Organocatalytic Biomimetic Decarboxylative Aldol Reaction of Fluorinated β‐Keto Acids with Unprotected Isatins

Abstract

A facile asymmetric synthesis of fluorinated 3-hydroxyoxindoles through the biomimetic decarboxylative aldol reaction of fluorinated b-keto acids with unprotected isatins catalyzed by quininederived urea catalyst has been achieved. One of the features of this work is that the easily available a, adifluoro/a-monofluoro-b-keto acids have been first applied in the enantioselective synthesis of fluorinated compounds as the masked fluoroenolates. Furthermore, the utility of this method was demonstrated by its ability to access a series of difluorinated 3-hydroxyoxindoles with up to 95% ee and monofluorinated 3hydroxyoxindoles with up to 90 : 10 d.r. and 94% ee.

Catalytic Enantioselective Synthesis of Difluoromethylated Tetrasubstituted Stereocenters in Isoindolones Enabled by a Multiple-Fluorine System

“…To construct difluoromethylated tetrasubstituted stereocenters, conventional synthetic methods mainly rely on asymmetric transformations with difluoromethylated electrophiles, such as ketones, imines, and alkenes, but often encountered with difficulty in substrate scope expansion . Complementary to this strategy, the reactions employing difluoromethylated nucleophiles have emerged as a feasible disconnection approach . For instance, Hu and co-workers pioneered the nucleophilic difluoromethylation with sulfoximines en route to enantioenriched difluoromethyl tertiary alcohols .…”

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

“…α,α‐Difluoro‐β‐keto acids 33 and α‐fluoro‐β‐keto acids 34 were successfully employed in the organocatalytic enantioselective decarboxylative aldol reaction with isatins 2 by Deng and co‐workers in 2018 (Scheme 20). [22] In this report, authors disclosed the decarboxylative aldol reaction of α,α‐difluoro‐β‐keto acids 33 with unprotected isatins 2 using a quinine‐derived urea catalyst E to obtain the difluorinated 3‐hydroxyoxindoles 35 bearing a fully substituted carbon atom in moderate to good yields (45–93 %) and with good to excellent enantioselectivities (75–95 % ee) under the optimized the reaction conditions. Regarding the application scope of this methodology, the reaction accommodated various unprotected isatins attached to electron‐donating and electron‐withdrawing groups and halogen substituents.…”

“…A host of α,α‐difluoro‐ hetero(aryl) β‐keto acids 33 worked well for this methodology. In the same report, [22] authors extended their work to employ α‐fluoro‐β‐keto acids 34 in the decarboxylative aldol reaction with unprotected isatins 2 using 10 mol% of the catalyst E but with different reaction conditions. The reaction tolerated a series of isatins and α‐fluoro‐β‐keto acids well, giving the monofluorinated 3‐hydroxyoxindoles 36 in good to excellent yields (45–95 %), good diastereoselectivites (78 : 22–90 : 10 dr) and excellent enantioselectivities (86–94 % ee).…”

The Asymmetric Difluoro‐Reformatsky Reaction

“…The mild reaction conditions in this aldol reaction clearly require highly reactive electrophilic reactants as they are given in indolindiones (Scheme 22). [73] The same type of targets are also accessible in an enantioselective way by using 2,2‐difluoro‐1,3‐diketones 104 that produce the difluoro‐enolate by a retro‐Claisen reaction. In this approach, a quinine‐derived thiourea 102 b was used to catalyze the conversion of isatins 100 b into difluorinated hydroxyindoles 103 b with substantial enantioselectivity (Scheme 22).…”