Compounds Prepared from Thebaine

As is often the case with complex natural products, opium, the dried sap from papaver somniferum, contains a number of structurally closely related compounds. One of these minor constituents, thebaine (6-1), although itself devoid of signihcant 

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). 

Catalytic hydrogenation of the hydrolysis product leads to the orally active compound oxycodenone (7-1), which is used in a number of analgesic drugs. Cleavage of the methyl ether to the free phenol leads to one of the most potent close analogues of morphine, oxymorphone (7-2) [5]. Note that both of these compounds carry the hazards of classical opiate dependence liability. 

Hydroxylation at the equivalent of the 14 position in morphine has much the same effect in the morphinan series in that it increases both potency and oral activity. The somewhat involved synthesis of such a compound begins with the 

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A series of dibenzazonines with the general structure 111 (R, R, = H, alkyl, alkoxy, halo R2 = H, alkyl R3 = H, alkyl, alkanoyl n = 1,2) were prepared from thebaine (45) and found to have antiarrhythmic activity similar to that of procainamide and local anaesthetic activity lasting longer than that of tetracaine (45). One compound of this series, named asocainol (111, R = R, = H, R2 = Me, R3 = H, n = 2), is a useful drug whose mechanism of action in isolated guinea pig papillary muscles has been studied in detail (78, 79). 

Oxidation of desmethoxydihydrosinomenine with silver nitrate results in linking of two molecules in the l T-position to give bis-1 T-desmethoxydihydrosinomenine, which can be degraded to bis-1 T-desmethoxydihydrosinomenine methine, bis-1 1 -desmethoxydihydrosinomenine dihydromethine, bis-1 T - 9 10-dehydro-( —)-thebenone, and bis-1 l -(—)-thebenone, all of which can be racemized with the corresponding compound prepared from the thebaine series [49]. 

It was postulated [152, 153] that the aryl amine is oxidized by direct oxygen transfer from Compound I to the substrate. In contrast, for the oxidation of alkaloids, e.g. morphine, codeine and thebaine (Eq. 12), to the corresponding N-oxi-des by hydrogen peroxide in the presence of HRP or crude enzyme preparation from poppy seedlings, a radical mechanism was proposed [154]. 

During investigations of the reaction between cyanogen bromide and cyclic bases von Braun [17] discovered that thebaine reacts with this compound to give a substance subsequently identified as cyanonorthe-benine [xv] [18]. This cannot be prepared from thebenine, nor can it be hydrolysed to northebonine. On catalytic reduction it absorbs eight... 

Many semisynthetic derivatives are made by relatively simple modifications of morphine or thebaine. Codeine is methyhnorphine, the methyl substitution being on the phenolic hydroxyl group. Thebaine differs from morphine only in that both hydroxyl groups are methylated and that the ring has two double bonds (A , A ). Thebaine has little analgesic action but is a precursor of several important 14-OH compounds, such as oxycodone and naloxone. Certain derivatives of thebaine are more than 1000 times as potent as morphine (e.g., etorphine). Diacetylmorphine, or heroin, is made from morphine by acetylation at the 3 and 6 positions. Apomorphine, which also can be prepared from morphine, is a potent emetic and dopaminergic agonist. 

Rapoport el al. described a simple preparation of 6-O-demethyl-salutaridine (43e) from thebaine with sodium bisulfite in an oxygen atmosphere (494). In another synthesis, 14-bromocodeinone (47b) in Claisen s alkali yields 6-O-demethylsalutaridine (495). Methylation of this compound with diazomethane gives rise to O-methylsalutaridine (43d). The following reaction sequence appears to account for the production of... 

Opiates, narcotic compounds extracted or derived from opium, are a remarkable source of lead compounds for their potent pharmaceutical effects such as analgesics, antitussives and ataractics, and of which many synthetic derivatives have been prepared [8, 72], Apomorphine (28), a dopamine agonist derivative from morphine (5) but without analgesic properties like morphine, was recently approved as a therapy for Parkinson s disease [73], Hydrocodone (30) is a narcotic agent derived from thebaine (29) and is commonly combined with other analgesics such as acetaminophen and ibuprofen as drugs to relieve pain. [74]. Naloxone (31) and naltrexone (32) are both opioid receptor antagonists. Naloxone is used as a treatment for opioid... 

Codeine has also been prepared in 70% overall yield, again without purification of intermediate compounds, from dihydrothebainone (132) by the route (132) — (137) shown in Scheme 4. The initial product of the action of bromine and then alkali on dihydrothebainone is the 1,7-dibromo-derivative of dihydro-codeinone, which can be reduced to dihydrocodeinone (133). This may be converted into 7-bromodihydrocodeinone dimethyl ketal (136), which on treatment with potassium t-butoxide in DMSO at 120 °C is converted exclusively into thebaine, but at 60 °C the product is codeinone dimethyl ketal (137), which can be hydrolysed to codeinone (131).154 The process has obvious value in the possible synthesis of codeine via dihydrothebainone, for which a patent has been filed covering a process that proceeds from the reduced isoquinoline (138) 155 the conversion of A-formylnordihydrothebainone into dihydrothebainone by hydrolysis and reductive methylation and by ketalization, reduction, and hydrolysis has been reported.156... 

Most phenanthrene alkaloids are easily synthesized by degradation of the corresponding aporphines. Many phenanthrenes were first prepared as aporphine derivatives for characterization or in the course of structural studies, and only later were they found in nature. Although the ready availability of most aporphines from natural sources makes this strategy very simple, it often does not constitute a formal total synthesis, and some approaches from simpler compounds have been published (29,105). Degradation of the morphine alkaloid thebaine (151) gives rise to a number of unnatural phenanthrenes (93,94,102, 104,113). 

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... 

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