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Research article2019Peer reviewed

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

Al-Smadi, Derar; Enugala, Thilak Reddy; Kessler, Vadim; Mhashal, Anil Ranu; Kamerlin, Shina Caroline Lynn; Kihlberg, Jan; Norberg, Thomas; Widersten, Mikael

Abstract

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.

Published in

Journal of Organic Chemistry
2019, Volume: 84, number: 11, pages: 6982-6991 Publisher: AMER CHEMICAL SOC

    UKÄ Subject classification

    Organic Chemistry

    Publication identifier

    DOI: https://doi.org/10.1021/acs.joc.9b00742

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/100707