Microwave-assisted "libraries from libraries" approach toward the synthesis of allyl- and C-cyclopropylalkylamides.
Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase "libraries from libraries" approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERalpha), revealing three potent lead compounds of a new structural type.
Wipf
Peter
P
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. pwipf@pitt.edu
Coleman
Claire M
CM
Janjic
Jelena M
JM
Iyer
Pravin S
PS
Fodor
Matthew D
MD
Shafer
Yvonne A
YA
Stephenson
Corey R J
CR
Kendall
Christopher
C
Day
Billy W
BW
D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D008872:Microwaves; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000498:Allyl Compounds; D000577:Amides; D047628:Estrogen Receptor alpha