Pyrrolizines—

Benzoyl-2,3-dihydro-lH-pyrrolizine-l-cai boxylic acid (ketorolac, L ) and 2-(3-benzoyl-phenyl)propionic acid (ketoprofen, L ) ai e biologically activ ligands used in medicine as non-steroidal anti-inflammatory dmgs. 

From the hair-pencils of butterflies in Danainae and Ithomiinae (Papilion-oidea Nymphalidae), a wider variety of pyrrolizines (la-d, and 6a-d) have been identified than from Arctiidae moths. These compounds are biosynthesized from pyrrolizidine alkaloids, which are included in host plants fed by the larvae and protect them from the attacks of other herbivores [122]. In addition to novel lactones (7, 8a, and 8b) derived from an acid part of the alkaloids, many volatiles of more than 100 compounds (aromatics, terpenoids, hydrocarbons, and others) constitute scent bouquets of the male butterflies [123]. For example, the hair-pencil of Idea leuconoe (Danainae) which is distributed in South-East Asia contained 16 compounds (6b, 8a, 8b, 9, and others), and a mixture of the major volatiles applied to a butterfly dummy elicited an abdomen-curling acceptance posture in the females as a crude extract of the male hair-pencils did [ 124]. A chiral GC analysis revealed the absolute config-... 

The naming of these three heterocyclic fused (5 5 5) ring systems has been carried out according to the IUPAC system of nomenclature. Some examples are given as follows compound la (Table 1) is named (3-hydroxy-4-methoxyphenylthieno[2,3-3]pyrrolizin-8-one. Compound 15a (Table 2) is dithieno[3,2-3 2, 3 - 1thiophene. Compound 23a (Table 2) is dithieno[3,2-3 2, 3 - 1pyrrole. Compound 20a (Table 2) is dithicno[3,2-3 2, 3 -r/]thiophene-4,4-dio ide. Compound 13b (Table 2) is 3,4-dimethyldithieno[3,2-3 2, 3 -i/]thiophene-7,7-dioxide. Compound 38 (Table 4) is fM, r, r-10-azatricyclo[5.2.1.01 10]deca-2,5,8-triene. Compound 39 (Table 4) is cis,cis, m-10-azatricyclo[5.2.1.01 10]deca-2,8-diene. The nomenclature of compound 40 (Table 4) is 1,4,7 triaza tricy-clo[5.2.1.01,10]decane. 

Thieno[3,4- ]pyrrolizin-8-one 4 <2004JEZ585> has been synthesized from 4-amino-thiophene-3-carboxylate 268 (Scheme 48). This useful starting material was converted into ester 269 and the amide 270, to afford 4 (Scheme 48). 

This class of tricyclic compound is dominated by the 377-pyrrolizines (systematically named 3//-pyrrolo[l,2- ]-pyrroles) and related systems, which are fused to another six-membered heterocyclic ring (Figure 1). 

Pyrrolizines fused to a pyridine ring can be prepared from pyrrolopyridinones such as 118. These can be alkylated both at the amide nitrogen and at the carbon a to that nitrogen, and so reaction of 118 with l-bromo-3-chloropropane and sodium hydroxide under phase-transfer conditions gives the tetrahydropyrido[2,3-tf]pyrrolizinone 119 <1990BCJ3047> (Equation 6). 

The fused indolopyrrolizidine 137 can be transformed into the tetrahydropyrrolizinoquinolone 138 upon reaction with Bu OK while oxygen is bubbled into the solution. (This is an apparently general strategy for the oxidation of indoles.) Compound 138 may then be oxidized with w-chloroperbenzoic acid (MCPBA) to give the dihydropyrido-pyrrolizine 139 <1997TL2997> (Scheme 37). 

The 977-pyrido[3,4- ]pyrrolizin-9-one 145 has been prepared for its photochemical properties. The preparation involves an intramolecular Friedel-Crafts acylation of the acid chloride formed from 3-(l-pyrrolyl)pyridine-4-carboxy-late (Scheme 40). The product is a photosensitizer, which absorbs visible light its absorption spectra are pH, solvent, and concentration dependent <1994SAA57>. 

Cycloaddition of the tetrahydropyrrolopyridine-2-carbaldehyde 153 with electron-depleted alkenes in the presence of a base leads to products, the 111 NMR spectra of which are consistent with their formulation as 154 rather than 155. In the case of the acrylonitrile adduct, the initially formed pyrrolizine reacts with another molecule of acrylonitrile to give a cyanoethyl-substituted derivative <1998CHE1418> (Scheme 43). 

Pyrimidine-fused pyrrolizines have been prepared from the functionalized tetrahydropyrroles 156 according to Scheme 45 <1989CHE691>. 

Dimethyl-3/7-indole reacts with diethyl oxaloacetate in acetic acid to give the pyrrolizine 157. Upon reaction of this product with guanidine for extended periods of time, the tetracyclic product 158 is formed in low yield <1988J(P1)451> (Scheme 46). 

---