Polyketides hemlock

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

Pinidine and Coniine.—Pinidine (8) and the hemlock alkaloid coniine (9) are unusual among simple piperidine alkaloids in being derived exclusively from acetate units. The combination is in each case a simple linear one and proceeds either via polyketide intermediates or, arguably in the case of coniine, via the fatty acid (10). Strong evidence from tracer and enzyme studies points to (11) as an intermediate... 

Thujone is a terpene that is thought to be the poisonous principle in absinthe— the drink that reduced many artists and writers to idiocy in Paris around 1900. Coniine is an alkaloid and the poison in hemlock with which Socrates was executed. Thromboxane is a polyketide involved in blood-clot formation and is a human natural product. 

Although the alkaloids coniine (48) and y-coniceine (51) bear a structural resemblance to the piperidine alkaloids, these compounds are derived from a polyketide pathway (Fig. 29.17). Lysine is a poor precursor, and early attempts to show incorporation of this compound resulted in failure. Acetate is a much better precursor. Coniine is a highly toxic alkaloid and is one of the toxic components of poison hemlock (Conium maculatum, Apiaceae) (Cutler, 1992). Otherwise, alkaloids are very uncommon in the Apiaceae. Coniine does occur in several other plants, for example, Sarracenia (Sarracenia). y-Coniceine is found in several species of Aloe (Liliaceae) (Dring et al., 1984). Coniine is toxic to the aquatic plant Lemna (Wink, 1993). The LDioo p.o. in the... 

The entire skeleton of coniine 6.14) derives from acetate, with labelling of C-2, C-2, C-4, and C-6 by [l- C]acetate. A polyketide pathway immediately seems likely and 5-oxo-octanoic acid 6.11) and the corresponding aldehyde 6.12), with the necessary functionality for inclusion of the nitrogen atom, were shown, by tracer and enzymic evidence, to be implicated in coniine biosynthesis, as was y-coniceine 6.13) which is also a hemlock alkaloid. These results [6, 7] lead in a straightforward way to the pathway shown in Scheme 6.5. Most curiously, however, it has been found that octanoic acid... 

Coniine from the hemlock plant Conium maculatum is a simple example of an alkaloid, although its biosynthesis is unusual. It was thought that coniine would be derived from the amino-acid lysine, but labelled lysine was not converted to coniine. It is unusual in being derived from a type I polyketide (Chapter 4). Both [6- C]-5-oxo-octanoic acid and [6- C]-5-oxo-octanal are well-incorporated into labelled coniine (Figure 9.3). 

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