Chiral ammonium fluoride

The quaternary ammonium salt 48 derived from (+)-ephedrine was utilized for the enantioselective addition of diethyl zinc to aldehydes.1421 The chiral ammonium fluorides 7 (R=4-CF3 or 2,4-(CF3)2, X=F) were also useful for the enantioselective trifluoro-methylation of aldehydes and ketones with moderate enantioselectivity,1431 shown in Scheme 17... 

M. D. Drew, N. J. Lawrence, W. Watson, S. A. Bowles, The Asymmetric Reduction of Ketones Using Chiral Ammonium Fluoride Salts and Silanes , Tetrahedron Lett. 1997, 38, 5857-5860. 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

Campagne and Bluet recently reported the catalytic asymmetric vinylogous Mukaiyama aldol (CAVM) reaction of aldehydes with dienol silyl ether 15 using chiral ammonium fluorides as an activator. For example, the CAVM reaction of isobutyr-aldehyde with 15 in the presence of 10 mol% of 4b in THF at room temperature led to the formation of the vinylogous aldol product 16 in 70% yield with 20% ee. The ee-value was improved to 30% by conducting the reaction at 0 °C (Scheme 9.6) [16]. 

The asymmetric synthesis of the C(2) diastereomer of amprenavir was also accomplished, similarly starting from N-tert-butoxycarbonyl-(S)-phenylalaninal (19), where the requisite chiral ammonium fluoride 4e was generated in situ from the corresponding bromide 3e in the initial nitro aldol process (Scheme 9.8) [18]. 

The hydrosilylation of carbonyl compounds with polymethylhydrosiloxane (PMHS) or other alkoxysilanes can be catalyzed by TBAF, at high efficiency [9]. The asymmetric version of this process has been developed by Lawrence and coworkers using chiral ammonium fluoride 7c prepared via the method of Shioiri [10]. The reduction of acetophenone was performed with trimethoxysilane (1.5 equiv.) and 7c (10 mol%) in THF at room temperature, yielding phenethyl alcohol quantitatively with 51% ee (R) (Scheme 4.6). A slightly higher enantioselectivity was observed in the reduction of propiophenone. When tris(trimethylsiloxy)silane was used as a hydride source, the enantioselectivity was increased, though a pro-... 

Figure 14.3a summarizes representative chiral ammonium fluoride and bifluoride catalysts. These catalysts have been applied to various asymmetric transformations with different silyl nucleophiles (Figure 14.3b) [26-29]. 

I 74 Chiral Onium Salts (Phase-Transfer Reactions) (a) Chiral Ammonium Fluorides... 

Figure 14.3 (a) Representative chiral ammonium fluoride and bifluoride catalysts (b) silyl nucleophiles. 

Although the reaction is usually conducted under homogeneous conditions, a chiral ammonium fluoride-catalyzed trifluoromethylation of carbonyl compounds should be described in this section. The catalytic asymmetric trifluoromethylation of an acetophenone derivative with Ruppert s reagent was investigated by a research group of Pfizer for process research and development of a substance-P (neuro-kini-1) receptor antagonist CJ-17,493 149 (Scheme 4.35). ° The commercially available alcohol 150 was acylated to... 

Recently, Levacher and co-workers reported on the total synthesis of two natural homoisoflavones using their asymmetric protonation protocol as a key step. Their concept focused on the use of chiral ammonium fluoride as a chiral ion pair to generate a naked enolate or a hypervalent silicate species, which might be trapped in an asymmetric concerted fashion by the proton coming from the chiral counter anion (Figure 31.1). 

Scheme 31.17). Indeed, the first esterification step between an acid fluoride and ethanol in the presence of a substoichiometric amount of a chiral amine delivers at will the chiral ammonium fluoride, which is then engaged in the protonation step. 

Reduction with Chiral Ammonium Fluoride Salts as Activators... 

Drew and Lawrence used the chiral ammonium fluoride salt 14 to activate polymethylhydrosiloxane (PMHS) and triethoxysilane, whereby the latter proved superior and was subsequently used to reduce prochiral ketones in excellent yields but only moderate enantioselectivities (Scheme 32.11). ... 

Drew M. The asymmetric reduction of ketones using chiral ammonium fluoride salts and silanes. Tetrahedron Lett. 1997 38 5857 5860. 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

Scheme 8-42. Asymmetric trifluoromethylation of carbonyl compounds by chiral quaternary ammonium fluorides.

The first promising asymmetric aldol reactions through phase transfer mode will be the coupling of silyl enol ethers with aldehydes utilizing chiral non-racemic quaternary ammonium fluorides,1371 a chiral version of tetra-n-butylammonium fluoride (TBAF). Various ammonium and phosphonium catalysts were tried138391 in the reaction of the silyl enol ether 41 of 2-methyl-l-tetralone with benzaldehyde, and the best result was obtained by use of the ammonium fluoride 7 (R=H, X=F) derived from cinchonine,1371 as shown in Scheme 14. 

A. Ando, T. Miura, T. Tatematsu, T. Shioiri, Chiral Quaternary Ammonium Fluoride. A New Reagent for Catalytic Asymmetric Adol Reactions , Tetrahedron Lett. 1993, 34,1507-1510. 

K. Iseki, T. Nagai, Y. Kobayashi, Asymmetric Trifluoro-methylation of Aldehydes and Ketones with Trifluoro-methyltrimethylsilane Catalyzed by Chiral Quaternary Ammonium Fluorides , Tetrahedron Lett. 1994, 35, 3137-3138. 

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. 

Chiral Quaternary Ammonium Fluorides for Asymmetric Synthesis... 

In-Situ Generation of Chiral Quaternary Ammonium Fluorides... 

In 1978, Wynberg and coworkers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone (Scheme 9.1) [3]. The reaction was performed in toluene at 20 °C with 10mol% of chiral ammonium salt 1 or 3a and excess potassium fluoride (KF, 15 equiv.), yielding the y-nitro ketone with 10-23% enantiomeric excess (ee). The requisite chiral... 

The usefulness of the present system was then demonstrated by its application to the in-situ generation of structurally rigid, C2-symmetric chiral quaternary ammonium fluorides of type 6 (X = F) from the corresponding hydrogen sulfate 6 (X = H S04), and their direct use for the asymmetric aldol reactions (Scheme 9.3). For instance,... 

Further application of the in-situ generation of chiral quaternary ammonium fluorides from the corresponding hydrogen sulfates has also been shown in the facile preparation of optically active esters via the alkylative kinetic resolution of secondary alkyl halides. For example, simple stirring of the mixture of 3-phenylpropionic acid, l-(l-bromoethyl)naphthalene, (S,S)-6b (X = HS04 2 mol%) and KF-2H20 (5 equiv.)... 

Table 9.1 Asymmetric Mukaiyama-type aldol reactions of a glycine derivative catalyzed by in situ-generated chiral quaternary ammonium fluoride.

Chiral Quaternary Ammonium Fluorides Preparation and Application to Organocatalytic Asymmetric Reactions... 

Corey and Zhang utilized chiral quaternary ammonium fluoride 4d possessing a 9-anthracenylmethyl group on nitrogen for the face-selective nitroaldol reaction of nitromethane with protected (S)-phenylalaninal. This was directed toward the... 

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