A Novel Solution‐ and Solid‐Phase Approach to 2,4,5‐tri‐ and 2,4,5,6‐tetrasubstituted pyrimidines and their conversion into condensed heterocycles

Abstract

A novel general synthesis of 2,4,5-tri-and 2,4,5,6-tetrasubstituted pyrimidines 5a-d and 7a, e, f, g by condensation of thiouronium salts of type 3 with (ethoxymethy1idene)malononitrile (4) and [bis(methylthio)methylidene]malononitrile (6), respectively, was first established in solution (Scheme f) and successfully transferred onto solid support by using the polymer-bound thiouronium salt 11 (Scheme 3). Further investigations were directed toward a multidirectional cleavage procedure of the 2-(alkylsulfinyl) intermediates, obtained from the 2-(alky1thio)pyrimidines 7a (Scheme 2) or 12 and 14 (Schemes 3 and 4), with different nucleophiles to form highly substituted pyrimidines. In addition, fused-heterocycle derivatives 22a-h, 24a-c, and 26a-e were generated in good-to-excellent yields by condensation of 7a, e, h with versatile isocyanates and isothiocyanates, with subsequent alkylation (Scheme 5).

Solution‐Phase Combinatorial Libraries: Modulating Cellular Signaling by Targeting Protein–Protein or Protein–DNA Interactions

“…Advances addressing each of these limitations have been made which continue to improve the implementation of solid-phase synthesis. Some of the most notable introductions include traceless linkers, [137][138][139] the resin release of product only upon successful synthesis, [140,141] resin-capture of only the desired reaction products, [142] the introduction of safety-catch linker [143][144][145] and backbone amide linker [146,147] strategies, multidirectional resin-cleavage methods, [148,149] and improved resin properties and loading capacities. [34][35][36][37][38] Limitations that cannot be altered are that solid-phase synthesis is incompatible with the use of heterogeneous catalysts or reagents, is necessarily restricted to a linear (as opposed to convergent) synthetic strategy, is not easily amenable to the synthesis of mixture libraries, and is not amenable to selection or dynamic library screening [4] involving target-assisted synthesis.…”

Kombinatorische Flüssigphasensynthese von Bibliotheken: auf der Suche nach Modulatoren für Protein‐Protein‐ und Protein‐DNA‐Wechselwirkungen in der zellulären Signaltransduktion

“…Durch Fortschritte bei der Microarray-Herstellung konnte die räumlich auflösende Parallelsynthese im großen Maßstab an verschiedenen Festphasen verbessert werden. [133][134][135][136] Da bei der Festphasensynthese die Isolierung des immobilisierten Produktes durch einfache Filtration möglich ist, können durch große Reagensüberschüsse in jeder Stufe hohe Umsätze erzielt werden (Tabelle 1 [137][138][139] Methoden, bei denen ausschließlich das Produkt vom Harz abgespalten wird [140,141] oder umgekehrt nur die gewünschten Reaktionsprodukte ans Harz gebunden bleiben, [142] Safety-CatchLinker, [143][144][145] Amidrückgrat-Linker, [146,147] multidirektionale Methoden zur Abspaltung des Produkts vom Harz [148,149] und Verbesserungen der Harzeigenschaften und der Beladungskapazitäten. [34][35][36][37][38] Einige systematische Nachteile wie die Unverträglichkeit mit heterogenen Katalysatoren und Reagentien oder die zwingend vorgeschriebene lineare Synthesestrategie bleiben jedoch.…”

Discovery of Inhibitors of Protein-Protein Interactions from Combinatorial Libraries

“…Consequently to the large acceptance achieved by the split-and-mix strategy, several identification techniques have been also developed, such as nucleotide- [45,46], peptide- [47,48], chemical- [49], radiofrecuency- [50], color- [51], and shape- [52][53][54] encoded or iterative [55][56][57] and recursive [58,59] [65], in which reagents used to cleave products from the solid support are incorporated into the product; use of scavenger resins [66]; the introduction of safety-catch linkers [67][68][69] or the improvement of resin properties and loading capacities [70][71][72].…”