Medicinal Chemistry of Isocyanides Massarotti, Alberto; Brunelli, Francesca; Aprile, Silvio ...
Chemical reviews,
09/2021, Volume:
121, Issue:
17
Journal Article
Peer reviewed
Open access
In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties. In 1859 the first isocyanide was synthesized by humans and in ...1950 the first natural isocyanide was discovered. Now, at the beginning of XXI century, hundreds of isocyanides have been isolated both in prokaryotes and eukaryotes and thousands have been synthesized in the laboratory. For some of them their ecological role is known, and their potent biological activity as antibacterial, antifungal, antimalarial, antifouling, and antitumoral compounds has been described. Notwithstanding, the isocyanides have not gained a good reputation among medicinal chemists who have erroneously considered them either too reactive or metabolically unstable, and this has restricted their main use to technical applications as ligands in coordination chemistry. The aim of this review is therefore to show the richness in biological activity of the isocyanide-containing molecules, to support the idea of using the isocyanide functional group as an unconventional pharmacophore especially useful as a metal coordinating warhead. The unhidden hope is to convince the skeptical medicinal chemists of the isocyanide potential in many areas of drug discovery and considering them in the design of future drugs.
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.
The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a ...4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.
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).
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.
Isocyanides, thanks to their multiple reactivities, are the main players in multicomponent reactions. While traditional approaches exploit their two‐electrons reactivity, they are currently “on ...stage”, shining in a new light thanks to the development of visible light photochemical reaction conditions. For more information, see the Review by Gian Cesare Tron and Mariateresa Giustiniano et al. (DOI: 10.1002/chem.202203150).
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An operationally simple multicomponent reaction utilizing (Z)-chloroximes, isocyanides and NH-heterocyclic rings (imidazole, benzimidazole, triazole, benzotriazole and tetrazole) ...affords a hitherto unknown class of compounds which cannot be obtained via a classical multistep two-component reaction. From this work, it appears evident: a) kinetic control dictated by the 3 + 1 cycloaddition between nitrile N-oxides and isocyanides; b) the chemical compatibility between the highly unstable nitrilium ion and the poorly nucleophilic imidazoles and related heterocycles, which quench the reaction allowing for the formation of a single product.
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