Synthesis of Structurally Diverse Substituted Aziridinyl Glycoconjugates via Base-Mediated One-Pot Post-Ugi Cyclization

Abstract

The base-promoted intramolecular cyclization of Ugi-azide adduct has been demonstrated for the synthesis of highly substituted aziridinyl glycoconjugates in one pot. The reactions are scalable and efficient and have an operationally simple broad substrate scope. To gain insight into the mechanism of aziridine formation, DFT and control experiments show that the cyclization of the aziridine glycoconjugate pathway was preferred, as it proceeds with a low activation energy barrier (0.57 kcal mol–1), which supports our experimental observation.

An Overview on the ChemicalN‐Functionalization of Sugars and Formation ofN‐Glycosides

“…Next, toward the enhancement for N-functionalization, our group first introduced a noval strategy to synthesize highly substituted azridinyl glycoconjugates from glycosyl amino alcohols in a one-pot manner via Isocyanide-based multicomponent Ugi reaction followed by intramolecular S N 2 cyclization (Scheme 12). [27] This versatile synthetic approach leads to a highly substituted azridinyl glycoconjugates rather than morpholine derivatives. The major aspects of this methodology are a) show unique reactivity associated with glycosyl amino alcohols b) formation of unprecedented extraordinary class of three-membered strained ring rather than the 6-membered morpholine ring c) highly substituted aziridinyl glycoconjugates via one-pot post Ugi-cyclization protocol.…”

“…Next, toward the enhancement for N ‐functionalization, our group first introduced a noval strategy to synthesize highly substituted azridinyl glycoconjugates from glycosyl amino alcohols in a one‐pot manner via Isocyanide‐based multicomponent Ugi reaction followed by intramolecular S N 2 cyclization (Scheme ) …”

Catalyst‐ and Base‐free One‐pot, Multicomponent, De Novo Assembly of Structurally Diverse Morpholine Glycoconjugates

“…Additionally, the widely studied Ugi four‐component reaction (Ugi‐4CR) has long been recognized for its capacity to construct countless bioactive scaffolds effectively [15] . More fascinatingly our previous work unveiled, when halo substituted ketone like chloroacetone along with glycosyl amino alcohol were used as substrates, only the normal Ugi tetrazole reaction took place followed by base mediated post‐intramolecular cyclization to obtain strained aziridinyl glycoconjugates in place of morpholine skeletons (Scheme 1b) [16] . A unified strategy to access structurally diverse and highly substituted morpholine glycoconjugates based on a versatile de novo approach using multicomponent reaction chemistry would be an ideal alternative to the existing methods.…”

“…[15] More fascinatingly our previous work unveiled, when halo substituted ketone like chloroacetone along with glycosyl amino alcohol were used as substrates, only the normal Ugi tetrazole reaction took place followed by base mediated postintramolecular cyclization to obtain strained aziridinyl glycoconjugates in place of morpholine skeletons (Scheme 1b). [16] A unified strategy to access structurally diverse and highly substituted morpholine glycoconjugates based on a versatile de novo approach using multicomponent reaction chemistry would be an ideal alternative to the existing methods. Recently, introducing a sugar moiety with privileged scaffolds has appealed to the field of glycoscience because of the improvement in the pharmacokinetic (PK) properties and metabolic stability including biological functions, etc.…”

Intramolecular 6-exo-dig Post-Ugi Cyclization of N-Substituted 2-Alkynamides: Direct Access to Functionalized Morpholinone Glycoconjugates

“…The metal free, site-selective, mild reaction condition remains an unresolved issue in this development that we anticipated from a glycosyl amino alcohol via N-substituted 2-alkynamides Ugi adducts. Recently, our group exploited the unique behavior of a glycosyl amino alcohol in which their Ugi tetrazole adducts from chloroacetone underwent post-Ugi cyclization into strained aziridinyl glycoconjugates rather than morpholine . Taking advantage of this unique reactivity profile of a glycosyl amino alcohol, we further explored it via performing acid Ugi followed by cyclization to grant the fast and various functionalized morpholinone glycoconjugates.…”