Design and synthesis of a 3,4-dehydroproline amide discovery library.
The synthesis of a discovery library of 80 3,4-dehydroproline amides was achieved in a four-step reaction sequence from easily accessible 3-aminoallene-3-carboxylate methyl esters. Diversification of these proline mimics was introduced at five different sites: the substituents at the 3-pyrroline unit (R1, R2, R3), at the nitrogen (R4), and the C-terminus (R5). The 3-pyrroline scaffold was synthesized in excellent yields by a silver-catalyzed intramolecular cyclization of aminoallenes, followed by N-functionalization reactions. Maximum diversity was introduced in the final step of the reaction sequence by taking advantage of the carboxylic acid handle of the 3-pyrroline subunit. Amide coupling reactions using polystyrene-carbodiimide (PS-carbodiimide) and 1-hydroxybenzotriazole (HOBt) under microwave irradiation led to 3,4-dehydroproline amides that were obtained in purities greater than 85% by LC/MS/ESLD after scavenging the excess HOBt on a silica-bound carbonate SPE cartridge.
Werner
Stefan
S
Center for Chemical Methodologies and Library Development (UPCMLD), University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. stw15@pitt.edu
Kasi
Dhanalakshmi
D
Brummond
Kay M
KM
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016208:Databases, Factual; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
D000577:Amides; D011392:Proline