Morphinan skeleton

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. 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

Fig. 20 Fourteen-step synthesis of the complete morphinan skeleton of morphine and codeine, starting with the enzymatically formed diol providing ring C of the carbon frame work of these alkaloids [129, 130]...

The term promorphinane compounds is used for bases without an ether bridge between the rings A and D of the morphinane skeleton. 

Thebaine was isolated from opium in 1835 by Pelletier (439). The therapeutic applicability of thebaine was studied by Balint et al. (440). It was found to be more toxic than morphine. It is a more effective narcotic but a weaker analgesic than morphine. The analgesic effect of thebaine in doses of 0.01 g/kg is greater than that of amidopyrine this effect persists, however, only over a period of 30 min. Dihydro-thebaine is somewhat more effective but it is more toxic (441). The number and the location of the double bonds in ring D of the morphinane skeleton is of importance for the analgesic effect. Teraoko... 

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). 

Modifications to the C-ring of the morphinan structure can produce compounds with increased activity, as well as changes in the receptor selectivity profiles [18]. Most pronounced is oxidation of the 6-hydroxy to the 6-keto derivative. With the 7,8-olefin in place, the activity is reduced when compared to morphine. However, reduction of the 7,8-olefin produces compounds with increased activity. Combining the 7,8-dihydro and 6-keto modifications to the morphinan skeleton produces compounds with greatly increased activities (10-fold) over morphine. 

Further Reduction of the Morphinan Skeleton Produced the Benzomorphans... 

Incorporation of an 14-a-oxygen into the normal morphinan skeleton was achieved by synthesis of the tetrahydropyran (19, X = O) with a 14-/3-methyl group. 60 This compound is a potent agonist (100 x the deoxy analog),... 

The direct synthesis of the morphinan skeleton (107) from (105) involves the intramolecular ring opening by the enolate anion of the in situ generated aziridine cation (106) (Scheme 41) <88J0C2144>. Compound (108) was found to rearrange thermally to the thermodynamically favored azabicyclo-[3.3.1]octane (110) via the aziridinium ion (109) (Scheme 42) <93CC758>. 

MAO was used in vivo and in vitro as a catalyst for the production of norlaudano-sine from dopamine (Fig. 16.7-14)[35]. Norlaudanosine is an important synthon for benzylisoquinoline alkaloids, providing the upper isoquinoline portion of the morphinan skeleton. In vitro and in vivo yields were in the range of 20 %. 

In this review, the term promorphinane compounds has been used for those bases which have no ether bridge between the rings A ind D of the morphinane skeleton. These compounds were found to occur both in the Papaveraceae and the Menispermaceae. 

Fuchs elegant approach to the morphinan skeleton utilized an intramolecular conjugate addition/alkylation sequence, in which connections C12-C13 and C9-C14 were formed as a result of one tandem process.73-74 Mitsunobu condensation between alcohol 164 (from 2-allylcyclohexene-l,3-dione in five steps and 43% overall yield) and phenol 163 (from isovanilline in 6 steps and overall yield of 40%)73c gave the ether 165, Scheme 19. TBDMS deprotection followed by an oxidation/reduction sequence set the aryl ether... 

Other examples of alkaloids possessing the morphinan skeleton include sinomenine [6—8] isolated from the roots of Sinomenium acutum (Menisper-maceae), and metaphanine [9—14] isolated from the stems of Stephania japonica (Menispermaceae). Sinomenine possesses the mirror image skeleton to that of morphine, and is derived from (S)-reticuline. On the other hand, metaphanine possesses the hasubanan skeleton. Total syntheses of metaphanine have been reported [15,16]. 

Both enantiomers of the morphinan skeleton occur in nature. 

Even more than 60 years after the first total synthesis of morphine by Gates [139, 140], the ongoing interest of synthetic chemists in the natural product is evidenced by the numerous approaches to the morphinan skeleton, as well as formal and total syntheses of the natural product. The progress in morphine synthesis has been reviewed on several occasions [141-143]. 

In these aberrant biosyntheses of the morphinan skeleton from reticullne analogs, the retention of tritium at C-1 is remarkable, since reticuline itself loses considerable tritium from this position). 

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