Efficient asymmetric epoxidation of α,β-unsaturated ketones using a soluble triblock polyethylene glycol-polyamino acid catalyst

Article abstract of DOI:10.1021/ol007005l

Equation presented Polyethlene glycol (PEG)-bound poly-L-leucine acts as a THF-soluble catalyst for the Julia-Colonna asymmetric epoxidation of enones. Excellent enantioselectivities may be obtained even with short chain length polyleucine. FT-IR investigations have determined that the catalytically active polyleucine components of these copolymers have an α-helical structure.

Full text of DOI:10.1021/ol007005l

ORGANIC
LETTERS
2001
Vol. 3, No. 5
683-686
Efficient Asymmetric Epoxidation of
r,â-Unsaturated Ketones Using a
Soluble Triblock Polyethylene
Glycol−Polyamino Acid Catalyst
Robert W. Flood, Thomas P. Geller, Sarah A. Petty, Stanley M. Roberts,*
John Skidmore, and Martin Volk
Department of Chemistry, UniVersity of LiVerpool, LiVerpool L69 7ZD, UK
sj11@liVerpool.ac.uk
Received December 15, 2000
ABSTRACT
Polyethylene glycol (PEG)-bound poly-L-leucine acts as a THF-soluble catalyst for the Julia´−Colonna asymmetric epoxidation of enones. Excellent
enantioselectivities may be obtained even with short chain length polyleucine. FT-IR investigations have determined that the catalytically
active polyleucine components of these copolymers have an r-helical structure.
The polyamino acid catalyzed asymmetric epoxidation of
R,â-unsaturated ketones was discovered1 and developed2 by
Julia´ and Colonna. Modifications to the original protocol
have been reported which allow the epoxidation of a wide
range of substrates.3
The polyamino acid remains insoluble under all the
reaction conditions reported thus far. Immobilization of the
polyamino acid on silica provides the optimum heterogeneous
catalyst in terms of efficiency, stability, and ease of
recycling.4
In this paper, we report the preparation, conformational
analysis, and synthetic use of the first soluble version of the
Julia´-Colonna catalyst, thus adding a new example to the
armory of “liquid phase” synthetic technology.5
Poly-L-leucine, for synthetic applications, is normally
prepared from the N-carboxyanhydride of L-leucine (L-Leu
NCA) by adding a nucleophilic initiator to effect polymer-
ization. Using standard initiators such as benzylamine, 1,3-
diaminopropane, or cross-linked aminomethyl polystyrene,6
the polyamino acid obtained is insoluble in water and organic
solvents. We reasoned that if the chosen initiator is an
appropriate organic solvent-soluble polymer, the resulting
(1) Julia´, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980,
19, 929-931.
(2) (a) Julia´, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.; Annuziata,
R.; Molinari, H. J. Chem. Soc., Perkin Trans. 1 1982, 1317-1324. (b)
Colonna, S.; Molinari, H.; Banfi, S.; Julia´, S.; Masana, J.; Alvarez, A.
Tetrahedron 1983, 39, 1635-1641.
(3) (a) Bentley, P. A.; Bergeron, S.; Cappi, M. W.; Hibbs, D. E.;
Hursthouse, M. B.; Nugent, T. C.; Pulido, R.; Roberts, S. M.; Wu, L. E.
Chem. Commun. 1997, 739-740. (b) Allen, J. V.; Drauz, K.-H.; Flood, R.
W.; Roberts, S. M.; Skidmore, J. Tetrahedron Lett. 1999, 40, 5417-5420.
(4) (a) Geller, T. P.; Roberts, S. M.; J. Chem. Soc., Perkin Trans. 1 1999,
1397-1398. (b) Carde, L.; Davies, H.; Geller, T. P.; Roberts, S. M.;
Tetrahedron. Lett. 1999, 40, 5421-5424.
(5) (a) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-509. (b)
Wentworth, P.; Janda, K. D. Chem. Commun. 1999, 1917-1924. (c) Toy,
P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546-554.
(6) Itsuno, S.; Sakakura, M.; Ito, K. J. Org. Chem. 1990, 55, 6047-
6049.
10.1021/ol007005l CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

copolymeric catalyst might also be soluble in the same
organic solvents.7 The initiator chosen for this work was the
commercially available O,O′-bis(2-aminoethyl)polyethylene
glycol (diaminoPEG) of average molecular weight 3350,
which is a conveniently handled solid at room temperature.
DiaminoPEG was preferred to PEG as an initiator because
the amide linkage formed to the polypeptide should be stable
under the basic epoxidation conditions.
Table 1. Epoxidation of Chalcone (5) with Soluble Polyleucine
Catalysts
catalyst
1
2
3
4
time
(h)
ca
ee
ca
ee
ca
ee
ca
ee
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
Interestingly, such diaminoPEG/polyleucine copolymers
have been constructed before7 and studied in connection with
their potential use as wound dressings.8 Soluble polypeptides
rich in L-leucine residues have also been prepared by the
strategic placement of aminoisobutyric acid (Aib) residues
within the peptide chains. These polymers have been tested
for activity in Julia´-Colonna epoxidations.9
1
24
39
80
97
98
39
80
97
97
36
63
98
95
34
58
97
96
a c ) conversion.
the insoluble peroxide carrier by filtration, rendering the
reaction homogeneous.12
A series of copolymers 1-4 was prepared by polymeri-
zation of L-Leu NCA in THF using PEG:NCA ratios of 1:10
(1), 1:20 (2), 1:30 (3), and 1:40 (4). After polymerization,
addition of diethyl ether caused precipitation of a white solid
which was collected, washed with ether, and filtered10 to give
the THF-soluble triblock copolymers H(L-Leu)YNHCH2-
CH2(OCH2CH2)XNH(L-Leu)YH. The aVerage chain lengths
of polypeptide on diaminoPEG (Y) for the copolymers 1-4
were determined by microanalysis on the basis of the known
value for the average chain length of the diaminoPEG (X )
71):11
Remarkably, the catalysts 1 and 2, containing smaller
quantities of polypeptide, were efficient catalytic agents, the
conversion of 5 to 6 being greater than for catalysts 3 and 4
(for the same amount of soluble polymer). This increased
catalytic activity may reflect the greater number of amino
termini present for the lower molecular weight materials,
since the catalysts contained the same weight of polyamino
acid in each experiment. This provides further evidence that
the region adjacent to the N-terminus is responsible for
catalytic activity and stereocontrol in the Julia´-Colonna
epoxidation.13
The catalytic activity of the copolymers containing short
polyamino acid chains compares very favorably with in-
soluble short chain poly-L-leucines prepared using a peptide
synthesizer. Thus, for comparison, a series of oligoleucines
H(L-Leu)X-R (X-mers) was constructed14 and used to epoxi-
dize chalcone (5) under biphasic conditions15 (comparable
to the homogeneous conditions used for the soluble polymers
above).
For example, the 6-mer gave epoxychalcone 6 with an ee
of only 8% after 1.5 h at which point the conversion was
33%. Even the 18-mer only gave epoxide with an ee of 77%
(also after 1.5 h, conversion 34%). For intermediate chain
lengths, the ee ranged smoothly between these limits and
the extent of conversion after 1.5 h never exceeded 40%.
Even accounting for the slightly different16 ratios of
polyamino acid:chalcone involved in these experiments, the
difference in stereoselectivity between the soluble and
insoluble catalysts is clear. For a direct comparison, some
of the soluble catalysts were tested for the epoxidation of
1: H(L-Leu)3.9NHCH2CH2(OCH2CH2)71NH(L-Leu)3.9H
2: H(L-Leu)7.5NHCH2CH2(OCH2CH2)71NH(L-Leu)7.5H
3: H(L-Leu)11.6NHCH2CH2(OCH2CH2)71NH(L-Leu)11.6
H
H
4: H(L-Leu)12.2NHCH2CH2(OCH2CH2)71NH(L-Leu)12.2
Each of the catalysts 1-4 was tested for the epoxidation
of chalcone (5) (Scheme 1), and the extent of conversion to,
Scheme 1
and the enantiomeric excess of, epoxychalcone 6 was
determined by chiral HPLC (Table 1). The reaction condi-
tions involved prestirring the oxidant (urea-H2O2) in THF
for 20 min to generate a solution of H2O2 and then removing
(12) Typical procedure: urea-H2O2 (0.5 g) was stirred in THF (49.5
mL) and DBU (0.5 mL) under N2 at rt for 20 min. The solution was filtered,
and 1.7 mL of the filtrate was added to a vial containing copolymer including
polyleucine (17 mg) and chalcone (17 mg). A second aliquot of oxidant
and base in THF (1.7 mL) was added after 4 h.
(13) Bentley, P. A.; Cappi, M. W.; Flood, R. W.; Roberts, S. M.; Smith,
J. A. Tetrahedron Lett. 1998, 38, 9297-9300.
(14) R refers to the solid support, see Supporting Information.
(15) Biphasic conditions: To a stirred solution of chalcone (1) (50 mg)
in dry THF (1.5 mL) at rt was added polyleucine (100 mg). Urea-H2O2
(28 mg, 1.2 equiv) and DBU (56 µL, 1.5 equiv) were added. After 30, 90,
and 150 min the same quantities of urea-H2O2 and DBU were added.
(16) By mass the PLL:chalcone ratio varied from ca. 1:5 (for the 6-mer)
to 1:2 (for the 18-mer) and was always 1:1 in the experiments with the
soluble polymer. More importantly, the ratio (number of polypeptide chains):
chalcone was not varied significantly using this protocol.
(7) Kricheldorf, H. R.; Mu¨ller, D. Int. J. Biol. Macromol. 1983, 5, 171-
178.
(8) Kim, H.-J.; Choi, E.-Y.; Oh, J.-S.; Lee, H.-C.; Park, S.-S.; Cho, C.-
S. Biomaterials 2000, 21, 131-141.
(9) Takagi, R.; Shiraki, A.; Manabe, T.; Kojima, S.; Ohkata, K. Chem.
Lett. 2000, 366-367.
(10) Some THF insoluble product was present. As this was also shown
to be a good catalyst for asymmetric epoxidation presumably it arose from
polymerization of the L-leucine NCA by adventitious water.
(11) Determined by the % N in the copolymers. The amino-PEG is
assumed to be fully bifunctionalized. Obviously, the polyleucine units on
each end of the copolymers are not necessarily the same length.
684
Org. Lett., Vol. 3, No. 5, 2001

chalcone (5) under the standard biphasic conditions, in which
the peroxide carrier is not separated by filtration. After 30
min the conversion was at least 50% and the enantioselec-
tivities remained high; for example, catalyst 1 gave a 57%
conversion to epoxychalcone 6 (93% ee). For catalyst 3, the
corresponding figures were 70% conversion and 95% ee, and
for catalyst 4, 94% conversion and 97% ee were observed
after this time.
To test just how short the average polypeptide unit can
be while still maintaining catalytic activity, another soluble
polymer was prepared with a different initiator:L-Leu NCA
ratio. The structure of the resulting polymer (7) was
determined, by microanalysis, to be H(L-Leu)1.8NHCH2-
CH2(OCH2CH2)71NH(L-Leu)1.8H. This proved too short a
chain length for good enantioselectivity to be obtained in
the epoxidation reaction, with chalcone epoxide 6 being
generated with an ee of only 5% when material 7 was used
as the catalyst.17
Julia´ and Colonna have speculated that the R-helical
structure of catalysts such as polyleucine and polyalanine is
a necessary requirement for their activity.2b The newly
prepared soluble polyamino acids provided an opportunity
to investigate the relationship between length, conformation,
and activity.
Figure 1. FTIR spectra of catalysts 2-4 and 7 (solid lines, different
chain lengths as indicated in figure) and compounds 8 (dashed line)
and 9 (dotted line) in the amide I region. For better comparability,
the spectra have been normalized to the same total absorbance (area
under the spectrum).
It was found that all the spectra can be reproduced
simultaneously with a minimum of five Lorentzians. Rep-
resentative deconvoluted spectra are shown (Figure 2), and
the fit results are summarized (Table 2).
Consequently, the conformations of the PEG-bound poly-
leucines were investigated by FTIR spectroscopy.18 The
frequency of the amide I band of peptides and proteins is
known to be a sensitive indicator of secondary structure.19
Two reference compounds (8 and 9) were prepared by
stepwise addition of leucine residues to diaminoPEG:20
8: H(L-Leu)NHCH2CH2(OCH2CH2)71NH(L-Leu)H
9: H(L-Leu)2NHCH2CH2(OCH2CH2)71NH(L-Leu)2H
The FTIR spectra of the polyamino acids 2-4 and 7 show
distinct differences to those for 8 and 9 (Figure 1). Whereas
the short oligoleucines (8 and 9) have a broad absorbance,
centered near 1657 cm-1, the longer chain catalysts (2-4)
are characterized by a narrow band with a maximum around
1652 cm-1. Clearly, the amide I band of the shortest
polyamino acid prepared by NCA polymerization (7) is a
composite of these two features.
For a more quantitative analysis, the spectra were fitted
to a number of Lorentzian bands in a global fit procedure.21
(17) This ee was obtained under a different set of homogeneous
conditions involving an anhydrous solution of H2O2 in a mixture of TBME
and THF. Catalysts 1-4 gave significantly higher ees of epoxide 6 when
tested under this protocol.
(18) FTIR measurements were made using samples dissolved in chlo-
roform (10-50 mg/mL) and a 150 µm path length cell with CaF2 windows.
FTIR spectra were measured with a Bio-Rad FTS-40 spectrometer,
averaging over 1000 scans at a resolution of 2 cm-1 and subtracting any
residual water vapor lines.
(19) (a) Arrondo, J. L. R.; Muga, A.; Castresana, J.; Gon˜i, F. M. Prog.
Biophys. Mol. Biol. 1993, 59, 23-56. (b) Krimm, S.; Bandekar, J. AdV.
Protein Chem. 1986, 38, 181-364. (c) Surewicz, W. K.; Mantsch, H. H.;
Chapman, D. Biochemistry 1993, 32, 389-394.
(20) Compounds 8 and 9 show no catalytic activity, but were prepared
to provide short reference polyleucine samples unable to form a well-defined
secondary structure, in particular unable to form an R-helix. Their
preparation is given in the Supporting Information.
Figure 2. FTIR spectra of catalysts 4 (A) and 7 (B) in the amide
I region, showing the deconvolution into separate Lorentzian bands
(dotted and dashed lines, with the dashed line indicating the broad
band centered at 1657.3 cm-1, which dominates the amide I band
of compounds 8 and 9), as obtained from the global fit of all data
(Table 2).
Org. Lett., Vol. 3, No. 5, 2001
685

interpreted as two distinct bands but as representing a
distribution of bands, which are too close to be resolved,
reflecting the distribution of peptides of differing lengths in
the samples. Upon increasing the average chain length, the
center of this distribution shifts from 1654 to 1650 cm-1
(see Table 2). This corresponds to the shift of the R-helix
amide I frequency toward smaller values with growing chain
length, which has been predicted on theoretical grounds24
and observed for helical peptides in aqueous solution.25 These
results indicate that polyleucine chains attached to diamino-
PEG predominantly adopt an R-helical structure in organic
solvents,26 provided the chain length exceeds the minimum
number of residues required for forming one helical turn.27
This minimum number here is four residues, assuming that
the first helical hydrogen bond is formed from the N-terminal
residue carbonyl to the amide group of PEG. Chains shorter
than this minimum length, on the other hand, form a
disordered structure.
Table 2. Results of a Global Fit of the FTIR Spectra of the
Polymers 2-4 and 7-9 in the Amide I Regiona
band center, width (cm-1
)
chain 1638.6, 1649.8, 1654.7, 1657.3, 1678.5,
polymer length
20.5
12.0
14.8
38.5
22.8
8
9
7
2
3
4
1b
0.5
5.2
8.8
3.0
7.6
6.0
89.3
90.7
46.0
27.5
19.5
13.1
10.2
2.8
6.1
3.3
1.5
0.5
2b
1.3
9.0
31.3
36.7
46.9
1.8c
7.5c
11.6c
12.2c
30.1
34.9
34.6
33.4
a Shown are the center frequencies and widths of the five Lorentzian
bands needed to obtain a satisfactory simultaneous fit of all spectra and the
relative contributions of these bands to the total absorbance of each sample
(in %) (as determined by the area under each band). b Exact length of
polypeptide chain on each end of PEG. c Average length of polypeptide
chain on each end of PEG.
Acknowledgment. The authors thank the EPSRC for
funding (R.W.F. and J.S.) and Dr. John Smith (School of
Biological Sciences, University of Liverpool) for supplying
the fixed length solid-supported oligopeptides.
Compounds 8 and 9, with only one or two leucines coupled
to diaminoPEG, are unable to form significant secondary
structure, and their FTIR spectra are dominated by one broad
band at 1657 cm-1. This corresponds to the amide I
frequency previously reported for unordered peptide struc-
tures.19,22
Some contribution of this band is also observed for
polymers 2-4 and 7, although its relative importance
decreases for the longer chain catalysts. Thus, with increasing
average chain length the amount of disordered structure
decreases, probably due to the smaller number of polyleucine
chains with less than four residues, the minimum number of
residues for forming an R-helix.
Supporting Information Available: Experimental pro-
cedures for the synthesis of the oligopeptides used. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL007005L
(24) Nevskaya, N. A.; Chirgadze, Yu. N. Biopolymers 1976, 15, 637-
648.
(25) Graff, D. K.; Pastrana-Rios, B.; Venyaminov, S. Y.; Prendergast,
F. G. J. Am. Chem. Soc. 1997, 119, 11282-11294.
(26) These conclusions are in general agreement with those obtained in
a recent publication on insoluble oligo-L-leucines of varying chain lengths,
where it was shown that the efficiency of oligo-L-leucine as a Julia´-Colonna
catalyst is related to its R-helical structure: Takagi, R.; Manabe, T.; Shiraki,
A.; Yoneshige, A.; Hiraga, Y.; Kojima, S.; Ohkata, K. Bull. Chem. Soc.
Jpn. 2000, 73, 2115-2121. Insoluble oligo-L-leucines show a significant
contribution of â-sheet structure, which is thought to be formed upon
aggregation of the insoluble polymer chains. No significant aggregation is
observed for the soluble poly-L-leucines investigated here.
For the longer chain catalysts, two narrow bands at 1649.8
and 1654.7 cm-1 become dominant. These bands fall into
the spectral region which is typical of the amide I frequency
of R-helices.19,23 Most likely, the two bands should not be
(21) The amide I spectra of all compounds were fitted simultaneously
to the sum of a variable number of Lorentzian bands, using a nonlinear
least-squares (Levenberg-Marquardt) fitting routine. The same Lorentzian
band centre frequencies and widths, but different relative amplitudes, were
used for all spectra. It was found that a minimum of five Lorentzians was
needed to obtain a satisfactory fit. The use of six or more Lorentzians did
not significantly improve the quality of the fit.
(22) Chirgadze, Y. N.; Shestopalov, B. V.; Venyaminov, S. Y. Biopoly-
mers 1973, 12, 1337-1351.
(23) Chirgadze, Y. N.; Brazhnikov, E. V. Biopolymers 1974, 13, 1701-
1712.
(27) Two minor bands at 1638.6 and 1678.5 cm-1 are needed to obtain
a satisfactory fit (Table 2). Although these wavelengths are characteristic
of â-sheet structures (see refs 19, 22), at the present moment it is not clear
whether these bands indicate a minor population of â-sheet structures for
amino-PEG bound polyleucine or are due to some artifact, possibly related
to the insoluble product found during catalyst synthesis. A more detailed
investigation of these minor contributions is currently in preparation. The
main conclusion, namely, that PEG-bound polyleucine is found to adopt a
predominantly R-helical structure, is not affected by these minor bands.
686
Org. Lett., Vol. 3, No. 5, 2001