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

Abstract

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.

Biomimetic syn‐Aldol Reaction of Dihydroxyacetone Promoted by Water‐Compatible Catalysts

“…Based on our earlier development of syn-aldol reactions of hydroxyacetone catalyzed by amino acids, [14,15] we initially screened various bis(amides) containing primary amines. The four isomeric bis(serinamides) 7a-7d demonstrated activity and stereoselectivity superior to that obtained previously by other authors.…”

Towards Sustainable Amino Acid Derived Organocatalysts for Asymmetric syn‐Aldol Reactions

“…In contrast to high‐molecular‐weight enzymes, small catalysts 1 – 5 are not recyclable , . To the best of our knowledge, just two supported primary amino acid derived catalysts for the syn ‐aldol reaction, 6 and 7 , have been reported to date (Figure b).…”

“…However, in the presence of organocatalysts bearing primary amino groups or their native enzyme prototypes (aldolases), syn ‐aldols, which are key structural fragments of carbohydrates, are formed. In a series of primary amine organocatalysts, amino acids 1 [4a,b], and 2 ; their amides 3 , 4 , and 5 ; and some other amino catalysts exhibit promising catalytic performances (Figure a).…”

Novel L-threonine-based ionic liquid supported organocatalyst for asymmetric syn-aldol reaction: activity and recyclability design

“…10 Over the past decade, a number of similar syn-aldol reactions have been realized in laboratory (though, with a somewhat lower stereoselectivity) in the presence of properly designed primary aminocatalysts. Among them, O-protected serine or threonine amino acids, [11][12][13][14][15][16] their amides, 17 valine, 18 leucine, 19 iso-leucine 20 or tert-leucine derivatives 21 and some primary-tertiary 1,2-diamine organocatalysts [22][23][24][25][26][27] exhibited promising catalytic performance. However, unlike enzymes, these valuable catalysts could be used just once and until recently no information on their recovery and reuse in the catalytic process has been available.…”