Two Decades of Progress in the Asymmetric Intramolecular aza‐Michael Reaction

Abstract

The asymmetric intramolecular aza-Michael reaction (IMAMR) is a very convenient strategy for the generation of heterocycles bearing nitrogen-substituted stereocenters. Due to the ubiquitous presence of these skeletons in natural products, the IMAMR has found widespread applications in the total synthesis of alkaloids and biologically relevant compounds. The development of asymmetric versions of the IMAMR are quite recent, most of them reported in this century. The fundamental advances in this field involve the use of organocatalysts. Chiral imidazolidinones, diaryl prolinol derivatives, Cinchone-derived primary amines and quaternary ammonium salts, and BINOL-derived phosphoric acids account for the success of those methodologies. Moreover, the use of N-sulfinyl imines with a dual role, as nitrogen nucleophiles and as chiral auxiliaries, appeared as a versatile mode of performing the asymmetric IMAMR.

Weak Nucleophiles in the Aza‐Michael Reaction

“…The most impressive results are discussed in the excellent review by del Pozo. [1] The first asymmetric N-alkylation of indoles is reported in 2008. The base catalyzed intramolecular conjugate nucleophilic addition of indoles with tethered enoate proceeds through a 5-or 6-exo-trigcyclization to afford five-or six-membered rings (Scheme 28).…”

“…The most comprehensive review articles on this subject have been published for the last decade. [1][2][3][4][5][6] While the impressive results have been achieved in the addition of strong nucleophiles to Michael acceptors, the reactions of weak nucleophiles have received much less attention. At the same time, these transformations are gained increasing popularity because they can provide an easy access to valuable β-amino carbonyl derivatives bearing important pharmacophore moieties.…”

“…However, these reports have mainly focused on the use of strong Michael donors such as primary or secondary aliphatic and aromatic amines. The most comprehensive review articles on this subject have been published for the last decade [1–6] …”

Pull‐Pull Alkenes in the Aza‐Michael Reaction

“…Among the nucleophilic conjugate addition reactions the addition of nitrogen nucleophiles (so-called aza-Michael reaction) holds a special place. [1][2][3][4][5][6] It is a simplest and shortest pathway to β-amino ketones, β-amino acids and their derivatives which are ubiquitous motifs in natural products and constitute an important class of building blocks in organic synthesis. This reaction exhibits a great versatility and atom economy.…”

“…Finally, last but not least, the polyfunctional alkenes are versatile and valuable building blocks in the synthesis of multifunctional molecules which are often relevant to synthetic and pharmaceutical chemistry. Among the nucleophilic conjugate addition reactions the addition of nitrogen nucleophiles (so‐called aza‐Michael reaction) holds a special place [1–6] . It is a simplest and shortest pathway to β‐amino ketones, β‐amino acids and their derivatives which are ubiquitous motifs in natural products and constitute an important class of building blocks in organic synthesis.…”