•Efficient synthesis of the unnatural amino acids for stapled peptide was developed.•Synthesis strategy by chiral Ni(II) complex was modified and optimized.•α-Bisalkenyl amino acid was synthesized by achiral Ni(II) complex strategy.•Reaction condition, yield, atom economy, and optical purity were optimized.The procedures for the synthesis of various α-alkenyl and alkyne amino acids were systematically optimized in light of enhancing atom economy, reducing hazardous reagent usage, and simplifying workup. By starting with Boc-Pro-OH and coupling with EDCI/DMAP followed by alkylation, chiral auxiliary was synthesized with high yield and enantioselectivity. For alkylation of the chiral complex, tBuONa was found and proved by quantitative calculation to be superior to tBuOK in generating more nucleophilic enolate salt, thereby can significantly enhance yield under room temperature. Final Fmoc protection was also dramatically facilitated in one-pot sequential manner by adding EDTA-2Na as the nickel chelator. Synthesis of α-bisalkenyl amino acid was also accomplished by achiral complex approach with high yield and efficacy. Accordingly, five most commonly used N-Fmoc protected α-alkenyl and alkynyl amino acids were synthesized and characterized.Download high-res image (92KB)Download full-size image

A novel strategy of solid phase synthesis of N-cycloguanidinyl-formyl peptides has been established and investigated which involved coupling orthogonal protected diaminoacid with resin bound peptide, α-amino group deprotection, guanidinylation of α-amino group by bis-Cbz-1H-pyrazole-1-carboxamidine followed by cleavage and cyclization in solution, and finally removing Cbz by palladium catalyzed hydrogenation. Through this method, cycloguanidine could be introduced to either N-terminus or sidechain of designated peptides. The reaction conditions were facile, straightforward, and totally adaptive to common solid phase peptide synthesis strategy.

A convenient one-step synthesis of five-membered or six-membered imino-protected cyclic guanidine via an intramolecular ring-closure reaction of alkyl diamine (2a–2g) with 1, 3-diamino-protected methylisothiourea (1a and 1b) was established and investigated. Amino guanidine such as 3-(2-aminoethyl)-1, 2-dibenzyloxycarbonylguanidine (4a) has been proved to be the intermediate of the reaction via utilizing mono-protected diamine as starting material. The intramolecular ring closure of 4a results in 2-benzyloxycarbonyliminoimidazolidine (3a). This new one-step synthesis has advantages of simple condition, easy workup procedure and reasonable yield.