Amines II: Alkaloids


In our introduction to the chemistry of amines, we defined alkaloids as natural products that contain an amino group. The name is derived from the fact that aqueous solutions of these compounds are slightly basic, i.e. alkaline, due to the presence of the amino group. The reactions that produce alkaloids generally involve the secondary metabolism of amino acids. In particular, most alkaloids are derived from four different amino acids; lysine, phenylalanine, tyrosine, and tryptophan. The structures of these amino acids are shown in Figure 1. Some of the carbon atoms are numbered for reference to structures in later figures.

Figure 1

Amino Acids as Alkaloid Precursors

Alkaloids Derived from Lysine

The structures of five lysine-derived alkaloids are shown in Figure 2. Pelletierine and pseudopelletierine are found in the bark of pomegranate trees. Sedamine is one of over 600 alkaloids isolated from the genus Sedum, a common garden plant,while halosaline is a minor constituent from the species Haloxyon salicornicum. Lycopodine is obtained from various species of the moss Lycopoodium.

Figure 2

Lysine-Based Alkaloids

Comparison the structures of pelleterine, sedamine, and halosaline suggests that each of these molecules arises from the reaction of a common intermediate with a different b-ketoacid as shown in Figure 3. The most likely intermediate is thought to be D1-piperideine, a compound that we invoked during our discussion of the role of the Mannich reaction in the biosynthesis of nicotine.

Figure 3

The Origin of Three Species

Exercise 1 Pseudopelletierine is thought to arise by methylation of pelletierine, oxidation of the resulting N-methylpelletierine, and an intramolecular Mannich reaction. Draw the structure of compound that undergoes this intramolecular addition.

Alkaloids Derived from Phenylalanine and Tyrosine

The simplest members of this group of alkaloids are compounds that contain the b-phenylethylamine, C6H5CH2CH2NH2, skeleton. Figure 4 presents the structures of several members of this family whose names should be familiar to you.

Figure 4

A Familiar Family

Figure 5 delineates the biosynthetic path from phenylalanine to mescaline, 3,4,5-trimethoxyphenylethylamine. Mescaline, a mild hallucinogen, is obtained from the peyote cactus, Lophophora williamsi.

Figure 5

The Biosynthesis of Mescaline

All of the reactions summarized in Figure 5 are enzyme catalyzed. Investigation of the details of biosynthetic transformations such as those shown in Figure 5 involve isotopic labeling studies. One approach involves in vivo labeling, wherein compounds with isotopically labeled atoms (the most common isotopes are 2H, 3H, 13C, 14C, and 15N) are fed to seedlings. The alkaloid of interest is then isolated from the mature plant and the positions of the labeled atoms are determined, either by degradation of the alkaloid to simple compounds that are easily identified or by NMR spectroscopy. For example, when 14C1-phenylalanine is fed to L. williamsi, the mescaline isolated from the plant does not contain any radioactivity. However, when 15N2-phenylalanine is used, the the labeled nitrogen ends up in the amino group of the mescaline.

Because plant feeding experiments take a long time, in vitro methods are often used. This approach involves addition of the labeled compounds to cell-free extracts from the organism of interest. These extracts contain the enzymes-hydroxylases, decarboxylases, methyl transferases, etc.-that are responsible for transformations like those shown in Figure 5.

While the reactions shown in Figure 5 are catalyzed by enzymes, the mechanisms of those reactions are similar to those deduced from investigations of non-enzymatic systems. For example, the decarboxylation of tyrosine is thought to proceed by a pathway similar to that outlined in Figure 6. The transformation begins with the nucleophilic addition of the amino group of tyrosine to the aldehyde function of an enzyme-bound molecule of pyridoxyl phosphate. The N=C unit of the resulting imine presumably activates the carboxylic acid group for an intramolecular proton transfer similar to that which occurs with b-keto acids. Elimination of CO2 generates the imine shown in brackets, tautomerization of which produces a third imine, that upon hydrolysis yields tyramine, while at the same regenerating the pyridoxyl phosphate.

Figure 6

Decarboxylation of an Amino Acid

It is interesting to note that tyramine occurs in many foods such as aged cheese, smoked fish, and sausage. It also occurs in some beers and wines. Elevated levels of tyramine, due to ingestion of these foods and beverages, cause blood vessels to constrict and blood pressure to rise. In fact, tyramine is suspected as a possible cause of migraine headaches.

Referring back to Figure 5, the O-methylation reactions all involve the transfer of a methyl group from S-adenosylmethionine as shown in general terms in Equation 1.

This reaction is an excellent example of a nucleophilic aliphatic substitution reaction. The S-adenosylmethionine is a biological equivalent of methylating agents such as methyl iodide or methyl bromide.

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Exercise 2 Draw the structure of the product in each of the following reactions:

a. 2

b. 3

Exercise 3 Draw the structure of the product of the following reaction:

4 Include both the cation and the anion.

Mescaline was first synthesized in 1919 by the pathway summarized in Figure 7.

Figure 7

The First Total Synthesis of Mescaline

While many of the reagents shown in Figure 7 may be unfamiliar, you should be able to select a modern day counterpart that would achieve the same outcome for each of the steps shown in the figure.

Exercise 4 Enter the formula for the reagent that you would use to convert 3,4,5-trimethoxybenzoic acid to its acid chloride.

Exercise 5 Which reagent in Table 1 of the topic entitled Oxidation and Reduction Reactions in Organic Chemistry would you select to reduce the acid chloride shown in Figure 5 to the corresponding aldehyde?

Exercise 6 The reaction of the aldehyde mentioned in Exercise 2 with nitromethane is a condensation that is a typical reaction of aldehydes. What type ofcondensation is it?

Exercise 7 Which reagent in Table 1 of the topic entitled Oxidation and Reduction Reactions in Organic Chemistry would you select to reduce the nitro alkene shown in Figure 5 to mescaline?

Alkaloids Derived from Tryptophan

Figure 8 presents a small sampling of alkaloids that are derived from tryptophan.

Figure 8

A Small Selection of Tryptophan-Based Alkaloids

While the connection between tryptophan and serotonin is obvious, it is not apparent that quinine is derived from this amino acid. This is, in part, because the quinine skeleton includes atoms derived from non-amino acid sources, in particular the terpene geraniol. However, feeding experiments using isotopically labelled geraniol and tryptophan have shown that molecular rearrangements must also be involved. Figure 9 presents a composite of the results of several such experiments. Since many of the steps along the biosynthetic pathway to quinine are uncertain, we will not elaborate further. However, it should be obvious that the biosynthetic pathway involved in the synthesis of quinine is a twisted one indeed.

Figure 9

A Proposed Pathway for the Biosynthesis of Quinine