Chemoenzymatic synthesis of optically active 1,2-disubstituted ferrocenes with planar chirality

A new pathway for the synthesis of 2-substituted ferrocenyl compounds with planar chirality using a chemoenzymatic resolution as the key step is described. The kinetic resolution of racemic 2-hydroxymethyl phenylthioferrocene 4 has been optimised and carried out on a multi-gram scale using CAL-B lipase, giving the resulting acetate and remaining alcohols in ee’s >99%. The enantiomerically enriched sulfides have been transformed via a two-step sequence, in a new family of 2-substituted ferrocenyl alcohol by using a sulfoxide–lithium exchange/electrophilic trapping sequence; this gives straightforward access to non-racemic ferrocenyl alcohols with planar chirality.     

Chemoenzymatic access to all four enantiopure stereoisomers of 1-ferrocenyl-1,3-butanediol

The kinetic resolution of ferrocenyl aldol 2 was achieved by a lipase-catalyzed esterification in organic solvent. Lipase from Candida antarctica was also found effective in promoting the enantioselective alcoholysis of acetate (±)-3 with n-BuOH. Both enantiomers of 2 were obtained in enantiopure form and subjected to chemical reduction to afford the corresponding syn- and anti-diols. These diols serve as starting materials for the preparation of new ferrocenyl amino alcohols bearing two stereocenters in the side chain.     

Synthesis of new C2-symmetric bis(β-hydroxy amide) ligands and their applications in the enantioselective addition of alkynylzinc to aldehydes

A series of chiral C₂-symmetric bis(β-hydroxy amide) ligands was synthesized via the reaction of isophthaloyl dichloride and amino alcohols derived from l-amino acid. The titanium(IV) complex of C₂-symmetric chiral ligand 3b was effective for the asymmetric alkynylation of aldehydes and the propargyl alcohols were obtained in high yields (up to 94%) and high enantiomeric excesses (up to 98%) under optimized conditions. The results obtained using ligand 3h support that the two β-hydroxy amide moieties in these ligands behave as two independent ligands in the catalytic system.     

Chiral ferrocenyl amino alcohols for enantioselective additions of diethylzinc to aldehydes

Optically active ferrocenyl amino alcohols have been prepared from commercially available l-alaninol, l-leucinol and l-valinol. They have been utilized as chiral ligands in the catalytic addition of diethylzinc to aldehydes. The influence of the substituents on the stereogenic centers of the ligand has been studied. Enantioselectivities up to 95% have been obtained.     

Synthesis of chiral ferrocenyl aziridino alcohols and use in the catalytic asymmetric addition of diethylzinc to aldehydes

A series of novel chiral ferrocenyl aziridino alcohols 5a–i were conveniently synthesized from L-serine and ferrocenecarboxaldehyde. These compounds have been used as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes and the effects of the ligand structures on the enantioselectivity was studied. Enantioselectivities up to 98.8% have been obtained.     

Catalytic enantioselective addition of diethylzinc to aldehydes using aziridine based chiral ligands

The readily available ferrocenyl substituted aziridinylmethanol 1 (FAM-1) was used as a chiral catalyst in the diethylzinc addition reaction to aromatic and aliphatic aldehydes to give secondary alcohols in high yields and up to 99% enantiomeric excess at room temperature. The catalyst can be recovered and used without losing its activity.     

Chiral Ferrocenyl Amino Alcohols：Preparation and Application as Catalysts in the Enantioselective Reduction of Ketones Using NaBH4／I2

Five novel chiral ferrocenyl amino alcohols were prepared from natural amino acids and used as catalysts in the asymmetric reduction of prochiral ketones with NaBH4/I2 combination.The incorporation of the ferrocenyl moiety into the molecule of the chiral amino alcohols greatly improved their enantioselectivity in the catalysis.The optically active secondary alcohols were obt5ained in moderate to good enantiomeric excesses and high chemical yields.     

New C2-symmetrical ferrocenyl diamines as ligands for ruthenium catalyzed transfer hydrogenation

The new C₂-symmetrical ferrocenyl diamines 5–7 and 13 proved to be good ligands for the ruthenium catalyzed enantioselective transfer hydrogenation of unsymmetrical ketones. The stereocontrolled and highly flexible synthetic route to the new diamines made it possible to vary the ligand structure in an efficient manner. A short trial and error process led to a very active catalytic system with diamine 6a as the ligand, which is capable of reducing ketones even at −30°C using 2-propanol as a hydrogen source. Enantioselectivities up to 90% were reached in the reduction of 1′-acetonaphthone.     

Highly enantioselective addition of methyl propiolate to aldehydes catalyzed by a titanium(IV) complex of a β-hydroxy amide

Three chiral β-hydroxy amide ligands were prepared by the reaction of benzyl chloride with amino alcohols derived from l-tyrosine. The titanium(IV) complex of chiral ligand 4a was found to be an effective catalyst for the asymmetric addition of methyl propiolate to aliphatic and aromatic aldehydes. The γ-hydroxy-α,β-acetylenic esters were obtained in excellent enantiomeric excesses (up to 94% ee) under optimized conditions.     

Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl]₂. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.     

Synthesis of new β-hydroxy amide ligands and their Ti(IV) complex-catalyzed enantioselective alkynylation of aliphatic and vinyl aldehydes

Three new chiral β-hydroxy amide ligands were synthesized via the reaction of benzyl chloride and amino alcohols derived from l-tyrosine. The titanium(IV) complex of chiral ligand 8b was found to be an effective catalyst for the asymmetric alkynylation of aliphatic, vinyl and aromatic aldehydes. The propargyl alcohols were obtained in highly enantiomeric excesses (up to 96% ee) under optimized conditions.     

Synthesis of ferrocene-based phosphine ligands via Cu-catalyzed reductive coupling of ferrocenyl ketone-derived tosylhydrazones and H-phosphorus oxides

Ferrocene-based phosphine oxides with various substituents at phosphorous atoms were synthesized by Cu-catalyzed reductive coupling of ferrocenyl ketone-derived tosylhydrazones and H-phosphorus oxides. Followed by the reduction of ferrocene-based phosphine oxides, 1-substituted ferrocene-based phosphine ligand 7 and 1,1′-disubstituted ferrocene-based phosphine ligand 9 were obtained. Josiphos type ligand 8 were produced after ortho-lithiation of 7 and trapping with chlorodiphenyl phosphine or chlorodicyclohexylphosphine.     

Etherification of Ferrocenyl Alcohol by Highly‐efficient Ytterbium Triflate

Nucleophilic substitution of ferrocenyl alcohols with various aliphatic alcohols in the presence of a catalytic amount of ytterbium triflate [Yb(OTf)₃] was studied. It was found the unsymmetrical ferrocenyl ethers could be easily obtained in excellent yields when the reactions were performed in primary and secondary alcohols. However, in other organic non‐alcoholic solvents such as acetonitrile, the formation of symmetrical ferrocenyl ethers rather than unsymmetrical ones was observed.     

Chiral ligands derived from abrine. Part 6: Importance of a bulky N-alkyl group in indole-containing chiral β-tertiary amino alcohols for controlling enantioselectivity in addition of diethylzinc toward aldehydes

A number of chiral β-amino alcohols possessing a 3-indolylmethyl group have been synthesized from the alkaloid, (S)-abrine and elucidated for potency in the catalytic enantioselective ethylation of PhCHO with Et₂Zn. In general, the secondary amines 15a–d bearing a dialkylhydroxymethyl group induced (R)-1-phenyl-1-propanol, whereas 15e–g and 18 bearing a diarylhydroxymethyl group favored the (S)-enantiomer. In contrast, the β-tertiary amino alcohols 20b–d and 21 produced (R)-1-phenyl-1-propanol, regardless of the substituents at the carbon bearing the hydroxy group. Enantiomeric excess of 87.5% was obtained for (R)-1-phenyl-1-propanol using ligand 21 as the promoter. Eleven substituted benzaldehydes and naphthaldehydes were examined for enantioselective ethylation by using 21 and the chiral alcohols were obtained in 93–97% ee, except for o-BrC₆H₄CHO and p-Me₂NC₆H₄CHO. Excellent enantioselectivity was also observed in the ethylation of cyclohexanecarboxaldehyde (94.8% ee) and 2-thiophenecarboxaldehyde (94.9% ee) by using catalytic 21. The anti 5/4/4-fused tricyclic TS I was proposed to rationalize the asymmetric induction. The diethylhydroxymethyl and N-2-t-butylethyl groups are believed to enforce the preference for the anti-TS(R) I and it results in high enantioselectivity.     

3-Aminoquinazolinones as chiral ligands in catalytic enantioselective diethylzinc and phenylacetylene addition to aldehydes

A series of readily known enantiomerically pure 3-aminoquinazolinones 1a–d were synthesised from easily accessible chiral pool α-hydroxy acids and α-amino acids in only four steps without any requirement of chromatography. These quinazolinones were examined as chiral ligands for catalytic enantioselective diethylzinc and phenylacetylene additions to aldehydes. For enantioselective alkylations, the effects of temperature, solvent, diethylzinc and ligand criteria were analysed, and the desired chiral alcohols were obtained in up to 86% ee. 3-Aminoquinazolinones 1a–d were also shown to be very useful ligands in enantioselective alkynylations of aldehydes. Based upon the optimised conditions, the corresponding propargylic alcohols were obtained in up to 94% ee.     

Combination of CuBr2 and multi-functional ligand bearing a bidentate nitrogen unit,a phenol group and a TEMPO moiety as catalyst for the aerobic oxidation of primary alcohols

A novel ligand (L) bearing a bidentate nitrogen ligand unit, a phenol group and a TEMPO moiety has been synthesized. The ligand has been used as a catalyst precursor for the copper-catalyzed aerobic oxidation of alcohols to aldehydes, in the presence of K₂CO₃. The complex obtained in-situ from the ligand with copper(II) bromide (CuBr₂) in a 2:1 acetonitrile/water mixture, selectively catalyzes the aerobic oxidation of primary benzylic and allylic alcohols to their corresponding aldehydes, and no over-oxidation products are detected.     

Carbohydrate-derived alcohols as organocatalysts in enantioselective aldol reactions of isatins with ketones

The catalytic activity of carbohydrate-derived amino alcohols in the enantioselective aldol reaction of ketones with isatin and its derivatives has been examined for the first time. The carbohydrate-derived amino alcohols 5 were found to be efficient organocatalysts for asymmetric aldol reactions. A variety of isatins were used as substrates and the corresponding aldol products were obtained in high yields (up to 99%) and with moderate enantioselectivities (up to 75%).     

Synthesis of novel chiral Schiff-base ligands and their application in asymmetric nitro aldol (Henry) reaction

Chiral Schiff-bases prepared from chiral amino alcohols catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and p-nitrobenzaldehyde in the presence of Cu(OTf)₂ and Zn(OTf)₂. Zn(OTf)₂ promoted the reaction yield, while Cu(OTf)₂ promoted the enantiomeric excess. The highest enantioselectivities were observed with ligand 3 (44% ee) and ligand 5 (47% ee).     

Synthesis,characterization and cytotoxic activity of ferrocenyl hydrazone complexes containing a furan moiety

A ferrocenyl ligand 1 was prepared from condensation of 5-methyl-2-furaldehyde with l,l′-diacetylferrocene dihydrazone. This ligand forms 1:1 complexes with cobalt(II), nickel(II), copper(II) and zinc(II) 2–5 in good yield. Characterization of the ligand and complexes was carried out using infrared, nuclear magnetic resonance, mass spectra, electronic absorption, magnetic susceptibility, molar conductivity, and elemental analysis. Cytotoxic activity of the prepared ligand and its complexes were tested against different human cancer cell lines. The results suggested that the synthesized compounds were more potent than the comparative standards drugs used in most cases, whereas they had less activity in the others.     

Catalytic ferrocenyl sulfides for the asymmetric transformation of aldehydes into epoxides

Six ferrocenyl sulfides, exhibiting planar and central chiralities, have been screened as a catalytic source of asymmetric sulfonium ylides. A one-pot reaction has been achieved, involving the addition of an aldehyde, benzyl bromide, 20% molar equivalent of the ferrocenyl sulfide, sodium iodide in a mixture of tert-butanol and water. The best results were observed with enantiopure sulfide 3a, bearing a tert-butyl group. Good yields of stilbene oxides were obtained, with enantiomeric excesses ranging from 74% to 94%. trans/cis-Diastereomeric ratios ranged from 60:40 to 86:14. The chiral sulfide was recovered. An unexpected case of stereoconvergence was observed with diastereoisomers 3a and 3b. A model is proposed to account for the asymmetric induction, based on a conformation locked by the tert-butyl group and the interplay of planar and remote central chiralities.