Synthesis of fused heteroarylprolines and pyrrolopyrroles.
Fused heteroarylprolines were prepared starting from 4-oxo-N-(PhF)proline benzyl ester (6, PhF = 9-(9-phenylfluorenyl)) following two approaches. First, allylation of oxoproline 6 followed by Wacker oxidation gave 1,4-dione 8 that was selectively converted to pyrroloproline 10b, pyrrolopyrrole 12, and pyridazinoproline 9. Second, aldol condensation of oxoproline 6 with a series of N-(Boc)-alpha-amino aldehydes 15a-e and acid-catalyzed cyclization gave pyrroloprolines 17a-e possessing a variety of pyrrole 5-position substituents. Conditions for the selective deprotection and alkylation of the pyrrole nitrogen of pyrroloprolines 17 were developed to expand the diversity of the heteoaryl systems. Finally, hydrogenolytic cleavage of the PhF and benzyl groups followed by subsequent protection with Boc, Fmoc, and Moz groups was performed to obtain analogues suitable for peptide synthesis. The enantiomeric purity of N-(Boc)pyrrolo-proline 21a was ascertained by coupling to l- and d-phenylalanine methyl ester and examination of the diastereotopic pyrrole protons, which demonstrated the dipeptides to be of >99% diastereomeric purity. These approaches have thus delivered the first series of enantiopure fused arylprolines for application as arylglycine-proline chimeras in structure-activity studies of biologically active compounds.
Jeannotte
Guillaume
G
Département de chimie, Université de Montréal, C.P. 6128, Succursale CentreVille, Montréal, Québec, Canada H3C 3J7.
Lubell
William D
WD
D020650:Combinatorial Chemistry Techniques; D007202:Indicators and Reagents; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010649:Phenylalanine / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D011758:Pyrroles / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011758:Pyrroles; D010649:Phenylalanine; D011392:Proline