Deoxy Derivatives of L-like 5'-Noraristeromycin

Abstract

Several base variations of 2'- and 3'-deoxy derivatives of (+)-4'-deoxy-5'-noraristeromycin have been prepared from enantiomerically pure precursors following standard purine nucleoside construction. These carbocyclic nucleosides were evaluated against hepatitis B virus (HBV) and found to be inactive. No cytotoxicity to the cell line was observed.

Introduction

Many years ago, the study of carbocyclic nucleosides lacking a methylene group at the 5'-position (5'-Norcarbanucleosides) was initiated.¹ Within this series of compounds, (+)-5'-noraristeromycin 1 (L-like) (Figure 1) was the first to show significant activity towards hepatitis B virus (HBV), while the (−)-enantiomer (D-like) was inactive.² Further investigation led to the discovery of (+)-4'-deoxy-5'-noraristeromycin 2,³ which is ten times more potent in its activity against HBV. As part of an ongoing effort to determine the structural entities necessary for activity, base and cyclopentyl variations (compounds 3–8) were designed and synthesized.

Figure 1.

Lead and target compounds

Chemistry

As depicted in scheme 1, target compounds 3–5 can be derived from S_N2 reaction of mesylate⁴ 9 (prepared from dicyclopentadiene in six steps) and a suitable base. For the preparation of 3, the mesylate was added to a suspension of adenine 10 and sodium hydride in dimethylformamide (DMF). This resulted in the formation of the protected nucleoside 13. The acetate group of 13 was then readily cleaved by using ammonia gas in anhydrous methanol to give 3. A similar procedure was utilized to achieve the synthesis of 4 and 5. A commercially available base, 2-amino-6-chloropurine 11, was used for the synthesis of 4. Compound 5, however, required the preparation of the 7-deazapurine base 12 prepared from ethyl cyanoacetate and bromoacetaldehyde diethyl acetal in five steps⁵. Ammonolysis was employed to complete the synthesis of both target compounds.

Scheme 1.

Preparation of 2ˡ-deoxy derivatives

Optically active amino alcohol 16 was used in the synthesis of 6 (Scheme 2). The compound was prepared by utilizing enantioselective ring opening reaction of cyclopentene oxide (using trimethylsilyl azide) followed by desilylation and reduction as shown by Jacobsen⁶. Under nucleophilic aromatic substitution conditions, displacement of one of the chlorine substituents of 5- amino-4,6-dichloropyrimidine 17 by the amino group of 16 yielded the purine nucleoside precursor 18. Heating 18 in diethoxymethyl acetate resulted in ring closure to give 19. Ammonolysis of 19 led to 6, while refluxing 19 in 1N hydrochloric acid yielded 8.

Scheme 2.

Preparation of 3ˡ-deoxy derivatives

Scheme 3 shows that compound 7 was accessible via standard carbocyclic ring construction⁷ using 2-amino-4,6-dichoropyrimidine 20 and amino alcohol 16. Refluxing these starting materials in 1-butanol in the presence of triethylamine afforded 21. Installation of the C-5 amino group on the pyrimidine ring began with a diazonium coupling reaction of 21 with 4-chlorobenzenediazonium chloride to yield 22. The azo compound 22 was reduced with zinc and acetic acid and then cyclized using diethoxymethyl acetate to give 24. The C-6 chlorine of 24 was replaced by an amino group in the final step.

Scheme 3.

Preparation of 7

Antiviral analysis

To investigate their biological potential, compounds 3–8 were subjected to antiviral screening versus hepatitis B virus. No activity was found. Furthermore, no cytotoxicity arose in the cell lines used in the antiviral assays.

Conclusion

The synthesis of several 2'- and 3'-deoxy derivatives of (+)-4'-deoxy-5'-noraristeromycin has been achieved. The use of amino alcohols such as 16 provides a convenient approach to enantiomerically pure modified nucleosides. The absence of antiviral activity suggests the importance of both 2' and 3' hydroxyl groups in the interaction with the biological target macromolecule.