Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands

Accounts of Chemical Research, Год журнала: 2019, Номер 52(9), С. 2657 - 2672

Опубликована: Июнь 19, 2019

ConspectusThe catalytic, asymmetric synthesis of complex molecules has been a core focus our research program for some time because developments in the area can have an immediate impact on identification novel strategies value-added molecules. In concert with this central interest, we emphasized design ligand scaffolds as tactic to discover and develop chemistry overcome well-recognized synthetic challenges. Based group's work chiral pool-derived diolefin ligands, designed implemented class hybrid (phosphoramidite,olefin) which combines properties both phosphoramidite olefin motifs impact, fine-tune, even override inherent reactivity metal center. Specifically, utilized these unique modifying ligands address several recognized limitations field iridium-catalyzed, allylic substitution. The methods documented typically employ branched, unprotected alcohols substrates obviate need rigorous exclusion air moisture.Following Takeuchi's seminal report demonstrating high aptitude Ir(I)-phosphite catalysts branch-selective substitution, concerted efforts from numerous laboratories led broadening utility reaction class. first section Account outlines process leading discovery unprecedented its validation iridium-catalyzed amination alcohols. This continues involving heteroatom-based nucleophiles within inter- intramolecular etherification, thioetherification spiroketalization processes. second highlights use readily available carbon possessing sp, sp2, sp3 hybridization series enantioselective carbon–carbon bond-forming reactions. We describe how alkylzinc, allylsilane, classes organotrifluoroborate be coupled enantioselectively enable construction key including 1,5-dienes, 1,4-dienes, 1,4-enynes. Since electronic steric renders (η3-allyl)-Ir(III) intermediate highly electrophilic, weak such alkyl olefins used. also show that more nucleophilic alkene enamines situ generated ketene acetals smoothly participate substitution reactions yield valuable piperidines γ,δ-unsaturated esters, respectively.The concept stereodivergent dual catalysis, synergistically amine catalysis iridium furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. enabled independent, stereoselective all four possible product stereoisomers single set starting materials, was highlighted Δ9-tetrahydrocannabinol. concludes overview organometallic mechanistic studies regarding relevant intermediates catalytic cycle These allowed us better understand origin characteristics exhibited by catalyst comparison related systems.

Язык: Английский

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Photochemical Asymmetric Nickel‐Catalyzed Acyl Cross‐Coupling

Angewandte Chemie International Edition, Год журнала: 2019, Номер 58(47), С. 16854 - 16858

Опубликована: Сен. 18, 2019

Abstract Photochemical enantioselective nickel‐catalyzed cross‐coupling reactions are difficult to implement. We report a visible‐light‐mediated strategy that successfully couples symmetrical anhydrides and 4‐alkyl dihydropyridines (DHPs) afford enantioenriched α‐substituted ketones under mild conditions. The chemistry does not require exogenous photocatalysts. It is triggered by the direct excitation of DHPs, which act as radical source reductant, facilitating turnover chiral catalytic nickel complex.

Язык: Английский

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Cobalt-Catalyzed Regio- and Enantioselective Allylic Amination

Journal of the American Chemical Society, Год журнала: 2019, Номер 141(29), С. 11430 - 11434

Опубликована: Июль 5, 2019

The first earth-abundant cobalt-catalyzed highly branched- and enantioselective allylic amination of racemic branched carbonates bearing alkyl groups with both aromatic aliphatic amines has been developed. process allows rapid access in high yields exclusively selectivity excellent enantioselectivities (normally 99% ee) under mild reaction conditions.

Язык: Английский

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Allenes and Dienes as Chiral Allylmetal Pronucleophiles in Catalytic Enantioselective C=X Addition: Historical Perspective and State‐of‐The‐Art Survey

Chemistry - A European Journal, Год журнала: 2021, Номер 27(52), С. 13107 - 13116

Опубликована: Июнь 29, 2021

Abstract The use of allenes and 1,3‐dienes as chiral allylmetal pronucleophiles in intermolecular catalytic enantioselective reductive additions to aldehydes, ketones, imines, carbon dioxide other C=X electrophiles is exhaustively catalogued together with redox‐neutral hydrogen auto‐transfer processes. Coverage limited processes that result both C−H C−C bond formation. alkynes latent multicomponent allylations involving dienes not covered. As illustrated this review, the ability serve tractable non‐metallic has evoked many useful transformations have no counterpart traditional chemistry.

Язык: Английский

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Asymmetric Synthesis of Remotely Chiral Naphthols and Naphthylamines via Naphthoquinone Methides

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(23), С. 12802 - 12811

Опубликована: Июнь 5, 2023

Quinone methides are well-established intermediates in asymmetric synthesis. In contrast, their extended analogues with the carbonyl and methide units distributed across two different rings have not been exploited Herein, we achieved first process involving such intermediates. Specifically, use of suitable chiral phosphoric acids enabled situ generation 2-naphthoquinone 8-methides corresponding aza counterparts for mild one-pot nucleophilic addition. These processes provided rapid access to a wide range previously less accessible remotely naphthols naphthylamines both high efficiency excellent enantioselectivity. Control experiment DFT calculations important insights into reaction mechanism, which likely involves acid molecules enantiodetermining transition states. This work serves as proof concept exploitation new types quinone versatile synthesis, thus providing platform efficient construction remote benzylic stereogenic centers aromatic compounds.

Язык: Английский

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Direct Catalytic Asymmetric and Regiodivergent N1‐ and C3‐Allenylic Alkylation of Indoles

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(21)

Опубликована: Март 21, 2023

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) this process can be switched efficiently. Using Cs2 CO3 at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with stereocenter non-adjacent (β) to nitrogen are produced good yields high enantioselectivity and complete N1-regioselectivity regardless electronic properties substitution patterns diverse indoles. K2 room temperature CH2 Cl2 , chiral C3-alkylated also obtained. Notably, introduce new class tri-substituted electrophiles that proceeded through different pathways from di-substituted electrophiles.

Язык: Английский

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Rhodium‐Catalyzed Enantio‐ and Regioselective Allylation of Indoles with gem‐Difluorinated Cyclopropanes

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(22)

Опубликована: Март 22, 2024

Abstract The use of gem ‐difluorinated cyclopropanes ( ‐DFCPs) as fluoroallyl surrogates under transition‐metal catalysis has drawn considerable attention recently but such reactions are restricted to producing achiral or racemic mono‐fluoroalkenes. Herein, we report the first enantioselective allylation indoles rhodium with ‐DFCPs. This reaction shows exceptional branched regioselectivity towards ‐DFCPs, which provides an efficient route enantioenriched fluoroallylated wide substrate scope and good functional group tolerance.

Язык: Английский

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Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

Angewandte Chemie International Edition, Год журнала: 2020, Номер 59(19), С. 7598 - 7604

Опубликована: Фев. 24, 2020

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4 )2 Lewis acid catalyst system to promote allylic substitution, providing C2-allylated products in typically high yields (40-99 %) enantioselectivities (83-99 % ee) with excellent regiocontrol. Experimental studies DFT calculations suggest that reaction proceeds via direct C2-allylation, rather than C3-allylation followed by situ migration. Steric congestion at indole-C3 position improved π-π stacking interactions have been identified as major contributors C2-selectivity.

Язык: Английский

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Rhodium-Catalyzed Regio- and Enantioselective Allylic Amination of Racemic 1,2-Disubstituted Allylic Phosphates

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(22), С. 8255 - 8260

Опубликована: Май 24, 2021

Alkynylphosphines are rarely used as ligands in asymmetric metal catalysis. We synthesized a series of chiral bis(oxazoline)alkynylphosphine and them Rh-catalyzed highly regio- enantioselective allylic amination reactions 1,2-disubstituted phosphates. Chiral amines were up to 95% yield with >20:1 branched/linear (b/l) ratio 99% ee from racemic precursors. The sterically smaller linear alkynyl group on the P atom was key fit new requirements introduction bulky 2-R' groups.

Язык: Английский

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Chiral Amines via Enantioselective π-Allyliridium-C,O-Benzoate-Catalyzed Allylic Alkylation: Student Training via Industrial–Academic Collaboration

Accounts of Chemical Research, Год журнала: 2022, Номер 55(15), С. 2138 - 2147

Опубликована: Июль 13, 2022

ConspectusCyclometalated π-allyliridium-C,O-benzoate complexes discovered in the Krische laboratory display unique amphiphilic properties, catalyzing both nucleophilic carbonyl allylation and electrophilic of diverse amines as well nitronates. Given importance chiral FDA-approved small-molecule drugs, a collaboration with medicinal chemists at Genentech that included on-site graduate student internships was undertaken to explore expand scope π-allyliridium-C,O-benzoate-catalyzed allylic amination related processes. As described this Account, our collective experimental studies have unlocked asymmetric aminations exceptionally broad utility scope. Specifically, using racemic branched alkyl-substituted acetate proelectrophiles, primary secondary aliphatic or aromatic amines, including indoles, engage highly regio- enantioselective amination. Additionally, unactivated nitronates were found be competent partners for alkylation, enabling entry β-stereogenic α-quaternary amines. Notably, these substitutions, which complete regioselectivity reactions allyl electrophiles, complement corresponding iridium phosphoramidite-catalyzed aminations, require aryl-substituted electrophiles promote high levels regioselectivity. Computational, kinetic, ESI-CID-MS, isotopic labeling understand mechanism processes, origins enantioselectivity. Isotopic suggest C–N bond formation occurs through outer-sphere addition π-allyl. DFT calculations corroborate via early transition states distinct trans effects diastereomeric chiral-at-iridium π-allyl render reaction less sensitive steric effects, accounting hindered amine nitronate nucleophiles. Reaction progress kinetic analysis (RPKA) reveals zero-order dependence on acetate, first-order catalyst, fractional-order amine. corroborated by ESI-CID-MS analysis, 0.4 order may reflect intervention cesium-bridged dimers, dissociate form monomeric cesium amide Hence, requirement carbonate (vs lower alkali metal carbonates) processes reside cesium's capacity Lewis acid-enhanced Brønsted acidification pronucleophile. Beyond development catalytic synthesis novel present research conducted students who benefited from career experiences associated training academic industrial laboratories.

Язык: Английский

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