Alkaloids hydroxylation

It is interesting to note that the occurrence of C-7 oxygenated aporphine alkaloids with the C-6a R configuration is limited to the families Annonaceae, Lauraceae, Magnoliaceae, and Menispermaceae. Aporphine alkaloids oxygenated at both C-4 and C-7 have been found in the Annonaceae, but (-)-stephadiolamine /3-A-oxide (48) is the first known alkaloid hydroxyl-ated at both C-4 and C-7 and having a cis relationship between H-6a and H-7. (-)-O-Acetylsukhodianine is the first known example of a naturally occurring 7-acetoxylated aporphine (30). 

Most significantly, haemanthamine provides a connecting link between the alkaloids hydroxylated in the 5-membered ring (haemanthamine, haemanthidine, haemultine, and crinamine) and the nonhydroxylated alkaloids mentioned earlier in this section. The parent ring system, 5,10b -ethano- 8,9-methylenedioxy-1,2,3,4,4a,5,6,10b-octahydrophen-anthridine (crinane), may be constructed in only two ways, CXCV and CXCVI. These two structures differ only in the manner of C D ring fusion which is tram in the former and cis in the latter. Since a number... 

Anthranilic acid and acetate biosynthesize the simple quinoline alkaloids, which are then prenylated with mevalonic acid at the C-3 position to 3-prenyl-2-quinolone alkaloids (e.g., pterecortine from Ptelea trifoliata and orixine from Orixa japonica). 3-Prenyl-2-quinolone alkaloids are then cyclized to dihydrofuro-or dihydropyranoquinoline alkaloids. Hydroxylation at the C-3 position of dihy-drofuroquinoline alkaloids and subsequent loss of the isopropyl side chain produce the furoquinoline alkaloids (Fig. 5.2.8) dictamnine is a skeletal alkaloid and skimmianine is the most common alkaloid. 

Experimental procedures have been described in which the desired reactions have been carried out either by whole microbial cells or by enzymes (1—3). These involve carbohydrates (qv) (4,5) steroids (qv), sterols, and bile acids (6—11) nonsteroid cycHc compounds (12) ahcycHc and alkane hydroxylations (13—16) alkaloids (7,17,18) various pharmaceuticals (qv) (19—21), including antibiotics (19—24) and miscellaneous natural products (25—27). Reviews of the microbial oxidation of aUphatic and aromatic hydrocarbons (qv) (28), monoterpenes (29,30), pesticides (qv) (31,32), lignin (qv) (33,34), flavors and fragrances (35), and other organic molecules (8,12,36,37) have been pubflshed (see Enzyp applications, industrial Enzyt s in organic synthesis Elavors AND spices). 

Biotransformations are carried out by either whole cells (microbial, plant, or animal) or by isolated enzymes. Both methods have advantages and disadvantages. In general, multistep transformations, such as hydroxylations of steroids, or the synthesis of amino acids, riboflavin, vitamins, and alkaloids that require the presence of several enzymes and cofactors are carried out by whole cells. Simple one- or two-step transformations, on the other hand, are usually carried out by isolated enzymes. Compared to fermentations, enzymatic reactions have a number of advantages including simple instmmentation reduced side reactions, easy control, and product isolation. 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Nonalcoholic and strong drinks (tea, wine) contain a number of aromatic substances with amino and hydroxyl groups (first of all, there are polyphenolic compounds and alkaloids) which defined sort and quality of drinks. 

Pellotine, C13H19O3N, erystallises from aleohol in tablets, m.p. 111-2°. The hydroehloride, B. HCl, forms rhombie prisms the auriehloride melts at 147-8° and the pierate at 166-8°. The alkaloid eontains a methylimino group, two methoxyl groups and a phenolie hydroxyl group. The methiodide, B. CHgl. HjO, crystallises in small prisms, m.p. 198-9°. 

The position of the free hydroxyl group in these two alkaloids is either C or C , since Spath has shown that the OiV-diacetyl derivative of -5-hydroxy-3 4-dimethoxyphenylethylamine, when heated in toluene solution with phosphoric oxide, yields a product which must be either 6-acetoxy-7 8-dimethoxy-, or 8-acetoxy-6 7-dimethoxy-l-methyl-3 4-dihydrowoquinoline. On reduction with tin and hydrochloric acid t is converted into anhalonidine, which must therefore be 6-hydroxy-7 8-dimethoxy- (or 8-hydroxy-6 7-dimethoxy-)-l-methyl-l 2 3 4-tetrahydrofsoquinoline. Similarly the methiodide of the acetoxy-com-pound on reduction yields, by loss of acetic acid and addition of two hydrogen atoms, pellotine, proving the latter to be A -methylanhalonidine. The position of the free hydroxyl group was finally shown by Spath to... 

Codeine, C18H21O3N. This alkaloid was isolated from opium by Robiquet in 1833. It occurs in opium to the extent of 0-1 to 3 per cent., and is isolated therefrom as the hydrochloride along with morphine hydrochloride in the first stage of Gregory s process. It is a methyl ether of morphine and is usually made from the latter by methylation, for which there are numerous patents. An extensive series of ethers of morphine and its isomerides, including ethers of the alcoholic hydroxyl group (Aeterocodeines) has been prepared by Faris and SmaU. ... 

The three alkaloids concerned, morphine, codeine and thebaine, all behave as tertiary bases. Morphine contains two hydroxyl groups of which one is phenolic and the other a secondary alcohol group. On methylation of the phenolic hydroxyl codeine results. On oxidation, codeine is transformed into codeinone by conversion of the secondary alcohol group into a carbonyl group, and when thebaine is boiled with A-sulphuric acid for a few minutes, it is hydrolysed into codeinone and methyl sulphate, and in other ways thebaine has been shown to contain two methoxyl groups. That the relationship between the three alkaloids is close may be illustrated by the following slightly extended formula —... 

It is assumed that these alkaloids are formed by junetion at C that is, in the par -position to the hydroxyl group in ring I, beeause (1) the diazo-reaction in the two bimoleeular alkaloids is much less intense than with sinomenine, and (2) neither of the monobromosinomenines, in which the bromine atom is assumed to be at C, can be oxidised to a bimolecular... 

Oripavine, CigHjiOgN (Item 56 list, p. 173). Tliis alkaloid was isolated by extracting the dried leaves, moistened with ammonia, with ethylene dichloride. It crystallises from alcohol in colourless needles, has m.p. 200-1°, [a]o — 211-8° (CHCI3), yields a hydrochloride, m.p. 244-5°, and a methiodide, m.p. 207-8°. The base is soluble in sodium hydroxide solution, giving a crystalline sodium derivative. It contains one hydroxyl, one methoxyl and one methylimiiio group. 

Floripavidine, CjjHjgOjN. This occurs in the crude mixture of non-phenolic bases, and is separated from fioribundine by repeated crystallisation of the mixed hydrochlorides from water. The base crystallises from alcohol in prisms, has m.p. 241-2°, and [a]n — 156-25° (MeOH) the hydrochloride, m.p. 209-10°, hydriodide, and methiodide, m.p. 228-30°, were prepared. The alkaloid contains no hydroxyl group (Zerewitinoff), but a methoxyl, a dioxymethylene, and a methylimino group are present. 

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