Basic techniques

Basic techniques of alkaloid modification are grounded on the following reactions: (1) the Schiff formation and Mannich reaction, (2) Aldol and Claisen Reactions, (3) Wagner-Meerwein Rearragements, (4) Nucleophilic substitution, (5) Electrophilic addition, (6) Decarboxylation, (7) the Transamination reaction, (8) Enzymatic reactions (oxidation, reduction and dehydrogenation), (9) Elimination reactions, (10) Coupling reactions, (11) Reactions with reagents. The Schiff formation is a reaction in the formation of C—N bonds, with a nucleophilic addition followed by the elimination of water and the given imine (Schiff base). The Mannich reaction is also connected with C—N bonds formation. Meanwhile, the protonated form of imine reacts with the nucleophilic addition.

The Aldol and Claisen reactions are connected with C—C bond formation. Wagner-Meerwein rearrangements are related to the generation of more stable carbocations. Nucleophilic substitution is connected with SAM, which produces positively charged sulphur and promotes nucleophilic substitution (SN2). Elec-trophilic addition is connected with the C5 isoprene unit in the form of DMAPP, which can ionize to generate a resonance-stabilized allylic carbocation and can then react with IPP. Decarboxylation is the reduction of carbon, while transamination is the exchange within the amino group of an amino acid to a keto acid (the introduction or removal of nitrogen). Enzymatic reactions change the oxidation and hydroxylation state of the molecule through the activity of enzymes. Elimination reactions are connected to exchange within hydroxyl, amino or mercapto groups. Coupling reactions are connected with the unification of two or more phenolic systems in a process readily rationalized by means of free radical reactions. The solvent reaction of NH- and CH-acids with alkaloid can produce modification. Some other reagents and some solvent-stabilised Pt and Pd nanoparticles can accelerate and modify alkaloids, as for example in the case of Cinchona alkaloids304.

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-O-methyl ether of morphine, the mono-O-methylation occurs in the acidic phenolic hydroxyl. Pholcodine is obtained by modification of morphine through alkylation with N-(chloroethyl)morpholine. Moreover, dihydrocodeine, hydro-morphone and heroine are also obtained from morphine through modifications.

Modification of alkaloids is very important for their use in medicine306'307'397. In particular, modification through biological processes and bioengineering may lead to a new generation of compounds for medical applications.

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