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

Abstract

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 (CH 2) 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 NaBH 4 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.