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.

Title

Journal of Organic Chemistry

Publisher

American Chemical Society

Publisher Country

Sweden

Indexing

Thomson Reuters

Impact Factor

4.75

Publication Type

Both (Printed and Online)

Volume

84

Year

2019

Pages

9