Synthesis of chiral polyaminothiazoles

Abstract

An efficient approach toward the parallel solid-phase synthesis of highly diversified chiral polyaminothiazoles employing Hantzsc’s thiazole synthesis is presented. The treatment of resin-bound chiral polyamines with Fmoc-isothiocyanates generated polythioureas which were further reacted with a variety of α-halogenoketones to afford following cleavage from the solid support the desired chiral polyaminothiazoles in good yield and purity.

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, 0°C, 90 min.

Table 1.

Individual products of dithiazolo derivatives

Entry	R1	R2	R3	R4	MW obtaineda	Purity (%)b
5a	—CH3	—H	—CH3	—H	269.08 (MH+)	88
5b	—CH3	—H	—CH3	—CH3	297.11 (MH+)	84
5c	—CH3	—H	—(CH2)4–		349.19 (MH+)	85
5d	—CH2C6H5	—H	—CH3	—H	345.13 (MH+)	91
5e	—CH2C6H5	—H	—CH3	—CH3	373.15 (MH+)	86
5f	—CH2C6H5	—H	—(CH2)4–		425.24 (MH+)	82
5g	—CH(CH3)2	—H	—CH3	—H	297.10 (MH+)	90
5h	—CH(CH3)2	—H	—CH3	—CH3	325.14 (MH+)	88
5i	—CH(CH3)2	—H	—(CH2)4–		377.25 (MH+)	85
5j	—CH3	—CH2CH3	—CH3	—H	297.08 (MH+)	92
5k	—CH3	—CH2CH3	—CH3	—CH3	325.11 (MH+)	87
5l	—CH3	—CH2CH2C6H5	—CH3	—CH3	401.17 (MH+)	89
5m	—CH3	—CH2CH2C6H5	—(CH2)4–		453.17 (MH+)	84
5n	—CH2C6H5	—CH2CH3	—CH3	—H	373.17 (MH+)	90
5o	—CH2C6H5	—CH2CH3	—CH3	—CH3	401.13 (MH+)	92
5p	—CH2C6H5	—CH2CH2C6H5	—CH3	—CH3	477.20 (MH+)	88
5q	—CH2C6H5	—CH2CH2C6H5	—(CH2)4–		529.30 (MH+)	84
5r	—CH(CH3)2	—CH2CH 3	—CH3	—H	325.13 (MH+)	93
5s	—CH(CH3)2	—CH2CH3	—CH3	—CH3	353.15 (MH+)	85
5t	—CH(CH3)2	—CH2CH2C6H5	—CH3	—CH3	429.21 (MH+)	89
5u	—CH(CH3)2	—CH2CH2C6H5	—(CH2)4–		481.28 (MH+)	87
5v	—CH2)3c—		—CH3	—CH3	322.13 (MH+)	94

^aDetermined by ESI-MS.

^bThe products were run on a Vydac column, gradients 5 to 95% formic acid in ACN in 7 min. The purity was estimated on analytical traces at λ = 214 nm and 254 nm.

^cDerived from proline.

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

Entry	R1	R2	R3	MW obtaineda	Purity (%)b
PT-1	—CH2C6H5	—CH2C6H5	—CH2CH(CH3)2	771 (MH+)	83
PT-2	—CH2C6H5	—CH2C6H4OH	—CH2CH(CH3)2	787 (MH+)	85
PT-3	—CH2C6H5	—CH2CH(CH3)2	—(CH2C6H5	771 (MH+)	88
PT-4	—CH2C6H5	—CH2CH(CH3)2	—CH2CH(CH3)2	737 (MH+)	85
PT-5	—CH2C6H4OH	—CH2C6H5	—CH2C6H5	821 (MH+)	88
PT-6	—CH2C6H4OH	—CH2C6H5	—CH2CH(CH3)2	787 (MH+)	85
PT-7	—CH2C6H4OH	—CH2CH(CH3)2	—(CH2CH(CH3)2	752 (MH+)	82

^dDetermined by ESI-MS.

^eThe products were run on a Vydac column, gradients 5 to 95% formic acid in ACN in 7 min. The purity was estimated on analytical traces at λ = 214 nm and 254 nm.

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.