Synthesis and application of phosphinoferrocenylaminophosphine ligands for asymmetric catalysis

A new class of bidentate ligands utilizing a phosphine-aminophosphine structure has been prepared on a ferrocenylethyl backbone in a straightforward and scalable fashion from acetylferrocene. The unique property of the alpha-ferrocenyl carbonium ion that allows the replacement of a variety of "leaving groups" with retention of configuration greatly facilitates the synthesis, and a number of ligands have been prepared by varying the nitrogen and phosphorus substituents on the aminophosphine. These readily prepared phosphinoferrocenylaminophosphines, known as BoPhoz ligands, show surprising hydrolytic and air stability, with no degradation after 3 years open to the air. The rhodium complexes of these ligands show exceedingly high enantioselectivities (generally >95% ee) and activities often in excess of 50,000 catalyst turnovers per hour for the asymmetric hydrogenation of a wide variety of dehydro-alpha-amino acid and itaconic acid derivatives. They also show high activity and good to excellent enantioselectivity for the hydrogenation of a number of alpha-ketoesters.     

Imidazole-based potential Bi- and tridentate nitrogen ligands: synthesis, characterization and application in asymmetric catalysis

Twelve new imidazole-based potential bi- and tridentate ligands were synthesized and characterized. Whereas in the first series the alpha-amino acid and imidazole moieties were linked by an amino bond, in the second series the tridentate ligands, containing two imidazole groups, were separated by an amide bond. The first series was obtained by the reductive amination of 2-phenylimidazole-4-carboxaldehyde with alpha-amino acid esters. The tridentate ligands were prepared from 2-phenylimidazole-4-carboxylic acid and chiral amines. In the Henry reaction, the amines were revealed as a more reactive species than the less nucleophilic amides, however the enantiomeric excesses were generally poor.     

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives

The development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity- and stereoselectivity-control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring-opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL-derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio- and rate-determining.     

Chiral bicyclic phosphoramidites--a new class of ligands for asymmetric catalysis

The development of new ligands for catalytic asymmetric C-C bond formation is of great interest to organic synthesis. We describe here a new class of chiral phosphoramidites that embody one or two binaphthol units attached to an achiral azabicyclic [3.3.1] or [3.3.0] framework. These ligands were easily accessible from (R)1,1'-binaphthyl-2,2'-dioxaphosphorchloridite (4) and the corresponding heterobicyclic core 1, 2, or 3. They were employed in enantioselective Cu-catalyzed additions of different dialkylzinc reagents to cyclic and acyclic enones. The chiral ketones were obtained with an enantiomeric ratio up to 91:9. The choice of the best ligand proved to be strongly dependent on each substrate. In addition, ligand 6 was found to be the most suitable for Rh-catalyzed hydrogenations of a,beta-unsaturated esters, giving rise to dimethyl 2-methylsuccinate and methyl N-acetylalaninate with enantiomer ratios up to 95:5.     

Synthesis and application in asymmetric catalysis of camphor-based pyridine ligands

This tutorial review deals with the synthesis and application in asymmetric catalysis of camphor-based pyridine ligands. These ligands can be roughly divided into two groups: those in which the camphor is annulated in the 2,3-positions to the beta-face of the pyridine ring and those in which the pyridine is contained as a pendant on the C2 or C3 of the camphor framework. Camphor-based pyridine ligands can also contain other donor centers located on the pyridine ring or camphor skeleton. Some of these ligands have provided interesting enantioselectivities in several asymmetric reactions, such as S(N)2' reactions, allylic oxidations, carbonyl additions with organozinc reagents and hydrogenations. This review contains a lot of chemistry on ligand synthesis and readers will find it of value and also perhaps an inspiration for the development of more active and improved versions.     

Design and synthesis of a tridentate ligand for asymmetric bifunctional catalysis

Covalent attachment of a quinine moiety to a Schiff base ligand through an ester linkage generates a novel tridentate ligand that gives a new Lewis acid-Lewis base (LA-LB^∗) bifunctional catalyst having a mixture of the LA configurations. The LB^∗-dependent asymmetric bifunctional catalysis was demonstrated using the addition of diethylzinc to 2-methoxybenzaldehyde as a test reaction and the substrate scope of the new catalyst was illustrated using aromatic aldehydes.     

Five-membered cyclopalladated complex containing bidentate phosphine ligands; Synthesis,characterization, and highly efficient Suzuki cross-coupling reactions

A nonsymmetric phosphorus ylide and its palladium(II) complex have been synthesized as potential catalytically active compounds. The reaction of 1 equiv nonsymmetric phosphorus ylide, Ph₂PCH₂PPh₂C(H)C(O)PhBr with [Pd(dppe)Cl₂], followed by treatment with 2 equiv AgOTf led to [(dppe)Pd(Ph₂PCH₂PPh₂C(H)C(O)PhBr)](OSO₂CF₃)₂, which contains a five-membered P,P chelate ring on one side and a five-membered P,C chelate ring on the other side. The palladium complex was synthesized and investigated by fourier transform infrared spectroscopy (FT-IR), UV–visible, multinuclear (¹H, ³¹P and ¹⁹F) nuclear magnetic resonance (NMR), and electrospray ionisation-mass spectroscopic techniques. FT-IR and ³¹P NMR studies revealed that the phosphorus ylide is coordinated to palladium via the terminal phosphorus (P_c) of the ylide and methene group (CH). Suzuki reactions for varying aryl halides using the cyclopalladated complex as an efficient catalyst were performed. Various aryl halides were coupled with arylboronic acids in DMF, under air, in the presence of 0.001?mol% of the homogeneous catalyst to afford the corresponding cross-coupled products in good to excellent yields.     

The synthesis of new planar chiral heterobidentate chelate ligands for asymmetric catalysis

A series of new heterobidentate N,S; N,O and N,P chelate ligands have been synthesised where the sole source of chirality is derived from a planar chiral ferrocene unit and have been shown to give up to 79% ee (R) in the palladium catalysed allylic substitution reaction, suggesting that they may be suitable in other palladium catalysed processes.     

Synthesis of new tridentate chiral aminoalcohols by a multicomponent reaction and their evaluation as ligands for catalytic asymmetric Strecker reaction

A one-step, multicomponent Mannich-type reaction between phenols, paraformaldehyde, and β-aminoalcohols in the presence of LiCl afforded N-2-hydroxybenzyloxazolidines with high ortho-selectivity. Hydrolytic or reductive ring opening of the oxazolidines provided a series of N-salicyl-β-aminoalcohols in 84-92% overall yield. The synthesized compounds were evaluated as ligands for a titanium-catalyzed catalytic asymmetric Strecker reaction. The reaction employing 10 mol % of catalyst provided the Strecker products in excellent yields and up to 98% ee.     

Synthesis of alpha-substituted beta-amidophosphines by diastereoselective alkylation. A new access to chiral ligands for asymmetric catalysis

Chiral beta-amidophosphine boranes 7a-f can be diastereoselectively alkylated, using O-protected amino-alcohols as chiral inducers, to furnish alpha-substituted beta-amidophosphine boranes 8a-f and 9-12 with up to 72% diastereoisomeric excess. Selective deprotection afforded optically pure carboxylic derivative 13 which is a key intermediate for the synthesis of various potential chiral ligands for asymmetric catalysis.     

Synthesis and characterization of new galactosylated-based N2O-donors tridentate ligands

The synthesis and characterization of three novel N₂O-donor ligands containing the group 4-[1-β-d-2,3,4,6-tetra-O-acetyl-galactosyl)]benzaldehyde are presented. The insertion of this group was designed to increase the absorption of the prodrug in tumor cells, and is part of an ongoing work in our group with tridentate ligands to develop potential cobalt(III) prodrugs. The synthetic route described here allowed the isolation of pure ligands with yields ranged 81–89%. Finally, compounds were characterized by IR, NMR and HRMS (ESI⁺).     

Novel benzoferrocenyl chiral ligands: Synthesis and evaluation of their suitability for asymmetric catalysis

Four benzoferrocenyl phosphorus chiral ligands were conveniently prepared in good overall yields. These ligands were found to be stable in solid form and in solution. Two of the four ligands were resolved by chiral HPLC. Unlike a reported bis(phosphino-η⁵-indenyl)iron(II) complex, in which the indenyl ligands undergo ring flipping through an η¹-intermediate, these two ligands were found to be configurationally stable in solution and in solid state. The suitability of these ligands for enantioselective catalysis was assessed in studies on allylic alkylation reactions. When the two less sterically hindered ligands were used, excellent chemical yields were obtained, but the other two more sterically hindered ones gave lower yields. When the two enantiopure ligands were used, enantioselectivity of up to 51% ee was observed. These findings suggest that benzoferrocene derivatives may be used as chiral ligands for asymmetric catalysis.     

The preparation and resolution of 2-phenyl-Quinazolinap,a new atropisomeric phosphinamine ligand for asymmetric catalysis

The preparation and resolution of an axially chiral quinazoline-containing phosphinamine ligand is described. The biaryl linkage was formed in a Pd-catalysed coupling of 4-chloro-2-phenylquinazoline 10 with 2-methoxy-1-naphthylboronic acid 11. Demethylation of the product ether 12 afforded alcohol 13 which was converted into the corresponding triflate 14 by treatment with trifluoromethanesulphonic anhydride. An Ni-catalysed phosphinylation gave the required phosphinamine ligand 9 as a racemate. Diastereomeric palladacycles 16, formed from 9 and (+)-di-μ-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C₂,N]dipalladium(II) 15 were separated to give diastereomerically pure materials. An X-ray crystal structure of the (R,R)-16 palladacycle was determined and is discussed. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane gave enantiopure 2-phenyl-Quinazolinap 9, a new atropisomeric phosphinamine ligand for asymmetric catalysis.     

Synthesis of novel chiral phosphinocyrhetrenyloxazoline ligands and their application in asymmetric catalysis

Several novel planar chiral phosphinocyrhetrenyloxazolines have been synthesized, and their catalytic activities have been evaluated in a variety of asymmetric catalytic reactions. Preferable effects as compared to their ferrocenyl analogues have been observed in asymmetric allylic amination and asymmetric hydrosilylation, and up to 97% ee and 72% ee were reached, respectively. The Lewis basicity of the phosphorus on the ferrocene and the cyrhetrene, which contributes to their different behavior in catalysis, has been deduced by 31P NMR spectroscopy analysis, as indicated by 1J(77Se-31P) in the corresponding phosphine selenides.     

A new class of readily available and conformationally rigid phosphino-oxazoline ligands for asymmetric catalysis

A new class of conformationally rigid phosphino-oxazoline ligands 3 were synthesized via an efficient ortho-substitution of phenyl glycinol as the key step. Divergent synthetic routes for easy ligand modulation, as well as a procedure suitable for scale-up synthesis, were established. The catalytic potential of ligands 3 has been demonstrated in the highly enantioselective Ir-catalyzed hydrogenation of alkenes and Pd-catalyzed allylic substitution and intermolecular Heck reactions.     

Coupling of bulky,electron-deficient partners in aryl amination in the preparation of tridentate bis(oxazoline) ligands for asymmetric catalysis

A new class of tridentate bis(oxazoline) ligands 7, in which an N-phenylaniline unit links the two oxazoline rings, has been prepared. The key step in their synthesis is a Hartwig-Buchwald type Pd-catalyzed aryl amination between the two bulky o-substituted coupling partners, 2-(2'-bromophenyl)oxazolines 8 and 2-(o-aminophenyl)oxazolines 9. By varying the substituent on the coupling partners, a range of 10 ligands has been prepared in good yield. During the synthesis of 2-(o-aminophenyl)oxazolines 9a-d, a number of products of unexpected side reactions were isolated in two of the three steps. Alternatively, the required 2-(o-aminophenyl)oxazolines 9 were obtained by a DAST-promoted cyclodehydration of hydroxyamides 12a-d without formation of any byproducts.     

Iron catalysis for the synthesis of ligands: Exploring the products of hydrophosphination as ligands in cross-coupling

Catalytic hydrophosphination is a useful technique for the synthesis of phosphines, however, the phosphine products have been little exploited as ligands in catalysis. We have selected three phosphines prepared by iron catalyzed hydrophosphination and used them as ligands in a series of cross-coupling reactions: Heck, Suzuki-Miyaura and Buchwald-Hartwig. Rather than limit the chemistry to simple cross-coupling partners which are almost guaranteed to perform well in these transformations, industrially relevant substrates which are challenging from and electronic and/or steric perspective, along with substrates which contain several heteroatoms, were explored in order to gauge the true potential of these phosphine ligands.     

Synthesis of new 8-arylisoquinoline derivatives by application of palladium-catalyzed Suzuki cross-coupling reactions

New 8-(het)aryltetrahydroisoquinolines (10-14), 8-aryltetrahydroisoquinolin-4-ols (15,16), and 8-phenylisoquinolin-4-ol (17), flexible analogues of aporphine, were synthesized in good yields using palladium-catalyzed Suzuki cross-coupling reactions from 8-bromotetrahydroisoquinolin-4-one (6) as a common intermediate. We also describe the synthesis of this novel intermediate through an easy and efficient method, which involved intramolecular Friedel-Crafts cyclization.