Fluorination enantioselective

Purser S, Odell B, Claridge TDW, Moore PR, Gouvemeur V. Sequential desymmetrization fluorination enantioselective synthesis of fluorinated cychtols. Chem. Eur. J. 2006 12 9176-9185. 

Morpholinosulfur trifluoride is more thermally stable and therefore safer to handle than DAST and gives a slightly higher yield of the fluoride in the fluorination of cyclohexanol [95, ISO] Both solvent and conformational effects are pronounced in the fluorination of cyclohexanols [550] The chiral (S)-2-(methoxymethyl)pyr-rolidin-l-ylsulfur tnfluonde is an effective enantioselective fluorodehydroxylating agent [ISI]... 

Compounds lb and 2b were the Urst fluorinated ligands tested in Mn-catalyzed alkene epoxidation [5,6]. The biphasic Uquid system perfluorooc-tane/dichloromethane led to excellent activity and enantioselectivity (90% ee) in the epoxidation of indene with oxygen and pivalaldehyde (Scheme 1, Table 1). In addition, the fluorous solution of the catalyst was reused once and showed the same activity and selectivity. This represents a considerable improvement over the behavior in the homogeneous phase, where the used catalyst was bleached and reuse was impossible. Unfortunately, indene was the only suitable substrate for this system, which failed to epoxidize other alkenes (such as styrene or 1,2-dihydronaphthalene) with high enantioselectivity. The system was also strongly dependent on the oxidant and only 71% ee was obtained in the epoxidation of indene with mCPBA at - 50 °C. 

Rovis and co-workers have also extended the intermolecular Stetter reaction to inclnde nitroaUcenes as the electrophilic component. Fluorinated triazolinm precatalyst 155 was effective in catalysing the reaction of a variety of heteroaromatic aldehydes 153 with nitroalkenes 154 to generate P-nitroketones in excellent yields and enantioselectivities. The authors propose that stereoelectronically induced conformational effects on the catalyst skeleton are key to the high selectivities observed with flnorinated catalyst 155 (Scheme 12.33) [69],... 

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. 

A very impressive example of the synthetic utility of this chemistry is the one-pot enantioselective double G-H activation reaction of 86 to generate chiral spiran 87 (Equation (73)).172 In this case, the phthalimide catalyst Rh2(enantiotopically selective aromatic C-H insertions of diazo ketoesters (Equation (74)).216 Moreover, dirhodium(n) tetrakisIA-tetrafluorophthaloyl- )-/ /-leucinate], Rh2(hydrogen atoms of the parent dirhodium(n) complex are substituted by fluorine atoms, dramatically enhances the reactivity and enantioselectivity (up to 97% ee). Catalysis... 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

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). 

A series of fluorinated biaryl ketones (13) was reported by Denmark and coworkers in 1999 and 2002 (Fig. 4) [22, 40]. The introduction of fluorine atoms at the a-position of the reacting carbonyl increased the efficiency of the epoxidation. Fluorinated ketones 13b and 13c displayed high reactivity and good enantioselectivity... 

In 1998, Armstrong and coworkers reported tropinone-based fluorinated ketone 23a to give good enantioselectivities for several fran -olefms (Fig. 7) (Table 2, entries 1, 6) [48, 49]. The replacement of the fluorine atom with an acetate group... 

C. Lemaire, P. Damhaut, A. Plevenaux, D. Comar, Enantioselective synthesis of 6-[fluorine-18]fluoro-L-DOPA from no-carrier-added fluorine-18-fluoride, J. Nucl. Med. 35 (1994) 1996-2002. 

Catalytic enantioselective fluorination has recently emerged. Both organocatalysis and metal catalysis have been successfully developed. Chiral N-F reagents have been prepared or formed in situ starting form a chiral amine derivative and a classical N-F reagent vide supra)P These reagents allow the enantioselective fluorination of... 

Asymmetric electrophilic fluorination has already found application in medicinal chemistry. For example, the enantioselective synthesis of a fluorooxindole, Maxipost (BMS-204352), has been reported. This compound is an effector for opening calcium channels and is currently in development for the treatment of cerebral ischemia (Figure 2.5). ... 

---