3- Hydroxy-3-pyrrolidinones, oxidation

In THF at -20°C the N-trimethylsilylated 2-pyrrolidinone 388 is converted by LDA into the a-anion which, on reaction with 1949 and subsequent acidification with AcOH, gives 43% 3-hydroxy-2-pyrrolidinone 1962 [150]. Lithium enolates of ketones such as camphor react with BTSP 1949 to give >95% of a mixture of exo-and mdo-2-hydroxycamphor [151]. Lithiated methyl heterocycles such as lithiated 2-methylpyridine 1963 are converted into mixtures of the 0-SiMe3 1964 and C-SiMe3 1965 compounds and C-methylated compounds such 1966 [152]. 2-Lithioto-luene 1967 is oxidized by 1949 into 1968 [140, 145] (Scheme 12.42). 

In intact cell systems or vivo, the primary products of a-hydroxylation, 22. have not been detected. The principal urinary metabolites of NNN resulting from a-hydroxylation are keto acid 21 from 2 -hydroxyl at ion and hydroxy acid 21 from 5 -hydroxylation. Trace amounts of 7 y 21> H ve also been detected as urinary metabolites (34). The interrelationships of these metabolites as shown in Figure 2 have been confirmed by administration of each metabolite to F-344 rats (37). The other metabolites which are routinely observed in the urine are NNN-1-N-oxide U1 and 5-(3-pyridyl)-2-pyrrolidinone [norcotinine, ]. The p-hydroxy derivatives 2. 1 were also detected in the urine of NNN treated rats, but at less than 0.1% of the dose (36). An HPLC trace of the urinary metabolites of NNN is shown in Figure 3. Urine is the major route of excretion (80-90% of the dose) of NNN and its metabolites in the F-344 rat in contrast to NPYR which appears primarily as CO2 (70%) after a dose of 16 mg/kg (17). This is because the major urinary metabolite of NNN, hydroxy acid 21> fs not metabolized further, in contrast to 4-hy-droxybutyric acid [2, Figure 1] which is converted to CO2. In addition, a significant portion of NNN is excreted as NNN-l-N-oxide U ], a pathway not open to NPYR. 

Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-0 bond reduction. Addition of iV-acryloyl-(2/()-bomane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85 15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline A-oxide to chiral pentenoates using (-)-/rans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The... 

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