Organocatalytic Domino Michael–Heterocyclization Reaction of α,β‐Unsaturated Aldehydes and α‐Cyano Ketones: Synthesis of Enantioenriched 4,5,6‐Trisubstituted 3,4‐Dihydropyranones

Abstract

α,β‐Unsaturated aldehydes with aliphatic, electron‐poor aromatic, or electron‐withdrawing substituents at the β position easily react with different ketones leading to enantioenriched hemiacetals, which were further oxidized to give 4,5,6‐trisubstituted‐3,4‐dihydropyranones in good yields and with excellent enantioselectivities. The behavior of the ketones is dependent on the α substituent of the carbonyl group, and a fine‐tuning of the pKa values is necessary to obtain good results.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…4,5,6‐Trisubstituted‐3,4‐dihydropyranones 141 were synthesized by Pedrosa and co‐workers via an asymmetric domino Michael/hemiacetalization reaction between α,β‐unsaturated aldehydes 42 and α‐cyano ketones 139 catalyzed by ( S )‐ 45 followed by a PCC oxidation (Scheme ) . However, the reaction outcomes were found to be highly dependent on the chiral secondary amine catalyst and the substrates used.…”

“…), or if α‐nitro ketones were used, the reaction only provided the Knoevenagel adduct 142 . Also, when R 2 of 139 was a benzoyl group, the reaction provided the substituted phenol 143 instead (Scheme ) …”

Organocatalytic Cascade Reaction of Aliphatic Enals and Benzoylnitromethane: Synthesis of Enantioenriched Tetrasubstituted Cyclohexene Carbaldehyde

“…e first step of the study involved the reaction between 1a and crotonaldehyde (2a), initially following the method as described in the literature [38]. TLC analysis of the reaction showed the formation of two products; these derivatives were purified by column chromatography and characterized via spectral techniques, including 1 H-NMR, 13 C-NMR, and 2D-NMR experiments (see Supplementary Materials (available here)).…”

“…is is attributable to the fact that increasing the acidity of the ketone's α-protons induces the spontaneous cyclization of the Michael adduct into cyclic hemiacetals or into 3-hydroxy-cyclohexanones [38]. Instances where the Michael adduct is stable and does not spontaneously cycle have been documented, but only when the pKa of the ketone's a-protons remains close to 19, as described by [37,39].…”

“…An interesting example is the formation of Michael adducts and their subsequent intramolecular cyclization, promoting the formation of cycles with consecutive stereocenters, which can be used as building blocks for more complex molecules. In this way, the influence of the pKa [36][37][38][39][40] of (pronucleophiles) is decisive in obtaining the type of product. For example, nucleophiles with pKa values of 9 used as Michael donors form Michael adducts that spontaneously cycle into hemiacetals via an intramolecular reaction [37], while nucleophiles with pKa of 10-14 lead to the formation of cyclic derivatives with a carbonyl function (Figure 1).…”