Hydantoin scaffold

The hydantoin scaffold is among the earliest described diversity-generating systems in combinatorial chemistry [12]. The first procedures were appropriate for syntheses of small arrays, but not suitable for large libraries. Practical limitations such as the small range of suitable building blocks available from commercial vendors, as well as conceptual limitations in the number of diversity sites modifiable directly on the solid phase, made it necessary to design improved approaches for a more extensive exploitation of this template s diversity potential. 

Microwave reactions can also be used in the formation of hydantoin scaffolds (Scheme 9.14). After deprotection of the N-terminal of the resin-bound amino acid 107 with piperidine in DCM, 4 equiv of isocyanate 109 was reacted with 108 in THF in a microwave reactor at 60°C for 10 min, generating the urea ester intermediate 110. Cyclocleavage was achieved by using triethylamine in THF DMF (4 1) at 110°C with the microwave for 15 min, affording the hydantoin core 111. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The R-alcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold . The achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, OOCC1835>. 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

Resin-bouda-amino esters, besides being traditionally used for making peptides, have served as key intermediates for the construction of various heterocyclic scaffolds. Thus, they react smoothly with isocyanates to form ureas, which upon heating under acidic conditions cyclize to form hydantoins 53 [27]. A one-pot, three-component condensation of resin-bound a-amino esters with aldehydes and a-mercapto acids affords 4-thiazolidi-... 

Bonnet and Ganesan [12] developed a new route toward the solid-phase synthesis of tetrahydro-P-carboline hydantoins, which appear in a diverse array of biologically active alkaloids. Due to the presence of tetrahydro-P-carbolines and diketo-piperazine ring skeletons in several bioactive natural products, these two scaffolds became attractive targets for developing a combinatorial chemistry program. 

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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