Diversity-Oriented Syntheses of β-Substituted α-Amino γ-Lactam Peptide Mimics with Constrained Backbone and Side Chain Residues

Abstract

α- N-(Fmoc)Amino-γ-lactam dipeptides with a variety of β-substituents were synthesized stereoselectively with minimal β-elimination by routes employing, respectively, Mitsunobu chemistry and cyclic sulfamidate nucleophilic ring opening from trans- and cis-β-hydroxy-α-amino-γ-lactam precursors. This diversity-oriented method provides stereochemically pure dipeptide mimics bearing Cys, Ser, Thr, Dap, Dab, His, and other amino acid residues with constrained backbone and side chain conformations.

Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

“…tert -Butyl (3 R , 4 S , 2′ R )-2-[3-(Fmoc)amino-4-hydroxy-2-oxopyrrolidin-1-yl]-3-methylbutanoate [(3 R , 4 S , 2′ R )-12] was prepared as previously described (Geranurimi and Lubell, 2018).…”

Stereoselective synthesis of a b -methylthio a-amino g-lactam dipeptide, a S-methyl-Cys-Val mimic

“…[3][4][5] Recently, a set of β-substituted α-amino-γ-lactam residues were synthesized using β-hydroxy-α-amino-γlactam (Hgl) residue 1 as a convenient precursor (Figure 1). [5,6] Mitsunobu reactions on the trans isomer of Hgl trans-1 with pro-nucleophiles having pKa values between 3 and 7 provided a variety of cis-β-substituted Agl analogs 2a-g in 49-80% yields. [6] Moreover, treatment of trans-Hgl 1 with diphenylphosphoryl azide (DPPA) as a hydrazoic acid equivalent under Mitsunobu conditions gave in 60% yield the corresponding β-azido-Agl residue, which was further converted to its phenyltriazole counterpart in 80% yield by copper-catalyzed azide alkyne cycloadditions.…”

“…[5,6] Mitsunobu reactions on the trans isomer of Hgl trans-1 with pro-nucleophiles having pKa values between 3 and 7 provided a variety of cis-β-substituted Agl analogs 2a-g in 49-80% yields. [6] Moreover, treatment of trans-Hgl 1 with diphenylphosphoryl azide (DPPA) as a hydrazoic acid equivalent under Mitsunobu conditions gave in 60% yield the corresponding β-azido-Agl residue, which was further converted to its phenyltriazole counterpart in 80% yield by copper-catalyzed azide alkyne cycloadditions. [6] Attempts to employ Mitsunobu reaction on cis-Hgl cis-1 gave however only dehydro-lactam.6 Cyclic sulfamidate 3 was thus synthesized from cis-Hgl cis-1 to disfavor β-elimination to dehydro-lactam.…”

“…[6] Moreover, treatment of trans-Hgl 1 with diphenylphosphoryl azide (DPPA) as a hydrazoic acid equivalent under Mitsunobu conditions gave in 60% yield the corresponding β-azido-Agl residue, which was further converted to its phenyltriazole counterpart in 80% yield by copper-catalyzed azide alkyne cycloadditions. [6] Attempts to employ Mitsunobu reaction on cis-Hgl cis-1 gave however only dehydro-lactam.6 Cyclic sulfamidate 3 was thus synthesized from cis-Hgl cis-1 to disfavor β-elimination to dehydro-lactam. [6] Ring opening of sulfamidate 3 has already provided β-azido-Agl 4a and constrained protected cysteine 4b ( Figure 1).…”

“…[6] Attempts to employ Mitsunobu reaction on cis-Hgl cis-1 gave however only dehydro-lactam.6 Cyclic sulfamidate 3 was thus synthesized from cis-Hgl cis-1 to disfavor β-elimination to dehydro-lactam. [6] Ring opening of sulfamidate 3 has already provided β-azido-Agl 4a and constrained protected cysteine 4b ( Figure 1). Exploring the chemistry of sulfamidate 3 further, we now report a method to provide constrained S-alkyl Cys residues (e.g., 5).…”