Synthesis of Spirocyclic and Fused Isoxazoline Building Blocks

Abstract

A highly efficient multigram synthesis of spirocyclic and fused isoxazoline building blocks is described. Isoxazoline‐3‐carboxylates were synthesized via a regioselective 1,3‐dipolar cycloaddition reaction of 2‐chloro‐2‐(hydroxyimino)acetate and carbo‐ or heterocyclic alkenes bearing endo‐ or exocyclic C=C double bonds, resulting in fused or spirocyclic isoxazolines, respectively. The preparation of up to 300 g of these compounds was achieved in a single run. The ester group of isoxazolines was then subjected to common synthetic transformations for the synthesis of corresponding building blocks, including alcohols, chlorides, azides, amines, aldehydes, carboxylic acids, amino acids and their derivatives, difluoromethyl‐substituted compounds, and bicyclic γ‐lactones. Additionally, a direct cycloaddition‐based approach to the synthesis of aminoalkyl‐ and chloromethyl‐substituted isoxazolines was proposed to improve their preparation. The described isoxazoline building blocks are expected to be valuable tools for drug discovery.

Palladium-Catalyzed Aerobic Oxidative Spirocyclization of Alkyl Amides with Maleimides via β-C(sp3)–H Activation

“…These compounds have been widely isolated from many biologically active compounds and also exhibit antiviral, antipsychotic, and antitumor activities. Because of the importance of such scaffolds, there have been many synthetic approaches to spirodiamine molecules, but strategies involving transition-metal-catalyzed C­(sp 3 )–H bond activation followed by functionalization have hardly been explored. , Functionalization of aliphatic C­(sp 3 )–H bonds possesses various challenges such as their inert nature, high conformational degrees of freedom, and the absence of a π bond that causes difficulty in the interaction of the transition metal with the target C–H bond. To deal with such challenges, directing group-assisted C­(sp 3 )–H bond activation and subsequent functionalization were explored.…”