Organocatalytic Asymmetric Synthesis of Highly Substituted Tetrahydrofurans and Tetrahydropyrans via Double Michael Addition Strategy

Abstract

An efficient organocatalytic asymmetric synthesis of 2,3,4-trisubstituted tetrahydrofurans and tetrahydropyrans has been developed using tandem iminiumÀ enamine catalysis. The process comprises of a double Michael addition reaction between γ/δ-hydroxy-α,β-unsaturated carbonyls and enals. The products of this reaction are obtained in high enantio-and diasteroselectivities and some further synthetic transformations have been performed.

Organocatalytic Asymmetric Synthesis of Tetrahydrofuran and 1,2‐Dihydrobenzofuran Scaffolds

“…Pan and co‐workers also achieved 2,3,4‐trisubstituted tetrahydrofurans and tetrahydropyrans through prolinol catalyzed asymmetric Michael/Michael iminium‐enamine catalysis reaction sequence . They validated their strategy by conducting a double Michael addition reaction between γ/δ ‐hydroxy‐ α, β ‐unsaturated carbonyls 13 and enals 14 in presence of catalyst 9 and benzoic acid as additive; the desired major product 15 was isolated in good yield with excellent diastereo‐ and enantioselectivity.…”

“…Pan and co-workers also achieved 2,3,4-trisubstituted tetrahydrofurans and tetrahydropyrans through prolinol catalyzed asymmetric Michael/Michael iminium-enamine catalysis reaction sequence. [23] They validated their strategy by conducting a double Michael addition reaction between γ/δ-hydroxy-α, -unsaturated carbonyls 13 and enals 14 in presence of catalyst 9 and benzoic acid as additive; the desired major product 15 was isolated in good yield with excellent diastereo-and enantioselectivity. The scope of the reaction was quite broad, different aromatic enals were well tolerated under this catalytic system to provide a variety of substituted THFs and THPs, although aliphatic enals did not work well in this reaction condition (Scheme 2).…”

Recent advances in the transition metal-free synthesis of heterocycles from α,β-unsaturated ketones

“…An organocatalytic double Michael addition strategy for the synthesis of trisubstituted tetrahydropyrans 216 and trisubstituted tetrahydrofurans 214 was reported by Mondal and co-workers (Scheme 82). 90 The reaction involves γ -hydroxy- α,β -unsaturated carbonyl 213 and enal 108 as the reaction partners to achieve the synthesis of tetrahydrofuran derivatives 214 . But tetrahydrofurans are obtained as a mixture of two diastereomers and the major diastereomer is formed with better enantioselectivity.…”

Alcohol Dehydrogenase‐Triggered Oxa‐Michael Reaction for the Asymmetric Synthesis of Disubstituted Tetrahydropyrans and Tetrahydrofurans

“…The syntheses of these motifs often commence from the chiral pool, to provide the desired enantiomer of the nucleophilic alcohol, prior to the IMOMR. This chiral centre has also been installed via asymmetric catalysis, but the scope of this chemistry is limited …”