Enantioselective Radical Cascade Cyclization to Axially Chiral Medium‐Sized Lactones

ABSTRACT

We report a synergistic photoredox/copper‐catalyzed radical cascade cyclization for the enantioselective synthesis of axially chiral medium‐sized lactones. Compared with conventional ionic pathways that require stringent polarity matching and substrate prefunctionalization, the present strategy employs alkyl halides as radical precursors, wherein photoredox mediated single electron transfer (SET) generates radicals that undergo radical addition to non‐polarized alkenes followed by C–O bond formation. High stereocontrol and efficiency are achieved through a carboxylate‐coordinated chiral copper complex (up to 83% yield, up to 96% e.e., >20:1 d.r.). The synthetic utility is demonstrated by the late‐stage diversification of bioactive molecules. Theoretical calculations reveal that the stereodetermining step occurs during C–O bond formation, and that thermodynamic stability facilitates a central‐to‐axial chirality relay, thereby governing axial stability in the flexible seven‐membered scaffolds.

A synergistic photoredox/chiral copper‐catalyzed asymmetric radical cascade cyclization is reported for synthesizing axially chiral medium‐sized lactones. This method offers access to molecules with multiple stereogenic elements, including axial and point chirality, and potentially inherent medium‐ring chirality, using readily available alkyl halides and non‐polarized alkenes.

1. Introduction

Axially chiral medium‐sized rings (MSRs) have attracted sustained interest due to their combination of structural rigidity and tunable conformational flexibility [1, 2, 3], which contributes to their broad utility in medicinal chemistry [4, 5, 6, 7], materials science [8, 9, 10, 11], and asymmetric catalysis [12, 13, 14, 15]. Consequently, substantial efforts have been devoted to their catalytic asymmetric synthesis. Current strategies for the catalytic asymmetric synthesis of MSRs primarily involve preformed medium‐sized ring substrates, exemplified by kinetic resolution (KR) [16, 17, 18, 19] and post synthetic modification (PSM) [20, 21, 22, 23, 24, 25, 26]. While these approaches have achieved notable success, they are constrained by their reliance on preassembled ring frameworks, which limits the accessible structural diversity of the resulting scaffolds. In this context, catalytic asymmetric cyclization has offers an alternative approach, enabling direct assembly of axially chiral medium‐sized frameworks and facilitating scaffold diversification [27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. However, a majority of reported asymmetric cyclizations proceed through ionic pathways, often requiring substrate prefunctionalization (e.g., installation of leaving groups or strongly electron‐withdrawing substituents) to achieve appropriate electronic matching and reactivity (Scheme 1a, left). Therefore, the development of more general cyclization methods remains an important area of research.

SCHEME 1.

The background and our project design.

With ongoing advances in radical stereochemistry [46, 47, 48, 49, 50, 51, 52], enantioselective radical cascade cyclizations have emerged as a powerful strategy for accessing enantioenriched small‐ring frameworks [53, 54, 55, 56], particularly five‐ and six‐membered systems [57, 58, 59, 60, 61]. These reactions can construct multiple bonds and stereogenic elements efficiently in a single operation, often exhibit broad functional‐group tolerance, and can mitigate the stringent electronic matching often associated with ionic two‐electron manifolds, thus reducing the need for extensive substrate prefunctionalization (Scheme 1a, right). Considering these advantages, we hypothesized that employing a radical cascade cyclization approach could offer an efficient and complementary strategy for the construction of axially chiral MSRs. However, the application of such enantioselective radical methodologies to axially chiral MSRs has not been extensively explored to date. This primarily arises from the inherent challenges associated with stereocontrol in the radical‐mediated assembly of axially chiral MSRs. Specifically, medium‐ring closure is often slow and entropically disfavored due to their inherent conformational flexibility [62, 63, 64, 65, 66], whereas radical addition processes are intrinsically fast and proceed over low energy barriers. This kinetic mismatch significantly narrows the time window for catalyst‐governed stereodiscrimination in the cyclization step. In addition, under commonly employed oxidative conditions, radical‐polar crossover pathways can lead to nonselective background ionic cyclization, which can further impact stereocontrol [67, 68, 69].

We herein describe a synergistic photoredox/chiral copper‐catalyzed asymmetric radical cascade cyclization enabling the synthesis of axially chiral medium‐sized lactones that incorporate multiple stereogenic elements, including axial chirality, central chirality, and potentially medium‐ring inherent chirality (Scheme 1b) [70, 71]. In this dual catalytic system, the alkyl halide undergoes single electron transfer (SET) under mild conditions to generate a transient alkyl radical, which can circumvent the preactivation and polarity constraints often associated with ionic strategies. Concurrently, the chiral copper catalyst coordinates with the alkene substrate via a carboxylate coordinating group, establishing a well‐defined and conformationally biased chiral environment. This combined approach facilitates radical capture and subsequent ring closure, contributing to high stereochemical fidelity. While seven‐membered rings often exhibit low axis‐inversion barriers, computational studies suggest that axial stability is influenced by a thermodynamically driven central‐to‐axial chirality relay [29, 34, 35, 72, 73]. This work presents dual photoredox/transition‑metal catalysis as a powerful platform for stereoselective radical cascades, providing efficient access to axially chiral MSRs.

2. Results and Discussion

2.1. Optimization Studies

To assess the feasibility of our radical cascades cyclization strategy for accessing axially chiral MSRs, we selected 2’‐(1‐phenylvinyl)‐[1,1’‐biphenyl]‐2‐carboxylic acid 1 as the model substrate and ethyl bromodifluoroacetate 2 as the reductive radical precursor, which generates the highly reactive CF₂COOEt radical upon single electron transfer (SET) to drive the transformation [74]. We initially screened various photocatalysts to optimize the reaction efficiency. A negative correlation was observed between photocatalyst oxidation potential and enantioselectivity. This is likely because elevated potentials promote overoxidation of the carbon‐centered radical to an undesired carbocation via a competing background ionic cyclization pathway, thereby reducing stereo selectivity (see Supporting Information). Among the catalysts screened, 3DPA2FBN proved to be the optimal photocatalyst for this transformation. We next examined a series of indane‐derived bisoxazoline (Box) ligands bearing different substituents at the bridging geminal position (Figure 1a). L2, in which the hydrogen atoms at this position are replaced by methyl groups, delivered only moderate efficiency and stereocontrol (63% yield, 74% e.e.), whereas its gem‐dibenzyl analogue L3 exhibited slightly improved enantioselectivity (76% e.e.) relative to L2. These results underscore the pivotal role of the side‐arm effect in governing stereochemical outcomes in this remote enantioselective process. Encouraged by these findings, we next explored further structural modifications using L3 as a lead scaffold. Introduction of 3,5‐dimethyl substituents on the benzyl rings (L4) increased the enantiomeric excess to 86%. Conversely, introducing electron‐withdrawing trifluoromethyl groups (L5) or bulkier tert‐butyl groups (L6) led to diminished yields and enantioselectivities, indicating that subtle electronic and steric tuning is crucial. Extending the scaffold by introducing phenyl groups to the side arms further enhanced enantioselectivity but compromised yield (L7, 58% yield, 91% e.e.), implying that an elongated ligand framework can function as an extended steric barrier to modulate stereoselectivity. This steric effect was further investigated through systematic substitution at the ortho and para positions of the pendent phenyl rings (L8–L13), including CF₃, ^t Bu, OMe, 3,5‐dimethoxy, 3,5‐dimethyl, and naphthyl groups. The para‐methoxy substitution (L10) proved optimal, affording product 3 in 73% isolated yield with 92% e.e. Notably, all examples afforded a single diastereomer (>20:1 d.r.). Control experiments were conducted to establish the critical role of each reaction component. The absence of either photocatalyst or light completely inhibited the reaction (Figure 1b, entries 1 and 2). Notably, conducting the reaction without Cu(OAc)₂ or L10 resulted in the formation of racemic product 3 in yields (24% and 38%, respectively). These results point towards a non‐stereoselective background pathway, likely driven by carbocationic intermediates or unbound radicals (Figure 1b, entries 3 and 4). Additionally, the omission of Na₂CO₃ dramatically eroded both yield and e.e., underscoring the necessity of substrate deprotonation for effective coordination and chiral induction (Figure 1b, entry 5).

FIGURE 1.

Optimization of the reaction conditions. (a) Evaluation of the chiral ligand. (b) Control experiments with L10 in above conditions. ^cIsolated yield. The yield was determined by HPLC using 2‐naphthol as the internal standard. The e.e. values were based on HPLC analysis. Unless otherwise stated, all examples performed a single diastereomer (>20:1 d.r.).

2.2. Substrate Scope

With the optimized reaction conditions established, we investigated the substrate scope with respect to terminal alkenes (Figure 2). Incorporating a methoxy group at the C‐4 position of the upper aryl ring in substrate 1 delivered the desired product 4 in good yield and with excellent enantioselectivity (76% yield, 95% e.e.), representing an improvement over the parent axially chiral medium‐sized lactone 3. A systematic evaluation of various fluoroalkyl halides revealed that methyl, ethyl, and benzyl derivatives were all competent coupling partners, furnishing lactones 4–6 in 66%–76% yields with consistently high enantioselectivities (95% e.e.). The absolute configuration of (M,S)‐5 was unambiguously determined by X‐ray crystallographic analysis, and the configurations of the remaining products were assigned by analogy (CCDC 2422254, Figure 2, and Table S8) [75]. We next examined benzyl esters bearing diverse substituents. Alkyl groups, including dimethyl (7), methyl (8), and iso‐propyl (9), were well tolerated. Substrates featuring electron‐withdrawing substituents on the aromatic ring, such as fluoro, trifluoromethyl, and methoxycarbonyl groups, afforded the corresponding lactones 10–12 in moderate to good yields (55%–77%) and high enantioselectivities (92%–94% e.e.). Extending the ester chain length had negligible impact on either reaction efficiency or stereocontrol (13–15). Notably, amide substrates were also compatible, providing lactones 16–19 in moderate yields with good enantioselectivities. Subsequent exploration of the alkene scope demonstrated broad functional group tolerance. Alkenes bearing alkyl or fluoro substituents delivered products 20–24 in moderate to good yields with high e.e. values. Notably, the introduction of a trifluoromethyl group (25) further enhanced enantioselectivity. However, replacing the C‐4 methoxy group on the upper aryl ring with fluoro group resulted in a slight erosion of enantioselectivity (26–27). A methyl substituent at the C‐5 position of the upper aryl ring proved challenging under standard conditions, likely due to steric effects that increase ring‐closing resistance. Reducing the loading of ethyl bromodifluoroacetate 2 to 1.2 equivalents successfully afforded product 28 (34% yield, 84% e.e.). Furthermore, substrates bearing fluoro or chloro substituents at the C‐4′ or C‐5′ positions of the lower aryl ring generated 29–32 in 67%–77% yields with excellent enantioselectivities (93%–95% e.e.). Ethyl 2‐bromo‐2‐fluoroacetate was also found to be compatible with this catalytic system, delivering the target product 33 in 71% yield with 92% e.e. and 1.6:1 d.r., thereby highlighting the broad utility of this protocol. By contrast, employing ethyl 2‐bromo‐2,2‐dichloroacetate did not deliver the corresponding product 34. This can be attributed to the insufficient reducing power of the excited‐state photocatalyst to reduce ethyl 2‐bromo‐2,2‐dichloroacetate.

FIGURE 2.

Substrate scope. The reactions were performed by using terminal alkenes (0.10 mmol), fluoroalkyl halides (0.40 mmol), 3DPA2FBN (5.0 mol%), Cu(OAc)₂ (10 mol%), L10 (15 mol%), Na₂CO₃ (0.10 mmol) and 2‐Me‐THF (0.1 M), N₂, 25°C, blue LEDs, 24 h reaction time. (a) Cu(CH₃CN)₄BF₄ (10 mol%) was used. (b) fluoroalkyl halides (0.12 mmol) and Cu(CH₃CN)₄BF₄ (10 mol%) were used. Unless otherwise stated, all examples performed a single diastereomer (>20:1 d.r.). Isolated yield by silica gel chromatography. The e.e. values were based on HPLC analysis.

2.3. Synthetic Applications

Encouraged by the excellent performance of this catalytic system, we next explored its applicability to the late‐stage functionalization of bioactive molecules (Figure 3a). The protocol exhibited broad substrate scope and high chemoselectivity, proving effective even with sterically congested or multifunctional scaffolds. Reactions with fluoroalkyl halides derived from (L)‐Menthol and (+)‐Fenchol afforded the corresponding products 35 and 36 in moderate yields with excellent diastereoselectivity. Similarly, the naturally occurring terpene (–)‐α‐Terpineol underwent smooth conversion to 37 in 30% yield, leaving the internal olefin moiety intact. This result underscores the remarkable chemoselectivity of the transformation. The method was also successfully applied to steroid derivatives, such as Dihydrocholesterol and Epiandrosterone, which were transformed into the corresponding products 38 and 39 in good yields under standard conditions. Furthermore, a B enzocaine derivative, representing a local anesthetic agent, reacted smoothly to produce 40 with high enantioselectivity. These results highlight the versatility of this method and its potential for constructing axially chiral medium‐ring frameworks within complex bioactive environments.

FIGURE 3.

Synthetic applications. (a) Late‐stage modification of natural products and medicinally relevant molecules. (b) Scale‐up preparation and transformations of chiral products.

To demonstrate the synthetic practicality of this protocol, a gram‐scale synthesis of 4 was conducted under the optimized conditions, affording the product in 63% isolated yield and 95% e.e (Figure 3b). The axially chiral medium‐sized lactones generated by this method serve as versatile synthetic intermediates, amenable to various derivatizations without erosion of stereochemical integrity. For instance, treatment of 4 with Lawesson's reagent delivered the sulfur‐containing analog 42 (73% yield, 94% e.e.), and chemoselective reduction of 4 afforded the polyhydroxylated product 43 in excellent yield (90% yield, 96% e.e., 2.3:1 d.r.). Remarkably, exposure of 4 to aqueous KOH resulted in the formation of a chiral hemiacetal 44 (63% yield, 92% e.e., 1:1 d.r.), presumably formed through sequential hydrolysis and intramolecular condensation (CCDC 2517451, Figure 3, and Table S9) [75].

2.4. Mechanistic Studies

To gain insight into the reaction mechanism, we conducted a series of control experiments. Radical trapping assays employing butylated hydroxytoluene (BHT) or 2,2,6,6‐tetramethylpiperidin‐1‐yl oxyl (TEMPO) markedly suppressed the transformation, suggesting the involvement of radical intermediates. Specifically, high‐resolution mass spectrometry (HRMS) analysis identified the TEMPO adduct 45, providing direct evidence for the formation of a difluoroalkyl radical intermediate (Figure 4a). Furthermore, light on/off experiments demonstrated that the formation of 3 occurred only under continuous irradiation, thereby excluding a radical chain propagation pathway (Figure 4b). Stern‐Volmer quenching studies revealed that ethyl bromodifluoroacetate exhibited a significantly more pronounced quenching effect on the excited state of 3DPA2FBN compared to the copper catalyst. This suggests that the difluoroalkyl radical is generated via a SET process initiated by the photocatalyst rather than the copper complex (Figure 4c).

FIGURE 4.

Mechanistic discussion. (a) Radical trapping experiments. (b) Light on/off experiments. (c) Stern‐Volmer experiments. (d) The effect of the base additive. (e) Up, the ligand controls the absolute configuration of the product 3. Down, relationship between the e.e. of L10 and the e.e. of product 3. (f) Control experiments with different substituents of the alkene.

We next investigated the factors governing stereochemical control. A positive correlation between the equivalents of Na₂CO₃ and enantioselectivity was observed. Specifically, the e.e. value increased sharply with increasing base loading and reached a plateau at 1.0 equivalents. This trend suggests that the base plays a crucial role in suppressing a competitive racemic background pathway, likely by facilitating the complete deprotonation of substrate 1 to ensure its coordination with the chiral copper catalyst, thereby channeling the reaction through the enantioselective manifold (Figure 4d). Replacing ligand L10 with its enantiomer, ent‐L10, under standard conditions yielded the opposite enantiomer of the product (P,R‐3) in 73% yield with ‐88% e.e., confirming that the ligand configuration dictates the stereochemical outcome. Additionally, a distinct linear correlation between the e.e. of the product and that of L10 was observed, suggesting that the enantiodetermining step involves a monomeric copper species (Figure 4e). During the substrate scope examination, an intriguing electronic and steric effect was noted (Figure 4f). Replacing the phenyl substituent on the alkene moiety with a methyl group completely inhibited the reaction. Conversely, substitution with a hydrogen atom allowed the reaction to proceed but resulted in a racemic product 49. These findings indicate that the phenyl substituent is essential not only for stabilizing the radical intermediate but also for facilitating efficient stereochemical induction, presumably through π–π stacking interactions with the chiral ligand.

Based on these observations, a plausible catalytic cycle (Figure 5a) and stereochemical model (Figure 5b) for the radical cascade cyclization are proposed. Upon blue light irradiation, the ground‐state photocatalyst (PC) is excited to its highly reducing excited state (PC*), which subsequently reduces the bromodifluoroacetate via SET process to generate a transient electrophilic difluoroalkyl radical 50 along with the oxidized photocatalyst PC^•+ . Concurrently, base‐mediated ligand exchange with the precatalyst generates the active chiral Cu(II) species 51, wherein the substrate is tightly coordinated. This critical coordination positions the alkene moiety directly within a well‐defined chiral pocket created by the finely tuned Box ligand. Consequently, the subsequent addition of radical 50 to the alkene 52 does not occur as a free background reaction; Instead, it proceeds in a highly facial‐selective manner under the strict stereocontrol of the chiral ligand framework, affording the tertiary carbon‐centered radical intermediate 53. However, direct capture of this tertiary radical by the copper center via a conventional oxidative addition pathway is kinetically disfavored, as it would necessitate the formation of a highly strained and conformationally unstable eight‐membered metallacyclic transition state. Instead, the chiral Cu(II) species intercepts radical 53 via a radical substitution manifold to effect enantioselective C–O bond formation, delivering the axially chiral lactone 3 and releasing a Cu(I) species 54. To further elucidate the origin of the observed selectivity difference, theoretical calculations for the radical substitution process were performed. The (M,S)‐Ts2 transition state (preceding the formation of (M,S)‐3) exhibits a lower activation energy barrier (ΔΔG ^‡ = 1.1 kcal mol⁻¹) compared to (M,R)‐Ts2, rendering this pathway kinetically favorable. IGMH (Independent Gradient Model based on Hirshfeld partition) analysis revealed considerable steric repulsion between the ligand and the difluoromethyl substituent in (M,R)‐Ts2 (H–H distance = 2.0 Å), which likely contributes to the observed selectivity difference [76]. This thermodynamically driven medium‐ring closure not only establishes the central chirality but also selectively locks the conformation, relaying the stereochemical information to construct the challenging axial chirality of the MSRs. Finally, the catalytic cycle is closed by the oxidation of Cu(I) species 54 by PC^•+ , regenerating the active Cu(II) species 51 and the ground‐state photocatalyst.

FIGURE 5.

Mechanistic discussion. (a) Proposed reaction pathways. (b) IGMH analysis of the radical cyclization transition states.

3. Conclusion

In summary, we have developed a novel dual‐catalytic platform for the highly enantioselective synthesis of axially chiral medium‐sized lactones via a radical cascade cyclization. Under mild photoredox conditions, commercially available alkyl halides undergo single‐electron transfer to generate transient alkyl radicals, successfully circumventing the laborious preactivation and polarity constraints inherent to traditional ionic pathways. Excellent stereocontrol is achieved by employing a chiral copper catalyst coordinated with a carboxylate moiety, which creates a well‐defined and conformationally biased environment. Computational investigations reveal that the radical substitution process leading to C–O bond formation constitutes the stereodetermining step. This strategy accommodates a diverse array of nonpolar alkenes, providing efficient access to previously elusive scaffolds. Notably, while seven‐membered rings typically exhibit low axis‐inversion barriers, our experimental and computational studies reveal that the structural integrity in this system is governed by a thermodynamically driven central‐to‐axial chirality relay. Overall, this work establishes dual transition‐metal/photoredox catalysis as a robust tool for stereoselective radical cascades, delivering novel axially chiral MSRs that hold consequential potential for medicinal chemistry and drug discovery.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Detailed experimental procedures, characterization data, copies of NMR and HPLC spectra, and crystallographic data.

Supporting File 1: anie73472‐sup‐0001‐SuppMat.pdf.

Supporting File 2: anie73472‐sup‐0002‐cif.zip.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.