Thebaine Diels-Alder adducts

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). 

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. 

Bentley KW, Horsewood P, Kirby GW, Singh S (1969) Diels-Alder adducts from thebaine and nitroso-arenes. J Chem Soc D 1411... 

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. ... 

The diethyl ester derived from the Diels-Alder adduct of thebaine with maleic anhydride has been converted into the lactone (124), by methylmagnesium iodide, and into a diol by lithium aluminium hydride. The diol has been dehydrated to the diene (125), which undergoes Diels-Alder addition of N-phenylmaleimide to give the adduct (126). °... 

Further rearrangements of the Diels-Alder adducts of thebaine and their derivatives have been studied. Thebainequinol and one of its methyl ethers are rearranged to flavothebaone derivatives by alkalis. The reaction is analogous... 

Substituted nitrosobenzenes have been reported to add both regioselec-tively and stereoselectively to thebaine at room temperature to afford Diels-Alder adducts in high yields [Eq. (3)].9... 

A Diels-Alder adduct (206) was obtained when thebaine was treated with nitrosyl chloride and silver cyanide, the reactive intermediate probably being nitrosyl cyanide, ONCN. ... 

Bentley and his colleagues7 describe the structure-activity relationships of a wide variety of structures derived from Diels-Alder adducts of thebaine. Among this group are found some of the most potent analgesics known. Particular attention should be directed toward the fine application of nuclear magnetic resonance spectroscopy, by Fulmor and his associates to elucidate the stereochemical configurations of these interesting compounds. 

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... 

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). 

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. 

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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