4,6-disubstituted quinolizidine alkaloids

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. 

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]. 

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... 

There have been no studies on the biological activity of the above quinolizidine alkaloids. It is expected that they, like the 5,8-disubstituted indolizidines and other lipophilic dendrobatid alkaloids, will be noncompetitive blockers of nicotinic receptor-channels. 

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... 

Fig. (14). Proposed structures of the alkaloid 275A [16] 4,6-Disubstituted Quinolizidines...

All the currently known indolizidine and quinolizidine alkaloids isolated from ants are illustrated in Fig. 6. (+ )-Monomorine I (427), the well-studied trail pheromone constituent of the Pharaoh ant Monomorium pharaonis), and the analogs 428-431 were described in the earlier volumes in this series. These five compounds are 3,5-disubstituted indolizidines bearing short saturated or mono-unsaturated hydrocarbon chains. The relative stereochemistry in monomorine VI (430) still remains unknown, while that of 431 was atypical for the class at the time of its isolation 380). The structural resemblance of fiiis group of alkaloids to the... 

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

Liebeskind s synthesis of (lil,4il,9aS)-quinolizidine 251AA (2297), referred to above, was an extension of the route his team had previously used in the synthesis of 5,8-disubstituted indolizidine alkaloids (cf. Scheme 241 Section 6.2.5). In brief, the chiral molybdenum complex (—)-1909 was converted in six steps into the 2,3-iraHS-2,6-n 5-tetrahydropyr-idine (2S,3il,6il)-(—)-2298 (Scheme 293). Tandem hydrogenation of the alkene and hydrogenolysis of the protecting groups followed by ring closure of the amino alcohol (—)-2299 under Mitsunobu conditions then completed the synthesis of (—)-quinolizidine 251AA (2297) (Scheme 293). 

Kobayashi, M., Miyamoto, Y, Aoki, S., Murakami, N., Kitagawa. 1., In, Y, and Ishida, T. (1998) Marine natural products. XXXIX. Isomerization of dimeric 2,9-disubstituted 1-oxa-quinolizidine alkaloids and structural revision of araguspongines B and E from a marine sponge ofXestospor a sp. Heterocydes, 47,195—203. 

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). 

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