New dihydroxy bis(oxazoline) ligands for the palladium-catalyzed asymmetric allylic alkylation: experimental investigations of the origin of the reversal of the enantioselectivity

The origin of the reversal of the enantioselectivity in the palladium-catalyzed allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate anion using chiral dihydroxy bis(oxazoline) "BO" ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol was investigated. To determine the structural effects of the dihydroxy BO ligand on this unique phenomenon, new homochiral dihydroxy BO ligands were prepared from L-threonine and L-serine and were assessed in the transformation. The results obtained with these novel BO ligands, compared with the one obtained by using the dihydroxy BO ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, reveal that the reversal in the enantioselectivity observed with the dihydroxy BO ligand depends on the structure of the ligand. The effect of different bases used to generate the dimethyl malonate anion was also examined. The results are discussed in terms of the interaction of one hydroxy group in the intermediate pi-allyl palladium complex with the dimethyl malonate anion.     

Effective synthesis of bicyclodienes via palladium-catalyzed asymmetric allylic alkylation and ruthenium-catalyzed cycloisomerization

[n.3.0]Bicycles (n = 3–6) can be synthesized using palladium-catalyzed asymmetric allylic alkylation followed by ruthenium-catalyzed cycloisomerization. New types of triarylphosphino-1,2-diaminooxazoline ligands show the same high levels of enantioselectivity observed with Trost ligand when employed in Pd-catalyzed allylic alkylation reactions. The enyne products of these allylic alkylation reactions were further elaborated using a Ru-catalyzed redox isomerization process, for which a mechanism is proposed.     

Synthesis of chiral 2-alkyl-8-quinolinyl-oxazoline ligands: reversal of enantioselectivity in the asymmetric palladium-catalyzed allylic alkylation

New chiral 2-alkyl-8-quinolinyl-oxazolines were synthesized from 2-alkyl-8-quinolinecarboxylic acids and enantiomerically pure amino alcohols using a convenient procedure. Enantioselective palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of 2-alkyl-8-quinolinyl-oxazolines provided an alkylation product with an opposite configuration compared to those obtained from unsubstituted quinolinyl-oxazoline ligands.     

Ligand bite governs enantioselectivity: electronic and steric control in Pd-catalyzed allylic alkylations by modular fenchyl phosphinites (FENOPs)

Modular fenchyl phosphinites (FENOPs) containing different aryl units-phenyl (1), 2-anisyl (2), or 2-pyridyl (3)-are efficiently accessible from (-)-fenchone. For comparison of the influence of the different aryl units on enantioselectivities and reactivities, these FENOPs were employed in Pd-catalyzed allylic alkylations. The strongly chelating character of P,N-bidentate 3 is apparent from X-ray structures with PdCl2 ([Pd3Cl2]), and with allyl-Pd units in ([Pd3(eta1-allyl)] and [Pd3(eta3-allyl)]). FENOP3 gives rise to a PdL* catalyst of moderate enantioselectivity (42 % ee, R product). Surprisingly, higher enantioselectivities are found for the hemilabile, monodentate FENOPs 1 (83 % ee, S enantiomer) and 2 (69 % ee, S enantiomer). Only small amounts of 1 or 2 generate selective PdL* catalysts, while complete abolition of enantioselectivity appears with unselective PdL*2 species with higher FENOP concentrations in the cases of 1 or 2. Computational transition structure analyses reveal steric and electronic origins of enantioselectivities. The nucleophile is electronically guided trans to phosphorus. endo-Allyl arrangements are favored over exo-allyl orientations for 1 and 2 due to Pd-pi-pyridyl interactions with short "side-on" Pd-aryl interactions. More remote "edge-on" Pd-pi-aryl interactions in 3 with Pd-N(lp) coordination favor endo-allyl units slightly more and explain the switch of enantioselectivity from 1 (S) and 2 (S) to 3 (R).     

Modular phosphite-oxazoline/oxazine ligand library for asymmetric pd-catalyzed allylic substitution reactions: scope and limitations-origin of enantioselectivity

A library of phosphite-oxazoline/oxazine ligands L1-L15 a-h has been synthesized and screened in the Pd-catalyzed allylic substitution reactions of several substrate types. These series of ligands can be prepared efficiently from easily accessible hydroxyl amino acid derivatives. Their modular nature enables the substituents/configurations in the oxazoline/oxazine moiety, alkyl backbone chain and in the biaryl phosphite moiety to be easily and systematically varied. By carefully selecting the ligand components, therefore, high regio- and enantioselectivities (ee values up to 99 %) and good activities have been achieved in a broad range of mono- and disubstituted linear hindered and unhindered liner and cyclic substrates. The NMR studies on the Pd-pi-allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity. It also indicates that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphite moiety.     

The effect of hydrogen bonding on allylic alkylation and isomerization reactions in ionic liquids

Neutral allylic alkylation reactions, in which a base is generated in situ and which hence require no external bases, can significantly be retarded when carried out in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]). Evidence suggests that the base or base precursor enters into hydrogen bonding with the imidazolium cation and is thus made less readily available for deprotonation of pre-nucleophiles. However, the reaction proceeds well in the presence of stronger bases that are capable of deprotonation. Whilst the phenomenon of hydrogen bonding in ionic liquids can be detrimental to reactions such as allylic alkylation, it can be exploited to suppress unwanted allylic isomerization.     

Fluorous chiral bisoxazolines. Synthesis and applications to an asymmetric allylic alkylation

The easily accessible fluorous bisoxazolines 3a-b bearing two fluorous ponytails are efficient ligands in the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate with carbonucleophiles in benzotrifluoride or CH₂Cl₂, enantioselectivities of up to 95% being obtained. The ligand is easily separated from the reaction mixture by simple extraction with a fluorous solvent.     

Platinum-catalysed allylic alkylation: reactivity, enantioselectivity, and regioselectivity

The use of platinum complexes as catalysts for allylic substitution has been studied. A variety of different complexes catalyse the reaction, and several substrates have been tested. In the alkylation of mono(alkyl)-substituted allylic acetates, regioselectivity is highly dependent on ligand choice. By using tricyclohexylphosphine as the ligand, almost complete formation of branched products is observed. The development of a highly enantioselective (ca. 80-90% ee) reaction that makes use of chiral diphenylphosphinooxazoline ligands (abbreviated as (S)-PN) is also described. The enantioselectivity is highly dependent on the ratio of ligand to platinum (when the ratio ligand/Pt is greater than 1:1, the ee drops off dramatically). This is in contrast to palladium and is interpreted in terms of differing coordination chemistry for the two metals ((S)-PN is hemilabile when complexed to platinum) and should be of significance to future systems that utilise heterobidentate ligands. The crystal structures of two isoelectronic platinum and palladium complexes [[(S)-PN]MCl2] are also described.     

Screening of a phosphite-phosphoramidite ligand library for palladium-catalysed asymmetric allylic substitution reactions: the origin of enantioselectivity

We have designed a new library of readily available, highly modular phosphite-phosphoramidite ligands for asymmetric allylic substitution reactions. They are easily prepared in one step from commercially available chiral 1,2-amino alcohols. The introduction of a phosphoramidite moiety into the ligand design is highly advantageous for the product outcome. This ligand library affords high reaction rates (TOFs of up to 800 mol (mol h)(-1)) and enantioselectivities (ees of up to 99%) and, at the same time, contains a broad range of disubstituted hindered and unhindered substrate types. NMR study of the Pd-pi-allyl intermediates provide a deeper understanding of the effect of the ligand parameters on the origin of enantioselectivity.     

Chiral ditopic receptors. Application to palladium-catalyzed allylic alkylation

Chiral pyridinooxazoline, quinolinooxazoline, bis(oxazolino)pyridine (pybox), and bisoxazoline (box) derivatives containing crown ether residues were prepared. Some of the ligands were assessed in substrate binding studies and in palladium catalyzed allylic alkylations.     

Use of zinc enolate, free from other metals, in enantioselective palladium-catalyzed allylic alkylation

Zinc enolate, free from other metal cations directly prepared from malonate and diethylzinc, was proven to be an excellent nucleophile for enantioselective palladium-catalyzed allylic alkylation, particularly for the allylic cation bearing aromatic rings at the 1- and 3-positions.     

Molybdenum-catalyzed asymmetric allylic alkylation of 3-alkyloxindoles: reaction development and applications

We report a full account of our work towards the development of Mo‐catalyzed asymmetric allylic alkylation reactions with 3‐alkyloxindoles as nucleophiles. The reaction is complementary to the Pd‐catalyzed reaction with regard to the scope of oxindole nucleophiles. A number of 3‐alkyloxindoles were alkylated successfully under mild conditions to give products with excellent yields and good‐to‐excellent enantioselectivities. Applications of this method to the preparation of indoline alkaloids such as (?)‐physostigmine, ent‐(?)‐debromoflustramine B, and the indolinoquinoline rings of communesin B are reported.