1. Introduction

Very few fields in chemistry have shown such a considerable interest as fluoroorganic chemistry. Fluorine is perhaps the element that has experienced the greatest recent interest as pointed out by the exceptionally high number of publications and the high percentage of fluorinated new molecules over recent decades.¹ Today, the significant expansion in the use of fluorinated chemicals has attracted the attention of organic, agricultural, medicinal, and material chemists.^2-10 The replacement of hydrogen by fluorine, the most electronegative element, alters sterically and electronically the properties of the molecules, affecting the basicity or acidity of neighboring groups, dipole moment, and overall reactivity and stability. Fluorine is often regarded as an isostere of hydrogen despite the fact that their van der Waals radii are different (1.47 versus 1.20 Å).¹¹ The carbon-fluorine bond length (1.39 Å) is similar to the carbon-oxygen one (1.43 Å), suggesting an isosteric behavior. The high carbon-fluorine bond energy (485.7 kJ/mol)¹² confers relative stability against metabolic transformations. In addition, fluorine can participate in hydrogen bonding interactions with H-C even if hydrogen bonds to C-F are definitely much weaker than those observed to oxygen or nitrogen.^13,14 Nevertheless, the controversy remains on the existence of hydrogen bonds between the C-F group and -OH or -NH donors.^15-17 With regard to the CF₃ group, its size (van der Waals volume) is relatively large, between those of the i-Pr and the t-Bu groups.¹⁸ The CF₃ group has an electronegativity similar to that of oxygen¹⁹ and a large hydrophobic parameter.²⁰ The trifluoromethyl group appears in many biologically active pharmaceutical and agrochemical compounds. The increased lipophilicity, and a superior metabolic stability compared to that of the trimethyl analogues, often accounts for an improved activity profile. Higher fluoroalkyl groups, which are the perfluoroalkyl groups, are introduced mainly to increase the lipophilicity, and also in the context of fluorous chemistry.²¹

One of the most fascinating aspects of organofluorine chemistry is the asymmetric synthesis of fluorinated molecules.^22-27 It is a very challenging topic with great potential in numerous areas. Several examples of asymmetric reactions have been successfully applied to fluorinated substrates although new problems have been raised due to the unpredictable chemistry of fluorinated molecules.²⁸ Asymmetric synthesis is now a mature area of organic chemistry; however, asymmetric fluorination and perfluoroalkylation are developing relatively slowly. Nevertheless, we are witnessing, since the beginning of the new century, a remarkable renewal of interest principally for enantioselective fluorination. Asymmetric perfluoroalkylation, taking in trifluoromethylation, is still a timid area, although promising new reagents and methodologies are now available to accomplish such reactions. For the purpose of this review, only asymmetric syntheses, in which the formation of a C-F, C-CF₃, or C-R_f bond is concomitant to the stereocontrolled creation of a new stereogenic center, have been considered. Stereospecific transformations (for example, fluorodehydroxylations with DAST, or replacements of tertiary deactivated hydrogen in steroids) and classical resolutions, which are not asymmetric syntheses, will not be considered, with the exception of kinetic resolutions, which will be mentioned. The electrophilic fluorination-nucleophilic addition reaction upon glycals and other ethylenic systems was intentionally not covered.^29,30 Reactions involving fluorinated chiral building blocks are beyond the scope of this review. Four generations of asymmetric synthesis exist. In the first generation, the stereoselectivity is directed intramolecularly by an enantiomerically pure substrate, almost exclusively of natural origin, which remains incorporated in the product. The second generation is similar to the first one with an intramolecular control of the stereoselectivity, but requires a chiral enantiomerically pure auxiliary that is first covalently linked to the substrate for the diastereoselective reaction, and then removed for potential recycling. In the third and fourth generations, an achiral substrate is transformed into a chiral product with concomitant creation of a stereogenic center with the aid of a chiral stoichiometric reagent (third generation) or a chiral catalyst (fourth generation). Reactions reported in this review belong to all four generations of asymmetric synthesis. The review is organized by fluorine group introduction: F, CF₃, and R_f, with each section dealing with electrophilic, nucleophilic, and radical reactions as well as diastereo- and enantioselective approaches. The literature in this review is comprehensively covered through the end of June 2004.

2. Asymmetric Fluorination Reactions

A wide variety of electrophilic fluorinating agents have been developed over the past few decades.^31,32 For the majority of them, they must be prepared from molecular fluorine. Molecular fluorine itself is a versatile reagent able to perform many selective reactions;³³ however, it is quite indiscriminate as a reagent in asymmetric synthesis. Cationic fluorine, F⁺, has only been observed spectroscopically in the gas phase; consequently, the ability of electrophilic fluorinating agents to deliver positive fluorine is the subject of some controversy. There is no evidence supporting the existence of the fluoronium ion in solution, while an S_N2 pathway for electrophilic N-fluoro reagents was demonstrated.^34,35 Some reviews covering specific electrophilic fluorinating reagents and recent advances in electrophilic fluorination have been published.^36,37

2.1.1. Diastereoselective Fluorination

This section principally reviews diastereoselective synthetic routes to compounds possessing an -fluorocarbonyl moiety. A partial coverage of diastereoselective electrophilic fluorinations may be found in previous reviews.^38,39 Compounds having an -fluorocarbonyl moiety present interesting biological activities; in particular, they are effective mimics of -hydroxy ketones, they are useful probes for various biological processes, and they can act as enzyme inhibitors. In addition, these compounds are valuable synthons for the construction of active compounds.

2.1.1.1. -Fluoro Ketones. In all the examples, the stereoselectivity is the result of an intramolecular control from an enantiomerically pure substrate. The chirality remains present in the product, but can be cleaved off as in the case of Enders' -silyl ketones (vide infra). The following examples illustrate the concept of fluoro analogues of bioactive compounds (steroids, vitamins, -lactams, cephalosporins, amino acids).

A wide range of electrophilic fluorinating agents (F₂/N₂, XeF₂, O-F, N-F) have been used for the synthesis of fluorosteroids, and the literature is abundant on this subject. Recent work preferably utilized the N-F class of fluorinating agents, which are easier to handle and safer, for the fluorination at activated positions of steroids. Stavber and co-workers described a direct -fluorination of two keto steroids (5-cholestan-3-one and 3-hydroxy-5-androstan-17-one) with Accufluor NFTh [1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)], providing the corresponding -fluoro steroids 1 and 2, respectively, as single diastereomers by selective -face fluorination (Figure 1).⁴⁰

Figure 1 Examples of fluoro steroids.

This direct fluorination was generally superior in terms of diastereoselectivity compared to the methods which require the preparation of enol derivatives used as substrates in the fluorination reaction, such as enol ethers,^41-44 enol acetates,^42,45-50 enamides,⁵¹ or enamines.^52,53

Using conjugated enol ethers raised the problem of regioselectivity. Selective -fluorination of various steroids was realized by Poss and co-workers as exemplified on 4-cholesten-3-one (3), leading to an /-isomer ratio of 1/7.8 (Scheme 1).⁵⁴ The potassium dienoxyboronate generated in situ was reacted with NFSI (N-fluorobenzenesulfonimide) to produce the 6-fluoro steroid derivative 4, preferentially giving the -isomer. Here again, direct fluorination of conjugated ketones did not require the preparation of intermediate species such as dienamines, dienol ethers, or acetates.^45,47,55-62

Scheme 1

In comparison to the high number of fluorinations of enol ether and ester steroid derivatives, fluorinations of steroidal metal enolates are seldom seen, probably due to undesirable formation of side products.^63,64

Dauben and Greenfield reported fluoro C/D ring ketones as fluorinated chirons for vitamin D₃ syntheses.⁶⁵ Kinetic and thermodynamic silyl enol ethers 5 and 7 reacted with N-fluoropyridinium triflate to afford mixtures of fluorinated products, in poor yields and diastereoselectivities, and nonfluorinated side products (Scheme 2).

Scheme 2

The synthesis of 2-(R)-fluorodehydroquinic acid (9) has been achieved from quinic acid including an electrophilic fluorination step by means of Selectfluor [(1-chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (Scheme 3). After recrystallization, a single diastereomer was obtained in 89% yield.⁶⁶

Scheme 3

In the synthesis of 12-fluoroforskolin, the fluoro intermediate 10 was obtained by reaction of the lithium enolate with acetyl hypofluorite; a single diastereomer was obtained in 42% yield (Scheme 4).⁶⁷

Scheme 4

A fluorinated member of a new family of -lactam antibiotics, tribactam 12, was prepared utilizing fluorination of a lithium enolate by NFSI in the key step. A mixture of two diastereomers of 11 (ratio 7/3) was obtained in 95% yield, with both isomers having the cyclohexanone trans disubstituted (Scheme 5).^68,69

Scheme 5

Monofluoro ketone peptide isosteres possess therapeutic potential as enzyme inhibitors. The first synthesis of such fluoro peptides utilized fluorination of a silyl enol ether with the aid of XeF₂ in a mixture acetonitrile/1,1,2-trichlorotrifluoroethane, leading to the desired product in 71% yield without any diastereoselectivity.⁷⁰ The incorporation of fluorine into dipeptides was further developed by Hoffman and co-workers. (2R,5S)-N-tritylated ketone dipeptides 13 were converted to their trimethylsilyl enol ethers and fluorinated with Selectfluor in the presence of TBAF (tetrabutylammonium fluoride). The cooperative stereocontrol between the N-tritylamine group and the alkyl group at C-2 allowed high diastereoselectivities, and good yields, 65-76%, of 14 (Scheme 6), to be reached.^71-73

	Scheme 6
	Figure 2 -Fluoro ketones used in asymmetric epoxidation.

The asymmetric epoxidation of unfunctionalized alkenes by dioxiranes derived from chiral -fluoro ketones is an active area of research. Several groups have embarked on the design and the synthesis of new chiral -fluoro ketones (Figure 2). Denmark and Matsuhashi developed the tropinone-based ketone 15, which required the fluorination of the sodium enolate of the corresponding -keto ester by Selectfluor in DMF (26-39%) followed by decarboxylation. An enantiomer resolution was performed to provide optically pure 15.⁷⁴ The same group also reported the quite lengthy synthesis of the biphenyl-based ketone 16 requiring two fluorination steps by Selectfluor and epimerization in triethylamine to afford a single diastereomer.⁷⁴ Armstrong and co-workers have synthesized 2-fluoro-N-carbethoxytropinone (17) via a silyl enol ether and 2 equiv of Selectfluor in 63% yield. The fluorination occurred exclusively on the less hindered exo face of the silyl enol ether.⁷⁵ An enantioselective version of the synthesis of 17 was reported by the same group; see section 2.1.2.5. Behar and Stearman prepared chiral binaphthyl -fluoro ketones by a sequential deprotonation of the corresponding ketone by potassium hydride and fluorination with NFSI at -78 C to produce the monofluorinated ketone 18 in 77% yield (other distributions of fluorine atoms were also reported).⁷⁶ Solladié-Cavallo and co-workers synthesized the -fluoro ketone 19 by fluorination of the silyl enol ether with Selectfluor, providing a mixture of two diastereomers (54/46) which were separated by column chromatography.^77,78 Other structurally similar -fluoro ketones were evaluated by the same group in asymmetric oxidation of silyl enol ethers.⁷⁹

Enantiopure -silyl ketones 20 were prepared by diastereoselective silylation of the (S)- or (R)-1-amino-2-methoxymethylpyrrolidine (SAMP/RAMP) hydrazone and used as substrates in diastereoselective electrophilic fluorinations in which the silyl group acts as a traceless directing group.^80,81 Lithium enolates of 20 generated by LDA were fluorinated with NFSI in good yields and with high diastereomeric excesses (37% 98% de) (Table 1). Interestingly, LiHMDS allowed reverse diastereoselectivity to be obtained, whereas the impact on the de's was inconclusive. The diastereoselectivity was found to reflect the ratio of enolate stereomers, with NFSI reacting only from the less sterically hindered enolate face.

This concept was also applied to silyl enol ether 22; however, the fluorination gave rise to a significant amount of regioisomers 23 and 24 (Scheme 7).⁸¹ The unpredictable formation in various amounts (up to 100%) of the regioisomer bearing the fluorine atom on the side of the silyl group is obviously a disadvantage of the method. Desilylation of the enantiopure fluoro ketones was readily accomplished by treatment with HF/TBAF without epimerization.

Scheme 7

2.1.1.2. -Fluoro Esters and Amides. The following examples belong to the first generation of asymmetric synthesis (Figure 3). 2-Fluoropodophyllotoxin (25), a potent antitumor agent, was obtained by a completely diastereoselective fluorination of the sodium enolate with NFSI in 99% yield; the stereochemistry at the ring junction was trans.^82,83 Liotta and co-workers have also reported a completely diastereoselective electrophilic fluorination of a chiral nonracemic lactone which was further transformed into 2'-fluoronucleosides. Indeed, fluorolactone 26 could be obtained in 50-70% yield with 100% de.⁸⁴ Enantiomerically pure 2-pyrrolidinone derived from L-glutamic acid was fluorinated to give 27 in 57% yield and 100% de by reaction with LDA, followed by NFSI in THF at -78 C. 27 was further converted to the desired (2S,4R)-4-fluoroglutamic acid as a single stereomer.⁸⁵ Fluoro analogues of the side chain of the antitumor agent paclitaxel were synthesized by Davis and Reddy starting from chiral -amino esters. Treatment of the dianion, generated from LDA (2.2 equiv), with NFSI at -78 C gave the fluorinated target 28 in 65% yield and a moderate 62% de.⁸⁶ The -fluoro analogue of Corey's lactone (29), an important intermediate in the synthesis of prostaglandins, was synthesized by generation of the ketene silyl acetal followed by fluorination with the aid of 2,6-bis(methoxymethyl)pyridinium triflate in 65% overall yield. The configuration of the fluorinated carbon center was not determined.⁵⁶ The fluorolactone 29 could also be obtained using NFSI, but was immediately converted to the desired difluorolactone for the synthesis of difluoroprostacyclins.⁸⁷

Figure 3 Examples of -fluoro esters and amides.

Elaboration of fluorinated antibiotics was conducted via electrophilic fluorination of functionalized azetidinone 30 by means of NFSI. Attack of the fluorine atom by the less hindered face of the stabilized sodium enolate gave predominantly 31 having the fluorine atom trans to the ester moiety (Scheme 8).⁸⁸

Scheme 8

In the chemistry of carbapenems, Wildonger and co-workers prepared 1-fluoro-1-methylcarbapenem 32 by fluorination of the corresponding enolate using N-fluoro-N-(exo-2-norbornyl)-p-toluenesulfonamide (33).⁸⁹ The desired diastereoisomer was purified and isolated pure in 35% yield; however the diastereoselectivity was not reported (Scheme 9).⁹⁰

Scheme 9

An early example of diastereoselective fluorination with perchloryl fluoride was the preparation of 7-fluorocephalosporin Schiff base 34 (Scheme 10).⁹¹

Scheme 10

Examples of second-generation asymmetric fluorination are more frequent in the literature. Fukumoto and co-workers published a series of papers on diastereoselective fluorination of malonates 35 bearing a chiral phenylmenthyl auxiliary for the construction of quaternary fluorinated stereogenic centers (Scheme 11).^92-94

Scheme 11

A similar strategy was applied for the synthesis of menthyl-2-fluoro-1-tetralone-2-carboxylate from the corresponding chiral -keto ester by fluorination of the sodium enolate with Selectfluor in 94% yield; the diastereoselectivity was not provided, and the diastereomers were separated by column chromatography.⁹⁵

Davis and co-workers greatly contributed to diastereoselective electrophilic fluorinations. They selected Evans' oxazolidinones as chiral auxiliaries and N-fluoro-O-benzenedisulfonimide (NFOBS) or NFSI as the fluorinating agent.^96-98 Good to excellent diastereoselectivities were obtained by selective approach of the fluorinating agent from the less hindered si face of the chiral imide enolate (Table 2). The authors suggested that the fluorination occurred by an S_N2-type mechanism for transfer of fluorine to enolate species.⁹⁹ Some racemization occurred on removal of the auxiliary with LiOH or LiOOH due to the enhanced acidity of the -fluoro proton. However, the reduction of 38 with LiBH₄ took place without epimerization leading to the -fluorohydrins.

Interestingly, conversion into the N-methoxy-N-methylamides (Weinreb amides) followed by addition of Grignard reagents provided the corresponding -fluoro ketones without racemization.⁹⁷ This synthetic route complements Enders' method (vide supra).

Diastereoselective fluorination of ,-unsaturated chiral oxazolidinone 39 was conducted by reaction of LiHMDS followed by addition of NFSI to produce a single diastereomer in 76% yield (Scheme 12). The complete diastereoselectivity reached with NFSI, compared to 82% de with NFOBS, was attributed to the greater steric bulk of NFSI. The reaction provided a nice example of deconjugative electrophilic fluorination. The acyclic fluoro compound 40 was employed in the synthesis of fluoro carbohydrates.^100,101

Scheme 12

The success of the method stimulated significant efforts to improve the scope of the process. Marquez and co-workers synthesized the key fluorinated intermediate 41 for the preparation of active anti-HIV compounds FddA and FddC. The fluorination proceeded with complete diastereoselectivity (Scheme 13).¹⁰²

Scheme 13

A chiral oxazolidinone auxiliary was also used by Stauton and co-workers to direct the addition of a fluorine atom in the preparation of fluoro analogue 42 as a biosynthetic precursor of the ionophore antibiotic tetronasin (Scheme 14).¹⁰³

Scheme 14

Recently, in 2004, Duggan and co-workers described an elegant tandem conjugate addition of a chiral lithium amide on tert-butyl cinnamate followed by a diastereoselective electrophilic fluorination of the intermediate enolate by NFSI. The -amino--fluoro ester 43 was obtained quantitatively with 64% de (Scheme 15).¹⁰⁴

Scheme 15

2.1.1.3. -Fluoro Phosphonates. -Monofluoroalkylphosphonates are more effective analogues of phosphate esters than alkyl phosphates because the CHF group is a better phosphate mimic.¹⁰⁵ Among the numerous entries to -monofluoroalkylphosphonates, the direct electrophilic fluorination of alkylphosphonate carbanions is a convenient method. Early work by Differding and co-workers described the reaction of NFSI at -78 C with phosphonate carbanions generated by KDA. Unfortunately, when chiral centers were present on the alkyl chain, the diastereoselectivity was not provided.¹⁰⁶ The search for effective enzyme inhibitors motivated the development of asymmetric fluorination of alkylphosphonates. Taylor and co-workers prepared enantiomerically pure -monofluoroalkylphosphonic acids for evaluation as inhibitors of protein tyrosine phosphatase 1B. The key step was a diastereoselective electrophilic fluorination of phosphonamidates bearing trans-(R,R)-1,2-bis(N-methylamino)cyclohexane or (-)-ephedrine as a chiral auxiliary (Table 3). The diastereoselectivity was strongly dependent on the nature of the base and counterion with de's ranging from 2% to 72%. While LiHMDS gave good results with 44, NaHMDS was preferred in the case of 46 (Table 3). Separation of the diastereomeric products 47 by flash chromatography was followed by a racemization-free removal of the ephedrine auxiliary to obtain enantiomerically pure -fluoro phosphonic acids. The absolute stereochemistry was established by X-ray crystallography.¹⁰⁷

-Monofluorinated phosphonate mimics of phosphoserine and phosphothreonine were synthesized via electrophilic fluorination of Schöllkopf's bislactim ethers derived from cyclo[L-(2-amino-4-phosphonobutanoic acid)-D-valine]. However, the chiral auxiliary only produced moderate to no diastereoselectivity in the fluorination with NFSI (Scheme 16).¹⁰⁸

Scheme 16

2.1.1.4. Miscellaneous Compounds. Shibata and co-workers reported the synthesis of fluorobrevianamide E (50) and fluorogypsetin (51) by a novel tandem electrophilic fluorination-cyclization. Despite an elegant synthetic route, the diastereoselectivity was poor for 50 and the sequence of reactions was nonselective for 51 (Scheme 17).¹⁰⁹

Scheme 17

Few reports described electrophilic fluorination of sulfoxides and sulfones. Some -fluoro--keto sulfoxides^110-112 and sulfones^113,114 were synthesized but are not of interest for this review since the fluorinated stereogenic centers are configurationally labile. Moreover, the chirality is often lost in further transformations (bis--fluorination and elimination reactions).

2.1.2. Enantioselective Fluorination

One of the most fascinating aspects of modern organofluorine chemistry is the discovery of efficient reagents and methods for enantioselective fluorination.^115,116 The formation of a carbon-fluorine bond with concomitant generation of a new stereogenic center from an achiral substrate is now considered state-of-the-art. A variety of chiral nonracemic N-F fluorinating agents were developed for direct enantioselective fluorination of C-H acidic substrates. More recently, the enantioselective electrophilic fluorination with the aid of an achiral fluorinating agent and a catalytic chiral complex of a transition metal and a chiral ligand was reported. Other approaches involve phase-transfer catalysis, fluorodesilylation of allylsilanes, and the use of chiral bases.

2.1.2.1. Chiral N-Fluoro Reagents. The pioneering work of Differding and Lang in 1988 led to the development of the N-fluorocamphorsultams 52 and 53 (Figure 4) as the first enantioselective fluorinating agents.¹¹⁷ Their syntheses require several steps from camphorsulfonyl chloride and the use of molecular fluorine in the last step to create the N-F bond.

Figure 4 N-Fluorocamphorsultams.

Although the fluorination of various prochiral metal enolates proceeded in low to moderate enantioselectivities, these results demonstrated the possibility of reagent-controlled asymmetric fluorination by reaction with an electrophilic fluorine atom (Table 4).

Further studies on N-fluorocamphorsultams 52, 54, and 55 (Figure 4) were carried out by Davis and co-workers on tertiary enolates, affording quaternary -fluoro carbonyl compounds in modest yields and enantiomeric excesses (Table 5). The secondary enolate of propiophenone gave racemic 62 due to facile base-catalyzed epimerization. Both enantiomers of reagent 54 were synthesized to give access to the two optically enriched enantiomers of the fluorinated products.^118,119

To develop novel chiral electrophilic fluorinating agents, Takeuchi and co-workers exploited phenylglycine and -phenethylamine as chiral starting materials, which were fluorinated with either perchloryl fluoride (FClO₃) or diluted F₂ to produce reagents 64-66 (Figure 5). Four model substrates were fluorinated via in situ generation of metal enolates; the best results did not exceed 54% ee for 26% yield (Table 6).¹²⁰

Figure 5 Chiral electrophilic fluorinating agents by Takeuchi and co-workers.

Subsequently, Takeuchi's group embarked on the design of three new chiral N-F sulfonamides (69,¹²¹ 70,¹²² and 71;¹²³ Figure 6). These reagents were generally more efficient than the previous ones, albeit their direct comparison is difficult due to different reaction conditions. Nevertheless, reagent 69 led to 2-fluoro-2-benzyl-1-tetralone (67a) in an excellent 88% ee and with 79% isolated yield.¹²¹ Selected results with reagents 69-71 are summarized in Table 7.

Figure 6 Chiral N-F sulfonamides by Takeuchi and co-workers.

A general feature of all the N-F fluorinating agents so far described is their arduous multistep synthesis, and the handling of molecular fluorine or perchloryl fluoride. In addition, these N-F reagents have drawbacks such as insufficient levels of enantioselectivity and limited scope for the substrates.

A major breakthrough in the field of enantioselective electrophilic fluorination was the introduction of a fundamentally new class of reagents derived from naturally occurring cinchona alkaloids. Simultaneously and independently, we^124,125 and Shibata's group^126,127 reported a substantially similar approach to prepare N-fluoroammonium salts of cinchona alkaloids. A one-step transfer fluorination¹²⁸ on cinchona alkaloids (CAs) 77 with the aid of Selectfluor gave the fluorinating reagents (F-CA-BF₄) 78 (Scheme 18).

Scheme 18

In our case, these new reagents were synthesized, isolated as pure products, and applied in the enantioselective fluorination of enolates and silyl enol ethers of various ketones. We further demonstrated that the transfer fluorination on cinchona alkaloids with the aid of an achiral N-F fluorine-transfer reagent was also effective with NFSI, Accufluor (NFTh), and N-fluoro-2,6-dichloropyridinium tetrafluoroborate. Moreover, the stereoselectivities observed using the reagents prepared in that way were comparable to those observed using Selectfluor for the transfer fluorination.¹²⁹ For their part, Shibata and co-workers did not isolate the reagent, preferring the in situ generation from a combination of alkaloid and Selectfluor. We obtained the X-ray structure of one [N-F]⁺ reagent (F-CD-BF₄, N-fluorocinchonidinium tetrafluoroborate), which allowed us to ascertain its structure.¹³⁰ Advantageously, cinchona alkaloids are readily available in diastereomeric forms [cinchonidine (CD)/cinchonine (CN) and quinidine (QD)/quinine (QN)], known to behave as pseudoenantiomers in asymmetric synthesis. We also designed this new class of reagents for their stronger fluorinating power (charged [N-F]⁺ versus neutral N-F); thus, fluorination of enol derivatives such as silyl enol ethers can now be considered. Both our results and Shibata's data are brought together in Table 8. Our isolated pure [N-F]⁺ reagents are presented using the general descriptor F-CA-BF₄, whereas CA/Selectfluor combinations are given for Shibata's reagents. In Figure 7 are depicted some of the cinchona alkaloid derivatives used by Shibata and co-workers. The fluorination of metal enolates was only tackled by us, whereas Shibata's group evaluated spontaneously enolizable -keto esters and -cyano esters as well as oxindoles. A tentative comparison of the two approaches is only possible for the fluorination of silyl enol ethers; however, a precise comparison of the results is difficult.

Figure 7 Some cinchona alkaloid derivatives used in combination with Selectfluor as described by Shibata's group.

To date, attempts to render catalytic in cinchona alkaloid the electrophilic fluorination failed because the fluorination is faster than the transfluorination step, consequently leading to racemic fluorinated products.

We applied our successful enantioselective fluorination approach to the synthesis of -fluoro--phenylglycine derivatives. A study of the relationship between structure and enantioselectivity led to a new range of [N-F]⁺ reagents that displayed enantiomeric excesses as high as 94% in the synthesis of -fluoro-N-phthaloylphenylglycinonitrile (94b) with O-(p-methoxybenzoyl)-N-fluoroquininium tetrafluoroborate (F-pMeOBzQN-BF₄) (Scheme 19).¹³¹

Scheme 19

The significantly higher ee's observed for the nitrile derivative, compared to the ethyl ester, could be explained by the different natures of the corresponding metalated intermediates. Deprotonation of esters typically leads to a prochiral sp² enolate (eventually as a mixture of Z and E isomers), and the asymmetric step consists of a facial enantiodifferentiation. On the other hand, nitrile anions presumably exist as metalated ketenimines bearing an axial chirality, in which racemization occurs rapidly even at low temperature. In this case, enantioselective fluorination results in a kinetic dynamic resolution of the two enantiomers (Scheme 20). With continuing interest in the development of fluorinated bioactive compounds, we further investigated the asymmetric fluorination of dipeptides either by enantioselective fluorination with the aid of chiral [N-F]⁺ reagents or by diastereoselective fluorination of enantiopure dipeptides.¹³²

Scheme 20

One of the most remarkable demonstrations of the effectiveness of [N-F]⁺ reagents came from our application to the enantioselective synthesis of BMS-204352 (MaxiPost, 96), a potent opener of maxi-K channels, which is evaluated in a worldwide phase III clinical trial for treatment of acute ischemic stroke. Oxindole 95, prepared in five steps from 3-trifluoromethylaniline, reacted with the N-fluoroammonium salt F-2NaphtQN-BF₄ in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO) as base, producing the target product (S)-BMS-204352 in excellent yield and high enantioselectivity, a single recrystallization allowing enantiomerically pure 96 to be obtained (Scheme 21).¹³³ Shibata's group also reported the synthesis of BMS-204352 in a slightly lower ee of 84% using the combination (DHQ)₂AQN/Selectfluor.¹³⁴

Scheme 21

Although the chiral [N-F]⁺ reagents are efficient and of wide scope, some limitations remain, such as the poor choice of solvents (restricted to acetonitrile or acetone), the requirement for low temperature to reach high enantioselectivity, and the difficult recovery of the cinchona alkaloid. With the aim to circumvent these limitations, we have demonstrated that fluorination can be performed in ionic liquids (ILs), for instance, [hmim][PF₆] (1-butyl-3-methylimidazolium hexafluorophosphate), at 0 C instead of acetonitrile at -40 C, with comparable, indeed somewhat higher, enantioselectivities. In addition, ILs selectively dissolve cinchona alkaloids, in preference to diethyl ether, allowing IL and cinchona alkaloid recycling without significant alteration in the enantioselectivity.¹³⁵

The development of recoverable and recyclable reagents supported on polymeric matrixes is a valuable approach. We prepared a collection of new polystyrene-bound cinchona alkaloids for the design of unprecedented enantioselective electrophilic fluorinating agents. For example, soluble polymeric cinchona alkaloids were easily synthesized by polymerization of the dihydro cinchona alkaloid O₉-(4-vinylbenzoate) in the presence of a catalytic amount of AIBN in refluxing dry benzene. Compared to nonsupported [N-F]⁺ reagents, the polystyrene-bound N-fluoroammonium salts of cinchona alkaloids showed comparable efficiency and ready purification of the fluorinated reaction products (Scheme 22). Poly[O₉-(4-vinylbenzoate)-DHQN] was recycled three times without loss of stereochemical performance.¹³⁶

Scheme 22

2.1.2.2. Transition-Metal Catalysts. This section is concerned with the synthesis of -fluoro--keto esters by catalytic enantioselective electrophilic fluorination, nicely illustrating the fourth generation of asymmetric synthesis. However, this approach is, so far, strictly limited to the fluorination of -keto esters for the ease of enolate formation.

Simultaneously with the work on cinchona alkaloid N-fluoroammonium salts, the first transition-metal-catalyzed fluorination has been achieved by Togni and co-workers. In this reaction, it was anticipated that catalytic transition-metal complexes would accelerate enolization of -keto esters. The fluorination of various acyclic -keto esters, with Selectfluor in the presence of 5 mol % of [TiCl₂((R,R)-TADDOLato)] catalyst 97, was reported to give high yields (80%), and up to 90% ee (Table 9).^137,138 In this approach, computational and experimental studies strongly supported a single-electron-transfer (SET) mechanism as a pathway for the fluorination.¹³⁹ Interestingly, compounds 104 and 105 were synthesized in a one-pot enantioselective heterodihalogenation of the -keto esters with N-chlorosuccinimide and Selectfluor by sequential addition.¹⁴⁰

Following Togni's pioneering work, Sodeoka and co-workers reported an efficient enantioselective fluorination of various -keto esters using chiral BINAP-palladium complexes.¹⁴¹ The fluorination was carried out with NFSI in ethanol in the presence of 2.5 mol % catalyst 106a,c or 107, leading to excellent enantiomeric excesses up to 94% (Table 10). The reaction is not sensitive to water, can be run on a 1 g scale, and proceeds via a palladium enolate complex as already mentioned for the titanium-TADDOL catalyst. Furthermore, the palladium complexes were immobilized in ionic liquids, and their application to catalytic enantioselective fluorination was demonstrated. Efficiently, catalyst 106b was reused 10 times with a level of enantioselectivity comparable to those obtained in the usual organic solvents.¹⁴²

Inspired by these results, we evaluated nitrogen-containing ligands, which are complementary to the oxygen- and phosphorus-containing ligands investigated, respectively, by Togni and Sodeoka. We recently reported a new efficient catalytic enantioselective electrophilic fluorination of both cyclic and acyclic -keto esters by means of chiral bis(oxazoline)-copper complexes. As low as 1 mol % bis(oxazoline)-copper triflate catalyzed the fluorination with NFSI. Selectfluor and N-fluoropyridinium triflate produced ee's ca. 10% lower than that of NFSI. In addition, the use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), as an additive, allowed 10-15% enantiomeric excess to be gained in all the reactions (Table 11).¹⁴³ Other combinations of chiral ligand (sparteine, cinchona alkaloids, PyBOX, Trost's ligand, BINOL) and metal (Zn, Mg, Al, Sc, La) as well as various N-F reagents were screened, leading to enantioenriched -fluoro--keto esters in high yields and moderate enantioselectivities (up to 67% ee).¹⁴⁴

2.1.2.3. Phase-Transfer Catalysis. The first example of catalytic enantioselective electrophilic fluorination under phase-transfer conditions with the aid of quaternary ammonium salts derived from cinchona alkaloids was reported by Kim and Park.¹⁴⁵ This organocatalytic approach is limited, here again, to the fluorination of -keto esters. Treatment of -keto esters with NFSI in the presence of 10 mol % chiral phase-transfer catalyst and 6 equiv of base afforded the -fluoro--keto esters in excellent yields and moderate enantioselectivities (Table 12). It is claimed in this paper that the reactions were completed within 10 min; however, the trick behind this success is the preformation of the enolate for up to 10 h prior to the slow addition of NFSI. Among the various cinchoninium salts evaluated, 117 provided the highest enantioselectivity; surprisingly, diastereomeric cinchonidine as well as quinine and quinidine were not discussed.

2.1.2.4. Fluorodesilylation. -Fluorocarbonyl compounds are the targets of most of the above-mentioned studies. Interestingly, Gouverneur and co-workers developed a regio- and enantioselective synthesis of allylic fluorides 118 by electrophilic fluorodesilylation of allylsilanes.¹⁴⁶ The in situ generation of the fluorinated cinchona alkaloids was preferred in this reaction, leading to allylic fluorides with excellent enantioselectivity of 96% and high conversion (Scheme 23). The best alkaloid for this transformation was (DHQ)₂PYR, leading to high ee values. Additionally, the steric bulk of the silyl group was important with regard to enantioselectivity, with the triphenylsilyl group being responsible for higher enantioselectivities.

Scheme 23. Enantioselective Fluorodesilylation of Allylsilanes

2.1.2.5. Chiral Bases. Armstrong and co-workers realized a chiral lithium amide base desymmetrization via in situ generation of an intermediate silyl enol ether, which was fluorinated with Selectfluor to afford the enantiomerically enriched chiral -fluoro-N-carbethoxytropinone (120) in 55% yield and 60% ee (Scheme 24).⁷⁵

Scheme 24

Asymmetric anodic fluorination was generally very difficult due to the small size of the fluoride ion and the use of polar solvents for electric conductivity. Nevertheless, some studies have been reported. For instance, Laurent and co-workers observed a diastereoselective fluorination at the benzylic position of 121 by oxidation at a platinum anode in Et₃N·3HF/CH₃CN; moderate diastereomeric excesses in the range 10-60% were recorded (Scheme 25).¹⁴⁷ The best results were obtained with the 8-phenylmenthyl chiral auxiliary.

Scheme 25

Following this pioneering work, Fuchigami's group embarked on several studies on diastereoselective anodic fluorination. They obtained much lower de's (20%) in the anodic fluorination of -phenylthioacetates having chiral auxiliaries similar to those explored by Laurent.¹⁴⁸ Next, N-protected thiazolidines 123 derived from L-cysteine were electrofluorinated in Et₃N·4HF/DME with moderate yield and high diastereoselectivity favored by the steric hindrance of the N-substituent. The reaction was assumed to proceed in a Pummerer-type reaction mechanism (Table 13).¹⁴⁹ Electrofluorination on a platinum anode of 1,3-oxazolidines 125 derived from L-serine and L-threonine gave the -fluorinated products in moderate yields with observed diastereoselectivity only for the L-threonine derivative.¹⁵⁰ Under similar conditions, a single diastereomer was obtained in the fluorination of chiral 1,3-oxathiolan-5-ones 127 derived from camphorsulfonamides and thioglycol acid.¹⁵¹ Sulfide 129, having a dioxolane moiety, was fluorinated via a Pummerer mechanism with good diastereoselectivity (up to 80% de).¹⁵² Other diol protections and various para-substituted phenyls were investigated by electrofluorination; however, lower diastereoselectivities were obtained.¹⁵² In some of the studies, Fuchigami attempted the chemical fluorination using electrophilic N-F reagents, but the method failed to produce the fluorinated compounds, thus showing the advantage of anodic fluorination.

2.2.2. Enantioselective Nucleophilic Fluorination

The first and only example of enantioselective nucleophilic fluorination, described by Haufe and co-workers, concerned the ring-opening of meso-epoxides 131 with hydrofluorinating reagents mediated by Jacobsen's (Salen)chromium chloride complex 132.¹⁵³ Ring-opening reaction of racemic terminal epoxides, such as styrene oxide, almost exclusively lead to the fluorine in the primary position; therefore, the fluorine atom was not introduced on a stereogenic center. Initial attempts of ring-opening of meso-epoxides with 5-10 mol % Eu(hfc)₃ or zinc tartrate led to poor enantioselectivity (4-10% ee). Higher enantiodifferentiation was observed with the aid of a stoichiometric amount of Jacobsen's catalyst, whereas the enantiomeric excess dropped dramatically with a catalytic amount of the chiral Lewis acid. In addition, chlorohydrin 134 was formed as a side product in nonnegligible amounts. Various fluorinating agents were tested [Et₃N·3HF, KHF₂ (+18-crown-6), Bu₄N⁺H₂F₃^-, AgF]; better results were obtained with 1.5 equiv of silver fluoride in CH₃CN (Table 14).^154,155

Although kinetic resolutions are not asymmetric syntheses in the strict sense, we think it is of interest to mention two examples of kinetic resolution by fluorodehydroxylation and fluorodebromination. The first case was reported in 1989 by Sampson and Hann, who have synthesized the first chiral aminofluorosulfurane 135 as a chiral analogue of DAST (diethylaminosulfur trifluoride) to conduct an enantioselective fluorodehydroxylation (Scheme 26).¹⁵⁶ The kinetic resolution of 2-trimethylsilyloxypropionic acid ethyl ester (136) resulted in a poor enantiomeric excess of 16% for the 2-fluoropropionic acid ethyl ester (137).

Scheme 26

Beaumont and co-workers reported the second example in 2001. Chiral phosphonium salt 138, prepared from (-)-menthyl chloride, was used in the asymmetric nucleophilic fluorination of 2-bromopropiophenone (139) to give enantiomerically enriched 2-fluoropropiophenone (140) in 35% yield; unfortunately, the enantiomeric excess was not provided (Scheme 27).¹⁵⁷

Scheme 27

3. Asymmetric Trifluoromethylation Reactions

Among fluoroorganic compounds, trifluoromethyl-substituted molecules have gained growing interest during the past decade.^20,158 The introduction of a trifluoromethyl group with strong electron-withdrawing ability can lead to significant changes in the physical, chemical, and biological properties of the molecules. As a consequence, the development of asymmetric approaches for the direct introduction of a trifluoromethyl group is an important synthetic challenge. Methods for the incorporation of the trifluoromethyl group into organic molecules may be considered as nucleophilic, electrophilic, or free radical processes. Nucleophilic trifluoromethylation is now tamed thanks to the extensive use of Ruppert's compound (TMS)CF₃ (TMS = Me₃Si),^159-161 while electrophilic trifluoromethylation has been developed relatively slowly.¹⁶²

Since the initial report in 1989 by Prakash and co-workers on the trifluoromethylating properties of (TMS)CF₃, the utilization of this compound as a nucleophilic trifluoromethylating agent has rapidly become the method of choice.^160,163-165 Indeed, (TMS)CF₃ was used as a precursor to the trifluoromethide anion, which was liberated by activation with a fluoride source (nucleophilic initiator). Most commonly, tetraalkylammonium fluorides are used as initiators. For example, upon addition of a catalytic amount of TBAF to the reaction mixture of a carbonyl compound and (TMS)CF₃ in a suitable solvent, the process commences with the initial formation of Me₃SiF and alkoxide adduct 141, stabilized by the tetrabutylammonium cation. The reaction between (TMS)CF₃ and 141 leads to the formation of the pentavalent complex 142^166,167 followed by the transfer of the trifluoromethyl group to the electrophilic carbon of the carbonyl function until all of the starting material has reacted (Scheme 28). Other nucleophilic initiators such as alcoholates, amines, phosphines, and even derivatives of arsenic and antimony are also suitable for this purpose. This method has proven to be successful for asymmetric addition to a large number of electrophiles.

Scheme 28

3.1.1. Diastereoselective Trifluoromethylation

3.1.1.1. Trifluoromethylation of Amino Acid Derivatives. (TMS)CF₃ was employed to prepare trifluoromethylated amino alcohols from the corresponding protected amino acid derivatives such as t-Boc-L-phenylalanal (143) (Scheme 29). The reaction of (TMS)CF₃ with 143 in the presence of a catalytic amount of TBAF afforded the trifluoromethylated amino alcohol 144 as a mixture of (S,S) and (S,R) diastereomers (ratio not provided). Appropriate deprotection gave good yields of amino alcohol, which was used to prepare trifluoromethyl-substituted tripeptides as potential inhibitors of human leukocyte elastase.¹⁶⁸

Scheme 29

Recently, Qing and co-workers described an efficient approach for the synthesis of N-Boc-cis-4-trifluoromethyl-L-proline (147) (Scheme 30).¹⁶⁹ The reaction of N-Boc-4-oxo-L-proline 145 with (TMS)CF₃ in the presence of a catalytic amount of TBAF gave the adduct 146 with the CF₃ group trans to the ester group. 146 was further dehydrated, hydrogenated, and debenzylated to yield diastereomerically pure 147. This group also reported trifluoromethylation of Garner's aldehyde with (TMS)CF₃; unfortunately, the diastereoselectivity was not provided.¹⁷⁰

Scheme 30

Ruppert's compound was reacted with a variety of amino acid derived N-substituted oxazolidin-5-ones 148 to produce compounds 149 in excellent yields. Replacement of TBAF by CsF and sonication resulted in substantially improved yields. Although the chirality was lost in the end, the trifluoromethylation step was highly diastereoselective since products were obtained as single diastereomers (Scheme 31).^171-173

Scheme 31

3.1.1.2. Trifluoromethylation of Carbohydrate and Inositol Derivatives. Introduction of the hydrophobic trifluoromethylated moiety in place of the methyl group of carbohydrates is suggested to play an important role in molecular recognition.¹⁷⁴ Furthermore, the inductive effect of the trifluoromethyl group decreases the rate of hydrolysis, thus leading to more stable carbohydrates with increased lifetime that are regarded as useful tools for in vivo ¹⁹F NMR spectroscopy and for biomedical purposes.^175,176 In particular, the construction of 2-C-trifluoromethyl carbohydrates is expected to inhibit the development of a positive charge at the anomeric center, as in the case of 2-C-fluoro derivatives.^177,178 The trifluoromethyl group can also modify the cyclization equilibrium between pyranose and furanose. Synthetic methods for preparing carbohydrates bearing a C-branched fluoroalkyl substituent have been recently reviewed.¹⁷⁹

Toyokuni and co-workers have developed trifluoromethylation of an acyclic derivative of D-lyxose (150) with (TMS)CF₃ and a catalytic amount of TBAF to give trifluoromethyl adduct 151 in 79% yield, but without stereoselectivity (entry 1, Table 15).¹⁷⁴ Kozak and Johnson reported that ribulose derivative 152 reacted with (TMS)CF₃ in the presence of TBAF to give trifluoromethylated alcohol analogue 153 in 69% yield as a mixture of D-ribo and L-lyxo epimers in a 4/1 ratio (entry 2, Table 15).¹⁸⁰ They also realized the synthesis of 3'-C-trifluoromethyl ribonucleosides, which involved a diastereoselective addition of (TMS)CF₃ to 5-O-benzoyl-1,2-O-isopropylidene--D-erythro-pentos-3-ulose (154). The reaction is catalytic in fluoride, but 1.5 equiv of TBAF was used also to cleave the TMS-protected alcohol (entry 3, Table 15).¹⁸¹

Trifluoromethylation of the cyclic D-erythrose derivative 156 was described by Anker and co-workers in the aim to circumvent the previously encountered stereoselectivity problems in the trifluoromethylation of noncyclized carbohydrate. However, the stereoselectivity was poor despite the more strained cyclic structure (entry 4, Table 15).¹⁸² Because of the low diastereoselectivity, the addition of the CF₃ group was realized on lactone 168, which provided hemiketal 169 as an equilibrium mixture of - and -isomers.¹⁸⁷ It is worth noting that subsequent reduction showed different selectivity depending on the reducing agent, and tuning of the conditions allowed the preparation of CF₃-substituted diol 170 in high stereoselectivity (Scheme 32).¹⁸⁸

Scheme 32

Pentodialdose derivatives 158a,b were trifluoromethylated with (TMS)CF₃ in the presence of a catalytic amount of [Ph₃SnF₂]^-n-Bu₄N⁺ to give quantitatively the corresponding products 159a,b as mixtures of L-ido and D-gluco epimers with good stereoselectivity, whereas a similar reaction on 3-oxoglucose 160 gave the d-allo adduct 161 with complete stereoselectivity (entries 5 and 6, Table 15).¹⁸³ Trifluoromethylation of chiral aldehyde 158a was also carried out by slow addition of trifluoromethyl iodide to a mixture of zinc and aldehyde in DMF under ultrasonication, allowing a comparison with the (TMS)CF₃ reaction. The trifluoromethyl iodide procedure afforded 159a, in a moderate 47% yield with a lower ratio of L-ido to D-gluco epimers of 2.5/1, clearly demonstrating the superiority of (TMS)CF₃ in this reaction (Scheme 33).¹⁸⁹ Under identical conditions, trifluoromethylation of D-glyceraldehyde derivative 171 also gave a mixture of diastereomers 172 (Scheme 33).¹⁸⁹

Scheme 33

Schmit employed ketone 162 as the starting material for the synthesis of the 2'-trifluoromethylcarbinol 163 (entry 7, Table 15).¹⁸⁴ The reaction afforded a single stereomer resulting from the attack of the CF₃ group of (TMS)CF₃ by the -face of the sugar ring. Further treatment including radical deoxygenation with tributyltin hydride and coupling with bis(silylated) thymine furnished the corresponding -nucleoside.

Portella and co-workers disclosed an interesting sequence of nucleophilic trifluoromethylation with (TMS)CF₃ followed by radical deoxygenation to obtain 3-deoxy-3-C-trifluoromethyl-D-ribose derivatives. Reaction of the silyl ether 164 with (TMS)CF₃ under catalytic fluoride activation led to the single 3-C-trifluoromethyl-D-ribose derivative 165 (entry 8, Table 15).¹⁸⁵ Burger and co-workers reported the synthesis of 2-C-trifluoromethyl-D- and -L-ribose via trifluoromethylation of pentopyranosid-2-uloses 166 with Ruppert's compound; only one diastereomer of 167 was formed by preferential attack of the trifluoromethyl anion from the si face of the carbonyl group (entry 9, Table 15).¹⁸⁶

Fluorinated inositols have demonstrated excellent biological activities and enzymatic inhibitory effects.^190,191 Starting from L-quebrachitol diacetonide (173), Kozikowski and co-workers prepared 3-C-trifluoromethyl-myo-inositol derivative 174 by a Swern oxidation followed by trifluoromethylation of the unstable ketone with the aid of Ruppert's compound (Scheme 34). A single configuration was assigned at C-3 due to complete -face selectivity.¹⁹²

Scheme 34

3.1.1.3. Trifluoromethylation of Steroidal Derivatives. Asymmetric introduction of a trifluoromethyl group into a strategic position of the steroidal skeleton is expected to influence the biological activity. Olah and Prakash demonstrated that (TMS)CF₃ activated by a catalytic amount of TBAF allowed conversion of the ketonic function of steroids into the corresponding trifluoromethylcarbinols as single stereomers (175 and 176; Figure 8).¹⁶⁴ Wang and co-workers developed a similar procedure for the preparation of trifluoromethylated silyl ethers from ketones in which tetramethylammonium fluoride (TMAF) having a small ammonium cation was found to be superior to TBAF in promoting the CF₃ group transfer, particularly for hindered ketones. The O-silylated products were readily converted into trifluoromethylated carbinols by means of 40% aqueous HF (177-179; Figure 8).¹⁹³

Figure 8 Trifluoromethylated steroidal derivatives.

3.1.1.4. Trifluoromethylation of Sulfinimines and Azirines. Trifluoromethylated chiral amines are important fluorinated building blocks for pharmaceutical research and asymmetric synthesis. Direct asymmetric synthesis of trifluoromethylated amines was recently achieved by Prakash and co-workers.¹⁹⁴ The reactivity and stereoselectivity of the reaction are dependent on the fluoride source. Chiral sulfinimines 180 reacted with (TMS)CF₃ in the presence of DeShong's tetrabutylammonium difluorotriphenylsilicate (TBAT)¹⁹⁵ in THF to give the trifluoromethylated products 181 with high diastereoselectivities and yields, which can be hydrolyzed to the chiral amine salts 182 (Scheme 35).

Scheme 35

In marked contrast, a stoichiometric amount of CsF provided the trifluoromethylated sulfinamides 181 only in 50-65% yields with moderate diastereoselectivity (50-80% de). The authors described a mechanistic rationale to account for this high stereoselectivity (Scheme 36). In the presence of a stoichiometric amount of fluoride source, the pentavalent intermediate 183 preferably adds to the imines from the less hindered re face to give the selective Cram products 181.

Scheme 36

The same group has also developed the asymmetric synthesis of trifluoromethylated allylic amines 185 using ,-unsaturated N-2-methyl-2-propanesulfinimines 184 and (TMS)CF₃ (Scheme 37).¹⁹⁶ Nucleophilic addition reactions depended not only on the electrophilicity of the substrates but also on the steric volume of the nucleophiles. Due to the steric congestion, long allyl chain substitutions at the -position of the substrates gave lower yields of adducts; however, complete diastereoselectivity was observed. On the other hand, reducing the steric volume of the effective nucleophile increased the yields of the products. Indeed, when TMAF was used as a fluoride source, the sterically bulky sulfinimines gave the corresponding adducts in good yields.

Scheme 37 a TMAF was used as the fluoride source.

Somewhat later, Prakash and co-workers showed that the trifluoromethylated vicinal ethylenediamines 188 can be obtained in high yields and stereoselectivities by treatment of -amino N-2-methyl-2-propanesulfinimines 186 with (TMS)CF₃ (Scheme 38).¹⁹⁷

Scheme 38

By using TMAF as the fluoride source, sulfinimines 186 derived from the L-amino aldehydes were trifluoromethylated to give the vicinal ethylenediamine adducts 187 in good to high yields with excellent diastereoselectivities. However, the imine derived from the D-amino aldehydes gave the corresponding adduct in an 80/20 diastereomeric ratio in 60% yield for the major diastereomer (R¹ R² R³ Bn). These observations suggested that both the chiral centers present in the molecule direct the incoming nucleophile to the re face of the imines.

The addition of (TMS)CF₃ was studied on the carbon nitrogen double bond of azirines 189 to obtain exclusively the (E)-aziridines 190 in satisfactory yields.¹⁹⁸ The high strain release upon addition of CF₃ to the azirine with concomitant formation of the relatively weak silicon nitrogen bond renders this reaction catalytic in fluoride source (Scheme 39).

Scheme 39

3.1.2. Enantioselective Trifluoromethylation

The importance of enantiopure trifluoromethylated compounds in medicinal chemistry, agrochemistry, electronics, and optics (liquid crystals) has been well recognized.^20,23,199 Several reports deal with attempts of enantioselective trifluoromethylation of aldehydes and ketones with (TMS)CF₃. According to the mechanism of the trifluoromethylation by (TMS)CF₃ mediated by a tetraalkylammonium fluoride, the ammonium cation is closely associated with the alkoxy adduct during the reaction. It is therefore reasonable to expect that the process could show enantioselectivity if a chiral ammonium cation is used. Prakash and co-workers reported that the use of N-benzylquinidinium fluoride in dichloromethane at -78 C allowed the trifluoromethylation of 9-anthraldehyde in 95% ee (entry 1, Table 16).^200,201 Iseki and co-workers employed 1-20 mol % N-[4-(trifluoromethyl)benzyl]cinchonium fluoride as an effective catalyst for asymmetric introduction of the trifluoromethyl group into carbonyl compounds to give the corresponding alcohols in high yields and with moderate enantiomeric excesses (entries 2-7, Table 16).²⁰²

Noteworthy, quinine itself was capable of enantioselective trifluoromethylation of aldehydes using related Et₃SiCF₃, although with low enantioselectivities and yields.^203,204

Iseki and co-workers have developed the chiral triaminosulfonium salt 191, which functions as a Lewis base catalyst in the enantioselective trifluoromethylation.²⁰⁵ (TMS)CF₃ reacted with aldehydes in the presence of 10 mol % chiral salt 191 at -78 C in diethyl ether to give the corresponding alcohols with ee's ranging from 10% to 52% (Scheme 40).

Scheme 40

With the aim of obtaining the enantiomerically enriched trifluoromethylated silylated alcohol 192, an in-depth catalyst structure-enantioselectivity relationship study was undertaken by Caron and co-workers.²⁰⁶ They found that the introduction of a bulky subunit at the quinuclidine nitrogen atom of cinchona alkaloids led to an enhancement of the stereoselectivity. Alkaloids having the O-(9)-hydroxyl group etherified did not promote the reaction. Easily prepared cinchonine-derived catalysts 193 were used in amounts as low as 4 mol % in the trifluoromethylation to afford the desired product 192 in up to 92% ee (Scheme 41). However, these catalysts did not prove to be generally applicable to a variety of model aldehydes and ketones, albeit no optimization was conducted.

Scheme 41

We did not find any example of reagent-controlled nucleophilic trifluoromethylation. However, efforts directed toward the design of enantioselective nucleophilic trifluoromethylating reagents are ongoing in the group of Langlois and Billard. Indeed, they have recently reported enantiopure trifluoroacetamide 194 (Figure 9) derived from ephedrine, which was able to trifluoromethylate benzophenone, benzaldehyde, and acetophenone in the presence of 10 mol % cesium fluoride or TBAT in 58-89% yields.²⁰⁷ Unfortunately, the enantioselectivity was not discussed at this stage.

Figure 9 Potential enantioselective nucleophilic trifluoromethylating reagent.

Asymmetric electrophilic trifluoromethylation has been developed relatively slowly. Yagupol'skii reported in 1984 the first electrophilic trifluoromethylating reagents 195a,b (Figure 10), which showed low reactivity.²⁰⁸ The research work of Umemoto and co-workers in the early 1990s led to the development of highly reactive trifluoromethyl dibenzoheterocyclic salts 196 (Figure 10) as electrophilic trifluoromethylating agents.^209-213

Figure 10 Electrophilic trifluoromethylating reagents.

Umemoto and co-workers reported a comparison of diastereoselectivity for the trifluoromethylation of the trimethylsilyl enol ether 197 and the boron-mediated trifluoromethylation of the corresponding potassium enolate 199 with 196 (A = S).^210,211 The / ratio of product 198 was 3.6/1 for the former reaction and 1/2.5 for the latter one (entries 1 and 2, Table 17). The conformation of the intermediate complex 200, in which the bulky Lewis acid is complexed with the enolate oxygen from the less hindered -face of the potassium enolate, would force the trifluoromethylating agent to attack the complex from the -face, predominantly giving the -isomer (Figure 11). The preferential formation of -CF₃ steroid isomer 202 can be explained by a similar rationale (entry 3, Table 17).

Figure 11 Proposed intermediate for the boron-mediated trifluoromethylation of enolate 199.

The first and only example to date of enantioselective electrophilic trifluoromethylation was achieved by the same group. In the presence of optically active boron compound 206 or 207, the potassium enolate of propiophenone 203 was reacted with 196 (A = S), giving moderate enantioselectivities and low yields (entries 4 and 5, Table 17). The enantioselectivity could arise from the attack of the resulting chiral borate complex by the trifluoromethylating agent.

Surprisingly, 10 years later, this research area has not experienced any progress. We have recently initiated a research program dedicated to new approaches in electrophilic trifluoromethylation.¹⁶² Promising results were obtained under phase-transfer catalysis with the aid of cinchona alkaloid ammonium salts; optimization of the enantioselectivity is the subject of active research.²¹⁴

A diastereoselective approach, according to the second generation of asymmetric synthesis, employing chiral enamine 208 was described by Kitazume and Ishikawa.²¹⁵ The asymmetric introduction of the trifluoromethyl group in the presence of zinc powder and a catalytic amount of dichlorobis(-cyclopentadienyl)titanium was promoted by ultrasound; up to 76% ee was obtained with CF₃Br (Scheme 42).

Scheme 42

Early work by Elliot and co-workers concerned dienyl enol triflate 209 of a steroidal system. Irradiation of 209 in pyridine photochemically gave 6-trifluoromethyl ,-unsaturated ketone 210 (Scheme 43). A radical process was suggested for the fragmentation-rearrangement reaction.²¹⁶

Scheme 43

The trifluoromethylation of lithium enolates of chiral N-acyloxazolidinones 211 with iodotrifluoromethane mediated by triethylborane was achieved by Iseki and co-workers.^217,218 The trifluoromethylation proceeded in good yields and diastereoselectivities to afford -trifluoromethyl carboximides 212, which were treated with LiBH₄ to provide the corresponding -trifluoromethyl alcohols without racemization (Scheme 44).

Scheme 44 a In parentheses is given the configuration of the major isomer.

The lack of reaction in the absence of triethylborane, or with added galvinoxyl (a radical scavenger) presented evidence for the proposed radical mechanism. The diastereoselectivity of the reaction can be explained by the trifluoromethyl radical reaction on the si face of the lithium-chelated transition state (Figure 12).

Figure 12 Proposed radical mechanism.

To synthesize 7-perfluoroalkylestradiol, Blazejewski and co-workers developed an approach for direct introduction of the trifluoromethyl group by reaction of silyl enol ether 213 of a steroidal ketone with Umemoto's reagent 196 (A = S). Under thermal conditions similar to those employed by Umemoto, the yield was low (15%), while UV irradiation of the reaction mixture led to an excellent yield (90%) of the ketone 214, although in a poorer selectivity (/ = 5/4) than that observed in the perfluoroalkyl series (vide infra) (Scheme 45).²¹⁹

Scheme 45

A tandem radical trifluoromethylation-nucleophilic cyclization of the glucose-derived ketene dithioacetal 215 has been proposed as the key step toward trifluoromethylated lactone 217 (Scheme 46).²²⁰ The reaction exhibited poor diastereoselectivity (dr = 3/2), with the two diastereomers of 216 being separable by silica gel chromatography.

Scheme 46

A higher degree of diastereoselection (>90/10) was reached starting from a mannose-derived substrate. Depending on the sulfur substitution and the trifluoromethyl halide, the dithioketal lactone 218 or the acyclic sugar 219 was predominantly obtained (Scheme 47).²²¹

Scheme 47

4. Asymmetric Perfluoroalkylation Reactions

The presence of one or more perfluoroalkyl groups in molecules can be used for various purposes taking advantage of several useful properties of these units.²⁶ For example, the CF₂ group is known for its isosteric and isopolar relation to oxygen, a property which has been explored in the area of difluorinated analogues of carbohydrates and other oxygenated biomolecules.²²² Additionally, the introduction of a difluoromethylene group into peptides has brought about the discovery of potent protease inhibitors which function as transition-state mimics.²²³ In the case of long-chain perfluoroalkylations, some perfluoroalkylated carbohydrates have been synthesized, for example, for the formation of biocompatible oxygen carriers.²²⁴ The development of asymmetric procedures for the straightforward introduction of a perfluoroalkyl group has been the subject of continuous investigations in recent years.

The addition of pentafluoroethyllithium and some perfluoroalkylzinc derivatives to chiral arenechromium tricarbonyl aldehydes 220 has been carried out by Solladié-Cavallo and co-workers (Table 18).^225-227 The preferred diastereomer of 221 was the same in the two cases (from lithium compounds or from zinc compounds). The addition of the perfluoroalkyl group occurred trans to the Cr(CO)₃ tripod, and the asymmetric induction was highly dependent on the R¹ ring substituent. On decomplexation under irradiation, optically active perfluoroalkylcarbinols were obtained.

Some of the obtained complexed alcohols 221 proved to be good inducers of chirality in the Prelog-type asymmetric synthesis of -hydroxy acids 222 (Scheme 48).²²⁸

Scheme 48

Perfluoroalkyllithiums, generated in situ from the reaction of primary perfluoroalkyl iodides and MeLi-LiBr, in the presence of boron trifluoride, reacted with chiral aldimines 223 and 224 derived from lactic acid or from aldehyde and chiral amines (Table 19). The diastereofacial selectivity observed in the reaction did not agree with Cram's chelation model; thus, the authors proposed a model involving an interaction of BF₃ with the perfluoroalkyllithium.²²⁹

Since the report of Fried,²³⁰ the Reformatsky reaction of difluoroorganozinc with chiral aldehydes has become a frequently used methodology for the preparation of interesting biomolecules with a difluoromethylene moiety. For example, condensation of the zinc derivative of ethyl bromodifluoroacetate²³¹ and n-pentylbromodifluoromethylacetylene²³² with glyceraldehyde acetonide 225 (R¹ = H) gave the desired difluorohydroxy products 226 and 227 with moderate diastereoselectivities (Scheme 49). It is worth noting that difluoroketene acetal generated in situ from methyl iododifluoroacetate, zinc, and trialkylchlorosilane was applied to this reaction, allowing higher diastereoselectivities to be reached for compound 228.²³³

Scheme 49

The diastereoselective synthesis of ,-difluoro-,-dihydroxy esters 229 can also be promoted by Lewis acids to enhance face differentiation. Cp₂TiCl₂ allowed a higher anti selectivity than the reaction run without Lewis acid to be reached (Scheme 50).²³⁴

Scheme 50

When diol-protected glyceraldehydes were used in the Reformatsky reaction, the anti condensation products were formed preferentially and the stereochemical course was rationalized according to Felkin's model. In contrast, the formation of the syn compounds was favored when benzylimines 230 were used as electrophilic species (Scheme 51). In this case a chelation between the imine and zinc halide was proposed to rationalize the preferential formation of syn-lactams 231.²³⁵

Scheme 51

When chiral -amino aldehyde 232 was employed as an electrophile in the Reformatsky reaction, the anti compound 233 was obtained as a single diastereomer and was further transformed into 2'-difluoro nucleoside analogues (Scheme 52).²³⁶

Scheme 52

Alternatively, chiral oxazolidines 234 derived from (R)-phenylglycinol or (R)-aminobutanol were diastereoselectively perfluoroalkylated with BrCF₂CO₂Et in the presence of activated zinc dust to furnish difluoroazetidinones 235 with up to 99% de (Scheme 53).²³⁷

Scheme 53

Somewhat less diastereoselective was the addition of BrCF₂CO₂Et to alkyl- and aryl-substituted N-tert-butylsulfinimines 236, furnishing -N-tert-butylsulfinamyl -substituted ,-difluoropropionates 237 in de's ranging from 60% to 90% (Scheme 54).²³⁸

Scheme 54

A considerable number of papers dealing with the Reformatsky reaction employing ethyl bromodifluoroacetate appeared in the literature, but the stereochemistry was sometimes poor or not always discussed; consequently, these examples will not be detailed in this review.^168,239-250

Another readily available bromofluorocarbon is 1,1-dibromoperfluoroethane (CF₃CFBr₂), which was reacted with Garner's aldehyde 238. The reaction proceeded smoothly in the presence of zinc powder and catalytic AlCl₃ and was highly diastereoselective, affording the anti product 239 in 54% yield with a diastereomeric excess greater than 98% (Scheme 55).²⁵¹

Scheme 55

Portella and co-workers described the perfluoroalkylation of carbohydrate 240 with perfluoroalkylmagnesium reagents and perfluoroalkyltrimethylsilanes. A comparison of the two types of reagents was provided. Silyl reagents added with complete stereoselectivity to the -face, giving the D-allo derivatives 241 as unique observable products, whereas a mixture of D-allo and D-gluco epimers 241 and 242 was obtained from magnesium reagents (Scheme 56).¹⁸³

Scheme 56

4.1.2. Enantioselective Perfluoroalkylation

In 1995, Braun and co-workers disclosed the enantioselective Reformatsky reaction of bromodifluoroacetate with aldehydes. The reaction proceeded with an excess of the Reformatsky reagent in the presence of (1R,2S)-N-methylephedrine (243) to provide the corresponding ,-difluoro--hydroxy esters 244 in good yields and enantioselectivities. Interestingly, the enantioselection was dependent on the amount of chiral ligand. Use of 10 mol % ligand 243 led to a dramatic decrease of enantioselectivity. In addition, aromatic aldehydes gave rather better optical yields than aliphatic aldehydes (Scheme 57).²⁵²

Scheme 57

Andrés and co-workers also reported the asymmetric synthesis of optically active ,-difluoro--hydroxy esters mediated by chiral amino alcohol ligands 245-247 (Figure 13). Aromatic aldehydes led to good enantioselectivities (60-83% ee), while aliphatic ones gave up to 58% ee. Chiral ligands 245 and 246 were equipotent, and 247 was somewhat less efficient.²⁵³

Figure 13 Chiral amino alcohol ligands for enantioselective Reformatsky reaction of bromodifluoroacetate with aldehydes.

The Mukaiyama aldol reaction of silyl enol ethers is one of the most important carbon-carbon bond forming reactions in organic synthesis. The asymmetric Mukaiyama aldol reaction of difluoroketene silyl acetal 248 with various aldehydes, in nitroethane, using Masamune's catalyst 250²⁵⁴ or Kiyooka's catalyst 251²⁵⁵ yielded ,-difluoro--hydroxy esters 249 with excellent yields and high enantioselectivities (Scheme 58). Kiyooka's catalyst was more efficient in the enantioselection with secondary aldehydes than Masamune's catalyst.^256,257

Scheme 58

Additionally, the bromofluoroketene silyl acetal 252 (E/Z = 62/38) was reacted with various aldehydes in the presence of Masamune's catalyst 250 to afford a mixture of syn- and anti-aldol products 253. Although the diastereoselectivity was low, both diastereomers were obtained with high enantioselectivities (90-99% ee) (Scheme 59).²⁵⁸ It is noteworthy that the stereochemical outcome was found to be dependent on the reaction temperature. The reaction of aldehydes with difluoroketene acetal at -78 and -45 C (-20 C in the case of bromofluoroketene acetal) afforded aldol products having opposite signs of optical rotation (Scheme 59). Different transition structures might account for the reversal of the enantioselection.²⁴

Scheme 59

An excellent review on electrophilic perfluoroalkylating reagents has been published by Umemoto; however, no example of asymmetric electrophilic perfluoroalkylation (R_f > CF₃) was reported.²¹² The first report with stereochemical information concerned the perfluoroalkylation of chiral enamine 254 derived from (S)-proline (Scheme 60).²¹⁵ Treatment of enamines 254 with a perfluoroalkyl halide in the presence of Cp₂TiCl₂, Zn powder, and ultrasound afforded the corresponding -perfluoroalkyl ketones 255 with moderate stereoselection.

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Scheme 60 a Reaction run with an (R)-proline auxiliary.

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Blazejewski and co-workers described the synthesis of 7-perfluorohexylestradiol. Reaction of FITS-6 (perfluorohexylphenyliodonium trifluoromethanesulfonate) with silyl enol ether 213 provided the perfluorohexyl steroid 256 in 80% yield with high diastereoselectivity (/ = 10/1) (Scheme 61).

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Scheme 61

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Triethylborane is an effective radical initiator for perfluoroalkyl iodides, which induced the asymmetric trifluoromethylation of chiral N-acyloxazolidinones as reported by Iseki and co-workers.^217,218 The same group extended the method to diastereoselective perfluoroalkylation (R_f)²⁵⁹ of 257, but also to ethoxycarbonyl difluoromethylation (EtO₂CCF₂),²⁶⁰ diethylphosphonate difluoromethylation [(EtO)₂POCF₂],²⁶¹ and bromodifluoromethylation^262,263 (Scheme 62). Various perfluoroalkyl iodides were applicable to the perfluoroalkylation of lithium enolates of N-acyloxazolidinones 257 employing the triethylborane-mediated radical procedure; the corresponding -perfluoroalkylated carboximides 258 were produced in good yields and diastereoselectivities (55-93% de).²⁵⁹ The diastereoselective introduction of the EtO₂CCF₂ group into 257 proceeded under similar conditions provided the chiral imide enolate is added to a solution of ethyl difluoroiodoacetate and triethylborane.^260,264 Diethyl difluoroiodophosphonate [ICF₂PO(OEt)₂] also reacted with the lithium enolate of N-acyloxazolidinone 260 in the presence of Et₃B to provide the diethylphosphonodifluoromethylated product 261 in 92% yield and 77% de.²⁶¹ Interestingly, triethylborane was not necessary for the diastereoselective bromodifluoromethylation of 257 using either dibromodifluoromethane or bromodifluoromethane. An ionic mechanism involving the insertion of difluorocarbene can account for the observations.²⁶⁵

Scheme 62 a In parentheses are given the results of reactions run with CHBrF2.

5. Concluding Remarks

6. References