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Optically Active Alcohols from 1,3‐Dioxan‐4‐ones. A Practical Version of Enantioselective Synthesis with Nucleophilic Substitution at Acetal Centers Secondary alcohols in enantiomeric excesses above 90% are accessible from 2‐substituted 6‐methyl‐1,3‐dioxan‐4‐ones ( Scheme 4 ). The dioxanones are prepared from aldehydes and readily available ( R )‐or ( S )‐3‐hydroxybutanoic acid. Treatment of the dioxanones with silyl nucleophiles or triisopropoxy(methyl)titanium in the presence of Cl 3 TiX yields the corresponding 3‐alkoxy acids in diastereoselectivities ≥ 95%. The ‘chiral auxiliary’ is removed from the alkoxy acids by treatment with LiN(i‐Pr) 2 to give the secondary alcohols with ≤ 90% 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 synthese 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.
Seebàch et al. (Wed,) studied this question.