The synthesis of dendritic BINOL ligands and their applications in the asymmetric addition of diethylzinc to benzaldehyde

The synthesis of Fréchet-type dendritic BINOL ligands is described. These dendritic BINOL ligands were found to be effective in the enantioselective addition of diethylzinc to benzaldehyde both in the presence and absence of Ti(O-i-Pr)₄. In the latter case, the novel dendritic chiral BINOL ligands showed slightly higher enantioselectivities than their monomeric analogue.     

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.     

Preparation of enantiopure 1,4-amino alcohols derived from [3]ferrocenophanes: use in the asymmetric addition of diethylzinc to benzaldehyde

A series of enantiopure 1,4-amino alcohols with a [3]ferrocenophane backbone have been synthesized. Candida rugosa lipases were used in a key step allowing the resolution of amino alcohol (1S,R_p)-1. Two other amino alcohols (1S,2S,R_p)-2 and (1S,2S,R_p)-3 were prepared starting from (1S,R_p)-1. The new ligands have been used in the asymmetric ethylation of benzaldehyde by diethylzinc and gave good catalytic properties. One of these ligands was particularly efficient, while the yield of the catalytic test reaction was near to 100% and the enantiomeric excess was about 80%. All the ligands directed the catalytic process towards the same (1R)-1-phenylpropanol.     

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 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.     

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.     

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%.     

Increased enantioselectivity in the addition of diethylzinc to benzaldehyde by the use of chiral ligands containing the alpha-phenylethylamino group in combination with achiral ligands

Chiral ligands (S,S)-1, (S,S)-2, (S,S)-3, (S)-4, (S)-5, (S,S)-6, (S,S)-7, and (S,S)-8 turned out to be effective promoters in the enantioselective addition of diethylzinc to benzaldehyde. Interestingly, diamine (S,S)-3 and amino alcohols (S)-5 and (S,S)-7 induce the preferential formation of carbinol (R)-10 (unlike stereoinduction) whereas amido analogues (S,S)-2, (S)-4, and (S,S)-6 favor (S)-10 (like stereoinduction). Molecular modeling at the semiempirical PM3 level provided a reasonable interpretation based on conformational effects in the corresponding transition structures. Combinations of chiral ligands 1-8 with an achiral, flexible ligand (9) gave rise to an activated catalytic system that resulted in faster and higher yielding reactions. Furthermore, substantial increases in the observed enantiomeric excesses of product 10 confirmed the relevant role of achiral bis(sulfonamide) 9 as activator and "chiral environment amplifier".     

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.     

N-Substituent effects on the diethylzinc addition to benzaldehyde catalysed by bicyclic 1,4-amino alcohols

Chiral enantiopure bicyclic 1,4-amino alcohols were synthesised by a new methodology that provided a common precursor, which was easily N-functionalised with a wide variety of substituents. The final compounds were used as chiral ligands in a model study of the enantioselective addition of diethyl zinc to benzaldehyde, aimed at understanding the influence of the N-substituent on both the rate and stereoselectivity of the reaction. This set of experiments also provided interesting insight into the non-catalysed addition that occurred by employing commercially available Et₂Zn solutions.     

New chiral amino-phosphite and phosphite-phosphoroamidite ligands for the copper-catalyzed asymmetric 1,4-addition of diethylzinc to cyclohexenone

We have designed a series of amino-phosphite and phosphite-phosphoroamidite ligands 1–6 derived from inexpensive d-(+)-xylose. These ligands were screened in the Cu-catalyzed asymmetric 1,4-addition of diethylzinc to cyclohexenone. High reaction rates (TOF >1200 h⁻¹) and moderate enantioselectivities (up to 63% e.e.) were obtained. The results showed that the configuration of the stereogenic carbon atom C(3) at the ligand backbone and the different substituents at the amino group had remarkable effects on the activity and enantioselectivity.     

New bis-steroidal axially chiral diols as ligands for the asymmetric addition of diethylzinc to aldehydes

New axially chiral steroidal binaphthols, prepared from estrone, were applied in the form of their Ti-alkoxides as catalysts for the addition of diethylzinc to aldehydes. The addition reactions proceeded with high yields and enantioselectivities up to 86%.     

Enantioselective addition of diethylzinc to benzaldehyde in the presence of ephedrine derivatives

Diethylzinc reacts with benzaldehyde derivatives to yield 1-aryl-1-propanols. In the presence of ephedrine and its derivatives an optical yield of up to 80% is obtained for reaction at room temperature without special precautions.     

Aminosubstituted tert-butylsulfinylferrocenes as a new family of chiral ligands: asymmetric addition of diethylzinc to aldehydes

A ready access to a new family of planar chiral ferrocenes, the (RFc,RS)-2-amino substituted 1-tert-butylsulfinylferrocenes, is described; in the case of the sulfonamide series enantioselectivities of up to 96% were obtained in the addition of Et2Zn to aromatic aldehydes.     

Hydroxyamides versus amino alcohols in the enantioselective addition of diethylzinc to benzaldehyde

Two series of structurally related enantiopure isoborneols (10-amino- and 10-amino-10-oxoisoborneols) have been obtained from ketopinic acid and compared as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde in the absence of Ti(O-i-Pr)₄. The results obtained (chemical yields and enantiomeric excesses) show that identical structural factors (functionalization grade and symmetry group) exert very different effects on both series. The observed differences have been rationalized on the basis of the coordination ability of each ligand type to form the corresponding reactive zinc-chelate catalyst.     

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.     

Polyoxygenated ketopinic-acid-derived γ-amino alcohols in the enantioselective diethylzinc addition to benzaldehyde

Three N,N-dialkylated γ-amino alcohols, specifically 10-(dialkylamino)isoborneols, with different grades of oxygenation in the nitrogen’s alkyl groups (alkoxyalkyl groups), have been obtained from commercial (+)-ketopinic acid and tested as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde, in order to evaluate the effect of polyoxygenation on the ligand’s catalytic activity. An interesting effect of the oxygen atoms on the ligand activity is observed. The observation is in agreement with two unique previous results on amino-acid-derived polyoxygenated β-amino alcohols. A noticeable dependence of the observed effect with the conformational flexibility of the polyoxygenated chains is also demonstrated. The effect is explained by a pincer role of the polyoxygenated dialkylamino moiety, activating and directing a diethylzinc molecule.     

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.