Enantioselective One Pot Construction of Bridged Tricyclic Lactones

A bridged tricyclic scaffold with an sp3-rich framework offers a versatile core structure for the design of bioactive molecules that resemble those found in numerous natural products with notable biological activities. This scaffold faces key challenges in medium-sized ring synthesis, such as poor site selectivity and stereoselectivity and competing reaction pathways, which are prevalent in current synthetic methods. Here, we describe a highly efficient and one pot method for constructing a bridged tricyclic scaffold using a bifunctional cinchona alkaloid-derived squaramide catalyst. The reaction between 3-hydroxy-2-pyridones and α,β-unsaturated aldehydes results in the formation of a [4+2] cycloaddition adduct as an intermediate. The catalyst directs both enantioselectivity and diastereoselectivity in the initial cycloaddition step and subsequently functions as a Lewis base in the rearrangement process, thus driving the formation of the tricyclic compound in a one-pot reaction. This methodology provides a versatile approach for accessing various bridged tricyclic scaffolds that exhibit excellent enantio- and diastereoselectivities (up to 99% ee and dr > 20:1). The protocol is scalable to gram quantities and was successfully applied for the first total synthesis of the enantiomer of the alkaloid (-)-peduncularine and the preparation of analogous derivatives, which highlights the method’s utility in the synthesis of complex, enantioenriched natural product derivatives.