Desoxycodeines

A novel approach towards the construction of the morphine skeleton is demonstrated by the total synthesis of ( )-desoxycodeine-D. One of the key steps for this synthesis is the palladium-catalyzed intramolecular Heck reaction. Therefore, this synthetic strategy for the construction of the polycyclic ring systems has provided an efficient access to the complete pentacyclic skeleton of morphine <00TL915>. 

No extensive work on this series has been reported. Oxidation 1031 of the (+)-demethoxydesoxydihydrosinomenine (104), (-)-14-hydroxytetrahydro-desoxycodeine (105) and (+)-3-methoxy- N-methylmorphinan (dextromethorphan) with sodium dichromate or chromic oxide in sulfuric acid gave the expected attack at the benzylic position, thus affording 10-oxo derivatives. 

A new approach to the morphine skeleton was demonstrated by the total synthesis of (+)-desoxycodeine-D by C.-Y. Cheng and co-workers." " The key step was the formation of the B ring by the Stevens rearrangement of a tetrahydroisoquinoline-derived quaternary ammonium salt upon treatment with phenyllithium. 

Final proof of the Gulland and Robinson formulae for the morphine alkaloids has been obtained by the synthesis of racemic tetrahydro-desoxycodeine [lxiv] by Grewe, Mondon, and Nolte [94] and of dl-dihydrodesoxycodeine-B methyl ether [lxv] by Gates and Tschudi [95], The former, whilst fixing the point of attachment of the nitrogen end of the side-chain, did not eliminate the possibility of a spirane structure such as [Lxm], but the latter definitely established the location of the carbon end of the side-chain at C-13. (See Chap. XXVIII.)... 

Dihydro-electrolytic reduction of desoxycodeine-C [xv] to dihydro-desoxycodeine-B [lxxiv], and dihydro-i/r-codeine-C the structure [lxxhi] by analogy with the sodium and alcohol reduction of desoxycodeine-C to dihydrodesoxycodeine-C [lxxv] sodium and alcohol reductions have a known tendency to effect 1 4 addition of hydrogen to an allylic ether [248, 281, 423]. (Cf. the reduction of thebaine [lxxvii] to dihydrothebaine-< [lxxvih] [265, 405, 424].)... 

CH—CH=CH—CH—OH to give desoxycodeine-A [lxxix], which is known to give [lxxiv] and [lxxv] on sodium and alcohol reduction [281, 425]. (5 6-addition is improbable as it would involve an activating influence of the double bond not found in codeine, and 3 6-addition would yield desoxycodeine-E [lxxx] in which the double bond occupies a position that precludes reduction by sodium and alcohol [423].)... 

An intractable phenolic substance is produced by the prolonged boiling of neopine hydrobromide with Raney nickel in alcohol [7], Lithium aluminium hydride reduction of p-toluenesulphonylneopine gives desoxyneopine (desoxycodeine-D) [vm] [8] (see Chap. IX). 

Reduction of a-chlorocodide with zinc-dust and dilute hydrochloric acid [25] or alcohol [20, 26] gives desoxycodeine-A [xi] by... 

Electrolytic reduction of/3-chlorocodide also gives desoxycodeine-A [22, 27]. 

This base is formed together with a small quantity of 1 8-dichloro-dihydrocodide by the action of phosphorus pentachloride on dihydro-i/r-codeine-A [xlih] and its epimer dihydroallo- -codeine-A. It is an exceptionally stable substance, being unaffected by electrolytic or socjium and alcohol reduction heating with sodium methoxide under pressure simply causes demethylation to 8-chlorodihydromorphide [19], but prolonged boiling with sodium in cycZohexanol causes loss of hydro-genchloride and production of desoxycodeine-D [lh, R = Me] and a small amount of the demethylated substance, desoxymorphino-D [lii, R = H] [19, 80]. 

Wright claimed to have isolated a desoxycodeine and a desoxy-morphine from the products obtained by heating bromocodide with hydrobromic acid [81, 87-89]. 

The name desoxycodeine should logically be applied only to the substance of structure [i], in which the alcoholic oxygen of codeine [n] has been eliminated it is, however, also applied to two isomers of [i] differing in the position of the double bond, and to a phenolic base [m] having an additional double bond in ring C. 

Desoxycodeine-A [m] was first prepared by Knorr and Waentig [1] (and called simply desoxycodeine) by reducing a-chlorocodide [iv] with zinc-dust and alcohol, a process that must involve 1 4-addition of... 

Desoxycodeine-A is phenolic, being soluble in alkali, giving a colour with ferric chloride and forming a methyl ether [1]. The phenol may be degraded to a methine base [vi, R = H], which oxidizes rapidly in air, and the methyl ether to [vi, R = Me], which decomposes spontaneously to an amine and dimethylmorphol [vn] [1],... 

Reduction of desoxycodeine-A with sodium and alcohol gives a mixture of dihydrodesoxycodeines-B and -C [1] and catalytic hydrogenation affords tetrahydrodesoxycodeine [4] (see below). 

Bromination of the aromatic nucleus occurs when desoxycodeine-A is treated with bromine, and the hydrogen bromide thus formed adds (1 4 ) to the diene system, giving dibromodihydrodesoxycodeine, also obtained by addition of hydrogen bromide to desoxycodeine-A followed by bromination. Acetolysisofthe dibromide yields l-bromo-3-methoxy-4-acetoxyphenanthrene (structure proved by conversion to the 3 4-dimethoxycompound and synthesis of the latter), also prepared by the degradation of 1-bromocodeine [5]. 

Desoxycodeine-B, first thought to be a definite entity, was subsequently shown to be anhydrous desoxycodeine-A containing a small amount of a very persistent impurity. It was obtained by the electrolytic reduction of a- and /3-chlorocodide [3-4]. Freund believed it to be a dihydrodesoxycodeine and claimed it was formed in the electrolytic reduction of desoxycodeine-A and of 6-chlorodihydrocodide [4], In fact the two latter reactions yield isomeric dihydrodesoxycodeines [3],... 

Small and Cohen [3] showed that desoxycodeine-B is indeed a desoxycodeine and that on reduction it yields the same substances as does desoxycodeine-A and accordingly suggested the structure [vin] for it. However, Small and Morris [6], finding that electrolytic reduction of a-chloromorphide gives desoxymorphine-A, which can be methylated to desoxycodeine-A, re-examined desoxycodeine-B and discovered that it is identical with desoxycodeine-A. 

Desoxycodeine-C [ix] was the first of the non-phenolic desoxy-codeines to be isolated. It is obtained by heating 6-chlorodihydrocodide [x] with sodium methoxide in methyl alcohol at 140° C. [3] previously no reaction had been observed at 120° C. [7]. Desoxycodeine-C was presumably obtained by Knoll and Co. in this way, but was believed to bo a dihydrodosoxycodoino [8-9]. It is allotted the structure [ix] on aooount of tho ease with which phonolio substanoos are produced during... 

The non-phenolic dihydrodesoxycodeine-D [xin] is produced, together with tetrahydrodesoxycodeine [xiv], by the hydrogenation of desoxycodeine-C hydrochloride in glacial acetic acid over platinum oxide [6], but only tetrahydrodesoxycodeine is formed by hydrogenation of the base. Electrolytic reduction proceeds with opening of the cyclic ether and production of dihydrodesoxycodeine-B [xv], obtained together with dihydrodesoxycodeine-C [xvi] by reduction with sodium and alcohol [3, 10],... 

The cyclic ether link is activated by the presence of the 6 7-double bond, and desoxycodeine-C will react with Grignard reagents giving phenolic bases probably of the type [xvn] (see Chap. XIX) [11], and with ethyl mercaptan to give ethylthiodihydrodesoxycodeine-C [xvm] [12]. 

Cyanogen bromide reacts with desoxycodeine-C to give cyanonor-desoxycodeine-C [xix] [13]. Oxidation of the base with 1 per cent, potassium permanganate solution affords 7-hydroxydihydrocodeine [xx] [14]. 

The optical antipode of desoxycodeine-C can be prepared in the sinomenine series [15] (see Chap. XXVII). 

Bromination of desoxycodeine-C affords 1 6 7-tribromodihydro-desoxycodeine-D [xxi] this absorbs three moles of hydrogen on hydrogenation, giving a bromotetrahydrodesoxycodeine not identical with that obtained from tetrahydrodesoxycodeine, and this on reduction with sodium and alcohol yields a substance isomeric with tetrahydrodesoxycodeine [5]. 

Desoxycodeine-E [xxx] pan be prepared by the lithium aluminium hydride reduction of codeine [n] p-toluenesulphonyl ester [17-18], Its structure is shown to be [xxx] by hydrogenation of the base to dihydrodesoxycodeine-D [xiii], degradation of the methiodide to desoxy-a-codeimethine [xxix], and isomerization of the latter to desoxy-/3-codeimethine [xxvin], production of cyanonordesoxy codeine-E [xxxi] by the action of cyanogen bromide on the base, and by the facts that desoxycodeine-E is neither a phenol nor an enol ether [17]. Desoxycodeine-E can be demethylated to desoxymorphine-E [62]. 

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