Natural Tetraponerines: A General Synthesis and Antiproliferative Activity

A stereocontrolled
general methodology to access all natural tetraponerines from (+)-T1 to (+)-T8 is detailed. Two consecutive indium-mediated
aminoallylations with the appropriate enantiomer of chiral N-tert-butylsulfinamide and a thermodynamic
control at the aminal stereocenter allow the formation of each natural
tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal
in the first aminoallylation leads to the formation of 5–6–5
tetraponerines, while 5-bromopentanal is required to build the scaffold
of 6–6–5 tetraponerines. A cross-metathesis reaction
of the second aminoallylation product with cis-3-hexene
is used to elongate the side chain up to 5 carbons so as to prepare
the tetraponerines T5 to T8. The anticancer
activity of these heavier tetraponerines against four different carcinoma
human cell lines is examined, observing a promising cytotoxic activity
of (+)-T7 against breast carcinoma cell line MCF-7.