Synthesis of Polyoxygenated Tropolones and their Antiviral Activity against Hepatitis B Virus and Herpes Simplex Virus-1

Abstract

Polyoxygenated tropolones possess a broad range of biological activity, and as a result are promising lead structures or fragments for drug development. However, structure-function studies and subsequent optimization have been challenging, in part due to the limited number of readily available tropolones and the obstacles to their synthesis. Oxidopyrylium [5+2] cycloaddition can effectively generate a diverse array of seven-membered ring carbocycles, and as a result can provide a highly general strategy for tropolone synthesis. Here, we describe the use of 3-hydroxy-4-pyrone-based oxidopyrylium cycloaddition chemistry in the synthesis of functionalized 3,7-dimethoxytropolones, 3,7-dihydroxytropolones, and isomeric 3-hydroxy-7-methoxytropolones through complementary benzyl alcohol-incorporating procedures. The antiviral activity of these molecules against herpes simplex virus-1 and hepatitis B virus is also described, highlighting the value of this approach and providing new structure-function insights relevant to their antiviral activity.

Keywords: hepatitis B antivirals; herpes simplex virus antivirals; oxidopyrylium cycloaddition; structure-function analysis; tropolones.

Figure 1.

Examples of synthetic, highly oxygenated tropolones and associated biological activity. HIV = human immunodeficiency virus. IMPase = inositol monophosphatase. Crypto = Cryptococcus neoformans.

Figure 2.

Additional compounds with high relevance to structure-function analysis included in Tables 1 and 2.

Scheme 1.

Synthesis and Biological Activity of Highly Oxygenated Tropolones. (A) Overview of oxidopyrylium cycloaddition approach to oxygenated tropolones. (B) Binding mode of α–hydoxytropolones (αHTs) to dinuclear metalloenzymes. (C) Examples of molecules synthesized through this strategy with associated antiviral activity against hepatitis B virus (HBV) and Herpes Simplex Virus-1 (HSV-1)

Scheme 2.

Synthesis of 3,7-dimethoxytropolones 2a-d and 3,7-dihydroxytropolones 4a-d. Previously reported reaction with yields are denoted as [a] and [b], for reference and , respectively. [c] Two steps from 6 without isolation of 7a-d.

Scheme 3.

Synthesis of 3-hydroxy-7-methoxytropolones 10a-d.

Scheme 4.

Synthesis of 3-hydroxy-7-methoxytropolones 10e-f. ^aSynthesis of 2g and 4g was described in ref. .

Scheme 5.

Synthesis of 3-hydroxy-7-methoxytropolones (A) through benzyl alcohol incorporation (14a and 14d), and (B) through room temperature BCl₃ reaction for 8b.