Fluorinated aldehydes asymmetric

Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes. The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1). In some cases oxidation rather than fluorination occurred. Stereospecifically deuterium-labelled allylic isoprenoid diphosphates, e.g. (1), have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and Sn2 displacement with pyrophosphate (Scheme 2). ... 

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. 

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). 

Although efficient organocatalytic methods for the electrophilic a-fluorination of aldehydes and ketones have recently been developed [7], high enantiomeric excesses can only be reached with aldehydes so far. The asymmetric inductions in the case of ketone fluorinations have remained low ee < 36%) [7a]. Thus, the a-silyl ketone-controlled stoichiometric asymmetric synthesis of a-fluoroketones 10 (Scheme 1.1.1) still constitutes a practical method. 

Direct asymmetric a-fluorination of both branched and linear aldehydes has been carried out with a series of pyrrolidine-related catalysts.296... 

Another advantage was conferred by introducing 6,6 -substituents to BINOL. In general, catalytic asymmetric syntheses of fluorine-containing compounds are rather difficult.42 However, an effective asymmetric nitroaldol reaction of the rather unreactive a,ct-difluoro aldehydes proceeded satisfactorily when using the heterobimetallic asymmetric catalysts generated from 6,6 -bis[(triethylsilyl)-ethynyl]BINOL, as shown in Table 5 43 The -configuration of the nitroaldol adduct 71 showed that the nitronate reacted preferentially on the Si face of the... 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

Beeson TD, MacMillan DWC (2005) Enantioselective organocatalytic alpha-fluorination of aldehydes. J Am Chem Soc 127 8826-8828 Berkessel A, Groger H (2005) Asymmetric organocatalysis. Wiley-VCH, Weinheim... 

Steiner DD, Mase N, Barbas CF 3rd (2005) Direct asymmetric—fluorination of aldehydes. Angew Chem Weinheim Bergstr Ger 117 3772-3776 Stetter H (1976) Die katalysierte Addition von Aldehyden an aktivierte Doppel-bindungen-Ein neues Syntheseprinzip. Angew Chem Weinheim Bergstr Ger 88 695... 

DiRocco DA, Oberg KM, Dalton DM, Rovis T (2009) Catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes with nitroalkenes backbone fluorination improves selectivity. J Am Chem Soc 131 10872-10874... 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

The organocatalyst-based a-functionalisation strategy has been applied with much success to the asymmetric halogenation of aldehydes. The imidazolidi-none salt (5.110) has been used by MacMillan and coworkers, in combination with NFSI, to effect enantioselective fluorination of a range of aldehydes, for example (5.111). ... 

Scheme 5.32 Direct proline-catalysed, asymmetric a-fluorination of aldehydes.

Alexakis et al. proposed in 2010 the use of aminals deriving from 4-hydroxyproline for the asymmetric addition of aliphatic aldehydes to vinyl sulfones." " The idea that a fluorine atom at the C4 position of these pyrrolidine-based organocatalysts could be used to favour one single reactive enamine conformation was further exploited by the same authors in 2011, designing a catalyst (28) able to afford excellent yields and enantioselec-tivities (Scheme 11.24). ... 

The 1,2,3-triazole-linked fluorous proline organocatalyst 32 was introduced by Pericas and coworkers in 2013 for the asymmetric aldol reactions of acetone with aromatic aldehydes, giving higher enantioselectivities than other proline derivatives (Scheme 11.27). ° The fluorous tag and the use of a per-fluorinated solvent allowed the easy recycling and reuse of 32, for at least six times. 

The asymmetric electrophilic a-fluorination of aldehydes with 2,5-disub-stituted pyrrolidines was tested independently by Jorgensen and Barbas III, but in these reactions MacMillan s imidazolidinones (Chapter 18) or diatylprolinol silyl ethers (Chapter 8) afforded much better yields and higher enantioselectivities. 

In 2009, the Rovis group disclosed a remarkable study on the asymmetric intermoleeular Stetter reaction with heteroaromatic aldehydes and p-alkyl substituted nitroalkenes in excellent enantioselectivity. With the novel backbone-fluorinated NHC initially developed by their group, the Stetter reaction products were afforded with up to 99% yield and 96% ee. With detailed conformational analysis of the catalyst and DFT calculations, the authors demonstrated that the gawcAe-effect from the fluorine on the five-membered backbone of the catalyst plays a crucial role on increasing the enantioselectivity dramatically (Scheme 7.29). 

Houk, Rovis, and their co-workers later extended the scope of the asymmetric intermolecular Stetter reaction of p-nitrostyrenes to unactivated aliphatic aldehydes, which have rarely been utilized in this reaction due to their relatively lower electrophilicity compared with aryl aldehydes. Comparing to known scaffolds, tert-leucine derived trans-fluorinated catalyst leads to improved reactivity and enantioselectivity in this transformation. Computational studies show that the optimized catalyst is the most stereoselective one because the Re-face attack is stabilized by favorable electrostatic interactions between the phenyl group and the fluorine on the catalyst backbone (Scheme 7.31). 

Most recently, the Wang group and the Sun group described simultaneously the first NHC-catalyzed oxidative asymmetric a-fluorination of simple aliphatic aldehydes. NFSI serves both as an oxidant and as an F source. Under the optimized conditions, the desired a-fluorinated esters were obtained in up to 92% yield and 98% ee, while no competitive difluorination or nonfluorination occurred. A postulated mechanism of this reaction process is depicted via an NHC-bound enolate intermediate which behaves as a nucleophile to interact with the second NFSI to eventually form the a-flu-oro ester product. Furthermore, acyl fluoride was employed as the starting material under the optimized conditions. Pleasingly, with NFSI (only 1.1 equiv.), the expected a-fluoro ester was obtained in 90% yield and 96% ee, which supported the formation of an NHC-bound acyl azolium intermediate (Scheme 7.94). 

Scheme 7.94 NHC-catalyzed asymmetric oxidative a-fluorination of aliphatic aldehydes reported by Wang and Sun, respectively.

Another approach to facilitate the recovery of catalytic systems relies on the use of fluorinated analogues of classic chiral ligands. The recycling options offered by the fluorous catalysts have been explored in the field of asymmetric addition of dialkylzinc reagents to aldehydes in presence of titanium tetraisopropoxide. In 2000, the groups of Chan ° and Curran reported independently the synthesis of perfluoroallqrl-substituted BINOL ligands and their evaluation in the titanium-mediated enantioselective addition of diethylzinc to aromatic aldehydes in fluorous biphasic system (Scheme 7.27). 

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