Hydantoin library synthesis

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

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. 

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. 

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],... 

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.)... 

The method was developed further for the diastereoselective synthesis of isoxazoline derivative (Scheme 11.49). Later, a similar method was applied to the preparation of a diverse 990-member library of hydantoin and isoxazoline heterocycles with multipin technology. ... 

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