Podocarpic acid derivatives

Synthesis and carbon-13 NMR study of some podocarpic acid derivatives Ortellado, Maria Amelia A. C. Marsaioli, Anita J. 

Synthesis and Fungistatic Activity of Podocarpic Acid Derivatives... 

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 (II) and related podocarpic acid derivatives (III) have been reported to possess hormonal and anti-inflammatory properties (4). Other similar podolactones have been shown to inhibit the expansion and division of plant cells (IV) (5-10), to have antileukemic activity (V) (11), to have antibacterial activity (12), to have insect toxicity properties (13-15), and to exhibit antitumor activity (16-19). 

When one ortho position is blocked, lithiation occurs at the other ortho position [49,106]. When both ortho positions are blocked by methyl groups, lithiation occurs predominantly para to the MeO group [92], The ortho directing ability of the MeO group was used in the modification of the steroid 22 [63] and a podocarpic acid derivative [107]. 

For example, the cyclomangations of podocarpic acid a-carbonyl compound of diterpenoid easily proceed. Furthermore, the reaction of the above podocarpic acid derivative with an alkyn affords a steroid compound in a high yield by forming an indene ring as shown in eq. (14.31) [79,81]. 

The tricyclic alcohol (130) is an intermediate in the synthesis of rimuene. Hydroboronation of its tetrahydropyranyl ether and then oxidation with iodine and lead tetra-acetate afforded the 6—18 ether which could be cleaved and oxidized to a keto-acid. Such derivatives might form suitable intermediates for the synthesis of the rosane lactones. O-MethyI-14-methyl podocarpic acid has been synthesized "" by a conventional ring a + ring c route. 

The 1-and 9-hydroxyl groups define an important area for forskolln s action. The 1,9-dideoxyderlvative (7 ) is totally Inactive and the 1,9,6,7-dicarbonate ( ), and 1,9 sulfonate are very weak at activating adenylate cyclase. Other structurally related compounds which are unable to activate adenylate cyclase are 1,6-dlketoforskolin, the 14,15-oxide (12), virescenol-B, abietic acid, podocarpic acid, retene, glbberellln, and other diterpenes(13-15).23,83 Mone of the inactive dlterpenes antagonize forskolln stimulation of adenylate cyclase. Derivatives of... 

In view of their documented biological properties, it appeared worthwhile to evaluate a series of synthetic intermediates derived from podocarpic acid for fungistatic activity against other plant pathogens. This report describes the preparation of these derivatives and the results obtained from incubations of each compound with cultures of selected species of oomycetous and ascomycetous fungi. 

Commercial podocarpic acid is derived from naturai 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 (24,25). 

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 ... 

Podocarpic acid (I) and a number of Its chemical derivatives (X-XXXIV) were evaluated for their potential fungistatic activity as measured by their effects on the growth of the fungi on solid media (Table 1). All compounds evaluated were of 98% or greater purity (tic and glc analysis). Each structure ms consistent with Its... 

Table I. Comparison of the fungistatic properties of podocarpic acid and its derivatives ...

In conclusion, these studies have indicated that chemical modification of the basic podocarpic acid structure can produce new compounds with antifungal activity. The results derived from this study represent preliminary findings irtiich are subject to further investigation. We anticipate that more detailed studies will reveal information concerning the mechanism and mode of action of many of these compounds. In the meantime, we continue to develop new antifungal agents using selected natural products as model compounds. 

One of the first syntheses of natural drimenol (2) was accomplished by Wenkert and Strike [38] from dehydroabietic and podocarpic derivatives of the type (38), obtained from resin acids. Because of its complexity due to a multistep path (ca 25 steps) and also of no preparative importance, these syntheses are not discussed here. 

Scheme 1) with nitric acid in acetic acid (27-30). The number of nitro groups introduced onto the aromatic ring was controlled by the amount of nitric acid used in the reaction (one or two equivalents). The 13-nitro derivative X was methylated with dimethyl sulfate under basic condition to yield XIV. A similar methylation of I has been shown to produce methyl o-methyl podocarpate (XII) (4,1 ). Bromine was introduced at C (13) by the electrophilic substitution of bromine into the aromatic ring of XII using bromine in acetic acid. The fact that this reaction gives... 

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