Galanthamine type alkaloids

No new members of this series have been reported, but the structures of the individual alkaloids are now reasonably certain, based on the degradative, synthetic, biosynthetic, and X-ray research of the past six years. This group of alkaloids includes bodamine, chlidanthine, galanthamine, epigalanthamine, narcissamine, narwedine, and nivali-dine. Because the alkaloids are so closely related, it is most convenient to discuss them as a group rather than individually. 

Structure XCIV (R = CH8) (without stereochemical designations) was cited in Volume VI as the most likely structure for galanthamine. 

XCVII). Both the relative and absolute stereochemistry cited for (- )-galanthamine have been substantiated by X-ray methods 104). Bodamine (mp 208°-210° [a]p +0° in CHCI3) forms hydriodide (mp 245° decomp.) and methiodide (mp 265° decomp.) salts. The IR-spectrum of the alkaloid is identical with that of (— )-galanthamine and bodamine is considered to be ( )-galanthamine 24). 

Oxidation of XCIV with either manganese dioxide or chromium trioxide afforded (— )-narwedine (XCV). This ketone is racemized excep- 

Narwedine ([a]p - -100°) was reported to be a constituent of Texas daffodils (105). Repetition of this extraction in another laboratory (103) afforded a mixture of ( )-narwedine and (—)-galanthamine after chromatograph3 Recrystallization from benzene gave narwedine ([ Id +32°). Because of the ease of racemization and its resolution phenomenon in the presence of traces of various galanthamine derivatives the sign of optical rotation of the naturally occurring narwedine is unsettled. 

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Cyclization of the diarylamine 237 with hypervalent iodine (PIFA) afforded the two spirosystems 238 and 239 formed by p-p and p-o coupling, respectively (Equation 33) <1998JOC6625>. Substituents influenced the nature of the product and yields (up to 60%) were best when X = F1, R and R = -CPh2- (only product, 238 60%) or X = TMS, R and R = -CMer,which gave predominantly 239 (46%), with only 12% of the corresponding cyclized 238. These products act as precursors of galanthamine-type alkaloids. 

The structure of sanguinine (295) was initially based on spectroscopic comparisons with galanthamine (291) and related alkaloids, but this assignment was subsequently verified by its conversion to 291 by methylation with diazomethane in DMSO (62). Thus, 295 represented the second example of a phenolic base among the galanthamine-type alkaloids. 

Several other synthetic sequences have been developed that lead to the production of potentially useful intermediates for the total synthesis of galanthamine-type alkaloids. For example, the 4-arylbutyric acid 348 has been converted to the tetrahydrobenzazepine 349 by a modified Curtius reaction followed by cycliza-tion of the intermediate isocyanate with polyphosphoric acid (168). N-Methyla-tion of 349 and photooxidation of the resulting tertiary lactam in the presence of NBS gave 350. 

Scheme 13. Galanthamine-type alkaloids targeted by oxidative coupling methodology.

Tab. 11. A higher-yielding PIFA-mediated oxidative cyclization approach to galanthamine-type alkaloids.

Galanthamine-type alkaloids derived from a dibenzofuran ring Crinine-type alkaloids derived from 5,10b-ethanophenanthridine Montanine-type alkaloids derived from 5, 11b-... 

The galanthamine-type alkaloids are the only group among the Am-aryllidaceae alkaloids showing two ortho aromatic protons in ring A. This type of alkaloid often shows an A-methyl group, or occasionally A-formyl or A-acetyl... 

Galanthamine-type alkaloids have a dibenzofuran nucleus and are the only group in the Amaryllidaceae alkaloids showing two ortho aromatic protons in ring A -(Table 17.11). Galanthamine 9 and lycoramine 192 are the two most abundant alkaloids in the family Amaryllidaceae plants, especially in the genera Galanthus and Narcissus. 

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