Efficient synthesis of 6-amino-2-thiaspiro[3,3]heptane hydrochloride

Introduction

Unique properties of spiro heterocyclic compounds are spiroconjugation, spirohyperconjugation, and anomeric effect. Because their special space configurations can usually match different spatial structures of macromolecules in organisms, these compounds can show significant biological activity [1]. The spiro compounds are widely used as a pharmacophore unit in the synthesis of antineoplastic [2], antidepressant [3, 4], antiviral [5], antibacterial [6], and antianxiety [7–9] drugs.

Spiro[3,3]heptane and its derivatives has recently been used as the surrogates of piperazines, piperidines, morpholines, and thiomorpholines, which display pharmacological activity [10–12]. For example, Radchenko et al. [13] have reported the synthesis of 6-amino-2-azaspiro[3,3]heptane-6-carboxylic acid and 2-azaspiro[3,3]heptane-6-carboxylic acid, which are analogues of natural ornithine and γ-aminobutyric acid. These amino acids are sterically constrained compounds and can be selective ligands for various biological targets that are especially popular in the design of peptidomimetic drugs. The sterically constrained cyclobutane diamine derivative 6-amino-3-azaspiro[3,3]heptane has been evaluated as inhibitor of kinases CDK1, CDK2, CDK5, GSK-3, and PLK and can be used as insecticides and acaricides [14]. Fang et al. [15] have reported a new class of indole spiro compounds, which can be used for the treatment and prophylaxis of respiratory syncytial virus infection. Rice and Gorgan [16] have reported that the bismethonium salt derivatives of spiro[3,3]heptane have a weak hypotensive and curarimimetic activity. Therefore, design and synthesis of new spiro[3,3]heptane compounds, especially the spiro heterocyclic compounds, with better biocompatibility are of great significance for the development and efficacy of new drug screening.

In this paper, the short and efficient synthesis of a novel compound 6-amino-2-thia-spiro[3,3]heptane hydrochloride (10 in Scheme 1) is reported. The cheap compound 2,2-bis(bromomethyl)-1,3-propanediol (1) was used as the starting material. To protect the two exposed hydroxyls in 1, as originally proposed by Allinger and Tushaus [17], its dioxane dibromo derivative 2 was used in the synthesis. The treatment of dibromide 2 with malonic ester under basic conditions gave a diester derivative 3 with a cyclobutane structure. Similar syntheses have been reported [18]. This diester was hydrolyzed to the dicarboxylic acid 4. After a subsequent decarboxylation process [19], the monocarboxylic acid 5 was obtained. The resultant monocarboxylic acid derivative 5 was efficiently converted into N-Boc-protected amino derivative 6 by treatment with diphenylphosphoryl azide (DPPA) and triethylamine (Et₃N) in tert-butanol (t-BuOH). There are two ways of converting carboxylic acid to amine reported in the literature. In the first method, carboxylic acid is allowed to react with thionyl chloride or ethyl chloroformate to give an acyl chloride or ester, the treatment of which with ammonium hydroxide produces an amide. The amide can then be converted into an amino derivative [20, 21]. This method is complex and the yield is low. The superior second method [22–24] is shown in Scheme 1. Then, the protected diol moiety in 6 is deprotected by reduction with hydrogen to give the diol 7. This reaction was followed by mesylation, which yielded the bis-methanesulfonate ester 8, the bis-sulfonate functionality of which was transformed into a thiaspiro derivative 9 by reaction with sodium sulfide. In principle, the introduction of the sulfur atom in 9 could be accomplished starting with the bis-halomethyl analogues of 8. Such preparations are common in the literature [25–28]. However, compound 7 proved to be difficult to convert to a halide derivative. By contrast, the sulfonylation of 7 was efficient, and the resultant bis-ester 8 was easily cyclized into the thia derivative 9. As can be seen in Scheme 1, the desired product 10 was obtained by acid hydrolysis of the Boc-protected 2-thiaspiro[3,3]heptane 9.

Scheme 1

Total synthesis of 6-amino-2-thiaspiro[3,3]heptane hydrochloride (10).

In summary, 6-amino-2-thia-spiro[3,3]heptane (10) was successfully prepared in nine steps from commercially available starting materials, with an overall yield of 31%. The efficient synthetic procedures were designed based on a critical evaluation of analogous literature preparations.

Experimental details

Reactions were monitored by thin-layer chromatography (TLC) using Sanpont Silica gel GF254 plates. In addition, preparative chromatography (flash chromatography) was performed on silica gel (200–300 mesh) column, eluting with pentane/ethyl acetate (9:1). Melting points were measured on a WRS-2A apparatus. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Bruker AVANCE 400 spectrometer at room temperature. FT-IR spectra were obtained in KBr pellets on Avatar360 spectrometer. Mass spectra were acquired using a Waters Acquity-Quaptro Premier spectrometer equipped with electrospray ionization (ESI) source or chemical ionization (CI) source.