American Journal of Chemistry

p-ISSN: 2165-8749    e-ISSN: 2165-8781

2022;  12(1): 18-21

doi:10.5923/j.chemistry.20221201.03

Received: Mar. 1, 2022; Accepted: Mar. 16, 2022; Published: Mar. 24, 2022

 

The Mechanism of the Oxido-degradation of the Cinchona Alkaloids

Francisco Sánchez-Viesca, Reina Gómez

Organic Chemistry Department, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City (CDMX), Mexico

Correspondence to: Francisco Sánchez-Viesca, Organic Chemistry Department, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City (CDMX), Mexico.

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Copyright © 2022 The Author(s). Published by Scientific & Academic Publishing.

This work is licensed under the Creative Commons Attribution International License (CC BY).
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Abstract

The cinchona alkaloids, so important for malaria treatment, have been studied from different points of view such as chemical structure, biological properties and synthesis. However the reaction mechanisms involved in several oxidative degradations have not been advanced. In this communication we provide the electron flow that takes place in the reaction series with different oxidizers and substrates. The chemical deportment of both reagent and substrate has been taken into account: the dual function of chromic acid, that is, as nucleophile (chromate anion) and as electrophile (protonated chromium trioxide), as well as the successive reduction of Mn(VII) to Mn(V) and Mn(III), yielding finally Mn(IV) in manganese dioxide; also the reactivity of α-diketones to form a hydrate, a key intermediate for C─C fission to give a couple of carboxylic acids. The oxido-degradation by means of acidic potassium permanganate of the vinyl and carboxymethyl groups, present in quinuclidine and piperidine rings, has been traced to the end.

Keywords: Cinchonine, Cinchoninic acid, Cinchotenine, Meroquinene, Piperidine, Quinuclidine

Cite this paper: Francisco Sánchez-Viesca, Reina Gómez, The Mechanism of the Oxido-degradation of the Cinchona Alkaloids, American Journal of Chemistry, Vol. 12 No. 1, 2022, pp. 18-21. doi: 10.5923/j.chemistry.20221201.03.

Article Outline

1. Introduction
2. Antecedents
3. Discussion
4. Conclusions
ACKNOWLEDGEMENTS

1. Introduction

Malaria is caused by three species of protozoa, Plasmodium vivax, tertian parasite, Plasmodium malaria, quartan parasite, and Plasmodium falciparum, malignant tertian malaria, frequently results in fatalities unless a suitable drug is administered properly.
The natural cinchona alkaloids have antimalaria activity, quinine and cinchonine are found in Cinchona officinalis. Cinchonine is more efficient than quinine, it lacks a methoxy group present in quinine. One of the best sources of cinchonine is Cinchona micrantha bark.
Although the structures of these compounds and the degradation products are known, the mechanism of the oxidations carried out has not been advanced. In this communication we provide the electron flow in the reaction series that occurs during different oxido-degradation processes.
This paper is a follow up of our studies on reaction mechanism [1-5].

2. Antecedents

The nomenclature of the cinchona alkaloids is based in the ruban structure, Figure 1, from Rubiaceae [6], since Cinchona is a genus in that family.
Figure 1. Ruban and cinchonine structures
Cinchonine is 3-vinyl-9-rubanol, and quinine has an additional 6’-methoxyl. The alkaloidal molecule is composed of two portions, the quinoline ring and the quinuclidine nucleous, generally called the second half of the molecule. The two portions are connected by an alcoholic grouping. The presence of this secondary alcohol is essential.
The formula of cupreine is the same as for quinine except for the replacement of a methoxy by a hydroxy group. Hydrocuprein (ethyl for vinyl) has considerable value as an antimalarial [7].
There is a study on the response of Plasmodium falciparum to the main cinchona alkaloids [8], and an interesting communication on the therapeutics of the cinchona alkaloids [9].
By moderate oxidation of cinchonine with chromic acid a ketone, cinchoninone is produced [10], 3 vinyl-9-rubanone. Further oxidation with chromic and sulphuric acids [11] gives cinchoninic acid (quinoline-4-carboxylic acid) and meroquinene which is also an acid (3-vinyl-piperidin-4-yl-acetic acid), Figure 2.
Figure 2. Cinchoninic acid and meroquinene
When meroquinene is oxidized with an ice-cold mixture of sulphuric acid and potassium permanganate it gives formic acid plus cincholoiponic acid [12], the latter being a dicarboxylic acid (3-carboxypiperidin-4-yl-acetic acid).
The formation of formic acid shows the existence of a vinyl group in meroquinene. This was confirmed by the formation of formaldehyde on ozonolysis of meroquinene [13].
Cincholoiponic acid on further oxidation with KMnO4 yields loiponic acid, another dicarboxylic acid [14], piperidin-3,4-dicarboxylic acid, Figure 3.
Figure 3. Cincholoiponic acid and loiponic acid
Cinchotenine is produced when cinchonine is treated at ordinary temperatures with dilute permanganate [15]. This oxidation product contains a hydroxyl and a carboxyl group [16], (3-carboxy-9-rubanol).
When cinchonine is warmed with acetic acid and phosphoric acid it is converted into an isomeric compound cinchotoxine containing a ketone with concomitant ring opening of the quinuclidine nucleous, remaining a substituted piperidine ring. That is 3-(3-vinylpiperidin-4-yl)- 1-(quinolin-4-yl)propan-1-one, Figure 4. This hydramine fission takes place in compounds carrying a hydroxyl group and an amino group in vicinal carbon atoms [17].
Figure 4. Cinchotoxine (Cinchonicine)

3. Discussion

The oxidative degradation of cinchonine to cinchoninic acid and meroquinene goes through the first oxidation product, cinchoninone. The enolic form of this ketone reacts with protonated chromic trioxide, this electrophile coming from acid catalysed dehydration of chromic acid.
Acid hydrolysis of the organometallic intermediate yields the reduced H2CrO3 with Cr(IV) and a reactive carbinol-amine which forms a diketone and a secondary amine via ring fission, Figure 5.
Figure 5. From cinchoninone to the hydrated diketone after quinuclidine ring opening
After hydration of the aliphatic keto group to a geminal diol, a chromate anion adds to the protonated aromatic ketone (nucleophilic addition). Protonation of the chromic ester gives rise to a concerted mechanism, resulting H2CrO3 and two carboxylic acids are formed: cinchoninic acid and meroquinene, Figure 6.
Figure 6. Formation of H2CrO3, cichoninic acid and meroquinene
Ice cold oxidation of meroquinene with potassium permanganate and sulphuric acid gives formic acid and 3-carboxypiperidin-4-yl-acetic acid. Permanganic acid forms a cyclic ester with the vinyl group. The double bond disappears and manganese(VII) is reduced to manganese(V).
In absence of alkaline medium for hydrolysis to the diol, there is an oxidative cleavage via a concerted mechanism with reduction to manganese(III), C─C fission and formation of two aldehydes (oxygen transfer) whose oxidation affords formic acid and cincholoiponic acid, Figure 7. Cf. other cleavages [18].
Figure 7. Oxidation of the vinyl group in meroquinene to cincholoiponic acid
Reaction between the intermediates HMnO2 and HMnO3, with Mn(III) and and Mn(V), respectively, gives rise to two molecules of manganese dioxide with Mn(IV), as shown in Figure 8.
Figure 8. Formation of manganese dioxide from Mn(III) and Mn(V) intermediates
This equalization reaction, inverse to disproportionation [19] explains the formation of MnO2, as was observed [20], and shows d3 configuration as indicated for MnO2, [21].
Another permanganate oxidation transforms the –CH2-COOH group into carboxyl via protonated acid. There is reaction of an oxonium ion with permanganic acid, followed by HMnO3 elimination, and formation of carbonic acid and a primary carbonium ion. The latter reacts with water and the alcohol is oxidized to the aldehyde and to carboxyl, Figure 9.
Figure 9. First steps of the degradation of cincholoiponic acid to loiponic acid via elimination of carbonic acid
When cinchonine is oxidized with potassium permanganate cinchotenine is obtained, as mentioned in ‘Antecedents’.

4. Conclusions

The oxido-degradation of cinchonine by means of chromic acid goes through cinchoninone. An organometallic intermediate is formed via enolization and acid hydrolysis yields an unstable carbinolamine. A vicinal diketone is formed with concomitant ring fission of the quinuclidine moiety The aliphatic ketone is hydrated and the aromatic ketone adds a molecule of chromic acid. Protonation of the chromic ester gives raise a concerted mechanism affording cinchoninic acid and meroquinene.
KMnO4/H2SO4 oxidation of meroquinene in two experimental steps forms cincholoiponic and loiponic acids. The first acid is produced by interaction with a vinyl group: a cyclic Mn(V) intermediate is cleaved by reduction to Mn(III) and C─C fission. Two aldehydes are produced whose further oxidation gives cincholoiponic acid and formic acid.
Loiponic acid results by shortening of the carboxymethyl group to carboxyl. Formation of an oxonium ion permits reaction with permanganic acid. There is elimination of HMnO3 and carbonic acid, a primary carbocation remains whose reaction with water and two further oxidations affords a carboxyl.
This way the oxido degradations of cinchonine, representative cinchona alkaloid, have been studied.

ACKNOWLEDGEMENTS

Thanks are given to Martha Berros for support.

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