Tetrahydrothebaines Thebaine

The Diels-Alder reaction of thebaine with various electrophiles yields compounds (Fig. 7.19) that have extremely high potencies, over 1000-fold higher than morphine in some cases (see Refs. 370, 371). X-ray (372) and NMR (373) analysis of 19-propylthevinol, the 3-methyl ether of etorphine (42 above), indicates that the 6,14-etheno bridge is held inside (endo) the tetrahydrothebaine ring system and below the plane (a) of the Cy-Cg bond (see Fig. 7.19 and Ref 283) the C ring is held in a boat conformation by the 6,14-endo etheno bridge. 

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). 

The catalytic hydrogenation of thebaine was first investigated by Oldenberg [8-9], who isolated a crude, amorphous substance to which he gave the name tetrahydrothebaine and which was doubtless a complex mixture of bases. The non-phenolic dihydrothebaine [xi] may be prepared in only moderate yield by the hydrogenation of thebaine... 

Tetrahydrothebaine [xiv] was finally isolated by Schopf and Winter-halder [13] and shown to be identical with dihydromorphine dimethyl ether. It is obtained in good yield by hydrogenation of thebaine in acetic acid over platinum oxide [16-17] or in ethanol over highly active (W 6) Raney nickel [18],... 

Mild catalytic reduction of thebaine hydrochloride in aqueous or dilute acetic acid solution using a platinum [1] or colloidal palladium catalyst [2-6] results in saturation of the 8 14-double bond and production of dihydrothebaine [i]. The yield is never high, as considerable amounts of dihydrothebainone [n] and tetrahydrothebaine [hi] are produced simultaneously, not by further reduction of dihydrothebaine, which is stable under these conditions. 

Further work on the reduction of thebaine by chemical means has been published since Chapter 8 of Volume II was written. This supports the conclusions outlined previously (Vol. II, pp. 199-203), (402, 403). A careful search of the mother liquors from the commercial hydrogenation of thebaine has led to the isolation of about 1 % of neopine methyl ether (CCCLIII) (404). It is, of course, possible that more of this substance is formed than can be isolated since most of it might well be reduced further to tetrahydrothebaine which is also produced in the reduction. 

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