Convergent synthesis of phosphonopeptides via phospha-Mannich reactions: Rationale on reactivity and mechanistic insights

Abstract

Phospha-Mannich reactions of benzyl carbamate, aldehydes, and methyl dichlorophosphite followed by aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters produce N-Cbz(benzyloxycarbonyl)-protected phosphonopeptides or phosphonodepsipeptides. However, similar reactions do not work when Cbz-amino amides are used instead of the carbamate. Phospha-Mannich reactions of N-Cbz-amino amides/2-(Cbz-amino)alkanesulfonamides, aldehydes, and dichloroarylphosphines and subsequent aminolysis with amino acid esters or alcoholysis with hydroxyl acid esters yield phosphinopeptides or phosphinodepsipeptides and hybrid sulfonophosphinopeptides or sulfonophosphinodepsipeptides. The different reactivities and mechanistic insights are rationalized that the α-amino alcohols generated from aldehydes and amides/sulfonamides show weaker nucleophilicity than those generated from aldehydes and benzyl carbamate. They can react with stronger electrophilic dichloroarylphosphines rather than weaker electrophilic methyl dichlorophosphite. The nucleophilicity of α-amino alcohols (amine reagents, carbamates, amides, and sulfonamides) and the electrophilicity of phosphorus reagents (dichloroarylphosphines and ethyl dichlorophosphite) control the reactivity of the phospha-Mannich reactions. Phosphorus trichloride is also efficient phosphorus reagent in the phospha-Mannich reactions because it is stronger electrophile as well.