Enantioselective Synthesis of 3‐Fluorochromanes via Iodine(I)/Iodine(III) Catalysis

Abstract

The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3‐fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.

Fluorination and Fluoroalkylation Reactions Mediated by Hypervalent Iodine Reagents

“…value (Scheme 15). [33] X-ray crystallographic analyses of representative products revealed that the conformations of 77 enabled stabilizing stereoelectronic interactions, which render these molecules potentially valuable as drug candidates. Mechanistic interrogation of the reaction using deuterated probes showed that the process is stereospecific and likely proceeds through a type II inv pathway (Scheme 15).…”

“…Initially, selectfluor-mediated oxidation of iodoresorcinol catalyst in the presence of amine • HF in situ generates the transient difluoroiodoarene (78-I). [33] Ligand exchange at the iodine center of 78-I with alkene (76 a) and concomitant cyclization of 78-II occur in an enantioselective way by stabilizing aromatic interactions. Nucleophilic displacement of 78-III by fluoride ion eventually provides the relative syn-configuration and stereospecificity that was determined by the detailed NMR analysis, accomplishing the catalytic cycle.…”

“…Very recently, iodine(I)/(III)‐catalyzed direct fluorocyclization of aryl allyl ethers ( 76 ) with a simple C2‐symmetric iodoresorcinol catalyst in combination with selectfluor and amine ⋅ HF mixtures was disclosed by Gilmour and coworkers, forming biologically relevant enantio‐enriched 3‐fluorochromanes ( 77 ) with up to 7:93 e.r. value (Scheme ) . X‐ray crystallographic analyses of representative products revealed that the conformations of 77 enabled stabilizing stereoelectronic interactions, which render these molecules potentially valuable as drug candidates.…”

“…Mechanistic interrogation of the reaction using deuterated probes showed that the process is stereospecific and likely proceeds through a type II inv pathway (Scheme ). Initially, selectfluor‐mediated oxidation of iodoresorcinol catalyst in the presence of amine ⋅ HF in situ generates the transient difluoroiodoarene ( 78‐I ) . Ligand exchange at the iodine center of 78‐I with alkene ( 76 a ) and concomitant cyclization of 78‐II occur in an enantioselective way by stabilizing aromatic interactions.…”

Recent Application of Chiral Aryliodine Based on the 2-Iodo­resorcinol Core in Asymmetric Catalysis

“…In 2020, Gilmour and co-workers utilized another chiral aryliodine 5j instead of previous catalyst 8a to accomplish the enantioselective fluorocyclization of allyl phenyl ethers 54 (Scheme 21). 37 The terminal aliphatic alkenes 54 underwent direct cyclization in the presence of catalytic chiral aryliodine 5j and excess oxidant Selectfluor, which resulted in hypervalent ArIF 2 generation in situ, to afford 3-fluorochromanes 55 in good yields and enantioselectivities (up to 67% yield, 86% ee). In this catalytic strategy, under identical conditions subtle structural changes on the C=C bond affected the stereoselectivity in a striking manner, for example 4-bromophenyl methallyl ether gave the corresponding product in 51% yield and only 10% ee (see Scheme 21).…”