Base-Catalyzed Direct Aidolization of α-Alkyl-α-Hydroxy Trialkyl Phosphonoacetates

摘要

Catalytic direct aldol reactions offer a convenient method for the rapid construction of β-hydroxy carbonyl compounds through the coupling of carbonyl donors and aldehyde acceptors. The generation of the reactive enolate by a basic or nucleophilic catalyst obviates the heed to preform an enolate equivalent. Reaction subtypes can be broadly categorized by the oxidation state of the pronucleophile. Ketones and aldehydes can be used in direct aidolization because of their relatively high acidity (by Bronsted base catalysis) or their ability to form an enamine (by Lewis base catalysis). Catalytic direct aldol and Mannich reactions involving donors in the carboxylic acid oxidation state are considerably more elusive. Mechanistic nuances of these reactions are more diverse and reactions that give products that are fully substituted at the a carbon atom are difficult to achieve. We report herein a new base-catalyzed direct glycolate aldol addition that relies upon the strategic use of a [1,2] phosphonate-phosphate rearrangement (Scheme 1). This strategy was deployed in the development of highly enantio- and diastereoselective variants through the application of chiral iminophosphorane catalysts. A consequence of the reaction design is that products containing a leaving group are directly produced by the aidolization, a circumstance that is favorable for subsequent nucleophilic displacement reactions.