Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis

Abstract

The success of saturated, fluorinated heterocycles in contemporary drug discovery provides a stimulus for creative endeavor in main group catalysis. Motivated by the ubiquity of isochromans across the bioactive small molecule spectrum, the prominence of the anomeric effect in regulating conformation, and the metabolic lability of the benzylic position, iodine(I)/iodine(III) catalysis has been leveraged for the stereocontrolled generation of selectively fluorinated analogs. To augment the current arsenal of fluorocyclization reactions involving carboxylic acid derivatives, the reaction of readily accessible 2-vinyl benzaldehydes is disclosed (up to >95 : 05 d.r. and 97 : 03 e.r.). Key stereoelectronic interactions manifest themselves in the X-ray crystal structures of the products, thereby validating the [CH2-CHF] fragment as a stereoelectronic mimic of the [O-CH(OR)] acetal motif.