Methods for preparing internally constrained peptides and peptidomimetics
The present invention relates to a method for preparing a peptide having a stable, internally constrained alpha-helical, beta-sheet/beta-turn, 3 10 -helical, or pi-helical region and a method of stabilizing an alpha-helical, beta-sheet/beta-turn, 3 10 -helical, or pi-helical region within a peptide structure. The resulting peptides and methods of using them are also disclosed.
1. A method of preparing a compound of Formula II:
wherein
R is hydrogen, an amino acid side chain, an alkyl group, or an aryl group;
R 1 is an amino acid side chain, an alkyl group, or an aryl group;
R 2 is an amino acid, peptide, OR, CH 2 NH 2 , an alkyl group, an aryl group, or a group of formula:
wherein R 7 is an amino acid, peptide, OR, CH 2 NH 2 , an alkyl group, or an aryl group; R 3 is an amino acid, peptide, OR, CH 9 Mi 2 , an alkyl group, an aryl group, hydrogen, or a group of formula
is a single or double carbon-carbon bond; is a single bond and is cis or trans when is a double bond; n is 1 or 2; and m is any number, said method comprising:
providing a compound of Formula I:
and
reacting said compound of Formula I under conditions effective to produce a compound of Formula II; wherein said reacting comprises a ring-closing metathesis reaction.
2. The method according to claim 1 , wherein said metathesis reaction is performed with a metathesis catalyst of the formula:
3. The method according to claim 2 , wherein said metathesis catalyst is of the formula:
4. The method according to claim 1 , wherein said metathesis reaction is performed at a temperature between about 25° C. and 110° C.
5. The method according to claim 1 , wherein said metathesis reaction is performed with an organic solvent.
6. The method according to claim 5 , wherein said organic solvent is selected from the group consisting of dichloromethane, dichloroethane, trichloroethane, and toluene.
7. The method according to claim 6 , wherein said organic solvent comprises dichloroethane.
8. The method according to claim 1 , wherein said reacting is carried out on a solid support.