Conformational analysis tricyclic systems

The overall structure contains an indolizidine or a quinolizidine attached to a cyclohexane, all forming a complex tricyclic system whose conformation has proved difficult to determine. The first two examples of these structures were cylindridnes A and B, whose structures were confirmed by X-ray analysis. These two molecules have a chlorine atom and are interconvertible through an aziridinium ion. At room temperature a solution of either of the two molecules will be found after six days to contain a mixture of 60% cylindricine A and 40% cylindricine B (Blackman et al., 1993). This equilibrium, however, occurs only with free bases at room temperature salts (picrates) are regarded as stable in solution. 

Some of these systems have been examined by X-ray analysis in the solid state.375a When a single conformation was found to exist in solution, this is reflected in the crystal structure, as for the saturated tricyclic derivative 480 in the e4 and the tetrabenzyl monocyclic 491 in the aeae conformation. The unsaturated tricyclic 479 crystallizes in the ae3 unsymmetrical form, which is the largest component of the solution equilibrium. However, the 1,4-dimethyl - 2,5-dibenzyl monocyclic derivative 486 crystallizes in the aeae conformation, which contributes only 33% to the solution equilibrium. 1,4-Dimethylhexahydro-l,2,4,5-tetrazine crystallizes with the N-methyl groups equatorial and the IV-hydrogen atoms axial.376... 

The tricyclic spiro system having one methyl group was also examined (Fig. 6) (24, 25). This system can give the four isomers 23, 24, 26, and 27. The isomers 23 and 24 come from the cyclization of dihydroxyketone 22 whereas the isomers 26 and 27 come from the cyclization of the isomeric dihydroxyketone 25. In this case, 22 and 25 are not interconvertible under acidic conditions. Each spiro isomer can exist in two different conformations. The theoretical analysis, however, predicted that isomer 23 exists as a mixture of conformers 23A (0.5 kcal/mol) and 23B (0 kcal/mol) whereas isomer 24 exists in the conformation 24A (0 kcal/mol) (Fig. 6). Approximately, a 1 1 mixture of isomers 23 and 24 should therefore be isolated from the cyclization of dihydroxyketone 22. 

For the above mentioned tricyclic quinolizidines, a comparison of the HCCH dihedral angles determined by H NMR J analysis and those predicted by molecular modelling or established by X-ray structures, when available, was also performed, which corroborates the previous stereochemical analysis [200]. The reason indicated for the similarity of conformations of these alkaloids in the solid state and in solution is the partial flattening of ring B, caused by the presence of a flat system in ring A, that diminishes the steric hindrance of ring C in an all chair conformation. 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

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