Table 2 Epoxidation of chalcone (1) using mixed
D
- and
L
-Leu catalysts
Eec (%)
Table 4 Epoxidation of chalcone (1) using selected catalysts under
under triphasica conditions over 32 h
triphasica conditions over 18 h
Catalyst
Major product
Conversionb (%)
Catalyst
Conversionb (%)
Eec (%)
1L/5D/14L
2L/5D/13L
3L/5D/12L
4L/5D/11L
5L/5D/10L
3
3
2
2
2
99
96
100
99
67
11
89
86
88
H-(
H-(
H-(
H-(
L
L
L
L
-Leu)3-(
-Leu)4-(
-Leu)5-(
-Leu)6-(
D
D
D
D
-Leu-
-Leu-
-Leu-
-Leu-
L
L
L
L
-Leu)8-R
-Leu)8-R
-Leu)8-R
-Leu)8-R
55
52
95
98
64
64
92
91
99
a Ref. 2. b Determined by HPLC. c Determined by chiral HPLC, in each case
epoxide 2 was the major enantiomer.
a Ref. 2. b Determined by HPLC. c Determined by chiral HPLC.
poly- -leucine catalyst) in 89% ee; the oligomers 4L/5D/11L
L
helical peptide are not able to act as hydrogen bond donors to
carbonyl groups within the helix, thus providing a possible
explanation for the differentiation between the terminal region
and the bulk of the peptide. Kinetics and spectroscopy
experiments are being undertaken (using PEG-bound poly-
amino acids that are soluble in organic solvents11) to ascertain
which species is complexed to the chiral environment of the
polymer. Such experimentation seems prudent before more
detailed modelling can commence.
and 5L/5D/10L gave very similar results. From this study it
appears that the penultimate and antepenultimate residues from
the N-terminus play a dominant role in determining the
stereoselectivity of the Juliá–Colonna reaction.
We reasoned that, given the above results, the inclusion of
glycine residues close to the N-terminus might have a
significant effect on the catalytic activity of the peptide. Three
catalysts H-(
Leu)17-R and H-(
L
-Leu)-Gly-(
-Leu)-Gly3-(
L
-Leu)18-R, H-(
L
-Leu)-Gly2-(
L
-
L
L
-Leu)17-R were prepared. In-
We thank the EPSRC and BBSRC for studentships (R. W. F.,
P. A. B. and C. B. S.) and the EPSRC for a fellowship (J. S.).
clusion of three glycine residues reduces the ee of the epoxide
2 significantly; the effect of incorporating two glycine residues
is more modest and the substitution of Gly for
penultimate position has relatively little effect, when compared
to the polymer containing only -Leu residues (Table 3).
L
-Leu in the
Notes and references
L
† The oligoleucines were linked via a hydroxymethylphenoxyacetic acid
linker to PEG and thence to polystyrene resin (loading 0.18 mmol g21).
These oligomers are represented as H-(Leu)n-R where R = linker–PEG-
resin.
Interestingly, incorporation of the glycine residues results in a
reduced conversion to the epoxide as well as diminishing the
enantioselectivity.
‡ Strictly speaking this material is Me2NCH(CH2CHMe2)CO(
L-Leu)19R,
Table 3 Epoxidation of chalcone (1) using selected catalysts under
triphasica conditions over 24 h
the nomenclature Me2-( -Leu)20-R is used for convenience.
L
1 P. A. Bentley, Biotransformations, ed. D. R. Kelly, VCH, Weinheim,
2000, vol. 8b, ch. 12.
Catalyst
Conversionb (%) Eec (%)
2 The triphasic system consists of a solution of the substrate in an organic
solvent (typically toluene), aq. NaOH–H2O2 and the insoluble catalyst,
see S. Juliá, J. Masana and J. C. Vega, Angew. Chem., Int. Ed. Engl.,
1980, 19, 929; S. Juliá, J. Guixer, J. Masana, J. Rocas, S. Colonna, R.
Annuziata and H. Molinari, J. Chem. Soc., Perkin Trans. 1, 1982,
1317.
H-(
H-(
H-(
H-(
L
L
L
L
-Leu)20-R
-Leu)-Gly-(L-Leu)18-R
-Leu)-Gly2-(
-Leu)-Gly3-(
97
90
79
60
88
70
52
29
L
-Leu)17 -R
-Leu)17 -R
L
a Ref. 2. b Determined by HPLC. c Determined by chiral HPLC, in each case
3 (a) P. A. Bentley, S. Bergeron, M. W. Cappi, D. E. Hibbs, M. B.
Hursthouse, T. C. Nugent, R. Pulido, S. M. Roberts and L. E. Wu, Chem.
Commun., 1997, 739; (b) J. V. Allen, K. H. Drauz, R. W. Flood, S. M.
Roberts and J. Skidmore, Tetrahedron Lett., 1999, 40, 5417.
4 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; W. P. Chen and S.
M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1999, 103; L. Carde, D. H.
Davies and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 2000,
2455.
5 H. R. Kricheldorf, a-Aminoacid-N-Carboxy-Anhydrides and Related
Heterocycles: Syntheses, Properties, Peptide Synthesis, Polymerisation,
Springer-Verlag, Berlin, 1987; S. Itsuno, M. Sakakura and K. Ito, J.
Org. Chem., 1990, 55, 6047.
6 P. A. Bentley, W. Kroutil, J. A. Littlechild and S. M. Roberts, Chirality,
1997, 9, 198.
7 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.
8 P. A. Bentley, M. W. Cappi, R. W. Flood, S. M. Roberts and J. A. Smith,
Tetrahedron Lett., 1998, 39, 9297.
9 R. Takagi, T. Manabe, A. Shiraki, A. Yuneshige, Y. Hiraga, S. Kojima
and K. Ohkata, Bull. Chem. Soc. Jpn., 2000, 73, 2115.
10 S. M. Roberts and J. Skidmore, Chem. Br., 2000, 36, 31.
11 R. W. Flood, T. P. Geller, S. A. Petty, S. M. Roberts, J. Skidmore and
M. Volk, Org. Lett., 2001, 3, 683.
epoxide 2 was the major enantiomer.
Finally, on the evidence that the residues close to the amino
terminus of the polypeptide chain have the primary influence on
the stereochemistry of the oxidation reaction, the peptides H-(
L
-
Leu)n-( -Leu- -Leu)8-R, where n = 3–6, were prepared. These
D
L
have an equal mixture of the two enantiomers of leucine in the
bulk of the peptide chain and a different number of residues of
the -enantiomer at the amino terminus.
L
Table 4 shows that the polymers with five or six consecutive
-Leu residues at the amino terminus are excellent catalysts.
L
Surprisingly, even the polymer with just three
the amino terminus generates 2 with significant ee. It is
noteworthy that this polymer has only one change ( - to -Leu)
from a polymer with residues of alternating stereochemistry,
adding a little more weight to the postulate that polyamino acids
could potentially have been prebiotic catalysts,10 in as much as
these results show that even a small excess of one enantiomer in
an oligomeric structure, when correctly assembled, can lead to
an amplification and a diversification of chirality.
L
-Leu residues at
D
L
Overall, it appears that the enone substrate and/or the
peroxide reagent binds to the polyleucine near the N-terminus.
It may well be pertinent that the final four N–H groups of an a-
Chem. Commun., 2001, 1616–1617
1617