Synthesis and biological evaluation of (-) and (+)-spiroleucettadine and analogues.

A second generation enantiospecific synthesis of spiroleucettadine is described. The original reported antibacterial activity was not observed when repeated on the synthetic samples, however, significant anti-proliferative activity was uncovered for both enantiomers of spiroleucettadine. Comparison of the optical rotational data and ORD-CD spectra of both enantiomers and the reported spectrum from the natural source has not provided a definitive answer regarding the absolute stereochemistry of naturally occurring spiroleucettadine. Efforts then focussed on alteration at the C-4 and C-5 position of the slightly more active (-)-spiroleucettadine. Ten analogues were synthesised, with three analogues ( 21 , 22 and 24 ) found to possess similar anti-proliferative profiles to spiroleucettadine ( 3 ) against the H522 lung cancer cell line (0.31 μM, 0.38 μM and 0.28 μM vs 0.28 μM, respectively).