“Doubly Customizable” Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

Abstract

Readily available, low-cost 4R-hydroxy-l-proline (Hyp) is introduced as a “doubly customizable” unit for the generation of libraries of structurally diverse compounds. Hyp can be cleaved at two points, followed by the introduction of new functionalities. In the first cycle, the removal and replacement of the carboxylic group are carried out, followed (second cycle) by the scission of the 4,5-position and manipulation of the resulting chains. In this way, three new chains are generated and can be transformed independently to afford a diversity of products with tailored substituents, such as β-amino aldehydes, diamines, β-amino acid derivatives, including N-alkylated ones, or modified peptides. Many of these products are high-profit compounds but, in spite of their commercial value, are still scarce. Moreover, the process takes place with stereochemical control, and either pure R or S isomers can be obtained with small variations of the synthetic route.

Site-selective modification of peptide backbones

“…The site-selective modification of C-α positions often uses "customizable units" which can be differentiated from the other amino acid residues. 11 Among them, glycine is the most frequently employed. Other units are serine, threonine, glutamic acid, proline and hydroxyproline.…”

“…Other units are serine, threonine, glutamic acid, proline and hydroxyproline. [11][12] The special case of dehydroaminoacid units will be discussed as well. 13 The first significative advance was reported by Seebach et al, who generated glycine enolates at low temperatures, and trapped them with electrophiles, while the other aminoacids in the peptide remained unaffected.…”

“…49a The drawback of many of these procedures is the moderate stereocontrol. Therefore, a significative advance was obtained with the development of customizable units, such as hydroxyproline by Boto et al 11,50 and proline by White et al, 12 that allowed the generation of new residues retaining a high optical purity.…”

“…52 Recently the use of Hyp as a doubly customizable unit was reported by the same group (Scheme 17). 11 A one-pot radical decarboxylation-oxidation-addition of C-nucleophiles allowed the modification of the C-terminal position of the peptide 67 and replacement of the carboxyl group by a variety of other chains, with high stereoselectivity due to the presence of an stereogenic center at C-4. Deprotection of the hydroxyl group activated the unit 68 for C 4 -C 5 cleavage of the pyrrolidine ring, affording a β-amino aldehyde that could be converted into other derivatives as seen before.…”

“…10 Other strategies such as scission reactions of serine, threonine, hydroxyproline, glutamic acid or C-terminal residues, followed in situ by the addition of new chains, have also been reported, providing from α,β-α,γ-or α,δ-peptide hybrids to peptides with a variety of N-substituents. 11 The oxidation of proline with iron catalysts affords open-chain counterparts. 12 The transformation of rigid, cyclic residues into acyclic ones or viceversa can have a strong impact on peptide conformation.…”