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Published before final editing as: Nat Synth. 2025 May 22:10.1038/s44160-025-00809-4. doi: 10.1038/s44160-025-00809-4

Synthesis of chiral difluoromethyl cyclopropanes through desymmetric difluoromethylation of cyclopropenes enabled by enantioselective copper catalysis

Decai Ding 1, Su Chen 1, Lingfeng Yin 1, Wei-Ting Ou 2, Jeanette A Krause 1, Mu-Jeng Cheng 2, Wei Liu 1,✉
PMCID: PMC12366757  NIHMSID: NIHMS2095125  PMID: 40852334

Abstract

The incorporation of enantioenriched difluoromethyl cyclopropane (DFC) groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to the unique ability of the DFC groups to serve as conformationally rigid hydrogen-bond donors. Despite their potential, the widespread use of chiral DFC groups has been limited by their challenging synthesis. Here we report the use of difluoromethyl–copper complexes for the development of a desymmetric difluoromethylation reaction, using enantioselective copper catalysis. Through desymmetric difluoromethylation of cyclopropenes and subsequent electrophilic functionalization, this method achieves high efficiency and enantioselectivity, enabling the modular construction of chiral DFC moieties. The synthetic utility of this strategy is demonstrated through the synthesis of a variety of chiral DFC-containing compounds, including analogues of pharmacologically relevant molecules. This reactivity of difluoromethyl–copper species opens opportunities for broader application in medicinal chemistry and the development of reactions for the construction of difluoromethyl-containing stereocentres.

In medicinal chemistry, incorporating conformationally rigid hydrogen-bond donors into pharmacologically active molecules can enhance their desired biological activity1,2. This enhancement is largely due to the reduced entropic losses during the conformational adaptation of hydrogen-bonding groups to the active site of a biological target. Consequently, organic molecules that contain stereochemically defined difluoromethyl cyclopropane (DFC) groups have gained increasing interest in the pharmaceutical industry due to the unique combination of the difluoromethyl (CF2H) group with cyclopropane (Fig. 1a). The electronegative nature of the fluorine atoms enhances the polarity of the C–H bond in the CF2H group, rendering it a unique lipophilic hydrogen-bond donor3–7. The planar structure of the cyclopropane ring contributes to the rigidity of the organic molecule8. Furthermore, cyclopropane rings and CF2H groups can modulate key pharmacokinetic properties such as the bioavailability, metabolic stability and lipophilicity of drug candidates. These beneficial features of DFC groups are evident in the recent Food and Drug Administration (FDA) approval of two hepatitis C virus protease inhibitors, glecaprevir and voxilaprevir, both of which feature stereochemically defined DFC groups. Beyond the increased metabolic stability conferred by the CF2H groups9, X-ray crystallography studies on a related compound revealed hydrogen-bond interactions between the C–H bond of the CF2H group and the backbone carbonyl group of the NS3/4A protease10. Structure–activity relationship studies have demonstrated that this interaction increases enzyme inhibitory potency by over 10-fold compared with the CF3 or CH3 analogues, and more importantly, its diastereomer, which cannot enable hydrogen bonding.

Fig. 1 |. Development of copper-catalysed enantioselective desymmetric difluoromethylation for the modular construction of CF2H–cyclopropanes.

Fig. 1 |

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a. Importance of chiral CF2H–cyclopropanes in the pharmaceutical industry. b. Conventional approaches for their synthesis24,25. c. Proposed strategy that can enable modular construction of CF2H–cyclopropane moieties. d. This work: copper-catalysed enantioselective desymmetric difluoromethylation. DAST, diethylaminosulfur trifluoride; RAS, renin–angiotensin system; SHP2, Src homology-2 domain-containing protein tyrosine phosphatase-2; Bz, benzoyl.

Despite the intriguing properties of chiral DFCmoieties in the pharmaceutical industry, widespread exploration of this medicinal scaffold has been hampered by their synthetic challenges—largely due to the lack of methods for enantioselective difluoromethylation11–22 (Fig. 1b). Conventional approaches typically rely on the deoxyfluorination of enantioenriched cyclopropyl aldehydes, but the preparation of these enantiopure precursors often requires laborious and multiple-step synthesis. The high reactivity of deoxyfluorination reagents, such as diethylaminosulfur trifluoride, limits the functional group tolerance and often leads to side reactions, including ring-opening products23. Pioneering work by Jubault and Charette showed that chiral rhodium complexes could catalyse the enantioselective addition of diazo reagents to difluoroalkenes to form DFCs24. Subsequent work by Fasan and Jubault demonstrated that these reactions could be conducted through biocatalysis with good enantioselectivity25. Jubault has recently shown that a chiral ruthenium catalyst can enable the enantioselective cyclopropanation of alkenes using a difluorodiazo reagent26, originally developed by Ma27. Although these methods are highly enabling, the need for electron-withdrawing groups to stabilize the diazo reagents, along with the compatibility being limited to 1,1-disubstituted alkenes, constrains the diversity of chiral DFC products that can be synthesized.

Enantioselective functionalization of cyclopropenes has emerged as a powerful approach to constructing chiral cyclopropane structures28–32. However, despite considerable efforts at synthesizing cyclopropanes with carbon–carbon33–38 and carbon–heteroatom39–44 stereocentres, few examples are available to construct chiral fluoroalkylated cyclopropanes via this method45–48. Of particular relevance is the recent work by Zhang on the hydrodifluoroalkylation of cyclopropenes with an electrophilic difuoroalkylation reagent, although this approach yielded products with low enantioselectivity45. We envisioned an alternative strategy for the modular construction of chiral DFC moieties through the sequential addition of a CF2H group followed by an electrophile to a 3,3-disubstituted cyclopropene (Fig. 1c). In this pathway, a metal-catalysed nucleophilic difluoromethylation of a cyclopropene in an enantioselective and diastereoselective manner would result in the formation of a CF2H-containing stereocentre while desymmetrizing the three-membered ring. Subsequent electrophilic functionalization of the enantioenriched cyclopropyl synthon would furnish the desired chiral DFC structure. Given the modularity of the substituents on cyclopropenes and various electrophiles that could potentially be engaged, this approach could modularly construct the DFC ring while simultaneously controlling the stereochemistry of all three carbons on the cyclopropane rings.

Our group49–51 and others52,53 recently showed that Cu–CF2H species, generated catalytically in situ, could react with alkyl electrophiles to construct C(sp3)–CF2H bonds, and very recently it was shown this could be achieved enantioselectively54. Additionally, Cu–CF2H species are well known to react with aryl electrophiles to form aryl–CF2H products55–60. In these processes, it is generally accepted that Cu–CF2H intermediates undergo oxidative addition with electrophiles, followed by reductive elimination to yield the desired products61. Considering the growing importance of CF2H groups, we sought to unlock an under-developed reactivity of Cu–CF2H species: their addition to cyclopropenes, ideally in an enantioselective pathway within a chiral environment. By trapping the resulting intermediates with proton sources or suitable electrophiles, we envisioned achieving enantioselective desymmetric hydrodifluoromethylation or difluoromethyl functionalization. This pathway could open a door for synthesizing chiral DFC moieties. Here we report the successful implementation of this strategy, developing a copper-catalysed desymmetric difluoromethylation reaction that enables a highly modular synthesis of chiral DFC scaffolds with high efficiency and enantioselectivity (Fig. 1d).

Results and discussion

Unlocking the desymmetric difluoromethylation reactivity

We commenced our study by identifying conditions that allow for the generation of difluoromethyl–copper species under simple and catalytically relevant conditions. We chose (DMPU)Zn(CF2H)2 1 (DMPU, N,N′-dimethylpropyleneurea)—a reagent developed by Vicic62 and Mikami63,64—as the CF2H source, given that we49–51 and others18,63,65 have shown its ability to facilitate difluoromethylation via copper catalysis. Previous work by Mikami has demonstrated that transmetallation of 1 to copper(I) salts in polar solvents afforded difluoromethyl–copper complexes in low yield (<30%), accompanied by decomposition products including HF2C–CF2H and HFC═CFH (ref. 63,64), Interestingly, low-temperature 19F NMR spectroscopy experiments revealed the high-yielding formation of a CuI–CF2H species upon mixing [Cu(CH3CN)4]PF6 with 1 in a 1:1 ratio at −20 °C in tetrahydrofuran (THF)/DMPU (Fig. 2a and Supplementary Fig. 1). Subsequently, a cyclopropene 2 was added to this solution of Cu–CF2H, followed by quenching the reaction mixture with water, resulting in the formation of a difluoromethylated product 3 in 51% yield and with a d.r. of 11:1 (Fig. 2b and Supplementary Fig. 2). Notably, only trace products were observed when 2 reacted with a bisdifluoromethyl–copper complex PPh4+[Cu(CF2H2)]−, recently isolated by Shen57.

Fig. 2 |. Unlocking the enantioselective desymmetric difluoromethylation reactivity.

Fig. 2 |

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a, Formation of Cu–CF2H species at low temperature in THF/DMPU. b, Reactivity of Cu–CF2H toward a cyclopropene. c, Development of a catalytic enantioselective desymmetric difluoromethylation reaction. d, DFT analysis of the enantioselective desymmetric difluoromethylation reactivity at the B3LYP-D3/LACV3P++**//B3LYP-D3/LACVP** level of theory. e, Origin of the enantioselectivity. Roman numerals denote the four quadrants of the coordination space. f, Proposed catalytic cycle for the copper-catalysed enantioselective desymmetric difluoromethylation reaction. iBu, iso-butyl; Me, methyl; Ph, phenyl; TS, transition state.

Having demonstrated that difluoromethyl–copper species could react with a cyclopropene, we next explored if this difluoromethylation reaction could proceed catalytically, diastereoselectively and enantioselectively with the aid of a suitable ligand. To our delight, with a commercially available chiral phosphine ligand L*, [Cu(CH3CN)4]PF6 catalysed the formation of 3 in 81% yield and with 92% e.e. (Fig. 2c). The involvement of a zincation intermediate 4 was indicated by 19F NMR spectroscopy (Supplementary Fig. 3). Consistent with this zincation pathway, a deuterated product was isolated when D2O was used to quench the reaction (Supplementary Fig. 4). Notably, the use of other transition metal catalysts, including palladium66–69, nickel62,70 and iron71—the difluoromethyl complexes of which have been isolated or proposed—failed to yield the desired products, highlighting the unique reactivity of Cu–CF2H species.

We conducted density functional theory (DFT) calculations to gain further insights into this enantioselective desymmetric difluoromethylation reactivity (Fig. 2d). The DFT analysis revealed an initial reversible coordination of a cyclopropene to the ligand-bound Cu–CF2H intermediate, forming π-complexes Int-S or Int-R. These intermediates subsequently undergo concerted difluoromethyl-cupration, forming either the Pro-R or Pro-S product. With (R,R)-L* as the chiral ligand, the transition state TS-R, which leads to the formation of Pro-R, proceeds with a lower activation barrier (∆G‡ = 17.5 kcal mol−1) compared with its counterpart, TS-S (∆G‡ = 18.7 kcal mol−1).

To understand the origin of the enantioselectivity, we analysed the coordination space of the transition states by dividing the C2-symmetric catalyst into four quadrants (Fig. 2e). The phenyl substituents of the ligands in quadrants I and III project out of the plane of the paper, rendering these two regions sterically hindered for the substrate. In contrast, quadrants II and IV are less hindered. In the disfavoured transition state TS-S, the methyl group of the substrate primarily occupies the sterically encumbered quadrant III, with a distance of 3.58 Å between the methyl group and ligand’s phenyl group in this quadrant. In comparison, in the favoured transition state TS-R, the methyl group resides mainly in the unhindered quadrant IV, maintaining a longer distance of 3.98 Å to the nearest phenyl group in quadrant I. Consequently, the Pro-R complex is formed as the major cupration intermediate.

Based on these studies, a plausible catalytic cycle for this enantioselective desymmetric difluoromethylation reaction was proposed (Fig. 2f). The Cu–CF2H intermediate first coordinates to the cyclopropene substrate, followed by an irreversible difluoromethyl-cupration reaction to afford a cyclopropyl–copper species in an enantioselective manner. Finally, transmetallation with the zinc reagent 1 yields the difluoromethyl zinc product, which can react with a proton source or various electrophiles to form substituted DFCs in a modular manner.

Scope of the hydrodifluoromethylation reaction

Having unlocked this enantioselective desymmetric hydrodifluoromethylation reaction, we next explored the scope of cyclopropenes (Fig. 3). Substituents at the para or meta positions of the phenyl rings showed minimal impact on the efficiency and enantioselectivity of the hydrodifluoromethylation reaction (3–9, 90–93% e.e.). Notably, a thioether group (6) was well tolerated despite its known tendency to bind with copper catalysts. The compatibility with aryl bromides (8 and 9) suggests the potential for further functionalization of the enantioenriched products. In particular, the reaction successfully engaged a 1,1,4,4-tetramethyltetralin ring (10, 92% e.e.), a structural motif often found in drug candidates. Replacing the phenyl rings with naphthalenes had no substantial effect on the enantioselectivity of the reaction (11 and 12), although moderate enantioselectivity was observed with a ferrocene-derived (13, 80% e.e.) or a diphenyl-substituted substrate (14, 83% e.e.). Additionally, replacing the methyl group with an ether group did not affect the enantioselectivity of the reaction (15, 92% e.e.). Cyclopropenes attached to chromane rings were also efficiently converted to the CF2H products (16–18, 89–98% e.e.). Notably, a cyclopropene ring adjacent to a bulky tertiary centre underwent efficient hydrodifluoromethylation with good enantioselectivity (18, 94% e.e.). Tetralin-derived substrates with various substitutions on the phenyl group provided the desired products in good yield and high enantioselectivity (19–23, 93–99% e.e.), with near-perfect enantioselectivity achieved for a brominated molecule (23, 99% e.e.). Additionally, functional groups including sulfone (24), conjugated alkene (25) and carboxamide (26), along with several medicinally relevant heterocycles including indole (27), benzofuran (28) and pyridine (29), were all compatible with this transformation. The absolute configuration of the hydrodifluoromethylation product has been determined from X-ray crystallography analysis of compound 23, CCDC 2409661, synthesized using (S,S)–L*, which revealed the trans-stereochemistry between the CF2H group and the aryl ring, with an R-configuration at the CF2H-containing stereocentre.

Fig. 3 |. Scope for copper-catalysed enantioselective desymmetric hydrodifluoromethylation.

Fig. 3 |

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Reactions were performed with 0.2 mmol cyclopropene, 0.4 mmol (DMPU)2Zn(CF2H)2, 0.006 mmol (3 mol%) [Cu(CH3CN)4] PF6 and 0.012 mmol (6 mol%) (S,S)- or (R,R)-L* in 1.5 ml THF/DMPU (4:1) at –20 °C for 48 h. Yields were based on isolated products. Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase. All examples had d.r. ≥20:1 as determined by 19F NMR spectroscopic analysis of crude reaction mixture.

Scope of the electrophiles

Given the success of this desymmetric hydrodifluoromethylation reaction, we then investigated whether the DFC synthon could be trapped by electrophiles other than protons (Fig. 4). To our delight, the addition of acetyl chloride at the end of the difluoromethylation reaction efficiently allowed for the installation of an acetyl group on the DFC ring, affording the product 30 in 81% yield and with 90% e.e. Additional cyclopropenes were evaluated with this acetyl-difluoromethylation protocol. Substrates with substituted phenyl rings (31–33) or with a thiophene ring (34) were compatible with this protocol. Apart from methyl groups, longer alkyl chains (35 and 36) or an indane ring (37) could also be engaged in this transformation. Notably, a similar enantioselectivity was observed with the bromotetralin-derived product (38) as the hydrodifluoromethylation reaction, indicating the involvement of the same intermediate in these two reactions. Other acyl chlorides, including furoyl and benzoyl chloride, could also efficiently be incorporated into the DFC ring in good yield and with high enantioselectivity (39 and 40).

Fig. 4 |. Scope of electrophiles for the modular synthesis of chiral DFC moieties.

Fig. 4 |

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All examples had d.r. >20:1 as determined from the isolated products. The electrophilic addition step was performed with or without the addition of CuCN·2LiCl. See Supplementary Methods 2 and 3 for detailed conditions. DABSO, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide); Ts, toluenesulfonyl; Et, ethyl.

Moreover, various electrophiles other than acyl chlorides were found to participate in this desymmetric difluoromethylation reaction. Electrophilic halogenation reagents, including N-chlorosuccinimide (41), bromine (42) and iodine (43), efficiently introduced halogen atoms into the DFC rings, offering opportunities for further modification of the cyclopropane structure. Alkyl groups were easily incorporated using the corresponding alkyl halides, such as methyl iodide (44), benzyl bromide (45) and allyl bromide (46). Eschenmoser’s salt (N,N-dimethylmethaniminium iodide) enabled the incorporation of a dimethylaminomethyl group (47), while ethyl vinyl ketone could undergo a Michael addition reaction (48). Additionally, a phenyl group was incorporated by using an arenediazonium salt (49), enabling the construction of trans-aryl DFC rings with high enantioselectivity. An alkynyl group was introduced by using the corresponding alkynyl bromide (50), while the use of a propargyl bromide allowed for the installation of an allenyl group (51) in good yield and with good enantioselectivity. DFC rings containing ester and carboxamide groups were constructed using the corresponding chloroformate (52) or carbamoyl chloride (53), respectively. A nitrile group could be efficiently installed using commercially available p-toluenesulfonyl cyanide (54). Carbon–chalcogen bonds could also be installed in good yield and with excellent control of stereochemistry. For instance, a sulfone group could be installed using 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) as the SO2 source, followed by the addition of methyl iodide (55). Thioether and selenoether bonds could be formed by using benzenesulfenyl (56) or benzeneselenenyl chloride (57), respectively. Carbon–phosphine bonds could also be constructed using chlorodiphenylphosphine (58), potentially enabling the synthesis of CF2H-containing chiral phosphine ligands. Finally, a group of medicinally relevant nitrogen-containing heterocycles, including pyrrolidone (59), piperidine (60), morpholine (61) and piperazine (62), could be installed using the corresponding O-benzoylhydroxylamines. X-ray crystallography analysis of compound 40 (CCDC 2380720), synthesized with (R,R)-L*, revealed that the benzoyl group is on the same side as the CF2H group and an S configuration for the CF2H-containing stereocentre.

Synthetic applications

The utility of this method was then demonstrated through the synthesis of a diverse range of medicinally relevant molecules (Fig. 5). First, the compatibility of the methoxymethoxy (OMOM) group with the reaction allowed for the synthesis of DFC-containing building blocks (Fig. 5a). For example, deprotection of the methoxymethyl (MOM) protecting group in 63 using LiBF4 produced the alcohol product 64 in 81% yield while maintaining the chiral centres (90% e.e.). Subsequent Swern oxidation of 64 afforded the aldehyde product 65, which could be further converted to a carboxylic acid product 66, with all stereocentres preserved. This approach was also successfully applied to the late-stage functionalization of pharmacologically active compounds (Fig. 5b). Paroxetine, an antidepressant, and desloratadine, an H1 blocker, were converted to their DFC analogues using their benzoate derivatives (67 and 68). In addition, a precursor to rosuvastatin was installed on the DFC ring from its alkyl bromide derivative (69, 62% yield, 99% e.e.). Finally, two cyclooxygenase inhibitors, indomethacin and isoxepac (70 and 71), along with a triglyceride-lowering drug, gemfibrozil (72), were successfully functionalized using their acyl chlorides.

Fig. 5 |. Synthetic applications of copper-catalysed desymmetric difluoromethylation reactions.

Fig. 5 |

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a, Synthesis of chiral DFC-containing building blocks. b, Late-stage installation of chiral DFC moieties to medicinally relevant molecules. c, Synthesis of CF2H analogues of cyclopropane-containing pharmaceuticals. d, Synthesis of conformationally rigid analogues of pharmaceuticals. Boc, tert-butyloxycarbonyl; cat., catalysed. LiHMDS, lithium bis(trimethylsilyl)amide; tBu, tert-butyl.

Moreover, given that CF2H groups are known to enhance metabolic stability and introduce additional binding interactions in cyclopropanes, we extended this protocol to synthesize analogues of cyclopropane-containing pharmaceutically relevant molecules (Fig. 5c). The simultaneous introduction of a CF2H and a nitrile group allowed for the synthesis of compounds 73 and 74 in good yield and with good enantioselectivity. Reduction of the nitrile group in 73 via CoBr2-catalysed reduction in the presence of (Boc)2O, allowed for the synthesis of the CF2H analogue (76) of a precursor to milnacipran, a clinical medicine for treating fibromyalgia. Additionally, the desymmetric difluoromethyl esterification enabled the simultaneous installation of a CF2H group and an ester group of 76. The deprotection of the MOM group in 76 allowed for the synthesis of a CF2H-containing lactone 77, which could be converted to the precursor of a CF2H analogue 78 of lemborexant, an orexin antagonist.

Finally, we aimed to synthesize chiral DFC analogues of pharmacologically relevant molecules (Fig. 5d). In particular, the incorporation of a cyclopropane ring into the open structure of a drug candidate is a widely applicable tool to enhance the conformational rigidity and, consequently, the desired pharmacological activity of the drug candidate72,73. Accordingly, the DFC analogue of nabumetone (79), a non-steroidal anti-inflammatory drug, was synthesized by means of the acetyl-difluoromethylation approach in 72% yield and with 92% e.e. Additionally, analogues of terfenadine (80), amorolfine (81) and rotigotine (82) were synthesized through the enantioselective amino-difluoromethylation reactions in good yield and with good enantioselectivity (89–94% e.e.).

Conclusion

We report herein the unlocking of the desymmetric difluoromethylation reactivity of Cu–CF2H species, enabling the enantioselective and desymmetric addition of CF2H groups onto cyclopropenes. The use of the (DMPU)2Zn(CF2H)2 reagent serves as both the CF2H source while the zinc transmetallates with the cyclopropyl–copper intermediate. This reactivity enables the development of a highly enantioselective desymmetric difluoromethylation reaction, making possible the modular synthesis of chiral DFC moieties. The synthetic utility of this protocol has been further highlighted by the synthesis of a diverse range of analogues of pharmacologically relevant molecules. We expect that this protocol will find wide application in the field of medicinal chemistry. More importantly, we anticipate that this reactivity of Cu–CF2H species should inspire the development new reactions for the construction of CF2H- and other fluoroalkyl-containing stereocentres.

Methods

General procedure for enantioselective desymmetric hydrodifluoromethylation

In a glovebox filled with argon, an oven-dried 4-ml vial equipped with a stir bar was charged with [Cu(CH3CN)4]PF6 (2.3 mg, 0.006 mmol, 3.0 mol%), ligand L* (6.1 mg, 0.012 mmol, 6.0 mol%) and anhydrous THF (0.5 ml). The mixture was allowed to stir at room temperature for 15 min, then taken out of the glovebox and cooled to −20 °C. Subsequently, a solution of (DMPU)2Zn(CF2H)2 (176 mg, 2.0 equiv.) in 0.3 ml DMPU was added via syringe followed by cyclopropenes (1.0 equiv.) in anhydrous THF (0.7 ml). After stirring for 48 h at this temperature, the reaction mixture was quenched with 1.0-M HCl (0.5 ml). The mixture was purified by column chromatography on silica gel (hexane/ethyl acetate), affording the corresponding products. The d.r. of the products was determined by 19F NMR spectroscopy of the crude reaction mixture and the e.e. of the products was determined by high-performance liquid chromatography (HPLC) or gas chromatography (GC) with chiral stationary phases.

General procedure for enantioselective desymmetric difluoromethylation with different electrophiles

In a glovebox filled with argon, an oven-dried 4-ml vial equipped with a stir bar was charged with [Cu(CH3CN)4]PF6 (2.3 mg, 0.006 mmol, 3.0 mol%), ligand L* (6.1 mg, 0.012 mmol, 6.0 mol%) and anhydrous THF (0.5 ml). The mixture was allowed to stir at room temperature for 15 min, then taken out of the glovebox and cooled to −20 °C. Subsequently, a solution of (DMPU)2Zn(CF2H)2 (176 mg, 2.0 equiv.) in 0.3 ml DMPU was added via syringe followed by cyclopropenes (1.0 equiv.) in anhydrous THF (0.7 ml). After stirring for 48 h at this temperature, the electrophilic reagents (2.0 equiv.) in 0.7 ml anhydrous THF were added via syringe. The reaction was stirred for 4.0 h at room temperature and then quenched with H2O. The mixture was purified by column chromatography on silica gel (hexane/ethyl acetate), affording the corresponding products. The d.r. of the products was determined by 19F NMR spectroscopy of the crude reaction mixture and the e.e. of the products was determined by HPLC or GC with chiral stationary phases.

General procedure for enantioselective desymmetric difluoromethylation with different electrophiles (with CuCN·2LiCl)

In a glovebox filled with argon, an oven-dried 4-ml vial equipped with a stir bar was charged with [Cu(CH3CN)4]PF6 (2.3 mg, 0.006 mmol, 3.0 mol%), ligand L* (6.1 mg, 0.012 mmol, 6.0 mol%) and anhydrous THF (0.5 ml). The mixture was allowed to stir at room temperature for 15 min, then taken out of the glovebox and cooled to −20 °C. Subsequently, a solution of (DMPU)2Zn(CF2H)2 (176 mg, 2.0 equiv.) in 0.3 ml DMPU was added via syringe followed by cyclopropenes (1.0 equiv.) in anhydrous THF (0.7 ml). After stirring for 48 h at this temperature, a solution of CuCN·2LiCl (1.0 M in THF; 0.4 ml, 0.4 mmol, 2.0 equiv.) was added, followed by electrophilic reagents (2.5 equiv.) in 0.7 ml anhydrous THF, via syringe. The reaction was stirred for 4.0 h at room temperature and then quenched with H2O. The mixture was purified by column chromatography on silica gel (hexane/ethyl acetate), affording the corresponding products. The d.r. of the products was determined by 19F NMR spectroscopy of the crude reaction mixture and the e.e. of the products was determined by HPLC or GC with chiral stationary phases.

Supplementary Material

Supplementary Material

Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s44160-025-00809-4.

Acknowledgements

This work was supported by the National Institute of General Medical Science (R35GM146765, W.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Science. Mechanistic studies were supported by the National Science Foundation under grant number CHE-2237757 (W.L.). The synthesis of agrochemical molecules was supported by the ACS Herman Frasch Foundation (926-HF22, W.L.). NMR spectroscopy experiments were performed using a Bruker AVANCE NEO 400 MHz NMR spectrometer, funded by NSF-MRI grant CHE-1726092. Funding for the D8 Venture diffractometer was through NSF-MRI grant CHE-1625737.

Footnotes

Competing interests

The authors declare no competing interests.

Peer review information Nature Synthesis thanks Hyunwoo Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information (experimental procedures, characterization data and DFT details). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2409661 (23) and 2380720 (40). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  • 1.Lawson ADG, MacCoss M & Heer JP Importance of rigidity in designing small molecule drugs to tackle protein–protein interactions (PPIs) through stabilization of desired conformers. J. Med. Chem 61, 4283–4289 (2018). [DOI] [PubMed] [Google Scholar]
  • 2.Hanessian S & Auzzas L The practice of ring constraint in peptidomimetics using bicyclic and polycyclic amino acids. Acc. Chem. Res 41, 1241–1251 (2008). [DOI] [PubMed] [Google Scholar]
  • 3.Sessler CD et al. CF2H, a hydrogen bond donor. J. Am. Chem. Soc 139, 9325–9332 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Caminati W, Melandri S, Moreschini P & Favero PG The C–F⋯H–C “anti-hydrogen bond” in the gas phase: microwave structure of the difluoromethane dimer. Angew. Chem. Int. Ed 38, 2924–2925 (1999). [DOI] [PubMed] [Google Scholar]
  • 5.Erickson JA & McLoughlin JI Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem 60, 1626–1631 (1995). [Google Scholar]
  • 6.Zafrani Y et al. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem 60, 797–804 (2017). [DOI] [PubMed] [Google Scholar]
  • 7.Zafrani Y et al. CF2H, a functional group-dependent hydrogen-bond donor: is it a more or less lipophilic bioisostere of OH, SH, and CH3? J. Med. Chem 62, 5628–5637 (2019). [DOI] [PubMed] [Google Scholar]
  • 8.Talele TT The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem 59, 8712–8756 (2016). [DOI] [PubMed] [Google Scholar]
  • 9.Taylor JG et al. Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): a component of Vosevi®. Biorg. Med. Chem. Lett 29, 2428–2436 (2019). [DOI] [PubMed] [Google Scholar]
  • 10.Zheng B et al. Potent inhibitors of hepatitis C Virus NS3 protease: employment of a difluoromethyl group as a hydrogen-bond donor. ACS Med. Chem. Lett 9, 143–148 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sap JBI et al. Late-stage difluoromethylation: concepts, developments and perspective. Chem. Soc. Rev 50, 8214–8247 (2021). [DOI] [PubMed] [Google Scholar]
  • 12.Briand M, Anselmi E, Dagousset G & Magnier E The revival of enantioselective perfluoroalkylation—update of new synthetic approaches from 2015–2022. The Chemical Record 23, e202300114 (2023). [DOI] [PubMed] [Google Scholar]
  • 13.Yang XY, Wu T, Phipps RJ & Toste FD Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev 115, 826–870 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Banik SM, Medley JW & Jacobsen EN Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters. Science 353, 51 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Peng L, Wang H & Guo C Copper-catalyzed enantioselective difluoromethylation of amino acids via difluorocarbene. J. Am. Chem. Soc 143, 6376–6381 (2021). [DOI] [PubMed] [Google Scholar]
  • 16.Gao X, Cheng R, Xiao Y-L, Wan X-L & Zhang X Copper-catalyzed highly enantioselective difluoroalkylation of secondary propargyl sulfonates with difluoroenoxysilanes. Chem 5, 2987–2999 (2019). [Google Scholar]
  • 17.Gu Y, Lu C, Gu Y & Shen Q Ligand-controlled copper-catalyzed highly regioselective difluoromethylation of allylic chlorides/bromides and propargyl bromides. Chinese J. Chem 36, 55–58 (2018). [Google Scholar]
  • 18.Endo Y, Ishii K & Mikami K Chiral copper-catalyzed enantioselective Michael difluoromethylation of arylidene Meldrum’s acids with (difluoromethyl)zinc reagents. Tetrahedron 75, 4099–4103 (2019). [Google Scholar]
  • 19.Rong M-Y, Li J-S, Zhou Y, Zhang F-G & Ma J-A Catalytic enantioselective synthesis of difluoromethylated tetrasubstituted stereocenters in isoindolones enabled by a multiple-fluorine system. Org. Lett 22, 9010–9015 (2020). [DOI] [PubMed] [Google Scholar]
  • 20.Wang Y et al. Asymmetric α-electrophilic difluoromethylation of β-keto esters by phase transfer catalysis. Org. Biomol. Chem 19, 4788–4795 (2021). [DOI] [PubMed] [Google Scholar]
  • 21.Hock KJ, Mertens L & Koenigs RM Rhodium catalyzed synthesis of difluoromethyl cyclopropanes. Chem. Commun 52, 13783–13786 (2016). [DOI] [PubMed] [Google Scholar]
  • 22.Boyle BT, Dow NW, Kelly CB, Bryan MC & MacMillan DWC Unlocking carbene reactivity by metallaphotoredox α-elimination. Nature 631, 789–795 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Cink RD et al. Development of the enabling route for glecaprevir via ring-closing metathesis. Org. Process Res. Dev 24, 183–200 (2020). [Google Scholar]
  • 24.Bos M et al. Catalytic enantioselective synthesis of highly functionalized difluoromethylated cyclopropanes. Angew. Chem. Int. Ed 56, 13319–13323 (2017). [DOI] [PubMed] [Google Scholar]
  • 25.Carminati DM, Decaens J, Couve-Bonnaire S, Jubault P & Fasan R Biocatalytic strategy for the highly stereoselective synthesis of CHF2-containing trisubstituted cyclopropanes. Angew. Chem. Int. Ed 60, 7072–7076 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Zhao C, Besset T & Jubault P Ruthenium(II)-catalyzed enantioselective synthesis of 1,2-trans-disubstituted PhSO2CF2-containing cyclopropanes. Adv. Synth. Catal 366, 3423–3429 (2024). [Google Scholar]
  • 27.Zhang Z-Q et al. Catalytic enantioselective cyclopropenation of internal alkynes: access to difluoromethylated three-membered carbocycles. Angew. Chem. Int. Ed 58, 18191–18196 (2019). [DOI] [PubMed] [Google Scholar]
  • 28.Rubin M, Rubina M & Gevorgyan V Transition metal chemistry of cyclopropenes and cyclopropanes. Chem. Rev 107, 3117–3179 (2007). [DOI] [PubMed] [Google Scholar]
  • 29.Cohen Y & Marek I Regio- and diastereoselective carbometalation reaction of cyclopropenes. Acc. Chem. Res 55, 2848–2868 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Dian L & Marek I Asymmetric preparation of polysubstituted cyclopropanes based on direct functionalization of achiral three-membered carbocycles. Chem. Rev 118, 8415–8434 (2018). [DOI] [PubMed] [Google Scholar]
  • 31.Zhu Z-B, Wei Y & Shi M Recent developments of cyclopropene chemistry. Chem. Soc. Rev 40, 5534–5563 (2011). [DOI] [PubMed] [Google Scholar]
  • 32.Rubin M, Rubina M & Gevorgyan V Recent advances in cyclopropene chemistry. Synthesis 2006, 1221–1245 (2006). [Google Scholar]
  • 33.Müller DS & Marek I Asymmetric copper-catalyzed carbozincation of cyclopropenes en route to the formation of diastereo- and enantiomerically enriched polysubstituted cyclopropanes. J. Am. Chem. Soc 137, 15414–15417 (2015). [DOI] [PubMed] [Google Scholar]
  • 34.Dian L, Müller DS & Marek I Asymmetric copper-catalyzed carbomagnesiation of cyclopropenes. Angew. Chem. Int. Ed 56, 6783–6787 (2017). [DOI] [PubMed] [Google Scholar]
  • 35.Luo Y, Teng H-L, Nishiura M & Hou Z Asymmetric yttrium-catalyzed C(sp3)–H addition of 2-methyl azaarenes to cyclopropenes. Angew. Chem. Int. Ed 56, 9207–9210 (2017). [DOI] [PubMed] [Google Scholar]
  • 36.Sherrill WM & Rubin M Rhodium-catalyzed hydroformylation of cyclopropenes. J. Am. Chem. Soc 130, 13804–13809 (2008). [DOI] [PubMed] [Google Scholar]
  • 37.Zhang H, Huang W, Wang T & Meng F Cobalt-catalyzed diastereo- and enantioselective hydroalkenylation of cyclopropenes with alkenylboronic acids. Angew. Chem. Int. Ed 58, 11049–11053 (2019). [DOI] [PubMed] [Google Scholar]
  • 38.Huang W & Meng F Cobalt-catalyzed diastereo- and enantioselective hydroalkylation of cyclopropenes with cobalt homoenolates. Angew. Chem. Int. Ed 60, 2694–2698 (2021). [DOI] [PubMed] [Google Scholar]
  • 39.Zhang S, Jiang N, Xiao J-Z, Lin G-Q & Yin L Copper(I)-catalyzed asymmetric hydrophosphination of 3,3-disubstituted cyclopropenes. Angew. Chem. Int. Ed 62, e202218798 (2023). [DOI] [PubMed] [Google Scholar]
  • 40.Wang M et al. Copper-catalyzed hydroamination: enantioselective addition of pyrazoles to cyclopropenes. J. Am. Chem. Soc 145, 14573–14580 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Parra A et al. Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: synthesis of cyclopropylboronates. J. Am. Chem. Soc 136, 15833–15836 (2014). [DOI] [PubMed] [Google Scholar]
  • 42.Simaan M & Marek I Asymmetric catalytic preparation of polysubstituted cyclopropanol and cyclopropylamine derivatives. Angew. Chem. Int. Ed 57, 1543–1546 (2018). [DOI] [PubMed] [Google Scholar]
  • 43.Rubina M, Rubin M & Gevorgyan V Catalytic enantioselective hydrostannation of cyclopropenes. J. Am. Chem. Soc 126, 3688–3689 (2004). [DOI] [PubMed] [Google Scholar]
  • 44.Rubina M, Rubin M & Gevorgyan V Catalytic enantioselective hydroboration of cyclopropenes. J. Am. Chem. Soc 125, 7198–7199 (2003). [DOI] [PubMed] [Google Scholar]
  • 45.Gao X, Ren X, Deng W & Zhang X Copper-catalyzed highly stereoselective hydrodifluoroallylation of cyclopropenes and alkenyl boronates with 3,3-difluoroallyl sulfonium salts. Chinese J. Chem 41, 3521–3527 (2023). [Google Scholar]
  • 46.Myronova V, Cahard D & Marek I Stereoselective preparation of CF3-containing cyclopropanes. Org. Lett 24, 9076–9080 (2022). [DOI] [PubMed] [Google Scholar]
  • 47.An L, Tong F-F, Zhang S & Zhang X Stereoselective functionalization of racemic cyclopropylzinc reagents via enantiodivergent relay coupling. J. Am. Chem. Soc 142, 11884–11892 (2020). [DOI] [PubMed] [Google Scholar]
  • 48.Liu C, Feng T, Wu X & Zhu C Fe-catalyzed regioselective C(sp3)–H-abstraction by tertiary cyclopropyl radicals. ACS Catal 13, 8394–8401 (2023). [Google Scholar]
  • 49.Zeng XJ et al. Copper-catalyzed decarboxylative difluoromethylation. J. Am. Chem. Soc 141, 11398–11403 (2019). [DOI] [PubMed] [Google Scholar]
  • 50.Zeng X et al. Copper-catalyzed deaminative difluoromethylation. Angew. Chem. Int. Ed 59, 16398–16403 (2020). [DOI] [PubMed] [Google Scholar]
  • 51.Cai A, Yan W, Wang C & Liu W Copper-catalyzed difluoromethylation of alkyl iodides enabled by aryl radical activation of carbon–iodine bonds. Angew. Chem. Int. Ed 60, 27070–27077 (2021). [DOI] [PubMed] [Google Scholar]
  • 52.Zeng X et al. Copper difluorocarbene enables catalytic difluoromethylation. J. Am. Chem. Soc 146, 16902–16911 (2024). [DOI] [PubMed] [Google Scholar]
  • 53.Aikawa K, Ishii K, Endo Y & Mikami K Copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl)zinc reagent. J. Fluorine Chem 203, 122–129 (2017). [Google Scholar]
  • 54.Ding D et al. Enantioconvergent copper-catalysed difluoromethylation of alkyl halides. Nat. Catal 7, 1372–1381 (2024). [Google Scholar]
  • 55.Fier PS & Hartwig JF Copper-mediated difluoromethylation of aryl and vinyl iodides. J. Am. Chem. Soc 134, 5524–5527 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Jiang XL, Chen ZH, Xu XH & Qing FL Copper-mediated difluoromethylation of electron-poor aryl iodides at room temperature. Org. Chem. Front 1, 774–776 (2014). [Google Scholar]
  • 57.Zhao H, Leng XB, Zhang W & Shen Q [Ph4P]+[Cu(CF2H)2]−: a powerful difluoromethylating reagent inspired by mechanistic investigation. Angew. Chem. Int. Ed 61, e202210151 (2022). [DOI] [PubMed] [Google Scholar]
  • 58.Prakash GKS et al. Copper-mediated difluoromethylation of (hetero)aryl iodides and β-styryl halides with tributyl(difluoromethyl)stannane. Angew. Chem. Int. Ed 51, 12090–12094 (2012). [DOI] [PubMed] [Google Scholar]
  • 59.Matheis C, Jouvin K & Goossen LJ Sandmeyer difluoromethylation of (hetero-)arenediazonium salts. Org. Lett 16, 5984–5987 (2014). [DOI] [PubMed] [Google Scholar]
  • 60.Bour JR, Kariofillis SK & Sanford MS Synthesis, reactivity, and catalytic applications of isolable (NHC)Cu(CHF2) complexes. Organometallics 36, 1220–1223 (2017). [Google Scholar]
  • 61.Luo Y et al. Oxidative addition of an alkyl halide to form a stable Cu(III) product. Science 381, 1072–1079 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Xu L & Vicic DA Direct difluoromethylation of aryl halides via base metal catalysis at room temperature. J. Am. Chem. Soc 138, 2536–2539 (2016). [DOI] [PubMed] [Google Scholar]
  • 63.Serizawa H, Ishii K, Aikawa K & Mikami K Copper-catalyzed difluoromethylation of aryl iodides with (difluoromethyl)zinc reagent. Org. Lett 18, 3686–3689 (2016). [DOI] [PubMed] [Google Scholar]
  • 64.Aikawa K, Serizawa H, Ishii K & Mikami K Palladium-catalyzed Negishi cross-coupling reaction of aryl halides with (difluoromethyl)zinc reagent. Org. Lett 18, 3690–3693 (2016). [DOI] [PubMed] [Google Scholar]
  • 65.Kim S & Kim H Cu-electrocatalysis enables vicinal bis(difluoromethylation) of alkenes: unraveling dichotomous role of Zn(CF2H)2(DMPU)2 as both radical and anion source. J. Am. Chem. Soc 146, 22498–22508 (2024). [DOI] [PubMed] [Google Scholar]
  • 66.Pan F, Boursalian GB & Ritter T Palladium-catalyzed decarbonylative difluoromethylation of acid chlorides at room temperature. Angew. Chem. Int. Ed 57, 16871–16876 (2018). [DOI] [PubMed] [Google Scholar]
  • 67.Jiang X et al. Pd-catalyzed divergent site-selective difluoromethylation and difluoromethylcarbonylation of aryl sulfonium salts. ACS Catal 14, 13557–13566 (2024). [Google Scholar]
  • 68.Lu C, Gu Y, Wu J, Gu Y & Shen Q Palladium-catalyzed difluoromethylation of heteroaryl chlorides, bromides and iodides. Chem. Sci 8, 4848–4852 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Feng Z, Min Q-Q, Fu X-P, An L & Zhang X Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem 9, 918–923 (2017). [DOI] [PubMed] [Google Scholar]
  • 70.Li H, Wang F, Zhu S & Chu L Selective fluoromethyl couplings of alkynes via nickel catalysis. Angew. Chem. Int. Ed 61, e202116725 (2022). [DOI] [PubMed] [Google Scholar]
  • 71.Miao W et al. Iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone. J. Am. Chem. Soc 140, 880–883 (2018). [DOI] [PubMed] [Google Scholar]
  • 72.Yonezawa S et al. Conformational restriction approach to β-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode. J. Med. Chem 55, 8838–8858 (2012). [DOI] [PubMed] [Google Scholar]
  • 73.Novakov I et al. Synthesis and structure–activity relationships of cyclopropane-containing analogs of pharmacologically active compounds. Russ. Chem. Bull 67, 395–418 (2018). [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
NIHMS2095125-supplement-Supplementary_Material.pdf (39.6MB, pdf)

Data Availability Statement

The data that support the findings of this study are available within the paper and its Supplementary Information (experimental procedures, characterization data and DFT details). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2409661 (23) and 2380720 (40). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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