A General Strategy to Access All Stereosequences in a Synthetic Polymer

The control of main-chain stereocenters in synthetic polymers remains a longstanding challenge, with traditional polymerization methods typically yielding only three types of well-defined stereosequences: isotactic, syndiotactic, and heterotactic. Here, we show that a broader range of stereochemical patterns can be accessed using iterative phosphoramidite chemistry. Two monomers bearing opposite configurations at a carbon stereocenter were synthesized and employed in automated solid-phase synthesis to construct poly(phosphodiester amide)s with defined stereosequences. High coupling efficiencies enabled the generation of polymers with exact chain lengths and primary structures. Comprehensive characterization by high-resolution mass spectrometry, ion-exchange HPLC, NMR spectroscopy, and circular dichroism confirmed the high stereochemical fidelity of the resulting materials. This approach enabled the synthesis of perfectly isotactic and syndiotactic polymers (100% <i>m</i> or <i>r</i> dyads), surpassing the precision achievable through conventional polymerization. More importantly, the method also facilitated access to nonclassical and previously unattainable stereosequences, including periodic, stereomutated, and stereocoded arrangements. For polymers with 20 stereocenters, this methodology allows for the theoretical creation of over one million unique stereosequences. These findings establish a new paradigm in stereocontrolled polymer synthesis, expanding the structural and functional landscape of synthetic macromolecules.