Catalytic Enantioselective Protonation of Gold Enolates Enabled by Cooperative Gold(I) Catalysis.

Enantioselective protonation is a versatile approach to the construction of tertiary α-stereocenters, which are common structural motifs in various natural products and biologically relevant compounds. Herein we report a mild access to these chiral centers using cooperative gold(I) catalysis. From cyclic ketone enol carbonates, this asymmetric catalysis provides highly enantioselective access to cyclic ketones featuring an α tertiary chiral center, including challenging 2-methylsuberone. In combination with the gold-catalyzed formation of cyclopentadienyl carbonates in a one-pot, two-step process, this chemistry enables expedient access to synthetically versatile α'-chiral cyclopentenones with excellent enantiomeric excesses from easily accessible enynyl carbonate substrates.

Chiral Bifunctional Phosphine Ligand Enables Asymmetric Trapping of Catalytic Vinyl Gold Carbene Species.

Bifunctional ligand-enabled cooperative gold catalysis accelerates nucleophilic attacks and offers a versatile strategy to achieve asymmetric gold catalysis. Distinct from the prior studies employing alkyne/allene as the electrophilic site, this work engages an in situ-generated alkenyl/acyl gold carbene in a ligand-facilitated attack by an alcoholic nucleophile. With an amide-functionalized chiral binaphthylphosphine ligand, γ-alkoxy-α,ß-unsaturated imides are formed with excellent enantiomeric excesses. The intermediacy of a carbene species is supported by its alternative access via dediazotization. The reaction tolerates a broad range of alcohols and can accommodate dienynamide substrates, in addition to arylenynamides. This work avails a versatile strategy to enrich gold chemistry and achieve challenging enantioselective gold catalysis via ligand-facilitated enantioselective trapping of reactive intermediates.

Desymmetrization and Parallel Kinetic Resolution of 1-Ethynylcyclobutanols via Asymmetric Cooperative Gold Catalysis.

Enantioselective gold catalysis remains a challenging area of research. By harnessing gold-ligand cooperation in the presence of a chiral bifunctional phosphine ligand featuring a novel 3'-phosphine oxide moiety, highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved, permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers. This cooperative gold catalysis also enables parallel kinetic resolution in gold catalysis, delivering cyclopentanone regioisomers with excellent enantiomeric excesses. DFT calculations of the transition states support the distinct mechanism of asymmetric induction via controlling the conformation of the bound substrate and hence dictating the ring bond undergoing migration.

Asymmetric Dearomatization of Phenols via Ligand-Enabled Cooperative Gold Catalysis.

By employing a chiral bifunctional phosphine ligand, a gold(I)-catalyzed efficient and highly enantioselective dearomatization of phenols is achieved via versatile metal-ligand cooperation. The reaction is proven to be remarkably general in scope, permitting substitutions at all four remaining benzene positions, accommodating electron-withdrawing groups including strongly deactivating nitro, and allowing carbon-based groups of varying steric bulk including tert-butyl at the alkyne terminus. Moreover, besides N-(o-hydroxyphenyl)alkynamides, the corresponding ynoates and ynones are all suitable substrates. Spirocyclohexadienone-pyrrol-2-ones, spirocyclohexadienone-butenolides, and spirocyclohexadenone-cyclopentenones are formed in yields up to 99 % and with ee up to 99 %.

Chiral Bifunctional Phosphine Ligand Enabling Gold-Catalyzed Asymmetric Isomerization of Alkyne to Allene and Asymmetric Synthesis of 2,5-Dihydrofuran.

The asymmetric isomerization of alkyne to allene is the most efficient and the completely atom-economic approach to this class of versatile axial chiral structure. However, the state-of-the-art is limited to tert-butyl alk-3-ynoate substrates that possess requisite acidic propargylic C-H bonds. Reported here is a strategy based on gold catalysis that is enabled by a designed chiral bifunctional biphenyl-2-ylphosphine ligand. It permits isomerization of alkynes with nonacidic α-C-H bonds and hence offers a much-needed general solution. With chiral propargylic alcohols as substrates, 2,5-disubstituted 2,5-dihydrofurans are formed in one step in typically good yields and with good to excellent diastereoselectivities. With achiral substrates, 2,5-dihydrofurans are formed with good to excellent enantiomeric excesses. A novel center-chirality approach is developed to achieve a stereocontrol effect similar to an axial chirality in the designed chiral ligand. The mechanistic studies established that the precatalyst axial epimers are all converted into the catalytically active cationic gold catalyst owing to the fluxional axis of the latter.

Total Synthesis and Structure Revision of Diplobifuranylone B.

An asymmetric total synthesis of diplobifuranylone B was achieved in 10 steps for the longest linear sequence and in 15.8% overall yield from commercially available methyl (R)-(+)-lactate and l-glutamic acid. This synthesis features a stereoselective construction of the key 2,5-dihydrofuran ring in the natural product via a recently developed asymmetric gold catalysis. The stereochemical flexibility offered by the catalysis enables an expedient revision of the reported structure of diplobifuranylone B, where the relative stereochemistry of the 2,5-dihydrofuran moiety was previously misassigned as cis instead of trans.

Gold-Catalyzed Asymmetric Transformation of Hydroxylated Propargylic Esters.

By combining tandem asymmetric gold catalysis and subsequent stereoconvergent hydrolysis of enol ester in a one-pot process, hydroxylated propargylic esters are converted into chiral ß-oxygenated ketones with mostly good enantiomeric ratios and in largely good to excellent yields. The product chiral center is formed via stereoselective cyclization of a hydroxylated allenyl ester intermediate, which is enabled by asymmetric gold-ligand cooperation.