Indolizidine-containing compounds

A complete review on the synthesis of indolizines has appeared <2000HOU(10)745>. This chapter is an extension of the reviews in CHEC(1984) <1984CHEC-I(4)443> and CHEC-II(1996) <1996CHEC-II(8)237>, mainly focusing on the development of synthetic methods aimed at the synthesis of natural alkaloids and important bioactive compounds containing the indolizidine nucleus. 

An impressive number of alkaloids and bioactive compounds containing the indolizidine skeleton have been synthesized. These belong principally to three classes which will be separately analyzed. Other natural products not belonging to these classes will be collected in section 11.09.8.3. 

The preparation of alkaloids (cyclic compounds containing nitrogen atoms) is very important, as most alkaloids are biologically active. Eq. 3.10 shows the preparation of alkaloids (27), a precursor of gephyrotoxin, via an a-amino radical formed from y-thiophenoxylactam (26). Other alkaloids such as indolizidine and pyrrolizidine can be also prepared similarly via a-amino radicals and a-acylamino radicals. 

Simple bicyclic compounds form a rather small subset of the lupine (or lupin) alkaloids, the overwhelming majority of which have tricyclic or tetracyclic structures based on the quinolizidine motif. These alkaloids are characteristic metabolites of the Papilionoideae, a sub-family of the Leguminosae (Fabaceae), although representative examples have also been isolated from several other plant families. The simple lupine quinolizidines were surveyed in Volume 28 of this treatise (7), while later reviews in Volumes 31 (5) and 47 (9) comprehensively covered all classes of lupine alkaloids, including those containing indolizidine components. Much relevant material is also to be found in the review on the biosynthesis of pyrrolizidine and... 

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. 

Indolizines, indolizidines, indoles, and other bicyclic or polycyclic compounds containing a fused pyrrole or pyrrolidine moiety often possess potent and useful biological activities. There have been several approaches to the preparation of fluorinated analogues of these heterocycles, mainly based on 1,3-dipolar addition reactions using fluorinated synthons either as the dipole or as the dipolarophile. Several examples of this strategy are given below. 

In another example, a vinyl iodide bearing a cyclic alkene on the heteroatom-containing side chain was employed (Scheme 6.28) [79]. It describes the asymmetric synthesis of indolizidine derivatives with optimized conditions to get asymmetric 108 with good ee of 81%. As compound 107 can be readily isomerized to 108 using Pd/C in methanol, this method gives ready access to a whole range of indoUzidines. 

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