The Pinus Alkaloids

The complete stereochemistry of pinidine (CII) has been elucidated (166). The relative configuration of the 2,6-alkyl substituents was shown by conversion of the propenyl group into a methyl group. Pinidine was benzoylated and oxidized to (-I-)-iV-benzoyl-6-methylpipecolic acid 

The geometry about the double bond was shown to be trans by the presence of a band in the IR-spectra of pinidine and its derivatives at 970 cm i and hy the 18 cps coupling between the olefinic protons in the NMR-spectrum. The absolute configuration was determined by hydrogenation of A-methylpinidine methiodide to give (-f- )-2-dimethylamino-nonane which was enantiomeric with synthetic S — )-2-dimethylamino-nonane prepared from S-(-I-)-2-nonanol. Pinidine is thus 2-(i )-methyl-6- (jR)- (2-frows-propenyl)-piperidine (CII). 

Nonane has been obtained from wilfordic acid and hydroxywilfordic acid by the technique of hydrogenolytic gas chromatography 168). This result, coupled with a study of the NMR-spectra of wilfordic acid and hydroxywilfordic acid, has lead to a revision of the structures of these acids to CVI and CVII respectively. 

Santiaguine (OIX) was synthesized by heating isotripiperideine with a-truxillyl chloride 170). Methylation of santiaguine followed by acid hydrolysis gives tetrahydro-iV -methylanabasine (CX) 171). Details of the syntheses of ammodendrine and orensine have been published 172). Isoorensine has been shown to be a stereoisomer, not a structural isomer, of orensine 173). Condensation of isotripiperideine with phenylpropiolyl chloride followed by hydrolysis and partial hydrogenation gave the cis-cinnamoyl isomer (CXI), identical with isoorensine. Orensine is the trans isomer. 

In a survey of a number of species of the genus Pinna for alkaloids it was discovered that three species, i.e., P. aabiniana Dougl., P. jejfreyi Balfour, and P. torreyana Parry contained appreciable quantities of an alkaloid that was named pinidine. These three species differed from others in not containing any bicyclic terpenes. P. aabiniana, which was chosen for a detailed study, was found to contain as well as pinidine a low-boiling alkaloid identified as (-(-)-a-pipecoline (77). 

The alkaloid wilfordine isolated from the roots of Tripterygium vnlfordii Hook (79) has been shown by coimtercurrent distribution to consist of a mixture (80) from which fom ester alkaloids have been obtained by partition chromatography. These are wilforine, wilfordine, wilforgine, and wilfortrine (81, 82). 

Upon saponification wilforine and wilfordine yielded 1 mole of benzoic acid, 5 moles of acetic acid, and 2 moles of acid nonvolatile in steam per mole of alkaloid. Wilforgine and wilfortrine yielded 1 mole of 3-furoic acid, 5 moles of acetic acid, and 2 moles of acid nonvolatile in steam per mole of alkaloid. 

In addition the saponification of wilforine yielded a steam nonvolatile nitrogenous dibasic acid of molecular formula C11HJ3O4N, m.p. 196-196°. From wilforgine, an identical acid was obtained. 

A different nitrogenous dibasic acid, CxjHisOsN, m.p. 178-179° was obtained from both wilfordine and wilfortrine. 

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Figure 6. An example of a pseudoalkaloid. Acetate-derived alkaloid pinidine is extracted from the Pinus species, for example, from Pinus penderosa. (Photo T. Aniszewski). Pinidine has antimicrohial activity.

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

Pin IIS alkaloids. For a long time, pinidine (2/ )-ci5-2-methyl-6-((E)-l-propenyl)piperidine, C9H,7N, Mr 139.24, [a] -10.5° isolated from the American pine Pinus sabiniana was the only alkaloid known from the Pinaceae. ... 

Tkllent W H, Stronberg V L, Horning E C 1955 Pinus alkaloids. The alkaloids of P. sabiniana Dougl. and related species. J Am Chem Soc 77 6361-6364... 

In addition to lupines, poison-hemlock and Nicotiana spp., other plant species of the genera Genista, Prosopis, Lobelia, Cytisus, Sophora, Pinus, Punica, Duboisia, Sedum, Withania, Carica, Hydrangea, Dichroa, Cassia, Ammondendron, Liparia, and Colidium contain potentially toxic and teratogenic piperidine alkaloids. Many plant species or varieties from these genera may be included in animal and human diets (Keeler and Crowe, 1984). 

Occasional reports of alkaloids and amino acids have appeared with respect to species of Abies and Pinus, but the family is best known for its assortment of terpenoids. 

Additional 2,6-disubstituted piperidine alkaloids detected in Picea and Pinus include pinidinone and epipinidinone (191 and 194, from Picea pungens), 193 (from Picea abies, P. pungens), 195 (from Pinus nigra, P. sylvestris, P. ponderosa) and 196 (from Picea pungens, Pinus ponderosa, P. sylvestris, P. nigra)[467]. Pinidinone, an alcohol from reduction of pinidinone, and 196 have also been detected in the Mexican Bean Beetle, Epilachna varivestis [468]. 

The subalpine zone of Tenerife (450-1800 m) includes the pine forest dominated by the endemic Pinus canariensis [4], This pine forest is an open community with several shrub species including endemic senecios characterized by their content in sesquiterpenes, sesquiterpene lactones and pyrrolizidine alkaloids [29-31]. 

Diastereoselective hydride addition is quite versatile, and it provides facile synthetic access to ( —)-pinidine (661), an alkaloid isolated from several species of Pinus, as well as its unnatural isomer (+ )-pinidine (660b). The unstable aldehyde 655, prepared in four steps from 624 [202], undergoes Grignard addition with 4-pentenylmagnesium bromide followed by Swem oxidation to afford ketone 656 in 90% yield for the two steps. Stereoselective hydride addition with L-Selectride provides the -yn-alcohol 657 (91 9), while zinc borohydride reduction provides almost exclusively the anri-alcohol 658 (>99 1) (Scheme 144). 

Recently, some further, structurally related derivatives were found and it was demonstrated that 2,6-disubsti-tuted piperidines occur in all investigated species of Pinus (pine) and Picea (spruce). The P. a. are found in all parts of the plants. First observations suggest that the potentially toxic alkaloids (structural similarities with coniine) serve as a defence against herbivores. ... 

Very few alkaloids of polyketide origin are known in nature, particularly in woody plants. Pinidine is one of them. This alkaloid has been isolated from the needles of the Pinaceae species Pinus jeffreyi, P. subiniana, and P. torreyana (153, 154). 

It is interesting to note that these three alkaloid-containing species are also characteristic in that their terpentines are devoid of a- and )ff-pinenes, which are the most widely spread bicyclic monoterpenes in the ordinary Pinus species. 

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