Phenolic alkaloids, alkylation with

The above mentioned reactions are widely used in alkaloid modification. A good example of alkaloid modifications for clinical curation purposes are opioides. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts. This is one reason why it is produced synthetically from morphine by modification. As codeine is the 3-0-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with A-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications. 

N-Methylation of secondary amines is usually accomplished either with CH20/HC02H (Leuckart/Clarke-Eschweiler reaction) or with CH20 followed by NaBH4 reduction. Methyl iodide treatment of secondary or tertiary bisben-zylisoquinoline alkaloids leads ultimately to the bis quaternary salts, and, in the presence of base, phenolic alkaloids are also O-alkylated. For example, lin-doldhamine (165) on treatment with ethyl bromide in 0.5 N ethanolic KOH gave the N,N,0,0,0-pentaethy 1 derivative (108, Section II,C,56) daurisoline was similarly permethylated with Mel and base (68, Section II,C,19). 

Phenolic methyl ethers were usually prepared by treatment of the alkaloid with dimethyl sulfate and sodium hydroxide or with diazomethane 17). In the first case a side reaction was N-methylation or even cleavage of the lactone (3). In decodine (6) the C-17 OH group was methylated on treatment with ethereal diazomethane. The hindered C-21 OH group was alkylated with methanolic CH2N2 (77). 

Alkaloids. Some of the most difficult oxygen alkylations are those involving the alkaloids, where the alkylation is often carried out to replace the hydrogen of the hydroxyl group in the presence of the tertiary nitrogen of the alkaloid. The best commercial example of the work that has been done with this particular group of compounds is the formation of codeine by the alkylation of the phenolic hydroxyl in morphine. Outlines of this alkylation with quaternary atnmonium compounds are given under Codeine. Such a procedure is also used for theobromine, antipyrine, etc. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

SCHEME 5.13 Asymmetric alkylation of phenols with carbonyl compounds in the presence of chiral Cinchona alkaloids (PH 9-phenanthryl). 

The scope of this F-C hydroxyalkylation of indoles was extended to a range of different carbonyl compounds, giving rise to the desired compounds in high yields (up to 97%) and enantioselechvities (up to 99% ee) in the presence of catalysts 13 and 14 [18]. Catalyst 14 also proved to be highly selective when carrying out the first example of cinchona alkaloid mediated F-C alkylation of phenols with 45 (Scheme 35.8) [58]. Chiral phosphoric acids were also used to mediate F-C alkylation in the presence of ethyl trifluoropyravate [31], trifluoroacetate [59], and trif-luoromethyl ketones [60]. 

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