The organocatalyzed domino Michael–aldol reaction revisited. Synthesis of enantioenriched 3-hydroxycyclohexanone derivatives by reaction of enals with α,α′-diaryl-substituted acetone

Abstract

Abstract.The reaction of enals with ´-diaryl-substituted acetones (pKa > 18) catalyzed by (S)-1-(2-pyrrolidinylmethyl) pyrrolidine provides a direct access to enantioenriched 2,5,6-trisubstituted-3-hydroxy cyclohexanones. The process constitutes a highly stereoselective organocatalytic tandem Michael-intramolecular aldol reaction. It has been demonstrated that the stereoselection is dependent on the reaction conditions because only syn diastereoisomers are able to cyclize, and that anti diastereoisomers participate in a retro-Michael process decreasing the enantioselection.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…No further cyclization of 230 was observed in these cases. The authors also demonstrated experimentally that only the syn ‐ 230 intermediates could undergo the final aldol cyclization to produce 231 , while the anti ‐ 230 isomers remained unreacted (Scheme ) …”

“…The same catalyst 144 was used in the synthesis of 2,5,6‐trisubstituted‐3‐hydroxycyclohexanones 231 by reacting enals 42 with α,α′‐diaryl‐substituted acetones 229 via an asymmetric domino Michael/aldol reaction, as reported by Pedrosa and co‐workers . When both aryl substituents in 229 were 4‐methoxyphenyl groups or one of the aryl group was replaced with an alkyl group, the reaction would stop at the Michael reaction step, leading to the formation of the intermediate 230 .…”

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

“…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).…”

“…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).…”