A study into asymmetric Nicholas cyclisation reactions

Three systematic approaches have been employed to investigate asymmetric Nicholas reactions. We found that the use of a chiral N-enoyl derivative provided acceptable levels of selectivity for an intermolecular Nicholas reaction, however, we were unable to identify an auxiliary that could be utilized in an asymmetric conjugate addition and a tandem inter/intramolecular series of Nicholas reactions. The use of chiral pool non-racemic propargyl alcohols, derived from citronellal, provided enhanced levels of selectivity. As a result of these studies we developed a series of Nicholas cyclisations derived from chiral non-racemic salicylaldehyde derivatives. These underwent an extremely rapid and highly efficient cyclisation, under Nicholas conditions, to afford a range of benzopyrans. The adjacent stereogenic centres appear to be formed with high levels of stereocontrol.