Enhancement of stereoselectivities in asymmetric synthesis using fluorinated solvents, auxiliaries, and catalysts

Abstract

Organofluorine compounds find diverse applications in the medicinal, agricultural, and material sciences. As a new application, certain organofluorine compounds have been used as ancillary materials in asymmetric synthesis. In this paper, we introduce the asymmetric transformations in which fluorinated solvents, additives, auxiliaries, and catalysts function to improve the stereoselectivities and/or the chemical yields.

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Tsuyuka Sugiishi

Tsuyuka Sugiishi was born in Tokyo. She received Ph.D. in Chemistry from Gakushuin University under the direction of Prof. Hiroyuki Nakamura (2012). And she has worked as a postdoctoral fellow in Institute for Molecular Science for 2 years with Prof. Hidehiro Sakurai (2012–2014). Now, she belongs to Gunma University as an assistant professor. Her interests are discoveries and developments of novel reactions in organic synthesis.

Masato Matsugi

Masato Matsugi was born in Aichi, Japan. He received his B.S. and M.S. degrees from Toyama University and received his Ph.D. degree from Osaka University (supervisor: Prof. Yasuyuki Kita). After working at Otsuka Pharmaceutical Co., Ltd, he moved to Osaka University (Prof. Masatomo Nojima group) as an Assistant Professor in 2000. As a visiting scientist he joined the group of Prof. Dennis P. Curran at University of Pittsburgh (2003–2005). He moved to Meijo University and promoted to Professor in 2010. His current research interests are process chemistry including fluorous chemistry, asymmetric synthesis, and natural product synthesis.

Hiromi Hamamoto

Hiromi Hamamoto was born in Kyoto, Japan, in 1974. He received his B.S. and M.S. degrees from Okayama University and received his Ph.D. (2003) degree from Osaka University under the direction of Professor Yasuyuki Kita. He joined the group of Professor Shiro Ikegami at Teikyo University as a research associate. Then he moved to Kinki University. Since 2012 he is an associate professor at Meijo University. He received the Pharmaceutical Society of Japan Award for a Young Chemist in 2011. His present research focuses on the development of novel synthetic methodology and its application to biologically important compounds.

Hideki Amii

Hideki Amii was born in Hyogo in 1968. He graduated from Kyoto University, where he received his doctorate degree in 1996 under the direction of Prof. Yoshihiko Ito and Prof. Masahiro Murakami. During 1996–2003, he worked as Research Associate of Okayama University (Prof. Kenji Uneyama's group). He carried out postdoctoral work in France with Dr Guy Bertrand at Université Paul Sabatier during 2000–2001. In 2003, he was appointed to Associate Professor of Kobe University. Now, he joins Gunma University as Professor of Chemistry. His research interest focuses in the synthesis of organofluorine compounds by the use of metal reagents.

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1. Introduction

The development of asymmetric synthesis has continued to grow exponentially over the last three decades.¹ Production of single enantiomers is quite important because most of chiral drugs exhibit different pharmacological effects between their homochiral and racemate forms. Due to the increased demand of optically active substances in academic and industrial fields, catalytic asymmetric transformations are vigorously studied all over the world for the effectiveness of synthetic processes. However, even now, asymmetric synthesis of chiral molecules is still often faced with problems such as low stereoselectivities of the reactions. Therefore, a new technology for highly selective synthesis of enantiomerically pure compounds has been required.

Organofluorine compounds are the substances of considerable interest in various industrial fields.² Introducing of fluorine atoms often endows the parent (non-fluorinated) organic molecules with attractive properties. Fluorine is now an important element by virtue of unique properties associated with the atom and its bond to carbon, its high electronegativity and the relatively small size. Due to these attractive properties, organofluorine compounds have been widely used in the design of pharmaceuticals, agrochemicals, refrigerants, dyes, liquid crystals, optical fibers, and highly durable polymers. Recently, certain fluoroorganic compounds have been applied as ancillary materials in asymmetric synthesis. For instance, the conformational study of organofluorine compounds has impacted on asymmetric catalysts.^3,4 In 2014, Cahard and Bizet have published the excellent tutorial reviews titled ‘the influence of fluorine in asymmetric catalysis’ and ‘fluorine as a control element in asymmetric synthesis’.⁵ They introduced the unique properties of organofluorine compounds as mainly substrates and catalysts in asymmetric transformations. Herein, we focus on the asymmetric transformations in which fluorinated solvents, auxiliaries, and catalysts play important roles to enhance the stereoselectivities and/or the chemical yields (Scheme 1).

Scheme 1 Asymmetric synthesis with fluorinated compounds as controlling tools.

2. Organocatalysis in fluoroaromatic solvents

Benzotrifluoride (BTF), fluorobenzene (PhF), and hexafluorobenzene (C₆F₆) are well-known commercially available fluoroaromatic materials, which can be used in screening of solvent effects (Fig. 1). In particular, it was reported that BTF can behave as an alternative solvent to dichloromethane because of its dissolving potential in organic synthesis.⁶ Not only in order to substitute for the other solvents avoiding shortcomings in the original reactions, but also to find unique physical properties fluoroaromatic solvents have, it is significant to survey the asymmetric synthesis in which fluoroaromatic solvents are employed.

Fig. 1 Representatives of fluoroaromatic compounds.

First, the examples using BTF solvent are introduced. Shibata et al. reported asymmetric allylic monofluoromethylation of Morita–Baylis–Hillman carbonates with fluorobis(phenylsulphonyl)methane (FBSM) using a bis(cinchona alkaloid), which provides chiral α-methylene β-monofluoromethyl esters with high ee values (Scheme 2).⁷ Toluene and BTF were found to be suitable for this reaction with a catalytic amount of (DHQD)₂AQN. The yield of 1 was improved at a slightly higher reaction temperature.

Scheme 2 Asymmetric organocatalysed allylic monofluoromethylation of Morita–Baylis–Hillman carbonates.

BTF was also used for N-acylaminophosphine-catalysed asymmetric [4 + 2] cycloaddition of allenoates and imines reported by Zhao and coworkers.⁸ An examination of the solvent effects revealed that BTF, which has no hydrogen-bonding acceptor atom (O or N) but is a polar aromatic solvent, was favorable in terms of the enantioselectivity and reaction time, albeit with moderate yields (Scheme 3). As a compromise between yield and ee value, the reaction could be performed in a co-solvent of CH₂Cl₂ and BTF (v/v = 1/1).

Scheme 3 Asymmetric [4 + 2] cycloaddition.

Fluorobenzene and hexafluorobenzene are common chemicals. In 2013, Alexakis et al. reported that fluorobenzene was effective as a solvent for the enantioselective fluorination-induced Wagner–Meerwein rearrangement because of the highly hydrophobic, yet strongly solubilizing ability (Scheme 4).⁹ Since nonpolar solvents favor ion pairing, the asymmetric synthesis is an example of anionic phase-transfer catalysis, where a lipophilic chiral anion extracts the insoluble fluorinating reagent such as selectfluor into the organic layer, thus rendering it chiral. Accordingly, employing a 1 : 1 mixture of fluorobenzene and n-hexane, and lower temperature led to an increase of the enantioselectivity obtained to 86% ee.

Scheme 4 Asymmetric Wagner–Meerwein rearrangement.

The enantioselective fluorocyclisations using selectfluor and anionic phase-transfer phosphoric acid catalysts in nonpolar solvents was developed by Toste.¹⁰ Both BTF and fluorobenzene were effective for the enantioselective fluoroamination via 1,4-addition to conjugated dienes (Scheme 5).¹¹ Screening of the reaction conditions afforded the complete conversion of the starting materials with high enantioselectivity (96% ee) in BTF or PhF.

Scheme 5 Enantioselective fluoroamination via 1,4-addition to conjugated dienes.

Hexafluorobenzene, an electron-poor arene, is very famous by the π–π interaction with benzene to make C₆F₆–C₆H₆ cocrystals.¹² The effect of C₆F₆ on the asymmetric α,α-l-diaryl prolinol-catalysed nitro-Michael addition was disclosed by Lattanzi and Cavallo et al. (Scheme 6).¹³ Optimisation study with trans-β-nitrostyrene, cyclic β-keto ester, and catalyst 5 or 6 in toluene afforded modest values of the diastereo- and enantioselectivity. However, when catalyst 5 was employed, screening in fluoroaromatic solvents such as BTF and C₆F₆ showed significant improvement of diastereo and enantioselectivity. Moreover, much higher stereoselectivity was observed in the reaction with catalyst 6 performed in C₆F₆. DFT calculations indicate C₆F₆ would have electrostatic interaction with electron density delocalised on the enolate π orbitals on the stereoselectivity determining step. C₆F₆ ring stacked over the enolate moieties would generate steric interactions with the reaction system to increase the optimal preference.

Scheme 6 Asymmetric α,α-l-diaryl prolinol-catalysed nitro-Michael addition.

3. Metal-catalysed reactions in fluoroaromatic solvents

Development of novel catalyst systems involving transition metals for enantioselective transformation is one of the most fascinating and important subjects in organic synthesis. To date, asymmetric catalysis in fluoroaromatic solvents have been investigated.¹⁴ In the study of asymmetric copper(II)-catalysed Friedel–Crafts alkylation of indols with nitroalkanes, BTF was the best solvent which led to the high ee value keeping quantitative conversion of the substrate at a lower temperature (Scheme 7).¹⁵

Scheme 7 Asymmetric copper(II) catalysed Friedel–Crafts alkylation of indoles with nitroalkanes.

Enantioselective [2 + 1] cycloaddition of alkynes with carbenes is one of the most powerful methods for the synthesis of chiral cyclopropenes. For asymmetric reactions of alkynes with acceptor/acceptor-substituted diazo reagents involving cobalt(II)-based metalloradical catalysis, BTF performed significantly better than other solvents screened (Scheme 8).¹⁶ The reaction did not proceed in high yields, and neither high ee values were observed even in the cases other aromatic solvents such as PhCl, PhF, PhMe, and PhH were used.

Scheme 8 Asymmetric [2 + 1] cycloaddition via cobalt(II)-based metalloradical catalysis.

Trost et al. employed palladium-catalysed asymmetric allylic alkylation of malonates as a key transformation for synthesis of (−)-ranirestat, an aldose reductase inhibitor (Scheme 9).¹⁷ In the optimisation study of reaction conditions, enantioselectivities were improved with the use of aromatic solvents. Hexafluorobenzene proved to be the optimal solvent for this transformation, providing the allylated product 10 in 90% yield and 84% ee.

Scheme 9 Asymmetric palladium-catalysed allylic alkylation of malonates.

For [7]helicene synthesis via asymmetric olefin metathesis, Collins and Grandbois examined aromatic solvents in the screening of reaction conditions (Scheme 10).¹⁸ With regard to enantioselectivity, a modest increase was produced by switching from CH₂Cl₂ to benzene as the solvent, and a further increase was observed when BTF was used. The use of hexafluorobenzene afforded the highest ee, however the reaction in a 1 : 1 mixture of CH₂Cl₂ and C₆F₆ resulted in a decrease in ee and conversion. The solvent obviously plays an important role in the stereochemistry of [7]helicene, and plausibly interact with the substrate.

Scheme 10 [7]Helicene synthesis via asymmetric olefin metathesis.

Fluoroaromatic solvents are also utilised for oxidation of organic compounds.¹⁹ Asymmetric epoxidation of aromatic olefins using salen catalyst was reported by Matsugi and co-workers.²⁰ During the study, to use the co-solvent of acetonitrile and BTF was found to be effective for the enantioselectivity (Scheme 11). The enantiomeric excess was increased by addition of BTF with acetonitrile to 65% ee in 1 : 1 ratio of BTF and acetonitrile.

Scheme 11 Asymmetric epoxidation of aromatic olefins using salen catalyst 11.

4. Catalytic asymmetric hydrogenation in fluoroalcohol solvents

Fluoroalcohols attract attentions since they differ from other usual alcohols in following properties: (1) high polarity, (2) high acidity, (3) excellent proton donor, (4) low nucleophilicity, and (5) strong tolerance to oxidation.²¹ Among fluorinated solvents, 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) are representative commercially available fluoroalcohols, so that some of asymmetric reactions have been achieved using TFE or HFIP (Fig. 2).

Fig. 2 Typical examples of fluoroalcohols.

Tolerance toward oxidation

Catalytic asymmetric synthesis of fluorinated amino acids is a subject of considerable interest.²² For the construction of chiral centres of α-amino acids, enantioselective reactions of the imino (C=N) moieties in fluorinated iminoesters provide a promising route. In general, enantioselective transformation of imines have been still a challenging subject in organic chemistry.²³ Uneyama et al. have reported the first successful asymmetric transition-metal-catalysed hydrogenation of acyclic α-iminoesters for synthesis of β-fluorinated α-amino esters, which was achieved by the use of fluorinated alcohol solvents. In ordinary (nonfluorinated) solvents, when α-iminoester 13 was subjected to hydrogen pressure in the presence of a small amount of chiral palladium complex, α-aminoester 14 formed in low to moderate ee (Table 1).²⁴ Nucleophilic solvents such as ethanol and methanol attacked the imino carbon of 13 to give α-alkoxylated aminoesters. In 2,2,2-trifluoroethanol (TFE), both the yield and ee were dramatically improved.

Table 1 Effects of solvents on asymmetric hydrogenation

Entry	Solvent	Yield^a, %	ee^b, %
a Isolated yields.b Determined by HPLC.c Pd(OCOCH3)2 was used.d Reaction temperature was 35 °C.e 5 eq. of n-Bu4NHSO4 was added.
1	Toluene^c^,^d	52	39 (S)
2	CH3CO2H^c	39	4 (R)
3	i-PrOH^c	Trace	61 (S)
4	TFE	>99	88 (R)
5^e	TFE	84	91 (R)
6	CF3CF2CH2OH	94	88 (R)
7	HFIP	>99	69 (R)

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As a practical application, they succeeded in the asymmetric hydrogenation of the bromodifluoromethyl iminoester 15 to the synthesis of optically active β,β-difluoroglutamic acid derivative 18 and β,β-difluoroproline derivative 19 (Scheme 12).²⁵ The present application suggests that the Pd/BINAP/TFE system for catalytic asymmetric hydrogenation gave successful outcomes from the viewpoint of the development of biologically active fluorinated compounds.

Scheme 12 Application of asymmetric hydrogenation with fluorinated iminoester 15 and Pd/BINAP/TFE system.

A study of fluoroalcohol effects on catalytic asymmetric hydrogenation was carried out by Mikami and co-workers. Mikami et al. demonstrated asymmetric synthesis of perfluoroalkyl amines catalysed by iridium complex with BINAP. When an electron-withdrawing benzonitrile-derived imine, which has a sterically demanding phenyl group at the α-position, was employed, the use of acidic TFE as a solvent led to the significant increase in enantioselectivity. Comparing with the lower ee value in the case of the reaction in CH₂Cl₂, the hydrogen bonding network between TFE solvent and the perfluoroalkyl substituted imine including the weak electrostatic attraction of C–H/F–C type might stabilise the geometry of the imine to prevent it from isomerizing (Scheme 13).²⁶

Scheme 13 Iridium-catalysed asymmetric hydrogenation.

Independently, Zhou et al. explored the palladium-catalysed asymmetric hydrogenation of non-fluorinated imines^27a,27b and functionalised ketones^27c to find only TFE is effective in terms of the conversion and enantioselectivity (Scheme 14). In 2010, they reported palladium-catalysed asymmetric hydrogenation of unprotected indoles (Scheme 15).²⁸ In the reaction, unprotected indoles undergo the hydrogenation through formation of iminium salt by addition of camphorsulfonic acid (CSA). TFE has been the best solvent, and combination of dichloromethane (DCM) and TFE in 1 : 1 ratio resulted in complete conversion and higher ee.

Scheme 14 Palladium-catalysed asymmetric hydrogenation of non-fluorinated imines and functionalised ketones.

Scheme 15 Palladium-catalysed asymmetric hydrogenation of unprotected indoles.

Fluorinated alcohols such as TFE and HFIP have been employed for stereoselective hydrogenation of unsaturated organic molecules.^21b,29 As overviewed above, several beneficial effects using fluoro alcohol solvents on the selectivities in asymmetric hydrogenation have been observed. Fluorinated alcohols will be widely used for good candidates of solvent for catalytic hydrogenation.

5. Enantioselective transformation using fluoroalcohol additives

Besides enantioselective hydrogenations, carbon–carbon and carbon-heteroatom bond forming reactions have been explored to date. In asymmetric piperidine synthesis, polar protric acids such as MeOH and EtOH performed well, but the enantioslectivities were moderate (Scheme 16).³⁰ Desired compound 21 was obtained with higher enantioinselectivity in TFE, a more acidic solvent.

Scheme 16 Organocatalysed asymmetric piperidine synthesis.

The flavin-catalysed asymmetric Baeyer–Villiger reaction³¹ in TFE as a sole solvent gave (S)-22 with low enantioselectivity, because the non-catalysed reaction with hydrogen peroxide occurs fast. When a mixture of solvents (TFE/MeOH/water 6 : 3 : 1) was used, both non-catalysed reaction and ketalisation were retarded, and higher enantioselectivity was observed (Scheme 17). A protic solvent is essential to obtain higher enantioselectivity, which indicates that the hydrophobic π–π stacking between the aromatic ring of the catalyst 23 and that of a substrate seems to play an important role in asymmetric induction.

Scheme 17 Flavin-catalysed asymmetric Baeyer–Villiger reaction.

Evans et al. succeeded in the development of asymmetric amination of silylenolates with a chiral bis(oxazoline) copper(II) complex, in which rate-limiting catalyst turnover was improved by addition of 1 equiv. of TFE (Scheme 18).³² On the other hand, in the Michael reactions of silylenolates to alkylidene malonates (Scheme 19)³³ or imides (Scheme 20),³⁴ HFIP was utilised in order to promote catalyst turnover and to inhibit oligomerisation of silyl enolates.

Scheme 18 Asymmetric amination of silylenolates with a bis(oxazoline) copper(II) complex.

Scheme 19 Asymmetric Michael addition of silylenolates to alkylidene malonates.

Scheme 20 Asymmetric Michael addition of silylenolates to imides.

In the case of asymmetric conjugate addition of silylenolates to β-enamidomalonates reported by Sibi et al., nonuse of HFIP as an additive had a negative influence on both yield and enantioselectivity (Scheme 21).³⁵ However, the HFIP is not absolutely necessary for turnover in contrast to Evans' results. It may be that the enamide functions as a proton source in the absence of HFIP.

Scheme 21 Asymmetric conjugate addition of silylenolates to β-enamidomalonates.

Kobayashi et al. demonstrated an approach to the synthesis of α-aminophosphonates from silylenolates and N-acyl-α-iminophosphonates catalysed by a chiral copper(II)-diamine complex (Scheme 22).³⁶ It was found that HFIP was suitable as an additive for the reaction to improve the yields and enantioselectivity. Considering the reaction mechanism, HFIP would release the copper catalyst from the product α-aminophosphonates, which is a strong Lewis base.

Scheme 22 Copper(II)-diamine-catalysed addition of silylenolates to N-acyl-α-iminophosphonates.

Fluorination and fluoroalkylation of organic molecules are one of the most useful approaches to organofluorine compounds.³⁷ Cahard et al. reported asymmetric copper(II)-bis(oxazoline)-catalysed fluorination of β-ketoesters (Scheme 23).³⁸ Interestingly, addition of one equivalent of HFIP led to an increase in enantioselectivity.

Scheme 23 Copper(II)-bis(oxazoline)-catalysed asymmetric fluorination.

Wang and Zhou et al. speculated the use of alcoholic additives to improve the reactivity of the asymmetric Strecker reaction (Scheme 24).³⁹ HFIP (1.0 equiv.) was able to promote the reaction without loss of ee, most of the other alcohols or phenols decreased enantioselectivity instead.

Scheme 24 Asymmetric Strecker reaction.

6. The use of fluoroalcohols as chiral auxiliaries and catalyst ligands

Asymmetric protonation of prochiral lithium enolates was achieved in 97% ee using a chiral β-hydroxy sulfoxide which has a chiral trifluoromethylalcohol moiety (Scheme 25).⁴⁰ The reaction completed below −50 °C due to the considerably high acidity of the proton induced by strong electron-withdrawing CF₃-substituted.

Scheme 25 Asymmetric protonation of lithium enolates.

Katagiri and Uneyama et al. developed asymmetric Simmons–Smith cyclopropanation of allylic amines taking advantage of the α-trifluoromethyl-β-aminoalcohol auxiliary (Scheme 26).⁴¹ The cyclopropanation resulted in not only dramatic acceleration of reaction rate by the strong electron-withdrawing trifluoromethyl group but also excellent diastereoselectivity by bulkiness of the trifluoromethyl group.

Scheme 26 Asymmetric cyclopropanation with the fluoroalcohol auxiliary.

α-Trifluoromethyl-β-aminoalcohol 31 worked effectively as a chiral ligand in asymmetric Reformatsky reaction (Scheme 27).⁴² The Reformatsky reagent which was prepared from ethyl iodoacetate underwent 1,2-addition to benzaldehyde to give β-hydroxyesters in a highly stereo-controlled manner.

Scheme 27 Asymmetric Reformatsky reaction with α-trifluoromethyl-β-aminoalcohol.

Omote et al. developed various fluoroalcohols 32–34 as chiral organo catalysts (Scheme 28).⁴³ Particularly, perfluoroalkylated ligand 34 showed an excellent asymmetric induction on the addition of dimethylzinc to aldehydes, although only a small number of studies on the methylation have been reported with the other catalysts probably due to the lower reactivity of dimethylzinc than those of its higher homologues.^43a

Scheme 28 Various fluoroalcohols designed for chiral organocatalysts.

Amii et al. found the axially chiral phosphine compound (R)-35 endowed with a fluoroalcohol moiety to be an effective ligand for Rh(I)-catalysed asymmetric arylation of aromatic aldehydes with arylboronic acids (Scheme 29).⁴⁴ Despite the difficulty of high enantioselective synthesis with arylboronic acids, the presence of a weakly acidic fluoroalcohol moiety in the ligand (R)-35 afforded enantiomerically enriched diaryl methanol (Scheme 30). The substrate scope in the Rh-catalysed arylation using ligand (R)-35 is shown in Table 2 with higher enantioselectivities. It was suggested that ligand (R)-35 with transition metals would form the suitable catalysts, in which structure bulky trifluoromethyl groups would create the chiral coordination environment.

Scheme 29 Axially chiral phosphine ligand with a fluoroalcohol moiety.

Scheme 30 Effect of a fluoroalcohol moiety in axially chiral phosphine ligand (R)-35.

Table 2 Rhodium-catalysed 1,2-addition of arylboronic acids to aromatic aldehydes

Entry	Ar^1	Ar^2	Yield^a%	ee^b%
a Isolated yield.b Enantiomeric excesses were determined by HPLC analyses.c These reactions were carried out at 30 °C for 24 h.
1	4-MeC6H4	Ph	78	82 (R)
2	2,4-Me2C6H3	Ph	75	82 (R)
3^c	4-^iPrC6H4	Ph	68	86 (R)
4^c	4-MeOC6H4	Ph	56	90 (R)
5	3,4-(OCH2O)C6H3	Ph	96	81 (R)
6	4-MeC6H4	4-AcC6H4	57	80 (+)
7^c	Ph	4-ClC6H4	99	87 (S)
8^c	4-MeC6H4	4-ClC6H4	64	88 (S)
9^c	4-MeOC6H4	4-ClC6H4	84	89 (S)
10^c	4-MeOC6H4	3-ClC6H4	73	92 (S)
11^c	2-Thienyl	4-ClC6H4	93	90 (S)
12^c	2-Thienyl	3-ClC6H4	74	91 (S)

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7. Application of perfluoroalkylated molecular catalysts to asymmetric synthesis

Funabiki et al. investigated the application of fluoroalkylated prolinols as chiral molecular catalysts (Scheme 31).⁴⁵ Particularly, as the purification of product and the recycle of the catalyst are facile, fluorous⁴⁶ oxaborolidine boran complex 37 showed high functionality as a chiral reduction catalyst. They also prepared prolinol methyl ether 38, which is the derivative of prolinol 36, and investigated its application as an asymmetric organocatalyst for the Michael reactions of nitroalkenes with aldehydes (Scheme 32).⁴⁷ The diastereoselectivity with 38 was much higher than that with non-fluorinated prolinol methyl ethers 39 and 40, which have two n-octyl groups or two phenyl groups respectively in place of (perfluorohexyl)ethyl groups. From the advantageous point of reusability, the catalyst 38 was recoverable by solid-phase extraction using fluorous reverse-phase silica gel.

Scheme 31 Application of fluoroalkylated prolinol.

Scheme 32 Effect of fluoroalkyl chains in chiral prolinol ethers on diastereoselectivity.

Perfluoroalkylsulphonyl groups in chiral organic molecules can act as a controlling tool in asymmetric synthesis. Direct asymmetric aldol reactions in brine in the presence of fluoroalkyl sulphonamides 41 and 42 yield anti-aldol products 43 and 44, respectively (Scheme 33).⁴⁸ Interestingly, by the use of the same chiral source, the positional difference of fluoroalkylsulfonyl groups between organocatalysts 41 and 42 afforded the opposite absolute configuration of products 43 and 44 to each other. The acidity of sulphoamides 41 and 42 might be enhanced by the electron withdrawing effect of fluoro alkyl groups. It is possible that the acidic proton of sulphonamide group in the enamine intermediate coordinates to aldehyde to stabilise the rigid transition state.

Scheme 33 Asymmetric aldol reactions with chiral fluoroalkyl sulphonamides.

Fluoroalkyls groups on aryl rings in organocatalysts are a key element for stereoselective synthesis. In the screening of cinchona alkaloid catalysts for asymmetric Michael addition of 1-fluorobis(phenylsulphonyl)methane (FBSM) to α,β-unsaturated ketones, the quinidiniums bearing various benzyl substituents on each quaternary nitrogen atom were examined. The benzyl substituent which has two 3,5-bis(trifluoromethyl)phenyl groups provided Michael adduct (S)-46 in high yield with excellent enantioselectivity (Scheme 34).⁴⁹

Scheme 34 Asymmetric Michael addition of FBSM.

In 2014, Ishihara and co-workers reported asymmetric synthesis of tocopherols via oxidative cyclisation by using chiral ammonium iodides and hydroperoxides. The biphenyl groups at the 3,3′ positions in chiral ammonium iodide (R,R)-47 led generation of product (S)-48 in major, and the fluoroalkyl-substituents of the 3,3′-binaphthyl moiety in (R,R)-47 had drastic effects on enantioselectivity and reactivity (Scheme 35).⁵⁰

Scheme 35 Asymmetric synthesis of tocopherols via oxidative cyclisation using chiral ammonium iodides.

8. Fine-tuning of stereoselectivity by a C–F bond

Concerning with C–F bond, which is the fundamental unit of organofluorine compounds, O'Hagan highlighted the electrostatic character,⁵¹ and Hunter introduced the conformational effect in the review.³ And Gilmour et al. published the reviews about molecular design of organocatalysts comprehensively.⁴ Configurations of fluoroaliphatic compounds depend not only on their steric requirements but also on their electronic properties, relating with the explanation of the fluorine “gauche effect”. The high electronegativity of fluorine polarises the C^δ+–F^δ− bond, and hyperconjugative electron-donation from a vicinal C–H bonding σ orbital to antibonding orbital of the C–F bond stabilises the gauche conformation. Contrast to the steric repulsion of fluorine with the heteroatom (X), the gauche conformation is preferable rather than anti conformation (Fig. 3).

Fig. 3 Gauche effect.

Accordingly, the configurationally defined fluorine substituents are able to behave differently from other substituents. Therefore catalysis tuning by a C–F bond is one of the splendid stereocontrol strategies because fluorine substituents can stabilize preferential molecular conformations and enhance the enantioselectivities.⁵² List et al. noticed that proline catalysts bearing a substituent at the 4-position could give elevated levels of enantiocontol, in addition to (S)-proline itself catalysing asymmetric reactions. The trans-4-fluoro derivative gave the highest enantioselectivity in the transannular aldol reaction (Scheme 36).⁵³ The configulationally stabilised iminium intermediates would contribute to the stereoselectivity.

Scheme 36 Proline-catalysed asymmetric transannular aldol reaction.

Gilmour and co-workers et al. revealed the gauche effect of β-fluoroiminium ion with design of (S)-2-(fluorodiphenylmethyl) pyrrolidine 49.⁵⁴ Furthermore, application of catalyst 49 to enantioselective aziridination of enals was achieved (Scheme 37).⁵⁵ Asymmetric catalytic epoxidation using trans-cinnamaldehydes proceeded diastereo- and enantioselectively due to the stable β-fluoroiminium ion intermediate. Electrostatic/charge-dipol (σ_C–H → σ*_C–F; F^δ−⋯N⁺) interactions would render the C–H and C–F bonds antiperiplanar and the torsion angle F^δ−–C_β–C_α–N⁺ small in the intermediate.

Scheme 37 Fluorinated pyrrolidine-catalysed enantioselective aziridination.

Triazolium salts have been employed as NHC (N-heterocyclic carbene) catalysts 50 for enantioselective reactions. Rovis and co-workers demonstrated that fluorinated bicyclic triazolium salt 50b improved the enantioselectivity in Stetter reaction (Scheme 38).⁵⁶ It is proposed that the fluorine atom would induce a conformational stabilisation of transition state with a gauche effect to orient the incoming nitroalkene electrophile.

Scheme 38 Fluorinated NHC catalyst for intermolecular asymmetric Stetter reaction.

Another example of NHC catalyst 51 was developed for asymmetric Steglich rearrangement of oxazolecarbonates (Scheme 39).⁵⁷ A couple of fluorines located on each position of F^δ−–C_β–C_α–N⁺ systems in catalyst 51 confer the most significant advantage as far as Gilmour et al. investigated.

Scheme 39 Fluorination of NHC catalyst for asymmetric Steglich rearrangement.

Cinchona alkaloids are versatile catalysts for asymmetric synthesis because of the remarkable performance in transformations, the natural abundance, and commercial availability. Gilmour and co-workers designed C9-substituted alkaloid catalysts 52 expecting fluorine stereoelectronic and electrostatic effects for conformational control (Scheme 40).⁵⁸ Comparison of C9-fluorinated catalyst 52a with the other functionalized catalysts 52b–52e elucidates the restricted internal rotation around C8–C9 (F^δ−–C_β–C_α–N⁺) by gauche effect of β-fluoroiminiumes. They applied fluorinated cinchona alkaloids to heterogeneous asymmetric hydrogenation of α-ketoesters.⁵⁹

Scheme 40 C9-substituted alkaloid catalysts for asymmetric fluorination.

As highlighted so far, a fluoro group can stabilise preferential molecular conformations and enhance the enantioselectivities. Besides asymmetric transformation, Grubbs and co-workers demonstrated that fluorinated NHC ligands showed a significant rate enhancement in Ru-catalysed olefin metathesis through intramolecular F⋯Ru interaction.⁶⁰ Recently, a drastic change of regioselectivity taken place by fluorine acting as a steering group has been reported by Yu et al.⁶¹ A fluorine atom incorporated in the directing group of the starting material amines effects on the meta-selective C–H olefination.

9. Conclusion

In summary, the notable examples of catalytic stereoselective transformations with assistance provided by organofluorine compounds have been described. Needless to say, fluorine-containing molecules have been utilised in many areas including medicine, agriculture, electronics, materials. As highlighted here, organofluorine compounds (as solvents, auxiliaries, additives, and catalysts) exhibit profound effects on stereoselectivities in asymmetric transformations. New exciting advances of organofluorine compounds as a powerful tool for selective transformations to afford useful materials will undoubtedly emerge in the future.

Acknowledgements

The financial support of the Ministry of Education, Culture, Sports, Science and Technology of Japan and Japan Science and Technology Agency (JST) (ACT-C: Creation of Advanced Catalytic Transformation for the Sustainable Manufacturing at Low Energy, Low Environmental Load). We would like to thank Prof. Tsuyoshi Miura (Tokyo University of Pharmacy and Life Sciences) and Prof. Kazuaki Ishihara (Nagoya University) for their useful suggestions.

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