Efficient synthesis of (R)-harmonine--the toxic principle of the multicolored Asian lady beetle (Harmonia axyridis).

Nadja C Nagel,Wilhelm Boland,Anita Masic,Uta Schurigt

doi:10.1039/c5ob00461f

Abstract

A flexible synthetic route to (R)-harmonine ((R)-1), the toxic principle of the Asian lady beetle Harmonia axyridis (H. axyridis), via reductive olefination of the macrocyclic lactone (S)-5, is reported. High enantiomeric purity is achieved by enantioselective saponification of the lactone rac-5 with horse liver esterase. Minor modifications in the synthetic route give access to racemic and chiral harmonine ()1, analogs and putative biosynthetic precursors. In addition, the antimicrobial activity of harmonine against Leishmania major (L. major) is demonstrated and provides the rationale for harmonine-based drug development against parasitic diseases.

Highlights

The multicolored Asian lady beetle H. axyridis, known as the harlequin ladybird, is natively distributed from southern Siberia to southern China and from the Altai mountains to the Pacific coast.[1]
We report the antiparasitic activity of harmonine against the causative agent of cutaneous leishmaniasis, L. major.[18]
According to Scheme 1 the harmonine backbone can be obtained from the lactone (S)-5 and the phosphonium salt 4 by a Wittig-type reaction

Summary

Introduction

The multicolored Asian lady beetle H. axyridis, known as the harlequin ladybird, is natively distributed from southern Siberia to southern China and from the Altai mountains to the Pacific coast.[1]. The cell morphology of L. major promastigotes was studied by means of transmitted light microscopy upon treatment with harmonine for 6 h, 10 h, and 24 h (Fig. 3). After removal of the solvents under reduced pressure, the crude product was purified by column chromatography on silica gel using hexane–ethyl acetate (5 : 1) for elution. Removal of the solvents yielded rac-6 as a colorless oil (49 mg, 0.13 mmol, 26%, (Z)/(E) > 98/2; ylide preparation with n-BuLi: 29%, (Z)/(E) 80/20).

Results

Conclusion