Of -indolizidine

Another Rhn-catalyzed decomposition of a a-diazoester as described by Sabe and coworkers [198] was used for the synthesis of indolizidine alkaloids (Scheme 6/2.8). It can be assumed that, first, an ammonium ylide is formed which then undergoes a 1,2-shift with ring-expansion. Thus, reaction of 6/2-40 with Rh2(OAc)4 led to a 72 28 mixture of 6/2-41 and 6/2-42 in 85 % yield. Cu(acac)2 can also be used with even better yields, but lower selectivity (65 35). 

The NMR spectra of indolizidine derivatives have already been described accurately <1984CHEC(4)443 1996CHEC-II(8)237> more recently, the extensive use of mono- and bidimensional H and 13C NMR spectra allowed the structural assignment of natural compounds such as grandisine A possessing an indolizidine nucleus (Figure 3) <2005JOC1889>. 

Reactions where the reduction of a functionalized nitrogen, or the deprotection of an amine group, start a domino process with the sequential formation of the two rings of the indolizidine system, find many examples in the literature. A recent one is provided by the synthesis of (—)-indolizidine 223AB <20040L1493> (Scheme 10). 

An efficient sequential reaction process was developed from y-amino chlorides 42 with propargylate 41 (Scheme 16). In the proposed mechanism, after the alkylation of the nitrogen atom, a subsequent cyclization by the same nucleophilic center induced the formation of intermediate 43, which cyclized to afford the indolizidine 44 <20010L3927, 20050L705>. This synthetic approach found application in the synthesis of indolizidine 223A. 

Again, rhodium-complexes, although in a completely different process, catalyzed the formation of indolizidine derivatives through the hydroformylation of pyrroles bearing a terminal double bond. The intermediate aldehyde reacted to afford the final product 74 (Scheme 23) <2004TA1821>. 

Some congeners of indolizidine 223A (compounds 135-138) were obtained, using, as the key step, the silylstan-nylation/cyclization of allenic aldehydes as described in Scheme 34 <2004JOC9151>. 

An oxidative Mannich cyclization methodology allowed the synthesis of indolizidine skeletons. The oxidation of the a-silylamide 140 with ceric ammonium nitrate (CAN) formed in situ an iV-acylaminium cation, which cyclized to afford the bicyclic compound 141 (Scheme 35) <1998JOC841>. 

Several other examples are reported in the literature on the synthesis of indolizidine skeleton through the intramolecular nucleophilic attack of the six-membered ring nitrogen atom onto an electrophilic center such as an alkyl halide <20000L3861, 1997S95>, triflate <20010L711>, and esters <1998TL5693>. 

Table 1 Structure of indolizidine alkaloids (bicyclic gephyrotoxins) synthesized since 1995...

A new synthesis of indolizidine (—)-223AB was also reported <2006JOC2547>. 

The venom of ants of the genus Myrmicaria is made up of indolizidine or pyrrole-indolizidine alkaloids [188,189]. The synthesis of some of these alkaloids has already been reported in the review of Leclercq et al. [114]. Thus, we will report here only on the syntheses published since 1999. 

Dreyer, D. L., Jones, . C. and Molyneux, R. L. (1985). Feeding deterrency of some pyrrolizidine, indolizidine, and quinolizidine alkaloids towards pea aphid (Acryrthosiphon pisum) and evidence of phloem transport of indolizidine alkaloid swainsonine. Journal of Chemical Ecology 11 1045-1051. 

Daly, J. W., Tokuyama, T., Fujiwara, T., Highet, R. J., Karle, I. L. A new class of indolizidine alkaloids from the poison frog, Dendrobates tricolor. X-ray analysis of 8-hydroxy-8-methyl-6-(2 -methylhexylidene)-1-azabicyclo[4.3.0]nonane, J. Am. Chem. Soc. 1980, 102, 830-836. 

The perhydroindolizine, named indolizidine, is the alkaloid <5-coniceine. There is a great number of indolizidine alkaloids. Since the chemistry of these alkaloids is reviewed regularly (see Sections 3.08.4 and 3.08.6 for references), only selected topics from the natural products field will be treated here. 

IR spectra of indolizidines are extremely useful for conformational assignments (71CR109), as shown in Section 3.08.2.4.2. 

Circular dichroism as well as dipole moments have been used only rarely for the elucidation of the conformation of indolizidines. It was claimed that the rate of methylation and the configuration of salts formed by protonation reflects the conformation of the free bases (79RCR262). There is an interesting new method depending on the kinetically controlled protonation of amines (77T915) which apparently has not been applied to indolizidines so far. 

Methylation of indolizidine gave a mixture of trans and cis fused methiodides (19) and (20), the structures of which have been substantiated by a comparison of the NMR spectra with those of the corresponding quinolizidine methiodides. 

Conformational and configurational influences on the reactivity of indolizidines have been reviewed (79RCR262). 

Much work has been done on the reactions of indolizidine immonium salts, which has been reviewed to some extent <78AHC(23)103). A general view may be obtained using Scheme 14, the chemistry of indolizidine itself being taken as an example. 

A comprehensive review of the methods used for the preparation of indolizidines is far beyond the scope of this article. Following a short description of the classical pathways, those methods are presented which have either been used extensively or met interest in the field of stereospecific synthesis. Several methods have already been described in Section 3.08.3. 

A great number of methods used generally for the synthesis of cyclic compounds have also been used for the synthesis of indolizidines and partially reduced indolizines... 

The easily accessible imides may be attractive starting materials for a synthesis of indolizidines. Thus (208) is formed in 68% yield in a one-pot reaction shown in Scheme 31 (81TL719). 

A calculation of the heat and free energy of the conformational isomerization of indolizidine has also been made by Russian workers.281... 

The stereochemistry of indolizidine and pyrrolizidine metho salts was studied by Meyer and Sapianchiay.289 They found that methylation of indolizidine gave a 50 50 mixture of isomers from which only the cis-metho salt could be obtained pure. Cyclization of either 250 or 251 gave only the cis isomer, which can be accounted for on the basis of less... 

As with the synthesis of (-)-halosaline, the proposed retrosynthetic strategy of (-)-indolizidine 167B includes use of the dimethylallylsilyl protecting group in the RCM-ROM-RCM sequence (Scheme 22).51... 

---