Concise total synthesis and stereochemical analysis of tetraponerines T3 and T4.

An efficient stereocontrolled preparation of tetraponerines T3 and T4 is detailed. The sequence takes advantage of two consecutive stereoselective aminoallylations of appropriate aldehydes with chiral tert-butanesulfinamide and in situ generated allyl indium species. The absolute configuration of the carbon stereogenic center at the aminal moiety is thermodynamically controlled. This was ascertained on the basis of an exhaustive DFT configurational study of tetraponerines, which fulfils the lack of detailed structural information for these systems. It was found that the trans-transoid-configuration of the AB rings is the most stable geometry for T3 and T4. However, the C ring prefers a cis-configuration in T3 (ttc-T3) and a trans-fusion in T4 (ttt-T4). Regarding their dynamic behavior, low activation barriers were found by DFT calculations for the inversion of the nitrogen at the indolizidine framework, allowing rapid equilibration between the major configurations (ttc and ttt) in T3 and T4.