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. 2025 Oct 17;27(43):12172–12177. doi: 10.1021/acs.orglett.5c03987

Enantioselective Construction of Fluorinated Tertiary Stereocenters by Rh-Catalyzed [2 + 2 + 2] Cycloaddition of 1,6-Enynes with α‑Fluoroacrylamides

Shintaro Hamada 1, Yu Sato 1, Yoshinobu Komiya 1, Ken Tanaka 1,*
PMCID: PMC12584140  PMID: 41102945

Abstract

We report the enantioselective construction of fluorinated tertiary stereocenters via [2 + 2 + 2] cycloaddition between 1,6-enynes and α-fluoroacrylamides using a chiral cationic Rh­(I) catalyst at room temperature with full retention of the fluorine atom. Coordination of the amide carbonyl to Rh may promote insertion and suppress β-fluoride elimination, enabling efficient formation of fluorinated cyclic products with high enantioselectivity. This strategy provides streamlined access to complex bicyclic systems bearing fluorinated tertiary stereocenters from readily available starting materials.

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Chiral fluorinated 3D molecules have garnered increasing interest in medicinal chemistry, as fluorine substitution can enhance biological activity, metabolic stability, and membrane permeability. However, the asymmetric synthesis of chiral 3D scaffolds with fluorinated tertiary stereocenters remains challenging due to steric hindrance and difficulties in stereocontrol. , The construction of fluorinated tertiary stereocenters has traditionally relied on two major strategies: − (1) asymmetric C–F bond formation using nucleophilic or electrophilic fluorinating reagents in combination with chiral catalysts (Figure a), − and (2) asymmetric C–C bond-forming reactions of fluorinated precursors, such as carbonyl α-substitution reactions − and cross-coupling reactions − (Figure b). Although these approaches have provided valuable tools, their substrate scope remains largely limited to specific structural classes. Therefore, the development of novel and more efficient methodologies is highly desirable to enable broader access to enantioenriched compounds bearing fluorinated tertiary stereocenters. Enantioselective cycloaddition reactions involving readily available fluoroalkenes have recently emerged as atom-economical and powerful strategies for the one-step construction of cyclic structures bearing fluorinated tertiary stereocenters. − However, current examples are limited to only two types of chiral Lewis acid-catalyzed low-temperature reactions: asymmetric Diels–Alder reactions developed by Yamamoto and Ishihara, and 1,3-dipolar cycloadditions reported by Wang and Fan/Huang (Figure c). These limitations highlight the pressing need for more general, efficient, and selective methods for the asymmetric synthesis of fluorinated cyclic scaffolds.

1.

1

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Enantioselective construction of fluorinated tertiary stereocenters (a–c).

Enantioselective transition-metal-catalyzed [2 + 2 + 2] cycloadditions of 1,6-enynes with alkenes have been reported as an effective approach to chiral 3D cyclic compounds. − In 2012, we reported enantioselective [2 + 2 + 2] cycloaddition with strongly coordinating acrylamides, yielding chiral cyclohexene derivatives (Figure a). In 2024, we found that acrylamides bearing an alkyl or phenyl substituent at the α-position do not undergo the [2 + 2 + 2] cycloaddition; instead, enantioselective hydroalkenylation − proceeds via C–H activation (Figure a).

2.

2

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Rh-catalyzed C–C bond-forming cycloaddition/C–H alkylation (a and d) and defluorination (b and c).

The successful development of a [2 + 2 + 2] cycloaddition reaction using α-fluoroacrylamides would enable the construction of cyclic frameworks bearing fluorinated tertiary stereocenters. However, a major concern using late transition metal catalysts is the possibility of undesired β-fluoride (β-F) elimination from key organometallic intermediates. In 2008, Murakami and co-workers reported the synthesis of gem-difluoroalkenes via Rh­(I)-catalyzed β-F elimination from 1-(trifluoromethyl)­styrene derivatives (Figure b). Later, in 2016, Hayashi and colleagues disclosed an enantioselective variant of this transformation. In 2025, Baik and co-workers performed DFT studies that revealed β-F elimination to be both thermodynamically favorable and irreversible, suggesting that the β-F elimination product is the dominant species under standard conditions. Furthermore, in 2022, Hughes, Baker, and co-workers demonstrated that β-F elimination is preferred to β-H elimination from a nickelacyclopentane intermediate, likely due to participation of the fluorine lone pairs (Figure c). In the Co2(CO)8-mediated Pauson–Khand reaction of 1,6-enynes bearing a vinyl fluoride moiety, , β-fluoride elimination from cobaltacycles was not observed; instead, HF elimination was observed in the resulting products. Here, we report the enantioselective construction of fluorinated tertiary stereocenters via a [2 + 2 + 2] cycloaddition between 1,6-enynes 1 and α-fluoroacrylamides 2, retaining the fluorine atom, promoted by a chiral cationic Rh­(I) catalyst at room temperature (Figure d).

We first examined the enantioselective construction of fluorinated tertiary stereocenters by the [2 + 2 + 2] cycloaddition of tosylamide-linked 1,6-enyne 1a with α-fluoroacrylamide 2a using a Rh­(I)+/(R)-H8–BINAP catalyst at room temperature. Pleasingly, this reaction afforded [2 + 2 + 2] cycloaddition (3aa) and hydroalkenylation (4aa) products in 34% and 52% yields, respectively, both with high enantioselectivity (Table , entry 1). This reactivity profile contrasts with that observed for acrylamide and methacrylamide, which afford only the [2 + 2 + 2] cycloaddition and hydroalkynylation products, respectively. As for the alkene substituent (R), α-fluoroacrylamide 2a (R = F) has an intermediate size between acrylamide (R = H) and methacrylamide (R = Me), which could explain their different product ratios. Screening various chiral biaryl bisphosphine ligands (entries 1–7) revealed that (R)-P-Phos delivers 3aa in the highest yield (72%) with complete enantioselectivity (entry 7), and sterically demanding (R)-xyl-BINAP shut down the reaction. In contrast, switching the 1,6-enyne substrate from 1a to 1b markedly improved both chemo- and enantioselectivity (entries 8–14), delivering 3ba in up to 82% yield and >99% ee, with negligible formation of 4ba. Among the ligands examined, (R)-BINAP (entry 9), (R)-tol-BINAP (entry 12), and (R)-P-Phos (entry 14) provided the best results, with the cost-effective (R)-BINAP selected as the optimal ligand.

1. Screening of Reaction Conditions .

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      3
4
entry 1 catalyst % yield (% ee) % yield (% ee)
1 1a (R)-H8 -BINAP 34 (94) 52 (79)
2 1a (R)-BINAP 54 (>99) 35 (82)
3 1a (R)-MeO-BIPHEP 50 (92) 25 (91)
4 1a (R)-Segphos 35 (97) 26 (79)
5 1a (R)-tol-BINAP 36 (95) 23 (96)
6 1a (R)-xyl-BINAP <1 <1
7 1a ( R )-P-Phos 72 (>99) 16 (69)
8 1b (R)-H8 -BINAP 22 (99) 0
9 1b ( R ) - BINAP 82 (>99) <1
10 1b (R)-MeO-BIPHEP 29 (>99) <1
11 1b (R)-Segphos 20 (>99) 0
12 1b (R)-tol-BINAP 81 (>99) <1
13 1b (R)-xyl-BINAP <1 <1
14 1b (R)-P-Phos 82 (>99) <1
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a

1 (0.10 mmol), 2 (0.12 mmol), [Rh­(cod)2]­BF4 (0.010 mmol), ligand (0.012 mmol), and CH2Cl2 (2.0 mL) were used.

b

Isolated yields.

We next explored the substrate scope using (R)-P-Phos (Figure ). Varying the N-substituent of α-fluoroacrylamide revealed that morpholine amide 2b gave cycloadduct 3ab in good yield with high enantioselectivity. In contrast, using sterically hindered alkenes 2c and 2d resulted in lower yields of 3ac and 3ad, due to the increased formation of hydroalkenylation products 4ac and 4ad. Substituent effects on 1,6-enynes revealed that electron-donating (1c) or -withdrawing (1d) aryl groups on the alkyne terminus did not markedly affect yield or enantioselectivity. The reaction of methyl-substituted 1,6-enyne 1e proceeded smoothly, and using (R)-xyl-BINAP suppressed the formation of 4ea, affording 3ea in high yield and enantioselectivity. X-ray crystallographic analysis of (−)-3ea established its absolute configuration as (5R,7aR) (Figure S1), consistent with the configuration obtained using unsubstituted acrylamide. For the alkene substituent (R2), increasing steric bulk in 1,6-enynes 1f and 1g increased the formation of hydroalkenylation products 4fa and 4ga, while reducing the yields of 3fa and 3ga. Regarding the linker moiety, using ether- and ester-linked 1,6-enynes 1h and 1i required excess 2a to prevent the homo-[2 + 2 + 2] cycloaddition of the 1,6-enynes, whereas using (R)-BINAP gave 3ha and 3ia in good yields. For malonate-linked 1,6-enyne 1j, HF elimination dominated under standard conditions, but using 20 mol % Rh­(cod)2OTf with 24 mol % (R)-BINAP enabled the formation of 3ja in good yield, along with moderate formation of 4ja.

3.

3

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Rh-catalyzed enantioselective [2 + 2 + 2] cycloaddition of 1,6-enynes with α-fluoroacrylamides. Cited yields are of isolated products. 1 (0.05–0.10 mmol), 2 (0.06–0.50 mmol), [Rh­(cod)2]­BF4 or [Rh­(cod)2]­OTf (0.005–0.020 mmol), ligand (0.006–0.024 mmol), and CH2Cl2 (1.0–2.0 mL) were used.

We also investigated 1,6-enynes lacking alkene substituents (R2 = H, 1b, 1k–1o) using (R)-BINAP (Figure ). Among α-fluoroacrylamides, pyrrolidinyl amide 2a gave 3ba in high yield and enantioselectivity, while 2b–2e showed reduced yields but retained excellent enantioselectivity. For 1,6-enynes, methoxy- and chloro-substituted 1,6-enynes 1k and 1l performed well, and ether- and ester-linked 1m and 1n also delivered cycloadducts in high enantioselectivity, although excess 2a was required. Malonate-linked 1,6-enyne 1o required Rh-OTf to achieve good yield and stereoselectivity for 3oa.

To demonstrate the synthetic utility, we explored preparative-scale reactions and subsequent transformations. 1,6-Enyne 1e or 1b (1 mmol) reacted with 2a under reduced catalyst loading (5 mol %) to afford (−)-3ea and (−)-3ba in high yields and enantioselectivity (Figure a). Oxidation of (−)-3ea with m-chloroperoxybenzoic acid (m-CPBA) gave epoxide (−)-5 in good yield but low diastereoselectivity. Hydrogenation with Pd/C gave the cyclohexane derivative (−)-6 and the double bond isomer (−)-7 in 31% and 57% yield, respectively, both as single diastereomers. X-ray crystallographic analysis established the absolute configuration of (−)-7 as (4R,5R) (Figure S2). Oxidation of (−)-7 with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) furnished pyrrole (−)-8. Treatment of (−)-3ea with LiAlH4 resulted in defluorinative hydroxylation to yield aminoalcohol (−)-9 as a single diastereomer.

4.

4

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Synthetic transformations (a), experimental mechanistic studies (b), and plausible reaction mechanisms (c).

To gain mechanistic insights, we conducted control experiments. Replacement of 2a with methyl α-fluoroacrylate under the stndard conditions (Table , entry 9) resulted in no observable reaction for both 1,6-enynes 1a and 1b, highlighting the essential role of the strongly coordinating amide moiety in facilitating the transformation. α-Fluoroacrylamide 2a failed to react with internal alkyne 13, suggesting that the direct C–H bond activation of 2a does not proceed (Figure b, left). Deuterium labeling showed that the use of 2a-D2 decreased the yield and ee of 4aa-D2, indicating that C–D bond cleavage is the rate-determining step in hydroalkenylation (Figure b, right). On the basis of these experiments, plausible reaction mechanisms are depicted in Figure c. The reaction of 1,6-enyne 1a with Rh­(I)+ generates rhodacyclopentene A. Insertion of α-fluoroacrylamide 2 into A forms seven-membered rhodacycle B, which undergoes reductive elimination to furnish the corresponding [2 + 2 + 2] cycloaddition product 3, while regenerating the Rh­(I)+ catalyst. Coordination of the amide carbonyl to Rh may promote insertion and suppress undesired β-F elimination, leading to Rh–F species C. Alternatively, C–H bond cleavage of α-fluoroacrylamide 2 by intermediate A generates alkenyl Rh­(III)+ intermediate D, which then undergoes reductive elimination to give 4, also regenerating the Rh­(I)+ catalyst. The steric bulk of the substituents on the 1,6-enyne 1 (R1) and α-fluoroacrylamide 2 (NR3R4) markedly influenced the selectivity between insertion and C–H activation pathways: smaller substitutents at R2 (H < Me < Ph) and NR3R4 (pyrrolidinyl < NMePh < NPh2) favored insertion, as did ligands with smaller dihedral angles (P-Phos < BINAP < H8-BINAP).

In conclusion, we have demonstrated that the use of α-fluoroacrylamides enables enantioselective [2 + 2 + 2] cycloadditions of 1,6-enynes with high enantioselectivity. Owing to the strong coordinating ability of the amide group, which may promote insertion and suppress β-fluoride elimination, α-fluoroacrylamides could serve as versatile substrates for a broad range of Rh-catalyzed cycloaddition reactions.

Supplementary Material

ol5c03987_si_001.pdf (9.7MB, pdf)

Acknowledgments

This work was supported by The Uehara Memorial Foundation and JSPS KAKENHI grant number JP24H00005 to K.T. from JSPS (Japan) and JST SPRING grant number JPMJSP2180 to S.H. from JST (Japan). We thank Mr. Shunsuke Suzuki for his preliminary experiment and Takasago International Corporation for the gift of H8-BINAP, tol-BINAP, xyl-BINAP, and Segphos.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c03987.

  • Synthetic procedures and data for compound characterization and structural determination (PDF)

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

ol5c03987_si_001.pdf (9.7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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