Glutarimide rings

Although slow hydrolysis of the glutarimide ring occurs in buspirone (4.197), ring opening proceeds by intramolecular catalysis, as discussed in Chapt. 11. 

One should not conclude from the above that the glutarimide ring is always resistant to hydrolysis. Indeed, its hydrolysis is a major metabolic pathway for the thalidomide analogue EM12 (4.198). After administration of EM 12 to marmoset monkeys, two products of hydrolysis, 4.199 and 4.200, were found in urine. The concentrations of the two metabolites were similar after administration of the racemate. In contrast, regioselectivity (i.e.. different ratios of the two metabolites) was seen after separate administration of the enantiomers [125],... 

We will now consider supidimide (5.66) as an example of a molecule containing a six-membered lactam ring. The piperidin-2-one ring of this potential sedative underwent slow chemical hydrolysis in buffer solution to yield 5.67, but was resistant to metabolic hydrolysis. The other amide bond was stable [175], Supidimide was primarily metabolized by oxidation of the pi-peridin-2-one ring to yield a glutarimide ring, which then was hydrolyzed as described in Sect. 4.4. 

In contrast to the AGT/j8-CyD complex, the NOE effect decreased for the H-5 protons and remained almost unchanged for H-3 protons when irradiating the protons in the meta position instead of the protons in the ortho position of the aromatic ring of AGT in the (+)-AGT/y-CyD complex (Fig. 6.6b). These data support a complex formation from the narrower primary side of y-CyD with the amino group ahead (Fig. 6.7b). The glutarimide ring is apparently less involved in the complex formation in this case. However, the involvement of the methyl group in complex formation by a still unknown mechanism cannot be completely excluded. Thus, as shown with this example, combined application of CE and a ROESY experiment may indicate the principal differences in the structure of analyte-CyD complexes in solution. 

All antibiotics related to cycloheximide have the glutarimide ring as a common structural feature. In addition most of these compounds have a dimethyl-cyclohexanone nucleus attached to position 4 of the glutarimide ring through a twocarbon bridge. The individual compounds differ either in substitution or in the degree of unsaturation of the dimethylcyclohexanone nucleus (Umezawa,... 

The distribution of radioactivity found in the cycloheximide produced when malonic acid-1,3was used as a precursor is shown in Fig. 4. The pattern of incorporation resembled that already observed when acetic acid-1was precursor except that there was sufficient radioactivity in carbons 2 and 6 to indicate that both of these atoms were directly derived from malonic acid carboxyl group. These results are also consistent with the idea that one malonate unit is incorporated into the glutarimide ring without decarboxylation. 

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