Asymmetric Catalysis Using Aromatic Aldehydes as Chiral α-Alkoxyalkyl Anions

Abstract

We have developed a new umpolung strategy for catalytically forming a chiral α-alkoxyalkyl anion from an aromatic aldehyde for use in asymmetric synthesis. The reaction between aromatic aldehydes and aryl or allyl electrophiles with a silylboronate utilizing a chiral copper−N-heterocyclic carbene catalyst and a palladium−bisphosphine catalyst in a synergistic manner occurred with high enantioselectivities to deliver the three-component coupling products, chiral silyl-protected secondary alcohol derivatives. Our method features the catalytic generation of enantioenriched chiral αalkoxyalkylcopper(I) intermediates from aldehydes and their subsequent palladium-catalyzed stereospecific crosscoupling.

Synergistic Cu/Pd‐Catalyzed Asymmetric Allenylic Alkylation of Azomethine Ylides for the Construction of α‐Allene‐Substituted Nonproteinogenic α‐Amino Acids

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An unprecedented asymmetrica llenylic alkylation of readily available imine esters, whichw as enabled by as ynergistic Cu/Pd catalysis, has been developed. [10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous work) and prochiral or racemic nucleophiles with achiral Pd/chiral Cu dualcatalysis( this work). [1] For example, these versatile structure motifs have been frequently found in unique enzyme inhibitors [2] and pharmacologically importantn onnatural peptides and proteinsw ith enhanced functionalities.

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“…[10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous work) and prochiral or racemic nucleophiles with achiral Pd/chiral Cu dualcatalysis( this work). Among these elegant methodologies using chiral palladium h 3 -butadienyl species as electrophiles, most of the reported examples focusedo nt he construction of allenes with axial chirality, [8] and the established protocols capable of achieving allene derivatives containingc entral chirality [8g, 9] are stillraretod ate (Scheme 1a).…”

“…Among these elegant methodologies using chiral palladium h 3 -butadienyl species as electrophiles, most of the reported examples focusedo nt he construction of allenes with axial chirality, [8] and the established protocols capable of achieving allene derivatives containingc entral chirality [8g, 9] are stillraretod ate (Scheme 1a). [10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous work) and prochiral or racemic nucleophiles with achiral Pd/chiral Cu dualcatalysis( this work). [10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous work) and prochiral or racemic nucleophiles with achiral Pd/chiral Cu dualcatalysis( this work).…”

“…Based on our previousw orks, [14] the initial study was conducted with Cu I /L1 complex and Pd(PPh 3 ) 4 as the combined catalysts and Cs 2 CO 3 as the base. Based on our previousw orks, [14] the initial study was conducted with Cu I /L1 complex and Pd(PPh 3 ) 4 as the combined catalysts and Cs 2 CO 3 as the base.…”

“…Furthermore, the enantiocontrol of nucleophiles has not been touched yet in all of the known cases,p robably due to the synthetic challenges in the palladium-catalyzed asymmetric allylation reaction, that is, the long distance between the catalytic site of the chiral palladium complexa nd the reaction site in nucleophile reagents. [10] Recently,w eand others have developedanew seto fd ual catalytic systemsf or efficient asymmetrica llylic alkylation reactions [10b, 11,12] of readily available iminee sters, in which ac hiral Cu I complex anda chiral [13] or chiral Pd 0 complex [14] has been combined and successfully used as the synergisticc atalysts, leading to various a-quaternary nonproteinogenic a-AAs [15] Scheme1.Catalytic asymmetric allenylic alkylation of non-prochiral nucleophiles withc hiral Pd complex (previous work) and prochiral or racemic nucleophiles with achiral Pd/chiral Cu dualcatalysis( this work). LG = leaving group.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.…”