Sequential kinetic resolution of C2-symmetric compounds as a key step in two-directional synthesis: structural requirements for efficient resolution of difuryl diols

Abstract

The C₂-symmetrical diols (R*,R*)-1,4-difuran-2-yl-butane-1,4-diol 13 and (1R*,3S*,4S*,6R*)-3,4-bis(tert-butyldimethylsilyloxy)-1,6-difuran-2-yl-hexane-1,6-diol 26 were synthesised in a two-directional manner: the reductions of (3R*,4R*)-3,4-bis(tert-butyldimethylsilyloxy)-1,6-difuran-2-ylhexane-1,6-dione with DIBAL-H and Red-Al were remarkably ^1,3syn selective, presumably as a result of reduction of chelates formed from the 3-silyloxy-1-(2-furyl)ketones. Sequential Sharpless kinetic resolutions of 13 and 26 were studied. The first step of the kinetic resolution of 26 was shown to proceed with an enantioselectivity factor of E = 1.9, and sequential resolution yielded the doubly oxidised product in 43% yield and 43% ee; this compares favourably with the enantiomeric excess (24% ee at 43% completion) of a product derived from a similarly enantioselective conventional kinetic resolution. The structural features of C₂-symmetric substrates which are required for efficient sequential kinetic resolution, and the relevance of these reactions in two-directional syntheses, are discussed.