Although the Ugi multicomponent reaction is more than 40 years old, there is still room for its application to the discovery of new multicomponent transformations, even within the constraints of its ...classic four‐reactant menu (aldehyde, amine, carboxylic acid, and isocyanide). Replacement of a primary amine with a secondary one thus allows the Mumm‐like rearrangement step to be avoided, freezing the reaction course at the stage of an imino‐anhydride intermediate susceptible to alternative nucleophilic trapping. Mainstream post‐transformation strategies can then add a further level of complexity. The potential of this approach to expedite access to molecular scaffolds of biological relevance and to create unprecedented chemical diversity is outlined.
The decade‐long development of modified Ugi reactions that use secondary rather than primary amines is summarized, highlighting the potential of this strategy to generate unprecedented chemical diversity and to provide shortcuts to various classes of nitrogen compounds (polyamines, heterocycles) of recognized value in biomedical research.
The particular and unique mechanism of the copper‐catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3‐trisubstituted 1,4‐triazoles in ...excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four‐component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as “interrupted click reactions”.
The copper‐catalyzed reaction between azides and alkynes, known as CuAAC, has allowed for the efficient synthesis of 1,2,3‐trisubstituted 1,4‐triazoles and the formation of a metallocycle intermediate. This intermediate can be used for creating new structures or generating multi‐component reactions, collectively referred to as “interrupted click reactions”
A chemistry professor explains the mechanism of the copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC) while suggesting that by interrupting the click reaction, it is possible to exploit the ...reactivity of the copper metallacycle intermediate to synthesize new products. The students who are listening are imagining novel synthetic pathways and finding ways to access products that are typically hard to obtain. More information can be found in the Review by M. Giustiniano, G. C. Tron and co‐workers (DOI: 10.1002/chem.202303844).
Biogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly ...increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ in their structure, have demonstrated high antitumor activity and are involved in clinical trials. The chemical synthesis of PAs and their conjugates require the correct choice of synthetic pathways-methods for constructing conjugates and the orthogonal protection of amino groups. The most common methods of synthesis of PA conjugates are acylation of regioselectively protected PAs or their alkylation under the conditions of the Fukuyama reaction. One of the most promising methods of PA synthesis is the use of a multicomponent Ugi reaction, which allows various PAs to be obtained in high yields. In this review, we describe and analyze various approaches that are used in the synthesis of polyamines and their conjugates.
Sulfur‐centered radicals have a key role in a plethora of synthetic organic transformations, whose scope has been further expanded thanks to the possibility to generate such species under visible ...light photocatalytic conditions. This review focuses on those transformations involving isocyanides and sulfur‐centered radicals with the aim to highlight the chemical space accessible, both in terms of complexity and diversity, and the mechanistic rational underpinning the current and future development of such chemical methodologies.
Sulfur‐centered radicals have a key role in a plethora of synthetic transformations, whose scope is ever‐expanding thanks to visible light photocatalysis. The current review focuses on those transformations involving isocyanides and S‐centered radicals and aims to highlight the chemical space accessible and the mechanistic rational underpinning current and future developments.
Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be ...synthesized
de novo
starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to re-form NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.
Isocyanide‐based multicomponent reactions claim a one century‐old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has ...boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical‐polar crossover pathways, to photoinduced and self‐catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions.
Isocyanide‐based Multicomponent Reactions in a new light! A review about challenges, potentialities, new trends, and future directions of exploiting isocyanide unique reactivity features under visible light irradiation.
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