Morphines, total synthesis

Keywords Chiral synthesis Codeine Morphine Total synthesis... 

Although morphine has been prepared by total synthesis, the complexity of the molecule makes such an approach unattractive on a commercial scale. The drug in fact is obtained by fractionation of opium obtained from the poppy morphine in turn is used as starting material for various derivatives. If it were not for the importance of these drugs in the clinic, some progress might have been made in eradication of the plant. 

Table 4.19 summarizes the metrics parameters for 10 total synthesis plans to morphine. Figure 4.46 shows a synthesis map of various starting materials for some of the better performing plans to this target. The Rice plan remains the most material efficient plan... 

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

Hong, C.Y, Kado, N., Overman, L.E. (1993) Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (—)- and (-f)-Dihydrocodeinone and (—)- and (-F)-Morphine. Journal of the American Chemical Society, 115, 11028-11029. 

Ogasawara and coworkers have also published a complete series of threefold anionic domino reactions, all of which are based on an initial retro-aldol process. For instance, starting from chiral bicyclo[3.2.1]octenone 2-437, a formal total synthesis of (-)-morphine (2-445) [233] has been successfully performed (Scheme 2.103) [234]. Transformation of 2-437 into the substrate 2-488, necessary for the domino reaction, was achieved in seven linear steps. The domino process was then initiated by simply refluxing a solution of 2-438 in benzene in the presence of ethy-... 

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

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. 

Examples of such an approach are found in the synthesis of strychnine [22] and morphine [23], labours which have been said to bear resemblance to Sysiphus s torment [24], since they involve linear sequences of more than 25 steps. However, the most illustrative example is found, perhaps, in the synthesis of penicillin (10 ). in the course of which the penicilloic acid derivative JJL was synthesised, though through a laborious and lenghty route. Because this intermediate was easily available from natural penicillin, it was convenient to resort to such a method of degradation in order to make it available in sufficient quantities for studying the last step -that requires the formation of a P-lactam- and thus accomplishing successfully the total synthesis [25]. 

Morphinans came about from early attempts at the total synthesis of morphine by a german chemist named R. Grew. Containing the complete carbon-nitrogen skeleton of morphine they are the closest chemical relatives which have been obtained by total synthesis. 

The development of schemes for the total synthesis of the carbon skeleton of morphine revealed that the fused furan ring was not necessary for biological activity. More recently it has been found that substitution of a pyran ring for the terminal ali cyclic is also consistent with... 

The first total synthesis of morphine [115] involves hydration of a tetracyclic intermediate. The attack of water from the more hindered face of the double bond could hardly have been predicted. However, the donor nitrogen atom of the molecule may have been responsible for the protonation at C-7 in favor of C-6 via a polarity alternation mechanism. 

The structure of morphine was first determined in 1925 by Sir Robert Robinson (1886— 1975) and John Masson Gulland (1898-1947). A total synthesis of morphine was achieved in 1952 at the University of Rochester by Marshall D. Gates (1915—2003) and his co-worker Gilg Tschudi. Since its first synthesis, a number of other processes have been used to synthesize morphine in the laboratory, but none of these is economically viable. Therefore morphine continues to be obtained through biosynthesis from poppy plants. 

The group of organic bases known as alkaloids (B-81MI10603) includes the active principles of some of the oldest remedies used in folk medicine, and many of them still have important uses. The manufacture of such compounds by total synthesis is usually unattractive, but some, for example morphine, undergo chemical manipulation to give drugs with improved properties, and some have served as models for simpler synthetic compounds. 

The discovery of morphine s analgesic activity in 1806 started a long series of studies of the alkaloids from the opium poppy, including morphine s first correctly postulated structure in 1925 and its total synthesis in 1952. The depressant action of the morphine group is the most useful... 

In the total synthesis of (-)-morphine, the pivotal tetracyclic intermediate was generated as depicted below. Thus, this core structure was synthesized by reduction of the enone to afford an allylic alcohol, which was then briefly exposed to BBr, to give the desired skeleton in 64% yield <02JA12416>. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

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. 

Kametani<23) in 1977 reviewed the total synthesis of isoquinoline alkaloids, including alkaloids of the morphine series. 

During the total synthesis of ( )3-deoxy-7,8-dihydromorphinone (72), a morphine derivative lacking aromatic ring substitution,<166,167) two novel aromatic ring substituted analogs were isolated as intermediates, 4,5-epoxy-2-hydroxy-N-methylmorphinan-6-one (71, R = H) and a related 1-bromo derivative (70), together with their respective methyl ethers. No biological data on these were reported. 

Evans and Mitch( 101 elaborated this synthesis to afford a general approach to morphinans and to include a total synthesis of ( )-morphine (Scheme 3.7). The diastereomerically pure aziridinium salt, 43, was prepared as illustrated and converted to the aldehyde (44) in 95% yield simply by dissolving in anhydrous DMSO at ambient temperature (Kornblum oxidation). Lewis acid catalyzed ring closure occurred in high yield (80%) to the isomorphinan-10-ol... 

A 10-hydroxy derivative of an isomorphinan was isolated during a total synthesis of ( )-morphine. 101)... 

With the assumption that reticulines are also precursors in mammalian synthesis of morphine, it was challenging to investigate whether they could be produced by enzymatic reactions similar to those utilized in benzylisoquinoline-producing plants (274). This plan focused attention on reactions controlled by the enzyme catechol 0-methyltransferase (COMT), using 5-adenosyl-L-methionine (SAM) for the methylation reaction. Mammalian COMT is present in mammalian tissues, particularly the liver, and an enzyme preparation from rat liver was used for the experiments. It was found that (S)-norcoclaurine, which is the first isoquinoline produced in benzylisoquinoline-producing plants, was similarly O-methylated in vitro by SAM in the presence of COMT, and a reverse proportion of methylated products was obtained with the (/ )-enantiomer (277). Similar 0-methylation of (5)-4 -demethylreticuline (3 -hydroxy-N-methylcoclaurine), prepared by total synthesis (162), however, afforded almost exclusively (5)-orientaline, with a methoxy group at C-3 and not at C-4 as in (5)-reticuline (Fig. 37) (762). 

Most phenanthrene alkaloids are easily synthesized by degradation of the corresponding aporphines. Many phenanthrenes were first prepared as aporphine derivatives for characterization or in the course of structural studies, and only later were they found in nature. Although the ready availability of most aporphines from natural sources makes this strategy very simple, it often does not constitute a formal total synthesis, and some approaches from simpler compounds have been published (29,105). Degradation of the morphine alkaloid thebaine (151) gives rise to a number of unnatural phenanthrenes (93,94,102, 104,113). 

---