Benzaldehyde, enantioselective ethylation

In the presence of a catalytic amount of a chiral P-amino alcohol, the enantioselective ethylation of benzaldehyde with diethylzinc affords enantiomerically en-... 

An efficient protocol for the diastereoselective synthesis of oxazolidine 35 has been established based on the three-component reaction involving imine 33, benzaldehyde and ethyl diazoacetate [75,76]. The oxazolidine 35 obtained by this methodology was applied to a short enantioselective synthesis of the C-13 side chain of taxol 38 (Scheme 11). 

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. 

As reported by Griengl and coworkers, benzaldehyde, decanal, undecanal, and dodecanal were reacted with HCN in a two-phase solvent system aqueous buffer and ionic liquids 1 -ethyl-3-methylimidazolium tetrafluoroborate, 1 -methyl-3-propylimidazolium tetrafluoroborate, and l-butyl-3-methyl-imidazolium tetrafluoroborate in the presence of the HNLs from Prunus amygdalus and Hevea brasiliensis. When compared with the use of organic solvents as the nonaqueous phase, the reaction rate was significantly increased and the enantioselectivity remained good [51]. 

Amplification of Chirality. Perhaps the most striking of the nonclas-sical aspects that emerge from the enantioselective alkylation is the phenomenon illustrated in Scheme 22 (3, 14, 16, 20k, 40). A prominent nonlinear relation that allows for catalytic chiral amplification exists between the enantiomeric purity of the chiral auxiliary and the enantiomeric purity of the methylation or ethylation product (Scheme 23). Typically, when benzaldehyde and diethylzinc react in the presence of 8 mol % of (-)-DAIB of only 15% ee [(-) (+) = 57.5 42.5], the S ethylation product is obtained in 95% ee. This enantiomeric excess is close to that obtained with enantiomerically pure (—)-DAIB (98%). Evidently, chiral and achiral catalyst systems compete in the same reaction. The extent of the chiral amplification is influenced by many factors including the concentration of dialkylzincs, benzaldehyde, and chiral... 

All the chiral materials are efficient in the enantioselective transfer of an ethyl group to benzaldehyde. Their efficiency depend on the synthetic method and on the initial pore diameter of the support. 

Asymmetric ethylation of benzaldehyde was conducted in the presence of 5 mol% of the ferrocenylzinc complex 5 in toluene or hexane (Scheme 3-6). Results are listed in Table 3-1. The iodoferrocene 4a itself bearing a simple iV-methyl-aminoalcohol side chain showed poor catalytic effect (entry 1) however, by chelation with zinc metal enantioselectivity was doubled (entry 2). With (S)-prolinol derivatives 4b and 4d, 1-phenylpropanol with R configuration was formed (entries... 

The polyvinylferrocene-supported ephedrines 19a—e were applied as chiral catalysts to the asymmetric ethylation of benzaldehyde in a heterogeneous system (hexane, room temperature). A quantity of 5 mol% of total ephedrine unit per benzaldehyde was used and the effect of the content of ephedrine unit in the polymers on enantioselectivity was investigated (Table 3-3). All chiral polymers 19a —e afforded (S)-l-phenylpropanol. Chiral polymer 19c, containing 32.8 mol% ephedrine units. 

Recently, Chen has synthesized and resolved chiral suberyl carbenium ions and utilized these as catalysts for enantioselective Mukaiyama aldol addition reactions (Eq. (8.22)) [34]. Thus the reaction of the ethyl acetate-derived silyl ketene acetal with benzaldehyde in the presence of 10-20 mol% of catalyst afforded the corresponding adduct in 50% ee. The enantioselectivity of the process proved sensitive to the nature of the cation, consistent with observations previously highlighted by Denmark in related studies [35]. Although at the current level of development the selectivities are modest, the study documents a novel class of metal-free Lewis acidic agents. 

Sasai developed miceUe-derived polymer-supported catalysts for a variety of enantioselective reactions, including diethylzinc addition [18]. The surfactant monomer 20 having tetraethylene glycol chains formed micelles in water and, followed by copolymerization with styrene, gave the spherical polymer. A coupling reaction of the polymer with a BINOL derivative and deprotection of the methoxymethyl groups of the BINOL moiety afforded the desired chiral polymer 21, as shown in Scheme 3.5. The catalytic asymmetric ethylation of benzaldehyde was... 

Table 7. Enantioselectivity for the ethylation of benzaldehyde with chiral polymers 150...

The catalytic properties of these various crosslinked polymer-supported ephedrines have been tested in the asymmetric addition reaction of diethylzinc to benzaldehyde and the results are smnmarized in Table 10. The reactions were carried out either in toluene or hexane at 0°C or 20-23 °C. As it can be noticed in Table 10, the enantioselectivities were higher in toluene. Compared to linear polymers 153-155, lightiy crosslinked chiral polymers led to the best results in terms of yield and ee. The use of Amberlite XAD-4 and Polyhipe as support proved to be not efficient. It was assumed that probably for both supports the catalytic sites are more in the inner surfaces of the pores and that result in a high local concentration of aminoalcohol residue which lead to a significant site-site interaction. Chiral polymer 156a was also used in the asymmetric ethylation of 2-methoxybenzaldehyde and 4-chlorobenzaldehyde imder similar conditions and ees reached 90-93% when the reaction was performed at 0°C. 

---