Studies in asymmetric catalysis: Lewis base catalyzed/Lewis acid mediated aldol reactions of ketone- and amide derived nucleophiles

The generality of Lewis-base catalyzed, Lewis-acid mediated, enantioselective aldol additions of ketone- and amide-derived nucleophiles has been investigated. In the presence of the catalytic amounts of a chiral phosphoramide, the weak Lewis acid silicon tetrachloride can be activated to form a strongly Lewis acidic chiral species through coordination and subsequent ionization of a chloride ligand. This in situ generated chiral phosphoramide-bound trichlorosilyl cation has proven a highly enantioselective catalyst for the aldol addition of simple methyl ketone-derived silyl enol ethers to conjugated aldehydes. When cyclic ketone-derived silyl enol ethers are used, high anti-diastereoselectivity can be obtained in the addition to aromatic aldehydes.; Additionally, the use of the silicon tetrachloride---chiral phosphoramide system has proven a competent catalyst for highly selective vinylogous aldol reactions between dienolates derived from a variety of alpha,beta-unsaturated carbonyl compounds to aldehydes. These reactions provided high levels of gamma-site selectivity for a variety of substitution patterns on the dienyl unit. Both ketone- and morpholine amide-derived dienol ethers afforded excellent enantio- and diastereoselectivity in the addition to conjugated aldehydes. Although ketone-derived dienolate did not react with aliphatic aldehydes, amide-derived dienolates were found to undergo addition at reasonable rates affording high yields of vinylogous aldol product. The enantioselectivity achieved with the morpholine derived-dienolate in the addition to aliphatic aldehydes was the highest afforded to date with the silicon tetrachloride---chiral phosphoramide system. Furthermore, the ability to cleanly convert the morpholine amide to a methyl ketone was demonstrated.