beta-peptides as catalysts: poly-beta-leucine as a catalyst for the Julia-Colonna asymmetric epoxidation of enones.

Article abstract of DOI:10.1039/b106368p

Poly-beta-leucines have been evaluated as catalysts for the Julia-Colonna asymmetric epoxidation of enones; the beta 3-isomer was found to be an effective catalyst for the epoxidation of chalcone (70% ee) and some analogues.

Full text of DOI:10.1039/b106368p

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b-Peptides as catalysts: poly-b-leucine as a catalyst for the
Juliá–Colonna asymmetric epoxidation of enones
Paul E. Coffey,a Karl-Heinz Drauz,b Stanley M. Roberts,*a John Skidmorea and John A. Smithc
a Department of Chemistry, University of Liverpool, Liverpool, UK L69 7ZD. E-mail: smrsm@liv.ac.uk
b Degussa-Hüls AG, Rodenbacher Chaussee 4, D-63457 Hanau-Wolfgang, Germany
c
School of Biological Sciences, University of Liverpool, Liverpool, UK L69 7ZB
Received (in Cambridge, UK) 17th July 2001, Accepted 26th September 2001
First published as an Advance Article on the web 25th October 2001
Poly-b-leucines have been evaluated as catalysts for the
Juliá–Colonna asymmetric epoxidation of enones; the b3-
isomer was found to be an effective catalyst for the
epoxidation of chalcone (70% ee) and some analogues.
afford 2 {[a]2D2 +35 (c 1.0, H2O) lit.9 +34.7 (c 1.0, H2O}
(Scheme 1).
Poly-a-amino acids are typically prepared from the corre-
sponding monomers by activation as the N-carboxyanhydride,
followed by polymerisation using a nucleophilic initiator.10
This approach is less effective in the case of b-amino acids10
and even employing recent synthetic improvements11 a pure
Peptides, generated from a-amino acids, can adopt a number of
stable conformations such as the a-helix and b-sheet. In
combination these secondary structural units allow a protein to
adopt a defined tertiary structure, which can lead to catalytic
behaviour. Recent work by Seebach,1 Gellman2 and others,3 as
well as earlier studies,4 has shown that peptides generated from
b-amino acids (so called b-peptides) show similar secondary
structural characteristics to their natural counterparts. This
suggests that, in principle, the b-analogues of proteins may
exhibit related catalytic behaviour. It is notable that short b-
peptides show promise as therapeutic agents as they can exhibit
similar biological profiles to a-peptides with increased stability
to peptidases, leading to improved bioavailability.5 Careful
tuning of b-amino acid structure has allowed a wide range of
structural units to be reliably prepared using the b-peptide
backbone.
3
sample of the b -leucine N-carboxyanhydride could not be
prepared.
We have shown that a 20-mer of poly- -a-leucine, prepared
L
using solid phase synthesis, exhibits similar catalytic activity to
material generated by polymerisation of
L
-leucine NCA.12
Moreover, Seebach has shown that solid phase techniques can
be used to prepare b-peptides.8 Thus, solid phase automated
peptide synthesis was carried out using the two isomeric Fmoc
2
protected b-leucines† to afford two 20-mer peptides b -Leu19-
3
a-Leu-R 7 and b -Leu19-a-Leu-R 8.‡13
The polymers 7 and 8 were tested under two sets of reaction
conditions; first, a triphasic protocol, consisting of aqueous
NaOH and H2O2 and a solution of the substrate in toluene,6a and
Work initiated by Juliá and Colonna6a has shown that
polyamino acids, typically containing 30 or more identical
residues of a-leucine or a-alanine, are capable of catalysing the
Weitz–Scheffer epoxidation of enones with remarkable levels
of asymmetric control.6 More recently, modifications have been
made to the original reaction conditions6b and as a result the
method is now applicable to a wide range of trans-enones.6c As
part of an ongoing program investigating and developing this
transformation, b-analogues of the Juliá–Colonna poly-a-
leucine catalysts have been prepared, in order to evaluate their
potential as asymmetric catalysts.
The addition of a methylene unit to an a-amino acid
generates two possible structurally-isomeric b-amino acids.
2
3
Seebach has termed these b and b depending on which carbon
bears the side chain.1 In order to prepare the two isomeric b-
Scheme 1 Synthesis of isomeric b-leucines. Reagents and conditions: (a)
TiCl4, TEA, ClCH2NHBz, DCM, –10 0C, 53%; (b) i. H2O2, LiOH, THF,
H2O, 0 0C, 82%; ii. aq. HCl, AcOH, 110 0C, 86%; (c) i. isobutyl-
chloroformate, TEA, THF, Et2O, 0 0C; ii. CH2N2, Et2O; iii. Na2CO3,
Na2S2O3, AgO2CCF3, dioxane, H2O, 53% over three steps where R =
Fmoc; (d) HBr, AcOH, 110 0C, 90% where R = Z.
2
3
leucine polymers, the monomer amino acids b -(1) and b -
leucine (2) were required in enantiomerically enriched form
(Fig. 1).
2
Following the method of Seebach, b -leucine 1 was prepared
by amidomethylation of 3 with N-(chloromethyl)benzamide
using the Evans auxiliary to control the formation of the
3
stereocentre (Scheme 1).†7 The b isomers are generally
synthesised using an Arndt–Eistert homologation of the corre-
sponding a-amino acids.8 Thus, we were able to prepare
3
protected b -leucines 6a and 6b from the corresponding a-
amino acids 5a and 5b. Compound 6a was then deprotected to
Fig. 1 Isomeric b-leucine monomers.
Scheme 2 Epoxidations.
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Chem. Commun., 2001, 2330–2331
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106368p

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Table 1 Epoxidation of enones using poly-b-amino acid catalysts
Major
product
Conversion Ee
Entry
Substrate
Catalyst
Activation
Conditions
Time/h
(%)a
(%)b
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10a
10b
10b
10c
10d
10d
a-Leu-R
None
None
None
None
Aq. NaOH–PhMee
DBU–PhMef
Aq. NaOH–PhMee
DBU–PhMef
DBU–PhMef
DBU–PhMef
DBU–PhMef
DBU–PhMef
Biphasicc
Biphasicc
Biphasicc
Triphasicd
Triphasicd
Biphasicc
Biphasicc
Triphasicd
Biphasicc
Biphasicc
Triphasicd
Biphasicc
11a
11a
11a
11a
11a
11a
11a
11b
11b
11c
11d
11d
1.5
4
1.5
4
24
24
24
24
24
24
24
24
66
21
20
15
92
96
77
98
98
10
25
35
89
3
2
b -Leu19-a-Leu-R 7
3
b -Leu19-a-Leu-R 8
23
25
70
39
20
15
28
85
22
9
3
b -Leu19-a-Leu-R 8
3
b -Leu19-a-Leu-R 8
3
b -Leu20-R 9
3
b -Leu20-R 9
3
b -Leu20-R 9
3
b Leu20-R 9
3
10
11
12
b -Leu20-R 9
3
b -Leu20-R 9
3
b -Leu20-R 9
a Determined by HPLC. b Determined by chiral HPLC, major enantiomer 11. c Substrate (0.24 mmol), urea–H2O2 (28 mg), DBU (56 ml), catalyst (100 mg)
in THF (1 ml). d Substrate (0.24 mmol), catalyst (100 mg), 30% aq. H2O2 (0.7 ml), 4 M aq. NaOH (0.5 ml) and PhMe (1 ml). e Catalyst (100 mg) stirred
with 4 M aq. NaOH (0.5 ml) and toluene (1 ml) for 70 hours, then filtered and dried. f Catalyst (100 mg) stirred with DBU (56 ml) in THF (1 ml) for 16 hours
then reagents for reaction added directly.
secondly, biphasic conditions, employing urea–H2O2 and DBU
Notes and references
† Fmoc b -leucine was prepared from 1 using FmocCl under standard
in THF.6b Like their a-analogues, the poly-b-leucines proved to
2
be insoluble in both organic and aqueous solvents.§
conditions {[a]2D2 = +12 (c 1.0, CHCl3) lit.8 +10.8 (c 0.6, CHCl3)}.
In the first instance, the poly-b-amino acids were tested as
‡ The oligoleucines were linked via a hydroxymethylphenoxyacetic acid
catalysts for the epoxidation of chalcone (10a) (Scheme 2).
Under the biphasic conditions, with catalysis by a-Leu20-R, the
(2R,3S)-epoxide 11a was obtained (66% conversion, 89% ee)
linker to PEG and thence to polystyrene resin (loading 0.18 mmol g21).
These oligomers are represented as Leun-R where R
resin.
= linker–PEG–
2
after 1.5 hours (Table 1, entry 1). Catalysis using b -Leu19-a-
§ The poly-b-amino acids remained attached to the support; the solubility of
the non-immobilised material was not investigated.
Leu-R 7 afforded essentially racemic epoxide under the same
2
¶ Ees using activated b -Leu19-a-Leu-R 7 remained below 10%.
conditions; moreover, the rate of reaction was considerably
3
diminished (entry 2). On the other hand, the b -Leu19-a-Leu-R
catalyst 8 gave a significant ee of (2R,3S)-11a under both
biphasic (23% ee) and triphasic (25% ee) reaction conditions,
albeit still with a decreased rate (entries 3 and 4 respectively).
Previous studies have shown that the activity of poly-a-
amino acid catalysts can be improved by various washing
procedures.14 Two such activations were investigated with the
1 D. Seebach and J. L. Matthews, Chem. Commun., 1997, 2015 and
references therein.
2 S. H. Gellman, Acc. Chem. Res., 1998, 31, 173 and references
therein.
3 M. García-Alveraz, A. Martínez de Ilarduya, S. León, C. Alemán and S.
Muñoz-Guerra, J. Phys. Chem. A, 1997, 101, 4215; B. W. Gung, D. Zou,
A. M. Stalcup and C. E. Cottrell, J. Org. Chem., 1999, 64, 2176.
4 See for example: J. Kovacs, R. Ballina, R. L. Rodia, D. Balasu-
bramamnian and J. Applequist, J. Am. Chem. Soc., 1965, 87, 119; J. D.
Glickson and J. Applequist, J. Am. Chem. Soc., 1971, 93, 3276; F. Chen,
G. Lepore and M. Goodman, Macromolecules, 1974, 7, 779; M. Narita,
M. Doi, K. Kudo and Y. Terauchi, Bull. Chem. Soc. Jpn., 1986, 59,
3553.
3
catalyst 8 and a third 20-mer: b -Leu20-R 9. In the first
procedure the catalyst was stirred for 70 hours in a mixture of 4
M aq. NaOH and toluene, before filtering, washing and
drying;14 in the second it was stirred with DBU in toluene for 16
hours before adding the reagents for epoxidation directly. Both
activation procedures significantly increased the enantiose-
lectivity of the catalysed epoxidation reaction. For example,
NaOH–PhMe-activated 8 catalysed the epoxidation of 10a with
92% conversion and 70% ee under the triphasic conditions
(entry 5).¶
5 M. Werder, H. Hauser, S. Abele and D. Seebach, Helv. Chim. Acta,
1999, 82, 1774.
6 (a) S. Juliá, J. Masana and J. C. Vega, Angew. Chem., Int. Ed. Engl.,
1980, 19, 929; (b) B. M. Adger, J. V. Barkley, S. Bergeron, M. W.
Cappi, B. E. Flowerdew, M. P. Jackson, R. McCague, T. C. Nugent and
S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1997, 3501; (c) M. J.
Porter, S. M. Roberts and J. Skidmore, Bioorg. Med. Chem., 1999, 7,
2145.
7 D. Seebach, S. Abele, K. Gademann, G. Guichard, T. Hintermann, B.
Jaun, J. L. Matthews and J. V. Schreiber, Helv. Chim. Acta, 1998, 81,
932.
8 For a recent example see: G. Guichard, S. Abele and D. Seebach, Helv.
Chim. Acta, 1998, 81, 187.
9 T. Yamada, S. Kuwata and H. Watanabe, Tetrahedron Lett., 1978, 19,
1813.
10 H. R. Kricheldorf, a-Aminoacid-N-Carboxy-Anhydrides and Related
Heterocycles: Syntheses, Properties, Peptide Synthesis, Polymerisation,
Springer-Verlag, Berlin, 1987.
11 J. Cheng, J. W. Ziller and T. J. Deming, Org. Lett., 2000, 2, 1943.
12 M. W. Cappi, W.-P. Chen, R. W. Flood, Y.-W. Liao, S. M. Roberts, J.
Skidmore, J. A. Smith and N. M. Williamson, Chem. Commun., 1998,
1159.
13 It was judged that the single a-leucine residue at the C-terminus would
play no role in the reaction, see: P. A. Bentley, M. W. Cappi, R. W.
Flood, S. M. Roberts and J. A. Smith, Tetrahedron Lett., 1998, 39,
9297.
The catalyst 9 was tested against a range of other substrates
10b–d. Using DBU–PhMe-activated 9 the ees for the epoxida-
tion of the b-ethyl enone 10b were somewhat lower than for
chalcone (entries 6, 8 and 9); under the biphasic conditions the
ethyl epoxide 11b had an ee of 28% (entry 9). On the other hand,
under similar conditions the tert-butyl ketone 10c was epoxi-
dised in a high ee (entry 10), however the reaction rate was
significantly retarded, with only 10% conversion to the epoxide
11c being obtained after 24 hours. The final substrate
investigated was 2-benzylidene-3,4-dihydronaphthalen-1(2H)-
one (10d). In this case the triphasic reaction conditions gave an
ee of 22%; however the reaction was again slow (entry 11).
In conclusion, peptides generated from b-amino acids exhibit
catalytic behaviour analogous to that shown by poly-a-amino
3
acids. Specifically, poly-b -leucine catalyses the epoxidation of
(E)-a,b-enones with significant enantioselectivity. Although
this methodology is not competitive with the poly-a-amino acid
analogues it is possible that variation of the b-amino acid
monomer may lead to altered catalytic behaviour. Results of
such studies and approaches to preparing poly-b-amino acids
via polymerisation reactions will be reported in due course.
14 See for example: J. V. Allen, K. H. Drauz, R. W. Flood, S. M. Roberts
and J. Skidmore, Tetrahedron Lett., 1999, 40, 5417.
Chem. Commun., 2001, 2330–2331
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