Route to Chiral Tetrahydrofuran Acetals via Pd-Catalyzed Asymmetric Allylic Cycloaddition of Vinyl Epoxides with β-Keto Enol Ethers

Abstract

An efficient method for the synthesis of functionalized chiral tetrahydrofuran (THF) acetals via Pd-catalyzed asymmetric allylic cycloaddition has been developed. With a palladium catalyst coordinated by a chiral phosphine ligand, the protocol is enabled to combine readily available vinyl epoxides and β-keto enol ethers to produce THF acetals bearing three stereocenters in a broad substrate scope with uniformly high levels of enantio-and diastereoselectivity.

Recent advances in Pd-catalyzed asymmetric cyclization reactions

“…91 Recently, the group of Zhang reported their studies on the Pd-catalyzed asymmetric allylic cycloaddition of vinyl epoxides with β-keto enol ethers 191 utilizing BINAP or OMe,Cl-Biphep as a chiral ligand, giving readily access to functionalized chiral tetrahydrofuran acetals 192 bearing three stereocenters. 92 Notably, the process provided a novel and useful method for late-state functionalization of natural products employing β-keto enol ethers bearing chiral alkoxides or natural fragments.…”

Stereoselective Total Synthesis of Formosanol, Tsugacetal, and Methyl β-Conidendral

“…Compound 8 could be traced back to the ideal intermediate of THF acetal 9 , primed with proper functionalities, via straightforward reduction of the ketone group, oxidation of the vinyl group, and the epimerization step. Most recently, we have developed an efficient stereoselective approach to the synthesis of chiral THF acetals bearing three continuous stereocenters via Pd-catalyzed asymmetric allylic cycloaddition of vinyl epoxide and β-keto enol ethers with high levels of enantio- and diastereoselectivity. , On the basis of this research results, we believe that the key intermediate 9 could be synthesized by Pd-catalyzed asymmetric allylic cycloaddition of vinyl epoxide 10 with β-keto enol ether 11 . Herein, we present the successful execution of the synthetic plan and report the first enantioselective total synthesis of aryltetralin lignan acetals, (−)-formosanol ( 3 ), (+)-tsugacetal ( 4 ), and (+)-methyl β-conidendral ( 5 ) and their enantiomers.…”

“…Our initial study was focused on the optimization of Pd-catalyzed asymmetric allylic cycloaddition of vinyl epoxide 10 with β-keto enol ether 11 based on our previous work (Table ). As we expected, the reaction proceeded smoothly in the presence of a catalyst generated in situ from Pd 2 (dba) 3 ·CHCl 3 and ( R )-BINAP ( L1 ) in THF at 0 °C for 20 h to afford desired THF acetal ent- 9 bearing three continuous stereogenic centers as almost a single diastereomer in 98% yield with excellent enantioselectivity (99% ee) (entry 1).…”

Recent updates on vinyl cyclopropanes, aziridines and oxiranes: access to heterocyclic scaffolds

“…In 2022, Zhang and colleagues 29 reported the palladium-catalyzed enantioselective synthesis of chiral tetrahydrofuran acetals, through a [3 + 2] cycloaddition reaction between vinyl oxirane and electron-deficient vinyl ether (Scheme 5). Here, β-keto enol ether 19 acts as a Michael acceptor to undergo [3 + 2] cycloaddition with vinyl oxirane 20 to furnish substituted tetrahydrofuran motifs.…”