Screening of a modular sugar-based phosphoroamidite ligand library in the asymmetric nickel-catalyzed trialkylaluminium addition to aldehydes

A modular sugar-based phosphoroamidite ligand library for the Ni-catalyzed trialkylaluminium addition to aldehydes has been synthesized and screened. After systematic variation of the sugar backbone, the substituents at the phosphoroamidite moieties and the flexibility of the ligand backbone, the monophosphoroamidite ligand 3-amine-3-deoxy-1,2:5,6-di-O-isopropylidene-((3,3′-di-trimethylsilyl-1,1′-biphenyl-2,2′-diyl)phosphite)-α-d-glucofuranose 1d were found to be optimal. Activities were high and enantioselectivities were good (ees up to 78%) for several aryl aldehydes.     

Screening of a modular sugar-based phosphite ligand library in the asymmetric nickel-catalyzed trialkylaluminum addition to aldehydes

We synthesized a modular sugar-based phosphite ligand library for the Ni-catalyzed trialkylaluminum addition to aldehydes. This library has been designed to rapidly screen the ligands to uncover their important structure features and determine the scope of the phosphite ligands in this catalytic reaction. After systematic variation of the sugar backbone, the substituents at the phosphite moieties, and the flexibility of the ligand backbone, the monophosphite ligand 1,2:5,6-di-O-isopropylidene-3-O-((3,3';5,5'-tetra-tert-butyl-1,1'-biphenyl-2,2'-diyl)phosphite)-alpha-D-glucofuranose 1c was found to be optimal, yielding high activities and enantioselectivities (ee's up to 94%) for several aryl aldehydes.     

Furanoside phosphite–phosphoroamidite and diphosphoroamidite ligands applied to asymmetric Cu-catalyzed allylic substitution reactions

A phosphite–phosphoroamidite and diphosphoroamidite ligand library was applied in the Cu-catalyzed allylic substitution of a range of cinnamyl-type substrates using several organometallic nucleophiles. Results indicated that selectivity depended strongly on the ligand parameters (position of the phosphoroamidite group at either C-5 or C-3 of the furanoside backbone, as well as the configuration of C-3, the introduction of a second phosphoroamidite moiety, the substituents and configurations in the biaryl phosphite/phosphoroamidite moieties), the nature of the leaving group of the substrate and the alkylating reagent. Good enantioselectivities (up to 76%) and activity combined with high regioselectivities were obtained.     

Pyranoside phosphite–phosphoroamidite ligands for Pd-catalyzed asymmetric allylic alkylation reactions

We have designed and synthesized a new family of readily available phosphite–phosphoroamidite ligands for Pd-catalyzed allylic substitution reactions of several substrates with different steric and electronic properties. These ligands are derived from d-glucosamine and contain several substituents in the biphenyl moieties, with different steric and electronic properties. Systematic variation of the ligand parameters indicates that enantioselectivities are mainly affected by the substituents at the para-positions of the biphenyl moieties. Enantiomeric excesses of up to 89% with high activities were obtained for rac-1,3-diphenyl-3-acetoxyprop-1-ene S1, rac-(E)-ethyl-2,5-dimethyl-3-hex-4-enylcarbonate S2 and rac-3-acetoxycycloheptene S5.     

Chiral diphosphites derived from D-glucose: new highly modular ligands for the asymmetric catalytic hydrogenation

A series of novel diphosphite ligands derived from readily available D-(+)-glucose have been synthesized. These ligands were screened in the Rh-catalyzed hydrogenation of a series of alpha,beta-unsaturated carboxylic acid derivatives. Both excellent enantioselectivities (ee up to >99%) and activities were achieved. The advantage of these ligands is that their modular nature allows an easy systematic variation in the configuration of the stereocenters (C-3, C-5) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in asymmetric hydrogenation can be determined. Results show that enantiomeric excesses depend strongly on the absolute configuration of C-3 and slightly on the stereocenter carbon C-5, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryls at the phosphite moieties. Moreover, the presence of bulky substituents at the ortho-positions of the biaryl diphosphite moieties has a positive effect on enantioselectivity.     

Sugar–phosphite–oxazoline and phosphite–phosphoroamidite ligand libraries for Cu-catalyzed asymmetric 1,4-addition reactions

Sugar–phosphite–oxazoline L1–L5a–g and phosphite–phosphoroamidite L6a–c ligand libraries were tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of cyclic and acyclic enones. Systematically varying the electronic and steric properties of the oxazoline and biaryl phosphite substituents and the functional groups attached to the basic sugar-backbone had a strong effect on the catalytic performance. In general, good activities and enantioselectivities were obtained. The enantioselectivity (up to 80%) was optimized with catalyst precursors containing the phosphite–oxazoline ligands L1c and L1f that contain encumbered biaryl phosphite moieties and a phenyl oxazoline group.     

Sugar-based phosphite and phosphoroamidite ligands for the Cu-catalyzed asymmetric 1,4-addition to enones

A modular sugar-based phosphoroamidite L1–L5a–g and phosphite L6–L9a–g ligand library was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted (cyclic and linear) and β,β′-disubstituted (cyclic) enones. The selectivity depended strongly on the configuration of carbon atom C-3, the size of the sugar backbone ring, the flexibility of the ligand backbone, the substituents and configurations in the biaryl phosphoroamidite moieties a–g, the type of functional group attached to the ligand backbone and the substrate structure. Therefore, by carefully selecting the ligand parameters, enantioselectivities of up to 60% for cyclic substrates and 72% for linear ones were achieved.     

Chiral diphosphites derived from d-glucose in the copper-catalyzed conjugate addition of diethylzinc to cyclohexenone

A series of diphosphite ligands 1–3 derived from readily available d-(+)-glucose and bisphenol or binaphthol derivatives have been applied as ligands in the Cu-catalyzed 1,4-addition of diethylzinc to cyclohexenone. Excellent reaction rates (TOF>1200 h⁻¹) and good enantioselectivities (e.e. of up to 84%) were achieved. The modular nature of these ligands allows easy systematic variation in the configuration of the stereocenters (C(3), C(5)) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in the asymmetric 1,4-addition can be determined. The results obtained show that the enantioselectivity induced by the ligand depends strongly on the absolute configuration of the C(3) stereogenic centre, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryl groups of the phosphite moieties.     

The application of pyranoside phosphite-pyridine ligands to enantioselective Ir-catalyzed hydrogenations of highly unfunctionalized olefins

Eight (biaryl)phosphite/pyridine ligands 1–2a–d have been prepared by the modular functionalization of positions C-2 and C-3 of two d-glucopyranoside backbones. The chiral ligands were examined in the iridium-catalyzed asymmetric hydrogenation of poorly functionalized alkenes, as a function of the relative position of the coordinating groups and the geometric properties of the biaryl phosphite moieties. Enantiomeric excesses of up to 90% were achieved in the hydrogenation of E-2-(4-methoxyphenyl)-2-butene by using 1a and 1c, which seemingly combine the beneficial effect of the phosphite at the 2-position with the matching (R_ax)-configuration of their encumbered biaryl substituents. The results of the hydrogenation of more challenging substrates, such as Z-trisubstituted alkenes, alkenes with a neighboring polar group or demanding 1,1-di-substituted alkenes, generally confirmed this trend, and in some significant cases, the chiral hydrogenated products were isolated with ees of 65–79%.     

Coordination studies on supramolecular chiral ligands and application in asymmetric hydroformylation

In this study we introduce a series of monodentate pyridine-based ligands for which the phosphorus coordination mode to rhodium can be controlled by the binding of Zn(II)-templates to the pyridyl group. A series of monodentate phosphoroamidite and phosphite ligands have been prepared and studied under hydroformylation conditions by in situ high-pressure NMR and IR techniques. These studies reveal the exclusive formation of rhodium hydride complexes in which the phosphorus atom of the ligand resides in an axial position, trans to the hydride, but only after addition of Zn(II)-template. In the absence of these templates the usual mono-coordinated rhodium hydrido complexes are formed, with the phosphorus ligated in the equatorial plane, cis to the hydride. The catalytic performance of these complexes is evaluated in asymmetric hydroformylation of unfunctionalised internal alkenes in which the supramolecular change is reflected in higher activity and selectivity.     

Copper‐Catalyzed Asymmetric Conjugate Addition with Chiral SimplePhos Ligands

SimplePhos ligands represent a novel class of monodentate chiral ligands based on a chiral amine moiety and flexible diaryl groups on the phosphorous atom. They can be easily prepared by two different pathways and they can be highly functionalised. Herein we report the copper‐catalysed asymmetric conjugate addition of diethyl zinc and trialkylaluminium reagents with SimplePhos ligands, which gives high enantioselectivity with cyclic enones, acyclic enones and nitro‐olefins, with up to 98.6 % ee. Of particular interest is the reaction of trialkylaluminium reagents with a wide range of 3‐substituted enones, thus allowing the formation of stereogenic quaternary carbon centres.     

Rh-catalyzed asymmetric hydrogenation using a furanoside monophosphite second-generation ligand library: scope and limitations

The ligand design of one of the most successful monophosphite ligand classes in Rh-catalyzed hydrogenation was expanded upon by introducing several substituents at the C-3 position of the furanoside backbone. A small but structurally important library of monophosphite ligands was developed by changing the substituents at the C-3 position of the furanoside backbone and the substituents/configurations at the biaryl phosphite group. These new furanoside monophosphite ligands were evaluated in the Rh-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acid derivatives and enamides. The results show that the effect of introducing a substituent at the C-3 position of the furanoside backbone on the enantioselectivity depends not only on the configuration at the C-3 position of the furanoside backbone and the binaphthyl group but also on the substrate. Thus, the new ligands afforded high to excellent enantioselectivities in the reduction of carboxylic acid derivatives (ee’s up to >99.9%) and moderate ee’s (up to 67%) in the hydrogenation of enamides.     

Extending the Substrate Scope of Bicyclic P‐Oxazoline/Thiazole Ligands for Ir‐Catalyzed Hydrogenation of Unfunctionalized Olefins by Introducing a Biaryl Phosphoroamidite Group

This study identifies a series of Ir‐bicyclic phosphoroamidite–oxazoline/thiazole catalytic systems that can hydrogenate a wide range of minimally functionalized olefins (including E‐ and Z‐tri‐ and disubstituted substrates, vinylsilanes, enol phosphinates, tri‐ and disubstituted alkenylboronic esters, and α,β‐unsaturated enones) in high enantioselectivities (ee values up to 99 %) and conversions. The design of the new phosphoroamidite–oxazoline/thiazole ligands derives from a previous successful generation of bicyclic N‐phosphane–oxazoline/thiazole ligands, by replacing the N‐phosphane group with a π‐acceptor biaryl phosphoroamidite moiety. A small but structurally important family of Ir‐phosphoroamidite–oxazoline/thiazole precatalysts has thus been synthesized by changing the nature of the N‐donor group (either oxazoline or thiazole) and the configuration at the biaryl phosphoroamidite moiety. The substitution of the N‐phosphane by a phosphoroamidite group in the bicyclic N‐phosphane–oxazoline/thiazole ligands extended the range of olefins that can be successfully hydrogenated.     

Furanoside phosphite–phosphoroamidite and diphosphoroamidite ligands for Cu-catalyzed asymmetric 1,4-addition reactions

A sugar-based phosphite–phosphoroamidite and diphosphoroamidite ligand library L1–L5a–g was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted and β,β′-disubstituted enones. Our results indicated that the selectivity was strongly dependent on the ligand parameters and on the substrate structure. Moderate-to-good enantioselectivities (ees up to 84%) were obtained in the 1,4-addition of several types of β-substituted cyclic and linear substrates. Of particular note is the high enantioselectivity (ees up to 90%) obtained for the more challenging β,β′-disubstituted 3-methyl-cyclohexenone.     

Highlights of the Rh-catalysed asymmetric hydroformylation of alkenes using phosphorus donor ligands

Rhodium is currently the metal of choice to achieve high enantioselectivities in the hydroformylation of a relatively high variety of alkene substrates. The elucidation of the different steps of the catalytic cycle and the characterisation of the resting state, together with the discovery of several types of ligands that are able to provide high enantioselectivities, have made the rhodium-catalysed hydroformylation a synthetically useful tool. For years, ligands containing phosphite moieties such as diphosphites and phosphine–phosphites were considered the most successful ligands to achieve high enantioselectivies in this process. In fact, the phosphite–phosphine BINAPHOS 43 and its derivatives are even today the most successful ligands in terms of selectivity and scope. Recently however, diphosphine derivatives were shown to provide high levels of selectivity. It can consequently be concluded that the key to achieve high enantioselectivities is not the type the phosphorus function involved in the coordination to the metal, but the particular spatial arrangement of the coordinated ligand.     

Diphosphite ligands based on ribose backbone as suitable ligands in the hydrogenation and hydroformylation of prochiral olefins

Rh(I) and Ir(I) cationic complexes [M(cod)(PP)]BF₄ have been synthesised from diphosphite ligands 4–6 derived from ribofuranose. They have been used in the rhodium and iridium catalysed asymmetric hydrogenation of acrylic acid derivatives. Ribose derivative ligands 4–6 have also been used as auxiliaries in the Rh-catalysed hydroformylation of styrene. Hydroformylation results have been explained on the basis of the species formed under hydroformylation conditions. Comparative experiments with the related epimer d-(+)-xylose derivatives showed that the configuration of the product is controlled by the absolute configuration of the stereogenic carbon atom C-3.     

The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands derived from D-(-)-tartaric acid

A series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition of organozincs to enones. There was a synergic effect between the stereogenic centers of the D-(-)-tartaric acid skeleton and the axially H₈-binaphthyl moieties of ligand 2c. And ligand 2c shows a comparative catalytic performance to ligand 1-N-benzylpyrrolidine-3,4-bis[(S)-1,1′-H₈-binaphthyl-2,2′-diyl]phosphite-L-tartaric acid1d derived from L-(+)-tartaric acid. Therefore, for cyclic enones, both enantiomers of the addition products can be obtained in high enantioselectivity (ees up to 96%) by simply selecting ligands 1d or 2c derived from D-(-)-tartaric acid or L-(+)-tartaric acid. Moreover, the sense of enantiodiscrimination of the products was mainly determined by the configuration of the binaphthyl phosphite moieties.     

Screening of a modular sugar-based phosphite ligand library in the Cu-catalyzed asymmetric 1,4-addition reactions

A sugar-based monophosphite ligand library L1–L5 was screened in the Cu-catalyzed asymmetric 1,4-addition to cyclic and aliphatic linear enones. These ligands are derived from d-glucose, d-galactose and d-fructose, which lead to a wide range of sugar backbones, and contain several substituents/configurations in the biaryl moiety, with different steric and electronic properties. Systematic variation of the ligand parameters indicates that the catalytic performance (activities and enantioselectivities) is highly affected by the configuration of C-4 of the carbohydrate backbone, the size of the ring of the sugar backbone and the cooperative effect between configurations of C-3 and of the binaphthyl phosphite moiety. Good activities and enantioselectivities up to 57% and 51% were achieved for cyclic and aliphatic linear enones, respectively.     

Modular Synthesis of Phosphite and Phosphoramidite Ligands for Rh-Catalyzed Hydroformylation

Rhodium-catalyzed hydroformylation of olefins is an important method for synthesizing aldehydes, and it is worth noting that regioselectivity and enantioselectivity of the product controlled by ligand are the most commonly used strategies. The modular synthesis of phosphite and phosphoramidite ligands have significant advantages of simple synthesis and high catalytic activity, which was why these ligands have been widely used in hydroformylation reactions. Herein, we focus on the synthesis methods and design ideas of such ligands, as well as their application effects in hydroformylation reactions. This review aims to provide a reference for the design and synthesis of ligands in hydroformylation subsequently.     

Modular furanoside phosphite ligands for asymmetric Pd-catalyzed allylic substitution.

A series of diphosphite, phosphine-phosphite, and thioether-phosphite ligands 1-5 with a furanoside backbone have been used in the enantioselective palladium-catalyzed allylic substitution of rac-1,3-diphenyl-2-propenyl acetate giving low to high enantioselectivies (from close to 0% to 97% ee). The modular nature of these ligands enables systematic investigations of the effect of the ligand structure on the enantioselectivity. The enantioselectivity is mainly determined by the configuration of the stereogenic center C-3 of the furanose backbone. From this we conclude that the attack of the nucleophile takes place trans toward the donating group at the stereogenic C-5 atom. Systematic variation of the donor group attached to the carbon atom C-5 indicated that the presence of a bulky phosphite functionality has a positive effect on enantioselectivity. Thus, the highest ee's are obtained using the bulky diphosphite ligand 1b containing a xylofuranoside backbone.