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Molecules 2016, 21(3), 350; doi:10.3390/molecules21030350

Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations

1,2,†,* , 2,†,* and 2,†
1
Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical College, 888 Yinxian Avenue Eastern Section, Ningbo 315100, China
2
Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 18 December 2015 / Revised: 2 March 2016 / Accepted: 3 March 2016 / Published: 15 March 2016
(This article belongs to the Section Organic Synthesis)
View Full-Text   |   Download PDF [3438 KB, uploaded 15 March 2016]   |  

Abstract

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields. View Full-Text
Keywords: proline and homologues; piperazine derivatives; peptidomimetics; solid-phase organic synthesis; combinatorial chemistry; Distributed Drug Discovery (D3); CNS agent. proline and homologues; piperazine derivatives; peptidomimetics; solid-phase organic synthesis; combinatorial chemistry; Distributed Drug Discovery (D3); CNS agent.
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Zhou, Z.; Scott, W.L.; O’Donnell, M.J. Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations. Molecules 2016, 21, 350.

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