Morphine structural elucidation

Butora G, Hudlicky T (1998) The story of morphine structure elucidation one hundred years of deductive reasoning. In Hudlicky T (ed) Organic synthesis theory and applications. JAI Press, Stamford, p 1... 

G. Butora T. Hudlicky, The Story of Morphine Structure Elucidation One Hundred Years of Deduction Reasoning. In Organic Synthesis Theory and Application T. Hudlicky, Ed. 1998 Vol 4, p 1. 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

Laszlo Szilagyi has been associated all his career with the University of Debrecen (formerly, L. Kossuth University) except for two postdoc periods in Strasbourg (with J.-M. Lehn) and Stanford (with O. Jardetzky). His research interests include application of NMR spectroscopy to the structure elucidation of natural products such as carbohydrates, aminoglycoside and macrolide antibiotics, flavonoids, morphine alkaloids, etc. conformational studies of... 

With Sertiimer s initial isolation of crystalline material,10 the formidable task of structural elucidation arose. Why did this prove so important a labor The answer of course lies in a consummate desire to separate morphine s equally powerful addictive and analgesic properties. With an established structure in hand, surely in rationalized chemical manipulation of the molecule could one curb its less desirable effects. As a result, morphine may not only be responsible for the birth of alkaloid chemistry, but also the study of structure-activity relationship. 

Structural elucidation work on the cancentrine alkaloids has been concisely reviewed. A biogenetic proposal for these unusual morphine-cularine dimers was also advanced. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

The first alkaloids were already isolated in the early 19th century (e.g., morphine, strychnine). Although the methods for identification and structure elucidation have changed a great deal, the methods of isolation used in the last century are still widely used. Originally, pure chemistry, like derivati-zation and degradation, was used to unravel the often complex structures of alkaloids. The structure elucidation of a well-known alkaloid, such as, for example, strychnine, took almost 140 years after its first isolation by Pelletier and Caventou in 1818. 

R. Simantov, S.H. Snyder, Morphine-like peptides in mammalian brain isolation, structure elucidation, and interactions with the opiate receptor, Proc. Nad. Acad. Sci. U.S.A 73 (1976) 2515-2519. 

The sleep-inducing principle of opium was identified in 1806 by the German pharmacist Friedrich Sertiimer. He succeeded in isolating crystalline morphine, which he named mor-phium after the Roman god of sleep Morpheus (Zenk and Jiinger, 2007). It took more than 100 years, until the chemical structure of morphine was elucidated (1924-1925) by Gulland and Robinson. Total synthesis of morphine turned out to be extremely difficult due to its five stereo centers, and it was achieved by Gates and Tschudi (1952). 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

As structure and function are intimely related. X-ray crystallography is the most comprehensive technique, which elucides the three-dimensional structure of the molecule. X-ray crystallographic study provides an accurate and complete chemical characterization of the compound. This method has successfully been used for the analysis of such opioid alkaloids as morphine and has evaluated as very precise and even suitable for the research of novelizations of compounds. The use of this method can also help the estimation of the receptor, because compound structure is important in binding to the receptor. 

Even though pure morphine has been available since 1803, its structure was finally elucidated only in 1925, by Sir Robert Robinson. Detailed structure-activity relationships have been worked out during the many years of study of morphine and its derivatives. 

Some of the most interesting applications of organic structural theory to the elucidation of biosynthetic pathways were stimulated by efforts to formulate mechanisms for the biosynthesis of alkaloids. Conversely, consideration of implied biogenetic relations have occasionally helped structural determination. An important aspect of theories concerning alkaloid biosynthesis has been the assumed role of the aromatic amino acids in their formation. Only limited experimental evidence is available in this area. The incorporation of tyrosine- 8-C into morphine has been shown to be in accordance with a theory for its formation from 3,4-dihydroxyphenyl-alanine plus 3,4-dihydroxyphenylacetaldehyde. A stimulating theory of the biosynthesis of indole alkaloids, based on a condensation between trypt-amine and a rearrangement product of prephenic acid, has recently been published. The unique stereochemistry of C15 of these alkaloids had an important part in the formulation of the theory. Experimental proof of this theory would be valuable for several areas of alkaloid chemistry and biosynthesis. 

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

Alkaline degradation of codeine methiodide affords a-codeimethine [xxi] [185, 285], which can be isomerized by alcoholic alkali to /3-codeimethine [xxn] [187, 286-7], also obtainable by the degradation of neopine [xm] methiodide [271]. The degradation of codeine ethiodide follows a similar course [288]. These bases suffer dehydration and loss of the basic side-chain when heated with acetic anhydride and sodium acetate (when acetylmethylmorphol [xxm] is formed [187, 289-90]), and when subjected to further Hofmann degradation (which leads to methylmorphenol [xxiv] [290-2]). The resulting aromatic phenan-threne derivatives are of considerable importance in the elucidation of the basic structure of the morphine alkaloids and are discussed in detail in Chapter XXVII. 

Nearly a hundred and fifty years have elapsed since the first vegetable alkaloid was discovered, and only recently has the structure proposed for this base in 1925 been vindicated by the total synthesis of the alkaloid. It would seem that the morphine chapter of organic chemistry is now all but closed and that all that remains is the filling in of details but it would be rash to assert this, as one of the most interesting of molecular rearrangements in this field was only fully elucidated five years ago, while yet another received a credible solution only after the completion of the main text of this monograph. The moment seems opportune, however, for the presentation, in one volume, of a comprehensive survey of the chemistry of all the morphine alkaloids. 

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