SPECIFIC INCLUSION CATALYSIS BY BETA-CYCLODEXTRIN IN THE ONE-STEP PREPARATION OF VITAMIN-K1 OR K2 ANALOGS

: Electrophilic allylation at the C3 position of 2-methylhydronaphthoquinone-1, 4 (5) with allyl (6a). crotyl (6b), methallyl (6c), or prenyl bromide (6d) was successfully developed to give a highly selective one-step preparation of the corresponding vitamin K1 (or K2) analogue (7a-d) by the use of β-cyclodextrin in dilute aqueous alkaline solution. In order to elucidatethe basis of this interesting inclusion catalysis which resembles “ligase and/or oxidase” reactions, mechanistic studies werecarried out. The specific inclusion binding of the substrate, 2-methylhydronaphthoquinone (5), by β-cyclodextrin {Ku = 490M-1, pH 3.55) facilitated the proton dissociation of 5, resulting a decrease in its pKa value from 9.45 for uncomplexcd 5 to 8.9for complexed 5. Based on kinetic results showing that the rate of allylation of α-naphthol at pH 10.4 was enhanced by 2.5 to3.5 times in the presence of jβ-cyclodextrin, it was concluded that the nuclcophilic reactivity of the partially charged carbanionincreased in the hydrophobic cavity and, therefore, the allylation reactions were accelerated by β-cyclodextrin. Another note-worthy aspect of the mechanism was seen in the interesting observation that 2-methylnaphthoscmiquinonc anion radical (detected by ESR) which was produced by oxidation of the allylated hydronaphthoquinonc by molecular oxygen was strongly bound by β-cyclodextrin. This indicated either the possibility that the oxidation proceeds predominantly through the complexed form of the allylated hydroquinonc or that the lifetime of the semiquinone anion radical is prolonged by the inclusionbinding. Vitamin K analogues 7 and 8, which were products, were found to be highly susceptible to oxidative degradation dueto the attack of hydrogen peroxide, which was shown to be another product of the oxidation step. β-Cyclodextrin effectivelyprotected those qunioncs from the attack by hydrogen peroxide, and their oxidation rates were from 1/9 to 1/17 of that for the uncomplexed quinone.© 1979, American Chemical Society. All rights reserved.