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.     

Enantiomerically pure α-pinene derivatives from material of 65% enantiomeric purity. Part 2: C2-symmetric N,N′-3-(2α-hydroxy)pinane diimines and diamines

The conversion of enantiomerically enriched (ee >99%) 2α-hydroxypinan-3-one and its oxime (obtained in previously described procedures¹ from α-pinene of 65% ee) into a range of derivatives with potential application in asymmetric synthesis was attempted. C₂-Symmetrical compounds, ligands for potential catalysts, were synthesized from 2α-hydroxypinan-3-one and either aliphatic or aromatic diamines. Reduction or etherification/reduction of selected diiminodiols afforded respective diaminodiols and diaminoethers, which were further transformed into azolium salts. Reactions of dipinanediaminoethers with dichlorophenylphosphine and subsequent in situ oxidation of the products afford the respective stable phosphinediamide oxides. Four selected compounds were crystallographically studied.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Chiral bispyridylamide metal complexes as catalysts for the enantioselective addition of TMSCN to aldehydes

The use of (1R,2R)-N,N′-bis(2-pyridinecarboxyamido)-1,2-diphenylethane metal complexes as catalysts for the enantioselective addition of trimethylsilyl cyanide to aldehydes is described. Enantioselectivities up to 70% ee were obtained with a Ti(IV) catalyst. Complexes with Zr(IV), Sc(III), Yb(III) and Cu(II) afforded less selective catalysts. For the Zr(IV) complex, a rate and selectivity enhancement was observed when adding 0.5 equiv. of water with respect to the catalyst. Studies of the metal complexes involved in the reaction were carried out by means of ¹H NMR spectroscopy. A Zr complex was shown by X-ray crystallography to exhibit distorted octahedral coordination, with the four nitrogen atoms of the doubly deprotonated ligand essentially in one plane.     

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.     

Catalytic asymmetric addition of arylboronic acids to N-Boc imines generated in situ using C2-symmetric cationic N-heterocyclic carbenes (NHCs) Pd diaquo complexes

The catalytic asymmetric addition of arylboronic acids to N-Boc imines generated in situ from stable and easily prepared α-carbamoyl sulfones was realized by using chiral cationic C₂-symmetric N-heterocyclic carbene (NHC) Pd²⁺ diaquo complexes 1a-c as the catalysts, producing the corresponding adducts in good to high yields (up to 89%) and good to high enantioselectivities (up to 90% ee).     

Enantioselective catalytic synthesis of ethyl mandelate derivatives using Rh(I)–NHC catalysts and organoboron reagents

Herein we describe for the first time the enantioselective catalytic arylation of ethyl glyoxalate using phenylboron reagents and chiral rhodium(I)–NHC catalysts. KO^tBu was the base of choice, along with tert-amyl alcohol as the solvent. A novel chiral bis-imidazolium salt was synthesized and evaluated for the first time in this catalytic transformation. Although moderate enantioselectivities (up to 34% ee) were obtained for the phenylation reaction, despite the excellent yields, very low enantioselectivities were obtained using other arylboronic acids with a variety of chiral rhodium(I)–NHC catalysts.     

Comparison of Ta–MCM-41 and Ti–MCM-41 as catalysts for the enantioselective epoxidation of styrene with TBHP

Chiral Ti–MCM-41 and Ta–MCM-41 catalysts have been prepared by grafting of Ti(OⁱPr)₄ and Ta(OEt)₅ and the modification with R-(+)-diethyl l-tartrate or R-(+)-diisopropyl l-tartrate. In general, the solid catalysts are more active and selective than their homogeneous counterparts in the epoxidation of styrene with tert-butyl hydroperoxide. The enantioselectivities depend on both the nature of the chiral ligand and the calcination temperature of the support, as it is supposed this controls the type of surface species that are formed. The best result of 71% ee is obtained with DIPT–Ta–MCM₅₅₀ and is the first example of the use of a Ta catalyst for the enantioselective epoxidation of unfunctionalized alkenes. Nonetheless, the recovered Ta catalysts are less active and selective.     

Asymmetric oxidative α-fluorination of 2-alkylphenylacetaldehydes with AgHF2 and ruthenium/PNNP catalysts

During attempts directed at epoxide ring opening with different HF sources, we discovered that the Lewis acidic [RuCl(PNNP)]⁺ (1) or [Ru(OEt₂)₂(PNNP)]²⁺ (2) catalysts promote the [1,2]-phenyl shift (Meinwald rearrangement) in phenyl-substituted epoxides to give the corresponding 2-alkylphenylacetaldehydes, which are fluorinated at the α-position in the presence of silver bifluoride (AgHF₂) (PNNP is (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine). The optimization of aldehyde fluorination with PhCH(R)CHO (R = Me, Et, ⁱPr, ^tBu) as substrates showed that catalyst [1]SbF₆ gives a moderate degree of enantioselectivity (up to 27% ee) and 35% yield. The substrate scope is limited to benzylic aldehydes. The reaction is unprecedented for transition metal catalysts. Circumstantial evidence suggests that the mechanism involves chemical oxidation followed by enantioselective fluorination with F⁻.     

8-Amino-5,6,7,8-tetrahydroquinolines as ligands in iridium(III) catalysts for the reduction of aryl ketones by asymmetric transfer hydrogenation (ATH)

Aqua iridium(III) complexes with 8-amino-5,6,7,8-tetrahydroquinolines CAMPY L1 and its derivatives as chiral ligands proved to be very efficient catalysts for the reduction of a wide range of prochiral aryl ketones, revealing a variety of behaviours in terms of reaction rate and stereoselectivity. As standard substrates, differently substituted acetophenones were studied and good enantioselectivity (86% ee) was achieved in the reduction of 1-(o-tolyl)ethan-1-one 6. Particularly interesting was the ATH reaction in the case of β-amino keto esters, precursors of β-lactams and azetidinones. The best results were obtained with [Cp¹Ir(H₂O)(L1)]SO₄ affording the corresponding diastereomeric alcohols in an (R,S)-configuration with an excellent 99% ee in the reduction of 2-(benzamido methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate 12.     

Synthesis of chiral β2-amino acids by asymmetric hydrogenation

The synthesis of chiral β²-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commercially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H₂-pressure, temperature, solvent), full conversions and products with up to 99% ee were achieved.     

Highly enantioselective synthesis of terutroban key intermediate via asymmetric hydrogenation

A chiral (R) key intermediate of the biologically active form of terutroban has been prepared by asymmetric hydrogenation. The catalysts are based on very easily accessible ruthenium complexes modified by chiral phosphorous ligands. The use of the chiral catASium^®T ligands family allowed us to realize this transformation efficiently in terms of yield and enantioselectivity (ee up to 92%) with high substrate/catalyst ratios.     

Asymmetric Mannich reactions catalyzed by proline and 4-hydroxyproline derived organocatalysts in the presence of water

The ability of amphiphilic catalysts based on proline and 4-hydroxyproline to catalyze the Mannich reaction in aqueous media is reported. With a 4-tert-butyldimethylsiloxy-substituted organocatalyst derived from N-prolylsulfonamide, the reaction of cyclohexanone with iminoglyoxylate proceeds with high enantioselectivity (>99% ee for the syn-diastereomer). This catalyst was also successfully applied in a reaction of an iminoglyoxylate with an aqueous tetrahydro-2H-pyran-2,6-diol to give the corresponding 2,3-disubstituted tetrahydropyridine with up to 95:5 dr and 98% ee.     

Phase-transfer catalyzed asymmetric arylacetate alkylation

Phenethyl arylacetates are alkylated under phase-transfer conditions with cinchona catalysts with alkyl halides in high yield with excellent enantioselectivity (84-99% ee) following recrystallization. Cinchonidine (CD) derived catalyst gave the (R)-product and cinchonine (CN) catalyst produced the (S)-product. The phenethyl (PE) ester group is removed, using ammonium formate and catalytic Pd/C, to give alkylated carboxylic acid products in high selectivity. The utility of the approach is demonstrated by a direct synthesis of (S)-naproxen^™.     

Highly enantioselective 1,4-conjugate addition of dialkylzinc to α,β-unsaturated lactone catalyzed by diphosphite-copper complexes

The 1,4-addition of diethylzinc and dimethylzinc to 5,6-hydro-2H-pyran-2-one using new chiral diphosphite-copper catalysts gave products in up to 98% ee.     

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.     

A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

Immobilization of catalysts derived from Cinchona alkaloids on modified poly(ethylene glycol)

The straightforward immobilization of some derivatives of Cinchona alkaloids on modified poly(ethylene glycol)s is reported. The compounds, obtained by simple reactions exploiting different sites for the attachment of the alkaloids to the polymer, were tested as catalysts in the enantioselective benzylation of the benzophenone imine of glycine t-butyl ester (ee up to 64%) and in the conjugate addition of thiophenol to cyclohexenone (ee 22%). The observed stereoselectivities were compared to those obtained either with the unsupported catalysts or with the catalysts immobilized on different polymeric matrixes. The influence of the poly(ethylene glycol) moieties on the catalytic activity is discussed.     

Chiral 2-aminobenzimidazole bifunctional organocatalysts: effect of di-CF3 and TFA on catalytic mechanisms

(S,S)-trans-Cyclohexanediamine-5,7-di-CF₃-benzimidazole (3b) was developed as a new chiral bifunctional organocatalyst and successfully applied to Michael addition of diethyl malonate to nitroolefins (up to 99%, 98% ee) under neutral condition. Systematic investigation on the catalytic mechanism revealed that the role of the guanidine moiety and the dimethylamine moiety in catalysts might be reversed with respect to Brønsted/Lewis acidic or basic functionalities, depending on the reaction conditions (neutral or TFA co-catalyst). Generally, di-CF₃ group substituted 2-aminobenzimidazole catalysts in neutral condition and non-substituted 2-aminobenzimidazole catalysts in co-catalyst (TFA) condition give high chemical yield and enantioselectivity.     

Macrocyclic receptors containing sucrose skeleton

Crown ether analogues with incorporated sucrose unit were prepared by reaction of 1′,2,3,3′,4,4′-hexa-O-benzylsucrose with polyethylene ditosylates in up to 52% yield. Stability constants of their complexes with Li⁺, Na⁺, K⁺, NH₄⁺ were determined by the NMR titration method. The macrocycles were also tested as catalysts in the enantioselective Michael reaction, but with little success (ee up to only 22%). The macrocycle containing nitrogen in the ring was also prepared in good yield. All prepared macrocycles were easily converted into the free sucrose crowns (H₂/Pd/C) without destroying the (very labile) glycosidic bond. The crystal structure of the selected receptor was determined.