On the Synthesis of Conformationally Modified Peptides through Isonitrile Chemistry: Implications for Dealing with Polypeptide Aggregation

Abstract

A method has been developed to introduce a dimethyleneoxy constraint joining the nitrogen atoms of two consecutive amino acids in the context of a polypeptide. Such a constraint can profoundly affect the tendency of a polypeptide to suffer aggregation and desolubilization. The constraint is readily removed under mild conditions.

Expanding the Limits of Isonitrile-Mediated Amidations: On the Remarkable Stereosubtleties of Macrolactam Formation from Synthetic Seco-Cyclosporins

“…7 Among other discoveries, two conceptually different but complementary approaches were developed to allow for ready access to N -methyl peptides (Scheme 1). In the first, a carboxylic acid and isonitrile are combined under microwave irradiation to provide an N -formyl amide (Type Ia).…”

“…In the first, a carboxylic acid and isonitrile are combined under microwave irradiation to provide an N -formyl amide (Type Ia). 7a The analogous transformation of thioacids into N -thioformyl amides is even more facile, proceeding at ambient temperature (Type Ib). 7h Under suitable reduction protocols, these Type I derived coupling products can be easily converted to their N -methylated counterparts.…”

“…7a The analogous transformation of thioacids into N -thioformyl amides is even more facile, proceeding at ambient temperature (Type Ib). 7h Under suitable reduction protocols, these Type I derived coupling products can be easily converted to their N -methylated counterparts. In the second method, the amide bond is fashioned when an exogenous secondary amine intercepts the presumed formimidate carboxylate mixed anhydride (FCMA) intermediate (Type II).…”

“…In the second method, the amide bond is fashioned when an exogenous secondary amine intercepts the presumed formimidate carboxylate mixed anhydride (FCMA) intermediate (Type II). 7k In this format, an isonitrile serves to activate the acid, but the N -bound functionality of the isonitrile is not incorporated into the product. Use of a sterically encumbered “throwaway” isonitrile 8 can be quite helpful in favoring the required bimolecular acylation pathway over internal O (or S ) → N rearrangement, which would lead to an N -formyl amide carrying the nitrogen-bound functionality.…”

“…Use of a sterically encumbered “throwaway” isonitrile 8 can be quite helpful in favoring the required bimolecular acylation pathway over internal O (or S ) → N rearrangement, which would lead to an N -formyl amide carrying the nitrogen-bound functionality. 7j …”