From Amino Acids to Nature-Inspired Molecular Scaffolds: Incorporation of Medium-Sized Bridged Heterocycles into a Peptide Backbone

Abstract

Novel molecular scaffolds comprising two to four bridged and fused heterocycles were synthesized from amino acids using seven-membered endocyclic N-acyliminium ions as key intermediates in acid-mediated tandem reactions with internal nucleophiles. This complexity-generating synthesis proceeds with high efficiency and with full stereocontrol of the newly generated stereogenic center. These results have extended the scope of medium-sized cyclic iminium ion chemistry, making it applicable as a regio- and stereoselective synthetic strategy for the generation of complex polycyclic structures. Furthermore, its compatibility with the traditional Merrifield synthesis of peptides on solid supports allowed the incorporation of the previously unexplored conformationally restricted cyclic systems into peptides without a need to independently synthesize the scaffold.

Synthesis of hybrid hydrazino peptides: protected vs unprotected chiral α-hydrazino acids

“…Intervention into peptide backbone by incorporation of non-natural amino acids or replacement of peptide bond with isosteres has a major implication on peptidomimetic properties. Medium-sized bridged heterocycles (La-Venia et al 2014 ), sulfono-γ-amino acids (Wu et al 2015 ), cyclopentane-based γ-amino acid (Giuliano et al 2013 ), 2-aminobenzenesulfonic acid (Kale et al 2013 ), N -amino-imidazolin-2-ones (Proulx and Lubell 2012 ) are some examples of effective secondary structure inducers upon incorporation into peptide backbone. Replacement of α-carbon or backbone extension leads to oligomers with well-established folding properties: azapeptides, azadepsipeptides, β- and γ-peptides, aminoxypeptides, and hydrazinopeptides (Avan et al 2014 ).…”

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

“…[50] To extendt he portfolioo ft arget compounds, we synthesized acyclic precursors with internal aromatic carbon nucleophiles activatedb ye lectron-donatingg roups (methoxy, methylenedioxy, BB1 {6}a nd {7}). To determine the effect of the nucleophile, we investigatedt he cyclization with diaminopropane, replacing the oxygen nucleophile by nitrogen{ 5}.…”

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

“…The isolation of these specific bicycles was not successful because of the formation of ac omplex mixture of isomers ((S)-10,( R)-10,a nd 13)i n addition to the dipeptide produced by acrolein elimination. [31,41] In addition, by changing the N-substituent of the internal nucleophile from sulfonamide (Nos) to carbamate (Alloc), only enamide 13{1,9,1,1} was formed duet od ecreased nucleophilicity (entry 11).…”

“…As described in our previousp aper,t he presence of ab ase in the reaction inducedt he elimination of acrolein from the aldehyde, providing N-substituted dipeptide 14. [31] Finally,t oe valuate the effect of incorporation of the sevenmembered fused bicycles as peptideb ackbone constraints, two simple modela cyclic precursors werep repared in which the fused cycle mimicked two amino acids of the peptide backbone. The first model (i.e.,t ripeptide(Nos-Fused bicycle-Ala-NH 2 ) 10{3,1,1,1})w as obtained from acyclic intermediate 4{3,1,1,1} in high crude purity (Table 1, entry 3).…”

“…We recently reported the regio-and stereoselectives olid-phase synthesis of medium-sized bridged heterocycles by using tandem N-acyliminium ion cyclization-nucleophilic addition. [31] In this communication, we report an analogousa pproach for the synthesis of molecular scaffoldsc omposed of medium-sized fused rings. Synthesis of biomimetic medium rings has recently attracted attention,a lthoughu sing different chemicalroutes.…”