Hydantoins library

Scheme 15. Synthesis of a hydantoin library via 1,3-dipolar cycloaddition.

Scheme 13.17 Five-component FMS of a 420-member fused-hydantoin library.

A hydantoin library of 800 compounds has been reported by Dress-mann et al. [61]. In this approach, 20 different amino acids and over 80 primary amines were incorporated. Selected amino acids were attached via their iV-terminus to hydroxymethyl polystyrene resin by using a carbamate linker. This enabled generation of the free acid resin-bound intermediates, which could then be converted to their corresponding amides by standard carbodiimide coupling reactions and excess primary amine. Concomitant... 

Fig. 9.1 Dataset from high-throughput screening (a hydantoin library).

The high-loading dendronized supports were used by Bradley and coworkers to prepare peptides and biaryls, as well as amidine, aryl ether, and hydantoin libraries (see, for instance. Scheme 15.33a and Poiy rea dendronized polystyrene was used as a support... 

Cyclative cleavage strategies release the final compound into solution following intramolecular attack of a nucleophile or electrophile upon the linkage site. Synthesis byproducts and intermediates do not incorporate the necessary nucleophile or electrophile therefore only the desired products are released into solution to yield high purity materials. Seminal examples of this approach are the library syntheses of benzodiazepines and hydantoins (Scheme 3). 

Kurth and co-workers40 (Novartis) prepared a 990-member compound library of hydantoin and isoxazohne containing heterocycles on amine-derived SynPhase Crowns. As shown in Scheme 15, the synthesis was... 

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

The technique of parallel synthesis is best illustrated by means of an example. Consider the general theoretical steps that would be necessary for the preparation of a combinatorial library of hydantoins by the reaction of isocyanates with amino acids (Figure 6.7) using a 96 well array. 

Figure 6.8 The pattern of well loading for the formation of a combinatorial library of 96 hydantoins...

A number of other solid-phase chemistries have been described for the generation of combinatorial libraries. This includes the synthesis of urea-linked diamines [51], bisamide phenols [52,53], polyphenols [54], thiazolidinones [55,56], thiazolines [57], hydantoins [58], and diaminoalcohols [59,60], Readers interested in more details of these libraries are referred to the section on small molecule libraries. 

Hanessian and Yang [16] have reported a high yielding general method for the preparation of5-alkoxyhydantoins (Fig. 3) both in solution and on solid support using a four-step procedure in a strategy allowing access to three points of diversity. It was used to produce two libraries of 25 distinct hydantoins in which each compound was fully characterised. 

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

Additional examples of libraries of isoxazolines prepared by 1,3-dipolar cycloaddition of Wang resin-<1998TL939> or chlorotrityl resin- <1998TL2447> supported dipolarophiles, generated in the presence of a variety of dipolarophiles, have been reported. The achiral hydantoin- and isoxazoline-substituted bis-spirocyclobutanoids 458 and 459 were produced using SPS (Scheme 105) <2000CC1835>. 

D. B., Fluorous mixture synthesis of two libraries with hydantoin- and benzodiazepinedione-fused heterocyclic scaffolds, J. Comb. Chem. (2006) 8, 687-695. Copyright (2006) American Chemical Society.)... 

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