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The design and synthesis of two pyrrolinone−peptide hybrid ligands (3 and 20) for the rheumatoid arthritis-associated class II MHC HLA-DR1 protein are described. The hybrids incorporate bispyrrolinones 4 and 21 as tetrapeptide mimics for amino acids VKQN (residues 309−312) of the virus hemagglutinin peptide HA 306−318 (PKYVKQNTLKLAT). Ligand construction employed our polypyrrolinone synthetic protocol, in conjunction with Fmoc-based solid-phase peptide synthesis. Bioaffinity studies reveal that hybrid ligand 3 bound the HLA-DR1 protein with affinity (IC50 = 137 nM) comparable to those of both the native HA 306−318 peptide (IC50 = 89 nM) and a control peptide (IC50 = 176 nM). This result demonstrates that the polypyrrolinone scaffold can be employed in the construction of bioactive peptide hybrid ligands, thus considerably expanding the scope and utility of the pyrrolinone scaffold.

The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous amide scaffold which incorportated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC50s in the 0.6 to 18 μM range. These compounds did not inhibit HIV-1 protease. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin. © 1994 John Wiley & Sons, Inc.

A new two-step method employs the intramolecular cyclization of metalated imino esters for the construction of scalemic 3,5,5-trisubstituted pyrrolin-4-ones (4). The imino esters in turn derive from α-disubstituted amino acids, the latter readily available via a new protocol exploiting the enantioretentive alkylation of oxazolidinones.

A new two-step method employs the intramolecular cyclization of metalated imino esters for the construction of scalemic 3,5,5-trisubstituted pyrrolin-4-ones (4). The imino esters in turn derive from α-disubstituted amino acids, the latter readily available via a new protocol exploiting the enantioretentive alkylation of oxazolidinones.

A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-scale syntheses and gives high isolated product yields that often require no further purification. This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted conditions, and the results with several compounds are outlined.