Benzaldehyde, enantioselective addition diethylzinc

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

Attached to the periphery of a lst-generation dendrimer, Ti(OCHMe2)2-com-plexes of the six TADDOL moieties in 84 catalyze - in homogeneous solution -the enantioselective addition of diethylzinc to benzaldehyde with about the same selectivity ((S) (R) 97 3) as do six monomeric TADDOL units [105],but, with a molecular weight of only 3833 Da, dendrimer 84 had to be separated by column chromatography rather than by ultrafiltration methods. 

Figure 9 Supported Ti-TADDOLate catalyst for enantioselective addition of diethylzinc to benzaldehyde...

Scheme 2-49. TADDOL and its analogs as titanium ligands in enantioselective addition of diethylzinc reagents to benzaldehyde.

Enantioselective addition of R2Zn to aldehydes. Corey and Hannon2 have prepared the diamino benzylic alcohol 1 from (S)-proline and (lS,2R)-( + )-ephed-rine and report that the chelated lithium salt of 1 is an effective catalyst for enantioselective addition of diethylzinc to aromatic aldehydes. Thus benzaldehyde can be converted into (S)-( - )-3 with 95% ee, via an intermediate tridentate lithium complex such as 2 formed from 1. Similar reactions, but catalyzed by diastereomers of 1, show that the chirality of addition of dialkylzincs to aldehydes is controlled by the chirality of the benzylic alcohol center of 1. 

DOLate was formed which was tested in the Lewis acid catalyzed enantioselective addition of diethylzinc to benzaldehyde. The authors note that the catalyst can be recovered by simple filtration and was active for at least more than twenty runs (refer also to Section 4.2.3) [102]. 

Enantioselective addition of diethylzinc to benzaldehyde has been promoted by indole-containing chiral oxazolidines (which are able to use both O and N atoms to effect metal coordination in the transition state), and by chiral o-hydroxyphenyl diaza-phospholidine oxide,and by chiral aziridino alcohols.Enantioselective addition of dialkylzinc to prostereogenic ketones has been promoted using chiral camphorsul-fonamide derivatives. 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

A series of chiral (3i ,5 RHlihvdroxypiperidine derivatives have been conveniently prepared from trans -4-hvdrox v- r.-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. 

A study of enantioselective additions of diethylzinc to benzaldehyde, using chiral carboline and oxazolidine auxiliaries, has examined the requirements to allow the conformations of the free ligands to be related to the ees and transition states, given that several steps intervene.228... 

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. 

As the nucleophilicity of dialkylzinc is accelerated by the presence of (3 amino-alcohol, diethylzinc adds to benzaldehyde to afford 1-phenylpropanol.2 Several duraTfS-aminoalcohols 1-7 have been proven to be highly enantioselective catalysts for the addition of primary dialkylzincs mostly to aromatic aldehydes. For example, 1-phenylpropanol is prepared with high ee from the enantioselective addition of diethylzinc to benzaldehyde using 1-7 (Fig. 12.1, the ee and configuration of prepared 1-phenylpropanol are shown in parentheses).3 8... 

Enantioselective addition of diethylzinc to benzaldehyde catalysed by titanium-TADDOLate (Structure 16)13... 

In this work, the synthesis of high surface densities of chlororopropyl groups covalently grafted on mesoporous micelle templated aluminosilicates (Al-MTS) of various initial pore diameters is presented. The hybrid chiral materials resulting from halogen substitution are applied in the enantioselective addition of diethylzinc to benzaldehyde. 

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. 

Catalytic Enantioselective Addition of Dialkylzincs to Aldehydes. DPMPM (1) is a chiral amino alcohol which is a precursor to a chiral catalyst for the enantioselective addition of dialkylzincs to aldehydes. In the presence of 2 mol % of (.S)-(l), optically active alcohols of up to 100% ee are obtained from the enantioselective addition of dialkylzincs to aldehydes (eq 1, Table 1). When benzaldehyde is allowed to react with Diethylzinc using (5)-(l) (2 mol %), (5)-l-phenylpropan-l-ol with 97% ee is obtained in quantitative yield (entry 1). When the lithium alkoxide of (5)-(l) (5 mol %) is employed as a chiral ligand in the addition to aromatic aldehydes, ee s of the alcohols obtained increase... 

Enantioselective Addition of Dialkylzincs to Aldehydes Using Chiral Amino Alcohols Derived from Ephedrine. Nucleophilic addition of dialkylzinc to aldehydes is usually very slow. Amino alcohols facilitate the addition of Diethylzinc to benzalde-hyde to afford l-phenylpropanol. When chiral amino alcohols possessing the appropriate stracture are used as a precatalyst, optically active secondary alcohols are obtained. Highly enantioselective chiral catalysts derived from ephedrine are known. (lR,25)-N-Isopropylephedrine functions as a precatalyst for the enantioselective addition of diethylzinc to benzaldehyde to afford (R)-l-phenylpropanol with 80% ee in 72% yield. The use of an excess amount of diethylzinc increases the enantioselectivity up to 97% ee (eq 17). ... 

Hyperbranched and dendritic macromolecules have recently been the subject of considerable interest. Bolm developed chiral hyperbranched macromolecules 57 that catalyzed the enantioselective addition of diethylzinc to benzaldehyde [75]. The enan-tiocontrol of the hyperbranched chiral catalysts was slightly lower than for the low-molecular-weight catalyst. TADDOLs linked with dendritic molecules have been synthesized [59]. For example, use of the first generation dendrimer 58 with six terminal TADDOL units resulted in high enantioselectivity. 

As for the reduction of the ketones, the amphoteric catalysts featuring acidic-basic sites have been found to be very effective for the enantioselective catalysis of C-C bond formation. Thus, Soai et al. were the first to report the enantioselective addition of dialkylzincs to aldehydes using enantiomerically pure phosphin-amides and analogues as chiral catalysts in the presence of titanium tetraiso-propoxide. Numerous chiral organophosphorus compounds have been prepared and applied in a test reaction between benzaldehyde and diethylzinc [48, 49]. An important difference in terms of enantioselectivity was observed between the behavior of P=S (47-48) and P=0 (49) groups. Thus, the enan-... 

Based on this concept, Seebach et al. developed the first example of TADDOL-cored dendrimers (Figure 4.41) immobilized in a PS matrix [116]. The resultant internally dendrimer-functionalized polymer beads were loaded with Ti(OiPr)4, leading to a new class of supported Ti-TADDOLate catalysts for the enantioselective addition of diethylzinc to benzaldehyde. Compared to the conventional insoluble polymer-supported Ti-TADDOLate catalysts, these heterogeneous dendrimer catalysts gave much higher catalytic activities, with turnover rates close to those of the soluble analogues. The polymer-supported dendrimer TADDOLs were recovered by simple phase separation and reused for at least 20 runs, with similar catalytic efficiency. 

Using optically active epoxides, chiral N-alkylated pyrazole and imidazole derivative ligands have been prepared by high pressure reactions with 103 or 104 their catalytic efficiency as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde has been tested. 

The synthesis and characterization of a chiral amino-alcohol ((1R-2S)-ephedrine) immobilized on MCM-41 type mesoporous silicas (MTS Micelle Template Silicas) are described. The activity of these supported catalysts in the enantioselective addition of diethylzinc to benzaldehyde are reported, and compared with those obtained with the corresponding silica gel supported catalysts. The observed differences are discussed in terms of the nature of the grafting which depends on the support structure. 

The two families of solids have been tested in the enantioselective addition of diethylzinc to benzaldehyde leading to the (R)-l-phenyl-propan-l-ol according to scheme 4 ... 

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