Si-directed regiocontrol in asymmetric Pd-catalyzed allylic alkylations using C1-ammonium enolate nucleophiles

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters using Si-substituted allyl electrophiles. The Si-substituent directs the regioselectivity of enantioselective bond formation and provides products containing synthetically versatile pentafluorophenyl ester and vinylsilane moieties. Critical to the efficacy of this process was the recognition that the ancillary ligand on palladium could be altered to prevent formation of a deleterious ether by-product, whilst retaining enantioselectivity through the Lewis base catalyst. Flexibility such as this is unique to cooperative catalysis events and provides efficient access to an array of enantioenriched products that are orthogonally functionalized and easily modified.     

Enamines: efficient nucleophiles for the palladium-catalyzed asymmetric allylic alkylation

Enamines were tested to be efficient nucleophiles for palladium-catalyzed asymmetric allylic alkylation, avoiding the use of unstablilized ketone enolates formed by strong bases. The influence of the chiral metallocene-based ligands upon this reaction was studied in detail. It was shown that planar chirality played an important role in enantioselectivities. Meanwhile, different kinds of enamines and allylic acetate to the reactions were also investigated. High catalytic activity and excellent enantioselectivity (up to 99% ee) were obtained with pyrrolidine enamines of both aliphatic and aromatic ketone.     

Rhodium-catalyzed asymmetric construction of quaternary carbon stereocenters: ligand-dependent regiocontrol in the 1,4-addition to substituted maleimides

A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to substituted maleimides has been described. The regioselectivity in this reaction is controlled by the choice of ligand (dienes or bisphosphines), and 1,4-adducts with a quaternary stereocenter can be obtained with high regio- and enantioselectivity by the use of (R)-H8-binap.     

tert-Butanesulfinylthioether ligands: synthesis and application in palladium-catalyzed asymmetric allylic alkylation

A class of novel chiral SO-S-type bidentate ligands based on the tert-butylsulfinyl moiety as the sole chiral source were designed and synthesized through a simple and efficient pathway. These ligands are effective catalyst precursors for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate and moderate to good stereoselectivities (up to 84% ee) were obtained.     

Efficient palladium-catalyzed asymmetric allylic alkylation of ketones and aldehydes

Palladium-catalyzed asymmetric allylic alkylation of ketones, via enamines generated in situ as nucleophiles, were carried out smoothly with chiral metallocene-based P,N-ligands. Under the same conditions, however, reactions of aldehydes could hardly be observed. Subsequently, this obstacle was resolved by using chiral metallocene-based P,P-ligands. Both ketones and aldehydes afforded excellent enantioselectivities with up to 98% ee and 94% ee, respectively.     

Studies toward asymmetric synthesis of leiodelide A

An enantioselective route for oxazoline 4, a key fragment toward the asymmetric synthesis of leiodelide A, is described. We synthesized northern subunit 6 through a Julia–Lythgoe olefination and subsequent Sharpless asymmetric dihydroxylation. Moreover, a highly diastereoselective method using well-established Evans’ asymmetric aldol condensation was developed for preparation of southern fragment 5. The additional feature of this synthetic route is the formation of oxazoline 4 through DAST-promoted cyclization of the amidation product from subunits 5 and 6.     

Modular chiral selenium-containing oxazolines: synthesis and application in the palladium-catalyzed asymmetric allylic alkylation

A new series of modular chiral selenium-containing oxazolines has been synthesized from inexpensive and commercially available l-serine and l-aspartic acid. These new compounds were evaluated as chiral ligands in the palladium-catalyzed asymmetric allylic alkylation reaction, furnishing the product in high enantiomeric excess, using Cs₂CO₃/CH₂Cl₂ as the base/solvent system.     

Strategy for employing unstabilized nucleophiles in palladium-catalyzed asymmetric allylic alkylations

We report a strategy for the employment of highly unstabilized anions in palladium-catalyzed asymmetric allylic alkylations (AAA). The "hard" 2-methylpyridyl nucleophiles studied are first reacted in situ with BF3.OEt2; subsequent deprotonation of the resulting complexes with LiHMDS affords "soft" anions that are competent nucleophiles in AAA reactions. The reaction is selective for the 2-position of methylpyridines and tolerates bulky aryl and alkyl substitution at the 3-, 4-, and 5-positions. Investigations into the reaction mechanism demonstrate that the configuration of the allylic stereocenter is retained, consistent with the canonical outer sphere mechanism invoked for palladium-catalyzed allylic substitution processes of stabilized anions.     

A new strategy for the synthesis of benzylic sulfonamides: palladium-catalyzed arylation and sulfonamide metathesis

An efficient two-step strategy has been developed to access diversely functionalized benzylic sulfonamides. Execution of this strategy required the development of two reaction methods: the palladium-catalyzed cross-coupling of aryl halides with CH-acidic methanesulfonamides and a metathesis reaction between the resulting alpha-arylated sulfonamides and diverse amines. The broad scope of the cross-coupling process combined with a versatile sulfonamide metathesis constitutes an efficient strategy for the synthesis of various benzylic sulfonamides.     

Massive parallel catalyst screening: toward asymmetric MCRs

[reaction: see text]. Hundreds of Lewis acid/ligand combinations have been screened for stereochemical induction in the Passerini multicomponent reaction. The combination of titan tetraisopropylate and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane was found to give enantiomeric excesses between 32% and 42% in several examples. The absolute stereo induction of one example was determined chemically and by means of X-ray crystallography. This comprises the first asymmetric Passerini reaction and the first example of a stereochemical induction in an isocyanide based multicomponent reaction by a chiral Lewis acid.     

Benzylic phosphates as electrophiles in the palladium-catalyzed asymmetric benzylation of azlactones

Palladium-catalyzed asymmetric benzylation has been demonstrated with azlactones as prochiral nucleophiles in the presence of chiral bisphosphine ligands. Benzylic electrophiles are utilized under two sets of reaction conditions to construct a new tetrasubstituted stereocenter. Electron density of the phenyl ring dictates the reaction conditions, including the leaving group. The reported methodology represents a novel asymmetric carbon-carbon bond formation in an amino acid precursor.     

Novel chiral P,N-ferrocene ligands in palladium-catalyzed asymmetric allylic alkylations

Novel chiral P,N-ferrocene ligands, 1-diphenylphosphino-1′-oxazolinylferrocenes, were prepared from ferrocene via 1,1′-bis(tributylstannyl)ferrocene and 1-diphenylphosphino-1′-methoxycarbonylferrocene as intermediates, and with this new kind of ligand up to 91% ee with 99% chemical yield was afforded for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethylmalonate anion. The complexation behavior of this kind of ligand with dichlorobis(acetonitrile)palladium and bis(μ-chloro)(1,3-diphenyl-η³-allyl)dipalladium was investigated.     

Aromatic spiroketal bisphosphine ligands: palladium-catalyzed asymmetric allylic amination of racemic morita-baylis-hillman adducts

Showing a backbone: The spiroketal backbone of the bis(phosphine) ligand 1 led to good regio- and enantioselectivity in the palladium-catalyzed asymmetric allylic amination of racemic Morita-Baylis-Hillman adducts with aromatic amines. The methodology provides a facile and efficient synthesis of precursors for optically active β-lactam derivatives, including the cholesterol drug Ezetimibe.     

A new class of chiral P,N-ligands and their application in palladium-catalyzed asymmetric allylic substitution reactions

An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The P,N-ligands were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one and a series of substituted chiral C(2)-symmetric 1,2-ethanediols (R = Me, i-Pr, and Ph). The ligands were evaluated for use in catalytic asymmetric synthesis in the palladium-catalyzed allylic substitution reactions of a racemic allylic acetate and dimethyl malonate. In the case of the P,N-ligand (R = Ph), the reaction was found to be highly stereoselective (90% ee).     

A novel class of nonbiaryl atropisomeric P,O-ligands for palladium-catalyzed asymmetric allylic alkylation

[structure: see text]. A novel class of nonbiaryl atropisomeric P,O-ligands possessing an N,N-dialkyl-1-naphthamide skeleton has been synthesized via an efficient chemical resolution process. It represents the first example of axially chiral P,O-ligands devoid of central chirality. Up to 94.7% ee was obtained for the Pd-catalyzed asymmetric allylic alkylation (AAA). Effects of solvent, base, and the bulk of the C8 oxygen group of the P,O-ligand on the AAA reaction were examined.     

P-stereogenic P/N hybrid ligands: a remarkable switch in enantioselectivity in palladium-catalyzed asymmetric allylation

Optically active P-stereogenic phosphine/oxazoline bidentate ligands (1) were prepared and applied to palladium-catalyzed allylic substitution of 1,3-diphenyl-1-acetoxy-2-propene with dimethyl malonate. The absolute configuration of the allylation product was remarkably switched by changing a palladium/ligand ratio between 1/1 and 1/2.     

A facile regiocontrol in the palladium-catalyzed annulation of fluorine-containing internal alkynes with variously substituted 2-iodoanilines: a new regioselective synthesis of 2- or 3-fluoroalkylated indole derivatives

Treatment of various types of fluoroalkylated alkynes with o-iodoaniline in the presence of Pd(PPh(3))(4) in DMF at 80 degrees C for 8 h mainly gave 2-fluoroalkylated indoles in high yields. The use of P(o-Tol)(3) instead of PPh(3) as a ligand led to the preferential formation of 3-fluoroalkylated indoles in high yields. Interestingly, the reaction of trifluoromethylated alkynes bearing a benzylic substituent afforded 2- or 3-trifluoroethylated indole derivatives in good yields.