Of 5,8-disubstituted indolizidine alkaloids

The mass spectra of 3,5-disubstituted indolizidine alkaloids usually show two major peaks corresponding to the loss of each of the alkyl chains by a-cleavage unless a methyl substituent group is present at C-3 or C-5 (the corresponding [M-15J+ fragment has small intensity). In ion-trap mass spectra, an additional peak at m/z 124, arising from a McLafferty type fragmentation, is also present. Fig. (2). 

The amphibian alkaloids considered to be 3,5-disubstituted indolizidines are tabulated below. Two other bicyclic alkaloids, proposed as monosub-stituted indolizidines in an earlier review, are included. These are 167B, which was considered likely to be a 5-n-propylindolizidine, based on its mass spectrum and biosynthetic considerations, and 209D, which was considered likely to be a 5-n-hexylindolizidine. These two indolizidines have been synthesized (130,131), but efforts to compare the synthetic indolizidines to natural 167B and 209D were thwarted when the natural trace alkaloids could no longer be detected in extracts. Structures of relatively well-characterized 3,5-disubstituted indolizidines from amphibians are shown in Fig. 11. 

Disubstituted indolizidines, unlike many classes of amphibian alkaloids, are not unique to amphibians. 3,5-Disubstituted indolizidines such as monomorine I [(5Z,9Z)-195B] occur in ants of the genera Monomorium and Solenopsis (125,129,134). Some of the ant indolizidines are as follows (5Z,9Z)-3-n-butyl-5-methylindolizidine (monomorine I), (5Z,9Z)-3- -ethyl-5-methylindolizidine, (5Z,9Z)-3-hexyl-5-methylindolizidine, and (5 ,9Z)-3-butyl-5-(4-pentenyl)indolizidine. A series of 5-substituted indolizidines, the piclavines, were reported recently from a marine tunicate (Clavelina picta) (135). 

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... 

Edwards MW, Daly JW, Myers CW (1988) Akaloids from a Panamanian poison frog, Dendrobates speciosus identification of pumiliotoxin-A and allopumiliotoxin class alkaloids, 3,5-disubstituted indolizidines, 5-substituted 8-methylindolizidines, and a 2-methyl-6-nonyl-4-hydroxypiperidine. J Nat Prod 51 1188-1197 Emsley L, Bodenhausen G (1989) Self-refocusing effect of 270° Gaussian pulses. Applications to selective two-dimensional exchange spectroscopy. J Magn Reson 82 211-221... 

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. 

Specific apphcations of the Liebeskind second-generation strategy to the synthesis of 5,8-disubstituted indolizidine alkaloids are shown in Scheme 241. From the chiral scafibld (—)-1909 the 2,3-trans-2,6-ds-tet-rahydropyridine (2S,3R,6R)- —)-t920 was obtained in six steps. Tandem... 

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). 

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... 

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]. 

By incorporating a chiral auxiliary, (+ )-rrans-2-(a-cumyl)cyclohexyl (TCC), into pyridinium salt 688, Comins and co-workers were assured of excellent asymmetric induction in a divergent synthesis of three 5,8-disubstituted amphibian indolizidine alkaloids (Scheme 93) (467,499). Addition of but-3-enylmagnesium bromide to 688 yielded the dlhydropyridone 689 as a single diastereomer in 91% yield after recrystallization. After a series of functional group manipulations, the C-8 methyl group was introduced stereoselectively by enolate alkylation (690 -> 691),... 

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