The Biosynthesis of Tropic Acid

Ansarin, M. and Woolley, J.G. (1993) The obligatory role of phenyllactate in the biosynthesis of tropic acid. Phytochemistry, 32,1183-7. 

Chesters, N.C.J.E., O Hagan, D. and Robins, R.J. (1994) The biosynthesis of tropic acid in plants evidence for the direct rearrangement of phenyllactate to tropate. /. Chem. Soc. Perkin Trans., 1,1159-62. 

C-16 arise from methionine. Of note is the fact that C-1 of phenylalanine appears at C-4 of tenellin and C-2 at C-6. The implied rearrangement finds analogy in the biosynthesis of tropic acid (51) from phenylalanine. 

Leete, E., 1,2-Migration of hydrogen during the biosynthesis of tropic acid from phenylalanine, J. Am. Chem. Soc., 106, 7271-7272 (1984). 

Some of the more significant advances which have been made during 1972 appear in Section 2 of this review. In these yearly reviews it is not possible to discuss the biosynthesis of all classes of alkaloids in depth. It is the plan to select different topics each year so that a more complete story can be told on the individual alkaloids. In Section 3 the biosynthesis of tropic acid is reviewed. Some progress is being made on the isolation of enzymes responsible for the biosynthesis of alkaloids and this appears in Section 4. The use of tissue cultures of various plant organs in studying alkaloid biosynthesis is covered in Section S. 

Besides tropic and phenyllactic acids, little is known about the biosynthesis of other acids esterifying the tropane nucleus. Leete [26] listed the acids found in tropane alkaloids whose biosynthesis has been studied, usually by feeding labelled precursors to intact plants. Thus, tiglic acid, the acidic moiety of tigloidine and meteloidine, has been shown to be derived from the amino-acid L-isoleucine, probably via 2-methylbutanoic acid [38],... 

Robins, R.J., Woolley, J.G., Ansarin, M., Eagles, J. and Goodfellow, B.J. (1994a) Phenyl-lactic acid but not tropic acid is an intermediate in the biosynthesis of tropane alkaloids in Datura and Brugmansia transformed root cultures. Planta, 194, 86-94. 

Takao (522) determined the structure and the relative configuration of cor3moline. This alkaloid can be derived from the alkaloids of the corydaline type (Table XV). These two groups of bases—corydaline and corynoline—have also been isolated from the plant genus Gorydalis. It has not yet been decided whether one of the initial compounds which arise during the biosynthesis of alkaloids of the corydaline type is a tropic acid derivative. 

Tropane Alkaloids.—An abundance of evidence points to phenylalanine as an intermediate in the biosynthesis of the tropic acid moiety [as (34)] of tropane alkaloids like atropine (33), but support has also been obtained for alternative precursors for this moiety. All nine of the carbon atoms of phenylalanine are incorporated into tropic acid (Scheme 7) in a rearrangement reaction which... 

Proline and ornithine would also appear to be the most probable amino acid precursors of 1-hyoscyamine, and, as such, the source of the nitrogen of the tropane nucleus. The biosynthesis of the tropic acid half of the molecule has not yet received attention. Such investigations as have been made up to the present have been based upon Robinson s (113) proposed tropinone synthesis from ornithine plus acetone, and have been principally concerned with the identification of the original nitrogenous precursor. 

Apart from the sizable primary literature on the biosynthesis of the tropanes, a substantial number of reviews on this topic has been published. The two most recent of these describe the work from the laboratory of the late Eddie Leete [6] and the encouraging results that have been obtained on an enzymological level [7]. Experiments aimed at elucidating the biosynthesis of the tropic acid moiety present in many tropane alkaloids have been reviewed recently by workers in the field [8] and will not be covered here. 

The tropane alkaloids commonly occur as esters of tropic acid [as 6.67) and tiglic acid [as 6.75) The former acid arises preferentially from phenylalanine possibly via cinnamic acid and the entire carbon skeleton is involved. The results of C-labelling studies show that, in the rearrangement which occurs during biosynthesis, it is the carboxy group which migrates (see Scheme 6.18). Proof of an... 

Phenylalanine as a Precursor.— Tropic acid is found in Nature as the add moiety of the ester alkaloids hyoscyamine and hyosdne. A large amount of information, some conflicting, has been published in the past decade on the origin of this relatively simple molecule. We will review these data critically in the hope that it will aid work on the currently unsolved problem of its biosynthesis. It was discovered in 1960 that the administration of [3- C]phenylalanine to intact Datura stramonium plants yielded tropic acid having essentially all its activity at C-2. Later workers confirmed this result in D. stramonium (intact plants) and D. metel (sterile root cultures). It was then established that the other carbons of the phenylalanine side-chain were used for the production of the side-chain of tropic acid. The pattern of labelling found in the tropic... 

The economic importance of the tropane alkaloids has resulted in them being much studied. They are esters of the base tropine (or a derivative of this base) with organic acids such as tropic, cinnamic or benzoic acids. Progress has been made in working out the biosynthesis of these alkaloids, although the associated enzymology is still obscure some of the steps in biosynthesis may indeed be non-enzymic. 

In moths, it was discovered in Helicoverpa zea that a peptide produced in the subesophageal ganglion portion of the brain complex regulates pheromone production in female moths (19). This factor has been purified and characterized in three species, Helicoverpa zea (20), Bombyx mori (21, 22), and Lymantria dispar (23). They are all a 33- or 34-amino acid peptide (named pheromone biosynthesis activating neuropeptide, PBAN) and have in common an amidated C-terminal 5-amino acid sequence (FXPRL-amide), which is the minimum peptide fragment required for pheromon-tropic activity. In the redbanded leafroller moth, it was shown that PBAN from the brain stimulates the release of a different peptide from the bursae copulatrix that is used to stimulate pheromone production in the pheromone gland found at the posterior tip of the abdomen (24). 

Methods for the capillary gas chromatographic separation of optical isomers of chiral compounds after formation of diastereoisomeric derivatives were developed. Analytical aspects of the GC-separation of diastereoisomeric esters and urethanes derived from chiral secondary alcohols, 2-, 3-, 4- and 5-hydroxy-acid esters, and the corresponding jf- and -lactones were investigated. The methods were used to follow the formation of optically active compounds during microbiological processes, such as reduction of keto-precursors and asymmetric hydrolysis of racemic acetates on a micro-scale. The enantiomeric composition of chiral aroma constituents in tropical fruits, such as passion fruit, mango and pineapple, was determined and possible pathways for their biosynthesis were formulated. 

Hydroxyacid esters are contained in several subtropical fruits like pineapple (26), passion fruit (27) and mango (2 ). 3-Hydroxyacid derivatives are formed as intermediates during de novo synthesis and P -oxidation of fatty acids, but the two pathways lead to opposite enantiomers. S-(+)-3-Hydroxyacyl-CoA-esters result from stereospecific hydration of 2,3-trans-enoyl-CoA during P -oxidation R-(-)-3-hydroxyacid derivatives are formed by reduction of 3-ketoacyl-S-ACP in the course of fatty biosynthesis. Both pathways may be operative in the production of chiral 3-hydroxyacids and 3-hydroxyacid esters in tropical fruits. 

Cinnamic acid (24), a metabolite of phenylalanine, has been linked with tropic acid biosynthesis via its epoxide on chemical grounds but neither of these compounds have previously been found to act as a tropic acid precursor. Results with cinnamoyltropine were similarly negative. " More recently examination of [2- C]cinnamic acid [as (24)] as a precursor for the acid moieties of hyoscyamine... 

Comprehensive reviews have recently appeared on the tropane alkaloids of the Solanaceae and on the biosynthesis and metabolism of the same type of alkaloids. The stereospecific hydroxylation of tropine to 6/3-hydroxytropine and the conversion of its tropic acid ester into 6,7-dehydrohyoscyamine and further into scopolamine have been conclusively proven. Hence, the total synthesis of scopolamine from 6-tropen-3a-yl esters is indeed a biomimetic synthesis. 

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