Recent advances in catalytic enantioselective construction of monofluoromethyl-substituted stereocenters

Abstract

Chiral organofluorine compounds featuring a monofluoromethyl (CH₂F)-substituted stereocenter are often encountered in a number of drugs and bioactive molecules. Consequently, the development of catalytic asymmetric methods for the enantioselective construction of CH₂F-substituted stereocenters has made great progress over the past two decades, and a variety of enantioselective transformations have been accordingly established. According to the types of fluorinated reagents or substrates employed, these protocols can be divided into the following major categories: (i) enantioselective ring opening of epoxides or azetidinium salts by fluoride anions; (ii) asymmetric monofluoromethylation with 1-fluorobis(phenylsulfonyl)methane; (iii) asymmetric fluorocyclization of functionalized alkenes with Selectfluor; and (iv) asymmetric transformations involving α-CH₂F ketones, α-CH₂F alkenes, or other CH₂F-containing substrates. This feature article aims to summarize these recent advances and discusses the possible reaction mechanisms, advantages and limitations of each protocol and their applications. Synthetic opportunities still open for further development are illustrated as well. This review article will be an inspiration for researchers engaged in asymmetric catalysis, organofluorine chemistry, and medicinal chemistry.

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Bo-Jie Li

Bo-Jie Li received the PhD degree from the Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, China, in 2013. He joined the Hubei Engineering University as a lecturer in 2014. He is currently working in Prof. Lei Zhu's group as a research assistant.

Yu-Long Ruan

Yu-Long Ruan was born in Henan, China. After obtaining his BSc degree from Donghua University in 2022, he joined the East China Normal University as a graduate student under the guidance of Prof. Jin-Sheng Yu. His thesis work focuses on the catalytic asymmetric desymmetrizations of functionalized Si-stereogenic organosilanes.

Lei Zhu

Lei Zhu received a BS degree from the University of Science and Technology of China, Hefei, in 2006, and a PhD degree from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China, in 2013, working with Professor T.-Y. Luh. He spent 2 years as a Postdoctoral Fellow and 1 year as an Assistant Professor at the University of Tokyo, Japan, working with Prof. S. Kobayashi. He joined Hubei Engineering University, Hubei, as a full Professor in 2016. His current research interests include green and biomaterial chemistry.

Jian Zhou

Jian Zhou obtained his PhD degree in 2004 from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, under the guidance of Prof. Yong Tang. After spending one year working as a postdoctoral fellow with Professor Shū Kobayashi at the University of Tokyo and three years with Professor Benjamin List at Max-Planck-Institut für Kohlenforschung, he joined the Shanghai Key Laboratory of Green Chemistry and Chemical Processes at East China Normal University as a professor at the end of 2008. His research interests include the development of new chiral catalysts and asymmetric reactions for the construction of tetrasubstituted carbon stereocenters.

Jin-Sheng Yu

Jin-Sheng Yu received his PhD degree from East China Normal University in 2016 under the guidance of Prof. Jian Zhou. After two years as a JSPS postdoctoral fellow with Prof. Masakatsu Shibasaki at the Institute of Microbial Chemistry, he joined East China Normal University as a Zijiang Young Scholar. His research interests include organosilicon and organofluorine chemistry, asymmetric catalysis, and biochemical pesticides.

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1. Introduction

The unique properties¹ of the fluorine atom and the carbon–fluorine bond make organofluorine compounds increasingly important in the discovery of modern pharmaceuticals, agrochemicals, and materials science,² as evidenced by the fact that approximately 30% of agrochemicals³ and 20–25% of all marketed pharmaceuticals⁴ feature at least one fluorine atom. This mainly results from the introduction of a fluorine atom or fluoroalkyl group, which can drastically modulate the physicochemical and/or biological properties of a molecule.⁵ As a consequence, tremendous efforts have been dedicated to developing efficient and facile synthetic methods for the selective construction of fluorinated molecules with structural diversity over the past decades.⁶

Among them, monofluoromethyl-containing compounds have recently found increasing applications in drug and agrochemical discovery,² because the monofluoromethyl (CH₂F) group proves to be an ideal bioisoster of methyl, hydroxymethyl, and other functionalities,⁷ which often significantly improve the biological properties of parent molecules once introduced.⁵ In particular, CH₂F-substituted stereocenters are widely present in drugs and bioactive molecules,^8–12 as illustrated in Fig. 1. For example, carmegliptin (1), bearing a CH₂F-substituted stereocenter, is an investigational oral anti-hyperglycemic drug for the treatment of type 2 diabetes;⁸ CH₂F-containing nucleoside SFDC (3) has high antiherpes and antitumor activities;⁹ florfenicol (4) is a broad-spectrum bacteriostatic antibiotic used exclusively in veterinary medicine to treat the pathology of farm and aquatic animals;¹⁰ and (S)-α-CH₂F-dopa (5) is an inhibitor of dopa decarboxylase.¹¹ In addition, the use of monofluoromethyl to replace the methyl group of (S)-ibuprofen significantly improves its inhibitory activity toward COX-1 with almost an equal pharmacokinetic profile, thus showing enhanced analgesic activity and reduced gastric damage.¹²

Fig. 1 Selected drugs or bioactive molecules with CH₂F-substituted stereocenters.

In this context, the development of catalytic asymmetric methods for the diverse construction of CH₂F-substituted stereocenters has gained much attention and has become a hot research topic. Accordingly, plenty of elegant, highly enantioselective catalytic transformations have been established to access various molecules featuring CH₂F-substituted stereocenters in the past two decades. As demonstrated in Fig. 2, these protocols can be classified into the following major categories, according to the types of fluorinated reagents or substrates used in the reaction: (1) enantioselective ring opening of epoxides or azetidinium salts by fluoride anions; (2) asymmetric monofluoromethylation with 1-fluorobis(phenylsulfonyl)methane (FBSM); (3) asymmetric fluorocyclization of functionalized alkenes with Selectfluor; (4) asymmetric reduction or nucleophilic addition of α-CH₂F ketones; (5) asymmetric transformations involving α-CH₂F alkenes; and (6) miscellaneous, e.g., hydromonofluoromethylation of activated alkenes with ICH₂F, or reductive desymmetrization of α-CH₂F-substituted malonic ester.

Fig. 2 Catalytic asymmetric synthetic strategies for CH₂F-substituted stereocenters.

Despite significant progress, however, to our knowledge, there is a lack of comprehensive review articles to summarize the advances in the catalytic enantioselective construction of CH₂F-substituted stereocenters¹³; in sharp contrast, many elegant reviews have been published to introduce advances in the selective difluoro- or trifluoroalkylation.⁶ In light of this, we feel it is necessary to present a timely review that focuses on elucidating the evolution of constructing CH₂F-substituted stereocenters, outlining the synthetic opportunities still open, thus providing related researchers with some reference and inspiration to develop more useful and diverse approaches for installing chiral organofluorine compounds bearing CH₂F-substituted stereocenters. In the following section, we introduce advances according to the classification shown in Fig. 2.

2. Enantioselective ring opening of epoxides or azetidinium triflates by fluoride anions

Although catalytic enantioselective ring opening of racemic epoxides and their analogs by various nucleophiles has been identified as a powerful method for the synthesis of chiral compounds,¹⁴ no report on employing fluoride as a nucleophile has been published until 2000. During the study in developing the first enantioselective ring opening of epoxides 8 with hydrofluorinating agents enabled by chiral Lewis acids, Bruns and Haufe found that the use of 50 mol% chiral salen-CrCl 10 could efficiently enable the ring opening of racemic styrene epoxide or phenyl glycidether 8 with KHF₂/18-crown-6 (eqn (1), Scheme 1).¹⁵ It could deliver the desired α-CH₂F substituted chiral secondary alcohols 9, which are value-added fluorinated building blocks for chemical synthesis, in 57–70% yields (based on converted epoxides) and 62–90% ee. Ten years later, by using a cooperative dual-catalyst system consisting of 5 mol% (R,R)-salen-Co(II) 11 with 4 mol% DBN, the Doyle group reported a highly enantioselective ring opening of terminal epoxides 8 with PhCOF/HFIP as the latent fluoride source, which delivered the corresponding α-CH₂F-substituted alcohols ent-9 with 88–99% ee and 36–44% yields (eqn (2), Scheme 1).¹⁶ Subsequently, they investigated the mechanism of this salen-Co(II) and amine-cocatalyzed asymmetric epoxide ring-opening, and a bimetallic mechanism, as shown in Scheme 1. The equilibrating active nucleophilic fluoride-bridged (salen)CoF dimer I first interacted with HFIP to provide adduct II, which then proceeded with the acyl transfer of the alkoxide with PhCOF. The obtained bifluoride containing dimer III was bound to the matched epoxide to afford intermediate IV, and the active monomeric components V and VI were generated after interaction with amidine. Finally, the desired ring-opening product is formed by the reaction of V and VI in the rate-limiting step. It should be mentioned that the axial ligation of the amine cocatalyst to (salen)Co facilitates dimer dissociation and is the origin of the observed cooperativity. On this basis, they found that the use of linked salen-Co(II) catalysts provided significant improvements in terms of rate, catalyst loading, enantioselectivity, and substrate scope. Seven α-CH₂F-substituted alcohols ent-9 were efficiently achieved with 90–99% ee under the catalysis of 0.13–0.5 mol% linked salen-Co(II) 12 and 0.2–0.8 mol% DBN (eqn (3), Scheme 1).¹⁷

Scheme 1 Enantioselective ring opening of terminal epoxides with fluorides.

In 2020, Gouverneur, Pupo and coworkers accomplished the first enantioselective ring opening of azetidinium triflates with fluorides by hydrogen bonding phase-transfer catalysis, which allowed the facile synthesis of enantioenriched γ-fluoroamines featuring an α-CH₂F substituted stereocenter (Scheme 2).¹⁸ Using a 5–10 mol% BINAM-derived N-isopropyl-bis(urea) catalyst 14, a series of azetidinium triflates 13 worked effectively with CsF to afford optically active γ-fluoroamines 15 in 51–99% yields and 65–94% ee. It was noted that chiral γ-fluoroamines bearing a tetrasubstituted stereocenter were also obtained from the corresponding disubstituted azetidinium triflates, albeit with moderate enantioselectivity. In addition, it was found that the N-substituents of the azetidinium triflates influenced the reactivity, but its configuration was not important for enantioselectivity. A possible transition state was proposed in which a chiral N-alkylated bis-urea catalyst served as the hydrogen bond donor to bring CsF in the solution, and the generated chiral urea–fluoride complex ion pairing interacted with aziridinium ions. Enantioselective nucleophilic fluorination was used to deliver the targets. Furthermore, the use of the current method was highlighted by the efficient synthesis of fluorinated analog 17 of lorcaserin, a selective serotonin 2C receptor agonist approved by the FDA for chronic weight management.

Scheme 2 Enantioselective ring opening of azetidinium salts with fluorides.

3. Asymmetric monofluoromethylation involving FBSM

1-Fluorobis(phenylsulfonyl)methane (FBSM)¹⁹ was identified as a useful monofluoromethylation reagent for creating CH₂F-substituted stereocenters in asymmetric reactions.²⁰ A variety of catalytic enantioselective nucleophilic monofluoromethylations, such as Tsuji–Trost allylation, Mannich, Michael addition, Morita–Baylis–Hillman reactions, have accordingly been reported using either asymmetric metal catalysis or organocatalysis over the past two decades. In 2006, Shibata, Toru, and coworkers first demonstrated that FBSM could act as a synthetic equivalent of the monofluoromethyl species in asymmetric transformations and developed a palladium-catalyzed asymmetric allylic monofluoromethylation of allyl acetates 19 with FBSM (Scheme 3).^19a The desired fluorobis(phenylsulfonyl)methylated allylic compounds 21 were obtained in 69–92% yields with 91–96% ee. In addition, the enantioselective fluoromethylation of cyclic meso diester 23 and racemic cyclohex-2-en-1-yl acetate with FBSM proceeded smoothly by using Trost ligand 24 and afforded the corresponding fluorobis(phenylsulfonyl)methylated products with excellent ee. Notably, the monofluoromethylated analogs of (S)-ibuprofen and β-D-carbaribofuranose 7 and 26 were readily obtained through asymmetric monofluoromethylation and sequential simple manipulations, which further highlighted the synthetic utility of this methodology.

Scheme 3 Palladium-catalyzed asymmetric monofluoromethylation of allyl acetates with FBSM.

In 2018, during their study in exploring Pd-catalyzed asymmetric allenylation of bis(phenylsulfonyl)methane or diethyl malonate with racemic 2,3-allenyl acetates, the Ma group investigated the asymmetric monofluoromethylation of racemic 2,3-allenyl acetate 27 with FBSM. The desired fluorobis(phenylsulfonyl)methylated allenylic product 29 was isolated in 81% yield with 97% ee using [Pd(π-cinnamyl)Cl]₂ (2.5 mol%), (R)-DTBM-Segphos 40 (6 mol%), and K₂CO₃ (2.0 equiv.) (Scheme 3).²¹ A monofluoromethylated chiral allene 30 bearing both axial and central chirality was readily obtained in 96% ee after reductive desulfonylation with Mg/MeOH.

Later in 2009, You, Zhao, and coworkers reported regio- and enantioselective allylic alkylation of FBSM with allylic carbonates 31 catalyzed by a chiral iridium complex consisting of chiral phosphoramidite 32 (4 mol%) and [Ir(COD)Cl]₂ (2 mol%), which allowed the access of a variety of α-fluorobis(phenylsulfonyl)methylated chiral allylic compounds 33 with 28–96% yields, 86 : 14 to >99 : 1 b/l and 70–96% ee (Scheme 4).²² The practicability of the current method was demonstrated by the gram-scale synthesis of 33g and its elaboration to monofluoromethylated (R)-ibuprofen in two steps without erosion of the enantioselectivity. In addition, monofluoromethylated (S)-ibuprofen and (R)- or (S)-naproxen were obtained from the corresponding fluorobis(phenylsulfonyl)methylated chiral allylic products.

Scheme 4 Iridium-catalyzed asymmetric monofluoromethylation of allyl carbonates with FBSM.

With their research interest in organofluorine chemistry and asymmetric catalysis,²³ the Yu group in 2022 established the highly regio- and enantioselective hydromonofluoromethylation of 1,3-dienes with FBSM 18 using low-cost and redox-neutral chiral nickel catalysis (Scheme 5).²⁴ Under the catalysis of P-chiral (S,S)-QuinoxP* 36 (5.5–11 mol%) and Ni(COD)₂ (5–10 mol%), various aromatic and aliphatic 1,3-dienes 35 reacted well to deliver fluorobis(phenylsulfonyl)methylated chiral allylic molecules 37 in 48–99% yields and 90–99% ee. Interestingly, they further realized a tandem hydromonofluorobis-(arylsulfonyl)methylation/reductive desulfonylation sequence, which allowed the access of enantioenriched α-CH₂F or α-CD₂F- substituted allylic molecules 38 with excellent ee. This method not only provides a facile strategy to construct diverse monofluoromethyl- or monofluoroalkyl-containing chiral allylic compounds but also represents the first catalytic enantio- and regioselective Markovnikov hydrofluoroalkylation of alkenes.

Scheme 5 Nickel-catalyzed regio- and enantioselective 1,3-diene hydromonofluoromethylation.

One year later, the Yu group utilized chiral nickel catalysis to accomplish the first asymmetric hydromonofluoromethylation of 1,3-enynes with FBSM (Scheme 6).^25a A combination of chiral (R)-MeO-BIPHEP 40 (11 mol%) and Ni(COD)₂ (10 mol%) effectively mediated the reaction and afforded a variety of monofluoromethyl-tethered axially chiral allenes 41 in 39–98% yields and 53–94% ee, in the presence of DABCO (1.0 equiv.). Notably, this constitutes the first asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost chiral nickel catalysis and opens an avenue for the activation of 1,3-enynes in developing asymmetric reactions. The mild reaction conditions, excellent substrate scope, and functionality tolerance highlighted the usefulness of this method. Moreover, tandem hydromonofluorobis(arylsulfonyl)methylation of a 1,3-enynes/reductive desulfonylation sequence was successfully achieved, which enabled the unprecedented preparation of CH₂F- or CD₂F-tethered chiral allenes 42 with 85–91% ee, which are otherwise inaccessible. In addition, Yu and coworkers explored the asymmetric hydromonofluoromethylation of alkoxyallenes, which delivered chiral monofluoromethylated allylic ethers with 68% ee when an (R)-^tBu-PHOX-decorated chiral Pd complex was used as the catalyst.^25b

Scheme 6 Nickel-catalyzed regio- and enantioselective 1,3-enyne hydromonofluoromethylation.

Aside from chiral metal-catalyzed monofluoromethylation using FBSM, asymmetric organocatalysis has also demonstrated its potential in developing enantioselective transformations involving FBSM. In 2007, using 5 mol% of N-benzylquinidinium chloride 44a as the chiral phase-transfer catalyst, Shibata, Toru, and coworkers developed an enantioselective monofluoromethylation of aryl or alkyl α-amido sulfones 43 with FBSM, and a variety of enantiomerically enriched N-Boc α-fluorobisphenylsulfonyl amines 45 were obtained in 70–98% yields with 87–99% ee (eqn (1), Scheme 7).²⁶ Later, in 2013, the Shibata group further employed chiral PTC catalysis to realize an asymmetric monofluormethylation of 2-aryl-3-(1-arylsulfonylmethyl)indoles 46 with FBSM. The use of 10 mol% cinchonine-derived PTC catalyst 47 with 1.2 equiv. Cs₂CO₃ afforded various monofluoromethyl substituted C2-arylindoles 48 with up to 97% ee (eqn (2), Scheme 7).²⁷ The in situ generated vinylogous imines from 2-aryl-3-(1-arylsulfonylmethyl)indoles were the real active electrophiles, which reacted with FBSM to deliver the desired chiral adducts using the chiral catalyst. Moreover, both N-Boc α-fluorobisphenylsulfonyl amines 45 and fluorobisphenylsulfonyl-substituted C2-arylindole 48a readily underwent reductive desulfonylation with Mg/MeOH to give their corresponding monofluoromethylated derivatives.

Scheme 7 Chiral PTC -catalyzed enantioselective monofluoromethylation of α-amido sulfones or 2-aryl-3-(1-arylsulfonylmethyl)indoles with FBSM.

Also, by chiral PTC catalysis, Shibata and coworkers achieved the highly enantioselective Michael addition of FBSM to α,β-unsaturated ketones (Scheme 8).²⁸ A series of β-alkyl or β-aryl-substituted α,β-unsaturated ketones 51 worked well with FBSM under the catalysis of 5 mol% quinidine-derived quaternary ammonium salt 44b and 3.0 equiv. Cs₂CO₃ to afford β-fluorobis(phenylsulfonyl)methylated ketones 52 in 32–91% yields with 85–98% ee. The elaboration of product 52a into monofluoromethylated derivatives 53 and 54 further demonstrated the practicability of this protocol.

Scheme 8 Chiral PTC-catalyzed asymmetric Michael addition of FBSM to enones.

As shown in Scheme 8, a possible transition state was proposed, in which the hydroxyl group of catalyst 44b captured enones via hydrogen-bonding interaction with the carbonyl group, while the aromatic π–π interactions between enones and the catalyst might stabilize the transition state. Finally, the FBSM approached the enone from its Re-face because the Si-face was effectively blocked by the bulky parts of the benzyl substituent in the catalyst.

One year later, Córdova and coworkers reported the highly enantioselective Michael addition of FBSM to α,β-unsaturated aldehydes using asymmetric iminium catalysis (Scheme 9).²⁹ It was found that the use of 20 mol% TMS-protected diarylprolinol 56 and 10 mol% Et₃N proved to be the optimal catalyst system, and various β-alkyl or phenyl substituted enals 55 reacted smoothly with FBSM to afford the desired γ-fluorobis(phenylsulfonyl)methyl alcohols 57 in 45–84% yields and 84–95% ee after in situ reduction with NaBH₄. A possible reaction involving chiral iminium catalysis was proposed, in which chiral secondary amine activated enals 55 to form the active iminium intermediate I, which reacted with FBSM to give the target, as shown in Scheme 9. Moreover, the monofluoromethylated alcohol could be readily obtained from product 57via reductive desulfonylation with Mg/MeOH.

Scheme 9 Asymmetric Michael addition of FBSM to enals via chiral iminium catalysis.

In 2011, Tan, Jiang, Huang and coworkers established the highly enantioselective allylic alkylation of MBH carbonates 59 with FBSM 18 catalyzed by cinchona alkaloid-derived chiral tertiary amine (eqn (1), Scheme 10).³⁰ In the presence of 10 mol% C2-symmetric (bis)cinchona alkaloid derivative (DHQD)₂AQN 58, the desired products 60 were obtained in 58–72% yields with >99.9% ee for all cases. It should be noted that the synthetic usefulness of this method was highlighted by the diastereoselective synthesis of enantiopure β-methyl-γ-monofluoromethyl alcohol 62 from the monofluoromethylated allylic alkylation adduct 60a in three steps. Almost simultaneously, the Shibata group also reported the allylic alkylation of MBH carbonates with FBSM using 10 mol% (DHQD)₂AQN, and they further improved the enantioselectivity of this reaction using a cooperative catalyst system consisting of (DHQD)₂AQN with Lewis acid FeCl₂ or Ti(OⁱPr)₄ (eqn (2), Scheme 10).³¹ In the presence of ⁿBu₃SnH and AIBN, an intramolecular radical cyclization of 60b proceeded smoothly to afford dihydroindene derivative 63, which could be converted into 1-monofluoromethylindene 64.

Scheme 10 Enantioselective allylic alkylation of MBH carbonates with FBSM.

4. Asymmetric fluorocyclization of alkenes with Selectfluor

The catalytic enantioselective fluorocyclization of functionalized alkenes with Selectfluor by chiral anionic phase transfer catalysis has emerged as an efficient protocol for constructing chiral heterocycles featuring a monofluoromethyl-substituted stereocenter. In 2011, Toste and colleagues explored the enantioselective fluorocyclization of unactivated alkene 66 with Selectfluor by employing chiral anionic phase-transfer catalysis during their study of the asymmetric electrophilic fluorination of alkenes with Selectfluor. Chiral heterocycle 68 with a CH₂F substituted stereocenter was obtained in 70% ee using 5 mol% chiral phosphoric acid 67 with 1.1 equiv. Na₂CO₃ in heptane (Scheme 11).³² Insoluble Selectfluor 65 was converted into chiral soluble fluorinated reagent I by anionic exchange, which plays a crucial role in controlling stereoselectivity.

Scheme 11 Enantioselective fluorocyclization of alkenes with Selectfluor.

In 2015, Hamashima et al. established the highly enantioselective fluorolactonization of o-vinylbenzoic acids 69 with electrophilic Selectfluor 65 using a newly designed bifunctional hydroxyl carboxylate catalyst 70 (Scheme 12).³³ The corresponding monofluoromethylated isobenzofuranones 71 were obtained in 40–99% yields and 44–94% ee values, in the presence of 10 mol% axially chiral bifunctional hydroxyl carboxylic acid 70a and 1.5 equiv. Na₃PO₄. Control experiments revealed that the presence of a primary hydroxyl group at an appropriate position in the catalyst is important to achieve high asymmetric induction because the use of catalyst 70b afforded the target with 68% ee, while almost no enantioselectivity was observed when using precatalysts 70c–e under otherwise identical conditions. As shown in Scheme 12, a plausible mechanism was proposed in which catalyst 70a was first deprotonated by potassium phosphate and tended to aggregate, and a binary complex I consisting of the catalyst and substrate was then formed after dissociation enabled by the substrate. Subsequently, complex I was reacted with Selectfluor 65 to generate active fluorinated species II in the liquid phase. Finally, targeted fluorolactones 71 were obtained after fluorolactonization, accompanied by the formation of species III. It should be noted that the hydroxyl group within the catalyst might play a crucial role in the interaction with o-vinylbenzoic acids by forming a hydrogen bond with the neighboring carboxylate anion to fix its position.

Scheme 12 Enantioselective fluorocyclization of o-vinylbenzoic acids with Selectfluor.

Four years later, the Hamashima group reported the enantioselective 5-exo-fluorocyclization of ene-oximes 72 with Selectfluor 65 using an axially chiral carboxylate phase transfer catalysis (Scheme 13).³⁴ A combination of 10 mol% linked-binaphthyl dicarboxylic acid precatalyst 73³⁵ with 1.5 equiv. Na₃PO₄ furnished the desired monofluoromethylated isoxazolines 74 in up to 69% yield and 84% ee. The aliphatic ene-oxime was less reactive for fluorocyclization because only a 12% yield of 74d was observed in the case of cyclohexyl-substituted ene-oxime even at room temperature. Notably, the hydrogen-bonding interaction between the hydroxyl in ene-oxime and the dianionic catalyst was essential for this transformation, as no reaction occurred when O-methylated ene-oxime 72f was subjected to the standard reaction conditions.

Scheme 13 Enantioselective fluorocyclization of ene-oximes with Selectfluor.

5. Asymmetric reduction or nucleophilic addition of α-CH₂F ketones

Catalytic asymmetric reactions involving α-CH₂F ketones have also been developed for the enantioselective access of α-CH₂F-substituted alcohols featuring a CH₂F-substituted stereocenter. In 2007, Tsuboi and coworkers reported an asymmetric reduction of two α-CH₂F aryl ketones 75 mediated by inexpensive Baker's yeast, producing chiral fluorohydrins 76 with 92–94% ee (eqn (1), Scheme 14).³⁶ Later, in 2013, by using a commercially available LBADH (Lactobacillus brevis ADH), Gotor, Lavandera and coworkers accomplished the enantioselective bioreduction of α-CH₂F aryl ketones 75, which allowed the synthesis of various enantiopure fluorohydrins ent-76 with >99% ee (eqn (2), Scheme 14).³⁷ Meanwhile, enantiopure R-configured fluorohydrins 76 was also achieved when employing E. coli/ADH-A instead of LBADH. In addition to enzymatic catalysis, the Hoff group developed the first example of asymmetric transfer hydrogenation of α-CH₂F aryl ketones by chiral Ru catalysis (eqn (3), Scheme 14).³⁸ Eight para-substituted α-CH₂F alcohols ent-76 were produced in 85–98% ee under the catalysis of 2 mol% RuCl(mesitylene)-(R,R)-TsDPEN 77, in the presence of HCO₂H/Et₃N.

Scheme 14 Asymmetric reduction of α-CH₂F aryl ketones.

In 2017, Hoveyda and coworkers developed an efficient method for the enantioselective construction of monofluoromethylated Z-homoallylic tertiary alcohols through chiral boron-catalyzed asymmetric allylation of α-CH₂F aryl ketones 75 (Scheme 15).³⁹ By using a combination of aminophenol 79 (2.5 mol%) with Zn(OMe)₂ (5 mol%), both Z- and E-γ-substituted boronic acid pinacol esters 78 performed well with several α-CH₂F aryl ketones, delivering the corresponding α-addition products 80 in up to 94% yield, 94% ee, >98 : 2 α : γ selectivity with >78 : 22 Z : E selectivity, and their diastereomers 80’ in up to 98% yield, 92% ee, >98 : 2 α : γ and Z : E selectivity. Mechanistic studies revealed that the presence of the fluoroalkyl group was the key factor for the formation of the higher energy α-addition Z-selective products, which might be ascribed to the electrostatic and steric interactions between the catalyst and monofluoromethyl group, as shown in the proposed transition state of Scheme 15. In addition, the presence of the Lewis acidic Zn(OMe)₂ might enhance the activity and efficiency of α-CH₂F aryl ketones 75 by reducing the carbonyl-boron coordination.

Scheme 15 Enantioselective allylation of α-monofluoromethyl ketones.

6. Asymmetric transformations involving CH₂F-substituted alkenes

Over the past decade, significant advances have been made in the enantioselective construction of α-CH₂F substituted stereocenters via catalytic asymmetric transformations using various CH₂F substituted alkenes. For instance, in 2012, the Alexakis group developed the first copper-free asymmetric allylic alkylation of γ-CH₂F substituted allyl bromides 81 with Grignard reagents 82 catalyzed by a chiral NHC ligand (Scheme 16).⁴⁰ An array of enantioenriched allylic products 84 featuring a CH₂F substituted quaternary stereocenter was obtained in 40–68% yields and 18–95% ee, in the presence of 3 mol% NHC bidentate ligand 83. Later in 2017, Zhang and coworkers reported the asymmetric allylation of β-aryl α,β-unsaturated aldehydes 55 with (E)-1-bromo-4-fluorobut-2-ene 81f by chiral chromium catalysis (Scheme 16).⁴¹ The merger of 5 mol% CrCl₂ and 11 mol% chiral carbazole-based bisoxazoline 85 enabled the enantioselective synthesis of β-CH₂F substituted homoallylic alcohols 86 with 93% ee and excellent anti-diastereoselectivity in the presence of a proton sponge (14 mol%), ZrCp₂Cl₂ (2.0 equiv.), Mn (1.0 equiv.) and LiCl (1.0 equiv.). The addition of LiCl might facilitate the formation of allyl species and their transmetallation to the chiral Cr complex, thus enhancing the reaction rate and enantioselectivity.

Scheme 16 Asymmetric allylation of γ-CH₂F substituted allyl bromides.

β-CH₂F-Substituted α,β-unsaturated carbonyl compounds have also found applications in forging CH₂F-substituted stereocenters. In 2017, Schaus, Thomson and coworkers investigated the enantioselective reductive allylation of β-CH₂F-β-phenyl disubstituted enal 87 during the study of the asymmetric traceless Petasis borono-Mannich reaction of various enals with 2-nitro-benzenesulfonyl hydrazide and allylboronate (Scheme 17).⁴² The in situ generated α,β-unsaturated hydrazone, from enal 87 and 2-nitro-benzenesulfonyl hydrazide 89, reacted smoothly with allyl boronate 88 to give the desired 1,4-diene 91 bearing a CH₂F-substituted stereocenter with 77% yield and 86% ee after undergoing allylic diazene rearrangement.

Scheme 17 Enantioselective reductive allylation of β-CH₂F enal.

In 2018, the Zhang group reported the ligand-controlled Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of α-substituted iminoester 93 with β-CH₂F-β-aryl disubstituted enone 92, which provided an efficient method for the enantioselective regiodivergent synthesis of CH₂F-substituted chiral pyrrolidine bearing two adjacent quaternary stereocenters or two discrete quaternary stereocenters (Scheme 18).⁴³ A combination of Cu(CH₃CN)₄BF₄ (10 mol%) with P,N-type ligand (S,Sp)-ⁱPr-Phosferrox 94 (11 mol%) afforded monofluoromethylated pyrrolidine 95 bearing two adjacent quaternary stereocenters with 65% yield, 6 : 1 rr and 99% ee, while pyrrolidine 97 with two discrete quaternary stereocenters was obtained in 71% yield, 11 : 1 rr, and 94% ee when using (S,R_p)-PPFA 96 as a chiral ligand. In the same year, they employed their Ming-Phos 99 derived chiral copper complex to realize the asymmetric 1,3-dipolar cycloaddition of glycine ketimines 98 with β-CH₂F β-aryl disubstituted enone 92, delivering product 100, featuring a CH₂F substituted stereocenter with 61% yield, 6 : 1 dr and 94% ee (Scheme 18).⁴⁴

Scheme 18 Asymmetric 1,3-dipolar cycloaddition of β-CH₂F substituted enone.

Asymmetric cyclopropanation of diazo compounds with CH₂F substituted alkenes by either chiral rhodium, gold catalysis or biocatalysis is identified as a powerful strategy for the stereoselective preparation of monofluoromethylated cyclopropanes.⁴⁵ In 2018, Zhou, Ma and coworkers developed the highly diastereo- and enantioselective cyclopropanation of unprotected diazooxindoles 101 with α-CH₂F styrenes 102 catalyzed by an SKP-derived chiral digold complex, allowing access to optically active spirocyclopropyloxindoles 104 with two adjacent quaternary stereocenters featuring a CH₂F group (Scheme 19).⁴⁶ The use of cationic digold complex derived from 4.0 mol% 103 (AuCl)₂ and 4.4 mol% AgOTf delivered a series of CH₂F-substituted cyclopropanes 104 in 57–93% yields, >20 : 1 dr and 87–95% ee. Interestingly, control experiments revealed a dramatic rate of acceleration when fluorobenzene was used as the solvent. By theoretical calculation study, the authors proposed that the formation of strong C–F⋯H–N interactions⁴⁷ between the solvent fluorobenzene and the N–H bond of diazooxindole-derived Au(I)–carbenoid intermediate played a key role, as shown in the proposed reaction mechanism in Scheme 19.

Scheme 19 Au-catalyzed asymmetric cyclopropanation of unprotected diazooxindoles 101 with α-CH₂F styrenes.

Meanwhile, the same group found that the use of 0.5 mol% Rh₂(R-DOSP)₄ could mediate the asymmetric cyclopropanation of aryl diazoacetates 105 with α-CH₂F styrenes 102, and afforded CH₂F-substituted chiral cyclopropanes 106 with adjacent quaternary stereocenters in 66–79% yields, >20 : 1 dr and 91–95% ee values (eqn (1), Scheme 20).⁴⁶ Shortly after, Jubault and coworkers also realized the same cyclopropanations by using 1 mol% of Rh₂(S-BTPCP)₄, providing chiral cyclopropanes 106 with 24–99% yields, >20 : 1 dr and 55–98% enantioselectivities (eqn (2), Scheme 20).⁴⁸ Later, in 2022, the Zhou group accomplished the highly diastereo- and enantioselective cyclopropanation of diazothiooxindoles 107 with α-CH₂F styrenes catalyzed by 0.5 mol% of Rh₂(S-TCPTTL)₄ (eqn (3), Scheme 20).⁴⁹ Several chiral CH₂F substituted spirocyclopropylthiooxindoles 108 bearing adjacent quaternary stereocenters were obtained in up to 96% yield, 18 : 1 dr, and 97% ee. By using 1 mol% of Rh₂(S-BTPCP)₄ as the catalyst, Zhu, Wu, and coworkers recently reported an asymmetric intramolecular cycloisomerization of CH₂F substituted enyne for the enantioselective synthesis of functionalized bicycle featuring a CH₂F substituted stereocenter.⁵⁰ In addition to chiral rhodium catalysis, Fasan, Jubault and coworkers attempted the enantioselective cyclopropanation of ethyl 2-diazoacetate 105a with α-CH₂F styrene 102a using Mb(H64V, V68A) as a biocatalyst, which delivered the desired CH₂F substituted cyclopropane 106a with 99% yield, 99% de, and 98% ee (eqn (4), Scheme 20).⁵¹

Scheme 20 Asymmetric cyclopropanation of α-CH₂F styrenes catalyzed by chiral Rh complexes or enzymes.

Aside from asymmetric cyclopropanation, the asymmetric dihydroxylation of α-CH₂F styrenes 102 was also explored by Jubault, Poisson, and coworkers in 2019 (Scheme 21).⁵² Under the catalysis of AD-mix-α or AD-mix-β (Os: 0.2 mol%), several optically active α-monofluoromethylated tertiary alcohols 109 were obtained in up to 93% yield and 98% ee. Additionally, various α-difluoromethylated styrenes were also tolerated, giving rise to the corresponding α-difluoromethylated chiral tertiary alcohols with excellent enantioselectivities.

Scheme 21 Asymmetric dihydroxylation of α-CH₂F styrenes.

In 2022, Andersson, Zhou and coworkers developed an efficient protocol for enantioselective synthesis of monofluoromethylated stereocenters by chiral Ir-catalyzed enantioselective hydrogenation of fluorinated alkenes (Scheme 22).⁵³ It was found that (E)-ethyl 4-fluoro-3-phenylbut-2-enoate 110 was efficiently hydrogenated with 5 bar H₂ to give ethyl (R)-4-fluoro-3-phenylbutanoate 112 featuring a CH₂F stereocenter with 85% ee, in the presence of 0.5 mol% Ir-N,P catalyst 111a. Moreover, the use of 1 mol% Ir-N,P catalyst 111b enabled the hydrogenation of various vinyl fluorides 113 to furnish a series of monofluoromethylated chiral molecules 114 in up to 99% yield and 98% ee values.

Scheme 22 Enantioselective hydrogenation of fluorinated alkenes.

7. Miscellaneous

In addition to the five strategies discussed above, several catalytic enantioselective transformations toward CH₂F substituted stereocenters have been recently reported. In 2021, Zhao and Yu developed a sequential organocatalyzed desymmetrization of 3-substituted glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination for the enantioselective preparation of chiral fluorides bearing a CH₂F substituted stereocenter (Scheme 23).⁵⁴ This sequence started with an enantioselective desymmetrizative alcoholysis of 3-substituted glutaric anhydrides 115 catalyzed by 10 mol% cinchona alkaloid derived sulfonamide bifunctional catalyst 117, and the resultant chiral carboxylic acids 118 underwent decarboxylic fluorination under 45 W blue LED irradiation in the presence of 2 mol% photocatalyst Ir(III) 119, 3 equiv. Selectfluor 65, and 2.0 equiv. Na₂HPO₄ base, delivering the desired chiral fluorides 120 in 41–58% yields and 68–98% ee values.

Scheme 23 Organocatalyzed desymmetrization of glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination.

As shown in Scheme 23, a plausible reaction mechanism for dicarboxylic fluorination was proposed, in which the photoexcitation of the ground-state photocatalyst Ir(III) by visible light resulted in excited *Ir(III), which then underwent oxidative quenching in the presence of Selectfluor to give Ir(IV). Subsequently, the resultant chiral glutaric acid monoester 118 underwent deprotonation, oxidation, and sequential elimination of CO₂ with the assistance of both the Na₂HPO₄ and oxidized photocatalyst Ir(IV) to afford the alkyl radical intermediate and re-generate photocatalyst Ir(III). Finally, chiral fluorides 120 were generated after fluorine transfer from Selectfluor to the alkyl radical species.

In the same year, the Huang group reported a chiral Zn-catalyzed asymmetric hydrosilylation of α-CH₂F substituted malonic ester 121, which allowed the access of a CH₂F substituted stereocenter (Scheme 24).⁵⁵ They found that chiral α-CH₂F substituted β-hydroxylester 123 was selectively obtained in 74% yield with 68% ee in the presence of 10 mol% of newly developed tetradentate chiral ligand 122a, 20 mol% of diethylzinc, and 3.0 equiv. of (MeO)₃SiH.^55a Interestingly, the use of a higher concentration of (MeO)₃SiH (6.0 equiv.) and pipecolinol-derived tetradentate ligands 122b instead of 122a enabled the aldehyde-selective desymmetrization, and afforded α-CH₂F substituted aldehyde 124 in 71% yield and 96% ee, with 6.8 : 1 aldehyde/alcohol selectivity.^55b

Scheme 24 Catalytic reductive desymmetrization of malonic esters.

Recently, Li, Huang, Xia and coworkers developed a nickel-catalyzed enantioselective hydromonofluoromethylation of enamides or enol esters 125 with ICH₂F 126 as a monofuoromethyl reagent (Scheme 25).⁵⁶ Combining 12 mol% cyclopropanyl substituted chiral Box ligand 127 and 10 mol% NiI₂ enabled the construction of various chiral α-monofluoromethylated amides and esters 128 in up to 96% yield and 99% ee in the presence of KF and poly(methylhydrosiloxane) (PMHS). Moreover, the practicability of this method was demonstrated by the preparation of chiral oxazoline 129 (42% yield, 94% ee) from 128fvia reduction with LiAlH₄, as well as the synthesis of α-monofluoromethylated tetrahydroquinoline 130 (70% yield, 84% ee) from 128g via Buchwald–Hartwig amination.

Scheme 25 Enantioselective hydromonofluoromethylation of alkenes with ICH₂F.

8. Conclusion and outlook

The past two decades have witnessed significant advances in the catalytic enantioselective construction of CH₂F-substituted stereocenters, with the emergence of new synthetic methods, new fluorinated agents and catalyst systems. As summarized in this feature article, a variety of asymmetric transformations, such as enantioselective ring opening of epoxides or azetidinium salts by fluoride anions; asymmetric monofluoromethylation with FBSM; asymmetric fluorocyclization of functionalized alkenes with Selectfluor; and asymmetric transformation of α-CH₂F ketones or α-CH₂F alkenes, have been established for constructing chiral organofluorine molecules featuring a CH₂F substituted stereocenter. Despite these remarkable achievements, many limitations still exist, and this research is in its infancy, with ample room for further exploration. First, there is a lack of more powerful monofluoromethylated reagents, as most of the currently reported approaches mainly rely on asymmetric transformations involving FBSM or α-CH₂F alkenes. Therefore, the development of new facile monofluoromethylated reagents or substrates for the diverse creation of CH₂F-substituted stereocenters would be highly desirable, yet an unsolved challenge in asymmetric reactions.¹³ Second, the structural diversity of reactant types should be further broadened in each strategy, as most reactions only provide one or a few examples. Third, the use of readily available fluoride anions in asymmetric reactions for constructing α-CH₂F substituted stereocenters is quite limited. This might provide another important and promising direction to design asymmetric transformations using nucleophilic fluoride anions as monofluoromethylated sources. Nevertheless, as anticipated, with the development of new strategies, fluorinated reagents and chiral catalyst systems, more elegant and facile protocols will be reported, thus demonstrating the application value of such privileged moieties in pharmaceutical and agricultural chemical discovery programs.

Data availability

No primary research results, software, or code were included, and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 22171087), the Shanghai Science and Technology Innovation Action Plan (No. 21N41900500), Technology Innovation Project of Shanghai Municipal Agricultural Committee [No. HNK(T2023302)], Central Leading Local Science and Technology Development Special Project of Hubei Province (2022BGE258), Liaoning Provincial Natural Science Foundation of China (No. 2022-KF-25-02), the Innovation Program of Shanghai Municipal Education Commission (No. 2023ZKZD37), the Ministry of Education (PCSIRT) and the Fundamental Research Funds for the Central Universities.

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Footnote

† These authors contributed equally to this work.

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