1.4- Disubstituted quinolizidine

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

SAM, samandarines BTX, batrachotoxins HTX, histrionicotoxins PTX, pumiliotoxins aPTX, allopumiliotoxins hPTX, homopumiliotoxins DHQ, 2,5-disubstituted decahydroquinolines 3,5-P, 3,5-d [substituted pyrrolizidines 3,5-1 and 5,8-1, disubstituted indolizidines 1,4-Q, 1,4-disubstituted quinolizidines Epi, epibatidine Pseudophry, pseudophrynamines. With the exception of 3,5-P and 3,5-1, these alkaloids are not known to occur in arthropods (see text). Histrionicotoxins may occur in Minyobates and Mantella, but the evidence is not conclusive. 

Disubstituted indolizidine 207A 1,4-Disubstituted quinolizidine 217A ... 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

A direct route to 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines was reported by Barluenga and co-workers <02OL1971> (Scheme 30). Hetero-Diels-Alder reaction followed by reduction and desilylation gave good yields of the key piperidine core 51. Further elaboration of the hydroxymethyl side chain followed by RCM and hydrogenation gave the targets in moderate yields. 

Over 30 amphibian alkaloids from dendrobatid frogs, bufonid toads, or ranid frogs now are assigned to the 1,4-disubstituted quinolizidine class. For many of these, FTIR data are not yet available. Thus, structural and stereochemical assignments to this class, and the proposed 4,10Z configuration, should be considered tentative for many of these alkaloids. A 4,6-disubstituted quinolizidine class, considered likely by analogy to the... 

Fig. 14. Structures of 1,4-disubstituted quinolizidines from amphibians. All have been characterized only by mass and FTIR spectral properties 73,81)- All have the 4, lOZ configuration. The configuration at the 1 position is as yet unknown.

Recently, the first isolation and full NMR characterisation of a 1,4-disubstituted quinolizidine, quinolizidine 217A, Fig. (12), was reported [27]. 

More recently, the 1,4-disubstituted quinolizidine 275A was reassigned a 4-methyl-9-non)myl-l-azabicyclo[5.3.0]decane structure by comparison with synthetic diastereomers. Fig. (14) [16]. Nevertheless complete characterisation has not yet been reported. 

Novel 1,4-disubstituted quinolizidines were first reported in 1993 (381,390), but detailed characterization has only been described quite recently after isolation of larger quantities from another Madagascan frog, M. baroni (430). Spectroscopic... 

Fig. 9. Recently synthesized 1,4-disubstituted quinolizidine and S,8-disubstituted indolizidine alkaloids and related compounds.

The spectral features of 1,4-disubstituted quinolizidines are quite similar to those of the 5,8-disubstituted indolizidine analogues. Their mass spectra are characterised by a major fragment arising from a-cleavage of the alkyl side-chain at C-4 and by an additional peak at m/z 110 (C H 2N+, ca. 30-50%) in ion-trap spectra, arising from a subsequent retro Diels-Alder process, Fig. (5). Since, as seen for the indolizidine analogues, the alkyl substituent at C-l is commonly a methyl group the base peak of... 

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