2,6-disubstituted piperidine alkaloids

Additional 2,6-disubstituted piperidine alkaloids detected in Picea and Pinus include pinidinone and epipinidinone (191 and 194, from Picea pungens), 193 (from Picea abies, P. pungens), 195 (from Pinus nigra, P. sylvestris, P. ponderosa) and 196 (from Picea pungens, Pinus ponderosa, P. sylvestris, P. nigra)[467]. Pinidinone, an alcohol from reduction of pinidinone, and 196 have also been detected in the Mexican Bean Beetle, Epilachna varivestis [468]. 

Kubizna P, sp iik I, Ko2i sek J, Szolcsanyi P. Synthesis of 2,6-disubstituted piperidine alkaloids from ladybird beetles calvia 10-guttata and calvia 14-guttata. Tetrahedron 2010 66(13) 2351-2355. 

Eor direct characterization of disubstituted piperidine alkaloids in extracts of L. inflata, tandem mass spectrometric method was developed using electrospray ionization. Analysis was performed in positive ion mode on a triple quadropole LC/MS system. The identification and structural elucidation of the alkaloids were performed by comparing their changes in molecular mass (AM), full-scan MS-MS spectra with those of lobeline, lobelanine, norlobelanine, and lobelanidine. These alkaloids and ten other derivatives were identified in the plant extracts. 

Hyperaspine (1), a perhydropyrido[l,2-c][l,3]oxazine alkaloid was isolated from the ladybird beetle H. campestris (01TL4621). 9-Epi-6-epipinidinol (90), a piperidine alkaloid, was prepared from a perhydropyrido[l,2-c][l,3]oxazin-l-one derivative (98T13505). Perhydropyrido[l,2-c][l,3]oxa-zin-l-ones were used to prepare 2,6-disubstituted piperidines (96CJC2434). 

The utility of strained disubstituted cycloheptenes in alkaloid syntheses is highlighted by Blechert s total syntheses of the bis-pyrrolidine alkaloid (+)-dihydrocuscohydrine (390) [161],thebis-piperidine alkaloid (-)-anaferin (in the form of its dihydrochloride 393) [162], and indolizine 167B (397) [163] (Scheme 77). 

Three piperidine alkaloids lythranine (72), lythranidine (73), and ly-thramine (74) belong to this group. All have a piperidine ring disubstituted at two a positions by two aralkyl C4-C6 groups joined by a biphenyl bond. 

In light of the present evidence the biogenesis of metacyclophane Ly-thraceae alkaloids required revision, since the only published proposal (9) was based on pelletierine. A new biogenetic scheme was proposed which invoked intermediacy of A piperideine and two C6-C4 units [derived from /i-kctoester (193)]. An intermediate disubstituted piperidine (194) would give rise to two types of metacyclophane alkaloids as a result of reduction and phenol coupling as well as Michael addition in the case of the quinoli-zidine bases (10). 

Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines II (95) and III (96) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32). 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

Disubstituted piperidines (and piperideines) are well known as constituents of myrmicine ant venoms, particularly in fire ants of the genus Solenopsis (125,134,149,161,164). Both cis and trans isomers occur. Cis-and/or rrans-2-methyl-6-nonylpiperidines are prominent ant alkaloids. These ant alkaloids have not been detected in amphibians, but the 4-hydroxy piperidine analog (241D) has. 

Piperidines, like pyrrolidines, appear to have a very limited distribution in dendrobatid frogs. Piperidine 241D occurs as a major alkaloid in one population of Dendrobates speciosus and as a trace alkaloid in a population of Dendrobates pumilio (1). 2,6-Disubstituted piperidines 225B and 2391 have been detected as trace alkaloids in Dendrobates histrionicus (two populations) and Epipedobates trivittatus (one population), respectively (1). In nondendrobatid frogs, 2,6-disubstituted piperidines have not been detected. 

Many 2-substituted piperidine alkaloids are produced by Sedum. In one study, for example, TLC and GC/MS were used, to survey alkaloids in sixteen Sedum species. The alkaloids reported were sedridine (167), /V-methylsedridine (168), pelletierine (169), N-methylpelletierine (170), 4-hydroxysedamine (172), norsedamine (177), allosedamine (178), 3-hydroxyallosedamine (175), as well as the 2,6-disubstituted piperidines sedacrine (231), sedinine (236), and sedinone (232) [426]. 

Ant venoms from the genus Solenopsis have provided an array of 2,6-disubstituted piperidines, including 197-206. A review of the fungicidal, insecticidal and repellent activity of these alkaloids has appeared [476]. Both solenopsin A (198a) and isosolenopsin A (200) were potent inhibitors (Ki = 0.16 pM and 0.24 pM, respectively) of [ HJ-perhydrohistrionicotoxin binding to sites associated with the nicotinic receptor-gated ion channel in the Torpedo califomica electric organ [477]. 

A rapid GC-FT1R method for determination of the cis or trans configuration of 2,6-disubstituted piperidines was developed using, among others, the Solenopsis alkaloids 198a, 198b, 202 and the Monomorium alkaloids 207-209 [480]. A method for determination of the absolute configuration of Solenopsis alkaloids was developed, in which the amines are... 

The Lobelia alkaloids were first detected by Procter in 1850. At the begiiming of the twentieth century, Wieland and Scheuing isolated the first alkaloids from L. inflata. The most important alkaloid of the family Lobeliaceae is lobeline, which is an a, ai-disubstituted piperidine. Further, other alkaloids of L. inflata have been isolated, with their structures described [29, 34, 35]. 

B. Carboni, L. Toupet, G. Dujardin, Chem. Commun. 2003, 276-277. A novel diastereoseleetive route to a-hydroxyalkyl dihydropyrans using an hetero Diels-Alder/allylboration sequence, (h) B. B. Toure, D. G. Hall, Angew. Chem. Int. Ed. 2004, 43, 2001-2004. Three-component sequential aza[4+2] cycloaddition/allylboration/retro-sulfinyl-ene reaetion a new stereocontrolled entry to palustrine alkaloids and other 2,6-disubstituted piperidines, (i) B. B. Toure, D. G. Hall, J. Org. Chem. 2004, 69, 8429-8436. Design of a nonreductive method for chemoselective cleavage of hydrazines in the presence of unsaturations application to a steieoconveigent three-component synthesis of (-)-methyl palustramate. 

Toure, B. B., Hall, D. G. (2004). Three-component seqnential aza[4-l-2] cycloaddition/allylboration/retro-sulfinyl-ene reaction a new stereocontroUed entry to palustrine alkaloids and other 2,6-disubstituted piperidines. Angewandte Chemie International Edition, 43, 2001-2004. 

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