A number of studies on the effect of sequence on the
catalytic efficiency can be found in the literature, both on
free” peptides and on those bound to either soluble PEG
polymers or to polystyrene supports by means of ester
linkers. In summary, all these studies showed that (i)
modifications at the N-terminal region of the peptide had
the most pronounced effect on catalyst performance and that
ii) there is a correlation between the degree of helicity (as
assessed by IR spectroscopy) and the catalytic activity of
the oligo-peptides.6
increasing proportion of R-helix present in the equilibrium
mixture of peptide conformers.
5,6
“
The obvious binding site for the partially negative charged
carbonyl oxygen atom of the substrate enone is the N-
terminus, with its partial positive charge and three NH bonds
not involved in intrahelix H-bonding. Numerous protein
X-ray crystal structures demonstrate that the N-terminus of
R-helices is a common motif for, for example, phosphate
(
8
binding. To probe the catalytic function of the N-terminus,
we synthesized an “inverse” L-Leu hexamer on TentaGel S
7
We reasoned that the most fundamental question to be
addressed is the minimum chain length of a catalytically
competent peptide. To eliminate complications by aggrega-
tion of free hydrophobic peptides in solution, we decided to
COOH. This oligopeptide, which is attached to the solid
phase by its N-terminus and has a free COOH group, was
indeed inactive (e1% conversion after 24 h).
â-Amino acids such as (1R,2R)-2-aminocyclohexanecar-
9
3
synthesize L-Leu oligomers of varying chain lengths (1-
boxylic acid 3 or (S)-â -leucine 4 are known to form stable
helices much more readily than R-amino acids. However,
the orientation of the NH bonds within the typical â-peptidic
7
2
0) directly on TentaGel S NH
2
. Thus, the peptides are
linked to the solid support by a chemically robust amide
group and the relatively low loading of the support favors
the monomeric state of the peptide(s). These materials were
employed in the triphasic epoxidation of chalcone 1 with
alkaline hydrogen peroxide, using methylene chloride as
1
helices (so-called 14- or 3 -helices) is opposite to those of
R-helices (Figure 2a,b). Starting from N-Fmoc-310 and
7
organic solvent. The results are summarized in Figure 1.
Figure 2. (a) Chalcone bound to the N-terminus of an R-helix
and hydrogen bonds between the carbonyl O-atom, the N-terminus,
and NH (n-2). (b) 14-Helix of the 2-aminocyclohexanecarboxylic
acid hexamer (from ref 9a). Note the opposite orientation of NH
bonds.
Figure 1. Effect of oligo-L-Leu chain length on catalytic perfor-
mance. The light columns denote the enantiomeric excess of
N-Fmoc-4,11 we synthesized the series of the 1-5-mers of
7
(2R,3S)-chalcone epoxide 2 and the black columns refer to the yield
3 and 4, again on TentaGel S NH
(Scheme 2). As it turned
2
of epoxide 2 obtained after 24 h.
out, none of these â-amino acid oligomers showed catalytic
activity (e1-2% conversion after 24 h). The above results
again emphasize the importance of hydrogen bonding at the
N-terminus.
To shed further light on the possible binding modes of
the substrate chalcone 1 to the N-terminus of a typical
R-helix, we initiated a molecular modeling study [docking
experiments, conformational analyses of the peptide-chal-
Maximum enantioselectivity (96-98% ee) is achieved with
as little as five L-Leu residues, whereas the epoxide yields
increase gradually and level off around the 14-mer. Since
four amino acid residues are required to form one turn of an
8
a
R-helix, we conclude that one intact helical turn is the
minimum structural element necessary for efficient asym-
metric induction. The increase of catalytic activity (i.e.,
epoxide yield, Figure 1) with chain length reflects the
(8) (a) Branden, C.; Tooze, J. Introduction to Protein Structure, 2nd ed.;
Garland: New York, 1999. (b) Hol, W. G. J.; van Duijnen, P. T.; Berendsen,
H. J. C. Nature 1978, 273, 443. (c) Hirshberg, M.; Hendrick, K.; Haire, L.
L.; Vasisht, N.; Brune, M.; Corrie, J. E.; Webb, M. R. Biochemistry 1998,
37, 10381.
(9) (a) Apella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 6206. (b) Gellman, S. H.
Acc. Chem. Res. 1998, 31, 173.
(10) Our synthesis of N-Fmoc 3 and N-Fmoc ent-3 will be published
elsewhere.
(11) (a) Guichard, G.; Abele, S.; Seebach, D. HelV. Chim. Acta 1998,
81, 187. (b) M u¨ ller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837.
(5) (a) Bentley, P. A.; Cappi, M. W.; Flood, R. W.; Roberts, S. M.; Smith,
J. A. Tetrahedron Lett. 1998, 39, 9297. (b) Bentley, P. A.; Flood, R. W.;
Roberts, S. M.; Skidmore, J.; Smith, C. B.; Smith, J. A. Chem. Commun.
2
001, 1616.
6) (a) Flood, R. W.; Geller, T. P.; Petty, S. A.; Roberts, S. M.; Skidmore,
(
J.; Volk, M. Org. Lett. 2001, 3, 683. (b) Takagi, R.; Shiraki, A.; Manabe,
T.; Kojima, S.; Ohkata, K. Chem. Lett. 2000, 366.
(7) See Supporting Information for preparative details.
3840
Org. Lett., Vol. 3, No. 24, 2001