Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di- and Tri-Hydroxypentanones

Polyhydroxylated
compounds are building blocks for the synthesis
of carbohydrates and other natural products. Their synthesis is mainly
achieved by different synthetic versions of aldol-coupling reactions,
catalyzed either by organocatalysts, enzymes, or metal–organic
catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one
derivatives from para- and meta-substituted phenylacetaldehydes by
three distinctly different strategies. The first involved a direct
aldol reaction with hydroxyacetone, dihydroxyacetone, or 2-hydroxyacetophenone,
catalyzed by the cinchona derivative cinchonine. The second was reductive
cross-coupling with methyl- or phenylglyoxal promoted by SmI2, resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or
1,4 bis-phenyl-substituted butanones, respectively. Finally, in the
third case, aldolase catalysis was employed for synthesis of the corresponding
1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic
route with cinchonine generated distereomerically enriched syn-products
(de = 60–99%), with moderate enantiomeric excesses (ee = 43–56%)
but did not produce aldols with either hydroxyacetone or dihydroxyacetone
as donor ketones. The SmI2-promoted reductive cross-coupling
generated product mixtures with diastereomeric and enantiomeric ratios
close to unity. This route allowed for the production of both 1-methyl-
and 1-phenyl-substituted 2,3-dihydroxybutanones at yields between
40–60%. Finally, the biocatalytic approach resulted in enantiopure
syn-(3R,4S) 1,3,4-trihydroxypentan-2-ones.