Synthesis of Unnatural Amino Acids from Serine Derivatives by β-Fragmentation of Primary Alkoxyl Radicals

Abstract

The fragmentation of primary alkoxyl radicals has been scarcely used in synthesis since other competing processes (such as oxidation or hydrogen abstraction) usually predominate. However, when serine derivatives were used as substrates, the scission took place in excellent yields. Tandem scission-allylation, -alkylation, or -arylation reactions were subsequently developed. This one-pot methodology was applied to the synthesis of unnatural amino acids, which are useful synthetic blocks or amino acid surrogates in peptidomimetics.

Microwave versus Conventional Light Activation of O‐Radical Scission Processes

“…Scheme shows the fragmentation of the serine derivative 22 ; the glycyl cation intermediate 23 was initially generated, which was trapped by acetate ions from the reagent to give the final product 24 . [1f], The scission of the serine customizable units in peptides can be challenging, because side‐reactions such as hydrogen abstraction or oxidation could take place. Nevertheless, the scission of dipeptide 25 via the glycyl cation 26 proceeded to give mainly the desired scission product 27 as a diastereomeric mixture.…”

“…Methyl 2‐Acetoxy‐2‐benzamidoacetate (24): [11a] Table , Entry 1: A solution of N ‐benzoylserine methyl ester ( 22 ; 45 mg, 0.2 mmol) in 1,2‐dichloroethane (3 mL) was treated according to Method A during 180 min. After the usual workup, the residue was purified by rotatory chromatography on silica gel (hexanes/EtOAc, 80:20) to yield compound 24 [11a] (45 mg, 89 %) as a white solid. Table , Entry 2: A solution of substrate 22 (45 mg, 0.2 mmol) in DCE (3 mL) was treated according to Method B during 15 min.…”

Site‐selective modification of peptides: From “customizable units” to novel α‐aryl and α‐alkyl glycine derivatives, and components of branched peptides

“…The conversion of peptides with serine residues into peptides with aryl glycine units was first studied using the dipeptide 18 (Scheme ) as a model substrate. Initially, compound 18 was treated under the conditions reported for the scission of simple serine derivatives [(diacetoxyiodo)benzene (DIB) and iodine, visible light] but a complex product mixture was formed. This result could be due to side reactions (hydrogen abstraction, oxidation) or to the formation of unstable fragmentation products.…”

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

“…Thus, substrate 1 underwent oxidative radical scission of the serine lateral chain. The resulting glycyl cation was trapped by acetate ions from the reagent to give the N,O‐acetal 2 . A phosphorylation process converted acetal 2 into 2‐(diethoxyphosphoryl)glycine derivative 3 ,…”