Papaver alkaloids

Papaver Alkaloids.—Biosynthesis of morphine (36) occurs, in Papaver somniferum, through reticuline (33) by way of thebaine (35). The sequence from (35) to (36) involves, inter alia, two O-demethylations, with that at the methoxy-group at C-6 occurring first.1,2 Confirmation that the other methoxy-group is not demethylated first in this Papaver species obtains from the failure to detect oripavine (37), which is found in other Papaver species, as a natural constituent of P. somniferum. The experiment involved attempted isolation of radioactive (37), using inactive alkaloid as carrier, following a feeding experiment with radioactive reticuline (33).37 

Oripavine 3-ethyl ether (38), an unnatural analogue of thebaine (35), was found to be metabolized to morphine 3-ethyl ether and to morphine (36). The efficiency of the conversion was comparable to that of natural biosynthesis. (For an examination of other unnatural compounds as substrates for the enzymes of the biosynthesis of morphine alkaloids, see Vol. 4, p. 15.) 

Further work on the biosynthesis of alkaloids by fractions of the latex of seed capsules of P. somniferum has been published.39 

Papaver Alkaloids.—Biosynthesis of benzylisoquinoline alkaloids involves the amino-acid dopa, which is in part implicated through decarboxylation to dopamine. The presence of L-dopa decarboxylase in Papaver orientale latex has recently been demonstrated.  

Coclaurine.—Coclaurine (63) is an intermediate of some significance in the biosynthesis of benzylisoquinoline alkaloids, e.g. bisbenzylisoquinolines (see below). Its biosynthesis, in Annona reticulata, has been investigated and found to follow an orthodox pathway, from two molecules of tyrosine. Radioactive tyramine, dopa, and dopamine (54) labelled the phenethylamine portion of (63) 

Chelidonine.—Chelidonine (66) has been proved to be a modified benzyl-isoquinoline arising along a pathway from (5)-reticuline, through (5)-scou-lerine, (S)-stylopine (64), and protopine (65) (detailed pathways are given in ref. 7, p. 12, and ref. 8, p. 14). The steps which lie beyond stylopine (64) manifestly involve fracture of the C-14—N and C-6—N bonds in (64). It has been shown that the pro-S proton at C-13, as well as the one at C-14, is lost on formation of chelidonine (those at C-5 and C-8 are retained). The most recent results are that in the scission of the C-6—N bond it is again the pro-S proton which is lost. It is interesting to note that all three protons are lost from the 5i-face of the molecule. 

Further evidence implicating (68) as an intermediate in isoquinoline biosynthesis comes from the efficient incorporation of labelled (68) into (70) and with the specific incorporation, albeit with low efficiency, of labelled (68) into morphine (71). The amino-acid (72) was a very poor precursor for morphine, which indicates that both aromatic building blocks must be dihydroxylated before they are joined together. Simple chemical decarboxylation of (68) affords (69), which was found to act as a precursor for morphine [the triphenol (73) was incorporated too but at a lower level]. These observations taken with the labelling of (69) by dopa in P. orientale suggest that the imine (69) may also be an intermediate in isoquinoline biosynthesis. 

If the amino-acid (68) is a biosynthetic intermediate it clearly arises in vivo from dopamine and 3,4-dihydroxyphenylpyruvic acid (67). The latter compound is derived from dopa by transamination and the conversion of dopa into (68) thus involves competing processes of decarboxylation and transamination. In P. orientale the former process was apparently favoured seven-fold over transamination whereas in P. somniferum [2- C]dopa was only incorporated into morphine via dopamine. An explanation of the latter result is that the dopa fed fails to penetrate to the site of the appropriate transaminase in this plant. 

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The papaver alkaloid Narcotoline (265) can be converted into the yellow colored Cotarnoline (267) on hydrolysis which adopts a zwitterionic ground state (56MI1, 57MI1) (Scheme 87). The corresponding dihydro derivative was also identified in nature. The UV spectrum of the zwitterionic Tarkonine (268), which forms red crystals from acetone, is shifted bathochromically in comparison to the chloride. Tarkonine is a very weak base (pA b = 9.58), which is well in accord with the formation of an inner salt, and Cotarnoline (267) is a stronger base than Tarkonine (268) (pA b = 9.15). The pK values are larger than 13 (66MI3). The methylated derivative of Narcotoline is Narcotine (266). 

Although the ion pair HPLC for emetine and cephaeline using sodium 1 -heptanesulfonate as a counter ion and methanol for a mobile phase was previously reported [20], compounds other than emetine and cephaeline in the leaf extract of ipecac were not well-separated. Therefore, a different type of ODS column, TSK gel ODS-120A column (4.6 mm i.d. x 250 mm, TOSOH Co., Japan) was selected because it previously provided a good separation of the tropane alkaloids [21-23] and the Papaver alkaloids [24]. 

RETENTION OF SOME PAPAVER ALKALOIDS AND RELATIVE DETECTOR RESPONSES3 54... 

The number of alkaloids based on the 1-substituted tetrahydroisoquinoline skeleton is legion and the structural variation which this skeleton affords, particularly in the case of 1-benzylisoquinolines, is rich. The 1-substituted isoquinoline skeleton of each kind probably arises by the common step of condensing a j8-arylethylamine with an appropriate carbonyl compound, for which the Pictet-Spengler reaction provides an analogy. In some cases the participation of a carbonyl compound is established but in others it is still speculative. Recently progress has been made in this area in studies on the biosynthesis of lophocerine, the Papaver alkaloids, and to some extent the cryptostyline alkaloids with their novel 1-phenylisoquinoline structures. 

Papaver Alkaloids.—It is well established that the 1-benzylisoquinoline skeleton [as (70)] found in the alkaloids of Papaver species, amongst many others, arises from two molecules of tyrosine, with dopamine serving as an intermediate for one half of the skeleton (see Scheme 11). In spite of the extensive and fruitful studies on H. Rosenberg and S. J. Stohs, Phytochemistry, 1974,13,1861. 

Studies of the isolation and the constitution of alkaloids of the Papaveraceae family have led to the investigation of the effect of various types of drying on the quantity of alkaloids in the leaves of Macleaya (Bocconia) microcarpa (52), the stability of some Papaver alkaloids (in different solvents) to sunlight (294), the accumulation of alkaloids in the latex of the Papaveraceae (243), the site of origin of the alkaloids in the studied plants (295, 296), the different geographical zones (297, 298), the time after flowering (299), and the seasonal variations in the content of the individual groups of alkaloids, particularly in P. somniferum (300). 

For the spectral data and physical constants of many Papaver alkaloids see Holubek s Atlas, Vols. I-VIII (1965-1973) (330). 

From a chemical structural viewpoint, they may be divided into several groups. The alkaloids in which the aliphatic carbon atom of the benzyl group is connected only to positions 1 and 1 comprise the opiiun bases papaverine, xanthaline, laudanosine, and various phenolic derivatives of these tetramethoxy compounds, as well as the Cocculus base coclaurine, the Papaver alkaloid armepavine, the Mahonia base neprotine, and a constituent of Corydalis, corpaverine. This chapter is devoted to a discussion of this group. 

Other methods employing reversed phase p Bondapak Cig column with UV detector at 254 nm or twin mobile phases are generally not so efficient for quantitation of Papaver alkaloids. 

With the growing demand for rapid chemical analysis to quantitate alkaloids, an array of chemical methods, each an improvement over the past, has been developed for five major opium alkaloids occurring in measurable quantity in Papaver. Among these, the reversed phase HPLC with a single run and with minimal sample preparation time is an easy and reproducible method for routine analysis of Papaver alkaloids. 

Although a large variety of compounds can reduce tris(2,2 -bipyridyl)ruthenium(III), only certain species (e.g., aliphatic amines, amino acids, NADH, some alkaloids, aminoglycoside or tetracycline antibiotics, and the oxalate ion) will produce the characteristic orange luminescence with this reagent. Subtle differences in chemical structure can have a dramatic effect on chemiluminescence intensity. This is exemplified by the determination of the papaver alkaloid codeine (11) compared to structurally similar morphine (12). At pH 6.8, codeine can be determined down to a concentration of 10 mol 1 whereas morphine produces a chemiluminescent response equivalent to that of the blank. In many applications this degree of selectivity is most desirable. 

Papaveraceae alkaloids, Papaver alkaloids, poppy alkaloids a group of Benzylisoquinoline alkaloids (see), oceurring especially in species of poppy (Papaver). They include the important Opium alkaloids (see). 

The discovery of morphine marked the begiiming of organic alkaloid chemistry, and the further analysis of papaver alkaloids proceeded quickly. There are over 50 papaver alkaloids in all, nitrogenous organic bases, but they can be divided into two major classes of papaver alkaloids - the isoquinolines and phenanthrenes. The phenanthrenes are the most medically significant, with morphine, codeine, and thebaine acting as important opioid agonists. 

The primary modem use of the papaver alkaloids is for analgesia. Morphine is considered the classic example of a high-potency opioid. Opiates are medications derived from the poppy opioids, the more general term, refer to medications that work at the opioid receptors. All opiates are therefore opioids, but not all opioids are opiates. 

Figure 6.28. N-oxides of Papaver alkaloids. Thebaine N-oxide, major isomer (1) minor isomer (2) codeine A -oxide. major isomer (3) minor isomer (4) morphine N-oxide, major isomer (5). 1 and 2 were isolated from P. bracteatum (thebaine-rich strain), 3, 4, and 5 were isolated from P. somniferum (Halle strain), courtesy of J. D. Phillipson and Pergamon Press, Ltd., copyright 1976.

Scott AI, Lee SL, Hirata T, Culver MG (1978a) Biosynthesis of plant products using cell free systems from tissue cultures. Rev. Latinoam Quim 9 131-138 Scott AI, Lee SL, Hirata T (1978b) The early stages of Papaver alkaloid biosynthesis. Cell-free synthesis of benzylisoquinolines. Heterocycles 11 159-163 Shamma M (1972) The isoquinoline alkaloids. Academic, London New York... 

Wilson ML, Coscia CJ (1975) Studies on the early stages of Papaver alkaloid biogenesis. J Am Chem Soc 97 431-432... 

Thureson-Klein A (1970) Observations on the development and fine structure of the articulated laticifers of Papaver somniferum. Ann Bot (London) 34 751-759 White PR (1954) The cultivation of plant and animal cells. Ronald Press, New York Wilson ML, Coscia CJ (1975) Studies on the early stages of Papaver alkaloid biogenesis. J Am Chem Soc 97 431-432... 

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