Enantioselective Pd-catalyzed Allylic Alkylation Research Articles

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.

Spiro Indane-Based Phosphine-Oxazolines as Highly Efficient P,N Ligands for Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles and Allylic Etherification.

A series of indane-based phosphine-oxazoline ligands with a spirocarbon stereogenic center were examined for palladium-catalyzed asymmetric allylic alkylation of indoles. Under optimized conditions, high yields (up to 98%) and enantioselectivities (up to 98% ee) were obtained with a broad scope of indole derivatives. The ligand was determined to be the most efficient P,N-ligand for this reaction. Moreover, the ligand was also efficient for Pd-catalyzed asymmetric allylic etherification with hard aliphatic alcohols as nucleophiles.

Palladium-catalyzed enantioselective decarboxylative allylic alkylation of fully substituted N-acyl indole-derived enol carbonates.

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted N-acyl indole-derived enol carbonates forming acyclic all-carbon quaternary stereocenters is reported. Excellent yields up to 99% and enantioselectivities up to 98% ee are obtained through the use of a new electron-deficient phosphinoxazoline (PHOX) ligand. Control of substrate enolate geometry is crucial for high selectivity. The obtained α-quaternary N-acyl indoles are formal ester equivalents, and represent a useful handle for further synthetic transformations.

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine A.

Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A.

Highly enantioselective Pd-catalyzed indole allylic alkylation using binaphthyl-based phosphoramidite-thioether ligands

A new type of phosphoramidite-thioether ligand has been developed for Pd-catalysed asymmetric C-3 allylic alkylation of indoles with excellent yields and enantioselectivities.

Synthesis of 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands and their application in regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates.

A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl)phosphine]-1’-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates.

Enantioselective Pd-catalyzed tandem allylic alkylation reaction using monodentate phosphoramidite ligands for the formal total synthesis of huperzine A

Enantioselective synthesis of a key intermediate to (−)-huperzine A by Pd-catalyzed tandem allylic alkylation using a novel monodentate phosphoramidite ligand.

Isolation and Characterization of a Chiral η1-Allyl Palladium DIPPAM Complex: Application to the Enantioselective Pd-Catalyzed Allylic Alkylation

In the presence of [Cl(C3H5)Pd]2, diphenylphosphinoazomethinylate salt (DIPPAM) 1a forms an original chiral η1-allyl palladium complex, 2. Precatalyst 2/MgBr2 is an efficient catalyst for asymmetric allylic alkylation, giving good yields and ee’s in the reactions of rac-4-acetoxy-2-pentene or rac-3-acetoxy-1,3-diphenyl-1-propene and dimethyl malonate (respectively 77% and 96% yield; 66% and 96% ee). Preliminary mechanistic studies have highlighted the key role of the η1-coordination mode of the allyl fragment.

Development of Novel Hemilabile Segphos P—P=O Ligands.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles by a New Class of Chiral Ferrocenyl P/S Ligands

Chiral ferrocenyl heterobidentate P/S ligands bearing both central and planar chirality were prepared from (S)-Ugi's amine via a three-step modular synthesis. Through systematic screening and optimization, L8 was found to be the best ligand for Pd-catalyzed asymmetric allylic alkylation of indoles with ee's up to 96% being attained.

Asymmetric Construction of Quaternary Carbon Stereocenter by Pd‐Hemilabile Ligand‐Catalyzed Allylic Substitution.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Highly Regio-, Diastereo-, and Enantioselective Pd-Catalyzed Allylic Alkylation of Acyclic Ketone Enolates with Monosubstituted Allyl Substrates

Pd-catalyzed asymmetric allylic alkylation reactions of acyclic ketones with monosubstituted allyl substrates using 1,1‘-P,N-ferrocene with H as substituent on the oxazoline ring as ligand gave products having two chiral centers with high yields and with high regio-, diastereo-, and enantioselectivities, with the ratio of branched and linear products being 98:2, anti:syn ratio for branched products being 7−21:1, and ee for the anti-products being 92−99%.

Asymmetric construction of quaternary carbon stereocenter by Pd-hemilabile ligand-catalyzed allylic substitution

The catalyst comprised [PdCl(η 3-C 3H 5)] 2 and a simple chiral hemilabile ferrocene ligand, 1′,2-bis(diphenylphosphinoethyl)ferrocenyl alcohol, provides synthetically acceptable results for an enantioselective Pd-catalyzed allylic alkylation of cyclohexanone derivatives bearing an electron-withdrawing group at the α-position to form the quaternary carbon with up to 90% enantioselectivity under mild reaction conditions.

Development of Novel Hemilabile Segphos P-P=O Ligands

Development of novel chiral hemilabile Segphos P-P=O ligands is described. The ligands are examined for enantioselective Pd-catalyzed allylic alkylation of cyclic allylic acetates.

On the formation of Pd(II) complexes of Trost modular ligand involving N–H activation or P,O coordination in Pd-catalyzed allylic alkylations

Specific chiral ligands have been designed by Trost et al. to perform enantioselective Pd-catalyzed allylic alkylations. It is shown that the Pd(0) complex formed by addition of the Trost ligand ( 4) to Pd 0(dba) 2 is not stable in most solvents (acetone, DMF, CH 2Cl 2). Indeed, Pd 0(dba)( 4) leads to the formation of a stable Pd II complex 5 (X-ray structure), likely by activation of the two N–H bonds of the ligand by the Pd 0 centre. The formation of the Pd II complex competes with the reaction of Pd 0( 4) with ( E)-PhCH CH–CH(OAc)–Ph, excluding any investigation of the kinetics of the latter reaction. The ionization steps from intermediate (η 2-PhCH CH–CH(OAc)–Ph)Pd 0( 4) were found to be very slow. The cationic P,P complex [(η 3-Ph–CH–CH–CH–Ph)Pd( 4)] +, expected to be generated by addition of 2 equiv. of 4 to the precursor [(η 3-Ph–CH–CH–CH–Ph)Pd(μ-Cl)] 2, in the presence of a chloride scavenger, leads to a complex mixture whereas addition of 1 equiv. of 4 affords a stable bis-cationic Pd II complex {[(η 3-Ph–CH–CH–CH–Ph)Pd] 2( 4)]} 2+, 2 ( BF 4 - ) (X-ray structure) via a P,O complexation of each allyl-Pd moieties. This dissymmetric P,O coordination will favour the enantioselectivity of Pd-catalyzed allylic alkylation of (E)-PhCH CH–CH(OAc)–Ph by the control of the regioselectivity of the nucleophilic attack onto the allylic ligand which is responsible of the enantioselectivity of the overall catalytic reaction.

Chiral P-monodentate phosphoramidite and phosphite ligands for the enantioselective Pd-catalyzed allylic alkylation

The improved synthesis of the chiral phosphoramidite Ia, based on a biphenol backbone and bearing chiral bis(1-phenylethyl)amine group on the phosphorus atom, is described together with its Pd(II) complex. The chiral complex cis-PdCl 2L 2 (L = Ia) has been characterized by X-ray crystal structure analysis and spectroscopic data. The series of the chiral P-monodentate phosphoramidite and phosphite ligands was tested in Pd-catalyzed enantioselective allylic substitution of different substrates. In the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylallyl acetate with dimethylmalonate, up to 79% ee was achieved with [Pd 2(dba) 3] × CHCl 3 as precatalyst.

Regio- and Enantioselective Pd-Catalyzed Allylic Alkylation of Ketones through Allyl Enol Carbonates

The Pd-catalyzed reorganization of enol allyl carbonates to allylated ketones occurs asymmetrically in the presence of chiral ligands previously developed in this group. With 2-methylcyclohexanone, asymmetric regioselective alkylation occurs at the more substituted carbon without complications of polyalkylation. Alkylation to create quaternary centers in indanones and benzonabenone occurs in much higher ee than using tin or lithium enolates. The sense of enantioinduction in tetralones is opposite from the tin and lithium enolate examples. For the first time, asymmetric creation of tertiary centers occurs with high ee (78-99%). The different results between this reaction and the use of lithium or tin enolates suggest different mechanisms may be involved.

Highly regio- and enantioselective Pd-catalyzed allylic alkylation and amination of monosubstituted allylic acetates with novel ferrocene P,N-ligands.

Highly regio- and enantioselective Pd-catalyzed allylic alkylation and amination of monosubstituted allylic acetates with novel ferrocene P,N-ligands.

A phosphorus-containing chiral amidine ligand for asymmetric reactions: enantioselective Pd-catalyzed allylic alkylation

Phosphorus-containing amidine 7 was prepared through several steps from L-valine 1. The new ligand for asymmetric reactions was evaluated in the palladium-catalyzed allylic alkylation of 1,3-diphenylprop-2-enyl acetate and pivalate 8a,b with the nucleophile derived from dimethyl malonate as a preliminary study. Excellent levels of asymmetric induction up to 95% e.e. were achieved along with an efficient conversion.

Syntheses of Novel Chiral Monophosphines, 2,5-Dialkyl-7-phenyl-7-phosphabicyclo- [2.2.1]heptanes, and Their Application in Highly Enantioselective Pd-Catalyzed Allylic Alkylations.

Syntheses of Novel Chiral Monophosphines, 2,5-Dialkyl-7-phenyl-7-phosphabicyclo- [2.2.1]heptanes, and Their Application in Highly Enantioselective Pd-Catalyzed Allylic Alkylations.