Organocatalytic Asymmetric Hetero-Diels–Alder Reaction of in Situ Generated Dienes: Access to α,β-Unsaturated δ-Lactones Featuring CF₃-Substituted Quaternary Stereocenter

Abstract

Chiral bifunctional urea-catalyzed asymmetric direct hetero-Diels–Alder reaction between alkylidene azlactone-derived dienes and trifluoromethyl aryl ketones is reported for the first time. The direct hetero-Diels–Alder reaction followed by ring opening results in densely functionalized α,β-unsaturated δ-lactones featuring a CF3-substituted quaternary stereocenter in high yields with excellent enantioselectivities. The method is compatible over a range of substrates. Moreover, the reaction is scaled up and the α,β-unsaturated δ-lactones were converted to amino acid derivatives decorated with trifluoromethylated carbinol functionality.

Extended Enolates: Versatile Intermediates for Asymmetric C‐H Functionalization via Noncovalent Catalysis

“…Xu and coworkers described the catalytic vinylogous aldol‐type addition of alkylidene azlactones 127 to α‐keto esters 128 followed by cyclisation to deliver densely functionalized α,β‐unsaturated δ‐lactones (dihydropyranones) 129 featuring a quaternary stereocenter in good yields and excellent enantioselectivities (Scheme 35). [84] Later, Singh and coworkers developed a variant using aryl trifluoromethyl ketones 130 as acceptors [85] . The reaction is believed to proceed through intramolecular O ‐acylation of the anionic aldolate with concomitant azlactone ring opening.…”

“… [84] Later, Singh and coworkers developed a variant using aryl trifluoromethyl ketones 130 as acceptors. [85] The reaction is believed to proceed through intramolecular O ‐acylation of the anionic aldolate with concomitant azlactone ring opening. Strikingly, TS models with opposite coordination geometries between the protonated catalyst and the Nu/Elec reactants were proposed in each work.…”

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

“…More recently another hetero‐Diels‐Alder reaction/ring opening cascade involving trifluoromethyl aryl ketones 138 was reported by Singh and coworkers (Figure 47). In a reaction with alkylidene azlactone‐derived dienes 140 , it was used as a means to obtain α,β‐unsaturated δ‐lactones 141 featuring a CF 3 ‐substituted quaternary stereocenter [121] . The reaction was thought to proceed via a bicyclic intermediate, e. g. 142 , which undergoes ring‐opening to afford the lactone.…”

“…In a reaction with alkylidene azlactone-derived dienes 140, it was used as a means to obtain α,β-unsaturated δ-lactones 141 featuring a CF 3substituted quaternary stereocenter. [121] The reaction was thought to proceed via a bicyclic intermediate, e. g. 142, which undergoes ring-opening to afford the lactone. Bifunctional urea-based catalyst C37 was the best for this transformation, affording a range of products in high yields and excellent ees.…”

“…Synthesis of α,β-unsaturated δ-lactones by a hetero-Diels-Alder reaction/ring opening cascade. [121] Figure 48. Vinylogous aldol/lactonization cascade reaction between β,γunsaturated amides and trifluoromethyl ketones to obtain trifluoromethyl dihydropyranones.…”