Organocatalytic syn ‐Aldol Reactions of Hydroxy Ketones with ( S )‐Isoserinal: Asymmetric Synthesis of 6‐Deoxy‐1,5‐iminohexitols and Related Compounds

An improved and convenient preparation of protected ( S )‐isoserinal on a large scale is reported. This key intermediate was reacted through organocatalyzed aldol reaction or Wittig based chain extension and functionalization to give enantiopure 1,5,6‐trideoxy‐1,5‐imino‐hexitols such as 10a ( L ‐ manno ) and 10b ( D ‐ gluco ). These two compounds are of interest as glycosidase inhibitors. The elaborated organocatalytic process includes diastereoselective syn aldol reaction of ( S )‐isoserinal hydrate and hydroxyacetone or 1‐hydroxy‐2‐octanone and is promoted by various amino acid‐based catalysts. Diastereoselectivities of up to 8:1 were achieved, thus establishing a new, efficient synthetic route to these important carbohydrate mimics.