Crystallization-induced diastereomer transformation assists the diastereoselective synthesis of 4-nitroisoxazolidine scaffolds

• Published in: Organic & biomolecular chemistry Vol. 22; no. 32; pp. 6582 - 6592
• Main Authors: Esteban, Alberto, Ortega, Pablo, Sanz, Francisca, Jambrina, Pablo G., Diez, David
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 14.08.2024; Royal Society of Chemistry
• Subjects: Aromatic compounds; Chemistry; Chemistry, Organic; Crystallization; Diastereoisomers; High temperature; Nitrogen dioxide; Physical Sciences; Science & Technology; Stereoselectivity; Synthesis; CYCLIC NITRONES; CONVERSION; 1.3-DIPOLARE ADDITIONEN; 1,3-DIPOLAR CYCLOADDITION; RESOLUTION; AZOMETHINE YLIDES; REGIOSELECTIVITY; PYRROLIZIDINES
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d4ob01014k

This communication describes a solution to the vexing problem of synthesis of 4-nitroisoxazolidine rings from cyclic nitrones and beta-nitrostyrenes. The trans-endo adduct 2 is quantitatively synthesised from E-beta-nitrostyrene under mild conditions avoiding purification, while the trans-exo adduct 4 is obtained at higher temperatures. Furthermore, a Crystallization-Induced Diastereomer Transformation (CIDT) process was used to epimerise the NO2 bond from 2 to the cis-exo adduct 3 with total conversion assisted by the para-halogen substitution of the aromatic ring without any additives. By combining these approaches, we can establish a simple synthetic methodology that allows the diastereoselective synthesis of three diastereoisomers, overcoming the previous problems described in the literature. The synthesis of chiral 4-nitroisoxazolidine scaffolds by cycloaddition of a nitrone to E-Z nitrostyrenes and stereochemistry tuned by CIDT or by raising the temperature is described. Mechanisms were established on electronic structure calculations.