Enantioselectivity retro-nitroaldol reaction

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

Interfacially active guanidinium-thiourea bifunctional catalyst 190 catalyzes highly enantioselective nitroaldol reactions in the presence of an external base such as KOH in toluene/water biphasic conditions. Although the retro-nitroaldol reactions generally proceed under basic conditions, addition of KI inhibits the retro-process. A cooperative reaction mode between guanidinium and thiourea moieties is supported by experiments using structural variants of 190. A positive nonlinear effect is observed between the enantiomeric excess of 190 and the product 191. These results support the hypothesis that self-a egation of 190 is necessary for catalysis (Scheme 28.22) (96, 97). Catalyst 190 has been used in the synthesis of chiral tertiary alcohol products obtained in nitroaldol reactions of nitroalkanes and a-ketoesters [98],... 

Organocatalytic Henry reactions with synthetically useful levels of yields and enantioselectivities came a decade later with the independent work of Nagasawa and Hiemstra. Nagasawa used guanidinium salt/thiourea brfimctional catalyst 2 for the reaction of nitromethane or nitroethane with aliphatic aldehydes (no reaction was observed when aromatic aldehydes were used) [7]. The reaction works under PTC with the assistance of KOH, and to overcome the retro-nitroaldol reaction K1 as an additive was required (Scheme 29.2). Two years later, the same group extended this reaction to nitroalkanes other than nitromethane, a process that yields the corresponding xyn-nitroalcohols preferentially. 

Based on catalytic double activation (guanidinium salt/thiourea moiety skeleton), Nagasawa et al. were able to achieve the reaction of nitromethane, nitro-ethane, and nitropropane with aliphatic a-ketoesters in moderate yields and selectivities (Scheme 29.10) [24]. The reaction works with the assistance of 10 mol% KOH and to overcome the retro-nitroaldol reaction, the presence of 50mol% K1 was required. The resulting Henry reaction adducts are obtained with good syn/anti ratios, and enantioselectivities of up to 98%. When aromatic a-ketoesters were subjected to the reaction unsatisfactory results were obtained (e.g., R = Ph, 5% yield and 5% ee). 

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