New types of soluble polymer-supported bisphosphine ligands with a cyclobutane backbone for Pd-catalyzed enantioselective allylic substitution reactions

A highly efficient and practical optical resolution of anti head-to-head racemic coumarin dimer 7 has been achieved by molecular complexation with TADDOL, (-)-8, through a hydrogen bonding interaction to afford the corresponding two enantiomers, (-)- and (+)-7, in 70 and 75 % yields, respectively, with >99 % ee. Starting from enantiopure (-)-7, a new type of C2-symmetric bisphosphine ligand (S,S,S,S)-3 with a cyclobutane backbone has been synthesized in good yield by facile transformations. The asymmetric induction efficiency of these chiral bisphosphine ligands in Pd-catalyzed asymmetric allylic substitution reactions was evaluated. Under the experimental conditions, the allylic substitution products could be obtained in excellent yields (up to 99 %) and enantioselectivities (up to 98.9 % ee). By taking advantage of the high enantioselectivity of this catalytic reaction and the easily derivable carboxylate groups on the cyclobutane backbone of ligand (S,S,S,S)-3, a new type of analogous ligand (S,S,S,S)-4 as well as the MeO-PEG-supported soluble ligand (S,S,S,S)-5 (PEG=polyethylene glycol) have also been synthesized and utilized in asymmetric allylic substitution reactions. In particular, the MeO-PEG supported (S,S,S,S)-5 b had a synergistic effect on the enantioselectivity of the reaction compared with its nonsupported precursor (S,S,S,S)-4 c, affording the corresponding allylation products 14 a and 14 b with excellent enantioselectivities (94.6 and 97.2 % ee, respectively). Moreover, the Pd complex of (S,S,S,S)-5 b could easily be recovered and recycled several times without significant loss of enantioselectivity and activity in the allylic substitution reactions.     

t-Bu-QuinoxP* ligand: applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation

The potential of the t-Bu-QuinoxP* ligand (1) as a chiral ligand in asymmetric synthesis was examined. The ligand exhibited good to excellent asymmetric induction in Pd-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asymmetric hydrogenation of ketones (up to 99.9% ee).     

New phosphorus dendrimers with chiral ferrocenyl phosphine-thioether ligands on the periphery for asymmetric catalysis

Chiral ferrocenyl phosphine-thioether ligands have been covalently bound on the periphery of 4 phosphorus dendrimers (generations 1-4) having a cyclotriphosphazene core and on one model compound. These new dendrimers proved to be efficient ligands for the palladium-catalyzed asymmetric allylic substitution reaction (ee up to 93%).     

Synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed asymmetric allylic substitution

The asymmetric synthesis of beta-substituted alpha-amino acids with use of iridium-catalyzed allylic substitution was described. The Ir-catalyzed allylic substitution of diphenylimino glycinate with allylic phosphates proceeded smoothly even at 0 degrees C and gave branch products with high enantioselectivity (up to 97% ee), when chiral bidentate phosphite bearing the 2-ethylthioethyl group was employed. In addition, both diastereomers of the branch products were synthesized stereoselectively by simply switching the base employed. These methods were also applied to the asymmetric synthesis of quaternary alpha-amino acids.     

StePHOX, a new family of optically active, tunable phosphine-oxazoline ligands: syntheses and applications

A new class of optically active phosphine-oxazoline ligands has been synthesized wherein backbone chirality of these new ligands is installed by a Sharpless asymmetric dihydroxylation. Different backbone protecting groups as well as different substitution patterns on the oxazoline ring were studied. These ligands were tested in allylic substitution (with ee's up to 97%) and asymmetric Tsuji allylation.     

Palladium-catalyzed asymmetric benzylation of 3-aryl oxindoles

Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety of unprotected 3-aryl oxindoles and benzylic methyl carbonates using chiral bisphosphine ligands. This methodology represents a novel asymmetric carbon-carbon bond formation between a benzyl group and a prochiral nucleophile to generate a quaternary center.     

Phosphites and diamidophosphites based on mono-ethers of BINOL: a comparison of enantioselectivity in asymmetric catalytic reactions

Novel P-monodentate phosphite-type ligands have been synthesized in one step from BINOL mono-tosylate and BINOL mono-(?)-menthylcarbonate. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylic substitution of (E)-1,3-diphenylallyl acetate and up to 99% ee in Rh-catalyzed asymmetric addition of phenylboronic acid to cyclohex-2-enone. The influence of the structural modules such as the nature of phosphorus-containing ring or exocyclic substituent on the enantioselectivity is discussed.     

A new methodology for synthesis of a chiral phosphinocarboxylic acid through Michael cyclization-aldol tandem reaction of chiral alpha,beta,chi,psi-unsaturated bisphosphine oxide and application in palladium-catalyzed asymmetric allylic alkylation

Upon successive treatment with lithium diisopropylamide and then benzaldehyde, a chiral alpha,beta,psi,omega-unsaturated bisphosphine oxide underwent Michael cyclization-aldol tandem reaction to afford the corresponding endo-alpha,beta-unsaturated cyclic bisphosphine oxides. Sequential stereoselective reduction and Horner-Wadsworth-Emmons olefination gave the corresponding monophosphine oxide. Oxidative conversion of an olefin moiety into a carboxyl group and subsequent deoxygenation of an oxide gave the corresponding chiral phosphinocarboxylic acid, which was successfully applied as a chiral and functionalized monophosphine ligand in a palladium-catalyzed asymmetric allylic alkylation.     

New phosphite-oxazoline ligands for efficient Pd-catalyzed substitution reactions

We have designed and synthesized a new family of readily available highly modular phosphite-oxazoline ligands for the Pd-catalyzed asymmetric allylic substitution reactions. The introduction of a pi-acceptor flexible bulky biphenyl phosphite moiety in the ligand design is highly adventitious in the product outcome. Thus, this ligand series affords excellent reaction rates (TOF's up to >2400 mol.(mol.h)-1) and enantioselectivities (ee's up to >99%) and, at the same time, shows a broad scope for different substrate types.     

Palladium catalyzed asymmetric sulfonylation mediated chiral β-hydroxy- and β-(o-diphenylphosphino)benzoyloxy (o-diphenyl phosphino)benzamides

The palladium catalyzed asymmetric allylic sulfonylation reaction has been investigated employing β-hydroxy- and β-(o-diphenylphosphino)benzoyloxy (o-diphenyl phosphino)benzamides as chiral, non-racemic ligands. The bisphosphine β-benzoyloxybenzamide ligands proved to be the best ligands for this process. Competitive transition states for the (1S,2R)-norephedrine derived ligand 14 are compared and a rationale is provided for the observed enantioselectivities.     

2-Phenallyl as a versatile protecting group for the asymmetric one-pot three-component synthesis of propargylamines

2-Phenallyl was found to be a versatile protecting group of primary amines for the asymmetric one-pot three-component synthesis of propargylamines which leads to enantiomeric excess of up to 96%; it can be easily removed with a palladium(0)-catalyzed allylic substitution using 1,3-dimethylbarbituric acid as a nucleophile.     

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.     

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.     

Synthesis of tunable bisphosphine ligands and their application in asymmetric hydrogenation of quinolines

A series of tunable axial chiral bisphosphine ligands have been synthesized from (S)-MeO-Biphep. The Ir complex of the MeO-PEG-supported ligand (S)-4k has been successfully applied in asymmetric hydrogenation of quinolines with up to 92% ee. The catalyst system is air-stable and recyclable.     

Asymmetric Synthesis of α,α‐Disubstituted Allylic Amines through Palladium‐Catalyzed Allylic Substitution

The first asymmetric synthesis of important α,α‐disubstituted N‐alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less‐reactive anilines is also feasible, providing enantioenriched α,α‐disubstituted N‐aryl allylic amines.     

Kinetic Resolution of Racemic Allylic Alcohols by Catalytic Asymmetric Substitution of the OH Group with Monosubstituted Hydrazines

A new strategy has been established for the kinetic resolution of racemic allylic alcohols through a palladium/sulfonyl‐hydrazide‐catalyzed asymmetric OH‐substitution under mild conditions. In the presence of 1 mol % [Pd(allyl)Cl]₂, 4 mol % (S)‐SegPhos, and 10 mol % 2,5‐dichlorobenzenesulfonyl hydrazide, a range of racemic allylic alcohols were smoothly resolved with selectivity factors of more than 400 through an asymmetric allylic alkylation of monosubstituted hydrazines under air at room temperature. Importantly, this kinetic resolution process provided various allylic alcohols and allylic hydrazine derivatives with high enantiopurity.     

Regio- and Enantioselective Substitution of Acyclic Allylic Sulfoximines with Butylcopper in the Presence of Lithium Iodide and Boron Trifluoride

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.     

Development of new P-chiral phosphorodiamidite ligands having a pyrrolo[1,2-c]diazaphosphol-1-one unit and their application to regio- and enantioselective iridium-catalyzed allylic etherification

Ten types of new P-chiral phosphorodiamidite ligands having pyrrolo[1,2-c][1,3,2]diazaphosphol-1-one backbone were designed and prepared. They were preliminarily utilized for iridium-catalyzed asymmetric allylic etherification of cinnamyl carbonate with phenol, where both R- and S-products were obtained with good enantioselectivity (up to 74% ee) by changing the N- and P-substituents of the ligands. The opposite enantioselectivity in iridium-catalyzed allylic substitution was explained by DFT calculations of the energy difference of the pi-allyliridium-phosphorodiamidite intermediates.     

Palladium-diphosphite catalysts for the asymmetric allylic substitution reactions

[structure: see text] We have designed a series of diphosphite ligands to study the effect of the backbone, the size of the chelate ring, and the substituents of the biphenyl moieties and to determine the scope of this type of ligand in the Pd-catalyzed asymmetric substitution reactions of different types of substrates. Good-to-excellent activities and enantioselectivities have been obtained for disubstituted linear substrate 11 (TOF's up to >2000 mol x (mol x h)(-1), ee values up to 99%) and cyclic substrate 14 (TOF up to 285 mol x (mol x h)(-1), ee values up to 92%). However, these ligands are inadequate for the Pd-catalyzed allylic alkylation of monosubstituted linear substrates because they provide low enantioselectivities.     

Counterions of BINAP-Pt(II) and -Pd(II) complexes: novel catalysts for highly enantioselective Diels-Alder reaction

[formula: see text] Platinum and palladium chiral bisphosphine complexes and their counterion effects in asymmetric Diels-Alder reactions have been investigated. The reaction of cyclopentadiene and various bidentate dienophiles in the presence of a catalytic amount of Pt(II)- or Pd(II)-BINAP complex proceeds with excellent endo/exo selectivity as well as endo enantioselectivity (up to 99% ee).