Access to Aryl‐Naphthaquinone Atropisomers by Phosphine‐Catalyzed Atroposelective (4+2) Annulations of δ‐Acetoxy Allenoates with 2‐Hydroxyquinone Derivatives

Although asymmetric phosphine catalysis is a powerful tool for the construction of various chiral carbon centers, its synthetic potential toward an enantioenriched atropisomer has not been explored yet. Reported herein is a phosphine‐catalyzed atroposelective (4+2) annulation of δ‐acetoxy allenoates and 2‐hydroxyquinone derivatives. The reaction provides expedient access to aryl‐naphthaquinone atropisomers by the de novo construction of a benzene ring. The two functionalities of the catalyst, a tertiary phosphine (Lewis base) and a tertiary amine (Brønsted base), cooperatively enable this process with high regio‐ and enantioselectivities.     

Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

The first highly enantioselective phosphine‐catalyzed formal [4+4] annulation has been developed. In the presence of amino‐acid‐derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole‐derived α,β‐unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight‐membered rings by phosphine catalysis.     

Dearomatization of 3‐Nitroindoles by a Phosphine‐Catalyzed Enantioselective [3+2] Annulation Reaction

The dearomatization of 3‐nitroindoles through a chiral‐phosphine‐mediated [3+2] annulation reaction is described. This method makes use of readily available 3‐nitroindoles as an aromatic feedstock and rapidly delivers a wide range of cyclopentaindoline alkaloid scaffolds in a highly enantioselective manner. Notably, phosphine‐triggered cyclization has not been utilized previously in a dearomatization process.     

(Dynamic) Kinetic Resolution of Enamines/Imines: Enantioselective N‐Heterocyclic Carbene Catalyzed [3+3] Annulation of Bromoenals and Enamines/Imines

The enantioselective N‐heterocyclic carbene catalyzed [3+3] annulation of α‐bromoenals by dynamic kinetic resolution (DKR) of enamines and normal resolution of α,α‐disubstituted imines were developed. The corresponding substituted dihydropyridones were isolated in good yields with excellent diastereo‐ and enantioselectivities, and a high selective factor (up to 83) was realized for the resolution of α,α‐disubstituted imines.     

Copper‐Catalyzed Propargylic Substitution of Dichloro Substrates: Enantioselective Synthesis of Trisubstituted Allenes and Formation of Propargylic Quaternary Stereogenic Centers

An easy and versatile Cu‐catalyzed propargylic substitution process is presented. Using easily prepared prochiral dichloro substrates, readily available Grignard reagents together with catalytic amount of copper salt and chiral ligand, we accessed a range of synthetically interesting trisubstituted chloroallenes. Substrate scope and nucleophile scope are broad, providing generally high enantioselectivity for the desired 1,3‐substitution products. The enantioenriched chloroallenes could be further transformed into the corresponding trisubstituted allenes or terminal alkynes bearing all‐carbon quaternary stereogenic centers, through the copper‐catalyzed enantiospecific 1,1/1,3‐substitutions. The two successive copper‐catalyzed reactions could be eventually combined into a one‐pot procedure and different desired allenes or alkynes were obtained respectively with high enantiomeric excesses.     

Rhodium(I)‐Catalyzed Enantioselective Activation of Cyclobutanols: Formation of Cyclohexane Derivatives with Quaternary Stereogenic Centers

The activation of carbon–carbon σ bonds is a complementary method to access uncommon and difficult‐to‐prepare organometallic species. Herein, we describe the activation of tert‐cyclobutanols through an enantioselective insertion of a chiral rhodium(I) complex into the C? C σ bond of the cyclobutane, forming a quaternary stereogenic center and an alkyl‐rhodium functionality that initiates ring‐closure reactions. This technology provides access to a variety of substituted cyclohexane derivatives with quaternary stereogenic centers. The formation of different product families can be controlled by the employed set of reaction conditions and additives. In general, high yields and excellent enantioselectivities of up to 99 % ee are obtained.     

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.     

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.     

Construction of Quaternary Stereogenic Carbon Centers through Copper‐Catalyzed Enantioselective Allylic Cross‐Coupling with Alkylboranes

A combination of an in situ generated chiral Cu^I/DTBM‐MeO‐BIPHEP catalyst system and EtOK enabled the enantioselective S_N2′‐type allylic cross‐coupling between alkylborane reagents and γ,γ‐disubstituted primary allyl chlorides with enantiocontrol at a useful level. The reaction generates a stereogenic quaternary carbon center having three sp³‐alkyl groups and a vinyl group. This protocol allowed the use of terminal alkenes as nucleophile precursors, thus representing a formal reductive allylic cross‐coupling of terminal alkenes. A reaction pathway involving addition/elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.     

Regio‐ and Enantioselective Rhodium‐Catalyzed Addition of 1,3‐Diketones to Allenes: Construction of Asymmetric Tertiary and Quaternary All Carbon Centers

An unprecedented highly regio‐ and enantioselective rhodium‐catalyzed addition of 1,3‐diketones to terminal and 1,1‐disubstituted allenes furnishing asymmetric tertiary and quaternary all‐carbon centers is reported. By applying a Rh^I/phosphoramidite/TFA catalytic system under mild conditions, the desired chiral branched α‐allylated 1,3‐diketones could be obtained in good to excellent yields, with perfect regioselectivity and in high enantioselectivity. The reaction shows a broad functional‐group tolerance on both reaction partners highlighting its synthetic potential.     

Construction of Quaternary Stereogenic Carbon Centers through Copper‐Catalyzed Enantioselective Allylic Alkylation of Azoles

Copper‐catalyzed enantioselective allylic alkylation of azoles with γ,γ‐disubstituted primary allylic phosphates was achieved using a new chiral N‐heterocyclic carbene ligand bearing a naphtholic hydroxy group. This reaction occurred with excellent branch regioselectivity and high enantioselectivity, thus forming a controlled all‐carbon quaternary stereogenic center at the position α to the heteroaromatic ring.     

Construction of Vicinal Quaternary Stereogenic Centers by Enantioselective Direct Mannich‐Type Reaction Using a Chiral Bis(guanidino)iminophosphorane Catalyst

A novel asymmetric direct Mannich‐type reaction of α‐iminophenylacetate esters with thionolactones, bearing a substituent at the α‐position, as a less acidic pronucleophile was developed. Using bis(guanidino)iminophosphorane as the chiral organosuperbase catalyst, the reaction afforded densely functionalized amino‐acid derivatives having vicinal quaternary stereogenic centers, one of which is an all‐carbon quaternary stereogenic center, in good yield with high diastereo‐ and enantioselectivities.