Opium alkaloid skeleton

Another example of a tandem reaction, in this case an intramolecular Heck insertion followed by a r-allylpalladium displacement, comes from our opium alkaloid total synthesis project (Scheme 6-25) L53J. Treatment of diene aryl iodide 142 under forcing Heck cyclization conditions provided 143 in 56% yield in which the two final rings of the opium alkaloid skeleton are constructed in this one key step. 

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. 

NOSCAPINE (NARCOTINE) As an optically active, laevorotatory substance noscapine is found in opium (2-12%). This alkaloid is, next to morphine, the most plentiful of the opium alkaloids. Structurally it differs from the phenanthrene derivatives morphine and codeine by its phthalide isoquinoline— skeleton. 

The idea that the opium alkaloid morphine is a modified benzyliso-quinoline provided the key to the structure 6.152) for the alkaloid twisting of the benzylisoquinoline skeleton into that shown for reticuline (6.127) in (6.148) illustrates this relationship and suggests a possible biogenesis. This was later proved correct in the course of a study which is one of the classics of alkaloid biosynthesis. In the first experiments ever to be carried out with complex plant-alkaloid precursors, [1- C]- and [S- Cj-norlaudanosoline [as (6.123) were fed to opium poppies [99, 100]. They were found to label morphine (6.152), codeine (6.153) and thebaine (6.151) specifically, thus establishing that these alkaloids are indeed benzylisoquinoline derivatives. The key intermediate [101] proved to be reticuline (6.148). Both (R) and (5)-isomers were utilized, the latter by way of (6.155) [101, 102] which allowed its conversion into (i )-reticuline (6.148), the correct intermediate, with the same configuration as the three opium alkaloids [as (6.151). ... 

As pointed out earlier, the structural diversity of this class of tyrosine-derived secondary metabolites arises from different aryl coupling reactions. The biosynthetic pathway to alkaloids of the protoberberine skeleton, as well as the aporphine and morphine skeleton, is outlined in Scheme 12.4 [14]. While protoberberine [18] and aporphine alkaloids [19-21] are obtained from (S)-reticuline (19), opium alkaloids are biosynthesized from the enantiomeric (/ )-configured natural product (20). 

Morphinans present by far the most important class of reticuline-derived natural products. In contrast to alkaloids of the protoberberine and aporphine skeleton, opium alkaloids are biosynthesized from (/ )-reticuline (20) via an ortho-para conpling reaction. For better comprehension, the structure of (f )-reticuhne (20) has been redrawn to highlight the position of the oxidative conpling reaction and to clearly picture the emerging morphine skeleton (24). Because of the pronounced medicinal and economic importance, opium alkaloids are discussed in detail in the following. 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Morphine (10) and codeine (11), constituents of opium, are the most interesting alkaloids found in nature. Morphine is also the oldest alkaloid isolated, in 1805, by the German pharmacist Sertiimer from opium, the sun dried latex of Papaver somniferum. The structure of morphine with its so-called morphinan skeleton, once called the acrobat under the alkaloids, was finally elucidated in 1952 by the first total synthesis performed by Gates and Tschudi. Many syntheses would follow [26], but all morphine used today, whether legal or illicit, originates in the natural source P. somniferum or its extract, opium. The latex may contain up to 20% morphine. Most legal morphine is converted into the anticough medicine codeine (Table 5.1) by treatment with trimethylanilinium methoxide, whereas almost all illicit morphine is acetylated to the diacetate heroin. 

Morphine (5) and codeine (methylmorphine) (6), two major morphinan-type alkaloids with an isoqninoline skeleton, are extracted from opium, the dried milky sap released from the immature finits of poppies (Papaver somniferum). Morphine and codeine can interact with opioid receptors distribnted in brain tissnes and the periphery, and are most widely nsed as narcotic analgesics, with codeine also having an antitussive effect [4, 25, 32]. 

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