Synthesis of multivalent aminoglycoside mimics via the Ugi multicomponent reaction

The synthesis of multivalent neoglycoconjugates with 2,6-diamino-2,6-dideoxyglucose is accomplished by a flexible Ugi multicomponent approach leading to mono-, di- and tri-valent carbohydrate clusters.     

Ugi multicomponent reaction with hydroxylamines: an efficient route to hydroxamic acid derivatives

Ugi condensations with O-protected hydroxylamines have been successfully performed in THF using ZnCl₂ as activating agent. This synthetic strategy opens up the route to a very convergent assemblage of `internal' hydroxamic acid derivatives (N-acyl-N-hydroxypeptides).     

A convergent synthesis of enantiopure bicyclic scaffolds through multicomponent Ugi reaction

An efficient and convergent Ugi synthesis of enantiomerically pure N-acyl-2,5-disubstituted pyrrolidines was coupled with an appropriate secondary transformation to give two series of bicyclic derivatives, namely hexahydro pyrrolo-oxazocinediones and -diazepinediones.     

Enantio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines through a multicomponent Ugi reaction and their transformation into bicyclic scaffolds

A new enantio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines through a multicomponent approach has been developed, using highly reactive pyrrolines 4 as preformed cyclic imines. The pyrrolidines obtained using protected aspartic acid as acid component in the Ugi condensation have been transformed into two epimeric bicyclic lactones 18, 19, which may find an application as external reverse turn inducers.     

Participation of ethyl 3-formylindole-2-carboxylate with the Ugi four-component condensation reaction

Multicomponent condensation of ethyl 3-formylindole 2-carboxylate, amines, isocyanide and (S)-N-boc-alanine or (S)-N-boc-serine is described. This Ugi four-component condensation (Ugi-4CC) reaction yielded a series of novel dipeptides containing an indolyl moiety. These compounds exhibit potential biological activity.     

Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution: convergent multicomponent synthesis of 1-sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives

A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi multicomponent reaction followed by a subsequent intramolecular SN2 reaction was studied. 1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were obtained in very high yield through a Ugi multicomponent reaction followed by Mitsunobu cyclization. On the other hand, aliphatic 1-sulfonyl 1,4-diazepan-5-ones 2 could be obtained employing different cyclization conditions (sulfuryl diimidazole). A similar approach toward diazocane rings using hydroxamates as nucleophiles was less successful, affording only O-cyclized adducts or unexpected side products. A mechanistic explanation of the observed outcomes is proposed.     

Imides: forgotten players in the Ugi reaction. One-pot multicomponent synthesis of quinazolinones

Up to now, the synthesis of quinazolinones has required lengthy synthetic procedures. Here, we describe an innovative one-pot multicomponent reaction leading to highly substituted quinazolinones. We believe that this novel transformation may open the door for the generation of new and pharmacologically active quinazolinones, but, most important of all, the resurrection of the imide-Ugi scaffold paves the way for the synthesis of novel molecular architectures.     

One-pot tandem complexity-generating reaction based on Ugi four component condensation and intramolecular cyclization

A novel complexity-generating reaction is described, which can be used in a high-throughput parallel solution-phase combinatorial format. The synthetic pathway features the Ugi four component reaction followed by intramolecular cyclization via C-C bond formation. Starting from readily available initial reactants, the described approach leads to generation of novel 3-oxoisoindoline-1-carboxamides with four points of diversity around the core scaffold. The scope and limitations of the involved chemistry and some chemical transformations of the synthesized compounds are discussed.     

Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-membered lactams

A new straightforward entry into unsaturated nine-membered lactams of potential use as external reverse turn inducers was developed. It is based on an Ugi multicomponent reaction using two unsaturated substrates, followed by highly stereoselective ring-closing metathesis (RCM). The synthesis of a nine-membered secondary lactam by RCM is reported for the first time.     

Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction

A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.     

Highly luminescent Eu(3+) and Tb(3+) macrocyclic complexes bearing an appended phenanthroline chromophore

A two-component ligand system (1) containing 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) as the hosting unit for the lanthanide cations and an appended asymmetrically functionalized 1,10-phenanthroline (phen) as the chromophore was synthesized. The 1:1 complexes with Eu(3+), Gd(3+), Tb(3+), and Yb(3+) have been prepared and studied in aqueous solution. For Gd.1, a relaxivity value of 2.4 mM(-1) s(-1) has been measured at 20 MHz and 25 degrees C, which indicates that there are no water molecules in the first coordination sphere of the metal ion. The analysis of high resolution (1)H NMR spectra of Yb.1 supports this view and suggests the direct involvement of the phen moiety in the coordination of the metal ion. For Eu.1 and Tb.1, the absorption and luminescence spectra, the overall luminescence efficiencies, and the metal-centered (MC) lifetimes were obtained; coordination features were also determined by comparing luminescence properties in water and deuterated water. For Eu.1 and Tb.1, the overall emission sensitization (se) process in air-equilibrated water was found to be notably effective with phi(se) = 0.21 and 0.11, respectively. A detailed study of the steps originating from light absorption at the phen unit and leading to MC sensitized emission was performed.     

Tandem one pot synthesis of 1,5-benzodiazocine-2-one by isocyanide based Ugi multicomponent reaction

We have developed an efficient one-pot, two-step reaction protocol for the synthesis of eight-membered 1,5-benzodiazocine-2-ones by Ugi four-center three-component coupling reaction (U-4C-3CR) and subsequent reductive cyclization using Fe/NH₄Cl in protic solvent.     

Applications of the Ugi reaction with ketones

A convenient synthesis of highly functionalized, α,α-disubstituted amino acid amide derivatives has been accomplished by using cyclic and acyclic ketones as the carbonyl inputs in the Ugi multicomponent reaction. An application of this extension of the Ugi reaction to the synthesis of α,α-divinyl amino acids that may be cyclized via ring-closing metathesis to provide highly substituted pyrrolidines is described.     

Solvent-free Ugi four-component condensation: application to synthesis of philanthotoxins-12 analogues

Philanthotoxins-12 analogues was synthesized by a highly convergent approach, utilizing an efficient, simple, and convenient one-pot Ugi four-component solvent-free method as key step, followed by removal of the protecting groups in the presence of trifluoroacetic acid.     

Synthesis of 11-aza-artemisinin derivatives using the Ugi reaction and an evaluation of their antimalarial activity

A series of new 11-aza-artemisinin derivatives were prepared from 11-aza-artemisinin using the Ugi reaction. An antimalarial activity evaluation against the FcB1 strain indicated that compounds 7, 10, and 16 had very strong inhibitory activity. Comparison of the activity among the synthetic derivatives of this series revealed that the length of the side chain R group on the amide nitrogen could be critical for their antimalarial properties.     

Novel succinct routes to quinoxalines and 2-benzimidazolylquinoxalines via the Ugi reaction

This Letter reveals a unique, user-friendly, concise two-step, one-pot protocol for the synthesis of highly substituted quinoxalines. Conducting the Ugi reaction with appropriately functionalized classical Ugi reagents with subsequent acid treatment of the Ugi adduct affords collections of diversified quinoxalines in good to excellent yields. The methodology exploits what may be viewed as a ‘convertible carboxylic acid’, which in addition may be captured in an intramolecular sense to generate structurally complex 2-benzimidazolylquinoxalines in a mere two steps.     

A novel highly selective chiral auxiliary for the asymmetric synthesis of L- and D-alpha-amino acid derivatives via a multicomponent Ugi reaction

This paper describes the synthesis of a bicyclic beta-amino acid scaffold in both pure enantiomeric forms and its application as chiral auxiliary in an intramolecular version of the Ugi multicomponent reaction (U-5C-4CR) to prepare alpha-amino acid derivatives of both D- and L-series in a straightforward and very stereoselective manner. The mild conditions required for the Ugi condensation and for the removal of the chiral auxiliary make this method very attractive to prepare a wide range of differently structured N-alkylated and unalkylated amino acid derivatives.     

Synthesis of novel glutarimide derivatives via the Ugi multicomponent reaction: affinity towards the E3 ubiquitin ligase substrate receptor Cereblon

The glutarimide moiety, common in many immuno-modulatory drugs, was decorated with lactam and diamide side chains via two variants of the Ugi reaction, namely, with isocyanide, aldehyde and acid or with isocyanide and oxo acid. The resulting diastereomerically pure compounds were evaluated for their affinity towards the E3 ubiquitin ligase substrate receptor Cereblon.