Stereocontrolled Synthesis of 1,5‐Stereogenic Centers through Three‐Carbon Homologation of Boronic Esters

Allylic pinacol boronic esters are stable toward 1,3‐borotropic rearrangement. We developed a Pd^II‐mediated isomerization process that gives di‐ or trisubstituted allylic boronic esters with high E selectivity. The combination of this method with lithiation–borylation enables the synthesis of carbon chains that bear 1,5‐stereogenic centers. The utility of this method has been demonstrated in a formal synthesis of (+)‐jasplakinolide.     

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

An unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C?H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.     

Asymmetric Ruthenium‐Catalyzed Hydrogenation of 2,6‐Disubstituted 1,5‐Naphthyridines: Access to Chiral 1,5‐Diaza‐cis‐Decalins

The first asymmetric hydrogenation (AH) of 2,6‐disubstituted and 2,3,6‐trisubstituted 1,5‐naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5‐naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4‐tetrahydro‐1,5‐naphthyridines with up to 99 % ee and full conversions. This facile and green protocol is applicable to the scaled‐up synthesis of optically pure 1,5‐diaza‐cis‐decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis.     

Asymmetric Synthesis of Secondary and Tertiary Boronic Esters

Non‐racemic chiral boronic esters are recognised as immensely valuable building blocks in modern organic synthesis. Their stereospecific transformation into a variety of functional groups—from amines and halides to arenes and alkynes—along with their air and moisture stability, has established them as an important target for asymmetric synthesis. Efforts towards the stereoselective synthesis of secondary and tertiary alkyl boronic esters have spanned over five decades and are underpinned by a wealth of reactivity platforms, drawing on the unique and varied reactivity of boron. This Review summarizes strategies for the asymmetric synthesis of alkyl boronic esters, from the seminal hydroboration methods of H. C. Brown to the current state of the art.     

Enantiodivergent Synthesis of Allenes by Point‐to‐Axial Chirality Transfer

An enantiodivergent method for the synthesis of multiply substituted allenes is described. Highly enantioenriched, point‐chiral boronic esters were synthesized by homologation of α‐seleno alkenyl boronic esters with lithiated carbamates and eliminated to form axially chiral allene products. By employing either oxidative or alkylative conditions, both syn and anti elimination could be achieved with complete stereospecificity. The process enables the synthesis of either M or P allenes from a single isomer of a point‐chiral precursor and can be employed for the enantioselective assembly of di‐, tri‐, and tetrasubstituted allenes.     

Development of Asymmetric Reactions Catalyzed by Chiral Organotin‐Alkoxide Reagents

Asymmetric catalysis under almost‐neutral reaction conditions is key for the efficient synthesis of optically active polar molecules. We have developed catalytic enantioselective reactions of acyclic or cyclic alkenyl esters by using an (S)‐BINOL‐derived chiral tin‐dibromide reagent that possesses a bulky aryl group at the 3 or 3′ position as the chiral pre‐catalyst in the presence of a sodium alkoxide and an alcohol, in which a chiral tin alkoxide bromide is generated in situ and recycled with the assistance of an alcohol. In this Personal Account, we describe three types of asymmetric transformation that proceed through a chiral tin enolate: 1) The asymmetric aldol reaction of alkenyl esters or unsaturated lactones with aldehydes or isatins; 2) the asymmetric three‐component Mannich‐type reaction of alkenyl esters and related cycloaddition reactions; and 3) the asymmetric N‐nitroso aldol reaction of unsaturated lactones with nitrosoarenes.     

Organocatalytic Formation of Chiral Trisubstituted Allenes and Chiral Furan Derivatives

A novel reaction that provides chiral allenes by amino catalytic activation of either aldehydes or α,β‐unsaturated aldehydes for reaction with alkynyl‐substituted enones is presented. The reaction forms a variety of trisubstituted allenes in high yields and with excellent stereoselectivities. The utility of the reaction concept is demonstrated by the synthesis of chiral furan derivatives in high yields and stereoselectivities.     

Aromatic Amide‐Derived Non‐Biaryl Atropisomers as Highly Efficient Ligands in Silver‐Catalyzed Asymmetric Cycloaddition Reactions

The synthesis of a series of aromatic amide‐derived non‐biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo‐ and enantioselectivities (up to >99:1 d.r., 95–99 % ee) as well as yields in the silver‐catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro‐substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction.     

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium‐labeled substrates, and control experiments revealed that nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C?O bonds at fully substituted carbon centers in the synthesis of chiral 2,2‐disubstituted benzomorpholines.     

Ir‐SpinPHOX Catalyzed Enantioselective Hydrogenation of 3‐Ylidenephthalides

The first asymmetric hydrogenation of 3‐ylidenephthalides has been developed using the Ir^I complex of a spiro[4,4]‐1,6‐nonadiene‐based phosphine‐oxazoline ligand (SpinPHOX) as the catalyst, affording a wide variety of chiral 3‐substituted phthalides in excellent enantiomeric excesses (up to 98 % ee). The utility of the protocol has been demonstrated in the asymmetric synthesis of chiral drugs NBP and BZP precursor, as well as the natural products chuangxinol and typhaphthalide.     

Enantioselective CpxRhIII‐Catalyzed Carboaminations of Acrylates

Enantioselective carboaminations of olefins constitute an attractive strategy for a rapid increase in molecular complexity from readily available starting materials. Reported here is an intermolecular asymmetric carboamination of acrylates using rhodium(III)‐catalyzed alkenyl C?H activations of N‐enoxysuccinimides to generate the nitrogen and carbon portion for the transfer. A rhodium complex equipped with a tailored bulky trisubstituted chiral Cp^x ligand ensures carboamination chemoselectivity as well high levels of enantioinduction. The transformation operates under mild reaction conditions at ambient temperatures and provides access to a variety of α‐amino esters in good yields and excellent enantiomeric ratios of >99.5:0.5.     

Biphenyl‐Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes

Because of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl‐derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one‐carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all‐carbon or heteroatom‐substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four‐carbon coupling partner is not the turnover‐limiting step of the catalytic cycle.     

Chiral Lewis Base-Catalysed Asymmetric Syntheses of Benzo-fused ϵ-Lactones

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.     

Stereospecific and Chemoselective Copper‐Catalyzed Deaminative Silylation of Benzylic Ammonium Triflates

A method for the synthesis of benzylsilanes starting from the corresponding ammonium triflates is reported. Silyl boronic esters are employed as silicon pronucleophiles, and the reaction is catalyzed by copper(I) salts. Enantioenriched benzylic ammonium salts react stereospecifically through an S_N2‐type displacement of the ammonium group to afford α‐chiral silanes with inversion of the configuration. A cyclopropyl‐substituted substrate does not undergo ring opening, thus suggesting an ionic reaction mechanism with no benzyl radical intermediate.     

Novel and practical asymmetric synthesis of β2,3-amino esters using asymmetric Michael addition of chiral amine

A practical method for the synthesis of chiral β^2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β^2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β^2,3-amino esters having various substituents.     

Nickel(0)‐Catalyzed Enantioselective Annulations of Alkynes and Arylenoates Enabled by a Chiral NHC Ligand: Efficient Access to Cyclopentenones

Cyclopentenones are versatile structural motifs of natural products as well as reactive synthetic intermediates. The nickel‐catalyzed reductive [3+2] cycloaddition of α,β‐unsaturated aromatic esters and alkynes constitutes an efficient method for their synthesis. Here, nickel(0) catalysts comprising a chiral bulky C₁‐symmetric N‐heterocyclic carbene ligand were shown to enable an efficient asymmetric synthesis of cyclopentenones from mesityl enoates and internal alkynes under mild conditions. The bulky NHC ligand provided the cyclopentenone products in very high enantioselectivity and led to a regioselective incorporation of unsymmetrically substituted alkynes.     

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene‐Oxetane Scaffolds

The first catalytic enantioselective cycloaddition reaction to α,β,β‐trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4‐dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene‐oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene‐cyclobutanes and ‐azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring‐opening of the oxetane.     

Ruthenium(II)‐Catalyzed Asymmetric Inert C−H Bond Activation Assisted by a Chiral Transient Directing Group

A ruthenium(II)‐catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3‐dihydrobenzofurans bearing chiral all‐carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.     

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd‐Catalyzed 1,4‐Arylboration of 1,3‐Enynes

A cooperative Cu/Pd‐catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl₂(dppf) complexes as catalysts, the 1,4‐arylboration of 1,3‐enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2‐substituted 1,3‐enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate‐limiting step of this transformation.     

Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

A Ru‐catalyzed direct asymmetric reductive amination of ortho‐OH‐substituted diaryl and sterically hindered ketones with ammonium salts is reported. This method represents a straightforward route toward the synthesis of synthetically useful chiral primary diarylmethylamines and sterically hindered benzylamines (up to 97 % yield, 93–>99 % ee). Elaborations of the chiral amine products into bioactive compounds and a chiral ligand were demonstrated through manipulation of the removable and convertible ‐OH group.