Designing chiral amido-oxazolines as new chelating ligands devoted to direct Cu-catalyzed oxidation of allylic CH bonds in cyclic olefins

A new type of amido-oxazoline ligands was conveniently synthesized from inexpensive and commercially available materials in high yields and enantiomeric excesses. The corresponding chiral copper complexes with this class of ligands [C₂ symmetric S,S-bis(amido-oxazoline-Cu(II) complex] were synthesized accordingly. The ORTEP diagram of ligand 6a and complex 6a-copper were compared and characterization of the complex confirmed the involvement of both dentate parts of the ligands, the oxygen and nitrogen atoms, in complexation with copper. The utilization of this amido-oxazoline ligands in the copper-catalyzed enantioselective esterification of allylic CH bonds of cyclic olefins with tert-butyl-4-nitrobenzoperoxoate resulted in the highest activities, yields (up to 95%) and enantioselectivities (up to 96%) in the presence of HZSM-5 zeolite. These new findings highlight the protocol as one of the most attractive and useful methods for the oxidation of the asymmetric allylic CH bond of cycloalkenes compared to other methodologies reported in the literature.     

Synthesis of chiral ortho-(p-tolylsulfinyl) benzyl ketones

(S)-ortho-(p-Tolylsulfinyl)benzyl alkyl (and aryl) ketones 1a-e were prepared in good yields by reaction of esters or nitriles with the lithium benzyl carbanion derived from 2-(p-tolylsulfinyl) methylbenzene. α-Methylbenzyl ketones 2 were prepared as ca. 1:1 diastereoisomeric mixtures by methylation of the unsubstituted ketones 1 with NaH/MeI. The use of the ethylbenzene derivative as the starting material afforded complex mixtures. The obtention of pure (S,(S)S)-2 diastereoisomers could be attained in good yields by oxidation with PCC of the alcohols (epimeric mixtures at the hydroxylic carbon) obtained from reactions of aldehydes with the lithium carbanion derived from 2-(p-tolylsulfinyl)ethylbenzene.     

Asymmetric allylation of N-benzoylhydrazones promoted by novel C2-symmetric bis-sulfoxide organocatalysts

Novel C₂-symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with (S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyridine/bis-sulfoxide (R,R)-6 was accomplished by means of Katritzky’s procedure (Fe⁰/AcOH). Both bis-sulfoxides (R,R)-5 and (R,R)-6 are efficient chiral organocatalysts in the asymmetric allylation of N-benzoyl hydrazones derived from both aldehydes and ketones.     

A practical synthesis of N-aryl-substituted oxazolidinone-containing ketone catalysts for asymmetric epoxidation

N-Aryl-substituted oxazolidinone-containing ketone catalysts for the asymmetric epoxidation of olefins can be efficiently prepared from d-glucose and anilines.     

Asymmetric synthesis of diverse α,α-diarylmethylamines via aryl Grignard additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines

A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethylamines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in high yields and high diastereoselectivities. Higher stereoselectivity was obtained for most of the examples studied when the reactions are performed at ambient temperature as compared to cryogenic conditions. N-2,4,6-Triisopropylbenzenesulfinamide was shown to be the optimal chiral auxiliary as it provided higher diastereoselectivities when compared to the more commonly employed tert-butanesulfinamide or p-toluenesulfinamide in the synthesis of diarylmethylamine synthons. A rationale for the improved selectivity derived from the triisopropylbenzyl auxiliary is presented.     

New chiral morpholine-pyrrolidine ligands affecting asymmetric selectivity in copper catalyzed Henry reaction

In this study, several chiral diamine (35, 36, 37 and 39), triamine (24 and 25), diaminol (38, 42 and 43) and triaminol ligands (29 and 30) having chiral morpholine and pyrrolidine moieties conjugated constitutes, were prepared from commercially available (S)-2-amino-2-phenylacetic acid and (S)-proline. These ligands were complexed with copper (II) salt in situ and applied to asymmetric Henry reaction. Asymmetric addition of various structurally divergent aldehydes and nitromethane in the presence of 5?mol% of chiral ligand with CuCl₂ furnished corresponding β-nitro alcohol in good yields (up to 55–79%) with good enantioselectivity (up to 89%).     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

Five novel sensors (R,R)-3–6 and (S, S)-6 were synthesized and developed for enantioselective recognition of chiral compounds. Sensor 6 with two thiourea groups and steric π-conjugation frameworks could discriminate different chiral substrates, including acidic compounds, basic compounds, and neutral compounds. These results disclosed that the outstanding performance of enantioselective discrimination could be attributed to the thiourea group which acted as a hydrogen-bonding donor and the bulky steric moiety of the hosts which provided appropriate chiral environment. This result will be of great practical value in the designation of chiral sensors and high-throughput assay of chiral products.     

Imidazolium-based chiral ionic liquids: synthesis and application

Synthesis of chiral ionic liquids containing an imidazole nucleus and chiral centers on N-substituents is reported. [(2S,3S)-2,3-Dihydroxybutane-1,4-bis(3-butylimidazolium)]-[bis(trifluoromethanesulfonyl)amide]₂ and [(4S,5S)-2-phenyl-1,3-dioxolane-4,5-bis(1-methylimidazolium)]-[bis(trifluoromethanesulfonyl)amide]₂ induced enantioselectivity in the Michael addition of malonic esters to chalcones.     

Asymmetric epoxidation of cis-β-methylstyrenes catalyzed by N-aryl substituted oxazolidinone-containing ketones. A beneficial substituent effect

Asymmetric epoxidation of substituted cis-β-methylstyrenes using N-aryl substituted oxazolidinone-containing ketones as catalysts shows that substituents on the phenyl group of the olefin have significant positive effects on the enantioselectivity of the epoxidation, indicating a beneficial interaction between the phenyl group of the olefin and the phenyl group of the ketone catalyst.     

Cyclohexanones derived from dihydrocarvone as precursor of chiral dioxiranes for epoxidation of olefins

New ketones having an axial α-fluorine atom and substituents other than fluorine at C8, derived from commercially available (+)-dihydrocarvone, have been prepared and used for epoxidations of trans stilbene, trans methyl p-methoxy cinnamate, trans cinnamyl alcohol and derivatives. It was found that replacement of the H at C8 by a substituent containing an oxygen atom increases the enantioselectivities in all cases. It was also shown that protic substituents (hydroxyl groups) provide a decrease in enantioselectivity in the case of cinnamates probably because of H-bonding dioxirane-substrate. It is noted that the absolute configurations of the various epoxides obtained hold with the usual model involving a spiro-approach on the dioxirane conformation C1 having the α-fluorine axial. Moreover, sub-stoichiometric amounts (0.3 equiv) of ketone can be used in all cases as these ketones do not undergo Baeyer-Villiger oxidation and are recovered.     

Structurally simple chiral thioureas as chiral solvating agents in the enantiodiscrimination of α-hydroxy and α-amino carboxylic acids

C₂-Symmetrical chiral thioureas (S,S)-1 and (S,S)-2 were prepared in good yield by the reaction of 2 equiv of inexpensive (S)-1-phenylethylamine, or the corresponding naphthyl analog, with 1 equiv of thiophosgene in the presence of excess triethylamine. The presence of asymmetric elements in (S,S)-1 and (S,S)-2, and their capacity to act as receptors for anionic species via hydrogen bonding were exploited in the development of ¹H NMR spectroscopic enantiodiscrimination of chiral carboxylic acids. In particular, the diastereomeric complexes derived from thioureas (S,S)-1 and (S,S)-2 with ammonium salts of the chiral acids gave rise to well separated signals of the α-hydrogens and simple integration provides the corresponding enantiomeric ratios. Furthermore, it was observed that C_α-H in the (R) enantiomers of the chiral α-hydroxy and α-amino carboxylic acids studied in this work consistently appears downfield relative to the same signals in the (S) enantiomers.     

(S)-(−)-Fluorenylethylchloroformate (FLEC); preparation using asymmetric transfer hydrogenation and application to the analysis and resolution of amines

Fluorenylethylchoroformate (FLEC) is a valuable chiral derivatisation reagent that is used for the resolution of a wide variety of chiral amines. Herein, we describe an improved preparation of (S)-(−)-FLEC using an efficient asymmetric catalytic transfer hydrogenation as the key step. We also demonstrate the application of FLEC as a chiral Fmoc equivalent for chiral resolution, with facile deprotection, of tetrahydroquinaldines, and its capacity for inducing regioselective outcomes in nitration reactions.     

Synthesis of some novel sulfonyl ester derivatives derived from d-mannitol

The preparation of sulfonate-derivatives of d-mannitol i.e. 1,2:3,4-di-O-isopropylidene-3,4-di-O-p-toluenesulfonate-d-mannitol (3a), 1,2:3,4-di-O-isopropylidene-3,4-di-O-methanesulfonate-d-mannitol (3b), and 1, 2:3,4-di-O-isopropylidene-3,4-di-O-trifluoromethanesulfonate-d-mannitol (3c) is described. Full characterization and methodologies of these sulfonate-d-mannitol derivatives have been described as well.     

Enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN3 catalyzed by chiral Lewis acids

A catalytic enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN₃ using chiral Lewis acids afforded products with high enantioselectivity. As proof of the utility of this procedure, the precursor of selective κ-opioid agonist (1S,2S)-(−)-U-50,488 was synthesized.     

Novel chiral solvating agents derived from natural amino acid: enantiodiscrimination for chiral α-arylalkylamines

Two benzo[de]isoquinoline 1,3-dione amino acids 1 and 2 were readily prepared, and their enantiodiscriminating ability were investigated by ¹H NMR spectroscopy. It was found that 1 exhibited an excellent chiral recognition ability toward chiral α-phenylethylamine and some of its derivatives, leading to clear baseline separation of the multiplet of the probe groups in two enantiomers. The stoichiometric ratio and association constants of some host-guest complexes were determined. The interactions between the hosts and guest 3 were further studied by intermolecular NOE experiment and ESI-MS.     

Evidence for the importance of conformational equilibria in Rh-diphosphine complexes for the enantioselection in Rh-catalyzed asymmetric hydrogenation

The conformations of the chelate cycles in the X-ray structures of norbornadiene- and cyclooctadiene-rhodium complexes of (R,R)-1,2-bis[(o-methylphenyl)phenylphosphino]ethane are dramatically different. Nevertheless, they demonstrate the same sense of enantioselection in asymmetric hydrogenation of dehydroamino acids.     

Chiral nitrogen-containing calix[4]crown—an excellent receptor for chiral recognition of mandelic acid

A chiral nitrogen-containing calix[4]crown 2 bearing optically pure 1,2-diphenyl-1,2-oxyamino residue at lower rim showed excellent chiral recognition between enantiomers of mandelic acid. Using competitive ¹H NMR titration the ratio of association constants of (S)- and (R)-mandelic acid with the chiral calix[4]crown was determined to be 102, that is 98% de, which is the best result obtained from artificial receptors for the chiral recognition of mandelic acid up to now.     

Determination of absolute configuration of 2-methyl-1-(o-tolyl)naphthalene and the related axially chiral biaryls

An enantiomerically enriched sample (84.3% ee) of (aS)-2-methyl-1-[(((o-triisopropylsilyl)oxy)methyl)phenyl]naphthalene was produced via catalytic asymmetric Suzuki-Miyaura cross-coupling using an atropisomeric naphthamide-derived phosphine (A²phos) as the chiral ligand. After one recrystallization, enantiopurity of the biaryl product was improved to 98.9% ee and its absolute configuration was determined by X-ray crystal structural analysis. Through chemical transformations, the (aS)-enantiomers of 1-[(o-hydroxymethyl)phenyl]-2-methylnaphthalene, 1-[(o-chloromethyl)phenyl]-2-methylnaphthalene, and 2-methyl-1-(o-tolyl)naphthalene were obtained. Several other chiral biaryls were synthesized and stereochemically assigned.     

Practical and highly stereoselective technology for preparation of enantiopure sulfoxides and sulfinamides utilizing activated and functionally differentiated N-sulfonyl-1,2,3-oxathiazolidine-2-oxide derivatives

A simple, general, and practical technology to prepare enantiopure 1,2,3-oxathiazolidine-2-oxide derivatives using chiral aryl N-sulfonyl aminoalcohol derivatives and thionyl chloride is reported. The versatility of these novel chiral building blocks (MIOO and TMPOO), was exemplified by the expedient production of a variety of unique chiral sulfoxides and valuable chiral sulfinamides in excellent yields and enantiopurities.     

Characterization of racemization of chiral pesticides in organic solvents and water

Eight chiral pesticides, which were selected to cover different pesticide species and origins of chirality, were investigated to explore their chiral stability in organic solvents and water. Profenophos, fenamiphos, quizalofop-ethyl, dichlorprop-methyl (DCPP-methyl) and acetochlor were showed stable under all test conditions. However, significant racemization was observed for malathion, phenthoate and fenpropathrin in methanol, ethanol and water, but not in n-hexane, isopropanol, acetone or methylene chloride. The kinetic parameters (rate constant k and half-life T_1/2) of the abiotic racemization were calculated through a mathematical model of the first-order reaction. Furthermore, the extent of racemization varied among the solvents and was also affected by temperature dependence. The racemization of malathion, phenthoate and fenpropathrin in water was documented to be pH-dependent and took place more rapidly at pH 7.0 than at pH 5.8. The observed racemization was deduced to occur via a proton exchange process at the chiral center, and the relationship between the abiotic racemization and pesticide structure was further explored. Findings from this study are useful for better understanding enantioselectivity of chiral pesticides in environment and also for proper analysis, formulating or handling of enantiopure products.