Nicotine syntheses

Table 4.7 Summary of reaction metrics and synthesis according to overall kernel (maximum) RME. tree parameters for nicotine synthesis plans ranked ...

Figure 4.30 Histograms showing individuai reaction performances for nicotine synthesis pians.

BALDWIN, I.T., SCHMELZ, E.A., OHNMEISS, T.E., Wound induced changes in root and shoot jasmonic acid pools correlate with induced nicotine synthesis in Nicotiana sylvestris. J. Chem. Extol., 1994,20,2139-2158. 

Figure 9.1. Different defense strategies of Nicotiana plants that evolved in response to herbivore attack. Besides a specialized germination-behavior that efficiently reduces the over-all number of potential herbivores, Nicotiana plants evolved the inducible nicotine synthesis as a direct defense and the inducible emission of volatiles to attract parasitoids of the herbivore as an indirect defense. A specialized defense mechanism is triggered in response to attack by the herbivore Mctduca sexta, adapted to Nicotiana plants. Attack results in an ethylene burst, which down regulates nicotine accumulation and results in a fundamental transcriptional re-organization within the plant.

In 1895 Am6 Pictet (1857-1937) published the first nicotine synthesis. [529,530] Key steps are the formation of 3-(lff-pyrrol-l-yl)-pyridine from 3-aminopyridine and mucic acid and its rearrangement to 3-(l//-pyrrol-2-yl)-pyridine at high temperatures. N-Methylation and sequential reduction give eventually racemic nicotine, which can be separated with tartaric acid into its enantiomers. 

Since the first nicotine synthesis by Am Pictet (1857-1937) in 1895, a whole host of other syntheses - mostly of racemic nicotine - has been recorded. [522, 541] The enantiomers can be separated with tartaric acid. The (R)-enantiomer is also obtainable by microbial degradation of the (S)-nicotine in the race-mate. [560] Surprisingly, only a few enantioselective total syntheses of nicotine have been published up to the present time. [561] Two of them, which look particularly elegant, are discussed below. 

Tropane alkaloids are found mainly in the Solanaceae [14] plant family. First biosynthetic step of tropane alkaloids starts with iV-methylation of putrescine (derived from L-omithine) to form Al-methylputrescine. After the conversion to 1-methyl-Al pyrrolinium cation, its condensation with nicotinic acid gives rise to nicotine synthesis, while other chemical conversions lead to the formation of tropinone, the precursor of many tropane alkaloids through branched pathways (Fig. 8.8a) [15]. 

Synthesis Photosynthctic Bactois.—A characteristic of the carotenoids of purple photosynthetic bacteria is the hydration of the terminal 1 and 1 double bonds. This is frequently followed by methylation of the hydroxyls at C-1 and C-1. Rarely does cyclization occur, but -carotene is formed in Rhodo-microbium vanneilii alongside the main pigment 1-hydroxy-1,2-dihydrolyco-pene (rhodopin). In the presence of 1 mmol 1" nicotine, synthesis of both pigments is inhibited and that of lycopene stimulated by a concomitant amount so nicotine not only inhibits cyclization, which involves the terminal... 

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

Syntheses of Nicotine. Pictet and Cr pieux found that 3-aminopyridine mueate on dry distillation yielded l-(3-pyridyl)pyrrole (I), and this, in accordance with the usual behaviour of such pyrrole derivatives, transfers its pyridyl substituent from the 1- to the 2-position at a red heat giving 2-(3-pyridyl)pyrrole (II), which is nomieotyrine. The potassium derivative of this reacts with methyl iodide to form l-methjd-2-(3-pyridyl)-pyrrole methiodide, which is identical with nieotyrine methiodide (III), and on distillation with lime yields nieotyrine (IV Cl — CH). For a re-investigation of this synthesis see Spath and Kainrath. ... 

The tetrahydronicotyrine produced by these methods is identical with dZ-nicotine, and this, by crystallisation of the d-ditartrate, was separated into d- and Z-nicotine. The salient steps in Pictet s original synthesis may be represented as follows —... 

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

The Hofmann-Loeffler-Freytag reaction has been described with A-chloro-as well as A-bromoamines—the former however usually give better yields. A-chlorinated primary amines react well in the presence of Fe-(II) ions. Just like the Barton reaction, the Hofmann-Loeffler-Freytag reaction has been applied mainly in steroid chemistry. An interesting example from alkaloid chemistry is the synthesis of nicotine 12 by Loeffler ... 

Conversion of the carboxylic acid to the diethyl amide interestingly leads to an agent that exhibits the properties of a respiratory stimulant. One synthesis of this agent starts with the preparation of the mixed anhydride of nicotinic and benzene-sulfonic acid (4). An exchange reaction between the anhydride and diethyl benzenesulfonamide affords nikethemide (5). ... 

Tndecanedione, 47, 95 Tnethylamine, 46, 18 dehydrobromination of o-bromo-y-butyrolactone with, 46, 23 dehydrobromination of or.a -dibromo-dibenzyl ketone, 47, 62 dehydrochlormation of cyclohexane-carbonyl chloride, 47, 34 in synthesis of nicotinic anhydride with phosgene, 47, 90 Tnethyl orthoformate, condensation with N,N diphenylethylene-diaminc, 47,14... 

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