Coenzyme Models.48. Novel Diastereo-Differentiating Hydrogen Transfer and “Rope-Skipping” Racemization in Chiral Flavinophanes and 5-Deazaflavinophanes

Cyclic flavins and 5-deazaflavins with planar chirality [Fl(n) and dFl(n), n = 6, 7, 8, 10, and 12] and their noncyclic analogues [Fl(Bu) and dFl(Bu)] were optically resolved for the first time by a liquid chromatographic method. They did not racemize below 40 °C, but Fl(n) and dFl(n) with a long strap (n ≥ 10) racemized invariably when they were reduced to the 1, 5-dihydro forms. This novel redox-induced “rope-skipping” racemization occurs because the flat (5-deaza)isoalloxazine plane is folded along a line through N(5) [or C(5)] and N(10) like butterfly wings in the reduced forms, and thus, rope-skipping racemization is facilitated. A similar racemization took place via the formation of sulfite adducts at N(5) or C(5), indicating that the adducts also employ the folded conformation. These chiral (5-deaza)flavinophanes could oxidize optically active thiols (62.8% enantiomeric excess) and NADH model compounds (60.0% enantiomeric excess) in an asymmetric manner. When dFl(n) were reduced to dFl_red(n), ¹H NMR gave a pair of doublets for the two C(5) protons. This indicates that the central ring in the reduced isoalloxazine employs a boat form and that the flip-flop motion is significantly suppressed by the ring structure. By use of the nuclear Overhauser effect, the two ¹H NMR peaks were assigned to axial proton (higher magnetic field) and equatorial proton (lower magnetic field). The tracer experiments using dFl(n) established for the first time that the hydrogen transfer to dFl(n) and from dFl_red(n) occurs exclusively at the “axial” C(5) position. These novel results were found owing to unique characteristics of cyclic (5-deaza)flavins. Furthermore, the high asymmetric discrimination suggests that planar chirality is a promising approach to the design of new flavoenzyme model systems.