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Expanding the complexity and functional diversity of bis-amino acid building blocks

Gupta, Sharad (2009) Expanding the complexity and functional diversity of bis-amino acid building blocks. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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We are developing a unique approach to the synthesis of macromolecules with programmable shape. These scaffolds are assembled from stereochemically pure orthogonally protected bis-amino acids that are interconnected by two amide bonds. This ladder-like arrangement restricts the conformational flexibility of bis-amino acids to a large extent which in turn drastically reduces the number of allowed conformations for an oligomer. As a result, significantly lesser computing power is needed for the final three-dimensional structure prediction. Several stereochemically pure bis-amino acid monomers have been synthesized by our research group and incorporated into a number of homo- and hetero-oligomers.In this dissertation we present the synthesis of a new pipecolic acid-based bis-amino acid building block pip5(2S5S). Assembly of this monomer into a short spiroladder oligomer utilizing solid-phase synthesis followed by in situ activation by dicyclohexylcarbodiimide and N-hydroxysuccinimide has been demonstrated. The structure of the oligomer was determined in aqueous solution using two-dimensional NMR. We report improved conditions for rapidly and simultaneously closing multiple diketopiperazines on solid support. These new conditions involve either heating of a suspension of solid supported amino-tetrafluoropropyl esters in acetic acid/triethylamine catalyst solution in a microwave oven or continuous flow of catalyst solution through the resin, heated in a special flow cell apparatus.Finally, the synthesis of the first functionalized bis-amino acid monomer proAc(2S3S4R) that carries an acetyl side chain is presented. This monomer was incorporated into a short oligomer and the solution phase structure was determined using two-dimensional nuclear magnetic resonance. The solution structure confirmed the intended connectivity and stereochemistry of the oligomer. This first functionalized bis-amino acid represents a milestone towards functionalized bis-peptide nanostructures for catalytic, molecular recognition and nanotechnology applications.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSchafmeister, Christian
Committee MemberWilcox, Craig Sdaylite@pitt.eduDAYLITE
Committee MemberDas, Subha
Committee MemberChapman, Tobytchapman@pitt.eduTCHAPMAN
Date: 30 September 2009
Date Type: Completion
Defense Date: 13 July 2009
Approval Date: 30 September 2009
Submission Date: 8 July 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bis-amino acids; diketopiperazine; foldamers; peptides
Other ID:, etd-07082009-204223
Date Deposited: 10 Nov 2011 19:50
Last Modified: 15 Nov 2016 13:45


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