HYDANTOIN GROUP

Several 3-vinyl- and 1,3-divinyl-hydantoin derivatives have been prepared and converted to polymers having pendant hydantoin groups, e.g. (66) (B-74MI11100). Interesting spiro hydantoin polymers (67) are readily prepared from the very reactive 5-methylenehydantoin, hydrolysis of which cleanly produces polymers containing a-aminoacrylic acid units and having corresponding polyampholytic properties. 

These amines have been quartemised by reaction with (CH30)2S02 and NaOH 67). A polymer with pendant hydantoin groups has been synthesized by the following reaction, Eq (21) S8 m, ... 

Material Hydantoin-group chemical prepared synthetically. 

The other major class of cyclic amino acid derivative used in dynamic resolution reactions is the hydantoin group. Like oxazolinones, hydantoins readily undergo racemisation under mild conditions. Systems involving a two step procedure using D-hydantoinase and a carbamoylase were reported to provide a route to D-amino acids[S2, 53). Dynamic resolution of a p-hydroxyphenyl substituted hydantoin was reported in 1987[541. Using the intact cells of Pseudomonas sp. AJ-11220, the amino acid was prepared in over 90% yield, as shown in Fig. 9-24. This hydrolytic procedure leads directly to the amino acid, and the same enantiomer of product, the D-amino acid, was obtained independently of the stereochemistry of the substrate. 

Hydantoin derivatives show weak absorption in the uv-visible region, unless a part of the molecule other than the imidazohdinedione ring behaves as a chromophore (13) however, piC values have been determined by spectrophotometry in favorable cases (14). Absorption of uvby thiohydantoins is more intense, and the two bands observed have been attributed to n — tt and n — tr transitions of the thiocarbonyl group (15,16). Several piC values of thiohydantoins have been determined by uv-visible spectrophotometry (16). 

H-nmr chemical shifts of N-1—H and N-3—H signals have been used as a criterion for distinguishing between N-l-substituted and N-3-substituted hydantoin derivatives (22). They can often be related to electronic properties, and thus good linear correlations have been found between the shifts of N—H and Hammett parameters of the substituents attached to the aryl group of 5-arylmethylenehydantoins (23). 

Hydantoins can react with electrophiles at both nitrogen atoms and at C-5. The electrophilic carbonyl groups can be attacked by nucleophiles, leading to hydrolysis of the ring or to partial or total reduction of the carbonyl system. Other reactions are possible, including photochemical cleavage of the ring. 

Reactions at G-5. The C-5 atom of hydantoins can be considered as an active methylene group, and therefore is a suitable position for base-cataly2ed condensation reactions with aldehydes (44). 2-Thiohydantoins give the reaction more readily than their oxygen counterparts ... 

Polymers with an antiplatelet agent of 5-(6-carboxyl-hexyl) l-(3-cyclohexyl-3-hydroxyropyl) hydantoin as an end group were synthesized by esterifying the hydantoin molecule with a haloalcohol, such as CCI3CH2OH or BrCH2CH20H, and using the product as coinitiator with... 

It has been found that the tris(tert-butyloxycarbonyl) protected hydantoin of 4-piperidone 2, selectively hydrolyses in alkali to yield the N-tert-butyloxycarbonylated piperidine amino acid 3. The hydrolysis, which is performed in a biphasic mixture of THF and 2.0M KOH at room temperature, cleanly partitions the deprotonated 4-amino-N -(tert-butyloxycarbonyl)piperidine-4-carboxylic acid into the aqueous phase of the reaction with minimal contamination of the hydrolysis product, di-tert-butyl iminodicarboxylate, which partitions into the THF layer. Upon neutralization of the aqueous phase with aqueous hydrochloric acid, the zwitterion of the amino acid is isolated. The Bolin procedure to introduce the 9-fluorenylmethyloxycarbonyl protecting group efficiently produces 4.8 This synthesis is a significant improvement over the previously described method9 where the final protection step was complicated by contamination of the hydrolysis side-product, di-tert-butyl iminodicarboxylate, which is very difficult to separate from 4, even by chromatographic means. 

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

Hydantoins are well-known anticonvulsant agents and as such have found extensive use in the treatment of epilepsy. Replacement of one of the carbonyl groups by thiocarbonyl is consistent with anticonvulsant activity. Thus, condensation of the ethyl ester... 

The Working Group on Status Epilepticus recommends that phenobar-bital be given after a BZ plus phenytoin has failed. Most practitioners agree that phenobarbital is the long-acting anticonvulsant of choice in patients with hypersensitivity to the hydantoins or in those with cardiac conduction abnormalities. 

A conceptually similar approach applied in an industrial process is described by the Bristol—Myers—Squibb group, who required l-6-OH norleucine as an intermediate in the synthesis of their drug Omapatrilat. T o avoid a lengthy chemical synthesis of the oxoacid, it was more convenient to start with the racemic amino acid, readily prepared by hydrolysis of the corresponding hydantoin (Equation (2)), and remove the D-isomer by oxidation using d-AAO. 

The two groups of enzymes discussed here have attracted attention because both offer a useful broad spectrum of substrate specificity. They are grouped together because in the context of amino acid synthesis they form a natural pair. Amino acid hydantoins are convenient from the standpoint of organic synthesis. The hydantoinases cleave the ring, producing the A-carbamoyl derivative of the amino acid. This must then be further hydrolyzed to obtain the free amino acid, and this step is likely to be strictly enantioselective (Equation (10)). 

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