TY - JOUR
T1 - Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di- and Tri-Hydroxypentanones
AU - Al-Smadi, Derar
AU - Enugala, Thilak Reddy
AU - Kessler, Vadim
AU - Mhashal, Anil Ranu
AU - Lynn Kamerlin, Shina Caroline
AU - Kihlberg, Jan
AU - Norberg, Thomas
AU - Widersten, Mikael
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/7
Y1 - 2019/6/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066950370&partnerID=8YFLogxK
U2 - 10.1021/acs.joc.9b00742
DO - 10.1021/acs.joc.9b00742
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C2 - 31066559
AN - SCOPUS:85066950370
SN - 0022-3263
VL - 84
SP - 6982
EP - 6991
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 11
ER -