Diamidophosphites with remote P1-stereocentres and their performance in Pd-catalyzed enantioselective reactions

Diamidophosphite ligands based on 1,1′-bis(hydroxymethyl)ferrocene or N¹,N²-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)oxalamide and bearing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms were obtained. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 70% ee in Pd-catalyzed desymmetrizations of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol bis-carbamate and up to 80% ee in Pd-catalyzed allylic alkylations of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate. Results obtained with a diamidophosphite containing an oxalamide framework show the considerable potential of such ligands in enantioselective catalysis.     

Diastereomeric P1-chiral diamidophosphites with terpene fragments in asymmetric catalysis

Diamidophosphite P¹-monodentate, ligands based on terpene alcohols and (S)- or (R)-(2-anilinomethyl)pyrrolidine, induce high enantioselectivities (ee’s up to 99%) in Pd-catalyzed allylic substitution reactions. In the Pd-catalyzed deracemization of ethyl (E)-1,3-diphenylallyl carbonate up to 92% enantioselectivity has been achieved. The Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters leads to a maximum of 56% ee with quantitative conversion. Diastereomeric diamidophosphites prepared from [(1S)-endo]-(−)-borneol were found to be the most efficient stereoselectors.     

BINOL-derived diphosphoramidites bearing unsymmetrical 1,2-diamine link and their application in asymmetric catalysis

New P,P-bidentate diastereomeric diphosphoramidite chiral ligands with mixed stereogenic elements and a C₁ backbone symmetry have been prepared from (S_a)- and (R_a)-1,1′-binaphthyl-2,2′-diol (BINOL) and (S)-N-benzyl-1-(pyrrolidin-2-yl)methanamine and are fully characterized. The use of these ligands provides up to 84% ee in the Pd-catalyzed asymmetric allylic substitution of (E)-1,3-diphenylallyl acetate and up to 95% ee in the Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters. The results indicate that the catalytic performance is highly affected by the axial chirality of the binaphthyl moieties of the ligand and the nature of the solvent.     

New modular P-chiral ligands for Rh-catalyzed asymmetric hydrogenation

New modular P-chiral ligands have been prepared from commercially available (S)-α,α-diphenylprolinol. With these new types of ligands, up to 95% ee was achieved in the Rh-catalyzed asymmetric hydrogenation of functionalized olefins.     

New amidophosphine-phosphinites (tLANOPs) as chiral ligands for asymmetric hydrogenation reactions

The new amidophosphine-phosphinite (AMPP) ligands 4a–g (called tLANOP ligands) derived from the chiral hydroxy amide (R)- or (S)-2-hydroxy-3,3,N-trimethylbutyramide have been prepared in 48–83% yield. The crystal structures of the square planar complexes [(SP-4-3)-Pd((R)-dmphea)((S)-4a)]BF₄ and [Rh((R)-4a)(COD)]BF₄ have allowed the absolute configurations of the ligands to be assigned. In both complexes the 7-membered chelating ring of 4a has virtually the same twist-boat conformation. With this class of ligands the rhodium catalyzed asymmetric hydrogenation of 4-oxoisophorone enol acetate gave (S)-phorenol acetate in up to 71% ee. The iridium catalyzed asymmetric hydrogenation of the cyclic iminium salts 16a and 16b afforded after work-up the corresponding cyclic secondary amine (S)-17 in up to 86% ee, when bulky groups were present on the phenyl substituents on the two phosphorus atoms.     

Synthesis of chiral ligands containing the N-(S)-α-phenylethyl group and their evaluation as activators in the enantioselective addition of Et2Zn to benzaldehyde

The synthesis of chiral ligands 4–18 derived from N-[(S)-α-phenylethyl]-trans-β-aminocyclohexanols (S,S,S)-1a and (R,R,S)-2 is described. Addition of diethylzinc to benzaldehyde catalyzed by ligands 4–18 (6 mol %) proceeds in fair to good yield (45–86%), and low to good enantioselectivities (1–76% ee). Highest enantioselectivities were induced by ligands (S,S,S)-4 and (S,S,S,S,R,R)-18 (76% and 68% ee, respectively). The configuration of the major enantiomer of carbinol 3 is (R) in both cases.     

Novel C2-symmetric bisoxazolines with a chiral trans-(2R,3R)-diphenylcyclopropane backbone: preparation and application in several enantioselective catalytic reactions

Various chiral bisoxazoline ligands with a chiral trans-(2R,3R)-diphenylcyclopropane backbone have been efficiently synthesized (five examples). These chiral ligands were tested and compared in palladium(0)-catalysed enantioselective allylic alkylations (up to 97% ee), copper(I)-catalysed enantioselective cyclopropanations (up to 89% ee) and aziridinations (up to 90% ee). We observed that the presence of a stereogenic centre on the oxazoline moiety is mandatory in order to obtain acceptable enantioselectivities.     

A class of readily available optically pure 7,7′-disubstituted BINAPs for asymmetric catalysis

A class of optically pure 7,7′-disubstituted BINAPs have been prepared starting with a catalytic asymmetric oxidative coupling reaction. A general, concise, and straightforward synthetic procedure has been established, and is suitable for all optically pure 7,7′-disubstituted BINAPs 1a-h, regardless of the substituents' structure in the 7,7′-positions. The catalytic potential of this class of ligands has been investigated in the highly enantioselective Rh-catalyzed 1,4-addition of aryl boronic acids to enones (up to 99.8% ee), and Ru-catalyzed asymmetric hydrogenation of simple aromatic ketones (up to S/C=100,000, up to 98% ee) and β-ketoesters (up to S/C=10,000, up to 99.8% ee), respectively.     

Highly enantioselective copper-catalyzed conjugate addition of diethylzinc to cyclic enones with spirocyclic phosphoramidite ligands

A series of spirocyclic phosphoramidite ligands 6-9 with different substituents on the amine moiety were synthesized from the chiral spirocyclic diol (R)-5. These monodentate ligands have been applied in copper-catalyzed conjugate addition of diethylzinc to cyclic enones. Excellent enantioselectivities (up to 99% ee) can be achieved by the use of ligand (R,S,S)-9 bearing stereochemically matched structure derived from the C₂-symmetric (S,S)-bis(α-methylbenzyl)amine.     

Enantioselective hydrogenation of functionalized olefins catalyzed by Rh-chiral bidentatephosphite complexes

A novel catalytic system for the hydrogenation of dimethyl itaconate has been developed by using rhodium–diphosphite complexes. These chiral diphosphite ligands were derived from glucopyranoside, d-mannitol derivatives, and binaphthyl or H₈-binaphthyl phosphochloridites. The ligands based on the methyl 3,6-anhydro-α-d-glucopyranoside backbone and (R)- and (S)-binaphthol and/or (R)- and (S)-2,2′-dihydroxy-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthol gave almost complete conversion of the dimethyl itaconate and both enantiomers of dimethyl 2-methylsuccinate with excellent enantioselectivities. The stereochemically matched combination of methyl 3,6-anhydro-α-d-glucopyranoside and H₈-(S)-binaphthyl in ligand 2,4-bis{[(S)-1,1′-H₈-binaphthyl-2,2′-diyl]-phosphite} methyl 3,6-anhydro-α-d-glucopyranoside was essential to afford dimethyl 2-methylsuccinate with up to 98% ee. The sense of the enantioselectivity of products was predominantly determined by the configuration of the biaryl moieties of the ligands. An initial screening of [Rh(cod)₂]BF₄ with these ligands in the hydrogenation of (E)-2-(3-butoxy-4-methoxybenzylidene)-3-methylbutanoic acid was carried out. Good enantioselectivity (75% ee) and low yield for (R)-2-(3-butoxy-4-methoxybenzyl)-3-methylbutanoic acid were obtained.     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

A facile synthesis and the asymmetric catalytic activity of BINOL-based thiazole (thiadiazole) thioether ligands

Four new BINOL-based thiazole (thiadiazole) thioether ligands (S)-1, (S)-2, (S,S)-3 and (S)-4 were prepared. When their catalytic effectiveness was tested, good results (up to 93% ee and 97% yield) were obtained in the asymmetric addition of diethylzinc to aldehydes while poor results were obtained in the asymmetric conjugate addition of diethylzinc to enones.     

Enantioselective synthesis of chiral 1,2-diamines by the catalytic ring opening of azabenzonorbornadienes: application in the preparation of new chiral ligands

In the presence of a rhodium catalyst (5 mol %) generated in situ from [Rh(cod)Cl]₂ and (S,S′)-(R,R′)-C₂-ferriphos-tolyl, the asymmetric ring-opening reaction of N-Boc-azabenzonorbornadienes with dibenzylamine proceeded with excellent enantioselectivity (up to >99% ee) to give the corresponding 1,2-diamine scaffolds in high yields. The sequential deprotection of the ring-opened products and treatment with tartaric acid gave the enantiomerically pure 1,2-diamine tartrate salts. These salts were used for the preparation of new chiral ligands such as the salen-type ligands and Trost-type ligands.     

Highly enantioselective Pd(II)-catalyzed Wacker-type cyclization of 2-allylphenols by use of bisoxazoline ligands with axis-unfixed biphenyl backbone

A series of axis-unfixed bisoxazoline ligands with different steric and electronic properties has been synthesized. Due to the different steric interactions, the ligands afforded only one of the two possible diastereomeric Pd(II)-complexes upon metal coordination. The palladium complex (S,aS)-8c showed excellent catalytic activities and enantioselectivities in Wacker-type cyclization of allylphenols with up to 98% ee.     

Enantioselective SiH insertion of methyl phenyldiazoacetate catalyzed by dirhodium(II) carboxylates incorporating N-phthaloyl-(S)-amino acids as chiral bridging ligands

Enantioselective insertion reactions of methyl phenyldiazoacetate into the SiH bond of silanes were effected by employing dirhodium(II) carboxylates incorporating N-phthaloyl-(S)-amino acids as chiral bridging ligands. The use of dirhodium(II) tetrakis[N-phthaloyl-(S)-phenylalaninate] as a catalyst produced methyl (2S)-(dimethylphenylsilyl)phenylacetate in 74% ee, whereas catalysis with dirhodium(II) tetrakis[N-phthaloyl-(S)-phenylglycinate] afforded its enantiomer in 72% ee.     

Enantioselective olefin epoxidation using homologous amine and iminium catalysts—a direct comparison

Homologous biphenyl and (diastereomeric) binaphthyl tertiary azepines and quaternary iminium salts were prepared from (+)-(S,S)-l-acetonamine. Both the amines and iminium ions behave as effective catalysts for the enantioselective epoxidation of unfunctionalized olefins (ee up to 83%).     

A P,N ligand with central and axial chiral elements: synthesis and application in allylic alkylation

Two epimers of 4-({5-[(diphenylphosphino)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl)-4,5-dihydro-3H-dinaphtho[1,2-e:2′,1′-c]azepine were prepared starting from (2S,3S)-4-amino-2,3-O-isopropylidenebutane-1,2,3-triol and (R)- and (S)-binaphthol. These ligands, in association with Pd(0) gave enantioselectivities up to 89% (S) and 36% (R) ee for the (S_A,4S,5R) and the (R_A,4S,5R) ligands in the alkylation of racemic 1,3-diphenylprop-2-enyl acetate with dimethyl malonate, showing that the binaphthyl moiety is the most important structure in the enantioselective creation of the new stereogenic center.     

Synthesis of new bis-BINOL-2,2′-ethers and bis-H8BINOL-2,2′-ethers evaluation of their Titanium complexes in the asymmetric ethylation of benzaldehyde

The preparation by means of different synthetic paths of a series of bis-BINOL and bis-H₈BINOL ligands is described. The ligands consist of two BINOL or H₈BINOL fragments, joined by diverse linkages through the oxygen at the 2′-position of the arylic fragments. These ligands were applied to the Ti(OⁱPr)₄ catalyzed asymmetric alkylation of benzaldehyde with Et₂Zn. The performance of these catalysts is very sensitive to the nature of the ether linkage. The ligand with a propylene link shows better enantioselectivity (ca. 70%) than those with two or four carbon atoms joining the BINOL fragments. Furthermore, using the propylene link, but replacing (R)-BINOL by (R)-H₈BINOL, a significant improvement in the stereoselectivity of the catalysts was achieved (ca. 80% ee in (R)-1-phenylpropan-1-ol). A cooperative effect was observed between the chirality at the BINOL fragment and that of a (S,S)-4,5-bis(methylene)-2,2-dimethyl-1,3-dioxolane link, derived from tartaric acid. When this chiral link combines with two (S)-BINOL fragments, the alkylation of benzaldehyde in toluene produces 70% ee of (S)-1-phenylpropan-1-ol, while the (R)-BINOL derivative ligand with the same link, in identical conditions, yields only 40% ee of the (R)-alcohol.     

Palladium-catalyzed asymmetric allylic alkylation of indoles by C–N bond axially chiral phosphine ligands

The palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate using P/N-type ligands such as N-aryl indole, C–N bond axially chiral aminophosphine (aS)-L4, gave the desired products 1 in good yields and with moderate to high enantioselectivities (up to 90% ee).     

Development of P1-monodentate diamidophosphites with a C1-symmetric 1,2-diamine backbone: the effects of substituents in the 1,3,2-diazaphospholidine cycle on Pd-catalyzed asymmetric allylations

We have designed and synthesized a small library of modular monodentate diamidophosphite ligands with stereogenic phosphorus atoms. The library was prepared efficiently from the commercially available and inexpensive (S)-N-Boc-amino acids. These novel ligands were screened in the Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate with dimethyl malonate as the C-nucleophile with up to 93% ee being obtained. The results showed that the different substituents in the 1,3,2-diazaphospholidine cycle had remarkable effects on the enantioselectivity.