Isoxazolidinone-isoxazolidine

Isoxazolidines and isoxazolidinones are a small class of compounds which has received only limited attention. Reviews have appeared dealing with isoxazolidines in 1962 (62HC(17)l,p.7) and 1977 (77AHC(21)207>. 

Three isoxazolidinones are possible, the 3-, 4- and 5-isoxazolidinones, with 3-isoxazolidinones being the group containing the most members. Only one synthesis of 4-isoxazolidinones has been reported, although a number of 4-arylmethylene compounds exist. A number of isoxazolidine-3,5-diones have been synthesized. A review by Quilico with nine references appeared in 1962 (62HC(17)l,p. 7> and since then the number of references has slightly more than tripled. 

Isoxazolidin-5-one, 2-methyl-3-phenyl-synthesis, 6, 113 Isoxazolidinones synthesis, 6, 112-114 IsoxazoIidin-3-ones synthesis, 6, 112 Isoxazolidin-4-ones synthesis, 6, 113 Isoxazolidin-5-ones synthesis, 6, 113... 

Stereoselective syntheses of 5-isoxazolidinones were also achieved through addition of lithiated chiral oxazolidines to nitrones. In solution, the spiro-fused isoxazolidine 554 was in equilibrium with its open hydroxylamino form 553. Acidic hydrolysis of the chiral auxiliary afforded the highly enantioenriched isoxazolidinone 555 in good yield (Scheme 134) <2003OL2723, 2003JOC9861>. 

Reduction of methyl [5-(bromomethyl)isoxazolidin-3-yl]acetates 324 with trihutyltin hydride in boiling toluene in the presence of AIBN led to opening of the isoxazolidine ring and formation of isoxazolidinones 579. The process is believed to go through the formation of nitroxide radical 577, followed by reduction to hydroxylamine 578 and cyclization to 579 with elimination of methanol (Equation 98) <1999SL79>. 

Alternatively, isoxazolidin-5-yl acetates were obtained by reduction and acetylation of suitable isoxazolidin-5-ones, which, in turn, were prepared by diastereoselective Michael addition of hydroxylamines to unsaturated esters or by nucleophilic addition of enolates to nitrones and subsequent cyclization of the resulting hydroxylamines. For example, the two diastereomeric isoxazolidinones 552 were converted into thymidine analogues 590 (Scheme 146) <1997JOC7430, 1998T6587, 2000TL9239, 2005CRC775>. 

A family of m-cyclopent[r-]isoxazolidine alkaloids named pyrinodemins was isolated from the marine sponge Amphimedon sp. <1999TL4819>. These compounds, which show potent cytotoxicity, were synthesized in racemic form by different groups in order to clarify their structures. The asymmetric total synthesis of (—)-pyrinodemin A was also accomplished <20030L2611>. Both the enantiomers of cycloserine (4-amino-3-isoxazolidinone) act as alanine racemase inhibitors and the mechanism of inactivation has been studied <1998JA2256, 1998JA2268, 2005B5317>. 

Several 2-aryl- and 2-phenylmethyl-3,5-isoxazolidine-dlones were synthesized and found to be bleaching herbicides with good tolerance by soybeans. The most active member, 2-(2-chlorophenyl)methyl-4,4-dimethyl-3,5-isoxazolidinedione, failed to perform in the field due to its instability in soil. To improve the chemical stability by molecular modifications, a series of 3-isoxazolidinones were prepared and found to be highly active bleaching herbicides with excellent soybean tolerance. Synthesis and structure-activity relationships are discussed. One of the most active compounds,... 

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