Functionalized cyclopentenes through a tandem NHC-catalyzed dynamic kinetic resolution and ambient temperature decarboxylation: mechanistic insight and synthetic application

Abstract

An unusual room temperature β-lactone decarboxylation facilitated a five-step enantioselective formal synthesis of the cyclopentane core of an estrogen receptor β-agonist. A computational study probed the underlying factors facilitating unprecedented, rapid decarboxylation. Aryl substitution promotes faster reaction in the retro-[2+2] as a result of conjugative stabilization with the forming olefin. Additionally, the configuration of the α-ester in these fused β-lactones leads to differential decarboxylation rates resulting in enantioselectivity.

N‐Heterocyclic Carbene (NHC)‐Organocatalyzed Kinetic Resolutions, Dynamic Kinetic Resolutions, and Desymmetrizations

“…Scheidt, Cheong, and co‐workers illustrated the critical roles that the non‐classical hydrogen bonds have played in the control of the stereoselectivities through computational studies. Moreover, these DKR/decarboxylation processes could be used in the enantioselective synthesis of a benzopyran estrogen receptor β‐agonist, as reported by Scheidt and co‐workers in 2015 …”

“…Moreover,t hese DKR/decarboxylation processes could be used in the enantioselective synthesis of ab enzopyran estrogen receptor b-agonist, as reportedb yS cheidt and co-workersin2 015. [48] Recently,B iju and co-workersr eportedt he DKR of multifunctional ketoacids 61 through an NHC-catalyzed enantioselective intramolecular aldol/lactonization reaction (Scheme 14). [49] Peptide coupling reagent 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxideh exafluorophosphate (HATU) was applied to pre-activate the carboxylic acid group in the substrate.…”

Oxetanes and Oxetenes: Fused-Ring Derivatives

“…117,118 When applied to electron-rich ketones (such as 156), this DKR strategy is followed by a spontaneous decarboxylation process that afforded cyclopentene 158. 119 This concerted asynchronous retro-[2+2] reaction was studied using quantum mechanical computations and it was found that the anti-selective process was favored based on steric interactions between the carboxylate and the a-substituent in the syn-transition state. Brown reported a novel palladium-catalyzed deallylative cyclization of 175 to synthesize b-lactone rings 176, an elegant strategy that was applied to the total synthesis of (±)-vibralactone, a natural product isolated from the culture of Basidiomycete Borestereum vibrans.…”

Kinetic Resolution, Dynamic Kinetic Resolution and Asymmetric Desymmetrization by N-Heterocyclic Carbene Catalysis

“…40 Further studies on the NHC-catalyzed aldol-lactonization approach enabled the Scheidt group to achieve the DKR of racemic -formyl aryl--ketoesters to generate cyclopentane-fused -lactones in high yields and stereoselectivities (Scheme 21), with preferential formation of the (1S,4R,5S)-configured isomers being observed. [43][44][45] Scheme 20 NHC-catalyzed asymmetric desymmetrization of 1,3-diketones via an aldol-lactonization sequence…”

“…44 Interestingly, the NHC-DKR-decarboxylation strategy has been very successfully applied as the key step in the enantioselective formal synthesis of an estrogen receptor agonist. 45 A strictly related DKR based on an aldol-lactonization reaction has been developed by Biju and co-workers, starting from acyclic ketoacids, to produce cyclopentane-fused -lactones with three contiguous stereocenters in diastereo-and enantioselective fashion (Scheme 22). 46 These compounds were eventually subjected to synthetic manipulations of the -lactone moiety via decarboxylation, methanol-promoted ring opening or reactions with primary amines.…”