The synthesis of dendritic BINOL ligands and their applications in the enantioselective Lewis acid catalyzed addition of diethylzinc to aldehydes

Novel dendritic chiral BINOL ligands have been synthesized through coupling of MOM-protected 3,3′-dihydroxymethyl-binaphthol with Fréchet-type polyether benzyl bromide dendrons followed by deprotection of the MOM groups using TsOH. These dendritic chiral BINOL ligands were found to be effective in the enantioselective addition of diethylzinc to benzaldehyde both in the presence and absence of Ti(O-iso-Pr)₄. The enantioselectivity decreased with increasing generation in both cases. In the latter case, the dendritic chiral BINOL ligands showed much higher catalytic activity and enantioselectivity than BINOL.     

Novel Frechet-type dendritic BINOL ligands and their applications in Ti（IV） complex catalyzed asymmetric addition of diethylzinc to aldehydes

New Frechet-type dendritic BINOL ligands bearing several BINOL units at the periphery have been successfully synthesized. The （dendritic BINOL） Ti（IV） complexes were proved to be efficient catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes. Moreover, these ligands could be quantitatively recovered and reused at least five times without a loss of the yield and enantioselectivity.     

The synthesis of silica-supported chiral BINOL: Application in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes

Chiral BINOL was covalently anchored on two different pore sized mesoporous silica (SBA-15 (7.5 nm) and MCF (14 nm)). These heterogenized ligands were used in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes. High catalytic activity with excellent enantioselectivity (up to 94% ee) for secondary alcohols was achieved using MCF supported chiral BINOL under heterogeneous reaction conditions. Good to excellent enantioselectivity (ee, 68–91%) was also achieved with various small to bulkier aldehydes. The MCF supported catalyst was reused in multiple catalytic runs without loss of enantioselectivity.     

Synthesis of 3 or 3,3′-substituted BINOL ligands and their application in the asymmetric addition of diethylzinc to aromatic aldehydes

Three new substituted BINOL ligands (R)-3-[4,6-bis(dimethylamino)-1,3,5-triazin-2-yl]-1,1′-bi-2-naphthol (R)-1, (R)-3,3′-bis[4,6-bis(dimethylamino)-1,3,5-triazin-2-yl]-1,1′-bi-2-naphthol (R)-2 and 2,4-bis(2,2′-dihydroxy-1,1′-binaphthalen-3-yl)-6-(p-tolyl)-1,3,5-triazine (R,R)-3 have been obtained by directed ortho-lithiation or Suzuki cross-coupling process. Ligand (R)-1 shows improved catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes.     

Dramatic catalyst evolution in the asymmetric addition of diethylzinc to benzaldehyde

We have observed product ee's that begin at 20% at low reaction conversion and rise to 79% ee at the completion of the reaction in the asymmetric addition of alkyl groups to benzaldehyde. This rare behavior is attributed to autoinduction, in which the catalyst evolves by incorporation of the product. Based on this, we have been able to optimize the catalyst by variation of achiral, rather than enantiopure ligands.     

Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(−)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respectively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).     

Chiral tetrahedral complex catalyzing asymmetric addition of diethylzinc to benzaldehyde

The optical active alkyne-bridged Mo-Co heterometal complexes are synthesized by the chiral phase transfer catalyst (N-benzylcinchorin chloride) induced metal exchange reaction. The complex is used as catalyst to promote the asymmetric addition of diethylzinc to benzaldehyde. The ee value of the product alcohol is 5.7%, which illustrates the asymmetric induction of the tet-rahedral framework chirality in asymmetric catalysis reaction for the first time.     

Synthesis of modified H4-BINOL ligands and their applications in the asymmetric addition of diethylzinc to aromatic aldehydes

Two new ligands (S,S)-3-(1,1′-bi-2-naphthol-3-yl)-5,6,7,8-tetrahydro-1,1′-bi-2-naphthol [(S,S)-1] and (S)-3-(morpholin-4-ylmethyl)-H₄-BINOL [(S)-2] have been synthesized via Suzuki cross-coupling reaction and a Mannich-type reaction, respectively. In the presence of titanium tetraisopropoxide, 0.8 mol % of ligand (S,S)-1 catalyzed the asymmetric addition of diethylzinc to aromatic aldehydes in good yield and with high enantioselectivity.     

Enantioselective addition of diethylzinc to benzaldehyde in the presence of sulfur-containing pyridine ligands

Diastereomerically pure hydroxy and thiol derivatives of (5S,7S)-5,7-methane-6,6-dimethyl-2-phenyl-5,6,7,8-tetrahydroquinoline were prepared and assessed in the enantioselective addition of diethylzinc to benzaldehyde: enantioselectivities up to 62% were obtained.     

Synthesis of new enantiopure aminodiols and their use as ligands for the addition of diethylzinc to benzaldehyde

The synthesis of new enantiopure aminodiols through aminolytic ring opening of chiral epoxy alcohols derived from (+)-camphor and (−)-fenchone is described. The absolute configurations were determined by NMR methods. The aminodiols catalyzed the addition of diethylzinc to benzaldehyde in high yields and with enantioselectivities of up to 80%.     

Fructose derived pyridyl alcohol ligands: synthesis and application in the asymmetric diethylzinc addition to aldehydes

Easily available chiral ketones were employed for the synthesis of optically active pyridyl alcohols, which were applied in the asymmetric diethylzinc addition to aldehydes, up to 89.4% e. e. was obtained using D-fructose-derived pyridyl alcohol.     

Synthesis of the bifunctional BINOL ligands and their applications in the asymmetric additions to carbonyl compounds

Efficient one-step syntheses of the bifunctional BINOL and H₈BINOL ligands (S)-6 and (S)-8 have been developed from the reaction of BINOL and H₈BINOL with morpholinomethanol, respectively. The X-ray analyses of these compounds have revealed their structural similarity and difference. The bifunctional H₈BINOL (S)-8 is found to be highly enantioselective for the reaction of diphenylzinc with many aliphatic and aromatic aldehydes and especially is the most enantioselective catalyst for linear aliphatic aldehydes. Unlike other catalysts developed for the diphenylzinc addition which often require the addition of a significant amount of diethylzinc with cooling (or heating) the reaction mixture in order to achieve high enantioselectivity, using (S)-8 needs no additive and gives excellent results at room temperature. (S)-8 in combination with diethylzinc and Ti(OⁱPr)₄ can catalyze the highly enantioselective phenylacetylene addition to aromatic aldehydes. It can also promote the phenylacetylene addition to acetophenone at room temperature though the enantioselectivity is not very high yet. Without using Ti(OⁱPr)₄ and a Lewis base additive, (S)-8 in combination with diethylzinc can catalyze the reaction of methyl propiolate with an aldehyde to form the highly functional γ-hydroxy-α,β-acetylenic esters except that the enantioselectivity is low at this stage. The bifunctional BINOL ligand (S)-6 in combination with Me₂AlCl is found to be a highly enantioselective catalyst for the addition of TMSCN to both aromatic and aliphatic aldehydes.     

Ionic liquids incorporating camphorsulfonamide units for the Ti-promoted asymmetric diethylzinc addition to benzaldehyde

New hydrophobic ionic liquids containing chiral camphorsulfonamide units were used as chiral auxiliaries in the titanium catalyzed asymmetric diethylzinc addition to benzaldehyde. The ionic catalyst system shows catalytic properties similar to those of related nonionic counterparts in terms of activity and enantioselectivity. Interestingly, the ionic ligands can easily be recycled and re-used without loss of activity or selectivity.     

Stereoselective syntheses of pinane-based 1,3-diamines and their application as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde

A library of 1,3-difunctionalized pinane derivatives was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate β-lactam 2 was prepared regio- and stereoselectively from (?)-apopinene 1. The treatment of 2 with di-tert-butyl dicarbonate afforded N-Boc β-lactam 3, while acid-catalyzed ring opening of 2 resulted in amino acid 4. Nucleophilic ring opening of 3 with dimethylamine, followed by deprotection and benzylation, furnished β-amino amides 5, 8, and 11, which were transformed in two steps into the corresponding N-tosyldiamines 7, 10, and 13, respectively. Since the use of other amines, such as diethylamine, to study the influence of dialkyl substitution was unsuccessful, an alternative synthetic route was applied. Amidation of tosylated β-amino acid 14 furnished amides 15–25. Reduction of 15, 16, 19, 20, and 24 resulted in N-tosyl diamines 26–30. The β-amino amides and N-tosylated diamines were used as chiral ligands in the enantioselective alkylation of benzaldehyde with diethylzinc, resulting in (R)- and (S)-1-phenyl-1-propanol. The (R)-enantiomer was predominant except when 17, 22, 23, and 25 were used as ligands, in which case the opposite stereochemistry was observed. The best ee values (up to 83%) were obtained when 17, 20, 23, and 25 were used as catalysts.     

Convenient synthesis of a new class of chiral hydroxymethyldihydrooxazole ligands and their application in asymmetric addition of diethylzinc to aromatic aldehydes

A number of chiral hydroxymethyl-substituted dihydrooxazoles were synthesized from D-or L-mandelic acid and amino alcohols. The chiral ligands thus obtained were tested as catalyst in the asymmetric addition of diethylzinc to aromatic aldehydes, and the structure-activity relationship was studied. The addition products were characterized by an enantiomeric excess of up to 91%. Published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 4, pp. 564–568. The text was submitted by the authors in English.     

Synthesis of novel chiral oligopyridine derivative ligands for the enantioselective addition of diethylzinc to benzaldehyde

Several chiral dipyridine and dithiophene derived ligands have been prepared from readily available homochiral materials such as ethyl L-lactate and naproxene methyl ester, based on the dialkylation strategy using heterocyclic organometallic reagents. Each of these chiral ligands was used for the catalytic enantioselective addition of diethylzinc to benzaldehyde. The best result was obtained for 3: 70% ee was achieved. A plausible mechanism for this asymmetric induction is offered, based on X-ray crystallographic data.     

A facile synthesis of 3 or 3,3′-substituted binaphthols and their applications in the asymmetric addition of diethylzinc to aldehydes

By using a direct ortho-lithiation, the ligands (S)-3-methoxymethyl-1,1′-bi-2-naphthol [(S)-1], (S)-3,3′-bis(methoxymethyl)-1,1′-bi-2-naphthol [(S)-2], (S)-3-(quinolin-2-yl)-1,1′-bi-2-naphthol [(S)-3] and (S)-3,3′-bis(quinolin-2-yl)-1,1′-bi-2-naphthol [(S)-4] have been synthesized. (S)-1 and (S)-3 show moderate catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes.     

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C₂-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.