1

Scheme 4

Procedure

To a stirring solution of 1 % crosslinked hydroxymethylpolystyrene (3.26 g, 3.26 mmol) was added p-nitrophenyl chloroformate (1.31 g, 6.5 mmol, 2 equiv.) in one portion and N-methyl morpholine (659 mg, 6.5 mmol, 2 equiv.) in DCM at 0° C.The reaction mixture was warmed to rt, stirred overnight, filtered and washed with DCM. Drying overnight in a vacuum oven gave 3.28 g of light pink resin 13.

An N-alkyl or N-aryl substituted amino acid (4 equiv.) was dissolved with gentle heating in DMF using N,0-bis(trimethylsilyl)acetamide (BSA; 10 equiv.) and then coupled with activated carbonate 13 in the presence of DMAP (2 equiv.) to obtain the free acid resin-bound intermediate 14 after 48 h at rt. The resin was washed extensively with DMF, then with MeOH and dried.

Following thorough washes with DMF, amide formation was carried out for 24 h using standard carbodiimide coupling conditions (DCC, 4 equiv., H0Bt.H20,4 equiv.) with an excess of a primary amine (4 equiv.) in DMF Intermediate 15 was obtained after exhaustive washing in DMF, followed by MeOH.

Treatment of 15 with excess triethylamine (14 equiv.) in methanol for 48 h at temperatures between 55-90° C afforded hydantoin 16, which was released into solution in purities of generally around 90 % and mass recoveries of 15-76 %.

Because of the wide range of reported therapeutic effects, new hydantoin derivatization strategies continue to attract the interest of medicinal chemists. An utmost pragmatic strategy, which is not uncommon in pursuing rapid generation of "small molecule" libraries for screening purposes, consists of applying much of the chemical diversification at exocyclic positions of the heterocyclic scaffold. This simplifies matters considerably in the validation phase for the production of new libraries, because many reactions steps remain unchanged from one diversity system to another, and may be carried over to a new reaction scheme. A new hydantoin derivatization scheme [23] was recently reported, where orthogonally protected diamino acids are bound to the solid support, thereby introducing two sites of diversity upfront (according to previously known procedures) before the five-membered hydantoin ring is built up with just one additional substituent.

While the procedure of Scheme 4 [22], like 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 scheme described recently [24] builds up the diversity stepwise on solid phase, which simplifies the logistics for automated library production. Intermediates may also be used to access thiohydantoins (see Scheme 6).

NHFmoc 20% Plperldine in DMF

Wang resin ^

NH 1- R!CHO NaBHjCN

10 min

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