Optically Active Alcohols from 1,3-Dioxan-4-ones. A Practical Version of Enantioselective Synthesis with Nucleophilic Substitution at Acetal Centers

Article abstract of DOI:10.1002/hlca.19870700226

Secondary alcohols in enantiomeric excesses above 90percent are accessible from 2-substituted 6-methyl-1,3-dioxan-4-ones.The dioxanones are prepared from aldehydes and readily available (R)- or (S)-3-hydroxybutanoic acid.Treatment of the dioxanones with silyl nuclophiles or triisopropoxy(methyl)titanium in the presence of yields the corresponding 3-alkoxy acids in diastereoselectivities >/= 95percent.The 'chiral auxiliary" is removed from the alkoxy acids by treatment with LiN(i-Pr)2 to give the secondary alcohols with >/= 90percent ee. cis/trans-Mixtures (9:1) of the dioxanones furnish products of the same configurational purity as those obtained from pure cis-isomers.In comparison with other variants of enantioselective syntheses with nucleophilic substitution at acetal centers, the following advantages of the dioxanone method are noteworthy: i) (R)- and (S)-3-hydroxybutanoic acids are both readily available; ii) reactions are not sensitive to changes in conditions; iii) the 'chiral auxiliary' is removed simply by base elimination, no oxidation is required; iv) no chromatographic purification steps are necessary.The overall reaction described here is an enantioselective nucleophilic addition to aldehydes with concomitant dehydration of enantiomerically pure 3-hydroxybutanoic to crotonic acid.