A multi-substrate screening approach for the identification of a broadly applicable Diels–Alder catalyst

Abstract

When developing a synthetic methodology, chemists generally optimize a single substrate and then explore the substrate scope of their method. This approach has led to innumerable and widely-used chemical reactions. However, it frequently provides methods that only work on model substrate-like compounds. Perhaps worse, reaction conditions that would enable the conversion of other substrates may be missed. We now show that a different approach, originally proposed by Kagan, in which a collection of structurally distinct substrates are evaluated in a single reaction vessel, can not only provide information on the substrate scope at a much earlier stage in methodology development, but even lead to a broadly applicable synthetic methodology. Using this multi-substrate screening approach, we have identified an efficient and stereoselective imidodiphosphorimidate organocatalyst for scalable Diels–Alder reactions of cyclopentadiene with different classes of α,β-unsaturated aldehydes.

Starke und sterisch begrenzte Säuren kontrollieren fünf stereogene Zentren in der katalytischen asymmetrischen Diels‐Alder‐Reaktion von Cyclohexadienonen mit Cyclopentadien

“…Erst kürzlich haben wir Imidodiphosphate (IDP), Iminoimidodiphosphate (iIDP) und Imidodiphosphorimidate (IDPi) als neuartige und privilegierte Säurekatalysatoren vorgestellt, die nahezu enzymartige, sterisch hocheingeschränkte reaktive Zentren besitzen, einen überaus breiten Säurestärke‐Bereich abdecken, der bis zu den Supersäuren reicht . Angesichts der erfolgreichen Anwendung dieser Katalysatoren in anspruchsvollen Brønsted‐ sowie Lewis‐Säure‐katalysierten C‐C‐ und C‐Heteroatom‐Bindungsbildungsreaktionen, inklusive enantioselektiver Diels‐Alder‐Reaktionen sowie weiterer Cycloadditionen, gingen wir davon aus, auch für die Cyclohexadienon‐Diels‐Alder‐Reaktion diese Katalysatorplattform zum Einsatz bringen zu können.…”

Strong and Confined Acids Control Five Stereogenic Centers in Catalytic Asymmetric Diels–Alder Reactions of Cyclohexadienones with Cyclopentadiene

“…We have recently disclosed novel and unique acid catalysts, including imidodiphosphates (IDP), iminoimidodiphosphates (iIDP), and imidodiphosphorimidates (IDPi) that display enzyme‐like, highly confined active sites and cover a broad range of acidities, approaching superacidic p K a values . Given our recent success in applying such confined acids in both Brønsted and Lewis acid catalysis in various challenging asymmetric carbon–carbon and carbon–heteroatom bond‐forming reactions, including diverse enantioselective Diels–Alder reactions and other [4+2] cycloadditions, we hypothesized that our acids might also provide a suitable catalyst platform for the cyclohexadienone Diels–Alder reactions under study here.…”

Synthesis and Evaluation of Nematicidal Activity of Compounds Derived from Norbornadiene

“…26 Bimolecular nucleophilic substitution reactions (S N 2) of alkyl and benzyl bromides with the dicarboxylate derived from compound 3 provided 21 esters in yields that varied from 22 to 89% after silica-gel column chromatography (Scheme 1). The dimethyl ester (4) was obtained by esterification with methanol catalyzed by concentrated sulfuric acid. The reaction mixture was neutralized with potassium carbonate and extracted with dichloromethane to provide the dimethyl ester in 98% yield.…”

“…Among the different synthetic strategies, the [4 + 2] cycloaddition, commonly known as Diels-Alder reaction, is gaining more and more prominence. [1][2][3][4] Several products synthesized by this reaction have effective application in our daily lives, and we can mention the case of the agrochemical Captan, which presents as key step the Diels-Alder reaction. With this reaction it is possible to obtain bicycles that are very active in the control of different biological agents.…”

“…With this reaction it is possible to obtain bicycles that are very active in the control of different biological agents. [5][6][7][8][9] A bicyclic compound that has been excelling in recent years is the norbornadiene, a homoalkyl diene system compound, 1,4 of great scientific interest in chemistry due to its high symmetry, unusual structure besides a high reactivity. 10,11 An area that can be mentioned is its use as a sensitizer in energy production processes.…”