Thebaine, Diels—Alder reactions

The groups of Kirby224,340 and of Revesz477 have studied the Diels-Alder reactions of thebaine 134 with ethyl thioxoacetate (equation 140) and other thioaldehydes, thus preparing several opiate antagonists. 

A semisynthetic route to morphine analogs was found (10) from thebaine (8) using Diels-Alder reactions in the C-ring. Adducts such as (9)have the distinction of enormous potency (U), sufficient to immobilize rhinoceroses at moderate dose levels Unfortunately, the addictive liability runs parallel to the increase in analgesic potency, a tendency that was partly overcome (12) in the analog buprenorphine (10). 

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. 

Figure 7.19. Diels-Alder reaction to give 6,14-encfoetheno derivatives cf thebaine (59) and the structures of buprenorphine (85) and BU48 (86). The structure of diprenorphine (43) is included for comparison.

The Stork group reported the synthesis of racemic codeine and thebaine utilizing the intramolecular Diels-Alder reaction as the key transformation in 2009 [45]. The key features of their synthesis are (1) a direct construction of a phenanthrofuran skeleton (A-B-C-E tetracyclic system) by the intramolecular Diels-Alder reaction of a diene tethered to the benzofuran ring and (2) a formation of the D-ring by the intramolecular SN2 reaction of an amino-mesylate. 

It was at this time that we, at Reckitt and Colman became interested in the work of Professor Gordon Kirby on Diels-Alder reactions of thebaine with nitroso derivatives with the objective of providing a viable synthesis of 14-aminocodei-none. This would allow access to a wide range of 14-acylamino- and 14-alkyla-mino-codeinones and morphinones which could be improvements on the available derivatives of 14-hydroxycodeinone and oxycodone. 

An efficient synthesis of the thebaine analogue (158), as outlined in Scheme 13, in which the nitrogen atom is translocated from C(17) to the 16-position has been reported.161 It was converted into the Bentley adduct (159) by successive Diels-Alder and Grignard reactions. Further work on the Diels-Alder reactions of morphine alkaloids is expected for example, the enamine (160) has been prepared specifically for this purpose.162... 

It has been known for some time that thebaine behaves as a diene in the Diels Alder reaction. In particular, its adduct with benzoquinone (CCCLXII) has been the object of considerable study (380). As is usual... 

It was realized early that the morphine-related alkaloid thebaine, because of the conjugated diene in ring C, was the most chemically reactive of the opium alkaloids. A large variety of dienophiles readily underwent a Diels-Alder reaction with thebaine, affording several adduct compounds with opioid properties, including analgesia. 

Thebaine-maleimide adducts have been prepared, and the Diels-Alder reaction of thebaine with cyclic azo-dienophiles has been investigated. " Nitrosation of thebaine hydrochloride with nitrosyl chloride or pentyl nitrite in methanol or ethanol gives 7-hydroxyiminoneopinone dimethyl or diethyl acetal. " The chemistry of 14-bromocodeinone and its dimethyl acetal has been studied in some detail, including catalytic hydrogenation, "" methanoly-sis, " debromination, "" dehydrobromination, " and solvolysis.Efforts are continuing in the preparation of novel analgesics in the morphine-thebaine series. 

The synthesis of buprenorphine has a certain similarity to that of etorphine. After the Diels-Alder reaction of thebaine with methyl vinyl ketone, the double bond is hydrogenated. Then follows a Grignard reaction with t-butyhnagnesium chloride. For modification of the tertiary amine, this is demethylated with cyanogen bromide (von Braun reaction) and treated with cyclopropanecarbonyl chloride. Following reduction with lithium aluminium hydride, the aromatic methoxy-group is finally replaced by nucleophihc substitution under forcing conditions. 

Thebaine acts as diene component in Diels-Alder reactions with methyl vinyl sulphone or divinyl sulphone. 1 1 Adducts are formed in both cases. The analgesic properties of some elaboration products of these adducts, e.g. (136), equal the potency of codeine. Cyclopentadiene adds... 

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