Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(4), P. 1959 - 1967

Published: Jan. 22, 2021

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic enantioselective synthesis of from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble wide range chiral enecarbamates (N-Cbz-protected enamines) halides with high regio- enantioselectivity. works for both nonactivated activated able produce enantiomerically enriched two minimally differentiated α-alkyl substituents. mild conditions lead functional group tolerance, which demonstrated in the postproduct functionalization many natural products drug molecules, well building blocks key intermediates compounds.

Language: Английский

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NiH-Catalyzed Functionalization of Remote and Proximal Olefins: New Reactions and Innovative Strategies

Accounts of Chemical Research, Journal Year: 2022, Volume and Issue: 55(23), P. 3519 - 3536

Published: Nov. 9, 2022

Transition metal hydride catalyzed functionalization of remote and proximal olefins has many advantages over conventional cross-coupling reactions. It avoids the separate, prior generation stoichiometric amounts organometallic reagents use preformed reagents, which are sometimes hard to access may compromise functional group compatibility. The migratory insertion complexes generated in situ into readily available alkene starting materials, hydrometalation process, provides an attractive straightforward route alkyl intermediates, can undergo a variety sequential In particular, with synergistic combination chain-walking chemistry nickel, NiH-catalyzed undergone particularly intense development past few years. This Account aims chronicle progress made this arena terms activation modes, diverse functionalizations, chemo-, regio-, enantioselectivity.We first provide brief introduction general reaction mechanisms. Taking hydroarylation as example, four oxidation states Ni have allowed us develop two different strategies form final product: Ni(I)-H/X-Ni(II)-H platform that relies on reductants Ni(I/II/III) cycle redox-neutral or FG-Ni(II)-H reacts substrate forms products via Ni(0/II) pathway. We also demonstrate functionalization, including C-C bond-forming reactions more challenging C-N/C-S could be realized. Moreover, employment appropriate chiral ligands successfully realize corresponding asymmetric hydrofunctionalization olefins, hydroalkylation, hydroarylation, hydroalkenylation, hydroalkynylation, hydroamination. Interestingly, enantio-determining step enantioselective hydronickelation, selective oxidative addition, reductive elimination. To hydrofunctionalization, we developed ligand relay catalytic strategy simple ligands, for second coupling. novel design single, possibly structurally complex promote both steps success multicomponent convenient approach gain molecules. Finally, halides used olefin precursors cross-electrophile coupling Applications these discussed. hope will inspire future field overcome key challenges, conceptually new strategies, high-performance systems enhanced reactivity selectivity, cutting-edge catalyst design, further mechanistic studies.

Language: Английский

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Ni/Photoredox-Catalyzed Enantioselective Cross-Electrophile Coupling of Styrene Oxides with Aryl Iodides

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(38), P. 15873 - 15881

Published: Sept. 20, 2021

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) biimidazoline (BiIm) ligands revealed that enantioselectivity correlates electronic properties the ligands, more electron-donating affording higher ee's. Experimental computational mechanistic studies were conducted, lending support hypothesis elimination enantiodetermining character influences by altering position transition state structure along coordinate. study demonstrates benefits utilizing statistical modeling as platform for understanding provides new insight into an emerging class chiral Ni Ni/photoredox cross-coupling.

Language: Английский

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Streamlined Alkylation via Nickel-Hydride-Catalyzed Hydrocarbonation of Alkenes

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(16), P. 7015 - 7029

Published: April 12, 2022

Compounds rich in sp3-hybridized carbons are desirable drug discovery. Nickel-catalyzed hydrocarbonation of alkenes is a potentially efficient method to synthesize these compounds. By using abundant, readily available, and stable as pro-nucleophiles, reactions can have broad scope high functional group tolerance. However, this methodology still an early stage development, the first examples were reported only 2016. Herein, we summarize progress emerging field, with emphasis on enantioselective reactions. We highlight major developments, critically discuss wide range possible mechanisms, offer our perspective state challenges field. hope Perspective will stimulate future works area, making widely applicable organic synthesis.

Language: Английский

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Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 13, 2021

Abstract Chiral aliphatic amine and alcohol derivatives are ubiquitous in pharmaceuticals, pesticides, natural products fine chemicals, yet difficult to access due the challenge differentiate between spatially electronically similar alkyl groups. Herein, we report a nickel-catalyzed enantioselective hydroalkylation of acyl enamines enol esters with halides afford enantioenriched α-branched amines good yields excellent levels enantioselectivity. The operationally simple protocol provides straightforward chiral secondary alkyl-substituted from starting materials great functional group tolerance.

Language: Английский

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NiH-catalyzed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 27, 2021

Enantiomerically pure chiral amines and related amide derivatives are privilege motifs in many pharmacologically active molecules. In comparison to the well-established hydroamination, transition metal-catalysed asymmetric hydrofunctionalization of enamines provides a complementary approach for their construction. Here we report NiH-catalysed enantio- regioselective reductive hydroarylation N-acyl enamines, allowing practical access broad range structurally diverse, enantioenriched benzylamines under mild, operationally simple reaction conditions.

Language: Английский

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Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(19), P. 8797 - 8806

Published: May 3, 2022

Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general modular approach for the direct enantioselective α-arylation of saturated azacycles acyclic N-alkyl benzamides nickel/photoredox dual This process exploits hydrogen atom transfer ability photoeliminated chlorine radicals convert corresponding α-amino alkyl that then coupled with ubiquitous inexpensive (hetero)aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, broad substrate scope, high enantioselectivities, applicable late-stage diversification medicinally relevant complex molecules. Mechanistic studies suggest nickel catalyst uncommonly plays multiple roles, accomplishing radical generation, capture, cross-coupling, induction.

Language: Английский

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Dual Nickel/Photoredox-Catalyzed Asymmetric Carbosulfonylation of Alkenes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(23), P. 12532 - 12540

Published: May 30, 2023

An asymmetric three-component carbosulfonylation of alkenes is presented here. The reaction, involving the simultaneous formation a C-C and C-S bond across π-system, uses dual nickel/photoredox catalytic system to produce both β-aryl β-alkenyl sulfones in high yields with excellent levels stereocontrol (up 99:1 er). This protocol exhibits broad substrate scope functional group tolerance its synthetic potential has been demonstrated by successful applications toward pharmacologically relevant molecules. A array control experiments supports involvement secondary alkyl radical intermediate generated through addition sulfonyl double bond. Moreover, stoichiometric cross-over further suggest an underlying Ni(0)/Ni(I)/Ni(III) pathway operative these transformations.

Language: Английский

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Nickel-Catalyzed Multicomponent Coupling: Synthesis of α-Chiral Ketones by Reductive Hydrocarbonylation of Alkenes

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(35), P. 14089 - 14096

Published: Aug. 26, 2021

A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation carbonylation from readily available starting materials has been developed. This modular hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range unactivated alkenes to produce wide variety unsymmetrical dialkyl ketones bearing functionalized α-stereocenter, including enantioenriched chiral α-aryl α-amino ketones. It uses bisoxazoline as ligand, silane reductant, chloroformate safe CO source, racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester protected acid alkylation reagent. The benign nature this process renders method suitable for late-stage functionalization complex molecules.

Language: Английский

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Enantioselective NiH‐Catalyzed Reductive Hydrofunctionalization of Alkenes

Chinese Journal of Chemistry, Journal Year: 2021, Volume and Issue: 40(5), P. 651 - 661

Published: Dec. 3, 2021

Comprehensive Summary Enantioselective NiH‐catalyzed reductive hydrofunctionalization of olefins has attracted much attention in recent years. Using simple chiral ligands, a wide array functionalized and electrophiles can undergo diverse transformations to afford hydrofunctionalized products, regio‐ enantioselectively. These processes avoid the prior preparation organometallic reagents, construct stereogenic center at carbon originating either from olefin or electrophile. This review discusses background, major progress mechanistic investigations this reaction.

Language: Английский

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