Coenzyme Models. 47. Synthesis and Reactivity Studies of Novel Flavinophanes and 5-Deazaflavinophanes: Correlation between Flavin Reactivity and Ring Strain

New flavinophanes Fl(n) and 5-deazaflavinophanes dFl(n) were synthesized in which N(3) and O(2′) in the 10-(2-hydroxyphenyl) group were linked by a -(CH₂)_n- chain (n = 6, 7, 8, 10, and 12). In the ^lH NMR spectra the chemical shift of 9-H in the isoalloxazine ring and 6'-H in the 10-phenyl ring moved to lower magnetic field with decreasing ring size. The change corresponds to the decrease in the dihedral angle between the isoalloxazine ring and the 10-phenyl ring. The NOE (nuclear Overhauser effect) measurement also supported that the distance between 9-H and 6'-H decreases with decreasing ring size. X-ray crystallographic studies of dFl(6) established that the dihedral angle (θ) between the isoalloxazine ring and the 10-phenyl ring is 76.5°, considerably smaller than the 90° that minimizes the steric crowding of conventional 10-phenylisoalloxazine derivatives. The ab initio MO calculation of 10-phenylisoalloxazine indicates that the equilibrium geometry is such that θ = 60-90° and Fl(n) and dFl(n), with the smaller θ, are destabilized because of steric hindrance. The steric strain induced by the short ring strap is reflected by the reactivities of Fl(n) and dFl(n): For the oxidation of 1-benzyl-1,4-dihydronicotinamide (BNAH), sterically strained Fl(6) and dFl(6) have rate constants 11 and 16 times greater than those for Fl(12) and dFl(12). For the reversible 5-adduct formation between Fl(n) and SO₃^2-, k_f (forward reaction) for Fl(6) is greater by a factor of 5.2 than that for Fl(12), while k_r (reverse reaction) for Fl(6) is smaller by a factor of 3.6 than that for Fl(12). These results can be explained by destabilization of the initial state due to steric strain induced by the ring strap.