Benzaldehyde, enantioselective additions

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. 

Kragl and Dreisbach (1996) have carried out the enantioselective addition of diethyl zinc to benzaldehyde in a continuous asymmetric membrane reactor using a homogeneous soluble catalyst, described in their paper. Here a,a-diphenyl-L-proline was used as a chiral ligand, coupled to a copolymer made from 2-hydroxy ethyl methacrylate and octadecyl methacrylate, which had a sufficiently high molecular weight to allow separation by ultra-filtration (U/F). The solvent-stable polyaramide U/F Hoechst Nadir UF PA20 retained more than 99.8% of the catalyst. The ee was 80 %, compared to 98 % for a noncoupled catalyst. 

On the other hand, sulfur-containing pyridine ligands have been prepared by Chelucci et al These ligands gave only moderate enantioselectivities (<51% ee) in the enantioselective addition of ZnEt2 to benzaldehyde, as shown in Scheme 3.17. 

Enantioselectivities ranging from 18 to 94% ee were obtained by Martens et al. by using C2-symmetric bis-p-amino alcohols derived from D-cysteine for the enantioselective addition of ZnEt2 to benzaldehyde (Scheme 3.27). ... 

The enantioselective addition of ZnEt2 to benzaldehyde was also performed in the presence of chiral 2,2-disubstituted thiaprolinol derivatives as ligands by Liu et al., providing the product with an enantioselectivity of up to 81% ee (Scheme 3.29). ... 

In 2008, Juaristi et al. developed the synthesis of a series of novel chiral thioureas that were further examined as possible ligands for the enantioselective addition of ZnEt2 to benzaldehyde." The expected carbinol was isolated in... 

In 1997, Chelucci et al. developed new chiral 2-(l-p-tolylsulfinyl)alk-ylpyridines and assessed these ligands in the enantioselective addition of ZnEt2 to benzaldehyde." This produced in all cases catalysts in good yields but with low enantioselectivities (< 19% ee). An examination of the results collected in Scheme 3.33 indicates that the enantioselectivity and the configuration of the resulting carbinol were independent of both the substituent and the configuration at the carbon centre. Therefore, this suggests that the stereochemical... 

In 2008, Rykowski et al. reported the synthesis of optically active 2,2 -bipyridine alkyl sulfoxides by asymmetric oxidation of their corresponding readily accessible 2,2 -bipyridine alkyl sulfides. These sulfoxides were further evaluated as ligands for the enantioselective addition of ZnEt2 to benzaldehyde, providing only low enantioselectivities of up to 14% ee (Scheme 3.34). 

In 2003, these authors developed the Ti-catalysed enantioselective addition of ZnEt2 to benzaldehyde in the presence of C2-symmetric bis(camphorsulfo-namides) ligands derived from achiral 1,2- and 1,3-diamines and ( + )-camphorsulfonic acid. These authors showed that the stereochemical outcome of the reaction was highly influenced both by the structure of the... 

On the other hand, several S/O ligands have been successfully applied to the enantioselective addition of ZnEt2 to aldehydes. As an example, Aral et al. have developed isoborneol-derived p-hydroxy-sulfide ligands and employed them in the enantioselective addition of ZnEt2 to benzaldehyde, providing enantio-selectivities of up to 88% ee (Scheme 3.54). These authors showed that the enantioselectivity of the reaction did not depend on the substituent of the sulfur atom. 

The latter effect has been demonstrated by Meijer et al., who attached chiral aminoalcohols to the peripheral NH2-groups of polypropylene imine) dendrimers of different generations [100]. In the enantioselective addition of diethyl-zinc to benzaldehyde (mediated by these aminoalcohol appendages) both the yields and the enantioselectivities decreased with increasing size of the dendrimer (Fig. 28). The catalyst obtained from the 5th-generation dendrimer carrying 64 aminoalcohol groups at its periphery showed almost no preference for one enantiomer over the other. This behavior coincides with the absence of measurable optical rotation as mentioned in Sect. 3 above. The loss of activity and selectivity was ascribed to multiple interactions on the surface which were... 

Fig. 28. Dependence of enantioselectivity from the number of generations or endgroups in the enantioselective addition of Et2Zn to benzaldehyde, using 0.02 equiv. amino alcohol equivalents in each case [100]...

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. 

Fig. 31. Selectivity comparison for the enantioselective addition of Et2Zn to benzaldehyde using different dendritic and non-dendritic homogeneous and heterogeneous Ti-TADDOLates as chiral catalysts [107,110], (S)-.(R) ratios refer to the 1-phenyl-propanol formed...

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. 

A symmetric activation is also observed in the combination of (/f)-BINOL and Zr(0 Bu)4, which promotes enantioselective synthesis of homoallylic alcohols (Scheme 8.13). A 2 1 ratio of (/ )-BINOL and Zr(0 Bu)4 without any other chiral source affords the homoallylic alcohol product in 27% ee and 44% yield. Addition of (7 )-(+)-a-methyl-2-naphthalenemethanol ((/ )-MNM) leads to higher enantiomeric excess (53% ee) than those using only (7 )-BINOL. Therefore, (7 )-MNM can act as a chiral activator a higher ee can be achieved via activation of the allylation of benzaldehyde by addition of (7 )-MNM as a product-like activator. 

Kragl 13) pioneered the use of membranes to recycle dendritic catalysts. Initially, he used soluble polymeric catalysts in a CFMR for the enantioselective addition of Et2Zn to benzaldehyde. The ligand a,a-diphenyl-(L)-prolinol was coupled to a copolymer prepared from 2-hydroxyethyl methyl acrylate and octadecyl methyl acrylate (molecular weight 96,000 Da). The polymer was retained with a retention factor > 0.998 when a polyaramide ultrafiltration membrane (Hoechst Nadir UF PA20) was used. The enantioselectivity obtained with the polymer-supported catalyst was lower than that obtained with the monomeric ligand (80% ee vs 97% ee), but the activity of the catalyst was similar to that of the monomeric catalyst. This result is in contrast to observations with catalysts in which the ligand was coupled to an insoluble support, which led to a 20% reduction of the catalytic activity. 

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). 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

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. 

The chiral ligands (32) and (33) have been used as catalysts in the enantioselective addition of Et2Zn to benzaldehyde.111 It has been observed that the presence of the cyclohexane core gave better enantioselection, presumably owing to a more rigid transition state for the addition reaction in the former ligand. 

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