Organocatalytic Asymmetric Conjugate Addition and Cascade Acyl Transfer Reaction of α-Nitroketones

Abstract

Organocatalytic asymmetric conjugate addition of α-nitroketones to β,γ-unsaturated α-keto esters has been developed. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst. The reaction was found to proceed via cascade conjugate addition and acyl transfer reaction. A number of α-nitroketones and β,γ-unsaturated α-keto esters were examined in this transformation. 5-Nitro-2-acyloxypent-2-enoates were obtained in good yields (up to 99%) and enantioselectivities (up to 99% ee). The products could be hydrolyzed to provide 5-nitro-2-oxopentanoates, which are not available from the direct addition of nitromethane to β,γ-unsaturated α-keto esters.

Acyl Transfer Strategies as Transient Activations for Enantioselective Synthesis

“…Yan showed that simple bifunctional tertiary aminethiourea catalyst cat1, derived from cyclohexane diamine, provided the expected acyl-protected enoates 3 with moderate to excellent enantiocontrol (62-97% ee, Scheme 4a). 8 The scope of the transformation is large with a limitation encountered using -substituted -nitroketones (R 1 = alkyl), resulting in moderate diastereocontrol (around 2:1 dr). It is of great importance to point out that the two diastereomers are formed with different enantioselectivity.…”

“…The acyl transfer constitutes a driving force for the reaction since it was previously shown that under the same conditions addition of -nitroketones to ,-unsaturated aldehydes with-out the phenol substituent did not induce the corresponding Michael addition. 8 Reduction of the obtained adduct provided an interesting entry into 4-substituted chromane derivatives.…”

Forty Years after “Heterodiene Syntheses with α,β-Unsaturated Carbonyl Compounds”: Enantioselective Syntheses of 3,4-Dihydropyran Derivatives

“…When the α-nitro ketone is an acyclic derivative ( 207 ), the dihydropyran 208 becomes unstable and is directly opened to enantioenriched 5-nitropentenoate through a retro-Henry reaction (Scheme ). − The best organocatalysts were XXXIV and XXXVI , which allowed the final valuable synthons 210 to be obtained with up to 99% yields with excellent enantioselectivities (in many examples, ee > 99%).…”

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones

“…Also, α-nitroketones have been found to be a popular nucleophilic acyl transfer reagent. In 2011, three research groups namely Wang, Yan and Kwong independently revealed the organocatalytic asymmetric conjugate addition of α-nitroketones to β,γ-unsaturated α-keto esters with the concomitant acyl transfer reaction to the keto group [11][12][13]. Consequently, our group developed an organocatalytic asymmetric Michael-acyl transfer reaction of α-nitroketones with unsaturated pyrazolones, 2-hydroxycinnamaldehydes, γ/δ-hydroxyenones, o-quinone methides, etc.…”