Synthesis of Tertiary Amines Using a Polystyrene (REM) Resin

Abstract

A range of tertiary amines was constructed using a “traceless” linker on a polystyrene resin (REM resin), starting from secondary amines, primary amines, and resin-bound “ammonia”. The methodology is characterized by three essential steps conducted under ambient conditions: (1) coupling of the starting amine (Michael addition) to the resin, (2) activation (quaternization), and (3) cleavage of the product amine (Hofmann elimination). The linker is compatible with both acid and base sensitive protecting group strategies. The nature of the chemistry ensures that the tertiary amine products are obtained in consistently high purity (95% or greater). After cleavage of the product, REM resin is regenerated and can be reused for repeat syntheses. The yield and purity of repeat batches is maintained over 5 cycles, allowing the automated synthesis of >0.5 g quantities of pure tertiary amine.

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.…”

Combinatorial Synthesis of New Cationic Lipids and High-Throughput Screening of Their Transfection Properties

“…[18] Reaction of the epoxide 3 with a long-chained amine yielded the polymer-bound secondary amine 4, with was converted into the tertiary amine 5 by reductive amination. [19] Quaternization of the tertiary amine with methyl iodide, [20] and cleavage from the solid phase gave the cationic lipid 6, which was further purified by preparative HPLC. Each step of the synthesis could be monitored by means of highresolution magic angle spinning NMR (HRMAS-NMR) spectroscopy.…”