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The solid-phase synthesis of novel imidazolines and dihydroimidazolylbenzimidazoles is described. Resin-bound diamines, derived from resin-bound N-acylated amino acid amides, were cyclized using Vilsmeier reagent to yield imidazolines following cleavage. Similarly, cyclization of resin-bound tetraamines having two secondary amines and an o-dianiline yielded dihydroimidazolylbenzimidazoles following cleavage.

The solid-phase synthesis of 1,3-disubstituted and 1,3,5-trisubstituted 1,3,5-triazine-2,4,6-triones from MBHA and Wang resin is described. Reaction of resin-bound amino acids with isocyanates yield resin-bound ureas, which further react with chlorocarbonyl isocyanate in toluene at 65 °C to selectively afford the resin-bound 1,3-disubstituted 1,3,5-triazine-2,4,6-triones. Selective alkylation at the N-5 position of the resin-bound 1,3-disubstituted 1,3,5-triazine-2,4,6-triones was accomplished by treatment with alkyl halides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The desired products were cleaved from their solid support and obtained in good yield and purity. The method can be employed in production of toltrazuril analogue libraries for identification of new anticoccidial agents.

An efficient method for the solid-phase synthesis of trisubstituted [1,3,5]triazino[1,2-a]benzimidazole-2,4(3H,10H)-diones from resin-bound amino acids is described. N-acylation of the primary amine of a resin-bound amino acid with 4-fluoro-3-nitrobenzoic acid, followed by displacement of the fluoro group and reduction of the nitro group, generated a resin-bound o-dianilino derivative. The dianilino compound was treated with cyanogen bromide to generate the corresponding iminobenzimidazole, which, following treatment with N-(chlorocarbonyl)isocyanate, afforded the resin-bound triazinodione derivative. Alkylation of the triazinodione compound with an alkyl halide yielded, following cleavage of the solid-support, the trisubstituted [1,3,5]triazino[1,2-a]benzimidazole-2,4(3H,10H)-dione.

The solid-phase syntheses of dihydroimidazolyl 2-alkylthiobenzimidazoles, dihydroimidazolyl 2-alkylsulfonylbenzimidazoles, dihydroimidazolyl dihydroquinoxalin-2,3-diones, and dihydroimidazolyl dihydrobenzimidazol-2-imines are described. Following reduction of a resin-bound amino acid amide, the primary amine of the resulting resin-bound diamine was N-acylated with 4-fluoro-3-nitrobenzoic acid. Treatment with POCl3 led to formation of a dihydroimidazole derivative via dehydrative cyclization. The resin-bound dihydroimidazole derivative was then used as the key starting material for the synthesis of the aforementioned biheterocycles. Following cleavage, the resulting compounds, obtained in moderate yield and good purity, were characterized by LC−MS and ¹H NMR and ¹³C NMR spectroscopy.

An efficient method for the solid-phase synthesis of hydantoins and thiohydantoins tethered to ureas, starting from a resin-bound amino acid, is presented. Following reduction of the amide with borane−THF, a second amino acid was selectively coupled to the primary amine followed by treatment of the secondary amine by an isocyanate to generate the corresponding urea. Hydantoin and thiohydantoin formation was achieved through the use of carbonyldiimidazole and thiocarbonyldiimidazole, respectively. Cleavage from the solid support using hydrogen fluoride, followed by extraction and lyophilization, provided the desired urea-linked heterocyclic compounds in good yield and high purity.

Efficient methods for the solid-phase synthesis of imidazoline-tethered 2,3-diketopiperazines, cyclic ureas, and cyclic thioureas are described. Following the exhaustive reduction of resin-bound dipeptides derived from orthogonally protected diamino acids, the primary amine of the resulting tetraamines was selectively protected with Dde. The compounds were then selectively cyclized via their secondary amines with three different diimidazole derivatives ((COIm)2, COIm2, CSIm2). Upon Dde removal, the compounds were selectively N-acylated and dehydratively cyclized with POCl3 to afford the imidazoline-tethered analogues in moderate yield and high purity. These procedures have been extended to prepare mixture-based combinatorial libraries. Details of the selection of building blocks for preparation of the positional scanning libraries based on the “libraries from libraries” approach are discussed.

An efficient method for the solid-phase synthesis of cyclic guanidines from N-acylated amino acid amides, bis cyclic guanidines from N-acylated dipeptides derived from orthogonally protected diamino acids, and N-acylated guanidines from disubstituted cyclic guanidines is described. The exhaustive reduction of N-acylated amino acid amides yields diamines that on treatment with cyanogen bromide lead to the formation of cyclic guanidines. Resin-bound orthogonally protected diamino acids (i.e., N^α-Fmoc-N^x-(Boc)-diamino acid, x = β, γ, δ, ε) were N-acylated following removal of the Fmoc group. Removal of the Boc functionality from the side chain then generated a primary amine. Subsequent coupling of Boc amino acids, followed by removal of the Boc group, generated dipeptides that were N-acylated. Exhaustive reduction of amide bonds of the N-acylated dipeptides generated tetraamines having four secondary amines, which upon cyclization with cyanogen bromide afforded the resin-bound trisubstituted bis cyclic guanidines. Treatment of the resin-bound disubstituted cyclic guanidines with carboxylic acids gave N-acylated guanidines. On the basis of their high yield and purity, bis cyclic guanidines derived from N^α-Fmoc-N^ε-Boc-lysine and N-acylated guanidines were chosen for preparation of mixture-based combinatorial libraries. Details of the preparation of these positional scanning libraries using the “libraries from libraries” concept are presented.

The general concept of tethered combinatorial libraries of compounds in which two pharmacophores are found is described. In particular, an improved method for the solid-phase synthesis of bicyclic guanidines from reduced N-acylated dipeptides, and its use in the synthesis of urea-linked bicyclic guanidines, is described. The exhaustive reduction of glutamine-containing resin-bound N-acylated dipeptides, using borane-THF, generated compounds containing three secondary amines and one primary amine. Following selective trityl protection of the primary amine, treatment of the three secondary amines with thiocarbonyldiimidazole (CSIm2) and mercuric acetate (Hg(OAc)2) generated the resin-bound bicyclic guanidines. Following trityl deprotection, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting group, the resulting primary amine was treated with hexyl isocyanate to generate the urea-linked bicyclic guanidines. The desired products were cleaved from the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library is discussed.

An efficient method for the solid-phase synthesis of 1,3,4-trisubstituted-2-imidazolidones and 1,3,4-trisubstituted-2-imidazolidinethiones from reduced N-acylated dipeptides is described. The complete reduction of the amide bonds of an N-acylated dipeptide with borane in THF results in two secondary and one tertiary amine. Reaction of the resulting resin-bound polyamine 4 with carbonyldiimidazole or thiocarbonyldiimidazole affords, respectively, cyclic ureas 6 and cyclic thioureas 7 in high yield and purity. Details on the selection of the building blocks and characterization of the controls for the libraries' synthesis will be presented. These procedures have also been used to generate parallel arrays and mixture-based combinatorial libraries of cyclic ureas and thioureas.

The immunodeterminant regions of the Escherichia coli heat-labile toxin B subunit were identified by determining the antigenicity, by using enzyme-linked immunosorbent assays, of synthetically produced peptides corresponding to various segments of its 124-amino-acid sequence. The addition of the 18-amino-acid sequence of heat-stable toxin (ST) to some of these peptides enhanced their B subunit antigenicity. Peptide residues containing the 26 amino acids of B subunit sequence 58 to 83 joined to the 18-amino-acid sequence of ST yielded a 44-amino-acid peptide whose antigenicity was 50% that of both native B subunit and ST. This peptide was completely nontoxic when tested in Chinese hamster ovary tissue culture, suckling mouse, and rat ligated ileal loop assays. Peroral immunization of rats with the polymeric form of this peptide yielded a dose-dependent response of intestinal immunoglobulin A antitoxin titers to both the ST and B subunit components and provided strong protection against challenge with viable ST- and heat-labile toxin-producing E. coli strains. The immunogenicity of the synthetic peptide in rats was the same as that of ST and about 50% that of native B subunit. The completely synthetic peptide vaccine has the following advantages over previously described toxoid vaccines that consist of synthetic ST chemically cross-linked to native B subunit derived from bacterial cultures: it is produced by a single synthetic process, it is completely nontoxic, and it is immunogenic for both ST and B subunit.

A traceless approach for the solid-phase synthesis of 6-amino-1,3,5-triazine-2,4-diones is described. Reaction of resin-bound S-methylisothiourea with isocyanates yielded resin-bound iminoureas 3, which reacted with amines to afford the corresponding guanidines 4. Following intramolecular cyclizative cleavage of the resin-bound guanidines using potassium ethoxide as a base, the desired products 5 were obtained in good yields and high purities.

The solid-phase synthesis of 1,7-disubstituted-1,3,5-triazepane-2,4-diones from resin-bound amino acids is described. The exhaustive reduction of solid-support bound amides with borane afforded the requisite secondary amines, which following treatment with phenyl isocyanatoformate and cleavage, provided the corresponding triazepane-2,4-diones.