Copper‐Catalyzed Borocarbonylative Coupling of Internal Alkynes with Unactivated Alkyl Halides: Modular Synthesis of Tetrasubstituted β‐Borylenones

Reported is a general procedure to synthesize tetrasubstituted enones, which are borylated in the β‐position, using a copper‐catalyzed four‐component coupling reaction of simple chemical feedstocks: internal alkynes, alkyl halides, bis(pinacolato)diboron (B₂pin₂), and CO. A broad scope of highly functionalized β‐borylated enones, a largely unknown class of organic compounds, can be accessed efficiently using this method. The synthesis of all‐carbon tetrasubstituted enones was realized by employing the β‐borylated enone unit, without purification, in a Suzuki–Miyaura coupling. The utility of the method was further demonstrated by various transformations, including halogenation, oxidation, and protodeboration, of the corresponding reduced oxaborole species to provide densely substituted allylic alcohol and ketone products.     

Copper‐Catalyzed Asymmetric Three‐Component Borylstannation: Enantioselective Formation of CSn Bond

In summary, a first copper‐catalyzed synthesis of α‐aryl‐β‐borylstannane compounds was accomplished through three‐component borylstannation of aryl‐substituted alkenes. In the exploration of an asymmetric variant, chiral sulfinylphosphine ligands proved advantageous in controlling stereochemistry of B?Cu addition and in promoting transmetalation of enantioenriched alkyl?Cu species. The stereochemical outcome supported a sequential syn‐borylcupration and configuration‐retentive transmetalation mechanism. Moreover, α‐chiral β‐borylstannanes were easily transformed into a diverse array of secondary alkylstannanes and triarylethane with high enantiomeric purity. The applications of chiral sulfinylphosphine ligands to other tandem Cu?B addition reactions are currently under investigation in our group.     

Copper‐Catalyzed Asymmetric Conjugate Addition with Chiral SimplePhos Ligands

SimplePhos ligands represent a novel class of monodentate chiral ligands based on a chiral amine moiety and flexible diaryl groups on the phosphorous atom. They can be easily prepared by two different pathways and they can be highly functionalised. Herein we report the copper‐catalysed asymmetric conjugate addition of diethyl zinc and trialkylaluminium reagents with SimplePhos ligands, which gives high enantioselectivity with cyclic enones, acyclic enones and nitro‐olefins, with up to 98.6 % ee. Of particular interest is the reaction of trialkylaluminium reagents with a wide range of 3‐substituted enones, thus allowing the formation of stereogenic quaternary carbon centres.     

Efficient P‐Chiral Biaryl Bisphosphorus Ligands for Palladium‐Catalyzed Asymmetric Hydrogenation

A series of structurally novel P‐chiral biaryl bisphosphorus ligands L1‐L5 (BABIBOPs) are developed, providing high efficiency for the first time in palladium‐catalyzed asymmetric hydrogenation of β‐aryl and β‐alkyl substituted β‐keto esters. With the Pd‐ L3 (iPr‐BABIBOP) catalyst, a series of chiral β‐hydroxyl carboxylic esters are formed in excellent enantioselectivities (up to>99% ee) and yields at catalyst loading as low as 0.01 mol%.     

Enantioselective and Regioselective Organocatalytic Conjugate Addition of Malonates to Nitroenynes

The first catalytic asymmetric conjugate addition of 1,3‐dicarbonyl compounds to nitroenynes catalyzed by cinchona alkaloid‐based thiourea organocatalysts has been developed. The 1,4‐addition adducts were obtained solely, in moderate to good yields (up to 93 %) with good enantioselectivities (up to 99 % ee). This protocol affords a conceptually different entry to the precursors of pharmaceutically important chiral β‐alkynyl acid derivatives and synthetically useful chiral nitroalkynes. Notably, the protocol worked well with both aryl‐ and alkyl‐substituted alkynyl substrates.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Highly modulated bisindoles: ligands for copper‐catalyzed Sonogashira reaction

Bisindoles (BIMs) were modulated as powerful N,N′ donor ligands for the copper‐catalyzed Sonogashira reaction. Ligand screening experiments on 11 BIM compounds found that 3,3′‐(4‐chlorophenyl)methylenebis(1‐methyl‐1H‐indole) (10%) efficiently accelerated CuCl (5%)‐catalyzed cross‐coupling of aryl iodides with terminal alkynes. A wide range of substituted aryl iodides and/or alkyl‐ and aryl‐substituted terminal alkynes were examined, leading to the corresponding coupling products with yields up to 99%. An efficient and scalable protocol for the synthesis of BIM ligands on a gram scale, with extremely low catalyst loading of o‐ClC₆H₄NH₃⁺Cl^?, was also developed with a reaction time of 20 min with yields up to 93%. This novel N,N′ ligand was air‐stable, easily available and highly modulated with low copper loading. Copyright © 2016 John Wiley & Sons, Ltd.     

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Herein a comprehensive study is provided on the asymmetric conjugate addition (ACA) of Grignard reagents to α‐substituted cyclic enones. After the elucidation of the optimal experimental conditions, the scope of Grignard reagents and Michael acceptors was examined. Whereas secondary Grignards gave better enantioselectivities with 2‐cyclopentenones, both linear and branched Grignard reagents were tolerated for the ACA to 2‐methylcyclohexenone. The sequential ACA–enolate trapping, which leads to quaternary stereocenters, was then studied. Thus, many electrophiles have been tested, thereby giving rise to highly functionalized cyclic ketones with contiguous α‐quaternary and β‐tertiary centers. The present technique is believed to bring a new approach to versatile terpenoid‐like skeletons of bioactive natural products. Straightforward derivatizations of enantioenriched saturated cyclic ketones further support the potential of the present methodology in synthesis.     

Synthesis of N‐Substituted Condensed Tetrahydropyridine‐Based Enaminones via Palladium‐Catalyzed Intramolecular C–N Cross‐coupling

A number of β‐enaminones with secondary amino group (alkyl, cyclopropyl, and aryl) were prepared from corresponding β‐diketones. Two general protocols for their palladium‐catalyzed intramolecular C–N cross‐coupling were established to give corresponding N‐substituted condensed tetrahydropyridines in good yields. The methodology is applicable for a wide variety of structural motifs. The work also extends the applicability of novel, recently established, palladium precatalysts to new substrates.     

An Unexpected Michael–Aldol–Smiles Rearrangement Sequence for the Synthesis of Versatile Optically Active Bicyclic Structures by Using Asymmetric Organocatalysis

A facile and simple organocatalytic procedure to generate optically active 6‐alkyl‐ and 6‐aryl‐substituted bicyclo[2.2.2]oct‐5‐en‐2‐ones is presented. The reaction is catalysed by a 9‐amino‐9‐deoxyepiquinine trifluoroacetic acid salt, which activates α,β‐unsaturated cyclic ketones for the 1,4‐addition of β‐keto benzothiazoyl sulfones in a stereoselective fashion. Subsequent intramolecular aldol reaction and Smiles rearrangement gives rise to important optically active bicycles, which are a common motif in natural products, ligands in asymmetric catalysis and substrates for Cope rearrangements, photochemical reactions, radical cyclisations and metathesis. Different bicyclic structures were obtained by utilisation of various cyclic enones or by performing ring‐expanding reactions. Furthermore, two possible mechanistic pathways are outlined and discussed.     

Enantioselective Synthesis of Quaternary α‐Amino Acids Enabled by the Versatility of the Phenylselenonyl Group

A novel Cinchona alkaloid‐catalyzed enantioselective conjugate addition of α‐alkyl substituted α‐nitroacetates to phenyl vinyl selenone was developed. The resulting enantio‐enriched α,α‐dialkyl substituted α‐nitroacetates were subsequently converted to various cyclic and acyclic quaternary α‐amino acids, taking advantage of the rich functionalities of the resulting Michael adducts. Novel protocols allowing chemoselective reduction of phenyl selenone to phenyl selenide and reduction of alkyl phenyl selenones to alkanes are also reported.     

Enantio‐ and Diastereoselective 1,2‐Additions to α‐Ketoesters with Diborylmethane and Substituted 1,1‐Diborylalkanes

The catalytic enantioselective synthesis of boronate‐substituted tertiary alcohols through additions of diborylmethane and substituted 1,1‐diborylalkanes to α‐ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce β‐hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α‐boryl‐copper‐alkyl intermediate.     

Regioselective Alkylative Carboxylation of Allenamides with Carbon Dioxide and Dialkylzinc Reagents Catalyzed by an N‐Heterocyclic Carbene–Copper Complex

The alkylative carboxylation of allenamide catalyzed by an N‐heterocyclic carbene (NHC)–copper(I) complex [(IPr)CuCl] with CO₂ and dialkylzinc reagents was investigated. The reaction of allenamides with dialkylzinc reagents (1.5 equiv) and CO₂ (1 atm.) proceeded smoothly in the presence of a catalytic quantity of [(IPr)CuCl] to afford (Z)‐α,β‐dehydro‐β‐amino acid esters in good yields. The reaction is regioselective, with the alkyl group introduced onto the less hindered γ‐carbon, and the carboxyl group introduced onto the β‐carbon atom of the allenamides. The first step of the reaction was alkylative zincation of the allenamides to give an alkenylzinc intermediate followed by nucleophilic addition to CO₂. A variety of cyclic and acyclic allenamides were found to be applicable to this transformation. Dialkylzinc reagents bearing β‐hydrogen atoms, such as Et₂Zn or Bu₂Zn, also gave the corresponding alkylative carboxylation products without β‐hydride elimination. The present methodology provides an easy route to alkyl‐substituted α,β‐dehydro‐β‐amino acid ester derivatives under mild reaction conditions with high regio‐ and stereoselectivtiy.     

Diastereo‐ and Enantioselective Copper(I)‐Catalyzed Intermolecular [3+2] Cycloaddition of Azomethine Ylides with β‐Trifluoromethyl β,β‐Disubstituted Enones

Reported herein is an asymmetric [3+2] cycloaddition reaction of azomethine ylides with β‐trifluoromethyl β,β‐disubstituted enones, a reaction which is enabled by a Ming‐Phos‐derived copper(I) catalyst (Ming‐Phos=chiral sulfinamide monophosphines, Figure 2 ). This method provides scalable and efficient access to the highly substituted pyrrolidines with a trifluoromethylated, all‐carbon quaternary stereocenter in good yields with up to greater than 20:1 d.r. and 98 % ee. The reaction has a broad substrate scope and tolerates a wide range of functional groups.     

Efficient Atropodiastereoselective Access to 5,5′‐Bis‐1,2,3‐triazoles: Studies on 1‐Glucosylated 5‐Halogeno 1,2,3‐Triazoles and Their 5‐Substituted Derivatives as Glycogen Phosphorylase Inhibitors

Whereas copper‐catalyzed azide–alkyne cycloaddition (CuAAC) between acetylated β‐D ‐glucosyl azide and alkyl or phenyl acetylenes led to the corresponding 4‐substituted 1‐glucosyl‐1,2,3‐triazoles in good yields, use of similar conditions but with 2 equiv CuI or CuBr led to the 5‐halogeno analogues (>71 %). In contrast, with 2 equiv CuCl and either propargyl acetate or phenyl acetylene, the major products (>56 %) displayed two 5,5′‐linked triazole rings resulting from homocoupling of the 1‐glucosyl‐4‐substituted 1,2,3‐triazoles. The 4‐phenyl substituted compounds (acetylated, O‐unprotected) and the acetylated 4‐acetoxymethyl derivative existed in solution as a single form (d.r.>95:5), as shown by NMR spectroscopic analysis. The two 4‐phenyl substituted structures were unambiguously identified for the first time by X‐ray diffraction analysis, as atropisomers with aR stereochemistry. This represents one of the first efficient and highly atropodiastereoselective approaches to glucose‐based bis‐triazoles as single atropisomers. The products were purified by standard silica gel chromatography. Through Sonogashira or Suzuki cross‐couplings, the 1‐glucosyl‐5‐halogeno‐1,2,3‐triazoles were efficiently converted into a library of 1,2,3‐triazoles of the 1‐glucosyl‐5‐substituted (alkynyl, aryl) type. Attempts to achieve Heck coupling to methyl acrylate failed, but a stable palladium‐associated triazole was isolated and analyzed by ¹H NMR and MS. O‐Unprotected derivatives were tested as inhibitors of glycogen phosphorylase. The modest inhibition activities measured showed that 4,5‐disubstituted 1‐glucosyl‐1,2,3‐triazoles bind weakly to the enzyme. This suggests that such ligands do not fit the catalytic site or any other binding site of the enzyme.     

Regio‐ and Stereoselective Conjugate Addition of Aldehydes to β‐Tosyl Enones under the Catalysis of a Binaphthyl‐Modified Chiral Amine

A simple axially chiral amine catalyst promoted the regio‐, diastereo‐, and enantioselective conjugate addition of aldehydes to β‐tosyl enones, which serve as ynone surrogates. The adducts were readily converted by treatment with L‐selectride into less accessible enones with a γ stereogenic center. Such compounds cannot be prepared through the amine‐catalyzed conjugate addition of aldehydes to ynones. The obtained enones underwent further conjugate addition of diorganozinc compounds in the presence of a copper catalyst.     

Palladium‐Catalysed C(sp3)−H Glycosylation for the Synthesis of C‐Alkyl Glycoamino Acids

We have developed a highly efficient and practical approach for palladium‐catalyzed trifluoroacetate‐promoted N‐quinolylcarboxamide‐directed glycosylation of inert β‐C(sp³)?H bonds of N‐phthaloyl α‐amino acids with glycals under mild conditions. For the first time, C(sp³)?H activation for glycosylation was achieved to build C‐alkyl glycosides. This method facilitates the synthesis of various β‐substituted C‐alkyl glycoamino acids and offers a tool for glycopeptide synthesis.     

Chiral N,O‐Ligand/[Cu(OAc)2]‐Catalyzed Asymmetric Construction of 4‐Aminopyrrolidine Derivatives by 1,3‐Dipolar Cycloaddition of Azomethine Ylides with α‐Phthalimidoacrylates

A protocol to access useful 4‐aminopyrrolidine‐2,4‐dicarboxylate derivatives has been developed. A variety of chiral N,O‐ligands derived from 2,3‐dihydroimidazo[1,2‐a]pyridine motifs have been evaluated in the asymmetric 1,3‐dipolar cycloaddition of azomethine ylides to α‐phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7‐Cl‐DHIPOH provided the highest level of stereoselectivity for the 1,3‐dipolar cycloaddition reaction. The reaction tolerates both β‐substituted and β‐unsubstituted α‐phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4‐aminopyrrolidine cycloadducts with excellent diastereo‐ (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH₄ reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

Benzylamine as Hydrogen Transfer Agent: Cobalt‐Catalyzed Chemoselective C=C Bond Reduction of β‐Trifluoromethylated α,β‐Unsaturated Ketones via 1,5‐Hydrogen Transfer

An efficient cobalt‐catalyzed chemoselective reduction of β‐CF₃‐α,β‐unsaturated ketones using benzylamine as hydrogen transfer agent involving intramolecular 1,5‐hydrogen transfer is reported. The reaction proceeded smoothly with a relatively wide range of substrates including those bearing aromatic heterocycles such as a furyl ring system in high yields (74–92 %). This provides an efficient method for the synthesis of β‐CF₃ saturated ketones in one‐pot. This methodology was also applied to the selective C=C reduction of other enone substrates bearing no β‐CF₃‐substituent, of which β‐substituted or β,β‐disubstituted enones are tolerated, giving the desired products in good yields (72–75 %). Mechanistic studies indicate that the reaction involves 1,5‐hydrogen transfer.