Dihydrothebainone methyl ether

A total synthesis of ( )-codeine also utilized the aziridinium salt 94 as a key intermediate, which was converted to 100 via epidihydrothebainone methyl ether (98) according to Evans s procedure. Specific ether cleavage reaction of 100 with NaSEt afforded dihy othebainone (101) in 100% yield. Since dihydrothebainone (101) had already been transformed into codeine (102), this synthesis constitutes a formal synthesis of 102 (Scheme 19). 

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... 

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]. 

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... 

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],... 

Dihydrothebainone [ix], obtained by the catalytic reduction of thebainone-A [v] [1] and thebainone-B [xm] [13], can be most conveniently prepared by the catalytic reduction of thebaine in acid solution [9-12, 25], and it can also be obtained by the hydrolysis of its two enol ethers (see below). It is a phenolic, ketonic, base, that shows the diazo-reaction in dilutions up to 1 in 2,000,000 [26-27], gives a methyl ether [28], oxime [9], semicarbazone [29], and a benzylidene [30] and piperonylidene [25] derivative. The optical antipode is produced by the sodium amalgam reduction of sinomenine [xxvi] and is known as desmethoxydihydrosinomenine [31]. 

This enol ether [xxxi] is the product of catalytic or sodium amalgam reduction of thebainone-A enol methyl ether [vn] [3], from which it arises by 1 4-addition of hydrogen to the conjugated system, and it can also be prepared by the hydrogenation of thebaine in neutral solution [3]. It is very readily hydrolysed to dihydrothebainone, which doubtless arises from this during the reduction of thebaine in acid solution. (Dihydrothebainone was prepared by Speyer and Ereunds [10] by the reduction of thebaine in neutral solution and no doubt arose from the enol ether by hydrolysis during the isolation of the product.)... 

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

Dihydrothebainone dihydromethine A -encil methyl ether. -dihydrothebainone dihydromethine... 

---