Two-step synthesis of chiral fused tricyclic scaffolds from phenols via desymmetrization on nickel

Abstract

Tricyclic furan derivatives with multiple chiral centers are ubiquitous in natural products. Construction of such tricyclic scaffolds in a stereocontrolled, step-economic, and atom-economic manner is a key challenge. Here we show a nickel-catalyzed highly enantioselective synthesis of hydronaphtho[1,8-bc]furans with five contiguous chiral centers via desymmetrization of alkynyl-cyclohexadienone by oxidative cyclization and following formal [4 + 2] cycloaddition processes. Alkynyl-cyclohexadienone was synthesized in one step from easily accessible phenols. This reaction represents excellent chemo-selectivity, regio-selectivity, diastereo-selectivity, and enantio-selectivity (single diastereomer, up to 99% ee). An extraordinary regioselectivity in the formal [4 + 2] cycloaddition step with enones revealed the diverse reactivity of the nickelacycle intermediate. Desymmetrization of alkynyl-cyclohexadienones via oxidative cyclization on nickel was supported by the isolation of a nickelacycle from a stoichiometric reaction. Enantioenriched tricyclic products contain various functional groups such as C=O and C=C. The synthetic utility of these products was demonstrated by derivatization of these functional groups.

Fe‐catalyzed hydrohalogenative cyclization of cyclohexadienone‐containing enynes

“…A number of cyclization methods with different coupling reagents such as acetic acid, arene C–H, azides bis(pinacolato)diboron, boronic acids, bromodifluoroalkanes, silylacetylenes, and silylboronate were developed for the synthesis of cyclohexenone‐annulated products in a chiral or achiral fashion. In addition, an enantioselective desymmetrization of alkynyl‐cyclohexadienone followed by intermolecular [4 + 2] cycloaddition with activated alkenes to give tricyclic products and reductive cyclization with various hydrogen donors were also reported. In this context, new methodology development for the desymmetrization of alkynyl‐cyclohexadienone would be beneficial for molecular construction.…”

Multidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds

“…2a ) 26 . Ogoshi described a one-pot desymmetrization of an alkynyl-cyclohexadienone via nickel-catalyzed cyclization in the presence of a chiral ligand 27 . Gaunt and coworkers utilized cyclohexadienone alkanal Michael addition for the asymmetric construction of bicyclohexenones 28 .…”

Visible Light Mediated Sulfenylation‐Annulation Cascade of Alkyne Tethered Cyclohexadienones

“…On the other hand, cascade cyclizations belong to a powerful class of transformations for the construction of carbocyclic and heterocyclic skeletons from relatively simple acyclic motifs . Along these lines, alkyne‐tethered cyclohexadienones have been extensively studied for the formation of fused carbocycles . The formation of 5,6‐fused carbocycles ( cis ‐hydrobenzofuranones) has been well explored using metal catalysts like Rh, Pd, Cu, and Ni .…”

“…Along these lines, alkyne‐tethered cyclohexadienones have been extensively studied for the formation of fused carbocycles . The formation of 5,6‐fused carbocycles ( cis ‐hydrobenzofuranones) has been well explored using metal catalysts like Rh, Pd, Cu, and Ni . In contrast, the formation of 6,6‐fused carbocycles remains relatively unexplored.…”