An enantioselective synthesis of chiral hydroxyurea based
5-lipoxygenase inhibitors is reported
via a five-step sequence in about 30% overall yield. The
synthesis is based on a novel tandem
nucleophilic addition−intramolecular cyclization reaction in which a
chiral nitrone functions as
the electrophilic acceptor species. A mannose-based chiral
auxiliary controls the diastereoselectivity
of the reaction in an 8:1 ratio. After the auxiliary removal and
appropriate functionalization, a
single recrystallization afforded the target structures in >99%
ee.
A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two-step homologation of ketones to secondary carboxylic acids.
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