Design, synthesis, and structure of pyrrolinone-based peptidomimetics / David Alan Favor.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Favor, David Alan.

Contributor:

Smith, Amos B., III, advisor.

Hirschmann, Ralph F., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xxii, 295 pages : illustrations ; 29 cm

Production:

1999.

Summary:

This dissertation describes studies on nitrogen and carbonyl displaced pyrrolinone-based peptidomimetics carried out in the collaborative research of Amos B. Smith, III and Ralph Hirschmann, a partnership that is now in its 11th year. Chapter 1 of this dissertation provides a review of a portion of their accomplishments.*

In Chapter 2 of this dissertation, the molecular modeling, synthesis, and elucidation of the solid state and solution structures of N-methylated 3,5-linked bispyrrolin-4-ones are described. Upon their successful synthesis, structural elucidation both in the solid state and in solution revealed the existence of two of the three low energy backbone conformers predicted by molecular modeling (&phis; = 165° and 289°). Two structures were particularly noteworthy and completely unexpected. Mono-N-methyl bispyrrolinone (-)- 28 was observed to self-assemble in the solid state to form a novel helix.*

Acetylene-linked tetrapyrrolinone none (-)-29 was designed to potentiate the observed helical array of (-)-28 Tetrapyrrolinone (-)-29 was constructed by coupling of bispyrrolinones (+)-56 and (-)-57.*

The structure of tetrapyrrolinone (-)-29 in the solid state and in solution demonstrated that it did not adopt the desired helical conformation. X-ray analysis of (-)-29 established that the dihedral angle &phis; between pyrrolinone rings a and b in (-)-29 is 168.3°, similar to the observed values in (-)-28 whereas the orientation of pyrrolinone rings c and d (&phis; = 289.4°) more closely resembles one of the other predicted low-energy conformers with a &phis; = 289°. The IR and NMR data support a solution conformation for (-)- 29 quite similar to that observed in the solid state. In particular, a dynamic hydrogen bond was observed between bispyrrolinone rings b and d. Moreover an observed NOE cross resonance is indicative of the same dihedral angle (&phis;) between pyrrolinone rings c and d in solution as observed in the crystal structure of (-)- 29.*

Chapter 3 presents progress towards comparison of the aggregation tendencies of polypyrrolinone beta-sheet mimetics with their peptidal counterparts. Peptides TFA beta-5 75 and beta-5 76 are to be compared with tetrapyrrolinones 77 and 78.*

Progress towards the construction of tetrapyrrolinones 77 and 78 has utilized the chemistry we developed for the construction of pyrrolinones with functionalized side chains. Pyrrolinone building blocks (-)-84, (-)-86, (+)-87, and (+)-89 have been synthesized and have been utilized in the construction of tetrapyrrolinone (-)-90.*

*Please refer to dissertation for diagrams.

Notes:

Supervisors: Amos B. Smith, III; Ralph F. Hirschmann.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 1999.

Includes bibliographical references and index.

Local Notes:

University Microfilms order no.: 99-26124.

OCLC:

187482419