Fukuyama–Mitsunobu alkylation in amine synthesis on solid phase revisited: N-alkylation with secondary alcohols and synthesis of curtatoxins

The Fukuyama–Mitsunobu amination strategy has emerged as an efficient means of N-alkylation of peptides and sulfonamides, as well as a method for synthesis of polyamines on solid phase. Here, an array of reagent combinations for solid-phase alkylation with secondary alcohols was examined in various solvents. The classical reagents DEAD–PPh3 as well as DEAD–PEt3 proved applicable for a single alkylation step. Sharply dropping yields in successive alkylation steps were identified as the most serious limitation of the use of Fukuyama–Mitsunobu reaction in SPS of polyamines using primary and in particular secondary alcohols.