Direct Access to β-Trifluoromethyl-β-hydroxy Thioesters by Biomimetic Organocatalytic Enantioselective Aldol Reaction

Abstract

A broadly applicable biomimetic enantioselective decarboxylative catalytic aldol reaction of trifluoromethyl ketones with malonic acid half-thioesters (MAHTs) is described. Utilizing cinchona-based thioureas as highly efficient polyketide synthase-mimic catalysts, chiral tertiary aldols, β-trifluoromethyl-β-hydroxy thioesters, were obtained in up to 99% yield and 95% ee. Facile transformation of the thioester moiety of the aldol adducts showcases the synthetic utility of this biomimetic aldol protocol to deliver a range of chiral trifluoromethylated tertiary aldol pharmacophores.

Catalytic Enantioselective Decarboxylative Aldol Reactions of Malonic Acid Half Thio(oxy)ester and β‐Ketoacids

“…[10] The Song group reported an asymmetric decarboxylative aldol reaction of malonic acid half-thioesters 1 (MAHTs) with trifluoromethyl ketones 17 catalyzed by a cinchonidine derived thiourea catalyst F to give enantioenriched β-CF 3 -β-hydroxy esters 18 (Scheme 9) bearing trifluoromethylated tertiary carbon center in low to excellent yields (3-99 %) and with good to excellent enantioselectivities (50-95 % ee). [11] The authors screened several MAHTs, out of which para-fluorophenyl substituted MAHT was found to be most suitable in terms of enantiomeric excess of the obtained product. The substrate scope regarding aryltrifluoromethyl ketones 17 is very broad and irrespective of the electronic and Additionally, heteroaromatic trifluoromethyl ketones and aliphatic trifluoromethyl ketones were also suitable and yielded the corresponding aldol products in moderate to good yields (44-78 %) and enantioselectivities (50-75 % ee).…”

“…Chiral β‐CF 3 ‐β‐hydroxy esters are attractive target molecules due to presence of their synthetic equivalency in some marketed drugs [10] . The Song group reported an asymmetric decarboxylative aldol reaction of malonic acid half‐thioesters 1 (MAHTs) with trifluoromethyl ketones 17 catalyzed by a cinchonidine derived thiourea catalyst F to give enantioenriched β‐CF 3 ‐β‐hydroxy esters 18 (Scheme 9) bearing trifluoromethylated tertiary carbon center in low to excellent yields (3–99 %) and with good to excellent enantioselectivities (50–95 % ee) [11] . The authors screened several MAHTs, out of which para ‐fluorophenyl substituted MAHT was found to be most suitable in terms of enantiomeric excess of the obtained product.…”

“…This protocol also tolerated ketones having a CF 2 CF 3 group and the corresponding product 18 j was obtained in 56 % yield with 81 % ee. Synthetic utility of the aldol products was illustrated by synthesis of key intermediates of the antiparasitic isoxazoline drugs [11] …”

“…To get insights into the reaction mechanism of this decarboxylative aldol reaction, [11] the authors performed in situ ESI‐MS analysis of the reaction of para ‐fluorophenyl substituted MAHT 1 with phenyl trifluoromethyl ketone 17 a in presence of catalyst F . They observed a signal at the m/z value corresponding to the intermediate 19 , which forms upon addition of 1 to 17 a (Scheme 10).…”

“…Synthetic utility of the aldol products was illustrated by synthesis of key intermediates of the antiparasitic isoxazoline drugs. [11] To get insights into the reaction mechanism of this decarboxylative aldol reaction, [11] the authors performed in situ ESI-MS analysis of the reaction of para-fluorophenyl substituted MAHT 1 with phenyl trifluoromethyl ketone 17 a in presence of catalyst F. They observed a signal at the m/z value corresponding to the intermediate 19, which forms upon addition of 1 to 17 a (Scheme 10). Based on this finding, authors proposed that the developed reaction proceeds through the nucleophilic addition of MAHT 1 to trifluoromethyl ketone 17 a followed by decarboxylation and release of product 18 a to close the catalytic cycle.…”