Dihydrothebaine methyl ether

The methyl ether of [xvi] arises from acid hydrolysis of dihydrothe-baine-< methyl ether methiodide and /3-dihydrothebaine methyl ether methine [5]. 

The reduction of thebaine methiodide with sodium in liquid ammonia leads to dihydrothebaine- dihydromethine [xxx], also accessible by the reduction of dihydrothebaine- methiodide the methyl ether can be prepared in the same way from dihydrothebaine methyl ether methiodide. [xxx] can be hydrolysed by mineral acids to the-bainone-B dihydromethine [xxxi], and reduced with difficulty to dihydrothebainone dihydromethine AB-enol methyl ether. Its methiodide on reduction with sodium and ammonia yields 4-hydroxy-3 6-dimethoxy-13-ethyl-7 13 9 10-tetrahydrophenanthrene [Xxxii] and on alkaline degradation gives A6,8-6-methoxythebendiene [xxxm] [11],... 

Catalytic or sodium and alcohol reduction of thebainone-A enol methyl ether [vi] affords a substance initially allotted the structure [ix] as it is different from an isomeric substance obtained by the catalytic reduction of dihydrotbebaine- >, at that time believed to be [n] [3]. It is now clear that this base is in fact dihydrothebainone A°-enol methyl ether [x] and is formed from [vi] by 1 4-addition of hydrogen to the conjugated system. The product of catalytic reduction of dihydrothebaine- must therefore be the isomeric AB-enol methyl ether [ix] produced by saturation of the 8 14-double bond of [iv]. Bentley, Robinson, and Wain [5] have in this way obtained a base different from that obtained by Small and Browning [3], but believe their product is the true dihydrothebainone-A5-enol methyl ether [ix] as it can also be prepared in 98 per cent, yield by the sodium and liquid ammonia reduction of dihydrothebaine [xi] [5]. 

Dihydrothebainone [xn] or its A6-enol methyl ether [x] is produced in considerable quantity in all reductions of thebaine even under mild conditions, and cannot arise from further reduction of dihydrothebaine. It undoubtedly arises from 1 6-reduction of the conjugated system to give thebainone-A enol methyl ether [vi], which then suffers further 1 4-reduction to dihydrothebainone A6-enol methyl ether [x], the latter boing hydrolysed in acid solution to dihydrothebainone [xn]. This mechanism was suggested by SchOpf and Winterhalder [14], but Small... 

Elimination of one of the double bonds of thebaine results in a compound more amenable to exhaustive methylation, and alkaline degradation of dihydrothebaine methiodide affords, in good yield, dihydrothebaine methine [ix] [1, 15-16], which can be hydrogenated to the dihydromethine [x] [1], Further degradation of the methine [ix] methiodide results partly in regeneration of the base and partly in production of 6-methoxy-13-vinyltetrahydromorphenol methyl ether [xi] [15-16], which can be hydrolysed to 6-keto-13-vinylhexahydro-morphenol methyl ether [xn]. 

Hydrolysis of dihydrothebaine methine [ix] affords dihydrocodeinone methine [xxi], which can be reduced catalytically to the dihydromethine [xix] or with aluminium amalgam to dihydrothebainone methine [xxn]. The nitrogen-free product of degradation of dihydrocodeinone methine [xxi] has not been isolated [3]. It was hoped to prepare the AB-enol methyl ether [xxm] of dihydrothebainone dihydromethine by the sodium and liquid ammonia reduction of dihydrothebaine methiodide, but only a complex mixture of products was obtained in this way. Sodium ammonia reduction of the methiodide of [vn] yielded only the original base, but [xxm] was finally obtained by the catalytic reduction of dihydrothebaine- dihydromethine [xxiv] [18]. 

The degradation of dihydrothebaine has been pursued further by Sargent and Small [16, 19] as follows. The methyl ether [xxv] of [xiv] was converted to the oxime [xxvi], which yielded 6-keto-13-ethylootahydromorphenol methyl ether [xm] whon subjected to... 

When thebaine [i] is reduced by sodium and boiling alcohol [1-3], or best by sodium in liquid ammonia [4-5], scission of the 4 5-oxygen bridge occurs with the addition of two atoms of hydrogen and production of a phenolic dihydrothebaine, for which the name dihydrothe-baine-< has now been adopted [5]. The sodium-ammonia reduction is rapid, simple, and results in excellent yields of product. Reduction of thebaine with lithium aluminium hydride also yields a phenolic base, /3-dihydrothebaine, which is isomeric with dihydrothebaine- [6], Dihydrothebaine- was first allotted the structure [n] on the basis of its reactions [3], and 3-dihydrothebaine the structure [m] with the abnormal configuration at C-14 on the basis of its hydrolysis to ]S-thebainone-A [iv] [6] thebainone-A enol methyl ether [m] with the normal configuration at C-14, which results from the isomerization of codeine methyl ether [v] under the influence of hot sodium ethoxide, is known to give thebainone-A [rv, C-14 epimer] on hydrolysis [3]. 

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]. 

S-Dihydrothebaine [n] absorbs two moles of hydrogen on reduction over platinum oxide, the product being dihydrothebainol-6-methyl ether [xm] [6], identical with the compound obtained in the reduction of thebaine in neutral solution [3]. The configuration at C-14 in [xm] is not known. A dihydro-derivative, dihydrothebainone A6-enol methyl ether [xi], can also be isolated from the products of reduction [12]. 

Thebainone-A enol methyl ether [m] can be reduced catalytically or with sodium and alcohol to dihydrothebainone A6-enol methyl ether [xi] [3, 12] (erroneously given the A5 structure [rx] at first [3]) and from the catalytic reduction dihydrothebainol-6-methyl ether, identical with the compound obtained from /3-dihydrothebaine, is also obtained [12]. The fact that tliebainono-A onol methyl other and /3-dihydrothebaine... 

No enol ether of /3-thebainone-A epimeric with thebainone-A enol methyl ether [vn] has been prepared /3-dihydrothebaine was first thought to be such a compound [16] but subsequently was shown to have the structure [hi] [17]. 

Dihydrothebainone dihydromethine A5-enol methyl ether [lvi] results from the hydrogenation of dihydrothebaine- dihydromethine [XXIV] [23]. 

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). 

The enol ether of dihydrocodeinone, dihydrothebaine, can be prepared by the action of methyl sulphate and potassium tertiary butoxide on the ketone [72]. 

Vigorous reduction of dihydrothebaine with sodium and isoamyl alcohol or catalytically [1] results in opening of the cyclic ether link and production of dihydrothobninone [n]. The intermediate in this reaction is doublloss diliydrothobainono A°-onol methyl ethor [vii], which oan... 

Phosphoryl chloride-Pyridine dehydration of alcohols [1, 878-879, at end]. Although thebaine (1) can be considered as the methyl enol ether of codeinone (2), no direct synthesis has been achieved. Rapoport123 has recently carried out a convenient indirect synthesis of (1) from Ae-dihydrothebaine (3). Addition of methyl hypobromite (generated from NBA in methanol) gave (4) in 62% yield, and this... 

These investigators succeeded in preparing codeinone dimethyl ketal (CCCLXXXV) starting with A -dihydrothebaine, which can itself be prepared by methylation of dihydrocodeinone with sodium <-butoxide and dimethyl sulfate (426). Addition of bromine in methanol to the enol ether gave a bromoketal which was dehydrobrominated to CCCLXXXV with potassium i-amyloxide. Direct preparation of codeinone dimethyl ketal from codeinone was not successful. Thebaine was obtained by warming CCCLXXXV with p-toluenesulfonic acid in chloroform. 

Ghosh AC, Portlock DE, DalzeU HC, Malberg C, Herligy P, Razdan RK (1983) Diels-Alder reaction of fi-dihydrothebaine and its 4-phenyl ether with methyl vinyl ketone synthesis of 6,14-exoethenomorphinans. J Org Chem 48 4137-4139 Glasel JA (1981) A comparison of solution solid state and theoretical conformations of morphine. Biochem Biophys Res Commun 102 703-709 Gordon M (1974) Annu Rep Med Chem 9 38-50... 

---