Phosphinooxazoline Ligands Research Articles

Sterically Demanding Planar Chiral P,N Ligands by Diastereoselective Ortho Lithiation of Pentaphenylferrocenyloxazolines and Their Application to Palladium-Catalyzed Substitutions with Cyclic Allylic Acetates

Functionalized 1′,2′,3′,4′,5′-pentaphenylferrocenes are known as valuable ligands and catalysts. Planar chiral derivatives—e.g. Fu’s pentaphenylferrocene fused pyridines or palladacycles developed in our group—have previously been described to be very efficient asymmetric catalysts for a number of applications. Nevertheless, protocols for diastereoselective ortho lithiations of 1′,2′,3′,4′,5′-pentaphenylferrocenes are still unknown. Such protocols could significantly increase the arsenal of accessible planar chiral pentaphenylferrocenes. In this full paper, we describe such diastereoselective ortho lithiations of pentaphenylferrocenyloxazolines. Both possible diastereomers can be produced in almost diastereomerically pure form depending on the choice of a Lewis base additive, which is required in the lithiation step for a sufficient reactivity. This development was utilized to prepare a set of planar chiral pentaphenylferrocene-based phosphino-oxazoline ligands. The latter were investigated in Pd-catalyzed allylic substitution reactions with cyclic allylic acetates to allow for a first comparison with related planar chiral ligands and provided good enantioselectivity with this challenging substrate class.

Investigation of the Electronic Origin of Asymmetric Induction in Palladium-Catalyzed Allylic Substitutions with Phosphinooxazoline (PHOX) Ligands by Hammett and Swain–Lupton Analysis of the13C NMR Chemical Shifts of the (π-Allyl)palladium Intermediates

Isomeric 4′- and 5′-substituted phosphinooxazoline (PHOX) ligands are used to probe the electronic origins of enantioselective nucleophilic additions to (1,3-diphenylallyl)palladium PHOX ligand complexes. Hammett analysis of the 13C NMR chemical shifts of the allyl C-1 and C-3 carbons shows that the major exo diastereomer is less susceptible to differential changes at C-1 and C-3 and that the location of the substituent has a smaller impact on these changes. In contrast, the minor endo diastereomer is more susceptible to differential 13C NMR changes at C-1 and C-3 and the location of the substituent has a greater impact on these changes. The endo diastereomer exhibits a pronounced “cis effect” by the ligating nitrogen and phosphorus atoms across the palladium center that explains its lower reactivity and, therefore, how the enantioselectivity typically obtained with PHOX ligands exceeds the approximately 8/1 ratio of exo to endo intermediates. Swain–Lupton analysis reveals the importance of both resonance and field effects by the substituents regardless of their location and supports the overall electronic control model for enantioselection by PHOX ligands. For rational chiral ligand design and electronic tuning of ligand properties, these results suggest that the overall electronic impact of a remote substituent generally depends more on its identity than on its location within the ligand.

ChemInform Abstract: Highly Enantioselective Asymmetric Hydrogenation of (E)‐β,β‐Disubstituted α,β‐Unsaturated Weinreb Amides Catalyzed by Ir(I) Complexes of SpinPhox Ligands.

The Ir(I) complexes of chiral spiro phosphino–oxazoline ligands (SpinPhox) have demonstrated good to excellent enantioselectivity in the asymmetric hydrogenation (AH) of a variety of (E)-β,β-disubstituted α,β-unsaturated N-methoxy-N-methylamides, affording the corresponding optically active Weinreb amides with up to 97% ee.

A novel and efficient total synthesis of shikonin

A novel and efficient synthesis of shikonin was accomplished with excellent enantiomeric excess (99.3% ee) and high overall yield (47%) in only six steps. The synthetic strategy involved an efficient Ru(II)-catalyzed asymmetric hydrogenation employing C2-symmetric planar chiral ruthenocene phosphinooxazoline ligand (L-3), followed by the subsequent removal of the methyl protecting groups. Meanwhile, it could be preliminarily confirmed that the chiral side chain of shikonin was difficult to be constructed in one step with both stereoselectivity and α-regioselectivity.

Efficient Ru(II)-catalyzed asymmetric hydrogenation of simple ketones with C2-symmetric planar chiral metallocenyl phosphinooxazoline ligands

C2-symmetric metallocenyl planar phosphinooxazoline ligands (2 and 3) have been applied in the Ru(II)-catalyzed asymmetric hydrogenation of simple ketones. This type of ligands enjoys the advantages of dual reaction sites as well as larger steric hindrance than their corresponding C1-symmetric counterparts. As a result, almost quantitative conversions and excellent enantioselectivities were obtained for a series of simple ketones. Under the optimal reaction conditions, up to 99.7% ee was obtained in many cases. It was also confirmed that hydrogen rather than reaction solvent i-PrOH is at work in the hydrogenation procedure.

Highly enantioselective asymmetric hydrogenation of (E)-β,β-disubstituted α,β-unsaturated Weinreb amides catalyzed by Ir(i) complexes of SpinPhox ligands

The Ir(I) complexes of chiral spiro phosphino-oxazoline ligands (SpinPhox) have demonstrated good to excellent enantioselectivity in the asymmetric hydrogenation (AH) of a variety of (E)-β,β-disubstituted α,β-unsaturated N-methoxy-N-methylamides, affording the corresponding optically active Weinreb amides with up to 97% ee.

Enantioselective decarboxylative alkylation reactions: catalyst development, substrate scope, and mechanistic studies.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

ChemInform Abstract: Synthesis of New Serine‐Based Phosphinooxazoline Ligands and Iridium Complexes for Asymmetric Hydrogenations.

AbstractNovel iridium catalysts (I) and (II) are prepared and compared with the known isomer (III).

ChemInform Abstract: Palladium‐Catalyzed, Asymmetric Baeyer—Villiger Oxidation of Prochiral Cyclobutanones with PHOX Ligands.

Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer–Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥ 93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center.

Palladium-catalyzed, asymmetric Baeyer–Villiger oxidation of prochiral cyclobutanones with PHOX ligands

Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer–Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center.

Synthesis of new serine-based phosphinooxazoline ligands and iridium complexes for asymmetric hydrogenations

A series of serine-based phosphinooxazoline ligands was synthesized and the corresponding iridum complexes were successfully applied in the asymmetric hydrogenation of various unfunctionalized olefines and acetophenone- N-phenyl-imine. The results show that these new derivatives are useful substitutes for the standard tert-leucine-derived PHOX ligands.

ChemInform Abstract: Asymmetric Synthesis of Indolines Bearing a Benzylic Quaternary Stereocenter Through Intramolecular Arylcyanation of Alkenes.

AbstractConditions A) in combination with chiral phosphinooxazoline ligands allows the enantioselective preparation of 3,3‐disubstituted indolines, which represent biologically interesting substructures of alkaloids.

New indenyl phosphinooxazoline complexes of iron and their catalytic activity in the Mukaiyama aldol reaction

Abstract New phosphinooxazoline (PHOX) η 5 -indenyl complexes of iron were synthesized and applied as catalysts in the Mukaiyama aldol reaction. Reaction of three different PHOX ligands with [Fe(η 5 -Ind)I(CO) 2 ] afforded the iodide salts of three complexes of the general formula [Fe(η 5 -Ind)(CO)(PHOX)] + in 73–81% isolated yields. The molecular structure of one of the new complexes was determined, revealing a pseudo octahedral coordination geometry about the iron center. The iron complexes are catalytically active in the Mukaiyama aldol reaction between aldehydes and 1-( tert -butyldimethylsilyloxy)-1-methoxyethene to give the corresponding aldol adducts (3 mol % catalyst, 15 min, room temperature, 48–83% isolated yields). A previously synthesized iron complex of the general formula [Fe(η 5 -Cp)(CO)(PHOX)] + was found to be catalytically active in the title reaction as well, but needed three hours at room temperature to convert the starting materials to the products.

Enantioselective Hydrogenation of α-Aryloxy and α-Alkoxy α,β-Unsaturated Carboxylic Acids Catalyzed by Chiral Spiro Iridium/Phosphino-Oxazoline Complexes

The iridium-catalyzed highly enantioselective hydrogenation of alpha-aryloxy and alpha-alkoxy-substituted alpha,beta-unsaturated carboxylic acids was developed. By using chiral spiro phosphino-oxazoline ligands, the hydrogenation proceeded smoothly to produce various alpha-aryloxy- and alpha-alkoxy-substituted carboxylic acids with extremely high enantioselectivities (ee up to 99.8%) and reactivities (TON up to 10,000) under mild conditions. The hydrogenation of alpha-benzyloxy-substituted alpha,beta-unsaturated acids provided an efficient alternative for the synthesis of chiral alpha-hydroxy acids after an easy deprotection. A mechanism involving a catalytic cycle between Ir(I) and Ir(III) was proposed on the basis of the coordination model of the unsaturated acids with the iridium metal center. The rationality of the catalytic cycle, with an olefin dihydride complex as the key intermediate, was supported by the deuterium-labeling studies. The X-ray diffraction analysis of the single crystal of catalyst revealed that the rigid and sterically hindered chiral environment created by the spiro phosphino-oxazoline ligands is the essential factor that permits the catalyst to obtain excellent chiral discrimination. A chiral induction model was suggested on the basis of the catalyst structure and the product configuration.

Asymmetric hydrogenation of simple ketones with planar chiral ruthenocenyl phosphinooxazoline ligands

Ruthenocenyl phosphinooxazoline ligands have been shown to be highly efficient catalysts in the asymmetric hydrogenation. Both simple aromatic and heteroaromatic ketones were examined and excellent conversions and enantioselectivities were achieved.

Highly Efficient Synthesis of (Phosphinodihydrooxazole)- (1,5-cyclooctadiene) Iridium Complexes

A highly efficient one-pot procedure for the synthesis of complexes of the type [Ir(COD)(Phox)]X, where Phox is a (chiral) phosphinooxazoline ligand, X = PF6 or B[(3,5-(CF3)2C6H3)]4 (BARF), is developed. Former reported syntheses demanded the isolation of pure ligands by column chromatography, but the ligands tend to adsorb irreversibly on silica. Moreover, the chromatography has to be performed with careful exclusion of air. The present method avoids this difficulties. The yields of the syntheses are comparable with those starting from the pure ligands. The method is also suitable for the preparation of complexes of the type [Rh(COD)(Phox)]BARF and [Rh(Phox)2]BARF.

ChemInform Abstract: New Types of o‐Carborane‐Based Chiral Phosphinooxazoline (Cab‐PHOX) Ligand Systems: Synthesis and Characterization of Chiral Cab‐PHOX Ligands and Their Application to Asymmetric Hydrogenation.

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 of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Oxidation of activated methylene groups to ketones catalyzed by new iron phosphinooxazoline complexes and by iron(II) triflate

The study describes the first catalytic application of iron phosphinooxazoline complexes and Fe(OTf) 2 in oxidation reactions. New iron phosphinooxazoline (PHOX) complexes of the general formulation [Fe(PHOX) 2] 2+[OTf] 2 ( 3, OTf = CF 3SO 3 −) were synthesized in virtually quantitative yield from anhydrous Fe(OTf) 2 and the corresponding PHOX ligands. The new complexes 3 as well as previously synthesized iron PHOX complexes of the general formula [Fe(Cp)(CO)(PHOX)] +[I] − ( 2) were employed as catalysts in the oxidation of benzylic CH 2 groups to the corresponding ketones. Whereas 3 showed catalytic activity at room temperature (about two equivalents t-BuOOH as the oxidant, 2 mol% catalyst, pyridine solvent, 12 h, 38–93% isolated yields), complexes of 2 were only active at elevated temperatures. The product profile is in accordance with a mechanism previously described as “oxygenated Fenton chemistry”, which is further corroborated by UV–vis investigations. They showed that an iron alkylperoxo species [Fe–OO tBu] might be involved in the catalytic cycle. The reaction follows a pseudo zero order rate law in substrate.

Use of 5,5-(Dimethyl)-i-Pr-PHOX as a Practical Equivalent to t-Bu-PHOX in Asymmetric Catalysis

The use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent of t-Bu-PHOX in asymmetric catalysis is reported. This new member of the phosphinooxazoline (PHOX) ligand family behaves similarly in terms of stereoinduction to t-Bu-PHOX with the key advantage of being readily accessible as both enantiomers starting from either (S)- or (R)-valine.

New Types of o-Carborane-Based Chiral Phosphinooxazoline (Cab-PHOX) Ligand Systems: Synthesis and Characterization of Chiral Cab-PHOX Ligands and Their Application to Asymmetric Hydrogenation

o-Carborane-based chiral phosphinooxazoline (Cab-PHOX) ligands were synthesized for the first time and applied to the iridium- and rhodium-catalyzed hydrogenation of unfunctionalized and functionalized olefins with an enantioselectivity of up to 98% and 96%, respectively. The modularity of the Cab-PHOX ligands is highlighted by the facile preparation of a variety of sterically and electronically different ligands.