Biomimetic approach to the catalytic enantioselective synthesis of tetracyclic isochroman

Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity. However, a general and stereoselective method towards the rapid construction of this structure remains challenging due to the inherent instability and complex stereochemistry of polyketide. By mimicking the biosynthetic pathway of this structurally diverse set of natural products, we herein develop an asymmetric hetero-Diels-Alder reaction of in-situ generated isochromene and ortho-quinonemethide. A broad range of tetracyclic isochroman frameworks are prepared in good yields and excellent stereoinduction (up to 95% ee) from readily available alpha-propargyl benzyl alcohols and 2-(hydroxylmethyl) phenols under mild conditions. This direct enantioselective cascade reaction is achieved by a Au(I)/chiral Sc(III) bimetallic catalytic system. Experimental studies indicate that the key hetero-Diels-Alder reaction involves a stepwise pathway, and the steric hindrance between in-situ generated isochromene and t-Bu group of Sc(III)/N,N'-dioxide complex is responsible for the enantioselectivity in the hetero-Diels-Alder reaction step. General and stereoselective synthesis of tetracyclic isochroman-containing polyketide oligomers is challenging. Here, the authors report on an Au(I)/chiral Sc(III) bimetallic catalyst for a biomimetic asymmetric hetero-Diels-Alder reaction for in-situ generation of isochromene and ortho-quinonemethide.

Automated summary

The study introduces a novel catalytic system for an asymmetric hetero-Diels-Alder reaction, leading to the synthesis of diverse tetracyclic isochroman frameworks with excellent stereoinduction. The key reaction involves a stepwise pathway, with steric hindrance playing a role in enantioselectivity.