Enantioselective Allylic Amination Research Articles

Theoretical investigations of Co-catalyzed allylic aminations

Cobalt-bisoxazolinephosphine-catalyzed regio- and enantioselective allylic amination of racemic n-propyl allylic carbonate and aniline was investigated by DFT calculations at the ωB97XD/6–31G(d,p) level (SDD for Co). The computational results revealed that cobalt-catalyzed allylic amination underwent mainly through oxidative addition of n-propyl allylic carbonate, coordination of aniline to cobalt, hydrogen migration, isomerization of allyl group, and reductive elimination. The oxidative addition of n-propyl allylic carbonate was the rate-determining step, the reductive elimination was the regioselectivity-limited and enantioselectivity-controlling step, and the most favorable product was of (R)-chirality, which was compatible with the experimental results. The oxidative addition, hydrogen migration, reductive elimination, and the reactivity of racemic n-propyl allylic carbonates were discussed at full length in this text.

Complexation with PdII and enantioselective allylic amination using new P*-monodentane bicyclic amidophosphite

Complexation with PdII and enantioselective allylic amination using new P*-monodentane bicyclic amidophosphite

Highly enantioselective allylic amination reaction through aerobic oxidative organo–organo dual catalytic system

An NHC/chiral tertiary amine dual catalytic system for the aerobic oxidation/allylic amination reaction has been developed. The combination of NHC with organo-catalysts especially with tertiary amine catalysts remains an underexplored area.

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.

Molybdenum-Catalyzed Regio- and Enantioselective Amination of Allylic Carbonates: Total Synthesis of (S)-Clopidogrel.

The first molybdenum-catalyzed highly regio- and enantioselective allylic amination of both aryl- and alkyl-substituted branched allylic carbonates has been developed. A wide variety of amines, including drugs and complex bioactive molecules, underwent successful amination with excellent reaction outcomes (up to 96% yield, >99% ee, and >20:1 b/l). The reaction could be scaled up and has been applied to the total synthesis of chiral drug molecule (S)-clopidogrel (Plavix).

Modular Synthesis of Enantioenriched α-Chiral Homoallylic Amidines Enabled by Relay Ir/Cu Catalysis.

The cascade of Ir-catalyzed enantioselective allylic amination and Cu-catalyzed alkyne-azide cycloaddition was designed for the asymmetric synthesis of homoallylic amidines. The nucleophilic addition of an in situ-generated enantioenriched tertiary allylamine to a ketenimine intermediate triggers a rapid and stereospecific zwitterionic aza-Claisen rearrangement in a 1,3-chiral transfer manner. The approach allows modular access to enantioenriched α-chiral homoallylic amidines in high yields with a high level of enantiomeric purity.

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.

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

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

Palladium-catalyzed asymmetric allylic amination of a vinylethylene carbonate with N-heteroaromatics

Highly enantioselective allylic amination of a vinylethylene carbonate with N-heteroaromatics is enabled by asymmetric palladium catalysis for the synthesis of chiral acyclic nucleosides and isonucleosides.

Cobalt-Catalyzed Regio- and Enantioselective Allylic Amination.

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

Synthesis of chiral titanium-containing phosphinoamide ligands for enantioselective heterobimetallic catalysis

The synthesis of six chiral titanium-containing phosphinoamide ligands is discussed. These ligands assemble chiral heterobimetallic Pd–Ti complexes, enable enantioselective intramolecular allylic aminations with hindered amine nucleophiles and achieve selectivity up to 53% ee. Mechanistic studies demonstrate the reversibility of the enantio-determining C–N bond forming step, which leads to a gradual increase in the % ee of the reaction over time. These results represent a rare example of enantioselective heterobimetallic catalysis and suggest that these new ligands could find broad application in enantioselective transition metal catalysis.

Enantioselective Syntheses of Tricyclic Benzimidazoles via Intramolecular Allylic Aminations with Chiral-Bridged Biphenyl Phosphoramidite Ligands.

The first iridium-catalyzed enantioselective intramolecular allylic aminations of benzimidazole-tethered allylic carbonates were developed, providing three classes of tricyclic benzimidazoles bearing a tertiary carbon stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, 99% ee). Wide substrate scope, excellent catalytic efficiency and mild conditions rendered this protocol particularly superior and practical. Impressively, the chiral bridge with a tunable structure was shown to provide a very good adjustment space for the chiral environment. The excellent catalytic performance of the ligands manifested their advantages over the bisphenol-based and BINOL-derived counterparts in these transformations. It also highlighted the potential application value of the chiral-bridged ligands.

Decarboxylative Organocatalytic Allylic Amination of Morita-Baylis-Hillman Carbamates.

The present study reports the organocatalytic enantioselective allylic amination of Morita-Baylis-Hillman carbamates efficiently catalyzed by a chiral amine in the presence of a Brønsted acid. Chiral allylic amines were produced in high yields (up to 98 %) and enantioselectivities (up to 97 % ee). This method provides an efficient and easily performed route to prepare α-methylene-β-lactams, and other optically active β-lactams, such as the cholesterol-lowering drug Ezetimibe.

Regio- and Enantioselective Allylic Amination of Aliphatic MBH Adducts with N-Heteroaromatics.

Palladium-catalyzed regio- and enantioselective allylic amination of aliphatic Morita-Baylis-Hillman (MBH) adducts with N-heteroaromatic nucleophiles (e.g., benzimidazole, 4,5-diphenylimidazole, benzotriazole, and purines) was achieved by using a spiroketal-based diphosphine (SKP) ligand, and afforded a range of chiral, branched N-allyl products with high selectivity.

Hydrogen Bond Direction Enables Palladium-Catalyzed Branch- and Enantioselective Allylic Aminations and Beyond.

The palladium-catalyzed branch- and enantioselective allylic amination of vinyl benzoxazinones was accomplished through controlling the hydrogen bond direction. This protocol provides a rapid and efficient route for synthesizing an important building block, chiral amino alkene, from widely available aliphatic amines in 64 → 99% yields with up to 99% ee. Furthermore, this transformation and the accompanying products were utilized to develop one-pot reactions through dual catalysis, affording chiral indolines with good synthetic efficiency and excellent enantiocontrol.

ChemInform Abstract: An Iridium(I) N‐Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions.

A chiral iridium(I) N-heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74-91 %) and excellent enantioselectivities (92-99 % ee). Preliminary mechanistic investigations reveal that the C-H activation occurs at the position ortho to the N-aryl group of the ligand.

An Iridium(I) N‐Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions

AbstractA chiral iridium(I) N‐heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C−H activation occurs at the position ortho to the N‐aryl group of the ligand.

An Iridium(I) N-Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions.

A chiral iridium(I) N-heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74-91 %) and excellent enantioselectivities (92-99 % ee). Preliminary mechanistic investigations reveal that the C-H activation occurs at the position ortho to the N-aryl group of the ligand.

ChemInform Abstract: Enantioselective Allylic Amination of Morita—Baylis—Hillman Acetates Catalyzed by Chiral Thiourea‐Phosphine.

The enantioselective allylic amination of Morita-Baylis-Hillman acetates catalyzed by chiral cyclohexane-based thiourea-phosphine catalysts was investigated. In the presence of 20 mol% rosin-derived thiourea-phosphine 3j, the chiral amines were obtained in up to 88% yield and up to 85% ee.

Iridium‐Catalyzed Asymmetric Allyl­ic Substitutions with Bulky ­Amines/Oxidative Double Bond Cleavage – Entry into the Reetz Synthesis of Amino Alcohols

AbstractBranched allylic amines were prepared by Ir‐catalyzed enantioselective allylic aminations with the bulky N‐nucleophiles HN(Boc)2 and HNBn2. The products were transformed into N‐protected amino aldehydes, which were either reduced or coupled diastereoselectively with organometallic compounds to give vicinal amino alcohols. A formal synthesis of the neurokinin receptor antagonist (+)‐L‐733060 was carried out as an application.