Library thiohydantoins

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

Fig. 3. Solid-phase synthesis of hydantoin and thiohydantoin libraries from resin-bound dipeptides.

The selected example by Sim and Ganesan [19] reported the design of a 3078-member discrete thiohydantoin library, prepared without purification of intermediates, with a three-step synthesis, which is shown in Figure 7.2. Nine amino acid esters were reacted with eighteen aromatic aldehydes to produce imines, which were reduced by sodium triacetoxyborohydride. The resulting amines were treated with nineteen isothiocyanates in the presence of triethylamine (TEA), producing intermediate isoureas, which eventually cyclized to the final thiohydantoins. 

FIGURE 7.2 Three step synthesis of 3078-membered discrete thiohydantoin library. 

Sim and Ganesan (56) have recently reported the partial synthesis of a 3078-member thiohydantoin library in solution (L2, Fig. 8.11). The initial studies were aimed at the preparation of a library of thiohydantoins in SP based on the adaptation of a previously... 

Figure 8.11 Synthetic scheme to the solution-phase, discrete thiohydantoin library L2.

While the procedure shown in Scheme 4 [26], Hke the original method, introduces much of the diversity (i. e., up to three variable positions) off the solid phase, thereby limiting the combinatorial potential available for split-and-mix protocols, another recently described scheme [30] builds up the diversity in a stepwise manner on the solid phase, which simpHfies the logistics for automated library production. Intermediates may also be used to access thiohydantoins (see Scheme 6). 

Figure 2 Synthesis of thiohydantoin library. Nine amino acids (Gly, Ala, Val, Phe, Asp, Ser, Met, Trp, His), 18 aromatic aldehydes (9 subst. Ph, 2 subst. Py, 4 five-member heterocyclic, bicyclic), and 19 isothiocyanates (12 aromatic, 1 bicyclic, 3 aliphatic, 3 sat. cyclic).

MM Sim, A Ganesan. Solution-phase synthesis of a combinatorial thiohydantoin library. J Org Chem 62 3230-3235, 1997. 

Similarly, thiohydantoins 29 were prepared by using thiophosgene or thiocarbonyldiimidazole as the reagent. A combinatorial library containing 6364 individual thiohydantoins was then assembled in the positional scanning format. For this library, 74 and 86 amino acids were used in the Rj and R3 positions, respectively. 

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