Dual side chain control in the synthesis of novel sequence-defined oligomers through the Ugi four-component reaction

Abstract

The synthesis of sequence-defined oligomers by the iterative application of the modular Ugi four-component reaction (U-4CR) and the efficient thiol-ene addition reaction is described. By varying the amine component in the U-4CR, a sequence-defined and monodisperse tetramer (M = 1568.5 10 g/mol) was obtained. More interestingly, if both the amine and the isocyanide components were varied simultaneously in the U-4CR, a double sequence-controlled, monodisperse pentamer (M = 2411.8 g/mol) bearing ten different and selectable side chains was obtained. All oligomers were 15 thoroughly characterized by NMR and IR spectroscopy, mass spectrometry and GPC.One of the most challenging topics of modern polymer chemistry is the control over the monomer sequence in synthetic polymers. 1 These highly defined synthetic polymers exhibit novel material 20 properties and special self-assembly behaviour, depending on the monomer sequence. 2 However, the most sophisticated and controlled monomer sequences are synthesized by nature, for instance in translation and replication processes. 3 Over the past decades, different approaches have been developed in order to 25 synthesize sequence-defined polymers. 1,4 On the one hand, controlled radical polymerizations like RAFT, 5-7 ATRP 8-11 and NMP 11-13 can be applied for the synthesis of sequence-controlled polymers. 14 These radical polymerizations take advantage of simple one-pot procedures, but due to the radical nature of those 30 methods, side reactions, such as chain transfer, occur, thus chain to chain deviations are present. 15 On the other hand, stepwise procedures providing monodisperse macromolecules by using (DNA)-templates, [16][17][18][19][20][21] or complex molecular machines are reported. 22, 23 Although these approaches are elegant, the 35 synthetic efforts are considerable and the reactions can only be carried out on small scales. Recently, other protocols for the stepwise synthesis of sequence-defined polymers were reported making use of orthogonal reactions providing sequence-defined macromolecules by the iterative application of Michael additions 40 and aminolysis reactions, 24 azide-alkyne cycloadditions and amidifications, 25 or photochemical couplings and retro Diels-Alder reactions. 26 Our group focusses on the use of multicomponent reactions to achieve sequence control. 27 The iterative application of the Passerini three-component reaction 45

Coding and decoding libraries of sequence-defined functional copolymers synthesized via photoligation

“…In parallel, strategies involving the consecutive insertion of single monomer units (vinyl or acrylate) based on radical processes started to emerge for the synthesis of sequence-defined polymers3738. Further, notable synthetic strategies towards sequence-defined polymers conducted in bulk include the use of thiolactones394041 and multi-component reactions424344. Concomitant to the development of new synthetic approaches to sequence-defined polymers, selected applications of such molecules are emerging, for example, bio-inspired structures for which high sequence definition is essential4546.…”

Recent Progress in the Design of Monodisperse, Sequence-Defined Macromolecules

“…The products of the P‐3CR were isolated by column chromatography and the products of the thiol‐ene addition were recrystallized, which led to comparably low yields for the thiol‐ene addition. The same strategy was subsequently followed for the synthesis of oligomers using the Ugi four‐component reaction (U‐4CR) . The U‐4CR uses, as additional component, an amine and thus the structural variance in the final products is greatly enlarged.…”

Combining Two Methods of Sequence Definition in a Convergent Approach: Scalable Synthesis of Highly Defined and Multifunctionalized Macromolecules

“…First, thiolactone‐carboxylic acid 1 was reacted in Passerini reactions with 10‐undecenal 2 as the aldehyde component in combination with different isocyanides 3 a – h , allowing subsequent thiol‐ene additions with mercaptopropionic acid 5 and thus the repetition of the iterative cycle (Scheme ) . All P‐3CRs were conducted in dichloromethane (DCM), except for the reactions leading to compounds 4 a – c , where the employed solvent system was a THF–water mixture (4:1) owing to the insolubility of 1 in DCM.…”