Imbuing an Old Heterocycle with the Power of Modern Catalysis: An Isoxazolidin-5-one Story

Abstract

Isoxazolidin-5-ones have been regarded as β-amino acid surrogates owing to their labile N-O bond. While many efforts have been devoted to the catalytic enantioselective synthesis of the core of this heterocycle, its further transformation has been less explored, especially in the context of catalysis. This review summarizes the author's research on the development of catalytic reactions using isoxazolidin-5-ones as substrates. Asymmetric catalysis has proven effective for C-C bond formation at the carbonyl α-carbon. Catalytic asymmetric allylation and direct Mannich-type reactions have been developed. Further, the resulting products have been readily converted into the corresponding quaternary β 2,2 -amino acids. Moreover, isoxazolidin-5-ones have been identified as alkyl nitrene precursors in the presence of a suitable metal catalyst. The generated metallonitrene undergoes either the electrophilic amination of the aromatic ring or aliphatic C-H insertion, affording a series of cyclic β-amino acids. A remarkable difference in chemoselectivity between rhodium and copper alkyl nitrenes has also been demonstrated, highlighting the unique nature of the underexplored reactive intermediates. The various linear and cyclic β-amino acids obtained through the study are likely to find great utility in a broad range of chemical sciences.

Photo-induced redox cascade reaction of nitroarenes and amines

“…This skeleton is a key substructure of many bioactive compounds, and constitutes a versatile platform for further chemical transformations. [35][36][37][38][39][40][41][42] The previous synthetic route [43][44][45][46] to this structural unit involves the utilization of unstable and perishable aldehydes and hydroxylamine, resulting in a limited substrate scope. For example, only the electron-withdrawing groups, such as Boc-and Cbz-protected hydroxylamines, are tolerated in these reactions.…”

Examining the effects of additives and precursors on the reactivity of rhodium alkyl nitrenes generated from substituted hydroxylamines

“…We previously reported that substituted isoxazolidin-5-ones (Annibaletto et al, 2017;Noda, 2021) acted as alkyl nitrene precursors in the presence of rhodium (Yu et al, 2019) or copper catalysts (Tak et al, 2021a). The generated metallonitrene reacted intramolecularly with an aromatic ring (Tak et al, 2021b) or C(sp 3 )-H bond (Espinosa et al, 2019) to afford the corresponding unprotected cyclic β-amino acids.…”

Stereoselective Syntheses of Masked β‐Amino Acid Containing Phthalides

“…Isoxazolidin-5-ones 1 emerged as powerful masked β 2amino acid (AA) derivatives over the last years. [1][2][3][4] The main value of these easily accessible heterocycles lies in the fact that they can directly be subjected to a variety of catalytic asymmetric α-functionalization reactions, which deliver the masked β 2,2 -AA derivatives 2 straightforwardly. [5 -17] So far, this strategy has been very successfully applied to asymmetric αheterofunctionalizations [6,14 -17] as well as CÀ C bond forming reactions [7 -13] either using chiral organocatalysts or asymmetric transition metal catalysis.…”

“…Isoxazolidin‐5‐ones 1 emerged as powerful masked β 2 ‐amino acid (AA) derivatives over the last years [1–4] . The main value of these easily accessible heterocycles lies in the fact that they can directly be subjected to a variety of catalytic asymmetric α‐functionalization reactions, which deliver the masked β 2,2 ‐AA derivatives 2 straightforwardly [5–17] .…”