The Isoquinoline Alkaloids

A Course in Organic Chemistry

K. W. Bentley, Robert Robinson

• Publisher: Pergamon
• Year: 2014
• Print ISBN:
  9780080106595
• eBook ISBN:
  9781483152233
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

The Isoquinoline Alkaloids: A Course in Organic Chemistry is a description of the chemical structures of alkaloids. The book discusses the processes for degradation of isoquinoline alkaloids to recognizable compounds such as oxidation and exhaustive methylation. The associated processes in removing the nitrogen atom are also explained. The commonly used Hofmann process and the interpretation of its result are evaluated in the degradation of alkaloids. The cactus ""pellote"" used by Mexican Indians to induce hallucinatory experiences is examined. The active ingredient is identified as mescaline; its composition is analyzed to contain one primary amino and three methoxyl groups. The different syntheses made to duplicate mescaline are described. The structures of morphine, codeine, and thebain, which are all alkaloids of opium, are also analyzed. Another example of a principal alkaloid found in a plant is emetine found in the root of the ipecac. The pharmacological bases of emetine are isolated and noted as emetamine, cephaeline, psychotrine, and O-methylpsychotrine. The text also traces many other structural relationships within the subgroups of the isoquinoline alkaloids. Chemists, students and professors in organic chemistry, and laboratory technicians whose work is related to pharmacology will find this book informative.

CHAPTER 1

Introduction

Publisher Summary

This chapter presents an introduction to the alkaloids of the isoquinoline group. The chemical structures of the alkaloids have been deduced by the classical methods of organic chemistry, which involve the degradation of the bases to simpler fragments, the structures of which are more readily determined. In these methods, an assembly of a satisfactory molecular formula from these fragments is used from the knowledge of nature of the reactions. All the alkaloids of the isoquinoline group contain aromatic nuclei bearing as the substituents methoxyl, methylenedioxy, hydroxyl, or aryloxy groups and saturated or unsaturated carbon side chains. Oxidation of such compounds with alkaline permanganate results in the destruction of phenolic nuclei and the carbon side chains, the products being methoxy, aryloxy, or methylenedioxy-substituted aromatic acids of generally easily determined structures, in which the positions of the carboxyl groups indicate the positions of the carbon side chains of the parent alkaloids.

FOR many centuries opium, the dried latex exuded from the cut seed capsule of the opium poppy, Papaver somniferum, has been greatly valued on account of its ability to alleviate pain and also to induce a euphoric state when eaten, or smoked. One particular chemical substance is responsible for both of these effects of opium, although the material contains a number of other compounds as well. Morphine, the euphoric and analgesic agent, was first isolated in 1805, and was the first nitrogenous base to be isolated from living sources. Although of considerable structural complexity, the complete constitution of the base was not elucidated until 1925, morphine belongs to a large general class of natural bases, to which the term alkaloid is applied, and to a smaller though still large subgroup all based on the isoquinoline structural unit.

The alkaloids of the isoquinoline group may be further subdivided into families, all of which are clearly related structurally and by their mode of formation in the plant. In this work an attempt has been made to order the presentation of each sub-group on the basis of a rational relationship to those first described. The account is not intended to be exhaustive, rather it is intended to indicate the methods used in the elucidation of the structures of new organic compounds, and for this purpose representative members of each sub-group of alkaloids are selected for discussion and the relationships of other members of the group to the selected compound are given. In the case of the alkaloids of the morphine group where great interest centres on the complex rearrangements that the alkaloids may be made to undergo, the chemical properties of the compounds are discussed at greater length. The rest of this chapter is devoted to a discussion of a few of the most important chemical processes used in the degradative studies necessary for the elucidation of the structures of the alkaloids.

The chemical structures of the alkaloids have been deduced by the classical methods of organic chemistry, namely the degradation of the bases to simpler fragments, the structures of which are more readily determined and the assembly of a satisfactory molecular formula from these fragments from a knowledge of the nature of the reactions used. In these days when the structures of complex natural products may be elucidated with scarcely a reaction done at the bench, by the application of the modern tools of ultraviolet, infrared, nuclear magnetic resonance and mass spectrometry, and X-ray crystallography greatly facilitated by modern high-speed computing techniques, it is easy to forget or belittle the impeccable work done with poor (by present standards) equipment by the pioneers in this field. It should be remembered that even catalytic reduction was only introduced as a new technique in the early 1920’s, at a time when the major researches of Hesse, Pschorr, Knorr, Wieland and Perkin had been completed and Robinson had been working for almost twenty years. While the chemist should never scorn new methods as if there was an inherent virtue in clinging to the more lengthy methods of the past, it should be remembered that the modern techniques of structure elucidation have only become of value because they have been built up on the massive foundation of knowledge gained so impressively by the classical techniques. The final proof of the correctness of any structure deduced from a complex of data, however, remains the total unambiguous synthesis of material of that structure and comparison of the product with material from natural sources, and this can only be done at the bench by drawing on the whole accumulated store of chemical knowledge and theory.

In the work described in the following chapters it will be found that two general processes have been repeatedly utilised for the degradation of alkaloids of the isoquinoline group to recognisable compounds, namely oxidation and exhaustive methylation and related processes for the removal of the nitrogen atom, and some space is here devoted to an explanation of these processes.

Oxidation

All of the alkaloids of the isoquinoline group contain aromatic nuclei bearing as substituents methoxyl, methylenedioxy, hydroxy or aryloxy groups and saturated or unsaturated carbon side-chains. Oxidation of such compounds with alkaline permanganate results in the destruction only of phenolic nuclei and the carbon side-chains, the products being methoxy, aryloxy or methylenedioxy-substituted aromatic acids of generally easily determined structures, in which the positions of the carboxyl groups indicate the positions of the carbon side-chains of the parent alkaloids since they are the residue of such chains. For this purpose a phenolic nucleus linked directly to a non-phenolic aromatic ring is regarded as a side-chain since the phenol is oxidised away to a carboxyl group; a phenolic nucleus not directly linked to another aromatic ring leaves no residue.

It is usually more instructive to methylate a phenol to its O- methyl ether before oxidation since the aromatic nucleus then survives and can be isolated as an acid from the products of the reaction. Still more instructive is oxidation after O-ethylation of the phenol since the position of the phenolic hydroxyl group in the original base, frequently in the presence of one or more OMe groups, can be deduced from the position of the ethoxyl group in the acid or acids obtained during oxidation.

Examples of these processes are given in formulae (1)–(12). Sometimes intermediate oxidation products are obtained, e.g. the amide corydaldine (2) may be isolated from the oxidation of tetra-hydropalmatine (1) and separately oxidised to m-hemipinic acid (4), and the restriction of the amount of permanganate used in the oxidation of berberine C₂₀H₁₉O₅N to considerably less than is

required for complete destruction to stable end-products leads to products of composition C₂₀H₁₇O₅N, C₂₀H₁₇O₆N, C₂₀H₁₇O₇N, C₂₀H₁₇O₈N and C₂₀H₁₉O₉N from the natures ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Inside Front Cover
• Copyright
• Preface
• Chapter 1: Introduction
• Chapter 2: β-Phenylethylamines and Simple Isoquinolines
• Chapter 3: Benzylisoquinolines
• Chapter 4: Bisbenzylisoquinolines
• Chapter 5: Cularine
• Chapter 6: The Aporphines
• Chapter 7: The Morphine Alkaloids
• Chapter 8: The Berberine and Tetrahydroberberine Alkaloids
• Chapter 9: Alkaloids Related to Cryptopine
• Chapter 10: Rhoeadine
• Chapter 11: The Phthalideisoquinolines
• Chapter 12: The α-Naphthaphenanthridines
• Chapter 13: Emetine and Related Compounds
• Chapter 14: The Biogenesis of the Isoquinoline Alkaloids
• Index