Bicyclic piperidine alkaloids

RRM of enantiopure cyclopentene 382, induced by commercially available catalyst C, was the key step in Blechert s total synthesis of the bis-piperidine alkaloid (+)-astrophylline (384) [159]. Exposure of metathesis precursor 382 to only 1 mol% C provided within 2 h bicycle 383 in 82% yield (Scheme 75). 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

DAB, DNJ, and DMJ. However, the pyrrolidine and piperidine alkaloids in species co-occur with a number of polyhydroxypyrrolizidines none of these bicyclic alkaloids were isolated from A. triphylla. 

This cleavage of the oxindole alkaloids, e.g. (100), or the 2,3-seco-derivatives of type (101) to bicyclic piperidine derivatives is of considerable interest, and has provided new pathways for the partial synthesis of other alkaloids. Alternative ways of achieving the cleavage involve the application of the Hobson reaction to pteropodine (100), followed by hydrogenolysis of the intermediate (106) (Scheme 14) a similar sequence of reactions on 2,3-seco-2,3-dihydroakuammigine (101)... 

Most amphibian alkaloids are not as complex in structure as the steroidal batrachotoxins and samandarines. Of the 300 known amphibian alkaloids, most have been characterized from the skin extracts of frogs of the family Dendrobatidae and, hence, have been referred to as dendrobatid alkaloids. The major bicyclic classes of dendrobatid alkaloids are the histrionicotox-ins, decahydroquinolines, and pumiliotoxin-A class. Because of the presence of a piperidine ring in most dendrobatid alkaloids, they also have been referred to as piperidine-based alkaloids. 

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). 

The previous review on Nuphar (water-lily) alkaloids in this treatise appeared in Volume 35, and covered the period 1974-1987 (7). It overlapped in part with the treatment of simple bicyclic Nuphar metabolites in Volume 28 (7). Nuphar alkaloids include sesquiterpenoid monomeric (C15) piperidine and quinolizidine alkaloids as well as more complex dimeric (C30) sulfur-containing metabolites. Related metabolites isolated from the scent glands of the Canadian beaver, Castor fiber, also include a unique indolizidine alkaloid 944 606). Only the indolizidine and simple quinolizidine alkaloids are relevant to the present review. Compounds mentioned in the ensuing discussion are illustrated in Fig. 18. 

---