MM3 force field prediction of the enantioselective preference in the asymmetric synthesis of a chiral 2-cyclohexen-1-ol using a chiral lithium amide reagent

Enantioselective preference in the asymmetric synthesis where cyclohexene oxide is transformed enantioselectively to chiral (S)- or (R)-2-cyclohexen-1-ol by the reaction with the appropriate chiral lithium amide reagent has been evaluated theoretically using the MM3 force field. The plausible possible structures for each precursor (reaction intermediate complex) leading to a (S)- or (R)-2-cyclohexen-1-ol have been optimized with the extended MM3 force field applicable to the lithium amide functional group, and the populations of their (S)- or (R)-reaction intermediate complexes at an ambient temperature (298 K) were calculated. The initial structure for evaluating the reaction intermediates of this asymmetric synthesis was constructed on the basis of the optimized ab initio transition state structure (MP2/6-31+G^∗) comprising lithium amide LiNH₂ and propene oxide. To the thus obtained transition state structure composed of LiNH₂ and propene oxide, the other remaining Cartesian coordinates for the actual reaction intermediates composed of the chiral lithium amides and cyclohexene oxide were added to make the reaction intermediate structure. The conformational search for the reaction intermediate has been carried out by using the Stochastic search Algorithm, and the optimized geometries and their conformational energies (steric energies) have been calculated by the MM3 force field. The populations calculated from the conformational energies of the reaction intermediate leading to the (S)- or (R)-2-cyclohexen-1-ol were shown to be linearly well correlated with the experimentally reported enantiomer excess (% ee) values. The critical factors to control the enantioselectivity were investigated on the basis of the optimized structures of the reaction intermediate complexes. The MM3 force field approach was shown to be applicable to the theoretical evaluation of the enantioselectivity and be useful for designing a new functional chiral lithium amide reagent for the asymmetric synthesis.     

(2S)-2-Anilinomethylpyrrolidine: an efficient in situ recyclable chiral catalytic source for the borane-mediated asymmetric reduction of prochiral ketones in refluxing toluene

(2S)-2-Anilinomethylpyrrolidine was successfully utilized as a chiral catalytic source in the borane-mediated asymmetric reduction of prochiral ketones in refluxing toluene to provide the corresponding secondary alcohols with enantiomeric excesses up to 91%. The potential of (2S)-2-anilinomethylpyrrolidine as an in situ recyclable chiral catalytic source in the borane-mediated chiral reduction processes has also been demonstrated.     

Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (−)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.     

Creation of a stereoselective solid surface by self-assembly of a chiral metal complex onto a nano-thick clay film

A stereoselective solid surface has been created by the self-assembly of a chiral osmium complex, λ-[Os(phen)₃](ClO₄)₂ (phen=1,10-phenanthroline), onto a single layered clay film deposited on an indium tin oxide (ITO) electrode; the Os^II–Os^III redox couple mediates the electrochemical oxidation of chiral 1,1^′-2-binaphthol in a stereoselective way or the S-isomer is oxidized at 1.4 times higher rate than the R-isomer.     

Enantioselective Strecker-type reaction to sulfonylimines having a 2-pyridylsulfonyl group as a novel stereocontroller

A catalytic enantioselective Strecker-type reaction to N-(2-pyridylsulfonyl)imines in the presence of chiral bis(oxazoline)s afforded the products with a high enantioselectivity. A dynamically induced new chiral center on the sulfur by discriminative coordination of a chiral Lewis acid to one of the sulfonyl oxygens efficiently controlled the enantioselectivity.     

1-Arylethylamino-substituted s-triazine derivatives as chiral solvating agents for the determination of the enantiomeric composition of chiral compounds

The development of 2-[(R)-1-(9-anthryl)ethylamino]-4-chloro-6-methoxy-1,3,5-triazine, 2-[(R)-1-(9-anthryl)ethylamino]-4-chloro-6-[(R)-1-(1-naphthyl)ethylamino]-1,3,5-triazine and 2-[(R)-1-(9-anthryl)ethylamino]-4,6-bis-[(R)-1-(1-naphthyl)ethylamino]-1,3,5-triazine as chiral solvating agents (CSAs) for the determination of the enantiomeric composition of derivatized and underivatized chiral compounds is presented. The comparison between the efficiency of these chiral auxiliaries with the corresponding 1-(1-naphthyl)ethylamino substituted s-triazine derivatives is also discussed.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

Chiral diphenylthiophosphoramides: a new class of chiral ligands for the silver(I)-promoted enantioselective allylation of aldehydes

Chiral C₂-symmetric diphenylthiophosphoramides 1 and 2 were prepared in high yields from the reaction of diphenylthiophosphinic chloride with (1R,2R)-(−)-1,2-diaminocyclohexane and (1R,2R)-(+)-1,2-diphenylethylenediamine, respectively. Another novel chiral ligand 4 was prepared from reaction of diphenylthiophosphinic chloride with (R)-(+)-1,1′-binaphthyl-2,2′-diamine using butyllithium as a base. They were used as catalytic chiral ligands in the silver(I)-promoted enantioselective allylation reaction of aldehydes with allyltributyltin.     

Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl-1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1?R,2?R,4?S + 2R,1?R,2?R,4?S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.     

Chiral diphenylselenophosphoramides: a new class of chiral ligands for the titanium(IV) alkoxide-promoted addition of diethylzinc to aldehydes

Chiral C₂-symmetric diphenylselenophosphoramides 1 and 2 were prepared from the reaction of diphenylselenophosphinic chloride with (1R,2R)-(−)-1,2-diaminocyclohexane and (1R,2R)-(+)-1,2-diphenylethylenediamine, respectively, in high yields. Another novel chiral ligand 3 was prepared from the reaction of diphenylselenophosphinic chloride with (R)-(+)-1,1′-binaphthyl-2,2′-diamine using butyllithium as the base. The ligands were used as catalytic chiral ligands in the titanium(IV) alkoxide-promoted enantioselective addition reaction of diethylzinc to aldehydes.     

Enantioselective Mannich-type reaction of sulfonylimines having 2-pyridylsulfonyl group as a novel stereocontroller

A catalytic enantioselective Mannich-type reaction of N-(2-pyridylsulfonyl)imines in the presence of chiral bis(oxazoline)s afforded the products with high enantioselectivity. Asymmetric induction was supposed to be efficiently controlled by a new chiral center on the sulfur dynamically induced through the discriminative coordination of a chiral Lewis acid to one of the sulfonyl oxygens.     

Synthetic study of tetramethyljulolidine—a key intermediate toward the synthesis of the red dopant DCJTB for OLED applications

The formation and characterization of a novel chiral sulfonic acid derivative obtained during the synthesis of 1,1,7,7-tetramethyljulolidine (TMJ), a key intermediate towards the red dopant 4-(dicyanomethylene)-2-t-butyl-6-(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran (DCJTB) used for organic electroluminescent devices, upon bis-annulation of N,N-bis(4-methyl-2-butenyl)aniline is described.     

Chemoenzymatic synthesis and application of a new,easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.     

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.     

Asymmetric induction in the conjugate addition of thioacetic acid to methacrylamides with chiral auxiliaries

The conjugate addition of thioacetic acid to methacrylamides with chiral C₂-symmetric trans-2,5-disubstituted pyrrolidines afforded the addition products in excellent stereoselectivities (>99% de) and good yields (80–90%). The high selectivity was attributed mainly to the steric effect of the chiral auxiliaries. The cyclic nature of the chiral auxiliaries seemed also important for both the stereoselectivity and the reaction rate. Acidic hydrolysis of the adduct containing (2R,5R)-bis(methoxymethyl)pyrrolidine gave (S)-3-mercapto-2-methylpropanoic acid, a key intermediate for captopril, in 98% ee and 96% yield. The chiral auxiliary was recovered in the demethylated form of N-Boc-(2R,3R)-bis(hydroxymethyl)pyrrolidine in 90% yield.     

Efficient construction of a chiral all-carbon quaternary center by asymmetric 1,4-addition and its application to total synthesis of (+)-bakuchiol

The conjugate addition of lithium divinylcuprate to (4S,2′E)-3-(6′-TBDPS-3′-methylhex-2′-enoyl)-4-phenyloxazolidin-2-one proceeded efficiently to create a chiral all-carbon quaternary center with a high diastereoselectivity (R:S = 95:5). The absolute configuration of the newly generated chiral center was confirmed by applying this methodology to the total synthesis of (+)-bakuchiol.     

Amino alcohol based chiral solvating agents: synthesis and applications in the NMR enantiodiscrimination of carboxylic acids

Four optically active amino alcohols were synthesized via the ring opening of (R)-N-(2,3-epoxypropyl)phthalimide with (R)-2-phenyl glycinol, (1R,2S)-cis-1-amino-2-indanol, (R)-2-amino-1-butanol and (S)-phenyl ethylamine in 73-93% yields. The enantioselective recognition of these receptors towards the enantiomers of racemic carboxylic acids was studied by ¹H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of the guests were determined by using Job plots and a non-linear least-squares fitting method, respectively. Large non-equivalent chemical shifts (up to 30.0 Hz) can be achieved in the presence of chiral amino alcohols 2 and 5. Amongst the chiral receptors used, compound 5 was found to be the best chiral shift reagent, and was effective in the determination of the enantiomeric excess of chiral carboxylic acids.     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

Development of a chiral host system tunable via changes in a 21-column packing structure

A tunable chiral host system was developed by the self-assembly of a chiral 2₁-column structure formed from (1R,2R)-1,2-diphenylethylenediamine and dicarboxylic acid. This host system can include guest molecules by changing the packing of a chiral 2₁-column enantioselectively.     

Some new protocols for the assignment of absolute configuration by NMR spectroscopy using chiral solvating agents and CDAs

The utility of enantiopure BINOL (1,10-Bi-2-naphthol), in a ternary ion-pair complex, which is obtained using a carboxylic acid and an organic base, as a versatile chiral solvating agent (CSA) has been demonstrated for chiral analysis and the absolute configuration assignment of hydroxy acids. Another protocol where the utility of NOBIN as a CSA has been developed for discrimination and absolute configuration assignment of acids, hydroxy acids and their derivatives with a distinct strategy where a third ingredient, p-toluenesulfonic acid (p-TsOH) serves as a linker. In addition some three component chiral derivatization protocols have been introduced, such as the use of 2-formylphenylboronic acid and enantiopure mandelic acid or a primary amine for the determination of the configuration of primary amines and hydroxy acids, respectively. A simple, rapid and highly efficient three component chiral derivatizing protocol has also been discussed which was developed for assigning the absolute configuration of chiral α-hydroxy acids and their derivatives, which involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and (S)-[1,1-binaphthalene]-2,2-diamine separately. In a few examples, the DFT based theoretical calculations have been carried out to determine the geometry optimized structures of the complexes.