Hydrophilic/hydrophobic patterning is a well-established design strategy to guide secondary structure formation of both natural as well as non-natural oligomers and polymers. This contribution explores the feasibility of a new approach for the synthesis of uniform, sequence-defined, hydrophilic/hydrophobic patterned oligo(alpha-hydroxy acid)s. The proposed strategy is based on post-modification of a reactive oligoester scaffold composed of an alternating sequence of hydrophobic [(2S)-2-hydroxy-4-methylpentanoic acid] and masked hydrophilic [(2S)-2-hydroxypent-4-enoic acid] alpha-hydroxy acids. The use of (2S)-2-hydroxypent-4-enoic acid instead of a complex side-chain-protected hydrophilic building block obviates the need for additional protective group chemistry during chain extension. In a subsequent post-modification step, the allyl side chains can be quantitatively modified via free-radical addition of different omega-functional thiols to afford hydrophilic/hydrophobic patterned oligoesters. The proposed synthetic strategy provides an interesting alternative to rapidly generate libraries of foldamers with identical chain length and monomer sequence but different side-chain functionalities. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)