Chiral Boronic Esters Research Articles

Enantioselective Synthesis of Benzylic Boronic Esters via Photoredox/Nickel-Catalyzed Multicomponent Cross-Couplings.

As a class of versatile building blocks, chiral benzylic boronic esters are important intermediates employed in modern organic chemistry. We describe herein the first stereoconvergent multicomponent cross-coupling reaction of vinyl boronates, alkyltrifluoroborates, and aryl halides through a dual photoredox/nickel catalysis methodology. This synergistic platform permitted the benign construction of various enantioenriched benzylic boronic esters with broad substrate tolerance and moderate to excellent enantioselectivity (up to 98:2 er) from commercially available starting materials. Moreover, experimental and computational studies shed light on the nickel catalytic transformation and the origin of the enantioselectivity.

Axially chiral α-boryl-homoallenyl boronic esters as versatile toolbox for accessing centrally and axially chiral molecules

Axially chiral allenes bearing organoboron groups are highly sought-after building blocks in organic synthesis due to their potential for generating a wide range of axially and centrally chiral molecules. However, the existing methods for preparing axially chiral allenes containing boron group are primarily limited to the synthesis of allenyl boronic esters, and strategies for accessing axially chiral homoallenyl boronic esters are still scarce. Here, we report the general method for synthesizing axially chiral α-boryl-homoallenyl boronic esters through a highly regio- and stereoselective copper-mediated SN2’-addition of newly prepared (diborylalkyl)copper species to chiral propargyl electrophiles. The reaction conditions were optimized to achieve high yields and excellent stereospecificity. The obtained products were successfully transformed into various axially chiral allenes and other chiral molecules by transforming diboron units. The potential for axial-to-central chirality transfer of axially chiral α-boryl-homoallenyl boronic esters is also demonstrated through the stereospecific addition to aldehydes and N-H aldimines, yielding enantioenriched 1,2-oxaborinin-3,5-dienes and 2-aminomethyl-1,3-dienes.

Stereoselective Synthesis of α‐Azido Esters and α‐Amino Acid Derivatives via Matteson Homologation of Boronic Esters

AbstractMatteson homologation with sodium azide in DMF proved to be an excellent highly stereoselective tool for the synthesis of complex α‐azido and α‐amino acids. Both enantiomers are easily accessible via the choice of the chiral boronic ester auxiliary.

Stereoselective Synthesis of Secondary and Tertiary Boronic Esters via Matteson Homologation.

Matteson homologations of chiral boronic esters with lithium dichlorocarbenoids and various nucleophiles proved to be a useful method for the synthesis of functionalized polyketides in a highly stereoselective fashion. Via repeated homologation steps, only 1,2-anti- and 1,3-syn-configured products were obtained. Homologation with substituted carbenoids followed by reaction with carbon nucleophiles resulted in configurationally inverted products and tertiary boronic esters in a highly stereoselective fashion. This approach significantly expands the potential of the Matteson reaction.

Nickel-Catalyzed Regio- and Enantioselective Borylative Coupling of Terminal Alkenes with Alkyl Halides Enabled by an Anionic Bisoxazoline Ligand.

Chiral boronic esters are a class of versatile building blocks. We describe herein an asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides. The success of this asymmetric reaction is ascribed to the application of a chiral anionic bisoxazoline ligand. This study provides a three-component strategy to access α- and β-stereogenic boronic esters from easily accessible starting materials. This protocol is characterized by mild reaction conditions, wide substrate scope and high regio- and enantioselectivity. We also showcase the value of this method in simplifying the synthesis of several drug molecules. Mechanistic studies suggest that the generation of enantioenriched boronic esters bearing an α-stereogenic center results from a stereoconvergent process, while the enantioselectivity-controlling step in the generation of boronic esters with a β-stereocenter is switched to the olefin migratory insertion step due to coordination of an ester group.

Stereoselective Synthesis of Highly Substituted O-Heterocycles via Matteson Homologation: A Ring-Closing Metathesis Approach

Matteson homologations of chiral boronic esters with the aid of unsaturated nucleophiles are powerful for gaining access to a range of different O-heterocycles via subsequent ring-closing metatheses. Using this protocol, six- to eight-membered rings become available and almost any position of the ring can be substituted and/or functionalized.

Diastereoselective Alkylation of Activated Nitrogen Heterocycles with Alkenyl Boronate Complexes

AbstractAlkenyl boronate complexes react with acylated quinolines and isoquinolines via 1,2‐metalate rearrangement to give alkylated, dearomatized heterocycles in good yields, diastereoselectivities, and regioselectivities. This multi‐component coupling is highly modular and can be used to access a wide scope of heterocyclic scaffolds. Chiral boronic esters made through this methodology possess high synthetic potential and can be transformed into various functional groups in one step without racemization.

Diastereoselective Alkylation of Activated Nitrogen Heterocycles with Alkenyl Boronate Complexes.

Alkenyl boronate complexes react with acylated quinolines and isoquinolines via 1,2-metalate rearrangement to give alkylated, dearomatized heterocycles in good yields, diastereoselectivities, and regioselectivities. This multi-component coupling is highly modular and can be used to access a wide scope of heterocyclic scaffolds. Chiral boronic esters made through this methodology possess high synthetic potential and can be transformed into various functional groups in one step without racemization.

A Dynamic Thermodynamic Resolution Strategy for the Stereocontrolled Synthesis of Streptonigrin.

We report that axially chiral biaryl boronic esters can be generated with control of atroposelectivity by a Binol-mediated dynamic thermodynamic resolution process. These intermediates can be progressed to enantioenriched products through stereoretentive functionalization of the carbon-boron bond. Finally, we have exploited this method in the first highly stereoselective total synthesis of P-streptonigrin.

A Dynamic Thermodynamic Resolution Strategy for the Stereocontrolled Synthesis of Streptonigrin

AbstractWe report that axially chiral biaryl boronic esters can be generated with control of atroposelectivity by a Binol‐mediated dynamic thermodynamic resolution process. These intermediates can be progressed to enantioenriched products through stereoretentive functionalization of the carbon–boron bond. Finally, we have exploited this method in the first highly stereoselective total synthesis of P‐streptonigrin.

Stereoselective Synthesis of a Protected Side Chain of Callipeltin A.

Matteson homologations of chiral boronic esters proved to be an excellent tool for the synthesis of highly functionalized amino and hydroxy acid residues. This method provides straightforward stereoselective access to the side chain of callipeltin A, a natural marine product with interesting biological activities. Furthermore, this protocol should allow for variations in the substitution pattern in future SAR studies, simply by choosing suitable nucleophiles during the homologation steps.

Matteson Homologation of Arylboronic Esters

AbstractCommercially available arylboronic acids can easily be converted into chiral boronic esters which can be subjected to Matteson homologations using Grignard reagents. The best results are obtained in one pot protocols without isolation of the α‐chloroboronic ester intermediates. Alkoxides can also be used as nucleophiles, but the corresponding homologated boronic esters are found to be not stable.

Enantioselective Cobalt-Catalyzed Hydroboration of Ketone-Derived Silyl Enol Ethers.

Catalytic asymmetric hydroboration of alkenes is a powerful tool for the synthesis of natural products, agrochemicals, and pharmaceuticals via the versatile transformations of chiral alkyl boronic esters. However, the scope of available alkenes is limited to styrenes, activated alkenes, and compounds with directing groups. The catalytic enantioselective hydroboration of heteroatom-substituted alkenes is rarely explored and those catalyzed by earth-abundant metals are yet to be reported. Herein, we report a cobalt-catalyzed asymmetric hydroboration of ketone-derived silyl enol ethers and provide a convenient approach to access valuable enantiopure β-hydroxy boronic esters. This protocol features mild reaction conditions, a broad substrate scope, and excellent enantioselectivities (up to 99 % ee). This approach was applied in the successful synthesis of salmeterol and albuterol, demonstrating its potential to streamline complex molecule synthesis.

Enantioselective Cobalt‐Catalyzed Hydroboration of Ketone‐Derived Silyl Enol Ethers

Catalytic asymmetric hydroboration of alkenes is a powerful tool for the synthesis of natural products, agrochemicals, and pharmaceuticals via the versatile transformations of chiral alkyl boronic esters. However, the scope of available alkenes is limited to styrenes, activated alkenes, and compounds with directing groups. The catalytic enantioselective hydroboration of heteroatom-substituted alkenes is rarely explored and those catalyzed by earth-abundant metals are yet to be reported. Herein, we report a cobalt-catalyzed asymmetric hydroboration of ketone-derived silyl enol ethers and provide a convenient approach to access valuable enantiopure β-hydroxy boronic esters. This protocol features mild reaction conditions, a broad substrate scope, and excellent enantioselectivities (up to 99 % ee). This approach was applied in the successful synthesis of salmeterol and albuterol, demonstrating its potential to streamline complex molecule synthesis.

Nickel-Catalyzed Enantioselective Hydroboration of Vinylarenes.

The enantioselective hydroboration of vinylarenes catalyzed by a chiral, nonracemic nickel catalyst is presented as a facile method for generating chiral benzylic boronate esters. Various vinylarenes react with bis(pinacolato)diboron (B2pin2) in the presence of MeOH as a hydride source to form chiral boronate esters in up to 92% yield with up to 94% ee. The use of anhydrous Me4NF to activate B2pin2 is crucial for ensuring fast transmetalation to achieve high enantioselectivities.

Chemo- and Stereoselective Dearomative Coupling of Indoles and Bielectrophilic β-Imino Boronic Esters via Imine-Induced 1,2-Boronate Migration.

A new imine-induced 1,2-boronate migration has been developed for achieving chemo- and stereoselective dearomative coupling of C3-substituted indoles and bi-electrophilic β-imino boronic esters, providing rapid access to complex chiral indoline boronic esters with four stereocenters including an all-carbon quaternary stereocenter and a tertiary α-aminoboronic ester. In contrast, coupling of indoles without C3 substitution and β-imino boronic esters provided tetrahydro-1H-pyrido[4,3-b]indoles via imine-induced 1,2-boronate migration followed by deborylative rearomatization.

A Pivotal Role of Chloride Ion on Nickel-Catalyzed Enantioselective Reductive Cross-Coupling to Perfluoroalkylated Boronate Esters

The enantioselective construction of perfluoroalkyl-containing molecules is essential in materials science, agrochemistry, and medicinal chemistry. Herein, a nickel-catalyzed reductive cross-coupling was reported to generate chiral perfluoroalkylated boronate esters from the easily prepared perfluoroalkyl-substituted α-iodoboronates. The simple and mild conditions enable a broad range of aryl iodides to deliver the products in good enantioselectivities. Additionally, compared with common acceleration by iodide salts on substrate activation, the effect of the additive was systematically investigated to disclose a pivotal role of chloride ion on nickel reduction for this transformation.

Enantioselective synthesis of tertiary boronic esters through catalytic asymmetric reversed hydroboration

Chiral tertiary boronic esters are important precursors to bioactive compounds and versatile synthetic intermediates to molecules containing quaternary stereocenters. The development of conjugate boryl addition to α,β-unsaturated amide has been hampered by the intrinsic low electrophilicity of the amide group. Here we show the catalytic asymmetric synthesis of enantioenriched tertiary boronic esters through hydroboration of β,β-disubstituted α,β-unsaturated amides. The Rh-catalyzed hydroboration occurs with previously unattainable selectivity to provide tertiary boronic esters in high enantioselectivity. This strategy opens a door for the hydroboration of inert Michael acceptors with high stereocontrol and may provide future applications in the synthesis of biologically active molecules.

Dual Ni/photoredox-catalyzed asymmetric cross-coupling to access chiral benzylic boronic esters

The flourishing Ni/photoredox-catalyzed asymmetric couplings typically rely on redox-neutral reactions. In this work, we report a reductive cross-coupling of aryl iodides and α-chloroboranes under a dual catalytic regime to further enrich the metallaphotoredox chemistry. This approach proceeds under mild conditions (visible light, ambient temperature, no strong base) to access the versatile benzylic boronic esters with good functional group tolerance and excellent enantioselectivities.

A dancing nickel in asymmetric catalysis: Enantioselective synthesis of boronic esters by 1,1-addition to terminal alkenes

Chiral benzylic boronic esters were synthesized through a simple three-component reaction involving a terminal alkene, an aryl bromide and B2pin2 using a nickel catalyst. Interestingly, the reaction yielded a 1,1-difunctionalized alkane instead of a 1,2-difunctionalized product. Mechanistic investigations supported a 1,2-Ni migration to achieve the 1,1-difunctionalized product. The 1,1-addition addition products were obtained in good yields and high chemo and regio-selectivity without the need for directing groups. When a chiral Ni catalyst was employed, the resulting boronic esters were prepared with excellent enantioselectivity.