Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

Abstract

Racemic 2-hydroxydihydropyran-5-ones react as unconventional O-pronucleophiles in a conjugate addition/Michael reaction cascade process under DKR, leading to the formation of a single stereoisomer out of 16 possible ones.

The Role of L-Proline and Co-Catalysts in the Enantioselectivity of OXA-Michael-Henry Reactions

“…23 The use of co-catalyst A allowed better ee on formation of 4; therefore, it was decided to evaluate the enantioselectivity of the reactions using other co-catalysts that had been shown to be efficient for organocatalysis. 25 When co-catalysts B and C were used, poor enantioselectivities were observed, the condition with toluene showing the best results ( Table 2, entries 16 and 19, 14 and 8%, respectively). Xu and co-workers 19 explain the success of co-catalyst B possibly by a dual performance in the process with the formation of the aromatic iminium and hydrogen-bonding interaction between the oxygen of the nitro group and phenolic hydrogen of B.…”

Organocatalytic Dynamic Kinetic Resolution: An Update

“…In an example reported in 2017, Vicario and Merino employed chiral proline derivatives to promote an asymmetric domino oxa‐Michael/Michael reaction between hydroxypyranone 205 as unconventional O ‐nucleophile and α,β‐unsaturated aldehydes, evolving through DKR and iminium/enamine activation (Scheme 45). [61] When β‐aryl substituted α,β‐unsaturated aldehydes 206 were involved as electrophiles, the best results were obtained by using 20 mol% of proline‐derived catalyst 207 in chloroform as the solvent in the presence of achiral thiourea 208 as an additive. Performed at room temperature, the cascade reaction afforded mixtures of two diastereomers 209 and 210 with good yields (61–87 %), moderate to high diastereoselectivities in favor of diastereomers 209 (34–82 % de ) and high enantioselectivities (86–97 % ee ).…”

Recent advances in organocatalytic asymmetric oxa-Michael addition triggered cascade reactions

“…Vicario's group 25 in 2017 reported a positive and effective method for the construction of bicyclic furo [2,3-b]pyranes via an oxa-Michael/Michael cascade reaction. Hydroxypyranones 49, active chiral racemic O-pronucleophiles, reacted with unsaturated aldehydes 11 providing the desired products 51 in good yields (up to 87%) with high stereoselectivities (up to 10 : 1 dr and 97% ee) under the catalysis of catalyst 12 and cocatalyst 50 in chloroform (Scheme 16a).…”