Diversity-Oriented Synthesis of a Library of Podocarpic Acid Derivatives

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Podocarpic acid 1 (Figure 1) was first isolated from the resin of Podocarpus cupressins, an important timber tree which is endemic to Java, and later from Podocarpus dacrydioides (“Kahikatea”) and Dacrydium cupressinum (“Rimu”), trees which are found in the timber regions of New Zealand. Since 1968, more than forty oxygenated metabolites of podocarpic acid have been isolated from various species of Podocarpus.Interest in these naturally occurring and synthetic lactones, podolactones, and related podocarpic acid derivatives has been mainly due to the novel structures of these compounds and the various types of biological activity possessed by them.

Octahydrophenanthrene lactones 2 (Figure 1) and related podocarpic acid derivatives 3 have been reported to possess hormonal and anti-inflammatory properties. Other similar podolactones have been shown to inhibit the expansion and division of plant cells, to have antileukemic activity, to have antibacterial activity, to have insect toxicity properties, and to exhibit antitumor activity.Other reports have indicated that these types of compounds, as a class, possess significant antifungal properties. The lactone 6 (Figure1), first isolated as a mold metabolite, was found to have significant activity against a number of fungi. The momilactones A 7 and B 8 have been shown to be fungitoxic towards Cladosporium cucumerinum. In a recent report several oxidized resin acid derivatives of dehydroabietic acid 9 (a-c) and 13-hydroxypodocarpic acid 9 (d) were found to be highly fungistatic against Dothistroma pini, a conifer pathogenic fungi. It was observed that mature trees were more resistant to fungal infection and contained a greater quantity of oxidized resin acid derivatives in their resin suggesting greater resistance.

More recently, some podocarpic acid analogs have been reported as cytokine release inhibitors and this has consequently led to the discovery of novel anti-inflammatory drugs. Other compounds, including a podocarpic acid anhydride, have been shown to be liver.X receptor α and β agonists. These two nuclear oxysterol receptors in the liver are involved in cholesterol and lipid metabolism. Thus, any of their agonists could be useful in the development of drugs for the treatment of atherosclerosis.In view of their documented biological properties, it appeared worthwhile to prepare a series of synthetic intermediates derived from podocarpic acid for potential biological activity. This report describes the preparation and characterization of these derivatives.Commercial podocarpic acid is derived from natural sources. Several recent studies have been directed towards the total synthesis of this resin acid to assure adequate future supplies of this material for use in agriculture and medicine.The goal of the present study was to prepare a series of derivatives related to podocarpic acid for use in structure/activity studies designed to reveal functional groups responsible for the molecules fungistatic properties. Four specific modifications were planned.