Synthesis of chiral polyaminothiazoles

The thiazole ring system is an important structural element found in numerous biologically active compounds.1 These have found applications in the development and preparation of drugs for the treatment of allergies,2 inflammation,3 schizophrenia,4 hypertension,5 as well as bacterial infections.6 Compounds containing the aminothiazole moiety are also known to be a ligand of estrogen receptors,7 adenosine receptor antagonists,8 while other analogues exhibit antitumoral properties.9 Moreover, thiazole derivatives are reported to be potential inhibitors of cyclin-dependent kinases (CDKs)10 and glycogen synthase kinase-3 (GSK-3).11 2-aminothiazoles were successfully employed as heterocyclic bioisosteres of the phenol moiety on dopamine agonists and the widely used antiparkinsonian agent pramipexole. These resulted in improved pharmacological properties including longer duration of action and improved bioavailability.12 Conjugated polyaminothiazole films were reported to display electrochemical properties with high thermal stability.13 Herein, we describe an efficient approach for the parallel synthesis of diversified oligoaminothiazoles. Staring from resin-bound peptides, a range of differing oligothiazoles were synthesized. Thiourea is known to be a convenient starting material to prepare 2-amino-1,3-thiazoles.14, 15 Our approach using Hantzsc’s synthesis for the solid-phase synthesis of a variety of diaminothiazoles is outlined in Scheme 1. The parallel synthesis was performed starting from p-methylbenzhydrylamine (MBHA) resin bound acylated amino acid 1. Following reduction of the amide bonds in the presence of borane-THF,16 the corresponding resin-bound diamines 2 were treated with Fmoc-isothiocyanate to generate the corresponding di-thioureas 3. Following Fmoc deprotection, the resin-bound dithioureas were treated with a variety of α-halogenoketones to afford following cleavage of the solid-support, the desired di-aminothiazoles 5. The compounds were obtained in good yield (80 to 90%) and high purity (Table 1). The only byproduct observed was the mono-thiazole due to an incomplete reaction of the amine attached to the solid-support with Fmoc-isothiocyanate. We selected the following amino acids, alanine, proline, valine and phenylalanine, and three different halogenoketones, chloroacetone, 3-chloro-2-butanone and 2-chlorocyclohexanone. Similar results were obtained with all the amino acids utilized and we did not observe any detrimental effect of the amino acid side chains on the reaction. Some incomplete reaction was observed with the 2-Chlorocyclohexanone. Scheme 1 (a) BH3-THF, 65°C, 4 days; (b) piperidine, 65°C, overnight; (c) 6 equiv. Fmoc-NCS in DMF (0.3 M), RT, overnight; (d) 20% piperidine/DMF; (e) 20 equiv. α– halogenoketones in DMF (0.3 M), 70°C, overnight; (f) HF/anisole, ... Table 1 Individual products of dithiazolo derivatives The same approach was employed for the synthesis of different lengths of chiral polyaminothiazoles from their corresponding resin-bound chiral polyamines.17 Table 2 shows examples of tetrathiazoles obtained from resin-bound tripeptides. All compounds were analyzed by LC-MS and selected ones by 1H-NMR and 13C-NMR. Table 2 Individual products of tetrathiazole derivatives Due to the well-understood chemistry, the availability of a wide diversity of chiral amino acids and the excellent synthetic purity and yields obtained during the solid- phase synthesis of peptides, the work presented offers a unique approach toward the synthesis of chiral polyaminothiazoles using resin-bound amino acids, peptides, and peptidomimetics as starting materials.