Synthesis of Spiro C-Arylglycoriboside via Pd(II)-Catalyzed Spirocyclization

Abstract

Spiro C-arylglycoriboside was synthesized in 21 steps via Pd(II)-catalyzed spirocyclization as a key reaction. Hemiketal was obtained in 47% overall yield from cis-2-butene-1,4-diol and spirocyclized with PdCl 2 (PhCN) 2 in dilute THF solution (0.01 M) to afford the 1,6-dioxaspiro[4.4]nonane skeleton in high yield. The spirocyclo adduct was transformed into spiro C-arylglycoriboside in five steps. Spiroketals such as 1,6-dioxaspiro[4.5]decane, 1,7-dioxaspiro[5.5]undecane and 1,6-dioxaspiro[4.4]nonane occur widely as substructures of natural products from many sources, including insects, microbes, plants, fungi and marine organisms. 1 Papulacandin D is also a naturally occurring spiroketal compound which contains a 1,6-dioxaspiro[4.5]decane skeleton with an aryl-b-D-Cglycopyranoside. 2 Its pharmacological activities, along with the structural complexity of spiro C-arylglycopyranosides, have triggered intense interest in the synthesis and chemical reactivity of these compounds. 3 On the other hand, spiro C-arylglycofuranoside does not occur naturally and has received less attention (Figure 1), although Carylnucleosides are biologically important nucleoside mimetics. 4 Recently, Yamamoto and co-workers have reported a synthesis of acetonide-protected spiro Carylglycoriboside using Cp*RuCl-catalyzed [2+2+2]-cycloaddition. 5 We report here a synthesis of spiro Carylglycoriboside via palladium(II)-catalyzed spirocyclization, in order to examine its pharmacological activities.Our retrosynthetic analysis is illustrated in Scheme 1. We envisioned that spiro C-arylglycoriboside would be obtained by transformation of the spiro compound 1, and its spiroketal moiety would be constructed by palladium(II)-catalyzed cyclization of the keto alcohol 2. The keto alcohol 2 would be readily prepared by side chain elongation of the acetate 3. 6 Optically active acetate 3 would be synthesized by asymmetric acetylation of the meso-diol 4 using lipase. Finally, the meso-diol 4 would be readily available from cis-2-butene-1,4-diol (5).Our synthesis commenced with benzoylation of the diol 5 followed by dihydroxylation with a catalytic amount of OsO 4 , using NMO as a reoxidant, to afford the diol 6. Protection of 6 as its acetonide, followed by methanolysis, gave the meso-diol 4 as a key intermediate. Then, the meso-diol 4 was subjected to asymmetric acetylation with lipase AK Amano 20 in vinyl acetate to give almost optiFigure 1 Spirocyclic compounds O HO RO OH HO