Thebaine addition products

Diethylazodicarboxylate may be employed as a reagent for the N-demethylation of thebaine to northebaine via an N-Me addition product. However, when thebaine was dissolved in diethylazodicarboxylate and allowed to stand, the hexacyclic product 251 was isolated,<9a) presumably from the Diels-Alder intermediate 249, and after hydrolysis gave 250. The putative intermediates 249 and 250 defied isolation. 

The product (6-2) from the reaction of thebaine with hydrogen peroxide can be viewed as the result from fromal 1,4 addition of two hydroxyl groups across the diene. The perspective depiction of thebaine reveals that the addition in fact occurs at the far more open face of the molecule. The product from this oxidation incorporates a new hydroxyl group at the 14(3 position and a hemiacetal at the 6 position. Treatment with a nuld acid leads to the hydrolysis of this last function and the formation of enone (6-3). 

The first group contains the natural products morphine, codeine and thebaine, which have been isolated from the natural product opium. In addition, the group contains various semi-synthetic derivatives of morphine, codeine and thebaine, which are prepared by chemical modifications of these natural products... 

The first reduction of thebaine [i] was achieved by sodium and boiling alcohol and resulted in the production of a phenolic dihydrothebaine in only moderate yield [1-3]. The same compound, now called dihydro-thebaine-, is more conveniently prepared in yields of up to 95 per cent, by the reduction of thebaine with sodium in liquid ammonia without the addition of alcohol [4-5]. 

Examination of the infra-red and ultra-violet absorption spectrum of /3-dihydrothebaine indicated that it has in fact the structure [n] initially allotted to dihydrothebaine- [6]. Such a conjugated diene would be expected to imdergo 1 4-addition of hydrogen with final production of [vm], a reduction parallel to the production of tetrahydrothebaine from thebaine (see below). 

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]. 

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.)... 

Fieser and Holmes [35], by the addition of butadiene and dimethyl-butadiene to ethyl 3 4-dihydro-a-naphthoate, were able to prepare [cxn, R = H] and [cxn, R = Me], and also the methoxy-compounds [cxm] and [cxiv] in a similar way [36], Reduction of [cxiv] afforded 3 4-dimethoxy-5 6 7 8 9 10 13 14-octahydrophenanthrene-13 -carb -oxylic acid [cxv], which is theoretically obtainable from [cxvi], a known product of degradation of thebaine [37].. Attempts to convert the carboxyl group of [cxv] to other substituents were made, and in this connexion [oxii, R = Me] was submitted to the Bouveault-Blano reduction followed by treatment of the product with phosphorus... 

New Diels-Alder adducts of thebaine with aromatic nitroso-compounds of structure (118 R = H, Me, Cl) have been prepared. These are unstable and can be hydrolysed to 14-aryIhydroxylaminocodeinones (119), which can be reduced to derivatives of the hitherto inaccessible 14-aminodihydrocodeinone (120). The base (119 R = H) is susceptible to base-catalysed displacement of the oxide bridge, the product being the 5,14-bridged thebainone derivative (121). ° The reaction between thebaine and excess of ethyl azodicarboxylate involves Diels-Alder addition and addition of the N-CH3 group to a second molecule of azo-ester. The primary product (122) has not been isolated pure, but yields ethyl hydrazodicarboxylate and the substituted codeinone (123) on hydrolysis. ... 

Scheme 1338. A representation of a pathway from thebaine to phenyldihydrothebaine, the product resnlting from the addition of phenyhnagnesium bromide to thebaine. After Holmes, H. L. Stork, G. The Alkaloids, Vol. 2, Academic, New York, 1952, p. 198.

Another essential factor that might induce the production of benzylisoquinolines could be the addition of biosynthetic precursors to the medium. Kamimura et al. (1976), for instance, described a stimulation of thebaine formation with the addition of tyrosine and dopa to the medium of Papaver bracteatum cultures. An increase from 0.05% of dry weight to 0.07% in the production of berberine in Argemone me-xicana (Menispermaceae) suspension cultures (Khanna et al. 1982) also was due to the addition of tyrosine, whereas phenylalanine in the medium only stimulated the growth index and the berberine yield remained constant. 

---