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

“…The reaction proceeded with higher yield (91%) and good enantioselectivity (80%) and excellent diastereoselectivity (dr 25:1) in DCE at room temperature (entry 14). However, only poor or moderate diastereoselectivities were observed in other solvents (entry 13,[15][16][17][18][19]. Furthermore, the effect of acid additives was also studied.…”

“…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, [18][19][20][21]. These dipoles can be easily prepared and give access to pharmaceutically attractive chiral substituted tetrahydroisoquinoline skeletons.…”

Two highly crystalline coordination polymers with two-dimensional PbS networks for photocatalytic synthesis of imines

“…Imines play important roles in the biological and pharmaceutical fields; therefore, it is necessary to explore efficient methods for the preparation of imines. [1][2][3] Traditional synthesis methods, such as direct condensation of amines with aldehydes and ketones, have disadvantages of low conversion and high energy consumption. [4][5][6] In recent years, the direct oxidation of amines to imines by a photocatalysis method, especially visible light catalysis, has attracted considerable attention due to its high conversion ratio, low energy consumption and environmentally benign nature.…”

Catalyst-free and oxidant-free tandem aza-Mannich/cyclization/aromatization of C,N-cyclic azomethine imines with enamides: facile synthesis of 5,6-dihydropyrazolo[5,1-a]isoquinolines

“…We envisioned that enamides 11 might be used to overcome the main challenge with C , N -cyclic azomethine imines since the protocol underwent a novel reaction pathway and mechanism (Scheme 1e). It is reasoned that aza-Mannich reaction would occur first to generate intermediate A , which then underwent annulation to give intermediate B .…”