Podocarpic acid

An alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been reported. In a stereoselective total synthesis of ( )-callitrisic acid and ( )-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). 

Involvement of arene oxides has been suggested in the biosynthesis of a number of natural products like 340 from 338 through intermediate 339.185 Formation of semiperivirol, totarol, ferruginol, and podocarpic acid from... 

In 1971, Zalkow and co-workers reported (175) the conversion of podocarpic acid (322) to a key intermediate 323 for the synthesis of the enatiomers of ajaconine (80) and atidine (79). Compound 323 contains the... 

Pinhey utilized the decarboxylative rearrangement of 2 to the nor-alkyl pyridyl sulfide 3, oxidation to the corresponding sulfoxide and thermal elimination sequence in a simple transformation of podocarpic acid 4 into useful synthons 5 (for example, in vitamin D3 synthesis) for steroid CD-ring systems, as shown in Scheme l.8... 

Fig (1) The diteipenoid compounds (1) to (5) were isolated by Yatagai et al [2,3], from the leaves of Chamaceyparis Pisifera endle. Ferruginol (6) is diterpene phenol, while dehydroabietic acid (7) and Podocarpic acid (8) are the resin acids. It is recommendable to consult the referencefl], to have important informations of compounds (6), (7) and (8). 

The low-temperature ozonolysis of podocarpa-8,1 l,13-trien-12-ol (59) to form the lactol (60) has been re-examined54 and the importance of slightly acidic reaction conditions has been noted. The conversion of podocarpic acid into 19-hydroxypodocarpa-8(14)-en-13-one has been described.55 The C-12 oxygen function was removed by hydrogenolysis of the 12-toluene-p-sulphonate. Details of the nitration of methyl 7-oxodehydroabietate have appeared.56 The conformational analysis of the ring C diene, levopimaric acid, has been discussed57 in terms of a folded conformation. 

The use of acylnitiene cyclizations in the synthesis of diteipene alkaloids goes back to the early 1960s, and although much of the early work has been reviewed, selected examples are included here. The acyl azide (19), readily prepared from podocarpic acid, was irradiated to give the 8-lactam (20 20%), which has the azabicyclononane ring system of the diteipene alkaloids such as atisine. ... 

Two further cytotoxic nor-diterpenoid dilactones, (73) and (74), have been isolated " from Podocarpus nagi. Nagilactone F (75) has been synthesized from podocarpic acid. Two unusual diterpenoids, hispanonic acid (76) and his-paninic acid (77), both of which possess a seven-membered ring c, have been isolated from Ballota hispanica (Labiatae). Some naphthalenic nor-diterpenoids [e.g. (78)] with the cleistanthane skeleton have been isolated from Vellozia stipitata and V. declinans. 

Riag B oxidation in the podocarpic acid series. Phenols of the podocarpic acid series undergo exclusive oxidation in ring B with 2,3-dichIoro-5,6-dicyanobcnzo-quinone in alcoholic solvents at room temperature. Thus oxidation of methyl podo-carpate (I) with 2.5 eq. of DDQ in methanol gives a mixture of two products, (2) and (3), the latter being the major product (77% yield). Use of 2 eq. of reagent results mainly in... 

Isomerization of the diterpeue A B ring juncture. The steroidal type A/B ring juncture of diterpenes can be isomerized to the antipodal one by treatment with a 10% palladium-charcoal catalyst in refluxing triglyme. Thus methyl 5a,10 -podocarpa-8,1 l,13-triene-15-oale (1) can be isomerized in 83% yield to methyl 5j, IOa-podocarpa-8,ll,13-triene-l3-oate (2). The reaction was used in a synthesis of (- J-podocarpic acid from (+)-dehydroabietic acid. 

The Chemistry of Ring A.—Two methods have been described for smoothly hydrolysing the highly-hindered axial C-4 methyl esters such as methyl 0-methyl podocarpate. The first uses boron trichloride in methylene chloride, and the otherlithium n-propyl mercaptide in hexamethylphosphoramide. The oxidative decarboxylation of dehydroabietic acid and 0-methyl podocarpic acid affords a mixture of C-4 olefins which are separable over 10 % silver nitrate by t.l.c. Thus in a partial synthesis of callitrisic acid, the 4(19)-epoxide prepared... 

The Chemistry of Ring B.—The isolation of taxodione (49), a diterpenoid tumour inhibitor, has stimulated interest in the introduction of oxygen functions at C-6. Taxodione itself has been synthesized from podocarpic acid. The latter was converted to ferruginol benzoate (46). The C-11 hydroxy-group was introduced via the diazo-compound and the product acetoxylated at C-7 to afford (47) this was converted into the A -olefin (48), which was epoxidized and isomerized to the C-6 ketone. The product was then oxidized to give the quinone-methide of taxodione (49). 

Studies aimed at the synthesis of the tetracyclic steroid skeleton from dehydro-abietic acid have centred, in their initial stages, on transformations of the C-13 isopropyl group. The full paper describing the conversion of methyl 12-acetyl-abieta-8,ll,13-trien-18-oate into methyl 13-hydroxypodocarpa-8,ll,13-trien-18-oate by nitrodeacylation and dealkylation reactions, has appeared. Birch reduction of the methyl ether of the phenol afforded the a/5-unsaturated ketone (56) which is a useful synthetic intermediate. Methods for the conversion of podocarpic acid into the a) -unsaturated ketones (57 R = CO2H and CHjOAc) have been investigated reduction of the ester (58 R = C02Me) with lithium in liquid ammonia, which was accompanied by decarboxylation, gave only a... 

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. 

A number of partial syntheses have been described in the bicyclic series. The synthesis of methyl (12S)- and (12i )-hydroxylabda-8(17)-en-19-oate utilized the aldehyde (10) as an intermediate. This was obtained from podocarpic acid. The synthesis of the furan methyl lambertianate (11) from dimethyl agathate has been described. Examination of the n.m.r. spectra of the levantenolides (12) has led to a revision of their C-12 stereochemistry. a-Levantenolide has the (12i ) configuration whereas jS-levantenolide has the (125) configuration. The functionalization at C-12 of labdanes by oxidation of C-15 alcohols with iodine and lead tetra-acetate has been described. ... 

Bicycloannelation.2 The a -enolate of an a,/J-cyclohexenone reacts with this phosphonium salt to form a tricyclo[3.2.1.02 7]octane in low to moderate yield. This reaction was used in a short synthesis of the pentacyclic diterpene trachyloban-19-oic acid (4). Reaction of the lithium enolate of 2, prepared from podocarpic acid, with I provided the pentacyclic ketone 3, which was reduced by the Wolff-Kishner reaction to 4. 

Aromatic rings. Ireland and Schiess effected efficient reduction of the phenolic ring of (1, from podocarpic acid) by hydrogenation with added ruthenium dioxide... 

It was most convenient to isolate the products after acidic conversion to cyclohexenones. Structures of the products were assigned by chemical correlation and circular dichroism and the enantiomeric purities were based on optical rotations. The selectivities obtained, although impressive for the era, are moderate at best, despite significant attempts to optimize the substrates and reaction conditions. Use of substituted cyclohexanones (29) and other aldehydes (30) lead to optically active products but the extent of enantiomeric induction in these products was not determined. This technology was used for the partial asymmetric synthesis of (+ )-mesembrine (12.1) (29) and (+ )-podocarpic acid (12.2) (31). 

C, Synthesis.—Atisine and Veatchine Types. Zalkow and co-workers developed syntheses of intermediates potentially transformable into atisine-type alkaloids, starting with podocarpic acid. The general approach is illustrated by a synthesis" of an ajaconine degradation product. Methyl O-methyl-7-keto-podocarpate (56) was reduced to the diol, which was converted by Birch reduction to dienone (57). The diene diol diacetate from this was converted to the 7,8-epoxide. Boron trifluoride converted this to the non-conjugated enone (58) which isomerised and... 

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