2,2-Difluoroaldehydes

This review describes the first catalytic asymmetric Mukaiyama-aldol reaction of fluorine-substituted ketene silyl acetals with aldehydes and the catalytic asymmetric He (nitroaldol) reaction of 2,2-difluoroaldehydes with nitromethane to provide the optically active aldols and nitroaldols, respectively, which must be versatile synthetic intermediates for the fluorinated protease inhibitors. 

Shibasaki and coworkers have developed lanthanoid-lithium-BINOL complexes (LLB catalysts) as efficient catalysts for the asymmetric nitroaldol (Henry) reaction (59-46). The heterobimetallic asymmetric catalysts effectively mediate the reaction of a variety of aldehydes with nitroalkanes to afford the corresponding desired nitroaldols with high enantioselectivity (Scheme 4). We examined the capability of the LLB complexes as asymmetric catalysts for the nitroaldol reaction of 2,2-difluoroaldehydes with nitromethane (47). 

In the lanthanoid-lithium-( )-BINOL-catalyzed nitroaldol reaction of 2,2-difluoroaldehydes, the nitronates were found to preferentially react on the Si face of the aldehydes. On the contrary, (/1)-LLB generdly causes attack with the Re facial selection as ahown in Figure 2 (39,40,42). Therefore, the enantiotopic face selection for 2,2-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. This stereoselectivity is identical with that of jS-oxaaldehydes, suggesting that fluorine atoms at the a position exert a significant influence on the enantioface selection. The fluorine atoms may coordinate with the rare earth or the lithium of LLB complexes. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Metcalf et al. (56) (Scheme 39) prepared difluorovinyl ethers (131) by base treatment of 130 and found that spontaneous rearrangement to the difluoroaldehyde (132) occurred under the reaction conditions. In similar fashion (Scheme 40) 133 was converted to 135 via the enol 134 (30). Alternatively, the enolate can also be trapped as the trimethylsilyl ether (137) prior to rearrangement (Scheme 41) (59). 

Asymmetric Nitroaldol Reaction of Various 2 -Difluoroaldehydes. The catalytic asymmetric nitroaldol reaction of several 2,2-cBfluoroaldehydes with nitromethane was carried out using 5 or 8 mol% of Sm-Li (/ )-6,6 -bis((triethylsilyl)ethynyl)-BINOL complex in THF at -40 C for 168 h to afford the correspon g nitroaldols in excellent-to-good optical yields as shown in Table VI 47). The highest enantioselectivity (95% ee) was obtained with 2-cyclohexyl-2,2-difluoroacetaldehyde (entry 5). 

Table VI. Asymmetric Nitroaldol Reaction of Various 2 -Difluoroaldehydes...

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