Cyclic Imines in Ugi and Ugi-Type Reactions

Abstract

Ugi four-component reactions (U-4CRs) are widely recognized as being highly efficient for the synthesis of pseudopeptides. However, the products of these reactions are not so interesting as drug candidates because they are not conformationally restricted enough for a potent interaction with biological targets. One possible way to overcome this problem is to replace amine and oxo components in the U-4CRs with cyclic imines in so-called Joullié−Ugi three-component reactions (JU-3CRs). This approach provides a robust single-step route to peptide moieties connected to N-heterocyclic motifs that are found as core skeletons in many natural products and pharmaceutical compounds. JU-3CRs also provide much better diastereoselectivity than their four-component analogues. We survey here the redesign of many synthetic routes for the efficient preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds connected to the peptide backbone. Additionally, in the Ugi reactions based on the cyclic imines, α-acidic isocyanides, or azides can be replaced with normal isocyanides or acids, respectively, leading to the synthesis of N-heterocycles attached to oxazoles or tetrazoles, which are of great pharmaceutical significance. This Review includes all research articles related to Ugi reactions based on the cyclic imines to the year 2020 and will be useful to chemists in designing novel synthetic routes for the synthesis of individual and combinatorial libraries of natural products and drug-like compounds.

Dibenzothiazepine Based MCR Chemistry

“…[16] Our retrosynthetic plan towards distinct cycles such as the tetrazole, imidazole, γand δ-lactams rings consists of MCR-based annulations, starting from the versatile building block 6 and targeting the imine bond (Scheme 1). [40]…”

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

“…Isocyanide‐based multicomponent reactions (IMCRs) provide excellent building blocks for post‐IMCR modifications [8–15] . IMCRs and post‐IMCR transformations help construct diverse small molecule libraries for drug discovery research, including applications in biomedical, pharmaceuticals and peptidomimetics [16–20] . Among the IMCRs, the Ugi four‐component reaction (U‐4CR) is one of the most widely explored reactions of this class, involving the condensation of an aldehyde/ketone, amine, acid, and isocyanide.…”

“…[8][9][10][11][12][13][14][15] IMCRs and post-IMCR transformations help construct diverse small molecule libraries for drug discovery research, including applications in biomedical, pharmaceuticals and peptidomimetics. [16][17][18][19][20] Among the IMCRs, the Ugi four-component reaction (U-4CR) is one of the most widely explored reactions of this class, involving the condensation of an aldehyde/ketone, amine, acid, and isocyanide. The reactivity of the Ugi adduct can be tuned by proper selection of the starting materials.…”

Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines

“…A number of transformations, in which isocyanide interacts with a previously prepared iminium salt or cyclic imines in the presence of protic acid, have been described [11][12][13][14][15]. The potency of methods, based on the Ugi reaction, increases with the possibility of subsequent modification or cyclization of obtained products of multicomponent reaction [16][17][18][19][20][21].…”