Asymmetric Total Synthesis of Aglacins A, B, and E.

An asymmetric photoenolization/Diels-Alder (PEDA) reaction between electron-rich 2-methylbenzaldehydes and unsaturated γ-lactones was developed to directly construct the basic tricyclic core of aryltetralin lactone lignans. This methodology enabled the first asymmetric total synthesis of aglacins A, B, and E and revision of the absolute configuration of these natural lignans. The strategy was also used to prepare the naturally occurring aryldihydronaphthalene-type lignans (-)-7,8-dihydroisojusticidin B and (+)-linoxepin in four and six steps, as well as 27 natural-product-like molecules containing a C8' quaternary center. We believe that the synthetic aglacins and small-molecule library provide new opportunities to carry out the SAR studies of the podophyllotoxin family of natural products.