Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles

Abstract

Multicomponent reactions (MCRs) are extremely popular owing to their facile execution, high atom-efficiency and the high diversity of products. MCRs can be used to access various heterocycles and highly functionalized scaffolds, and thus have been invaluable tools in total synthesis, drug discovery and bioconjugation. Traditional isocyanide-based MCRs utilize an external nucleophile attacking the reactive nitrilium ion, the key intermediate formed in the reaction of the imine and the isocyanide. However, when reactants with multiple nucleophilic groups (bisfunctional reactants) are used in the MCR, the nitrilium intermediate can be trapped by an intramolecular nucleophilic attack to form various heterocycles. The implications of nitrilium trapping along with widely applied conventional isocyanide-based MCRs in drug design are discussed in this review.

Toward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach

“…S3 ESI †). [26][27][28][29][30][31] However, the impact of this generated chiral center on the final product is minimized by the fact that it will be removed during the backbone amide deprotection step (Scheme 2). Moreover, the presence of only two diastereomers confirmed that the peptide's stereochemistry is conserved.…”

“…In this regard, the Ugi four-component reaction (Ugi-4CR) is very attractive as it offers a great inputs diversity to access complex molecules with high efficiency and atom economy. [26][27][28][29][30][31] The Ugi-4CR involves the reaction of isocyanide, carboxylic acid, amine and carbonyl compounds to afford a α-acylamino amide. 30,31 As the generated tertiary amide bond is formed between the amine and the acid components, the Ugi-4CR has been successfully used in the preparation of linear and macrocyclic peptides.…”

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

“…MCRs have been also applied in polymer [74], nucleoside [75] and carbohydrate [76] chemistry. Main field of application remains the production of heterocyclic compounds and many natural products by means of MCR [38,[77][78][79][80][81][82][83][84][85][86][87][88][89], leading directly towards drug design and discovery [90][91][92][93][94]. Scheme 9 presents a current brief of well-known multicomponent reactions [35,40,9,[95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110].…”

N-[2-(Cyclohexylamino)-2-oxoethyl]-N-(4-octyloxy)phenyl-prop-2-enamide

“…The field of peptidomimetics has seen an exciting development over the past several years, partly due to the considerable biological importance and putative proteolytic stability of synthetic peptoids over native peptides [1][2][3]. Recently, Ugi coupling [4][5][6][7][8] of various carboxylic acids, amines, isocyanates and aldehydes to a series of tripeptoids has been found to give excellent yields and these have also been reported to exhibit antifungal and antimicrobial activities [9][10][11][12][13].…”