Fluorous parallel synthesis of a piperazinedione-fused tricyclic compound library.
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.
Werner
Stefan
S
Center for Chemical Methodologies and Library Development (UPCMLD), Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Nielsen
Simon D
SD
Wipf
Peter
P
Turner
David M
DM
Chambers
Peter G
PG
Geib
Steven J
SJ
Curran
Dennis P
DP
Zhang
Wei
W
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
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