Norbelladine

Oxidative phenolic coupling. Biosynthesis of the alkaloid narwedine (3) is known to involve oxidative phenolic coupling of norbelladine derivatives (1), but the usual oxidants for such coupling in vitro convert 1(R = H) into the oxomaritidine skeleton (4) rather than 3. A new biomimetic synthesis of 3 involves the palladacycle 2, formed by reaction of 1(R = CH3) with Li2PdCl4, which is known to form complexes with allylic amines or sulfides (8,176-177). Oxidation of 2 with thallium(III) trifluoroacetate effects the desired coupling to give 3. 

From L-tyrosine, or alternatively from L-phenylalanine, there is one further alkaloid biosynthesis pathway. This is the galanthamine pathway (Figure 38). Galanthamine synthesizes with tyramine, norbelladine, lycorine, crinine, N-demethylnarwedine and Al-demethylgalanthamine. Schiff base and reduction reaction, oxidative coupling and enzyme NADPH and SAM activity occur in this pathway. Schiff base is a reaction for the ehmination of water in formation with the C—N bonds process. 

From norbelladine, through the activity of the SAM, the 4 -0-methylnorbelladine synthesizes, and again is transformed to lycorine, crinine and, by oxidative coupling, to A-demethylarwedine, which is the object of enzyme NADPH activity. Galanthamine is synthesized by transformation trough the activity of the SAM from A-demethylgalanthamine. 

One of the characteristics of intermedia is that in many cases it is not a stable compound (e.g., cadaverine). Intermedia is a compound which can be the final product of any pathway. However, an alkaloid can convert from an intermedia (e.g., norbelladine from tyramine in the galanthamine pathway), though this process is restricted. Generally, the synthesis pathway continues to establish the next compound, the obligatory intermedia. 

Non-depolarizing alkaloids 185 Non-natural alkaloids 6 Non-protein derived alkaloids 93, 94 Noradrenaline 110, 112, 187 Norbelladine 94, 110 Norcoclaurine 7, 176 Norephedrine 10 Norepinephrine 171, 194 Norevoninate alkaloids 108, 109... 

The norbelladine derivative 408, which served as the starting material for the synthesis of ( )-oxocrinine (415) (Scheme 35), may be readily prepared from the reductive animation of piperonal with tyramine followed by acylation with trifluoroacetic anhydride (191,192). When the N-acylated monophenol 408 was treated with excess thallium tris(trifluoroacetate) in methylene chloride, the di-enone 412 was obtained in 19% yield (191), whereas use of the oxidant vanadium oxyfluoride in trifluoroacetic acid/trifluoroacetic anhydride afforded 412 in 88% yield (192). Base-induced N-deacylation of 412 was accompanied by spontaneous cyclization to furnish racemic oxocrinine (415). Attempts to oxidize the free amine derived from 408 led to the formation of a number of products, some of which resulted from oxidation at nitrogen. 

The isolation of ryllistine (579) represented the first time that a 4-oxygenated norbelladine alkaloid had been isolated from the plants of the family Amaryllida-ceae. The structural assignment was based on spectroscopic methods including a complete assignment of the 13C NMR spectrum combined with its chemical synthesis by reductive amination of veratraldehyde and homoveratrylamine (6). 

Since the successful biogenetically patterned synthesis of the galanthamine skeleton from O V-dimethylnorbelladine (397) by oxidative coupling performed by Barton and Kirby several attempts have been carried out along these lines. However, several norbelladine derivatives were used in the hope that a decrease in the nitrogen lone pair availability might increase the yields in the oxidation phase. 

In the first the mode of incorporation of the amino phenol O-methyl-norbelladine 343 into 10 was examined. Thus, tritium labels were inserted ortho and para to the phenolic hydroxy groups of 343 by base-catalyzed exchange with tritiated water under conditions ensuring equal labeling in all exchangeable positions. Norpluviine biosynthetized from multiply labeled 343 in Texas daffodil was selectively degraded to locate the tritium labels. 

In daffodil plants, galanthamine (147) is biosynthesized from the aminophenols 397, 398, and 399 but not from 343 which is, however, in the same plants a good precursor of haemanthamine (318) and lycorine (1) (Vol. XI, p. 397). These experimental results were interpreted as proving the existence of a definite order of methylation of norbelladine (399) during the biosynthesis of 147. Thus, methylation takes place in the first instance at nitrogen to give 398, later converted into 397. 

The norbelladin derivative (186) undergoes oxidative coupling in ferric chloride solution, the product (187) suffering further coupling on hydrolysis to give the crinin derivative (188).207 That these... 

Studies directed toward the synthesis of amaryllidaceae alkaloids provide instructive examples of the combined use of spirocylization and Michael addition pathways in phenolic oxidations (03MI1). For example, treatment of the norbelladine derivative 164 with BTIB leads, by way of C,C-bond formation, to the spiroannulated azepine 165 (Scheme 47) (96JOC5857, 98JOC6625). Hydrolysis of the amide moiety in 165 results in Michael addition of the nitrogen center to the dienone ring and affords ( )-oxomaritidine (166). BTIB-oxidation of the appropriate... 

BTIB-oxidation of the norbelladine derivative 169 furnishes the spiroazepine 170 (Scheme 48) (98JOC6625). Exposure of 170 to trifluoroacetic acid initiates a deprotection-cyclization sequence... 

Similarly, the norbelladine derivative 489, prepared from L-tyrosine methyl ester and isovaniiine, was oxidized with PhI(OCOCF3)2 in trifiuoroethanol (TFE) at —40°C to afford in 64% yield an intramolecular coupled product 490. This is known as the key... 

Although norbelladine was shown not to be a precursor of galanthamine (101) in King Alfred daffodils, an incorporation of this compound with labels as shown (103), comparable to that for lycorine (104), has been obtained for galanthamine in Leucojum aestivum As expected, the lycorine showed loss of half its tritium. On the other hand, no loss of tritium was apparent in the galanthamine. The latter result suggested that in the biosynthesis of galanthamine conversion of (105) to narwedine (100) was either not reversible or, if so, enzy-mically controlled. 

Oxidative condensation (2, 258). Manganese dioxide elfects the oxidative condensation of the norbelladine derivative (1) to the dienone (2) in 10-13% yield.4 Polymeric material is also formed, but (2) is essentially the only monomeric oxidation product. Use of potassium ferricyanide gives an array of products. The dienone (2) undergoes acid-catalyzed rearrangement to (3), which has the ring system of the amaryllis alkaloid nivalidine. 

The fact that more than 50% of the tritium is retained suggests that O-methyl-norbelladine is incorporated into narciclasine via path a rather than path b and this conclusion was confirmed by degradation to show that the tritium in narciclasine resides at both C(2) and C(4) as would be expected. 

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