Macrocyclization of Linear Peptides Enabled by Amphoteric Molecules

Abstract

There has been enormous interest in both naturally occurring and synthetic cyclic peptides as scaffolds that preorganize a given amino acid sequence into a rigid conformation. Such molecules have been employed as nanomaterials, imaging agents, and therapeutics. Unfortunately, the laboratory synthesis of cyclic peptides directly from linear precursors is afflicted by several thermodynamic and kinetic challenges, resulting in low chemical yields and poor chemo- and stereoselectivities. Here we report that amphoteric amino aldehydes can be used for efficient syntheses of cyclic peptides in high yields and selectivities starting from alpha-amino acids or linear peptides. The cyclizations effectively operate at unusually high molar concentrations (0.2 M), while side processes such as epimerization and cyclodimerization are not observed. The products are equipped with sites that allow for a highly specific, late-stage structural modification. The overall efficiency of the macrocyclization is due to the coexistence of nucleophilic and electrophilic reaction centers in amphoteric amino aldehydes.

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

“…Electrostatic preorganization of amphoteric peptides has been discussed previously (63,64). The inner salts invoked here as intermediates formed at low concentration would likewise be expected to offset entropic costs associated with ring formation (64,65). It is also consistent with a general lack of oligomeric products formed in the catalysis, which can limit other peptide cyclization methods (45,66,67).…”

“…Reductive elimination or displacement of palladium would follow, leading to product. Electrostatic preorganization of amphoteric peptides has been discussed previously (63,64). The inner salts invoked here as intermediates formed at low concentration would likewise be expected to offset entropic costs associated with ring formation (64,65).…”

Multicomponent Reactions, Union of MCRs and Beyond

“…A novel MCR approach towards aspergillamide A (54) was described by Dömling et al using an Ugi 4CR between N-acetylleucine (50), methylamine (51), phenylacetaldehyde (52) and (E/Z)-3-(2-isocyanoethenyl)indole (53), and the natural product was obtained in one step (Scheme 9). [45] The natural product and proteasome inhibitor omuralide (59) has been synthesized in a stereocontrolled manner using an intramolecular U-4CR of the ketocarboxylic acid 55 as a key step (Scheme 10).…”

6.11 N-Acylation Reactions of Amines

“…346 ingenious ligation approach employing tert-butylisonitrile and an aziridine aldehyde to facilitate macrocyclization of linear tripeptides to afford cyclic peptides that contain reactive aziridine groups that can be derivatized as required. 347 Many cyclic peptide natural products have been prepared via intramolecular peptide bond-forming reactions using conventional coupling agents ( Figure 52), with the full power of 'onium' coupling agents having been demonstrated for the synthesis of the cyclic peptides didemnin A 348 and cyclosporin O ( Figure 53). 349 Thiol-based native chemical ligation approaches have also been used to cyclize acyclic peptides in good yield, 350,351 which is particularly useful for mediating peptide bond macrocyclization between the N-and C-termini of large peptide sequences for the synthesis of circular peptides/proteins (415 α-amino acids).…”