1,3‐Dipolar Cycloaddition between Dehydroalanines and C,N‐Cyclic Azomethine Imines: Application to Late‐Stage Peptide Modification

Abstract

Anon-catalytic,mild, and easy-to-handle protecting group switched 1,3-dipolar cycloaddition (1,3-DC) between bior mono-N-protected Dha and C,N-cyclic azomethine imines, which affordv arious quaternary amino acids with diverse scaffolds,i sd isclosed. Specifically,n ormal-electron-demand 1,3-DC reaction occurs between biN protected Dha and C,Ncyclic azomethine imines,w hile inverse-electron-demand 1,3-DC reaction occurs between mono-N-protected Dha and C,Ncyclic azomethine imines.A bove all, the reactions can be carried out between peptides with Dha residues at the position of interest and C,N-cyclic azomethine imines,both in homogeneous phase and on resins in SPPS.I tp rovides an ew toolkit for late-stage peptide modification, labeling,and peptide-drug conjugation. To shed light on the high regioselectivity of the reaction, DFT calculations were carried out, which were qualitatively consistent with the experimental observations.

Asymmetric Synthesis of Tetrahydroisoquinoline Derivatives through 1,3-Dipolar Cycloaddition of C,N-Cyclic Azomethine Imines with Allyl Alkyl Ketones

“…Such representative examples include ( S )-salsolidine [ 13 ], ( S )-carnegine [ 14 ], ( S )-xylopinine [ 15 ] (in Figure 1 ), and so on. Novel C , N -cyclic azomethine imines as efficient 1,3-dipoles [ 16 , 17 ], are readily accessible, stable compounds that have been employed recently in various metal-catalyzed and organocatalytic 1,3-dipolar cycloadditions (1,3-DCs) [ 18 , 19 , 20 , 21 ]. These dipoles can be easily prepared and give access to pharmaceutically attractive chiral substituted tetrahydroisoquinoline skeletons.…”