Coenzyme models 51. Structure and reactivity studies of 5-methyl-5-deazaflavinophanes: On the "axial preference" in a flavin redox system

Structures and reactivities of 5-deazaflavins were studied by using new 5-deazaflavinophanes dFl(n) in which N(3) and O(2′) in the 10-(2-hydroxy)phenyl group were linked by a (CH₂)_n chain (n = 8 and 12). dFl(Bu), having n-butyl groups at N(3) and O(2′), was used as a reference. X-ray crystallographic and ¹H NMR studies established that in the Grignard reaction with MeMgBr to yield dFlMe_red(n) the methyl group attacks the isoalloxazine plane from the axial side and is fixed at the axial position. In NaBH₄ reduction of dFlMe(n) to yield dFlMe_red(n) hydride attacks the isoalloxazine plane from the axial side, but the 5-methyl group is displaced from "equatorial" to "axial" by ring inversion in order to minimize steric hindrance. The axial preference observed for nucleophilic attacks is explained by a stereoelectronic effect. dFlMe_red(n), having only H_eq at the C(5)-position, was much less reactive as reductant than dFl_red(n) having both H_eq and H_ax. The deactivation is rationalized by such that (i) more reactive H_ax is lost by substitution with the methyl group and (ii) remaining H_eq, surrounded by bulky groups, behaves as a less reactive "buried hydride equivalent". These novei structure-reactivity relationships have important implications on biochemical studies of flavoenzymes.