Phenylalanine-Derived Alkaloids

2.1.2 Phenylalanine-Derived Alkaloids


It has been observed that the aromatic amino acid L-tyrosine is not only a common but also an extremely vital precursor of alkaloids; whereas, L-phenylalanine is found to be much less frequently employed, and normally it specifically contributes carbon atoms only, such as: C6C1, C6C2 or C6C3 units, without making available a N-atom from its amino function e.g., as in the biosynthesis of colchicine and lobeline.
The various typical examples of phenylalanine-derived alkaloids are: ephedrine, norpseudoephedrine (cathine) and capsaicin, which shall be described hereunder:
A. Ephedrine
Biological Source It occurs in the dried young stems of the Chinese wonder drug Ma HuangEmhedra vulgarisEphedra sinica Stapf., Ephedra equisetina Bunge belonging to family Ginetaceae, and also in several other Ephedra species. This is also found in Ephedra geradiana Wall ex. Stapf. (Ephedraceae) (Pakistani Ephedra). There are two most important forage ephedras in the United States, namely: E. nevadensis and E. viridis. The former are is E. nevadensis S. Wats (Ephedraceae) and known as Mormon Tea and Nevada Jointfir.
Chemical Structure

Ephedrine
α-[1-(Methylamino)ethyl] benzene methanol (C10H15HO).
Isolation Ephedrine usually exists singly in Ephedra sinica (1-3%) and E. equisetina (2%).
However, it occurs in association with ~| -Ephedrine (i.e.pseudoephedrine) in E. vulgaris.
However, the ephedrine and pseudoephedrine may be extracted conveniently from the dried young stems of the plant material by adopting the ‘general procedures for alkaloid extraction’ (section 1.7.3), by the help of successive benzene and dilute HCl extractions.
Preparation Ephedrine may be prepared by two methods, namely:
(i) Fermentation method, and
(ii) Synthetic method.
(aFermentation Method: It can be prepared commercially by fermenting a mixture of molasses** and benzaldehyde. The reaction product i.e., methyl benzyl alcohol ketone i.e., C6H5-CH(OH)COCH3, a keto-alcohol is subsequently mixed with a solution of methyl amine and freshly prepared H2-gas is made to pass though it. Thus, we have:

 Fermentation Method
(b) Synthetic Method: Manske et al.*** (1929) synthesized (±)-Ephedrine by the catalytic reduction of 1-phenylpropane-1, 2-dione (or benzoylacetyl) in the presence of methylamine in methanol solution as given below:

Synthetic Method: synthesized (±)-Ephedrine
Stereochemistry Since the ephedrine molecule contains two dissimilar chiral centres, four optically active isomers (or two pairs of enantiomers) are possible theoretically. Freudenberg (1932) put forward the following configurations of ephedrine and ψ-ephedrine (mp 118°C, [α]D ± 51.2°) are as follows:

ephedrine and ψ-ephedrine
Foder et al. (1949, 1950) confirmed that the ephedrine has the erythro-configuration, and yephedrine the threo-configuration as stated below:


erythro-configuration, and yephedrine the threo-configuration
The carbobenzoxy derivative of nor-ψ-ephedrine undergoes intramolecular rearrangement to the O-derivative in an acidic medium. In case, nor-ψ-ephedrine possesses the threo-configuration, then this ultimately gives rise to the favourable trans-orientation of the phenyl and methyl groups in the cyclic intermediate i.e., the steric repulsions are at a bear minimum level. Likewise, the nor-ephedrine shall, therefore, exhibit essentially the crythroconfiguration; and it was further revealed that its corresponding N-carbobenzoxy derivative does not undergo any molecular rearrangement whatsoever in an acidic environment to produce the O-derivative. Therefore, one may infer that the steric repulsions that would take place between the phenyl and methyl groups in Foder et al. (1949, 1950) confirmed that the ephedrine has the erythro-configuration, and ψ-ephedrine the threo-configuration as stated below: the cyclic intermediate is evidently too high to allow its subsequent formation. Thus, it is absolutely possible, on this basis, to differentiate and distinguish between the stereoisomers of ephedrine and ψ-ephedrine.


nor-ephedrine
Characteristic Features The characteristic features of various forms of ephedrine and its salts are as stated under:

The characteristic features of various forms of ephedrine
Special Features
(iEphedrine does not yield a precipitate with Mayer’s Reagent except in concentrated solution.
(ii) Ephedrine in chloroform solution after long standing or on evaporation usually forms ephedrine hydrochloride and phosgene.
(iii) Both ephedrine and pseudoephedrine are fairly stable to heat and when heated at 100°C for several hours does not undergo any decomposition.
(ivEphedrine hydrochloride on being heated with 25% HCl gets partially converted to pseudoephedrine; and this conversion is reversible and soon attains on equilibrium.
Identification Tests
(iColour Test: Dissolve 0.1 g ephedrine in 1 ml water with the addition of a few drops of dilute HCl. Add to it two drops of CuSO4 solution (5% w/v) followed by a few-drops of NaOH (1N) solution when a reddish colour is obtained. Add to it 2-3 ml of ether and shake vigorously, the ethereal layer becomes purple and the aqueous layer turns blue.
(iiFormation of Ephedrine Hydrochloride: Dissolve 0.2-0.3g of ephedrine in 35 ml of chloroform in a stoppered test tube and shake vigorously. Allow it to stand for 12 hours and evaporate the chloroform, when crystals of ephedrine HCl are obtained, and
(iiiFormation of Benzaldehyde Odour: Take 0.05 g of ephedrine in a small porcelain dish and triturate it with a few crystals of pure potassium ferricyanide, [K3Fe(CN)6], add a few drops of water and heat on a water-bath, it gives rise to a distinct odour of benzaldehyde.
Biosynthesis of Ephedrine Alkaloids Interestingly, phenylalanine and ephedrine not only have the same carbon and nitrogen atoms but also have the same arrangement of C and N-atoms i.e., the skeleton of atoms. Noticeably, L-phenylalanine is a precursor, possessing only seven carbons, a C6C1 fragment, gets actually incorporated. It has been observed that phenylalanine undergoes metabolism, probably via cinnamic acid to benzoic acid; and this perhaps in the form of its coenzyme–A ester, which is acylated with pyruvic acid and undergoes decarboxylation during the addition as shown below.

Biosynthesis of Ephedrine Alkaloids
A thiamine PP-mediated mechanism is put forward for the formation of the diketone, and a transamination reaction shall give rise to cathinone. Further reduction of the carbonyl moiety from either face yields the diastereomeric norephedrine or norpseudoephedrine (Cathine). Ultimately,
N-methylation would give rise to ephedrine or pseudoephedrine.
Uses
1. The l-ephedrine is extensively used as a bronchodilator.
2. The d-psendoephedrine is employed widely as a decongestant.
B. Norpseudoephedrine
Synonyms Cathine; Katine; Nor-y-ephedrine.
Biological Sources It occurs naturally as the D-threo-form in the leaves of the khat plantCatha edulis Forsk. (Celastraceae), which is widely found as an evergreen shrub native to Southern Arabia and Ethiopia. It is also found in relatively smaller amounts in the South American tree Maytenus krukovii A.C. Smith (Celastraceae); and in the mother liquors obtained from Ma Huang after the recovery of ephedrine.
Chemical Structure

Norpseudoephedrine
(R*, R*)-α-(1-Aminoethyl)-benzenemethanol.
Isolation It is isolated from the plant material as described under (A) in this section.
Characteristic Features The various physical parameters of different forms of norpseudoephedrine are summarized below:

The various physical parameters of different forms of norpseudoephedrine
Uses
1. It is widely employed as an anorexic.
2. It is also used in the optical resolution of externally compensated acids.
C. Capsaicin
Synonyms Axsain; Mioton; Zostrix.
Biological Source It is the pungent principle obtained in the fruit of various species of Capsicumviz., Capsicum annum L. (Solanaceae) (Chilli, Sweet Peppers, Paprika).
Chemical Structure

Capsaicin
(E)-N-[4-Hydroxy-3-methoxyphenyl)-methyl]-8-methyl-6-noenamide. It is phenolic in nature.
Isolation The capsicum fruits are crushed and extracted with either hot acetone or ethanol by using the method of percolation. The solvent i.e., hot acetone or ethanol is evaporated under vacuum.
The residue is extracted once again with successive quantities of warm acetone or ethanol until and unless the marc is completely free from any pungent principles. It contains approximately not less than 8% of capsaicin.
Characteristic Features
1. Capsaicin gives a distinct burning taste even when diluted to the extent of one part in one million parts of water. However, its pungency is destroyed by oxidation.
2. It is obtained as monoclinic, rectangular plates, scales from petroleum ether, having mp 65°C.
3. It has bp 0.01 210-220°C (air-bath temperature).
4. It has uv maximum: 227, 281 nm (€ 7000, 2500).
5. It is freely soluble in ether, benzene, chloroform; slightly soluble in CS2and practically in soluble in water.
Identification Tests
1. An alcoholic solution of capsaicin gives rise to a distinct bluish green colour upon adding a few drops of FeCl3 solution (0.5% w/v).
2. When capsaicin is dissolved in a few drops of concentrated H2SO4 and a few crystals of sucrose is added, it yields a violet colour after a few hours.
Uses
1. It is used as a topical analgesic.
2. It is often employed as a tool in neurobiological research.
3. It is used in creams to counter neuralgia caused by herpes infections and in other pain-relieving formulations.
Biosynthesis of Capsaicin The aromatic fragment of the capsaicin molecule is derived solely from phenylalanine through chemical entities, viz., ferulic acid and vanillin. The later compound, an aldehyde, is actually the substrate for transamination to yield vanillylamine. However, the acid part of the resulting amide structure is of polypeptide origin having essentially a branched-chain fatty acyl-CoA which is produced by chain extension of isobutyryl-CoA. The aforesaid source of reactions are as given under:

Biosynthesis of Capsaicin
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* Gosselin et al. Eds. Clinical Toxicology of Commercial Products, Williams and Wilkins, Baltimore, 5th ed., Sec-
II., pp. 249-250 (1984).
** Molasses: A thick brown viscous liquid obtained as a by product of ‘Sugar Industry’ containg 8-10% cane sugar.
*** Manske and Holmes (eds). The Alkaloids, Academic Press. N. York. Vol. 1 (1950)

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