Phenanthrene alkaloids structures

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). 

Phenanthrenoids are structurally classified into 5 subclasses, namely, phenanthrenes, 9,10-dihydrophenanthrenes, dimeric phenanthrenoids, phenanthrene alkaloids and other phenanthrenoids. 

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 structures of some recently isolated phenanthrene alkaloids are shown in Scheme 15.1. 

In relation to their chemical structure and action, they can be classified into two categories. The first are phenanthrene alkaloids and are under international control morphine (MO), codeine (COD), and thebaine (TB), which act on the central nervous system and are used as analgesics, narcotics, and potentially addicting compounds (pain relievers). Heroin is synthesized from MO. The second group is isoquinoline alkaloids Papaverine (PV) and narcotine (also known as noscapine). Narcotine acts only to relax involuntary smooth muscles, for which it is considered an antitussive, and lacks addictive, analgesic, respiratory, narcotic, depressant, and sedative properties. Next to MO, which constitute about 10% by weight of raw opium, is the second most abundant alkaloid present in opium. The three last alkaloids (PV, narcotine, and narceine) are not under international control specially, narcotine and narceine which have scarcely any medical or other uses. Consequently, the five economically significant alkaloids of opium are MO, COD, TB, PV, and narcotine. 

In the Hernandiaceae, only one benzylisoquinoline-phenanthrene alkaloid [( + )-hebridamine (VII.l)] was isolated from H. peltata Meissn. (46,47). This structural type is probably derived biogenetically from the oxidative coupling of two units of reticuline (II.8). 

The natural Aristolochia N-containing substances may be divided into three structural types nitrophenanthrenic acids, phenanthrene lactams, and isoquinoline alkaloids. 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Galanthamine is a phenanthrene-derivative alkaloid of molecular weight 368.43 its structure is shown in Figure 27.2. Galanthamine can be purified from the bulbs of different strains of Narcissus the quantity recovered per 100 mg of dried bulb ranges from 3.9 to 78.7 mg depending on the specific daffodil cultivar used. 

The photocyclization of stilbenes (211) (including its in situ oxidation) to phenanthrenes (213) and that of conjugated arylalkenes to polycyclic aromatics constitute one of the most studied and widely used applications of organic photochemistry. Its potential synthetic utility is amplified by the existence of a number of natural products (mainly alkaloids) that contain a phenanthrene subunit in their structure. In view of the plethora of examples contained in several excellent reviews, only selected examples will be presented here with focus on the selectivity of the process. 

Similarly, the photosensitized electron transfer mediated reactions of several 1-and 9-(aminoalkyl)phenanthrenes using DCB have been investigated by Lewis and coworkers (Scheme 69) [319], These reactions provide an efficient method of construction of skeletal structures of aporphine, phenanthropiperidine, phenanthroa-zepine and related alkaloids. The mechanism of these reactions involves an initial electron transfer from the ground state amine to the singlet arene followed by N-H proton transfer and biradical cyclization. 

Pure dried tylophorine is a yellow powder, and crystallization from common solvents is difficult. Spectral data, including MS, H-NMR, C-IMMR and chiroptical (ORD and CD), of phenanthroindolizidine alkaloids have been well established [18, 42, 44-45]. The three-dimensional crystal structure of tylophorine (1) was first determined by Wang et al [46]. The structure of tylophorine B, as the benzene solvate, has conjoined phenanthrene and indolizidine moieties. The aromatic rings lie almost in the same plane with dihedral angles of 1.7° (A/B), 2.8° (B/C), 2.2° (A/C), and 7.3° (B/D). The E ring adopts an envelope conformation and makes a dihedral angle of 6.7(3)° with the D ring [46]. 

Chemical/Pharmaceutical/Other Class Opiate analgesic an alkaloid and phenanthrene derivative of opium Chemical Structure ... 

The numbering of the phenanthrene ring in the following alkaloids is according to accepted practice [1,102-106], and is illustrated in the structure of northalicthuberine (63). 

The Knorr oxazine theory of morphine structure led to the preparation of a series of bases derived from morpholine [xxxm], so called on account of its supposed relationship to morphine [49-50]. In particular it was found that N-methylnaphthalanmorpholine [xxxrv] undergoes Hofmann degradation to a methine base [xxxv] that can be degraded further to naphthalene and /3-dimethylaminoethanol. The extraordinary ease with which this last stage takes place led Knorr to believe that an ort/to-attacbment of the nitrogen side-chain to the phenanthrene residue in the morphine alkaloids was improbable, and he accordingly advanced the structure [xxxvi] [51]). 

On closer comparison of these successful routes, several distinct styles are apparent. The early approaches of Gates and Ginsburg are truly "synthetic", effectively working blindfolded due to their reliance upon knowledge gained solely from the extensive, but essentially crude, degradative structural studies in fact, as a result, morphine synthesis has probably offered as much to phenanthrene, and in turn to steroid chemistry, as to actual production of the alkaloid itself ... 

Morphine (21a) was first isolated by Sertumer in 1806, followed by codeine (21b) in 1832 by Robiquet and then the non-morphine alkaloid, papaverine by Merck in 1848, all from crude opium preparations. With the invention of the hypodermic needle and the availability of the purified alkaloids, the benefits and problems associated with these compounds (and their synthetic derivative, heroin) rapidly became apparent, leading to the search for potent dmgs without the abuse potential of the morphinoids. With the exception of the semi-synthetic compound, buprenorphine (22), which is approximately 25-50 times more potent than morphine and has a lower addiction potential, none of the compounds made to date from modifications around the phenanthrene stmcture of morphine have exceeded the pain control properties without a concomitant addiction potential. An interesting compound, whose structure is based on that of morphine is pentazocine (Talwin ) (23). This has about 30% of the efficacy of morphine, but has a much lower incidence of abuse and does in fact cause withdrawal... 

Structure. The structure of glaucine was arrived at by Gadamer (12) by a process of intuitive reasoning supplemented by a synthesis. Co-rytuberine dimethyl ether and glaucine were known to be isomeric, and if a relation to papaverine were admitted only two structures were available for the two alkaloids. Pschorr (13), utilizing his well-known phenanthrene synthesis, had attempted to convert papaverine into an aporphine (IV) via the nitro (II) and the amino (III) derivatives. When papaverine is nitrated it yields 6 -nitropapaverine (II), from which the methochloride... 

V-Methyllaurotetanine, C20H23O4N, was obtained from the tertiary phenolic fraction of the alkaloids from L. citrata by Spath and Suominen (28). The alkaloid and its derivatives were amorphous for the greater part. However, the 0-ethyl ether was exhaustively degraded to a nitrogen-free compound which proved to be 3,4,6-trimethoxy-7-ethoxy-l-vinyl-phenanthrene (m.p. 140-141°), identical with a specimen already prepared from laurotetanine (27). The structure of this alkaloid is therefore XV. 

The most important experimental fact, however, reported for any of the miscellaneous bases concerns the unnamed base recently (90) isolated, which accompanies delphinine and staphisine in D. staphisagria. This base, which may not be correctly formulated, on dehydrogenation over selenium jdelds a crystalline hydrocarbon (CisHie), the ultraviolet absorption spectrum of which indicates the presence of a phenanthrene structure. The fact that the presence of a phenanthrene system can be established both in this new base and in staphisine, i.e., in both minor alkaloids accompanying delphinine, whilst delphinine itself does not readily yield a phenanthrene derivative on dehydrogenation (70), should stimulate further research in this field. If the reason for this difference in behavior can be ascertained, it should permit a better imderstanding of the nature of the polycyclic skeleton present in the atisines and in the aconitines and result in a great advance towards the complete elucidation of the structures of the Aconitum and Delphinium alkaloids. 

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