Unique Reactivity of α-Alkoxy Ginkgolide Lactones to Nucleophilic Reagents: Preparation of New Lactol Derivatives

Abstract

Abstract It has been found that nucleophilic reagents, i.e., NaBH4, Grignard reagents, and alkyl lithium, uniquely react with the α-alkoxy- or acyloxy-lactone moieties in ginkgolide and F-seco-ginkgolides to give rise to lactol derivatives. The reaction is rapid and stops at the lactol stage; the strong coordination of Na, Mg, and Li metals to the conformationally rigid cage structure is involved in both the initiation and termination stages. The NaBH4 reduction of F-seco-ginkgolides gives rise to an equilibrium mixture of α- and β-lactols, the separation of which becomes only possible after acylation by p-phenylbenzoic acid. The resulting acyl-lactol stereogenic centers were elucidated by both NOE and the CD/FDCD exciton chirality method utilizing the sterically hindered 7-hydroxyl. On the other hand, the alkylation of ginkgolide B derivatives proceeds regio- and stereoselectively at the C-11 lactone group, resulting from the approach of Grignard and alkyl lithium reagents to the convex face of the cage-shaped ginkgolide molecule. The additional new stereogenic centers of the quaternary lactol hydroxyls have been determined by NOE. This facile alkylation protocol gives rise to a deep-seated skeletal transformation of ginkgolides, resulting in a new class of ball-shaped heptacyclic ginkgolide derivatives via “olefin/olefin” and “olefin/alkyne” ring-closing metathesis.