0-methyl pisiferic acid

Fig (8) The transformation of lactone (53) to keto ester (58) is described. The unsaturated aldehyde (59) is converted to tricyclic ketone (60) by two steps (Michael addition, and intramolecular aldol condensation). And this on subjection to aromatization and hydrogenation respectively leads the formation of (62) whose transformation to (+)0-methyl pisiferic acid (2) is accomplished by methylation and hydrolisis. 

Methyl pisiferic acid (57, Figure 2.47) was first isolated in 1980 by Yatagai and Takahashi from the leaves of a Japanese tree Chamaecyparis pisifera.124 Discovery of its bioactivity as a mite-growth... 

Fig (7) The transformation of cyclohexene-l,3-dione (50) to ketone (52) is described. This involves reduction, terahydropyranilation, methoxy-carbonylation and Michael addition, with methyl vinyl ketone. Treatment of (52) with p-TsOH in methanol, leads the formation of lactone (53) and hydroxy ester (54). The lactone (53) is regarded as an appropiate intermediate for natural o-methyl pisiferic acid (+)(2)and hydroxi ester (54) is intermediate for (-)(55). 

Figure 2.47 Retrosynthetic analysis 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... 

Fig (4) The transformation of the ketone (24) to the cyclic ether (9) applying the standard organic reactions is described It wa subjected to three sequencial reactions with reagents mentioned for the conversion to cyclic ether (30). Isopropylation and by aromatization, it produces the phenol (31), which is converted to pisiferol (4). This on subjection to oxidation, esterification and deoxygenation respectively, furnish O-methyl pisiferate (5) and this is easily converted to pisiferic acid (1). 

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... 

The synthesis of (+)-pisiferic acid (1) presents many important aspects (i) functionalization of the angular methyl group to lactone, (ii) cleavage of lactone ring to carboxylic acid, and (iii) conversion of (78) to allylic alcohol (81) via iron carbonyl complex... 

Fig (10) The iron complex (80), prepared from methyl abietate (79) is converted to compound (81) utilizing standard organic reactions. It was converted to allylic alcohol (82) by treatment with iodine and potassium bicarbonate. The ketone (83) obtained from (82) undergoes aromatization on bromination and dehydrobromination. Yielding (84) whose transformation to lactone (87) is accomplished following the similar procedure adopted for the conversion of (68) to (74). It is converted to pisiferic acid (1) by treatment with aluminium bromide in... 

ABSTRACT The Wieland-Miescher ketone (1) and its methyl analog (2) have been utilized for the synthesis of several sesquiterpenes like warburganal, muzigadial, albicanol, etc. Similarly several bioactive diterpenes like taxodione, pisiferic acid, aphidicolin, etc., have been synthesized from these ketones. The utility of several reagents in the total synthesis of terpenoid compounds has been documented. The developments of several routes for a single terpene from these ketones have been discussed. 

The keto ether (187) on treatment with diethyl carbonate in presence of sodium hydride in 1,2-dimethoxyethane afforded the keto ether (188), which was made to react with methyl-lithium in ether, to obtain the tertiary alcohol (189). This on being refluxed with methanolic hydrochloric acid yielded the phenol (190). It was methylated to yield(191) and heated with zinc, zinc iodide and acetic acid to produce pisiferol (192). Its methyl derivative (193) on oxidation with Jones reagent at room temperature, followed by esterification, furnished the keto ester (194). Reduction of (194) with metal hydride produced an alcohol whose tosyl derivative on heating with sodium iodide and zinc dust furnished the ester (195). Its identity was confirmed by comparing its spectral data and melting point with an authentic specimen [77]. The transformation of the ester (195) to pisiferic acid (196) was achieved by treatment with aluminium bromide and ethanethiol. The identity of the resulting pisiferic acid (196) was confirmed by comparison of its spectroscopic properties (IR and NMR) with an authentic specimen [77]. 

Fig. (16). The alcohol (171) was converted to the keto ether (185) applying the standard organic reactions and this on subjection to Robinson annelation. The resulting adduct on treatment with sodium methoxide in methanol afforded the tricyclic ketone (187) which is converted to another keto ether (188). It is converted to tertiary alcohol (189) by treatment with methyllithium. Acid treatment of the alcohol produced the phenol (190). Its methyl derivative (191) is converted to pisiferol (192) by treatment with zinc and zinc iodide. Its methyl derivative (193) was converted to ester (195) via oxidation, reduction, tosylation and detosylation. The reagents mentioned accomplished its conversion to pisiferic acid (196).

An alternative route was also developed for the synthesis of ( )-pisiferic acid (196) as described in "Fig (17)". The starting material for the present synthesis was the already described alcohol (15), which on tetrahydropyranylation yielded the derivative (197). Metal hydride reduction of (197) afforded a mixture of alcohols whose tosyl derivative on heating with lithium bromide and lithium carbonate in dimethylformamide afforded the oily olefin (198). These conditions not only provoked the dehydrosulphonation but also the hydrolysis of the tetrahydropyranyl group, thus shortening the reaction sequence by one step. The oily olefin (198) on oxidation yielded the ketone (199), which was formylated, and subjected to Robinson annelation with methyl vinyl ketone prepared in situ following the procedure of Howell and Taylor [74]. The resulting adduct without purification was heated by boiling with sodium methoxide in methanol to obtain the tricyclic ketone (200). It was treated with... 

Fig. (17). The already described alcohol (15) prepared from the methyl analog of Wieland-Miescher ketone (2) is converted to olefinic compound (201) applying the standard organic reactions. Its transformation to the ketone (202) is subjected to hydroboration-oxidation with Jones reagent, metal hydride reduction respectively. Its conversion to pisiferic acid (196) was carried out by the procedures described in Fig. (16)" and thus requires no comments.

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