Thebaine structure

In the strict sense, opiates are drugs which are derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non-peptidic structures. The old term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, pqrtidic or non-peptidic, that produces morphine-like effects through an action on opioid receptors. 

More recent examples of biomimetic synthesis are the syntheses of thebaine [11] and usnic acid [12], as well as strychnine [13], morphine alkaloids [11] [14] and a great number of terpenic compounds [15]. On the other hand, hypothetic prebiotic considerations may also simplify tremendously the synthetic plans. Such is the case, for example, of the work of Eschenmoser on vitamin B12 who, after synthesising it in collaboration with Woodward by a linear sequence of almost fifty steps [16], investigated the prebiotic origen of this complex molecule. The experimental work undertaken in this direction demonstrates that the amount of "external instruction" required for "self-assembling" the different structural elements present in this molecule is surprisingly small. This fact could eventually lead to a very simple synthesis of vitamin Bj2 starting from a-amino nitriles which would involve only a few steps [17]. 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentaitil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise. 

According to historical records, around 1500 B.c. the use of opium, as well as its exportation, was beginning to take root. The city of Thebes was so well-known for its poppy fields that it lent its name to the active alkaloid in opium, thebaine. Alkaloids are any of a host of organic compounds, often complex in structure, derived from plants. Many [alkaloids] are useful as medicines and poisons. In medical texts left by the Egyptians, there are more than 700 medicines that contain opium. Under the... 

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... 

Thebaine (Figure 6.50) differs structurally from morphine/codeine mainly by its possession of a conjugated diene ring system. It is almost devoid of analgesic activity, but may be used as a morphine antagonist. Its main value is as substrate for the semi-synthesis of other drugs (see below). 

Papaverine (Figure 6.45) is a benzylisoquinoline alkaloid, and is structurally very different from the morphine, codeine, thebaine group of alkaloids (morphinans). It has little or no analgesic or hypnotic properties put possesses spasmolytic and vasodilator activity. It has been used in some expectorant preparations, and in the treatment of gastrointestinal spasms, but its efficacy was not substantiated. It is sometimes used as an effective treatment for male impotence, being administered by direct injection to achieve erection of the penis. 

The thebaine analog 52 reacts with methylmagnesium iodide to give a product for which the dibenzazonine structure 53 was proposed (Scheme 13). A more recent investigation of this reaction, however, showed the formation of two epi-mers, 54 and 55, which retain the morphinan skeleton 51). 

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). 

Codeine, 14-hydroxycodeine, neopine, and O-methylflavinantine have been isolated from Papaver bracteatum,146 flavinantine and amurine from Meconopsis cambrica,113 isosinoacutine from Stephania elegans,174 and a new alkaloid, tridictyophylline, for which the structure (96) was determined by X-ray crystallography, from Triclisia dictyophylla.175 Bound morphine, codeine, and thebaine have been found in P. bracteatum and P. somniferum,176 and the effect of the period of maturation of the plants on the yield of these three alkaloids from P. somniferum has been studied.177,178 Codeine has been isolated from cell suspension cultures of P. somniferum under conditions where no morphine, norcodeine, or thebaine could be detected.179... 

It has long been known that only morphine and codeine possess analgesic properties, whereas thebaine acts as a convulsant, similar to strychnine [16]. However, analogues produced from thebaine have provided some of the more interesting and clinically useful dmgs such as buprenorphine (see Section 11.5). Indeed, an early structure-activity relationship was realized between morphine and its methylated phenolic relative, codeine. Codeine (see below) is known to have about one-tenth the analgesic activity of morphine, and was also less likely to produce addiction. Additionally, an early diacetylated analogue of morphine, heroin (6) (Fig. 11.2), demonstrated an increased potency but also an increased addictive potential. 

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

During a study of the nitration of thebaine with tetranitromethane,(287) the unusual epoxide 183 was isolated when the nitration was performed in the presence of air. In establishing the structure of 183, two products (210a and b) oxygenated at C-10 were isolated. 

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 ... 

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. 

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). 

Since for general clinical use morphine has a number of disadvantages the main one of which is its addictive property, many attempts have been made to modify the structure by semi-synthesis even before the structure had been fully established (ref.64). In parallel with the use of morphine and thebaine as natural intermediates many compounds having a simple structural resemblance to morphine have been studied for their potential analgesic activity without addictive and other side effects (ref.65), a search which continues to this day. 

Alkaloid isolation and structural elucidation is summarized in Table 6. In addition to known constituents, codeine and neopine have been isolated from Papaver brac-teatum Although callus cells from this plant contain thebaine at early stages of subculturing, only traces are found later. - ° Thebaine was identified among seventeen isoquinoline alkaloids detected in, or isolated from P. syriacum. ... 

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