Enantioselective Synthesis of 3,4‐Dihydropyran‐2‐ones by Domino Michael Addition and Lactonization with New Asymmetric Organocatalysts: Cinchona‐Alkaloid‐Derived Chiral Quaternary Ammonium Phenoxides

Abstract

Chiral quaternary ammonium phenoxides were readily prepared from commercially available cinchona alkaloids and proved to be useful new asymmetric organocatalysts. Among various chiral quaternary ammonium phenoxides, a cinchonidine-derived catalyst that bears both a sterically hindered N1-9-anthracenylmethyl group and a strongly electron withdrawing 9-O-3,5-bis(trifluoromethyl)benzyl group were found to be highly effective for the Michael addition of ketene silyl acetals (derived from phenyl carboxylates) and alpha,beta-unsaturated ketones followed by lactonization. Optically active 3,4-dihydropyran-2-one derivatives were obtained in high yields with excellent control of enantio- and diastereoselectivity. This catalyst can be handled in air and stored at room temperature in a sealed bottle without decomposition for at least one month.

An Organocatalytic Approach to the Synthesis of Six-Membered Heterocycles

“…Among the outstanding examples offered by Mukaiyama through the years, noticeable in such a context is the domino Michael addition/lactonization reaction catalyzed by Cinchona-alkaloid-derived chiral quaternary ammonium phenoxides [99]. After having synthesized a wide range of such a new asymmetric organocatalysts, the resulting best chiral quaternary ammonium phenoxide 378, in term of overall yield and stereocontrol, was employed to perform the domino Michael addition and lactonization reaction between variously substituted ketene silyl acetals 377 and , -unsaturated ketones 376.…”

New Developments in Chiral Cooperative Ion Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From Protonation to Deprotonation Reactions.

“…Indeed, one could consider to associate the phenoxide anion with a chiral quaternary ammonium cation through a chiral quaternary ammonium phenoxide ion pair organocatalyst. Such a type of catalyst, even if already described in the literature mainly by the group of Mukaiyama in 2000′s, were then sparingly exploited in the literature. [21],[22] We thus decided to undertake the synthesis of such catalysts and to assess their performances in enantioselective protonation of silyl enol ethers 2 derived from cyclic aromatic ketones (Scheme ) …”

Chiral Ammonium Aryloxides: Efficient Multipurpose Basic Organocatalysts

“…Surprisingly, some of the catalysts were isolated as a 1:1 complex with a molecule of phenol. This complexation by an extra molecule of phenol seems to occur through hydrogen bonding when the catalysts bear an electron‐withdrawing group . The best catalyst ( CD + 3 , PhO − ) .PhOH was then involved in this tandem reaction with other α,β‐unsaturated ketones 1 to provide the 3,4‐dihydropyran‐2‐ones 3 in excellent yields (>86 %) and enantioselectivities (86–96 % ee ).…”