Diastereo‐ and Enantioselective Synthesis of β‐Aminoboronate Esters by Copper(I)‐Catalyzed 1,2‐Addition of 1,1‐Bis[(pinacolato)boryl]alkanes to Imines

Reported herein is an efficient copper(I)‐catalytic system for the diastereo‐ and enantioselective 1,2‐addition of 1,1‐bis[(pinacolato)boryl]alkanes to protected imines to afford synthetically valuable enantioenriched β‐aminoboron compounds bearing contiguous stereogenic centers. The reaction exhibits a broad scope with respect to protected imines and 1,1‐bis[(pinacolato)boryl]alkanes, thus providing β‐aminoboronate esters with excellent diastereo‐ and enantioselectivity. The synthetic utility of the obtained β‐aminoboronate ester was also demonstrated.     

Highly Diastereo‐ and Enantioselective Cu‐Catalyzed Borylative Coupling of 1,3‐Dienes and Aldimines

A Cu‐catalyzed diastereo‐ and enantioselective borylative coupling reaction of 1,3‐dienes with imines was realized. Branched homoallylic amines are readily prepared in a syn‐selective manner with high regio‐, diastereo‐ and enantioselectivity. Moreover, these three‐component coupling reactions feature good functional‐group compatibility and easy access to the substrates and catalyst.     

Rh/Lewis Acid Catalyzed Regio‐, Diastereo‐ and Enantioselective Addition of 2‐Acyl Imidazoles with Allenes

A highly regio‐, diastereo‐ and enantioselective addition of 2‐acyl imidazoles or 2‐acyl pyridines with allenes promoted by Rh/Lewis acid synergistically catalytic system is described. This atom economic approach leads to the formation of the branched allylic alkylated products including acyclic quaternary all‐carbon stereogenic centres in good yields with good to excellent diastereo‐ and enantioselectivities. Kinetic studies reveal that the rate‐determining step in this process is the oxidative addition of Rh(I) with C—H bond.     

Asymmetric Copper‐Catalyzed Carbomagnesiation of Cyclopropenes

The highly diastereo‐ and enantioselective formation of polysubstituted cyclopropanes was easily achieved through the asymmetric copper‐catalyzed carbomagnesiation reaction of nonfunctionalized cyclopropene derivatives. The carbometalated species generated in situ readily undergo C−C and C−X bond‐forming reactions with various electrophiles with complete retention of configuration.     

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni^II/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.     

Cu‐Catalyzed Diastereo‐ and Enantioselective Reactions of γ,γ‐Disubstituted Allyldiboron Compounds with Ketones

A catalytic diastereo‐ and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1‐diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.     

Brønsted Acid Catalyzed [3+2]‐Cycloaddition of 2‐Vinylindoles with In Situ Generated 2‐Methide‐2H‐indoles: Highly Enantioselective Synthesis of Pyrrolo[1,2‐a]indoles

Pyrrolo[1,2‐a]indoles are privileged structural elements of many natural products and pharmaceuticals. An efficient one‐step process for their highly diastereo‐ and enantioselective synthesis, comprising a direct [3+2]‐cycloaddition, has been developed. A chiral BINOL‐derived phosphoric acid catalyzes the reaction of in situ‐generated 2‐methide‐2H‐indoles with 2‐vinylindoles, furnishing the target products incorporating three contiguous stereogenic centers as single diastereoisomers and with excellent yields and enantioselectivities.     

Catalytic Enantioselective Formal (4+2) Cycloaddition by Aldol–Aldol Annulation of Pyruvate Derivatives with Cyclohexane‐1,3‐Diones to Afford Functionalized Decalins

The decalin structure is found in bioactive molecules. We have developed catalytic enantioselective formal (4+2) cycloaddition reactions via aldol–aldol cascade reactions between pyruvate‐derived diketoester derivatives and cyclohexane‐1,3‐dione derivatives that afford highly functionalized decalin derivatives. The reactions were performed using a quinidine‐derived catalyst under mild conditions. Decalin derivatives bearing up to six chiral carbon centers including tetrasubstituted carbon centers were synthesized with high diastereo‐ and enantioselectivities. Five to six stereogenic centers were generated from achiral molecules with the formation of two C?C bonds in a single transformation resulting in the formation of the decalin system.     

Diastereo‐ and Enantioselective Palladium‐Catalyzed Dearomative [3+2] Cycloaddition of 3‐Nitroindoles

Diastereo‐ and enantioselective cycloaddition of 3‐nitroindoles with vinyl aziridine was realized under Pd‐catalysis using commercially available Walphos as the ligand, affording pyrroloindolines in high yields with high diastereo‐ and enantioselectivities. The reaction can be scaled up to a gram scale and the reaction products are easily converted to amino pyrroloindoline and other pyrroloindoline derivatives.     

Metal‐Catalyzed Substrate‐Directed Enantioselective Functionalization of Unactivated Alkenes

Alkenes are versatile compounds that are available on large scales in industry or through chemical synthesis. Selective functionalization of unactivated alkenes in a chemo‐, regio‐, diastereo‐ and enantioselective fashion is a highly sought‐after goal in organic synthesis. Substrate‐directed enantioselective functionalization of unactivated alkenes provides an important strategy to achieve this goal. Using a functional group on the alkene substrate as a native coordinating group, a two‐point binding mode of the substrate to the metal center enables effective control of regio‐, diastereo‐ and enantioselectivities. Through this strategy, a variety of enantioselective functionalization methods have been developed recently. The recent advances in this area are highlighted here.     

Stereoselective Synthesis of Highly Functionalized Nitrocyclopropanes through the Organocatalyic Michael‐Addition‐Initiated Cyclization of Bromonitromethane and β,γ‐Unsaturated α‐Ketoesters

A highly diastereo‐ and enantioselective cyclopropanation of β,γ‐unsaturated α‐ketoesters with bromonitromethane has been successfully developed through a domino Michael‐addition/intramolecular‐alkylation strategy. Acceptable yields (up to 89 %) and enantioselectivities (up to 96 % ee) have been obtained.     

Highly Regio‐ and Stereodivergent Access to 1,2‐Amino Alcohols or 1,4‐Fluoro Alcohols by NHC‐Catalyzed Ring Opening of Epoxy enals

Described is an unprecedented NHC‐catalyzed (NHC=N‐heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three‐step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio‐ and stereodivergent synthesis of either 1,2‐amino alcohols/diamines or 1,4‐fluoro alcohols with excellent diastereo‐ and enantiopurity.     

Enantioselective Synthesis of Cyclobutylboronates via a Copper‐Catalyzed Desymmetrization Approach

The first catalytic enantioselective synthesis of cyclobutylboronates, by using a chiral copper(I) complex, is reported. A broad variety of cyclobutanes have been prepared with consistently high levels of diastereo‐ and enantiocontrol. Moreover, this method constitutes the first report of an enantioselective desymmetrization of meso‐cyclobutenes to prepare chiral cyclobutanes.     

Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β‐unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β‐unsaturated 7‐azaindoline amides act as reactive electrophiles to participate in catalytic diastereo‐ and enantioselective vinylogous conjugate addition of γ‐butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.     

Diastereo‐ and Enantioselective Iridium Catalyzed Carbonyl (α‐Cyclopropyl)allylation via Transfer Hydrogenation

The first examples of diastereo‐ and enantioselective carbonyl α‐(cyclopropyl)allylation are reported. Under the conditions of iridium catalyzed transfer hydrogenation using the chiral precatalyst (R)‐Ir‐ I modified by SEGPHOS, carbonyl α‐(cyclopropyl)allylation may be achieved with equal facility from alcohol or aldehyde oxidation levels. This methodology provides a conduit to hitherto inaccessible inaccessible enantiomerically enriched cyclopropane‐containing architectures.     

Asymmetric Synthesis of Spirocyclic β‐Lactams through Copper‐Catalyzed Kinugasa/Michael Domino Reactions

The first copper‐catalyzed highly chemo‐, regio‐, diastereo‐, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne‐tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β‐lactams possessing four contiguous stereocenters, including one quaternary and one tetra‐substituted stereocenter.     

Bifunctional Brønsted Base Catalyst Enables Regio‐, Diastereo‐, and Enantioselective Cα‐Alkylation of β‐Tetralones and Related Aromatic‐Ring‐Fused Cycloalkanones

The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner.     

Catalyst‐Controlled Stereoselective Olefin Metathesis as a Principal Strategy in Multistep Synthesis Design: A Concise Route to (+)‐Neopeltolide

Molybdenum‐, tungsten‐, and ruthenium‐based complexes that control the stereochemical outcome of olefin metathesis reactions have been recently introduced. However, the complementary nature of these systems through their combined use in multistep complex molecule synthesis has not been illustrated. A concise diastereo‐ and enantioselective route that furnishes the anti‐proliferative natural product neopeltolide is now disclosed. Catalytic transformations are employed to address every stereochemical issue. Among the featured processes are an enantioselective ring‐opening/cross‐metathesis promoted by a Mo monoaryloxide pyrrolide (MAP) complex and a macrocyclic ring‐closing metathesis that affords a trisubstituted alkene and is catalyzed by a Mo bis(aryloxide) species. Furthermore, Z‐selective cross‐metathesis reactions, facilitated by Mo and Ru complexes, have been employed in the stereoselective synthesis of the acyclic dienyl moiety of the target molecule.     

A Synthetic Route to Chiral Dihydrobenzothiazines through Ring Opening of Activated Aziridines with 2‐Halothiophenols/Copper‐Powder‐Mediated C−N Cyclization

A simple protocol for the synthesis of dihydrobenzothiazines through regio‐ and stereoselective S_N2‐type ring opening of N‐tosylaziridines with sulfur nucleophiles followed by copper‐powder‐mediated intramolecular C?N cyclization in excellent yields (up to 95 %) with high diastereo‐ and enantioselectivity (up to >99 %) is reported.     

Catalytic Enantioselective Inverse Electron Demand Hetero‐Diels–Alder Reaction with Allylsilanes

The first diastereo‐ and enantioselective inverse electron demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the β,γ‐unsaturated α‐ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.