Norbelladine derivatives

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. 

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. 

The synthesis of Amaryllidaceae alkaloids siculine, oxocrinine and peicrinine was reported using a key phenyliodine(III) bis(trifluoroacetate)-mediated intramolecular p-p diphenol coupling reaction of norbelladine derivatives followed by an intramolecular Michael addition <04T4901>. An alternative approach to isoquinoline derivatives was reported by Chang and coworkers. In this report the benzene nucleus is installed via an intramolecular electrophilic cyclization of 3,4-disubstituted lactams 87 to provide 3,4-dihydrobenzo[g]isoquinoline-l(27/)-one 88 and 3,4-dihydroisoquinoline-l(2/7)-one 89 derivatives in good yields <04TL10637>. 

The similar treatment of the norbelladine derivatives using PIFA proved to be a mild and efficient method for preparing the core structures of Amaryllidaceae alkaloids (Scheme 9), such as galanthamine for the treatment of Alzheimer s disease and related alkaloids, i.e., narwedine, norgalanthamine, sanguinine, lycoramine, and maritidine, by dearomatizing carbon-carbon bond formaticHis at the spiro centers [54, 55]. 

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

The substrate scope, the optimum reaction conditions and the presumed reaction pathway in a series of intramolecular couplings of phenyl ether derivatives have been well investigated by Kita et al. In the reaction of norbelladine derivative 27, which has 4-methoxyphenyl and 3,4-dimetho)y-phenyl groups, normal atyl-aryl C-C coupling products (28) are exclusively... 

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