title: Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations.
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.
authors.affiliation: Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical College, 888 Yinxian Avenue Eastern Section, Ningbo 315100, China. zhouzn@mail.zjpc.net.cn.|Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, USA. zhouzn@mail.zjpc.net.cn.
authors.forename: Ziniu
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, USA. zzn806@yahoo.com.
authors.forename: William L
authors.initials: WL
authors.lastname: Scott
authors.affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, USA. modonnel@iupui.edu.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: O'Donnell
mesh_terms: D000588:Amines / Q000737:chemistry*; D000598:Amino Acids, Cyclic / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry*; D011392:Proline / Q000138:chemical synthesis* / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000588:Amines; D000598:Amino Acids, Cyclic; D002264:Carboxylic Acids; D011392:Proline
keywords: CNS agent.; Distributed Drug Discovery (D3); combinatorial chemistry; peptidomimetics; piperazine derivatives; proline and homologues; solid-phase organic synthesis