2 research outputs found
Synthesis and functionalization of azetidineâcontaining small macrocyclic peptides
Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3âaminoazetidine (3âAAz) subunit as a new turnâinducing element for the efficient synthesis of small headâtoâtail cyclic peptides. Greatly improved cyclizations of tetraâ, pentaâ and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Postâcyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained fourâmembered azetidine. An special feature of this chemistry is that further lateâstage modification of the resultant macrocyclic peptides can be achieved via the 3âAAz unit.  This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a clickâbased approach employing a 2âpropynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, allâtrans conformation. Moreover, introduction of a 3âAAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.</p
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Synthesis and functionalization of azetidineâcontaining small macrocyclic peptides
Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3âaminoazetidine (3âAAz) subunit as a new turnâinducing element for the efficient synthesis of small headâtoâtail cyclic peptides. Greatly improved cyclizations of tetraâ, pentaâ and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Postâcyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained fourâmembered azetidine. An special feature of this chemistry is that further lateâstage modification of the resultant macrocyclic peptides can be achieved via the 3âAAz unit.  This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a clickâbased approach employing a 2âpropynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, allâtrans conformation. Moreover, introduction of a 3âAAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.</p