Syn-anti isomerization of aldols by enolization.

A variety of aldol adducts are shown to undergo efficient syn-anti isomerization in the presence of imidazole by an enolization mechanism. Isomerizations are high yielding and occur with little or none of the usual byproducts arising from competing elimination or retroaldol reactions. Most substrates reach equilibrium within 0.3-3 days at ambient temperature in chloroform, benzene, or dichloromethane containing 0.3-1 M imidazole. The process is particularly facile for aldols derived from tetrahydro-4H-thiopyran-4-one with rate constants for equilibration varying over ca. 1 order of magnitude for the adducts studied; structurally related aldols derived from cyclohexanone isomerized ca. 3-4 times slower. Isomerization of the acyclic aldol 5-hydroxy-4-methyl-5-phenyl-3-pentanone required heating to 60 degrees C but was achieved with minimal (<5%) retroaldol or elimination. A methoxymethyl ether derivative isomerized 30-40 times slower than the parent aldol. Isomerization of alpha,alpha'-disubstituted aldols and alpha,alpha'-bisaldols indicated low regioselectivity in the enolization. The synthetic utility of the process was demonstrated with the effective preparation of aldol stereoisomers unobtainable by direct methods.