Solid-phase synthesis of Nα-benzyl-Nα-cinnamyl lysine and glutamic acid derivatives

Several variations of a solid-phase strategy for the synthesis of Nα-benzyl-Nα-cinnamyl lysine and glutamic acid derivatives are presented. Starting from the corresponding Nα-Fmoc amino acids on Wang resin, reductive alkylation using nitrocinnamaldehyde or a substituted benzaldehyde was followed by nucleophilic displacement of a substituted benzyl halide or nitrocinnamyl bromide to provide resin-bound intermediates. Diversity was added by reduction of the nitro group and derivatization of the resulting aminocinnamyl moiety with a variety of acylating or sulfonylating reagents. Using an orthogonal protecting group strategy, Nε-Dde-protected lysine derivatives were further functionalized at the side-chain amino group prior to cleavage from resin. This method allows for the preparation of analog libraries having up to four points of diversity.