Methyl podocarpate

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 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. 

Birch reduction of 12-methoxypodocarpa-8,l l,13-trien-19-ol has been investigated and methods have been developed for converting the C-12 ketones into C-13 ketones. An alternative approachhas been used to transpose the aromatic oxygen function from C-12 to C-13. The best route involved mononitration of methyl podocarpate (57), reduction of the nitrophenol toluene-p-sulphonate (58) to an amine (59) with stannous chloride and then Raney nickel, and finally diazotization with isopentenyl nitrite in cold acidic methanol to atTord the phenol ether. 

During attempts to alkylate methyl podocarpate with substrates such as methoxyacetyl chloride, some dimeric products linked by a methylene bridge were obtained. 

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... 

A soln. of methyl podocarpate in dry methanol-methylene chloride treated 6 hrs. at -78 with a slight excess of ozone 8/ -hydroperoxy-8a-hydroxy-(13- 17)-pentanorlabd-9(ll)-ene-12,19-dioic acid 19-methyl ester 8a- 12-lactone (Y 68%) dissolved in ethanol, treated with 1 N NaOH, and heated 4 hrs. under Ng on a steam bath -> l/5-carbomethoxy-la,10/ -dimethyldecal-6-one (Y 70%). F. reactions of the intermediate lactone s. R. A. Bell and M. B. Gravestock, Can. J. Chem. 48, 1105 (1970). 

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). 

The 5 configuration of the induced quaternary center of (35 )-3-ethyl-tetrahydro-3-(ni-troethenyl)-2//-pyran-2-one was determined by conversion into (+ )-quebrachamine while the (SS J-S-methyl derivative w as converted into (-i-)-podocarpic acid23. 

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. 

Using (2) as catalyst provided the (R) enantiomer in 99% yield, 78% ee. The key introduction of asynunetry during the synthesis of (+)-podocarp-8(14)-en-13-one was the phase-transfer-catalyzed Robinson annulation of 6-methoxy-l-methyl-2-tetralone with ethyl vinyl ketone. The authors carried out a comparative study of the A/-(4-trifluoromethyl)benzyl derivatives of cinchonine, cinchonidine, dihydrocinchonine, and dihydrocinchonidine and found that (5) produced the highest ee of the desired (S) enantiomer at —45 °C using toluene and 60% aq KOH (eq 10). ... 

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. 

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... 

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. ... 

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... 

To a solution of 160 mg (0.24 mmol) of 8/ -benzoyloxymcthyl-7z-(2-bromo-1-ethoxyethoxy)-l/J-fe/r-butyldimethylsilyloxy-13-methyl-18,19-bisnor-9/ -podocarp-13-en-12-one as a mixture ofisomers in 15 mL of C6H6, are added 79 pL (0.39 mmol) of tributyltin hydride and 4 mg (0.024 mmol) of AIBN. The mixture is refluxed for 16 h and the reaction is quenched with iodomethane. The mixture is diluted with EtOAc, washed with brine, and dried. The crude product is chromatographed on a silica gel plate (EtOAc/hexane 1 3) to afford 115 mg (82%) of the product as a 3 2 inseparable mixture of diastereomers. 

A synthesis of methyl vinhaticoate and methyl vouacapenate has been described. The key steps involved the conjugate addition of dimethylcopper lithium to (128), prepared from podocarpic acid, the transformation of the product (129) into the methoxymethylene ketone (130), and the formation of the furan ring (131) by the copper-catalysed addition of ethoxycarbonylcarbene. 

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]. 

The synthesis of methyl D-podocarpate (3) is typical of the transformations that can be carried out with Mn(OAc)3. Oxidation of 1 with 2 equivalents of Mn(OAc)3 in AcOH at 15 °C afforded 50% of 2 as a single isomer that has been converted to methyl 0-methylpodocarpate by Clemmensen reduction (26). Both enantiomers of O-methylpodocarpic acid have been prepared using the appropriate phenylmenthyl ester (49). 

Podocarp-8(14)-en-15-oic acid, 13a-methyl-13-vinyl-. See Pimaric acid Podophyllin Podophyllotoxin Podophyllum. See Podophyllum resin Podophyllum resin... 

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