Wayne Best of Epichem has suggested an alternative route to (R)-PZQ, based on a Pictet-Spengler (PS) reaction of a chiral phenylethanolamine. This is an attractive route, since 1 to 2 should work well (good asymmetric induction) and the products resemble PZQ.
The PS has been used in the synthesis of PZQ, and we used it as the final step in our solid phase synthesis of PZQ, but both these syntheses were racemic. A chiral auxiliary-mediated PS was reported by Ma et al. (J. Chem. Res. 2004, 2004, 186-187 - paper doesn't seem to have a DOI?) where the key asymmetric step is shown below.
The use of an auxiliary is of course atom-inefficient. The use of a chiral starting material, in the generation of some analogue of PZQ, could be an interesting project. Anyone have a suggestion for a suitable commercially-available chiral starting material? Anyone want to have a go?
Mat