Morphinan-type alkaloids

A total of more than 20 total syntheses have been described which aim to generate the most important members of the morphinan-type alkaloids, morphine and codeine. These long-standing efforts in alkaloid synthesis have been primarily due to the exceptional pharmacological importance of both compounds, as the most efficacious therapies for pain and cough, respectively. 

The role of reticuline as an intermediate in the biosynthesis of the mor-phinan alkaloids (Fig. 2.8) was demonstrated by the isolation both of (S)-and (f )-reticuline from the opium poppy. An excess of the (S)-reticuline over the (f )-isomer was found in opium (poppy latex) obtained from the mature plant, in contrast to the roughly equal amounts of these two isomers that occur in poppy seedlings. Both isomers were found to be incorporated into morphine, the major alkaloid isolated from opium, although incorporation of the (f )-isomer was slightly more efficient. (f )-Reticuline is firmly established in P. somniferum as the precursor of the morphinan-type alkaloids (Loefer and Zenk, 1990). (S)-Reticuline, however, is the central intermediate in isoquinoline alkaloid biosynthesis. It has been postulated that (R)-reticuline is formed from (S)-reticuline by isomerization. This inversion of configuration can be explained by the intermediate formation of the 1,2-dehydroreticulinium ion originating from (S)-reticuline, followed by stereospecific reduction to yield the (R) counterpart. The 1,2-dehydroreticulinium ion is efficiently incorporated into opium alkaloids and its role as a precursor of the morphinan-t)q)e alkaloids has been unequivocally established (De-Eknamkul and Zenk, 1990, 1992). 

From the viewpoints of biological activities and structural architectures, a variety of benzylisoquinoline alkaloids have been chosen as synthetic target molecules. These alkaloids are well known to be biosynthesized by oxidative phenol coupling via a radical mechanism. However, White and coworkers demonstrated that hypervalent iodobenzenes are effective oxidants for syntheses of morphinane-type alkaloids such as (—)-codeine °. 

Opitim contains 10-25% alkaloids, and the main constituent is morphine. Other than morphine, more than 25 alkaloids are known, and among them are other morphinan-type alkaloids (codeine and thebaine), benzyl-isoquinoline-type alkaloids (papaverine and noscapine), and protopine-type alkaloids (protopine). The biosynthetic precursor of all of these alkaloids is phenylalanine. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

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]. 

A major study on 13C-NMR spectroscopy of hasubanan alkaloids was carried out by Matsui et al. (5) (Table III). They proposed assignments of all carbon atoms including the direct and long-range hetero coupling. The C-9 and JV-methyl carbons of hasubanan alkaloids reveal shifts of 6 and 20 ppm higher frequency than those reported for morphinan alkaloids (9). On the other hand, the iV-methyl carbons of hasubanans exhibit a lower frequency shift of 10 ppm relative to those of hasubanalactam-type alkaloids (5). These results have been utilized for structure elucidation in later works (4,7,10-12). 

Some years ago a general synthetic method 52) for the morphinan-dienone-type alkaloids was discovered by modifying the Pschorr reaction which had been used widely for the synthesis of the aporphine alkaloids and this method was applied to a synthesis of the homo-morphinandienone-type compounds. 

The Diels-Alder reaction of morphinan-6,8-dienes with nitroethene affords a novel type of opium alkaloids (Eq. 8.3).10a High reactivity of nitroethylene is demonstrated for the Diels-Alder reaction with thermally unstable dienes, and this is used for synthesis of polycyclic kopsane-like alkaloids.1013... 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

This is a 1,1-spirobenzyl intermediate to what is quite likely the entire family of the aporphines. The "pro" part of the name suggests that this is a biosynthetic precursor to these alkaloids. Very often there is a keto function at the 4-position of the benzyl group (equivalent to a hydroxyl group on the original benzyl), to facilitate the spiro loss of aromaticity needed to achieve this type of coupling. This is directly analogous to the (2,4a) attacks needed to get into the morphinans, where... 

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

The cytochrome P450 responsible for the oxidation of (S)-N-methylcoclaurine to (S)-3 -hydroxy-N-methylcocluarine has been overexpressed in opium poppy plants, and morphinan alkaloid production in the latex is increased subsequently to 4.5 times the level in wild-type plants (58). Additionally, suppression of this enzyme resulted in a decrease in morphinan alkaloids to 16% of the wild-type level. Notably, analysis of a variety of biosynthetic gene transcript levels in these experiments supports the hypothesis that this P450 enzyme plays a regulatory role in the biosynthesis of benzylisoquinoline alkaloids. Collectively, these studies highlight that the complex metabolic networks found in plants are not redirected easily or predictably in all cases. 

Although in P. somniferum and Sinomenium acutum the biosynthesis of the morphinane bases can be carried out with (+)-reticuline as starting material, these bases and also protopine (101a) cannot be obtained biosyn-thetically in satisfactory yield from (+)-tembetarine chloride (reticuline methochloride). Similar results were obtained with D. spectabilis (683). Important intermediates of the biosynthesis between tetrahydroprotober-berine and protopine alkaloids are the compounds of the dihydroprotopine type (102), which were prepared in high yield by partial synthesis with cyanogen bromide (von Braun method) (684). The biosynthesis of pro topine alkaloids is also discussed in Section III,N. 

Attempts have also been made to cultivate such a type of P. somniferum which would contain a large quantity of morphine/codeine alkaloids in the straw (846, 847). This material can be adapted agrotechnically for an easier industrial isolation of morphinane alkaloids by the Kabay method. 

S)-(+)-reticuline (20) and orientaline (25). The alkaloids of the Papaveraceae and Fumariaceae can be subdivided into several constitutional types (Fig. 3), viz., simple isoquinolines, benzylisoquinolines, pavines, isopavines, cularines, proaporphines, aporphines, promorphinanes, morphinanes, protoberberines, retroprotoberberines, secoberbines, benzophenanthridines, protopines, phthali-deisoquinolines, secophthalideisoquinolines, indenobenzazepines, spirobenzyl-isoquinolines, and rhoeadines. 

On the basis of the results of the studies of alkaloids of the section Miltantha, it is concluded that there exist at least three different chemical races in which the major alkaloidal types are either benzylisoquinolines and proaporphines, or morphinanes or rhoeadines. 

Alkaloids of the / -quinonoid-aporphine (IX.1-IX.3) type are present in H. sonora L. (32), while the morphinane (X.1-X.2) type, also known as promorphine alkaloids, occurs only in H. voyronii Jum. (S,9). These alkaloids did not inhibit platelet aggregation in vitro induced by thrombin, arachidonic acid, collagen, and PAF (32) (Table II). 

Enzymes of a secondary biosynthesis are usually localized in different cell types and different subcellular compartments. For instance, three cell types are involved in the biosynthesis of morphinane alkaloids in Papaver, a similar diversity of distribution holds true for the enzymes of terpenoid indole alkaloids in Catharanthus (Facchini... 

The biosynthesis of the various isoquinolines is reviewed in two chapters, one devoted solely to the morphinans and the other to the other skeletal types. Attempts to produce morphinan alkaloids by plant cell culture techniques has produced a flurry of activity in several laboratories throu out the world. Four chapters are concerned with plant cell culture techniques for the production of isoquinolines. A series of enzymes which catalyse specific steps in isoquinoline alkaloid biosynthesis have been isolated in recent years and the stage is now set for the isolation and characterization of the enzymes responsible for morphinan alkaloid biosynthesis. The utilization of these enzymes for biotechnological conversions is now envisaged. 

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