Norbelladines, oxidation

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. 

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. 

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. 

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... 

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. 

Barton and Cohen (116) proposed that norbelladine (85) or related compounds could undergo oxidative coupling of phenols in Amaryllidaceae plants, once ring A had been suitably protected by methylation, resulting in the different skeletons of the Amaryllidaceae alkaloids (Fig. 4). 

Tyramine and protocatechuic aldehyde are logical components for the synthesis of norbelladine (CXXVIII R, Ri, R2, R3 = H). This substance and various 0- and A-substituted derivatives were suggested as probable precursors of the Amaryllidaceae alkaloids. Barton and Cohen 167) proposed that compounds such as CCXXVIII could undergo oxidative phenyl-phenyl coupling in the plant to form the intermediate... 

Secondary cyclization is produced by an oxidative coupling of O-methyl-norbelladine. 

In Amaryllidaceae plants, an 0-methylation of norbelladine on the 3,4-DHBA aromatie ring takes place prior to intramolecular oxidative coupling which results in the formation of different skeletons of AAs. Thus, the key biosynthetic intermediate of AAs is 4 -0-norbelladine (Figure 4). 

In plants, norbelladine is produced from the condensation of protocatechuic aldehyde, and tyramine and the latter two metabolites arise from the naturally occurring L-Phe and L-Tyr, respectively (Scheme 17.2). Hydrogenation reduction of the resulting Schiffs base affords alkaloid norbelladine 2, which is further converted into 4 -methylnorbelladine 10 after methylation on the A -O position. Generally, alkaloid 4 -methylnorbelladine 10 was considered as the key precursor for alkaloids of this family [104]. Alkaloid 4 -methylnorbelladine 10 can be converted into other stmc-turally complicated alkaloids through three different oxidative coupling approaches (1) ortho-para, (2) para-para, and (3) para-ortho (Scheme 17.3). 

Further experimental results established norbelladine 6.180) and some of its methylated derivatives (clearly not others) as key biosynthetic intermediates in the biosynthesis of, e.g., lycorine 6.185), haemanthamine 6.187) and galanthamine 6.190) [125-128, 132, 133]. As elsewhere (see Section 6.3) hydroxy-groups ortho and/or para to sites of new bond formation between aromatic rings are essential for biosynthesis to proceed, a telling set of examples in support of the phenol-oxidative coupling hypothesis. Of further interest is the reported isolation of an enzyme, from a plant of the Amaryl-lidaceae, which, when incubated with norbelladine and 5-adenosylmethionine (source of methyl groups), yielded almost entirely the 0-methylnorbelladine, 6.181), that is involved in alkaloid biosynthesis [134]. 

The third group of alkaloids which arise from norbelladine 6.180) this time by para-para phenol oxidative coupling, is exemplified by haemanthamine 6.187)., and biosynthesis is proved to be by way of compounds of type 6.186). Haemanthamine 6.187) shows an extra hydroxy-group at C-11, which has been shown to arise by hydroxylation with normal retention of configuration [139, 140]. 

Table 8.1 PIFA-Induced intramolecular oxidative coupling of norbelladine derivatives under the various reaction conditions.

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