0.1 mmol) was
swollen in dry CH2Cl2 (10 mL) in a reaction flask under N2.
In another flask, the appropriate Fmoc-protected amino acid
(0.5 mmol), PyBOP (0.26 g, 0.5 mmol) and HOBt (0.067 g,
0.5 mmol) were dissolved in dry DMF (10 mL) under N2.
Anhydrous DIPEA (0.17 mL, 1 mmol) was then added to the
solution, which was stirred for a few minutes before it was
added to the resin. The mixture was stirred at rt for 3 h. The
resin was then filtered off and washed with acetone–CH3OH
(1 : 1) (3 mL × 5), acetone–CH3OH–H2O (1 : 1 : 1) (3 mL ×
5), acetone–CH3OH (1 : 1) (3 mL × 5), EtOAc (3 mL × 5),
CH2Cl2 (3 mL × 5) and HPLC-grade pentane (3 mL × 5). The
WG–Ala–Cys(Trt)–Leu–Val–Pro. Yield: 100%, calculated
from Fmoc test. mmax/cm−1 3330br (NH), 1740 (C O)ester, 1673br
=
=
(C O)amide
.
WG–Ala–Cys(Trt)–Leu–Val–Pro–Gly 3. Yield: 100%, calcu-
lated from Fmoc test. mmax/cm−1 3313br (NH), 1740 (C O)ester
,
=
=
1673br (C O)amide; dH (400 MHz, CDCl3) 7.47 (br s, NH Ala,
NH Cys, NH Leu, NH Val ), 4.94 (br s, NH2 Gly), 4.65 (br s, H-a
Leu), 4.52 (br s, H-a Ala, H-a Cys, H-a Val , H-a Pro), 3.75 (br s,
H-a Gly), 3.45 (br s, H-d Pro), 2.65 (br s, H-b Cys), 2.21 (br s,
H-b Val , H-b Pro), 1.59 (br s, H-c Leu, H-c Pro), 1.46 (br s, H-b
Leu), 1.35 (br s, H-b Ala), 0.92 (br s, H-d Val , H-d Leu).
◦
resin was dried in a vacuum oven for 3 h at 60 C. Fmoc test
or N-percentage analysis were used to determine the yield of
attachment of the amino acid. The deprotection of the Fmoc
group was performed by stirring the dried beads (0.36 g) in a
solution of 20% piperidine in DMF (5 mL) for 15 min. The resin
was then washed with CH2Cl2 and HPLC-grade pentane and
dried in a vacuum oven for 3 h at 60 ◦C.
4-[2-(10,15,20-Triphenyl-porphyrin-5-yl)-phenoxy]-butyric acid
ethyl ester 5. A mixture of 2-(10,15,20-triphenyl-porphyrin-5-
yl)-phenol 4 (0.1 g, 0.16 mmol), ethyl-4-bromobutyrate (74 ll,
0.52 mmol), anhydrous K2CO3 (0.1 g, 0.74 mmol) and a catalytic
amount of KI (50 mg, 0.3 mmol) was stirred in dry DMF (5 mL)
under N2 for 20 h at 60 ◦C. The mixture was then poured
into 24 mL of a H2O–CH3OH solution (5 : 1). The purple
precipitate formed was filtered and washed with a H2O–CH3OH
solution. The solid was purified by column chromatography
(silica gel, CHCl3–hexane 8 : 2). The first fraction corresponded
to the desired porphyrin ester as a purple solid and the second
WG–Ala–His(Trt)–Leu 1.
WG–Ala–His(Trt). Yield: 95%, calculated from Fmoc test.
mmax/cm−1 3377 (NH), 1718 (C O)ester, 1679 (C O)amide; dH
(400 MHz, CDCl3) 7.52 (br s, NH Ala), 4.97 (br s, NH2 His),
4.60 (br s, H-a Ala), 3.67 (br s, H-a His), 2.99 (br s, H-b His),
1.35 (br s, H-b Ala).
=
=
1 9 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 9 7 1 – 1 9 7 6

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fraction contained unreacted 2-(10,15,20-triphenyl-porphyrin-
5-yl)-phenol 4. Yield: 0.1 g, (0.14 mmol, 89%). Rf = 0.59
(CHCl3–hexane 8 :2 ); mp >220 ◦C; kmax(CH2Cl2)/nm 419 (e/L
mol−1cm−1 185 029), 514 (8089), 549 (2652), 589 (1893), 646
General procedure for the synthesis of supported
peptide-metalloporphyrin conjugates
The appropriate deprotected Wang supported peptide (1 mmol)
was swollen in dry CH2Cl2 (20 mL) under N2. In a separate
flask under N2, manganese(III) chloride 4-[2-(10,15,20-triphenyl-
porphyrin-5-yl)-phenoxy]-butyric acid 7 (3 mmol), PyBOP
(0.78 g, 3 mmol) and HOBt (0.2 g, 3 mmol) were dissolved
in anhydrous DMF (20 mL) under N2. Anhydrous DIPEA
(0.52 mL, 6 mmol) was then added to this solution, which was
stirred for a few minutes before addition to the resin. The mixture
was then stirred at rt for 3 h. The resin was filtered and washed
with acetone (3 mL × 5), acetone–H2O (1 : 1) (3 mL × 5),
acetone (3 mL × 5), EtOAc (3 mL × 5), CH2Cl2 (3 mL × 5)
and HPLC-grade pentane (3 mL × 5). The resin was dried in a
vacuum oven for 3 h at 60 ◦C.
(1492); mmax(CCl4 solution)/cm−1 3319 (NH), 1734 (C O); dH
=
(360 MHz, CDCl3) 8.86–8.82 (8H, m, H7, H8), 8.28–8.20 (6H,
ꢀ
m, H2 –Ph), 8.06 (1H, dd, J 7.3 and 1.6, H6–Ar), 7.80–7.71 (10H,
ꢀ
ꢀ
m, H4 –Ph, H3 –Ph, H4–Ar), 7.38 (1H, t, J 7.3 Hz, H5–Ar), 7.34
(1H, d, J 7.4, H3–Ar), 3.96 (2H, s br, OCH2CH2), 3.63 (2H,
q, J 7.1, OCH2CH3), 1.34 (4H, s br, CH2CO, CH2CH2CH2),
0.78 (3H, t, J 7.1, CH3), −2.72 (2H, s, NH); dC (90.5 MHz,
=
ꢀ
CDCl3) 173.2 (C O), 159.0 (C2–Ar), 142.7 (C1 –Ph, C1–Ar),
ꢀ
136.1 (C6–Ar), 135.0 (C2 –Ph), 133.0–131.0 (multiple broadened
ꢀ
and weak signals C7, C8), 130.3 (C4–Ar), 128.0 (C4 –Ph), 127.0
ꢀ
(C3 –Ph), 120.6 (C10), 120.4 (C5), 120.1 (C5–Ar), 116.7 (C3–
Ar), 67.5 (OCH2CH2), 61.1 (OCH2CH3), 23.0 (CH2CO), 24.2
(CH2CH2CH2), 14.2 (CH3); m/z (ES) 745 ([MH]+, 92%), 279
(8), 147 (15), 100 (28), 64 (100); HRMS (ES): exact mass calcd
for C50H40N4O3: 745.3173, found: 745.3185.
WG–Ala–Cys–(Trt)–Leu–o-MnP 8. Yield: 100%, Mn 1.00%.
mmax/cm−1 3396 (NH), 1720 (C O)ester, 1675 (C O)amide
.
=
=
WG–Ile–Ala–Leu–Pro–Gly–o-MnP 9. Yield: 88%, Mn 1.53%.
mmax/cm−1 3324br (NH), 1740 (C O)ester, 1665br (C O)amide
.
=
=
4-[2-(10,15,20-Triphenyl-porphyrin-5-yl)-phenoxy]-butyric acid
6. A solution of aqueous NaOH (60 mL, 1 M) was added to
a solution of 4-[2-(10,15,20-triphenyl-porphyrin-5-yl)-phenoxy]-
butyric acid ethyl ester 2 (0.15 g, 0.2 mmol) in THF (50 mL) at
rt. The mixture was stirred for 2 days at rt. A solution of acetic
acid–H2O (1 : 9) (ca. 50 mL) was then added to the reaction
mixture until pH = 7 was reached (pH paper). The reaction
mixture was then extracted with chloroform (3 × 50 mL).
The organic extracts were washed with a saturated NaHCO3
solution (2 × 30 mL), H2O (2 × 30 mL), dried (MgSO4), filtered
and evaporated to yield a purple solid. A minimum amount of
CH3OH was added to the flask containing the solid, which was
filtered off and washed with a small amount of CH3OH. The
purple solid was then dried under a vacuum. Yield: 0.12 g,
(0.16 mmol, 82%); mp >220 ◦C; kmax(CH2Cl2)/nm 418 (e/L
mol−1cm−1 153 078), 515 (8647), 550 (3088), 590 (2229), 646
(1719); mmax(CCl4 solution)/cm−1 3313 (NH), 2956 (OH), 1717
WG–Ala–Cys(Trt)–Leu–Val–Pro–Gly–o-MPn 10. Yield:
100%, Mn 1.93%. mmax/cm−1 3388br (NH), 1721 (C O)ester
,
=
=
1662br (C O)amide
.
General procedure for epoxidation
In a round-bottomed flask or in a Radley’s carousel reaction
tube, the appropriate catalyst (0.01 mmol), alkene (0.23 mmol)
and axial ligand (0.1 mmol) were stirred in CH3CN (3.7 mL) at
rt. In a separate flask, NaIO4 (0.46 mmol) was dissolved in H2O
(1.85 mL). This aq. solution of NaIO4 was added to the catalytic
mixture. The progress of the reaction was monitored by taking
aliquots of the solution at regular intervals via syringe and they
were analysed by GC-MS. The yields of epoxides were based on
the starting material and the precentage conversion corresponds
to the starting material consumed.
=
(C O); dH (360 MHz, CDCl3–CD3OD 3 : 1) 8.75–8.70 (8H,
Test for catalyst leaching
ꢀ
m, H7, H8), 8.15–8.08 (6H, m, H2 –Ph), 7.98 (1H, dd, J 7.3
ꢀ
ꢀ
and 1.6, H6–Ar), 7.68–7.64 (10H, m, H4 –Ph, H3 –Ph, H4–Ar),
7.29 (1H, t, J 7.3, H5–Ar), 7.20 (1H, m, H3–Ar), 3.83 (2H, t, J
5.3, OCH2CH2), 1.18–1.15 (4H, m, CH2CO, CH2CH2CH2); dC
(90.5 MHz, CDCl3–CD3OD 3 : 1) 177.8 (C O), 158.9 (C2–Ar),
142.6 (C1 –Ph, C1–Ar), 136.0 (C6–Ar), 135.9 (C2 –Ph), 133.0–
131.0 (multiple broadened and weak signals C7, C8), 130.3
(C4–Ar, C4 –Ph), 127.0 (C3 –Ph), 120.5 (C10), 120.4 (C5), 120.1
(C5–Ar), 116.5 (C3–Ar), 67.3 (OCH2CH2), 29.5 (CH2CO), 23.9
(CH2CH2CH2); m/z (ES) 717 ([MH]+, 100%), 142 (13), 121
(10), 149 (12), 64 (100); HRMS (ES): exact mass calcd for
C48H37N4O3: 717.2860, found: 717.2860.
In order to determine if catalyst leaching occurred, the solution
of the epoxidation reaction was extracted with CH2Cl2, washed
with water, dried over Na2SO4 and evaporated. A small amount
of the residue obtained was dissolved in dichloromethane and
analysed by UV spectroscopy. In case of leaching, a peak
corresponding to manganese(III) porphyrin would be visible at
k = 480 nm.
=
ꢀ
ꢀ
ꢀ
ꢀ
General procedure for the recovery and reuse of the catalyst
At the end of the epoxidation, the polymer-supported catalyst
was collected via a filter syringe. The catalyst beads in the syringe
were washed with water, CH2Cl2 and HPLC-grade pentane and
then dried under a vacuum at 50 ◦C for 2 h. The recovered
catalyst was then used for a second cycle of the epoxidation
reaction as described above.
Manganese(III) chloride 4-[2-(10,15,20-triphenyl-porphyrin-5-
yl)-phenoxy]-butyric acid 7. 4-[2-(10,15,20-Triphenyl-porphy-
rin-5-yl)-phenoxy]-butyric acid 6 (0.15 g, 0.2 mmol) was dis-
solved in anhydrous DMF (20 mL) under N2. The purple
solution was heated at reflux for 10 min before the addition of
solid MnCl2 (0.5 g, 4 mmol). The purple solution became green
after a few min and the progress of the reaction was monitored
by the disappearance of the UV absorption peak at 420 nm. At
the end of the reaction (about 30 min), the reaction mixture was
cooled in an ice bath and cold water (30 mL) was added until
a green precipitate appeared. The solid was filtered off, washed
with H2O and dried under a vacuum to yield the manganese
porphyrin. Yield: 0.13 g, (0.158 mmol, 79%); mp >220 ◦C;
kmax(CH2Cl2)/nm 345 (e/L mol−1cm−1 13 731), 380 (17 828),
402 (16 017), 478 (28 594), 580 (3056), 615 (2651); mmax(CHCl3
Acknowledgements
The authors thank King’s College London for studentship
support (to E. B.) and The Royal Society for a Dorothy Hodgkin
Fellowship (to Y. d. M.) and for an Instrumentation Grant for
the procurement of the QUEST210 reaction station.
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