Thebaine, synthesis

With a morphine biosynthetic gene in hand, we believed we could begin to address the question why only P. somniferum produces morphine, while other Papaver species such as P. rhoeas, P. orientale, and P. bracteatum do not. Unexpectedly, we found that the codeinone reductase transcript was present to some degree in all four species investigated. A review of the literature revealed no alkaloids reported in P. rhoeas for which codeinone reductase should participate in the synthesis. Similarly, P. orientale accumulates the alternate morphine biosynthetic precursor oripavine, but codeinone reductase is not involved in the biosynthesis of oripavine, acting instead after this alkaloid along the biosynthetic pathway to morphine.22 P. bracteatum produces the morphine precursor thebaine as a major alkaloid. As for oripavine in P. orientale, codeinone reductase would act in P. bracteatum after thebaine formation on the pathway to morphine. It appears, therefore, that the reason that P. rhoeas, P. orientale, and P. bracteatum do not produce morphine is not related to the absence of the transcript of the morphine biosynthesis-specific gene codeinone reductase. The expression of codeinone reductase may simply be an evolutionary remnant in these species. 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

For the synthesis of Diels-Alder adducts a morphinan-6,8-diene system, as present in thebaine, is indispensable. Older publications started from thebaine and methyl vinyl ketone (but-3-en-2-one), yielding, after a Grignard reaction with propylmagnesium bromide, etorphine (13), a 6,14-endoethenomorphinan that is over 1000x as active as morphine and is used in veterinary medicine (Scheme 5.10). 

More recent examples of biomimetic synthesis are the syntheses of thebaine [11] and usnic acid [12], as well as strychnine [13], morphine alkaloids [11] [14] and a great number of terpenic compounds [15]. On the other hand, hypothetic prebiotic considerations may also simplify tremendously the synthetic plans. Such is the case, for example, of the work of Eschenmoser on vitamin B12 who, after synthesising it in collaboration with Woodward by a linear sequence of almost fifty steps [16], investigated the prebiotic origen of this complex molecule. The experimental work undertaken in this direction demonstrates that the amount of "external instruction" required for "self-assembling" the different structural elements present in this molecule is surprisingly small. This fact could eventually lead to a very simple synthesis of vitamin Bj2 starting from a-amino nitriles which would involve only a few steps [17]. 

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]. 

Both morphine and codeine are valuable analgesics. Morphine is extracted from opium, the dried latex of the opium poppy, and codeine is usually obtained from morphine by semi-synthesis (see Box 6.2), since the amounts in opium are rather small. Thebaine is a valuable raw material for semi-synthesis of a wide range of morphine-like drugs. 

Tetrydamine, 352 Thalidomide, 296 Thebaine, 318 Theniurn closylate, 99 Theobromine, 456 Theophylline, 464 Thiabendazole, 352, 353 1,2,5-Thiadiazole synthesis,... 

Synthesis (Bentley (Reckitt Sons), 1963 1966 1969 Dorner, 1986, Kleemann et al., 1999 Husbands and Lewis, 2000 Christoph, 2002) condensation of thebaine and but-3-en-2-one yields 7-acetyl-6,14-endoetheno-... 

Synthesis (Bentley (Reckitt Colman), 1963 1966, Bentley (Reckitt Sons) 1969, Dorner, 1986 Kleemann et al., 1999) Starting from thebaine etorphine can be synthesized in a similiar way to buprenorphine (see buprenorphine) (Boehringer, 1912 Ehrhart and Ruschig, 1972 Trauner et al., 1983 Mulzer and Trauner, 1999). 

Synthesis (Krauli (E. Merck), 1925, Juby et al., 1968, Ehrhart and Ruschig 1972) Thebaine is oxidized with hydrogene peroxide to 14-hydroxycodeinone (Bentley 1954, Hauser 1974), which is hydrogenated directly or via its oxime, or its bromination products to oxycodone. The reduction of 14-hydroxycodeinone can also be carried out with sodium hydrosulfite. Alternatively 14-hydroxycodeinone is prepared by oxidation of codeine. 

Thebaine (Figure 6.50) differs structurally from morphine/codeine mainly by its possession of a conjugated diene ring system. It is almost devoid of analgesic activity, but may be used as a morphine antagonist. Its main value is as substrate for the semi-synthesis of other drugs (see below). 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

Morphinans (compactly fused Phe, C6, C5N, C6 and C40 rings) Codeine (opium-derived addictive, analgesic, antitussive, spasmolytic narcotic) morphine (opium-derived addictive, analgesic, antitussive, sedative, spasmolytic narcotic heroin is the semisynthetic diacetate) thebaine (non-analgesic, toxic, convulsant narcotic and semi-synthesis precursor of the anti-addiction drug naltrexone). 

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. 

Morphinans bearing a 6-oxygen function have proved to be a valuable source of precursors for the synthesis of natural opiates/53,55 58 Compounds such as dihydrothebainone (64, R = OMe R = H) may be derived from thebaine, whereas others are totally synthetic/8 ... 

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). 

Since for general clinical use morphine has a number of disadvantages the main one of which is its addictive property, many attempts have been made to modify the structure by semi-synthesis even before the structure had been fully established (ref.64). In parallel with the use of morphine and thebaine as natural intermediates many compounds having a simple structural resemblance to morphine have been studied for their potential analgesic activity without addictive and other side effects (ref.65), a search which continues to this day. 

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