Nitidine synthesis

The above biomimetic method was successfully applied to synthesis of 2,3,8,9-tetraoxygenated fully aromatized benzo[c]phenanthridine alkaloids such as nitidine (243) (134,135), fagaronine (244) (134,135), and oxyterihanine (242) (136) (Scheme 42). The former two alkaloids attract many synthetic... 

Scheme 42. Biomimetic synthesis of nitidine (243), fagaronine (244), and oxyterihanine (242) via enamide aldehydes.

Synthesis of all four 8,8a-secobenzophenanthridine alkaloids was carried out chiefly by Baeyer-Villiger oxidation of appropriate benzophen-anthridines (Scheme 32). Thus, arnottianamide (206) was obtained from chelerythrine (210) (172,175), iwamide (207) from N-methyldecarine (211) (168,172), integriamide (208) from avicine (212) (171,172), and isoarnottiamide (209) from nitidine (213) (172,175). The proposed mechanism of this reaction (168,172,175) consists of initial attack of the peroxide ion on the C=N+ double bond followed by rearrangement and hydrolysis. 

So far only a few examples of the uses of organosilicon compounds in cross-couplings have been published. Noteworthy is the smooth reaction with a sterically hindered substrate (87).295 The synthesis of the alkaloid nitidine included a cross-coupling step using an alkenylsilane (88),296 while the syntheses of some antitumor agents involved the alkenylation of unprotected iodouracyls using alkenyl-silicon species.297... 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

Avicine and Nitidine. Among many 2,3,8,9-tetrasubstituted alkaloids, nitidine (77) and fagaronine (79) have been shown to possess very potent antileukemic activity, therefore becoming targets for their synthesis 82,83). 

Begley and Grimshaw (94) reported a modified synthesis of nitidine (77) by shortening the steps in Kessar s route (88) by using the A -methylbenza-mide (93) under photochemical conditions. However, they failed to obtain benzo[c]phenanthridone by electrochemical means (94) (Scheme 47). 

Another application of the cro,ss-coupling reaction is demonstrated in Scheme 10-3 with an efficient synthesis [13] of the precursor of an alkaloid, nitidine, which inhibits DNA topoisomerase I. 

In 1978, the synthesis of the indenoisoquinoline NSC 314622 (Figure 6.16) was reported as the result of an unexpected transformation during a synthesis of nitidine chloride. Given its weak antitumor activity, it was not investigated further. 

There are several others that inhibit DNA replication. Fagaronine and nitidine have ben mentioned previously as intercalating agents, and this intercalation evidently inhibits the action of DNA polymerase [334]. Several benzophenanthridines and protoberberines inhibit reverse transcriptase, which catalyzes the synthesis of DNA with an RNA template [356, 357]. Mimosine at the cellular level, rather than directly on the process, is an inhibitor of DNA synthesis because it chelates iron [358] and because it blocks the synthesis of thymidylate, an essential precursor of DNA [359]. Vincristine may also act as an inhibitor of thymidylate synthesis, perhaps because it alkylates an essential thiol group of an enzyme [360]. 

Cyclization of aryl and/or heteroaryl groups by the light-induced elimination of halogen acids is a facile and widely applicable process, and has been used as a step in the synthesis of nitidine and avicine salts (104).153 Thus irradiation of (105)... 

Ninomiya et al. carried out the total synthesis of avicine, nitidine, and... 

A common intermediate in the synthesis of benzo[c]phenanthridines is the 2-aryl-l-tetralone, which provides rings A, B, and D of the alkaloid nucleus. In 1973, two independent research groups reported the synthesis of nitidine via the 3,4-dihydro-2-(3,4-dimethoxyphenyl)-6,7-methylenedioxy-(2/7)-naphthalone 29 (Scheme 2). The synthesis of this intermediate was arrived at by two different routes. Kametani ei al. (73JHC31) reduced 3-(3,4-methylenedioxyphenyl)proprionate 21 to the corresponding alcohol 22 with lithium aluminium hydride, which was then converted to the chloride 23 with thionyl chloride. After production of the nitrile 24 by reaction with sodium cyanide and subsequent hydrolysis to the carboxylic acid 25, Friedel-Crafts cyclization of the acid chloride 26 afforded the tetralone intermediate 27. Reaction with l-bromo-3,4-dimethoxybenzene 28 in the presence of sodium amide yielded the tetralone intermediate 29 in an overall yield of 4%. 

A patent has been published covering the synthesis of nitidine-like compounds.Chelilutine has been correlated with nitidine and iso-arnottianamide. ... 

This methodology was successfully appHed in the formal synthesis of biologically relevant benzo[c]phenanthridine alkaloids nitidine and NK109 (Scheme 3.28) [36],... 

This approach has been used by Ninomiya, Ishii, and their co-workers in the synthesis of such aromatic benzophenanthridine alkaloids as dihydro-nitidine and dihydroavicine. ... 

A short synthesis of nitidine involves Mannich cyclization of the cis amine 17 as indicated below... 

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