Spirohydantoin

Several electrophiles, such as acetic anhydride, nitric acid or alternative nitrating agents, such as ammonium nitrate in trifluoroacetic anhydride (41), or sodium hypochlorite, react at N-1, which is followed by reaction at N-3 under suitable conditions. In the case of acetic anhydride, the reaction can take place exclusively at N-3 if N-1 is hindered this fact has served as a criterion for studying the stereochemistry of 5-spirohydantoin derivatives (42,43). 

Esters undergo hydrolysis and conversion to amides under the usual conditions, and amide side chains have also been formed from the acid and amine with DCCI. Acids have been formed from the corresponding spirohydantoins via ureido derivatives (Section 2.15.15.6.1), and undergo decarboxylation in the usual manner. 

Notably, some substrates possess enough steric bias to exert sterospecificity for the Bucherer-Bergs reaction. For instance, ketone 21, derived from enone 20 via a Corey-Chaykovsky reaction, underwent a Bucherer-Bergs reaction to fashion spirohydantoin 22 as a single isomer. 

Similarly, McCapra and Leeson (1976) have reported that reaction of some dimeric peroxides with 1,3,10-trimethylisoalloxazinium perchlorate [42] gives light. These authors suggest that this reaction proceeds by addition of the hydroperoxide to the lOa-position to give eventually the spirohydantoin [43] as shown in (50). 

Z)-l-Acyl-3-methyl-5-(cyanomethylidene)imidazolidine-2,4-diones such as 807 readily undergo 1,3-dipolar cycloadditions with various 1,3-dipoles. The final products depend both on the nature of the dipoles and the dipolarophiles. Thus, spirohydantoins 808 and 809 are formed under neutral conditions with diazomethane or a nitrile oxide whereas further isomerization occurs under either basic or acidic conditions leading to acylureas such as 811 via 810 (Scheme 200) <2001HCA3403>. 

The glycosylamine 296 anomerizes in methanolic solution. The spirohydantoins 298 and 299 form an equilibrium mixture under basic conditions [231] ( Scheme 60. 

Analogously, 1-aminocyclopropanecarboxylic acid (20) was prepared from cyclopropane-1,2-biscarboxamide (18) via spirohydantoin 19 in good yield. ... 

Similarly, the diethyl 2-(3-oxocyclopentyl)- and 2-(4-oxocyclohexyl)ethylphosphonates have been subjected to the standard Bucherer-Berg reaction conditions [KCN, (NH4)2CO, NH4CI in EtOH-HjO at 60°C] to give spirohydantoins, which are isolated as a mixture of cis- and trans-isomers. Hydrolysis of hydantoins needs heating at 150°C in a sealed tube with concentrated HCl to provide the amino acid hydrochlorides. ... 

Substitutions of N-9 in the spirohydantoin as shown in compounds E to H (see Fig. 11) fetched about no enhancement of the inhibition. Their K[ values... 

Figure 12 shows a crystal structme of a GP-glucopyranose spirohydantoin complex at 1.8 A resolution (PDB code 1A81) [62]. 

Bridgehead nitrogen hydantoins have been obtained from imidazole-, pyrrolidine-, and piperidine-2-carboxylates,19 as well as spirohydantoins, such as 15, derived from the aminolysis products of isatincarboxamides.20 Amino nitriles react in a similar manner.1,3,21,22... 

Chlorosulfonyl isocyanate is uniquely useful for the formation of hy-dantoins from sterically hindered acid- and base-labile amino nitriles, e.g., the synthesis of optically active spirohydantoins such as the biologically active (4S)-2,3-dihydro-6-fluorospiro(4H-1 -benzopyran-4,4 -imidazolidine)-2, 5 -dione.23... 

Afs,(V10-Dialkylisoalloxazines react with molecular oxygen to give 4a-hydroperoxides (43a), which provide, on spontaneous decomposition, 4a-pseudobases (43b). These intermediates undergo ring contraction in basic medium to yield spirohydantoins (44).87... 

The autooxidation of l,3,5,6,7-pentamethyl-5,6,7,8-tetrahydrolumazine also yields spirohydantoins identified by X-ray analysis.88 Early results... 

Spirohydantoins have also been found to result from reactions of several nucleophiles with 1,3,10-trimethylflavinium perchlorate.91 In the same context is described the pyrimidine ring contraction of the flavinium cation 47 with OH- through the 4a-adduct 48 or its isomer lOa-adduct 49 to the spirohydantoins 50 and 51.92... 

A related reaction uses cyclic peraminoethylenes, particularly A2,2 -bis(l,3-disubstituted imidazolidines) (64), as starting materials. These powerful bases are extremely reactive and, in the presence of isocyanates or isothiocyanates, yield inner salts (65) with a 1,3-dipolar structure, which undergo cycloaddition with suitable dipolarophiles, such as isocyanates or isothiocyanates, to give the corresponding spirohydantoins. In many cases the spiro derivative is obtained in one step.113... 

Recently, antidiabetic activity has been reported for some spirohydantoins. Thus compounds of type 138-145 are potent inhibitors of aldose reductase activity and sorbitol accumulation, being particularly useful in treatment of chronic diabetic complications.344-352... 

Table 8.7. AR INHIBITORS CONTAINING ACIDIC HETEROCYCLE OTHER THAN A SPIROHYDANTOIN... 

---