Morphine biosynthetic route

Barton s approach was truly biomimetic, as it pursued an initially described conversion of labelled reticuline 76 to radioactive morphine 77, thus supporting the proposed biosynthetic route. Figure 10. 

Figure 3 Two established biosynthetic routes, starting from thebaine, to morphine in Papaver somnUerunr. A) the route via neo-pinone and codeinone B) the route via oripavine and morphi-none.

Morphine can be detected in the skin of toads (Fig. 5.51), [86] rats and rabbits, as well as in the hypothalamus and kidneys of cattle and the cerebrospinal fluid of humans. Also breast mUk and cow s mUk contain 200-500 ng/litre of morphine. It is therefore assumed, that aU species employ the same biosynthetic route as the opium poppy. [87] Meinhart H. Zenk (1933-2011) was able to prove that human neuroblastoma and pancreas-carcinoma cells can produce [ 0]-labelled morphine in the presence of 02. [88]... 

A minor alternative route in the morphine biosynthetic pathway involves the demethylation of the 3-methyl group of thebaine by CODM to generate oripavine. The latter is demethylated by T60DM to morphinone, which is ultimately reduced by COR to morphine (Figure 6.20) [102]. 

Figure 6.20 Alternative route in the morphine biosynthetic pathway.

The same group also reported that (S)-[6-0 CH3]coclaurine was incorporated into thebaine, but that (R)-[6-0 CH3]coclaurine was not incorporated, su esting the importance of (S)-reticuline. In addition, it was clarified that when L-[2- C]tyrosine was incorporated, the C-9 and C-16 positions of thebaine were labeled. On the other hand, only the C-16 position of thebaine was labeled when [8- C]tyramine was fed. Two biosynthetic routes from thebaine to morphine, namely, via neopinone, codeinone. 

Or they may be grouped according to the genus of their plant source (morphine and codeine, Section 23-2, are examples of opium alkaloids), or by their physiological effects (antimicrobials, antibiotics, analgesics), or by similarities in the route by which they are synthesized by the organism (biosynthesis). The structural and biosynthetic classifications make the most sense to the chemist and is the organization chosen here. 

The very short and highly efficient biomimetic synthesis of morphine [16, 32] by Rice stands out in terms of overall yield and brevity no subsequent contribution to this area exceeds this milestone achievement. The route follows the biosynthetic pathway and delivers dihydrocodeinone in almost 30% overall yield. 

Morphine Rice, 1980 In 1980, Rice achieved a short and highly efficient synthesis of morphine [144, 147]. The route, outlined in Scheme 12.41, closely follows the biosynthetic pathway and features an electrophilic cyclization reaction as first described by Grewe (233 to 234) as key step for the closure of the B ring [148]. Although this route was published nearly 35 years ago. Rice s synthesis of morphine stiU stands out in respect to brevity and overall efficiency and is considered a milestone achievement in morphine research. 

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