Thebaine, Diels—Alder

Base (KOH) catalyzed rearrangements of la- and 7/3-ketones of the 6,14-endo-etheno and endo-ethanotetrahydrothebaines (e.g., nepenthone, 213, R = Ph) have also been shown to afford bridged systems [e.g., 218 (R = Ph)], the chemistry of which was investigated/351) A product of photochemical rearrangement of thebaine Diels-Alder adduct with dimethyl acetylenedicar-boxylate has been shown to be an unsaturated analog of 218 (R = OMe).(352)... 

Thebaine Diels-Alder Adducts—Structure-Activity Relationships... 

Extensive assignments of 13C bands for 4,5-epoxymorphinans have been published/397 398 Carroll and co-workers(298) examined 25 derivatives of morphine, 14-hydroxymorphine, and 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaines. Assignments were aided by off-resonance decoupled spectra and by deuterium labeling. These reports have been reviewed/399 Thebaine Diels-Alder adducts were found to have A-, B-, and D-rings with spatial orientations similar to morphine. The C-ring, however, differed in conformation in agreement with the distortion seen in X-ray structures/400 ... 

There are two types of pharmaceutically important derivatives (a) Compounds with a hydroxyl substituent at position 14, such as in oxycodone and the antagonists naloxone and naltrexone, and (b) Diels-Alder adducts such as etorphine and buprenorphine, where the latter compounds are all derived from another opium alkaloid, (—)-thebaine (12) (Scheme 5.10). Because thebaine is a rather scarce alkaloid, several syntheses have been investigated. Quite recently, Australian scientists have been able to modify P. somniferum in such a way that thebaine is now a main alkaloid, so that it is becoming better available [28],... 

For the synthesis of Diels-Alder adducts a morphinan-6,8-diene system, as present in thebaine, is indispensable. Older publications started from thebaine and methyl vinyl ketone (but-3-en-2-one), yielding, after a Grignard reaction with propylmagnesium bromide, etorphine (13), a 6,14-endoethenomorphinan that is over 1000x as active as morphine and is used in veterinary medicine (Scheme 5.10). 

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. 

Details of the Diels-Alder addition of aromatic nitroso-compounds to thebaine to give adducts (117), the ring-opening of these to 14-hydroxylamino-compounds (118 R = OH), the reduction of these to 14-arylamino-compounds (118 R = H), and cyclization to (119) have been published.162 Dihydro-thebaine-< 4-phenyl ether (120 R = OPh) has been transformed into the benzylisoquinoline (121) by potassamide in liquid ammonia, but the same transformation could not be effected with the free phenol (120 R = H) or with the deoxy-compound (120 R = H).163... 

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. 

Derivatives of Diels-Alder adducts of thebaine constitute the most important variants of the 4,5-epoxymorphinan system, Several other compounds... 

Diels-Alder adducts of thebaine may exhibit exceptionally high levels of opioid activity. The crystal structure of 7a-(l-(i )-hydroxy-l-methylbutyl)-6,14-endo-ethenotetrahydrothebaine hydrobromide (Etorphine 221) was determined 00 and the C-ring cage structure was found to be severely distorted relative to the idealized Dreiding model. 

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.

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