Pisiferic acid synthesis

ABSTRACT This article reviews the literature published dealing with the synthesis of some bioactive diterpenes. It describes the biological activity and synthesis of only four diterpenes pisiferic acid, camosic acid, triptolide and miltirone. This review excludes the discussions of Taxodione, a bioactive diterpene, because it has already been reviewed [85], The utility of several reagents in the total synthesis of terpenoid compounds has been documented. It can be observed that several routes have been developed for the synthesis of a single diterpene. 

Matsumoto and Usui [8] reported the first total synthesis of ( )-pisiferic acid (1) and ( )-methylpisiferate (3) and this is depicted in Fig. (2). In this synthesis the fundamental skeleton of pisiferic acid has been constructed by the cyclization of enone (9). The introduction of C-10 carboxylic acid in pisiferic acid was accomplished by transannular oxidation. The depicted synthesis has been divided in two parts, Fig. (2) describes the preparation of the alcohol (17) and Fig. (3) deals with the conversion of the alcohol (17) to pisiferic acid (1). 

Next step of this synthesis consisted in the conversion of alcohol (17) to pisiferic acid (1) and this has been described in Fig. (3). The alcohol (17) in hexane was treated with Pb(OAc)4 in presence of iodine at room temperature to obtain the epoxy triene (19) (51%) whose structure was confirmed by spectroscopy. Treatment of (19) with acetyl p-toluene-sulfonic in dichloromethane yielded an olefinic acetate (20) and this was hydrogenated to obtain (21). The compound (22) could be isolated from (21) on subjection to reduction, oxidation and esterification respectively. The conversion of (22) to (23) was accomplished in three steps (reduction with sodium borohydride, immediate dehydration in dichloromethane and catalytic hydrogenation). Demethylation of (23) with anhydrous aluminium bromide and ethanethiol at room temperature produced pisiferic acid (1). Similar treatment of (23) with aluminium chloride and ethanethiol in dichloromethane yielded methylpisiferate (3). 

An alternative synthesis of ( )-pisiferic acid (1) was developed by Baneijee and collaborators [9] and this is depicted in Fig. (4). 

The starting material for the present synthesis was Wieland-Miescher ketone (24), which was converted to the known alcohol (25) by the published procedure [10], Tetrahydropyranylation of alcohol (25) followed by hydroboration-oxidation afforded the alcohol (26), which on oxidation produced ketone (27). Reduction of (27) with metal hydride gave the alcohol (28) (56%). This in cyclohexane solution on irradiation with lead tetraacetate and iodine produced the cyclic ether that was oxidized to obtain the keto-ether (29). Subjection of the keto-ether (29) to three sequential reactions (formylation, Michael addition with methyl vinyl ketone and intramolecular aldol condensation) provided tricyclic ether (30) whose NMR spectrum showed it to be a mixture of C-10 epimers. The completion of the synthesis of pisiferic acid (1) did not require the separation of epimers and thus the tricyclic ether (30) was used for the next step. The conversion of (30) to tricyclic phenol (31) was... 

Another approach [9] was also made to accomplish the synthesis of pisiferic acid and is depicted in Fig. (5). 

In the present synthesis, the preparation of two cyclic ethers (31) and (41) and their transformations to pisiferic acid (1) are described. In this synthesis, the introduction of carboxylic acid at angular position has been accomplished by transannular oxidation. 

Pal and Mukerjee [14] developed another total formal synthesis of racemic pisiferic acid (1) and this is described in Fig. (6). 

Geiwiz and Hasslinger [17] have developed an attractive synthesis of (+)-pisiferic acid (1) from dehydroabietic acid (64a). This is depicted in Fig. (9). 

Figure 2.48 Synthesis of O-methyl pisiferic acid. Modified by permission of Shokabo Publishing Co., Ltd...

Figure 2.47 shows our retrosynthetic analysis of O-methyl pisiferic acid (57).126 The starting material is the same (.S )-3-hydroxy ketone A as employed by us for the synthesis of glycinoeclepin A (see Figure 2.36). The ready availability of A by reduction of 2,2-dimethyl-1,3-cyclohexanedione with baker s yeast makes A a versatile starting material in terpene synthesis.104 Conversion of A to two diastereomeric compounds B and C enables the synthesis of both (+)-57 and (—)-57. ...

Our synthesis of the enantiomers 57 and 57 of O-methyl pisiferic acid is summarized in Figure 2.48.126 Annulation of A to give bicyclic intermediates was not stereoselective, giving both B and C. As shown in... 

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