Enantioselective oxidative coupling of methyl 3-hydroxy-2-naphthoate using mono-N-alkylated octahydrobinaphthyl-2,2′-diamine ligand

Mono-N-alkylated octahydrobinaphthyl-2,2′-diamine (H₈-BINAM) chiral ligands were employed in the catalytic and asymmetric oxidative coupling of methyl 3-hydroxy-2-naphthoate to the corresponding binaphthol derivative. The diamine ligand with one N-(3-pentyl) group shows highest enantioselectivity in the biaryl coupling among other BINAM derivatives, and the coupling reaction proceeds faster than the reactions using alkanediamine ligands.     

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.     

1,1′-Binaphthyl ligands with bulky 3,3′-tertiaryalkyl substituents for the asymmetric alkyne addition to aromatic aldehydes

The BINOL ligand (R)-2 that contains bulky 3,3′-tertiaryalkyl groups shows improved catalytic properties over the previously reported 3,3′-substituted BINOL ligands in the asymmetric alkyne addition to aromatic aldehydes. It catalyzes the phenylacetylene addition to aromatic aldehydes with high enantioselectivity (86-94% ee) and good yields without using Ti(OⁱPr)₄ and a Lewis base additive. The catalytic properties of several analogs of (R)-2 in the asymmetric alkyne addition to aldehydes have also been studied.     

Studies on Cu-catalyzed asymmetric alkynylation of tetrahydroisoquinoline derivatives

Enantioselective C–C bond formations between the sp³ C–H bond of prochiral CH₂ and terminal alkynes via the cross-dehydrogenative coupling (CDC) reaction were studied. Efficient asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives were achieved by using a catalytic amount of CuOTf together with PyBox chiral ligand. When dihydroisoquinolinium salts were used as electrophiles, the combination of CuBr/QUINAP provided the best results for asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives. The factors influencing the enantioselectivity were studied.     

Catalytic asymmetric conjugate reduction with ethanol: A more reactive system Pd(II)-Pr-DUPHOS complex with molecular sieves 4A

We describe herein the catalytic asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds using a novel cationic Pd-ⁱPr-DUPHOS complex. In this reaction, EtOH worked well as a solvent and a reducing agent, and the reaction was completed within several hours in most cases to afford the reduced compounds almost quantitatively with modest to good enantioselectivity (up to 72% ee). It was found that the Pd-ⁱPr-DUPHOS complex was more reactive than the previously reported Pd-BINAP complex when molecular sieves 4A was added as an additive. Based on an X-ray structural analysis of [Pd{(S,S)-ⁱPr-duphos}](OTf)₂ complex, a working hypothesis of the reaction mechanism is also described.     

The synthesis of novel C2-symmetric P,N-chelation ruthenocene ligands and their application in palladium-catalyzed asymmetric allylic substitution

Novel air-stable C₂-symmetric tetrasubstituted ruthenocene-based ligands were readily synthesized and used for palladium-catalyzed asymmetric allylic substitution showing excellent enantioselectivity and high catalytic activity.     

General and practical catalytic enantioselective Strecker reaction of ketoimines: significant improvement through catalyst tuning by protic additives

Significant improvement in enantioselectivity and catalyst activity was achieved for the catalytic enantioselective Strecker reaction. Using a catalyst (1-2.5 mol %) prepared from Gd(OⁱPr)₃ and d-glucose derived ligand 1, and in the presence of 2,6-dimethylphenol as an additive, high enantioselectivity was obtained from a wide range of ketoimines, including heteroaromatic and cyclic ketoimines. The new method was applied to an efficient catalytic asymmetric synthesis of sorbinil, a therapeutic agent for diabetic complications.     

Asymmetric deprotonation of N-Boc-piperidines

A selection of chiral ligands was screened for the asymmetric deprotonation of N-Boc-piperidine. The asymmetric deprotonation of this compound is notoriously difficult and reasonable yields are obtained only with non-hindered ligands, such as tetramethylethylene diamine (TMEDA). Chiral versions of TMEDA were investigated but even small increases in steric bulk of the ligand caused significant reduction in the yields of the product after electrophilic quench. The ligands studied focused on diamines or amino-alcohols with one or two stereocentres, including C₂-symmetric ligands. In general these promoted low levels of enantioselectivity in this transformation; however a C₂-symmetric ligand first reported by Alexakis et al. gave a high enantiomer ratio but a low yield of the product. The substrate N-Boc-piperidine is therefore much more sensitive to steric factors in comparison with the related and highly enantioselective deprotonation of N-Boc-pyrrolidine. The application of the chemistry to two 4-substituted piperidines was also investigated and variable enantiomer ratios were obtained.     

Reversal in enantioselectivity for the palladium-catalyzed asymmetric allylic substitution with novel metallocene-based planar chiral diphosphine ligands

The novel C₂-symmetric metallocene-based ligands with only planar chirality were synthesized easily and applied in palladium-catalyzed asymmetric allylic substitution with excellent enantioselectivity and high catalytic activity. When two ester groups on Cp rings of the metallocene were replaced by hydroxymethyl groups, opposite configuration of the product was obtained with high catalytic activity and excellent enantioselectivity. The opposite configuration of products was also obtained when the hydroxyl groups were protected as esters or ethers. These results might be attributed to the different configuration of the diphosphine ligands-Pd(II) complexes.     

Chiral C2-symmetric ligands containing two binaphthyl units linked by 2,2′-bipyridyl bridge in asymmetric catalysis

The catalytic activities of new chiral C₂-symmetric ligands 1–4 in the asymmetric alkylation of aromatic aldehydes with diethylzinc to give 1-arylpropanols are studied. In most cases, the yields were good and enantioselectivities up to 87% were observed. Copper-catalyzed cyclopropanation proceeded with ⩽51% enantioselectivity and ∼3:1 trans/cis-diastereoselectivity.     

Nonsimple relationships between the P-chiral diamidophosphite and the arylphosphine moieties in Pd-catalyzed asymmetric reactions: combinatorial approach and P,P-bidentate phosphine-diamidophosphites

A small family of P,P^∗-bidentate C₁-symmetric ligands containing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms has been prepared. Palladium catalytic systems with these phosphine-diamidophosphites afforded 95% and 63% ees in asymmetric allylic substitution and desymmetrization processes, respectively. The influence of the nature of both the phosphine and diamidophosphite moieties of these compounds on the enantioselectivity is discussed. The ‘mixed-ligand approach’ in Pd-catalyzed asymmetric allylation with participation of some new P^∗-monodentate diamidophosphites and PPh₃ is also considered.     

SPANamine derivatives in the catalytic asymmetric α-fluorination of β-keto esters

The use of C₂-symmetric enantiopure nitrogen ligands in the asymmetric catalytic α-fluorination of β-ketoesters is described. SPANamine 1 in the presence of nickel salts gives up to 63% ee in the fluorination of tert-butyl 2-oxocyclopentanecarboxylate with N-fluorosuccinimide (NFSI). The same enantioselectivity is obtained when SPANamine 1 is used as an organocatalyst, although the reaction is much slower.     

Axially dissymmetric binaphthyldiimine chiral salen-type ligands for copper-catalyzed asymmetric aziridination

Axially dissymmetric chiral salen-type ligands 1–4 and 7 were prepared from the reaction of (R)-(+)-1,1′-binaphthyl-2,2′-diamine with 2,6-dichlorobenzaldehyde, 2,3-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde or salicylaldehyde in high yields, respectively. The catalytic asymmetric aziridination of alkenes has been examined using these novel chiral ligands. Excellent enantioselectivity in the aziridination of cinnamates has been achieved using the C₂-symmetric chiral ligand 1.     

Reversal of enantioselectivity by adding Ti(OiPr)4: novel sulfamide-amine alcohol ligands for the catalytic asymmetric addition of diethylzinc to aldehydes

Novel sulfamide-amine alcohol ligands (6) derived from (−)-ephedrine (4a) and (+)-pseudoephedrine (4b) with multiple stereogenic centers were applied to the catalytic asymmetric addition of diethylzinc to aldehydes, providing (S)-products in high yields and good enantioselectivities. These sulfamide-amine alcohols together with Ti(OⁱPr)₄ were shown to obtain the (R)-products in significant enantiomeric excesses (e.e.) and high yields. In addition, sulfamide-amine alcohols were superior to the original chiral sources 4a and 4b, which afforded no enantioselectivity in the Ti(OⁱPr)₄-mediated reaction.     

A correlation study of bisphosphine ligand bite angles with enantioselectivity in Pd-catalyzed asymmetric transformations

Among the bisphosphine ligands, we have previously developed C_n-TunePhos (n = 1-6) as a family of ligands with tunable bite angles. The increase in spacer -CH₂- groups in this family of ligands causes changes in ligand dihedral angle, which in turn causes P-Pd-P bite angle variation. Pd-catalyzed asymmetric alkylations and cycloadditions have been tested with C_n-TunePhos ligands. This study aims at a possible correlation between ligand bite angles with enantioselectivity of the Pd-catalyzed asymmetric products.     

Metal/linked-BINOL complexes: Applications in direct catalytic asymmetric Mannich-type reactions

Development of metal/linked-BINOL complexes and their applications in direct catalytic asymmetric Mannich-type reactions of hydroxyketones are reviewed. A Et₂Zn/linked-BINOL complex was effective for diastereo- and enantioselective synthesis of β-amino alcohols. By choosing the proper protective groups on the imine nitrogen, either anti- or syn-β-amino alcohol was obtained in excellent enantioselectivity (up to >99.5% ee) using the same zinc catalysis. Y{N(SiMe₃)₂}₃/linked-BINOL complex was effective for various hydroxyketones, affording syn-β-amino alcohols with high enantioselectivity (up to 98% ee). To broaden the nucleophile scope to carboxylic acid derivatives, N-acylpyrrole was utilized as an ester equivalent donor. In(O-iPr)₃/linked-BINOL complex was effective for generating an In-enolate from N-acylpyrrole in situ, giving Mannich adducts with high enantioselectivity (up to 98% ee).     

A comparison of palladium complexes of BINAP and diphenylphosphinooxazoline ligands in the catalytic asymmetric synthesis of cis-decalins

BINAP and a range of oxazoline-containing phosphinamine ligands were screened in the palladium-catalysed asymmetric intramolecular Heck cyclisation to form cis-decalins. Complexes formed from Pd₂(dba)₃ and BINAP gave cyclised products in up to 65% yield and 85% ee. The t-leucine-derived diphenylphosphinoferrocenyloxazoline ligand afforded our optimal enantioselectivity of 85% for the range of phosphinamine ligands tested. Variation of solvent and base appears to indicate that this system is sensitive to catalyst deactivation and that a combination of either toluene or N-methylpyrrolidine with potassium carbonate as base was required for acceptable catalytic activity. Catalysts prepared from palladium complexes of diphenylphosphinoaryloxazoline ligands were less reactive than the corresponding BINAP catalysts as the optimal yield obtained was 47%.     

Synthesis of novel P-ketimine bidentate ferrocenyl ligands with central and planar chirality and comparsion in the catalytic activity between P-ketimine and P-aldimine

A series of novel ferrocenylphosphine-ketimine ligands 6 were prepared by reaction of (R,S_p)-PPFNH₂-R or (S,S_p)-PPFNH₂ with a variety of m-substituted acetophenones. A different catalytic activity was observed between ferrocenylphosphine-ketimine ligands and corresponding aldimine ligands. The efficiency and diastereomeric impact of these ferrocenylphosphine-ketimine ligands in Pd-catalyzed asymmetric allylic alkylation were first investigated, and higher enantioselectivity of over 98% e.e. with 95% yield was obtained by the use of ferrocenylphosphine-ketimine ligands. However, in Rh-catalyzed asymmetric hydrosilylation of aryl ketones, only 42% e.e. was obtained by the use of ferrocenylphosphine-ketimine ligands compared to 90% e.e. with the use of aldimine ligands.     

New C2-symmetric chiral phosphinite ligands based on amino alcohol scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones

Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts are attracting increasing interest from synthetic chemists due to their operational simplicity. C₂-symmetric catalysts have also received much attention and been used in many reactions. A series of new chiral C₂-symmetric bis(phosphinite) ligands has been prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-butanol through a three- or four-step procedure. Their structures have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ¹H-³¹P NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. In situ prepared ruthenium catalytic systems were successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving the corresponding optical secondary alcohols in 99% yield and up to 79% ee.     

Rh(I) complexes with new C2‐symmetric chiral diphosphoramidite ligands: Catalytic activity for asymmetric hydrogenation of olefins

The design and synthesis of three new C ₂‐symmetric chiral diphosphoramidite ligands starting from simple and cheap building blocks have been developed. Rhodium(I) cationic complexes bearing these chelate ligands have been prepared and applied in asymmetric hydrogenation of model olefins. A rhodium complex with a diphosphoramidite containing a chiral diamine configurationally stable and two fluxional chiral biphenyl units gave higher enantioselectivity with increasing hydrogen pressure (87% ee) in the hydrogenation of dimethyl itaconate.