One-Pot Sequential Organocatalytic Michael–Tishchenko–Lactonization Reactions. Synthesis of Enantioenriched 4,5,6-Trisubstituted δ-Lactones

Abstract

Enantioenriched trisubstituted lactones were obtained in good yields and moderate to very good enantioselectivities in one-pot process, which implies a sequential organocatalyzed Michael addition of ketones to enals, followed by catalytic intramolecular diastereoselective Tishchenko reaction and lactonization. The final lactones were obtained as single diastereoisomers, demonstrating that the mixture of the anti and syn diastereomers epimerized to the syn hydroxy ester during the oxido-reduction step.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[72,73] 4,5,6-Trisubstituted-3,4-dihydropyranones 141 were synthesized by Pedrosa andc o-workers via an asymmetricd omino Michael/hemiacetalization reactionb etween a,b-unsaturated aldehydes 42 and a-cyano ketones 139 catalyzed by (S)-45 followed by aP CC oxidation (Scheme 36). [74] However, the reactiono utcomesw ere found to be highly dependent on the chiral secondary amine catalyst and the substrates used. If 144 was useda st he catalyst instead of (S)-45, or if the R 1 group in 42 was an electron-rich aryl group (4-MeOC 6 H 4 ,2 -furyl, etc.…”

“…), or if a-nitro ketones were used, the reactiono nly provided the Knoevenagel adduct 142.A lso,w hen R 2 of 139 wasa benzoylg roup,t he reactionp rovidedt he substituted phenol 143 instead(Scheme 36). [74] Using 51 as the catalyst, Lopp and co-workers realized an asymmetric organocatalytic domino Michael/ cyclization reactionb etween cyclopentane-1,2-dione (145)a nd enals 42 for the synthesis of substituted dihydropyran derivatives 146,w hich were further transformed to 3-substituted cyclopentane-1,2-diones 147 throughreduction(Scheme 37). [75] Liu, Li, and co-workersr ealized aq uadruple domino oxa-Michael/Michael/Michael/aldol condensation reactionb etween b-aryl enals 42 and 2-vinylphenol derivatives 148 using (S)-45 as the catalyst (Scheme 38).…”

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).…”

Ytterbium Triflate Catalyzed Synthesis of Heterocycles

“…Pedrosa and co-workers reported the one-pot synthesis of enantioenriched trisubstituted tetrahydro-2H-pyran-2ones (lactones) in good yields by sequential stereoselective organocatalyzed Michael addition of ketones to enals, followed by Yb(OTf) 3 -catalyzed diastereoselective Tishchenko reaction and lactonization (Scheme 50). 66 The reaction showed good results for benzyl ketones and ketosulfones as nucleophiles, and for both β-substituted alkyl and aryl enals as electrophiles. For a few cases, the hydroxy ester failed to cyclize to give the lactone product.…”