Addition of Diethylzinc to Aldehydes

Reactions of diethylzinc with benzaldehyde and heptanal were carried out in the presence of a catalytic amount (5 mol%) of 8 or 9, in order to examine the effect of the substitution pattern (R, R ) of catalysts 8 or 9 on the enantioselectivity. Results are summarized in Table 3-2. The secondary amine 8a was catalytically less active and less enantioselective than tertiary amine catalysts (entry 1). Tertiary amines 9a, 9b and 9c afforded (S)-l-phenylpropanol by reaction with benzaldehyde 

In summary, the effect of the iV-alkyl and A-ferrocenyl alkyl substituents of 8 and 

Other iV,iV-disubstituted norephedrine catalysts such as iV-isopropylephedrine 

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Table 28. Addition of Diethylzinc to Aldehydes under Chiral Catalysis...

On the other hand, S/O ligands have been developed to a lesser extent, but their efficient use as chiral ligands was proven in the enantioselective addition of diethylzinc to aldehydes and also in the copper-catalysed asymmetric conjugate addition. 

In some cases, direct, uncatalyzed 1,2-addition of diethylzinc to aldehydes becomes a significant problem. Triethylsilane for intramolecular reactions or triethylborane for intermolecular reactions is often helpful to address this issue. 

Chiral quaternary ammonium salts in solid state have also been used as catalysts for the enantioselective addition of diethylzinc to aldehydes (Scheme 2-45).112 In most cases, homogeneous chiral catalysts afford higher enantio-selectivities than heterogeneous ones. Scheme 2-45 presents an unusual asymmetric reaction in which chiral catalysts in the solid state afford much higher enantioselectivities than its homogeneous counterpart.112... 

With the knowledge that the presence of Ti(OPr )4 promotes the alkylation of diethylzinc to benzaldehyde, Ho et al.118 demonstrated that the chiral tetra-dentate sulfonamide ligand 125 catalyzes the addition of diethylzinc to aldehyde in the presence of Ti(OPr )4 with good yield and enantioselectivity (Scheme 2-48). 

K. Soai, M. Watanabe, Chiral Quaternary Ammonium Salts as Solid State Catalysts for the Enantioselective Addition of Diethylzinc to Aldehydes , J. Chem Soc, Chern. Commun 1990, 43-44. 

The 1,2-addition of diethylzinc to aldehydes is a powerful method for C-C bond formation. As there is a wide variety of possible transition states, the reaction is very sensitive to changes in the ligand structure. For this reason the diethylzinc addition in Scheme 2.1.3.2 is a suitable test reaction for developing and establish-... 

Recently, dendrimers, which are hyperbranched macromolecules, were found to be an appropriate support for polymer catalysts, because chiral sites can be designed at the peripheral region of the dendrimers (Scheme 5). Seebach synthesized chiral dendrimer 14, which has TADDOLs on its periphery and used an efficient chiral ligand in the Ti(IV)-promoted enantioselective alkylation [21]. We developed chiral hyperbranched hydrocarbon chain 15 which has six p-ami-no alcohols [22], It catalyzes the enantioselective addition of diethylzinc to aldehydes. We also reported dendritic chiral catalysts with flexible carbosilane backbones [23]. 

Novel norephedrine-based chiral ligands with multiple stereogenic centers have been conveniently prepared from norephedrine and. -substituted pyrrole.112 These novel chiral ligands have been used to catalyse the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. 

The direct strong steric interaction between substrate substituents and ligand substituents has been demonstrated in asymmetric addition of diethylzinc to aldehydes catalysed by sterically congested ferrocenyl aziridino alcohol derivatives.114 In addi- tion, this non-bonded steric repulsion influenced enantioselectivities significantly, and even led to inversion of the absolute configuration. This fact was further confirmed by theoretical calculations and the design of a new chiral ferrocenyl aziridino alcohol ligand. 

Enantioselective addition of diethylzinc to aldehydes has been catalyzed by diastere-omeric monosubstituted [2.2]paracyclophane-based A,0-ligands.117 A remarkable cooperative effect of planar and central chiralities has been observed. 

Cyclic derivatives of 1,2- and 1,3-amino alcohols have been trialled as chiral catalysts in the addition of diethylzinc to benzaldehyde.229 Enantioselective addition of diethylzinc to benzaldehyde is the subject of other reports,230,231 including the use of triazinyl-BINOLs as enantioselective catalysts of addition to araldehydes, using Ti(IV) tetraisopropoxide.232 Two optically active amino thiocyanate derivatives (60) of (-)-norephedrine act as aprotic ligands for enantioselective addition of diethylzinc to aldehydes in up to 96% ee.233 The ee drops drastically if the -SCN group is changed to -SR. 

Synthesis of a series of iV-sulfonylated amino alcohols and their use as ligands of titanium(IV) in enantioselective addition of diethylzinc to aldehydes has been described.234... 

Optically active amino thiocyanate derivatives of (—)-norephedrine [e.g. (44)] have been found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes.115 This reaction has provided optically active secondary alcohols with ee up to 96%. 

Solvent-free enantioselective additions of diethylzinc to aldehydes and to N-diphenylphos-phinoylimines using /i-amino alcohols as chiral catalysts afforded chiral sec-alcohols and N-... 

The most fully understood system in this class of reactions, however, is the DAIB-catalyzed addition of diethylzinc to aldehydes, due to the very detailed mechanistic studies performed by Noyori et al.32-37 They were able to determine the structure of several intermediates involved in the reaction and established the kinetic law. Part of the catalytic cycle is depicted in Scheme 13. The origin of the asymmetric amplification lies in the formation of dimers of DAIB-zinc alkoxides. The heterochiral dimer is quite stable in the concentration range of the experiment (2 x 10 1 to 5 x 10 1 M in toluene for DAIB), whereas the homodimers are prone to dissociation and react further with diethylzinc to give a di-zinc complex that is the active species in the catalytic cycle. They react with benzaldehyde and give rise to the asymmetric transfer of the ethyl group. The final product, as a zinc alkoxide, does not interfere with the reaction (and hence there is no autoinduction), since it... 

D. The use of chiral oxazaborolidines as enantioselective catalysts for the reduction of prochiral ketones, imines, and oximes, the reduction of 2-pyranones to afford chiral biaryls, the addition of diethylzinc to aldehydes, the asymmetric hydroboration, the Diels-Alder reaction, and the aldol reaction has recently been reviewed.15b d The yield and enantioselectivity of reductions using stoichiometric or catalytic amounts of the oxazaborolidine-borane complex are equal to or greater than those obtained using the free oxazaborolidine.13 The above procedure demonstrates the catalytic use of the oxazaborolidine-borane complex for the enantioselective reduction of 1-indanone. The enantiomeric purity of the crude product is 97.8%. A... 

Figure 4. Synthesis of amino alcohols on a solid phase as potential ligands for the addition of diethylzinc to aldehydes.

Table 4. Asymmetric addition of diethylzinc to aldehydes in the presence of chiral ferrocenyl compounds...

Among DASF derivatives examined, the compound 32 prepared from the diselenide 2 and cyclohexene oxide was revealed to be the best catalyst for this addition, giving up to 94 % ee. It is noteworthy that the sulfur (33) and tellurium analogues (34) of 32 also catalyzed the reaction to afford the alcohol, but with lower enantioselectivity (52% and 46% ee, respectively). Related compounds 35 and 36 do not act at all as a catalyst for the reaction, indicating that the presence of both hydroxyl and dimethylamino groups in 32 are indispensable to act as an efficient asymmetric catalyst. Typical results of enantioselective addition of diethylzinc to aldehydes other than benzaldehyde catalyzed by 32 are also summarized in Table 4. 

Enantioselective Addition of Diethylzinc to Aldehydes. Oxazaborolidines derived from ephedrine have been used to catalyze the addition of Diethylzinc to aldehydes (eq 13). Both... 

Chiral amino alcohols can be prepared by reaction of chiral epoxides with amines. Enantiopure (25, 3.R)-2,3-epoxy-3-phenylpropanol anchored to Merrifield resin has been used for ring-opening with secondary amines in the presence of lithium perchlorate to afford polymer-supported chiral amino alcohols 47 (Eq. 18) [56], By analogy, (2i ,35)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-l,2-propanediol has been anchored to a 2-chlorotrityl chloride resin (48). Although this polymer had high catalytic activity in the enantioselective addition of diethylzinc to aldehydes, the selectivity of the corresponding monomeric catalyst was higher (97 % ee) in the same reaction. 

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