3,5-Disubstituted indolizidine

Disubstituted pyrrolizidine 223H 3,5-Disubstituted indolizidine 195B... 

A diastereoselective synthesis of 3,5-disubstituted indolizidines based on an intermol. addition of an allylsilane on an acyliminium ion derived from (d )-pyroglutamic acid, is described <2006TA1253>. 

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. 

Fig. II. Structures of 3,5-disubstituted indolizidines from amphibians. The absolute configuration of natural levorotatory (S ,9 )-223AB, (5 .9 )-239AB, and (5 .9 )-239CD, are known. Natural dextrorotatory (S ,9 )-195B has the opposite absolute configuration as that shown above U29a). The configurational nomenclature is based on that introduced by Sonnet et at. (122), where the H-S and H-9 configurations are related to that of H-3 and are either cis (Z) or trans ( ).

Optical rotations of 3,5-disubstituted indolizidines are given in Table... 

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). 

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). 

An important contribution to the establishment of the relative configuration of 3,5-disubstituted indolizidines is ustrally afforded by the analysis of the Bohlmaim band absorption region in IR spectra distinctive C-H stretching bands appear below 2800 cm whenever two or more a-C-H are tram antiparallel to the nitrogen lone pair and these bands are more intense for the cis diastereomer than for the tram [20]. 

In solution, 3,5-disubstituted indolizidines can adopt four different... 

Two new 3,5-disubstituted indolizidines, (-)-myrmicarin 237A and (+)-myrmicarin 237B, Fig. (7), were isolated as the major components of the poison gland secretion of the afiican ant Myrmicaria eumenoides [22]. NMR data analysis ( H, COSY, COLOC and... 

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... 

Despite their structural complexity, it appears that these compounds derive from fairly straightforward dimerization or trimerization of a simple 15-carbon precursor. Although their biosynthesis has not been investigated yet, it seems probable that unsaturated derivatives of myrmicarin 237 (81) such as the hypothetical 141 could represent an immediate precursor, which through a series of intra- and/or intermolecular condensation steps could give rise to myrmicarins 215A/B, 430A, 645, and 663. ° In fact, synthetic studies have shown that the 3,5-disubstituted indolizidine 145 is a suitable precursor for myrmicarin 217 (87). ° ... 

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