Enantioselective Allylic Alkylation Research Articles

Phosphine-Catalyzed Asymmetric Allylic Alkylation of Isoxazol-5(4H)-ones with Morita-Baylis-Hillman Carbonates

Aims: Phosphine-catalyzed asymmetric allylic alkylation of isoxazol-5(4H)-ones with achiral Morita-Baylis-Hillman (MBH) carbonates has been developed. A series of isoxazol-5(4H)- ones bearing all-carbon quaternary stereocenters were obtained in 55-96% yield with 75-90% ee. Gram-scale reaction and further transformation of allylation products were conducted to demonstrate the synthetic practicability. Methods: Under Ar atmosphere, the mixture of isoxazol-5-one 1 (0.1 mmol), MBH carbonate 2 (0.12 mmol, 1.2 equiv), catalyst P5 (10 mol%), and 4Å MS (10 mg) in toluene (1 mL) was stirred at 0 oC for 24 h. The solvent was removed under vacuum, and the residue was purified by flash chromatography (petroleum ether/ethyl acetate = 3/1) to provide product 3. Result and Conclusion: We developed an efficient and enantioselective allylic alkylation of isoxazol- 5(4H)-ones with achiral MBH carbonates in the presence of chiral phosphine catalyst. A broad range of isoxazol-5(4H)-ones bearing all-carbon quaternary stereocenters were prepared with high efficiency and enantioselectivity. Importantly, the organocatalytic δ-stereocontrol of MBH carbonates was achieved via the synthetic strategy.

Iridium/Acid Dual-Catalyzed Enantioselective Aza-ene-type Allylic Alkylation of Nitro Ketene Aminals with Racemic Allylic Alcohols.

The enantioselective allylic alkylation of nitro ketene aminals with racemic allylic alcohols was realized by iridium/acid dual catalysis. An allyl group was installed on the α-position of nitro ketene aminals in a branched-selective manner in high efficiency with excellent enantioselectivities (93-99% ee). The protocol was applied to the late-stage modification of neonicotinoid insecticides, which directly furnished a novel neonicotinoid analogue with good insecticidal activity against Aphis craccivora (LC50 = 6.40 mg/L). On the basis of the control experiment, an aza-ene-type allylic alkylation reaction mechanism was proposed.

Axially Chiral N,N-Ligand-Promoted Pd-Catalyzed Enantioselective Allylic Amination and Alkylation.

An axially chiral N,N-ligand developed from a [1,1'-binaphthalene]-2,2'-diol (BINOL)-based skeleton and phenanthroline is found to be capable of promoting Pd-catalyzed asymmetric allylic amination and alkylation of allyl acetates. The reaction is compatible with cyclic and acyclic secondary amines, primary aliphatic amines, malononitrile, and dialkyl malonates, affording the corresponding chiral products in up to 99% yield and with up to >99% enantiomeric excess.

Highly regio- and enantioselective Cu/Pd co-catalyzed allylic alkylation of α-pyridyl-α-fluoroesters: construction of quaternary C-F stereocenters.

New methods for preparation of chiral alkyl fluorides have been studied intensively in recent years due to the favorable physicochemical and biological properties of those structures. Herein, we describe the regio- and enantioselective allylic alkylation of α-pyridyl-α-fluoroesters with allyl acetates promoted by Cu/Pd synergistic catalysis, constructing the carbon- fluorine quaternary stereocenters. In this co-catalytic system, palladium catalyst mainly constructed the C-C bond, while chiral copper catalyst controlled the enantioselectivity. A series of aryl- and aliphatic-substituted allyl acetates are applied, giving the corresponding products in high yield, excellent enantioselectivity and E/Z (up to 98% yield, 98:2 er, E/Z >20:1).

Asymmetric Formal Abnormal Claisen Rearrangement Enabled by Rh-Catalyzed Regio- and Enantioselective Allylic Alkylation

Asymmetric Formal Abnormal Claisen Rearrangement Enabled by Rh-Catalyzed Regio- and Enantioselective Allylic Alkylation

Enantioselective Synthesis of Skipped Dienes via Iridium-Catalyzed Allylic Alkylation of Phosphonates.

An enantioselective synthesis of skipped dienes has been developed based on an iridium-catalyzed allylic alkylation of phosphonates and Horner-Wadsworth-Emmons olefination. This two-step protocol uses easily accessible substrates and delivers C2-substituted skipped dienes bearing a C3 stereogenic center, generally with outstanding enantioselectivities (up to 99.5:0.5 er). This is the first catalytic enantioselective allylic alkylation of phosphonates, and the overall process represents a formal enantioselective α-C(sp2)-H allylic alkylation of α,β-unsaturated carbonyls and acrylonitrile.

Organocatalytic Regio- and Enantioselective Allylic Alkylation of Indolin-2-imines with MBH Carbonates toward 3-Allylindoles.

An organocatalytic asymmetric C3-allylic alkylation of indolone-2-imines with MBH carbonates has been developed for the first time. As opposed to previous reports, an "interrupted" annulation was achieved, affording 3-allylindoles in generally high yields with excellent stereoselectivities. The representative scale-up reaction and transformation of 3-allylindoles were examined. A possible mechanism was also proposed.

Palladium-catalyzed enantioselective decarboxylative allylic alkylation of α-benzyl cyanoacetates: access to chiral acyclic quaternary carbon stereocenters

A palladium-catalyzed enantioselective decarboxylative allylic alkylation of α-benzyl cyanoacetates with methylene cyclic carbamates was developed for the construction of nitrile-containing acyclic quaternary carbon stereocenters with good results.

Enantioselective reductive allylic alkylation enabled by dual photoredox/palladium catalysis.

A dual photoredox/palladium catalyzed regio- and enantioselective reductive cross-coupling of allylic acetates with tertiary/secondary alkyl bromides has been achieved, and Hantzsch ester is used as a homogeneous organic reductant. This straightforward protocol enables the stereoselective construction of C(sp3)-C(sp3) bonds under mild reaction conditions. Mechanistic studies suggest that this reaction involves radical pathways and a chiral Pd complex enables the control of the regio- and enantioselectivities.

Design and synthesis of a new family of planar and central chiral ferrocenyl phosphine ligands.

A family of planar chiral indene-fused ferrocenes were prepared through an intramolecular asymmetric C-H arylation in excellent yields (up to 99%) with excellent enantioselectivities (up to 99% ee). They were thereafter successfully transformed to chiral ferrocenyl phosphines, featuring both planar and central chiralities, in good yields (up to 83%) and excellent diastereoselectivities (up to 99% de) through highly diastereoselective phosphination. This protocol offers a general method for planar and central chiral ferrocenyl phosphines. The potential applications of the newly developed ligands were demonstrated by a Pd-catalyzed enantioselective allylic alkylation reaction, in which high enantioselectivity (92% ee) and good yield (89%) were obtained.

Dual-Catalytic Enantioselective Allylation of N-(Heteroaromatic-methyl)imine Derivatives.

We report the dual-catalytic enantioselective allylic alkylation of 2-(pyridylmethyl)amine-derived ketimines with allylic carbonates. The reaction proceeds under mild reaction conditions to generate α-amino heteroaryl benzylamine stereocenters in good yield and enantioselectivity. Enantioselectivity is achieved through the use of a copper catalyst modified with chiral bisphosphine ligand (2S,4S)-bis(diphenylphosphino)pentane.

Rhodium-Catalyzed Regio- and Enantioselective Direct Allylation of Methyl Ketones

AbstractWe report a highly branch-selective and enantioselective allylic alkylation of simple ketones with racemic aliphatic allylic carbonates under mild conditions. By using a Rh–bisoxazolinephosphine system and catalytic amounts of a base in THF, a series of chiral β-branched γ,δ-unsaturated ketones were obtained with excellent regio- and enantioselectivities. An outer-sphere nucleophilic substitution C–C bond-formation process is proposed on the basis of mechanistic studies.

Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-β-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines.

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.

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

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

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions with Nitrile-Stabilized Carbanions

AbstractThis Account summarizes our recent work on rhodium-catalyzed allylic alkylation reactions with nitrile-stabilized carbanions. Despite the challenges associated with employing nitrile-stabilized nucleophiles in transition-metal-catalyzed reactions, we have developed enantiospecific and enantioselective allylic alkylation reactions. Notably, these novel reactions permit expedient and selective access to an array of acyclic ternary and quaternary stereogenic centers present in important biologically active and functional molecules.1 Introduction2 Enantiospecific Allylic Alkylation Reactions with Nitrile-Stabilized Anions3 Enantioselective Allylic Alkylation Reactions with Nitrile-Stabilized Anions4 Conclusion

Ir-Catalyzed Asymmetric Allylic Alkylation of Dialkyl Malonates Enabling the Construction of Enantioenriched All-Carbon Quaternary Centers.

An enantioselective iridium-catalyzed allylic alkylation of malonates with trisubstituted allylic electrophiles to form all-carbon quaternary stereocenters is reported. This reaction proceeds at ambient temperature and enables the preparation of a wide range of enantioenriched products in up to 93% yield and 97% ee. The quaternary products can be readily converted to several valuable building blocks such as vicinal quaternary products and β-quaternary acids.

Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives.

An unprecedented Ir-catalyzed enantioselective double allylic alkylation of less bulky cyclic imine glycinate (azlactone) was rationally designed and developed, providing various bisallylated chiral amino acid derivatives. Control experiments revealed that this transformation proceeds in a sequential manner featuring quasi-dynamic kinetic resolution of the initially-formed monoallylation intermediates.

Nickel-Catalyzed Enantioselective Allylic Alkylation of Phosphinates

Key words nickel catalysis - phosphinates - allylic substitution - enantioselectivity

Enantioselective Palladium-Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation of Benzofurans: Diversity-Oriented Synthesis of Flavaglines

AbstractWith the introduction of new Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the highly efficient and enantioselective palladium-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved. This enabled a diversity-oriented synthesis (DOS) of previously unreachable flavaglines, which features two diversification stages. A new avenue for developing flavagline-based drugs was thus established.1 Introduction2 The Dearomative Asymmetric Allylic Alkylation of Benzofurans3 Synthesis of Flavaglines4 Conclusion and Outlook

Nickel/Enamine Cooperative Catalysis Enables Highly Enantioselective Allylic Alkylation of α-Branched Aldehydes

All-carbon quaternary stereocenters constitute a significant portion of natural products and bioactive compounds. Here we disclose a nickel and chiral amine cooperative catalysis to enable a highly...