Iterative, aqueous synthesis of beta3-oligopeptides without the use of coupling reagents.

Format:

Book

Thesis/Dissertation

Author/Creator:

Carillo, Nancy.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Chemistry, Organic.

0490.

Local Subjects:

0490.

Physical Description:

281 pages

Contained In:

Dissertation Abstracts International 71-11B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The discovery that oligomers of beta-amino acids fold into highly defined ordered structures and their resistance to proteolysis has attracted considerable attention in the synthesis, study and application of these peptidomimetics. Although the synthesis of short beta-peptides is a well-established method, difficulties in the preparation of longer poly-beta-peptides include problems associated with hydrophobic collapse, deprotection, and insolubility of the growing peptide.

Based on our recently reported amide-bond forming reaction between alpha-ketoacids and hydroxylamines, we have developed a new approach to the synthesis of poly-beta-peptides. This unprecedented amide formation proceeds in water, produces only carbon dioxide and methanol as by-products and does not require coupling reagents or protecting groups. Our approach towards the synthesis of beta 3-oligopeptides takes advantage of the chemoselective amide bond formation of the growing peptide chain with enantiopure isoxazolidine monomers. Amide bond formation results in N--O bond cleavage rendering and alpha-ketoester which following hydrolysis is poised for iterative chain elongation. A major challenge in adapting our methodology for the preparation of beta 3-oligopeptides was the synthesis of the enantiopure isoxazolidine monomers. We overcame this difficulty by employing a sugar-assisted 1,3-dipolar cycloaddition offering access to a variety of enantiopure monomers.

To address the synthesis of longer beta3-oligopeptides we turned towards a solid-phase implementation of our method. Several notable challenges needed to be overcome: the peptide would be assembled in an inverse N→C direction requiring the design and synthesis of a new linker, and identification of a water-compatible solid support was crucial as aqueous conditions would be employed. We developed a seven-step protocol to the synthesis of a linker for inverse peptide synthesis and identified a water-compatible solid support. Our approach towards the iterative solid phase synthesis of beta 3-oligopeptides begins by attaching the new ketoacid linker. Subsequent hydrolysis unmasks the alpha-ketoacid that can be directly coupled with the unprotected isoxazolidine monomers. We have demonstrated that this two-step coupling/hydrolysis iteration can be executed to assemble short sequences beta 3-pentamers. This new approach to peptide synthesis offers great potential in facilitating the preparation of beta3-oligopeptides promoting their study and applications as peptidomimetics.

Notes:

Source: Dissertation Abstracts International, Volume: 71-11, Section: B, page: 6778.

Adviser: Jeffrey W. Bode.

Thesis (Ph.D.)--University of Pennsylvania, 2010.

Local Notes:

School code: 0175.

ISBN:

9781124276977

Access Restriction:

Restricted for use by site license.