Models for the solution state structure of the (6–4) photoproduct of thymidylyl‐(3′ → 5′)‐thymidine derived via a distance‐ and angle‐constrained conformation search procedure

The further spectroscopic analysis and molecular modeling of the recently reported (6–4) photoproduct of thymidylyl‐(3′ → 5′)‐thymidine is described. Three‐hundred megahertz equilibrium difference nuclear Overhauser effect (NOE) spectra were obtained for the four proton singlets of the molecule, two of which have uncovered previously unreported NOEs between the TpH₃′ proton and the TpH₆ and pT methyl protons. Torsion angle and interproton distance information was derived from coupling constants, difference NOE data, and molecular mechanics calculations. This information, along with softened van der Waals calculations and ring‐closure constraints, was used to constrain conformation searches utilizing the SYBYL molecular modeling program subroutine SEARCH. Sets of angles derived from the ring‐search procedure were then used to construct three structures whose geometries were optimized by the energy minimization subroutines MAXIMIN and SIMPLEX. One‐, two‐, and three‐state models composed of these three structures are proposed for the solution state structure of the (6–4) product. These models are energetically sound and are consistent with the nmr data. The three derived structures are also compared to B‐form TpT.