Development and Optimization of the Multi-Gram Synthesis of the Antiviral 18-(Phthalimide-2-yl)ferruginol

Abstract

: Virus-induced diseases are very common in our society, and we continuously need new treatments for these challenging infections. We discovered by serendipity some years ago that the molecule 18-(Phthalimide-2-yl)ferruginol, an analogue of the natural diterpenoid (+)-ferruginol, a pharmacologically active molecule, was able to inhibit the spread of dengue virus type-2 (DENV-2) and human herpes virus 1 and 2 (HHV-1 and HHV-2). During the development and further study of the above-mentioned analogue, we required the scaling-up of the semisynthesis of the target molecule. The synthesis was already reported by Waldvogel and co-workers in 2007, starting from the commercially available ca. 60% (+)-dehydroabietylamine. In this communication, we describe the several issues that we faced and propose an optimized experimental procedure in order to obtain this broad-spectrum antiviral, which we found is even active against several strains of Zika virus. which had 1 H and 13 C NMR and specific optical rotation ([ α ] 23D —31.4 (c 0.7, DCM) data in agreement with reported [7]. Anal. calcd. for C 28 H 33 NO 3 : C, 77.9; H, 7.7; N, 3.2. Found: C, 77.6; H, 7.8;