Investigation of Sulfur-related Influences on the Construction and Ring Opening of a Six-membered Cyclic Xanthate Derived from d -Thymidine and CS2

With an interest in sustainable polymers derived from nucleoside building blocks, d-thymidine and carbon disulfide (CS2) were used as synthetic precursors to construct a trans-fused, 6,5-membered bicyclic xanthate, 3′,5′-cyclic N3-(3-butenyl)-d-thymidine trans xanthate, for ring-opening polymerization (ROP) to yield stereo- and regiochemically defined homopolymer analogs of nucleic acids bearing thiocarbonate backbones. Screenings for CS2 insertion and succeeding cyclization to form the targeted monomer revealed two additional d-thymidine-derived cyclic moieties, including a xanthate and trithiocarbonate of cis-fused configurations, isolated in low yields. Therefore, ROP experiments using alkoxy-based initiators and organobase catalysts at room temperature and supporting DFT calculations for enthalpies of ring opening were extended to all three potential monomers, with only the trans-fused bicyclic xanthate undergoing ROP. Structural characterization by MALDI-TOF mass spectrometry and NMR spectroscopy of polymers obtained from ROPs of 3′,5′-cyclic N3-(3-butenyl)-d-thymidine trans xanthate conducted at or somewhat below ambient temperatures indicated the presence of linear and cyclic species having primarily dimeric 5′,5′-trithiocarbonate-co-3′,3′-thionocarbonate connectivities from an alternating C–S and C–O cleavage pathway. Other minor trithiocarbonate, xanthate, and thionocarbonate functionalities were proposed to arise from backbiting reactions and/or minor regiorandom cleavages. In contrast, ROPs conducted at reduced temperatures (≤ −20 or −40 °C depending on the organobase) achieved selective C–S cleavage to yield 3′,5′-xanthate-connected polymers of N3-(3-butenyl)-d-thymidine with more structural similarity to native DNA. These fundamental advances extend the breadth of nucleoside-derived polymers, emphasizing the influence of sulfur incorporation during monomer synthesis and upon subsequent ROPs, with outcomes being temperature-mediated alternating vs. unidirectional backbone compositional and structural regioregularity.