Thebaine rearrangements

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... 

The mechanistic aspects of the rearrangement of thebaine and codeine analogues in methanesulphonic acid have been clarified, and have led to an... 

A parallel biogenetic scheme has been suggested by Theuns et al. (24) for the formation of neodihydrothebaine (7) in Papaver bracteatum. In this case the route proceeds through the isomeric salutaridinol (103), which is derived by para-ortho coupling of reticuline (Scheme 29). It has been suggested that salutaridinol (103) (or thebaine) is the precursor of bractazonine (8), but in this case via a proerythrinadienone formed by aryl migration in the dienol-benzene rearrangement (24) (Scheme 30). 

Base (KOH) catalyzed rearrangements of la- and 7/3-ketones of the 6,14-endo-etheno and endo-ethanotetrahydrothebaines (e.g., nepenthone, 213, R = Ph) have also been shown to afford bridged systems [e.g., 218 (R = Ph)], the chemistry of which was investigated/351) A product of photochemical rearrangement of thebaine Diels-Alder adduct with dimethyl acetylenedicar-boxylate has been shown to be an unsaturated analog of 218 (R = OMe).(352)... 

Further work by Schopf and Borkowsky [86] indicated the need for modification of the structure with attachment of the side-chain at C-14 in metathebainone [lvih], which is formed by the reduction of thebaine with stannous chloride in concentrated hydrochloric acid [27], The true thebainono [lix] was later isolated from the stannous chloride reduction under difforont conditions. Metathebainone arises as a result of rearrangement of thebaine in concentrated hydrochloric acid, now believed to involve the intermediate [i.x], which is also believed to be common to the morphothobaino and thobouino transformations [88-80J. (Hoc Chap. XXV,)... 

Thebaine [v] is an enol ether and though fairly stable in cold dilute acid is hydrolysed to codeinone [vi] on standing with N. sulphuric acid for several weeks in the cold or six to seven minutes at 100° C. [75], and codeinone can also be isolated from the orange-red solution of thebaine in concentrated hydrochloric acid [76], In this way the relationship of the alkaloid to codeine and morphine was established. The yield of codeinone is very poor (< 7 per cent.), doubtless as a result of the ease with which thebaine undergoes rearrangement in acid solution. 

Thebaine behaves as an active conjugated diene in undergoing addition of maleic anhydride [42-43], benzoquinone [42-43], 1 4-naphthoquinone [42], and acrolein [102], The adduct with benzoquinone undergoes deep-seated rearrangement on heating for three hours with concentrated hydrochloric acid to give flavothebaone [43-44] (see Chap. XXI). 

Thebaine readily reacts with Grignard reagents to give phenolic bases having unexpected properties. The reaction involves a new type of molecular rearrangement [82-83, 109] and is discussed in Chapter XX. 

Dihydro thebaine-< absorbs only one mole of hydrogen on catalytic reduction, yielding dihydrothebainone AB-enol methyl ether [ix], which is identical with the product of sodium and liquid ammonia reduction of the non-phenolic dihydrothebaine [x] [5]. (A compound of different melting-point and specific rotation was prepared by Small and Brown-ing [3] by the catalytic reduction of dihydrothebaine-< and allotted the structure [xi] owing to a misconception of the structure of the latter. It is probably a mixture [5].) Dihydrothebainone [xn] is produced by the hydrolysis of [ix] showing that no rearrangement of the thebaine skeleton occurs during sodium and alcohol reduction [5]. 

When thebaine-hydroquinone is heated with glacial acetic acid and concentrated hydrochloric acid [2, 4] or with 50 per cent, sulphuric acid [4] profound rearrangement of the molecule occurs, and a new base, flavothebaone , is obtained. 

The structure of flavothebaone has been arrived at as a result of the consideration of the mechanism of the thebaine —morphothebaine rearrangement, which leads to two formulae for the rearranged substance, one of which has been shown to be untenable. 

Two mechanisms have been suggested for the thebaine - morphothebaine rearrangement (see Chap. XXIII) these are briefly as follows. 

Applying mechanism (a) to the rearrangement of thebaine-hydro-quinono we have attack of the cyclic ether oxygen by a proton and demethylation of the methoxyl group, followed by the electron-shifts a, b, c, d (formula xxxiv]), loss of a proton from the hydroxyl group... 

Applying the mechanism (6) for the thebaine -> morphothebaine rearrangement to the transformation of thebaine-hydroquinone to flavothebaone we have the following ... 

Again (p. 27) he states that Knorr s formula explained satisfactorily the complex rearrangements of morphine and thebaine. The first statement is misleading and the second will be seen to be incorrect on inspection of the details. Eor example, Knorr-codeinone to thebenine demands either a migration of carbonyl, or of the ethanamine chain, which cannot be theoretically justified, or based on analogy in any simple manner. 

In the last decade the subject of rearrangements in the thebaine group has been twice awakened from sleep. The first occasion was signalled by elucidation of the constitution of phenyldihydrothebaine, discovered by Freund and carefully studied by Small. 

Bentley KW, Hardy DG (1967) Novel analgesics and molecular rearrangements in the morphine-thebaine group. 3. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine. J Am Chem Soc 89 3281-3292... 

Further rearrangements of the Diels-Alder adducts of thebaine and their derivatives have been studied. Thebainequinol and one of its methyl ethers are rearranged to flavothebaone derivatives by alkalis. The reaction is analogous... 

It has been proposed that the dihydrothebaine formed hy sodium reduction of thebaine (so-called phenolic dihydrothebaine) be renamed dihydrothebaine-

trivial name for an older one does not appear legitimate once a structure is established beyond doubt. We would prefer the term A < >-dehydrothebainol methyl ether for the sodium-ethanol or sodium-ammonia reduction product (CCCLIV), The lithium aluminum hydride reduction product would then be A h4).(jeijy(ji.o< hel3ajnol methyl ether (CCCLV), and the third isomer, obtained by base-catalyzed rearrangement of codeine methyl ether, would be A -dehydrothebainol methyl ether (CCCLVI). 

An improved N-demethylation of morphine, codeine, and 6,7-benzo-morphane was carried out in 90% overall yield (523). The demethylation of thebaine to 6-O-demethylsalutaridine (43e) has been reported (494). Attention was also paid to the preparation of tosyloxy and mesyloxy derivatives of some morphinanes, e.g., morphine, codeine, dihydromorphine (49c), dihydrocodeine (49a), 14-hydroxycodeine (46), and 14-hydroxydihydrocodeine (49b) (524). The rearrangements of all these derivatives as well as the Beckmann and Schmidt rearrangements of 6-oxomorphine bases have also been studied (525). 

Photolysis of the adduct (123) gave the rearranged product (124), which was subjected to a number of chemical transformations. (See also Vol. 4 for photochemistry of a similar adduct.) Treatment of thebaine (125) with 4-phenyl-... 

The rearrangement of thebaine and northebaine to morphothebaine and normorphothebaine, using concentrated hydrochloric acid under pressure, has been described.Substitution of methanesulphonic acid at ambient pressure facilitated this rearrangement, with the generation of aporphines (20) and (21). ... 

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