Metal‐Free, Site‐Selective Peptide Modification by Conversion of “Customizable” Units into β‐Substituted Dehydroamino Acids

Abstract

Our site-selective modification of serine or threonine units in peptides allows the generation of β-substituted dehydroamino acids, which increase peptide resistance to hydrolysis and may improve their biological properties. Both the terminal and internal positions can be modified, and different customizable units can be activated separately. Remarkably, high Z selectivity is achieved, even at internal positions. The conversion involves a one-pot oxidative radical scission/phosphorylation process by using the low-toxicity (diacetoxyiodo)benzene/iodine system as the scission reagent. The resulting α-amino phosphonates undergo a Horner-Wadsworth-Emmons reaction to produce the dehydroamino acid derivatives (in a Z/E ratio of usually >98:2) under mild and metal-free conditions.

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

“…Finally, the one-pot scission-addition of phosphorous nucleophiles was studied for the site-selective modification of peptides ( Boto, Gallardo et al, 2005b ; Saavedra et al, 2012d ; 2018 ). After the oxidative radical scission a phosphite was added, and an aminophosphonate such as compound 72 was formed.…”

“…Our group and others have described different applications of the β-scission of O -radicals, generated from alcohols, acetals or acids under Suárez conditions, to the preparation of bioactive products or their analogs ( Saavedra et al, 2020 ; Cuevas et al, 2021 and references cited therein). However, in these protocols a further development was introduced: coupling these oxidative scission processes to the addition of carbon, nitrogen, phosphorous, oxygen, hydrogen, sulfur and other nucleophiles ( Boto, Gallardo et al, 2006 ; 2007a ; Boto, Hernández et al, 2008a,b ; 2009 ; Batchu et al, 2014 ; Carro et al, 2017 ; Saavedra et al, 2018 ; Santana and González, 2020 ). In effect, the scission generates a C -radical that can be readily oxidized to a cationic intermediate when the latter is stabilized by adjacent groups.…”

The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs

“…In a second approach for the generation of peptide libraries by site-selective modification, the core of the starting amino acid (customizable unit) undergoes a scission process and is converted into a very different one (e.g., by cleavage of the lateral chain and attachment of a new one). Recently, our group has introduced new customizable units that allow the site-selective modification of peptides and the creation of both cationic or hydrophobic residues [ 111 , 115 , 116 , 117 , 118 , 119 ]. Peptide ligation is also possible, as shown in the Scheme 8 .…”

Selective modification of sulfamidate-containing peptides

“…The site-selective modification of peptides with enriched biological functions, particularly in near-physiologic conditions, entails a significant challenge for chemical biology due to the similar reactivity of their amino acid constituents. [1][2][3] Considerable progress has been made in this field by using tagged [4][5][6] or customizable units, [7][8][9][10] although differentiating among similar units within the same or coexisting peptides, commonly poses an additional problem. In this context, performing chemical reactions on a solid support has considerable advantages with respect to solution phase chemistry.…”