title: Fluorous parallel synthesis of a piperazinedione-fused tricyclic compound library.
abstract: A fluorous-linker-assisted solution-phase protocol has been developed and applied to parallel synthesis of a piperazinedione-fused tricyclic compound library. The one-pot [3 + 2] cycloaddition of fluorous amino esters, aldehydes, and maleimides afforded bicyclic proline derivatives. The intermediates were subjected to N-acylation with chloroacetyl chloride, followed by displacement reactions with amines. Linker cleavage with concomitant lactamization yielded the final products. Microwave heating was employed to facilitate several reaction steps and fluorous solid phase extraction (F-SPE) was employed to purify the intermediates. During the method development, a small library containing sixteen analogs was prepared. The optimized conditions were applied to the synthesis of a production library containing ninety analogs.
authors.affiliation: Center for Chemical Methodologies and Library Development (UPCMLD), Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Werner
authors.forename: Simon D
authors.initials: SD
authors.lastname: Nielsen
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: David M
authors.initials: DM
authors.lastname: Turner
authors.forename: Peter G
authors.initials: PG
authors.lastname: Chambers
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Geib
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Curran
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003500:Cyclization; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry; D008872:Microwaves; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry; D052616:Solid Phase Extraction / Q000379:methods
chemical_list: D000588:Amines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004952:Esters; D017611:Fluorine Compounds; D008301:Maleimides; D010879:Piperazines; D054852:Small Molecule Libraries; C003905:3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione; D011392:Proline