Enantioselective Ethylation Research Articles

Deciphering the mechanism behind efficient enantioselective ethylation with thiazolidine‐based amino alcohols

Taking advantage of the opposite chirality of two privileged starting materials, l‐cysteine and d‐penicillamine, a wide range of thiazolidine‐based amino alcohols was synthesized. l‐Cysteine derivatives were more efficient chiral inductors than the d‐penicillamine ones, with ee up to 92% in the enantioselective ethylation of benzaldehyde. The scope of the best catalyst was evaluated using several aromatic, heteroaromatic, and aliphatic aldehydes, providing excellent (S)‐enantioselectivities. Given the opposite chirality of the l‐cysteine and d‐penicillamine thiazolidines, it was expected that the use of one or the other type of derivative as ligand would allow the formation of opposite configurations of the alkylated product. However, whereas the l‐cysteine thiazolidines predominantly gave the (S) form of the alkylated product, the d‐penicillamine ones led to both configurations. The significant difference in the stereochemical outcome of this reaction when catalyzed by the two types of ligands prompted us to investigate the reasons behind such results. Extensive quantum chemical calculations were performed in order to identify the transition state structures by which the enantioselective ethylation of benzaldehyde in the presence of these type of amino alcohols can proceed. An alternative path for the rate‐determining step was also explored and found decisive for the rationalization of the experimental outcomes. It was observed that the type of ligand dictates the accessible reaction paths for the formation of the chiral product, which ultimately determine the balance between the two possible configurations.

Chiral thiazolidines in the enantioselective ethylation of aldehydes: An experimental and computational study

A library of new chiral thiazolidines was prepared starting from l-cysteine and d-penicillamine in a simple, one-step procedure. 2-Arylthiazolidines were obtained, as diastereoisomeric mixtures, with good yields and in short reaction times, through a new and greener procedure, using microwave irradiation. Their use as chiral ligands in the enantioselective ethylation of aromatic aldehydes was studied and optimized, originating good to excellent conversions and ee up to 94% in 6 h. A series of heteroaromatic and aliphatic substrates were also enantioselectively ethylated with success, with ee up to 77%. The distinct opposite chirality in l-cysteine and d-penicillamine makes the use of these ligands an interesting approach for obtaining both the (S) and (R) enantiomers of the chiral alcohols, compounds with potential applications in the area of fine chemistry. NMR studies were carried out using a diastereoisomeric mixture of thiazolidines, allowing the identification of the most stable structure. Computational studies confirmed this result and also gave important insight into the species involved in the catalytic cycle of the enantioselective alkylation.

Synthesis, characterization and aggregation properties of non-peripherally (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol substituted optically active zinc phthalocyanine and its catalytic application in enantioselective ethylation of aldehydes

The novel optically active zinc(II) phthalocyanine having four (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol 1 at non-peripheral positions has been synthesized in a condensation using optically active phthalonitrile 2, and characterized by 1H NMR, IR, UV–Vis, Circular Dichroism (CD) and HRMS-TOF spectral data. The spectral and aggregation properties of novel optically active zinc(II) phthalocyanine 3 were investigated. The aggregation behavior of phthalocyanine 3 was investigated at different concentrations in N,N-dimethylformamide and tetrahydrofuran. No aggregation behavior was observed in both solvents at concentrations between 10 × 10−6 and 2 × 10−6 mol dm−3. The applicability of these chiral ligands 1–3 was evaluated in the enantioselective diethyl zinc addition of aldehydes. The addition of diethylzinc to 2-methoxybenzaldehyde was achieved with excellent enantioselectivity (87% ee, 80% yield) under catalysis with (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol 1. At the same condition, optically active zinc(II) phthalocyanine 3 afforded the corresponding chiral secondary alcohol with the enantiomeric excess of 11%.

Synthesis of New Chiral Monosulfonamides Prepared from (11R,12R)-11,12-Diamino-9,10-dihydro-9,10-ethanoanthracene and their Use as Ligands for Asymmetric Catalysis

New chiral monosulfonamides …6-16 containing (11R,12R)-diamino-9,10-dihydro-9,10-ethanoanthracene as carbon skeleton were prepared. Compounds 6-12, 15 and 16 were used as optically active ligands in the enantioselective ethylation of benzaldehyde. Moreover, the monosulfonamides 6-10 were tested in the asymmetric transfer hydrogenation (ATH) of acetophenone with Rh(Cp*)L* complex.

Biosourced Ligands from Isosorbide for the Ethylation of Aldehydes or Alkynylation of Imines

Abstractβ‐Amino alcohol and diamine ligands were prepared from isosorbide as a chiral renewable resource. The efficiencies of these ligands were evaluated for the metal‐catalyzed enantioselective ethylation of aldehydes and the alkynylation of aldimines.

ChemInform Abstract: Novel Tridentate Ligands Derived from (+)‐Camphoric Acid for Enantioselective Ethylation of Aromatic Aldehydes.

Novel tridentate ligands were prepared from (+)-camphoric acid, using simple synthetic sequences. The synthesized ligands were used in enantioselective ethylations of benzaldehydes, showing enantioselectivities up to 92%, at room temperature. Extending the reaction to other aromatic aldehydes, very good results (almost quantitative yields and ee up to 97%, for m-anisaldehyde) were obtained. Structural features such as no substitution in the salicylaldehyde moiety of the Schiff base and an ethyl group in the nitrogen at the C1 position of the cyclopentane ring seem to be essential for obtaining high enantioselectivities.

ChemInform Abstract: A New Class of C2 Chiral Photodimer Ligands for Catalytic Enantioselective Diethylzinc Addition to Arylaldehydes.

A new class of C2 chiral materials was easily prepared by the photodimerization reaction of (R)-N-phenethyl-2-chromonecarboxamide followed by recrystallization. Reduction of the photodimer gave the corresponding alcohol stereoselectively. Both C2 chiral materials worked effectively as ligands for enantioselective ethylation of arylaldehydes using diethylzinc.

Novel tridentate ligands derived from (+)-camphoric acid for enantioselective ethylation of aromatic aldehydes

Novel tridentate ligands were prepared from (+)-camphoric acid, using simple synthetic sequences. The synthesized ligands were used in enantioselective ethylations of benzaldehydes, showing enantioselectivities up to 92%, at room temperature. Extending the reaction to other aromatic aldehydes, very good results (almost quantitative yields and ee up to 97%, for m-anisaldehyde) were obtained. Structural features such as no substitution in the salicylaldehyde moiety of the Schiff base and an ethyl group in the nitrogen at the C1 position of the cyclopentane ring seem to be essential for obtaining high enantioselectivities.

A new class of C2 chiral photodimer ligands for catalytic enantioselective diethylzinc addition to arylaldehydes

A new class of C2 chiral materials was easily prepared by the photodimerization reaction of (R)-N-phenethyl-2-chromonecarboxamide followed by recrystallization. Reduction of the photodimer gave the corresponding alcohol stereoselectively. Both C2 chiral materials worked effectively as ligands for enantioselective ethylation of arylaldehydes using diethylzinc.

The first catalytic asymmetric addition of diethylzinc to aldehyde promoted by chiral thiourea

Abstract A series of C 2 -symmetric and asymmetric chiral thiourea derivatives were synthesized from commercial l -phenylalanine. All of the new compounds have been fully characterized by IR, 1 H NMR, 13 C NMR, MS spectra and elemental analyses. The chiral thioureas were used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc, the corresponding sec-alcohols were gained with excellent enantioselectivities (up to 87.1% ee ) and high yields (up to 76.7%) after the conditions were optimized.

ChemInform Abstract: Synthesis of Sterically Constrained Tricyclic Pyrrolidinyl Alcohol Ligands for the Enantioselective Ethylation of Aryl Aldehydes: Assessment of the Influence of Ring Strain and N‐Alkyl Chain Length on Asymmetric Induction.

AbstractNovel tricyclic pyrrolidinyl alcohol ligands are synthesized and applied in the enantioselective ethylation of aldehydes.

Synthesis of sterically constrained tricyclic pyrrolidinyl alcohol ligands for the enantioselective ethylation of aryl aldehydes: assessment of the influence of ring strain and N-alkyl chain length on asymmetric induction

A series of chiral sterically constrained tricyclic pyrrolidinyl alcohol ligands were synthesized from the appropriate amino acids, and a comparative study of the activity and selectivity of the ligands for the enantioselective ethylation of aromatic aldehydes was carried out. The results obtained were compared with those previously reported for related monocyclic analogues; it was found that the bicyclo[2.2.2]octane backbone fused to pyrrolidine and the groups attached to the carbinol centre, as well as the chain length of the β-amino alcohol, had a marked effect on the enantioselectivity. The enantioselective addition of dialkylzincs to aryl aldehydes in the presence of ligands with diethyl substituents on the carbinol carbon afforded ( R)- sec-alcohols in up to 99% enantiomeric excess (ee).

ChemInform Abstract: Ketopinic Acid Derived Bis(hydroxy amides) as Cheap, Chiral Ligands for the Enantioselective Ethylation of Aromatic Aldehydes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Enantioselective Ethylation of Aldehydes with 1,3‐N‐Donor Ligands Derived from (+)‐Camphoric Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantioselective ethylation of aromatic aldehydes catalysed by titanium(IV)– bis-BINOLate-2′,2″-propylether complexes: An inside view of the catalytic active species

A series of bis-BINOL-2′,2″-propyl ethers with different substituents at the propyl ether bridge, were investigated in the asymmetric titanium catalysed ethylation of arylaldehydes with Et 2Zn, with conversions up to 99% and enantiomeric excesses up to 80%. Semiempirical PM6 calculations indicate that the higher ability of the unsubstituted ligand to form chelated titanium complexes could be related to its higher enantioselectivity. Catalytic experiments with partially optically enriched ligand put in evidence a negative non-linear effect (−)-NLE that suggest the presence of two ligand molecule in the active titanium species. Further catalytic data, together with 1H NMR and circular dichroism (CD) titrations of the ligand with Ti( iPrO) 4, as well as ESI-MS experiments, allow to propose a trinuclear species [Ti 3L 2(O i Pr) 8] (L = dianion of (1 R,1′ R)-2′,2″-(propane-1,3-diyl) bis(oxy)di-1,1′-binaphthyl-2-ol) as responsible for the catalytic asymmetric addition of Et 2Zn to aldehydes. This catalytic species is only formed with great Ti(O i Pr) 4/ligand molar ratios ( ca. 8).

Highly Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Novel Chiral tert-Amino Alcohols

A series of novel chiral tert-amino alcohols 4a-h derived from enantiomerically pure phenylalanine were synthesized efficiently and used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc (diethylzinc-to-aldehyde addition). The use of 10 mol % of the amino alcohols led to the corresponding sec-alcohols with excellent enantioselectivities (up to 100% ee) and high yields.

Ketopinic Acid Derived Bis(hydroxy amides) as Cheap, Chiral Ligands for the Enantioselective Ethylation of Aromatic Aldehydes

AbstractReadily accessible, C2‐ and pseudo‐C2‐symmetric bis(hydroxy amides), derived from commercially available (+)‐ketopinic acid and protic diamines, are promising, cheap, chiral ligands for the synthetically valuable, enantioselective addition of organozinc reagents to carbon electrophiles. A series of ligands of this type, having key structural differences, has been synthesized and tested in the enantioselective ethylation of benzaldehydes and (E)‐cinnamaldehyde, in order to gain information on the origin of ligand efficiency. The results obtained allow for the definition of a privileged structural pattern for the design of improved cheap ligands and support interesting models proposed for both the acting catalytic species and the controlling transition states. The most efficient ligands proved to be less efficient than commercially available (–)‐MIB; nevertheless, an impressive efficiency level was obtained, which should sustain interest in this cheap type of ligands.

Enantioselective ethylation of aldehydes with 1,3- N-donor ligands derived from (+)-camphoric acid

Derivatives of (+)-camphoric acid were prepared by a short and simple synthetic sequence and proved to be excellent ligands for the enantioselective ethylation of benzaldehyde with diethylzinc, with ees of up to 96% being obtained. The most efficient ligand was tested with several aromatic aldehydes and ees of up to 99% were observed. Structural features of the ligands are determinant for achieving high enantioselectivities.

Chiral amide from (1 S,2 R)-(+)-norephedrine alkaloid in the enantioselective addition of diethylzinc to aryl and heteroaryl aldehydes

Chiral amide synthesized from (1 S,2 R)-(+)-norephedrine and furoic acid was found to catalyze the enantioselective ethylation of aromatic and heteroaromatic aldehydes to secondary alcohols with 99.8% enantioselectivity at 0 °C without the addition of a promoter such as titanium tetraisopropoxide.

Addition of Nucleophiles to Ketones with Polymer-Supported Sulfonamide

Polymer-supported chiral disulfon-amide 3 was prepared by mixing of compound 1 and polymer 2 in the presence of AIBN in THF. The polymer-supported chiral disulfonamide 3 assisted the enantioselective ethylation of ketones with Et2Zn in the presence of Ti(Oi-Pr)4 to give the corresponding products (29-94% yield, up to >99% ee).