Difluoroketene silyl acetals

For the addition of difluoroketene silyl acetals, see Iseki K, Kuroki Y, Asada D, Taka-hashi M, Kishimoto S, Kobayashi Y (1997) Tetrahedron53 10271 Corey EJ, Cywin CL, Roper TD. (1992) Tetrahedron Lett 33 6907... 

Bioactive compounds that contain the difluoromethylene group adjacent to the carbonyl functionality have been the subject of increased research efforts in recent yearsf 59). The most widely utilized methods that have been employed to introduce this group into organic molecules have been (a) Reformatsky reaction of halodifluoroacetates (60-66) (b) elaboration of difluoroketene silyl acetals (67-69) (c) metal catalyzed addition of 3-bromo-3,3-difluoropropene to aldehydes and ketones (70) and (d) alkylation of CuCF2COOR(77). The modest yields associated with these methods prompted us to explore alternative methodology for the preparation of this useful building block. 

Only a few enantioselective approaches to optically active 2,2-difluoro-3-hjrdroxy esters, key S)mthetic interme ates for a variety of important chiral fluorinated molecules, have been reported. Braun et al and Andrds et al. have independently reported that the Reformatsky reagents generated from bromodifluoroacetates react with aromatic aldehydes in the presence of stoichiometric amounts of chiral amino alcohols such as iV-methylephediine to afford the corresponding desired aldols in good optical yields (22,23). However, these methods are not catalytic, and the decrease in quantity of the chiral ligands dramatically suppresses the enantioselectivity. Thus, we became very interested in developing an unprecedented catalytic asymmetric aidol reaction of difluoroketene silyl acetals promoted by chiral Lewis acids. 

Molecular Orbital Calculation of a Difluoroketene Silyl Acetal. In order to determine why the fluorinated acetals 1 and 2 are more mactive than the fluorine-free acetal 3 under the uncatalyzed conditions, the geometries of two model acetals were optimized using ab initio molecular orbital calcdations (RHF/6-31G basis set) (29). Fluorine-free acetal 4 has a planar structure where the silicon-oxygen bond is on the same plane with the carbon-carbon double bond. On the other hand, the silicon-oxygen bond in difluoroketene acetal 5 is out of the carbon-carbon double bond plane. This torsion of the silicon-oxygen bond in 5 seems to be ascribed to the +I5t effect of the fluorine atoms. 

Asymmetric Aldol Reaction of Difluoroketene Silyl Acetal 1 Catalyzed by Chiral Lewis Acids. We turned our attention to evaluating several chiral Lewis acid catalysts, which are known to be capable of serving as asymmetric catalysts in the aldol reaction of nonfluorinated ketene silyl acetals, for Ifaeir usefulness in the reaction of the difluoroketene acetal 1 with aldehydes. A couple of boron complexes, Masamune s catalyst 6 (55,56) and Kiyooka s catalyst 7 (57, 58), were found to be effective for our study. For Masamune s catalyst 6, the reaction was carried out by adding an aldehyde in nitroethane to a solution of the acetal 1 and the catalyst 6 in the same solvent over 3 h at -78 C with stining at fliat temperature for an additional hour prior to quenching. With Kiyooka s catalyst 7, an aldehyde in nitroethane was added to a solution of the acetal 1 and the catalyst 7 in nitroethane at -45 C for 5 min, followed by stirring at -45 C for 2 h (28,29), Nitroethane is the best medium for the enantioselectivity. 

Effects of Reaction Temperature on the Stereoselection during the Aldol Reaction with Difluoroketene Silyl Acetal 1. As shown in Table III, the enantioface selection for aldehydes depends on the reaction temperature during the aldol reaction... 

The uncatalyzed aldol reaction of highly reactive enoxysilanes such as enoxysilacyclobutanes has previoudy been reported to proceed through six-membeied cyclic transition states (32,55), and the torsional structure of the difluoroketene acetal 5 is considered to be more suitable for the uncatalyzed aldol reaction tfian the planar geometry of 4 because the acetal 5 has a geometrical similarity to the ketene acetal in die cyclic transition states. As mentioned above (Scheme 1), a 60 40 mixture of the syn- and anri-aldols was obtained at 40°C from the bromofluoroketene silyl acetal 2 (E/Z =62/38), suggesting that the uncatalyzed aldol reaction of the fluorine-substituted ketene acetals 1 and 2 proceeds preferentially through boat-like cyclic transition states. Denmark et aL proposed diat the boat-like transition states are extremely predominant in the uncatalyzed aldol reaction of enoxysilacyclobutanes and trichlorosilyl enolates (55,54). 

Figure 1 shows the NMR of a 1 1 mixture of the difluoroketene acetal 1 and the catalyst 6 in nitroethane-ds at -78 and -20 C (Iseki, K. Kuroki, Y. Kobayashi, Y., MEC Laboratory, Daikin Indushies, Ltd., unpublished data.). The appearance of new peaks at the higher temperature may suggest the formation of a boron enolate. A siniilar change was observ in the NMR of a 1 1 mixture of the bromofluoroketene acetal 2 and 6 (31). On the contrary, the NMR of a 1 1 mixture of c-labeled dimethylketene silyl acetal 3 in nitroethane-ds at -20 C provided almost the same spectrum as that at -78°C. 

Reactions with imines also occur under similar conditions leading to the formation of difluorinated /1-lactams [196,197]. Formally, this reaction corresponds to a [2+ 2]-cycloaddition across an imine there is also an isolated report of a difluoroketene reaction, shown in Eq. (63) [198]. Useful chemistry of a silyl difluoroketene acetal was reported recently Eq. (64) shows the efficient asymmetric reaction between this reactive carbon nucleophile and aldehydes catalysed by chiral Lewis acids [199]. 

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