2,4-Oxazolidinediones spirocyclic

Benkovic and co-workers also isolated spirocyclic 2-amino-4(5/7)-oxazolones during their studies on pterin-dependent amino acid hydroxylases (Scheme 6.24). Reaction of 91 with 0-methyl hydroxylamine or semicarbazide at pH 4.8 yielded 92a and 92b, respectively. The authors showed that 92 does not simply result from reaction of the corresponding oxazolidinedione with either reagent. Further, by using H2 0 as the solvent they demonstrated that there was no incorporation into the product. Two different but precedented mechanisms were proposed to account for this rearrangement. The stereochemistry of 92b was confirmed by single-crystal X-ray. 

Spirocyclic 2,4-oxazolidinedione analogues have been prepared and evaluated as cholinergic agents by Japanese workers (Scheme 6.52). For example, condensation of the a-hydroxy ester 226 with urea produced 227a quantitatively, whereas reaction with thiourea afforded 227b in poor yield together with 228. 

TABLE 6.9. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES EROM CYCEIZATION OE a-HYDROXY IMIDATES"... 

Imperial Chemical Industries (ICI) chemists " prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists approached 5-substituted isatin spirocyclic analogues 243 via a-hydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium ferf-butoxide then produced 243 in acceptable yield (Scheme 6.54 Table 6.10, Fig. 6.20). 

Sollhuber s group " extended the scope of their earlier work using chlorosulfonyl isocyanate to synthesize spirocyclic 2,4-oxazolidinediones. They prepared 188a, 214, 218, and 232 together with several additional examples using this methodology. 

On the other hand, Wyeth-Ayerst chemists ° encountered limitations with this methodology during their syntheses of spirocyclic 2,4-oxazolidinediones derived from isoindole (Scheme 6.55). For example, reaction of 246 with chlorosulfonyl isocyanate followed by cyclization with potassium terf-butoxide afforded poor to modest yields of 247 when R was a substituted benzyl group. Cyclization of 246 using ethyl chloroformate (ECF), triethylamine and 4-(dimethylamino)pyridine (DMAP) in refluxing tetrahydrofuran (THF) gave 247 in only 29% yield when R was methyl and failed completely if R was an isopropyl group. However,... 

TABLE 6.10. SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM 5- OR 7-SUBSTITUTED ISATINS... 

Mannich reactions of 2,4-oxazolidinediones, particularly spirocyclic analogues, for example, 214, and 218-220, usually proceed readily at N-3 in good to excellent... 

TABLE 6.9 SPIROCYCLIC 2,4-OXAZOLIDINEDIONES FROM CYCLIZATION OF a-HYDROXY IMIDATES, 101... 

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