5.6.8- trisubstituted indolizidine alkaloids

The 5,6,8-trisubstituted indolizidine alkaloids form another class of amphibian skin alkaloids that has grown enormously since the first member of this group was reported in 1997. At present approximately 70 such alkaloids have been tentatively or positively identified.As has so often happened with minor or trace components of the skin extracts, very few of them have been characterized completely, and the relative configurations are almost entirely unknown other than for a few in which strong or weak Bohlmann bands in the FTIR spectra imply cis- or iram-relationships respectively between the hydrogen atoms on C-5 and C-8a. 

The synthesis of 2,4,6-trisubstituted piperidines has been reported via the generation of a fused cyclic intermediate in a three-component reaction using typical palladium-based chemistry (Scheme 112) <20060L3813, 20060L3809>. Stereocontrol was observed and the same intermediate was used in the stereoselective synthesis of the indolizidine alkaloid (—)-dendroprimine. 

Indolizidine and quinolizidine alkaloids found in amphibians and ants were studied by Daly and co-workers who classified them in two different classes, A and B, Fig. (1) [2,15-17]. The former include 3,5- and 5,8-disubstituted indolizidines, 5,6,8-trisubstituted indolizidines and 1,4- and 4,6-disubstituted quinolizidines that can be derived from straight-chain carbon precursors. The latter contain one or more isoprene units, and include pumiliotoxins (PTX-A), allopumiliotoxins (a//o-PTX-A or... 

The isolation and characterisation from a Panamian population of Dendrobates pumilio Schimdt of indoiizidine 223A [25], formerly identified as 1,4-dipropyl quinolizidine [5], established a new type of class A alkaloids the 5,6,8-trisubstituted indolizidines. 

The alkaloid 249H, Fig. (11), was isolated from the skin extracts of the poisonous frog Dendrobates auratus of the Isla Taboga of the Pacific coast of Panama [26]. A sample containing only traces of impurities was obtained by successive column chromatography of the methanolic skin extract. H and C NMR spectroscopy and correlation spectra were only consistent with a branched substituent, the first to be reported for simple indolizidines isolated from frog skin, and an unusual cw-fused trisubstituted indolizidine nucleus. 

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... 

---