Synthesis coniceine

A synthesis of 5-coniceine by a transannular reaction has been reported (81TL2075). Treatment of N-allyl-N-3-butenyl-N-benzyloxycarbonylamine with thexylborane followed by cyanidation afforded an azacyclanone in 35% yield which could be transformed into 5-coniceine by catalytic reduction (Scheme 28). 

The indolizines constitute the core structure of many naturally occurring alkaloids, such as (-)-slaframine, (-)- dendroprimine, indalozin 167B and coniceine. There are a number of different routes to the synthesis of indolizines and they are most commonly synthesised by sequential N-quaternisation, intramolecular cyclocondensation reactions or the cycloaddition reaction of /V-acyl/alkyl pyridinium salts. 

The recent synthesis of ( ) 8-coniceine (190) involved a pyrroline derivative (191) as a key intermediate as it was relatively stable. It was cyclized with methanolic hydrogen chloride, desulfurized with Raney... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

In addition to the syntheses of these classes mentioned in previous sections, RCM was applied to the total synthesis of the pyrrolizidine alkaloid (-)-croalbinecine and the indolizidine alkaloid (-)-coniceine <01TA2621, 00CC1027> (Scheme 69). 

Roberts, M.R (1981) Enzymic synthesis of coniceine in Conium maculatum chloroplasts and mitochondria. Plant Cell Rep., 1,10-13. 

This base does not occur in hemlock but is obtained from coniine. In a new synthesis of this substance, l-(2-pyridyl)-3-bromopropanol prepared from ethylene oxide, picolyllithium, and bromobenzene, is hydrogenated catalytically. The product is 8-coniceine identified through its picrate, m.p. 224-227°, its chloroaurate, m.p. 185-188°, its chlor-platinate, m.p. 209-211°, and its mercuric salt, m.p. 233-237° (40). 

This route was used in a synthesis of the simple indolizidine alkaloid 8-coniceine (41). AAAcylimines are only transient intermediates in these Diels-Alder reactions and are not usually detected. However, Lasne et al.,i7 using a flash vacuum pyrolysis (FVP) technique, have generated neutral AAacylimines and showed that they are indeed involved in Diels-Alder cycloadditions. 

The synthesis of indolizidine alkaloids, including tylophorine and 6-coniceine as well as Elaeocarpus alkaloids, by the intramolecular imino Diels-Alder method (cf. vol.12, p.71) has been pub-... 

An elegant synthesis of pelletierine acetal has been reported (497) although it has not yet been possible to synthesize the alkaloid itself. /3-(2-pyridyl) - propionaldehyde diethylacetal, obtained in 28-29% yield from lithium picolyl and bromoacetal, is hydrogenated in glacial acetic acid over a platinum catalyst to 3-(2-piperidyl)-propionaldehyde diethylacetal. It is of interest to note that if the hydrogenation be carried out in dilute solution, the product is 6-coniceine (498). However, hydrolysis of the acetal succeeds only if the secondary nitrogen is first blocked (497, 518). 

In the course of a study of a synthesis of dZ-pelletierine, Beets and Wibaut (498) discovered a new mode of preparation of 5-coniceine. The catalytic hydrogenation of j8-(2-pyridyl)-propionaldehyde diethyl acetal in glacial acetic acid solution over platinum leads to different products, depending on the concentration used. If the hydrogenation be carried out in concentrated solution, the product is dZ-pelletierine diethyl acetal, but if a dilute solution is used, 5-coniceine is obtained. Solutions of medium concentration afford mixtures of the two products. 

In the other synthesis 75), the Leuckart reaction on y-ketosuberic acid gave 3-(6-oxopiperidyl)propionic acid which on heating yielded LII. Lithium aluminum hydride reduction of LII gave S-coniceine (L). 

The acid-catalysed decomposition of tertiary azides derived from cyclopentane to give a-substituted piperideines has been applied to the synthesis of certain piperidine alkaloids such as y-coniceine, ( )-coniine, and ( )-dihydropinidine. 

Yoda, H., Katoh, H., Ujihara, Y. and Takabe, K. (2001) SmI2-mediated hetero-coupUng reaction of lactams with aldehydes synthesis of indolizidine alkaloids, (—)-D-coniceine, (-l-)-5-epiindolizidine 167B and (-l-)-lentiginosine. Tetrahedron Lett., 42, 2509-12. 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

Fig. 69. Synthesis of different types of polyketides with eight C-atom 1 y-Coniceine reductase...

Later experimental work provided evidence that the 8-carbon polyketoacid intermediate in the synthesis of y-coniceine is derived from octanoic acid since this acid was shown to be readily incorporated into coniine. Further work indicated that 5-keto-octanoic acid and 5-keto-octanal were produced during the biosynthesis of y-coniceine. A transaminase (L-alanine 5-keto-octanal aminotransferase) was obtained from C. maculatum. This transaminase catalyzes the reaction between 5-keto-octanal with L-alanine as the amino group donor to form the piperidine ring and the propyl side chain. Another C. maculatum alkaloid, A-methylconiine, was shown to be produced by another enzyme from the plant a coniine methyltransferase which acts as a transmethylator utilizing 5-adenosyl-L-methionine as a methyl group donor. 

A study of transannular cyclizations in nine-membered azaolefins has led to a ready synthesis of the indolizidine alkaloid 5-coniceine (46) and a number of its congeners (Scheme 78)." Cyclic olefinic lactones may also be used to prepare the indolizidine ring system, by regiospecific ring closure, when treated with a suitable... 

The total alkaloid concentration bases of both varieties of Conium maculatum since they are a reflection of both the rate of synthesis as well as that of turnover. The large pool of y -coniceine in var. California compared with var. Minnesota would appear to be due to a combination of a faster rate of synthesis (35 m)Ltmol/hr/g) and a slower turnover (4 days) compared with the slower rate of synthesis (4.5 m/umol/hr/g) and a faster turnover (1 day) for var. Minnesota. In either case the methylation of coniine does not appear to be limiting since it did not occur at a measurable rate in var. Minnesota which had total activity and pool ratios consistent with a rapid conversion of y-coniceine into coniine. 

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